Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Release Notes Frontmatter Part 1 - General Pathology Part 2 - Diseases of Organ Systems Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Release Notes Frontmatter Part 1 - General Pathology Part 2 - Diseases of Organ Systems Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 1 - GENERAL PATHOLOGY 1 - Cellular Pathology I: Cell Injury and Cell Death 2 - Cellular Pathology II: Adaptations, Intracellular Accumulations, and Cell Aging 3 - Acute and Chronic Inflammation 4 - Tissue Repair: Cellular Growth, Fibrosis, and Wound Healing 5 - Hemodynamic Disorders, Thrombosis, and Shock 6 - Genetic Disorders 7 - Diseases of Immunity 8 - Neoplasia 9 - Infectious Diseases 10 - Environmental and Nutritional Pathology 11 - Diseases of Infancy and Childhood Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 12 - Blood Vessels 13 - The Heart 14 - Red Cells and Bleeding Disorders 15 - White Cells, Lymph Nodes, Spleen, and Thymus 16 - The Lung 17 - Head and Neck 18 - The Gastrointestinal Tract 19 - The Liver and the Biliary Tract 20 - The Pancreas 21 - The Kidney 22 - The Lower Urinary Tract 23 - The Male Genital Tract 24 - The Female Genital Tract 25 - The Breast 26 - The Endocrine System 27 - The Skin 28 - Bones, Joints, and Soft Tissue Tumors 29 - Peripheral Nerve and Skeletal Muscle 30 - The Central Nervous System 31 - The Eye Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Af -- Am An -- Ao Ap -- As At -- Az B -- Be Bi -- Bo Br -- By C -- Cap Car -- Ce Cf -- Ch Ci -- Com Con -- Cr Cs -- Cy Da -- De Di -- Dy Ea -- En Eo -- Ey Fa -- Fi Fl -- Fu G -- Gi Gl -- Gy Ha -- Hem Hen -- Hi Hl -- Hyd Hyg -- Hyp I -- Ins Int -- It J K La -- Le Li -- Lo Lu -- Ly M -- Mel Mem -- Mi
Ml -- Mu Mya -- Myx N O P -- Pa Pc -- Phe Phi -- Pla Ple -- Prn Pro -- Pyo Q Ra -- Res Ret -- Ru S -- Sep Seq -- Sm So -- Sta Ste -- Sy T -- Th Ti -- Tre Tri -- Tz U V W X Y Z Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
proudly presents... Robbins Pathologic Basis of Disease, 6th Edition
(c) 1999, W. B. Saunders Company
- Release Notes Source: MDConsult Ripped/Converted by: ZD Rip Date: March 2002 Release Date: March 11, 2002 Release Type: Reference Book
Version: No Images (4.1MB) Platform: PalmOS Required: PalmOS PDA, 4.3MB free internal or external RAM, iSilo v3.0 or later. Recommended: 33MHz+ PalmOS v4.0 or later PDA w/ expansion and hi-res, 16-bit display.
- Release Info First a word from the publisher: --Presenting the latest edition of this popular, comprehensive and practical text of pathology. Written with great clarity for easy readability, this reference offers detailed discussions of genetic disorders, cellular injury and death, neoplasia, the skeletal system and soft tissue tumors, and much more. Completely revised and updated, this edition is even more user-friendly with the use of text boxes for key topics in each chapter and a new full-color design. Features 1200 excellent 4-color illustrations! 1,440 pp. 1548 ills. 1438 in color ISBN: 072167335X Price: $85.00 --Another iSilo release a few people may want is here: Robbins (as provided by MDConsult). If you're new to this, take a look at the fully functioning Table of Contents and Index. Also give the "navigation bar" at the top and bottom of each page a try. This "nav-bar" allows you to quickly jump to the table of contents, index, and each section of the book from anywhere in the document. It also allows you to go to the previous and next page in the text (the left and right arrows). A quick tip: to get to the nav-bar from the middle of a long page, just use the top and end of page shortcuts (/0 and /Z respectively) via grafitti. This release is best viewed with the following iSilo settings: Set "Font" to "small" under Display Options; set "Title bar" to "hide" and "Scroll bar" to "none" under Interface options; And "Region 1" set to "Line Up", "Region 2 and 3" to "Drag" and "Region 4" to Line Down" under Region options. There may be two versions of this release, one with images and one without. With images the file right now balloons to about 135MB (the book has A LOT of images). I am starting to realize that iSilo is not the ideal platform for having a massive amount of images (well atleast without making major sacrifices in image quality). I am looking into what other options are present on the Palm to best resolve this issue. Shrinking the images in my opinion makes them pretty useless. I would like to hear your opinions. - Conversion Info In order to cut down on size, the thumbnail images (those pretty useless miniature
versions of the full figures) were removed and replaced with a standard icon. Otherwise, with the exception of a few minor formatting changes and making the hyperlinks that point to tables actually work (they don't on MDConsult), *NO* TEXT CONTENT WAS ALTERED OR REMOVED IN THE CREATION OF THIS FILE. What you see is what I got from MDConsult. - Known Issues Since you're not reading this on a PocketPC, you'll have to give the tables a few seconds or (a lot) longer to correctly render depending on the complexity and length of the page. You can still scroll and "click" while it is doing this. Palms just were not made for this kind of stuff. Using the iSilo toolbar page-back and page-forward buttons (the ones surrounding the current page number) won't do you much good since the page numbers in the book don't follow that order. Use the page-back and page-forward buttons on the nav-bar instead (that's what they are there for). - Greetings Respect goes to MedScut (the iSilo king), the PDA People, the "group" moderators and those that have made and still make the Skyscape stuff possible. - Comments Please send your constructive comments/criticisms to: E-mail:
[email protected] Web: http://zd.pros.at/ You may also find me on the "groups" and where the PDA People stay. Look for more MDConsult titles coming soon. And remember, IF YOU LIKE IT, BUY IT!!! - ZD '02 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Frontmatter Title Page Copyright Page Dedication Contributors Preface Acknowledgments Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
1A
3A
Robbins PATHOLOGIC BASIS of DISEASE
Sixth Edition Ramzi S. Cotran M.D. Frank Burr Mallory Professor of Pathology, Harvard Medical School, Chairman, Department of Pathology, Brigham and Women's Hospital, The Children's Hospital, Boston, Massachusetts
Vinay Kumar M.D., F.R.C.Path. Vernie A. Stembridge Chair in Pathology, Department of Pathology, The University of Texas, Southwestern Medical School, Dallas, Texas
Tucker Collins M.D., Ph.D. Professor of Pathology, Harvard Medical School, Pathologist, Brigham and Women's Hospital, Boston, Massachusetts
W.B. Saunders Company A Division of Harcourt Brace & Company Philadelphia London Toronto Montreal Sydney Tokyo
4A
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 1 - GENERAL PATHOLOGY
1
Chapter 1 - Cellular Pathology I: Cell Injury and Cell Death INTRODUCTION TO PATHOLOGY Pathology is literally the study (logos) of suffering (pathos). More specifically, it is a bridging discipline involving both basic science and clinical practice and is devoted to the study of the structural and functional changes in cells, tissues, and organs that underlie disease. By the use of molecular, microbiologic, immunologic, and morphologic techniques, pathology attempts to explain the whys and wherefores of the signs and symptoms manifested by patients while providing a sound foundation for rational clinical care and therapy. Traditionally, the study of pathology is divided into general pathology and special or systemic pathology. The former is concerned with the basic reactions of cells and tissues to abnormal stimuli that underlie all diseases. The latter examines the specific responses of specialized organs and tissues to more or less well defined stimuli. In this book, we first cover the principles of general pathology and then proceed to specific disease processes as they affect particular organs or systems. The four aspects of a disease process that form the core of pathology are its cause (etiology), the mechanisms of its development (pathogenesis), the structural alterations induced in the cells and organs of the body (morphologic changes), and the functional consequences of the morphologic changes (clinical significance). Etiology or Cause. The concept that certain abnormal symptoms or diseases are "caused" is as ancient as recorded history. For the Arcadians (2500 B.C.), If Someone Became Ill, It Was The Patient 's own fault (for having sinned) or the makings of outside agents, such as bad smells, cold, evil spirits, or gods. [1] In modern terms, there are the two major classes of
etiologic factors: intrinsic or
2
genetic and acquired (e.g., infectious, nutritional, chemical, physical). Knowledge or discovery of the primary cause remains the backbone on which a diagnosis can be made, a disease understood, or a treatment developed. The concept, however, of one etiologic agent to one disease--developed from the study of infections or single-gene disorders--is no longer sufficient. Genetic factors are clearly involved in some of the common environmentally induced maladies, such as atherosclerosis and cancer, and the environment may also have profound influences on certain genetic diseases. Pathogenesis. Pathogenesis refers to the sequence of events in the response of the cells or tissues to the etiologic agent, from the initial stimulus to the ultimate expression of the disease. The study of pathogenesis remains one of the main domains of pathology. Even when the initial infectious or molecular cause is known, it is many steps removed from the expression of the disease. For example, to understand cystic fibrosis is to know not only the defective gene and gene product but also the biochemical, immunologic, and morphologic events leading to the formation of cysts and fibrosis in the lung, pancreas, and other organs. Indeed, as we shall see throughout the book, the molecular revolution has already identified mutant genes underlying a great number of diseases and promises to map the entire human genome before too long. Nevertheless, the functions of the encoded proteins and how mutations induce disease are often still obscure. Thus, the study of pathogenesis has never been more exciting scientifically or more relevant to the development of new therapies. Morphologic Changes. The morphologic changes refer to the structural alterations in cells or tissues that are either characteristic of the disease or diagnostic of the etiologic process. Functional Derangements and Clinical Significance. The nature of the morphologic changes and their distribution in different organs or tissues influence normal function and determine the clinical features (symptoms and signs), course, and prognosis of the disease. Virtually all forms of organ injury start with molecular or structural alterations in cells, a concept first put forth in the 19th century by Rudolf Virchow, known as the father of modern pathology. We therefore begin our consideration of pathology with the study of the origins, molecular mechanisms, and structural changes of cell injury. Yet different cells in tissues constantly interact with each other, and an elaborate system of extracellular matrix is necessary for the integrity of organs. Cell-cell and cell-matrix interactions contribute significantly to the response to injury, leading collectively to tissue
and organ injury, which are as important as cell injury in defining the morphologic and clinical patterns of disease. [2]
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS
493
Chapter 12 - Blood Vessels Frederick J. Schoen Ramzi S. Cotran
Vascular disorders are responsible for more morbidity and mortality than any other category of human disease. Vascular abnormalities cause clinical disease by two principal mechanisms: Narrowing or completely obstructing the lumens of vessels, either progressively (e.g., by atherosclerosis) or precipitously (e.g., by thrombosis), often inducing downstream deficiency of blood flow to the tissue perfused by that vessel Weakening of the walls of vessels, leading to dilation or rupture
494
NORMAL VASCULATURE The architecture of the vasculature varies with and reflects distinct functional requirements at different locations. To withstand the pulsatile and higher blood pressures in arteries, arterial walls are generally thicker than their venous counterparts. Arterial wall thickness gradually diminishes as the vessels become smaller, but the ratio of wall thickness to lumen diameter becomes greater. Veins have a larger overall diameter, a larger lumen, and a thinner wall than corresponding arteries. Arteries are divided into three types, based on their size and structural features: (1) large or elastic arteries, including the aorta and its large branches (e.g., aorta and innominate, subclavian, common carotid, iliac, and pulmonary arteries); (2)
medium-sized or muscular arteries comprising other branches of the aorta (such as the coronary or renal arteries), also referred to as distributing arteries; and (3) small arteries (usually 1 month), fatigue, weight loss, and diarrhea; the CD4+ cell count is reduced below 500 cells/mul. After a variable period, serious opportunistic infections, secondary neoplasms, or clinical neurologic disease (grouped under the rubric AIDS-defining conditions) supervene, and the patient is said to have developed AIDS. In addition, according to current guidelines of the CDC, any HIV-infected person with fewer than 200 CD4+ T cells/mul is considered to have AIDS. In the absence of treatment, most but not all patients with HIV infection progress to
AIDS after a chronic phase lasting from 7 to 10 years. Exceptions to this typical course are exemplified by long-term nonprogressors and by rapid progressors. Nonprogressors are defined as HIV-1-infected individuals who remain asymptomatic for 10 years or more, with stable CD4+ counts and low levels of plasma viremia. In rapid progressors, the middle, chronic phase is telescoped to 2 to 3 years after primary infection. The possible basis for these variant outcomes is discussed later. With this overview of the three phases of HIV infection, we can consider some details of host-parasite relationships during the course of a typical HIV infection. The initial entry of the virus may be through a mucosal surface, as in vaginal intercourse or via blood exposure (breach in rectal mucosa, intravenous drug use). From the mucosal portal, the virus is carried to the regional lymph nodes by Langerhans cells. Virus inoculated into the blood is rapidly cleared by the spleen and lymph nodes. Thus, with either mode of entry, the virus initially replicates in the lymphoid organs then spills over into the blood. The patient now experiences the acute HIV syndrome described earlier. This phase is characterized initially by high levels of virus in plasma and an abrupt, sometimes severe, reduction in CD4+ T cells. During this period, HIV can be readily isolated from the blood, and there are high levels of HIV p24 antigen in serum. Soon, however, a virus-specific immune response develops, evidenced by seroconversion (usually within 3 to 7 weeks of presumed exposure) and, more importantly, by the development of virus-specific CD8+ cytotoxic T cells. HIV-specific cytotoxic T cells are detected in blood at about the time viral titers begin to fall and are most likely responsible for the containment of HIV infection.[129] As viral replication abates, CD4+ T cells return to near-normal numbers, signaling the end of the early acute phase. Although plasma viremia declines, there is widespread dissemination and seeding of the virus, especially in the lymphoid organs. With the formation of anti-HIV antibodies, immune complexes containing virions are trapped by follicular dendritic cells in the germinal centers. As discussed earlier, both latent and replicating HIV can be found in CD4+ T cells and macrophages within the lymph nodes, and viral particles are readily detected on the surface of follicular dendritic cells. The viral load at the end of the acute phase is a reflection of the equilibrium reached between the virus and the host after the initial battle, and in a given patient it remains fairly stable for several years. This level of steady-state viremia, or the viral "set-point," is an extremely important predictor of the rate of progression of HIV disease. In one study, only 8% of patients with a viral load of less than 4350 copies of viral mRNA/mm3 progressed to full-blown AIDS in 5 years, whereas 62% of those with a viral load of greater than 36,270 copies had developed AIDS in the same period. [130] From a practical standpoint, therefore, the extent of viremia, measured as HIV-1 RNA, is the best surrogate marker of HIV disease progression and is of great clinical value in the management of patients with HIV infection.[131] Regardless of the viral burden, during the middle or chronic phase, there is a continuing battle between HIV and the host immune system. The CD8+ cytotoxic T-cell response remains activated, and extensive viral and CD4+ cell turnover continues. As emphasized earlier, however, because of the immense regeneration capacity of the immune system, a large proportion of the lost CD4+ cells is replenished. Thus, the decline in the CD4+ cell count in blood is modest. After an extended and variable period of time, there begins a gradual erosion of the CD4+ T cells. Concomitant with the loss of
CD4+ T cells, host defenses begin to wane, and the proportion of the surviving CD4+ cells infected with HIV increases, as does the viral burden per CD4+ cell. Not unexpectedly, HIV spillover into the plasma increases. How the HIV escapes immune control is not entirely clear. CD8+ cytotoxic T cells presumably control the virus by lysing virus-infected CD4+ cells before completion of viral life cycle. CD8+ T cells also secrete C-C chemokines, such as MIP-1, that can block viral entry into CD4+ cells by occupying the CCR5 coreceptor. During the prolonged chronic phase, with extensive viral replication, mutant HIV virions whose envelope proteins are not recognized by cytotoxic T cells emerge. This could contribute to escape from immune containment, but the picture is still quite murky. [132] Because the loss of immune containment is associated with declining CD4+ cell counts, the CDC classification of
247
HIV infection stratifies patients into three categories on the basis of CD4+ cell counts: CD4+ greater than or equal to 500 cells/mul, 200 to 499 cell/mul, and fewer than 200 cells/mul. Patients in the first group are generally asymptomatic; counts below 500 are associated with early symptoms, and a decline of CD4+ levels below 200 is associated with severe immunosuppression. For clinical management, CD4+ counts are an important adjunct to HIV viral load measurements. The significance of these two measurements, however, is slightly different: Whereas CD4+ cell counts indicate where the patient's disease is at the time of measurement, the viral load provides information regarding the direction in which the disease is headed. It should be evident from our discussion that in each of the three phases of HIV infection, viral replication continues to occur. Even in the clinical latent phase, before the severe decline in CD4+ cell count, there is extensive turnover of the virus. In other words, HIV infection lacks a phase of true microbiologic latency, that is, a phase during which all the HIV is in the form of proviral DNA, and no cell is productively infected. Therefore, antiretroviral therapy must be commenced early in the course of disease, before clinical symptoms appear. Before this discussion of the virus-host relationship is ended, some comments on those patients who are considered long-term nonprogressors are in order. Individuals in this group remain asymptomatic for long periods of time (10 years), have low levels of viremia, and have stable CD4+ cell counts. Patients with such an uncommon clinical course have attracted great attention in the hope that their study may shed light on host and viral factors that influence disease progression. Studies to date suggest that this group is heterogeneous with respect to the factors that influence the course of the disease. In a small subset of nonprogressors, the infecting HIV had deletions or mutations in the nef gene, suggesting that nef proteins are critical to disease progression. In most cases, the viral isolates do not show any qualitative abnormalities. In all cases, there is evidence of vigorous anti-HIV immune response. These patients have high levels of HIV-specific cytotoxic CD8+ cells, and these levels are maintained over the course of infection. It is not clear whether the robust CD8+ response is the
cause or consequence of the slow progression. Further studies, it is hoped, will provide the answers to this and other questions critical to disease progression. Clinical Features.
The clinical manifestations of HIV infection can be readily surmised from the foregoing discussion. They range from a mild acute illness to severe disease. Because the salient clinical features of the acute early and chronic middle phases of HIV infection were described earlier, here we summarize the clinical manifestations of the terminal phase, commonly known as AIDS. In the United States, the typical adult patient with AIDS presents with fever, weight loss, diarrhea, generalized lymphadenopathy, multiple opportunistic infections, neurologic disease, and, in many cases, secondary neoplasms. The infections and neoplasms listed in Table 7-13 are included in the surveillance definition of AIDS. [133] Opportunistic infections account for approximately 80% of deaths in patients with AIDS. Their spectrum is constantly TABLE 7-13 -- AIDS-DEFINING OPPORTUNISTIC INFECTIONS AND NEOPLASMS FOUND IN PATIENTS WITH HIV INFECTION Infections Protozoal and Helminthic Infections Cryptosporidiosis or isosporidiosis (enteritis) Pneumocytosis (pneumonia or disseminated infection) Toxoplasmosis (pneumonia or CNS infection) Fungal Infections Candidiasis (esophageal, tracheal, or pulmonary) Cryptococcosis (CNS infection) Coccidioidomycosis (disseminated) Histoplasmosis (disseminated) Bacterial Infections Mycobacteriosis (atypical, e.g., M. avium-intracellulare, disseminated or extrapulmonary; M. tuberculosis, pulmonary or extrapulmonary) Nocardiosis (pneumonia, meningitis, disseminated) Salmonella infections, disseminated Viral Infections Cytomegalovirus (pulmonary, intestinal, retinitis, or CNS infections) Herpes simplex virus (localized or disseminated)
Varicella-zoster virus (localized or disseminated) Progressive multifocal leukoencephalopathy Neoplasms Kaposi sarcoma B-cell non-Hodgkin lymphomas Primary lymphoma of the brain Invasive cancer of uterine cervix CNS, central nervous system. changing, as a result of improvements in prophylaxis and the increasing life span of HIV-infected individuals. A brief summary of selected opportunistic infections is provided here. Extensive reviews on the subject are available. [134] Pneumonia caused by the opportunistic fungus P. carinii (representing reactivation of a prior latent infection) is the presenting feature in about 20% of cases, and approximately 50% of AIDS patients develop this infection at some time during the course of their illness. The risk of developing this infection is extremely high in individuals with fewer than 200 CD4+ cells/mul. In recent years, there has been a substantial decline in the incidence of this infection because of the development of effective prophylaxis. An increasing number of patients present with an opportunistic infection other than P. carinii pneumonia. Among the most common pathogens are Candida, cytomegalovirus, atypical and typical mycobacteria, Cryptococcus neoformans, Toxoplasma gondii, Cryptosporidium, herpes simplex virus, papovaviruses, and Histoplasma capsulatum.[135] Candidiasis is the most common fungal infection in patients with AIDS. Candida infection of the oral cavity (thrush) and esophagus are the two most common clinical manifestations of candidiasis in HIV-infected patients. In asymptomatic HIV-infected individuals, oral candidiasis is a sign of immunologic decompensation, and it often heralds
248
the transition to AIDS. Invasive candidiasis is not common in patients with AIDS, and it usually occurs when there is drug-induced neutropenia or use of indwelling catheters. Cytomegalovirus may cause disseminated disease, although, more commonly, it affects the eye and gastrointestinal tract. Chorioretinitis occurs in approximately 25% of patients, whereas gastrointestinal disease, seen in about 10% of cases, manifests as esophagitis and colitis, the latter associated with multiple mucosal ulcerations. Cytomegalovirus retinitis occurs almost exclusively in patients with CD4+ cell counts below 50/mm3 . Disseminated bacterial infection with atypical mycobacteria (mainly M. avium-intracellulare) also occurs late, in the setting of severe immunosuppression. Approximately 40% of patients with AIDS have clinical evidence of disseminated infection, but the incidence at autopsy approaches 80%. Coincident with the AIDS
epidemic, the incidence of tuberculosis has risen dramatically. [136] Patients with AIDS have reactivation of latent pulmonary disease as well as outbreaks of primary infection. [137] In contrast to infection with atypical mycobacteria, M. tuberculosis manifests itself early in the course of AIDS. As with tuberculosis in other settings, the infection may be confined to lungs or may involve multiple organs. The pattern of expression depends on the degree of immunosuppression; dissemination is more common in patients with very low CD4+ cell counts. Most worrisome are reports indicating that a growing number of isolates are resistant to multiple drugs. Cryptococcosis occurs in about 10% of AIDS patients. Among fungal infections that prey on HIV-infected individuals, it is second only to candidiasis. As in other settings with immunosuppression, meningitis is the major clinical manifestation of cryptococcosis. In contrast to Cryptococcus, T. gondii, another frequent invader of the central nervous system in AIDS, causes encephalitis and is responsible for 50 to 60% of all mass lesions in the central nervous system. JC virus, a human papovavirus, is another important cause of central nervous system infections in HIV-infected patients. It causes progressive multifocal leukoencephalopathy (Chapter 30) . Herpes simplex virus infection is manifested by mucocutaneous ulcerations involving the mouth, esophagus, external genitalia, and perianal region. Persistent diarrhea, so common in patients with AIDS, is often caused by infections with protozoans such as Cryptosporidium, Isospora belli, or microsporidia. These patients have chronic, profuse, watery diarrhea with massive fluid loss. Diarrhea may also result from infection with enteric bacteria, such as Salmonella and Shigella, as well as M. avium-intracellulare. Depressed humoral immunity renders AIDS patients susceptible to severe, recurrent bacterial pneumonias. Patients with AIDS have a high incidence of certain tumors, especially Kaposi sarcoma (KS), non-Hodgkin lymphoma, and cervical cancer in women. [138] The basis of the increased risk of malignancy is multifactorial: profound defects in T-cell immunity, dysregulated B-cell and monocyte functions, and multiple infections with known (e.g., human herpesvirus type 8, EBV, human papillomavirus) and unknown viruses. KS, a vascular tumor that is otherwise rare in the United States, is the most common neoplasm in patients with AIDS. The morphology of KS and its occurrence in patients not infected with HIV is discussed in Chapter 12 . At the onset of the AIDS epidemic, up to 40% of the reported cases had KS, but in recent years there has been a definite decline in its incidence. There are several peculiar features of this tumor in patients with AIDS. It is far more common in homosexual or bisexual men than in intravenous drug abusers or patients belonging to other risk categories. The lesions can arise early, before the immune system is compromised, or in advanced stages of HIV infections. There is still some uncertainty regarding the nature of the proliferating cells and whether the lesions represent an exuberant hyperplasia or a neoplasm. The lesions contain spindle cells that share features with endothelial cells and smooth muscle cells and are in all likelihood primitive mesenchymal cells that can form vascular channels. Studies indicate that these cells are monoclonal in origin, even in patients with multicentric lesions, indicating therefore that KS is a neoplasm. [139] Although the cause and pathogenesis of KS are still not clear, a model that favors a complex web of interaction between a sexually transmitted infectious agent, altered
expression and response to cytokines, and modulation of cell growth by HIV gene products is currently favored.[138] [140] Each of these three is considered individually, followed by a schema that incorporates the role of all three cofactors (Fig. 7-44) . Both epidemiologic and molecular studies support the role of an infectious agent in the causation of KS. The high rate of KS in homosexual men relative to patients with parenterally acquired HIV infection points to a sexually transmitted agent. [140A] The decline in the incidence of KS is in keeping with the decline of AIDS in homosexual men. The observation that KS is much more common in women who have sex with bisexual men than in other women with AIDS is also consistent with sexual transmission. The discovery in 1994 that a novel type of human herpesvirus is present in KS lesions has bolstered the case for a viral cofactor in the pathogenesis of KS lesions. The genomic sequences of this herpesvirus, aptly labeled KS herpesvirus (KSHV), are found in virtually all KS lesions, including those that occur in HIV-negative populations. DNA of KSHV, also called human herpesvirus type 8, is also found in a rare type of body cavity-based B-cell lymphoma that occurs in HIV-infected patients. Approximately 50% of the circulating B cells in patients with KS also harbor the KSHV. Although the association of this virus with KS is firmly established, its precise role in the causation of these tumors is much less clear. A study of the viral genes of KSHV has revealed that it encodes homologs of several human genes that can participate in cell proliferation. These include the cytokine IL-6, the chemokine MIP-1alpha, a G-protein coupled chemokine receptor, cyclin D, and bc1-2. [141] [142] [143] The virally encoded IL-6, similar to human IL-6, is mitogenic for spindle cells in the lesions, and the chemokine receptor encoded by the virus binds to IL-8 with high affinity. IL-8 is mitogenic for endothelial cells and promotes angiogenesis. As is discussed in greater detail in Chapter 8 , bc1-2 is an antiapoptosis gene, and cyclin D regulates the transition from G1 to S phase of cell cycle. In addition to the virally encoded
249
Figure 7-44 Proposed role of HIV, KSHV (HHV-8), and cytokines in the pathogenesis of Kaposi sarcoma. Cytokines are produced by
the mesenchymal cells infected by KSHV, by B cells infected by KSHV, or by HIV-infected CD4+ cells.
growth-promoting factors, KS cells produce a variety of other cytokines, including TNF-alpha, IL-1, IL-6, GM-CSF, basic fibroblast growth factor, and oncostatin M. These mediators stimulate the growth of spindle cells in an autocrine and paracrine fashion. What drives the production of these cytokines is not entirely clear. Perhaps infection with KSHV endows the mesenchymal cells to secrete these factors; KS herpesvirus-infected B cells within the lesions could also be the source of these mediators. There is some evidence that HIV-encoded transactivating (tat) protein also plays a role in the proliferation of spindle cells. Although there is no HIV in the KS cells, HIV-infected CD4+ cells produce soluble tat that can bind to integrins on the surface of KS cells. This stimulates them to proliferate and to produce proinflammatory and angiogenic cytokines. Mice transgenic for the HIV- tat gene also develop KS-like vascular lesions, albeit transiently. It should be remembered that KS can develop in
HIV-negative individuals (Chapter 12) , hence HIV or its products are not obligatory for the development of all forms of KS. To summarize, KS is composed of mesenchymal cells that form blood vessels; the proliferation of these cells is driven by a variety of cytokines and growth factors that are derived from the tumor cells themselves and from HIV-infected T cells. KS herpesvirusinfected B cells may also contribute to the cytokine soup. What triggers the outpouring of this mitogenic brew is not clear, but it seems linked to infection of the tumor cells by KS herpesvirus. Clinically the AIDS-associated KS is quite different from the sporadic form (Chapter 12) . In HIV-infected individuals, the tumor is generally widespread, affecting the skin, mucous membranes, gastrointestinal tract, lymph nodes, and lungs. These tumors also tend to be more aggressive than classic KS. With prolonged survival, the number of AIDS patients who develop non-Hodgkin lymphoma has increased steadily. It is currently believed that approximately 6% of all patients with AIDS develop lymphoma during their lifetime. Thus, the risk of developing non-Hodgkin lymphoma is approximately 120-fold greater than in the general population. In contrast to KS, immunodeficiency is firmly implicated as the central predisposing factor. It appears that patients with CD4+ cell counts below 50/mm3 incur an extremely high risk. [138] AIDS-related lymphomas can be divided into three groups on the basis of their location: systemic, primary central nervous system, and body cavity-based lymphomas. [144] Systemic lymphomas involve lymph nodes as well as extranodal, visceral sites; they constitute 80% of all AIDS-related lymphomas. Central nervous system is the most common extranodal site affected, followed by gastrointestinal tract and, less commonly, virtually any other location, including the orbit, salivary glands, and lungs. The vast majority of these lymphomas are aggressive B-cell tumors that present in an advanced stage (Chapter 15) . In addition to being commonly involved by systemic non-Hodgkin lymphomas, central nervous system is also the primary site of lymphomatous involvement in 20% of HIV-infected patients who develop lymphomas. Primary central nervous system lymphoma is 1000 times more common in patients with AIDS than in the general population. The third category of AIDS-related lymphomas is rare but has an unusual distribution. It grows exclusively in body cavities in the form of pleural, peritoneal, and pericardial effusions. The pathogenesis of AIDS-associated B-cell lymphomas probably involves sustained polyclonal B-cell activation, followed by the emergence of monoclonal or oligoclonal B-cell populations. It is believed that during the frenzy of proliferation, some clones undergo somatic mutations and neoplastic transformation (Chapter 8) . There is morphologic evidence of B-cell activation in lymph nodes, and it is believed that such triggering of B cells is multifactorial. [145] Patients with AIDS have high levels of several cytokines, some of which, including IL-6, are important growth factors for B cells. In addition, there seems to be a role for EBV, known to be a polyclonal mitogen for B cells. The EBV genome is found in approximately 50% of the systemic B-cell lymphomas and in virtually all lymphomas primary in the central nervous system. Other evidence of EBV
infection includes oral hairy leukoplakia (white projections on the tongue), believed to result from EBV-driven squamous cell proliferation of the oral mucosa (Chapter 17) . In cases in which molecular footprints of EBV infection
250
cannot be detected, other viruses and microbes may initiate polyclonal B-cell proliferation. There is no evidence that HIV by itself is capable of causing neoplastic transformation. The rare body cavity-based B-cell lymphomas are uniformly associated with the presence of the human herpesvirus type 8 genome, discussed earlier. also have an increased occurrence of carcinoma of the uterine cervix. This is most likely due to a high prevalence of human papillomavirus infection in patients with AIDS. [146] This virus is believed to be intimately associated with squamous cell carcinoma of the cervix and its precursor lesions, cervical dysplasia and carcinoma in situ (Chapters 8 and 24) . Human papillomavirus-associated cervical dysplasia is ten times more common in HIV-infected women as compared with uninfected women attending family planning clinics. Hence it is recommended that gynecologic examination be part of a routine work-up of HIV-infected women. A large variety of other neoplasms, including Hodgkin disease and T-cell lymphomas, have been reported in patients with AIDS. It is not clear, however, whether the incidence of these tumors is increased with HIV infection. Involvement of the central nervous system is a common and important manifestation of AIDS. Ninety per cent of patients demonstrate some form of neurologic involvement at autopsy, and 40 to 60% have clinically manifest neurologic dysfunction. Importantly, in some patients, neurologic manifestations may be the sole or earliest presenting feature of HIV infection. In addition to opportunistic infections and neoplasms, several virally determined neuropathologic changes occur. These include a self-limited meningoencephalitis occurring at the time of seroconversion, aseptic meningitis, vacuolar myelopathy, peripheral neuropathies, and, most commonly, a progressive encephalopathy designated clinically as the AIDS-dementia complex (Chapter 30) . MORPHOLOGY.
The anatomic changes in the tissues (with the exception of lesions in the brain) are neither specific nor diagnostic. In general, the pathologic features of AIDS are those characteristic of widespread opportunistic infections, KS, and lymphoid tumors. Most of these lesions are discussed elsewhere because they also occur in patients who do not have HIV infection. To appreciate the distinctive nature of lesions in the central nervous system, they are discussed in the context of other disorders affecting the brain. Here we concentrate on changes in the lymphoid organs. Biopsy specimens from enlarged lymph nodes in the early stages of HIV infection reveal a marked follicular hyperplasia. [147] The enlarged follicles have irregular, sometimes
serrated borders, and they are present not only in the cortex, but also in the medulla and may even extend outside the capsule. The mantle zones that surround the follicles are markedly attenuated, and hence the germinal centers seem to merge with the interfollicular area. These changes, affecting primarily the B-cell areas of the node, are the morphologic reflections of the polyclonal B-cell activation and hypergammaglobulinemia seen in patients with AIDS. In addition to B-cell expansion within germinal centers, activated monocytoid B cells are present within and around the sinusoids and trabecular blood vessels. Under the electron microscope and by in situ hybridization, HIV particles can be detected within the germinal centers. Here they seem to be concentrated on the villous processes of follicular dendritic cells, presumably trapped in the form of immune complexes. During the early phase of HIV infection, viral DNA can be found within the nuclei of CD4+ T cells located predominantly in the follicular mantle zone. With disease progression, the frenzy of B-cell proliferation subsides and gives way to a pattern of severe follicular involution. The follicles are depleted of cells, and the organized network of follicular dendritic cells is disrupted. The germinal centers may even become hyalinized. During this advanced stage, viral burden in the nodes is reduced, in part because of the disruption of the follicular dendritic cells. These "burnt-out" lymph nodes are atrophic and small and may harbor numerous opportunistic pathogens. Because of profound immunosuppression, the inflammatory response to infections both in the lymph nodes and at extranodal sites may be sparse or atypical. For example, mycobacteria may not evoke granuloma formation because CD4+ cells are deficient. In the empty-looking lymph nodes and in other organs, the presence of infectious agents may not be readily apparent without the application of special stains. As might be expected, lymphoid depletion is not confined to the nodes; in later stages of AIDS, spleen and thymus also appear to be "wastelands." Non-Hodgkin lymphomas, involving the nodes as well as extranodal sites, such as the liver, gastrointestinal tract, and bone marrow, are primarily high-grade diffuse B-cell neoplasms (Chapter 15) . Since the emergence of AIDS in 1981, the concerted efforts of epidemiologists, immunologists, and molecular biologists have resulted in spectacular advances in understanding of this disorder. Despite all this progress, however, the prognosis of patients with AIDS remains dismal. Approximately 12 million people had succumbed to the disease worldwide by the end of 1997. Although the mortality rate has begun to decline in the United States as a result of the use of potent combinations of antiretroviral drugs, the treated patients still carry viral DNA in their lymphoid tissues. Can there be a cure with persistent virus? [148A] Although a considerable effort has been mounted to develop a vaccine, many hurdles remain to be crossed before vaccine-based prophylaxis or treatment becomes a reality. Molecular analyses have revealed an alarming degree of polymorphism in viral isolates from different patients; this renders the task of producing a vaccine remarkably
251
Figure 7-45 Amyloidosis. A , A section of the liver stained with Congo red reveals pink-red deposits of amyloid in the walls of blood
vessels and along sinusoids. B , Note the yellow-green birefringence of the deposits when observed by polarizing microscope. (Courtesy of Dr. Trace Worrell and Sandy Hinton, Department of Pathology, University of Texas Southwestern Medical School, Dallas TX.)
difficult. This task is further complicated by the fact that the nature of the protective immune response is not yet fully understood. At present, therefore, prevention and effective public health measures remain the mainstay in the fight against AIDS. Amyloidosis Immunologic mechanisms are suspected of contributing to a large number of diseases in addition to those already described in this chapter. Some of the entities are discussed in the chapters dealing with individual organs and systems. Amyloidosis is described here. There is strong evidence that in most patients some derangement in the immune apparatus underlies this disease, and as a systemic disease it cannot be assigned to any single organ or system. Amyloid is a pathologic proteinaceous substance, deposited between cells in various tissues and organs of the body in a wide variety of clinical settings. Because amyloid deposition appears so insidiously and sometimes mysteriously, its clinical recognition ultimately depends on morphologic identification of this distinctive substance in appropriate biopsy specimens. With the light microscope and standard tissue stains, amyloid appears as an amorphous, eosinophilic, hyaline, extracellular substance that, with progressive accumulation, encroaches on and produces pressure atrophy of adjacent cells. To differentiate amyloid from other hyaline deposits (e.g., collagen, fibrin), a variety of histochemical techniques, described later, are used. Perhaps most widely used is the Congo red stain, which under ordinary light imparts a pink or red color to tissue deposits, but far more dramatic and specific is the green birefringence of the stained amyloid when observed by polarizing microscopy (Fig. 7-45) . Despite the fact that all deposits have a uniform appearance and tinctorial characteristics, it is quite clear that amyloid is not a chemically distinct entity. There are three major and several minor biochemical forms. These are deposited by several different pathogenetic mechanisms, and therefore amyloidosis should not be considered a single disease; rather it is a group of diseases having in common the deposition of similar-appearing proteins.[148] At the heart of the morphologic uniformity is the remarkably uniform physical organization of amyloid protein, which we consider first. This is followed by a discussion of the chemical nature of amyloid. Physical Nature of Amyloid.
By electron microscopy, amyloid is seen to be made up largely of nonbranching fibrils of indefinite length and a diameter of approximately 7.5 to 10 nm. This electron microscopic structure is identical in all types of amyloidosis. X-ray crystallography and infrared spectroscopy demonstrate a characteristic cross beta-pleated sheet conformation (Fig. 7-46) . This conformation
Figure 7-46 Structure of an amyloid fibril, depicting the beta-pleated sheet structure and binding sites for the Congo red dye, which is used for diagnosis of amyloidosis. (Modified from Glenner GG: Amyloid deposit and amyloidosis. The beta-fibrilloses. N Engl J Med 52:148, 1980. By permission of The New England Journal of Medicine.)
252
is seen regardless of the clinical setting or chemical composition and is responsible for the distinctive staining and birefringence of Congo red-stained amyloid. In addition to amyloid fibrils, other minor components are always present in amyloid. These include serum amyloid P component, proteoglycans, and highly sulfated glycosaminoglycans. These nonproteinaceous substances are presumably derived from the connective tissue in which amyloid is deposited. Chemical Nature of Amyloid.
Approximately 95% of the amyloid material consists of fibril proteins, the remaining 5% being the P component and other glycoproteins. Of the 15 biochemically distinct forms of amyloid proteins that have been identified, three are most common: (1) AL (amyloid light chain) is derived from plasma cells (immunocytes) and contains immunoglobulin light chains, (2) AA (amyloid-associated) is a unique nonimmunoglobulin protein synthesized by the liver, [149] and (3) Abeta amyloid is found in the cerebral lesion of Alzheimer disease and is hence discussed in greater detail in Chapter 30 . The two noncerebral amyloid proteins are deposited in distinct clinicopathologic settings. The AL protein is made up of complete immunoglobulin light chains, the NH2 -terminal fragments of light chains, or both. Most of the AL proteins analyzed are composed of lambda light chains (particularly lambda VI type) or their fragments, but in some cases kappa chains have been identified. As might be expected, the amyloid fibril protein of the AL type is produced by immunoglobulin-secreting cells, and their deposition is associated with some form of monoclonal B cell proliferation. The second major class of amyloid fibril protein (AA) does not have structural homology to immunoglobulins. It has a molecular weight of 8500 and consists of 76 amino acid residues. The AA protein is found in those clinical settings described as secondary amyloidosis. AA fibrils are derived from a larger (12,000 daltons) precursor in the serum called SAA (serum amyloid-associated) protein that is synthesized in the liver and circulates in association with the HDL3 subclass of lipoproteins. Several other biochemically distinct proteins have been found in amyloid deposits in a variety of clinical settings. Transthyretin (TTR) is a normal serum protein that binds and transports thyroxine and retinol, hence the name trans-thy-retin. It was previously called prealbumin because it precedes serum albumin on serum electrophoresis. A mutant form of
transthyretin (and its fragments) is deposited in a group of genetically determined disorders referred to as familial amyloid polyneuropathies.[150] Amyloid transthyretin (ATTR) deposited in the tissues differs from its normal counterpart by a single amino acid. Transthyretin is also deposited in the heart of aged individuals (senile systemic amyloidosis), but in such cases the transthyretin molecule is structurally normal. beta2 -microglobulin, a component of the MHC class I molecules and a normal serum protein, has been identified as the amyloid fibril subunit (Abeta2 m) in amyloidosis that complicates the course of patients on long-term hemodialysis. Abeta2 m fibers are structurally similar to normal beta2 m protein. beta- amyloid protein (Abeta), not to be confused with beta 2 -microglobulin, is a 4000-dalton peptide that constitutes the core of cerebral plaques found in Alzheimer disease as well as the amyloid deposited in walls of cerebral blood vessels in patients with Alzheimer disease. The Abeta protein is derived from a much larger transmembrane glycoprotein, called amyloid precursor protein (APP). In addition to the foregoing, amyloid deposits derived from diverse precursors such as hormones (procalcitonin) and keratin have also been reported. The P component, a glycoprotein, is distinct from the amyloid fibrils but is closely associated with them in all forms of amyloidosis. It has a striking structural homology to C-reactive protein, a well-known acute-phase reactant. The serum P component has an affinity for amyloid fibrils, and it may be necessary for tissue deposition. Its presence in amyloid is responsible for staining with periodic acid-Schiff (PAS), which led early observers to believe that amyloid was a saccharide. Classification of Amyloidosis.
According to devoted "amyloidologists," who congregate every few years to discuss their favorite protein, amyloid should be classified based on its constituent chemical fibrils into categories such as AL, AA, and ATTR and not based on clinical syndromes. [151] Because a given biochemical form of amyloid (e.g., AA) may be associated with amyloid deposition in diverse clinical settings, we follow a combined biochemical-clinical classification for our discussion (Table 7-14) . Amyloid may be systemic (generalized), involving several organ systems, or it may be localized, when deposits are limited to a single organ, such as the heart. As should become evident, several different biochemical forms of amyloid are encompassed by such a segregation. On clinical grounds, the systemic, or generalized, pattern is subclassified into primary amyloidosis, when associated with some immunocyte dyscrasia, or secondary amyloidosis, when it occurs as a complication of an underlying chronic inflammatory or tissue destructive process. Hereditary or familial amyloidosis constitutes a separate, albeit heterogeneous group, with several distinctive patterns of organ involvement. Immunocyte Dyscrasias With Amyloidosis (Primary Amyloidosis).
Amyloid in this category is usually systemic in distribution and is of the AL type. With approximately 1275 to 3200 new cases every year in the United States, this is the most
common form of amyloidosis. In many of these cases, the patients have some form of plasma cell dyscrasia. Best defined is the occurrence of systemic amyloidosis in 5 to 15% of patients with multiple myeloma, a form of plasma cell neoplasia characterized by multiple osteolytic lesions throughout the skeletal system (Chapter 15) . The malignant B cells characteristically synthesize abnormal amounts of a single specific immunoglobulin (monoclonal gammopathy), producing an M (myeloma) protein spike on serum electrophoresis. In addition to the synthesis of whole immunoglobulin molecules, only the light chains (referred to as Bence Jones protein) of either the kappa or the lambda variety may be elaborated and found in the serum. By virtue of the small molecular size of the Bence Jones protein, it is frequently excreted in the urine. Almost
253
TABLE 7-14 -- CLASSIFICATION OF AMYLOIDOSIS Clinicopathologic Category Associated Major Chemically Related Diseases Fibril Precursor Protein Protein Systemic (Generalized) Amyloidosis Immunocyte dyscrasias with amyloidosis (primary amyloidosis)
Multiple myeloma and other monoclonal B-cell proliferations
Reactive systemic amyloidosis Chronic (secondary amyloidosis) inflammatory conditions Hemodialysis-associated amyloidosis
AL
Immunoglobulin light chains, chiefly lambda type
AA
SAA
Chronic renal failure Abeta2 m beta2 -microglobulin
Hereditary amyloidosis Familial Mediterranean fever Familial amyloidotic neuropathies (several types) Systemic senile amyloidosis
--
AA
SAA
--
ATTR
Transthyretin
--
ATTR
Transthyretin
Abeta
APP
A Cal
Calcitonin
AIAPP
Islet amyloid peptide
Localized Amyloidosis Senile cerebral
Alzheimer disease
Endocrine Medullary carcinoma of thyroid Islet of Langerhans
-Type II diabetes
Isolated atrial amyloidosis
--
AANF
Atrial natriuretic factor
all the patients with myeloma who develop amyloidosis have Bence Jones proteins in the serum or urine, or both, but a great majority of myeloma patients who have free light chains do not develop amyloidosis. Clearly, therefore, the presence of Bence Jones proteins, although necessary, is by itself not enough to produce amyloidosis. We discuss later the other factors, such as the type of light chain produced ( amyloidogenic potential) and the subsequent handling (possibly degradation) that may have a bearing on whether Bence Jones proteins are deposited as amyloid. The great majority of patients with AL amyloid do not have classic multiple myeloma or any other overt B-cell neoplasm; such cases have been traditionally classified as primary amyloidosis because their clinical features derive from the effects of amyloid deposition without any other associated disease. In virtually all such cases, however, monoclonal immunoglobulins or free light chains, or both, can be found in the serum or urine. Most of these patients also have a modest increase in the number of plasma cells in the bone marrow, which presumably secrete the precursors of AL protein. Clearly, these patients have an underlying B-cell dyscrasia in which production of an abnormal protein, rather than production of tumor masses, is the predominant manifestation. Whether the condition of most of these patients would evolve into multiple myeloma if they lived long enough can only be a matter for speculation. Reactive Systemic Amyloidosis.
The amyloid deposits in this pattern are systemic in distribution and are composed of AA protein. This category was previously referred to as secondary amyloidosis because it is secondary to the associated inflammatory condition. The feature common to most of the conditions associated with reactive systemic amyloidosis is protracted breakdown of cells resulting from a wide variety of infectious and noninfectious chronic inflammatory conditions. At one time, tuberculosis, bronchiectasis, and chronic osteomyelitis were the most important underlying conditions, but with the advent of effective antimicrobial chemotherapy, the importance of these conditions has diminished. More commonly now, reactive systemic amyloidosis complicates rheumatoid arthritis, other connective tissue disorders such as ankylosing spondylitis, and inflammatory bowel disease, particularly regional enteritis and ulcerative colitis. Among these, the most frequent associated condition is rheumatoid arthritis. Amyloidosis is reported to occur in approximately 3% of patients with rheumatoid arthritis and is clinically significant in one half of those affected. Heroine abusers who inject the drug subcutaneously also have a high occurrence rate of generalized AA amyloidosis. The chronic skin infections associated with "skin-popping" of narcotics seem to be responsible for amyloidosis in this group of patients. Reactive systemic amyloidosis may also occur in association with non-immunocyte-derived tumors, the two most common being renal cell carcinoma and Hodgkin disease. Hemodialysis-Associated Amyloidosis.
Patients on long-term hemodialysis for renal failure develop amyloidosis owing to deposition of beta2 -microglobulin. This protein is present in high concentrations in the serum of patients with renal disease and is retained in circulation because it cannot be filtered through the cuprophane dialysis membranes. In some series, as many as 60 to 80% of the patients on long-term dialysis developed amyloid deposits in the synovium, joints, and tendon sheaths. [152] Heredofamilial Amyloidosis.
A variety of familial forms of amyloidosis have been described. Most of them are rare and occur in limited geographic areas. The most common and best studied is an autosomal recessive condition called familial Mediterranean fever. This is a febrile disorder of unknown cause characterized by attacks of fever accompanied by inflammation of serosal surfaces, including peritoneum, pleura, and synovial membrane. This disorder is
254
encountered largely in individuals of Armenian, Sephardic Jewish, and Arabic origins. It is associated with widespread tissue involvement indistinguishable from reactive systemic amyloidosis. The amyloid fibril proteins are made up of AA proteins, suggesting that this form of amyloidosis is related to the recurrent bouts of inflammation that characterize this disease. The gene for familial Mediterranean fever has been cloned, and its product is called pyrin; although its exact function is not known, it has been suggested that pyrin is responsible for regulating acute inflammation, presumably by inhibiting the function of neutrophils. With a mutation in this gene, minor traumas unleash a vigorous, tissue-damaging inflammatory response. [153] In contrast to familial Mediterranean fever, a group of autosomal dominant familial disorders is characterized by deposition of amyloid predominantly in the nerves--peripheral and autonomic. [154] These familial amyloidotic polyneuropathies have been described in different parts of the world. For example, neuropathic amyloidosis has been identified in individuals in Portugal, Japan, Sweden, and the United States. As mentioned previously, in all of these genetic disorders, the fibrils are made up of mutant transthyretins (ATTR). Localized Amyloidosis.
Sometimes amyloid deposits are limited to a single organ or tissue without involvement of any other site in the body. The deposits may produce grossly detectable nodular masses or be evident only on microscopic examination. Nodular (tumor-forming) deposits of amyloid are most often encountered in the lung, larynx, skin, urinary bladder, tongue, and the region about the eye. Frequently, there are infiltrates of lymphocytes and plasma cells in the periphery of these amyloid masses, raising the question of whether the mononuclear infiltrate is a response to the deposition of amyloid or instead
is responsible for it. At least in some cases, the amyloid consists of AL protein and may therefore represent a localized form of immunocyte-derived amyloid. Endocrine Amyloid.
Microscopic deposits of localized amyloid may be found in certain endocrine tumors, such as medullary carcinoma of the thyroid gland, islet tumors of the pancreas, pheochromocytomas, and undifferentiated carcinomas of the stomach, and in the islets of Langerhans in patients with type II diabetes mellitus. In these settings, the amyloidogenic proteins seem to be derived either from polypeptide hormones (medullary carcinoma) or from unique proteins (e.g., islet amyloid polypeptide [IAPP]). Amyloid of Aging.
Several well-documented forms of amyloid deposition occur with aging. [155] Senile systemic amyloidosis refers to the systemic deposition of amyloid in elderly patients (usually in their seventies and eighties). Because of the dominant involvement and related dysfunction of the heart, this form was previously called senile cardiac amyloidosis. Those who are symptomatic present with a restrictive cardiomyopathy and arrhythmias. The amyloid in this form is composed of the normal transthyretin molecule. In addition to the sporadic senile systemic amyloidosis, another form, affecting, predominantly, the heart, that results from the deposition of a mutant form of transthyretin has also been recognized. Approximately 4% of the black population in the United States is a carrier of the mutant allele, and cardiomyopathy has been identified in both homozygous and heterozygous patients. The precise prevalance of patients with this mutation who develop clinically manifest cardiac disease is not known. [156] Pathogenesis.
Although the precursors of virtually all amyloid proteins have been identified, several aspects of their origins still are not clear. In reactive systemic amyloidosis, it appears that long-standing tissue destruction and inflammation lead to elevated SAA levels (Fig. 7-47) . SAA is synthesized by the liver cells under the influence of cytokines such as IL-6 and IL-1; however, increased production of SAA by itself is not sufficient for the deposition of amyloid. Elevation of serum SAA levels is common to inflammatory states but in most instances does not lead to amyloidosis. There are two possible explanations for this. According to one view, SAA is normally degraded to soluble end products by the action of monocyte-derived enzymes. Conceivably, individuals who develop amyloidosis have an enzyme defect that results in incomplete breakdown of SAA, thus generating insoluble AA molecules.
Figure 7-47 Proposed schema of the pathogenesis of two major forms of amyloid fibrils.
255
Alternatively a genetically determined structural abnormality in the SAA molecule itself renders it resistant to degradation by monocytes. In the case of immunocyte dyscrasias, there is an excess of immunoglobulin light chains, and amyloid can be derived by proteolysis of immunoglobulin light chains in vitro. Again, defective degradation has been invoked, and perhaps particular light chains are resistant to complete proteolysis. In contrast to the two examples already cited, in familial amyloidosis the deposition of transthyretins as amyloid fibrils does not result from overproduction of transthyretins. It has been proposed that genetically determined alterations of structure render the transthyretins prone to abnormal aggregation and proteolysis. The cells involved in the conversion of the precursor proteins into the fibrils are not fully characterized, but macrophages seem to be the most likely candidates. MORPHOLOGY.
There are no consistent or distinctive patterns of organ or tissue distribution of amyloid deposits in any of the categories cited. Nonetheless a few generalizations can be made. Amyloidosis secondary to chronic inflammatory disorders tends to yield the most severe systemic involvements. Kidneys, liver, spleen, lymph nodes, adrenals, and thyroid as well as many other tissues are classically involved. Although immunocyte-associated amyloidosis cannot reliably be distinguished from the secondary form by its organ distribution, more often it involves the heart, kidney, gastrointestinal tract, peripheral nerves, skin, and tongue. Macroscopically the affected organs are often enlarged and firm and have a waxy appearance. If the deposits are sufficiently large, painting the cut surface with iodine imparts a yellow color that is transformed to blue violet after application of sulfuric acid. As noted earlier, the histologic diagnosis of amyloid is based almost entirely on its staining characteristics. The most commonly used staining technique employs the dye Congo red, which under ordinary light imparts a pink or red color to amyloid deposits. Under polarized light, the Congo red- stained amyloid shows a green birefringence (see Fig. 7-43) (Figure Not Available) . This reaction is shared by all forms of amyloid and is due to the cross-beta-pleated configuration of amyloid fibrils. Confirmation can be obtained by electron microscopy. AA, AL, and transthyretin amyloid can be distinguished in histologic sections by specific immunohistochemical staining. Because the pattern of organ involvement in different clinical forms of amyloidosis is variable, each of the major organ involvements is described separately. Kidney.
Amyloidosis of the kidney is the most common and potentially the most serious form of organ involvement. In most reported series of patients with amyloidosis, renal
amyloidosis is the major cause of death. On gross inspection, the kidney may appear normal in size and color, or it may be enlarged. In advanced cases, it may be shrunken and contracted owing to vascular narrowing induced by the deposition of amyloid within arterial and arteriolar walls. Histologically the amyloid is deposited primarily in the glomeruli, but the interstitial peritubular tissue, arteries, and arterioles are also affected. The glomerular deposits first appear as subtle thickenings of the mesangial matrix, accompanied usually by uneven widening of the basement membranes of the glomerular capillaries. In time, the mesangial depositions and the deposits along the basement membranes cause capillary narrowing and distortion of the glomerular vascular tuft. With progression of the glomerular amyloidosis, the capillary lumens are obliterated, and the obsolescent glomerulus is flooded by confluent masses or interlacing broad ribbons of amyloid (Fig. 7-48) . Spleen.
Amyloidosis of the spleen may be inapparent grossly or may cause moderate to marked splenomegaly (up to 800 gm). For completely mysterious reasons, one of two patterns of deposition is seen. In one, the deposit is largely limited to the splenic follicles, producing tapioca-like granules on gross inspection, designated sago spleen. Histologically the entire follicle may be replaced in advanced cases. In the other pattern, the amyloid appears to spare the follicles and instead involves the walls of the splenic sinuses and connective tissue framework in the red pulp. Fusion of the early deposits gives rise to large, maplike areas of amyloidosis, creating what has been designated the lardaceous spleen. Liver.
The deposits may be grossly inapparent or may cause moderate to marked hepatomegaly. The amyloid appears first in the space of Disse then progressively encroaches on adjacent hepatic
Figure 7-48 Amyloidosis of the kidney. The glomerular architecture is almost totally obliterated by the massive accumulation of
amyloid.
256
parenchymal cells and sinusoids. In time, deformity, pressure atrophy, and disappearance of hepatocytes occur, causing total replacement of large areas of liver parenchyma. Vascular involvement and Kupffer cell depositions are frequent. Normal liver function is usually preserved despite sometimes quite severe involvement of the liver.
Heart.
Amyloidosis of the heart may occur in any form of systemic amyloidosis, much more commonly in persons with immunocyte-derived disease. It is also the major organ involved in senile systemic amyloidosis. The heart may be enlarged and firm, but more often it shows no significant changes on cross-section of the myocardium. Histologically the deposits begin in focal subendocardial accumulations and within the myocardium between the muscle fibers. Expansion of these myocardial deposits eventually causes pressure atrophy of myocardial fibers (Fig. 7-49) . In most cases, the deposits are separated and widely distributed, but when they are subendocardial, the conduction system may be damaged, accounting for the electrocardiographic abnormalities noted in some patients. Other Organs.
Amyloidosis of other organs is generally encountered in systemic disease. The adrenals, thyroid, and pituitary are common sites of involvement. In the adrenals, the intercellular deposits begin adjacent to the basement membranes of the cortical cells, usually first in the zona glomerulosa. With progression, large sheets of amyloid may replace considerable amounts of the cortical parenchyma. Similar patterns are seen in the thyroid and pituitary. The gastrointestinal tract may be involved at any level, from the oral cavity (gingiva, tongue) to the anus. The early lesions mainly affect blood vessels but eventually extend
Figure 7-49 Cardiac amyloidosis. The atrophic myocardial fibers are separated by structureless, pink-staining amyloid.
to involve the adjacent areas of the submucosa, muscularis, and subserosa. Nodular depositions in the tongue may cause macroglossia, giving rise to the designation tumor-forming amyloid of the tongue. The respiratory tract may be involved focally or diffusely from the larynx down to the smallest bronchioles. As mentioned earlier, a distinct chemical form of amyloid has been found in the brain of patients with Alzheimer disease. It involves so-called plaques as well as blood vessels (Chapter 30) . Amyloidosis of peripheral and autonomic nerves is a feature of several familial amyloidotic neuropathies. Depositions of amyloid in patients on long-term hemodialysis are most prominent in the carpal ligament of the wrist, resulting in compression of the median nerve (carpal tunnel syndrome). These patients may also have extensive amyloid deposition in the joints. Clinical Correlation.
Amyloidosis may be found as an unsuspected anatomic change, having produced no clinical manifestations, or it may cause death. The symptoms depend on the magnitude
of the deposits and on the particular sites or organs affected. Clinical manifestations at first are often entirely nonspecific, such as weakness, weight loss, lightheadedness, or syncope. Somewhat more specific findings appear later and most often relate to renal, cardiac, and gastrointestinal involvement. Renal involvement gives rise to proteinuria and is an important cause of the nephrotic syndrome (Chapter 21) . Progressive obliteration of glomeruli in advanced cases ultimately leads to renal failure and uremia. Cardiac amyloidosis may present as an insidious congestive heart failure. The most serious aspects of cardiac amyloidosis are the conduction disturbances and arrhythmias that may prove fatal. Occasionally, cardiac amyloidosis produces a restrictive pattern of cardiomyopathy and masquerades as chronic constrictive pericarditis (Chapter 13) . Gastrointestinal amyloidosis may be entirely asymptomatic, or it may present in a variety of ways. Amyloidosis of the tongue may cause sufficient enlargement and inelasticity to hamper speech and swallowing. Depositions in the stomach and intestine may lead to malabsorption, diarrhea, and disturbances in digestion. The diagnosis of amyloidosis depends on demonstration of amyloid deposits in tissues. The most common sites biopsied are the kidney, when renal manifestations are present, or rectal or gingival tissues in patients suspected of having systemic amyloidosis. Examination of abdominal fat aspirates stained with Congo red is an extremely useful technique for the diagnosis of systemic amyloidosis. In suspected cases of immunocyte-associated amyloidosis, serum and urine protein electrophoresis and immunoelectrophoresis should be performed. Bone marrow aspirates in such cases often show plasmacytosis even in the absence of overt multiple myeloma. The prognosis for patients with generalized amyloidosis is poor. Those with immunocyte-derived amyloidosis (not including multiple myeloma) have a median survival of 2
257
years after diagnosis. Patients with myeloma-associated amyloidosis have a poorer prognosis. [157] The outlook for patients with reactive systemic amyloidosis is somewhat better and depends to some extent on the control of the underlying condition. Resorption of amyloid after treatment of the associated condition has been reported, but this is a rare occurrence. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
REFERENCES 1.
Weiss A: Structure and function of the T cell antigen receptor. J Clin Invest 86:1015, 1990.
Reiser H, Stadecker MJ: Costimulatory B7 molecules in the pathogenesis of infection and autoimmune diseases. N Engl J Med 335:1369, 1996. 2.
3.
Abbas AK, et al: Functional diversity of helper T lymphocytes. Nature 383:787, 1996.
4.
Clarke LB, Noelle RJ: CD40 and its ligand. Adv Immunol 63:43, 1996.
4A.
. Banchereau J, Steinman RM: Dendritic cells and the control of immunity. Nature 392:245, 1998.
Luster AD: Chemokines--chemotactic cytokines that mediate inflammation. N Engl J Med 338:436, 1998. 5.
Monaco JJ: A molecular model of MHC class-I-restricted antigen processing. Immunol Today 13:173, 1992. 6.
Brown JH: Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature 364:33, 1993. 7.
8.
Neefjes JJ, Ploegh HL: Intracellular transport of MHC class II molecules. Immunol Today 13:179, 1992.
Costa JJ, et al: The cells of the allergic response: mast cells, basophils, and eosinophils. JAMA 278:1815, 1997. 9.
10.
Baraniuk JN: Pathogenesis of allergic rhinitis. J Allergy Clin Immunol 99:5763, 1997.
Howarth PH: ABC of allergies. Pathogenic mechanisms: a rational basis for treatment. BMJ 316:758, 1998. 10A.
11.
Borish L, Joseph B: Inflammation and allergic response. Med Clin North Am 76:765, 1992.
12.
Krishna MT, et al: Molecular mediators of asthma. Hosp Pract 31:115, 1996.
13.
Desreumax P, Capron M: Eosinophils in allergic reactions. Curr Opin Inmmunol 8:790, 1996.
14.
Bochner BS, Lichtenstein LM: Anaphylaxis. N Engl J Med 324:1785, 1991.
Daniels SE, et al: A genome-wide search for quantitative trait loci underlying asthma. Nature 383:247, 1996. 15.
16.
Holgate ST: Asthma genetics: waiting to exhale. Nat Genet 15:227, 1997.
Martin J, Abbot G: Serum sickness like illness and antimicrobials in children. N Z Med J 108:123, 1995. 17.
18.
Liu C, et al: Lymphocyte-mediated cytolysis. N Engl J Med 335:1651, 1996.
Sayegh MH, Turka LA: The role of T-cell costimulatory activation pathways in transplant rejection. N Engl J Med 338:1813, 1998. 19.
20.
VanBuskirk AM, et al: Transplantation immunology. JAMA 278:1993, 1997.
21.
Pardo-Mindan FJ, et al: Pathology of renal transplantation. Semin Diagn Pathol 9:185, 1992.
Takemoto S, et al: Survival of nationally shared, HLA-matched kidney transplants from cadaveric donors. N Engl J Med 327:834, 1992. 22.
Lu CY, et al: Prevention and treatment of renal allograft rejection: new therapeutic approaches and new insights into established therapies. J Am Soc Nephrol 4:1239, 1993. 23.
Kumar V, et al: Role of murine NK cells and their receptors in hybrid resistance. Curr Opin Immunol 9:52, 1997. 24.
25.
Miller JFAP, Basten A: Mechanisms of tolerance to self. Curr Opin Immunol 8:815, 1996.
26.
Cornall RJ, et al: The regulation of self-reactive B cells. Curr Opin Immunol 7:804, 1995.
Parijs LV, Abbas AK: Homeostasis and self-tolerance in the immune system: turning lymphocytes off. Science 280:243, 1998. 26A.
27.
Winoto A: Cell death in the regulation of immune responses. Curr Opin Immunol 9:365, 1997.
28.
Kruisbeek AM, Amsen D: Mechanisms underlying T cell tolerance. Curr Opin Immunol 8:233, 1996.
Shull M, et al: Targeted disruption of the mouse transforming growth factor-b1 gene results in multifocal inflammatory disease. Nature 359:693, 1992. 29.
30.
Tivol EA, et al: Costimulation and autoimmunity. Curr Opin Immunol 8:822, 1996.
Groux H, et al: A CD4+ T cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389:737, 1997. 31.
Barnaba V, Sinigaglia F: Molecular mimicry and T cell-mediated autoimmune disease. J Exp Med 185:1529, 1997. 32.
Benoist C, Mathis D: Autoimmune diabetes: retrovirus as trigger, precipitator or marker? Nature 388:833, 1997. 33.
Theofilopoulos AN: The basis of autoimmunity: Part I. mechanisms of aberrant self recognition. Imunol Today 16:90, 1995. 34.
35.
Lanzavecchia A: How can cryptic epitopes trigger autoimmunity? J Exp Med 181:1945, 1995.
36.
Vanderlugt CJ, Miller SD: Epitope spreading. Curr Opin Immunol 8:831, 1996.
Theofilopoulos AN: The basis of autoimmunity: Part II. Genetic predisposition. Immunol Today 16:150, 1995. 37.
Dalton TA, Bennett JC: Autoimmune diseases and the major histocompatibility complex: therapeutic implications. Am J Med 92:183, 1992. 38.
Hammer RE, et al: Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders. Cell 63:1099, 1990. 39.
40.
Steinman L, Conlon P: Viral damage and breakdown of self-tolerance. Nat Med 3:1085, 1997.
Michet CJ Jr, et al: Epidemiology of SLE and other connective tissue diseases in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc 60:105, 1985. 41.
42.
Kotzin BL: Systemic lupus erythematosus. Cell 85:303, 1996.
Kotzin AL, O'Dell JR: Systemic lupus erythematosus. In Frank MM, et al (eds): Samter's Immunologic Diseases, 5th ed. Boston, Little, Brown, 1995, p 667. 43.
43A.
Hahn BH: Antibodies to DNA. N Engl J Med 338:1359, 1998.
Hietarinta M, Lassila O: Clinical significance of antinuclear antibodies in systemic rheumatic diseases. Ann Med 28:283, 1996. 44.
Hang LM, Nakamura RM: Current concepts and advances in clinical laboratory testing for autoimmune diseases. Crit Rev Clin Lab Sci 34:275, 1997. 45.
Galli M, et al: Antiphospholipid antibodies: predictive value of laboratory tests. Thromb Hemost 78:75, 1997. 46.
47.
Shapiro SS: The lupus anticoagulant-antibody syndrome. Ann Rev Med 47:533, 1996.
48.
Kotzin BL: Susceptibility loci for lupus: guiding light from murine models? J Clin Invest 99:557, 1997.
49.
Deapen D, et al: A revised estimate of twin concordance in SLE. Arthritis Rheum 35:311, 1992.
50.
Schur PH: Genetics of SLE. Lupus 4:425, 1995.
51.
Tsokos GC: Lymphocyte abnormalities in human lupus. Clin Immunol Immunopathol 63:7, 1992.
Belmart HM, Abramson SB: Pathology and pathogenesis of vascular injury in SLE. Arthritis Rheum 39:9, 1996. 52.
Pollak VE, Pirani CL: Lupus nephritis. In Wallace DJ, Hahn BH (eds): Dubois' Lupus Erythematosus, 4th ed. Philadelphia, Lea & Febiger, 1993, p 525. 53.
Moore PM, Lisak RP: Systemic lupus erythematosus: immunopathogenesis of neurologic dysfunction. Springer Semin Immunopathol 17:43, 1995. 54.
Roldan CA, et al: An echocardiographic study of valvular heart disease associated with SLE. N Engl J Med 335:1424, 1996. 55.
Boumpas DT, et al: Systemic lupus erythematosus: emerging concepts. Ann Intern Med 122:940, 1995. 56.
57.
Rasaratnam I, Ryan PFJ: Systemic lupus erythematosus. Med J Aust 166:266, 1997.
Iliopoulos AG, Toskos GC: Immunopathogenesis and spectrum of infection in SLE. Semin Arthritis Rheum 25:318, 1996. 58.
59.
Donnelly AM, et al: Discoid lupus erythematosus. Australas J Dermatol 36:3, 1995.
60.
Sontheimer R: Subacute cutaneous lupus erythematosus. Clin Dermatol 3:58, 1985.
61.
258
Yung RL, Richardson BC: Drug-induced lupus. Rheum Dis Clin North Am 20:61, 1994. 62.
Fox RI, Kang HI: Pathogenesis of Sjogren syndrome. Rheum Dis Clin North Am 18:517, 1992.
63.
Sumida T, et al: TCR in Sjogren syndrome. Br J Rheumatol 36:622, 1997.
Haneji N, et al: Identification of a-fodrin as a candidate autoantigen in primary Sjogren syndrome. Science 276:604, 1997. 64.
Venables PJW, Rigby SP: Viruses in the etiopathogenesis of Sjogren syndrome. J Rheumatol 24(suppl 50):3, 1997. 65.
Manthorpe R, et al: Primary Sjogren syndrome: diagnostic criteria, clinical features, and disease activity. J Rheumatol 24(suppl 50):8, 1997. 66.
Geppert T: Southwestern Internal Medicine Conference: Clinical features, pathogenic mechanisms, and new developments in the treatment of systemic sclerosis. Am J Med Sci 299:193, 1990. 67.
68.
White B: Immunopathogenesis of systemic sclerosis. Rheum Dis Clin North Am 22:695, 1996.
69.
LeRoy EC: Systemic sclerosis: a vascular perspective. Rheum Clin North Am 22:675, 1996.
Furst DE, Clements PJ: Hypothesis for the pathogenesis of systemic sclerosis. J Rheumatol 24(suppl 48):53, 1997. 70.
71.
Jimenez SA, et al: Pathogenesis of scleroderma: collagen. Rheum Dis Clin North Am 22:647, 1996.
72.
Okano Y: Antinuclear antibody in systemic sclerosis. Rheum Dis Clin North Am 22:709, 1996.
73.
Rothfield N: Autoantibodies in scleroderma. Rheum Dis Clin North Am 18:483, 1992.
74.
Mitchell H, et al: Scleroderma and related conditions. Med Clin North Am 81:129, 1997.
75.
Amato AA, Barohn RJ: Idiopathic inflammatory myopathies. Neurol Clin 15:615, 1997.
Dalakas M, Sivakumar K: The immunopathologic and inflammatory differences between dermatomyositis, polymyositis, and sporadic inclusion body myositis. Curr Opin Neurol 9:235, 1996. 76.
77.
Targoff IN: Autoantibodies in polymyositis. Rheum Dis Clin North Am 18:455, 1992.
Lundberg I, Hedfors E: Clinical course of patients with anti-RNP antibodies: a prospective study of 32 patients. J Rheumatol 18:1511, 1991. 78.
79.
Citera G, et al: Mixed connective tissue disease: fact or fiction. Lupus 4:255, 1995.
World Health Organization Scientific Group: Primary immunodeficiency diseases. Clin Exp Immunol 109(suppl):1, 1997. 80.
Ochs HD, Smith CID: X-linked agammaglobulinemia: a clinical and molecular analysis. Medicine 75:287, 1996. 81.
82.
Rosen FS, et al: The primary immunodeficiencies. N Engl J Med 333:431, 1995.
Sneller MC (moderator): New insights into common variable immunodeficiency. Ann Intern Med 118:720, 1993. 83.
84.
Burrows PD, Cooper MD: IgA deficiency. Adv Immunol 65:245, 1997.
85.
Lanzavecchia A: Licence to kill. Nature 393:413, 1998.
Thomas JA, Graham JM Jr: Chromosome 22q11 deletion syndrome: an update and review for primary pediatricians. Clin Pediatr 36:253, 1997. 86.
Resta R, Thompson LF: SCID: the role of adenosine deaminase deficiency. Immunol Today 18:371, 1997. 87.
Blaese RM, et al: T-lymphocyte directed gene therapy for ADA-SCID: initial trial result after 4 years. Science 270:475, 1995. 88.
89.
Puck JM: Primary immunodeficiency diseases. JAMA 278:1635, 1997.
90.
Huber, J, et al: Pathology of congenital immunodeficiencies. Semin Diagn Pathol 9:31, 1992.
91.
Featherstone C: Research News. The many faces of WAS protein. Science 275:27, 1997.
Frank MM: Complement in disease: inherited and acquired complement deficiencies. In Frank MM, et al (eds): Samter's Immunologic Diseases, 52nd ed. Boston, Little, Brown, 1995, p 487. 92.
93.
Acardi M, Agostoni A: Hereditary angioedema. N Engl J Med 334:1666, 1996.
Update: mortality attributable to HIV infection among persons aged 25-44 years--United States, 1994. MMWR 45:121, 1996. 94.
95.
Quinn TC: Global burden of the HIV pandemic. Lancet 348:99, 1996.
95A.
Balter M: Global program struggles to stem the flood of new cases.Science 280:1863, 1998.
96.
Royce RA, et al: Sexual transmission of HIV. N Engl J Med 336:1072, 1997.
97.
Schreiber GB, et al: The risk of transfusion-associated viral infections. N Engl J Med 334:1685, 1996.
98.
Wizinia AA, et al: Pediatric HIV infection. Med Clin North Am 80:1309, 1996.
Cardo DM, et al: A case control study of HIV seroconversion in health care workers after percutaneous exposure. N Engl J Med 337:1485, 1997. 99.
Geberding JL, et al: Risk of transmitting the human immunodeficiency virus to health care workers exposed to patients with AIDS and AIDS-related conditions. J Infect Dis 156:1, 1987. 100.
101.
O'Brien J, Goedert JJ: HIV causes AIDS: Koch's postulates fulfilled. Curr Opin Immunol 8:613, 1996.
102.
Hardy WD: The human immunodeficiency virus. Med Clin North Am 80:1239, 1996.
103.
Barre-Sinoussi F: HIV as the cause of AIDS. Lancet 348:31, 1996.
104.
Emerman M: HIV-1 and the cell cycle. Curr Biol 6:1096, 1996.
Goh WC, et al: HIV-1 vpr increases viral expression by manipulation of the cell cycle: a mechanism for selection of vpr in vivo. Nat Med 4:65, 1998. 105.
Johnson RP: Upregulation of Fas ligand by Simian immunodeficiency virus: a nef-arious mechanism of immune evasion. J Exp Med 186:1, 1997. 106.
Collins KL, et al: HIV-1 nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Nature 391:397, 1998. 107.
108.
Miller RH, Sarver N: HIV accessory proteins as therapeutic targets. Nat Med 4:389, 1997.
Doms RW, Peiper SC: Unwelcomed guests with master keys: how HIV uses chemokine receptors for cellular entry. Virology 235:179, 1997. 109.
110.
Binley J, Moore JP: The viral mousetrap. Nature 387:346, 1997.
111.
O'Brien SJ, Dean M: In search of AIDS resistance genes. Sci Am 277:46,1997.
112.
Moore JP: Coreceptors: implications for HIV pathogenesis and therapy. Science 276:51, 1997.
113.
Graziosi C, Pantaleo G: The multifaceted personality of HIV. Nat Med 3:1318, 1997.
114.
Research News. Exploiting the HIV-chemokine nexus. Science 275:1261, 1997.
115.
Nolan G: Harnessing viral devices or pharmaceuticals: fighting HIV-1's fire with fire. Cell 90:821,1997.
116.
Ho D: Dynamics of HIV-1 replication in vivo. J Clin Invest 99:2505, 1997.
Wolthers KC, et al: T cell telomere length in HIV-1 infection: no evidence for increased CD4+ T cell turnover. Science 274:1543, 1996. 117.
118.
Research News. HIV's other immune system targets: macrophages. Science 24:1464, 1997.
Orenstein JM, Wahl SM: Macrophages as a source of HIV during opportunistic infections. Science 276:2857, 1997. 119.
Knight SC, Patterson S: Bone-marrow derived dendritic cells, infection with human immunodeficiency virus, and immunopathology. Ann Rev Immunol 15:593, 1997. 120.
Embretson J, et al: Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 362:359, 1993. 121.
122.
Wain-Hobson S: Down or out in blood and lymph? Nature 387:123, 1997.
123.
Cohen OJ, et al: Host factors in the pathogenesis of HIV disease. Immunol Rev 159:31, 1997.
124.
Glass JD, Johnson RT: Human immunodeficiency virus and the brain. Ann Rev Neurosci 19:1, 1996.
Adamson DC, et al: Immunologic NO synthetase: elevation in severe AIDS dementia and induction by HIV gp41. Science 274:1917, 1996. 125.
126.
Dewhurst S, et al: Neuropathogenesis of AIDS. Mol Med Today 2:16, 1996.
127.
259
Pantaleo G, et al: The immunopathogenesis of human immunodeficiency virus infection. N Engl J Med 328:327, 1993. Shacker T, et al: Clinical and epidemiologic features of primary HIV infection. Ann Intern Med 125:257, 1996. 128.
Musey L, et al: Cytotoxic T cell responses, viral load and disease progression in early human immunodeficiency virus type 1 infection. N Engl J Med 337:1306, 1997. 129.
Mellors JW, et al: Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 272:1167, 1996. 130.
131.
Sage MS: Use of HIV viral load in clinical practice: back to the future. Ann Intern Med 126:983, 1997.
McMichael AJ, Phillips RE: Escape of human immunodeficiency virus from immune control. Ann Rev Immunol 15:271, 1997. 132.
133.
Centers for Disease Control and Prevention: 1993 revised classification system and expanded
surveillance definition for AIDS among adolescents and adults. MMWR 41(RR-17):1, 1992. Gold JWM, et al (eds): Management of the HIV-infected patient: Part II. Med Clin North Am 81:299, 1997. 134.
135.
Kessler HA, et al: AIDS: Part II. Dis Mon 38:695, 1992.
Markowitz N, et al: Incidence of tuberculosis in the United States among HIV-infected persons. Ann Intern Med 126:123, 1997. 136.
Telzak EE: Tuberculosis and human immunodeficiency virus infection. Med Clin North Am 81:345, 1997. 137.
138.
Nasti G, et al: Malignant tumors and AIDS. Biomed Pharmacother 51:243, 1997.
139.
Rabkin CS, et al: Monoclonal origin of multicenter KS lesions. N Engl J Med 336:988, 1997.
140.
Kroll MH, Shandera WX: AIDS-associated Kaposi's sarcoma. Hosp Pract 33:85, 1998.
Martin JN, et al: Sexual transmission and natural history of human herpesvirus 8 infection. N Engl J Med 338:948, 1998. 140A.
141.
Murphy PM: Pirated genes in KS. Nature 385:296, 1997
Nicholas J, et al: KS-associated human herpes virus-8 encodes homologs of macrophage inflammatory protein-1, and interleukin-6. Nat Med 3:287, 1997. 142.
143.
Boshoff C: Coupling herpesvirus to angiogenesis. Nature 391:24, 1998.
Knowles DM: Molecular pathology of acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma. Semin Diagn Pathol 14:87, 1997. 144.
Levine R: Lymphoma in the setting of human immunodeficiency virus infection. In Canellos GP, et al (eds): The Lymphomas. Philadelphia, WB Saunders, 1998, p 507. 145.
146.
Shah KV: Human papillomavirus and anogenital cancers. N Engl J Med 337:1386, 1997.
Knowles DM, Chadburn A: Lymphadenopathy and the lymphoid neoplasms associated with the acquired immune deficiency syndrome. In Knowles DM (ed): Neoplastic Hematopathology. Baltimore, Williams & Wilkins, 1992, p 773. 147.
148.
Shah KV: Human papillomavirus and anogenital cancers. N Engl J Med 337:1386, 1997.
148A.
Ho DD: Toward HIV eradication or remission: the tasks ahead.Science 280:1866, 1998.
Belloti V, Merlini G: Current concepts in the pathogenesis of systemic amyloidosis. Nephrol Dial Transplant 2(suppl 9):53, 1996. 149.
Codho T: Familial amyloid polyneuropathy: new developments in genetics and treatment. Curr Opin Neurol 9:355, 1996. 150.
151.
Buxbaum J: The amyloidosis. Mt Sinai Med J 63:16, 1996.
Campistol JM, Argiles A: Dialysis-related amyloidosis: visceral involvement and protein constitutents. Nephrol Dial Transplant 11(suppl 3):142, 1996. 152.
153.
Kastner DL: Familial Mediterranean fever: the genetics of inflammation. Hosp Pract 33:131, 1998.
154.
Benson MD: Inherited amyloidosis. J Med Genet 28:73, 1991.
Cornwell GG, et al: The age related amyloids: a growing family unique biochemical substances. J Clin Pathol 48:984, 1995. 155.
Jacobson DR, et al: Variant sequence transthyretin (isoleucin 122) in late onset cardiac amyloidosis in black Americans. N Engl J Med 336:466, 1997. 156.
157.
Kyle RA, Gertz MA: Systemic amyloidosis. Crit Rev Oncol Hematol 10:49, 1990.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-1 The T-cell receptor (TCR) complex: schematic illustration of TCR and TCRalpha and TCRbeta polypeptide chains linked to the CD3 molecular complex.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-2 Schematic representation of antigen recognition by CD4+ T cells. Note that the T-cell receptor (TCR heterodimer) recognizes a peptide fragment of antigen bound to the major histocompatibility complex (MHC) class II molecule. The CD4 molecule binds to the nonpolymorphic portion of the class II molecule. The interaction between the TCR and the MHC-bound antigen provides signal 1 for T-cell activation. Signal 2 is provided by the interaction of the CD28 molecule with the costimulatory molecules (B7-1 and B7-2) expressed on antigen presenting cell.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-3 Lymph node cortex showing a lymphoid follicle, the B cell-containing area. (Courtesy of Dr. Jon Aster, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-4 A highly activated natural killer cell with abundant cytoplasmic granules. (Courtesy of Dr. Noelle Williams, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-5 Schematic representation of NK cell receptors and killing. Normal cells are not killed because inhibitory signals from normal MHC class I molecules override activating signals. In tumor cells, or virus-infected cells, reduced expression or alteration of MHC molecules interrupts the inhibitory signals, allowing activation of NK cells and lysis of target cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-6 Schematic representation of the HLA complex and its subregions. The relative distances between various genes and regions are not drawn to scale.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-7 Schematic diagram of HLA class I molecule.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-8 Schematic illustration of antigen recognition by CD8+ T cells. Note that the T-cell receptor (TCR heterodimer) recognizes a complex formed by the peptide fragment of the antigen and MHC class I molecule. The CD8 molecule binds to the nonpolymorphic portion of the class I molecule and thus acts as an accessory structure during antigen recognition.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 1 - GENERAL PATHOLOGY 8 - Neoplasia NOMENCLATURE Benign Tumors Malignant Tumors Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
NOMENCLATURE All tumors, benign and malignant, have two basic components: (1) proliferating neoplastic cells that constitute their parenchyma and (2) supportive stroma made up of connective tissue and blood vessels. Although parenchymal cells represent the proliferating "cutting edge" of neoplasms and so determine their nature, the growth and evolution of neoplasms are critically dependent on their stroma. An adequate stromal blood supply is requisite, and the stromal connective tissue provides the framework for the parenchyma. In some tumors, the stromal support is scant, and so the neoplasm is soft and fleshy. Sometimes the parenchymal cells stimulate the formation of an abundant collagenous stroma--referred to as desmoplasia. Some tumors, for example, some cancers of the female breast, are stony hard or scirrhous. The nomenclature of tumors is, however, based on the parenchymal component. Benign Tumors. In general, benign tumors are designated by attaching the suffix -oma to the cell of origin. Tumors of mesenchymal cells generally follow this rule. For example, a benign tumor arising from fibroblastic cells is called a fibroma. A cartilaginous tumor is a chondroma, and a tumor of osteoblasts is an osteoma. In contrast, nomenclature of benign epithelial tumors is more complex. They are variously classified, some based on their cells of origin, others on microscopic architecture, and still others on their macroscopic patterns. Adenoma is the term applied to the benign epithelial neoplasm that forms glandular patterns as well as to the tumors derived from glands but not necessarily reproducing glandular patterns. On this basis, a benign epithelial neoplasm that arises from renal tubular cells growing in the form of numerous tightly clustered small glands would be termed an adenoma, as would a heterogeneous mass of adrenal cortical cells growing in no distinctive pattern. Benign epithelial neoplasms producing microscopically or macroscopically visible finger-like or warty projections from epithelial surfaces are referred to as papillomas (Fig. 8-1) . Those that form large cystic masses, as in the ovary, are referred to as cystadenomas. Some tumors produce papillary patterns that protrude into cystic spaces and are called papillary cystadenomas. When a neoplasm, benign or malignant, produces a macroscopically visible projection above a mucosal surface and projects, for example, into the gastric or colonic lumen, it is termed a polyp (Fig. 8-2) . The term polyp preferably is restricted to benign tumors. Malignant polyps are better designated polypoid cancers. Malignant Tumors. The nomenclature of malignant tumors essentially follows the same schema used for
benign neoplasms, with certain additions. Malignant tumors arising in mesenchymal tissue are usually called sarcomas
Figure 8-1 Papilloma of the colon with finger-like projections into the lumen. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
262
Figure 8-2 Colonic polyp. A, This benign glandular tumor (adenoma) is projecting into the colonic lumen and is attached to the mucosa by a distinct stalk. B, Gross appearance of several colonic polyps.
(Greek sar=fleshy) because they have little connective tissue stroma and so are fleshy (e.g., fibrosarcoma, liposarcoma, and leiomyosarcoma for smooth muscle cancer and rhabdomyosarcoma for a cancer that differentiates toward striated muscle). Malignant neoplasms of epithelial cell origin, derived from any of the three germ layers, are called carcinomas. Thus, cancer arising in the epidermis of ectodermal origin is a carcinoma, as is a cancer arising in the mesodermally derived cells of the renal tubules and the endodermally derived cells of the lining of the gastrointestinal tract. Carcinomas may be further qualified. One with a glandular growth pattern microscopically is termed an adenocarcinoma, and one producing recognizable squamous cells arising in any epithelium of the body is termed a squamous cell carcinoma. It is further common practice to specify, when possible, the organ of origin (e.g., a renal cell adenocarcinoma or bronchogenic squamous cell carcinoma). Not infrequently, however, a cancer is composed of undifferentiated cells and must be designated merely as a poorly differentiated or undifferentiated malignant tumor. In most neoplasms, benign and malignant, the parenchymal cells bear a close resemblance to each other, as though all were derived from a single cell, as we know to be the case with cancers. Infrequently, divergent differentiation of a single line of parenchymal cells creates what are called mixed tumors. The best example is the mixed tumor of salivary gland origin. These tumors contain epithelial components scattered within a myxoid stroma that sometimes contains islands of apparent cartilage or even bone (Fig. 8-3) (Figure Not Available) . All these elements, it is believed, arise from epithelial and myoepithelial cells of salivary gland origin; thus the preferred designation of these neoplasms is pleomorphic adenoma. The great majority of neoplasms, even mixed tumors, are composed of cells representative of a single germ layer. The teratoma, in contrast, is made up of a variety of parenchymal cell types representative of more than one germ layer, usually all three. They arise from totipotential cells and so are principally encountered in the gonads, although, rarely, they occur in sequestered primitive cell rests elsewhere. These totipotential cells differentiate along various germ lines, producing, for example, tissues that can be identified as skin, muscle, fat, gut epithelium, tooth structures, and, indeed, any tissue of the body. A particularly common pattern is seen in the ovarian cystic teratoma (dermoid cyst), which differentiates
principally Figure 8-3 (Figure Not Available) This mixed tumor of the parotid gland contains epithelial cells forming ducts and myxoid stroma that resembles cartilage. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
263
along ectodermal lines to create a cystic tumor lined by skin replete with hair, sebaceous glands, and tooth structures (Fig. 8-4) . The nomenclature of the more common forms of neoplasia is presented in Table 8-1 . It is evident from this compilation that there are some inappropriate but deeply entrenched usages. For generations, carcinomas of melanocytes have been called melanomas, although correctly they should be referred to as melanocarcinomas. Analogously, carcinomas of testicular origin are stubbornly called seminomas. Other instances are encountered in which innocent designations belie ugly behavior. The converse is also true when ominous terms are applied to usually trivial lesions. An ectopic rest of normal tissue is sometimes called a choristoma--as, for example, a rest of adrenal cells under the kidney capsule. Occasionally a pancreatic nodular rest in the mucosa of the small intestine may mimic a neoplasm, providing some partial justification for the use of a term that implies a tumor. Analogously, aberrant differentiation may produce a mass of disorganized but mature specialized cells or tissue indigenous to the particular site, referred to as a hamartoma. Thus, a hamartoma in the lung may contain islands of cartilage, blood vessels, bronchial-type structures, and lymphoid tissue. Sometimes the lesion is purely cartilaginous or purely angiomatous. Although these might be construed as benign neoplasms, the complete resemblance of the tissue to normal cartilage or blood vessels and the occasional admixture of other elements favor a hamartomatous origin. In any event, the hamartoma is totally benign. TABLE 8-1 -- NOMENCLATURE OF TUMORS Tissue of Origin Benign Malignant Composed of One Parenchymal Cell Type Mesenchymal tumors Connective tissue and derivatives
Fibroma
Fibrosarcoma
Lipoma
Liposarcoma
Chondroma
Chondrosarcoma
Osteoma
Osteogenic sarcoma
Hemangioma
Angiosarcoma
Lymphangioma
Lymphangiosarcoma
Endothelial and related tissues Blood vessels Lymph vessels
Synovium
Synovial sarcoma
Mesothelium
Mesothelioma
Brain coverings
Meningioma
Invasive meningioma
Blood cells and related cells Hematopoietic cells
Leukemias
Lymphoid tissue
Malignant lymphomas
Muscle Smooth
Leiomyoma
Leiomyosarcoma
Striated
Rhabdomyoma
Rhabdomyosarcoma
Squamous cell papilloma
Squamous cell or epidermoid carcinoma
Epithelial tumors Stratified squamous Basal cells of skin or adnexa
Basal cell carcinoma
Epithelial lining Glands or ducts
Adenoma
Adenocarcinoma
Papilloma
Papillary carcinoma
Cystadenoma
Cystadenocarcinoma
Respiratory passages
Bronchogenic carcinoma Bronchial adenoma (carcinoid)
Neuroectoderm
Nevus
Malignant melanoma
Renal epithelium
Renal tubular adenoma
Renal cell carcinoma
Liver cells
Liver cell adenoma
Hepatocellular carcinoma
Urinary tract epithelium (transitional)
Transitional cell papilloma
Transitional cell carcinoma
Placental epithelium (trophoblast)
Hydatidiform mole
Choriocarcinoma
Testicular epithelium (germ cells)
Seminoma Embryonal carcinoma
More Than One Neoplastic Cell Type-- Mixed Tumors, Usually Derived From One Germ Layer Salivary glands
Pleomorphic adenoma Malignant mixed tumor of (mixed tumor of salivary gland origin salivary origin)
Breast
Fibroadenoma
Renal anlage
Malignant cystosarcoma phyllodes Wilms tumor
More Than One Neoplastic Cell Type Derived From More Than One Germ Layer-- Teratogenous Totipotential cells in gonads or in embryonic rests
Mature teratoma, dermoid cyst
Immature teratoma, teratocarcinoma
264
Figure 8-4 A , Gross appearance of an opened cystic teratoma of the ovary. Note the presence of hair, sebaceous material, and tooth. B , A microscopic view of a similar tumor shows skin, sebaceous glands, fat cells, and a tract of neural tissue (arrow).
The nomenclature of tumors is important because specific designations have specific clinical implications. The historically sanctified term seminoma connotes a form of carcinoma that tends to spread to lymph nodes along the iliac arteries and aorta. Further, these tumors are extremely radiosensitive and can be eradicated by radiotherapy; thus few patients with seminomas die of the neoplasm. By contrast, the embryonal carcinoma of the testis is not radiosensitive and tends to invade locally beyond the confines of the testis and spread throughout the body. There also are other varieties of testicular neoplasms, and so the designation cancer of the testis tells little of its clinical significance.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 1 - GENERAL PATHOLOGY 8 - Neoplasia CHARACTERISTICS OF BENIGN AND MALIGNANT NEOPLASMS Differentiation and Anaplasia Rate of Growth Local Invasion Metastasis PATHWAYS OF SPREAD Seeding of Body Cavities and Surfaces Lymphatic Spread Hematogenous Spread Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
CHARACTERISTICS OF BENIGN AND MALIGNANT NEOPLASMS In the great majority of instances, the differentiation of a benign from a malignant tumor can be made morphologically with considerable certainty; sometimes, however, a neoplasm defies categorization. It has been said, "All tumors need not of necessity be either benign or malignant." Certain anatomic features may suggest innocence, whereas others point toward cancerous potential. Ultimately, all morphologic diagnosis is subjective and constitutes prediction of the future course of a neoplasm. Occasionally, this prediction is confounded by a marked discrepancy between the morphologic appearance of a tumor and its biologic behavior: An innocent face may mask an ugly nature. Such deception or ambiguity, however, is not the rule; in general, there are criteria by which benign and malignant tumors can be differentiated, and they behave accordingly. These differences can conveniently be discussed under the following headings: (1) differentiation and anaplasia, (2) rate of growth, (3) local invasion, and (4) metastasis. Differentiation and Anaplasia The terms differentiation and anaplasia apply to the parenchymal cells of neoplasms. Differentiation refers to the extent to which parenchymal cells resemble comparable normal cells, both morphologically and functionally. Well-differentiated tumors are thus composed of cells resembling the mature normal cells of the tissue of origin of the neoplasm (Fig. 8-5) . Poorly differentiated or undifferentiated tumors have primitive-appearing, unspecialized cells. In general, benign tumors are well differentiated (Fig. 8-6) . The neoplastic cell in a benign smooth muscle tumor--a leiomyoma--so closely resembles the normal cell as to make it impossible to recognize it as a tumor cell on high-power examination. Only the massing of these cells
Figure 8-5 Leiomyoma of the uterus. This benign, well-differentiated tumor contains interlacing bundles of neoplastic smooth muscle
cells that are virtually identical in appearance to normal smooth muscle cells in the myometrium.
265
Figure 8-6 Benign tumor (adenoma) of the thyroid. Note the normal-looking (well-differentiated), colloid-filled thyroid follicles. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
into a nodule discloses the tumorous nature of the lesion. One may get so close to the tree that one loses sight of the forest. Malignant neoplasms, in contrast, range from well differentiated to undifferentiated. Malignant neoplasms composed of undifferentiated cells are said to be anaplastic. Lack of differentiation, or anaplasia, is considered a hallmark of malignant transformation. Literally, anaplasia means "to form backward," implying a reversion from a high level of differentiation to a lower level. There is substantial evidence, however, that cancers arise from stem cells present in all specialized tissues. The well-differentiated cancer (Fig. 8-7) evolves from maturation or specialization of undifferentiated cells as they proliferate, whereas the undifferentiated malignant tumor derives from proliferation without maturation of the transformed cells. Lack of differentiation then is not the consequence of dedifferentiation. Lack of differentiation, or anaplasia, is marked by a number of morphologic and functional changes. Both the cells and the nuclei characteristically display pleomorphism--variation in size and shape (Fig. 8-8) . Cells may be found that are many times larger than their neighbors, and other cells may be extremely small and primitive appearing. Characteristically the nuclei contain an abundance of DNA and are extremely dark staining ( hyperchromatic). The nuclei are disproportionately large for the cell, and the nuclear-to-cytoplasmic ratio may approach 1:1 instead of the normal 1:4 or 1:6. The nuclear shape is usually extremely variable, and the chromatin is often coarsely clumped and distributed along the nuclear membrane. Large nucleoli are usually present in these nuclei. As compared with benign tumors and some well-differentiated malignant neoplasms, undifferentiated tumors usually possess large numbers of mitoses, reflecting the higher proliferative activity of the parenchymal cells. The presence of mitoses, however, does not necessarily indicate that
Figure 8-7 Malignant tumor (adenocarcinoma) of the colon. Note that compared with the well-formed and normal-looking glands characteristic of a benign tumor (see Fig. 8-6) , the cancerous glands are irregular in shape and size and do not resemble the normal
colonic glands. This tumor is considered differentiated because gland formation can be seen. The malignant glands have invaded the muscular layer of the colon. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
a tumor is malignant or that the tissue is neoplastic. Many normal tissues exhibiting rapid turnover, such as bone marrow, have numerous mitoses, and non-neoplastic proliferations such as hyperplasias contain many cells in mitosis. More important as a morphologic feature of malignant neoplasia are atypical, bizarre mitotic figures sometimes producing tripolar, quadripolar, or multipolar spindles (Fig. 8-9) . Another feature of anaplasia is the formation of tumor giant cells, some possessing only a single huge polymorphic nucleus and others having two or more nuclei. These giant cells are not to be confused with inflammatory Langhans
Figure 8-8 Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma). Note the marked cellular and nuclear pleomorphism, hyperchromatic nuclei, and tumor giant cells. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
266
Figure 8-9 High-power detail of anaplastic tumor cells to show cellular and nuclear variation in size and shape. The prominent cell in
the center field has an abnormal tripolar spindle.
or foreign body giant cells, which possess many small, normal-appearing nuclei. In the cancer giant cell, the nucleus is hyperchromatic and is large in relation to the cell. In addition to the cytologic abnormalities described here, the orientation of anaplastic cells is markedly disturbed (i.e., they lose normal polarity). Sheets or large masses of tumor cells grow in an anarchic, disorganized fashion. Although these growing cells obviously require a blood supply, often the vascular stroma is scant, and in many anaplastic tumors, large central areas undergo ischemic necrosis. As mentioned at the outset, malignant tumors differ widely in the extent to which their morphologic appearance deviates from the norm. On one end of the spectrum are the extremely undifferentiated, anaplastic tumors, and at the other end are cancers that bear striking resemblance to their tissues of origin. Certain well-differentiated adenocarcinomas of the thyroid, for example, may form normal-appearing follicles, and some squamous cell carcinomas contain cells that do not differ cytologically from normal squamous epithelial cells (Fig. 8-10) . Thus, the morphologic diagnosis of malignancy in well-differentiated tumors may sometimes be quite difficult. In between the two extremes lie tumors that are loosely referred to as moderately well differentiated. Before we leave the subject of differentiation and anaplasia, we should discuss dysplasia, a term that literally means disordered growth. Dysplasia is encountered principally in the epithelia, and it is characterized by a constellation of changes that include a loss in the uniformity of the individual cells as well as a loss in their architectural orientation. Dysplastic cells also exhibit considerable pleomorphism (variation in size and shape) and often possess deeply stained (hyperchromatic) nuclei, which are abnormally large for the size of the cell. Mitotic figures are more abundant than usual, although almost invariably they conform to normal patterns. Frequently the mitoses appear in abnormal locations within the epithelium. Thus, in dysplastic stratified squamous epithelium, mitoses are not confined to the basal layers and may appear at all levels and even in surface cells. There is considerable architectural anarchy. For example, the usual progressive maturation of tall cells in the basal layer to flattened squames on the surface may be lost and replaced by a disordered scrambling of dark basal-appearing cells. When dysplastic changes are marked and involve the entire thickness of the epithelium, the lesion is considered a preinvasive neoplasm and is referred to as carcinoma in situ (Fig. 8-11) . Although dysplastic changes are often
found adjacent to foci of invasive carcinoma and in long-term studies of cigarette smokers, epithelial dysplasia almost invariably antedates the appearance of cancer, dysplasia does not necessarily progress to cancer. Mild-to-moderate changes that do not involve the entire thickness of epithelium may be reversible, and with removal of the putative inciting causes, the epithelium may revert to normal. Turning to the functional differentiation of neoplastic cells, as you might presume, the better the differentiation of the cell, the more completely it retains the functional capabilities found in its normal counterparts. Thus, benign neoplasms and well-differentiated carcinomas of endocrine glands frequently elaborate the hormones characteristic of their origin. Well-differentiated squamous cell carcinomas of the epidermis elaborate keratin, just as well-differentiated hepatocellular carcinomas elaborate bile. Highly anaplastic undifferentiated cells, whatever their tissue of origin, come to resemble each other more than the normal cells from which they have arisen. In some instances, however, unanticipated functions emerge. Some tumors may elaborate fetal proteins (antigens) not produced by the comparable cells in the adult. Analogously, carcinomas of nonendocrine origin may assume hormone synthesis to produce so-called ectopic hormones. For example, bronchogenic carcinomas may produce adrenocorticotropic hormone, parathyroid-like hormone, insulin, and glucagon as
Figure 8-10 Well-differentiated squamous cell carcinoma of the skin. The tumor cells are strikingly similar to normal squamous epithelial cells, with intercellular bridges and nests of keratin pearls (arrow). (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
267
Figure 8-11 A , Carcinoma in situ. This low-power view shows that the entire thickness of the epithelium is replaced by atypical
dysplastic cells. There is no orderly differentiation of squamous cells. The basement membrane is intact and there is no tumor in the subepithelial stroma. B , A high-power view of another region shows failure of normal differentiation, marked nuclear and cellular pleomorphism, and numerous mitotic figures extending toward the surface. The basement membrane (below) is not seen in this section.
well as others. More is said about these phenomena later. Despite exceptions, the more rapidly growing and the more anaplastic a tumor, the less likely it is that there will be specialized functional activity. The cells in benign tumors are almost always well differentiated and resemble their normal cells of origin; the cells in cancer are more or less differentiated, but some loss of differentiation is always present. Rate of Growth The generalization can be made that most benign tumors grow slowly over a period of years, whereas most cancers grow rapidly, sometimes at an erratic pace, and eventually spread and kill their hosts. Such an oversimplification, however, must be
extensively qualified. Some benign tumors have a higher growth rate than malignant tumors. Moreover, the rate of growth of benign as well as malignant neoplasms may not be constant over time. Factors such as hormone dependence, adequacy of blood supply, and likely unknown influences may affect their growth. For example, leiomyomas (benign smooth muscle tumors) of the uterus are common. Not infrequently, repeated clinical examination of women bearing such neoplasms over the span of decades discloses no significant increase in size. After the menopause, the neoplasms may atrophy and later be found to be replaced largely by collagenous, sometimes calcified, tissue. Leiomyomas frequently enter a growth spurt during pregnancy. These neoplasms to some extent depend on the circulating levels of steroid hormones, particularly estrogens. In general, the growth rate of tumors correlates with their level of differentiation, and thus most malignant tumors grow more rapidly than do benign lesions. There is, however, a wide range of behavior. Some malignant tumors grow slowly for years then suddenly increase in size virtually under observation, explosively disseminating to cause death within a few months of discovery. It is believed that such behavior results from the emergence of an aggressive subclone of transformed cells. At the other extreme are those that grow more slowly than benign tumors and may even enter periods of dormancy lasting for years. On occasion, cancers have been observed to decrease in size and even spontaneously disappear, but the handful of "miracles" fills only a small volume. To examine this variable behavior more closely, we consider what is known about the life history of cancer, including the cell kinetics of cancer growth and the influences that modify the growth of malignant tumors, in a later section. Local Invasion Nearly all benign tumors grow as cohesive expansile masses that remain localized to their site of origin and do not have the capacity to infiltrate, invade, or metastasize to distant sites, as do malignant tumors. Because they grow and expand slowly, they usually develop a rim of compressed connective tissue, sometimes called a fibrous capsule, that separates them from the host tissue. This capsule is derived largely from the stroma of the native tissue as the parenchymal cells atrophy under the pressure of expanding tumor. Such encapsulation tends to contain the benign neoplasm as a discrete, readily palpable, and easily movable mass that can be surgically enucleated (Figs. 8-12 and 8-13) . Although a well-defined cleavage plane exists around most benign tumors, in some it is lacking. Thus, hemangiomas (neoplasms composed of tangled blood vessels) are often unencapsulated and may appear to permeate the site in which they arise (commonly the dermis of the skin). The growth of cancers is accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. In general, they are poorly demarcated from the
268
Figure 8-12 Fibroadenoma of the breast. The tan-colored, encapsulated small tumor is sharply demarcated from the whiter breast
tissue.
surrounding normal tissue, and a well-defined cleavage plane is lacking (Figs. 8-14 and 8-15) . Slowly expanding malignant tumors, however, may develop an apparently enclosing fibrous capsule and may push along a broad front into adjacent normal structures. Histologic examination of such apparently encapsulated masses almost always discloses tiny crablike feet penetrating the margin and infiltrating the adjacent structures. Most malignant tumors are obviously invasive and can be expected to penetrate the wall of the colon or uterus, for example, or fungate through the surface of the skin. They recognize no normal anatomic boundaries. Such invasiveness makes their surgical resection difficult, and even if the tumor appears well circumscribed, it is necessary to remove a considerable margin of apparently normal tissues about the infiltrative neoplasm. Next to the development of metastases, invasiveness is the most reliable feature that differentiates malignant from benign tumors. We noted earlier that some cancers seem to evolve from a preinvasive stage referred to as carcinoma in situ. This is best illustrated by carcinoma of the uterine cervix (Chapter 24) . In situ cancers display the cytologic features of malignancy without invasion of the basement membrane. They may be considered one step removed from invasive cancer, and with time, most penetrate the basement membrane and invade the subepithelial stroma. Metastasis Metastases are tumor implants discontinuous with the primary tumor. Metastasis unequivocally marks a tumor as malignant because benign neoplasms do not metastasize. The invasiveness of cancers permits them to penetrate into blood vessels, lymphatics, and body cavities, providing the opportunity for spread. With few exceptions, all cancers can metastasize. The major exceptions are most malignant neoplasms of the glial cells in the central nervous system, called gliomas, and basal cell carcinomas of the skin. Both are highly invasive forms of neoplasia (the latter being known in the older literature as rodent ulcers because of their invasive destructiveness), but they rarely metastasize. It is evident then that the properties of invasion and metastasis are separable. In general, the more aggressive, the more rapidly growing, and the larger the primary neoplasm, the greater the likelihood that it will metastasize or already has metastasized. There are innumerable exceptions, however. Small, well-differentiated, slowly growing lesions sometimes metastasize widely, and, conversely, some rapidly growing lesions remain localized for years. No judgment can be made about the probability of metastasis from pathologic examination of the primary tumor. Many factors relating to both invader and host are involved, as is pointed out later. Approximately 30% of newly diagnosed patients with solid tumors (excluding skin
cancers other than melanomas) present with metastases. Metastatic spread strongly reduces the possibility of cure; hence short of prevention of cancer, no achievement would confer greater benefit on patients than methods to prevent distant spread.
Figure 8-13 Microscopic view of fibroadenoma of the breast seen in Figure 8-12 . The fibrous capsule (below) sharply delimits the tumor from the surrounding tissue. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
269
Figure 8-14 Cut section of an invasive ductal carcinoma of the breast. The lesion is retracted, infiltrating the surrounding breast
substance, and would be stony hard on palpation.
PATHWAYS OF SPREAD
Dissemination of cancers may occur through one of three pathways: (1) direct seeding of body cavities or surfaces, (2) lymphatic spread, and (3) hematogenous spread. Although direct transplantation of tumor cells, as for example on surgical instruments, may theoretically occur, it is rare and, in any event, an artificial mode of dissemination that is not discussed further. Each of the three major pathways is described separately. Seeding of Body Cavities and Surfaces.
Seeding of body cavities and surfaces may occur whenever a malignant neoplasm penetrates into a natural "open field." Most often involved is the peritoneal cavity, but any other cavity--pleural, pericardial, subarachnoid, and joint space--may be affected. Such seeding is particularly characteristic of carcinomas arising in the ovaries, when, not infrequently, all peritoneal surfaces become coated with a heavy layer of cancerous glaze. Remarkably the tumor cells may remain confined to the surface of the coated abdominal viscera without penetrating into the substance. Sometimes mucus-secreting ovarian and appendiceal carcinomas fill the peritoneal cavity with a gelatinous neoplastic mass referred to as pseudomyxoma peritonei. Lymphatic Spread.
Transport through lymphatics is the most common pathway for the initial dissemination of carcinomas (Fig. 8-16) , but sarcomas may also use this route. The emphasis on lymphatic spread for carcinomas and hematogenous spread for sarcomas is misleading because ultimately there are numerous interconnections between the vascular and the lymphatic systems. The pattern of lymph node involvement follows the natural routes of drainage. Because carcinomas of the breast usually arise in the upper outer quadrants, they generally disseminate first to the axillary lymph nodes. Cancers of the inner
quadrant may drain through lymphatics to the nodes within the chest along the internal mammary arteries. Thereafter the infraclavicular and supraclavicular nodes may become involved. Carcinomas
Figure 8-15 The microscopic view of breast carcinoma seen in Figure 8-14 illustrates the invasion of breast stroma and fat by nests and cords of tumor cells (compare with Fig. 8-13) . The absence of a well-defined capsule should be noted. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
of the lung arising in the major respiratory passages metastasize first to the perihilar tracheobronchial and mediastinal nodes. Local lymph nodes, however, may be bypassed--"skip metastasis"--because of venous-lymphatic
Figure 8-16 Axillary lymph node with metastatic breast carcinoma. The subcapsular sinus (left) is distended with tumor cells. Nests of tumor cells have also invaded the subcapsular cortex. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
270
Figure 8-17 A liver studded with metastatic cancer.
anastomoses or because inflammation or radiation has obliterated channels. In many cases, the regional nodes serve as effective barriers to further dissemination of the tumor, at least for a time. Conceivably the cells, after arrest within the node, may be destroyed. A tumor-specific immune response may participate in this cell destruction. Drainage of tumor cell debris or tumor antigens, or both, also induces reactive changes within nodes. Thus, enlargement of nodes may be caused by (1) the spread and growth of cancer cells or (2) reactive hyperplasia (Chapter 15) . Therefore, nodal enlargement in proximity to a cancer does not necessarily mean dissemination of the primary lesion. Hematogenous Spread.
Hematogenous spread is typical of sarcomas but is also used by carcinomas. Arteries, with their thicker walls, are less readily penetrated than are veins. Arterial spread, however, may occur when tumor cells pass through the pulmonary capillary beds or pulmonary arteriovenous shunts or when pulmonary metastases themselves give rise to additional tumor emboli. In such arterial spread, a number of factors (to be discussed) condition the patterns of distribution of the metastases. With venous invasion, the blood-borne cells follow the venous
Figure 8-18 Microscopic view of liver metastasis. A pancreatic adenocarcinoma has formed a metastatic nodule in the liver. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
flow, draining the site of the neoplasm. Understandably the liver and lungs are most frequently involved secondarily in such hematogenous dissemination (Figs. 8-17 and 8-18) . All portal area drainage flows to the liver, and all caval blood flows to the lungs. Cancers arising in close proximity to the vertebral column often embolize through the paravertebral plexus, and this pathway is probably involved in the frequent vertebral metastases of carcinomas of the thyroid and prostate. Certain cancers have a propensity for invasion of veins. Renal cell carcinoma often invades the branches of the renal vein and then the renal vein itself to grow in a snakelike fashion up the inferior vena cava, sometimes reaching the right side of the heart. Hepatocellular carcinomas often penetrate portal and hepatic radicles to grow within them into the main venous channels. Remarkably, such intravenous growth may not be accompanied by widespread dissemination. Histologic evidence of penetration of small vessels at the site of the primary neoplasm is obviously an ominous feature. Such changes, however, must be TABLE 8-2 -- COMPARISONS BETWEEN BENIGN AND MALIGNANT TUMORS Characteristics Benign Malignant Differentiation/anaplasia Well differentiated; structure may be typical of tissue of origin
Some lack of differentiation with anaplasia; structure is often atypical
Rate of growth
Usually progressive and slow; Erratic and may be slow to may come to a standstill or rapid; mitotic figures may be regress; mitotic figures are numerous and abnormal rare and normal
Local invasion
Usually cohesive and expansile well-demarcated masses that do not invade or infiltrate surrounding normal tissues
Locally invasive, infiltrating the surrounding normal tissues; sometimes may be seemingly cohesive and expansile
Metastasis
Absent
Frequently present; the larger and more undifferentiated the primary, the more likely are metastases
271
Figure 8-19 Comparison between a benign tumor of the myometrium (leiomyoma) and a malignant tumor of similar origin
(leiomyosarcoma).
viewed guardedly because, for reasons discussed later, they do not indicate the inevitable development of metastases. The differential features discussed in this overview of the specific characteristics of benign and malignant tumors are summarized in Table 8-2 and Figure 8-19 . With this background on the structure and behavior of neoplasms, we now discuss the origin of tumors, starting with insights gained from the epidemiology of cancer and followed by the molecular basis of transformation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 1 - GENERAL PATHOLOGY 8 - Neoplasia EPIDEMIOLOGY Cancer Incidence Geographic and Environmental Factors Age Heredity Inherited Cancer Syndromes Familial Cancers Autosomal Recessive Syndromes of Defective DNA Repair Acquired Preneoplastic Disorders Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
EPIDEMIOLOGY Because cancer is a disorder of cell growth and behavior, its ultimate cause has to be defined at the cellular and subcellular levels. Study of cancer patterns in populations, however, can contribute substantially to knowledge about the origins of cancer. For example, the concept that chemicals can cause cancer arose from the astute observations of Sir Percival Pott, who related the increased incidence of scrotal cancer in chimney sweeps to chronic exposure to soot. Thus, major insights into the cause of cancer can be obtained by epidemiologic studies that relate particular environmental, racial (possibly hereditary), and cultural influences to the occurrence of malignant neoplasms. In addition, certain diseases associated with an increased risk of developing cancer can provide insights into the pathogenesis of malignancy. Therefore, in the following discussion, we first summarize the overall incidence of cancer to provide an insight into the magnitude of the cancer problem, then review a number of factors relating to both the patient and the environment that influence predisposition to cancer. Cancer Incidence In some measure, an individual's likelihood of developing a cancer is expressed by national incidence and mortality rates. For example, residents of the United States have about a one in five chance of dying of cancer. There were, it is estimated, about 564,000 deaths from cancer in 1998, representing 23% of all mortality. [1] These data do not include an additional 1 million, for the most part readily curable, nonmelanoma cancers of the skin and 100,000 cases of carcinoma in situ, largely of the uterine cervix but also of the breast. The major organ sites affected and overall frequency are cited in Figure 8-20 (Figure Not Available) . The age-adjusted death rates (number of deaths per 100,000 population) for many forms of cancer have significantly changed over the years (Fig. 8-21) (Figure Not Available) . Many of the temporal comparisons are noteworthy. Over the last 50 years, in men, the overall cancer death rate has significantly increased, whereas in women, it has fallen slightly. The increase in men can be largely attributed to lung cancer. The improvement in women is mainly attributable to a
272
Figure 8-20 (Figure Not Available) Cancer incidence and mortality by site and sex. (Adapted from Landis SH, et al: Cancer statistics. CA 48:6, 1998.)
Figure 8-21 (Figure Not Available) Age-adjusted cancer death rates for selected sites in the United States. (Adapted from Landis SH, et al: Cancer statistics. CA 48:6, 1998.)
273
significant decline in death rates from cancers of the uterus, stomach, and liver and notably carcinoma of the cervix, one of the frequent forms of malignant neoplasia in women. Striking is the alarming increase in deaths from carcinoma of the lung in both sexes. Although the deaths from lung cancer have begun to decline in men, the curve in women continues to point upward--a consequence of the increasing use of cigarettes by women. In women, carcinomas of the breast are about 2.5 times more frequent than those of the lung. Because of a striking difference in the cure rates of these two cancers, however, bronchogenic carcinoma has become the leading cause of cancer deaths in women. The decline in the number of deaths caused by uterine, including cervical, cancer probably relates to earlier diagnosis and more cures made possible by the Papanicolaou (Pap) smear. Much more mysterious is the downward trend in deaths from stomach and liver carcinomas. This trend may be due to a decrease in some dietary carcinogens. Geographic and Environmental Factors Remarkable differences can be found in the incidence and death rates of specific forms of cancer around the world. For example, the death rate for stomach carcinoma in both men and women is seven to eight times higher in Japan than in the United States. In contrast, the death rate from carcinoma of the lung is slightly more than twice as great in the United States as in Japan, and in Belgium it is even higher than in the United States. Skin cancer deaths, largely caused by melanomas, are six times more frequent in New Zealand than in Iceland, which is probably attributable to differences in sun exposure. Although racial predispositions cannot be ruled out, it is generally believed that most of these geographic differences are the consequence of environmental influences. This is best brought out by comparing mortality rates for Japanese immigrants to the United States and Japanese born in the United States of immigrant parents (Nisei) with those of long-term residents of both countries. Figure 8-22 indicates that cancer mortality rates for first-generation Japanese immigrants are intermediate between those of natives of Japan and natives of California, and the two rates come closer with each passing generation. This points strongly to environmental and cultural factors rather than genetic predisposition. There is no paucity of environmental factors: They are found in the ambient environment, in the workplace, in food, and in personal practices. The carcinogenicity of ultraviolet (UV) rays and many drugs is discussed in a later section. Asbestos, vinyl chloride, and 2-naphthylamine can serve as examples of occupational hazards, and many others are listed in Table 8-3 ; the risks may be incurred in lifestyle and personal exposures (e.g., dietary influences). Overall, mortality data indicate that persons more than 25% overweight have a higher death rate from cancer than do their slimmer counterparts. Alcohol abuse alone increases the risk of carcinomas of the oropharynx (excluding lip), larynx, and esophagus and,
Figure 8-22 The change in incidence of various cancers with migration from Japan to the United States provides evidence that the
occurrence of cancers is related to components of the environment that differ in the two countries. The incidence of each kind of cancer is expressed as the ratio of the death rate in the population being considered to that in a hypothetical population of California whites with the same age distribution; the death rates for whites are thus defined as 1. The death rates among immigrants and immigrants' sons tend consistently toward California norms. (From Cairns J: The cancer problem. In Readings from Scientific American--Cancer Biology. New York, WH Freeman, 1986, p 13. © 1975 by Scientific American, Inc. All rights reserved.)
through the intermediation of alcoholic cirrhosis, carcinoma of the liver. Smoking, particularly of cigarettes, has been implicated in cancer of the mouth, pharynx, larynx, esophagus, pancreas, and bladder but most significantly is responsible for about 77% of lung cancer among men and 43% among women (Chapter 10) . Cigarette smoking has been called the single most important environmental factor contributing to premature death in the United States. Alcohol and tobacco together multiply the danger of incurring cancers in the upper aerodigestive tract. The risk of cervical cancer is linked to age at first intercourse and the number of sex partners. These associations point to a possible causal role for venereal transmission of cervical viral infections. It begins to appear that everything one does to gain a livelihood or for pleasure is fattening, immoral, illegal, or, even worse, oncogenic. Age Age is an important influence on the likelihood of being afflicted with cancer. Most carcinomas occur in the later years of life ( 55 years). Each age group has its own predilection to certain forms of cancer, as is evident in Tables 8-4 and 8-5 . Here the striking increase in mortality from cancer in the age group 55 to 74 years should be noted. The decline in deaths in the 75-year-and-over group
274
Agents or Groups of Agents
TABLE 8-3 -- OCCUPATIONAL CANCERS Human Cancer Site for Typical Use or Occurrence Which Reasonable Evidence Is Available
Arsenic and arsenic compounds
Lung, skin, hemangiosarcoma
Byproduct of metal smelting. Component of alloys, electrical and semiconductor devices, medications and herbicides, fungicides, and animal dips
Asbestos
Lung, mesothelioma; gastrointestinal tract (esophagus, stomach, large intestine)
Formerly used for many applications because of fire, heat, and friction resistance; still found in existing construction as well as fire-resistant textiles, friction materials (i.e., brake linings), underlayment and roofing papers, and floor tiles
Benzene
Leukemia, Hodgkin disease
Principal component of light oil. Although use as solvent is discouraged, many applications exist in printing and lithography, paint, rubber, dry cleaning, adhesives and coatings, and detergents. Formerly widely used as solvent and fumigant
Beryllium and beryllium compounds
Lung
Missile fuel and space vehicles. Hardener for lightweight metal alloys, particularly in aerospace applications and nuclear reactors
Cadmium and Prostate cadmium compounds
Uses include yellow pigments and phosphors. Found in solders. Used in batteries and as alloy and in metal platings and coatings
Chromium compounds
Component of metal alloys, paints, pigments, and preservatives
Lung
Ethylene oxide Leukemia
Ripening agent for fruits and nuts. Used in rocket propellant and chemical synthesis, in fumigants for foodstuffs and textiles, and in sterilants for hospital equipment
Nickel compounds
Nickel plating. Component of ferrous alloys, ceramics, and batteries. Byproduct of stainless steel arc welding
Nose, lung
Radon and its Lung decay products
From decay of minerals containing uranium. Can be serious hazard in quarries and underground mines
Vinyl chloride
Refrigerant. Monomer for vinyl polymers. Adhesive for plastics. Formerly inert aerosol propellant in pressurized containers
Angiosarcoma, liver
Modified from Stellman JM, Stellman SD: Cancer and workplace CA 46:70, 1996.
TABLE 8-4 -- REPORTED DEATHS FOR THE FIVE LEADING CANCER SITES FOR MALES BY AGE, UNITED STATES, 1994 All Ages Under 15 yr 15- 34 yr 35- 54 yr 55- 74 yr 75+ yr All sites * 280,465
All sites 919
All sites 3570 All sites 29,296
All sites 140,843
All sites 105,826
Lung and bronchus 91,825
Leukemia 299
Leukemia 728
Lung and bronchus 54,381
Lung and bronchus 28,597
Lung and bronchus 8684
Prostate 34,902
Brain and ONS 254
Non-Hodgkin Colon and lymphoma rectum 2703 471
Colon and rectum 28,471
Endocrine system 111
Brain and ONS 452
Pancreas 12,920 Non-Hodgkin lymphoma 11,280
Colon and rectum 13,574
Prostate 22,712
Non-Hodgkin Prostate lymphoma 11,789 1828
Colon and rectum 11,972
Non-Hodgkin Colon and lymphoma 61 rectum 221
Brain and ONS 1655
Pancreas 6896
Pancreas 4557
Soft tissue 49 Soft tissue 204
Pancreas 1431
Non-Hodgkin Leukemia lymphoma 4207 5002
ONS, other nervous system. Data source: Vital Statistics of the United States, 1997. * All sites excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
275
TABLE 8-5 -- REPORTED DEATHS FOR THE FIVE LEADING CANCER SITES FOR FEMALES BY AGE, UNITED STATES, 1994 All Ages Under 15 15- 34 yr 35- 54 yr 55- 74 yr 75+ yr yr All sites * 253,845
All sites 711
All sites 3226
All sites 31,135
All sites 112,203
All sites 106,565
Lung and bronchus 57,535
Leukemia 251
Breast 564
Breast 9548
Lung and bronchus 32,098
Lung and bronchus 19,793
Breast 43,644
Brain and ONS 195
Leukemia 394
Lung and bronchus 5516
Breast 18,705
Colon and rectum 16,074
Colon and rectum 28,936
Endocrine system 87
Cervix (uterus)322
Colon and rectum 2115
Colon and rectum 10,596
Breast 14,827
Pancreas 13,914
Bones and Brain and ONS Ovary 1892 joints 39 307
Ovary 6457 Pancreas 7150
Ovary 13,500
Soft tissue 36
Pancreas 5863
Non-Hodgkin Cervix lymphoma 231 (uterus)1676
Non-Hodgkin lymphoma 5086
ONS, other nervous system. Data source: Vital Statistics of the United States, 1997. * All sites excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
merely reflects the dwindling population reaching this age. Also to be noted is that children under the age of 15 are not spared. Cancer accounts for slightly more than 10% of all deaths in this group in the United States and is second only to accidents. Acute leukemia and neoplasms of the central nervous system are responsible for approximately 60% of these deaths. The common neoplasms of infancy and childhood include neuroblastoma, Wilms tumor, retinoblastoma, acute leukemias, and rhabdomyosarcomas. These are discussed in Chapter 11 and elsewhere in the text. Heredity One frequently asked question is: "My mother and father both died of cancer. Does that mean I am doomed to get it?" Based on current knowledge, the answer must be carefully qualified. [3] The evidence now indicates that for a large number of types of cancer, including the most common forms, there exist not only environmental influences, but also hereditary predispositions. For example, lung cancer is in most instances clearly related to cigarette smoking, yet mortality from lung cancer has been shown to be four times greater among nonsmoking relatives (parents and siblings) of lung cancer patients than among nonsmoking relatives of controls. Hereditary forms of cancers can be divided into three categories (Table 8-6) . Inherited Cancer Syndromes.
Inherited cancer syndromes include several well-defined cancers in which inheritance of a single mutant gene greatly increases the risk of developing a tumor. The predisposition to these tumors shows an autosomal dominant pattern of inheritance. Childhood retinoblastoma is the most striking example in this category. Approximately 40% of retinoblastomas are familial. Carriers of this gene have a 10,000-fold increased risk of developing retinoblastoma, usually bilateral. They also have a greatly increased risk of developing a second cancer, particularly osteogenic sarcoma. As is discussed later, a cancer-suppressor gene has been implicated in the pathogenesis of this tumor. Familial adenomatous polyposis (FAP) is another hereditary disorder marked by an extraordinarily high risk of cancer. Individuals who inherit the autosomal dominant mutation have at birth, or soon thereafter, innumerable polypoid adenomas of the colon and in virtually 100% of cases are fated to develop a carcinoma of the colon by age 50. There are several features that characterize inherited cancer syndromes: In each syndrome, tumors involve specific sites and tissues.
276
For example, in the multiple endocrine neoplasia (MEN) syndrome type 2, thyroid, parathyroid, and adrenals are involved. There is no increase in predisposition to cancers in general. Tumors within this group are often associated with a specific marker phenotype. For example, there may be multiple benign tumors in the affected tissue, as occurs in familial polyposis of the colon and in MEN. Sometimes, there are abnormalities in tissue that are not the target of transformation (e.g., Lisch nodules and cafe-au-lait spots in neurofibromatosis type 1; Chapter 6) . As in other autosomal dominant conditions, both incomplete penetrance and variable expressivity are noted.
TABLE 8-6 -- INHERITED PREDISPOSITION TO CANCER Inherited Cancer Syndromes (Autosomal Dominant) Inherited predisposition indicated by strong family history of uncommon cancer and/or associated marker phenotype Familial retinoblastoma Familial adenomatous polyps of the colon Multiple endocrine neoplasia syndromes Neurofibromatosis types 1 and 2 Von Hippel-Lindau syndrome Familial Cancers Evident familial clustering of cancer but role of inherited predisposition may not be clear in an individual case Breast cancer Ovarian cancer Colon cancers other than familial adenomatous polyps Autosomal Recessive Syndromes of Defective DNA Repair Xeroderma pigmentosum Ataxia-telangiectasia Bloom syndrome Fanconi anemia Modified from Ponder BAJ: Inherited predisposition to cancer. Trends Genet 6:213, 1990.
Familial Cancers.
Virtually all the common types of cancers that occur sporadically have also been reported to occur in familial forms. Examples include carcinomas of colon, breast, ovary, and brain. Features that characterize familial cancers include early age at onset, tumors arising in two or more close relatives of the index case, and sometimes multiple or bilateral tumors. Familial cancers are not associated with specific marker phenotypes. For example, in contrast to the familial adenomatous polyp syndrome, familial colonic cancers do not arise in preexisting benign polyps. The transmission pattern of familial cancers is not clear. In general, sibs have a relative risk between 2 and 3. Segregation analyses of large families usually reveals that predisposition to the tumors is dominant, but multifactorial inheritance cannot be easily ruled out. As discussed later, certain familial cancers can be linked to the inheritance of mutant genes. Examples include linkage of BRCA-1 and BRCA-2 genes to familial breast and ovarian cancers. Autosomal Recessive Syndromes of Defective DNA Repair.
Besides the dominantly inherited precancerous conditions, a small group of autosomal recessive disorders is collectively characterized by chromosomal or DNA instability. One of the best studied examples is xeroderma pigmentosum, in which DNA repair is defective. This and other familial disorders of DNA instability are described in a later section. It is impossible to estimate the contribution of heredity to the fatal burden of human cancer. The best "guesstimates," however, suggest that no more than 5 to 10% of all human cancers are included in the three categories just listed. What can be said about the influence of heredity on the large preponderance of malignant neoplasms? It could be argued that they are entirely or largely of environmental origin. There is increasing realization, however, that lack of family history does not preclude a genetic hereditary component. For example, if a dominant cancer-susceptibility gene has low penetrance, familial cases are uncommon. Furthermore, the genotype can significantly influence the likelihood of developing environmentally induced cancers. It is likely that inherited variations (polymorphisms) of enzymes that metabolize procarcinogens to their active carcinogenic forms (see Initiation of Carcinogenesis) may well influence the susceptibility to cancer. Of interest in this regard are genes that encode the cytochrome P-450 enzymes. As discussed later under Chemical Carcinogenesis, polymorphism at one of the P-450 loci confers inherited susceptibility to lung cancers in cigarette smokers. More such correlations are likely to be found, and it is suspected that genetic predisposition contributes to many, if not most, spontaneous tumors of humans. Acquired Preneoplastic Disorders The only certain way of avoiding cancer is not to be born; to live is to incur the risk. The risk is greater than average, however, under many circumstances, as is evident from the predisposing influences discussed earlier. Certain clinical conditions are also important. Because cell replication is involved in cancerous transformation, regenerative, hyperplastic, and dysplastic proliferations are fertile soil for the origin of a malignant
neoplasm. There is a well-defined association between certain forms of endometrial hyperplasia and endometrial carcinoma and between cervical dysplasia and cervical carcinoma (Chapter 24) . The bronchial mucosal metaplasia and dysplasia of habitual cigarette smokers are ominous antecedents of bronchogenic carcinoma. About 80% of hepatocellular carcinomas arise in cirrhotic livers, which are characterized by active parenchymal regeneration (Chapter 19) . Other examples could be offered, but although these settings constitute important predispositions, in the great majority of instances they are not complicated by neoplasia. Certain non-neoplastic disorders-- the chronic atrophic gastritis of pernicious anemia; solar keratosis of the skin; chronic ulcerative colitis; and leukoplakia of the oral cavity, vulva, and penis--have such a well-defined association with cancer that they have been termed precancerous conditions. This designation is somewhat unfortunate because in the great majority of instances no malignant neoplasm emerges. Nonetheless, the term persists because it calls attention to the increased risk. Analogously, certain forms of benign neoplasia also constitute precancerous conditions. The villous adenoma of the colon, as it increases in size, develops cancerous change in up to 50% of cases. It might be asked: Is there not a risk with all benign neoplasms? Although some risk may be inherent, a large cumulative experience indicates that most benign neoplasms do not become cancerous. Nonetheless, numerous examples could be offered of cancers arising, albeit rarely, in benign tumors: for example, a leiomyosarcoma beginning in a leiomyoma, and carcinoma appearing in long-standing pleomorphic adenomas. Generalization is impossible because each type of benign neoplasm is associated with a particular level of risk ranging from virtually never to frequently. Only follow-up studies of large series of each neoplasm can establish the level of risk, and always the question remains: Was the tumor an indolent form of cancer from the outset, or was there a malignant focus in the benign tumor?
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 1 - GENERAL PATHOLOGY 8 - Neoplasia MOLECULAR BASIS OF CANCER Oncogenes and Cancer PROTEIN PRODUCTS OF ONCOGENES Growth Factors Growth Factor Receptors Signal-Transducing Proteins Nuclear Transcription Proteins Cyclins and Cyclin-Dependent Kinases ACTIVATION OF ONCOGENES Point Mutations Chromosomal Rearrangements Gene Amplification Cancer-Suppressor Genes PROTEIN PRODUCTS OF TUMOR-SUPPRESSOR GENES Molecules That Regulate Nuclear Transcription and Cell Cycle Rb Gene p53 gene. BRCA-1 and BRCA-2 Genes Molecules That Regulate Signal Transduction Cell Surface Receptors Other Tumor-Suppressor Genes Genes That Regulate Apoptosis Genes That Regulate DNA Repair Telomeres and Cancer Molecular Basis of Multistep Carcinogenesis Karyotypic Changes in Tumors Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
MOLECULAR BASIS OF CANCER It could be justifiably argued that the proliferation of literature on the molecular basis of cancer has outpaced the
277
growth of even the most malignant of tumors! Understandably, therefore, it is easy to get lost in the growing forest of information. We list some fundamental principles before delving into the details of the genetic basis of cancer. Nonlethal genetic damage lies at the heart of carcinogenesis. Such genetic damage (or mutation) may be acquired by the action of environmental agents, such as chemicals, radiation, or viruses, or it may be inherited in the germ line. The genetic hypothesis of cancer implies that a tumor mass results from the clonal expansion of a single progenitor cell that has incurred the genetic damage (i.e., tumors are monoclonal). This expectation has been realized in most tumors that have been analyzed. Clonality of tumors is assessed quite readily in women who are heterozygous for polymorphic X-linked markers, such as the enzyme glucose-6-phosphate dehydrogenase (G6PD) or X-linked restriction fragment length polymorphisms. The principle underlying such an analysis is illustrated in Figure 8-23 . Three classes of normal regulatory genes-- the growth-promoting protooncogenes, the growth-inhibiting cancer-suppressor genes (antioncogenes), and genes that regulate programmed cell death, or apoptosis-- are the principal targets of genetic damage. Mutant alleles of protooncogenes are considered dominant because they transform cells despite the presence of their normal counterpart. In contrast, both normal alleles of the tumor-suppressor genes must be damaged for transformation to occur, so this family of genes is sometimes referred to as recessive oncogenes. Genes that regulate apoptosis may be dominant, as are protooncogenes, or they may behave as cancer-suppressor genes. In addition to the three classes of genes mentioned earlier, a fourth category of genes, those that regulate repair of damaged DNA, is also pertinent in carcinogenesis. The DNA repair genes affect cell proliferation or survival indirectly by influencing the ability of the organism to repair nonlethal damage in other genes, including protooncogenes, tumor-suppressor genes, and genes that regulate apoptosis. A disability in the DNA repair genes can predispose to mutations in the genome and hence to neoplastic transformation. Both alleles of DNA repair genes must be inactivated to induce such genomic instability; in this sense, DNA repair genes may also be considered as tumor-suppressor genes. Carcinogenesis is a multistep process at both the phenotypic and the genetic
levels. A malignant neoplasm has several phenotypic attributes, such as excessive growth, local invasiveness, and the ability to form distant metastases. These characteristics are acquired in a stepwise fashion, a phenomenon called tumor progression. At the molecular level, progression results from accumulation of genetic lesions that in some instances are favored by defects in DNA repair.
Figure 8-23 Diagram depicting the use of X-linked isoenzyme cell markers as evidence of the monoclonality of neoplasms. Because
of random X inactivation, all females are mosaics with two cell populations (with G6PD isoenzyme A or B in this case). When neoplasms that arise in women who are heterozygous for X-linked markers are analyzed, they are made up of cells that contain the active maternal (XA ) or the paternal (XB )X chromosome but not both.
With this overview (Fig. 8-24) , we now address in some detail the molecular pathogenesis of cancer then discuss the carcinogenic agents that inflict genetic damage. Oncogenes and Cancer Oncogenes, or cancer-causing genes, are derived from protooncogenes, cellular genes that promote normal growth and differentiation. As often happens in science, the discovery of protooncogenes was not straightforward. These cellular genes were first discovered as "passengers" within the genome of acute transforming retroviruses, by the Nobel Laureates Varmus and Bishop. These retroviruses cause rapid induction of tumors in animals and can also transform animal cells in vitro. Molecular dissection of their genomes revealed the presence of unique transforming sequences (viral oncogenes [v- oncs]) not found in the genomes of nontransforming retroviruses. Most surprisingly, molecular hybridization revealed that the v- onc sequences were almost identical to sequences found in the normal
278
Figure 8-24 Flow chart depicting a simplified scheme of the molecular basis of cancer.
cellular DNA. From this evolved the concept that during evolution, retroviral oncogenes were transduced (captured) by the virus through a chance recombination with the DNA of a (normal) host cell that had been infected by the virus. Because they were discovered initially as viral genes, protooncogenes are named after their viral homologs. Each v- onc is designated by a three-letter word that relates the oncogene to the virus from which it was isolated. Thus, the v- onc contained in feline sarcoma virus is referred to as v- fes, whereas the oncogene in simian sarcoma virus is called v- sis. The corresponding protooncogenes are referred to as fes and sis by dropping the prefix. v- oncs are not present in several cancer-causing RNA viruses. One such example is a
group of so-called slow transforming viruses that cause leukemias in rodents after a long latent period. The mechanism by which they cause neoplastic transformation implicates protooncogenes. Molecular dissection of the cells transformed by these leukemia viruses has revealed that the proviral DNA is always found to be integrated (inserted) near a protooncogene. One consequence of proviral insertion near a protooncogene is to induce a structural change in the cellular gene, thus converting it into a cellular oncogene ( c-onc) . Alternatively, strong retroviral promoters inserted in the vicinity of the protooncogenes lead to dysregulated expression of the cellular gene. This mode of protooncogene activation is called insertional mutagenesis. Although the study of transforming animal retroviruses provided the first glimpse of protooncogenes, these investigations did not explain the origin of human tumors, which (with rare exceptions) are not caused by infection with retroviruses. Hence the question was raised: Do nonviral tumors contain oncogenic DNA sequences? The answer was provided by experiments involving DNA-mediated gene transfer (DNA transfection). When DNA extracted from several different human tumors was transfected into mouse fibroblast cell lines in vitro, the recipient cells acquired some properties of neoplastic cells. The conclusion from such experiments was inescapable: DNA of spontaneously arising cancers contains oncogenic sequences, or oncogenes. Many of these transforming sequences have turned out to be homologous to the ras protooncogenes that are the forbears of v- oncs contained in Harvey (H) and Kirsten (K) sarcoma viruses. Others, such as the c- erb B2 oncogene, represent novel transforming sequences that have never been detected in retroviruses. To summarize, protooncogenes may become oncogenic by retroviral transduction (v-oncs) or by influences that alter their behavior in situ, thereby converting them into cellular oncogenes (c-oncs). Two questions follow: (1) What are the functions of
279
oncogene products? (2) How do the normally "civilized" protooncogenes turn into "enemies within"? These issues are discussed next. PROTEIN PRODUCTS OF ONCOGENES
Oncogenes encode proteins called oncoproteins, which resemble the normal products of protooncogenes, with the exception that (1) oncoproteins are devoid of important regulatory elements, and (2) their production in the transformed cells does not depend on growth factors or other external signals. To aid in the understanding of the nature and functions of oncoproteins, it is necessary to review briefly the sequence of events that characterize normal cell proliferation. (These are discussed in more detail in Chapter 4.) Under physiologic conditions, cell proliferation can be readily resolved into the following steps: The binding of a growth factor to its specific receptor on the cell membrane Transient and limited activation of the growth factor receptor, which, in turn, activates several signal-transducing proteins on the inner leaflet of the plasma membrane
Transmission of the transduced signal across the cytosol to the nucleus via second messengers Induction and activation of nuclear regulatory factors that initiate DNA transcription Entry and progression of the cell into the cell cycle, resulting ultimately in cell division With this background, we can readily identify oncogenes and oncoproteins as altered versions of their normal counterparts and group them on the basis of their role in the signal transduction cascade and cell cycle regulation (Table 8-7) . [4] [5] Growth Factors.
A number of polypeptide growth factors that stimulate proliferation of normal cells have been described (Chapter 4) , and many are suspected to play a role in tumorigenesis. [6] Mutations of genes that encode growth factors can render them oncogenic. Such is the case with the protooncogene c- sis, which encodes the beta chain of platelet-derived growth factor (PDGF). This oncogene was first discovered in the guise of the viral oncogene contained in v- sis. Subsequently, several human tumors, especially astrocytomas and osteosarcomas, have been found to produce PDGF. Furthermore, it appears that the same tumors also express receptors for PDGF and are hence subject to autocrine stimulation. Although an autocrine loop is considered to be an important element in the pathogenesis of several tumors, in most instances the growth factor gene itself is not altered or mutated. More commonly, products TABLE 8-7 -- SELECTED ONCOGENES, THEIR MODE OF ACTIVATION, AND ASSOCIATED HUMAN TUMORS Category Protooncogene Mechanism Associated Human Tumor Growth Factors PDGF-B chain
sis
Overexpression
Astrocytoma Osteosarcoma
Fibroblast growth factors
hst-1
Overexpression
Stomach cancer
int-2
Amplification
Bladder cancer Breast cancer Melanoma
Growth Factor Receptors EGF-receptor family
erb-B1
Overexpression
Squamous cell carcinomas of lung
erb-B2
Amplification
Breast, ovarian, lung, and stomach cancers
erb-B3
Overexpression
Breast cancers
fms
Point mutation
Leukemia
Point mutation
Multiple endocrine neoplasia 2A and B. Familial medullary thyroid carcinoma
Rearrangement
Sporadic papillary carcinomas of thyroid
ret
*
Proteins Involved in Signal Transduction GTP-binding
ras
Point mutations
A variety of human cancers, including lung, colon, pancreas; many leukemias
Nonreceptor tyrosine kinase
abl
Translocation
Chronic myeloid leukemia Acute lymphoblastic leukemia
Nuclear Regulatory Proteins Transcriptional activators
myc
Translocation
Burkitt lymphoma
N- myc
Amplification
Neuroblastoma Small cell carcinoma of lung
L- myc
Amplification
Small cell carcinoma of lung
cyclin D
Translocation
Mantle cell lymphoma
Amplification
Breast, liver, esophageal cancers
Amplification or point mutation
Glioblastoma, melanoma, sarcoma
Cell Cycle Regulators Cyclins
Cyclin-dependent kinase
CDK4
PDGF, platelet-derived growth factor; EGF, epidermal growth factor; CSF, colony-stimulating factor; GTP, guanosine triphosphate. * ret protooncogene is a receptor for glial cell line-derived neurotrophic factor.
280
of other oncogenes such as ras (that lie along the signal transduction pathway) cause overexpression of growth factor genes, thus forcing the cells to secrete large amounts of growth factors, such as transforming growth factor-alpha (TGF-alpha). This growth factor is related to epidermal growth factor (EGF) and induces proliferation by binding to the EGF receptor. TGF-alpha is often detected in carcinomas that express high levels of EGF receptors. In addition to c- sis, a group of related oncogenes that encode homologs of fibroblast growth factors (FGFs) (e.g., hst-1 and int-2) is activated in several gastrointestinal and breast tumors; bFGF, a member of the fibroblast growth factor family, is expressed in human melanomas but not in normal melanocytes. Small cell lung carcinomas produce bombesin-like peptides that stimulate their proliferation. Despite extensive documentation of growth factor-mediated autocrine stimulation of transformed cells, increased growth factor production is not sufficient for neoplastic transformation. Extensive cell proliferation, in all likelihood, contributes to the malignant phenotype by increasing the risk of spontaneous or induced mutations in the cell population. Growth Factor Receptors.
The next group in the sequence of signal transduction involves growth factor receptors, and, not surprisingly, several oncogenes that encode growth factor receptors have been found. To understand how mutations affect the function of these receptors, it should be recalled that several growth factor receptors are transmembrane proteins with an external ligand-binding and a cytoplasmic tyrosine kinase domain (Chapter 4) . In the normal forms of these receptor tyrosine kinases, the kinase activity is transiently activated by binding of their specific growth factors, followed rapidly by receptor dimerization and tyrosine phosphorylation of several substrates that are a part of the mitotic cascade. The oncogenic versions of these receptors are associated with persistent dimerization and activation without binding to the growth factor. Hence the mutant receptors deliver continuous mitogenic signals to the cell. Growth factor receptors are activated in human tumors by several mechanisms. These include mutations, gene rearrangements, and overexpression. The ret protooncogene, a receptor tyrosine kinase, exemplifies oncogenic conversion via mutations and gene rearrangements. [7] The ret protein is a receptor for the glial cell line-derived neurotrophic factor that is normally expressed in neuroendocrine cells, such as parafollicular C cells of the thyroid, adrenal medulla, and parathyroid cell precursors. Point mutations in the ret protooncogene are associated with dominantly inherited MEN types 2A and 2B and familial medullary thyroid carcinoma (Chapter 26) . In MEN 2A, point mutations in the extracellular domain cause constitutive dimerization and activation, whereas in MEN 2B, point mutations in the cytoplasmic catalytic domain activate the receptor. In all these familial tumors, the affected individuals inherit the ret mutation in the germ line. By
contrast, sporadic papillary carcinomas of the thyroid are associated with somatic rearrangements of the ret gene. In these tumors, the tyrosine kinase domain of the ret gene is juxtaposed with one of four different partner genes. The fused genes encode hybrid proteins in which the tyrosine kinase domain is constitutively activated, and hence the cell is led to believe that the ret receptor is being continuously activated by its ligand. Oncogenic conversions by mutations and rearrangements have also been noted with other growth factor receptor genes. In myeloid leukemias, point mutations that activate c- fms, the gene encoding the colony-stimulating factor 1 (CSF-1) receptor, have been detected. In certain chronic myelomonocytic leukemias with the t(12;9) translocation, the entire cytoplasmic domain of the PDGF receptor is fused with a segment of the ETS family transcription factor, resulting in permanent dimerization of the PDGF receptor. Far more common than mutations of these protooncogenes is overexpression of the normal forms of growth factor receptors. Three members of the EGF receptor family are the ones most commonly involved. [8] The normal form of c- erb B1, the EGF receptor gene, is overexpressed in up to 80% of squamous cell carcinomas of the lung and, less commonly, in carcinomas of the urinary bladder, gastrointestinal tract, and astrocytomas. In some cases, increased receptor expression results from gene amplification. In most others, the molecular basis of increased receptor expression is not fully known. In contrast, the c- erb B2 gene (also called c- neu), the second member of the EGF receptor family, is amplified in a high percentage of human adenocarcinomas arising within the breast, ovary, lung, stomach, and salivary glands. A third member of the EGF receptor family, c- erb B3, is also overexpressed in breast cancers. It might be suspected that tumors that overexpress the growth factor receptors, such as c- erb B2, would be exquisitely sensitive to the growth-promoting effects of a small amount of growth factors and hence likely to be more aggressive. This hypothesis is supported by the observation that high levels of c- erb B2 protein on breast cancer cells are a harbinger of poor prognosis. Signal-Transducing Proteins.
Several examples of oncoproteins that mimic the function of normal cytoplasmic signal-transducing proteins have been found. Most such proteins are strategically located on the inner leaflet of the plasma membrane, where they receive signals from outside the cell (e.g., by activation of growth factor receptors) and transmit them to the cell's nucleus. Biochemically the signal-transducing proteins are heterogeneous. The best and most well studied example of a signal transducing oncoprotein is the ras family of guanine triphosphate (GTP)-binding proteins. This is discussed next. The ras proteins were discovered initially in the form of viral oncogenes. Approximately 10 to 20% of all human tumors contain mutated versions of ras proteins. [9] In some tumors (e.g., carcinomas of the colon, pancreas, and thyroid), the incidence of ras mutation is even higher. Mutation of the ras gene is the single most common abnormality of dominant oncogenes in human tumors. Several studies indicate that ras plays an important role in mitogenesis induced by growth factors. For example, blockade of ras function by microinjection of specific antibodies blocks the proliferative response to EGF, PDGF, and CSF-1. Normal ras proteins are tethered to the
cytoplasmic aspect of plasma membrane, and they flip back and forth between an activated, signal-transmitting form and an inactive, quiescent state. In the inactive state, ras proteins bind guanosine
281
diphosphate (GDP); when cells are stimulated by growth factors or other receptor-ligand interactions, ras becomes activated by exchanging GDP for GTP (Fig. 8-25) . The activated ras, in turn, excites the MAP kinase pathway by recruiting the cytosolic protein raf-1. The MAP kinases so activated target nuclear transcription factors and thus promote mitogenesis. In normal cells, the activated signal-transmitting stage of ras protein is transient because its intrinsic GTPase activity hydrolyzes GTP to GDP, thereby returning ras to its quiescent ground state. The orderly cycling of the ras protein depends on two reactions: (1) nucleotide exchange (GDP by GTP), which activates ras protein, and (2) GTP hydrolysis, which converts the GTP-bound, active ras to the GDP-bound, inactive form. [10] [11] Both these processes are enzymatically regulated. The removal of GDP and its replacement by GTP during ras activation is catalyzed by a family of guanine nucleotide releasing proteins that are recruited to the cytosolic aspect of activated growth factor receptors by adapter proteins. Much more importantly, the GTPase activity intrinsic to normal ras proteins is dramatically accelerated by GTPase-activating proteins (GAPs). These widely distributed proteins bind to the active ras and augment its GTPase activity by more than 1000-fold, leading to rapid hydrolysis of GTP to GDP and termination of signal transduction. Thus, GAPs function as "brakes" that prevent uncontrolled ras activity. The response to this braking action of GAPs seems to falter when mutations affect the ras gene. Mutant ras proteins bind GAP, but their GTPase activity fails to be augmented. Hence the mutant proteins are "trapped" in their excited GTP-bound form, causing, in turn, a pathologic activation of the mitogenic signaling pathway. The importance of GTPase activation in normal growth control is underscored by the fact that a disabling mutation of neurofibromin (NF-1), a GTPase-activating protein, is also associated with neoplasia (see Cancer-Suppressor Genes). Recent studies have revealed that, in addition to its role in transducing growth factor-initiated activating signals, ras is also involved in the regulation of cell cycle. As detailed later, the passage of cells from G 0 to the S phase is modulated by a series of proteins called cyclins and cyclin-dependent kinases (CDKs). ras, it seems, controls the levels of CDKs by unknown mechanisms. [12]
Figure 8-25 Model for action of ras genes. When a normal cell is stimulated through a growth factor receptor, inactive (GDP-bound) ras is activated to a GTP-bound state. Activated ras recruits raf-1 and stimulates the MAP-kinase pathway to transmit growth-promoting signals to the nucleus. The mutant ras protein is permanently activated because of inability to hydrolyze GTP, leading to continuous stimulation of cells without any external trigger. The anchoring of ras to the cell membrane by the farnesyl
moiety is essential for its action.
282
Because ras is mutated so often in human cancers, much effort has been devoted to devising means by which the activity of renegade ras can be controlled. To block ras activity, researchers have taken advantage of the fact that to receive activating signals from growth factor receptors, ras must be anchored under the cell membrane close to the cytoplasmic domain of the growth factor receptors. Such anchoring is made possible by attachment of an isoprenyl lipid group to the ras molecule by the enzyme farnesyl transferase. The farnesyl moiety forms the bridge between ras and the lipid membrane. Inhibitors of farnesyl transferase can disable ras by preventing its normal localization. Such drugs seem to have activity in animal models of tumors and are likely to be tested in humans. [13] In addition to ras, several nonreceptor-associated tyrosine kinases also function in the signal transduction pathways. Mutant forms of nonreceptor-associated tyrosine kinases that have acquired transforming potential are commonly found in the form of v- oncs in animal retroviruses (e.g., v- abl, v- src, v- fyn, v- fes, and many others). With the exception of c- abl, however, they are rarely activated in human tumors. The abl protooncogene has tyrosine kinase activity, which is dampened by negative regulatory domains. In chronic myeloid leukemia and some acute lymphoblastic leukemias, however, this activity is unleashed because the c- abl gene is translocated from its normal abode on chromosome 9 to chromosome 22; here it fuses with part of the bcr ( break-point cluster region) gene on chromosome 22, and the hybrid gene has potent tyrosine kinase activity. The molecular pathways activated by the bcr-c-abl hybrid gene are poorly understood. There is accumulating evidence that the abl gene acts not only in the growth-promoting pathway, but also in pathways that control cell death. New evidence suggests that c- abl, similar to p53 (discussed later), is activated after DNA damage and hence may play a role in regulating apoptosis. [14] [15] Nuclear Transcription Proteins.
Ultimately, all signal transduction pathways enter the nucleus and impact on a large bank of responder genes that orchestrate the cells' orderly advance through the mitotic cycle. This process (i.e., DNA replication and cell division) is regulated by a family of genes whose products are localized to the nucleus, where they control the transcription of growth-related genes. The transcription factors contain specific amino acid sequences or motifs that allow them to bind DNA or to dimerize for DNA binding. Examples of such motifs include helix-loop-helix, leucine zipper, zinc-finger, and homeodomains. Many of these proteins bind DNA at specific sites from which they can activate or inhibit transcription of adjacent genes. Not surprisingly, therefore, mutations affecting genes that encode nuclear transcription factors are associated with malignant transformation. A whole host of oncoproteins, including products of the myc, myb, jun, and fos oncogenes, have been localized to the nucleus. Of these, the myc gene is most commonly involved in human tumors, and hence a brief overview of its function is warranted. [16] The c- myc protooncogene is expressed in virtually all eukaryotic cells
and belongs to the immediate early growth response genes, which are rapidly induced when quiescent cells receive a signal to divide. After a transient increase of c- myc mRNA, the expression declines to a basal level. The importance of c- myc in cell proliferation is underscored by experiments in which specific inhibition of c- myc expression by antisense oligonucleotides prevents the entry of cells into the S phase. The molecular basis of c- myc function in cell replication is not entirely clear, but some general principles have emerged. After translation, the c- myc protein is rapidly translocated to the nucleus. Either before or after transport to the nucleus, it forms a heterodimer with another protein, called max. The myc-max heterodimer binds to specific DNA sequences (termed E-boxes) and is a potent transcriptional activator. Mutations that impair the ability of myc to bind to DNA or to max also abolish its oncogenic activity. In addition to forming a heterodimer with myc, the max protein can also form homodimers that are transcriptionally inactive. Furthermore, mad, another member of the myc superfamily of transcriptional regulators, can also bind max to form a dimer. The mad-max heterodimer functions as a transcription repressor. Thus, the emerging theme seems to be that the degree of transcriptional activation by c- myc is regulated not only by the levels of myc protein, but also by the abundance and availability of max and mad proteins. In this network, myc-max favors proliferation, whereas mad-max inhibits cell growth. mad may therefore be considered an antioncogene (or tumor-suppressor gene). [17] Although there is little doubt that myc-max heterodimers bind to DNA and activate transcription, it has been difficult to determine the nature of the genes that obey their commands. [18] Several candidates have emerged, including genes for ornithine decarboxylase (necessary for DNA synthesis), certain CDKs (regulating cell cycle, see later), and eIF2-alpha (a rate-limiting enzyme for protein translation). It is becoming increasingly evident that myc not only controls cell growth, but also it can drive cell death by apoptosis. Thus, when myc activation occurs in the absence of survival signals (growth factors), cells undergo apoptosis. This deviation has been dubbed the "conflict" model. It proposes that apoptosis occurs when there is a conflict between "stop" (no growth factors) and "go" (c- myc is activated). The molecular mechanisms that execute the conflict signal are under intense scrutiny. [19] One thing is clear, however: Cell growth and cell death are closely interlinked, and the boundary between these two is quite precarious. In contrast to the regulated expression of c- myc during normal cell proliferation, oncogenic versions are associated with persistent expression, and in some cases overexpression, of the myc protein. This may lead to sustained transcription of critical target genes and possibly neoplastic transformation. Dysregulation of c- myc expression resulting from translocation of the gene occurs in Burkitt lymphoma, a B-cell tumor; cmyc is amplified in breast, colon, lung, and many other carcinomas; the related N- myc and L- myc genes are amplified in neuroblastomas and small cell cancers of lung. Cyclins and Cyclin-Dependent Kinases.
The ultimate outcome of all growth-promoting stimuli is the entry of quiescent cells into the cell cycle. As discussed in Chapter 4 , the orderly progression of cells through the
various phases of cell cycle is orchestrated by cyclins and cyclin-dependent
283
kinases (CDKs) and their inhibitors. Mutations in genes that encode these cell cycle regulators have been found in several human cancers. To understand the cancer-associated derangements in cell cycle, it is essential to review the normal functions and regulation of these proteins. Cyclin-dependent kinases drive the cell cycle by phosphorylating critical target proteins that are required for progression of the cells to the next phase of the cell cycle (Fig. 8-26) . Cyclin-dependent kinases are expressed constitutively during the cell cycle but in an inactive form. They are activated by phosphorylation after binding to another family of proteins, called cyclins. By contrast with CDKs, cyclins are synthesized during specific phases of the cell cycle, and their function is to activate the CDKs. On completion of this task, cyclin levels decline rapidly. While cyclins arouse the CDKs, their inhibitors, of which there are several, silence the CDKs and thus exert another level of control over the cell cycle. Although each phase of the cell cycle circuitry is carefully monitored, the transition from G1 to S is an extremely important checkpoint in the cell cycle clock because once cells cross this barrier they are committed to progress into S phase. [20] When a cell receives growth-promoting signals, the synthesis of D type cyclins that bind CDK4 and CDK6 is stimulated in the early part of G1 . Later in the G1 phase of cell cycle, the synthesis of E cyclin is stimulated, which, in turn, binds to CDK2. The cyclin D/CDK4, CDK6, and cyclin E/CDK2 complexes phosphorylate the retinoblastoma protein (pRb) (Fig. 8-27) . This is a critical reaction, for as we discuss later, underphosphorylated pRb binds to the E2F family of transcription factors. Phosphorylation of pRb unshackles the E2F proteins, and they, in turn, activate the transcription of several genes whose products are essential for progression through the S phase. These include DNA polymerases, thymidine kinase, dihydrofolate reductase, and many others. Further progress of cells from the S phase into the G2 phase is facilitated by up-regulation of cyclin A, which binds to CDK2 and to CDK1. The targets phosphorylated by cyclin A/CDK2, CDK1 are not fully known. Early in the G2 phase, B cyclin takes over. By forming complexes with CDK1, it helps the cell move from G2 to M. The cyclin B/CDK1 complex phosphorylates a variety of proteins required for mitosis. The activity of CDKs is regulated by two families of CDK inhibitors (CDKIs). One family of CDKIs, composed of three proteins, called p21, p27, and p57, inhibits the CDKs broadly, whereas the other family of CDKI has selective effects on cyclin D/CDK4 and cyclin D/CDK6. The four members of this family (p15, p16, p18, p19) are sometimes called INK4 proteins (because they are INhibitors of CD K4 and CDK6). With this background, it is easy to appreciate that mutations that dysregulate the activity of cyclins and CDKs would favor cell proliferation. Indeed, mishaps affecting the expression of cyclin D or CDK4 seem to be a common event in neoplastic transformation. The cyclin D genes are overexpressed in many cancers, including those affecting the breast, esophagus, and liver, and in a subset of lymphomas. Amplification
of the CDK4 gene occurs in melanomas, sarcomas, and glioblastomas. Mutations affecting cyclin
Figure 8-26 Schematic illustrating the role of cyclins and cyclin-dependent kinases (CDKs) in regulating the cell cycle. In the depicted
example, inactive CDK is constitutively expressed; it is activated by binding to cyclin D, which is synthesized in G1 . The activated CDK allows the cell to cross the G1 S checkpoint by phosphorylating retinoblastoma (Rb) protein. After the cell enters the S phase, cyclin D is degraded, returning CDK to the inactive state.
284
Figure 8-27 Schematic illustration of the role of cyclins, CDKs, and cyclin-dependent kinase inhibitors (CDKIs) in regulating the cell
cycle. The shaded arrows represent the phases of cell cycle during which specific cyclin/CDK complexes are active. As illustrated, cyclin D/CDK4, cyclin D/CDK6, and cyclin E/CDK2 regulate the G1
S transition by phosphorylation of the Rb protein (pRb).
Cyclin A/CDK2 and cyclin A/CDK1 are active in the S phase. Cyclin B/CDK1 is essential for the G2 M transition. Two families of CDK inhibitors, so-called INK4 inhibitors composed of p16, p15, p18, and p19, act on cyclin D/CDK4 and cyclin D/CDK6. The other family of three inhibitors, p21, p27, and p57, can inhibit all CDKs.
B and cyclin E and other CDKs also occur in certain malignant neoplasms, but they are much less frequent than those affecting cyclin D/CDK4. ACTIVATION OF ONCOGENES
In the preceding section, we discussed how mutant forms of protooncogenes may provide gratuitous growth-stimulating signals. Next we focus on mechanisms by which protooncogenes are transformed into oncogenes. This is brought about by two broad categories of changes: Changes in the structure of the gene, resulting in the synthesis of an abnormal gene product (oncoprotein) having an aberrant function Changes in regulation of gene expression, resulting in enhanced or inappropriate production of the structurally normal growth-promoting protein We can now discuss the specific lesions that lead to structural and regulatory changes that affect protooncogenes. Point Mutations.
The ras oncogene represents the best example of activation by point mutations. Several distinct mutations have been identified, all of which dramatically reduce the GTPase activity of the ras proteins. Most of them involve codon 12. As mentioned in an earlier
section, the intrinsic GTPase activity of normal ras proteins is augmented greatly by GAPs; in contrast, the GTPase activity of mutant ras proteins is poorly stimulated by GAPs. The mutant ras thus remains in the active GTP-bound form. A large number of human tumors carry ras mutations. The frequency of such mutations varies with different tumors, but in some types it is high. For example, 90% of pancreatic adenocarcinomas and cholangiocarcinomas contain a ras point mutation, as do about 50% of colon, endometrial, and thyroid cancers and 30% of lung adenocarcinomas and myeloid leukemias. In general, carcinomas have mutations of K- ras, whereas hematopoietic tumors bear N- ras mutations. ras mutations are infrequent or even nonexistent in certain other cancers, particularly those arising in the uterine cervix or breast. It should be obvious therefore that although ras mutations are extremely common, their presence is not essential for carcinogenesis. As discussed later, there are many pathways to cancer, and ras mutations happen to lie on one of the well-traveled roads. In addition to ras, activating point mutations have been found in the c- fms gene in some cases of acute myeloid leukemia. Chromosomal Rearrangements.
Two types of chromosomal rearrangements can activate protooncogenes-translocations and inversions. Of these, chromosomal translocations are much more common. Translocations can activate protooncogenes in two ways:
285
1. In lymphoid tumors, specific translocations result in overexpression of protooncogenes by placing them under the regulatory elements of the immunoglobulin or T-cell receptor loci. 2. In many hematopoietic tumors, the translocations allow normally unrelated sequences from two different chromosomes to recombine and form hybrid genes that encode growth-promoting chimeric proteins. Translocation-induced overexpression of a protooncogene is best exemplified by Burkitt lymphoma. All such tumors carry one of three translocations, each involving chromosome 8q24, where the c- myc gene has been mapped, as well as one of the three immunoglobulin gene-carrying chromosomes. At its normal locus, the expression of the myc gene is tightly controlled and is expressed only during certain stages of the cell cycle (Chapter 4) . In Burkitt lymphoma, the most common form of translocation results in the movement of the c- myc-containing segment of chromosome 8 to chromosome 14q band 32 (Fig. 8-28) . This places c- myc close to the immunoglobulin heavy-chain (IgH) gene. The molecular mechanisms of the translocation-associated activation of c- myc are variable, as are the precise breakpoints within the gene. In some cases, the translocation renders the c- myc gene subject to relentless stimulation by the adjacent enhancer element of the immunoglobulin gene. In others, the translocation causes mutations in the regulatory sequences of the myc gene. In all instances, the coding sequences of the gene remain intact, and the c- myc gene is constitutively expressed at high levels. The invariable presence of the translocated c-
myc gene in Burkitt lymphomas attests to the importance of c- myc overexpression in the pathogenesis of this tumor. The immunoglobulin heavy chain locus is involved in translocation-mediated overexpression of several other genes as well. In mantle cell lymphoma, the cyclin D1 gene on chromosome 11q32 is overexpressed by juxtaposition to the IgH locus on 14q32. In follicular lymphoma, a t(14;18)(q32;q21) translocation causes activation of the bcl-2 gene (described later). Not unexpectedly, all these tumors in which the immunoglobulin gene is involved are of B-cell origin. In an analogous situation, overexpression of several protooncogenes in T-cell tumors results from translocations affecting the T-cell antigen receptor locus. The affected oncogenes are diverse, but in most cases, similar to c- myc, they encode nuclear transcription factors. The Philadelphia chromosome, characteristic of chronic myeloid leukemia and a subset of acute lymphoblastic leukemias, provides the prototypic example of an oncogene formed by fusion of two separate genes. In these cases, a reciprocal translocation between chromosomes 9 and 22 relocates a truncated portion of the protooncogene cabl (from chromosome 9) to the bcr on chromosome 22. The hybrid c- abl-bcr gene encodes a chimeric protein that has tyrosine kinase activity (Fig. 8-28) . Although the translocations are cytogenetically identical in chronic myeloid leukemia and acute lymphoblastic leukemias, they differ at the molecular level. In chronic myeloid leukemia, the chimeric protein has a molecular weight of 210 kD, whereas in the more aggressive acute leukemias, a slightly different, 180-kD, abl-bcr fusion protein is formed.
Figure 8-28 The chromosomal translocation and associated oncogenes in Burkitt lymphoma and chronic myelogenous leukemia.
Gene fusions often involve transcription factors. [21] One such transcription factor, encoded by the MLL (myeloid, lymphoid leukemia) gene on 11q23, is known to be involved in 25 different translocations with several different partner genes, some of which themselves encode a transcription factor. The MLL gene is involved in approximately 5 to 10% of all acute leukemias. It encodes the mammalian homolog of the Drosophila trithorax ( trx) gene and is believed to regulate the expression of homeobox ( Hox) genes in hematopoietic progenitor cells. In addition to hemopoietic neoplasms, many sarcomas have specific translocations that result in the formation of chimeric genes encoding transcription factors. [22] The Ewing Sarcoma ( EWS) gene at 22q12, first described in the t(11;22)(q24;12) translocation of Ewing sarcoma, is translocated in several types of sarcomas. EWS is itself a transcription factor, and all of its partner genes analyzed so far also encode a transcription
286
factor. In Ewing tumor, for example, the EWS gene fuses with the FL-1 gene; the resultant chimeric EWS-FL-1 protein is a transactivator of the c- myc promoter and hence can cause overexpression of c- myc. Some examples of oncogene activation by
translocation are provided in Table 8-8 . Gene Amplification.
Activation of protooncogenes associated with overexpression of their products may result from reduplication and manifold amplification of their DNA sequences. Such amplification may produce several hundred copies of the protooncogene in the tumor cell. The amplified genes can be readily detected by molecular hybridization with the appropriate DNA probe. In some cases, the amplified genes produce cytogenetic changes that can be identified microscopically. Two mutually exclusive patterns are seen: multiple small, chromosome-like structures called double minutes (dms) or homogeneous staining regions (HSRs). The latter derive from the assembly of amplified genes into new chromosomes; because these regions containing amplified genes lack a normal banding pattern, they appear homogeneous in a G-banded karyotype (Fig. 8-29) . The most interesting cases of amplification involve N- myc in neuroblastoma and cerb B2 in breast cancers. These genes are amplified in 30 to 40% of these two tumors, and in both settings this amplification is associated with poor prognosis. [23] Similarly, amplification of L- myc and N- myc correlates strongly with disease progression in small cell cancer of the lung. Other genes frequently amplified include c- myc (breast, ovarian, and lung carcinomas) and cyclin D (breast carcinomas and several squamous cell carcinomas). TABLE 8-8 -- SELECTED EXAMPLES OF ONCOGENES ACTIVATED BY TRANSLOCATION Malignancy Translocation Affected Genes Chronic myeloid leukemia
(9;22)(q34;q11)
Ab1 9q34 bcr 22q11
Acute leukemias (AML and ALL)
(4;11)(q21;q23)
AF4 4q21 MLL 11q23
(6;11)(q27;q23)
AF6 6q27 MLL 11q23
Burkitt lymphoma
(8;14)(q24;q32)
c- myc 8q24 IgH 14q32
Mantle cell lymphoma
(11;14)(q13;q32) Cyclin D 11q13 IgH 14q32
Follicular lymphoma
(14;18)(q32;q21) IgH 14q32 bcl-2 18q21
T-cell acute lymphoblastic leukemia
(8;14)(q24;q11)
c- myc 8q24 TCR-alpha 14q11
(10;14)(q24;q11) Hox 11 10q24 TCR-alpha 14q11 Ewing sarcoma
(11;22)(q24;q12) FL-1 11q24 EWS 22q12
Melanoma of soft parts
(12;22)(q13;q12) ATF-1 12q13 EWS 22q12
Underlined genes are involved in multiple translocations. AML, acute myeloid leukemia: ALL, acute lymphoblastic leukemia.
Figure 8-29 Amplification of the N- myc gene in human neuroblastomas. The N- myc gene, normally present on chromosome 2p,
becomes amplified and is seen either as extra chromosomal double minutes or as a chromosomally integrated, homogeneous staining region. The integration involves other autosomes, such as 4, 9, or 13. (Modified from Brodeur GM: Molecular correlates of cytogenetic abnormalities in human cancer cells: implications for oncogene activation. In Brown EB (ed): Progress in Hematology, Vol 14, Orlando, FL, Grune & Stratton, 1986, pp 229-256.)
Cancer-Suppressor Genes While protooncogenes encode proteins that promote cell growth, the products of tumor-suppressor genes apply brakes to cell proliferation. In a sense, the term tumor-suppressor genes is a misnomer because the physiologic function of these genes is to regulate cell growth, not to prevent tumor formation. Because the loss of these genes is a key event in many, possibly all, human tumors and because their discovery resulted from the study of tumors, the names tumor suppressor and antioncogene persist. Similar to many discoveries in medicine, the cancer-suppressor genes were discovered by studying rare diseases, in this case retinoblastoma, a tumor that affects about 1 in 20,000 infants and children. Approximately 60% of retinoblastomas are sporadic, and the remaining 40% are familial, with the predisposition to develop the tumor being transmitted as an autosomal dominant trait. To explain the familial and sporadic occurrence of an apparently identical tumor, Knudson proposed his now famous "two-hit" hypothesis of oncogenesis. He suggested that in hereditary cases, one genetic change ("first hit") is inherited from an affected parent and is therefore present in all somatic cells of the body, whereas the second mutation "second hit" occurs in one of the many retinal cells (which already carry the first mutation). In sporadic cases, however, both mutations (hits) occur somatically within a single retinal cell, whose progeny then form the tumor. Knudson's hypothesis
287
has been amply substantiated by cytogenetic and molecular studies and can now be formulated in more precise terms: The mutations required to produce retinoblastoma involve the Rb gene, located on chromosome 13q14. In some cases, the genetic damage is large enough to be visible in the form of a deletion of 13q14. Both normal alleles of the Rb locus must be inactivated (two hits) for the development of retinoblastoma (Fig. 8-30) . In familial cases, children are born with one normal and one defective copy of the Rb gene. They lose the intact copy in the retinoblasts through some form of somatic mutation (point mutation, interstitial deletion of 13q14, or even complete loss of the normal chromosome 13). In sporadic cases, both normal Rb alleles are lost by somatic mutation in one of the retinoblasts. The end result is the same: A retinal cell that has lost both normal copies of the Rb
gene gives rise to cancer. Patients with familial retinoblastoma are also at greatly increased risk of developing osteosarcoma and some other soft tissue sarcomas. Furthermore, inactivation of the Rb locus has been noted in several other tumors, including adenocarcinoma of the breast, small cell carcinoma of the lung, and bladder carcinoma. Thus the loss of Rb genes has implications beyond the development of retinoblastoma. At this point, we should clarify some terminology. A child carrying an inherited mutant Rb allele in all somatic cells is perfectly normal (except for the increased risk of developing cancer). Because such a child is heterozygous at the Rb locus, it implies that heterozygosity for the Rb gene does not affect cell behavior. Cancer develops when the cell becomes homozygous for the mutant allele or, put another way, loses heterozygosity for the normal Rb gene. Because the Rb gene is associated with cancer when both normal copies are lost, it is sometimes referred to as a recessive cancer gene. The Rb gene stands as a paradigm for several other genes that act similarly. For example, one or more genes on the short arm of chromosome 11 play a role in the formation of Wilms tumor, hepatoblastoma, and rhabdomyosarcoma. Consistent and nonrandom loss of heterozygosity has provided important clues to the location of several cancer-suppressor genes. A list of selected tumor-suppressor genes is provided in Table 8-9 . A discussion of their function follows. PROTEIN PRODUCTS OF TUMOR-SUPPRESSOR GENES
The signals and signal-transducing pathways for growth inhibition are much less well understood than those for growth promotion. Nevertheless, it is reasonable to assume that, similar to mitogenic signals, growth inhibitory signals originate outside the cell and use receptors, signal transducers, and cell cycle and nuclear transcription regulators to accomplish their effects. The tumor-suppressor genes seem to encode various components of this growth inhibitory pathway. We begin our discussion from the inside out, with those tumor-suppressor genes that control the cell TABLE 8-9 -- SELECTED TUMOR-SUPPRESSOR GENES INVOLVED IN HUMAN NEOPLASMS Subcellular Gene Function Tumors Tumors Location Associated with Associated with Somatic Inherited Mutations Mutations Cell surface
TGF-beta receptor
Growth inhibition
E-cadherin Cell adhesion
Carcinomas of colon
Unknown
Carcinoma of stomach, breast
Familial gastric cancer
Under plasma membrane
NF-1
Inhibition of ras signal transduction
Schwannomas
Neurofibromatosis type I and sarcomas
Cytoskeleton NF-2
Unknown
Schwannomas Neurofibromatosis and meningiomas type II; acoustic schwannomas and meningiomas
Cytosol
APC
Inhibition of signal Carcinomas of transduction stomach, colon, pancreas; melanoma
Familial adenomatous polyposis coli; colon cancer
Nucleus
Rb
Regulation of cell cycle
Retinoblastoma; osteosarcoma; carcinomas of breast, colon, lung
Retinoblastomas, osteosarcoma
p53
Regulation of cell cycle and apoptosis in response to DNA damage
Most human cancers
Li-Fraumeni syndrome; multiple carcinomas and sarcomas
WT-1
Nuclear transcription
Wilms tumor
Wilms tumor
p16(INK4a) Regulation of cell Pancreatic, cycle by inhibiting esophageal cyclin-dependent cancers kinases
Malignant melanoma
BRCA-1
DNA repair
Carcinomas of female breast and ovary
BRCA-2
DNA repair
Carcinomas of male and female breast
288
Figure 8-30 Pathogenesis of retinoblastoma. Two mutations of the Rb locus on chromosome 13q14 lead to neoplastic proliferation of
the retinal cells. In the familial form, all somatic cells inherit one mutant Rb gene from a carrier parent. The second mutation affects the Rb locus in one of the retinal cells after birth. In the sporadic form, on the other hand, both mutations at the Rb locus are acquired by the retinal cells after birth.
289
cycle and nuclear transcription, because they hold the key to cell division. Molecules That Regulate Nuclear Transcription and Cell Cycle.
Ultimately, all positive and negative signals converge on the nucleus, where decisions to divide or not to divide are made. In keeping with this, products of several tumor-suppressor genes ( Rb, WT-1, and p53) are localized to the nucleus. Rb Gene.
Much is known about the Rb gene because this was the first tumor-suppressor gene discovered. [24] [25] pRb, the product of the Rb gene, is a nuclear phosphoprotein that plays a key role in regulating the cell cycle. It is expressed in every cell type examined, where it exists in an active underphosphorylated and an inactive hyperphosphorylated state. In its active state, pRb serves as a brake on the advancement of cells from the G 1 to the S phase of the cell cycle. When the cells are stimulated by growth factors, the Rb protein is inactivated by phosphorylation (pRb-P), the brake is released, and the cells transverse the G1 S checkpoint. Once the cells enter S phase, they are committed to divide without additional growth factor stimulation. During the ensuing M phase, the phosphate groups are removed from pRb by cellular phosphatases, thus regenerating the dephosphorylated form of pRb. The molecular basis of this braking action has been unraveled in elegant detail. [20] Quiescent cells (in G0 or early G1 ) contain the active hypophosphorylated form of pRb. In this state, pRb prevents cell replication by binding, and possibly sequestering, the E2F family of transcription factors. When the quiescent cells are stimulated by growth factors, the concentrations of the D and E cyclins (see earlier) goes up, and the resultant activation of cyclin D/CDK4, cyclin D/CDK6, and cyclin E/CDK2 leads to phosphorylation of pRb (Fig. 8-31) . The hyperphosphorylated form of pRb releases the E2F transcription factors. The released E2F proteins then form heterodimers with the DP family of proteins (Fig. 8-31) and activate the transcription of several target genes. E2F-DNA binding sites have been identified in the regulatory region of a number of genes whose products are required for the S phase of cell cycle. The exact workings of the pRb-E2F nexus in regulating the G1 S transition are not entirely clear. According to one view, hypophosphorylated pRb prevents the activation of E2F-responsive genes by physical sequestration of
Figure 8-31 The role of pRb in regulating the G1
S checkpoint of cell cycle. Hypophosphorylated pRb complexed to the E2F transcription factors binds to DNA and inhibits transcription of genes whose products are required for the S phase of the cell cycle. When pRb is phosphorylated by the cyclin D/CDK4, 6, and cyclin E/CDK2 complexes, it releases E2F. The latter then activates
transcription of S-phase genes. The phosphorylation of pRb is inhibited by CDK inhibitors because they inactivate cyclin/CDK complexes. Virtually all cancer cells show dysregulation of the G1 S checkpoint owing to mutation in one of four genes that regulate the phosphorylation of pRb; these genes ( Rb, CDK4, cyclin D, and p16 ) are indicated by an asterisk.
290
E2F proteins. More recent evidence suggests that hypophosphorylated pRb is not a mere sponge that holds back E2F from its target genes; rather the pRb-E2F complex binds to DNA and actively inhibits the transcription of the S phase genes. [26] Regardless of the precise mechanism by which pRb regulates the function of E2F, it is clear that the state of pRb phosphorylation is a critical determinant of cell cycle progression. It should be obvious from this discussion that if the Rb protein is absent (owing to gene deletions) or its ability to regulate E2F transcription factors is derailed by mutations, the molecular brakes on the cell cycle are released, and the cells move blithely into the S phase. The mutations of Rb genes found in tumors are localized to a region, called the " Rb pocket," that is involved in binding to E2F. It was mentioned previously that germ line loss or mutations of the Rb gene predispose to occurrence of retinoblastomas and to a lesser extent osteosarcomas. Furthermore, somatically acquired mutations have been described in glioblastomas, small cell carcinomas of lung, breast cancers, and bladder carcinomas. Given the presence of pRb in every cell and its importance in cell cycle control, two questions arise: (1) Why do patients with germ line mutation of the Rb locus develop only retinoblastomas? (2) Why are inactivating mutations of pRb not much more common in human cancer? The basis for the occurrence of tumors restricted to the retina in patients who inherit one defective allele of Rb is not fully understood, but some clues have emerged from the study of mice with targeted disruption of the Rb locus. Rb=/- mice die in utero with evidence of apoptosis in their nervous system and hematopoietic cells. This suggests that homozygous loss of the Rb gene triggers apoptosis. There is evidence that unrestrained action of E2F proteins (as would occur with loss of both Rb alleles) not only drives the cell cycle, but also triggers apoptosis. This action of E2F requires the function of the p53 gene (see later). It thus seems plausible that although in most tissues, homozygous loss of Rb induces cell death, the retinoblasts are relatively resistant to such apoptosis-inducing effect. In these cells, therefore, dysregulated E2F gives rise to neoplastic proliferation. With respect to the second question (i.e., why the loss of Rb is not much more common in human tumors), the answer is much simpler: Mutations in other genes that control pRb phosphorylation can mimic the effect of pRb loss; such genes are mutated in many cancers that seem to have normal Rb genes. Thus, for example, mutational activation of cyclin D or CDK4 would favor cell proliferation by facilitating pRb phosphorylation. As previously discussed, cyclin D is overexpressed in many tumors because of gene amplification or translocation. Mutational inactivation of CDK inhibitors would also drive the cell cycle by unregulated activation of cyclins and CDKs. One such inhibitor, encoded by the p16 gene (also called inhibitor of kinase 4 or INK4a) is an extremely common target of deletion or mutational inactivation in human tumors.26a Germ line
mutations of p16 are associated with a subset of hereditary melanomas. Somatically acquired deletion or inactivation of p16 is seen in 75% of pancreatic carcinomas; 40 to 70% of glioblastomas; 50% of esophageal cancers; and 20% of non-small cell lung carcinomas, soft tissue sarcomas, and bladder cancers. Thus, the emerging paradigm is that loss of normal cell cycle control is central to malignant transformation and that at least one of the four key regulators of cell cycle (p16, cyclin D, CDK4, Rb) is mutated in the vast majority of human cancers. [5] In cells that harbor mutations in p16, cyclin D, or CDK4, the function of the Rb gene is disrupted even if the Rb gene itself is not mutated. Several other pathways of cell growth regulation, some to be discussed in more detail later, also converge on pRb (Fig. 8-31) . TGF-beta induces inhibition of cellular proliferation. This effect of TGF-beta is induced, at least in part, by up-regulation of the CDK inhibitors p27 and p15. The transforming proteins of several oncogenic animal and human DNA viruses seem to act, in part, by neutralizing the growth inhibitory activities of pRb. SV40 and polyoma virus large T antigens, adenoviruses EIA protein, and human papillomavirus (HPV) E7 protein all bind to the hypophosphorylated form of pRb. The binding occurs in the same pRb pocket that normally sequesters E2F transcription factors. Thus, the pRb protein, unable to bind the E2F transcription factors, is functionally deleted, and the transcription factors are free to cause cell cycle progression. The p53 gene, a well-known tumor-suppressor gene, described next, exerts its growth-inhibiting effects at least in part by up-regulating the synthesis of the CDK inhibitor p21. p53 gene.
p53, the other well-studied tumor-suppressor gene, is located on chromosome 17p13.1, and it is the single most common target for genetic alteration in human tumors. A little over 50% of human tumors contain mutations in this gene. Homozygous loss of the p53 gene is found in virtually every type of cancer, including carcinomas of the lung, colon, and breast--the three leading causes of cancer deaths. In most cases, the inactivating mutations affecting both p53 alleles are acquired in somatic cells. Less commonly, some individuals inherit a mutant p53 allele. As with the Rb gene, inheritance of one mutant allele predisposes individuals to develop malignant tumors because only one additional "hit" is needed to inactivate the second, normal, allele. Such individuals, said to have the Li-Fraumeni syndrome, have a 25-fold greater chance of developing a malignant tumor by age 50 compared with the general population. [27] In contrast to patients who inherit a mutant Rb allele, the spectrum of tumors that develop in patients with the Li-Fraumeni syndrome is quite varied; the most common types of tumors are sarcomas, breast cancer, leukemia, brain tumors, and carcinomas of the adrenal cortex. As compared with sporadic tumors, those that afflict patients with the Li-Fraumeni syndrome occur at a younger age, and a given individual may develop multiple primary tumors. The fact that p53 mutations are common in a variety of human tumors suggests that the p53 protein serves as a critical gatekeeper against the formation of cancer. Indeed, it is evident that p53 acts as a "molecular policeman" that prevents the propagation of
genetically damaged cells. [28] The p53 protein is localized to the nucleus, and when called into action, it functions primarily by controlling the
291
transcription of several other genes. Under physiologic conditions, p53 has a short half-life (20 minutes), presumably because of ubiquitin-mediated proteolysis, and hence, in contrast to pRb, it does not police the normal cell cycle. p53 is called in to apply emergency brakes, however, when DNA is damaged by irradiation, UV light, or mutagenic chemicals. With such an assault on genetic material, there are dramatic changes in the otherwise sleepy p53 (Fig. 8-32) . Through poorly understood mechanisms, there is a rapid increase in p53 levels and activation of p53 as a transcription factor. The accumulated wild-type p53 binds to DNA and stimulates transcription of several genes that mediate the two major effects of p53: cell-cycle arrest and apoptosis. p53-induced cell cycle arrest occurs late in the G1 phase and is caused by the p53-dependent transcription of the CDK inhibitor p21. The p21 gene, as discussed earlier, inhibits the cyclin/CDK complexes and thus prevents the phosphorylation of pRb necessary for cells to enter the S phase. Such a pause in cell cycling is welcome because it allows the cells time to repair the DNA damage inflicted by the mutagenic agent. p53 also helps in this process directly by inducing the transcription of GADD45 ( Growth Arrest and DNA Damage), a protein involved in DNA repair. GADD45 also assists in G1 arrest by unknown mechanisms. If the DNA damage is repaired successfully, quite ingeniously, p53 activates a gene called mdm2, whose product binds to and down-regulates p53, thus relieving the cell cycle block. If during the pause in cell division the DNA damage cannot be successfully repaired, normal p53, perhaps as a last-ditch effort, sends the cell to the graveyard by inducing the activation of apoptosis-inducing genes. bax and IGF-BP3 are the two p53-responsive genes that carry the cell death commands of p53. bax, as we discuss later, binds to and antagonizes the apoptosis-inhibiting protein bcl-2. IGF-BP3 binds to the receptor of the insulin-like growth factor (IGF) and presumably induces apoptosis by blocking IGF-mediated intracellular signaling. It should be emphasized that transcriptional activation of downstream genes, such as p21, GADD45, and bax, is central to the normal functioning of
Figure 8-32 The role of p53 in maintaining the integrity of the genome. Activation of normal p53 by DNA-damaging agents or by
hypoxia leads to cell cycle arrest in G1 and induction of DNA repair, by transcriptional up-regulation of the cyclin-dependent kinase inhibitor p21 , and the GADD45 genes, respectively. Successful repair of DNA allows cells to proceed with the cell cycle; if DNA repair fails, p53 -induced activation of the bax gene promotes apoptosis. In cells with loss or mutations of p53 , DNA damage does not induce cell cycle arrest or DNA repair, and hence genetically damaged cells proliferate, giving rise eventually to malignant neoplasms.
292
p53. In keeping with this notion, the most common mutations that disable p53 affect its
DNA-binding domain, thus preventing the p53-dependent transcription of genes. Whether p53 also mediates some of its effects by protein-protein interactions is considered quite likely, but this is not fully understood. To summarize, p53 senses DNA damage by unknown mechanisms and assists in DNA repair by causing G1 arrest and inducing DNA repair genes. A cell with damaged DNA that cannot be repaired is directed by p53 to undergo apoptosis (Fig. 8-32) . In view of these activities, p53 has been rightfully called a " guardian of the genome." With homozygous loss of p53, DNA damage goes unrepaired, mutations become fixed in dividing cells, and the cell turns onto a one-way street leading to malignant transformation. Yet another mechanism by which normal p53 may prevent tumor growth has been discovered recently. It seems that, in addition to DNA damage, hypoxia can also stimulate the activation of normal p53. [29] As discussed in more detail later, tumor angiogenesis is critical to the growth of tumor cells. Tumor cells that are hypoxic undergo apoptosis if they have normal copies of the p53 gene. If the p53 gene is mutated, however, the hypoxic tumor cells are resistant to apoptosis. Thus, hypoxia selects for cells in which the p53 gene is inactive, and propagation of p53-deficient cells is favored. In addition to somatic and inherited mutations, p53 gene functions can be inactivated by other mechanisms. As with pRb, the transforming proteins of several DNA viruses, including the E6 protein of human papillomaviruses, can bind to and degrade p53. The cellular p53-binding protein, mdm2, which normally down-regulates p53 activity, is overexpressed in a subset of human soft tissue sarcomas as a result of gene amplification. By promoting rapid degradation of p53, [30] mdm2 acts as an oncogene. The ability of p53 to control apoptosis in response to DNA damage has some practical therapeutic implications. Radiation and chemotherapy, the two common modalities of cancer treatment, mediate their effects by inducing DNA damage and subsequent apoptosis. It follows that tumors that retain normal p53 genes are more likely to respond to such therapy than tumors that carry mutant p53. Such is the case with testicular teratocarcinomas [31] and childhood acute lymphoblastic leukemias. By contrast, tumors such as lung cancers and colorectal cancers, which frequently carry p53 mutations, are relatively resistant to chemotherapy and radiotherapy. In closing this discussion of the p53 gene, it should be pointed out that for almost 20 years after its discovery, the p53 gene was the only known gene of its kind, both structurally and functionally. In late 1997, this situation changed dramatically with the discovery of the p73 gene (dubbed the big brother of p53). Located on 1p36, this gene encodes a protein that bears many similarities to p53. It has a DNA-binding domain that resembles the corresponding region of p53, and similar to the latter it can cause cell cycle arrest as well as apoptosis under appropriate conditions. [32] [33] Deletions of 1p36, where the p73 gene resides, are common in a variety of tumors, including neuroblastoma and colon and breast cancers. Much interest is now focused on this missing relative of the p53 gene.
BRCA-1 and BRCA-2 Genes.
BRCA-1, on chromosome 17q12-21, and BRCA-2, on chromosome 13q12-13, are two recently discovered tumor-suppressor genes that are associated with the occurrence of breast and several other cancers. As with other tumor-suppressor genes, individuals who inherit mutations of BRCA-1 or BRCA-2 are highly susceptible to the development of breast cancer. With germ line mutations of the BRCA-1 gene, there is, in addition, a substantially higher risk of epithelial ovarian cancers and a slightly increased risk of prostate and colon cancers. Likewise, mutations in the BRCA-2 gene increase the risk of developing cancers of the male breast, ovary, and, possibly, prostate, pancreas, and larynx. [34] Approximately 5 to 10% of breast cancers are familial, and mutations in BRCA-1 and BRCA-2 account for 80% of the familial cases. Mutations of BRCA-1 and BRCA-2 are rarely found in sporadic breast cancer. Thus, it seems that, in contrast to many other tumor-suppressor genes ( Rb, p53, NF-1) associated with heritable cancer syndromes, neither of the two BRCA genes is associated with the development of nonfamilial (sporadic) forms of breast cancer. The functions of BRCA-1 and BRCA-2 are not fully defined. Protein products of both genes are localized to the nucleus and are believed to be involved in transcriptional regulation. Some data suggest that BRCA-1 and BRCA-2 are involved in DNA repair. This conclusion is based on the observation that the BRCA-1 and BRCA-2 proteins interact with Rad 51, a protein implicated in the regulation of recombination and double-stranded DNA repair. [35] According to this view, mutations in BRCA genes, similar to mutations in other DNA repair genes (see later), do not directly regulate cell growth; rather they predispose to errors in DNA replication, thus leading to mutations in other genes that directly affect cell cycle and cell growth. This hypothesis is not entirely consistent with the observation that, similar to p53, BRCA-1 can negatively regulate the cell cycle by transcriptional activation of the CDK inhibitor p21. [36] These complexities are currently under active investigation. Molecules That Regulate Signal Transduction.
Down-regulation of growth-promoting signals is another potential area in which products of tumor-suppressor genes may be operative. The products of the NF-1 gene and the APC gene fall into this category. Germ line mutations at the NF-1 (17q11.2) and the APC (5q21) loci are associated with benign tumors that are precursors of carcinomas that develop later. In the case of the APC ( adenomatous polyposis coli) gene, individuals born with one mutant allele invariably develop hundreds or even thousands of adenomatous polyps in the colon during their teens or twenties (familial adenomatous polyposis [FAP]; Chapter 18) . Almost invariably, one or more of these polyps undergo malignant transformation, giving rise to colon cancer. As with other tumor-suppressor genes, both copies of the APC gene must be lost for tumor development. When this occurs, adenomas form. This conclusion is supported by the development of colonic adenomas in mice, with targeted disruption of APC genes in the colonic mucosa. [37] As discussed later, several additional mutations must occur for cancers to develop in adenomas (see p. 296). In addition to
cancers arising
293
in the setting of FAP, the majority (70 to 80%) of nonfamilial colorectal carcinomas and sporadic adenomas also show homozygous loss of the APC gene, thus firmly implicating APC loss in the pathogenesis of colonic tumors. The molecular basis of APC action and the basis of its tumor-suppressor activity have been learned by the study of homologous genes in the fruitfly Drosophila and the amphibian Xenopus. [38] The APC protein is located in the cytoplasm, where it interacts with several other intracellular proteins, including beta-catenin, a protein that can enter the nucleus and activate transcription of growth-promoting genes. An important function of the APC protein is to cause degradation of beta -catenin, thus maintaining low levels of the latter in the cytoplasm. Inactivation of APC gene, and the consequent loss of APC protein, increases the cellular levels of beta-catenin, which, in turn, translocates to the nucleus and up-regulates cellular proliferation. Thus, APC is a negative regulator of beta-catenin signaling. [39] The importance of the APC-beta-catenin signaling pathway in tumorigenesis is attested to by the fact that in those colonic cancers that have normal APC genes, beta-catenin levels are elevated because mutations in beta-catenin render it refractory to the degrading action of APC. [40] Dysregulation of the APC-beta-catenin pathway is not restricted to colon cancers; mutations in either APC or beta-catenin have also been found in nearly 30% of melanoma cell lines. Both beta-catenin and APC have other cellular partners as well, suggesting that their normal functions extend beyond the regulation of beta-catenin signaling. Of interest, beta-catenin binds to the cytoplasmic aspect of E-cadherin, a cell surface protein that maintains intercellular adhesiveness. Cancer cells have reduced adhesiveness, resulting possibly from defects in the cadherin-catenin axis. The NF-1 gene behaves similar to the APC gene. Individuals who inherit one mutant allele develop numerous benign neurofibromas, presumably as a result of inactivation of the second copy of the NF-1 gene. This condition is called neurofibromatosis type 1 (Chapter 6) . Some of the neurofibromas later develop into neurofibrosarcomas. Children with neurofibromatosis-1 also are at increased risk of developing acute myeloid leukemia. [41] The function of neurofibromin, the protein product of the NF-1 gene, is to regulate signal transduction via the ras protein (see earlier). Recall that the ras protein, involved in transmitting growth-promoting signals, flips back and forth between GDP-binding (inactive) and GTP-binding (active) states. Neurofibromin is a GTPase activating protein that facilitates conversion of active ras to inactive ras. With a loss of NF-1, ras is trapped in an active, signal-emitting state. Cell Surface Receptors.
Several types of molecules expressed on the cell surface can regulate cell growth and behavior. Such molecules include receptors for growth-inhibitory factors, such as TGF-beta, and proteins that regulate cellular adhesions, such as the cadherins. The binding of TGF-beta to its receptors up-regulates transcription of growth-inhibitory
genes. It mediates this effect, in part, by stimulating the synthesis of cyclin-dependent kinase (CDK) inhibitors. These block the cell cycle by inhibiting the actions of cyclin/CDK complexes. Mutations of the TGF-beta receptor and its signaling pathway have been discovered in many cancers. For example, the gene encoding a TGF-beta receptor is inactivated in approximately 15% of colon cancers; similarly, SMAD2 and SMAD4 genes, which encode proteins in the TGF-beta growth-inhibitory pathway, are also deleted or inactivated in certain colon and pancreatic cancers. [42] Cadherins are a family of glycoproteins that act as glues between epithelial cells. Loss of cadherins can favor the malignant phenotype by allowing easy disaggregation of cells, which can then invade locally or metastasize. Reduced cell surface expression of E-cadherin has been noted in many types of cancers, including those that arise in the esophagus, colon, breast, ovary, and prostate. [43] Furthermore, loss of E-cadherin is causally related to the transition of an adenoma to a carcinoma in a mouse model of pancreatic beta-cell tumors. [43A] Recent studies indicate that like many other tumor-suppressor genes, germ line mutations of the E-cadherin gene can predispose to familial gastric carcinoma. [43B ] The molecular basis of reduced E-cadherin expression is varied. In a small proportion of cases, there are mutations in the E-cadherin gene (located on 16q); in other cancers, E-cadherin expression is reduced secondary to mutations in the catenin genes. Catenins, as discussed earlier, bind to the intracellular portion of cadherins and stabilize their expression. Deleted in colon carcinoma ( DCC) is a gene located on chromosome 18q21. Because this chromosome region is frequently deleted in human colon and rectum carcinomas, the DCC gene has been considered a candidate tumor-suppressor gene. Its structure resembles other cell surface molecules that are involved in cell-to-cell and cell-to-matrix interactions; hence it was proposed that the DCC gene may regulate cell growth and differentiation by integrating signals from the cell's environment. Study of DCC knockout mice, however, has raised serious doubts regarding the likelihood of DCC being a tumor-suppressor gene. Instead, it appears that DCC is a cell surface receptor important in axonal growth. [44] Thus, it seems that some other gene in close linkage with DCC on chromosome 18q21 is the real culprit for carcinogenesis. Other Tumor-Suppressor Genes.
There is little doubt that many more tumor-suppressor genes remain to be discovered. Often, their location is suspected by the detection of consistent sites of chromosomal deletions or by loss-of-heterozygosity studies. Some of the tumor-suppressor genes of unknown function that are associated with well-defined clinical syndromes are briefly described below: NF-2 gene: Germ line mutations in the NF-2 gene predispose to the development of neurofibromatosis type 2. As discussed in Chapter 6 , patients with NF-2 develop bilateral schwannomas of the acoustic nerve. In addition, somatic mutations affecting both alleles of NF-2 have also been found in sporadic meningiomas and ependymomas. The product of the NF-2 gene, called merlin, shows a great deal of homology with the red cell membrane cytoskeletal protein 4.1 (Chapter 14) . [45] Merlin binds, on one hand, to actin and, on the other hand, to CD44, a
transmembrane protein that is involved in cell-matrix interactions; how loss of merlin leads to transformation is not known. VHL: Germ line mutations of the Von Hippel- Lindau 294
( VHL) gene on chromosome 3p are associated with hereditary renal cell cancers, pheochromocytomas, hemangioblastomas of the central nervous system, retinal angiomas, and renal cysts. Mutations of the VHL gene have also been noted in sporadic renal cell cancers (Chapter 21) . The VHL protein regulates transcription elongation by RNA polymerase. How this function is related to tumorigenesis is not understood at present. PTEN: Phosphatase and tensin homolog, deleted on chromosome 10 gene ( PTEN), mapped on chromosome 10q23, is frequently deleted in many human cancers, including glioblastomas, prostate cancer, endometrial cancer, and breast cancer. The structure of this gene suggests that it may negatively regulate cell interactions with extracellular matrix by dephosphorylating undefined substrates. [46] [46A ]
WT-1: WT-1 gene, located on chromosome 11p13, is associated with the development of Wilms tumor. Both inherited and sporadic forms of Wilms tumor occur, and mutational inactivation of the WT-1 locus has been seen in both forms. The WT-1 protein is a transcriptional regulator that presumably inhibits transcription of growth-promoting genes. In addition to WT-1, Wilms tumor is also associated with two other genes, one located on 11p15 and the other at a site not linked to chromosome 11 (Chapter 11) . Genes That Regulate Apoptosis For many years, oncogenes and cancer-suppressor genes held center stage in the understanding of the molecular basis of tumorigenesis. Although they act quite differently, ultimately genes belonging to both of these classes regulate cell proliferation. It is now appreciated that genes that prevent or induce programmed cell death are also important variables in the cancer equation. [47] A large family of genes that regulate apoptosis has been identified. [48] Mercifully for nonexperts, these genes can be remembered as a series of three-letter words beginning with b. The first antiapoptotic gene identified, bcl-2 is a member of a large family of homodimerizing and heterodimerizing proteins, some of which inhibit apoptosis (such as bcl-2 itself and bcl-xL), whereas others (such as bax, bad, and bcl-xS) favor programmed cell death. The discovery of bcl-2, the prototypic gene in this category, began with the observation that approximately 85% of B-cell lymphomas of the follicular type (Chapter 15) carry a characteristic t(14;18)(q32;q21) translocation. Recall that 14q32, the site where immunoglobulin heavy-chain genes are found, is also involved in Burkitt lymphoma. Juxtaposition of this transcriptionally active locus with bcl-2 (located at 18q21) causes overexpression of the bcl-2 protein. By mechanisms not yet clear, overexpression of bcl-2 protects lymphocytes from apoptosis and allows them to survive for long periods; thus there is a steady accumulation of B lymphocytes, resulting in lymphadenopathy and marrow infiltration. Because bcl-2 overexpressing lymphomas arise in large part from
reduced cell death rather than explosive cell proliferation, they tend to be indolent (slow growing) compared with most other lymphomas. Supporting the role of bcl-2 in lymphomagenesis is the observation that mice transgenic for bcl-2 develop B-cell lymphomas. Not only is the function of bcl-2 unusual, but also its location is different from most cancer-associated genes. It is localized on the outer leaflet of the mitochondrial membrane, the endoplasmic reticulum, and the nuclear membrane. The mitochondrial location of bcl-2 and other members of the bcl-2 family may have bearing on the functioning of these genes. The biochemical basis of bcl-2 action, also discussed in Chapter 1 , is not entirely clear. Apoptosis is the end point of a cascade of molecular events that are initiated by several stimuli and lead ultimately to the activation of proteolytic enzymes responsible for cell death. The bcl-2 family of proteins regulates the activation of these proteolytic enzymes (caspases). How, precisely, the bcl-2 family members influence the activation of caspases is under intense scrutiny. The following represents an outline of the current thinking on the action of bcl-2. [49] [50] [51] (In this rapidly moving field, however, hypotheses are proposed and rejected more rapidly than the growth of highly malignant tumors!) In many models of apoptosis, release of cytochrome C from the mitochondria appears to be a critical step in the chain of events that lead to apoptosis. One function of the released cytochrome C seems to be to assist in the activation of the proteolytic enzyme caspase 9. [52] Located strategically on the outer mitochondrial membranes, bcl-2 and its partners are believed to regulate the exit of cytochrome C from the mitochondrion to the cytoplasm. How exactly this transit of cytochrome C is regulated is not entirely clear, but there is some evidence that bax, a proapoptotic member of the bcl-2 family, forms a channel in the mitochondrial membrane that allows the exit of cytochrome C (and hence apoptosis), whereas bcl-2 blocks the channel-forming activity of bax. The proapoptotic and antiapoptotic members of the bcl-2 family act as a rheostat in regulating programmed cell death. The ratio of death antagonists ( bcl-2, bcl-xL) to agonists ( bax, bcl-xS, bad, bid) determines whether a cell will respond to an apoptotic stimulus (Fig. 8-33) . This rheostat is operated, at least in part, by competitive dimerization between various family members. Thus, whereas bcl-2 homodimers favor cell survival (possibly by displacing the channel-forming bax from the mitochondrial membrane), bax homodimers favor apoptosis. It follows that factors that regulate the transcription of bcl-2 family members can influence apoptosis. As previously discussed, the proapoptotic action of the tumor-suppressor gene p53 seems to be mediated by up-regulation of the bax gene. In keeping with this notion, up-regulation of bax in bax-transgenic mice suppresses tumor growth by promoting apoptosis. [53] Finally, although the bcl-2 family of genes plays an important role in regulating apoptosis, at least two other cancer-associated genes are also intimately connected with apoptosis: the p53 gene and the protooncogene c- myc. The molecular mechanisms of cell death induced by these two intersect with the bcl-2 pathways. Activation of p53, as discussed previously, up-regulates bax synthesis and hence
295
Figure 8-33 Regulation of cell death by bcl-2, bax, and p53. bcl -2 dimers favor cell accumulation by inhibiting apoptosis; bax dimers favor apoptosis. The apoptosis-inducing effect of normal p53 genes is mediated in part by increasing the synthesis of bax protein.
counteracts the antiapoptotic action of bcl-2. c- myc induces apoptosis when cells are driven by c- myc activation, but growth is restricted by the limited availability of growth factors in the milieu. When confronted by such conflicting signals, the cells are programmed to die by up-regulation of p53 and other undefined signals. Overexpression of bcl-2 can rescue cells from c- myc-initiated apoptosis. Thus, it appears that myc and bcl-2 may collaborate in tumorigenesis: c- myc triggers proliferation, and bcl-2 prevents cell death, even if growth factors become limiting. This is one of many examples in which two or more cancer genes cooperate in giving rise to cancer. Genes That Regulate DNA Repair Humans literally swim in a sea of environmental carcinogens. Although exposure to naturally occurring DNA-damaging agents, such as ionizing radiation, sunlight, and dietary carcinogens, is common, cancer is a relatively rare outcome of such encounters. This happy state of affairs results from the ability of normal cells to repair DNA damage and thus prevent mutations in genes that regulate cell growth and apoptosis. In addition to possible DNA damage from environmental agents, the DNA of normal dividing cells is also susceptible to alterations resulting from errors that occur spontaneously during DNA replication. Such mistakes, if not repaired promptly, can also push the cells along the slippery slope of neoplastic transformation. The importance of DNA repair in maintaining the integrity of the genome is highlighted by several inherited disorders in which genes that encode proteins involved in DNA repair are defective. Those born with such inherited mutations of DNA repair proteins are at a greatly increased risk of developing cancer. Several examples are discussed next. The role of DNA repair genes in predisposition to cancer is illustrated dramatically by the hereditary non polyposis colon cancer ( HNPCC) syndrome. This disorder is characterized by familial carcinomas of the colon affecting predominantly the cecum and proximal colon (Chapter 18) . In contrast to the carcinomas in patients with germ line APC mutations, the cancers in HNPCC do not arise in adenomatous polyps. There are several types of DNA damage, and, correspondingly, there are many forms of DNA repair. HNPCC results from defects in genes involved in DNA mismatch repair. When a strand of DNA is replicating, mismatch repair genes act as "spell checkers." Thus, for example, if there is an erroneous pairing of G with T, rather than the normal A with T, the mismatch repair genes correct the defect. [54] Without these proofreaders, errors slowly accumulate in several genes, including protooncogenes and tumor-suppressor genes. DNA repair genes themselves are not oncogenic, but they allow mutations in other genes during the process of normal cell division. Cells with such defects in DNA repair are said to have the replication error (RER)
phenotype, which can be readily documented by examination of microsatellite sequences in the tumor cell DNA. Microsatellites are tandem repeats of one to six nucleotides scattered throughout the genome (Chapter 6) . Microsatellite sequences of an individual are fixed for life and are the same in every tissue. With errors in mismatch repair, there are expansions and contractions of these repeats in tumor cells, creating alleles not found in normal cells of the same patient. Such microsatellite instability is a hallmark of defective mismatch repair. Of the various DNA mismatch repair genes, at least four are involved in the pathogenesis of HNPCC. Germ line mutations in hMSH2 (2p16) account for tumor development in 50% of the families with HNPCC. In roughly 30% of HNPCC cases, the mutation affects the hMLH1 gene, on chromosome 3p21. The remaining 20% of cases have mutations in hPMS1 and hPMS2 and other mismatch repair genes. [55] Each affected individual inherits one defective copy of one of the several DNA mismatch repair genes
296
and acquires the "second hit" in the colonic epithelial cells. Thus, DNA repair genes behave similar to cancer-suppressor genes in their mode of inheritance, but, in contrast to tumor-suppressor genes, they do not affect cell growth directly. Because mutations occur more readily and more rapidly in patients with HNPCC, the evolution of tumors occurs more rapidly, and hence patients develop colon cancers at a much younger age (110 mm Hg). This form of arteriolar disease can be identified with the light microscope by virtue of its onion-skin, concentric, laminated thickening of the walls of arterioles with progressive narrowing of the lumens (Fig. 12-17 B). With the electron microscope, the laminations consist of smooth muscle cells and thickened and reduplicated basement membrane. Frequently, these hyperplastic changes are accompanied by deposits of fibrinoid and acute necrosis of the vessel walls, referred to as necrotizing arteriolitis. The arterioles in all tissues throughout the body may be affected, but the favored site is the kidney (Chapter 21) . Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 12 - Blood Vessels VASCULAR DISEASES - Part 2 Inflammatory Disease--The Vasculitides Pathogenesis of Non-Infectious Vasculitis Immune Complexes Antineutrophil Cytoplasmic Antibodies Other Mechanisms Classification GIANT CELL (TEMPORAL) ARTERITIS MORPHOLOGY Pathogenesis Clinical Features TAKAYASU ARTERITIS MORPHOLOGY Clinical Features POLYARTERITIS NODOSA (CLASSIC) MORPHOLOGY Clinical Course KAWASAKI SYNDROME (MUCOCUTANEOUS LYMPH NODE SYNDROME) Pathogenesis MORPHOLOGY MICROSCOPIC POLYANGIITIS (MICROSCOPIC POLYARTERITIS, HYPERSENSITIVITY OR LEUKOCYTOCLASTIC VASCULITIS) MORPHOLOGY Clinical Features WEGENER GRANULOMATOSIS Pathogenesis MORPHOLOGY Clinical Features THROMBOANGIITIS OBLITERANS (BUERGER DISEASE) MORPHOLOGY Clinical Features VASCULITIS ASSOCIATED WITH OTHER DISORDERS
INFECTIOUS ARTERITIS Raynaud Disease Aneurysms and Dissection ABDOMINAL AORTIC ANEURYSMS MORPHOLOGY Pathogenesis Clinical Course SYPHILITIC (LUETIC) ANEURYSMS MORPHOLOGY Clinical Features AORTIC DISSECTION (DISSECTING HEMATOMA) MORPHOLOGY Pathogenesis Clinical Course Veins and Lymphatics VARICOSE VEINS MORPHOLOGY Clinical Course THROMBOPHLEBITIS AND PHLEBOTHROMBOSIS OBSTRUCTION OF SUPERIOR VENA CAVA (SUPERIOR VENA CAVAL SYNDROME) OBSTRUCTION OF INFERIOR VENA CAVA (INFERIOR VENA CAVAL SYNDROME) LYMPHANGITIS AND LYMPHEDEMA Tumors BENIGN TUMORS AND TUMOR-LIKE CONDITIONS Hemangioma Capillary Hemangioma MORPHOLOGY Cavernous Hemangioma MORPHOLOGY Pyogenic Granuloma (Lobular Capillary Hemangioma) Lymphangioma Simple (Capillary) Lymphangioma Cavernous Lymphangioma (Cystic Hygroma) Glomus Tumor (Glomangioma) MORPHOLOGY Vascular Ectasias
Nevus Flammeus Spider Telangiectasia (Arterial Spider) Hereditary Hemorrhagic Telangiectasia (OslerWeber-Rendu Disease) Bacillary Angiomatosis MORPHOLOGY INTERMEDIATE-GRADE (BORDERLINE, LOW-GRADE MALIGNANT) TUMORS Kaposi Sarcoma MORPHOLOGY Pathogenesis Clinical Course Hemangioendothelioma MALIGNANT TUMORS Angiosarcoma MORPHOLOGY Clinical Features Hemangiopericytoma Pathology of Therapeutic Interventions in Vascular Disease BALLOON ANGIOPLASTY AND RELATED TECHNIQUES VASCULAR REPLACEMENT Coronary Artery Bypass Graft Surgery Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
VASCULAR DISEASES - Part 2 Inflammatory Disease--The Vasculitides Inflammation of the walls of vessels, called vasculitis, is encountered in diverse diseases and clinical settings. Vessels of any type in virtually any organ can be affected; this leads to a wide spectrum of clinical manifestations, which often includes constitutional signs and symptoms, such as fever, myalgias, arthralgias, and malaise. The two most common mechanisms of vasculitis are immune-mediated inflammation and direct invasion of vascular walls by infectious pathogens (Table 12-6) (Table Not Available) . Infections can indirectly induce a noninfectious vasculitis, for example, by generating immune complexes or triggering cross-reactivity. In a particular patient, it is critical to distinguish between directly infectious and immunologic mechanisms because the treatment approaches differ widely; for example, the immunosuppressive therapy appropriate for immune-mediated vasculitis would be potentially harmful for infectious vasculitis. Moreover, physical and chemical injury, such as irradiation, mechanical trauma, and toxins, can also cause vascular damage. In such cases, one or a relatively few vessels may be affected, as, for example, in a localized area of infection, irradiation, or mechanical trauma. TABLE 12-6 -- CLASSIFICATION OF VASCULITIS BASED ON PATHOGENESIS (Not Available) Data form Jennette JC, Falk RJ: Update on the pathobiology of vasculitis. In Schoen FJ, Gimbrone MA (eds): cardiovascular Pathology: Clinicpathologic Correlations and Pathogenetic Mechanisms. Baltimore . Williams & Wilkins, 1995, p 156; and Jennette JC, Falk Rj: Small-vessel vasculitis. N Engl J Med 1337:1512, 1997.
516
Pathogenesis of Non-Infectious Vasculitis.
Most noninfectious vasculitides appear to be initiated by one of several immunologic mechanisms. Such processes often induce relatively distinctive clinicopathologic entities, in which the vasculitis is widespread. Of these so-called systemic necrotizing vasculitides, several types affect the aorta and medium-sized vessels; most affect vessels smaller than arteries, such as arterioles, venules, and capillaries (designated small vessel vasculitis). [55] [56]
Immune Complexes.
The evidence for involvement of immune complexes in vasculitides can be summarized as follows: The vascular lesions resemble those found in experimental immune complex-mediated conditions, such as the local Arthus phenomenon and serum sickness. Immune reactants and complement can be detected in the serum or vessels of patients with vasculitis. For example, DNA-anti-DNA complexes are present in the vascular lesions of systemic lupus erythematosus-associated vasculitis; IgG, IgM, and complement in cryoglobulinemic vasculitis; and a number of other antigens in isolated cases. Hypersensitivity to drugs causes approximately 10% of vasculitic skin lesions. Some, such as penicillin conjugate serum proteins, whereas others such as streptokinase are foreign proteins; both can lead to vascular deposits of immune complexes. The most impressive evidence comes from vasculitis associated with viral infections, particularly hepatitis. There is a high incidence of hepatitis B antigen (HBsAg) and HBsAg-anti-HBsAg immune complexes in the serum and, with complement, in the vascular lesions of some patients with vasculitis, particularly those with large vessel polyarteritis nodosa and less commonly in those with membranous or membranoproliferative glomerulonephritis or leukocytoclastic vasculitis. [57] Importantly, immunosuppressive treatment results in a remission of the vasculitis but perpetuates the hepatitis B virus infection. Chronic hepatitis C virus (HCV) infection leads to glomerulonephritis, in which HCV/RNA and cryoprecipitates containing anti-HCV antibodies are detected in glomeruli. Whether complexes accrue in vessel walls by deposition from the circulation, by in situ formation, or by a combination of these mechanisms is not known (Chapter 21) . Moreover, many small vessel vasculitides show a paucity of vascular immune deposits, [58 ] and therefore other mechanisms have been sought for these so-called pauci-immune vasculitides. Antineutrophil Cytoplasmic Antibodies.
Serum from many patients with vasculitis in small vessels reacts with cytoplasmic antigens in neutrophils, indicating the presence of antineutrophil cytoplasmic autoantibodies (ANCA). ANCA comprise a heterogeneous group of autoantibodies against enzymes mainly found within the azurophil or primary granules in neutrophils but also found in the lysosomes of monocytes and in endothelial cells. [59] ANCA can be detected in serum by immunofluorescent microscopy of ethanol-fixed neutrophils and by immunochemical assays. Two main patterns of immunofluorescent staining distinguish different ANCA types. One ANCA type shows cytoplasmic localization of the staining (c-ANCA), and the most common target antigen is proteinase 3 (PR-3), a neutrophil granule constituent. The second type shows perinuclear staining (p-ANCA) and is usually specific for myeloperoxidase (MPO). Either ANCA specificity may occur in a patient with ANCA-associated small vessel vasculitis, but c-ANCA (PR-3 specificity) are
typically found in Wegener granulomatosis and p-ANCA (MPO specificity) are found in most cases of microscopic polyangiitis and Churg-Strauss syndrome. Approximately 10% of patients with these disorders, however, do not demonstrate ANCA by typical assays. ANCA serve as useful quantitative diagnostic markers for these disorders, and their discovery has led to segregation of a group of these disorders as the ANCA-associated vasculitides. [60] [61] The close association between ANCA titers and disease activity, particularly c-ANCA in Wegener granulomatosis, suggests that they may be important in the pathogenesis of this disease, but the precise mechanisms by which ANCA induce injury are unknown. One scenario currently being pursued postulates the following events: An autoimmune process of yet uncertain cause and mechanism initiates the formation of ANCA. Proinflammatory cytokines produced during an infection, by malignancy, or possibly triggered by drugs induce surface expression of the ANCA target antigens PR-3 and MPO on susceptible cells, thereby making them accessible to the respective antibodies. Binding of circulating ANCA to these antigens leads to neutrophil degranulation and endothelial cell injury with subsequent vascular damage. Other Mechanisms.
Antibodies to endothelial cells, perhaps induced by defects in immune regulation, may predispose to certain vasculitides, such as those associated with systemic lupus erythematosus and Kawasaki disease. Additionally, in Goodpasture syndrome the glomerulitis and pneumonitis are caused by anti-glomerular basement membrane antibodies. Finally, there is experimental evidence that certain viruses (e.g., herpes, coxsackievirus) may cause vasculitis by immune mechanisms involving T-cell action and gamma-interferon. [43] Classification.
The systemic vasculitides are classified on the basis of the size of the involved blood vessels, the anatomic site and histologic characteristics of the lesion, and the clinical manifestations. There is considerable clinical and pathologic overlap among these disorders. The nomenclature used here is that developed at the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitides (Table 12-7 (Table Not Available) and Fig. 12-18) (Figure Not Available) , [62] and the sequence of entities discussed follows that in Table 12-7 (Table Not Available) . GIANT CELL (TEMPORAL) ARTERITIS
Giant cell ( temporal) arteritis, the most common of the vasculitides, is an acute and chronic, often granulomatous, inflammation of medium-sized and small arteries. It
affects
517
TABLE 12-7 -- CLASSIFICATION AND CHARACTERISTICS OF VASCULITIS(Not Available) Modified form Jennette JC, et al: Nomenclature of systemic vasculatides: the proposal of an internation consensus conference. Arthritis Rheum 37:187. 1994. principally the arteries in the head-- especially the temporal arteries-- but also the vertebral and ophthalmic arteries. The latter may lead to blindness. In other expressions of this disorder, lesions have been found in arteries throughout the body, and in some cases the aortic arch has been involved to produce so-called giant cell aortitis. MORPHOLOGY.
Characteristically, short segments of one or more affected arteries develop nodular thickenings with reduction of the lumen, possibly to a slitlike orifice, which may become thrombosed. Histologically, two patterns are seen. In the more common variant, there is granulomatous inflammation of the inner half of the media centered on the internal elastic membrane marked by a mononuclear infiltrate, multinucleate giant cells of both foreign body and Langerhans type, and fragmentation of the internal elastic lamina (Fig. 12-19) . In the other, less common pattern, granulomas are rare or absent, and there is only a nonspecific panarteritis with a mixed inflammatory infiltrate composed largely of lymphocytes and macrophages admixed with some neutrophils and eosinophils but no giant cells. Occasionally in this variant, there is some fibrinoid necrosis. The later healed stage of both of these patterns reveals only collagenous thickening of the vessel wall: organization of the luminal thrombus sometimes transforms the artery into a fibrous cord. Giant cells are present in only two thirds of cases of temporal arteritis, and many histologic sections may have to be examined before one is detected. In the healed phase, the artery has considerable scarring that may be difficult to distinguish from aging changes. Pathogenesis.
The cause of this relatively common disease remains unknown. The morphologic alterations suggest an immunologic reaction against a component of the arterial wall, such as elastin. On the basis of the granulomatous nature of the inflammation, association with certain human leukocyte DR antigens (HLA-DR), and the response to corticosteroid therapy, T cell-mediated injury is suspected. These concepts are supported by experiments in which temporal artery segments from patients with giant cell arteritis were inserted into immunodeficient mice; selective proliferation of T cells in
the grafted arteries suggested recognition of a locally expressed antigen. [63] Clinical Features.
The disease is most common in older individuals and rare before the age of 50. Clinically, it begins with only vague constitutional symptoms--fever, fatigue, weight loss--without localizing signs or symptoms, but in most instances there is facial pain or headache, which is severe, sometimes unilateral, and often most intense along the course of the superficial temporal artery. The vessel itself may be nodular and painful to palpation. More serious are ocular symptoms, which appear quite abruptly in about half of patients and range from diplopia
518
Figure 12-18 (Figure Not Available) Diagrammatic representation of the preferred site of the vasculature involved by the major forms
of vasculitis. The widths of the trapezoids indicate the frequencies of involvement of various portions. Note that large-, medium-, and small-vessel vasculitis affects arteries, but only small-vessel vasculitis involves vessels smaller than arteries. LCA, leukocytoclastic angiitis. (From Jennette JC, Falk RJ: Small-vessel vasculitis. N Engl J Med 337:1512, 1997. Copyright © 1997, Massachusetts Medical Society. All rights reserved.)
to transient or permanent complete vision loss. Because treatment with anti-inflammatory agents is remarkably effective, there is urgency in establishing the diagnosis promptly. The diagnosis depends on biopsy and histologic confirmation, but because of the segmental nature of the involvement, adequate biopsy requires at least a 2- to 3-cm length of artery, and a negative biopsy result does not rule out the condition. Approximately one third of biopsies of the temporal artery are negative in patients with classic manifestations of this disease, and it must be assumed that the lesions were focal and missed on biopsy. In the absence of morphologic confirmation, it is often necessary to institute therapy on clinical grounds alone. Involvement of visceral vessels may give rise to manifestations of myocardial ischemia, gastrointestinal disturbances, or neurologic derangements.
Figure 12-19 Temporal (giant cell) arteritis. A , H&E stain of giant cells at the degenerated internal elastic membrane in active arteritis. B , Elastic tissue stain demonstrating focal destruction of internal elastic membrane ( arrow) and intimal thickening (IT) characteristic
of long-standing or healed arteritis.
519
TAKAYASU ARTERITIS
Takayasu arteritis is a granulomatous vasculitis of medium and larger arteries that was described in 1908 by Takayasu as a clinical syndrome characterized principally by ocular disturbances and marked weakening of the pulses in the upper extremities
(pulseless disease), related to fibrous thickening of the aortic arch with narrowing or virtual obliteration of the origins or more distal portions of the great vessels arising in the arch (Fig. 12-20) . It has been reported in most areas of the world, including the United States. The illness is seen predominantly in women younger than 40 years old. The cause and pathogenesis are unknown, although immune mechanisms are suspected. MORPHOLOGY.
Although Takayasu arteritis classically involves the aortic arch, in one third of cases, it also affects the remainder of the aorta and its branches and often the pulmonary arteries. The gross morphologic changes comprise, in most cases, irregular thickening of the aortic or branch vessel wall with intimal wrinking (Fig. 12-20 A and B) When the aortic arch is involved, the orifices of the major arteries to the upper portion of the body may be markedly narrowed or even obliterated by intimal thickening, accounting for the designation pulseless disease. The coronary and renal arteries may be similarly affected. Sometimes the lesions extend for some distance into the aortic branches and in half of cases involve the pulmonary arteries. Histologically the early changes consist of an adventitial mononuclear infiltrate with perivascular cuffing of the vasa vasocrum. Later, there may be intense mononuclear inflammation in the media, in some cases accompanied by granulomatous changes, replete with giant cells and patchy necrosis of the media (Fig. 12-20 C). The morphologic changes of Takayasu arteritis may be indistinguishable from those in giant cell (temporal) arteritis. [64] Thus, distinctions among active giant cell lesions of the aorta are based largely on clinical data, including the age of the patient. Moreover, the description Takayasu arteritis is currently being used widely to designate most giant cell lesions of the aorta in young patients. As the disease runs its course or after treatment with steroids, the inflammatory reaction is predominantly marked by collagenous fibrosis involving all layers of the vessel wall but particularly the intima, accompanied by lymphocytic infiltration. When the root of the aorta is affected, it may undergo dilation, producing aortic valve insufficiency. Narrowing of the coronary ostia may lead to myocardial infarction. Clinical Features.
The salient clinical features include weakening of the pulses and markedly lower blood pressure in the upper extremities with coldness or numbness of the fingers; ocular disturbances, including visual defects,
Figure 12-20 Takayasu arteritis. A , Aortic arch angiogram showing narrowing of brachiocephalic, carotid, and subclavian arteries ( arrows). B , Gross photograph of two cross-sections of the right carotid artery taken at the autopsy of the patient shown in A , demonstrating marked intimal thickening with minimal residual lumen. C, Histologic view of active Takayasu aortitis, illustrating
destruction of the arterial media by mononuclear inflammation with giant cells.
retinal hemorrhages, and total blindness; hypertension; and various neurologic deficits, ranging from dizziness and focal weakness to complete hemiparesis. Involvement of the more distal aorta may lead to claudication of the legs and of cranial vessels, leading to visual disturbances and neurologic manifestations. Involvement of pulmonary arteries
may lead to pulmonary hypertension and manifestations of 520
cor pulmonale. The course of the disease is variable. In some persons, there is rapid progression, but in others a quiescent stage is reached in 1 or 2 years, permitting long-term survival, albeit sometimes with visual or neurologic deficits. The course of the disease is quite variable. POLYARTERITIS NODOSA (CLASSIC)
Polyarteritis nodosa is a systemic vasculitis manifested by transmural necrotizing inflammation of small or medium-sized muscular arteries, typically involving renal and visceral vessels and sparing the pulmonary circulation. Neither glomerulonephritis nor vasculitis of arterioles, capillaries, or venules is present. The involvement is peculiarly focal, random, and episodic. It often produces irregular aneurysmal dilation, nodularity, and vascular obstruction and sometimes infarctions. To differentiate this disorder from other similar vasculitides, which are now thought to be distinct entities, the term classic is sometimes added to the designation. MORPHOLOGY.
In classic cases, polyarteritis nodosa involves arteries of medium to small size in any organ, with the possible exception of the lung. The distribution of lesions, in descending order of frequency is kidneys, heart, liver, and gastrointestinal tract, followed by pancreas, testes, skeletal muscle, nervous system, and skin. Individual lesions are sharply segmental, may involve only a portion of the vessel circumference, and have a predilection for branching points and bifurcations. Segmental erosion with weakening of the arterial wall owing to the inflammatory process may cause aneurysmal dilation or localized rupture that is perceived clinically as a palpable nodule and can be demonstrated by arteriography. Impairment of perfusion causing ulcerations, infarcts, ischemic atrophy, or hemorrhages in the area supplied by these vessels may provide the first clue to the existence of the underlying disorder. Sometimes, however, the lesions are exclusively microscopic and produce no gross changes. Histologically the vasculitis during the acute phase is characterized by transmural inflammation of the arterial wall with a heavy infiltrate of neutrophils, eosinophils, and mononuclear cells, frequently accompanied by fibrinoid necrosis of the inner half of the vessel wall (Fig. 12-21) . Typically the inflammatory reaction permeates the adventitia. The lumen may become thrombosed. In some lesions, only a portion of the circumference is affected, leaving segments of normal arterial wall juxtaposed to areas of vascular inflammation. At a later stage, the acute inflammatory infiltrate begins to disappear and is replaced by fibrous thickening of the vessel wall accompanied by a mononuclear infiltrate. The fibroblastic proliferation may extend into the adventitia, contributing to the firm nodularity that sometimes marks
Figure 12-21 Polyarteritis nodosa. Polyarteritis nodosa with segmental fibrinoid necrosis and thrombotic occlusion of the lumen of this small artery. Note that part of the vessel wall at the upper right ( arrow ) is uninvolved. (Courtesy of Sid Murphree, MD, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
the lesions. At a still later stage, all that remains is marked fibrotic thickening of the affected vessel, devoid of significant inflammatory infiltration. Particularly characteristic of polyarteritis nodosa is that all stages of activity may coexist in different vessels or even within the same vessel. Thus, whatever the inflammatory insult, it is apparently recurrent and strangely haphazard. Clinical Course.
Classic polyarteritis nodosa is a disease of young adults, although it may occur in children and older individuals. The course may be acute, subacute, or chronic and is frequently remittent, with long symptom-free intervals. Because the vascular involvement is widely scattered, the clinical signs and symptoms of this disorder may be varied and puzzling. The most common manifestations are malaise, fever of unknown cause, and weight loss; hypertension, usually developing rapidly; abdominal pain and melena (bloody stool) owing to vascular lesions in the alimentary tract; diffuse muscular aches and pains; and peripheral neuritis, which is predominantly motor. Renal involvement is one of the prominent manifestations of polyarteritis nodosa and a major cause of death. Because small vessel involvement is absent, however, there is no glomerulonephritis. About 30% of patients with polyarteritis nodosa have hepatitis B antigen in their serum. Unlike microscopic polyarteritis (microscopic polyangiitis, see later), classic polyarteritis nodosa has little association with ANCA. The diagnosis can usually be definitely established by the identification of necrotizing arteritis on tissue biopsy specimens, particularly medium-sized arteries of clinically involved tissue, such as kidney and nodular skin lesions. Angiography shows vascular aneurysms or occlusions of main visceral arteries in 50% of cases. Untreated, the disease is fatal in most cases, either during an acute fulminant
521
attack or after a protracted course, but therapy with corticosteroids and cyclophosphamide results in remissions or cures in 90%. Effective treatment of the hypertension is a prerequisite for a favorable prognosis. KAWASAKI SYNDROME (MUCOCUTANEOUS LYMPH NODE SYNDROME)
Kawasaki syndrome is an arteritis involving large, medium-sized, and small arteries (often the coronary arteries) that is associated with the mucocutaneous lymph node syndrome, usually in young children and infants (80% younger than 4 years old). The
acute illness is manifested by fever, conjunctival and oral erythema and erosion, edema of the hands and feet, erythema of the palms and soles, a skin rash often with desquamation, and enlargement of cervical lymph nodes. It is usually self-limited. [65] Epidemic in Japan, the disease has also been reported in Hawaii and increasingly in the United States. Approximately 20% of patients develop cardiovascular sequelae, with a range of severity from asymptomatic vasculitis of the coronary arteries, coronary artery ectasia, or aneurysm formation to giant coronary artery aneurysms (7 to 8 mm) with rupture or thrombosis, myocardial infarction, or sudden death. Kawasaki syndrome is the leading cause of acquired heart disease in children in the United States. Acute fatalities occur in approximately 1% of patients owing to coronary arteritis with superimposed thrombosis or ruptured coronary artery aneurysm. Pathologic changes outside the cardiovascular system are rarely significant. Pathogenesis.
The cause of the condition is unknown, but there is evidence that the vasculitis is based on an immunoregulatory defect characterized by T-cell and macrophage activation, secretion of cytokines, polyclonal B-cell hyperactivity, and the formation of autoantibodies to endothelial and smooth muscle cells, leading to acute vasculitis. The nature of the initiating antigen remains unknown, but it is currently speculated that in genetically susceptible persons, a variety of common infectious agents (most likely viral) may trigger the sequence of changes described. MORPHOLOGY.
Although the vasculitis resembles that of polyarteritis nodosa, with necrosis and pronounced inflammation affecting the entire thickness of the vessel wall, fibrinoid necrosis is usually less prominent in Kawasaki syndrome. Coronary artery lesions range from severe destruction of all constituents of the wall by a segmental necrotizing process, with moderate fibrinoid changes and dense infiltrate of inflammatory cells, to mild changes involving the intima only. [66] The acute phase eventually begins to subside spontaneously or in response to treatment, but it is during this subsiding phase that the acute vasculitis of the coronary arteries often leads to aneurysm formation and sometimes associated thrombosis with myocardial infarction. MICROSCOPIC POLYANGIITIS (MICROSCOPIC POLYARTERITIS, HYPERSENSITIVITY OR LEUKOCYTOCLASTIC VASCULITIS)
While classic polyarteritis nodosa is restricted to arteries, this type generally affects arterioles, capillaries, and venules, although in unusual cases arteries may be involved. Moreover, in contrast to polyarteritis nodosa, in a single patient, all lesions tend to be of the same age, and ANCA are present in the majority of cases. The lesions are thought to represent a hypersensitivity reaction, and it involves the skin, mucous membranes, lungs, brain, heart, gastrointestinal tract, kidneys, and muscle. Necrotizing glomerulonephritis (90% of patients) and pulmonary capillaritis are particularly common. The major resultant clinical features are hemoptysis, hematuria, and proteinuria; bowel pain or bleeding; and muscle pain or weakness. In many cases, the lesions are limited to the skin ( cutaneous leukocytoclastic vasculitis). Cutaneous vasculitis (Chapter 27) is
manifested by palpable purpura. In many cases, reaction to an antigen such as drugs (e.g., penicillin), microorganisms (e.g., streptococci), heterologous proteins, and tumor antigens can be traced as the precipitating cause, but there are few or no immune deposits in this type of vasculitis. MORPHOLOGY.
The lesions of microscopic polyangiitis are often histologically similar to those of polyarteritis nodosa, but muscular and large arteries are usually spared. Thus, macroscopic infarcts similar to those seen in polyarteritis nodosa are uncommon. Histologically, segmental fibrinoid necrosis of the media may be present, but in some the change is limited to infiltration with neutrophils, which become fragmented as they follow the vessel wall (leukocytoclasia). The term leukocytoclastic angiitis is given to such lesions, most commonly found in postcapillary venules (Fig. 12-22) . Immunoglobulins and complement components may be present in the vascular lesions of the skin, especially if these are examined within 24 hours of development, but in general there is a paucity of immunoglobulin demonstrable by immunofluorescence microscopy ( pauci-immune injury). Clinical Features.
Greater than 80% of patients have ANCA, most often p-ANCA. Most patients with isolated cutaneous vasculitis respond well simply to removal of the offending agent, but those with systemic disease may develop organ failure unless treated. Small vessel vasculitis may also appear in distinct diseases, including Henoch-Schonlein purpura, essential mixed cryoglobulinemia, and certain connective tissue disorders, and associated with malignancy. They are discussed with the specific entities elsewhere in this book. ANCA are usually not present. In allergic granulomatosis and angiitis (the Churg-Strauss syndrome),
522
Figure 12-22 Leukocytoclastic vasculitis in a skin biopsy showing fragmentation of neutrophil nuclei in and around vessel walls. (Courtesy of Scott Granter, MD, Brigham and Women's Hospital, Boston, MA.)
the vascular lesions may be histologically identical to those of classic polyarteritis nodosa and microscopic polyangiitis. There is a strong association, however, with allergic rhinitis, bronchial asthma, and eosinophilia. Vessels in the lung, heart, spleen, peripheral nerves, and skin are frequently involved by intravascular and extravascular granulomas, and infiltration of vessels and perivascular tissues by eosinophils is striking. Severe renal disease is infrequent. Coronary arteritis and myocarditis are the principal causes of morbidity and mortality. p-ANCA are present in 70% of patients.
WEGENER GRANULOMATOSIS
Wegener granulomatosis is a necrotizing vasculitis characterized by the triad of (1) acute necrotizing granulomas of the upper respiratory tract (ear, nose, sinuses, throat), the lower respiratory tract (lung), or both; (2) focal necrotizing or granulomatous vasculitis affecting small to medium-sized vessels (e.g., capillaries, venules, arterioles, and arteries), most prominent in the lungs and upper airways but affecting other sites as well; and (3) renal disease in the form of focal or necrotizing, often crescentic, glomerulitis. [67] Some patients who do not manifest the full triad are said to have limited Wegener granulomatosis, in which the kidneys are unaffected and the involvement is restricted to the respiratory tract. Men are affected somewhat more often than women, at an average age of about 40 years. Pathogenesis.
The striking resemblance to polyarteritis nodosa and serum sickness suggests that Wegener granulomatosis may represent some form of hypersensitivity, possibly to an inhaled infectious or other environmental agent, but this is unproved. Immune complexes have been seen in the glomeruli and vessel walls in occasional patients. The presence of granulomas and dramatic response to immunosuppressive therapy also strongly suggest an immunologic mechanism, perhaps of the cell-mediated type. c-ANCA are present in the serum in 90% of patients with active generalized disease, and this appears to be a good marker for disease activity. During treatment, a rising titer of c-ANCA suggests a relapse; most patients in remission have a negative test, or the titer falls significantly. MORPHOLOGY.
Morphologically the upper respiratory tract lesions range from inflammatory sinusitis resulting from the development of mucosal granulomas to ulcerative lesions of the nose, palate, or pharynx, rimmed by necrotizing granulomas and accompanying vasculitis. In the lungs, dispersed focal necrotizing granulomas may coalesce to produce nodules that may undergo cavitation. Microscopically the granulomas reveal a geographic pattern of necrosis rimmed by lymphocytes, plasma cells, macrophages, and variable numbers of giant cells. In association with such lesions, there is a necrotizing or granulomatous vasculitis of small and sometimes larger arteries and veins (Fig. 12-23) . Almost identical with those of the acute phase of PAN, these lesions often contain granulomas, which may be within, adjacent to, or clearly separated from the vessel wall. These areas are generally surrounded by a zone of fibrolastic proliferation with giant cells and leukocytic infiltrate and may become cavitary creating a more than superficial resemblance to a tubercle. Thus, the major pathologic differential is mycobacterial or fungal infection. Lesions may ultimately undergo progressive fibrosis and organization.
Figure 12-23 Wegener granulomatosis. There is inflammation (vasculitis) of a small artery along with adjacent granulomatous inflammation, in which epithelioid cells and giant cells ( arrows) can be seen. (Courtesy of Sid Murphree, MD, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
523
The renal lesions are of two types (Chapter 21) . In milder forms or early in the disease, there is acute focal proliferation and necrosis in the glomeruli, with thrombosis of isolated glomerular capillary loops (focal necrotizing glomerulonephritis). More advanced glomerular lesions are characterized by diffuse necrosis, proliferation, and crescent formation (crescentic glomerulonephritis). Patients with focal lesions may have only hematuria and proteinuria responsive to therapy, whereas those with diffuse disease can develop rapidly progressive renal failure. Clinical Features.
The peak incidence is in the forties. Typical clinical features include persistent pneumonitis with bilateral nodular and cavitary infiltrates (95%), chronic sinusitis (90%), mucosal ulcerations of the nasopharynx (75%), and evidence of renal disease (80%). Other features include skin rashes, muscle pains, articular involvement, mononeuritis or polyneuritis, and fever. Untreated, the course of the disease is malignant; 80% of patients die within 1 year. When the diagnosis is established, appropriate therapy (i.e., immunosuppressive drugs, cyclophosphamide, possibly prednisone, and sometimes antibacterial drugs) produces a gratifying response in most patients, with only occasional relapses. Sometimes difficult to differentiate from Wegener granulomatosis is a condition called lymphomatoid granulomatosis, characterized by pulmonary infiltration by nodules of lymphoid and plasmacytoid cells, often with cellular atypia. Although these infiltrates invade vessels, giving the histologic appearance of a vasculitis, they do not constitute a true vasculitis. About one third of patients eventually show similar lesions in the kidneys, liver, brain, and other organs. Lymphomatoid granulomatosis probably represents an evolving lymphoproliferative disorder because up to 50% develop a lymphoid malignancy, most commonly non-Hodgkin lymphoma. THROMBOANGIITIS OBLITERANS (BUERGER DISEASE)
Thromboangiitis obliterans ( Buerger disease) is a distinctive disease characterized by segmental, thrombosing, acute and chronic inflammation of medium-sized and small arteries, principally the tibial and radial arteries and sometimes secondarily extending to veins and nerves of the extremities. [68] The condition had occurred almost exclusively in men who were heavy cigarette smokers. There has been an increase in reported cases in women, probably reflecting increases in smoking by women in the past several
decades. Buerger disease begins before the age of 35 years in most patients and before 20 years in some. Buerger disease often leads to vascular insufficiency. The relationship to cigarette smoking is one of the most consistent aspects of this disorder, and most patients show hypersensitivity to intradermally injected tobacco extracts. Several possibilities have been postulated for this association, including direct endothelial cell toxicity induced by or hypersensitivity to some tobacco products. There is an increased prevalence of the human leukocyte antigens-A9 and HLA-B5 in these patients, and the condition is far more common in Israel, Japan, and India than in the United States and Europe, all of which hints at genetic influences. MORPHOLOGY.
Thromboangiitis obliterans is characterized by sharply segmental acute and chronic vasculitis of medium-sized and small arteries with secondary spread to contiguous veins and nerves. Often the vascular supply to the extremities, upper as well as lower, is affected. By contrast, atherosclerosis affects predominantly the larger arteries, mostly those in the lower extremities. Microscopically acute and chronic inflammation permeates the arterial walls, accompanied by thrombosis of the lumen, which may undergo organization and recanalization. Characteristically the thrombus contains small microabscesses marked by a central focus of neutrophils surrounded by granulomatous inflammation (Fig. 12-24) . Clinical Features.
The early manifestations are a superficial nodular phlebitis, cold sensitivity of the Raynaud type (see later) in the hands, and pain in the instep of the foot induced by exercise (so-called instep claudication). In contrast to the insufficiency caused by atherosclerosis, in Buerger disease the insufficiency tends to be accompanied by severe pain, even at rest, related undoubtedly to the neural involvement. Chronic ulcerations of the toes, feet, or fingers may appear, perhaps followed in time by frank gangrene. Abstinence from cigarette smoking in the early stages of the disease often brings dramatic relief from further attacks.
Figure 12-24 Thromboangiitis obliterans (Buerger disease). The lumen is occluded by a thrombus containing two abscesses ( arrows).
The vessel wall is infiltrated with leukocytes.
524
VASCULITIS ASSOCIATED WITH OTHER DISORDERS
Vasculitis may sometimes be associated with an underlying disorder, such as an immunologic connective tissue disease, a malignancy, or systemic illnesses such as mixed cryoglobulinemia and Henoch-Schonlein purpura. Usually of the hypersensitivity
angiitis pattern, it may resemble classic polyarteritis nodosa in some cases. Of the connective tissue disorders, rheumatoid arthritis and systemic lupus erythematosus, as pointed out earlier, commonly manifest a vasculitis (Fig. 12-25) . Rheumatoid vasculitis usually affects small and medium-sized arteries in multiple organs and may thereby result in life-threatening visceral infarction but also may cause a clinically significant aortitis. [69] It occurs predominantly after long-standing rheumatoid arthritis in patients who also exhibit rheumatoid nodules, hypocomplementemia, and high titers of rheumatoid factor. Malignancies associated with vasculitis are commonly of the lymphoproliferative type. INFECTIOUS ARTERITIS
Localized arteritis is most frequently caused by the direct invasion of infectious agents--usually bacteria or fungi, particularly aspergillosis and mucormycosis. Vascular lesions frequently accompany bacterial pneumonia or occur adjacent to caseous tuberculous reactions, in the neighborhood of abscesses, or in the superficial cerebral vessels in cases of meningitis. Much less commonly, they arise from the hematogenous spread of bacteria, in cases of septicemia or embolization from infective endocarditis. Vascular infections may weaken the arterial wall and result in the formation of a mycotic aneurysm (see later). Clinically, infectious arteritis may be important on several counts. By inducing thrombosis, it adds an element of infarction to tissues that are already the seat of an inflammatory reaction and worsen the initial infection. In bacterial meningitis, for example, inflammation of the superficial
Figure 12-25 Vasculitis with fibrinoid necrosis in a patient with active systemic lupus erythematosus.
vessels of the brain may predispose to vascular thromboses, with subsequent infarction of the brain substance and extension of the subarachnoid infection into the brain tissue. Raynaud Disease Raynaud disease refers to paroxysmal pallor or cyanosis of the digits of the hands or feet and infrequently the tips of the nose or ears (acral parts). It is caused by intense vasospasm of local small arteries or arterioles, principally of young, otherwise healthy women. Characteristically the fingers change color in the sequence white, blue, red. No organic changes are present in the arterial walls except late in the course, when intimal proliferation can appear. Of uncertain cause, Raynaud disease reflects an exaggeration of normal central and local vasomotor responses to cold or emotion. The course of Raynaud disease is usually benign, but long-standing, chronic cases can have atrophy of the skin, subcutaneous tissues, and muscles. Ulceration and ischemic gangrene are rare. In contrast, Raynaud phenomenon refers to arterial insufficiency of the extremities
secondary to the arterial narrowing induced by various conditions, including systemic lupus erythematosus, progressive systemic sclerosis (scleroderma), atherosclerosis, or Buerger disease (see earlier). Raynaud phenomenon may be the first manifestation of any of these conditions. Aneurysms and Dissection An aneurysm is a localized abnormal dilation of a blood vessel that occurs most commonly in the aorta or the heart. Aneurysms can be either true or false. A true aneurysm is bounded by generally complete but often attenuated arterial wall components. The blood within a true aneurysm remains within the confines of the circulatory system. Atherosclerotic, syphilitic, and congenital vascular aneurysms and the typical left ventricular aneurysm that can follow a myocardial infarction are of this type. In contrast, a false aneurysm (also called pseudoaneurysm) is an extravascular hematoma that communicates with the intravascular space (thus a pulsating hematoma). The vascular wall has been breached, and the external wall of the aneurysmal sac consists of only outer arterial layers, perivascular tissue, or blood clot. A leak at the junction ( anastomosis) of a vascular graft with a natural artery produces this type of lesion. Arterial dissections, usually of the aorta (sometimes called dissecting aneurysms), arise when blood enters the wall of the artery, dissecting between its layers and creating a cavity within the vessel wall itself. The two most important causes of true aortic aneurysms are atherosclerosis and cystic medial degeneration, but any vessel may be affected by a wide variety of disorders that weaken arterial walls, including congenital defects, infections (mycotic aneurysms), syphilis, trauma (traumatic aneurysms or arteriovenous aneurysms), or systemic diseases. Arterial aneurysms can also be caused by vascular immunologic injury, as in polyarteritis nodosa, Kawasaki syndrome, and other vasculitides; trauma leading to arteriovenous
525
aneurysms; or congenital defects, such as that producing berry aneurysms (Chapter 30) . Infection of a major artery that weakens its wall is called a mycotic aneurysm. A mycotic aneurysm can be either true or false; thrombosis and rupture are possible complications. Mycotic aneurysms may originate (1) at the site of sticking of a dislodged septic embolus within a vessel, usually as a complication of infective endocarditis; (2) as an extension of an adjacent suppurative process; or (3) by circulating organisms directly infecting the arterial wall. Aneurysms are often classified by macroscopic shape and size. Saccular aneurysms are essentially spherical (involving only a portion of the vessel wall) and vary in size 5 up to 20 cm in diameter, often partially or completely filled by thrombus. A fusiform aneurysm is a gradual, progressive dilation of the complete circumference of the vessel. Fusiform aneurysms vary in diameter (up to 20 cm) and in length; many involve the
entire ascending and transverse portions of the aortic arch, whereas others may involve large segments of the abdominal aorta or even the iliacs. These shapes, however, are not specific for any disease or clinical manifestations. ABDOMINAL AORTIC ANEURYSMS
Atherosclerosis, the most frequent cause of aneurysms, causes arterial wall thinning through medial destruction secondary to plaque that originates in the intima. Atherosclerotic aneurysms most frequently occur in the abdominal aorta (abdominal aortic aneurysm), but the common iliac arteries, the arch, and descending parts of the thoracic aorta can be involved. MORPHOLOGY.
Abdominal aortic aneurysms are usually positioned below the renal arteries and above the bifurcation of the aorta (Fig. 12-26) . Abdominal aortic aneurysms take the form of saccular (balloon-like), cylindroid, or fusiform swellings, sometimes up to 15 cm in greatest diameter and of variable length (up to 25 cm). As would be expected, at these sites there is severe complicated atherosclerosis, which destroys the underlying tunica media and thus weakens the aortic wall. Mural thrombus frequency is found within the aneurysmal sac. In saccular forms, the thrombus may completely fill the outpouching. The elongated fusiform or cylindroid patterns more often have layers of mural thrombus that only partially fill the dilation. Occasionally the aneurysm may affect the origins of the renal, superior, and inferior mesenteric arteries, either by involving these vessels directly or by narrowing or occluding their ostia with mural thrombi. Not infrequently, they are accompanied by smaller fusiform or saccular dilations of the iliac arteries. The aneurysm often contains atheromatous ulcers covered by mural thrombi, with consequent thinning and destruction of the media, prime sites for the formation
Figure 12-26 Gross photographs of an abdominal aortic aneurysm that ruptured. A , External view of the large aneurysm; the rupture site is indicated by the arrow. B , Opened view with the location of the rupture tract indicated by a probe. The wall of the aneurysm is
exceedingly thin and the lumen is filled by a large quantity of layered but largely unorganized thrombus.
of atheroemboli that can lodge in the vessels of the kidneys or lower extremities. Two variants of abdominal aortic aneurysm merit special mention. Inflammatory abdominal aneurysms are characterized by dense periaortic fibrosis containing an abundant lymphoplasmacytic inflammatory reaction with many macrophages and often giant cells. [70] Their cause is uncertain. Mycotic abdominal aneurysms are atherosclerotic abdominal aortic aneurysms that have become infected by deposition of circulating organisms in the wall, particularly in bacteremia from a primary Salmonella gastroenteritis. In such cases, suppuration further destroys the media, potentiating rapid dilation and rupture.
Pathogenesis.
Atherosclerosis is a major cause of abdominal aortic aneurysms, but other factors contribute to aneurysm formation in this and other sites. [71] Abdominal aortic aneurysms rarely develop before the age of 50 and are much more common in men. Aortic aneurysms have been shown to be familial--beyond the familial and genetic predisposition to atherosclerosis or hypertension. As discussed subsequently in the section on Marfan syndrome and dissecting aneurysms, genetic defects in structural components of the aorta can themselves produce aneurysms and dissections. It has been postulated that subtle defects in a connective tissue component responsible for the strength of blood vessels could provide a particularly susceptible
526
substrate on which atherosclerosis or hypertension, or both, could act to weaken the aortic wall. [72] [73] There is also evidence that matrix metalloproteinases (MMPs) and plasminogen activators, which degrade extracellular matrix (ECM) (Chapter 4) , contribute to aneurysm formation. [74] Clinical Course.
The clinical consequences of abdominal aortic aneurysms depend primarily on their location and size. They give rise to clinical symptoms and recognition by various effects: [75 ]
Rupture into the peritoneal cavity or retroperitoneal tissues with massive or fatal hemorrhage Occlusion of a branch vessel by either direct pressure or mural thrombus formation, particularly of the iliac, renal, mesenteric, or vertebral branches that supply the spinal cord Embolism from the atheroma or mural thrombus Impingement on an adjacent structure, such as compression of a ureter or erosion of vertebrae Presentation as an abdominal mass (often palpably pulsating) that simulates a tumor Rupture is the most feared consequence, and the risk is directly related to the size of the aneurysm. It varies from about 2% for a small abdominal aortic aneurysm (400,000 per year). Bypasses are done using grafts of either autologous reversed saphenous vein or internal mammary artery (usually the left internal mammary artery is used owing to proximity to the heart). Although most patients do well for extended periods after their surgery, many develop late recurrence of symptoms because of either graft occlusion or progression of atherosclerosis in their native coronary arteries distal to the grafts. The long-term patency of saphenous vein grafts is 50% at 10 years, owing to pathologic changes, including thrombosis (usually occurs early), intimal thickening (which usually occurs several months to several years postoperatively), and atherosclerosis in the
Figure 12-37 Anastomotic hyperplasia at the distal anastomosis of a synthetic femoropopliteal graft. A , Angiogram demonstrating constriction ( arrow ). B , Photomicrograph demonstrating expanded polytetrafluoroethylene graft ( arrow ) with prominent intimal proliferation and a very small residual lumen ( asterisk). ( A courtesy of Anthony D. Whittemore, MD, Brigham and Women's Hospital, Boston, MA.)
540
graft, sometimes with superimposed plaque rupture, thrombi, or aneurysms (usually more than 2 to 3 years). [91] In contrast, the internal mammary artery has a greater than 90% patency at 10 years. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
REFERENCES 1.
Pober J, Cotran RS: Cytokines and endothelial cell biology. Physiol Rev 70:427, 1990.
2.
Davies MG, Hagen PO: Pathology of intimal hyperplasia. Br J Surg 81:1254, 1994.
Okamoto E, et al: Diversity of the synthetic-state smooth-muscle cells proliferating in mechanically and hemodynamically injured rabbit arteries. Lab Invest 74:120, 1996. 3.
4.
Allaire E, Clowes AW: The intimal hyperplastic response. Ann Thorac Surg 64:S38, 1997.
Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, WB Saunders, 1989, p 33. 5.
Braunwald E: Cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities. N Engl J Med 337:1360, 1997. 6.
Amarenco P, et al: Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 331:1474, 1994. 7.
Mintz GS, et al: Determinants and correlates of target lesion calcium in coronary artery disease: a clinical, angiographic and intravascular ultrasound study. J Am Coll Cardiol 29:268, 1997. 8.
Rumberger JA, et al: Electron beam computed tomography and coronary artery disease: scanning for coronary artery calcification. Mayo Clin Proc 71:369, 1996. 9.
Berenson GS, et al: Atherosclerosis of the aorta and coronary arteries and cardiovascular risk factors in persons aged 6 to 30 years and studied at necropsy (The Bogalusa Heart Study). Am J Cardiol 70:851, 1992. 10.
Stary HO, et al: A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. Circulation 92:1355, 1995. 11.
12.
Kannel WB, Wilson PWF: An update on coronary risk factors. Med Clin North Am 79:951, 1995.
Neaton JD, Wentworth D: Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease: overall findings and differences by age for 316,099 white men. Arch Intern Med 152:56, 1992. 13.
14.
Strong JP: The natural history of atherosclerosis in childhood. Ann N Y Acad Sci 623:9, 1991.
15.
Grodstein F, et al: Postmenopausal hormone therapy and mortality. N Engl J Med 336:1769, 1997.
16.
Liebermann EH, et al: Estrogen improves endothelium-dependent, flow-mediated vasodilation in
post-menopausal women. Ann Intern Med 121:936, 1994. 17.
Dammerman M, Breslow JL: Genetic basis of lipoprotein disorders. Circulation 91:505, 1995.
Kuivenhoven JA, et al: The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. N Engl J Med 338:86, 1998. 18.
19.
Gotto AM: Cholesterol management in theory and practice. Circulation 96:4424, 1997.
Pedersen TR, et al: Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344:1383, 1994. 20.
Sacks FM, et al: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 335:1001, 1996. 21.
Shepard J, et al: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 333:1301, 1995. 22.
23.
Breslow JL: Mouse models of atherosclerosis. Science 272:685, 1996.
Schmidt EB, Dyerberg J: Omega-3 fatty acids: current status in cardiovascular medicine. Drugs 47:405, 1994. 24.
Ascherio A, et al: Dietary intake of marine n-3 fatty acids, fish intake, and the risk of coronary disease among men. N Engl J Med 332:977, 1995. 25.
Hu FB, et al: Dietary fat intake and the risk of coronary heart disease in women. N Engl J Med 337:1491, 1997. 26.
SHEP Cooperative Research Group: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program. JAMA 265:3255, 1991. 27.
McCully KS: Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol 56:111, 1969. 28.
29.
Welch GN, Loscalzo J: Homocysteine and atherothrombosis. N Engl J Med 338:1042, 1998.
30.
Rimm EB, et al: Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart
disease among women. JAMA 279:359, 1998. Ridker PM, et al: Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. New Engl J Med 336:973, 1997. 31.
32.
Nachman RL: Lipoprotein(a): molecular mischief in the microvasculature. Circulation 96:2485, 1997.
Thun J, et al: Alcohol consumption and mortality among middle-aged and elderly U.S. adults. N Engl J Med 337:1705, 1997. 33.
34.
Ross R: The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362:801, 1993.
Cybulsky MI, Gimbrone MA: Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 251:788, 1991. 35.
O'Brien KD, et al: Neovascular expression of E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 in human atherosclerosis and their relation to intimal leukocyte content. Circulation 93:672, 1996. 36.
Gimbrone MA, Nagel T, Topper JN: Biomechanical activation: an emerging paradigm in endothelial adhesion biology. J Clin Invest 99:1809, 1997. 37.
38.
Steinberg D: Oxidative modification of LDL and atherogenesis. Circulation 95:1062, 1997.
Treasure CB, et al: Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 332:481, 1995. 39.
Anderson TJ, et al: The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med 332:488, 1995. 40.
Murry CE, et al: Monoclonality of smooth muscle cells in human atherosclerosis. Am J Pathol 151:697, 1997. 41.
Libby P, et al: Roles of infectious agents in atherosclerosis and restenosis: an assessment of the evidence and need for future research. Circulation 96:4095, 1997. 42.
Weck KE, et al: Murine gamma-herpesvirus 68 causes severe large-vessel arteritis in mice lacking interferon-gamma responsiveness: a new model for virus-induced vascular disease. Nat Med 3:1346, 1997. 43.
44.
Buja LM: Does atherosclerosis have an infectious etiology? Circulation 94:872, 1996.
Gupta S, et al: Elevated Chlamydia pneumoniae antibodies, cardiovascular events, and azithromycin in male survivors of myocardial infarction. Circulation 96:404, 1997. 45.
Berenson GS, et al: Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. N Engl J Med 338:1650, 1998. 46.
Strong JP: Atherosclerotic lesions: natural history, risk factors, and topography. Arch Pathol Lab Med 116:1268, 1992. 47.
Antiplatelet Trialists' Collaboration: Collaborative overview of randomised trials of antiplatelet therapy: I. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ 308:81, 1994. 48.
Kaplan NM: Systemic hypertension: mechanisms and diagnosis. In Braunwald E. (ed): Heart Disease, 5th ed. Philadelphia, WB Saunders, 1997, p 807. 49.
Lijnen P: Alterations in sodium metabolism as an etiological model for hypertension. Cardiovasc Drugs Ther 9:377, 1995. 50.
51.
Cowley AW, Roman RJ: The role of the kidney in hypertension. JAMA 275:1581, 1996.
52.
Hingorani AD, Brown MJ: Identifying the genes for human hypertension. Nephrol Dial Transplant
11:575, 1996. 53.
Lifton RP: Molecular genetics of human blood pressure variation. Science 272:676, 1996.
54.
Thibonnier M, Schork NJ: The genetics of hypertension. Curr Opin Genet Dev 5:362, 1995.
55.
Jennette JC, Falk RJ: Small-vessel vasculitis. N Engl J Med 337:1512, 1997. 541
Allen NB, Bressler PB: Diagnosis and treatment of the systemic and cutaneous necrotizing vasculitis syndromes. Med Clin North Am 81:243, 1997. 56.
57.
Lee WM: Hepatitis B virus infection. N Engl J Med 337:1733, 1997.
Cotran RS, Pober JS: Recent insights into the mechanisms of vascular injury: implications for the pathogenesis of vasculitis. In Simionescu N, Simionescu M (eds): Endothelial Cell Dysfunctions. New York, Plenum Press, 1992, p 183. 58.
Gross WL: Antineutrophil cytoplasmic autoantibody testing in vasculitides. Rheum Dis Clin North Am 21:987, 1995. 59.
Jennette JC, Falk RJ: Update on the pathobiology of vasculitis. In Schoen FJ, Gimbrone MA (eds): Cardiovascular Pathology: Clinicopathologic Correlations and Pathogenetic Mechanisms. Baltimore, Williams & Wilkins, 1995, p 156. 60.
Mayet WJ, Helmreich-Becker I, Buschenfelde KHM: The pathophysiology of anti-neutrophil cytoplasmic antibodies (ANCA) and their clinical relevance. Crit Rev Oncol Hematol 23:151, 1996. 61.
Jennette JC, et al: Nomenclature of systemic vasculitides: the proposal of an international consensus conference. Arthritis Rheum 37:187, 1994. 62.
63.
Brack A, et al: Giant cell vasculitis is a T cell-dependent disease. Mol Med 3:350, 1997.
64.
Hall S, et al: Takayasu arteritis: a study of 32 North American patients. Medicine 64:89, 1985.
65.
Rowley AH, et al: Kawasaki syndrome. Curr Probl Pediatr 21:387, 1991.
Naoe S, et al: Kawasaki disease: with particular emphasis on arterial lesions. Acta Pathol Jpn 41:785, 1991. 66.
Hoffman GS, et al: Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 116:488, 1992. 67.
68.
Joyce JW: Buerger's disease (thromboangiitis obliterans). Rheum Dis Clin North Am 16:463, 1990.
Gravallese EM, et al: Rheumatoid aortitis: a rarely recognized but clinically significant entity. Medicine 68:95, 1989. 69.
Sterpetti AV, et al: Inflammatory aneurysms of the abdominal aorta: incidence, pathologic, and etiologic considerations. J Vasc Surg 9:643, 1989. 70.
Patel MI, et al: Current views on the pathogenesis of abdominal aortic aneurysms. J Am Coll Surg 181:371, 1995. 71.
Kuivaniemi H, et al: Genetic causes of aortic aneurysms: Unlearning at least part of what the textbooks say. J Clin Invest 88:1441, 1991. 72.
Prockop D: Mutations in collagens as a cause of connective tissue diseases. N Engl J Med 326:540, 1992. 73.
Knox JB, Sukhova GK, Whittemore AD, Libby P: Evidence for altered balance between matrix metalloproteinases and their inhibitors in human aortic diseases. Circulation 95:205, 1997. 74.
75.
Ernst CB: Abdominal aortic aneurysms. N Engl J Med 328:1167, 1993.
Cigarra JE, et al: Diagnostic imaging in the evaluation of suspected aortic dissection. N Engl J Med 328:35, 1993. 76.
77.
Callam MJ: Epidemiology of varicose veins. Br J Surg 81:167, 1994.
Rosen SB, Sturk A: Activated protein C resistance--a major risk factor for thrombosis. Eur J Clin Chem Clin Biochem 35:501, 1997. 78.
79.
Weinmann EE, Salzman EW: Deep-vein thrombosis. N Engl J Med 331:1630, 1994.
Calonje E, Fletcher CDM: Tumors of blood vessels and lymphatics. In CDM Fletcher (ed): Diagnostic Histopathology of Tumors. New York, Churchill Livingstone, 1995, p 43. 80.
Shovlin CL, et al: Characterization of endoglin and identification of novel mutations in hereditary hemorrhagic telangiectasia. Am J Hum Genet 61:68, 1997. 81.
82.
Folkman J, D'Amore PA. Blood vessel formation: what is its molecular basis? Cell 87:1153, 1996.
Relman DA, et al: The agent of bacillary angiomatosis: an approach to the identification of uncultured pathogens. N Engl J Med 323:1573, 1990. 83.
Koehler JE, et al: Molecular epidemiology of bartonella infections in patients with bacillary angiomatosis-pelosis. N Engl J Med 337:1876, 1997. 84.
Kemeny L, et al: Kaposi's sarcoma-associated herpesvirus/human herpesvirus-8: a new virus in human pathology. J Am Acad Dermatol 37:107, 1997. 85.
Waller BF, et al: Coronary artery and saphenous vein graft remodeling: a review of histologic findings after various interventional procedures--part IV. Clin Cardiol 19:960, 1996. 86.
87.
Gottsauner-Wolf M, et al: Restenosis: an open file. Clin Cardiol 19:347, 1996.
Landzberg BR, et al: Pathophysiology and pharmacological approaches for prevention of coronary artery restenosis following coronary artery balloon angioplasty and related procedures. Prog Cardiovasc 88.
Dis 34:361, 1997. 89.
Bittl JA: Advances in coronary angioplasty. N Engl J Med 335:1290, 1996.
90.
Zdrahala RJ: Small caliber vascular grafts: Part I. state of the art. J Biomater Appl 10:309, 1996.
91.
Nwasokwa ON: Coronary artery bypass graft disease. Ann Intern Med 123:528, 1995.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 13 - The Heart NORMAL HEART Myocardium Blood Supply Valves Effects of Aging on the Heart Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 13 - The Heart PRINCIPLES OF CARDIAC DYSFUNCTION Heart Failure CARDIAC HYPERTROPHY: PATHOPHYSIOLOGY AND PROGRESSION TO FAILURE LEFT-SIDED HEART FAILURE MORPHOLOGY Lungs Kidneys Brain RIGHT-SIDED HEART FAILURE MORPHOLOGY Liver and Portal System Drainage Kidneys Brain Pleural and Pericardial Spaces Subcutaneous Tissues Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
PRINCIPLES OF CARDIAC DYSFUNCTION Although many diseases can involve the heart and blood vessels, [5] [6] cardiovascular dysfunction results from five principal mechanisms: 1. Failure of the pump itself: In the most frequent circumstance, damaged muscle contracts weakly or inadequately, and the chambers cannot empty properly. In some conditions, however, the muscle cannot relax sufficiently. 2. An obstruction to flow, owing to a lesion preventing valve opening or otherwise causing increased ventricular chamber pressure (e.g., aortic valvular stenosis, systemic hypertension, or aortic coarctation): This overworks the chamber behind the obstruction. 3. Regurgitant flow (e.g., mitral or aortic valvular regurgitation) that causes some of the output from each contraction to reflux backward: This necessarily adds a volume workload on the ventricle. 4. Disorders of cardiac conduction (e.g., heart block) or arrhythmias owing to uncoordinated generation of impulses (e.g., ventricular fibrillation): These lead to nonuniform and inefficient contractions of the muscular walls. 5. Disruption of the continuity of the circulatory system (e.g., gunshot wound through the thoracic aorta): This permits blood to escape. Heart Failure The above-listed abnormalities often culminate in heart failure, an extremely common result of many forms of heart disease. In heart failure, often called congestive heart failure, the heart is unable to pump blood at a rate commensurate with the requirements of the metabolizing tissues or can do so only from an elevated filling pressure. Although usually caused by a slowly developing deficit in myocardial contraction, a similar clinical syndrome is present in some patients with heart failure caused by conditions in which the normal heart is suddenly presented with a load that exceeds its capacity or in which ventricular filling is impaired. Congestive heart failure is a common and often recurrent condition with a poor prognosis (mortality of more than 50% in less than 5 years) that is the underlying or contributing cause of death of an estimated 300,000 individuals annually in the United States and for which 2 million individuals are currently being treated. It is the leading discharge diagnosis in hospitalized patients over 65 years of age. The cardiovascular system acts to maintain arterial pressure and perfusion of vital organs by responding to excessive hemodynamic burden or disturbance in myocardial
547
contractility by a number of mechanisms. [7] The most important are as follows: The Frank-Starling mechanism, in which the increased preload of dilation helps to sustain cardiac performance by enhancing contractility Myocardial hypertrophy with or without cardiac chamber dilation, in which the mass of contractile tissue is augmented Activation of neurohumoral systems, especially (1) release of the neurotransmitter norepinephrine by adrenergic cardiac nerves (which increases heart rate and augments myocardial contractility), (2) activation of the renin-angiotensin-aldosterone system, and (3) release of atrial natriuretic peptide These adaptive mechanisms may be adequate to maintain the overall pumping performance of the heart at relatively normal levels, but their capacity to sustain cardiac performance may ultimately be exceeded. Most instances of heart failure are the consequence of progressive deterioration of myocardial contractile function ( systolic dysfunction), as often occurs with ischemic injury, pressure or volume overload, or dilated cardiomyopathy (DCM). [8] The most frequent specific causes are hypertension and IHD (to be discussed subsequently). Sometimes, however, failure results from an inability of the heart chamber to relax, expand, and fill sufficiently during diastole to accommodate an adequate ventricular blood volume ( diastolic dysfunction), as can occur with massive left ventricular hypertrophy, myocardial fibrosis, deposition of amyloid, or constrictive pericarditis. [9] Whatever its basis, congestive heart failure is characterized by diminished cardiac output (sometimes called forward failure) or damming back of blood in the venous system (so-called backward failure), or both. CARDIAC HYPERTROPHY: PATHOPHYSIOLOGY AND PROGRESSION TO FAILURE
In many pathologic states, the onset of heart failure is preceded by cardiac hypertrophy, the compensatory response of the myocardium to increased mechanical work (see later) or trophic signals (e.g., hyperthyroidism through stimulation of beta-adrenergic receptors). These stimuli increase the rate of protein synthesis, the amount of protein in each cell, the size of myocytes, the number of sarcomeres and mitochondria, and consequently the mass and size of the heart. The response is also accompanied by selective up-regulation of several immediate early response genes and embryonic forms of contractile and other proteins (Chapter 2) . Because adult cardiac myocytes cannot divide, augmentation of myocyte number ( hyperplasia) cannot occur. The pattern of hypertrophy reflects the nature of the stimulus. Pressure-overloaded ventricles (e.g., hypertension or aortic stenosis) develop pressure (also called concentric) hypertrophy of the left ventricle, with an increased wall thickness and a normal to reduced cavity diameter. In contrast, volume-overloaded ventricles (e.g., mitral or aortic valve regurgitation) develop hypertrophy accompanied by dilation with increased ventricular diameter (Fig. 13-1) (Figure Not Available) . Moreover, as emphasized by Figure 13-1 (Figure Not Available) , wall thickness does not necessarily correlate with the pathologic state; despite its increased mass, a heart in which both
hypertrophy and dilation has occurred may have increased, decreased, or normal wall thickness. The extent of hypertrophy varies for different underlying causes. Heart weight usually ranges to 600 gm (up to approximately two times normal) in pulmonary hypertension and IHD; to 800 gm (up to two to three times normal) in systemic hypertension, aortic stenosis, mitral regurgitation, Figure 13-1 (Figure Not Available) Left ventricular hypertrophy. A , Pressure hypertrophy due to left ventricular outflow obstruction. The left ventricle is on the lower right in this apical four-chamber view of the heart. B , Altered cardiac configuration in left ventricular hypertrophy without and with dilation, viewed in transverse heart sections. Compared with a normal heart (center), the pressure hypertrophied hearts ( left and in A ) have increased mass and a thick left ventricular wall, but the hypertrophied and dilated heart (right) has increased mass but a diminished wall thickness. (From Edwards WD: Cardiac anatomy and examination of cardiac specimens. In Emmanouilides GC, et al [eds]: Moss and Adams' Heart Disease in Infants, Children, and Adolescents: Including the Fetus and Young Adults, 5th ed. Baltimore, Williams & Wilkins, 1995, p 86.)
548
or DCM; and to 1000 gm (three or more times normal) in aortic regurgitation or HCM. Hearts weighing more than 1000 gm are rare. The structural, biochemical, and molecular basis for myocardial contractile failure is obscure in many cases. Nevertheless, in some instances (e.g., myocardial infarction), there is obvious death of myocytes and loss of vital elements of the pump; consequently, noninfarcted regions of cardiac muscle are overworked. In contrast, in valvular heart disease, increased pressure or volume work affects the myocardium globally. The increased myocyte size that occurs in cardiac hypertrophy is usually accompanied by decreased capillary density, increased intercapillary distance, and deposition of fibrous tissue. The molecular and cellular changes in hypertrophied hearts that initially mediate enhanced function may contribute to the development of heart failure. [7] [10] With prolonged hemodynamic overload, gene expression is altered, leading to re-expression of a pattern of protein synthesis analogous to that seen in fetal cardiac development; other changes are analogous to events that occur during mitosis of normally proliferating cells (Chapter 2) . Thus, proteins related to contractile elements, excitation-contraction coupling, and energy use may be significantly altered through production of different isoforms that either may be less functional than normal or may be reduced or increased in amount. Alterations of intracellular handling of calcium ions may also contribute to impaired contraction and relaxation. [11] Additional proposed mechanisms potentiating congestive heart failure include reduced adrenergic drive, decreased calcium availability, impaired mitochondrial function, and microcirculatory spasm. Evidence suggests that loss of myocytes because of apoptosis may contribute to progressive myocardial dysfunction in hypertrophic states. [12] Most often associated with dividing cells, apoptosis may represent an aborted response to pathophysiologic stimuli that reactivate the fetal growth program in cardiac myocytes, presumably because such
cells are no longer capable of progressing through the cell cycle to mitosis. Clearly the geometry, structure, and composition (cells and extracellular matrix) of the hypertrophied heart are not normal. Cardiac hypertrophy then constitutes a tenuous balance between adaptive characteristics (including new sarcomeres) and potentially deleterious structural, biochemical, and molecular alterations (including decreased capillary-to-myocyte ratio; increased fibrous tissue; and synthesis of abnormal, perhaps dysfunctional, proteins). It should not be surprising therefore that sustained cardiac hypertrophy often evolves to cardiac failure. The proposed sequence of initially beneficial and later harmful events in the response to increased cardiac work is summarized in Figure 13-2 . Besides predisposing to congestive heart failure, left ventricular hypertrophy is an independent risk factor for cardiac mortality and morbidity, especially for sudden death. [13] Interestingly, and in contrast to the pathologic hypertrophy just discussed, hypertrophy that is induced by regular strenuous exercise ( physiologic hypertrophy) seems to be an extension of normal growth and have minimal or no deleterious effect.
Figure 13-2 Schematic representation of the sequence of events in cardiac hypertrophy and its progression to heart failure,
emphasizing cellular and extracellular changes.
Whatever the underlying basis for congestive heart failure, a variety of compensatory mechanisms come into play when the hypertrophied heart can no longer accommodate the increased demand. Eventually, however, the compensatory mechanisms themselves constitute an added burden. Myocardial hypertrophy itself may become increasingly detrimental because of the increased metabolic requirements of the enlarged muscle mass and the increased wall tension, both major determinants of the oxygen consumption of the heart. The other major determinants are heart rate and contractility (inotropic state, or force of contraction). Ultimately the primary cardiac disease and the superimposed compensatory burdens further encroach on the myocardial reserve. Then begins the downward slide of stroke volume and cardiac output that often ends in death. At autopsy, the hearts of patients having congestive heart failure are generally characterized by increased weight, chamber dilation, and thin walls, with microscopic changes of hypertrophy, but the extent of these changes varies among patients.
549
The degree of structural abnormality does not always reflect the level of dysfunction, and it may be impossible from morphologic examination of the heart to distinguish a damaged but compensated heart from one that has decompensated. Moreover, many of the significant adaptations and morphologic changes noted in congestive heart failure are distant from the heart and are produced by the hypoxic and congestive effects of the
failing circulation on other organs and tissues. Thus, congestive heart failure represents a clinical syndrome characterized primarily by findings outside the cardiovascular system--in both forward (e.g., poor organ perfusion) and backward (pulmonary and peripheral edema) directions, to be discussed subsequently. To some extent, the right and left sides of the heart act as two distinct anatomic and functional units. Thus, left-sided and right-sided failure can occur independently. Nevertheless, because the cardiovascular system is a closed circuit, failure of one side cannot exist for long without eventually producing excessive strain on the other, terminating in global heart failure. Despite this interdependency, the clearest understanding of the pathologic physiology and anatomy of heart failure is derived from a consideration of each side separately. LEFT-SIDED HEART FAILURE
As discussed, left-sided heart failure is most often caused by (1) IHD, (2) hypertension, (3) aortic and mitral valvular diseases, and (4) nonischemic myocardial diseases. The morphologic and clinical effects of left-sided congestive heart failure primarily result from progressive damming of blood within the pulmonary circulation and the consequences of diminished peripheral blood flow. MORPHOLOGY.
Except with obstruction at the mitral valve or other processes that restrict the size of the left ventricle, this chamber is usually hypertrophied and often dilated, sometimes quite massively. Secondary enlargement of the left atrium with resultant atrial fibrillation (i.e., uncoordinated, chaotic contraction of the atrium) may either compromise stroke volume or cause blood stasis and possible thrombus formation (particularly in the appendage). A fibrillating left atrium carries an increased risk of embolic stroke. The extracardiac effects of left-sided failure are manifested most prominently in the lungs, although the kidneys and brain may also be affected. Lungs.
Pressure in the pulmonary veins mounts and is ultimately transmitted retrogradely to the capillaries and arteries. The result is pulmonary congestion and edema, with heavy, wet lungs as described in detail in Chapters 5 and 16 . It is sufficient to note here that the pulmonary changes include, in sequence, (1) a perivascular and interstitial transudate, particularly in the interlobular septa, responsible for Kerley B lines on x-ray; (2) progressive edematous widening of alveolar septa; and (3) accumulation of edema fluid in the alveolar spaces. Iron-containing proteins in edema fluid and hemoglobin from erythrocytes, which leak from congested capillaries, are phagocytosed by macrophages and converted to hemosiderin. Hemosiderin-containing macrophages in the alveoli (called siderophages or heart failure cells) denote previous episodes of pulmonary edema. These anatomic changes produce striking clinical manifestations. Dyspnea
(breathlessness), usually the earliest and the cardinal complaint of patients in left-sided heart failure, is an exaggeration of the normal breathlessness that follows exertion. With further impairment, there is orthopnea, which is dyspnea on lying down that is relieved by sitting or standing. Thus, the orthopneic patient needs to sleep while sitting upright. Paroxysmal nocturnal dyspnea is an extension of orthopnea that consists of attacks of extreme dyspnea bordering on suffocation, usually occurring at night. Cough is a common accompaniment of left-sided failure. Kidneys.
Decreased cardiac output causes a reduction in renal perfusion, which activates the renin-angiotensin-aldosterone system, inducing retention of salt and water with consequent expansion of the interstitial fluid and blood volumes. This compensatory reaction can contribute to the pulmonary edema in left-sided heart failure. Salt retention is counteracted by the release of atrial natriuretic peptide through atrial dilation, which acts to decrease excessive blood volume. If the perfusion deficit of the kidney becomes sufficiently severe, impaired excretion of nitrogenous products may cause azotemia, in this instance, prerenal azotemia (Chapter 21) . Brain.
In far-advanced congestive heart failure, cerebral hypoxia may give rise to hypoxic encephalopathy (Chapter 30) , with resultant irritability, loss of attention span, and restlessness, which may even progress to stupor and coma. RIGHT-SIDED HEART FAILURE
Isolated right-sided heart failure occurs in only a few diseases. Usually, it is a secondary consequence of left-sided failure because any increase in pressure in the pulmonary circulation incident to left-sided failure inevitably produces an increased burden on the right side of the heart. The causes of right-sided failure must then include all those that induce left-sided heart failure. Pure right-sided failure most often occurs with chronic severe pulmonary hypertension and thus is called cor pulmonale (see later) . In these cases, the right ventricle is burdened by a pressure workload owing to increased resistance within the pulmonary circulation. Hypertrophy and dilation are generally confined to the right ventricle and atrium, although bulging of the ventricular septum to the left can alter the shape of the heart and may cause dysfunction of the left ventricle. The major morphologic and clinical effects of pure right-sided
550
failure differ from those of left-sided failure in that pulmonary congestion is minimal,
whereas engorgement of the systemic and portal venous systems may be pronounced. MORPHOLOGY.
Liver and Portal System Drainage.
The liver is usually increased in size and weight ( congestive hepatomegaly), and a cut section displays prominent chronic passive congestion (see Figs. 5-3 and 19-35) . Congested red centers of the liver lobules are surrounded by paler, sometimes fatty, peripheral regions. In some instances, especially when left-sided failure is also present, the severe central hypoxia produces centrilobular necrosis along with the sinusoidal congestion. With long-standing severe right-sided cardiac failure, the central areas in time can become fibrotic, creating so-called cardiac sclerosis or cardiac cirrhosis (Chapter 19) . Right-sided heart failure also leads to elevated pressure in the portal vein and its tributaries. Congestion produces a tense, enlarged spleen ( congestive splenomegaly). Microscopically, there may be marked sinusoidal dilation. With long-standing congestion, the enlarged spleen may achieve a weight of 300 to 500 gm (normal, approximately 150 gm). Chronic edema of the bowel wall can also occur and in some patients may interfere with absorption of nutrients. In addition, abnormal accumulations of transudate in the peritoneal cavity may give rise to ascites. Kidneys.
Congestion of the kidneys is more marked with right-sided heart failure than with left-sided failure, leading to greater fluid retention, peripheral edema, and more pronounced azotemia. Brain.
Symptoms essentially identical to those described in left-sided failure may occur, representing venous congestion and hypoxia of the central nervous system. Pleural and Pericardial Spaces.
Pleural (particularly right) and pericardial effusions may appear. Pleural effusions can range from 100 ml to well over 1 liter. Large effusions can cause partial atelectasis of the corresponding lung. Subcutaneous Tissues.
Peripheral edema of dependent portions of the body, especially ankle (pedal) and pretibial edema, is a hallmark of right-sided failure. In chronically bedridden patients, the
edema may be primarily presacral. Generalized massive edema is called anasarca. Thus, the effects of pure left-sided heart failure are largely due to pulmonary congestion and edema. In contrast, respiratory symptoms may be absent or quite insignificant in right-sided failure, in which there is a systemic (and portal) venous congestive syndrome, with hepatic and splenic enlargement, peripheral edema, pleural effusion, and ascites. In many cases of frank chronic cardiac decompensation, however, the patient presents with the picture of biventricular congestive heart failure, encompassing the clinical syndromes of both right-sided and left-sided heart failure.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 13 - The Heart TYPES OF HEART DISEASE - Part 1 Ischemic Heart Disease Epidemiology Pathogenesis Role of Fixed Coronary Obstructions Role of Acute Plaque Change Role of Coronary Thrombus Role of Vasoconstriction ANGINA PECTORIS MYOCARDIAL INFARCTION Transmural Versus Subendocardial Infarction Incidence and Risk Factors Pathogenesis Coronary Arterial Occlusion Myocardial Response MORPHOLOGY Infarct Modification After Reperfusion by Thrombolysis, Angioplasty, or Coronary Bypass Graft Surgery Clinical Features Consequences and Complications of Myocardial Infarction CHRONIC ISCHEMIC HEART DISEASE MORPHOLOGY SUDDEN CARDIAC DEATH MORPHOLOGY Hypertensive Heart Disease SYSTEMIC (LEFT-SIDED) HYPERTENSIVE HEART DISEASE MORPHOLOGY PULMONARY (RIGHT-SIDED) HYPERTENSIVE HEART DISEASE (COR PULMONALE) MORPHOLOGY Valvular Heart Disease VALVULAR DEGENERATION CAUSED BY CALCIFICATION Calcific Aortic Stenosis MORPHOLOGY
Clinical Features Calcification of a Congenitally Bicuspid Aortic Valve Mitral Annular Calcification MYXOMATOUS DEGENERATION OF THE MITRAL VALVE (MITRAL VALVE PROLAPSE) MORPHOLOGY Pathogenesis Clinical Features RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE MORPHOLOGY Pathogenesis Clinical Features INFECTIVE ENDOCARDITIS Cause and Pathogenesis MORPHOLOGY Clinical Features NONINFECTED VEGETATIONS Nonbacterial Thrombotic Endocarditis MORPHOLOGY Pathogenesis Endocarditis of Systemic Lupus Erythematosus (Libman-Sacks Endocarditis) MORPHOLOGY CARCINOID HEART DISEASE MORPHOLOGY COMPLICATIONS OF ARTIFICIAL VALVES Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
TYPES OF HEART DISEASE - Part 1 With the introduction to general principles of cardiac functional anatomy and heart failure that has just been presented, we now turn to a discussion of the major forms of heart disease. Five categories of disease account for nearly all cardiac mortality: 1. 2. 3. 4. 5.
IHD Hypertensive heart disease (systemic and pulmonary) Valvular heart disease Nonischemic (primary) myocardial disease Congenital heart disease
Because IHD is responsible for 80 to 90% of these deaths, it is discussed first. Ischemic Heart Disease IHD is the generic designation for a group of closely related syndromes resulting from myocardial ischemia--an imbalance between the supply (perfusion) and demand of the heart for oxygenated blood. Ischemia is characterized by not only insufficiency of oxygen, but also reduced availability of nutrient substrates and inadequate removal of metabolites (Chapter 1) . Isolated hypoxemia (i.e., diminished transport of oxygen by the blood) induced by cyanotic congenital heart disease, severe anemia, or advanced lung disease is less deleterious than ischemia because perfusion (including metabolic substrate delivery and waste removal) is maintained. In more than 90% of cases, the cause of myocardial ischemia is reduction in coronary blood flow because of atherosclerotic coronary arterial obstructions. Thus, IHD is often termed coronary artery disease or coronary heart disease. In most cases, there is a long period (decades) of silent, slowly progressive, coronary atherosclerosis before these disorders become manifest. Thus, the syndromes of IHD are only the late manifestations of coronary atherosclerosis that probably began during childhood or adolescence (Chapter 12) . Certain conditions aggravate ischemia through increase in cardiac energy demand (e.g., hypertrophy), lowered systemic blood pressure (e.g., shock), or hypoxemia. Moreover, increased heart rate not only increases demand through more contractions per unit time, but also decreases supply (by decreasing the length of diastole--when coronary perfusion occurs--relative to systole). The risk of an individual developing detectable IHD depends in part on the number, distribution, and degree of narrowing by atheromatous plaques. The clinical
manifestations of IHD, however, are not strongly predicted by these anatomic observations. Moreover, there is an extraordinarily
551
broad spectrum of the expression of disease from elderly individuals with extensive coronary atherosclerosis who have never had a symptom to the previously asymptomatic young adult in whom modestly obstructive disease comes unexpectedly to medical attention as a result of acute myocardial infarction (MI) or sudden cardiac death. The reasons for clinical heterogeneity of the disease are complex. However, the often precipitous and variable onset largely depends on the pathologic basis of the so-called acute coronary syndromes of IHD (comprising unstable angina, acute MI and, for our purposes owing to the frequently similar pathophysiologic basis, sudden death)-unpredictable and abrupt conversion of a stable atherosclerotic plaque to an unstable, potentially life-threatening atherothrombotic lesion through superficial erosion, ulceration, fissuring, rupture or deep hemorrhage, usually with superimposed thrombosis. For purposes of simplicity herein, this spectrum of alteration in atherosclerotic lesions is termed either disruption or acute plaque change. In general, however, the clinical manifestations of IHD can be divided into four syndromes: 1. MI, the most important form of IHD, in which the duration and severity of ischemia is sufficient to cause death of heart muscle 2. Angina pectoris, of which there are three variants--stable angina, Prinzmetal angina, and unstable angina (the last-mentioned is the most threatening since it is frequently a harbinger of MI) 3. Chronic ischemic heart disease with heart failure 4. Sudden cardiac death Epidemiology.
IHD in its various forms is the leading cause of death for both men and women in the United States and other industrialized nations. Each year, nearly 500,000 Americans die of IHD. Awesome as these data may be, they represent an improvement over those that prevailed several decades ago. Since 1980, the overall death rate from IHD has fallen in the United States by approximately one third, owing to both (1) prevention achieved by modification of determinants of risk, such as smoking, elevated blood cholesterol, hypertension, and a sedentary life style, [14] [15] and (2) therapeutic advances, including new medications, coronary care units, thrombolysis for MI, percutaneous transluminal coronary angioplasty (PTCA), intravascular stents, coronary bypass surgery, and improved control of arrhythmias. [16] [17] Additional risk reduction may potentially be associated with maintenance of normal blood glucose levels in diabetic patients, postmenopausal estrogen replacement therapy, lipid lowering and antioxidant therapy, and aspirin prophylaxis in middle-aged men (see Chapter 12) . However, the death rate from cardiovascular disease is presently increasing in the United States and worldwide.
Pathogenesis.
The dominant influence in the causation of the IHD syndromes is diminished coronary perfusion relative to myocardial demand, owing largely to a complex dynamic interaction among fixed atherosclerotic narrowing of the epicardial coronary arteries, intraluminal thrombosis overlying a disrupted atherosclerotic plaque, platelet aggregation, and vasospasm. The individual elements and their interactions are discussed subsequently. Role of Fixed Coronary Obstructions.
More than 90% of patients with IHD have coronary atherosclerosis, which compromises blood flow ( fixed obstructions). Most--but not all--have one or more lesions causing at least 75% reduction of the cross-sectional area of at least one of the major epicardial arteries, a threshold of obstruction at which the augmented coronary flow provided by compensatory vasodilation is no longer sufficient to meet even moderate increases in myocardial demand. Although only a single major coronary epicardial trunk may be affected, more often two or all three--LAD, LCX, RCA--are involved. Clinically significant stenosing plaques may be located anywhere within these vessels but tend to predominate within the first several centimeters of the LAD and LCX and the entire length of the RCA. Sometimes the major secondary epicardial branches are also involved (i.e., diagonal branches of the LAD, obtuse marginal branches of the LCX, or posterior descending branch of the RCA, but atherosclerosis of the intramural branches is rare). The onset of symptoms and prognosis of IHD, however, depend not only on the extent and severity of fixed, chronic anatomic disease, but also critically on dynamic changes in coronary plaque morphology (to be discussed). Role of Acute Plaque Change.
In most patients, the myocardial ischemia underlying the acute coronary syndromes--unstable angina, acute MI, and (in many cases) sudden cardiac death--is precipitated by abrupt plaque change followed by thrombosis (Figs. 13-3 and 13-4) . [18] [19 ] Most often, the initiating event is disruption of previously only partially stenosing plaques with Hemorrhage into the atheroma, expanding its volume Rupture or fissuring, exposing the highly thrombogenic plaque constituents Erosion or ulceration, exposing the thrombogenic subendothelial basement membrane to blood Although the factors that trigger these acute alterations in plaque configuration are uncertain, disruption implies an inability of plaque to withstand imposed mechanical stresses. Several extrinsic and intrinsic influences seem important. Adrenergic stimulation can elevate physical stresses on the plaque through systemic hypertension or local vasospasm. The adrenergic stimulation associated with awakening induces a
pronounced circadian periodicity for the time of onset of acute MI, with a peak incidence at 6 AM to 12 noon, concurrent with a surge in blood pressure and immediately following heightened platelet reactivity. [20] Aspirin, a drug well known to interfere with platelet function, depresses the morning peak in the incidence of acute MI. Interestingly, an unexpected increase in individuals suffering sudden cardiac death that accompanied the Northridge (Los Angeles) earthquake in 1994 has been attributed to emotional stress-related adrenergic stimulation. [21] The structure and composition of plaque are dynamic and may contribute to the propensity to disruption.[22] [23] Disrupted lesions characteristically have a markedly eccentric configuration (in which the plaque is not uniform around the vessel circumference), a large soft core of necrotic debris and lipid, a high density of macrophages, and
552
Figure 13-3 Atherosclerotic plaque rupture. A , Plaque rupture without superimposed thrombus in a patient who died suddenly. B ,
Acute coronary thrombosis superimposed on an atherosclerotic plaque with focal disruption of the fibrous cap, triggering fatal myocardial infarction. C, Massive plaque rupture with superimposed thrombus, also triggering a fatal myocardial infarction (special stain highlighting fibrin in red). In both A and B an arrow points to the site of plaque rupture. ( B from Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, WB Saunders, 1989, p 61.)
Figure 13-4 Schematic representation of sequential progression of coronary artery lesion morphology, beginning with stable chronic plaque responsible for typical angina and leading to the various acute coronary syndromes. (Modified and redrawn from Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, WB Saunders, 1989, p 63.)
553
only a thin fibrous cap. Degradation of collagen, the major structural component of the fibrous cap, may be an important contributor to plaque rupture. Such breakdown involves the action of metalloproteinases, expressed by macrophages in atheroma. Moreover, fissures frequently occur at the junction of the fibrous cap and the adjacent normal plaque-free arterial segment, a location at which the blood flow-inducing mechanical stresses within the plaque are highest. It is now recognized that the preexisting culprit lesion in patients who develop MI and other acute coronary syndromes is often not a severely stenotic and hemodynamically significant lesion before its acute change. The most dangerous lesions are the moderately stenotic (usually 50 to 75%), lipid-rich atheromas, which are themselves insufficient to induce stable angina before disruption. Thus, a rather large number of now asymptomatic adults in the industrial world have a real but unpredictable risk of a catastrophic coronary event. Several factors underlie this rather disquieting realization. First, an atheroma of moderate size often has a complex configuration with a
well-developed soft core capable of disruption. Second, plaques causing obstruction sufficient to limit flow severely may have correspondingly reduced mechanical stresses in their walls, thus making disruption less likely. Third, high-grade but slowly developing occlusions stimulate collateral vessel formation that may protect against infarction. Finally, repetitive nonlethal myocardial ischemia may be protective to infarction by a mechanism yet unknown (termed preconditioning--see later). Accumulating evidence indicates that plaque disruption and the ensuing platelet aggregation and intraluminal thrombosis are common, repetitive, and often clinically silent complications of atheroma. Moreover, healing of subclinical plaque disruption and overlying thrombosis comprises an important mechanism of growth of atherosclerotic lesions. Role of Coronary Thrombus.
As mentioned earlier, partial or total thrombosis associated with a disrupted plaque is critical to the pathogenesis of the acute coronary syndromes. In acute transmural MI, thrombus superimposed on a disrupted but previously only partially stenotic plaque has converted it to a total occlusion (see discussion of transmural versus subendocardial infarction later). In contrast, with unstable angina, acute subendocardial infarction, or sudden cardiac death, the extent of luminal obstruction by thrombosis is usually incomplete. Moreover, in unstable angina, there is a temporal relation between chest pain and generation of thromboxane A2 and other platelet constituents in the coronary circulation, suggesting that these mediators are available at sites of plaque disruption and transient mural thrombosis to promote further platelet aggregation and vasoconstriction. [24] Factors not related to platelets may augment thrombotic potential, including elevated blood concentrations of fibrinogen, low plasminogen activator inhibitor 1 (an inhibitor of fibrinolysis), and high lipoprotein (a) (a form of low-density lipoprotein that inhibits fibrinolysis). Mural thrombus can also embolize. Small fragments of thrombotic material in the distal intramyocardial circulation or microinfarcts may be found at autopsy of patients who have had unstable angina. Finally, thrombus is a potent activator of multiple growth-related signals in smooth muscle cells that can contribute to the growth of atherosclerotic lesions (Chapter 12) . Role of Vasoconstriction.
Vasoconstriction itself compromises lumen size and can increase the local mechanical forces that can contribute to plaque fracture. Vasoconstriction at sites of atheroma is stimulated by (1) circulating adrenergic agonists, (2) locally released platelet contents, (3) impaired secretion of endothelial cell relaxing factors (e.g., nitric oxide) relative to contracting factors (e.g., endothelin) owing to atheroma-associated endothelial dysfunction, and potentially (4) mediators released from perivascular inflammatory cells (e.g., mast cells). To summarize, the acute coronary syndromes-- acute MI, unstable angina, and often
sudden death-- share a common pathophysiologic basis in coronary atherosclerotic plaque disruption and associated intraluminal platelet-fibrin thrombus formation (Table 13-2) . Stable angina results from an increase in myocardial oxygen demand that outstrips the ability of markedly stenosed coronary arteries to increase oxygen delivery but is not usually associated with plaque disruption. Unstable angina derives from a sudden change in plaque morphology, which induces partially occlusive platelet aggregation or mural thrombus, and vasoconstriction leading to severe but transient reductions in coronary blood flow. In some cases, distal microinfarction occurs secondary to thromboemboli. In MI, acute plaque change induces total thrombotic occlusion. Finally, sudden cardiac death frequently involves a coronary lesion in which disrupted plaque and often partial TABLE 13-2 -- CORONARY ARTERY PATHOLOGY IN ISCHEMIC HEART DISEASE Syndrome Stenoses Plaque Plaque-Associated Thrombus Disruption Stable angina
>75%
No
No
Unstable angina
Variable
Frequent
Nonocclusive, often with thromboemboli
Transmural myocardial infarction
Variable
Frequent
Occlusive
Subendocardial myocardial infarction
Variable
Variable
Widely variable, may be absent, partial/complete or lysed
Sudden death
Usually severe
Frequent
Often small platelet aggregates or thrombi and/or thromboemboli
554
thrombus have led to regional myocardial ischemia that induces a fatal ventricular arrhythmia. Each of these important syndromes is now discussed in detail. ANGINA PECTORIS
Angina pectoris is a symptom complex of IHD characterized by paroxysmal and usually recurrent attacks of substernal or precordial chest discomfort (variously described as constricting, squeezing, choking, or knifelike) caused by transient (15 seconds to 15 minutes) myocardial ischemia that falls short of inducing the cellular necrosis that defines infarction. There are three overlapping patterns of angina pectoris: (1) stable or typical angina, (2) Prinzmetal or variant angina, and (3) unstable or crescendo angina. They are caused by varying combinations of increased myocardial demand and decreased myocardial perfusion, owing to fixed stenosing plaques, disrupted plaques, vasospasm, thrombosis, platelet aggregation, and embolization. Moreover, it is being increasingly recognized that not all ischemic events are perceived by patients, even though such events may have adverse prognostic implications ( silent ischemia).
Stable angina, the most common form and therefore called typical angina pectoris, appears to be caused by the reduction of coronary perfusion to a critical level by chronic stenosing coronary atherosclerosis; this renders the heart vulnerable to further ischemia whenever there is increased demand, such as that produced by physical activity, emotional excitement, or any other cause of increased cardiac workload. Typical angina pectoris is usually relieved by rest (thereby decreasing demand) or nitroglycerin, a strong vasodilator (which although the coronary arteries are usually maximally dilated by intrinsic regulatory influences also decreases cardiac work by dilating the peripheral vasculature). In particular instances, local vasospasm may contribute to the imbalance between supply and demand. Prinzmetal variant angina is an uncommon pattern of episodic angina that occurs at rest and has been documented to be due to coronary artery spasm. Usually there is elevation of the ST segment of the electrocardiogram (ECG), indicative of transmural ischemia. Although individuals with this form of angina may well have significant coronary atherosclerosis, the anginal attacks are unrelated to physical activity, heart rate, or blood pressure. Prinzmetal angina generally responds promptly to vasodilators, such as nitroglycerin and calcium channel blockers. Unstable or crescendo angina refers to a pattern of pain that occurs with progressively increasing frequency, is precipitated with progressively less effort, often occurs at rest, and tends to be of more prolonged duration. As discussed earlier, in most patients, unstable angina is induced by disruption of an atherosclerotic plaque with superimposed partial (mural) thrombosis and possibly embolization or vasospasm (or both). Although the ischemia that occurs in unstable angina falls precariously short of inducing clinically detectable infarction, unstable angina is a harbinger of subsequent acute MI in many patients. Thus, this syndrome is sometimes referred to as preinfarction angina. In the spectrum of IHD, unstable angina lies intermediate between stable angina on the one hand and MI on the other. MYOCARDIAL INFARCTION
MI, also known as heart attack, is overwhelmingly the most important form of IHD and alone is the leading cause of death in the United States and industrialized nations. About 1.5 million individuals in the United States suffer an acute MI annually, and approximately one third of them die. At least 250,000 people a year die of heart attack before they reach the hospital. Transmural Versus Subendocardial Infarction.
Most myocardial infarcts are transmural, in which the ischemic necrosis involves the full or nearly full thickness of the ventricular wall in the distribution of a single coronary artery. This pattern of infarction is usually associated with chronic coronary atherosclerosis, acute plaque change, and superimposed, completely obstructive thrombosis (as discussed previously). In contrast, a subendocardial (nontransmural) infarct constitutes an area of ischemic necrosis limited to the inner one third or at most one half of the ventricular wall; it may extend laterally beyond the perfusion territory of a
single coronary artery. As previously pointed out, the subendocardial zone is normally the least well-perfused region of myocardium and therefore most vulnerable to any reduction in coronary flow. In the majority of subendocardial infarcts, there is diffuse stenosing coronary atherosclerosis and reduction of coronary flow but neither plaque disruption nor superimposed thrombosis. The two types of infarcts, however, are closely interrelated because, in experimental models, the transmural infarct begins with a zone of subendocardial necrosis that progressively encompasses the full thickness of the ventricular wall (see later). Therefore, a subendocardial infarct can occur as a result of a plaque disruption followed by a coronary thrombus that becomes lysed before myocardial necrosis extends across the major thickness of the wall. Subendocardial infarcts, however, can also result from sufficiently prolonged and severe reduction in systemic blood pressure, as in shock; in cases of global hypotension, resulting subendocardial infarcts are usually circumferential rather than limited to the distribution of a single major coronary artery. Incidence and Risk Factors.
The risk factors for atherosclerosis, the major underlying cause of IHD in general, are discussed in detail in Chapter 12 and are not reiterated here. MI may occur at virtually any age, but the frequency rises progressively with increasing age and when predispositions to atherosclerosis are present, such as hypertension, cigarette smoking, diabetes mellitus, genetic hypercholesterolemia, and other causes of hyperlipoproteinemia. Nearly 10% of myocardial infarcts occur in people under age 40 years, and 45% occur in people under age 65. Blacks and whites are affected equally often. Throughout life, men are at significantly greater risk of MI than women, the differential progressively declining with advancing age. Except for those having some predisposing atherogenic condition, women are remarkably protected against MI during the reproductive years. The decrease of estrogen after menopause can permit rapid development of
555
coronary heart disease. Epidemiologic evidence strongly suggests that postmenopausal hormone replacement therapy protects women against MI through favorable adjustment of risk factors, albeit with slightly increased risk of breast and endometrial cancer. [25] Pathogenesis.
We now consider the basis for and subsequent consequences of myocardial ischemia, particularly as they relate to the transmural infarct. Coronary Arterial Occlusion.
In nearly all transmural acute myocardial infarcts, a dynamic interaction has occurred among several or all of the following--severe coronary atherosclerosis, acute atheromatous plaque change (such as rupture), superimposed platelet activation,
thrombosis, and vasospasm--eventuating in an occlusive intracoronary thrombus overlying a disrupted plaque. In addition, either increased myocardial demand (as with hypertrophy or tachycardia) or hemodynamic compromise (as with a drop in blood pressure) can worsen the situation. Collateral circulation may provide perfusion to ischemic zones from a relatively unobstructed branch of the coronary tree, bypassing the point of obstruction and protecting against the effects of an acute coronary occlusion. In the typical case of MI, the following sequence of events can be proposed: The initial event is a sudden change in the morphology of an atheromatous plaque (i.e., disruption)--manifest as intraplaque hemorrhage, erosion or ulceration, or rupture or fissuring. Exposed to subendothelial collagen and necrotic plaque contents, platelets undergo adhesion, aggregation, activation, and release of potent aggregators, including thromboxane A2 , serotonin, and platelet factors 3 and 4; vasospasm is stimulated. Other mediators activate the extrinsic pathway of coagulation and add to the bulk of the thrombus. Frequently within minutes, the thrombus evolves to occlude completely the lumen of the culprit coronary vessel. The evidence for this sequence is compelling and derives from (1) autopsy studies of patients dying with acute MI, (2) angiographic studies demonstrating a high frequency of thrombotic occlusion early after MI, (3) both the high success rate of therapeutic thrombolysis and primary angioplasty and the demonstration of residual disrupted atherosclerotic lesions by angiography after thrombolysis. Although coronary angiography performed within 4 hours of the onset of apparent MI shows a thrombosed coronary artery in almost 90% of cases, the observation of occlusion, however, falls to about 60% when angiography is delayed until 12 to 24 hours after onset. [26] Thus, with the passage of time, at least some occlusions appear to clear spontaneously owing to lysis of the thrombus or relaxation of spasm or both. Spontaneous lysis occurring after more than several hours following MI onset is incapable of salvaging substantial useful myocardium. In approximately 10% of cases, transmural acute MI is not associated with atherosclerotic plaque thrombosis stimulated by disruption. In such situations, other mechanisms may be involved, as follows: Vasospasm: Isolated, intense, and relatively prolonged, with or without coronary atherosclerosis, perhaps in association with platelet aggregation Emboli: From the left atrium in association with atrial fibrillation, a left-sided mural thrombus, or vegetative endocarditis, or paradoxical emboli from the right side of the heart or the peripheral veins, which cross to the systemic circulation, through a patent foramen ovale, to cause coronary occlusion Unexplained: In about one third of such cases, the coronary arteries are free of obstruction by angiography. Some such cases may involve unusual diseases of small intramural coronary vessels, hematologic abnormalities such as
hemoglobinopathies, or other disorders. Myocardial Response.
The consequence of coronary arterial obstruction is the loss of critical blood supply to the myocardium (Fig. 13-5) , which induces profound functional, biochemical, and morphologic consequences. Occlusion of a major coronary artery results in ischemia and potentially cell death throughout the anatomic region supplied by that artery (called area at risk), most pronounced in the subendocardium. The outcome largely depends on the severity and duration of flow deprivation. The principal early biochemical consequence of myocardial ischemia is the cessation of aerobic glycolysis (and therefore onset of anaerobic glycolysis) within seconds, leading to inadequate production of high-energy phosphates (e.g., creatine phosphate and adenosine triphosphate [ATP])
Figure 13-5 Postmortem angiogram demonstrating the posterior aspect of the heart of a patient who died during evolution of acute myocardial infarction. There is total occlusion of the distal right coronary artery by an acute thrombus (arrow) and a large zone of myocardial hypoperfusion involving the posterior left and right ventricles (arrowheads). The heart has been fixed by coronary arterial
perfusion with glutaraldehyde and cleared with methyl salicylate, followed by intracoronary injection of silicone polymer. Photograph courtesy of Lewis L. Lainey. (From Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, WB Saunders, 1989, p 60. Courtesy of Lewis L. Lainey.)
556
and accumulation of potentially noxious breakdown products (e.g., lactic acid). Since myocardial function is exceedingly sensitive to severe ischemia, striking loss of contractility occurs within 60 seconds of onset of ischemia and can precipitate acute heart failure. As detailed in Chapter 1 , ultrastructural changes also develop within a few minutes after onset of ischemia (e.g., myofibrillar relaxation, glycogen depletion, cell and mitochondrial swelling). Nevertheless, these early changes are potentially reversible, and cell death is not immediate. As demonstrated experimentally in the dog, only severe ischemia lasting at least 20 to 40 minutes or longer leads to irreversible damage (necrosis) of some cardiac myocytes. Ultrastructural evidence of irreversible myocyte injury (primary structural defects in the sarcolemmal membrane) develops after 20 to 40 minutes in severely ischemic myocardium (with blood flow of 10% or less of normal). [27] Microvascular injury follows. This time frame is summarized in Table 13-3 . Classic acute MI with extensive damage occurs when the perfusion of the myocardium is reduced severely below its needs for an extended interval (usually hours), causing profound, prolonged ischemia and resulting in permanent loss of function through cell death (typically by coagulation necrosis). In contrast, if restoration of myocardial blood flow (known as reperfusion) follows briefer periods of flow deprivation (less than 20 minutes in the most severely ischemic myocardium), loss of cell viability generally does not result. This provides the rationale for the early detection of acute MI-- to permit early therapy such as thrombolysis, establish reperfusion of the area at risk, salvage as much
ischemic but not yet dead myocardium as possible, and consequently minimize infarct size. Myocardial ischemia also contributes to arrhythmias through complex, largely uncertain mechanisms. [28] Sudden death, a leading cause of mortality in IHD patients, is usually due to ventricular fibrillation caused by myocardial irritability induced by ischemia or infarction. Interestingly, studies of resuscitated survivors of sudden death show that the majority do not develop acute MI; in such cases, ischemia owing to severe chronic coronary arterial stenosis and, in many cases, acute plaque change with minimal thrombus presumably led directly to the fatal arrhythmia. Apoptosis is a recently recognized component of the lethal cell injury that follows severe myocardial ischemia. Apoptosis occurs in experimental and human MI. [29] [30] TABLE 13-3 -- APPROXIMATE TIME OF ONSET OF KEY EVENTS IN ISCHEMIC CARDIAC MYOCYTES Feature Time Onset of ATP depletion
Seconds
Loss of contractility
1 hr
ATP, adenosine triphosphate. Apoptotic cell death occurs rapidly after ischemia onset, and novel early therapeutic interventions that inhibit apoptotic events could conceivably promote myocyte preservation during ischemic injury. The relative importance of apoptosis rather than typical coagulation necrosis in clinical infarcts and the roles of ischemia, reperfusion, and other factors in inducing apoptosis are still unclear, however, and are under intense scrutiny. The progression of ischemic necrosis in the myocardium is summarized in Figure 13-6 . Irreversible injury of ischemic myocytes occurs first in the subendocardial zone. With more extended ischemia, a wavefront of cell death moves through the myocardium to involve progressively more of the transmural thickness of the ischemic zone. The precise location, size, and specific morphologic features of an acute myocardial infarct depend on the following: The location, severity, and rate of development of coronary atherosclerotic obstructions The size of the vascular bed perfused by the obstructed vessels The duration of the occlusion
The metabolic/oxygen needs of the myocardium at risk The extent of collateral blood vessels The presence, site, and severity of coronary arterial spasm Other factors, such as alterations in blood pressure, heart rate, and cardiac rhythm The extent of necrosis is largely complete within 3 to 6 hours in experimental models, involving nearly all of the ischemic myocardial bed at risk supplied by the occluded coronary artery. Progression of necrosis, however, frequently follows a more protracted course in humans (possibly over 6 to 12 hours or longer), in whom the coronary arterial collateral system, often stimulated by chronic ischemia, is better developed and thereby more effective. MORPHOLOGY.
The evolution of the morphologic changes in acute MI and its healing are summarized in Table 13-4 . Virtually all transmural infarcts involve at least a portion of the left ventricle (including the ventricular septum). About 15 to 30% of those that affect the posterior free wall and posterior portion of the septum transmurally extend into the adjacent right ventricular wall. Isolated infarction of the right ventricle, however, occurs in only 1 to 3% of cases. Infarction of the atrial wall accompanies a large posterior left ventricular infarct in some cases. Transmural infarcts usually encompass nearly the entire perfusion zone of the occluded coronary artery. However, almost always there is a narrow rim (approximately 0.1 mm) of preserved subendocardial myocardium sustained by diffusion of oxygen and nutrients from the lumen. The frequencies of critical narrowing (and thrombosis) of each of the three main arterial trunks and the
557
Figure 13-6 Schematic representation of the progression of myocardial necrosis after coronary artery occlusion. Necrosis begins in a
small zone of the myocardium beneath the endocardial surface in the center of the ischemic zone. This entire region of myocardium (dashed outline) depends on the occluded vessel for perfusion and is the area at risk. Note that a very narrow zone of myocardium immediately beneath the endocardium is spared from necrosis because it can be oxygenated by diffusion from the ventricle.
corresponding sites of myocardial lesions (in the typical right dominant heart) are as follows:
LAD (40 to Anterior wall of left ventricle near apex; anterior portion of ventricular 50%) septum; apex circumferentially
RCA (30 to Inferior-posterior wall of left ventricle; posterior portion of ventricular 40%) septum; inferior-posterior right ventricular free wall in some cases LCX (15 to Lateral wall of left ventricle except at apex 20%)
Other locations of critical coronary arterial lesions causing infarcts are sometimes encountered, such as the left main coronary artery or the secondary branches (e.g., diagonal branches of the LAD or marginal branches of the LCX). In contrast, stenosing atherosclerosis or thrombosis of a penetrating intramyocardial branch of the coronary arteries is almost never encountered. Occasionally the observation of multiple severe stenoses or thromboses in the absence of myocardial damage suggests that intercoronary collaterals were protective. Several infarcts of varying age are frequently found in the same heart. Repetitive necrosis of adjacent regions yields progressive extension of
558
TABLE 13-4 -- EVOLUTION OF MORPHOLOGIC CHANGES IN MYOCARDIAL INFARCTION Time Gross Features Light Microscope Electron Microscope Reversible Injury 0-½ hr None
None
Relaxation of myofibrils; glycogen loss; mitochondrial swelling Sarcolemmal disruption; mitochondrial amorphous densities
Irreversible Injury ½ -4 hr
None
Usually none; variable waviness of fibers at border
4-12 hr
Occasionally dark mottling
Beginning coagulation necrosis; edema; hemorrhage
12-24 Dark mottling hr
Ongoing coagulation necrosis; pyknosis of nuclei; myocyte hypereosinophilia; marginal contraction band necrosis; beginning neutrophilic infiltrate
1-3 days
Mottling with yellow-tan infarct center
Coagulation necrosis, with loss of nuclei and striations; interstitial infiltrate of neutrophils
3-7 days
Hyperemic border; central yellow-tan softening
Beginning disintegration of dead myofibers, with dying neutrophils; early phagocytosis of dead cells by macrophages at infarct border
7-10 days
Maximally yellow-tan and soft, with depressed red-tan margins
Well-developed phagocytosis of dead cells; early formation of fibrovascular granulation tissue at margins
10-14 Red-gray days depressed infarct borders
Well-established granulation tissue with new blood vessels and collagen deposition
2-8 wk Gray-white scar, progressive from border toward core of infarct
Increased collagen deposition, with decreased cellularity
>2 mo Scarring complete
Dense collagenous scar
an individual infarct over a period of days to weeks. Examination of the heart in such cases often reveals a central zone of infarction that is days to weeks older than a peripheral margin of more recent ischemic necrosis. An initial infarct may extend because of retrograde propagation of a thrombus, proximal vasospasm, progressively impaired cardiac contractility that renders flow through moderate stenoses critically insufficient, development of platelet-fibrin microemboli, or appearance of an arrhythmia that impairs cardiac function. Areas of damage undergo a progressive sequence of changes that consist of typical ischemic coagulative necrosis, followed by inflammation and repair that parallels that occurring after injury at other, noncardiac sites. Thus, the appearance of an infarct at autopsy depends on the duration of survival of the patient after MI. Early recognition of acute myocardial infarcts by pathologists can be a difficult problem, particularly when death has occurred within a few hours after the onset of symptoms. Myocardial infarcts fewer than 12 hours old are usually inapparent on gross examination. It is often possible, however, to highlight the area of necrosis that first becomes apparent after 2 to 3 hours by immersion of tissue slices in a solution of triphenyltetrazolium chloride. This dye imparts a brick-red color to intact, noninfarcted myocardium where the dehydrogenase activity is preserved. Because dehydrogenases are depleted in the area of ischemic necrosis (i.e., they leak out through the damaged cell membranes), an infarcted area is revealed as an unstained pale zone (Fig. 13-7) . Subsequently, lesions are often visible grossly. By 12 to 24 hours, the lesion can be identified in routinely fixed gross slices owing to a red-blue hue as a result of stagnated, trapped blood. Progressively thereafter, the infarct becomes a more sharply defined, yellow-tan, somewhat softened area (with inflammatory cells) that by 10 days to 2
weeks is rimmed by a hyperemic zone of highly vascularized granulation tissue. Over the succeeding weeks, the injured region evolves to a fibrous scar. The histopathologic changes also have a more or less predictable sequence (summarized in Table 13-4 and Fig. 13-8) . Using light microscopy of sections stained by routine tissue stains, the typical microscopic changes of coagulative necrosis become detectable variably in the first 4 to 12 hours. Wavy fibers may be present at the periphery of the infarct; these changes probably result from the forceful systolic tugs by the viable fibers immediately adjacent to the noncontractile dead fibers, thereby stretching and buckling them. An
559
Figure 13-7 Acute myocardial infarct, predominantly of the posterolateral left ventricle, demonstrated histochemically by a lack of
staining by the triphenyltetrazolium chloride (TTC) stain in areas of necrosis. The staining defect is due to the enzyme leakage that follows cell death. Note the myocardial hemorrhage at one edge of the infarct that was associated with cardiac rupture, and the anterior scar (lower left) , indicative of old infarct. (Specimen oriented with posterior wall at top.)
additional but sublethal ischemic change may be seen in the margins of infarcts: so-called vacuolar degeneration or myocytolysis, comprising large vacuolar spaces within cells, probably containing water. This potentially reversible alteration is particularly frequent in the thin zone of viable subendocardial cells. Subendocardial myocyte vacuolization in other contexts may signify severe chronic ischemia. The necrotic muscle elicits acute inflammation (typically most prominent at 2 to 3 days). Thereafter, macrophages remove the necrotic myocytes (most pronounced at 5 to 10 days), and the damaged zone is progressively replaced by the ingrowth of highly vascularized granulation tissue (most prominent at 2 to 4 weeks), which progressively becomes less vascularized and more fibrous. In most instances, scarring is well advanced by the end of the sixth week, but the efficiency of repair depends on the size of the original lesion. A large infarct may not heal as readily as a small one. Moreover, once a lesion is completely healed, it is impossible to distinguish its age (i.e., an 8-week-old lesion and a 10-year-old lesion can look similar). The morphology of evolving subendocardial and transmural infarcts is qualitatively similar. By definition, however, the necrosis in subendocardial lesions is limited to the inner third to one half of the left ventricular wall and may be multifocal, cover an arc of the circumference of the left ventricle, or sometimes totally encircle it. Infarct Modification After Reperfusion by Thrombolysis, Angioplasty, or Coronary Bypass Graft Surgery.
Thrombolytic therapy is used in an attempt to dissolve the thrombus that initiated acute MI, to reestablish blood flow to the area at risk for infarction, and possibly to rescue the ischemic (but not yet necrotic) heart muscle. The effectiveness of thrombolysis by streptokinase or tissue-type plasminogen activator is based on the ability of these
agents to activate the human fibrinolytic system. Thrombolysis reestablishes flow through the occluded coronary artery in most cases; early reperfusion can salvage myocardium and thereby limit infarct size, with consequent improvement in both short-term and long-term function and survival. [31] As discussed previously, loss of myocardial viability in infarction is progressive, occurring over a period of at least several hours. Thus, reperfusion of jeopardized myocardium offers an effective approach to restoring the balance between myocardial perfusion and need. The potential benefit clearly is related to the rapidity with which the coronary occlusion is alleviated, and the first 3 to 4 hours after onset of symptoms are critical. Thrombolysis, however, can at best remove a thrombus occluding a coronary artery; it does not significantly alter the underlying disrupted atherosclerotic plaque that initiated it . In contrast, PTCA not only eliminates a thrombotic occlusion, but also relieves some of the original obstruction caused by the underlying plaque [32] (see earlier). Severe ischemia does not cause immediate cell death even in the most severely affected regions of myocardium, and not all regions of myocardium are equally ischemic. Therefore, the outcome distal to the occlusion after restoration of flow to previously ischemic myocardium may vary from region to region. Reperfusion of myocardium sufficiently early (within 15 to 20 minutes) after onset of ischemia may prevent all necrosis. Reperfusion after a longer interval may not prevent necrosis but can salvage (i.e., prevent necrosis of) at least some myocytes that would have died with more prolonged or permanent ischemia. The gross and histologic appearance of an infarct that has been reperfused is illustrated in Figure 13-9 . A partially completed then reperfused infarct is hemorrhagic because some vasculature injured during the period of ischemia becomes leaky on restoration of flow. Moreover, disintegration of myocytes that were critically damaged by the preceding ischemia is accentuated or accelerated by reperfusion. Microscopic examination reveals that myocytes already irreversibly injured at the time of reflow often have necrosis with contraction bands. Contraction bands are intensely eosinophilic transverse bands composed of closely packed hypercontracted sarcomeres. They are most likely produced by exaggerated contraction of myofibrils at the instant perfusion is reestablished, at which time the internal portions of an already dead cell whose membranes have been damaged by ischemia are exposed to a high concentration of calcium ions from the plasma. Thus, reperfusion not only salvages reversibly injured cells, but also alters the morphology of tissue with cells already lethally injured at the time of reflow. Moreover, despite the potential for myocardial salvage on reperfusion of ischemic myocardium, some small amount of new cellular damage may occur that blunts the
560
Figure 13-8 Microscopic features of myocardial infarction. A , One-day-old infarct showing coagulative necrosis, wavy fibers with elongation, and narrowing, compared with adjacent normal fibers (lower right). Widened spaces between the dead fibers contain edema fluid and scattered neutrophils. B , Dense polymorphonuclear leukocytic infiltrate in an area of acute myocardial infarction of 3 to 4 days' duration. C, Nearly complete removal of necrotic myocytes by phagocytosis (approximately 7 to 10 days). D, Granulation tissue with a rich vascular network and early collagen deposition, approximately 3 weeks after infarction. E , Well-healed myocardial infarct with replacement of the necrotic fibers by dense collagenous scar. A few residual cardiac muscle cells are present. (In D and E , collagen is highlighted as blue in this Masson trichrome stain.)
561
Figure 13-9 Gross and microscopic appearance of myocardium modified by reperfusion. A , Large, densely hemorrhagic, anterior wall
acute myocardial infarction from a patient with left anterior descending (LAD) artery thrombus treated with streptokinase intracoronary thrombolysis (TTC-stained heart slice). B , Myocardial necrosis with hemorrhage and contraction bands, visible as dark bands spanning some myofibers (arrows) . This is the characteristic appearance of markedly ischemic myocardium that has been reperfused. (Specimen in A oriented with posterior wall up.)
beneficial effect of reperfusion itself ( reperfusion injury). [33] As discussed in Chapter 1 , reperfusion injury is mediated, at least in part, by the generation of oxygen free radicals, but their source is uncertain. Although most of the viable myocardium existing at the time of reflow ultimately recovers after alleviation of ischemia, critical abnormalities in cellular biochemistry and function of myocytes salvaged by reperfusion may persist for several days ( prolonged postischemic ventricular dysfunction, or stunned myocardium). Myocardium subjected to persistently low flow, or which is repetitively stunned, has chronically depressed function and is said to be hibernating.[34] Paradoxically, short-lived transient severe ischemia as might occur in repetitive angina pectoris or silent ischemia may protect the myocardium against a greater subsequent ischemic insult (a phenomenon known as preconditioning) by mechanisms that are yet uncertain. [35] Clinical Features.
Patients with MI have rapid, weak pulse and are often diaphoretic. Dyspnea owing to impaired contractility of the ischemic myocardium is common and accompanied by pulmonary congestion and edema. In about 10 to 15% of MI patients, the onset is entirely asymptomatic, and the disease is discovered only later by ECG changes, usually consisting of new Q waves. Such silent MIs are particularly common in patients with underlying diabetes mellitus and in elderly patients. Laboratory evaluation is based on measurement of release into the circulation of intracellular macromolecules that leak out of fatally damaged myocardial cells through a compromised sarcolemmal membrane. Creatine kinase (CK) is an enzyme that is highly concentrated in brain, myocardium,
and skeletal muscle and composed of two dimers designated M and B. The isoenzyme CK-MM is derived predominantly from skeletal muscle and heart; CK-BB from brain, lung, and many other tissues; and CK-MB principally from myocardium, although variable amounts of the MB form are also present in skeletal muscle. Total CK activity begins to rise within 2 to 4 hours of onset of MI, peaks at about 24 hours, and returns to normal within approximately 72 hours. The peak is accelerated in patients who have had reperfusion. Total CK activity is sensitive but not specific because CK is also elevated in other conditions, such as skeletal muscle injury. Specificity is enhanced by measurement of the CK-MB fraction. CK-MB rises within 4 to 8 hours, peaks at 18 hours, and usually disappears by 48 to 72 hours. An absence of a change in the levels of CK and CK-MB during the first 2 days of chest pain essentially excludes the diagnosis of MI. Isoforms of CK-MB may refine the early and specific diagnosis of MI. Lactate dehydrogenase (LDH) is released from cardiac myocytes following injury (but later than CK), and its isoenzymes were previously measured in this context. However, this analysis will likely be superseded by the newer cardiac-specific markers discussed below. The ideal marker would be an abundant cardiac-specific protein released into the serum following injury in amounts proportional to the extent of injury, and be persistent and inexpensively, rapidly and easily assayed. [36] Troponins are proteins that regulate calcium-mediated contraction of cardiac and skeletal muscle. Troponin I (TnI) and troponin T (TnT) are not normally detectable in the circulation, and different genes encode these proteins in skeletal muscle and myocardium. Therefore, serum elevations are abnormal, and cardiac and skeletal muscle forms can be distinguished by specific antibodies that also permit quantitative immunologic assays. After acute MI, both TnT and TnI levels arise at about the same time as CK-MB. The diagnostic sensitivity of cardiac troponin measurements is similar to that of CK-MB in the early stages. Troponin levels remain elevated for 7 to 10 days after the acute event, however, allowing the diagnosis of acute MI long after CK-MB levels have returned to normal. [37] Other diagnostic modalities, such as echocardiography (for visualization of abnormalities of regional wall motion), radioisotopic studies (such as radionuclide angiography for chamber configuration), perfusion scintigraphy (for regional perfusion), and magnetic resonance imaging (for structural characterization), sometimes provide additional anatomic, biochemical, and functional data.
562
Consequences and Complications of Myocardial Infarction.
Extraordinary progress has been made in the outcome of patients with acute MI. Concurrent with the marked decrease in the overall mortality of IHD since the 1960s, the in-hospital death rate has declined from approximately 30% then to 10 to 13% today overall (and approximately 7% in those receiving aggressive reperfusion therapy). Nevertheless, half of the deaths associated with acute MI occur within 1 hour of onset and these individuals never reach the hospital. Factors associated with a poor prognosis include advanced age, female gender, diabetes mellitus, and a history of previous MI. Nearly three fourths of patients have one or more complications after acute MI, which
include the following (some of which are illustrated in Figs. 13-10 and 13-11) : Contractile dysfunction: Myocardial infarcts produce abnormalities in left ventricular function approximately proportional to their size. Most often, there is some degree of left ventricular failure with hypotension, pulmonary vascular congestion, and transudation into the interstitial pulmonary spaces, which may progress to pulmonary edema with respiratory embarrassment. Severe pump failure (cardiogenic shock), which occurs in 10 to 15% of patients after acute MI, generally indicates a large infarct (often greater than 40% of the left ventricle). Cardiogenic shock has a nearly 70% mortality rate and accounts for two thirds of in-hospital deaths. Arrhythmias: Many patients have conduction disturbances or myocardial irritability after MI, which undoubtedly is responsible for many of the sudden deaths. MI-associated arrhythmias include sinus bradycardia or tachycardia, ventricular premature contractions or ventricular tachycardia, ventricular fibrillation, or asystole. Owing to the location of portions of the AV conduction system (bundle of His) in the inferoseptal myocardium, infarcts of this region may also be associated with heart block. Prompt intervention by mobile and hospital coronary care units has succeeded in controlling potentially lethal arrhythmias in many patients. Myocardial rupture: Illustrated in Figure 13-10 , the cardiac rupture syndromes result from the mechanical weakening that occurs in necrotic and subsequently inflamed myocardium and include (1) rupture of the ventricular free wall (most commonly), with hemopericardium and cardiac tamponade and usually fatal; (2) rupture of the ventricular septum (less commonly), leading to a left-to-right shunt; and (3) papillary muscle rupture (least commonly), resulting in the acute onset of severe mitral regurgitation. Free wall rupture may occur at almost any time after MI but is most frequent approximately 3 to 7 days after onset. Incomplete rupture of the free wall, although rare, results in the formation of a pseudoaneurysm whose wall consists only of thrombus. Pericarditis: A fibrinous or fibrohemorrhagic pericarditis usually develops about the second or third day after a transmural infarct and usually resolves over time (Fig. 13-11 A). 563
Pericarditis is the epicardial manifestation of the underlying myocardial inflammation. Right ventricular infarction: Although isolated infarction of the right ventricle is unusual, infarction of the right ventricular myocardium often accompanies ischemic injury of the adjacent posterior left ventricle and ventricular septum. A right ventricular infarct of either type can yield serious functional impairment. Infarct extension: New necrosis may occur adjacent to an existing infarct. Infarct expansion: Owing to the weakening of necrotic muscle, there may be disproportionate stretching, thinning, and dilation of the infarct region (especially with anteroseptal infarcts), which is often associated with mural thrombus (Fig. 13-11 B). Mural thrombus: With any infarct, the combination of a local myocardial abnormality in contractility (causing stasis) with endocardial damage (causing a thrombogenic surface) can foster mural thrombosis (Chapter 5) and potentially thromboembolism. Ventricular aneurysm: This is a late complication that most commonly results from
a large transmural anteroseptal infarct that heals into a large region of thin scar tissue, which paradoxically bulges during systole (Fig. 13-11 C). Complications of ventricular aneurysms include mural thrombus, arrhythmias, and heart failure, but rupture of the fibrotic wall rarely occurs. Papillary muscle dysfunction: Postinfarct mitral regurgitation is most commonly due to early ischemic dysfunction of a papillary muscle and underlying myocardium without rupture and later to papillary muscle fibrosis and shortening or ventricular dilation (see later). Progressive late heart failure: This is illustrated in Figure 13-11 C and discussed as chronic ischemic heart disease later.
Figure 13-10 Cardiac rupture syndromes complicating acute myocardial infarction. A , Anterior myocardial rupture in an acute infarct (arrow). B , Rupture of the ventricular septum (arrow). C, Complete rupture of a necrotic papillary muscle.
Figure 13-11 Complications of myocardial infarction. A , Fibrinous pericarditis, with a dark, roughened epicardial surface overlying an acute infarct. B , Early expansion of an anteroapical infarct with wall thinning and mural thrombus (arrow). (From Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, WB Saunders, 1989.) C , Large apical left ventricular aneurysm. The left ventricle is on the right on this apical four-chamber view of the heart. (Courtesy of William D. Edwards, MD, Mayo Clinic, Rochester, MN.)
The propensity toward specific complications and the prognosis after MI depend primarily on infarct size, site, and transmural extent (i.e., the fractional thickness of the myocardial wall that is damaged-- subendocardial or transmural). Large transmural infarcts yield a higher probability of cardiogenic shock, arrhythmias, and late congestive heart failure. Patients with anterior transmural infarcts are at greatest risk for rupture, expansion, mural thrombi, and aneurysm and thus have a substantially worse clinical course than those with inferior (posterior) infarcts. In contrast, posterior transmural infarcts are more likely to be complicated by serious conduction blocks, right ventricular involvement, or both. Mural thrombi may form on the endocardial surface of subendocardial infarcts, but pericarditis, rupture, and aneurysms rarely occur. Multiple dynamic structural changes maintain cardiac output after acute MI. Both the necrotic zone and the noninfarcted segments of the ventricle undergo progressive changes in size, shape, and thickness comprising early wall thinning, healing, hypertrophy and dilation, and late aneurysm formation, collectively termed ventricular remodeling.[38] Clearly the initial compensatory hypertrophy of noninfarcted myocardium is hemodynamically beneficial. The adaptive effect of remodeling, however, may be overwhelmed by expansion and ventricular aneurysm or late depression of regional and global contractile function owing to degenerative changes in viable myocardium. Late impairment of ventricular performance may result. Long-term prognosis after MI depends on many factors, the most important of which are the quality of left ventricular function and the extent of vascular obstructions in vessels that perfuse viable myocardium. The overall total mortality within the first year is about 30%, including those who die before reaching the hospital. Thereafter, there is a 3 to
4% mortality among survivors with each passing year. Attempts to prevent infarction in those who have never experienced MI through control of risk factors ( primary prevention) or prevent reinfarction in those who have recovered from an acute MI ( secondary prevention) are under investigation.
564
CHRONIC ISCHEMIC HEART DISEASE
The designation chronic IHD is used here to describe the cardiac findings in patients, often but not exclusively elderly, who develop progressive heart failure as a consequence of ischemic myocardial damage. In most instances, there has been prior MI and sometimes previous aortocoronary bypass graft surgery. Chronic IHD usually constitutes postinfarction cardiac decompensation owing to exhaustion of the compensatory hypertrophy of noninfarcted viable myocardium that is itself in jeopardy of ischemic injury (see earlier discussion of cardiac hypertrophy). In other cases, however, severe obstructive coronary artery disease may be present without acute or healed infarction but with diffuse myocardial dysfunction. MORPHOLOGY.
Hearts from patients with chronic IHD are usually enlarged and heavy, secondary to left ventricular hypertrophy and dilation (Fig. 13-11 C). Invariably, there is moderate to severe stenosing atherosclerosis of the coronary arteries and sometimes total occlusions. Discrete, gray-white scars of healed previous infarcts are usually present. The mural endocardium is generally normal except for some superficial, patchy, fibrous thickenings. The major microscopic findings include myocardial hypertrophy, diffuse subendocardial vacuolization, and scars of previous healed infarcts. The term ischemic cardiomyopathy is often used by clinicians to describe chronic IHD. The clinical diagnosis is made largely by the insidious onset of congestive heart failure in patients who have past episodes of MI or anginal attacks. In some individuals, however, progressive myocardial damage is entirely silent, and heart failure is the first indication of chronic IHD. The diagnosis rests largely on the exclusion of other forms of cardiac involvement. SUDDEN CARDIAC DEATH
Sudden cardiac death strikes down about 300,000 to 400,000 individuals annually in the United States. Sudden cardiac death is most commonly defined as unexpected death from cardiac causes early (usually within 1 hour) after or without the onset of symptoms. In the vast majority of cases in adults, sudden cardiac death is a complication and often the first clinical manifestation of IHD. With decreasing age of the victim, the following nonatherosclerotic causes of sudden cardiac death become increasingly probable: [39] [40] Congenital structural or coronary arterial abnormalities
Aortic valve stenosis Mitral valve prolapse Myocarditis Dilated or hypertrophic cardiomyopathy Pulmonary hypertension Hereditary or acquired abnormalities of the cardiac conduction system Isolated hypertrophy, hypertensive or unknown cause: Increased cardiac mass is an independent risk factor for cardiac death; thus some young patients who die suddenly, including athletes, have hypertensive hypertrophy or unexplained increased cardiac mass as the only finding. [13] [39] [40] The ultimate mechanism of sudden cardiac death is almost always a lethal arrhythmia (e.g., asystole, ventricular fibrillation). Although ischemic injury can impinge on the conduction system and create electromechanical cardiac instability, in most cases the fatal arrhythmia is triggered by electrical irritability of myocardium distant from the conduction system induced by ischemia or other cellular abnormalities. MORPHOLOGY.
Marked coronary atherosclerosis with critical (>75%) stenosis involving one or more of the three major vessels is present in 80 to 90% of victims; only 10 to 20% of cases are of nonatherosclerotic origin. Usually, there are high-grade stenoses (>90%), and acute plaque disruption is common. A healed myocardial infarct is present in about 40%, but in those who were successfully resuscitated from sudden cardiac arrest, new MI is found in only one third or less. Subendocardial myocyte vacuolization indicative of severe chronic ischemia is common. Hypertensive Heart Disease Hypertensive heart disease is the response of the heart to the increased demands induced by systemic hypertension. Pulmonary hypertension also causes heart disease and is referred to as right-sided hypertensive heart disease or cor pulmonale. SYSTEMIC (LEFT-SIDED) HYPERTENSIVE HEART DISEASE
The minimal criteria for the diagnosis of systemic hypertensive heart disease are the following: (1) left ventricular hypertrophy (usually concentric) in the absence of other cardiovascular pathology that might have induced it and (2) a history or pathologic evidence (see Chapter 12) of hypertension. The Framingham Heart Study established unequivocally that even mild hypertension (levels only slightly above 140/90 mm Hg), if sufficiently prolonged, induces left ventricular hypertrophy. [41] Approximately 25% of the U.S. population suffers from hypertension of at least this degree. The pathogenesis of hypertension is discussed in Chapter 12 . In hypertension, hypertrophy of the heart is an adaptive response to pressure overload, which can lead to myocardial dysfunction, cardiac dilation, congestive heart failure, and sudden death (see section on cardiac hypertrophy earlier).
565
MORPHOLOGY.
Because systemic hypertension induces left ventricular pressure overload, the heart in compensated left-sided hypertensive heart disease is characterized by circumferential hypertrophy without dilation of the left ventricle. The thickening of the left ventricular wall increases the ratio of its wall thickness to radius and increases the weight of the heart disproportionately to the increase in overall cardiac size (Fig. 13-12) . The left ventricular wall thickness may exceed 2.0 cm, and the heart weight may exceed 500 g. In time, the increased thickness of the left ventricular wall imparts a stiffness that impairs diastolic filling. This often induces left atrial enlargement. Microscopically the earliest change of systemic hypertensive heart disease is an increase in transverse myocyte diameters, which may be difficult to appreciate on routine microscopy. At a more advanced stage, the cellular and nuclear enlargement becomes somewhat more prominent and irregular, with variation in cell size among adjacent cells and interstitial fibrosis. The biochemical, molecular, and morphologic changes that occur in hypertensive hypertrophy are similar to those noted in other conditions of myocardial overload. Compensated systemic hypertensive heart disease may be asymptomatic and suspected only in the appropriate clinical
Figure 13-12 Hypertensive heart disease with marked concentric thickening of the left ventricular wall causing reduction in lumen size. The left ventricle is on the right in this apical four-chamber view of the heart. A pacemaker is incidentally present (arrow) with
the lead terminating in the right ventricle.
setting by ECG or echocardiographic indications of left ventricular enlargement. As already emphasized, other causes for such hypertrophy must be excluded. In many patients, systemic hypertensive heart disease comes to attention by the onset of atrial fibrillation (owing to left atrial enlargement) or congestive heart failure with cardiac dilation, or both. Depending on the severity of the hypertension, its duration, the adequacy of therapeutic control, and underlying basis, the patient may enjoy normal longevity and die of unrelated causes, may develop progressive IHD owing to the effects of hypertension in potentiating coronary atherosclerosis, may suffer progressive renal damage or cerebrovascular accident, or may experience progressive heart failure or sudden cardiac death. There is substantial evidence that effective control of hypertension can prevent or lead to regression of cardiac hypertrophy and its associated risks. [41] PULMONARY (RIGHT-SIDED) HYPERTENSIVE HEART DISEASE (COR PULMONALE)
Cor pulmonale, as pulmonary hypertensive heart disease is frequently called, constitutes right ventricular hypertrophy, dilation, and potentially failure secondary to
pulmonary hypertension caused by disorders of the lungs or pulmonary vasculature (Table 13-5) and is the right-sided counterpart of left-sided (systemic) hypertensive heart disease. Although quite common, right ventricular thickening and dilation caused either by congenital heart diseases or by diseases of the left side of the heart and the resultant pulmonary venous hypertension owing to postcapillary obstruction to blood flow are excluded from this definition of cor pulmonale. Based on the suddenness of development of pulmonary TABLE 13-5 -- DISORDERS PREDISPOSING TO COR PULMONALE Diseases of the Pulmonary Parenchyma Chronic obstructive pulmonary disease Diffuse pulmonary interstitial fibrosis Pneumoconioses Cystic fibrosis Bronchiectasis Diseases of Pulmonary Vessels Recurrent pulmonary thromboembolism Primary pulmonary hypertension Extensive pulmonary arteritis (e.g., Wegener granulomatosis) Drug-, toxin-, or radiation-induced vascular obstruction Extensive pulmonary tumor microembolism Disorders Affecting Chest Movement Kyphoscoliosis Marked obesity (pickwickian syndrome) Neuromuscular diseases Disorders Inducing Pulmonary Arterial Constriction Metabolic acidosis Hypoxemia Chronic altitude sickness Obstruction to major airways Idiopathic alveolar hypoventilation
566
hypertension, cor pulmonale may be acute or chronic. Acute cor pulmonale can follow massive pulmonary embolism. Chronic cor pulmonale usually implies right ventricular
hypertrophy (and dilation) secondary to prolonged pressure overload owing to obstruction of the pulmonary arteries or arterioles or compression or obliteration of septal capillaries (e.g., owing to primary pulmonary hypertension or emphysema). MORPHOLOGY.
In acute cor pulmonale, there is marked dilation of the right ventricle without hypertrophy. On cross-section, the normal crescent shape of the right ventricle is transformed to a dilated ovoid. In chronic cor pulmonale, the ventricular wall thickens, sometimes up to 1.0 cm or more, and may even come to approximate that of the left ventricle (Fig. 13-13) . More subtle stages of right ventricular hypertrophy may be observed as thickening of the muscle bundles in the outflow tract, immediately below the pulmonary valve, or of the moderator band, the muscle bundle that connects the ventricular septum to the anterior right ventricular papillary muscle. Sometimes, there is secondary compression of the left ventricular chamber or tricuspid regurgitation with fibrous thickening of this valve. Valvular Heart Disease Valvular involvement by disease causes stenosis, insufficiency (regurgitation), or both. Stenosis is the failure of a
Figure 13-13 Chronic cor pulmonale characterized by a markedly dilated and hypertrophied right ventricle, with thickened free wall
and hypertrophied trabeculae (apical four-chamber view of the heart, right ventricle on the left). The shape of the left ventricle (to the right) has been distorted by the right ventricular enlargement. Compare with Figure 13-12 .
valve to open completely, thereby impeding forward flow. Insufficiency, regurgitation, or incompetence, in contrast, results from failure of a valve to close completely, thereby allowing reversed flow. These abnormalities can be either pure, when only stenosis or regurgitation is present, or mixed, when both stenosis and regurgitation coexist in the same valve, but one of these defects usually predominates. Dysfunction may affect a single valve ( isolated disease) or multiple valves ( combined disease). Functional regurgitation results when a valve becomes incompetent owing to ventricular dilation, which causes the right or left ventricular papillary muscles to be pulled down and outward, thereby preventing coaptation of otherwise intact leaflets during systole. Abnormalities of flow often produce abnormal heart sounds known as murmurs. Valvular dysfunction can vary in degree from slight and physiologically unimportant to severe and rapidly fatal. The clinical consequences depend on the valve involved, the degree of impairment, the rate of its development, and the rate and quality of compensatory mechanisms. [42] For example, sudden destruction of an aortic valve cusp by infection (as in infective endocarditis; see later) may cause rapidly fatal cardiac failure owing to massive regurgitation. In contrast, rheumatic mitral stenosis usually develops over years, and its clinical effects may be remarkably well tolerated. Depending on degree, duration, and cause, valvular stenosis or insufficiency often produces secondary changes in the heart, blood vessels, and other organs, both
proximal and distal to the valvular lesion. Most important are the myocardial hypertrophy and pulmonary and systemic changes discussed earlier. Moreover, a patch of endocardial thickening often occurs at the point where a jet lesion impinges, such as the focal endocardial fibrosis in the left atrium secondary to a regurgitant jet of mitral insufficiency. Valvular abnormalities may be caused by congenital disorders (see later) or by a variety of acquired diseases. Most frequent are acquired stenoses of the mitral and aortic valves, which account for approximately two thirds of all valve lesions. Valvular insufficiency may result from either intrinsic disease of the valve cusps or damage to or distortion of the supporting structures (e.g., the aorta, mitral annulus, tendinous cords, papillary muscles, ventricular free wall) without primary changes in the cusps. It may appear acutely with infective endocarditis or chronically with leaflet scarring and retraction. In contrast, valvular stenosis almost always is due to a primary cuspal abnormality and is virtually always a chronic process. The most important causes of acquired heart valve dysfunction are summarized in Table 13-6 and are discussed in the following sections. In contrast to the many potential causes of valvular insufficiency, only a relatively few mechanisms commonly produce acquired valvular stenosis. The most frequent chronic causes of the major functional valvular lesions are as follows: Mitral stenosis--rheumatic heart disease Mitral insufficiency--myxomatous degeneration (mitral valve prolapse) Aortic stenosis--calcification of anatomically normal and congenitally bicuspid aortic valves 567
Aortic insufficiency--dilation of the ascending aorta, related to hypertension and aging
TABLE 13-6 -- MAJOR CAUSES OF ACQUIRED HEART VALVE DISEASE Mitral Valve Disease Aortic Valve Disease Mitral Stenosis
Aortic Stenosis
Postinflammatory scarring (rheumatic heart disease)
Postinflammatory scarring (rheumatic heart disease) Senile calcific aortic stenosis Calcification of congenitally deformed valve
Mitral Regurgitation
Aortic Regurgitation
Abnormalities of leaflets and commissures
Intrinsic valvular disease
Postinflammatory scarring Infective endocarditis Mitral valve prolapse Abnormalities of tensor apparatus
Postinflammatory scarring (rheumatic heart disease) Infective endocarditis Aortic disease Degenerative aortic dilation
Rupture of papillary muscle
Syphilitic aortitis
Papillary muscle dysfunction (fibrosis)
Ankylosing spondylitis
Rupture of chordae tendineae
Rheumatoid arthritis
Abnormalities of left ventricular cavity and/or annulus
Marfan syndrome
Left ventricular enlargement (myocarditis, dilated cardiomyopathy) Calcification of mitral annulus Modified from Schoen FJ: Surgical pathology of removed natural and prosthetic valves. Hum Pathol 18:558, 1987.
VALVULAR DEGENERATION CAUSED BY CALCIFICATION
The heart valves are subjected to high repetitive mechanical stresses, particularly at the hinge points of the cusps and leaflets owing to (1) 40 million or more cardiac cycles per year, (2) substantial tissue deformations at each cycle, and (3) transvalvular gradients in the closed phase of approximately 120 mm Hg for the mitral and 80 mm Hg for the aortic valve. It is therefore not surprising that these normally delicate structures can suffer cumulative damage complicated by deposition of calcium phosphate mineral, which may lead to clinically important disease (Chapter 1) . The most frequent calcific valvular diseases (Fig. 13-14) are calcific aortic stenosis, calcification of a congenitally bicuspid aortic valve, and mitral annular calcification. Each comprises primarily dystrophic calcification with less prominent lipid deposition and cellular proliferation, a process that is distinct from but with some features of atherosclerosis. [43] Calcific Aortic Stenosis
Aortic stenosis is the most frequent of all valvular abnormalities; it can be congenital (when the valvular obstruction is present from birth) or acquired. Acquired aortic stenosis is usually the consequence of either calcification induced by wear and tear of congenitally bicuspid (or unicuspid) valves (see later) or calcification of aortic valves with previous normal anatomy in aged individuals. The overwhelming majority of cases represent age-related degenerative calcification. With the decline in the incidence of rheumatic fever in North America, rheumatic aortic stenosis now accounts for less than 10% of cases of acquired
Figure 13-14 Valvular calcific degeneration. A , Degenerative calcific aortic stenosis of a previously normal valve having three cusps (viewed from the aortic aspect). Nodular masses of calcium are heaped up within the sinuses of Valsalva (arrow). Note that the commissures are not fused, as in postrheumatic aortic valve stenosis (see Fig. 13-16 E ). B , Calcific aortic stenosis occurring on a congenitally bicuspid valve. One cusp has a partial fusion at its center, called a raphe (arrow). C and D, Mitral annular calcification with calcific nodules at the base (attachment margin) of the anterior mitral leaflet (arrows) . C, Left atrial view; D, cut section of
myocardium.
568
aortic stenosis. Aortic stenosis comes to clinical attention primarily in individuals in their fifties to sixties with congenitally bicuspid valves (see later) but not until the seventies and eighties with previously normal valves having three cusps; hence the term senile calcific aortic stenosis to describe the latter condition. MORPHOLOGY.
The morphologic hallmark of nonrheumatic, calcific aortic stenosis (with either tricuspid or bicuspid valves) is heaped-up calcified masses within the aortic cusps that ultimately protrude through the outflow surfaces into the sinuses of Valsalva, preventing the opening of the cusps. The calcific deposits distort the cuspal architecture, primarily at the bases; the free cuspal edges are usually not involved (Fig. 13-14 A). The calcific process begins in the valvular fibrosa, at the points of maximal cusp flexion (the margins of attachment), and the microscopic layered architecture is largely preserved. An earlier hemodynamically insignificant stage of the calcification process is called aortic valve sclerosis. Notably, in contrast to rheumatic aortic stenosis (see Fig. 13-16 E), commissural fusion is usually absent in degenerative aortic stenosis. By the time these changes are seen at surgical resection or postmortem examination, however, the cusps may be fibrosed and thickened and the commissures fused. The mitral valve is generally normal in patients with calcific aortic stenosis, other than mitral annular calcification or direct extension of aortic valve calcific deposits onto the mitral anterior leaflet. In contrast, virtually all patients with rheumatic aortic stenosis have concomitant and characteristic structural abnormalities of the mitral valve (see later). Clinical Features.
In calcific aortic stenosis or calcification of a bicuspid aortic valve, the obstruction to left ventricular outflow leads to a gradually increasing pressure gradient across the calcified valve, which may reach 75 to 100 mm Hg in severe cases. Left ventricular pressure must consequently rise to 200 mm Hg or more in such instances, and cardiac output is maintained by the development of concentric left ventricular (pressure overload) hypertrophy. Eventually as the stenosis worsens, angina or syncope may appear. Angina is probably a consequence of impaired microcirculatory perfusion of the
hypertrophied myocardium, but the basis of syncope is poorly understood. Eventually, cardiac decompensation with congestive heart failure may ensue. The onset of such symptoms (angina, syncope, or congestive heart failure) in aortic stenosis heralds the exhaustion of compensatory cardiac hyperfunction and carries a poor prognosis if not treated by surgery, with death, sometimes sudden, occurring in more than 50% of patients within 3 years. Because the rate of development of valvular obstruction varies greatly among patients, noninvasive techniques, such as Doppler echocardiography (which measures flow velocities as well as structure), can be used repetitively to examine the progression of disease with time. Calcification of a Congenitally Bicuspid Aortic Valve
An estimated 1 to 2% of the population has a congenitally bicuspid aortic valve as an isolated abnormality. The two cusps are usually of unequal size, with the larger cusp having a midline raphe, resulting from the incomplete embryologic separation; less frequently the cusps are of the same size and the raphe is absent. Valves that become bicuspid owing to an acquired deformity (e.g., postinflammatory commissural fusion in rheumatic valve disease) have a conjoined cusp containing the fused commissure that is generally twice the size of the nonconjoined cusp. The mitral valve is normal in patients with a congenitally bicuspid aortic valve. Bicuspid aortic valves are generally neither stenotic nor symptomatic at birth or throughout early life, but they are predisposed to progressive degenerative calcification, similar to that occurring in aortic valves with initially normal anatomy (Fig. 13-14 B). The raphe that composes the incomplete commissure is frequently a major site of calcific deposits. Once stenosis is present, the clinical course is similar to that described earlier for calcific aortic stenosis. Bicuspid aortic valves may also become incompetent as a result of aortic dilation or cusp prolapse, and they are predisposed to infective endocarditis. They are also associated with aortic coarctation, aneurysm, and dissection, for inexplicable reasons. Mitral Annular Calcification
Degenerative calcific deposits can develop in the ring ( annulus) of the mitral valve, visualized on gross inspection as irregular, stony hard, and occasionally ulcerated nodules (2 to 5 mm in thickness) that lie behind the leaflets (Fig. 13-14 C). The process generally does not affect valvular function. In unusual cases, however, it may lead to regurgitation by interfering with systolic contraction of the mitral valve ring, to stenosis by impairing opening of the mitral leaflets, or to arrhythmias and occasionally sudden death by the calcium deposits penetrating sufficiently deeply to impinge on the AV conduction system. Because ulcerated calcific nodules may provide a site for thrombi that can embolize, some patients with mitral annular calcification have an increased risk of stroke. The calcific nodules can also be the nidus for infective endocarditis. Heavy calcific deposits are sometimes visualized on echocardiography or seen as a distinctive, ringlike opacity on chest radiographs. Mitral annular calcification is most common in women over 60 years of age and individuals with myxomatous mitral valve (see later) or elevated left ventricular pressure (as in systemic hypertension, aortic stenosis, or
hypertrophic cardiomyopathy, discussed later). MYXOMATOUS DEGENERATION OF THE MITRAL VALVE (MITRAL VALVE PROLAPSE)
Myxomatous degeneration of the mitral valve (mitral valve prolapse) is estimated to affect 3% or more of adults
569
in the United States, most often young women, and is considered the most common form of valvular heart disease in the industrialized world. In this valvular abnormality, one or both mitral leaflets are enlarged, hooded, redundant or floppy, and prolapse or balloon back into the left atrium during systole. Usually an incidental finding on physical examination, mitral valve prolapse, as it is known clinically, may lead to serious complications in a small minority of those who are affected. MORPHOLOGY.
The characteristic anatomic change in myxomatous degeneration is intercordal ballooning (hooding) of the mitral leaflets or portions thereof (Fig. 13-15) . The affected leaflets are often thick and rubbery. Frequently involved, the tendinous cords are elongated, thinned, and occasionally ruptured. Annular dilation is characteristic, a finding that is rare in other causes of mitral insufficiency. Concomitant involvement of the tricuspid valve is present in 20 to 40% of cases, and the aortic or pulmonic valve (or both) may also be affected. Commissural fusion, which typifies rheumatic heart disease, is absent. Histologically the essential change is attenuation of the fibrosa layer of the valve, on which the structural integrity of the leaflet depends, accompanied by focally marked thickening of the spongiosa layer with deposition of mucoid (myxomatous) material. The collagenous structure of the cords is attenuated. Secondary changes reflect the stresses and injury incident to the billowing leaflets: (1) fibrous thickening of the valve leaflets, particularly where they rub against each other; (2) linear fibrous thickening of the left ventricular endocardial surface where abnormally long cords snap against it; (3) thickening of the mural endocardium of the left atrium as a consequence of friction-induced injury induced by the prolapsing leaflets; (4) thrombi on the atrial surfaces of the leaflets, particularly in the recesses behind the ballooned
Figure 13-15 Myxomatous degeneration of the mitral valve. A , Long axis view of the left ventricle demonstrating hooding with prolapse of the posterior mitral leaflet into the left atrium (arrow). The left ventricle is on the right. (Courtesy of William D. Edwards, MD, Mayo Clinic, Rochester, MN.) B , Opened valve showing pronounced hooding of the posterior mitral leaflet with thrombotic plaques at sites of leaflet-left atrium contact (arrows) . C, Opened valve with pronounced hooding from a patient who died suddenly. Note also the
mitral annular calcification.
570
cusps and on the atrial walls they contact; and (5) focal calcifications at the base of the posterior mitral leaflet. Changes of myxomatous degeneration can also occur secondarily in mitral valves having regurgitation due to another cause (e.g., ischemic dysfunction). Pathogenesis.
The basis for the changes within the valve leaflets and associated structures is unknown. Favored is the proposition of a developmental anomaly of connective tissue, because this valvular abnormality is one common feature of Marfan syndrome caused by mutations in the gene encoding fibrillin (Chapter 6) and occasionally occurs with other hereditary disorders of connective tissue. Even in the absence of these well-defined conditions, there are hints of extracardiac systemic structural abnormalities in some individuals with the floppy mitral valve syndrome, such as scoliosis, straight back, and high-arched palate. Subtle defects in structural proteins may predispose connective tissues rich in microfibrils and elastin (such as cardiac valves) to damage by long-standing hemodynamic stress. A fibrillin mutation has been found in a patient with the so-called MASS phenotype (which includes mitral valve prolapse and borderline aortic dilation without dissection as prominent features). [44] Clinical Features.
Most patients with mitral valve prolapse are asymptomatic, and the condition is discovered only on routine examination by the presence of a midsystolic click. It is usually an incidental finding on physical examination but in a small fraction of those affected may lead to serious complications. Auscultation may reveal a midsystolic click or clicks corresponding to snapping or tensing of an everted cusp, scallop, or tendinous cord. The valve may become incompetent, and the mitral regurgitation induces an accompanying late systolic or sometimes holosystolic murmur. Echocardiography reveals varying degrees of mitral valve prolapse. A minority of patients have chest pain mimicking angina, dyspnea, and fatigue or, curiously, psychiatric manifestations, such as depression, anxiety reactions, and personality disorders. Although the great majority of patients with mitral valve prolapse have no untoward effects, approximately 3% develop any of four serious complications: Infective endocarditis, manyfold more frequent in these patients than in the general population Mitral insufficiency requiring surgery, either slow onset attributed to leaflet deformity, dilation of the mitral annulus, or cordal lengthening, or sudden owing to cordal rupture Stroke or other systemic infarct, resulting from embolism of leaflet or atrial wall thrombi Arrhythmias: Both ventricular and atrial arrhythmias can develop. Sudden death can occur but is uncommon. The mechanism of ventricular arrhythmia is unknown in
most cases. The risk of these complications is higher in men, older patients, and those with either arrhythmias or some mitral regurgitation, as evidenced by holosystolic murmurs and left-sided chamber enlargement. [45] RHEUMATIC FEVER AND RHEUMATIC HEART DISEASE
Rheumatic fever is an acute, immunologically mediated, multisystem inflammatory disease that occurs a few weeks after an episode of group A (beta -hemolytic) streptococcal pharyngitis and often involves the heart. Acute rheumatic carditis, which complicates the active phase of rheumatic fever, may progress to chronic valvular deformities. Rheumatic fever does not follow infections by other strains of streptococci at other sites, such as the skin. The incidence and mortality rate of rheumatic fever have declined remarkably in many parts of the world over the past 30 years owing to improved socioeconomic conditions, rapid diagnosis and treatment of streptococcal pharyngitis, and an unexplained decrease in the virulence of group A streptococci. [46] Nevertheless, in third world countries and in many crowded, economically depressed urban areas in the Western world, rheumatic fever remains an important public health problem. Fortunately, rheumatic fever occurs in only about 3% of patients with group A streptococcal pharyngitis. After an initial attack, however, there is increased vulnerability to reactivation of the disease with subsequent pharyngeal infections. Rheumatic fever is characterized by a constellation of findings that includes as major manifestations (1) migratory polyarthritis of the large joints, (2) carditis, (3) subcutaneous nodules, (4) erythema marginatum of the skin, and (5) Sydenham chorea-- a neurologic disorder with involuntary purposeless, rapid movements. The diagnosis is established by the so-called Jones criteria: evidence of a preceding group A streptococcal infection, with the presence of either two of the major manifestations just listed or one major and two minor manifestations (nonspecific signs and symptoms, which include fever, arthralgia, or elevated acute-phase reactants). The most important consequence of rheumatic fever is chronic rheumatic heart disease, characterized principally by deforming fibrotic valvular disease (particularly mitral stenosis), which can produce permanent dysfunction and severe, sometimes fatal, cardiac dysfunction decades later. MORPHOLOGY.
Key pathologic features of acute rheumatic fever and chronic rheumatic heart disease are summarized in Figure 13-16 . During acute rheumatic fever, widely disseminated but focal inflammatory lesions are found in various sites. They are most distinctive within the heart where they are called Aschoff bodies. They constitute foci of fibrinoid degeneration surrounded by lymphocytes (primarily T cells), occasional plasma cells, and plump macrophages called Anitschkow cells (pathognomonic for rheumatic fever). These distinctive cells have abundant amphophilic cytoplasm and central round-to-ovoid nuclei in which the chromatin is disposed in a central, slender, wavy ribbon (hence the designation caterpillar cells). Some of the larger altered histiocytes become
multinucleated to form Aschoff giant cells.
571
Figure 13-16 Acute and chronic rheumatic heart disease. A , Acute rheumatic mitral valvulitis superimposed on chronic rheumatic heart disease. Small vegetations (verrucae) are visible along the line of closure of the mitral valve leaflet (arrowheads). Previous episodes of rheumatic valvulitis have caused fibrous thickening and fusion of the tendinous cords. B , Microscopic appearance of an
Aschoff body in a patient with acute rheumatic carditis. The myocardial interstitium has a circumscribed collection of mononuclear inflammatory cells, including some large histiocytes with prominent nucleoli, a prominent binuclear histiocyte, and central necrosis. C and D, Mitral stenosis with diffuse fibrous thickening and distortion of the valve leaflets, commissural fusion (arrow in C), and thickening and shortening of the tendinous cords. Marked dilation of the left atrium is noted in the left atrial view ( C). D, Opened valve. Note the neovascularization of the anterior mitral leaflet (arrow). E , Surgically removed specimen of rheumatic aortic stenosis demonstrating thickening and distortion of the cusps with commissural fusion ( E from Schoen FJ, St. John-Sutton M: Contemporary issues in the pathology of valvular heart disease. Hum Pathol 18:568, 1967.)
During acute rheumatic fever, diffuse inflammation and Aschoff bodies may be found in any of the three layers of the heart--pericardium, myocardium, or endocardium--hence a pancarditis. In the pericardium, they are accompanied by a fibrinous or serofibrinous pericardial exudate, described as a bread-and-butter pericarditis, which generally resolves without sequelae. The myocardial involvement-- myocarditis--takes the form of scattered Aschoff bodies within the interstitial connective tissue, often perivascular. Concomitant involvement of the endocardium and the left-sided valves by inflammatory foci typically comprises fibrinoid necrosis within the cusps or along the tendinous cords on which sit small (1 to 2 mm) vegetations-- verrucae--along
572
the lines of closure. These irregular, warty projections probably result from the precipitation of fibrin at sites of erosion related to underlying inflammation and fibrinoid degeneration. These acute valvular changes cause little disturbance in cardiac function. Subendocardial lesions, perhaps exacerbated by regurgitant jets, may induce irregular thickenings called MacCallum plaques, usually in the left atrium. Chronic rheumatic heart disease is characterized by organization of the acute inflammation and subsequent deforming fibrosis. In particular, the valvular leaflets become thickened and retracted, causing permanent deformity. In chronic disease, the mitral valve is virtually always deformed, but involvement of another valve, such as the aortic, may be the most clinically important in some cases. The cardinal anatomic changes of the mitral (or tricuspid) valve are leaflet thickening; commissural fusion; and shortening, thickening, and fusion of the tendinous cords (Fig. 13-16 C and D). Microscopically, there is diffuse fibrosis and often neovascularization that obliterate the originally layered and avascular leaflet architecture. Aschoff bodies are replaced by fibrous scar; diagnostic forms are rarely seen in surgical specimens or autopsy tissue from patients with chronic rheumatic heart
disease at extended intervals after acute rheumatic fever. Rheumatic heart disease is overwhelmingly the most frequent cause of mitral stenosis (99% of cases). In patients with rheumatic heart disease, the mitral valve alone is involved in 65 to 70% of the cases, mitral and aortic in about 25%; similar but generally less severe fibrous thickenings and stenoses can occur in the tricuspid valve and rarely in the pulmonary. Fibrous bridging across the valvular commissures and calcification create fish mouth or buttonhole stenoses. With tight mitral stenosis, the left atrium progressively dilates and may harbor mural thrombus either in the appendage or along the wall. The long-standing congestive changes in the lungs may induce pulmonary vascular and parenchymal changes and in time lead to right ventricular hypertrophy. The left ventricle is normal with isolated pure mitral stenosis. Pathogenesis.
It is strongly suspected that acute rheumatic fever is a hypersensitivity reaction induced by group A streptococci, but the exact pathogenesis remains uncertain. [47] It is proposed that antibodies directed against the M proteins of certain strains of streptococci cross-react with tissue glycoproteins in the heart, joints, and other tissues. The onset of symptoms usually 2 to 3 weeks after infection and the absence of streptococci from the lesions support the concept that rheumatic fever results from an immune response against the offending bacteria. Because the nature of cross-reacting antigens has been difficult to define, it has also been suggested that the streptococcal infection evokes an autoimmune response against self-antigens. Because only a minority of infected patients develop rheumatic fever, it is suspected that genetic susceptibility regulates the hypersensitivity reaction. The proposed pathogenetic sequence is summarized in Figure 13-17 . The chronic sequelae result from progressive fibrosis because of both healing of the acute inflammatory lesions and the turbulence induced by ongoing valvular deformities. Clinical Features.
Acute rheumatic fever occurs from 10 days to 6 weeks after an episode of pharyngitis caused by group A streptococci. Acute rheumatic fever appears most often in children between the ages of 5 and 15 years, but about 20% of first attacks occur in middle to later life. Although pharyngeal cultures for streptococci are negative by the time the illness begins, antibodies to one or more streptococcal enzymes, such as streptolysin O and DNAse B, are present and can be detected in the sera of most patients. The predominant clinical manifestations are those of arthritis and carditis. Far more common in adults than in children, arthritis typically begins with migratory polyarthritis accompanied by fever in which one large joint after another becomes painful and swollen for a period of days and then subsides spontaneously, leaving no residual disability. Clinical features related to acute carditis include pericardial friction rubs, weak heart sounds, tachycardia, and arrhythmias. The myocarditis may cause cardiac dilation that may evolve to functional mitral valve insufficiency or even heart failure. Overall the prognosis for the primary attack is generally good, and only 1% of patients die from fulminant rheumatic fever.
After an initial attack, there is increased vulnerability to reactivation of the disease with subsequent pharyngeal infections, and the same manifestations are likely to appear with each recurrent attack. Carditis is likely to worsen with each recurrence, and damage is cumulative. Other hazards include embolization from mural thrombi, primarily within the atria or their appendages, and infective endocarditis superimposed on deformed valves. Chronic rheumatic carditis usually does not cause clinical manifestations for years or even decades after the initial episode of rheumatic fever. The signs and symptoms of valvular disease depend on which cardiac valve or valves are involved. In addition to various cardiac murmurs, cardiac hypertrophy and dilation, and heart failure, patients with chronic rheumatic heart disease may suffer from arrhythmias (particularly atrial fibrillation in the setting of mitral stenosis), thromboembolic complications, and infective endocarditis. The long-term prognosis is highly variable. In some cases, there is a relentless cycle of valvular deformity yielding hemodynamic abnormality, which begets further deforming fibrosis. Surgical replacement of diseased valves with prosthetic devices has greatly improved the outlook for patients with rheumatic heart disease. INFECTIVE ENDOCARDITIS
Infective endocarditis, one of the most serious of all infections, is characterized by colonization or invasion of the heart valves, the mural endocardium, or other cardiovascular sites by a microbiologic agent, leading to the formation of bulky, friable vegetations composed of thrombotic debris and organisms, often associated with destruction
573
Figure 13-17 The pathogenetic sequence and key morphologic features of acute rheumatic heart disease.
of the underlying cardiac tissues. The aorta, aneurysmal sacs, other blood vessels, and prosthetic devices can also become infected. Although fungi, rickettsiae (Q fever), and chlamydiae have at one time or another been responsible for these infections, most cases are bacterial; hence the usual term bacterial endocarditis. Prompt diagnosis and effective treatment of endocarditis can significantly alter the outlook for the patient. Traditionally, endocarditis has been classified on clinical grounds into acute and subacute forms. This subdivision expresses the range of severity of the disease and its tempo, determined in large part by the virulence of the infecting microorganism and the presence of underlying cardiac disease. Acute endocarditis describes a destructive, tumultuous infection, frequently of a previously normal heart valve with a highly virulent organism, that leads to death within days to weeks of more than 50% of patients despite antibiotics and surgery. In contrast, organisms of low virulence can cause infection in a previously abnormal heart, particularly on deformed valves. In such cases, the disease may appear insidiously and, even untreated, pursue a protracted course of weeks to
months ( subacute endocarditis). Most patients with subacute infective endocarditis recover after appropriate therapy. The highly virulent organisms of acute endocarditis tend to produce necrotizing, ulcerative, invasive valvular infections, whereas the lower virulence organisms of subacute disease are less destructive, and the vegetations often show
574
evidence of healing. Both the clinical and the morphologic patterns, however, are points along a spectrum, and a clear delineation between acute and subacute disease does not always exist. Cause and Pathogenesis.
As stated previously, infective endocarditis may develop on previously normal valves, but a variety of cardiac and vascular abnormalities predispose to this form of infection. In years past, rheumatic heart disease was the major contributor, but now more common is myxomatous mitral valve, degenerative calcific valvular stenosis, bicuspid aortic valve (whether calcified or not), and artificial (prosthetic) valves and vascular grafts. Host factors such as neutropenia, immunodeficiency, therapeutic immunosuppression, diabetes mellitus, and alcohol or intravenous drug abuse are predisposing influences. Sterile platelet-fibrin deposits that accumulate at sites of impingement of jet streams caused by preexisting cardiac disease or indwelling vascular catheters may also be important in the development of endocarditis. The causative organisms differ somewhat in the major high-risk groups. Endocarditis of native but previously damaged or otherwise abnormal valves is caused most commonly (50 to 60% of cases) by alpha-hemolytic (viridans) streptococci; this is not the organism responsible for rheumatic disease discussed earlier. In contrast, the more virulent Staphylococcus aureus organisms commonly found on the skin can attack either healthy or deformed valves; they are responsible for 10 to 20% of cases overall and are the major offender in intravenous drug abusers. The roster of the remaining bacteria includes enterococci and the so-called HACEK group ( Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella), all commensals in the oral cavity. Prosthetic valve endocarditis is caused most commonly by coagulase-negative staphylococci (e.g., Staphylococcus epidermidis). Other agents causing endocarditis include gram-negative bacilli and fungi. In about 10% of all cases of endocarditis, no organism can be isolated from the blood ( culture-negative endocarditis) because of prior antibiotic therapy, other difficulties in isolation of the offending agent, or deeply embedded organisms within the enlarging vegetation are not released into the blood. Foremost among the factors predisposing to the development of endocarditis is seeding of the blood with microbes. The portal of entry of the agent into the bloodstream may be an obvious infection elsewhere; a dental or surgical procedure that causes a bacteremia; injection of contaminated material directly into the bloodstream by
intravenous drug users; or an occult source from the gut, oral cavity, or trivial injuries. Recognition of predisposing anatomic substrates and clinical conditions causing bacteremia facilitates prevention by appropriate antibiotic prophylaxis. [48] MORPHOLOGY.
Both the subacute and the acute forms of the disease have friable, bulky, and potentially destructive vegetations containing fibrin, inflammatory cells, and bacteria or other organisms, most commonly on the heart valves (Fig. 13-18) . The aortic and mitral valves are the most common sites of infection, although the valves of the right side of the heart may also be involved, particularly in intravenous drug abusers. The vegetations may be single or multiple and may involve more than one valve. Vegetations are often destructive and sometimes erode into the underlying myocardium to produce an abscess cavity ( ring abscess), one of several important complications (Fig. 13-18 B). The appearance of the vegetations is influenced by the type of organism responsible, the degree of host reaction to the infection, and previous antibiotic therapy. Fungal endocarditis, for example, tends to cause larger vegetations than does bacterial infection. In the subacute form of the disease, vegetations are smaller and less often erode or perforate the cusps. Systemic emboli may occur at any time because of the friable nature of the vegetations, and they may cause infarcts in the brain, kidneys, myocardium, and other tissues. Because the embolic fragments contain large numbers of virulent organisms, abscesses often develop at the sites of such infarcts ( septic infarcts). Microscopically the vegetations of typical subacute infective endocarditis often have granulation tissue at their bases. With the passage of time, fibrosis, calcification, and a chronic inflammatory infiltrate may develop. Figure 13-19 compares the gross appearance of the vegetations of infective endocarditis with those of the valve lesions characterized by noninfective thrombotic vegetations (nonbacterial thrombotic endocarditis [NBTE]) and the endocarditis of systemic lupus erythematosus, called Libman-Sacks endocarditis (see later). Clinical Features.
Fever is the most consistent sign of infective endocarditis. With subacute disease, however, particularly in the elderly, fever may be slight or absent, and the only manifestations are sometimes nonspecific fatigue, loss of weight, and a flulike syndrome. Murmurs are present in 90% of patients with left-sided lesions but may merely relate to the preexisting cardiac abnormality predisposing to endocarditis. The previously important clinical findings of petechiae, subungual hemorrhages, and Roth spots in the eyes (secondary to retinal microemboli) have now become uncommon owing to the shortened clinical course of the disease as a result of antibiotic therapy. In contrast, acute endocarditis has a stormy onset with rapidly developing fever, chills, weakness, and lassitude. Complications generally begin within the first weeks of the onset of the disease. Murmur is common because of the large size of the vegetations or leaflet destruction. Ring abscess is frequent, and the vegetations are also more likely to
embolize. Sometimes complications involving the heart or extracardiac sites call attention to endocarditis. They include the following: Cardiac complications: Valvular insufficiency or stenosis with cardiac failure Myocardial ring abscess, with possible perforation of 575
576
aorta, interventricular septum or free wall, or invasion of the conduction system Suppurative pericarditis With endocarditis on artificial valves, partial dehiscence with paravalvular leak Embolic complications: With left-sided lesions--to the brain (cerebral infarct or abscess, meningitis), heart (MI), spleen (abscess), kidneys (abscess), other sites With right-sided lesions--to the lungs (infarct, abscess, pneumonia) Renal complications: Embolic infarction Focal and diffuse glomerulonephritis, owing to trapping of antigen-antibody complexes, which may lead to hematuria, albuminuria, or renal failure (Chapter 21) Multiple abscesses--especially with acute staphylococcal endocarditis
Figure 13-18 Bacterial infective endocarditis. A , Endocarditis of the mitral valve (subacute, caused by Streptococcus viridens ). The irregular, large friable vegetations are denoted by arrows. B , Acute endocarditis of a congenitally bicuspid aortic valve (caused by Staphylococcus aureus ) with severe cuspal destruction and ring abscess (arrow). C, Histologic appearance of vegetation of endocarditis with extensive acute inflammatory cells and fibrin. Bacterial organisms were demonstrated by tissue Gram stain. D, Gross
photograph illustrating healed endocarditis with perforations on bicuspid aortic valve.
Figure 13-19 Diagrammatic comparison of the lesions in the four major forms of vegetative endocarditis. The rheumatic fever phase
of RHD (rheumatic heart disease) is marked by a row of warty, small vegetations along the lines of closure of the valve leaflets. IE (infective endocarditis) is characterized by large, irregular masses on the valve cusps that can extend onto the cords (see Fig. 13-18 A ). NBTE (nonbacterial thrombotic endocarditis) typically exhibits small, bland vegetations, usually attached at the line of closure. One or many may be present (see Fig. 13-20) . LSE (Libman-Sacks endocarditis) has small or medium-sized vegetations on either or both sides of the valve leaflets.
Although the diagnosis can be suspected based on the appearance of one or more of the complications mentioned, a positive blood culture is required for confirmation. With repeated blood samples, positive cultures can be obtained in about 90% of cases. As important as the diagnosis of infective endocarditis is its prevention by the prophylactic
use of antibiotics in the patient with some form of cardiac anomaly or artificial valve who is about to have a dental, surgical, or other invasive procedure. NONINFECTED VEGETATIONS Nonbacterial Thrombotic Endocarditis
NBTE is characterized by the deposition of small masses of fibrin, platelets, and other blood components on the leaflets of the cardiac valves. In contrast to the vegetations of infective endocarditis, discussed previously, the valvular lesions of NBTE are sterile, do not contain microorganisms, and are only loosely attached to the underlying valve. NBTE is often encountered in debilitated patients, such as those with cancer or sepsis--hence the previously used term marantic endocarditis. Although the local effect on the valves is unimportant, NBTE may achieve clinical significance by producing emboli and resultant infarcts in the brain, heart, or elsewhere. MORPHOLOGY.
NBTE is characterized by the deposition of masses of fibrin and other blood elements on the valve leaflets of either side of the heart, usually on previously normal valves. In contrast to infective endocarditis, the vegetations of NBTE are sterile, nondestructive, noninflammatory, and small (1 to 5 mm) and occur singly or multiply along the line of closure of the leaflets or cusps (Fig. 13-20) . Histologically, they are composed of bland thrombus without accompanying inflammatory reaction or induced valve damage. Should the patient survive the underlying disease, organization may occur, leaving delicate strands of fibrous tissue. Pathogenesis.
NBTE frequently occurs concomitantly with venous thromboses or pulmonary embolism, suggesting a common origin in a hypercoagulable state with systemic activation of blood coagulation such as disseminated intravascular coagulation. This may be related to some underlying disease, such as a cancer and, in particular, mucinous adenocarcinomas of the pancreas. The striking association with mucinous adenocarcinomas in general may relate to the procoagulant effect of circulating mucin, and thus NBTE can be a part of the Trousseau syndrome. Lesions of NBTE, however, are also seen occasionally in association with non-mucin-producing malignancy, such as acute promyelocytic leukemia, and in other debilitating diseases
Figure 13-20 Nonbacterial thrombotic endocarditis (NBTE). A , Nearly complete row of thrombotic vegetations along the line of closure of the mitral valve leaflets. B , Photomicrograph of NBTE showing bland thrombus, with virtually no inflammation in the valve cusp (c) or the thrombotic deposit. The thrombus is only loosely attached to the cusp (arrow).
577
or conditions promoting hypercoagulability (e.g., hyperestrogenic states, extensive burns, or sepsis). Endocardial trauma as from an indwelling catheter is also a well-recognized predisposing condition, and one frequently encounters right-sided valvular and endocardial thrombotic lesions along the track of a Swan-Ganz pulmonary artery catheter. Endocarditis of Systemic Lupus Erythematosus (Libman-Sacks Endocarditis)
In systemic lupus erythematosus, mitral and tricuspid valvulitis with small, sterile vegetations called Libman-Sacks endocarditis is occasionally encountered. Thrombotic heart valve lesions with sterile vegetations or rarely fibrous thickening commonly occur with the antiphospholipid syndrome [49] (Chapter 7) . Circulating antiphospholipid antibodies are also commonly associated with venous or arterial thrombosis, recurrent pregnancy loss, or thrombocytopenia. The mitral valve is more frequently involved than the aortic; regurgitation is the usual functional abnormality. MORPHOLOGY.
The lesions are small single or multiple, sterile, granular pink vegetations ranging from 1 to 4 mm in diameter. Frequently the lesions are located on the undersurfaces of the AV valves, but they may be scattered on the valvular endocardium, on the cords, and on the mural endocardium of atria or ventricles. Histologically the verrucae consist of a finely granular, fibrinous eosinophilic material that may contain hematoxylin bodies (the tissue equivalent of the lupus erythematosus cell of the blood and bone marrow; Chapter 7) . An intense valvulitis may be present, characterized by fibrinoid necrosis of the valve substance that is often contiguous with the vegetation. Leaflet vegetations can be difficult in some cases to distinguish from those of infectious endocarditis or NBTE. Subsequent fibrosis and serious deformity can result that resemble chronic rheumatic heart disease and require surgery. CARCINOID HEART DISEASE
Principally involving the endocardium and valves of the right side of the heart, cardiac lesions involve one half of patients with the carcinoid syndrome, itself characterized by episodic flushing of the skin, cramps, nausea, vomiting, and diarrhea (Chapter 18) . MORPHOLOGY.
The cardiovascular lesions associated with the carcinoid syndrome are distinctive, comprising fibrous intimal thickenings on the inside surfaces of the cardiac chambers and valvular leaflets, mainly in the right ventricle and tricuspid and pulmonic valves, and occasionally the major blood vessels (Fig. 13-21) . The endocardial plaquelike thickenings are composed predominantly of smooth muscle cells and sparse collagen fibers embedded in an acid mucopolysaccharide-rich matrix material that expands the
endocardium. Elastic fibers are not present. Underlying structures are intact, including the valve layers and the subendocardial elastic tissue layer. Occasionally, left-sided lesions are also encountered. The clinical and pathologic findings relate to the elaboration by carcinoid tumors of a variety of bioactive products, including serotonin (5-hydroxytryptamine), kallikrein, bradykinin, histamine, prostaglandins, and tachykinins. Which of the secretory products induces the syndrome or the cardiac pathology is still not clear, but there is a correlation of the plasma levels of serotonin urinary excretion of the serotonin metabolite 5-hydroxyindoleacetic
Figure 13-21 Carcinoid heart disease. A , Characteristic endocardial fibrotic lesion involving the right ventricle and tricuspid valve. B ,
Microscopic appearance of carcinoid heart disease with intimal thickening. Movat staining shows underlying myocardial elastic tissue as black and acid mucopolysaccharides as blue-green.
578
acid with the severity of the right-sided heart lesions. [50] The fact that the cardiac changes are largely right-sided is explained by inactivation of both serotonin and bradykinin in the blood during passage through the lungs by the monoamine oxidase found in the pulmonary vascular endothelium. In the absence of hepatic metastases, gastrointestinal carcinoids (with venous drainage via the portal system) do not usually induce the carcinoid syndrome because there is rapid metabolism of serotonin during passage of blood through the liver. In contrast, carcinoid tumors primary in organs outside of the portal system of venous drainage (e.g., ovary or lung), whose venous drainage bypasses the liver, may induce the syndrome without antecedent hepatic metastases. Left-sided lesions can occur when blood containing the responsible mediator enters the left side of the heart owing to incomplete inactivation of high blood levels or with a pulmonary carcinoid or patent foramen ovale with right-to-left flow. Rarely, similar left-sided plaques are found in patients who receive methysergide or ergotamine therapy for migraine headaches; these serotonin analogs are metabolized to serotonin as they pass through the pulmonary vasculature. Left-sided valve lesions with pathologic features similar to those seen in the carcinoid syndrome have also been reported to complicate the use of fenfluramine and phentermine ( fen-phen), appetite suppressants used for the treatment of obesity that may affect systemic serotonin metabolism. [51] COMPLICATIONS OF ARTIFICIAL VALVES
Replacement of damaged cardiac valves with prostheses has now become a common and often lifesaving mode of therapy. [52] Artificial valves fall primarily into two categories:
(1) Mechanical prostheses use various rigid, mobile occluders composed of nonphysiologic biomaterials, such as caged balls, tilting discs, or hinged semicircular flaps, and (2) tissue valves are usually bioprostheses that consist of chemically treated animal tissue, especially porcine aortic valve tissue, which has been preserved in a dilute glutaraldehyde solution and subsequently mounted on a frame (called a stent). Tissue valves are flexible and function somewhat like natural semilunar valves. Approximately 60% of substitute valve recipients develop a serious prosthesis-related problem within 10 years postoperatively. [53] Although the frequency of total prosthetic valve-related events is similar among valve categories, the nature of these complications differs among types (Table 13-7 and Fig. 13-22) . Thromboembolic complications constituting local obstruction of the prosthesis by thrombus or distant thromboemboli are the major problem with mechanical valves (Fig. 13-22) ]. This problem necessitates long-term anticoagulation in patients with these devices. Moreover, hemorrhagic complications, such as stroke or gastrointestinal bleeding, may arise secondarily in patients who receive long-term anticoagulation. Infective endocarditis is infrequent but serious. Always with mechanical valves and frequently with bioprostheses, endocarditis is located at the prosthesis-tissue interface, causing a ring abscess, which can eventuate in a paravalvular regurgitant blood leak. In addition, vegetations may directly involve bioprosthetic valvular cusps. The major organisms causing such infections are staphylococcal skin contaminants (e.g., S. aureus, S. epidermidis) and streptococci. Structural deterioration uncommonly causes failure of contemporary mechanical valves. It is a major failure mode of bioprostheses, however, usually with calcification or cuspal tearing, or both, causing secondary regurgitation. Other complications include hemolysis induced by high blood shear, mechanical obstruction to flow inherent in all artificial valves, and dysfunction owing to overgrowth by fibrous tissue.
TABLE 13-7 -- CAUSES OF FAILURE OF CARDIAC VALVE PROSTHESES Thrombosis/thromboembolism Anticoagulant-related hemorrhage Prosthetic valve endocarditis Structural deterioration (intrinsic) Wear, fracture, poppet escape, cuspal tear, calcification Nonstructural dysfunction Pannus, suture/tissue entrapment, paravalvular leak, disproportion, hemolytic anemia, noise
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 13 - The Heart TYPES OF HEART DISEASE - Part 2 Myocardial Disease DILATED CARDIOMYOPATHY MORPHOLOGY Clinical Features HYPERTROPHIC CARDIOMYOPATHY MORPHOLOGY Pathogenesis Clinical Features RESTRICTIVE CARDIOMYOPATHY MORPHOLOGY MYOCARDITIS Cause and Pathogenesis MORPHOLOGY Clinical Features OTHER SPECIFIC CAUSES Doxorubicin and Other Drugs Catecholamines Amyloidosis MORPHOLOGY Iron Overload MORPHOLOGY Hyperthyroidism and Hypothyroidism MORPHOLOGY Pericardial Disease PERICARDIAL EFFUSION AND HEMOPERICARDIUM PERICARDITIS Acute Pericarditis Serous Pericarditis MORPHOLOGY Fibrinous and Serofibrinous Pericarditis MORPHOLOGY Purulent or Suppurative Pericarditis
MORPHOLOGY Hemorrhagic Pericarditis Caseous Pericarditis Healed Pericarditis Adhesive Mediastinopericarditis Constrictive Pericarditis RHEUMATOID HEART DISEASE Neoplastic Heart Disease PRIMARY CARDIAC TUMORS Myxoma MORPHOLOGY Lipoma Papillary Fibroelastoma MORPHOLOGY Rhabdomyoma MORPHOLOGY Sarcoma CARDIAC EFFECTS OF NONCARDIAC NEOPLASMS Congenital Heart Disease Incidence Cause and Pathology Clinical Features LEFT-TO-RIGHT SHUNTS--LATE CYANOSIS Atrial Septal Defect MORPHOLOGY Ventricular Septal Defect MORPHOLOGY Patent Ductus Arteriosus Atrioventricular Septal Defect RIGHT-TO-LEFT SHUNTS--EARLY CYANOSIS Tetralogy of Fallot MORPHOLOGY Transposition of Great Arteries Truncus Arteriosus Tricuspid Atresia Total Anomalous Pulmonary Venous Connection OBSTRUCTIVE CONGENITAL ANOMALIES Coarctation of Aorta
Pulmonary Stenosis and Atresia Aortic Stenosis and Atresia Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
TYPES OF HEART DISEASE - Part 2 Myocardial Disease It should be clear from the previous sections that myocardial dysfunction occurs commonly but secondarily in a
Figure 13-22 Thrombosis of a mechanical prosthetic heart valve.
579
number of different conditions, such as IHD, hypertension, and valvular heart disease. Far less frequently observed is disease whose cause is intrinsic to the myocardium. Myocardial diseases are a diverse group that includes inflammatory disorders ( myocarditis), immunologic diseases, systemic metabolic disorders, muscular dystrophies, genetic abnormalities in cardiac muscle cells, and an additional group of diseases of unknown cause. The term cardiomyopathy (literally, heart muscle disease) could be applied to almost any heart disease but by convention is used to describe heart disease resulting from a primary abnormality in the myocardium. This definition is somewhat arbitrary and often frustrating as one attempts to wade through various classification schemes, [54] [55] because some authors exclude any myocardial disorder of known cause, while others take a more ecumenical view and include any heart disease manifested by primary myocardial dysfunction. Although chronic myocardial dysfunction owing to ischemia should also be excluded from the cardiomyopathy rubric, the term ischemic cardiomyopathy has gained some popularity among clinicians to describe congestive heart failure caused by coronary artery disease. In many cases, cardiomyopathies are idiopathic (i.e., of unknown cause), but in some instances, well-defined myocardial diseases may, in the end, resemble those without known causes, both functionally and structurally. A major advance in understanding of myocardial disease has been the demonstration that specific genetic abnormalities in cardiac energy metabolism or structural and contractile proteins underlie myocardial dysfunction in many patients that previously was considered idiopathic. [57] Thus, etiologic distinctions have become somewhat blurred. Therefore, our discussion herein avoids the controversies associated with classification schemes and emphasizes
etiologic and mechanistic considerations in the context of clinicopathologic features. Without additional data, the clinician encountering a patient with myocardial disease is usually unaware of the cause. The clinical picture is largely determined by one of the following three clinical, functional, and pathologic patterns (Fig. 13-23 and Table 13-8) : Dilated cardiomyopathy (DCM) Hypertrophic cardiomyopathy (HCM) Restrictive cardiomyopathy Among these three categories, the dilated form is most common (90% of cases), and the restrictive is least prevalent. Within the hemodynamic patterns of myocardial dysfunction, there is a spectrum of clinical severity, and overlap of clinical features often occurs between groups. Moreover, each of these patterns can be either idiopathic or due to a specific identifiable cause or secondary to primary extramyocardial disease (Table 13-9) . Endomyocardial biopsies are used widely in the diagnosis and management of patients with myocardial disease and cardiac transplant recipients. Endomyocardial biopsy involves inserting a device (called a bioptome) transvenously into the right side of the heart and snipping a small piece of myocardium in its jaws. The resulting pieces of myocardium are examined histologically.
Figure 13-23 Representation of the three distinctive clinical-pathologic-functional forms of myocardial disease.
DILATED CARDIOMYOPATHY
DCM is applied to a form of cardiomyopathy characterized by progressive cardiac hypertrophy, dilation, and contractile (systolic) dysfunction. It is sometimes called congestive cardiomyopathy. This clinicopathologic picture can result from a number of different myocardial insults whose morphology and consequences resemble DCM. Myocarditis (see later): Viral nucleic acids from coxsackievirus B and other enteroviruses have been detected in the myocardium of some patients, and sequential endomyocardial biopsies have demonstrated progression from myocarditis to DCM in others, suggesting that, in at least some cases, DCM was a consequence of myocarditis. Alcohol or other toxicity: Alcohol abuse is also strongly associated with the development of DCM, raising the possibility that ethanol toxicity (Chapter 10) or a secondary nutritional disturbance may be the cause of the myocardial injury. Alcohol or its metabolites (especially acetaldehyde) have a direct toxic effect on the myocardium. Nevertheless, a cause-and-effect relationship with alcohol alone remains tenuous, and no morphologic features serve to distinguish alcoholic cardiomyopathy from
580
DCM of other etiology. Moreover, chronic alcoholism may be associated with thiamine deficiency, introducing an element of beriberi heart disease (also indistinguishable from DCM) (Chapter 10) . In yet other cases, a nonalcoholic toxic insult is the cause of the myocardial failure. Particularly important in this last group (as discussed later) is myocardial injury caused by certain chemotherapeutic agents, including doxorubicin (Adriamycin). In the past, cobalt has also caused congestive heart failure. Pregnancy-associated: A special form of DCM, termed peripartum cardiomyopathy, occurs late in pregnancy or several weeks to months postpartum. The cause of peripartum cardiomyopathy is poorly understood but is probably multifactorial. Pregnancy-associated hypertension, volume overload, nutritional deficiency, other metabolic derangement, or as yet poorly characterized immunologic reaction may be involved. Genetic: Genetic influences have been documented in some cases, particularly when multiple members of a family are affected. DCM has a familial occurrence in 20 to 30% of cases. Autosomal dominant, autosomal recessive, and X-linked inheritance have all been proposed for particular kindreds. Genetic linkage studies in some families have indicated deletions in the mitochondrial genes causing abnormal oxidative phosphorylation, mutations in genes encoding enzymes involved in beta-oxidation of fatty acids, and mutations in the gene for dystrophin. The last-mentioned, as described in Chapter 30 , is a cell membrane-based cytoskeletal protein that is thought to play a critical role in linking the internal cytoskeleton with the external basement membrane and is the protein mutated in Duchenne and Becker muscular dystrophies. [58] Some patients and families with dystrophin gene mutations have DCM as their primary clinical feature, suggesting either differences in dystrophin function or control of expression between cardiac and skeletal muscle.
TABLE 13-8 -- CARDIOMYOPATHY AND INDIRECT MYOCARDIAL DYSFUNCTION: FUNCTIONAL PATTERNS AND CAUSES Functional Left Mechanisms Causes Indirect Myocardial Pattern Ventricular of Heart Dysfunction (Not Ejection Failure Cardiomyopathy) * Fraction Dilated
75% found in smokers) than are squamous or small cell carcinomas (>98%). Small Cell Carcinoma.
This highly malignant tumor has a distinctive cell type. The epithelial cells are generally small, have little cytoplasm, and are round or oval and, occasionally, lymphocyte like (although they are about twice the size of a lymphocyte).
Figure 16-41 Histologic appearance of bronchogenic carcinoma: A , Well-differentiated squamous cell carcinoma showing keratinization. B , Gland-forming adenocarcinoma. C, Small cell carcinoma with islands of small deeply basophilic cells and areas of necrosis. D, Large cell carcinoma, featuring pleomorphic, anaplastic tumor cells and absence of squamous or glandular
differentiation.
745
This is the classic oat cell (Fig. 16-41 C). Other small cell carcinomas have spindle-shaped or polygonal cells and may be thus classified (spindle or polygonal small cell carcinoma). The cells grow in clusters that exhibit neither glandular nor squamous organization. Electron microscopic studies show dense-core neurosecretory granules in some of these tumor cells. The granules are similar to those found in the neuroendocrine argentaffin (Kulchitsky) cells present along the bronchial epithelium, particularly in the
fetus and neonate. The occurrence of neurosecretory granules, the ability of some of these tumors to secrete polypeptide hormones, and the presence (ascertained by immunohistochemical stains) of neuroendocrine markers such as neuron-specific enolase and parathormone-like and other hormonally active products suggest derivation of this tumor from neuroendocrine cells of the lining bronchial epithelium. Small cell carcinomas have a strong relationship to cigarette smoking; only about 1% occur in nonsmokers. Most often hilar or central, they are the most aggressive of lung tumors, metastasize widely, and are virtually incurable by surgical means. They are the most common pattern associated with ectopic hormone production (see later). Large Cell Carcinoma.
This anaplastic carcinoma has larger, more polygonal cells and vesicular nuclei. Large cell carcinomas probably represent squamous cell carcinomas and adenocarcinomas that are so undifferentiated that they can no longer be recognized. Some of these large cell carcinomas contain intracellular mucin, some exhibit larger numbers of multinucleate cells ( giant cell carcinoma), some have cleared cells and are termed clear cell carcinoma, and some have a distinctly spindly histologic appearance ( spindle cell carcinoma). Secondary Pathology.
Bronchogenic carcinomas cause related anatomic changes in the lung substance distal to the point of bronchial involvement. Partial obstruction may cause marked focal emphysema; total obstruction may lead to atelectasis. The impaired drainage of the airways is a common cause for severe suppurative or ulcerative bronchitis or bronchiectasis. Pulmonary abscesses sometimes call attention to a silent carcinoma that has initiated the chronic suppuration. Compression or invasion of the superior vena cava can cause venous congestion, dusky head and arm edema, and, ultimately, circulatory compromise--the superior vena cava syndrome. Extension to the pericardial or pleural sacs may cause pericarditis (Chapter 13) or pleuritis with significant effusions. Staging.
A uniform TNM system for staging cancer according to its anatomic extent at the time of diagnosis is extremely useful for many reasons, chiefly for comparing treatment results from different centers. The staging system in current use [95] is presented in Table 16-10 (Table Not Available) . Clinical Course.
Lung cancer is one of the most insidious and aggressive neoplasms in the whole realm of oncology. In the usual case, it is discovered in patients in their fifties whose symptoms are of approximately 7 months' duration. The major presenting complaints
are cough (75%), weight loss (40%), chest pain (40%), and dyspnea (20%). Increased sputum production is common and often contains diagnostic tumor cells when examined as cytologic specimens (Fig. 16-42 A). Similarly, cytologic examination of a fine-needle aspirate of a tumor mass can often provide the diagnosis (Fig. 16-42 B). Some of the more common local manifestations of tumor and their pathologic bases are listed in Table 16-11 . Not infrequently, the tumor is discovered by its secondary spread during the course of investigation of an apparent primary neoplasm elsewhere. The outlook is poor for most patients with bronchogenic carcinoma. Despite all efforts at early diagnosis by frequent radioscopic examination of the chest, cytologic examination of sputum and bronchial washings or brushings, and the many improvements in thoracic surgery, radiotherapy, and chemotherapy, the overall 5-year survival rate is on the order of 9%. In many large clinics, not more than 20 to TABLE 16-10 -- NEW INTERNATIONAL STAGING SYSTEM FOR LUNG CANCER (Not Available) Modified from Mountain C: Revisions in the International System for Staging Lung Cancer. Chest 111:1710, 1997.
746
Figure 16-42 Cytologic diagnosis of lung cancer is often possible. A , A sputum specimen shows an organophilic, keratinized squamous carcinoma cell with a prominent hyperchromatic nucleus (arrow). B , A fine-needle aspirate of an enlarged lymph node shows clusters of tumor cells from a small cell carcinoma, with molding and nuclear atypia characteristic of this tumor (see also Fig. 16-41 C); note the size of the tumor cells compared with normal polymorphonuclear leukocytes in the left lower corner.
30% of lung cancer patients have lesions sufficiently localized to permit even an attempt at resection. In general, the adenocarcinoma and squamous cell patterns tend to remain localized longer and have a slightly better prognosis than do the undifferentiated cancers, which usually are advanced lesions by the time they are discovered. The overall 5-year survival rate of men is approximately 10% for squamous cell carcinoma and adenocarcinoma but only 3% for undifferentiated lesions. Surgical resection for small cell carcinoma is so ineffective that the diagnosis essentially precludes surgery. Untreated, the survival time for patients with small cell cancer is 6 to 17 weeks. This cancer is particularly sensitive to radiation and chemotherapy, and potential cure rates of 15 to 25% for limited disease have been reported in some centers. Most patients have distant metastases on diagnosis. Thus, even with treatment, the mean survival after diagnosis is about 1 year.
TABLE 16-11 -- LOCAL EFFECTS OF LUNG TUMOR SPREAD Clinical Feature Pathologic Basis
Pneumonia, abscess, lobar collapse
Tumor obstruction of airway
Lipid pneumonia
Tumor obstruction; accumulation of cellular lipid in foamy macrophages
Pleural effusion
Tumor spread into pleura
Hoarseness
Recurrent laryngeal nerve invasion
Dysphagia
Esophageal invasion
Diaphragm paralysis
Phrenic nerve invasion
Rib destruction
Chest wall invasion
SVC syndrome
SVC compression by tumor
Horner syndrome
Sympathetic ganglia invasion
Pericarditis, tamponade
Pericardial involvement
SVC, superior vena cava.
Despite this discouraging outlook, many patients have been cured by lobectomy or pneumonectomy, emphasizing the continued need for early diagnosis and adequate prompt therapy. Indeed, In the uncommon instance of localized solitary tumors less than 4 cm in diameter, surgical resection results in up to 40% 5-year survival for patients with squamous cell carcinoma and 30% for patients with adenocarcinoma and large cell carcinoma. Paraneoplastic Syndromes
Bronchogenic carcinoma can be associated with a number of paraneoplastic syndromes [96 ] (Chapter 8) , some of which may antedate the development of a gross pulmonary lesion. The hormones or hormone-like factors elaborated include Antidiuretic hormone (ADH), inducing hyponatremia owing to inappropriate ADH secretion Adrenocorticotropic hormone (ACTH), producing Cushing syndrome Parathormone, parathyroid hormone- related peptide, prostaglandin E, and some cytokines, all implicated in the hypercalcemia often seen with lung cancer Calcitonin, causing hypocalcemia Gonadotropins, causing gynecomastia Serotonin, associated with the carcinoid syndrome The incidence of clinically significant syndromes related to these factors ranges from 1 to 10% of all lung cancer patients, although a much higher proportion of patients show elevated serum levels of these (and other) peptide hormones. Any one of the histologic types of tumors may occasionally produce any one of the hormones, but tumors producing ACTH and ADH are predominantly small cell carcinomas, whereas those producing hypercalcemia are mostly squamous cell tumors. The carcinoid syndrome is
associated rarely with small cell carcinoma but is more common with the bronchial carcinoids, described later. 747
Other systemic manifestations of bronchogenic carcinoma include the Lambert-Eaton myasthenic syndrome, in which muscle weakness is caused by autoimmune antibodies (possibly elicited by tumor ionic channels) directed to the neuronal calcium channel; [94] peripheral neuropathy, usually purely sensory; dermatologic abnormalities, including acanthosis nigricans (Chapter 27) ; hematologic abnormalities, such as leukemoid reactions; and finally a peculiar abnormality of connective tissue called hypertrophic pulmonary osteoarthropathy, associated with clubbing of the fingers. Apical lung cancers in the superior pulmonary sulcus tend to invade the neural structures around the trachea, including the cervical sympathetic plexus, and produce a group of clinical findings that includes severe pain in the distribution of the ulnar nerve and Horner syndrome (enophthalmos, ptosis, miosis, and anhidrosis) on the same side as the lesion. Such tumors are also referred to as Pancoast tumors. BRONCHIOLOALVEOLAR CARCINOMA
As the name implies, bronchioloalveolar carcinoma occurs in the pulmonary parenchyma in the terminal bronchioloalveolar regions. It represents, in various series, 1 to 9% of all lung cancers. Changes are similar histologically to an apparently infectious disease of South African sheep known as jagziekte. Numerous efforts to identify an infectious agent in humans or to transmit the disease to sheep with cell-free extracts of human carcinoma, however, have been unavailing. MORPHOLOGY.
Macroscopically the tumor almost always occurs in the peripheral portions of the lung either as a single nodule or, more often, as multiple diffuse nodules that sometimes coalesce to produce a pneumonia-like consolidation. The parenchymal nodules have a mucinous, gray translucence when secretion is present and otherwise appear as solid, gray-white areas that can be confused with pneumonia on casual inspection. Histologically, the tumor is characterized by distinctive, tall, columnar-to-cuboidal epithelial cells that line up along alveolar septa and project into the alveolar spaces in numerous branching papillary formations (Fig. 16-43) . Tumor cells often contain abundant mucinous secretions. The degree of anaplasia is quite variable, but most tumors are well differentiated and tend to preserve the native septal wall architecture. Ultrastructurally, bronchioloalveolar carcinomas are a heterogeneous group, consisting of mucin-secreting bronchiolar cells, Clara cells, or, rarely, type II pneumocytes. Clinical Course.
These tumors occur in patients of all ages from the twenties to the advanced years of
life. They
Figure 16-43 Terminal bronchioloalveolar carcinoma with characteristic tall, columnar cell papillary growth. Note the loose tumor cells
in the alveoli, which may account for the "aerogenous" spread of tumor often observed.
are equally distributed among males and females. The symptoms, which usually appear late, are similar to those of bronchogenic carcinoma, with cough, hemoptysis, and pain the major presenting findings. Because the tumor does not involve major bronchi, atelectasis and emphysema are infrequent. Occasionally, they may produce a picture of diffuse interstitial pneumonitis. Solitary lesions are surgically resectable, resulting in a 50 to 75% 5-year survival rate, but the overall survival rate is about 25%. Metastases are not widely disseminated or large, and they do not occur early. Eventually, however, they appear in up to 45% of cases. NEUROENDOCRINE TUMORS
Neuroendocrine tumors are pulmonary neoplasms that share morphologic and biochemical features with cells of the dispersed neuroendocrine cell system (Chapter 26) . [97] The normal lung contains neuroendocrine cells within the epithelium as single cells or as clusters, the neuroepithelial bodies. [1] [95] Neoplasms of neuroendocrine cells in the lung include benign tumorlets, small, inconsequential hyperplastic neuroendocrine cells seen in areas of scarring or chronic inflammation; carcinoids; and the (already discussed) highly aggressive small cell carcinoma of the lung. Bronchial Carcinoid
Bronchial carcinoids represent 1 to 5% of all lung tumors. They make up more than 90% of a group of bronchial tumors formerly classified as bronchial adenoma but now known to be often locally invasive or, occasionally, capable of metastasis. The remaining 10% of the group includes adenoid cystic carcinoma and mucoepidermoid carcinoma--tumors with histologic patterns reminiscent of similar tumors in salivary glands (Chapter 17) . Most patients with carcinoid tumors are younger than 40 years of age, and the incidence is equal for both sexes. There is no known relationship to cigarette smoking or other environmental
748
factors. Bronchial carcinoids show the neuroendocrine differentiation of the Kulchitsky cells of bronchial mucosa and resemble intestinal carcinoids, described in detail in Chapter 18 . They contain dense-core neurosecretory granules in their cytoplasm, secrete hormonally active polypeptides, and occasionally occur as part of multiple endocrine neoplasia.
MORPHOLOGY.
On gross examination, the tumors grow as finger-like or spherical polypoid masses that commonly project into the lumen of the bronchus and are usually covered by an intact mucosa (Fig. 16-44 A). They rarely exceed 3 to 4 cm in diameter. Most are confined to the main stem bronchi. Others, however, produce little intraluminal mass but instead penetrate the bronchial wall to fan out in the peribronchial tissue, producing the so-called collar-button lesion. Histologically the tumor is composed of nests, cords, and masses of cells separated by a delicate fibrous stroma. In common with the lesions of the gastrointestinal tract, the individual cells are quite regular and have uniform round nuclei and infrequent mitoses (Fig. 16-44 B). Occasional carcinoid adenomas display variation in the size and shape of cells and nuclei and, along with this pleomorphism, tend to demonstrate a more aggressive and more invasive behavior. On electron microscopy, the cells exhibit the dense-core granules characteristic of other neuroendocrine tumors and, by immunochemistry, are found to contain serotonin, neuron-specific enolase, bombesin, calcitonin, or other peptides. Clinical Features.
The clinical manifestations of bronchial carcinoids emanate from their intraluminal growth, their capacity to metastasize, and the ability of some of the lesions to elaborate vasoactive amines. Persistent cough, hemoptysis, impairment of drainage or respiratory passages with secondary infections, bronchiectasis, emphysema, and atelectasis all are byproducts of the intraluminal growth of these lesions. Many carcinoids show infiltration or spread to local lymph nodes at the time of resection with apparently little ill effect on prognosis. Most interesting, albeit rare, are functioning lesions of the argentaffinoma pattern capable of producing the classic carcinoid syndrome, that is, intermittent attacks of diarrhea, flushing, and cyanosis. Overall, most bronchial carcinoids do not have secretory activity and do not metastasize to distant sites but follow a relatively benign course for long periods and are therefore amenable to resection. The reported 5- to 10-year survival rates for typical carcinoids are 50 to 95%. A minority (10%) of tumors show cytologic atypia, necrosis, and aggressive behavior (50% recurrence or metastasis after 2 years) and are designated atypical carcinoids. MISCELLANEOUS TUMORS
Lesions of the complex category of benign and malignant mesenchymal tumors, such as fibroma, fibrosarcoma, leiomyoma, leiomyosarcoma, lipoma, hemangioma, hemangiopericytoma, and chondroma, may occur but are rare. Benign and malignant lymphoreticular tumors and tumor-like conditions, similar to those described in other organs, may also affect the lung, either as isolated lesions or, more commonly, as part of a generalized disorder. These include non-Hodgkin and Hodgkin lymphoma,
lymphomatoid granulomatosis, pseudolymphoma, and plasma cell granuloma. A lung hamartoma is a relatively common lesion usually discovered as an incidental, rounded focus of radiopacity ( coin lesion) on a routine chest film. A new nodule in the lung requires clinical evaluation to determine whether a benign or malignant neoplasm has arisen. Pulmonary hamartomas are rarely greater than 3 to 4 cm in diameter and are composed principally of mature hyaline cartilage. Occasionally the cartilage contains cystic or cleftlike spaces, and
Figure 16-44 A , Bronchial carcinoid growing as a spherical, pale mass (arrow) protruding into the lumen of the bronchus. B , Histologic
appearance of bronchial carcinoid, demonstrating small, rounded, uniform cells.
749
these may be lined by characteristic respiratory epithelium. At other times, there are admixtures of fibrous tissue, fat, and blood vessels. Recall that hamartomas are overgrowths of mature, normal tissues, in abnormal proportions (Chapter 8) . Tumors in the mediastinum either may arise in mediastinal structures or may be metastatic from the lung or other organs. They may also invade or compress the lungs. Table 16-12 lists the most common tumors in the various compartments of the mediastinum. Specific tumor types are discussed in appropriate sections of this book. METASTATIC TUMORS
The lung is frequently the site of metastatic neoplasms. Both carcinomas and sarcomas arising anywhere in the body may spread to the lungs via the blood or lymphatics or by direct continuity. Growth of contiguous tumors into the lungs occurs most often with esophageal carcinomas and mediastinal lymphomas. MORPHOLOGY.
The pattern of metastatic growth within the lungs is quite variable. In the usual case, multiple discrete nodules are scattered throughout all lobes (Fig. 16-45) . These discrete lesions tend to occur in the periphery of the lung parenchyma rather than in the central locations of the primary bronchogenic carcinoma. As a second macroscopic variant, metastatic growth may be confined to peribronchiolar and perivascular tissue spaces, presumably when the tumor has extended to the lung through the lymphatics. Here the lung septa and connective tissue are diffusely infiltrated with the gray-white tumor. The subpleural lymphatics may be outlined TABLE 16-12 -- MEDIASTINAL TUMORS AND OTHER MASSES
Superior Mediastinum Lymphoma Thymoma Thyroid lesions Metastatic carcinoma Parathyroid tumors Anterior Mediastinum Thymoma Teratoma Lymphoma Thyroid lesions Parathyroid tumors Posterior Mediastinum Neurogenic tumors (schwannoma, neurofibroma) Lymphoma Gastroenteric hernia Middle Mediastinum Bronchogenic cyst Pericardial cyst Lymphoma
Figure 16-45 Numerous metastases from a renal cell carcinoma. (Courtesy of Dr. Michelle Mantel, Brigham and Women's Hospital, Boston, MA.)
by the contained tumor, producing a gross appearance referred to as lymphangitis carcinomatosa. Least commonly, the metastatic tumor is totally inapparent on gross examination and becomes evident only on histologic section as a diffuse intralymphatic dissemination dispersed throughout the peribronchial and perivascular channels. In certain instances, microscopic tumor emboli fill the small pulmonary vessels and may result in life-threatening pulmonary hypertension. Pleura Pathologic involvement of the pleura is, with rare exceptions, a secondary complication of some underlying disease. Secondary infections and pleural adhesions are particularly common findings at autopsy. Occasionally the secondary pleural disease assumes a
dominant role in the clinical problem, as occurs in bacterial pneumonia with the development of empyema. Important primary disorders include (1) primary intrapleural bacterial infections that imply seeding of this space as an isolated focus in the course of a transient bacteremia and (2) a primary neoplasm of the pleura--mesothelioma (see later). Pleural effusion is a common manifestation of both primary and secondary pleural involvements. Normally, no more than 15 ml of serous, relatively acellular, clear fluid lubricates the pleural surface. Increased accumulation of pleural fluid occurs in five setting as follows: Increased hydrostatic pressure, as in congestive heart failure Increased vascular permeability, as in pneumonia Decreased oncotic pressure, as in nephrotic syndrome Increased intrapleural negative pressure, as in atelectasis Decreased lymphatic drainage, as in mediastinal carcinomatosis
750
TABLE 16-13 -- PLEURAL SPACE FLUID ACCUMULATIONS Condition Type of Fluid Common Associations Inflammatory Serofibrinous pleuritis
Serofibrinous exudate
Inflammation in adjacent lung Collagen vascular disease
Suppurative pleuritis (empyema)
Pus
Suppurative infection in adjacent lung
Hemorrhagic pleuritis
Bloody exudate
Tumor
Hydrothorax
Transudate
Congestive heart failure
Hemothorax
Blood
Ruptured aortic aneurysm, trauma
Chylothorax
Chyle (lymph)
Tumor obstruction of normal lymphatics
Noninflammatory
The character of the pleural effusion can be divided, for convenience, into inflammatory or noninflammatory, as summarized in Table 16-13 . INFLAMMATORY PLEURAL EFFUSIONS
Serous, serofibrinous, and fibrinous pleuritis all are caused by essentially the same processes. Fibrinous exudations generally reflect a later, more severe exudative
reaction that, in an earlier developmental phase, might have presented as a serous or serofibrinous exudate. The common causes of pleuritis are inflammatory diseases within the lungs, such as tuberculosis, pneumonia, lung infarcts, lung abscess, and bronchiectasis. Rheumatoid arthritis, disseminated lupus erythematosus, uremia, diffuse systemic infections, other systemic disorders, and metastatic involvement of the pleura can also cause serous or serofibrinous pleuritis. Radiation used in therapy for tumors in the lung or mediastinum often causes a serofibrinous pleuritis. In most instances, the serofibrinous reaction is only minimal, and the fluid exudate is resorbed with either resolution or organization of the fibrinous component. Accumulation of large amounts of fluid can sufficiently encroach on lung space to give rise to respiratory distress. A purulent pleural exudate (empyema) usually results from bacterial or mycotic seeding of the pleural space. Most commonly, this seeding occurs by contiguous spread of organisms from intrapulmonary infection, but occasionally it occurs through lymphatic or hematogenous dissemination from a more distant source. Rarely, infections below the diaphragm, such as the subdiaphragmatic or liver abscess, may extend by continuity through the diaphragm into the pleural spaces, more often on the right side. Empyema is characterized by yellow-green, creamy pus composed of masses of neutrophils admixed with other leukocytes. Although it may be difficult to visualize microorganisms on smears of the exudate, it should be possible to demonstrate them by culture. Although empyema may accumulate in large volumes (up to 500 to 1000 ml), usually the volume is small. Empyema may resolve, but this outcome is less common than organization of the exudate, with the formation of dense, tough fibrous adhesions that frequently obliterate the pleural space or envelop the lungs; either can seriously embarrass pulmonary expansion. True hemorrhagic pleuritis manifested by sanguineous inflammatory exudates is infrequent and is found in hemorrhagic diatheses, rickettsial diseases, and neoplastic involvement of the pleural cavity. The sanguineous exudate must be differentiated from hemothorax (see later). When hemorrhagic pleuritis is encountered, careful search should be made for the presence of exfoliated tumor cells. NONINFLAMMATORY PLEURAL EFFUSIONS
Noninflammatory collections of serous fluid within the pleural cavities are called hydrothorax. The fluid is clear and straw colored. Hydrothorax may be unilateral or bilateral, depending on the underlying cause. The most common cause of hydrothorax is cardiac failure, and for this reason it is usually accompanied by pulmonary congestion and edema. In cardiac failure, hydrothorax is usually, but not invariably, bilateral. Transudates may collect in any other systemic disease associated with generalized edema and are therefore found in renal failure and cirrhosis of the liver. Isolated right-sided hydrothorax occurs in Meig syndrome, an unusual combination of hydrothorax, ascites, and ovarian fibroma (Chapter 24) . In most instances, hydrothorax is not loculated, but in the presence of preexistent
pleural adhesions, local collections may be found walled off by bridging fibrous tissue. Except for these localized collections, the fluid usually collects basally, when the patient is in an upright position, and causes compression and atelectasis of the regions of the lung surrounded by fluid. If the underlying cause is alleviated, hydrothorax may be resorbed, usually leaving behind no permanent alterations. Relief of respiratory distress is accomplished by the withdrawal of large pleural transudates. The escape of blood into the pleural cavity is known as hemothorax. It is almost invariably a fatal complication of a ruptured aortic aneurysm or vascular trauma. Pure hemothorax is readily identifiable by the large clots that accompany the fluid component of the blood. Because this calamity often leads to death within minutes to hours, it is uncommon to find any inflammatory response within the pleural cavity. Rarely, nonfatal leakage of smaller amounts may provide a stimulus to organization and the development of pleural adhesions.
751
Chylothorax is an accumulation of milky fluid, usually of lymphatic origin, in the pleural cavity. Chyle is milky white because it contains finely emulsified fats. When it is allowed to stand, a creamy, fatty, supernatant layer separates. True chyle should be differentiated from turbid serous fluid, which does not contain fat and does not separate into an overlying layer of high fat content. Chylothorax may be bilateral but is more often confined to the left side. The volume of fluid is variable but rarely assumes the massive proportions of hydrothorax. Chylothorax is most often caused by thoracic duct trauma or obstruction that secondarily causes rupture of major lymphatic ducts. This disorder is encountered in malignant conditions arising within the thoracic cavity that cause obstruction of the major lymphatic ducts. More distant cancers may metastasize via the lymphatics and grow within the right lymphatic or thoracic duct to produce obstruction. PNEUMOTHORAX
Pneumothorax refers to air or gas in the pleural cavities and may be spontaneous, traumatic, or therapeutic. Spontaneous pneumothorax may complicate any form of pulmonary disease that causes rupture of an alveolus. An abscess cavity that communicates either directly with the pleural space or with the lung interstitial tissue may also lead to the escape of air. In the latter circumstance, the air may dissect through the lung substance or back through the mediastinum (interstitial emphysema), eventually entering the pleural cavity. Pneumothorax is most commonly associated with emphysema, asthma, and tuberculosis. Traumatic pneumothorax is usually caused by some perforating injury to the chest wall, but sometimes the trauma pierces the lung and thus provides two avenues for the accumulation of air within the pleural spaces. Resorption of the pleural space air occurs slowly in spontaneous and traumatic pneumothorax, provided that the original communication seals itself. Therapeutic pneumothorax was once a commonly practiced method of deflating the lung to favor the
healing of tuberculous lesions. Of the various forms of pneumothorax, the one that attracts greatest clinical attention is so-called spontaneous idiopathic pneumothorax. This entity is encountered in relatively young people; appears to be due to rupture of small, peripheral, usually apical subpleural blebs; and usually subsides spontaneously as the air is resorbed. Recurrent attacks are common and may be quite disabling. Pneumothorax can be identified anatomically only by careful opening of the thoracic cavity under water to detect the escape of gas or air bubbles. Pneumothorax may have as much clinical significance as a fluid collection in the lungs because it also causes compression, collapse, and atelectasis of the lung and may be responsible for marked respiratory distress. Occasionally the lung collapse is marked. When the defect acts as a flap valve and permits the entrance of air during inspiration but fails to permit its escape during expiration, it effectively acts as a pump that creates the progressively increasing pressures of tension pneumothorax, which may be sufficient to compress the vital mediastinal structures and the contralateral lung. PLEURAL TUMORS
The pleura may be involved in primary or secondary tumors. Secondary metastatic involvement is far more common than are primary tumors. The most frequent metastatic malignancies arise from primary neoplasms of the lung and breast. Advanced mammary carcinomas frequently penetrate the thoracic wall directly to involve the parietal and then the visceral pleura. They may also reach these cavities through the lymphatics and, more rarely, the blood. In addition to these cancers, malignancy from any organ of the body may spread to the pleural spaces. Ovarian carcinomas, for example, tend to cause widespread implants in both the abdominal and the thoracic cavities. In most metastatic involvements, a serous or serosanguineous effusion follows that may contain desquamated neoplastic cells. For this reason, careful cytologic examination of the sediment is of considerable diagnostic value. Solitary Fibrous Tumors (Pleural Fibroma)
This benign pleural neoplasm, sometimes called benign mesothelioma, is a localized growth that is often attached to the pleural surface by a pedicle. [98] The tumor may be small (1 to 2 cm in diameter) or may reach an enormous size, but it always remains confined to the surface of the lung. These tumors do not usually produce a pleural effusion. Grossly, they consist of dense fibrous tissue with occasional cysts filled with viscid fluid; microscopically the tumors show whorls of reticulin and collagen fibers among which are interspersed spindle cells resembling fibroblasts. The tumor cells are CD34+, keratin-negative by immunostaining. This feature can be diagnostically useful in distinguishing these lesions from true malignant mesotheliomas (which show the opposite phenotype). The benign fibrous tumor has no relationship to asbestos exposure.
Malignant Mesothelioma
Malignant mesotheliomas in the thorax arise from either the visceral or the parietal pleura. [99] [100] Although uncommon, they have assumed great importance in the past few years because of their increased incidence among persons with heavy exposure to asbestos (see the section on pneumoconioses earlier). In coastal areas with shipping industries in the United States and Great Britain and in Canadian and South African mining areas, up to 90% of reported mesotheliomas are asbestos-related. The lifetime risk of developing mesothelioma in heavily exposed individuals is as high as 7 to 10%. There is a long period of 25 to 45 years for the development of asbestos-related mesothelioma, and there seems to be no increased risk of mesothelioma in asbestos workers who smoke. This is in contrast to the risk of asbestos-related bronchogenic carcinoma, already high, and is markedly magnified by smoking. Thus, for asbestos workers ( particularly those who are also smokers), the risk of dying of lung carcinoma far exceeds that of developing mesothelioma.
752
Figure 16-46 Malignant mesothelioma. Note the thick, firm, white, pleural tumor tissue that ensheathes this bisected lung.
Asbestos bodies (see Fig. 16-30) are found in increased numbers in the lungs of patients with mesothelioma, and mesotheliomas can be induced readily in experimental animals by intrapleural injections of asbestos. [101] Another marker of asbestos exposure, the asbestos plaque, has been previously discussed. There is little doubt about the carcinogenicity of asbestos; the mechanisms of cancer induction are discussed in Chapter 8 . MORPHOLOGY.
Malignant mesothelioma is a diffuse lesion that spreads widely in the pleural space and is usually associated with extensive pleural effusion and direct invasion of thoracic structures. The affected lung is ensheathed by a thick layer of soft, gelatinous, grayish pink tumor tissue (Fig. 16-46) . Microscopically, malignant mesotheliomas consist of a mixture of two types of cells, either one of which might predominate in an individual case. Mesothelial cells have the potential to develop as either mesenchymal stromal cells or epithelium-like lining cells. The latter is the usual form of the mesothelium, an epithelium that lines the serous cavities of the body. The mesenchymal type of mesothelioma appears as a spindle cell sarcoma, resembling fibrosarcoma (sarcomatoid type), whereas the papillary type consists of cuboidal, columnar, or flattened cells forming a tubular and papillary structure (epithelial type), resembling adenocarcinoma (Fig. 16-47) . Epithelial
mesothelioma may at times be difficult to differentiate grossly and histologically from pulmonary adenocarcinoma. Special features that favor mesothelioma include the following [102] : (1) positive staining for acid mucopolysaccharide, which is inhibited by previous digestion by hyaluronidase; (2) lack of staining for carcinoembryonic antigen (CEA) and other epithelial glycoprotein antigens, markers generally expressed by adenocarcinoma; (3) strong staining for keratin proteins, with accentuation of perinuclear rather than peripheral staining (Fig. 16-48) ; and (4) on electron microscopy, the presence of long microvilli and abundant tonofilaments but absent microvillous rootlets and lamellar bodies (Fig. 16-48) . The mixed type of mesothelioma contains both epithelial and sarcomatoid patterns. Cytogenetic abnormalities occur in mesotheliomas but not reactive mesothelial proliferations, a diagnostically useful feature. [99] Clinical Course.
The presenting complaints are chest pain, dyspnea, and, as noted, recurrent pleural effusions. Concurrent pulmonary asbestosis (fibrosis) is present in only 20% of patients with pleural mesothelioma. Fifty per cent of those with pleural disease die within 12 months of diagnosis, and few survive longer than 2 years. Aggressive therapy (extrapleural pneumonectomy, chemotherapy, radiation therapy) appears to improve this poor prognosis in some patients. The lung is invaded directly, and there is often metastatic spread to the hilar lymph nodes and, eventually, to the liver and other distant organs. Mesotheliomas also arise in the peritoneum, pericardium, tunica vaginalis, and genital tract (benign adenomatoid tumor; Chapter 23) . Peritoneal mesotheliomas are particularly related to heavy asbestos exposure; 50% of such patients also have pulmonary fibrosis. Although in about 50% of cases the disease remains confined to the abdominal cavity, intestinal involvement frequently leads to death from intestinal obstruction or inanition.
Figure 16-47 Malignant mesothelioma, epithelial type. The tumor cells are immunoperoxidase positive for keratin, as shown (brown) ,
but would be carcinoembryonic antigen negative.
753
Figure 16-48 Ultrastructural features of pulmonary adenocarcinoma ( A ), characterized by short, plump microvilli, contrasted with those of mesothelioma ( B ), in which microvilli are numerous, long, and slender. (Courtesy of Dr. Noel Weidner, University of California, San Francisco, School of Medicine.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
REFERENCES Gould S, Hasleton P: Congenital abnormalities. In Hasleton P (ed): Spencer's Pathology of the Lung. New York, McGraw-Hill, 1996, pp 57-114. 1.
2.
Bigatello LM, Zapol WM: New approaches to acute lung injury. Br J Anaesth 77:99, 1996.
3.
Zapol W, Bloch K (eds): Nitric Oxide and the Lung. New York, Marcel Dekker, 1997.
Voelkel NF, Tuder RM: Cellular and molecular mechanisms in the pathogenesis of severe pulmonary hypertension. Eur Respir J 8:2129, 1995. 4.
5.
Rubin LJ: Primary pulmonary hypertension. N Engl J Med 336:111, 1997.
Mark E, et al: Brief report: Fatal pulmonary hypertension associated with short-term use of fenfluramine and phentermine. N Engl J Med 337:602, 1997. 6.
7.
Burke A, et al: The pathology of primary pulmonary hypertension. Mod Pathol 4:269, 1991.
Pietra G, et al: Histopathology of primary pulmonary hypertension: A qualitative and quantitative study of pulmonary blood vessels from 58 patients in the National Heart, Lung, and Blood Institute primary pulmonary hypertension registry. Circulation 80:1198, 1989. 8.
Fuster V, et al: Primary pulmonary hypertension: Natural history and the importance of thrombus. Circulation 70:580, 1984. 9.
Snider GL, et al: The definition of emphysema. Report of the National Heart, Lung, and Blood Institute, Division of Lung Diseases Workshop. Am Rev Respir Dis 132:182, 1985. 10.
11.
Wright JL: Emphysema: concepts under change--a pathologist's perspective. Mod Pathol 8:873; 1995.
Lamb D: Chronic bronchitis, emphysema, and the pathological basis of chronic obstructive pulmonary disease. In Hasleton P (ed): Spencer's Pathology of the Lung. New York, McGraw-Hill, 1996, pp 597-630. 12.
Gross P, et al: Enzymatically produced pulmonary emphysema: A preliminary report. J Occup Med 6:481, 1964. 13.
Senior RM, et al: The induction of pulmonary emphysema with human leukocyte elastase. Am Rev Respir Dis 116:469, 1977. 14.
Hautami R, et al: Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice. Science 277:2002, 1997. 15.
deMello D, Reid L: Chronic bronchitis. In Saldana M (ed): Pathology of Pulmonary Disease. Philadelphia, JB Lippincott, 1994, p 287. 16.
17.
Wright JL, et al: Diseases of the small airways. Am Rev Respir Dis 146:240, 1992.
Thurlbeck WM: Pathology of chronic airflow obstruction. In Cherniack NS (ed): Chronic Obstructive Pulmonary Disease. Philadelphia, WB Saunders, 1991, p 3. 18.
Hogg JC, et al: Site and nature of airway obstruction in chronic obstruction lung disease. N Engl J Med 278:1355, 1968. 19.
Cosio MG, et al: The relations between structural changes in small airways and pulmonary function tests. N Engl J Med 298:1277, 1978. 20.
21.
Colby TV: Bronchiolitis: pathologic considerations. Am J Clin Pathol 109:101, 1998.
22.
Busse W, Holgate S: Asthma and Rhinitis. Boston, Blackwell Scientific, 1995.
22A.
23.
Holgate S: Asthma genetics: Waiting to exhale. Nat Genet 15:227, 1997.
Vogel G: New clues to asthma therapies. Science 276:1643, 1997.
Barnes P: Inflammatory mediators and neural mechanisms in severe asthma. In Szefler S, Leung D (ed): Severe Asthma: Pathogenesis and Clinical Management. New York, Marcel Dekker, 1996, p 129. 24.
Galli SJ: The Paul Kallos Memorial Lecture: The mast cell: A versatile effector cell for a challenging world. Intl Arch Allergy Immunol 113:14, 1997. 25.
Lilly CM, et al: Expression of eotaxin by human lung epithelial cells: Induction by cytokines and inhibition by glucocorticoids. J Clin Invest 99:1767, 1997. 26.
754
27.
Shelhamer J, et al: Airway inflammation. Ann Intern Med 123:288, 1995.
Costa JJ, et al: The cells of the allergic response: mast cells, basophils, and eosinophils. JAMA 278:1815, 1997. 28.
29.
Corne JM, Holgate ST: Mechanisms of virus induced exacerbations of asthma. Thorax 52:380, 1997.
Luce L: Bronchiectasis. In Murray J, Nadel J (eds): Textbook of Respiratory Medicine, Vol 2. Philadelphia, WB Saunders, 1994, pp 1398-1417. 30.
Afzelius B: Ciliary dysfunction. In Crystal R, et al (eds): In The Lung: Scientific Foundations. Philadelphia, Lippincott-Raven, 1997, pp 2573-2578. 31.
Pennington JE: Respiratory Infections: Diagnosis and Management, 3rd ed. New York, Raven Press, 1994. 32.
Hasleton P: Atypical pneumonias. In Hasleton P (ed): Spencer's Pathology of the Lung. New York, McGraw-Hill, 1996, p 179. 33.
34.
Lomotan JR, et al: Aspiration pneumonia. Postgraduate Medicine 102:225, 229, 1997.
Barnes PF, et al: Tuberculosis in patients with human immunodeficiency virus infection. N Engl J Med 324:1644, 1991. 35.
36.
Bradford WZ, Daley CL: Multiple drug-resistant tuberculosis. Infect Dis Clin North Am 12:157, 1998.
37.
Shinnick T (ed): Tuberculosis. Berlin, Springer, 1996.
Rosenow EC: Diffuse pulmonary infiltrates in the immunocompromised host. Clin Chest Med 11:55, 1990. 38.
39.
Nash G, et al: The pathology of AIDS. Mod Pathol 8:199, 1995.
Colby TV, Carrington CB: Interstitial lung disease. In Thurlbeck W, Churg A (eds): Pathology of the Lung. New York, Thieme Medical Publishers, 1995, p 589. 40.
41.
Chan-Yeung M, Muller NL: Cryptogenic fibrosing alveolitis. Lancet 350:651, 1997.
Kumar R, Lykke A: Messages and handshakes: Cellular interactions in pulmonary fibrosis. Pathology 27:18, 1995. 42.
43.
Vaillant P, et al: The role of cytokines in human lung fibrosis. Monaldi Arch Chest Dis 51:145, 1996.
Lynch JPI, et al: Neutrophilic alveolitis in idiopathic pulmonary fibrosis: The role of interleukin-8. Am Rev Respir Dis 145:1433, 1992. 44.
Peters-Golden M: Lipid mediator synthesis by lung macrophages. In Lipscomb M, Russell S (eds): Lung Macrophages and Dendritic Cells in Health and Disease, Vol 102. New York, Marcel Dekker, 1997, pp 151-182. 45.
Dockery D, et al: An association between air pollution and mortality in six U.S. cities. N Engl J Med 329:1753, 1993. 46.
Pope C, et al: Health effects of particulate air pollution: Time for reassessment? Environ Health Perspect 103:472, 1995. 47.
Vallyathan V, Shi X: The role of oxygen free radicals in occupational and environmental lung diseases. Environ Health Perspect 105(Suppl 1):165, 1997. 48.
Vallyathan V, et al: Generation of free radicals from freshly fractured silica dust: Potential role in acute silica-induced lung injury. Am Rev Respir Dis 138:1213, 1988. 49.
Kamp DW, Weitzman SA: Asbestosis: Clinical spectrum and pathogenic mechanisms. Proc Soc Exp Biol Med 214:12, 1997. 50.
Green F, Vallyathan V: Coal workers' pneumoconiosis and pneumoconiosis due to other carbonaceous dusts. In Churg A, Green F (eds): Pathology of Occupational Lung Disease. Baltimore, 51.
Williams & Wilkins, 1998, p 129. Godleski J: The pneumoconioses: Silicosis and silicatosis. In Saldana M (ed): Pathology of Pulmonary Disease. Philadelphia, JB Lippincott, 1994, p 387. 52.
Vanhee D, et al: Cytokines and cytokine network in silicosis and coal workers' pneumoconiosis. Eur Respir J 8:834, 1995. 53.
Piguet P, et al: Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis. Nature 344:245, 1990. 54.
Hammar S, Dodson R: Asbestos. In Hammar S, Dail D (eds): Pulmonary Pathology. New York, Springer-Verlag, 1996, pp 901-984. 55.
Hammond E, et al: Asbestos exposure, cigarette smoking, and death rates. Ann N Y Acad Sci 330:473, 1979. 56.
57.
Tinkle SS, et al: Beryllium induces IL-2 and IFN-gamma in berylliosis. J Immunol 158:518, 1997.
Robinson B: Sarcoidosis. In Kradin R, Robinson B (eds): Immunopathology of Lung Disease. Boston, Butterworth-Heinemann, 1996, p 165. 58.
Moller D, et al: Bias toward use of specific T cell receptor B-chain variable region in a subgroup of individuals with sarcoidosis. J Clin Invest 82:1183, 1988. 59.
Balbi B, et al: Increased numbers of T lymphocytes with gammadelta-positive antigen receptors in a subgroup of individuals with pulmonary sarcoidosis. J Clin Invest 85:1353, 1990. 60.
Mangiapan G, Hance AJ: Mycobacteria and sarcoidosis: An overview and summary of recent molecular biological data. Sarcoidosis 12:20, 1995. 61.
Flint A, Colby TV: Surgical Pathology of Diffuse Infiltrative Lung Disease. Orlando, Grune & Stratton, 1987. 62.
Richerson HB: Immune complexes and the lung: A skeptical review. Surv Synthesis Pathol Res 3:281, 1984. 63.
Sharma OP, Fujimura N: Hypersensitivity pneumonitis: A noninfectious granulomatosis. Semin Respir Infect 10:96, 1995. 64.
Kita H, et al: Cytokine production at the site of disease in chronic eosinophilic pneumonitis. Am J Respir Crit Care Med 153:1437, 1996. 65.
Douglas N, Goetzl E: Pulmonary eosinophilia and eosinophilic granuloma. In Murray J, Nadel J (eds): Textbook of Respiratory Medicine. Philadelphia, WB Saunders, 1994, p 1913. 66.
Tazelaar HD, et al: Acute eosinophilic pneumonia: Histopathologic findings in nine patients. Am J Respir Crit Care Med 155:296, 1997. 67.
Katzenstein A-LA: Katzenstein and Askin's Surgical Pathology of Non-Neoplastic Lung Disease, 2nd ed. Philadelphia, WB Saunders, 1997. 68.
Yousem SA: The histological spectrum of pulmonary graft-versus-host disease in bone marrow transplant recipients. Hum Pathol 26:668, 1995. 69.
Kelly PT, Haponik EF: Goodpasture syndrome: Molecular and clinical advances. Medicine 73:171, 1994. 70.
71.
Travis WD, Fleming MV: Vasculitis of the lung. Pathology 4:23, 1996.
Nishinakamura R, et al: The pulmonary alveolar proteinosis in granulocyte macrophage colony-stimulating factor/interleukins 3/5 beta c receptor-deficient mice is reversed by bone marrow transplantation. J Exp Med 183:2657, 1996. 72.
Dirksen V, Nishinakamura R, Groneck P, et al: Human pulmonary proteinosis associated with a defect in GM-CSF/IL-3/IL-5 receptor common beta chain expression. J Clin Invest 100:2211, 1997. 72A.
73.
Movsas B, et al: Pulmonary radiation injury. Chest 111:1061, 1997.
Hasleton P, Doran H: Pulmonary changes after transplantation. In Hasleton P (ed): Spencer's Pathology of the Lung. New York, McGraw-Hill, 1996, p 723. 74.
Yousem SA, et al: Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: lung rejection study group. J Heart Transplant 15:1, 1996. 75.
Colby T, et al: Tumors of the Lower Respiratory Tract. Washington, DC, Armed Forces Institute of Pathology, 1995. 76.
77.
Landis SH, et al: Cancer statistics, 1998. CA Cancer J Clin 48:6, 1998.
78.
Samet JM (ed): Epidemiology of Lung Cancer. New York, Marcel Dekker, 1994.
Smoking and Health: A National Status Report. A Report to Congress. Washington, DC, Department of Health and Human Services, 1987. 79.
Auerbach O: Changes in bronchial epithelium in relationship to sex, age, residence, smoking and pneumonia. N Engl J Med 267:111, 1962. 80.
Auerbach O: Changes in bronchial epithelium in relationship to cigarette smoking, 1955-1960 vs. 1970-1977. N Engl J Med 300:285, 1979. 81.
Marchevsky AM: Pathogenesis and experimental models of lung cancer. In Marchevsky AM (ed): Surgical Pathology of Lung Neoplasms. New York, Marcel Dekker, 1990, p 7. 82.
83.
Samet JM: Indoor radon and lung cancer: Estimating the risks. West J Med 156:25, 1992.
Pershagen G, et al: Residential radon exposure and lung cancer in Sweden [see comments]. N Engl J Med 330:159, 1994. 84.
85.
Abelson PH: Uncertainties about health effects of radon (editorial). Science 250:353, 1990.
86.
Salgia R, Skarin AT: Molecular abnormalities in lung cancer. J Clin Oncol 16:1207, 1998.
87.
Sundaresan V, Rabbits P: Genetics of lung tumors. In Hasleton P (ed): Spencer's Pathology of the
Lung. New York, McGraw-Hill, 1996, p 987. 755
88.
Gazdar A: The molecular and cellular basis of human lung cancer. Anticancer Res 13:261, 1994.
Cho JY, et al: Correlation between K-ras gene mutation and prognosis of patients with nonsmall cell lung carcinoma. Cancer 79:462, 1997. 89.
Denissenko M, et al: Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in p53. Science 274:430, 1996. 90.
Barsky SH, et al: The extracellular matrix of pulmonary scar carcinomas is suggestive of a desmoplastic origin. Am J Pathol 124:412, 1986. 91.
Yesner R, et al (eds): International Histological Classification of Tumors. Geneva, World Health Organization, 1982. 92.
El-Torky M, et al: Significant changes in the distribution of histologic types of lung cancer. Cancer 65:2361, 1990. 93.
Hoffman D, et al: The biological significance of tobacco-specific N-nitrosamines: Smoking and adenocarcinoma of the lung. Crit Rev Toxicol 26:199, 1996. 94.
95.
Mountain C: Revisions in the International System for Staging Lung Cancer. Chest 111:1710, 1997.
96.
Patel A, et al: Paraneoplastic syndromes associated with lung cancer. Mayo Clin Proc 68:278, 1993.
97.
Marchevsky AM: Neuroendocrine tumors of the lung. Pathology 4:103, 1996.
Steinetz C, et al: Localized fibrous tumor of the pleura: Correlation of histopathological, immunohistochemical and ultrastructural features. Pathol Res Pract 186:344, 1990. 98.
99.
Corson JM: Pathology of malignant mesothelioma. Semin Thorac Cardiovasc Surg 9:347, 1997.
Churg A: Neoplastic asbestos-induced diseases. In Churg A, Green F (eds): Pathology of Occupational Lung Disease. Baltimore, Williams & Wilkins, 1998, p 329. 100.
Mossman BT, et al: Mechanisms of carcinogenesis and clinical features of asbestos-associated cancers. Cancer Invest 14:466, 1996. 101.
102.
Sheibani K, Stroup RM: Immunopathology of malignant mesothelioma. Pathology 4:191, 1996.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-1 Microscopic structure of the alveolar wall. Note that the basement membrane (yellow) is thin on one side and widened where it is continuous with the interstitial space. Portions of interstitial cells are shown.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 17 - Head and Neck ORAL CAVITY Inflammations HERPES SIMPLEX VIRUS INFECTIONS MORPHOLOGY APHTHOUS ULCERS (CANKER SORES) ORAL CANDIDIASIS (THRUSH) GLOSSITIS XEROSTOMIA Reactive Lesions Oral Manifestations of Systemic Disease HAIRY LEUKOPLAKIA Tumors and Precancerous Lesions LEUKOPLAKIA AND ERYTHROPLAKIA MORPHOLOGY SQUAMOUS CELL CARCINOMA Pathogenesis MORPHOLOGY Odontogenic Cysts and Tumors Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 17 - Head and Neck UPPER AIRWAYS Nose INFLAMMATIONS Infectious Rhinitis Allergic Rhinitis Nasal Polyps Chronic Rhinitis Sinusitis NECROTIZING LESIONS OF THE NOSE AND UPPER AIRWAYS Nasopharynx INFLAMMATIONS Tumors of the Nose, Sinuses, and Nasopharynx Nasopharyngeal Angiofibroma Inverted Papilloma Isolated Plasmacytomas Olfactory Neuroblastomas (Esthesioneuroblastomas) Nasopharyngeal Carcinomas MORPHOLOGY Larynx INFLAMMATIONS REACTIVE NODULES (VOCAL CORD POLYPS) CARCINOMA OF THE LARYNX Sequence of Hyperplasia, Dysplasia, Carcinoma MORPHOLOGY SQUAMOUS PAPILLOMA AND PAPILLOMATOSIS Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
UPPER AIRWAYS The term upper airways is used here to include the nose, pharynx, and larynx and their related parts. Disorders of
762
these structures are among the most common afflictions of humans, but fortunately the overwhelming majority are more nuisances than threats. Nose Inflammatory diseases, mostly in the form of the common cold, as everyone knows, are the most common disorders of the nose and accessory air sinuses. Most of these inflammatory conditions are viral in origin, but they are often complicated by superimposed bacterial infections having considerably greater significance. Much less common are a few destructive inflammatory nasal diseases and tumors primary in the nasal cavity or paranasal sinuses. INFLAMMATIONS Infectious Rhinitis.
Infectious rhinitis, the more elegant way of saying "common cold," is in most instances caused by one or more viruses. Major offenders are adenoviruses, echoviruses, and rhinoviruses (Chapter 9) . They evoke a profuse catarrhal discharge that is familiar to all and the bane of the kindergarten teacher. During the initial acute stages, the nasal mucosa is thickened, edematous, and red; the nasal cavities are narrowed; and the turbinates are enlarged. These changes may extend, producing a concomitant pharyngotonsillitis. Secondary bacterial infection enhances the inflammatory reaction and produces an essentially mucopurulent or sometimes frankly suppurative exudate. But as everyone knows, these infections soon clear up, usually in a week if appropriately treated but only after 7 days if ignored. Allergic Rhinitis.
Allergic rhinitis (hay fever) is initiated by sensitivity reactions to one of a large group of allergens, most commonly the plant pollens, fungi, animal allergens, and dust mites. [12] It affects 20% of the U.S. population. As is the case with asthma, allergic rhinitis is an immunoglobulin E-mediated immune reaction with an early- and late-phase response
(see section on type I hypersensitivity in Chapter 7) . The allergic reaction is characterized by marked mucosal edema, redness, and mucous secretion, accompanied by a leukocytic infiltration in which eosinophils are prominent. Nasal Polyps.
Recurrent attacks of rhinitis eventually lead to focal protrusions of the mucosa, producing so-called nasal polyps, which may reach 3 to 4 cm in length. On histologic examination, these polyps consist of edematous mucosa having a loose stroma, often harboring hyperplastic or cystic mucous glands and infiltrated with a variety of inflammatory cells, including prominently neutrophils, eosinophils, and plasma cells with occasional clusters of lymphocytes (Fig. 17-6) . In the absence of bacterial infection, the mucosal covering of these polyps is intact, but with chronicity, it may become ulcerated or infected. When multiple or large, they may encroach on the airway and impair sinus drainage. Although the features of nasal polyps point to an allergic etiology, most patients with nasal polyps are not atopic, and only 0.5% of atopic patients develop polyps. [13] Chronic Rhinitis.
Chronic rhinitis is a sequel to repeated attacks of acute rhinitis, whether microbial or allergic in origin, with the eventual development of superimposed bacterial infection. A deviated nasal septum or nasal polyps with impaired drainage of secretions contribute to the microbial invasion. Frequently, there is superficial desquamation or ulceration of the mucosal epithelium and a variable inflammatory infiltrate of neutrophils, lymphocytes, and plasma cells subjacent to the epithelium. These suppurative infections sometimes extend into the air sinuses. Sinusitis.
Acute sinusitis is most commonly preceded by acute or chronic rhinitis, but maxillary sinusitis occasionally arises by extension of a periapical infection through the bony floor of the sinus. The offending agents are usually inhabitants of the oral cavity, and the inflammatory reaction is entirely nonspecific. Impairment of drainage of the sinus by inflammatory edema of the mucosa is an important contributor to the process and, when complete, may impound the suppurative exudate, producing empyema of the sinus. Obstruction of the outflow, most often of the
Figure 17-6 A , Nasal polyps. Low-power magnification showing edematous masses lined by epithelium. B , High-power views showing
edema and eosinophil-rich inflammatory infiltrate.
763
frontal and next most often of the anterior ethmoid sinuses, occasionally leads to an
accumulation of mucous secretions in the absence of direct bacterial invasion, producing a so-called mucocele. Acute sinusitis may, in time, give rise to chronic sinusitis, particularly when there is interference with drainage. There is usually a mixed microbial flora, largely of normal inhabitants of the oral cavity. Particularly severe forms of chronic sinusitis are caused by fungi (e.g., mucormycosis), especially in diabetics. Uncommonly, sinusitis is a component of Kartagener syndrome, which also includes bronchiectasis and situs inversus (Chapter 16) . All these features are secondary to defective ciliary action. Although most instances of chronic sinusitis are more uncomfortable than disabling or serious, the infections have the potential of spreading into the orbit or of penetrating into the enclosing bone and producing osteomyelitis or, even, into the cranial vault, causing septic thrombophlebitis of a dural venous sinus. NECROTIZING LESIONS OF THE NOSE AND UPPER AIRWAYS
Necrotizing ulcerating lesions of the nose and upper respiratory tract may be produced by Spreading fungal infections (principally mucormycosis [Chapter 9]), particularly in the diabetic Wegener granulomatosis (discussed in Chapter 12) A condition once called lethal midline granuloma or polymorphic reticulosis and now thought to represent, in most cases, angiocentric non-Hodgkin lymphoma, a neoplasm of natural killer cells [14] (Chapter 15) . Ulceration and superimposed bacterial infection frequently complicate the process, confusing the histologic changes by producing tumor-related granulomatous inflammation. Concomitant lymphomatous lesions may be found in other organs and sites. At one time, these lesions were highly fatal owing to uncontrolled growth of the lymphoma, possibly with penetration into the cranial vault, or because of tumor necrosis with secondary bacterial infection and blood-borne dissemination of the infection. Currently, the treatment of the lymphoma with the usual modalities has proved to be effective, in many cases, in bringing the destructive process under control. Nasopharynx Although the nasopharyngeal mucosa, related lymphoid structures, and glands may be involved in a wide variety of specific infections (e.g., diphtheria, infectious mononucleosis discussed elsewhere) as well as by neoplasms, the only disorders mentioned here are nonspecific inflammations; tumors are discussed separately later. INFLAMMATIONS
Pharyngitis and tonsillitis are frequent concomitants of the usual viral upper respiratory infections. Most often implicated are the multitudinous rhinoviruses, echoviruses, and adenoviruses, and less frequently respiratory syncytial viruses and the various influenzal strains. In the usual case, there is reddening and slight edema of the nasopharyngeal mucosa, with reactive enlargement of the related lymphoid structures. Bacterial infections may be superimposed on these viral involvements, or the bacteria may be primary invaders. The most common offenders are the beta-hemolytic
streptococci, but sometimes Staphylococcus aureus or other pathogens may be implicated. Particularly severe forms of pharyngitis and tonsillitis are seen in infants and children who have not yet developed any protective immunity to such agents and in adults rendered susceptible by neutropenia, some form of immunodeficiency, uncontrolled diabetes, or disruption of the normal oral flora by antibiotics. In these circumstances, microbial opportunists may be involved. The inflamed nasopharyngeal mucosa may be covered by an exudative membrane (pseudomembrane), and the nasopalatine and palatine tonsils may be enlarged and covered by exudate. A typical appearance is of enlarged, reddened tonsils (due to reactive lymphoid hyperplasia) dotted by pinpoints of exudate emanating from the tonsillar crypts, so-called follicular tonsillitis. The major importance of streptococcal "sore throats" lies in the possible development of poststreptococcal complications, for example, rheumatic fever (Chapter 13) and glomerulonephritis (Chapter 21) . Whether recurrent episodes of acute tonsillitis favor the development of chronic tonsillitis (true chronic tonsillitis is extremely rare) is open to debate, but they may leave residual enlargement of the lymphoid tissue, inviting the tender mercies of the otolaryngologist. Tumors of the Nose, Sinuses, and Nasopharynx Tumors in these locations are infrequent but include the entire category of mesenchymal and epithelial neoplasms. [14] [15] Brief mention may be made of somewhat distinctive types. Nasopharyngeal Angiofibroma.
This is a highly vascular tumor that occurs almost exclusively in adolescent males. Despite its benign nature, it may cause serious clinical problems because of its tendency to bleed profusely during surgery. Inverted Papilloma.
These are benign but locally aggressive neoplasms occurring in both the nose and the paranasal sinuses. As the name implies, the papillomatous proliferation of squamous epithelium, instead of producing an exophytic growth, extends into the mucosa, that is, is inverted (Fig. 17-7) . If not adequately excised, it has a high rate of recurrence, with the potentially serious complication of invasion of the orbit or cranial vault; rarely, frank carcinoma may also develop. HPV DNA sequences have been identified in some patients. Isolated Plasmacytomas.
These extramedullary plasmacytomas (Chapter 15) arise in the lymphoid structures adjacent to the nose and sinuses. These may protrude within these cavities as polypoid growths, varying from 1 cm to several centimeters in diameter, covered usually by an
intact
764
Figure 17-7 Inverted papilloma. The masses of squamous epithelium are growing inward; hence, the term inverted. (Courtesy of Dr. James Gulizia, Brigham and Women's Hospital, Boston, MA.)
overlying mucosa. The histology is that of a malignant plasma cell tumor and is identical to that described in Chapter 15 . Only rarely do these lesions progress to multiple myeloma. Olfactory Neuroblastomas (Esthesioneuroblastomas).
These are uncommon, highly malignant tumors composed of small round cells resembling neuroblasts proliferating into lobular nests encircled by vascularized connective tissue. They arise most often superiorly and laterally in the nose from the neuroendocrine cells dispersed in the olfactory mucosa. The differential diagnosis of these neoplasms includes all other small cell tumors (Chapter 11) , such as lymphoma, Ewing sarcoma, and embryonal rhabdomyosarcoma. [16] The cells are of neuroendocrine origin and thus exhibit membrane-bound secretory granules on electron microscopy and stain immunohistochemically for neuron-specific enolase, S-100 protein, and chromogranin. Although they are thus classifiable as primitive neuroectodermal tumors, many do not share the 11;22 translocation or fuscin-gene products typical of Ewing sarcoma of bone (Chapter 28) and other primitive neuroectodermal tumors. [16] Some of these tumors also reveal trisomy 8. Olfactory neuroblastomas tend to metastasize widely. Combinations of surgery, radiation, and chemotherapy yield a 5-year survival rate of 50% to 70%. [17] Nasopharyngeal Carcinomas.
This tumor is characterized by a distinctive geographic distribution, a close anatomic relationship to lymphoid tissue, and an association with EBV infection. It takes one of three patterns: (1) keratinizing squamous cell carcinomas, (2) nonkeratinizing squamous cell carcinomas, and (3) undifferentiated carcinomas that have an abundant non-neoplastic, lymphocytic infiltrate. The last pattern has often been called, erroneously, lymphoepithelioma. Three sets of influences apparently affect the origins of these neoplasms: (1) heredity, (2) age, and (3) infection with EBV. Nasopharyngeal carcinomas are particularly common in parts of Africa, where they are the most frequent childhood cancer. In contrast, in southern China, they are the most common cancer in adults but rarely occur in children. In the United States, they are rare in both adults and children. Environment must play some role in this distribution, because migration from a high-incidence locale to a low-incidence locale is followed in the generations by a progressive decline in
incidence. The EBV genome has been identified in the tumor epithelial cells (not the lymphocytes) of most undifferentiated and nonkeratinizing squamous cell nasopharyngeal carcinomas. [18] Its role in the pathogenesis of this tumor is discussed in Chapter 8 . MORPHOLOGY.
On histologic examination, the keratinizing and nonkeratinizing squamous cell lesions more or less resemble usual well-differentiated and poorly differentiated squamous cell carcinomas arising in other locations. The undifferentiated variant is composed of large epithelial cells with oval or round vesicular nuclei, prominent nucleoli, and indistinct cell borders disposed in a syncytium-like array (Fig. 17-8) . Admixed with the epithelial cells are abundant, mature, normal-appearing lymphocytes. The three histologic variants present as masses in the nasopharynx or sometimes in other locations, such as the tonsils, posterior tongue, or upper airways. Nasopharyngeal carcinomas tend to grow silently until they have become unresectable and have often spread to cervical nodes or distant sites. Radiotherapy is the standard modality of treatment, yielding in most studies about a 50% to 70% 3-year survival rate. The undifferentiated carcinoma is the most radiosensitive, and the keratinizing the least radiosensitive.
Figure 17-8 Nasopharyngeal carcinoma, lymphoepithelioma-type. The syncytium-like nests of epithelium are surrounded by lymphocytes. (Courtesy of Dr. James Gulizia, Brigham and Women's Hospital, Boston, MA.)
765
Larynx The most common disorders that affect the larynx are inflammations. Tumors are uncommon but are amenable to resection, although often at the price of loss of natural voice. INFLAMMATIONS
Laryngitis may occur as the sole manifestation of allergic, viral, bacterial, or chemical insult, but it is more commonly part of a generalized upper respiratory tract infection or the result of heavy exposure to tobacco smoke. The larynx may also be affected in many systemic infectious diseases, such as tuberculosis and diphtheria. Although most nonspecific microbiologic involvements are self-limited, they may at times be serious, especially in infancy or childhood, when mucosal congestion, exudation, or edema may cause laryngeal obstruction. In particular, laryngoepiglottitis, caused by Haemophilus influenzae or beta-hemolytic streptococci in infants and young children with their small airways, may induce such sudden swelling of the epiglottis and vocal cords that a
potentially lethal medical emergency is created. This form of disease is uncommon in adults owing to the larger size of the larynx and the stronger accessory muscles of respiration. Croup is the name given to laryngotracheobronchitis in children, in which the inflammatory narrowing of the airway produces the inspiratory stridor so frightening to parents. The most common form of laryngitis, encountered in heavy smokers, constitutes an important predisposition to the development of squamous epithelial changes in the larynx and sometimes overt carcinoma. REACTIVE NODULES (VOCAL CORD POLYPS)
Reactive nodules, also called polyps, sometimes develop on the vocal cords, most often in heavy smokers or in individuals who impose great strain on their vocal cords (singers' nodules). Adults, predominantly men, are most often affected. These nodules constitute smooth, rounded, sessile or pedunculated excrescences, generally only a few millimeters in greatest dimension, located usually on the true vocal cords. They are usually covered by squamous epithelium that may become keratotic, hyperplastic, or even slightly dysplastic. The core of the nodule is a loose myxoid connective tissue that may be variably fibrotic or punctuated by numerous vascular channels. When nodules on opposing vocal cords impinge on each other, the mucosa may undergo ulceration. Because of their strategic location, with corresponding greater inflammatory infiltration of the core of the lesion, they characteristically change the character of the voice and often cause progressive hoarseness. They virtually never give rise to cancers. CARCINOMA OF THE LARYNX Sequence of Hyperplasia, Dysplasia, Carcinoma.
A spectrum of epithelial alterations is seen in the larynx. These are termed, from one end to the other, hyperplasia, atypical hyperplasia, dysplasia, carcinoma in situ, and invasive carcinoma. [19] Macroscopically, the epithelial changes range from smooth, white or reddened focal thickenings, sometimes roughened by keratosis, to irregular verrucous or ulcerated, white-pink lesions looking like cancer. When first seen, the orderly thickenings have almost no potential for malignant transformation, but the risk rises to 1% to 2% during the span of 5 to 10 years with mild dysplasia and 5% to 10% with severe dysplasia. In essence, there are all gradations of epithelial hyperplasia of the true vocal cords, and the likelihood of the development of an overt carcinoma is directly proportional to the level of atypia when the lesion is first seen. Only histologic evaluation can determine the gravity of the changes. The various changes described are most often related to tobacco smoke, the risk being proportional to the level of exposure. Indeed, up to the point of frank cancer, the changes often regress after cessation of smoking. However, alcohol is also clearly a risk factor and other factors may contribute to increased risk, including nutritional factors, exposure to asbestos, and irradiation. [20] [21] HPV sequences are present in about 5% of
cases. [7] MORPHOLOGY.
About 95% of laryngeal carcinomas are typical squamous cell lesions. Rarely, adenocarcinomas are seen, presumably arising from mucous glands. The tumor usually develops directly on the vocal cords, but it may arise above or below the cords, on the epiglottis or aryepiglottic folds, or in the pyriform sinuses. Those confined within the larynx proper are termed intrinsic, whereas those that arise or extend outside the larynx are called extrinsic. Squamous cell carcinomas of the larynx follow the growth pattern of all squamous cell carcinomas. They begin as in situ lesions that later appear as pearly gray, wrinkled plaques on the mucosal surface, ultimately ulcerating and fungating (Fig. 17-9) . The degree of anaplasia of the laryngeal tumors is highly variable. Sometimes massive tumor giant cells and multiple bizarre mitotic figures are seen. As expected with lesions arising from recurrent exposure to environmental carcinogens, adjacent mucosa may demonstrate squamous cell hyperplasia with foci of dysplasia, or even carcinoma in situ. Carcinoma of the larynx manifests itself clinically by persistent hoarseness. At presentation, about 60% of these cancers are confined to the larynx; as a result, the prognosis is better than for those that have spread into adjacent structures. Later, laryngeal tumors may produce pain, dysphagia, and hemoptysis. Patients with this condition are extremely vulnerable to secondary infection of the ulcerating lesion. With surgery, radiation, or combined therapeutic treatments, many patients can be cured, but about one third die of the disease. The usual cause of death is infection of the distal respiratory passages or widespread metastases and cachexia.
766
Figure 17-9 A , Laryngeal carcinoma. Note the large, ulcerated, fungating lesion involving the vocal cord and pyriform sinus. B ,
Histologic appearance of laryngeal squamous cell carcinoma. Note the atypical lining epithelium and invasive keratinizing cancer cells in the submucosa.
SQUAMOUS PAPILLOMA AND PAPILLOMATOSIS
Laryngeal squamous papillomas are benign neoplasms, usually on the true vocal cords, that form soft, raspberry-like excrescences rarely more than 1 cm in diameter (Fig. 17-10) . On histologic examination, the papilloma consists of multiple, slender, finger-like projections supported by central fibrovascular cores and covered by an orderly, typical, stratified squamous epithelium. When the papilloma is on the free edge of the vocal cord, trauma may lead to ulceration that can be accompanied by hemoptysis.
Figure 17-10 Diagrammatic comparison of a benign papilloma and an exophytic carcinoma of the larynx to highlight their quite
different appearances.
Papillomas are usually single in adults but are often multiple in children, in whom they are referred to as juvenile laryngeal papillomatosis. [22] However, multiple recurring papillomas also occur in adults. The lesions are caused by HPV types 6 and 11, do not become malignant, but frequently recur. They often spontaneously regress at puberty, but some affected patients endure numerous surgeries before this occurs. Cancerous transformation is rare.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 17 - Head and Neck EAR Inflammatory Lesions Otosclerosis Tumors Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
EAR Although disorders of the ear rarely shorten the quantity of life, many impair its quality. The most common aural disorders, in descending order of frequency, are (1) acute and chronic otitis (most often involving the middle ear and mastoid), sometimes leading to a cholesteatoma; (2) symptomatic otosclerosis; (3) aural polyps; (4) labyrinthitis; (5) carcinomas, largely of the external ear; and (6) paragangliomas, found mostly in the middle ear. Only those conditions that have distinctive morphologic features are described. Paragangliomas are discussed later. All these entities are characterized here, save for labyrinthitis, which has few distinctive morphologic changes. Inflammatory Lesions Inflammations of the ear, otitis media, acute or chronic, occur mostly in infants and children. They usually produce
767
a serous exudate (when viral in origin) but may become suppurative when bacterial infection becomes superimposed. The most common offenders are Streptococcus pneumoniae, H. influenzae, and beta-hemolytic streptococci. Repeated bouts of acute otitis media with failure of resolution lead to chronic disease. The causative agents of chronic disease are usually Pseudomonas aeruginosa, Staphylococcus aureus, or a fungus and, sometimes, a broadly mixed flora. Chronic infection has the potential to perforate the eardrum, encroaching on the ossicles or labyrinth, spreading into the mastoid spaces, and even penetrating into the cranial vault to produce there a temporal cerebritis or abscess. Otitis media in the diabetic person, when caused by P. aeruginosa, is especially aggressive and spreads widely (destructive necrotizing otitis media). Cholesteatomas associated with chronic otitis media are not neoplasms, nor do they always contain cholesterol. Rather, they are cystic lesions 1 to 4 cm in diameter, lined by keratinizing squamous epithelium or metaplastic mucus-secreting epithelium, and filled with amorphous debris (derived largely from desquamated squames). Sometimes they contain spicules of cholesterol. The precise events involved in their development are not clear, but it is proposed that chronic inflammation and perforation of the eardrum with ingrowth of the squamous epithelium or metaplasia of the secretory epithelial lining of the middle ear are responsible for the formation of a squamous cell nest that becomes cystic. A chronic inflammatory reaction surrounds the keratinous cyst. Sometimes rupture not only enhances the inflammatory reaction but also induces the
formation of giant cells that enclose partially necrotic squames and other particulate debris. These lesions, by progressive enlargement, can erode into the ossicles, the labyrinth, the adjacent bone, or the surrounding soft tissue and sometimes produce visible neck masses. Otosclerosis As the name implies, this condition refers to abnormal bone deposition in the middle ear about the rim of the oval window into which the footplate of the stapes fits. Both ears are usually affected. At first there is fibrous ankylosis of the footplate, followed in time by bony overgrowth anchoring it into the oval window. The degree of immobilization governs the severity of the hearing loss. This condition usually begins in the early decades of life; minimal degrees of this derangement are exceedingly common in the United States in young to middle-aged adults, but fortunately more severe symptomatic otosclerosis is relatively uncommon. In most instances it is familial, following autosomal dominant transmission with variable penetrance. The basis for the osseous overgrowth is completely obscure, but it appears to represent uncoupling of normal bone resorption and bone formation. Thus, it begins with bone resorption, followed by fibrosis and vascularization of the temporal bone in the immediate vicinity of the oval window, in time replaced by dense new bone anchoring the footplate of the stapes. In most instances, the process is slowly progressive during the span of decades, leading eventually to marked hearing loss. Tumors The large variety of epithelial and mesenchymal tumors that arise in the ear--external, medial, internal--are rare save for basal cell or squamous cell carcinomas of the pinna (external ear). These carcinomas tend to occur in elderly men and are thought to be associated with actinic radiation. By contrast, those within the canal tend to be squamous cell carcinomas, which occur in middle-aged to elderly women and are not associated with sun exposure. Wherever they arise, they morphologically resemble their counterparts in other skin locations, beginning as papules that extend and eventually erode and invade locally. Neither the basal cell nor the squamous cell lesions of the pinna often extend beyond local invasion, but squamous cell carcinomas arising in the external canal may invade the cranial cavity or metastasize to regional nodes and, indeed, account for a 5-year mortality of about 50%.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 17 - Head and Neck NECK Branchial Cyst (Lymphoepithelial Cyst) Thyroglossal Tract Cyst Paraganglioma (Carotid Body Tumor) MORPHOLOGY Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
NECK Most of the conditions that involve the neck have been described elsewhere (e.g., squamous cell and basal cell carcinomas of the skin, melanocarcinomas, lymphomas), or they are only a component of a systemic disorder (e.g., generalized rashes, the lymphadenopathy of infectious mononucleosis or tonsillitis). What remains for consideration here are a few uncommon lesions unique to the neck. Branchial Cyst (Lymphoepithelial Cyst) These benign cysts, usually appearing on the anterolateral aspect of the neck, arise either from remnants of the branchial arches or, as many believe, from developmental salivary gland inclusions within cervical lymph nodes. [23] Whatever their origin, they are circumscribed cysts, 2 to 5 cm in diameter, with fibrous walls usually lined by stratified squamous or pseudostratified columnar epithelium underlaid by an intense lymphocytic infiltrate or, more often, well-developed lymphoid tissue with reactive follicles. The cystic contents may be clear, watery to mucinous fluid or may contain desquamated, granular cellular debris. The cysts enlarge only slowly during the years, are rarely the site of cancerous transformation, and generally are readily excised. Similar lesions sometimes appear in the parotid gland or the oral cavity, beneath the tongue. Thyroglossal Tract Cyst Embryologically, the thyroid anlage begins in the region of the foramen caecum at the base of the tongue; as the gland develops, it descends to its definitive location in the
768
anterior neck. Remnants of this developmental tract may persist, producing cysts, 1 to 4 cm in diameter, that may be lined by stratified squamous epithelium when the cyst is near the base of the tongue or by pseudostratified columnar epithelium in lower locations. Obviously, transitional patterns are also encountered. The connective tissue wall of the cyst may harbor lymphoid aggregates or remnants of recognizable thyroid tissue. If the excision is not complete, stubborn recurrence can be expected. Malignant transformation within the lining epithelium has been reported but is rare. Paraganglioma (Carotid Body Tumor) Paraganglia are clusters of neuroendocrine cells dispersed throughout the body, some connected with the sympathetic nervous system and others with the parasympathetic
nervous system. The largest collection of these cells is found in the adrenal medulla, where they give rise to pheochromocytomas (Chapter 26) . Tumors arising in extra-adrenal paraganglia are not surprisingly referred to as paragangliomas. [24] Paragangliomas develop in two general locations: Paravertebral paraganglia (e.g., organs of Zuckerkandl and rarely bladder). Such tumors have sympathetic connections and are chromaffin positive; about half elaborate catecholamines, as do pheochromocytomas. Paraganglia related to the great vessels of the head and neck, the so-called aorticopulmonary chain, including the carotid bodies; aortic bodies; jugulotympanic ganglia; ganglion nodosum of the vagus nerve; and clusters located about the oral cavity, nose, nasopharynx, larynx, and orbit. These are innervated by the parasympathetic nervous system, and their tumors are referred to as nonchromaffin paragangliomas. These tumors infrequently release catecholamines, but because the neuroendocrine cells that make up these lesions sense oxygen and carbon dioxide tensions within adjacent vessels, the tumors are also sometimes referred to as chemodectomas. MORPHOLOGY.
The carotid body tumor is a prototype of a parasympathetic paraganglioma. It rarely exceeds 6 cm in diameter and arises close to or envelops the bifurcation of the common carotid artery. The tumor tissue is red-pink to brown. The microscopic features of all paragangliomas, wherever they arise, are remarkably uniform. They are composed of nests (zellballen) of polygonal chief cells enclosed by trabeculae of fibrous and sustentacular elongated cells. [16] The tumor cells have abundant, clear or granular, eosinophilic cytoplasm and uniform, round to ovoid, sometimes vesicular nuclei (Fig. 17-11) . In most tumors, there is little cell pleomorphism, and mitoses are scant. Electron microscopy often discloses well-demarcated neuroendocrine granules in paravertebral tumors, but they tend to be scant in nonfunctioning tumors. However, the cells in most tumors are argyrophilic and stain positively for neuroendocrine markers by immunohistochemistry (nonspecific enolase; S-100; chromogranin) as well as possibly other bioactive products (e.g., serotonin, gastrin, somatostatin, bombesin). Carotid body tumors (and paragangliomas in general) are rare. They usually arise in the sixth decade of life. They commonly occur singly and sporadically but may be familial, with autosomal dominant transmission in the multiple endocrine neoplasia II syndrome (Chapter 26) , and in this case, they are frequently multiple and sometimes bilaterally symmetric. Carotid body tumors frequently recur after incomplete resection, and despite their benign appearance, many metastasize to local and distant sites. About 50%
Figure 17-11 Carotid body tumor. A , Low-power view showing tumor clusters separated by septa (zellballen). B , High-power view of
large, eosinophilic, slightly vacuolated tumor cells with elongated sustentacular cells in the septa.
769
ultimately prove fatal largely because of infiltrative growth. Unfortunately, it is almost impossible histologically to judge the clinical course of a carotid body tumor--mitoses, pleomorphism, and even vascular invasion are unreliable. [25] Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 17 - Head and Neck SALIVARY GLANDS Inflammation (Sialadenitis) Sialolithiasis and Nonspecific Sialadenitis Neoplasms PLEOMORPHIC ADENOMA MORPHOLOGY Clinical Features WARTHIN TUMOR (PAPILLARY CYSTADENOMA LYMPHOMATOSUM) MORPHOLOGY MUCOEPIDERMOID CARCINOMA MORPHOLOGY OTHER SALIVARY GLAND TUMORS MORPHOLOGY Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
SALIVARY GLANDS There are three major salivary glands--parotid, submandibular, and sublingual--as well as innumerable minor salivary glands distributed throughout the mucosa of the oral cavity. All these glands, particularly the major ones, are subject to inflammation or to the development of neoplasms. Inflammation (Sialadenitis) Sialadenitis may be of viral, bacterial, or autoimmune origin. The most common form of viral sialadenitis is mumps, in which usually the major salivary glands, particularly the parotids, are affected (epidemic parotitis). Other glands (e.g., the pancreas and testes) may also be involved. Autoimmune disease underlies the inflammatory salivary changes of Sjogren syndrome, discussed in Chapter 7 . In this condition, the widespread involvement of the salivary glands and the mucus-secreting glands of the nasal mucosa induces xerostomia--dry mouth; associated involvement of the lacrimal glands produces dry eyes-- keratoconjunctivitis sicca. The combination of salivary and lacrimal gland inflammatory enlargement with xerostomia is sometimes called Mikulicz syndrome, a noncommittal term that includes all forms of involvement of these glands, including sarcoidosis, leukemia, lymphoma, and other tumors, that are sometimes accompanied by xerostomia. Xerostomia may also be secondary to radiation-induced salivary gland atrophy or to drugs (e.g., antihistamines, phenothiazines). Sialolithiasis and Nonspecific Sialadenitis.
Nonspecific bacterial sialadenitis most often involving the major salivary glands, particularly the submandibular glands, is an uncommon condition, usually secondary to ductal obstruction produced by stones (sialolithiasis). The common offenders are Staphylococcus aureus and Streptococcus viridans. The stone formation is sometimes related to obstruction of the orifices of the salivary glands by impacted food debris or by edema about the orifice after some injury. Frequently, the stones are of obscure origin. Dehydration with decreased secretory function may also predispose to secondary bacterial invasion, as sometimes occurs in patients receiving long-term phenothiazines that suppress salivary secretion. Perhaps dehydration with decreased secretion explains the development of bacterial suppurative parotitis in elderly patients with a recent history of major thoracic or abdominal surgery. Whatever the origin, the obstructive process and bacterial invasion lead to a nonspecific inflammation of the affected glands that may be largely interstitial or, when induced by staphylococcal or other pyogens, may be associated with overt suppurative necrosis and abscess formation. Unilateral involvement of a single gland is the rule. The inflammatory involvement causes painful enlargement and sometimes a purulent ductal
discharge. Neoplasms In view of their relatively undistinguished normal morphology, the salivary glands give rise to a surprising variety of benign and malignant tumors. [26] [27] [28] [29] A classification and the relative incidence of benign and malignant tumors are shown in Table 17-2 ; not included are the rare benign and malignant mesenchymal tumors. As indicated in Table 17-2 , only a relatively few epithelial neoplasms make up more than 90% of salivary gland tumors, and so our consideration can be restricted to them. Overall, these neoplasms are relatively uncommon and represent less than 2% of tumors in humans. About 65% to 80% arise within the parotid, 10% in the submandibular gland, and the remainder in the minor salivary glands, including the sublingual glands. Fifteen per cent to 30% of tumors in the parotid glands are malignant, in contrast to about 40% in the submandibular glands, 50% in the minor salivary glands, and 70% to 90% of sublingual tumors. [18] The likelihood then of a salivary gland tumor being malignant is more or less inversely proportional to the size of the gland. These tumors usually occur in adults, with a slight female predominance, but about 5% occur in children younger than 16 years. For unknown reasons, Warthin tumors occur much more often in males. The benign tumors most often appear in the fifth to seventh decades of life. The malignant ones tend, on average, to appear somewhat later. Whatever the histologic pattern, neoplasms in the parotid glands produce distinctive swellings in front of and below the ear. In general, when they are first diagnosed, both benign and malignant lesions range from 4 to 6 cm in diameter and are mobile on palpation except in the case of neglected malignant tumors. Although benign tumors are known to have been present usually for many months to TABLE 17-2 -- HISTOLOGIC CLASSIFICATION AND APPROXIMATE INCIDENCE OF BENIGN AND MALIGNANT TUMORS OF THE SALIVARY GLANDS Benign Malignant Pleomorphic adenoma (50%) (mixed tumor)
Mucoepidermoid carcinoma (15%) Adenocarcinoma (NOS) (10%)
Warthin tumor (5%-10%)
Acinic cell carcinoma (5%)
Oncocytoma (1%)
Adenoid cystic carcinoma (5%)
Other adenomas (5%-10%)
Malignant mixed tumor (3%-5%)
Basal cell adenoma
Squamous cell carcinoma (1%)
Canalicular adenoma
Other carcinomas (2%)
Ductal papillomas NOS, not otherwise specified. Data from Ellis GL, Auclair PL: Tumors of the Salivary Glands. Atlas of Tumor Pathology, Third Series. Washington, DC, Armed Forces Institute of Pathology, 1996.
770
Figure 17-12 Pleomorphic adenoma of the parotid. The transected, sharply circumscribed, yellow-white tumor protrudes above the
level of the surrounding glandular substance.
several years before coming to clinical attention, cancers seem to demand attention more promptly, probably because of their more rapid growth. Ultimately, however, there are no reliable criteria to differentiate, on clinical grounds, the benign from the malignant lesions, and morphologic evaluation is necessary. PLEOMORPHIC ADENOMA
Because of their remarkable histologic diversity, these neoplasms have also been called mixed tumors. They represent about 60% of tumors in the parotid, are less common in the submandibular glands, and are relatively rare in the minor salivary glands. In essence, they are epithelium-derived benign tumors that show both epithelial and mesenchymal differentiation. They are thus composed of epithelial elements dispersed throughout a matrix showing varying degrees of myxoid, hyaline, chondroid (cartilaginous), and even osseous tissue. In some tumors, the epithelial elements predominate; in others, they are present only in widely dispersed foci. Little is known about the origins of these neoplasms save that radiation exposure increases the risk. [27] Equally uncertain is the histogenesis of the various components, but favored today is the view that all neoplastic elements, including those that appear mesenchymal, are of either myoepithelial or ductal reserve cell origin (hence the designation pleomorphic adenoma). MORPHOLOGY.
Most pleomorphic adenomas present as basically rounded, well-demarcated masses rarely exceeding 6 cm in greatest dimension (Fig. 17-12) . Although they are encapsulated, in some instances the capsule is not fully developed, and expansile growth produces tongue-like protrusions into the surrounding gland, rendering enucleation of the tumor (in contrast with limited parotidectomy) hazardous. The cut surface is gray-white with variegated myxoid and blue translucent areas of chondroid. The dominant histologic feature is the great heterogeneity mentioned. The epithelial elements resembling ductal cells or myoepithelial cells are disposed in duct formations, acini, irregular tubules, strands, or sheets of cells. These elements
Figure 17-13 Pleomorphic adenoma. A , Low-power view showing a well-demarcated tumor with normal parotid acini below. B ,
High-power view showing amorphous myxoid stroma resembling cartilage, with interspersed islands and strands of myoepithelial cells. (Courtesy of Dr. E. Lee, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)
771
are typically dispersed within a mesenchyme-like background of loose myxoid tissue containing islands of chondroid and, rarely, foci of bone (Fig. 17-13) . Sometimes the epithelial cells form well-developed apparent ducts lined by cuboidal to columnar cells with an underlying layer of deeply chromatic, small myoepithelial cells. In other instances, there may be strands or sheets of myoepithelial cells. Islands of well-differentiated squamous epithelium may also occur. In most cases, there is no epithelial dysplasia or evident mitotic activity. There is no difference in biologic behavior between the tumors composed largely of epithelial elements and those composed only of seemingly mesenchymal elements. Clinical Features.
These tumors present as painless, slow-growing, mobile discrete masses within the parotid or submandibular areas or in the buccal cavity. The recurrence rate (perhaps months to years later) with adequate parotidectomy is about 4% but, with attempted enucleation, approaches 25% because of failure to recognize at surgery minute protrusions from the main mass. A carcinoma infrequently arises in a pleomorphic adenoma, referred to variously as a carcinoma ex pleomorphic adenoma or a malignant mixed tumor. The incidence of malignant transformation increases with the duration of the tumor, being about 2% for tumors present less than 5 years and almost 10% for those of more than 15 years' duration. The cancer usually takes the form of an adenocarcinoma or undifferentiated carcinoma, and often it virtually completely overgrows the last vestiges of the preexisting pleomorphic adenoma; but to substantiate the diagnosis of carcinoma ex pleomorphic adenoma, recognizable traces of the latter must be found. Regrettably, these cancers, when they appear, are among the most aggressive of all salivary gland malignant neoplasms, accounting for a 30% to 50% mortality in 5 years. WARTHIN TUMOR (PAPILLARY CYSTADENOMA LYMPHOMATOSUM)
This curious benign neoplasm with its intimidating histologic name is the second most common salivary gland neoplasm. It arises almost always in the parotid gland (the only tumor virtually restricted to the parotid) and occurs more commonly in males than in females, usually in the fifth to seventh decades of life. About 10% are multifocal and 10% bilateral. Smokers have eight times the risk of nonsmokers for developing tumors. MORPHOLOGY.
Most Warthin tumors (sometimes also called adenolymphomas) are round to oval, encapsulated masses, 2 to 5 cm in diameter, arising in most cases in the superficial parotid gland, where they are readily palpable. Transection reveals a pale gray surface punctuated by narrow cystic or cleft-like spaces filled with a mucinous or serous secretion. On microscopic examination, these spaces are lined by a double layer of epithelial cells resting on a dense lymphoid stroma sometimes bearing germinal centers (Fig. 17-14) . The spaces are frequently narrowed by polypoid projections of the lymphoepithelial elements. The double layer of lining cells is distinctive, with a surface palisade of columnar cells having an abundant, finely granular, eosinophilic cytoplasm,
Figure 17-14 Warthin tumor. A , Lower-power view showing epithelial and lymphoid elements. Note the follicular germinal center beneath the epithelium. B , Cleftlike spaces separate the lobules of tumor covered by a regular double layer of eosinophilic epithelial cells based on a lymphoid stroma. (Courtesy of Dr. James Gulizia, Brigham and Women's Hospital, Boston, MA.)
772
imparting an oncocytic appearance, resting on a layer of cuboidal to polygonal cells. Oncocytes are epithelial cells stuffed with mitochondria that impart the granular appearance to the cytoplasm. Secretory cells are dispersed in the columnar cell layer, accounting for the secretion within the lumens. On occasion, there are foci of squamous metaplasia. The histogenesis of these tumors has long been disputed. The occasional finding of small salivary gland rests in lymph nodes in the neck suggests that these tumors arise from the aberrant incorporation of similar inclusion-bearing lymphoid tissue in the parotids. Indeed, rarely, Warthin tumors have arisen within cervical lymph nodes, a finding that should not be misconstrued to imply a metastasis. These neoplasms are usually benign, with recurrence rates of only 2% after resection. MUCOEPIDERMOID CARCINOMA
These neoplasms are composed of variable mixtures of squamous cells, mucus-secreting cells, and intermediate hybrids. They represent about 15% of all salivary gland tumors, and while they occur preponderantly (60% to 70%) in the parotids, they account for a large fraction of salivary gland neoplasms in the other glands, particularly the minor salivary glands. Overall, they are the most common form of malignant tumor primary in the salivary glands and are the most common radiation-induced neoplasm. MORPHOLOGY.
Mucoepidermoid carcinomas range up to 8 cm in diameter and, while apparently circumscribed, lack well-defined capsules and are often infiltrative at the margins. Pale
gray-white on transection, they frequently reveal small, mucin-containing cysts. The basic histologic pattern is that of cords, sheets, or cystic configurations of squamous, mucous, or intermediate cells. The hybrid cell types often have squamous features, with small to large mucus-filled vacuoles, best seen when highlighted with mucin stains (Fig. 17-15 A, B). The tumor cells may be regular and benign-appearing on one end of the spectrum or, alternatively, highly anaplastic and unmistakably malignant. Accordingly, mucoepidermoid carcinomas are subclassified into low, intermediate, or high grades. Low-grade lesions tend to be composed largely of mucus-secreting cells, often forming glandular spaces. On the other hand, high-grade tumors are composed largely of squamous cells with only a scattering of mucus-secreting cells. The clinical course and prognosis depend on the grade of the neoplasm. Low-grade tumors may invade locally and recur in about 15% of cases, but only rarely do they metastasize and so yield a 5-year survival rate of more than 90%. By contrast, high-grade neoplasms and, to a somewhat lesser extent, intermediate-grade tumors are invasive and difficult to excise and so recur in about 25% to 30% of cases and, in 30% of cases, disseminate to distant sites. The 5-year survival rate of these tumors is only 50%. OTHER SALIVARY GLAND TUMORS
Two less common neoplasms merit brief description, adenoid cystic carcinoma and acinic cell tumor. Adenoid cystic carcinoma is a relatively uncommon tumor in the parotids but is the most common neoplasm in the other salivary glands, particularly the minor salivary glands about the mouth. Similar neoplasms have been reported in the nose, sinuses, and upper airways and elsewhere.
Figure 17-15 A , Mucoepidermoid carcinoma showing islands having squamous cells as well as clear cells containing mucin. B , Mucicarmine stains the mucin reddish-pink. (Courtesy of Dr. James Gulizia, Brigham and Women's Hospital, Boston, MA.)
773
Figure 17-16 Adenoid cystic carcinoma in a salivary gland. A , Low-power view. The tumor cells have created a cribriform pattern enclosing secretions. B , High-power view showing polygonal tumor cells surrounding the cystic space filled with secretions.
MORPHOLOGY.
In gross appearance, they are generally small, poorly encapsulated, infiltrative, gray-pink lesions. On histologic evaluation, they are composed of small cells having dark, compact nuclei and scant cytoplasm. These cells tend to be disposed in tubular,
solid, or cribriform patterns reminiscent of cylindromas arising in the adnexa of the skin. The spaces between the tumor cells are often filled with a hyaline material thought to represent excess basement membrane (Fig. 17-16) . Although slowly growing, these are "sneaky," unpredictable tumors with a tendency to invade perineural spaces (making them the most painful salivary gland neoplasm), and they are stubbornly recurrent. Eventually, 50% or more disseminate widely to distant sites such as bone, liver, and brain, sometimes decades after attempted removal. Thus, although the 5-year survival rate is about 60% to 70%, it drops to about 30% at 10 years and 15% at 15 years. Neoplasms arising in the minor salivary glands have, on average, a poorer prognosis than those primary in the parotids. The acinic cell tumor is composed of cells resembling the normal serous cells of salivary glands. They are relatively uncommon, representing only 2% to 3% of salivary gland tumors. Most arise in the parotids, the small remainder in the submandibular glands. They rarely involve the minor glands, which normally have only a scant number of serous cells. Like Warthin tumor, they are sometimes bilateral or multicentric. They are generally small, discrete lesions that may appear encapsulated. On histologic examination, they reveal a variable architecture and cell morphology. Most characteristically, the cells have apparent cleared cytoplasm, but the cells are sometimes solid or at other times vacuolated. The cells are disposed in sheets or microcystic, glandular, follicular, or papillary patterns. There is usually little anaplasia and few mitoses, but some tumors are occasionally slightly more pleomorphic. The clinical course of these neoplasms is somewhat dependent on the level of pleomorphism. Overall, recurrence after resection is uncommon, but about 10% to 15% of these neoplasms metastasize to lymph nodes. The survival rate is in the range of 90% at 5 years and 60% at 20 years.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
REFERENCES 1.
Hutton KP, Rogers RS III: Recurrent aphthous stomatitis. Dermatol Clin 5:761, 1987.
2.
Neville BW, et al (eds): Oral and Maxillofacial Pathology. Philadelphia, WB Saunders, 1995.
Sciubba JJ: Opportunistic oral infections in the immunosuppressed patient: oral hairy leukoplakia and oral candidiasis. Adv Dent Res 10:69, 1996. 3.
4.
van der Waal I, et al: Oral leukoplakia: a clinicopathological review. Oral Oncol 33:291, 1997.
Hogewind WFC, et al: Oral leukoplakia with emphasis on malignant transformation: a follow-up study of 46 patients. J Craniomaxillofac Surg 17:128, 1989. 5.
Boyle P, et al: Recent advances in the etiology and epidemiology of head and neck cancer. Curr Opin Oncol 2:529, 1990. 6.
Paz IB, et al: Human papillomavirus (HPV) in head and neck cancer. An association of HPV 16 with squamous cell carcinoma of Waldeyer's tonsillar ring. Cancer 79:595, 1997. 7.
Steinberg BM, DiLorenzo TP: A possible role for human papillomavirus in head and neck cancer. Cancer Metastasis Rev 15:91, 1996. 8.
9.
Jordan RC, Daley T: Oral squamous cell carcinoma: new insights. J Can Dent Assoc 63:517, 1997.
Cowan JM, et al: Cytogenetic evidence of the multistep origin of head and neck squamous cell carcinoma. J Natl Cancer Inst 84:793, 1992. 10.
Carter RL: Patterns and mechanisms of spread of squamous carcinomas of the oral cavity. Clin Otolaryngol 15:185, 1990. 11.
12.
Naclerio R, Solomon W: Rhinitis and inhaled allergens. JAMA 278:1842, 1997.
13.
Slavin RG: Nasal polyps and sinusitis. JAMA 278:1845, 1997.
Hyams VJ, et al: Tumors of the Upper Respiratory Tract and Ear. Atlas of Tumor Pathology, Second Series. Washington, DC, Armed Forces Institute of Pathology, 1988. 14.
Goodman ML, Pilch BZ: Tumors of the upper respiratory tract. In Fletcher DM (ed): Diagnostic Histopathology of Tumors. London, Churchill Livingstone, 1995, pp 79-126. 15.
774
Argani P, et al: Olfactory neuroblastoma is not related to the Ewing family of tumors. Am J. Surg Pathol 22:391, 1998. 16.
Broich G, et al: Esthesioneuroblastoma: a general review of the cases published since the discovery of the tumour in 1924. Anticancer Res 17:2683, 1997. 17.
Hawkins EP, et al: Nasopharyngeal carcinoma in children--a retrospective review and demonstration of Epstein-Barr viral genomes in tumor cell cytoplasm: a report of the Pediatric Oncology Group. Hum Pathol 21:805, 1990. 18.
Crissman JD, Zarbo RJ: Dysplasia, in situ carcinoma, and progression to invasive carcinoma of the upper aerodigestive tract. Am J Surg Pathol 13:5, 1989. 19.
20.
Cattaruzza MS, et al: Epidemiology of laryngeal cancer. Eur J Cancer B Oral Oncol 32B:293, 1996.
Koufman JA, Burke AJ: The etiology and pathogenesis of laryngeal carcinoma. Otolaryngol Clin North Am 30:1, 1997. 21.
22.
Bauman NM, Smith RJ: Recurrent respiratory papillomatosis. Pediatr Clin North Am 43:1385, 1996.
Regauer S, et al: Lateral neck cysts--the branchial theory revisited. A critical review and clinicopathological study of 97 cases with special emphasis on cytokeratin expression. APMIS 105:623, 1997. 23.
Capella C, et al: Histopathology, cytology, and cytochemistry of pheochromocytomas and paragangliomas including chemodectomas. Pathol Res Pract 186:176, 1988. 24.
25.
Wick MR, Rosai JR: Neuroendocrine tumors of the mediastinum. Semin Diagn Pathol 8:35, 1991.
Ellis GL, Auclair PL: Tumors of the Salivary Glands. Atlas of Tumor Pathology, Third Series, Fascicle 17. Washington, DC, Armed Forces Institute of Pathology, 1996. 26.
Simpson RH: Classification of salivary gland tumors--a brief histopathological review. Histol Histopathol 10:737, 1995. 27.
Shrestha P, et al: Primary epithelial tumors of salivary glands--histogenesis, histomorphological and immunohistochemical implications--diagnosis and clinical management. Crit Rev Oncol Hematol 23:239, 1996. 28.
Nagler RM, Laufer D: Tumors of the major and minor salivary glands: review of 25 years of experience. Anticancer Res 17:701, 1997. 29.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 17-1 Aphthous ulcer of the tongue in a young woman. Doesn't it look painful? (Courtesy of Dr. John Sexton, Chief, Oral and Maxillofacial Surgery, Beth Israel Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 17-2 "Pregnancy tumor" protruding from the margin of the upper gingiva. (Courtesy of Dr. John Sexton, Chief, Oral and Maxillofacial Surgery, Beth Israel Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 17-3 A, Leukoplakia of the hard palate. The numerous lesions have become virtually confluent. (Courtesy of Drs. E.E. Vokes, S. Lippman, et al, Department of Thoracic/Head and Neck Oncology, Texas Medical Center, Houston, TX. Reprinted with permission from The New England Journal of Medicine 328:184, 1993.) B, Leukoplakia caused by marked epithelial thickening and hyperkeratosis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 17-4 Schematic representation of the sites of origin of squamous cell carcinoma of the oral cavity, in numerical order of frequency.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 17-5 Carcinoma of the tongue. The tumor of the base of the tongue appears as a bulbous protruding mass. (Courtesy of Drs. E.E. Vokes, S. Lippman, et al, Department of Thoracic/Head and Neck Oncology, Texas Medical Center, Houston, TX. Reprinted with permission from The New England Journal of Medicine 328:184, 1993.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 18 - The Gastrointestinal Tract Esophagus NORMAL ESOPHAGUS PATHOLOGY Congenital Anomalies ATRESIA AND FISTULAS STENOSIS, WEBS, AND RINGS Lesions Associated With Motor Dysfunction ACHALASIA MORPHOLOGY Clinical Features HIATAL HERNIA DIVERTICULA LACERATIONS (MALLORY-WEISS SYNDROME) MORPHOLOGY Clinical Features Esophagitis REFLUX ESOPHAGITIS MORPHOLOGY Clinical Features BARRETT ESOPHAGUS MORPHOLOGY Clinical Features INFECTIOUS AND CHEMICAL ESOPHAGITIS MORPHOLOGY Clinical Features Esophageal Varices MORPHOLOGY Clinical Features Tumors BENIGN TUMORS MALIGNANT TUMORS Squamous Cell Carcinoma Etiology and Pathogenesis
MORPHOLOGY Clinical Features Adenocarcinoma Etiology and Pathogenesis MORPHOLOGY Clinical Features Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 18 - The Gastrointestinal Tract Stomach NORMAL STOMACH Gastric Mucosal Physiology ACID SECRETION MUCOSAL PROTECTION PATHOLOGY Congenital Anomalies PYLORIC STENOSIS Gastritis ACUTE GASTRITIS Pathogenesis MORPHOLOGY Clinical Features CHRONIC GASTRITIS (INCLUDING HELICOBACTER INFECTION) Pathogenesis Helicobacter pylori Autoimmune Gastritis MORPHOLOGY Regenerative Change Metaplasia Atrophy Hyperplasia Dysplasia Clinical Features Special Forms of Gastritis Peptic Ulcer Disease PEPTIC ULCERS Epidemiology Pathogenesis MORPHOLOGY Clinical Features ACUTE GASTRIC ULCERATION MORPHOLOGY
Clinical Features Miscellaneous Conditions HYPERTROPHIC GASTROPATHY Tumors BENIGN TUMORS MORPHOLOGY Clinical Features GASTRIC CARCINOMA Epidemiology Pathogenesis Environment Host MORPHOLOGY Clinical Features LESS COMMON GASTRIC TUMORS Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Stomach NORMAL STOMACH The stomach is a saccular organ with a volume of 1200 to 1500 ml but a capacity of greater than 3000 ml. It extends from just left of the midline superiorly, where it is joined to the esophagus, to just right of the midline inferiorly, where it connects to the duodenum. The concavity of the right, inner curve is called the lesser curvature, and the convexity of the left, outer curve is the greater curvature. An angle along the lesser curvature, the incisura angularis, marks the approximate point at which the stomach narrows before its junction with the duodenum. The stomach is divided into five anatomic regions (Fig. 18-11) . The cardia is the narrow conical portion of the stomach immediately distal to the gastroesophageal junction. The fundus is the dome-shaped portion of the proximal stomach that extends superolaterally to the gastroesophageal junction. The body, or corpus, comprises the remainder of the stomach proximal to the incisura angularis. The stomach distal to this angle is the antrum, demarcated from the duodenum by the muscular pyloric sphincter.
Figure 18-11 Anatomy of the stomach.
The gastric wall consists of mucosa, submucosa, muscularis propria, and serosa. The interior surface of the stomach exhibits coarse rugae. These infoldings of mucosa and submucosa extend longitudinally and are most prominent in the proximal stomach, flattening out when the stomach is distended. A finer mosaic-like pattern is delineated by small furrows in the mucosa. Finally, the delicate texture of the mucosa is punctuated by millions of gastric foveolae, or pits, leading to the mucosal glands. The entire mucosal surface as well as the lining of the gastric pits is composed of surface foveolar cells. These tall, columnar mucin-secreting cells have basal nuclei and crowded, small, relatively clear mucin-containing granules in the supranuclear region. Deeper in the gastric pits are so-called mucous neck cells, which have a lower content of mucin granules and are thought to be the progenitors of both the surface epithelium and the cells of the gastric glands. Mitoses are extremely common in this region, as the entire gastric mucosal surface is totally replaced every 2 to 6 days. The gastric glands vary between anatomic regions, as follows: Cardia glands contain mucus-secreting cells.
Gastric or oxyntic glands are found in the fundus and body and contain parietal cells, chief cells, and scattered endocrine cells. Antral or pyloric glands contain mucus-secreting cells and endocrine cells. The key cell types in the gastric glands are the following: Mucous cells populate the glands of the cardia and antral regions and secrete mucus and pepsinogen II. The mucous neck cells in the glands of the body and fundus secrete mucus as well as group I and II pepsinogens. Parietal cells line predominantly the upper half of gastric glands in the fundus and body. They are recognizable by their bright eosinophilia on hematoxylin and eosin preparations, attributable to their abundant mitochondria. The apical membrane of the parietal cell is invaginated, forming an extensive intracellular canalicular 788
system complete with microvilli. In the resting state, vesicles lie in close approximation to the canalicular system. These vesicles contain the hydrogen ion pump, a unique H+ ,K+ -ATPase that pumps hydrogen across membranes in exchange for potassium ions. Within minutes of parietal cell stimulation, the vesicles fuse with the canalicular system, thereby creating an apically directed, acid-secreting membrane of enormous surface area. Parietal cells also secrete intrinsic factor, which binds luminal vitamin B12 and permits its absorption in the ileum. Chief cells are concentrated more at the base of gastric fundus and body glands and are responsible for the secretion of the proteolytic proenzymes pepsinogen I and II. Chief cells are notable for their basophilic cytoplasm and ultrastructurally are classic protein-synthesizing cells, having an extensive subnuclear rough endoplasmic reticulum, a prominent supranuclear Golgi apparatus, and numerous apical secretory granules. On stimulation of chief cells, the pepsinogens contained in the granules are released by exocytosis. The pepsinogens are activated to pepsin by the low luminal pH and inactivated above pH 6 on entry into the duodenum. Endocrine, or enteroendocrine, cells are scattered among the epithelial cells of fundus, body, and antral glands. The cytoplasm of these triangular cells contains small, brightly eosinophilic granules that are concentrated on the basal aspect of the cell. These cells can act in an endocrine mode, releasing their products into the circulation, or a paracrine mode, via secretion into the local tissue. Gastric Mucosal Physiology ACID SECRETION
The hallmark of gastric physiology is secretion of hydrochloric acid, divided into three phases, as follows: The cephalic phase, initiated by the sight, taste, smell, chewing, and swallowing of palatable food, is mediated by vagal activity. The gastric phase involves stimulation of mechanical receptors by gastric
distention and is mediated by vagal impulses and gastrin release from endocrine cells in the antral glands, designated G cells. Gastrin release also is promoted by luminal amino acids and peptides. The intestinal phase, initiated when food containing digested protein enters the proximal small intestine, involves a polypeptide distinct from gastrin. All signals converge on the gastric parietal cell, as follows: [13] Cephalic-vagal or gastric-vagal afferents directly stimulate the parietal cell via the muscarinic type of cholinergic receptors for acetylcholine. Gastrin presumably activates a gastrin receptor. An oxyntic gland endocrine cell designated the enterochromaffin-like cell plays a central role: Gastrin and vagal afferents induce the release of histamine from the enterochromaffin-like cell, thereby stimulating the histamine2 receptor on parietal cells. MUCOSAL PROTECTION
At maximal secretory rates, the intraluminal concentration of hydrogen ion is 3 million times greater than that of the blood and tissues. The mucosal barrier protects the gastric mucosa from autodigestion and is created by the following: [14] Mucus secretion: The thin layer of surface mucus in the stomach and duodenum exhibits a diffusion coefficient for H+ that is one fourth that of water. Acid-containing and pepsin-containing fluid exits the gastric glands as jets passing through the surface mucous layer, entering the lumen directly without contacting surface epithelial cells. Bicarbonate secretion: Surface epithelial cells in both the stomach and the duodenum secrete bicarbonate into the boundary zone of adherent mucus, creating an essentially pH-neutral microenvironment immediately adjacent to the cell surface. Epithelial barrier: Intercellular tight junctions provide a barrier to the back-diffusion of hydrogen ions. Epithelial disruption is followed rapidly by restitution, in which existing cells migrate along the exposed basement membrane to fill in the defects and restore epithelial barrier integrity. Mucosal blood flow: The rich mucosal blood supply provides oxygen, bicarbonate, and nutrients to epithelial cells and removes back-diffused acid. When the mucosal barrier is breached, the muscularis mucosa limits injury. Superficial damage, limited to the mucosa, can heal within hours to days. When damage extends into the submucosa, weeks are required for complete healing. Imperfect as our understanding of these defensive mechanisms may be, they are clearly a physiologic marvel, or gastric walls would suffer the same fate as a piece of swallowed meat. PATHOLOGY Gastric lesions are frequent causes of clinical disease. In Western industrialized nations, peptic ulcers develop in up to 10% of the general population at some point
during life. Chronic infection of the gastric mucosa by the bacterium Helicobacter pylori is the most common infection worldwide. Lastly, gastric cancer remains a leading cause of death in the United States, despite its decreasing overall incidence. Congenital Anomalies
Heterotopic rests of normal tissue may be present at any site in the gastrointestinal tract and are usually asymptomatic.
789
With pancreatic heterotopia, nodules of essentially normal pancreatic tissue up to 1 cm in diameter may be present in the gastric or intestinal submucosa, in the muscle wall, or in a subserosal position. When in the pylorus, localized inflammation may lead to pyloric obstruction. With gastric heterotopia, small patches of ectopic gastric mucosa in the duodenum or in more distal sites may present as perplexing sources of bleeding, owing to peptic ulceration of adjacent mucosa. Defective closure of the diaphragmatic anlage leads to weakness or partial-to-total absence of a region of the diaphragm, usually on the left. Resultant herniation of abdominal contents into the thorax in utero produces a diaphragmatic hernia. Usually the stomach or a portion of it insinuates into the pouch, but occasionally small bowel and even a portion of the liver accompany it. The herniation may be asymptomatic or may engender potentially lethal respiratory embarassment in the newborn. PYLORIC STENOSIS
Congenital hypertrophic pyloric stenosis is encountered in infants as a disorder that affects boys three to four times more often than girls, occurring in 1 in 300 to 900 live births. Familial occurrence implicates a multifactorial pattern of inheritance; monozygotic twins have a high rate of concordance of the condition. Pyloric stenosis also may occur in association with Turner syndrome, trisomy 18, and esophageal atresia. Regurgitation and persistent, projectile, nonbilious vomiting usually appear in the second or third week of life. Physical examination reveals visible peristalsis and a firm, ovoid palpable mass in the region of the pylorus or distal stomach, the result of hypertrophy, and possibly hyperplasia, of the muscularis propria of the pylorus. Edema and inflammatory changes in the mucosa and submucosa may aggravate the narrowing. Surgical muscle splitting is curative. Acquired pyloric stenosis in adults is one of the long-term risks of antral gastritis or peptic ulcers close to the pylorus. Carcinomas of the pyloric region, lymphomas, or adjacent carcinomas of the pancreas are more sinister causes. In these cases, inflammatory fibrosis or malignant infiltration narrows the pyloric channel, producing pyloric outlet obstruction. In rare instances, hypertrophic pyloric stenosis is the result of prolonged pyloric spasm or delayed appearance of the childhood pattern.
Gastritis
The diagnosis of gastritis is both overused and often missed--overused when it is applied loosely to any transient upper abdominal complaint in the absence of validating evidence, and missed because most patients with chronic gastritis are asymptomatic. Gastritis is simply defined as inflammation of the gastric mucosa. Inflammation may be predominantly acute, with neutrophilic infiltration, or chronic, with lymphocytes, plasma cells, or both predominating and associated intestinal metaplasia and atrophy. ACUTE GASTRITIS
Acute gastritis is an acute mucosal inflammatory process, usually of a transient nature. The inflammation may be accompanied by hemorrhage into the mucosa and, in more severe circumstances, by sloughing of the superficial mucosa. This severe erosive form of the disease is an important cause of acute gastrointestinal bleeding. Pathogenesis.
The pathogenesis is poorly understood, in part because normal mechanisms for gastric mucosal protection are not clear. Acute gastritis is frequently associated with the following: Heavy use of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly aspirin Excessive alcohol consumption Heavy smoking Treatment with cancer chemotherapeutic drugs Uremia Systemic infections (e.g., salmonellosis) Severe stress (e.g., trauma, burns, surgery) Ischemia and shock Suicidal attempts, as with acids and alkali Gastric irradiation or freezing Mechanical trauma (e.g., nasogastric intubation) After distal gastrectomy One or more of the following influences are thought to be operative in these varied settings: increased acid secretion with back-diffusion, decreased production of bicarbonate buffer, reduced blood flow, disruption of the adherent mucus layer, and direct damage to the epithelium. Not surprisingly, mucosal insults can act synergistically. Thus, ischemic injury would worsen the effects of back-diffusion of hydrogen ions. Other mucosal insults have been identified, such as regurgitation of detergent bile acids and lysolecithins from the proximal duodenum and inadequate mucosal synthesis of prostaglandins. A substantial portion of patients have idiopathic gastritis, with no associated disorders.
MORPHOLOGY.
In its mildest form, the lamina propria exhibits only moderate edema and slight vascular congestion. The surface epithelium is intact, and scattered neutrophils are present among the surface epithelial cells or within the epithelial layer and lumen of mucosal glands. The presence of neutrophils above the basement membrane (within the epithelial space) is abnormal and signifies active inflammation (activity). With more severe mucosal damage, erosion and hemorrhage develop. Erosion denotes loss of the superficial epithelium, generating a defect in the mucosa that does not cross the muscularis mucosa. It is accompanied by a robust acute inflammatory infiltrate and extrusion of a fibrin-containing purulent exudate into the lumen. Hemorrhage may occur independently, generating punctate dark spots in an otherwise hyperemic mucosa, or in association with erosion. Concurrent erosion and hemorrhage is termed acute erosive gastritis (Fig. 18-12 A). Large areas of the gastric mucosa may
790
Figure 18-12 Acute gastritis. A , Gross view showing punctate erosions in an otherwise unremarkable mucosa; adherent blood is dark owing to exposure to gastric acid. B , Low-power microscopic view of focal mucosal disruption with hemorrhage; the adjacent
mucosa is normal.
be denuded, but the involvement is superficial and rarely affects the entire depth of the mucosa (Fig. 18-12 B). These lesions are but one step removed from stress ulcers, to be described later. Clinical Features.
Depending on the severity of the anatomic changes, acute gastritis may be entirely asymptomatic; may cause variable epigastric pain, nausea, and vomiting; or may present with overt hemorrhage, massive hematemesis, melena, and potentially fatal blood loss. Overall, it is one of the major causes of massive hematemesis, as in alcoholics. In particular settings, the condition is quite common. As many as 25% of persons who take daily aspirin for rheumatoid arthritis develop acute gastritis at some time, many with bleeding. CHRONIC GASTRITIS (INCLUDING HELICOBACTER INFECTION)
Chronic gastritis is defined as the presence of chronic mucosal inflammatory changes leading eventually to mucosal atrophy and epithelial metaplasia, usually in the absence of erosions. The epithelial changes may become dysplastic and constitute a background for the development of carcinoma. Chronic gastritis is notable for distinct causal
subgroups and for patterns of histologic alterations that vary in different parts of the world. In the Western world, the prevalence of histologic changes indicative of chronic gastritis exceeds 50% in the later decades of life. Pathogenesis.
The major etiologic associations of chronic gastritis are as follows: Chronic infection by H. pylori (Chapter 9) Immunologic ( autoimmune), in association with pernicious anemia Toxic, as with alcohol ingestion and cigarette smoking Postsurgical, especially after antrectomy with gastroenterostomy with reflux of bilious duodenal secretions Motor and mechanical, including obstruction, bezoars (luminal concretions), and gastric atony Radiation Granulomatous conditions Miscellaneous--amyloidosis, graft-versus-host disease Helicobacter pylori.
By far the most important etiologic association is chronic infection by the bacillus H. pylori. As evident in this and later discussions, this organism plays a critical role in several major gastric diseases (Table 18-2) . H. pylori is present in 90% of patients with chronic gastritis affecting the antrum. Colonization rates increase with age, reaching 50% in asymptomatic American adults over 50 years of age. Prevalence of infection among adults in Puerto Rico exceeds 80%. In this and other areas where infection is endemic, the organism seems to be acquired in childhood and persists for decades. Most infected persons also have the associated gastritis but are asymptomatic. Nevertheless, infected persons are at increased risk for the development of peptic ulcer disease and possibly gastric cancer. H. pylori is a nonsporing, curvilinear gram-negative rod measuring approximately 3.5×0.5 mum. [15] H. pylori is part of a genus of bacteria that have adapted to the ecologic niche provided by gastric mucus. The specialized traits that allow H. pylori to flourish include the following: Motility (via flagella), allowing it to swim through viscous mucus Elaboration of a urease, which produces ammonia from 791
endogenous urea, thereby buffering gastric acid in the immediate vicinity of the organism Binding of H. pylori organisms to gastric epithelial cells via a bacterial adhesin; binding is enhanced with epithelial cells that bear the blood group O antigen
TABLE 18-2 -- DISEASES ASSOCIATED WITH HELICOBACTER PYLORI INFECTION Chronic gastritis Strong causal association Peptic ulcer disease
Strong causal association
Gastric carcinoma
Postulated etiologic role
Gastric lymphoma
Postulated etiologic role
H. pylori strains that express the cagA gene are strongly associated with duodenal ulcer; the function of the 120- to 140-kD protein product is unknown. Such strains frequently express the vacA gene also, which codes for an 87-kD vacuolating cytotoxin. These two proteins, along with bacterial lipopolysaccharide (endotoxin) and other protein products, appear to act as proinflammatory substances. H. pylori appears to be capable of initiating and perpetuating a chronic state of gastric mucosal injury (Fig. 18-13) . Patients with chronic gastritis and H. pylori usually improve when treated with antimicrobial agents, and relapses are associated with reappearance of this organism. Autoimmune Gastritis.
This form of gastritis accounts for less than 10% of cases of chronic gastritis. It results from the presence of autoantibodies to the gastric gland parietal cells and intrinsic factor, including one against the acid-producing enzyme, H+ ,K+ -ATPase. [16] Gland destruction and mucosal atrophy lead to loss of acid production. In the most severe cases, production of intrinsic factor is lost, leading to pernicious anemia (Chapter 14) . This uncommon form of gastritis is seen in association with other autoimmune disorders, such as Hashimoto thyroiditis and Addison disease. MORPHOLOGY.
Chronic gastritis may affect different regions of the stomach and exhibit varying degrees of mucosal damage. [17] Autoimmune gastritis is characterized by diffuse mucosal damage of the body-fundic mucosa, with less intense-to-absent antral damage. Gastritis in the setting of environmental causes (including infection by H. pylori) tends to affect antral mucosa or both antral and body-fundic mucosa. By visual inspection, the mucosa is usually reddened and has a coarser texture than normal. The inflammatory infiltrate may create a boggy-appearing mucosa with thickened rugal folds, mimicking early infiltrative lesions. Alternatively, with long-standing atrophic disease, the mucosa may become thinned and flattened. Regardless of cause or location, the histologic changes are similar. An inflammatory infiltrate of lymphocytes and plasma cells is present within the lamina propria (Fig. 18-14) . Active inflammation is signified by the presence of neutrophils within the glandular and surface epithelial layer. Active inflammation may be prominent or absent. Lymphoid aggregates, some with germinal centers, are frequently observed within the mucosa. Several additional histologic features are characteristic.
Regenerative Change.
A proliferative response to
Figure 18-13 Schematic presentation of the presumed action of Helicobacter pylori in the development of chronic gastritis. H. pylori infection leads to exposure of the gastric mucosa to bacteria-derived urease and toxins, including lipopolysaccharide, cagA, and vacA. These, in concert with host-derived gastric acidity and peptic enzymes, produce a chronic state of gastric mucosal injury leading to chronic gastritis as depicted. Note that H. pylori do not colonize regions of intestinal metaplasia.
792
Figure 18-14 Chronic gastritis showing partial replacement of the gastric mucosal epithelium by intestinal metaplasia (upper left) and with inflammation of the lamina propria involving (right) lymphocytes and plasma cells.
the epithelial injury is a constant feature of chronic gastritis. In the neck region of the gastric glands, mitotic figures are increased. Epithelial cells of the surface mucosa, and to a lesser extent the glands, exhibit enlarged, hyperchromatic nuclei and a higher nuclear-to-cytoplasmic ratio. Mucus vacuoles are diminished or absent in the superficial cells. When regenerative changes are severe, particularly with ongoing active inflammation, distinguishing regenerative change from frank dysplasia may be difficult. Metaplasia.
Both antral and body-fundic mucosa may become partially replaced by metaplastic columnar absorptive cells and goblet cells of intestinal morphology ( intestinal metaplasia), both along the surface epithelium and in rudimentary glands. Occasionally, villus-like projections may appear. Although small intestinal features predominate, in some instances features of colonic epithelium may be present. Atrophy.
Atrophic change is evident by marked loss in glandular structures. Parietal cells, in particular, may be conspicuously absent in the autoimmune form. Persisting glands frequently undergo cystic dilation. Hyperplasia.
A particular feature of atrophic gastritis of autoimmune origin, or chronic gastritis treated by inhibitors of acid secretion, is hyperplasia of gastrin-producing G cells in the antral mucosa. This hyperplasia is attributed to the hypochlorhydria or
achlorhydria arising from severe loss of parietal cell acid secretion. In individuals infected by H. pylori, the organism lies in the superficial mucous layer and among the microvilli of epithelial cells. The distribution of organisms can be patchy and irregular, with areas of heavy colonization adjacent to those with no organisms. In extreme cases, the organisms carpet the luminal surfaces of surface epithelial cells, the mucous neck cells, and the epithelial cells lining the gastric pits; they do not invade the mucosa. The organisms are most easily demonstrated with silver stains (Fig. 18-15) , although organisms can be seen on Giemsa-stained and routine hematoxylin and eosin-stained tissue. Even in heavily colonized stomachs, the organisms are absent from areas with intestinal metaplasia. Conversely, organisms may be present in foci of pyloric metaplasia in an inflamed duodenum, and in gastric-type mucosa of Barrett esophagus. Dysplasia.
With long-standing chronic gastritis, the epithelium develops cytologic alterations, including variation in size, shape, and orientation of epithelial cells and nuclear enlargement and atypia. The cellular atypia tends to be most marked in long-standing autoimmune gastritis associated with pernicious anemia. Dysplastic alterations may become so severe as to constitute in situ carcinoma. As such, they probably account for the increased incidence of gastric cancer in atrophic forms of gastritis, particularly in association with pernicious anemia. Clinical Features.
Chronic gastritis usually causes few symptoms. Nausea, vomiting, and upper abdominal discomfort may occur. Individuals with advanced gastritis from H. pylori or other environmental causes are often hypochlorhydric, owing to parietal cell damage and atrophy of body-fundic mucosa. Because parietal cells are never completely destroyed, however, these patients do not develop achlorhydria or pernicious anemia. Serum gastrin levels are usually within the normal range or only modestly elevated.
Figure 18-15 H. pylori. A Steiner silver stain demonstrates the numerous darkly stained Helicobacter organisms along the luminal
surface of the gastric epithelial cells and within adherent mucus. Note that there is no tissue invasion by bacteria.
793
When severe parietal cell loss occurs in the setting of autoimmune gastritis, hypochlorhydria or achlorhydria and hypergastrinemia are characteristically present. Circulating autoantibodies to a diverse array of parietal cell antigens may be detected. A small subset of these patients (10%) may develop overt pernicious anemia after a period of years. The familial occurrence of pernicious anemia is well established; a high
prevalence of gastric autoantibodies is also found in asymptomatic relatives of patients with pernicious anemia. The distribution suggests that the inheritance of autoimmune gastritis is autosomal dominant. Most important is the relationship of chronic gastritis to the development of peptic ulcer and gastric carcinoma (see later). Most patients with a peptic ulcer, whether duodenal or gastric, have H. pylori infection. The long-term risk of gastric cancer in persons with autoimmune gastritis is 2 to 4%, which is considerably greater than the normal population. H. pylori has been implicated as contributing to the pathogenesis of both gastric carcinoma and lymphoma. Special Forms of Gastritis
Several diseases merit separate mention. Eosinophilic gastritis is an idiopathic condition that features a prominent eosinophilic infiltrate of the mucosa, muscle wall, or all layers of the stomach, usually in the antral or pyloric region. Typically affecting middle-aged women, the primary symptom is abdominal pain, although swelling of the pylorus may produce gastric outlet obstruction. This disease may occur in association with eosinophilic enteritis and often is accompanied by a peripheral eosinophilia. Steroid therapy is usually effective. Allergic gastroenteropathy is a disorder of children that may produce symptoms of diarrhea, vomiting, and growth failure. An infiltrate of eosinophils limited to the mucosa can usually be demonstrated in antral biopsy specimens. Lymphocytic gastritis is a condition in which lymphocytes densely populate the epithelial layer of the mucosal surface and pits. The intraepithelial lymphocytes are exclusively T lymphocytes, mostly CD8+ suppressor cells. This condition produces indistinct symptoms, such as abdominal pain, nausea, and vomiting. Although idiopathic in nature, it is increasingly associated with celiac sprue (see later). The presence of intramucosal epithelioid granulomas can usually be attributed to Crohn disease, sarcoidosis, infection (tuberculosis, histoplasmosis, anisakiasis), a systemic vasculitis, or a reaction to foreign materials. Granulomatous gastritis is the term reserved for patients with no such conditions. This idiopathic disorder is clinically benign. Peptic Ulcer Disease
An ulcer is defined as a breach in the mucosa of the alimentary tract, which extends through the muscularis mucosae into the submucosa or deeper. Although ulcers may occur anywhere in the alimentary tract, none are as prevalent as the peptic ulcers that occur in the duodenum and stomach. Acute gastric ulcers may also appear under conditions of severe systemic stress. PEPTIC ULCERS
Peptic ulcers are chronic, most often solitary, lesions that occur in any portion of the gastrointestinal tract exposed to the aggressive action of acid-peptic juices. Peptic
ulcers are usually solitary lesions less than 4 cm in diameter, located in the following sites, in order of decreasing frequency: Duodenum, first portion Stomach, usually antrum At the gastroesophageal junction, in the setting of gastroesophageal reflux Within the margins of a gastrojejunostomy In the duodenum, stomach, or jejunum of patients with Zollinger-Ellison syndrome Within or adjacent to a Meckel diverticulum that contains ectopic gastric mucosa Epidemiology.
In the United States, approximately 4 million people have peptic ulcers (duodenal and gastric), and 350,000 new cases are diagnosed each year. Around 100,000 patients are hospitalized yearly, and about 3000 people die each year as a result of peptic ulcer disease. The lifetime likelihood of developing a peptic ulcer is about 10% for American men and 4% for women. Peptic ulcers are remitting, relapsing lesions that are most often diagnosed in middle-aged to older adults, but they may first become evident in young adult life. They often appear without obvious precipitating influences and may then, after a period of weeks to months of active disease, heal with or without therapy. Even with healing, however, the propensity to develop peptic ulcers remains, in part because of the propensity for recurrent infections with H. pylori. The male-to-female ratio for duodenal ulcers is about 3:1 and for gastric ulcers about 1.5 to 2:1. Women are most often affected at, or after, menopause. For unknown reasons, there has been a significant decrease in the prevalence of duodenal ulcers over the past decades but little change in the prevalence of gastric ulcers. Pathogenesis.
Peptic ulcers appear to be produced by an imbalance between the gastroduodenal mucosal defense mechanisms and the damaging forces (Fig. 18-16) . Gastric acid and pepsin are requisite for all peptic ulcerations.[18] Hyperacidity is not a prerequisite because only a minority of patients with duodenal ulcers have hyperacidity, and it is even less common in those with gastric ulcers. Gastric ulceration can readily occur when mucosal defenses fall, however, as when mucosal blood flow drops, gastric emptying is delayed, or epithelial restitution is impaired. The apparent role of H. pylori in peptic ulceration cannot be overemphasized. H. pylori infection is present in virtually all patients with duodenal ulcers and about 70% of those with gastric ulcers. Furthermore, antibiotic treatment of H. pylori infection promotes healing of ulcers and tends to prevent their recurrence. Hence, much interest is focused on the possible mechanisms by which this tiny spiral organism tips the balance of mucosal defenses. Some likely possibilities include the following:
794
Figure 18-16 Diagram of aggravating causes of, and defense mechanisms against, peptic ulceration.
H. pylori secretes a urease, which generates free ammonia, and a protease, which breaks down glycoproteins in the gastric mucus. The organisms also elaborate phospholipases, which damage surface epithelial cells and may release bioactive leukotrienes and eicosanoids. Neutrophils attracted by H. pylori release myeloperoxidase, which produces hypochlorous acid, yielding, in turn, monochloramine in the presence of ammonia. Both hypochlorous acid and monochloramine can destroy mammalian cells. Both mucosal epithelial cells and lamina propria endothelial cells are prime targets for the destructive actions of H. pylori colonization. Thrombotic occlusion of surface capillaries also is promoted by a bacterial platelet-activating factor. In addition to H. pylori elaboration of enzymes, other antigens (including lipopolysaccharide) recruit inflammatory cells to the mucosa. The chronically inflamed mucosa is more susceptible to acid injury. Finally, damage to the mucosa is thought to permit leakage of tissue nutrients into the surface microenvironment, thereby sustaining the bacillus. Only 10 to 20% of individuals worldwide infected with H. pylori actually develop peptic ulcer. Hence, a key enigma is why most are spared and some are susceptible. Another perplexing observation is that in patients with duodenal ulcer, the actual infection by H. pylori is limited to the stomach. Some studies suggest that H. pylori ammonia elaboration stimulates gastrin release, thereby paradoxically increasing acid production. While the link between H. pylori infection and gastric and duodenal ulcers is established, the interactions leading to ulceration remain to be elucidated. Other events may act alone or in concert with H. pylori to promote peptic ulceration. Gastric hyperacidity, when present, may be strongly ulcerogenic. Hyperacidity may arise from increased parietal cell mass, increased sensitivity to secretory stimuli, increased basal acid secretory drive, or impaired inhibition of stimulatory mechanisms such as gastrin release. The Zollinger-Ellison syndrome (Chapter 20) exhibits multiple peptic ulcerations in the stomach, duodenum, and even jejunum, owing to excess gastrin secretion by a tumor and hence excess gastric acid production. Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs) suppresses mucosal prostaglandin synthesis; aspirin also is a direct irritant. Cigarette smoking impairs mucosal blood flow and healing. Alcohol has not been proved to cause peptic ulceration directly, but alcoholic cirrhosis is associated with an increased incidence of peptic ulcers. Corticosteroids in high dose and with repeated use promote ulcer formation. In some patients with duodenal ulcers, there is too rapid gastric emptying, exposing the duodenal mucosa to an excessive acid load. Duodenal ulcer also is more frequent in patients with alcoholic cirrhosis, chronic obstructive pulmonary disease, chronic renal
795
failure, and hyperparathyroidism. In the last two conditions, hypercalcemia, whatever its cause, stimulates gastrin production and therefore acid secretion. Genetic influences appear to play no role in peptic ulceration. Finally, there are compelling arguments that personality and psychological stress are important contributing factors, even though hard data on cause and effect are lacking. MORPHOLOGY.
At least 98% of peptic ulcers are located in the first portion of the duodenum or in the stomach, in a ratio of about 4:1. Most duodenal ulcers are generally within a few centimeters of the pyloric ring. The anterior wall of the duodenum is more often affected than the posterior wall. Gastric ulcers are predominantly located along the lesser curvature, in or around the border zone between the corpus and the antral mucosa. Less commonly, they may occur on the anterior or posterior walls or along the greater curvature. Although the great majority of individuals have a single ulcer, in 10 to 20% of patients with gastric ulceration there may be a coexistent duodenual ulcer. Wherever they occur, chronic peptic ulcers have a fairly standard, virtually diagnostic gross appearance (Fig. 18-17) . Small lesions (90%) are non-neoplastic and appear to be of a hyperplastic nature. These polyps are composed of a variable admixture of hyperplastic surface epithelium and cystically dilated glandular tissue, with a lamina propria containing increased inflammatory cells and smooth muscle. The surface epithelium may be regenerative in response to surface erosion and inflammation, but true dysplasia is not present. Most hyperplastic polyps are small and sessile; some may
approach several centimeters in diameter and have an apparent stalk. Multiplicity, sometimes numbering by the score, is observed in about 20 to 25% of cases. The adenoma of the stomach is a true neoplasm, representing 5 to 10% of the polypoid lesions in the stomach. By definition, an adenoma contains proliferative dysplastic epithelium and thereby has malignant potential. Adenomatous polyps are much more common in the colon (see later). Gastric adenomas may be sessile (without a stalk) or pedunculated (stalked). The most common location is the antrum. These lesions are usually single and may grow up to 3 to 4 cm in size before detection (Fig. 18-21) . In contrast to the colon, adenomatous change may carpet a large region of flat gastric mucosa without forming a mass lesion. Clinical Features.
Hyperplastic polyps are seen most frequently in the setting of chronic gastritis. They are regarded as having no malignant potential as such but are nevertheless found in about 20% of stomachs resected for carcinoma. This occurrence is attributed to the tendency of chronically inflamed gastric mucosa both to form hyperplastic polyps and to degenerate into malignancy. As with the colonic counterpart, the incidence of gastric adenomas increases with age, particularly into and beyond the sixties. The male-to-female ratio is 2:1. Up to 40% of gastric adenomas contain a focus of carcinoma at the time of diagnosis, particularly the larger lesions. [22] The risk of cancer in the adjacent gastric mucosa may be as high as 30%. Autoimmune gastritis and colonic polyposis syndromes (see later) also have a propensity toward gastric adenoma formation. Otherwise innocuous hyperplastic polyps may occasionally harbor foci of adenomatous epithelium. Because hyperplastic and adenomatous polyps cannot reliably be distinguished endoscopically, histologic examination of gastric polyps is mandatory. GASTRIC CARCINOMA
Among the malignant tumors that occur in the stomach, carcinoma is overwhelmingly the most important and the most common (90 to 95%). Next in order of frequency are
Figure 18-21 Adenomatous polyp of the stomach. Note the large size of the polyp and its lobulated configuration. A small ulceration ( arrow ) can be identified on its surface. (From Kasimer W, Dayal Y: Gastritis, gastric atrophy, and gastric neoplasia. In Chopra S, May RJ (eds): Pathophysiology of Gastrointestinal Disorders, Boston, Little, Brown, 1989.)
799
lymphomas (4%), carcinoids (3%), and malignant stromal cell tumors (2%).
Epidemiology.
Gastric carcinoma is a worldwide disease. Its incidence, however, varies widely, being particularly high in countries such as Japan, Chile, China, Portugal, and Russia and fourfold to sixfold less common in the United States, United Kingdom, Canada, Australia, and France. It is more common in lower socioeconomic groups and exhibits a male-to-female ratio of about 2:1. In most countries, there has been a steady decline in both the incidence and the mortality of gastric cancer over the past six decades. In 1930, gastric cancer was the most common cause of cancer death in the United States. Since that time, the annual mortality rate in the United States has dropped from about 38 to 7 per 100,000 population for men and from 28 to 4 per 100,000 for women. [8] Yet it remains among the leading killer cancers, representing 2.5% of all cancer deaths in the United States and still exceeding lung cancer as the leading cause of cancer death worldwide. [23] Although 5-year survival rates have improved since the advent of endoscopy in the 1960, they remain poor at less than 20% overall. Gastric carcinoma can be divided into two general histologic subtypes: (1) those exhibiting an intestinal morphology with the formation of bulky tumors composed of glandular structures and (2) those that are diffuse in the infiltrative growth of poorly differentiated discohesive malignant cells. The intestinal type exhibits a mean age of incidence of 55 years and a male-to-female ratio of 2:1. The diffuse type occurs in slightly younger patients (mean age, 48), with an approximately equal male-to-female ratio. The drop in incidence of gastric cancer has occurred only in the intestinal type. At the present time, the incidence is approximately the same for intestinal and diffuse cancer. Pathogenesis.
The major factors thought to affect the genesis of gastric cancer are summarized in Table 18-4 . They apply more to the intestinal type, as the risk factors for diffuse gastric cancer are not well defined. Environment.
Environmental influences are thought to be the most important. [24] When families migrate from high-risk to low-risk areas (or the reverse), successive generations acquire the level of risk that prevails in the new locales. The diet is suspected to be a primary offender, and adherence to certain culinary practices is associated with a high risk of gastric carcinoma. The presence of carcinogens, such as N-nitroso compounds and benzopyrene, appears to be particularly important. Thus, lack of refrigeration; consumption of preserved, smoked, cured, and salted foods; water contamination with nitrates; and lack of fresh fruit and vegetables are common themes in high-risk areas. Conversely, intake of green, leafy vegetables and citrus fruits, which contain antioxidants such as ascorbate (vitamin C), alpha-tocopherol (vitamin E), and beta-carotene, is negatively correlated with gastric cancer. [23]
Alcohol intake has not been proven to increase risk. Cigarette smoking imparts a 1.5-fold to 3.0-fold increased risk, although there is no clear dose relationship. Despite initial concern, to date there appears to be no increased risk of stomach cancer from the use of antacid drug therapies. A role for occupational exposure has been difficult to establish. TABLE 18-4 -- FACTORS ASSOCIATED WITH INCREASED INCIDENCE OF GASTRIC CARCINOMA Environmental Diet Nitrites derived from nitrates (water, preserved food) Smoked and salted foods, pickled vegetables Lack of fresh fruit and vegetables Low socioeconomic status Cigarette smoking Host Factors Chronic gastritis Hypochlorhydria: favors colonization with Helicobacter pylori Intestinal metaplasia is a precursor lesion Infection by H. pylori Present in most cases of intestinal-type carcinoma Partial gastrectomy Favors reflux of bilious, alkaline intestinal fluid Gastric adenomas 40% harbor cancer at time of diagnosis 30% have adjacent cancer at time of diagnosis Barrett esophagus Increased risk of gastroesophageal junction tumors Genetic Slightly increased risk with blood group A Family history of gastric cancer Hereditary nonpolyposis colon cancer syndrome
Host.
Host factors are the second major area of scrutiny. Infection by H. pylori leading to chronic gastritis and intestinal metaplasia is thought to be a contributing, but not sufficient, factor for gastric carcinogenesis. Autoimmune gastritis also carries an increased risk, presumably owing to the same process of chronic inflammation and metaplasia. The relative risk for gastric cancer in both conditions is approximately threefold over the general population (recognizing that H. pylori-infected individuals represent more than 50% of the adult population in many locales). Most persons infected with H. pylori never develop gastric cancer. Chronic gastritis also appears to be the substratum from which diffuse gastric cancer arises. Previous peptic ulcer disease per se does not impart increased risk. Only about 4% of patients with gastric cancer have a family history of this disease, and genetic factors are unlikely to be major influences. Dysplasia of the gastric mucosa represents the final common pathway by which intestinal-type gastric cancers arise. Gastric adenomas are known to turn malignant, and these are simply raised lesions containing mucosal dysplasia. The diffuse type of cancer appears to arise de novo, without evolution through dysplasia. Molecular mechanisms underlying cancer promotion have not yet been defined, although many molecular events have been described. In the intestinal type of gastric cancer, the overall pattern of allelic losses shows similarities with colon cancer, with a cumulative series of gene alterations. [25] Abnormalities in several growth factor receptor systems, including c- met, K- sam, and erb, also occur, with markedly different frequencies between the two histologic types. In contrast to colon and pancreatic cancer, the ras oncogene is rarely mutated. Suffice it to say that the disparities in
800
mutations implicate unique pathogenetic pathways, as yet unknown, for the development of intestinal and diffuse types of gastric cancer. MORPHOLOGY.
The location of gastric carcinomas within the stomach is as follows: pylorus and antrum, 50 to 60%; cardia, 25%; and the remainder in the body and fundus. The lesser curvature is involved in about 40% and the greater curvature in 12%. Thus, a favored location is the lesser curvature of the antropyloric region. Although less frequent, an ulcerative lesion on the greater curvature is more likely to be malignant. Gastric carcinoma is classified on the basis of (1) depth of invasion, (2) macroscopic growth pattern, and (3) histologic subtype. The morphologic feature having the greatest impact on clinical outcome is the depth of invasion. Early gastric carcinoma is defined as a lesion confined to the mucosa and submucosa, regardless of the presence or absence of perigastric lymph node metastases. Some early tumors cover large areas of the gastric mucosa (up to 10 cm in diameter) and yet show no
invasion into the muscular wall. Early gastric carcinoma is not synonymous with carcinoma in situ, as the latter is confined to the surface epithelial layer. Advanced gastric carcinoma is a neoplasm that has extended below the submucosa into the muscular wall and has perhaps spread more widely. All cancers presumably begin as early lesions, which develop over time into advanced lesions. The three macroscopic growth patterns of gastric carcinoma, which may be evident at both the early and the advanced stages, are (1) exophytic, with protrusion of a tumor mass into the lumen; (2) flat or depressed, in which there is no obvious tumor mass within the mucosa; and (3) excavated, whereby a shallow or deeply erosive crater is present in the wall of the stomach (Fig. 18-22) . Exophytic tumors are readily identified by radiographic techniques and at endoscopy and may contain portions of an adenoma. In contrast, flat or depressed malignancy may be inapparent to even the experienced eye except as regional effacement of the normal surface mucosal pattern. Excavated cancers may closely mimic, in size and appearance, chronic peptic ulcers. In advanced cases, cancerous craters can be identified by their heaped-up, beaded margins and shaggy, necrotic bases as well as the overt neoplastic tissue extending into the surrounding mucosa and wall (Fig. 18-23) . Uncommonly a broad region of the gastric wall, or the entire stomach, is extensively infiltrated by malignancy, creating a rigid, thickened leather bottle-like stomach, termed linitis plastica. Metastatic
Figure 18-22 Diagram of growth patterns and spread of gastric carcinoma. In early gastric carcinoma, tumor is confined to the
mucosa and submucosa and may exhibit an exophytic, flat or depressed, or excavated conformation. Advanced gastric carcinoma extends into the muscularis propria and beyond. Linitis plastica is an extreme form of flat or depressed advanced gastric carcinoma.
801
Figure 18-23 Ulcerative gastric carcinoma. The ulcer is large and irregular.
carcinoma, from the breast and lung, may generate a similar linitis plastica picture. The histologic subtypes of gastric cancer have been variously subclassified, but the two most important types, as noted earlier, are the intestinal type and diffuse type of the Lauren classification (Fig. 18-24) . The intestinal variant is composed of neoplastic intestinal glands resembling those of colonic adenocarcinoma, which permeate the gastric wall but tend to grow along broad cohesive fronts in an expanding growth pattern. [26] The neoplastic cells often contain apical mucin vacuoles, and abundant mucin may be present in gland lumens. The diffuse variant is composed of gastric-type mucous cells, which generally do not form glands but rather permeate the mucosa and wall as scattered individual cells or small clusters in an infiltrative growth pattern. These cells appear to arise from the middle
layer of the mucosa, and the presence of intestinal metaplasia is not a prerequisite. In this variant, mucin formation expands the malignant cells and pushes the nucleus to periphery, creating a signet ring conformation (Fig. 18-24 B). Regardless of cell type, the amount of mucin varies, and in poorly differentiated portions mucin may be absent. Whatever the variant, all gastric carcinomas eventually penetrate the wall to involve the serosa and spread to regional and more distant lymph nodes. For obscure reasons, gastric carcinomas frequently metastasize to the supraclavicular sentinel (Virchow) node as the first clinical manifestation of an occult neoplasm. Local invasion into the duodenum, pancreas, and retroperitoneum is characteristic. At the time of death, widespread peritoneal seedings and metastases to the liver and lungs are common. A notable site of visceral metastasis is to one or both ovaries ( Krukenberg tumor; Chapter 24) . Clinical Features.
Gastric carcinoma is an insidious disease that is generally asymptomatic until late in its course. The symptoms include weight loss; abdominal pain; anorexia; vomiting; altered bowel habits; and, less frequently, dysphagia, anemic symptoms, and hemorrhage. Because these symptoms are essentially nonspecific, early detection of gastric cancer is difficult. In Japan, where mass endoscopy screening programs are in place, early gastric cancer constitutes about 35% of all newly diagnosed gastric cancers. In Europe and the United States, this figure has remained at 10 to 15% over several decades. The prognosis for gastric carcinoma depends primarily on the depth of invasion and the extent of nodal and distant metastasis at the time of diagnosis; histologic type has minimal independent prognostic significance. The 5-year survival rate of surgically treated early gastric cancer is 90 to 95%, with only a small negative increment if lymph node metastases are present. [27] In contrast, the
Figure 18-24 Gastric cancer. A , Poorly differentiated intestinal-type adenocarcinoma. Note small glands. B , Diffuse signet ring cell carcinoma of the stomach, surrounding a residual benign gastric gland in the mucosa. (Courtesy of Dr. Robert Odze, Brigham and Women's Hospital, Boston, MA.)
802
5-year survival rate for advanced gastric cancer remains below 15%. LESS COMMON GASTRIC TUMORS
Gastric lymphomas represent 5% of all gastric malignancies and are similar to intestinal lymphomas; these are considered as a group later on. Gastric neuroendocrine cell (carcinoid) tumors are extremely rare and tend to be infiltrative tumors that metastasize in about one third of cases. These tumors are described in detail later. Lipomas are a
benign neoplasm of adipose tissue, usually present in the submucosa. A wide variety of mesenchymal neoplasms may arise in the stomach. They generally are of smooth muscle origin, hence the designations leiomyoma for the benign form and leiomyosarcoma for the malignant form. They may contain neural and fibroblastic elements, however, and as a class of tumors exhibit a spectrum of benign-to-malignant features, including a propensity to recurrence and metastasis. They are thus broadly classified under the term gastrointestinal stromal tumors. These lesions are discussed in the section on intestinal tumors. The inflammatory fibroid polyp is a striking lesion, in that it is a bulky submucosal growth composed of inflamed vascularized fibromuscular tissue with a prominent eosinophilic infiltrate and a tenuous mucosa stretched over the surface. These polyps may occur anywhere in the alimentary tract but are found most frequently in the stomach. As they protrude into the lumen, they may occlude the pyloric channel and present abruptly as acute gastric outlet obstruction. Their origin is unknown, although it is postulated that they are a benign, polypoid growth of endothelium and smooth muscle. Metastatic involvement of the stomach is unusual. The most common sources of gastric metastases are leukemia and generalized lymphoma. Metastases of malignant melanoma and carcinomas tend to be multiple and may develop central ulceration. Breast and lung carcinoma may mimic diffuse gastric carcinoma by diffusely infiltrating the gastric wall to generate linitis plastica, as described earlier.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 18 - The Gastrointestinal Tract Small and Large Intestines NORMAL SMALL AND LARGE INTESTINES Anatomy Vasculature Small Intestinal Mucosa Colonic Mucosa Endocrine Cells Intestinal Immune System Neuromuscular Function PATHOLOGY Congenital Anomalies ATRESIA AND STENOSIS MECKEL DIVERTICULUM CONGENITAL AGANGLIONIC MEGACOLON--HIRSCHSPRUNG DISEASE MORPHOLOGY Clinical Features Enterocolitis DIARRHEA AND DYSENTERY INFECTIOUS ENTEROCOLITIS Viral Gastroenteritis Bacterial Enterocolitis Bacterial Invasion MORPHOLOGY Clinical Features Necrotizing Enterocolitis MORPHOLOGY Clinical Features Antibiotic-Associated Colitis (Pseudomembranous Colitis) MORPHOLOGY Clinical Features Collagenous and Lymphocytic Colitis MISCELLANEOUS INTESTINAL INFLAMMATORY DISORDERS Parasites and Protozoa
Acquired Immunodeficiency Syndrome Complications of Transplantation Drug-Induced Intestinal Injury Radiation Enterocolitis Neutropenic Colitis (Typhlitis) Diversion Colitis Malabsorption Syndromes CELIAC SPRUE Pathogenesis MORPHOLOGY Clinical Features TROPICAL SPRUE (POSTINFECTIOUS SPRUE) MORPHOLOGY Clinical Features WHIPPLE DISEASE MORPHOLOGY Clinical Features DISACCHARIDASE (LACTASE) DEFICIENCY ABETALIPOPROTEINEMIA Idiopathic Inflammatory Bowel Disease ETIOLOGY AND PATHOGENESIS Genetic Predisposition Infectious Causes Abnormal Host Immunoreactivity Inflammation as the Final Common Pathway CROHN DISEASE Epidemiology MORPHOLOGY Mucosal Inflammation Chronic Mucosal Damage Ulceration Transmural Inflammation Affecting All Layers Noncaseating Granulomas Other Mural Changes Clinical Features ULCERATIVE COLITIS Epidemiology MORPHOLOGY
Clinical Features Vascular Disorders ISCHEMIC BOWEL DISEASE MORPHOLOGY Transmural Infarction Mucosal and Mural Infarction Chronic Ischemia Clinical Features ANGIODYSPLASIA HEMORRHOIDS MORPHOLOGY Diverticular Disease MORPHOLOGY Pathogenesis Clinical Features Intestinal Obstruction HERNIAS ADHESIONS INTUSSUSCEPTION VOLVULUS Tumors of the Small and Large Intestines TUMORS OF THE SMALL INTESTINE Adenomas Adenocarcinoma TUMORS OF THE COLON AND RECTUM Non-neoplastic Polyps MORPHOLOGY Juvenile Polyps Peutz-Jeghers Polyps Adenomas MORPHOLOGY Tubular Adenomas Villous Adenomas Tubulovillous Adenomas Clinical Features Familial Syndromes Colorectal Carcinogenesis Adenoma-Carcinoma Sequence
Molecular Carcinogenesis Adenomatous Polyposis Coli (APC) Hereditary Nonpolyposis Colon Carcinoma (HNPCC) Methylation Abnormalities K -ras DCC p53 Colorectal Carcinoma Epidemiology, Etiology, and Pathogenesis MORPHOLOGY Clinical Features Carcinoid Tumors MORPHOLOGY Clinical Features GASTROINTESTINAL LYMPHOMA MORPHOLOGY Clinical Features MESENCHYMAL TUMORS MORPHOLOGY Clinical Features Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Small and Large Intestines NORMAL SMALL AND LARGE INTESTINES Anatomy
The small intestine in the human adult is approximately 6 meters in length and the colon (large intestine) approximately 1.5 meters. The first 25 cm of the small intestine, the duodenum, is retroperitoneal; the jejunum marks the entry of the small intestine into the peritoneal cavity, terminating where the ileum enters the colon at the ileocecal valve. The demarcation between jejunum and ileum is not clearly defined; the jejunum arbitrarily constitutes the proximal third of the intraperitoneal portion and the ileum the remainder. The colon is subdivided into the cecum and the ascending, transverse, descending, and sigmoid colon. The sigmoid colon begins at the pelvic brim and loops within the peritoneal cavity, becoming the rectum at about the level of the third sacral vertebra. Halfway along its 15-cm length, the rectum passes between the crura of the perineal muscles to become extraperitoneal. The reflection of the peritoneum from the rectum over the pelvic floor creates a cul-de-sac known as the pouch of Douglas. Vasculature
The arterial supply of the intestine, from the proximal jejunum to the proximal transverse colon, is derived from the superior mesenteric artery. The inferior mesenteric artery feeds the remainder of the colon to the level of the rectum. Each artery progressively divides as it approaches the gut, with rich arterial interconnections via arching mesenteric arcades. Numerous collaterals connect the mesenteric circulation with the celiac arterial axis proximally and the pudendal circulation distally. The lymphatic drainage essentially parallels the vascular supply but does not have the intricate patterns of arcades. The upper rectum is supplied by the superior hemorrhoidal branch of the inferior mesenteric artery. The lower portion receives its blood supply from the hemorrhoidal branches of the internal iliac or internal pudendal artery. The venous drainage follows essentially the same distribution and is connected by an anastomotic capillary bed between the superior and inferior hemorrhoidal veins, providing a connection between the portal and systemic venous systems. Since the colon is a retroperitoneal organ in the ascending and descending portions, it derives considerable accessory arterial blood supply and lymphatic drainage from a wide area of the posterior abdominal wall. Small Intestinal Mucosa
The most distinctive feature of the small intestine is its mucosal lining, which is studded with innumerable villi (Fig. 18-25 A). These extend into the lumen as finger-like projections covered by epithelial lining cells. The central core of lamina propria contains blood vessels; lymphatics; a minimal population of lymphocytes, eosinophils, and mast cells; and scattered fibroblasts and vertically oriented smooth muscle cells. Between the bases of the villi are the pitlike crypts, which extend down to the muscularis mucosae. The muscularis mucosae forms a smooth, continuous
803
Figure 18-25 A , Normal small intestinal histology showing mucosal villi and crypts, lined by columnar cells. B , Normal colon histology
showing a flat mucosal surface and abundant vertically oriented crypts.
sheet, serving to anchor the configuration of villi and crypts alike. In normal individuals, the villus-to-crypt height ratio is about 4 to 5:1. Within the duodenum are abundant submucosal mucous glands, termed Brunner glands. These glands secrete bicarbonate ions, glycoproteins, and pepsinogen II and are virtually indistinguishable from the gastric pyloric mucous glands. The surface epithelium of the villi contains three cell types. Columnar absorptive cells are recognized by the dense array of microvilli on their luminal surface (the brush border) and the underlying mat of microfilaments (the terminal web). Interspersed regularly between the absorptive cells are mucin-secreting goblet cells and a few endocrine cells, described subsequently. Within the crypts reside undifferentiated crypt cells, goblet cells, more abundant endocrine cells, and scattered Paneth cells. The last-mentioned cells have apically oriented bright eosinophilic granules containing a variety of antimicrobial proteins that play a role in mucosal immunity. [28] The villi of the small intestinal mucosa are the site for terminal digestion and absorption of foodstuffs through the action of the columnar absorptive cells. The crypts secrete ions and water, deliver immunoglobulin A and antimicrobial peptides to the lumen, and serve as the site for cell division and renewal. The mucous cells of both crypts and villi generate an adherent mucous coat, which both protects the surface epithelium and provides an ideal local milieu for uptake of nutrients. Specific receptors for uptake of macromolecules also are present on the surface epithelial cells, such as those in the ileum for intrinsic factor-vitamin B12 complexes. Colonic Mucosa
The small intestine accomplishes its absorptive function with a highly liquid luminal stream. The purpose of the colon is to reclaim luminal water and electrolytes. In contrast to the mucosa of the small intestine, the colonic mucosa has no villi and is flat. The mucosa is punctuated by numerous straight tubular crypts that extend down to the
muscularis mucosa (Fig. 18-25 B). The surface epithelium is composed of columnar absorptive cells, which have shorter, less abundant microvilli than found in the small intestine, and goblet mucous cells. The crypts contain abundant goblet cells, endocrine cells, and undifferentiated crypt cells. Paneth cells are occasionally present at the base of crypts in the cecum and ascending colon. The regenerative capacity of the intestinal epithelium is remarkable. Cellular proliferation is confined to the crypts; differentiation and luminal migration serve to replenish superficial cells lost to senescence and surface abrasion. Within the small intestine, cells migrate out of the crypts and upward to the tips of the villi, where they are shed into the lumen. This journey normally takes between 96 and 144 hours, leading to normal renewal of the epithelial lining every 4 to 6 days. Turnover of the colonic surface epithelium takes 3 to 8 days. The rapid renewal of intestinal epithelium provides a remarkable capacity for repair but also renders the intestine particularly vulnerable to agents that interfere with cell replication, such as radiation and chemotherapy for cancer. Endocrine Cells
A diverse population of endocrine cells is scattered among the epithelial cells lining the gastric glands, small intestinal villi, and small and large intestinal crypts. Comparable cells are present in the epithelia lining the pancreas, biliary tree, lung, thyroid, and urethra. As a population, gut endocrine cells exhibit characteristic morphologic features. In most cells, the cytoplasm contains abundant fine eosinophilic granules, which harbor secretory products. The cytoplasmic portion of the cell is at the base of the epithelium, and the nuclei reside on the luminal side of the cytoplasmic granules. These cells exhibit a marked diversity of secretory peptides
804
and distribution of cell subtypes. Secretory granules are released at the basal surface of the endocrine cell or along the basal part of its lateral surface; apical secretion (into the lumen) has never been observed. The various secretory products, some of which are present also in the mural autonomic neural plexus, act as chemical messengers and modulate normal digestive functions by a combination of endocrine, paracrine, and neurocrine mechanisms. Each endocrine cell type therefore exhibits a distribution tailored to meet the physiologic needs pertinent to a gut segment. Intestinal Immune System
Throughout the small intestine and colon are nodules of lymphoid tissue, which either lie within the mucosa or span the mucosa and a portion of the submucosa. They distort the surface epithelium to produce broad domes rather than villi; within the ileum, confluent lymphoid tissue becomes macroscopically visible as Peyer patches. The surface epithelium over lymphoid nodules contains both columnar absorptive cells and M
(membranous) cells, the latter found only in small and large intestinal lymphoid sites. M cells are able to transcytose antigenic macromolecules intact from the lumen to underlying lymphocytes, thus serving as an important afferent limb of the intestinal immune system. Throughout the intestines, T lymphocytes are scattered within the surface epithelium ( intraepithelial lymphocytes), generally of cytotoxic phenotype (CD8+). The lamina propria contains helper T cells (CD4+) and educated B cells. The lymphoid nodules, mucosal lymphocytes, together with isolated lymphoid follicles in the appendix and mesenteric lymph nodes, constitute the mucosa- associated lymphoid tissue (MALT). [29] Neuromuscular Function
Small intestinal peristalsis, both anterograde and retrograde, mixes the food stream and promotes maximal contact of nutrients with the mucosa. Colonic peristalsis prolongs contact of the luminal contents with the mucosa. Although intestinal smooth muscle cells are capable of initiating contractions, both small and large intestinal peristalsis are mediated by intrinsic (myenteric plexus) and extrinsic (autonomic innervation) neural control. The myenteric plexus consists of two neural networks: Meissner plexus resides at the base of the submucosa, and Auerbach plexus lies between the inner circumferential and outer longitudinal muscle layers of the muscle wall; lesser neural twigs extend between smooth muscle cells and ramify within the submucosa. PATHOLOGY Many conditions, such as infections, inflammatory diseases, and tumors, affect both the small and large intestines. These two organs therefore are considered together. Collectively, disorders of the intestines account for a large portion of human disease. Congenital Anomalies
Rare anomalies of gut formation may occur, as follows: Duplication of the small intestine or colon, usually in the form of saccular to long, cystic structures Malrotation of the entire bowel, resulting from improper embryologic rotation of the gut Omphalocele, in which the abdominal musculature fails to form, leading to birth of an infant with herniation of abdominal contents into a ventral membranous sac Gastroschisis, in which a portion of the abdominal wall fails to form altogether, with ensuing extrusion of the intestines The above-listed lesions may be silent (malrotation) or catastrophic (gastroschisis). A far more common and innocuous lesion is heterotopia, usually of normal pancreatic tissue but occasionally gastric mucosa, appearing as small, 1- to 2-cm sized nodules in an aberrant gut location.
ATRESIA AND STENOSIS
Congenital intestinal obstruction is an uncommon but dramatic lesion that may affect any level of the intestines. Duodenal atresia is most common; the jejunum and ileum are equally involved and the colon virtually never. The obstruction may be complete ( atresia) or incomplete ( stenosis). Atresia may take the form of an imperforate mucosal diaphragm or a stringlike segment of bowel connecting intact proximal and distal intestine. Stenosis is less common and is due to a narrowed intestinal segment or a diaphragm with a narrow central opening. Single or multiple lesions appear to arise from developmental failure, intrauterine vascular accidents, or intussusceptions (telescoping of one intestinal segment within another) occurring after the intestine has developed. Failure of the cloacal diaphragm to rupture leads to an imperforate anus. MECKEL DIVERTICULUM
Failure of involution of the vitelline duct, which connects the lumen of the developing gut to the yolk sac, produces a Meckel diverticulum. This solitary diverticulum lies on the antimesenteric side of the bowel, usually within 2 feet (85 cm) of the ileocecal valve (Fig. 18-26) . This is a true diverticulum, in that it contains all three layers of the normal bowel wall: mucosa, submucosa, and muscularis propria. Meckel diverticula may take the form of only a small pouch or a blind segment having a lumen greater in diameter than that of the ileum and a length of up to 6 cm. Although the mucosal lining may be that of normal small intestine, heterotopic rests of gastric mucosa (or pancreatic tissue) are found in about one half of these anomalies. Meckel diverticula are present in an estimated 2% of the normal population, but most remain asymptomatic or are discovered incidentally. When peptic ulceration occurs in the small intestinal mucosa adjacent to the gastric
805
Figure 18-26 Meckel diverticulum. The blind pouch is on the antimesenteric side of the small bowel.
mucosa, mysterious intestinal bleeding or symptoms resembling those of an acute appendicitis may result. Alternatively, presenting symptoms may be related to intussusception, incarceration, or perforation. CONGENITAL AGANGLIONIC MEGACOLON--HIRSCHSPRUNG DISEASE
This disorder is characterized by the absence of ganglion cells in the large bowel, leading to functional obstruction and colonic dilatation proximal to the affected segment. Most cases are sporadic, but familiar forms occur. It should be recalled that the intestinal neuronal plexus develops from neural crest cells that migrate into the bowel
during development. Studies of familial forms and mouse models have traced the aganglionosis to heterogeneous defects in genes regulating migration and survival of neuroblasts (e.g., endothelin 3 and its receptor), neurogenesis (e.g., glial cell-derived growth factor, GDNF), and receptor tyrosine kinase activity. [30] MORPHOLOGY.
There is absence of ganglion cells in the muscle wall (Auerbach plexus) and submucosa (Meissner) of the affected segment. The rectum is always affected, with involvement of more proximal colon to variable extents. Most cases involve the rectum and sigmoid only, with longer segments in a fifth of cases and rarely the entire colon. This is sometimes accompanied by thickening and hypertrophy of nonmyelinated nerve fibers. Proximal to the aganglionic segment, the colon undergoes progressive dilation and hypertrophy, beginning with the descending colon. With time, the proximal innervated colon may become massively distended, sometimes achieving a diameter of 15 to 20 cm (megacolon). When distention outruns the hypertrophy, the colonic wall becomes markedly thinned and may rupture, usually near the cecum. Alternatively, mucosal inflammation or shallow, so-called stercoral ulcers may appear. Clinical Features.
Hirschsprung disease occurs in approximately 1 in 5000 to 8000 live births and is present with increased frequency (3.6%) in siblings of index cases. Males predominate 4:1. Short segment aganglionosis with megacolon is more common in boys, whereas long affected segments are more common in girls. Ten per cent of all cases of Hirschsprung disease occur in children with Down syndrome, and serious neurologic abnormalities are present in another 5%, raising the possibility that this disease is only one feature of more generalized abnormal development of the neural crest. Hirschsprung disease usually manifests itself in the immediate neonatal period by failure to pass meconium, followed by obstructive constipation. In those instances when only a few centimeters of the rectum are affected, the build-up of pressure may permit occasional passage of stools or even intermittent bouts of diarrhea. Abdominal distention develops if a sufficiently large segment of colon is involved. The major threats to life in this disorder are superimposed enterocolitis with fluid and electrolyte disturbances and perforation of the colon or appendix with peritonitis. Acquired megacolon is a condition of any age and may result from (1) Chagas disease (Chapter 8) , in which the trypanosomes directly invade the bowel wall to destroy the enteric plexuses; (2) organic obstruction of the bowel as by a neoplasm or inflammatory stricture; (3) toxic megacolon complicating ulcerative colitis or Crohn disease (see later); or (4) a functional psychosomatic disorder. Except for Chagas disease, in which inflammatory involvement of the ganglia is evident, the remaining forms of megacolon are not associated with any deficiency of mural ganglia.
Enterocolitis
Diarrheal diseases of the bowel make up a veritable Augean stable of entities. Many are caused by microbiologic agents; others arise in the setting of malabsorptive disorders and idiopathic inflammatory bowel disease, discussed in subsequent sections. Consideration should first be given to the conditions known as diarrhea and dysentery. DIARRHEA AND DYSENTERY
A typical adult in the United States imbibes 2 liters of fluid per day, to which is added 1 liter of saliva; 2 liters of gastric juice; 1 liter of bile; 2 liters of pancreatic juice, and 1 liter of intestinal secretions. Of these 9 liters of fluid presented to the intestine, less than 200 gm of stool are excreted per day, of which 65 to 85% is water. Jejunal absorption of water amounts to 3 to 5 liters/day; ileal absorption, 2 to 4 liters/day. [31] The colon normally absorbs 1 to 2 liters/day but is capable of absorbing almost 6 liters/day. A precise definition of diarrhea is elusive, given the considerable variation in normal bowel habits. An increase
806
in stool mass, stool frequency, or stool fluidity is perceived as diarrhea by most patients. For many individuals, this consists of daily stool production in excess of 250 gm, containing 70 to 95% water. More than 14 liters of fluid may be lost per day in severe cases of diarrhea (i.e., the equivalent of the circulating blood volume). Diarrhea is often accompanied by pain, urgency, perianal discomfort, and incontinence. Low-volume, painful, bloody diarrhea is known as dysentery. The major causes of diarrhea are presented in Table 18-5 . The principal mechanisms of diarrhea, one or more of which may be operative in any one patient, are as follows: Secretory diarrhea: Net intestinal fluid secretion leads to the output of greater than 500 ml of fluid stool per day, which is isotonic with plasma and persists during fasting. Osmotic diarrhea: Excessive osmotic forces exerted by luminal solutes lead to output of greater than 500 ml of stool per day, which abates on fasting. Stool exhibits an osmotic gap (stool osmolality exceeds electrolyte concentration by 50 mOsm). Exudative diseases: Mucosal destruction leads to output of purulent, bloody stools, which persist on fasting; stools are frequent but may be small or large volume. Malabsorption: Improper absorption of gut nutrients produces voluminous, bulky stools with increased osmolarity combined with excess stool fat (steatorrhea). The diarrhea usually abates on fasting. Deranged motility: Improper gut neuromuscular function may produce highly variable patterns of increased stool volume; other forms of diarrhea must be
excluded.
TABLE 18-5 -- MAJOR CAUSES OF DIARRHEAL ILLNESSES Secretory Diarrhea Infectious: viral damage to mucosal epithelium Rotavirus Norwalk virus Enteric adenoviruses Infectious: enterotoxin mediated Vibrio cholerae Escherichia coli Bacillus cereus Clostridium perfringens Neoplastic Tumor elaboration of peptides, serotonin, prostaglandins Villous adenoma in distal colon (non-hormone mediated) Excess laxative use Osmotic Diarrhea Disaccharidase (lactase) deficiencies Lactulose therapy (for hepatic encephalopathy, constipation) Prescribed gut lavage for diagnostic procedures Antacids (MgSO4 and other magnesium salts) Primary bile acid malabsorption Exudative Diseases Infectious: bacterial damage to mucosal epithelium Shigella Salmonella Campylobacter Entamoeba histolytica Idiopathic inflammatory bowel disease Typhlitis (neutropenic colitis in the immunosuppressed) Malabsorption Defective intraluminal digestion
Primary mucosal cell abnormalities Reduced small intestinal surface area Lymphatic obstruction Infectious: impaired mucosal cell absorption Giardia lamblia Deranged Motility Decreased intestinal transit time Surgical reduction of gut length Neural dysfunction, including irritable bowel syndrome Hyperthyroidism Diabetic neuropathy Carcinoid syndrome Decreased motility (increased intestinal transit time) Small intestinal diverticula Surgical creation of a blind intestinal loop Bacterial overgrowth in the small intestine
INFECTIOUS ENTEROCOLITIS (see also Chapter 9)
Intestinal diseases of microbial origin are marked principally by diarrhea and sometimes ulceroinflammatory changes in the small or large intestine. Infectious enterocolitis is a global problem of staggering proportions, causing more than 12,000 deaths per day from dehydration among children in developing countries and constituting one half of all deaths worldwide before age 5.[32] Although far less prevalent in industrialized nations, these infections still have attack rates of one to two illnesses per person per year, second only to the common cold in frequency. This rate results in an estimated 99 million acute cases of either vomiting or diarrhea per year in the United States, equivalent to 40% of the population. [33] Among the most common offenders are rotavirus and Norwalk virus and enterotoxigenic Escherichia coli. Many pathogens, however, can cause diarrhea; the major offenders vary with the age, nutrition, and immune status of the host; environment (living conditions, public health measures); and special predispositions, such as hospitalization, wartime dislocation, or foreign travel. In 40 to 50% of cases, the specific agent cannot be isolated. The various organisms causing infectious enterocolitis have been discussed in Chapter 9 , as have the major pathogenetic mechanisms. Here we consider clinical and pathologic features relevant to the gastrointestinal manifestations.
Viral Gastroenteritis
Symptomatic human infection is caused by several distinct groups of viruses (Table 18-6) . Rotavirus is the most common and accounts for an estimated 140 million cases and 1 million deaths worldwide per year. The target population is children 6 to 24 months of age, but young infants and debilitated adults are susceptible to symptomatic infection. The minimal infective inoculum is approximately 10 particles, whereas an individual with rotavirus gastroenteritis typically sheds up to 1012 particles/ml stool. Thus, outbreaks among pediatric populations in hospitals and daycare centers are legion. The clinical syndrome consists of an incubation period of approximately 2 days followed by vomiting and watery diarrhea for several days.
807
Virus
Rotavirus (group A)
TABLE 18-6 -- COMMON GASTROINTESTINAL VIRUSES Genome Size % of US Host Mode of Prodrome/Duration (nm) Childhood Age Transmission of Illness Hospitalizations dsRNA
70
35-40
6-24 mo
Person-to-person, 2 days/3-8 days food, water
Enteric dsDNA adenoviruses
80
5-20
Child 95%) are lecithins (phosphatidylcholine), which are hydrophobic and have no appreciable aqueous solubility of their own, and cholesterol, which is a negligibly soluble steroid molecule with a single polar hydroxyl group. Cholesterol solubility in bile is increased several million-fold by the presence of bile salts and lecithin. [51] About 95% of secreted bile salts is avidly reabsorbed in the intestines, primarily in the ileum, and returned to the liver by portal blood. The enterohepatic circulation of bile salts constitutes a highly efficient mechanism for reuse of these essential physiologic molecules. [52] Nevertheless, the obligatory fecal loss of about half a gram of bile salts per day constitutes the major route for elimination of body cholesterol, with a lesser contribution from free cholesterol secreted directly into bile.
Figure 19-45 Typical solute composition of gallbladder and hepatic bile in health. (From Carey MC: Biliary lipids and gallstone formation. In Csomos G, Thaler H (eds): Clinical Hepatology. Berlin, Springer-Verlag, 1983, pp 52-69.)
893
PATHOLOGY CONGENITAL ANOMALIES
Although major developmental anomalies of the gallbladder and bile ducts are rare,
anatomic variation is sufficiently common to present occasional surprises during surgery. The more distinctive variations, which may also be appreciated during ultrasonography, computed tomography, and magnetic resonance imaging scans, merit comment. The gallbladder may be congenitally absent, or there may be gallbladder duplication with conjoined or independent cystic ducts. [53] A longitudinal or transverse septum may create a bilobed gallbladder. Aberrant locations of the gallbladder occur in 5% to 10% of the population, most commonly partial or complete embedding in the liver substance. A folded fundus is the most common anomaly, creating the so-called phrygian cap (Fig. 19-46) . Agenesis of all or any portion of the hepatic or common bile ducts and hypoplastic narrowing of biliary channels (true "biliary atresia") are rare malformations. DISORDERS OF THE GALLBLADDER Cholelithiasis (Gallstones)
Gallstones afflict 10% to 20% of adult populations in developed countries. It is estimated that more than 30,000,000 persons in the United States have gallstones, totaling some 25 to 50 tons in weight! [54] About 1 million new patients annually are found to have gallstones, of whom half undergo surgery. Nevertheless, most gallstones
Figure 19-46 Phrygian cap of the gallbladder; the fundus is folded inward.
(>80%) are "silent," and most individuals remain free of biliary pain or stone complications for decades. There are two main types of gallstones. In the West, about 80% are cholesterol stones, containing more than 50% of crystalline cholesterol monohydrate. The remainder are composed predominantly of bilirubin calcium salts and are designated pigment stones. Prevalence and Risk Factors.
Certain populations are far more prone than others to develop gallstones. The following applies to cholesterol gallstones. [55] Ethnic-Geographic.
The prevalence rates of cholesterol gallstones approach 75% in Native Americans of the first migration from Asia, which includes the Pima, Hopi, and Navajo [56] --pigment stones are rare. Gallstones exhibit prevalence rates of around 25% in industrialized societies [57] but are uncommon in underdeveloped or developing societies. Age and Sex.
The prevalence of gallstones increases throughout life. In the United States, less than
5% of the population younger than 40 years has stones, in contrast to more than 30% of those older than 80 years. The prevalence in white women is about twice as high as in men (exceeding 50% by age 80 years). With both aging and gender, hypersecretion of biliary cholesterol appears to play the major role. Environmental Factors.
Estrogenic influences, including oral contraceptives and pregnancy, increase the expression of hepatic lipoprotein receptors and stimulate hepatic hydroxymethylglutaryl-coenzyme A (HMG CoA) reductase activity. Thus, both cholesterol uptake and biosynthesis, respectively, are increased. Clofibrate, used to lower blood cholesterol, increases hepatic HMG-CoA reductase and decreases conversion of cholesterol to bile acids by reducing cholesterol 7alpha-hydroxylase activity. The net result of these influences is excess biliary secretion of cholesterol. Obesity and rapid weight loss are also strongly associated with increased biliary cholesterol secretion. Acquired Disorders.
Although gastrointestinal conditions may severely impair intestinal resorption of bile salts, there is compensatory enhanced hepatic conversion of cholesterol to bile salts, leading to less cholesterol excretion, and no particular tendency to cholesterol stone formation. Gallbladder stasis, either neurogenic or hormonal, fosters a local environment favorable for both cholesterol and pigment gallstone formation. Hereditary Factors.
In addition to ethnicity, family history alone imparts increased risk, as do a variety of inborn errors of metabolism that (1) lead to impaired bile salt synthesis and secretion or (2) generate increased serum and biliary levels of cholesterol, such as defects in lipoprotein receptors (hyperlipidemia syndromes) that engender marked increases in cholesterol biosynthesis. Animal studies also implicate specific genetic susceptibilities from so-called lith genes to gallstone formation. [58] Certain risk factors are well established for the development of pigment stones. Disorders that are associated with elevated levels of unconjugated bilirubin in bile include hemolytic syndromes, severe ileal dysfunction (or bypass), and bacterial contamination of the biliary tree. Pigment gallstones are the predominant type of gallstones in non-Western
894
populations, primarily arising in the biliary tree in the setting of infections and parasitic infestations.
Pathogenesis
Cholesterol Stones.
Cholesterol is rendered soluble in bile by aggregation with water-soluble bile salts and water-insoluble lecithins, both of which act as detergents. When cholesterol concentrations exceed the solubilizing capacity of bile (supersaturation), cholesterol can no longer remain dispersed and nucleates into solid cholesterol monohydrate crystals. Cholesterol gallstone formation involves a tetralogy of simultaneous defects (Fig. 19-47) . [58] Bile must be supersaturated with cholesterol. Gallbladder hypomotility promotes nucleation. Cholesterol nucleation in bile is accelerated. Mucus hypersecretion in the gallbladder traps the crystals, permitting their agglomeration into stones.
Figure 19-47 Schematic representation of the four contributing factors for cholelithiasis: supersaturation, gallbladder hypomotility,
crystal nucleation, and accretion within the gallbladder mucous layer.
Biliary hypersecretion of cholesterol appears to be the primary defect, mediated possibly by enhanced delivery of plasma cholesterol in circulating lipoproteins to bile [59] and abnormal regulation of hepatic cholesterol biosynthetic pathways. [60] The abundant free cholesterol is toxic to the gallbladder, exceeding the ability of the mucosa to detoxify it by esterification. Hypomotility, mucin hypersecretion, and resultant sequestration of gallbladder bile promote nucleation and agglomeration. Superimposed environmental influences exacerbate defective gallbladder emptying: prolonged fasting, pregnancy, rapid weight loss, total parenteral nutrition, and spinal cord injury. Pigment Stones.
Pigment gallstones are mixtures of insoluble calcium salts of unconjugated bilirubin along with inorganic calcium salts. [61] Unconjugated bilirubin is normally a minor component of bile but increases when infection of the biliary tract leads to release of microbial beta-glucuronidases, which hydrolyze bilirubin glucuronides. Thus, infection with Escherichia coli, Ascaris lumbricoides, or, in Asia, the liver fluke Opisthorchis sinensis increases the likelihood of pigment stone formation. Alternatively, intravascular hemolysis leads to increased biliary excretion of conjugated bilirubin. Since a low level (about 1%) of bilirubin glucuronides is deconjugated in the biliary tree even normally, the aqueous solubility of free bilirubin may easily be exceeded under hemolytic conditions. MORPHOLOGY.
Cholesterol stones arise exclusively in the gallbladder and contain cholesterol contents ranging from 100% down to around 50%. Pure cholesterol stones are pale yellow and round to ovoid and have a finely granular, hard external surface, which on transection reveals a glistening radiating crystalline palisade. With increasing proportions of calcium carbonate, phosphates, and bilirubin, the stones exhibit discoloration and may be lamellated and gray-white to black on transection (Fig. 19-48) . Most often, multiple stones are present that range up to several centimeters in diameter. Rarely there is a single much larger stone that may virtually fill the fundus. Surfaces of multiple stones may be rounded or faceted owing to tight apposition. Stones composed largely of cholesterol are radiolucent; sufficient calcium carbonate is found in 10% to 20% of cholesterol stones to render them radiopaque. Pigment gallstones are trivially classified as black and brown.[61] In general, black pigment stones are found in sterile gallbladder bile, and brown stones are found in infected intrahepatic or extrahepatic ducts. Black pigment stones are composed of oxidized polymers of the calcium salts of unconjugated bilirubin; lesser amounts of calcium carbonate, calcium phosphate, and mucin glycoprotein; and a modicum of cholesterol monohydrate crystals. Brown pigment stones contain pure calcium salts of unconjugated bilirubin,
895
Figure 19-48 Cholesterol gallstones. Mechanical manipulation during laparoscopic cholecystectomy has caused fragmentation of
several cholesterol gallstones, revealing interiors that are pigmented because of entrapped bile pigments. The gallbladder mucosa is reddened and irregular as a result of coexistent chronic cholecystitis.
mucin glycoprotein, a substantial cholesterol fraction, and calcium salts of palmitate and stearate. The black stones are rarely greater than 1.5 cm in diameter, are almost invariably present in great number (Fig. 19-49) , and may crumble to the touch. Their contours are usually spiculated and molded. Brown stones tend to be laminated and soft and may have a soaplike or greasy consistency. Because of calcium carbonates and phosphates, approximately 50% to 75% of black stones are radiopaque. Brown stones, which contain calcium soaps, are radiolucent. Mucin glycoproteins constitute the scaffolding and interparticle cement of all stones, whether pigment or cholesterol. A incidental finding, pertinent to cholesterol biology but not directly related to gallstone formation, is cholesterolosis. Cholesterol normally entering the gallbladder mucosa by free exchange with the lumen may be esterified by acyl CoA:cholesterol acyltransferase. Cholesterol hypersecretion by the liver promotes excessive accumulation of cholesterol esters within the lamina propria of the gallbladder. The mucosal surface is studded with minute yellow flecks, producing the "strawberry gallbladder."
Clinical Features.
Gallstones may be present for decades before symptoms develop, and 70% to 80% of patients remain asymptomatic throughout their lives. It appears that asymptomatic patients convert to symptomatic ones at the rate of 1% to 3% per year, and the risk diminishes with time.[62] Prominent among symptoms is biliary pain, which tends to be constant, or an excruciating "colicky" (spasmodic) pain due to the obstructive nature of gallstones in the gallbladder or biliary tree proper. Inflammation of the gallbladder (cholecystitis; see later), in association with stones, also generates pain. More severe complications include empyema, perforation, fistulas, inflammation of the biliary tree (cholangitis), and obstructive cholestasis or pancreatitis with ensuant problems. The larger the calculi, the less likely they are to enter the cystic or common ducts to produce obstruction--it is the very small stones, or "gravel," that are the more dangerous. A large stone may occasionally erode directly into an adjacent loop of small bowel, generating intestinal obstruction ("gallstone ileus"). On occasion, progressive mucosal removal of luminal lipids in obstructed, uninflamed gallbladders may leave clear mucinous secretions, so-called hydrops or mucocele of the gallbladder. Most notable is the increased risk for carcinoma of the gallbladder, discussed later. Cholecystitis
Inflammation of the gallbladder may be acute, chronic, or acute superimposed on chronic. It almost always occurs in association with gallstones. In the United States, cholecystitis is one of the most common indications for abdominal surgery. Its epidemiologic distribution closely parallels that of gallstones. ACUTE CHOLECYSTITIS
Acute calculous cholecystitis is an acute inflammation of the gallbladder, precipitated 90% of the time by gallstone obstruction of the neck or cystic duct. It is the primary complication of gallstones and the most common reason for emergency cholecystectomy. Acute acalculous cholecystitis occurs in the absence of gallstones, generally in the severely ill patient. Most of these cases occur in the following circumstances: (1) the postoperative state after major, nonbiliary surgery; (2) severe trauma (car accidents, war injuries); (3) severe burns; (4) multisystem organ failure;
Figure 19-49 Pigment gallstones. Several faceted black gallstones are present in this otherwise unremarkable gallbladder from a
patient with a mechanical mitral valve prosthesis, leading to chronic intravascular hemolysis.
896
(5) sepsis; (6) prolonged intravenous hyperalimentation; and (7) the postpartum state.
Pathogenesis.
Acute calculous cholecystitis results from chemical irritation and inflammation of the obstructed gallbladder. The action of mucosal phospholipases hydrolyzes luminal lecithins to lysolecithins. The normally protective glycoprotein mucous layer is disrupted, exposing the mucosal epithelium to the direct detergent action of bile salts. Gallbladder dysmotility develops; distention and increased intraluminal pressure compromise blood flow to the mucosa. These events occur in the absence of bacterial infection; only later in the course may bacterial contamination develop. Acute acalculous cholecystitis is thought to result from direct ischemic compromise. The cystic artery is an end-artery with essentially no collateral circulation. Contributing factors are thought to include [63] Dehydration and multiple blood transfusions, leading to a pigment load Gallbladder stasis, as may occur with hyperalimentation and assisted ventilation Accumulation of biliary sludge, viscous bile, and gallbladder mucus, causing cystic duct obstruction in the absence of frank stone formation Inflammation and edema of the wall, compromising blood flow Bacterial contamination and generation of lysolecithins MORPHOLOGY.
In acute calculous cholecystitis, the gallbladder is usually enlarged and tense; it may assume a bright red or blotchy, violaceous to green-black discoloration imparted by subserosal hemorrhages (Fig. 19-50) . The serosal covering is frequently layered by fibrin and, in severe cases, by a definite suppurative, coagulated exudate. In most cases, an obstructing stone is present in the neck of the gallbladder or the cystic duct. In addition to other possible stones, the gallbladder lumen is filled with a cloudy or turbid
Figure 19-50 Acute calculous cholecystitis; the stone was not photographed.
bile that may contain large amounts of fibrin and frank pus as well as hemorrhage. When the contained exudate is virtually pure pus, the condition is referred to as empyema of the gallbladder. In mild cases, the gallbladder wall is thickened, edematous, and hyperemic. In more severe cases, it is transformed into a green-black necrotic organ, termed gangrenous cholecystitis, with small to large perforations. The inflammatory reactions are not histologically distinctive and consist of the usual patterns of acute inflammation, that is, edema, leukocytic infiltration, vascular congestion, frank abscess formation, or gangrenous necrosis. There are no specific morphologic differences between acute calculous and acalculous cholecystitis, save for the absence of macroscopic stones. As a result of either delay in
diagnosis or the disease itself, the incidence of gangrene and perforation is much higher than in calculous cholecystitis. [62] In rare instances, primary bacterial infection can give rise to acute acalculous cholecystitis, including agents such as Salmonella typhi and staphylococci. Acute emphysematous cholecystitis results from gas-forming organisms, notably clostridia and coliforms, typically in diabetics. Clinical Features.
Patients with acute calculous cholecystitis usually but not always have experienced previous episodes of biliary pain. Acute calculous cholecystitis may appear with remarkable suddenness and constitute an acute surgical emergency, or it may present with mild symptoms that resolve without medical intervention. An attack of acute cholecystitis begins with progressive right upper quadrant or epigastric pain, frequently associated with mild fever, anorexia, tachycardia, diaphoresis, and nausea and vomiting. The upper abdomen is tender, but a distended tender gallbladder is not usually evident. Most patients are free of jaundice; the presence of hyperbilirubinemia suggests obstruction of the common bile duct. Mild to moderate leukocytosis may be accompanied by mild elevations in serum alkaline phosphatase values. In the absence of medical attention, the attack usually subsides in 7 to 10 days and frequently within 24 hours. However, up to 25% of patients develop progressively more severe symptoms, requiring immediate surgical intervention. In those patients who recover, recurrence is common. Clinical symptoms of acute acalculous cholecystitis tend to be more insidious, since symptoms are obscured by the underlying conditions precipitating the attacks. A higher proportion of patients have no symptoms referable to the gallbladder; diagnosis therefore rests on a high index of suspicion. In the severely ill patient, early recognition of this condition is crucial, since failure to do so almost ensures a fatal outcome. A more indolent form of acute acalculous cholecystitis may occur in the outpatient population
897
in the setting of systemic vasculitis, severe atherosclerotic ischemic disease in the elderly, and acquired immunodeficiency syndrome (with infection). [64] CHRONIC CHOLECYSTITIS
Chronic cholecystitis may be a sequel to repeated bouts of mild to severe acute cholecystitis, but in many instances it develops in the apparent absence of antecedent attacks. Since it is associated with cholelithiasis in more than 90% of cases, the populations of patients are the same as for cholelithiasis. The evolution of chronic cholecystitis is obscure in that it is not clear that gallstones play a direct role in the initiation of inflammation or the development of pain. Microorganisms, usually E. coli and enterococci, can be cultured from the bile in about one third of cases. The symptoms for calculous chronic cholecystitis are similar to those of the acute form and range from biliary colic to indolent right upper quadrant pain and epigastric distress.
Since most gallbladders removed at elective surgery for gallstones exhibit features of chronic cholecystitis, one must conclude that biliary symptoms often emerge after long-term coexistence of gallstones and low-grade inflammation. MORPHOLOGY.
The morphologic changes in chronic cholecystitis are extremely variable and sometimes minimal. The serosa is usually smooth and glistening, but often it is dulled by subserosal fibrosis. Dense fibrous adhesions may remain as sequelae of preexistent acute inflammation. On sectioning, the wall is variably thickened, rarely to more than thrice normal. The wall has an opaque gray-white appearance and may be less flexible than normal. In the uncomplicated case, the lumen contains fairly clear, green-yellow, mucoid bile and usually stones (Fig. 19-51) . The mucosa itself is generally preserved. On histologic examination, the degree of inflammatory reaction is variable. In more developed cases, there is marked subepithelial and subserosal fibrosis, accompanied by mononuclear cell infiltration. Inflammatory proliferation of the mucosa and fusion of the mucosal folds may give rise to buried crypts of epithelium within the gallbladder wall. Outpouchings of the mucosal epithelium through the wall (Rokitansky-Aschoff sinuses) may be prominent. Superimposition of acute inflammatory changes implies acute exacerbation of a previously chronically injured gallbladder. In rare instances, extensive dystrophic calcification within the gallbladder wall may yield a porcelain gallbladder, notable for a markedly increased incidence of associated cancer. In xanthogranulomatous cholecystitis the gallbladder is shrunken and nodular and exhibits histiocytes packed with lipids admixed with an
Figure 19-51 Chronic cholecystitis demonstrating a thickened gallbladder wall and luminal stones.
exuberant fibrous tissue response. Gallstones are usually present. This rare condition can be confused macroscopically with a malignant neoplasm. Finally, an atrophic, chronically obstructed gallbladder may contain only clear secretions, a condition known as hydrops of the gallbladder. Clinical Features.
Chronic cholecystitis does not have the striking manifestations of the acute forms and is usually characterized by recurrent attacks of either steady or colicky epigastric or right upper quadrant pain. Nausea, vomiting, and intolerance for fatty foods are frequent accompaniments. Diagnosis of both acute and chronic cholecystitis is important because of the following complications:
Bacterial superinfection with cholangitis or sepsis Gallbladder perforation and local abscess formation Gallbladder rupture with diffuse peritonitis Biliary enteric (cholecystenteric) fistula, with drainage of bile into adjacent organs, entry of air and bacteria into the biliary tree, and potentially gallstone-induced intestinal obstruction (ileus) Aggravation of preexisting medical illness, with cardiac, pulmonary, renal, or liver decompensation
898
DISORDERS OF THE EXTRAHEPATIC BILE DUCTS Choledocholithiasis and Ascending Cholangitis
These conditions are considered together, since they so frequently go hand-in-hand. Choledocholithiasis is the presence of stones within the biliary tree, occurring in about 10% of patients with cholelithiasis. In Western nations, almost all stones are derived from the gallbladder, although both cholesterol and pigmented stones can form de novo in the biliary tree. In the Orient, there is a much higher incidence of primary ductal and intrahepatic stone formation, usually pigmented. Choledocholithiasis may be asymptomatic or may cause symptoms from (1) obstruction, (2) pancreatitis, (3) cholangitis, (4) hepatic abscess, (5) secondary biliary cirrhosis, and (6) acute calculous cholecystitis. Cholangitis is the term used for bacterial infection of the bile ducts. Cholangitis can result from any lesion creating obstruction to bile flow, most commonly choledocholithiasis. Uncommon causes include indwelling stents or catheters, tumors, acute pancreatitis, benign strictures, and rarely fungi, viruses, or parasites. Bacteria most likely enter the biliary tract through the sphincter of Oddi; infection of intrahepatic biliary radicles is termed ascending cholangitis. The bacteria are usually enteric gram-negative aerobes such as E. coli, Klebsiella, Clostridium, Bacteroides, or Enterobacter and group D streptococci. Cholangitis usually generates fever, chills, abdominal pain, and jaundice accompanied by acute inflammation of the wall of the bile ducts with entry of neutrophils into the luminal space. Intermittence of symptoms suggests bouts of partial obstruction. The most severe form of cholangitis is suppurative cholangitis, in which purulent bile fills and distends bile ducts, extending into the hepatic substance to cause liver abscesses. Because sepsis rather than cholestasis tends to dominate the picture, prompt diagnostic evaluation and intervention are imperative in these unstable patients. Biliary Atresia
The infant presenting with neonatal cholestasis has been discussed previously in the context of intrahepatic disorders. A major contributor to neonatal cholestasis is
extrahepatic biliary atresia, representing one third of infants with neonatal cholestasis and occurring in approximately 1:10,000 live births. Extrahepatic biliary atresia is defined as a complete obstruction of bile flow due to destruction or absence of all or part of the extrahepatic bile ducts. [65] It is the single most frequent cause of death from liver disease in early childhood and accounts for 50% to 60% of children referred for liver transplantation because of the rapidly progressing secondary biliary cirrhosis. Pathogenesis.
Most infants with extrahepatic biliary atresia are born with an intact biliary tree, which undergoes progressive inflammatory destruction in the weeks after birth. In rare cases, there is evidence of bile duct destruction before birth. The cause of extrahepatic biliary atresia remains unknown, despite efforts to ascribe the disease to Occult viral infection, particularly reovirus 3, cytomegalovirus, and rubella virus Exposure to environmental toxins Defective morphogenesis of bile ducts Disordered immunity with autoantibody formation to aberrant HLA class I or II antigen complexes Defects in the fetal and perinatal hilar blood flow Arguably, biliary atresia should be viewed as a common phenotype of a heterogeneous group of disorders, since multiple pathogenetic mechanisms may be operative. MORPHOLOGY.
The salient features of extrahepatic biliary atresia include inflammation and fibrosing stricture of the hepatic or common bile ducts, periductular inflammation of intrahepatic bile ducts, and progressive destruction of the intrahepatic biliary tree (Fig. 19-52) . On histologic examination of the liver, florid features of extrahepatic biliary obstruction are evident, that is, marked bile ductular proliferation, portal tract edema and fibrosis, and parenchymal cholestasis. When it is unrecognized or uncorrected, cirrhosis develops within 3 to 6 months of birth. Clinical Features.
Infants with extrahepatic biliary atresia present with neonatal cholestasis, discussed previously. These infants exhibit normal birth weight and postnatal weight gain, a slight female preponderance, and the progression of initially normal stools to acholic stools as the disease evolves. At the time of presentation, serum bilirubin values are usually in the 6 to 12 mg/dl range, with only moderately elevated transaminase and alkaline phosphatase levels.
Figure 19-52 Biliary atresia, schematized to show the pattern of biliary tract injury.
899
There is considerable variability in extrahepatic biliary atresia. When the disease is limited to the common (type I) or hepatic bile ducts (type II) with patent proximal branches, the disease is surgically correctable. Unfortunately, 90% of patients have type III biliary atresia, in which there is also obstruction of bile ducts at or above the porta hepatis. These cases are noncorrectable, since there are no patent bile ducts amenable to surgical anastomosis. Moreover, in most patients, bile ducts within the liver are initially patent but are progressively destroyed. Liver transplantation with accompanying donor bile ducts remains the primary hope for these young patients. Without surgical intervention, death usually occurs within 2 years of birth. Choledochal Cysts
Choledochal cysts are congenital dilations of the common bile duct, presenting most often in children before age 10 years with the nonspecific symptoms of jaundice or recurrent abdominal pain typical of biliary colic. Approximately 20% of cases become symptomatic only in adulthood; these sometimes occur in conjunction with cystic dilation of the intrahepatic biliary tree (Caroli disease, see earlier). The female to male ratio is 3 to 4:1. [66] These uncommon cysts may take the form of segmental or cylindrical dilation of the common bile duct; diverticula of the extrahepatic ducts; or choledochoceles, which are cystic lesions that protrude into the duodenal lumen. Choledochal cysts predispose to stone formation, stenosis and stricture, pancreatitis, and obstructive biliary complications within the liver. In the older patient, the risk of bile duct carcinoma is increased. TUMORS
Although heterotopic tissues, carcinoids, hemangiomas, and stromal tumors have been described in the biliary tract, the neoplasms of primary clinical importance are those derived from the mucosa. [67] Adenomas are benign epithelial tumors representing localized neoplastic growth of the lining epithelium and are similar to adenomas found elsewhere in the alimentary tract. Inflammatory polyps are sessile mucosal projections with a surface of columnar epithelial cells covering a fibrous stroma infiltrated with chronic inflammatory cells and lipid-laden macrophages. These lesions may be difficult to differentiate from neoplasms on imaging studies. Adenomyosis of the gallbladder is characterized by hyperplasia of the muscularis, containing intramural hyperplastic glands. Carcinoma of the Gallbladder
Carcinoma of the gallbladder is slightly more common in women and occurs most frequently in the seventh decade of life. Only rarely is it discovered at a resectable
stage, and the mean 5-year survival has remained for many years at about 1%, despite surgical intervention. Gallstones are present in 60% to 90% of cases, but not 100%; in Asia, where pyogenic and parasitic disease of the biliary tree is common, the coexistence of gallstones is much lower. Presumably, gallbladders containing stones or infectious agents develop cancer as a result of irritative trauma and chronic inflammation. Carcinogenic derivatives of bile acids may also play a role. MORPHOLOGY.
Carcinomas of the gallbladder exhibit two patterns of growth, infiltrating or exophytic. The infiltrating pattern is more common and usually appears as a poorly defined area of diffuse thickening and induration of the gallbladder wall that may cover several square centimeters or may involve the entire gallbladder. Deep ulceration may cause direct penetration of the gallbladder wall or fistula formation to adjacent viscera into which the neoplasm has grown. These tumors are scirrhous and have a firm consistency. The exophytic pattern grows into the lumen as an irregular, cauliflower mass but at the same time invades the underlying wall. The luminal portion may be necrotic, hemorrhagic, and ulcerated (Fig. 19-53 A). The most common sites of involvement are the fundus and neck; about 20% involve the lateral walls. Most carcinomas of the gallbladder are adenocarcinomas. Some are papillary and others are infiltrative and poorly differentiated to undifferentiated (Fig. 19-53 B). About 5% are squamous cell carcinomas or have adenosquamous differentiation. A minority may exhibit carcinoid or a variety of mesenchymal features. By the time these neoplasms are discovered, most have invaded the liver centrifugally, and many have extended to the cystic duct and adjacent bile ducts and porta hepatic lymph nodes. The peritoneum, gastrointestinal tract, and lungs are common sites of seeding. Clinical Features.
Preoperative diagnosis of carcinoma of the gallbladder is the exception rather than the rule, occurring in less than 20% of patients. Presenting symptoms are insidious and typically indistinguishable from those associated with cholelithiasis: abdominal pain, jaundice, anorexia, and nausea and vomiting. The fortunate patient will develop a palpable gallbladder and acute cholecystitis before extension of the tumor into adjacent structures or will have incidental carcinoma at the time of cholecystectomy for symptomatic gallstones. Carcinoma of the Extrahepatic Bile Ducts
Carcinomas of the extrahepatic biliary tree, down to the level of the ampulla of Vater, are uncommon tumors. They are extremely insidious tumors and generally produce painless,
900
Figure 19-53 Gallbladder adenocarcinoma. A , The opened gallbladder contains a large, exophytic tumor that virtually fills the lumen. B , Malignant glandular structures are present within a densely fibrotic gallbladder wall.
progressively deepening jaundice. They occur in older individuals and, unlike cancers of the gallbladder, occur slightly more frequently in men. Gallstones are present in only about a third of cases. As with intrahepatic biliary tract carcinomas (cholangiocarcinomas), risk is increased in patients with biliary tree fluke infections ( Clonorchis sinensis) in Asia or by preexisting primary sclerosing cholangitis, inflammatory bowel disease, or choledochal cysts. A subgroup of biliary tree carcinomas are those arising in the immediate vicinity of the ampulla of Vater. Tumors of this region also include pancreatic carcinoma and adenomas of the duodenal mucosa (discussed in Chapters 20 and 18 , respectively). Collectively, these tumors are referred to as periampullary carcinomas, and all are treated by surgical resection. MORPHOLOGY.
Because partial or complete obstruction of bile ducts rapidly leads to jaundice, these tumors tend to be relatively small at the time of diagnosis. Most tumors appear as firm, gray nodules within the bile duct wall; some may be diffusely infiltrative lesions creating ill-defined thickening of the wall; others are papillary, polypoid lesions. Most bile duct tumors are adenocarcinomas that may or may not be mucin secreting. Uncommonly, squamous features are present. For the most part, an abundant fibrous stroma accompanies the epithelial proliferation. Tumors arising at the confluence of the right and left hepatic ducts at the liver hilus are called Klatskin tumors.[68] These tumors are notable for their slow-growing behavior, marked sclerosing characteristics, and the infrequent occurrence of distal metastases. Clinical Features.
Jaundice generally arises because of obstruction, often accompanied by decoloration of the stools, nausea and vomiting, and weight loss. Hepatomegaly is present in about 50% and a palpable gallbladder in about 25% of cases. Associated changes are elevated levels of serum alkaline phosphatase and transaminases, bile-stained urine, and prolonged prothrombin time. Differentiation of obstructive jaundice due to calculous disease or other benign conditions from neoplasia is a major clinical problem, particularly because the presence of stones does not preclude the existence of concomitant malignant neoplasms. Despite their small size, most ductal cancers are not surgically resectable at the time of diagnosis. Mean survival times range from 6 to 18 months.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
REFERENCES Rapaport AM: The structural and functional units of the human liver (liver acinus). Microvasc Res 6:212, 1973. 1.
Jungermann K, Kietzmann T: Zonation of parenchymal and nonparenchymal metabolism in liver. Annu Rev Nutr 16:179-203, 1996. 2.
Tsukada N, et al: The structure and organization of the bile canalicular cytoskeleton with special reference to actin and actin-binding proteins. Hepatology 21:1106-1113, 1995. 3.
Ciotti M, et al: Genetic defects at the UGT1 locus associated with Crigler-Najjar type I disease, including a prenatal diagnosis. Am J Med Genet 68:173-178, 1997. 4.
Seppen J, et al: A mutation which disrupts the hydrophobic core of the signal peptide of bilirubin UDP-glucuronosyltransferase, an endoplasmic reticulum membrane protein, causes Crigler-Najjar type II. FEBS Lett 390:294-298, 1996. 5.
Bosma PJ, et al: The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med 333:1171-1175, 1995. 6.
Kartenbeck J, et al: Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin-Johnson syndrome. Hepatology 23:1061-1066, 1996. 7.
Bull LN, et al: A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat Genet 18:219-224, 1998. 8.
Mousseau DD, Butterworth RF: Current theories on the pathogenesis of hepatic encephalopathy. Proc Soc Exp Biol Med 206:329-344, 1994. 9.
10.
Van Roey G, Moore K: The hepatorenal syndrome. Pediatr Nephrol 10:100-107, 1996.
11.
Lange PA, Stoller JK: The hepatopulmonary syndrome. Ann Intern Med 122:521-529, 1995. 901
Henriksen JH: Cirrhosis: ascites and hepatorenal syndrome. Recent advances in pathogenesis. J Hepatol 23(Suppl 1):25-30, 1995. 12.
Crawford JM: Cellular and molecular biology of the inflamed liver. Curr Opin Gastroenterol 13:175-185, 1997. 13.
14.
Soltis RD: New concepts in viral hepatitis. Geriatrics 36:62, 1981.
15.
Hoofnagle JH: Type D (delta) hepatitis. JAMA 261:1321-1325, 1989.
16.
Lai MMC: The molecular biology of hepatitis delta virus. Annu Rev Biochem 64:259-286, 1995.
Goldsmith R, et al: Enzyme-linked immunosorbent assay for diagnosis of acute sporadic hepatitis E in Egyptian children. Lancet 339:328-331, 1992. 17.
18.
Mast EE, Krawczynski K: Hepatitis E: an overview. Annu Rev Med 47:257-266, 1996.
19.
Bertel CK, et al: Treatment of pyogenic hepatic abscesses. Arch Surg 121:554-558, 1986.
20.
Czaja AJ: The variant forms of autoimmune hepatitis. Ann Intern Med 125:588-598, 1996.
21.
Lee WM: Medical progress--drug-induced hepatotoxicity. N Engl J Med 333:1118-1127, 1995.
Carithers RL Jr: Alcoholic hepatitis and cirrhosis. In Kaplowitz N (ed): Liver and Biliary Diseases. Baltimore, Williams & Wilkins, 1992, pp 334-346. 22.
Lands WEM: Cellular signals in alcohol-induced liver injury: a review. Alcohol Clin Exp Res 19:928-938, 1995. 23.
Neuschwander-Tetri BA, Bacon BR: Nonalcoholic steatohepatitis. Med Clin North Am 80:1147-1166, 1996. 24.
Feder JN, et al: A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13:399-408, 1996. 25.
26.
Feder JN, et al: The hemochromatosis founder mutation in HLA-H disrupts beta 2 -microglobulin
interaction and cell surface expression. J Biol Chem 272:14025-14028, 1997. 27.
Santos M, et al: Defective iron homeostasis in beta2 -microglobulin knockout mice recapitulates
hereditary hemochromatosis in man. J Exp Med 184:1975-1985, 1996. Gordeuk V, et al: Iron overload in Africa: interaction between a gene and dietary iron content. N Engl J Med 326:95-100, 1992. 28.
Schilsky ML: Wilson disease: genetic basis of copper toxicity and natural history. Semin Liver Dis 16:83-95, 1996. 29.
30.
Andres JM: Neonatal hepatobiliary disorders. Clin Perinatol 23:321-352, 1996.
Craig JM, Landing BH: Forms of hepatitis in neonatal period simulating biliary atresia. Arch Pathol Lab Med 54:321-333, 1952. 31.
32.
McEvoy CF, Suchy FJ: Biliary tract disease in children. Pediatr Clin North Am 43:75-98, 1996.
33.
Berk PD: Primary biliary cirrhosis, Parts I and II. Semin Liver Dis 17:1-250, 1997.
34.
Ludwig J, et al: Floxuridine-induced sclerosing cholangitis: an ischemic cholangiopathy? Hepatology
9:215-218, 1989. Desmet VJ: Congenital diseases of intrahepatic bile ducts: variations on the theme "ductal plate malformation." Hepatology 16:1069-1083, 1992. 35.
36.
Caroli J: Diseases of the intrahepatic biliary tree. Clin Gastroenterol 2:147-161, 1973.
Gattone VH II, et al: Murine autosomal recessive polycystic kidney disease with multiorgan involvement induced by the cpk gene. Anat Rec 245:488-499, 1996. 37.
Hoffenberg EJ, et al: Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr 127:220-224, 1995. 38.
Li LH, et al: Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch 1. Nat Genet 16:243-251, 1997. 39.
European Polycystic Kidney Disease Consortium: The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell 77:881-894, 1994. 40.
Weinstein L: Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 142:159-167, 1982. 41.
Treem WR, et al: Acute fatty liver of pregnancy, hemolysis, elevated liver enzymes, and low platelets syndrome, and long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Am J Gastroenterol 91:2293-2300, 1996. 42.
Green RM, Crawford JM: Hepatocellular cholestasis: pathobiology and histological outcome. Semin Liver Dis 15:372-389, 1995. 43.
Shulman HM, et al: Venoocclusive disease of the liver after marrow transplantation: histological correlates of clinical signs and symptoms. Hepatology 19:1171-1181, 1994. 44.
Ng IOL, et al: Hepatocellular ballooning after liver transplantation: a light and electronmicroscopic study with clinicopathological correlation. Histopathology 18:323-330, 1991. 45.
Wanless IR: Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules. Hepatology 11:787-797, 1990. 46.
Beasley RP: Hepatitis B virus, the major etiology of hepatocellular carcinoma. Cancer 61:1942-1956, 1988. 47.
Geissler M, et al: Molecular mechanisms of hepatocarcinogenesis. In Okuda K, Tabor E (eds): Liver Cancer. New York, Churchill Livingstone, 1997, pp 59-88. 48.
Chen HL, et al: Seroepidemiology of hepatitis B virus infection in children: ten years mass vaccination in Taiwan. JAMA 270:906-908, 1996. 49.
Nagasue N, et al: The natural history of hepatocellular carcinoma. A study of 100 untreated cases. Cancer 54:1461-1465, 1984. 50.
51.
Carey MC, LaMont JT: Cholesterol gallstone formation. 1. Physical-chemistry of bile and biliary lipid
secretion. Prog Liver Dis 10:139-163, 1992. Carey MC, Cahalane MJ: The enterohepatic circulation. In Arias I, et al (eds): The Liver: Biology and Pathobiology, 2nd ed. New York, Raven Press, 1988, pp 573-616. 52.
Janson JA, et al: Choledocholithiasis and a double gallbladder. Gastrointest Endosc 38:377-379, 1992. 53.
Carey MC, O'Donovan MA: Gallstone disease: current concepts on the epidemiology, pathogenesis and management. In Harrison's Principles of Internal Medicine, Update V. New York, McGraw-Hill, 1984, pp 139-168. 54.
LaMont JT, Carey MC: Cholesterol gallstone formation. 2. Pathobiology and pathomechanics. Prog Liver Dis 10:165-191, 1992. 55.
56.
Gibbons A: Geneticists trace the DNA trail of the first Americans. Science 259:312-313, 1993.
Jorgensen T, et al: Are autopsy studies reliable in assessing gallstone prevalence in the community? Int J Epidemiol 23:566-569, 1994. 57.
Apstein MD, Carey MC: Pathogenesis of cholesterol gallstones: a parsimonious hypothesis. Eur J Clin Invest 26:343-352, 1996. 58.
Kozarsky KF, et al: Overexpression of the HDL receptor SR-B1 alters plasma HDL and bile cholesterol levels. Nature 387:414-417, 1997. 59.
Wang DQ-H, et al: Phenotypic characterizaton of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: physical chemistry of gallbladder bile. J Lipid Res 38:1395-1411, 1997. 60.
Cahalane MJ, et al: Physical-chemical pathogenesis of pigment gallstones. Semin Liver Dis 8:317-328, 1988. 61.
Malet PF: Complications of cholelithiasis. In Kaplowitz N (ed): Liver and Biliary Diseases. Baltimore, Williams & Wilkins, 1992, pp 610-627. 62.
63.
Williamson RCN: Acalculous disease of the gallbladder. Gut 29:860-872, 1988.
Savoca PE, et al: The increasing prevalence of acalculous cholecystitis in outpatients. Ann Surg 211:433-437, 1990. 64.
Balistren WF, et al: Biliary atresia: current concepts and research directions--summary of a symposium. Hepatology 23:1682-1692, 1996. 65.
66.
Lipsett PA, et al: Biliary atresia and biliary cysts. Baillieres Clin Gastroenterol 11:619-641, 1997.
Albores-Saavedra J, et al: The WHO Histological Classification of Tumors of the Gallbladder and Extrahepatic Bile Ducts: a commentary on the second edition. Cancer 70:410-414, 1992. 67.
Klatskin G: Adenocarcinoma of the hepatic duct at its bifurcation within the porta hepatis. Am J Med 38:241-256, 1965. 68.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-1 Microscopic liver architecture depicted schematically. The classic hexagonal lobule is centered around a central vein (terminal hepatic venule), with portal tracts at three of its apices. The triangular acinus has as its base the penetrating vessels, which extend from portal veins and hepatic arteries to penetrate the parenchyma. The apex is formed by the terminal hepatic vein. Zones 1, 2, and 3 represent metabolic regions increasingly distant from the blood supply.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-2 Photomicrograph of liver. (Trichrome stain.) Note blood-filled sinusoids and cords of hepatocytes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-3 Bilirubin metabolism and elimination. 1, Normal bilirubin production from heme (0.2-0.3 gm/day) is derived primarily from the breakdown of senescent circulating erythrocytes, with a minor contribution from degradation of tissue heme-containing proteins. 2, Extrahepatic bilirubin is bound to serum albumin and delivered to the liver. 3, Hepatocellular uptake and (4) glucuronidation in the endoplasmic reticulum generate bilirubin mono- and diglucuronides, which are water soluble and readily excreted into bile. 5, Gut bacteria deconjugate the bilirubin and degrade it to colorless urobilinogens. The urobilinogens and the residue of intact pigments are excreted in the feces, with some reabsorption and excretion into urine.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-4 Dubin-Johnson syndrome, showing abundant pigment inclusions in otherwise normal hepatocytes. (H&E.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-5 Illustration of the morphologic features of cholestasis ( right) and comparison with normal liver ( left). In the parenchyma (upper panel), cholestatic hepatocytes (1) are enlarged with dilated canalicular spaces (2). Apoptotic cells (3) may be seen, and Kupffer cells (4) frequently contain regurgitated bile pigments. In the portal tracts of obstructed livers (lower panel), there is also bile duct proliferation (5), edema, bile pigment retention (6), and eventually neutrophilic inflammation (not shown). Surrounding hepatocytes (7) are swollen and undergoing toxic degeneration.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-6 Proposed mechanisms for stimulation of collagen production by hepatic stellate cells in cirrhosis. Distortion of the extracellular matrix; secretion of cytokines from endothelial cells, Kupffer cells, hepatocytes, and inflammatory cells such as lymphocytes; and the direct action of toxins (or their metabolites) have all been proposed as possible stimuli for transforming hepatic stellate cells (lipocytes) into collagen-secreting myofibroblasts.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-7 The major clinical consequences of portal hypertension in the setting of cirrhosis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-8 Sequence of serologic markers in acute hepatitis A viral hepatitis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-9 Schematic of the approximate outcomes of hepatitis B infection in adults, with their approximate annual frequencies in the United States. (Population estimates courtesy of John L. Gollan, MD, PhD, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-10 Diagrammatic representation of the structure and transcribed components of the hepatitis B virion.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-11 Sequence of serologic markers for hepatitis B viral hepatitis demonstrating (A) acute infection with resolution and (B) progression to chronic infection.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-12 Schematic of the potential outcomes of hepatitis C infection in adults in the United States. The population estimates are for new infections. Including diagnoses of previously unsuspected cases of hepatitis C, the annual reported incidence of total cases actually exceeds 100,000, and total annual death rates from hepatitis C infection approach 10,000. (Population estimates based on the consensus report from the National Institutes of Health Consensus Development Conference. Hepatology 26:Suppl 1:1S-153S, 1997.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-13 Diagrammatic representation of the genomic structure of hepatitis C virus. A single open reading frame codes for core (C) and envelope (E) proteins, as well as for a series of nonstructural (NS) proteins. Notably, most of the genome exhibits variability, with only the 5
end being well-conserved among different genotypes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-14 Sequence of serologic markers for hepatitis C viral hepatitis demonstrating (A) acute infection with resolution and (B) progression to chronic relapsing infection.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-15 Differing clinical consequences of two patterns of combined hepatitis D virus and hepatitis B virus infection.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-16 Sequence of serologic markers for hepatitis D viral hepatitis depicting (A) coinfection with hepatitis B virus (HBV) and (B) superinfection of an HBV carrier.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-17 Diagrammatic representation of the morphologic features of acute and chronic hepatitis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-18 Ground-glass hepatocytes (arrow) in HBV infection (H & E.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-19 Acute viral hepatitis showing disruption of lobular architecture, inflammatory cells in the sinusoids, and hepatocellular apoptosis (arrow).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-20 Chronic viral hepatitis due to hepatitis C virus, showing portal tract expansion with inflammatory cells and fibrous tissue, and interface hepatitis with spillover of inflammation into the adjacent parenchyma. A lymphoid aggregate is present.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-21 Cirrhosis resulting from chronic viral hepatitis. Note broad scar and coarse nodular surface.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-22 Alcoholic liver disease. The interrelationships among hepatic steatosis, hepatitis, and cirrhosis are shown, along with a depiction of key morphologic features at the morphologic level.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-23 Alcoholic liver disease: macrovesicular steatosis, involving most regions of the hepatic lobule. The intracytoplasmic fat is seen as clear vacuoles. Some early fibrosis (stained blue) is present. (Masson trichrome.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-24 Alcoholic hepatitis. A, The cluster of inflammatory cells marks the site of a necrotic hepatocyte. A Mallory body is present in a second hepatocyte (arrow). B, Eosinophilic Mallory bodies are seen in hepatocytes, which are surrounded by fibrous tissue. (H&E.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-25 Alcoholic cirrhosis. A, The characteristic diffuse nodularity of the surface reflects the interplay between nodular regeneration and scarring. The average nodule size is 3 mm in this close-up view. The greenish tint of some nodules is due to bile stasis. B, The microscopic view shows nodules of varying sizes entrapped in blue-staining fibrous tissue. The liver capsule is at the top. (Masson trichrome.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-26 Genetic hemochromatosis. Hepatocellular iron deposition is blue in this Prussian blue-stained section of an early stage of the disease, in which parenchymal architecture is normal.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-27 alpha1 -Antitrypsin deficiency. Periodic acid-Schiff stain of the liver, highlighting the characteristic red cytoplasmic granules. (Courtesy of Dr. I. Wanless, Toronto Hospital, Toronto, Ontario, Canada.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-28 Biliary cirrhosis. Sagittal section through the liver demonstrates the fine nodularity and bile staining of end-stage biliary cirrhosis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-29 Primary biliary cirrhosis. A portal tract is markedly expanded by an infiltrate of lymphocytes and plasma cells. The granulomatous reaction to a bile duct undergoing destruction (florid duct lesion) is highlighted by the arrowheads.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-30 Primary sclerosing cholangitis. A bile duct undergoing degeneration is entrapped in a dense, "onion-skin" concentric scar.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-31 Bile duct anomalies. The morphologic features of the four major groups are diagrammed, along with apparent patterns of inheritance and associations with polycystic kidney disease.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-32 Hepatic circulatory disorders. The forms and clinical manifestations of compromised blood flow are contrasted.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-33 Liver infarct. A thrombus is lodged in a peripheral branch of the hepatic artery and compresses the adjacent portal vein; the distal hepatic tissue is pale, with a hemorrhagic margin.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-34 Centrilobular hemorrhagic necrosis. The cut liver section, in which major blood vessels are visible, is notable for a variegated, mottled, red appearance (nutmeg liver).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-35 Budd-Chiari syndrome. Thrombosis of the major hepatic veins has caused extreme blood retention in the liver.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-36 Veno-occlusive disease. A reticulin stain reveals the parenchyma framework of the lobule and the marked deposition of collagen within the lumen of the central vein.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-37 Eclampsia. Subcapsular hematoma dissecting under the Glisson capsule in a fatal case of eclampsia. (Courtesy of Dr. Brian Blackbourne, Los Angeles, CA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-38 Focal nodular hyperplasia. A, Resected specimen showing lobulated contours and a central stellate scar. B, Microscopic view of the center of the lesion showing the stellate scar.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-39 Nodular regenerative hyperplasia. Autopsied liver showing diffuse nodular transformation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-40 Adenoma. A, Resected specimen presenting as a pendulous mass arising from the liver. B, Microscopic view showing cords of hepatocytes, with an arterial vascular supply (arrows) and no portal tracts.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-41 Hepatocellular carcinoma. A, Autopsied liver showing a unifocal, massive neoplasm replacing most of the right hepatic lobe in a noncirrhotic liver; a satellite tumor nodule is directly adjacent. B, In this microscopic view of a well-differentiated lesion, tumor cells are arranged in nests, sometimes with a central lumen, one of which contains bile (arrow). Other tumor cells contain intracellular bile pigment.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-42 Fibrolamellar carcinoma. A, Resected specimen showing a demarcated nodule in an otherwise normal liver. B, Microscopic view showing nests and cords of malignant-appearing hepatocytes separated by dense bundles of collagen.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-43 Cholangiocarcinoma. A, Autopsied liver showing a massive neoplasm in the right hepatic lobe and innumerable metastases permeating the entire liver. B, Microscopic view showing tubular glandular structures embedded in a dense sclerotic stroma.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-44 Multiple hepatic metastases from a primary colon adenocarcinoma.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 20 - The Pancreas The Exocrine Pancreas NORMAL PATHOLOGY CONGENITAL ANOMALIES Ectopic Pancreas PANCREATITIS Acute Pancreatitis MORPHOLOGY Pathogenesis Clinical Features Chronic Pancreatitis Pathogenesis MORPHOLOGY Clinical Features CYSTS Pseudocysts MORPHOLOGY TUMORS Cystic Tumors Carcinoma of the Pancreas Pathogenesis and Genetics MORPHOLOGY Clinical Features Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 20 - The Pancreas The Endocrine Pancreas DIABETES MELLITUS Classification and Incidence Pathogenesis NORMAL INSULIN PHYSIOLOGY PATHOGENSIS OF TYPE 1 DIABETES MELLITUS Genetic Susceptibility Autoimmunity Environmental Factors Viruses Others PATHOGENESIS OF TYPE 2 DIABETES MELLITUS Deranged beta-Cell Secretion of Insulin Insulin Resistance Obesity Amylin GENETIC DEFECTS OF beta-CELL FUNCTION Maturity-Onset Diabetes of the Young (MODY) PATHOGENESIS OF THE COMPLICATIONS OF DIABETES Nonenzymatic Glycosylation Intracellular Hyperglycemia with Disturbances in Polyol Pathways Morphology of Diabetes and its Late Complications MORPHOLOGY Pancreas Vascular System Diabetic Microangiopathy Diabetic Nephropathy Diabetic Ocular Complications Diabetic Neuropathy Clinical Features ISLET CELL TUMORS Hyperinsulinism (Insulinoma) MORPHOLOGY
Zollinger-Ellison Syndrome (Gastrinomas) MORPHOLOGY Other Rare Islet Cell Tumors Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
The Endocrine Pancreas The endocrine pancreas consists of about 1 million microscopic clusters of cells, the islets of Langerhans. In the aggregate the islets in the adult human weigh only 1 to 1.5 gm. Embryologically, islet cells are of endodermal origin and form at many points along the pancreatic tubuloductal system. The first evidence of islet formation in the human fetus is seen at 9 to 11 weeks. [27] In human adults, most islets measure 100 to 200 mum and consist of four major and two minor cell types. The four main types are beta, alpha, delta, and PP (pancreatic polypeptide) cells. These make up about 68%, 20%, 10%, and 2%, respectively, of the adult islet cell population. They can be differentiated morphologically by their staining properties, by the ultrastructural structure of their granules, and by their hormone content (Fig. 20-11) . The beta cell produces insulin, as detailed in the discussion of diabetes. The insulin-containing intracellular granules contain a crystalline matrix with a rectangular profiles, surrounded by a halo. The alpha cell secretes glucagon, inducing hyperglycemia by its glycogenolytic activity in the liver. alpha-Cell
912
Figure 20-11 Immunoperoxidase staining shows a dark reaction product for insulin in beta cells ( A ), glucagon in alpha cells ( B ), and somatostatin in delta cells ( C). D, Electron micrographs of beta cells show the characteristic membrane-bound granules, each containing a dense, often rectangular core and distinct halo. E , Portions of an alpha cell ( left) and delta cell ( right ) also exhibit granules, but with closely apportioned membranes. The alpha-cell granule exhibits a dense, round center. (Electron micrographs courtesy of Dr. A. Like, University of Massachusetts Medical School, Worcester, MA.)
913
granules are round, with closely applied membranes and a dense center. delta cells contain somatostatin, which suppresses both insulin and glucagon release; they have large, pale granules with closely applied membranes. PP cells contain a unique pancreatic polypeptide that exerts a number of gastrointestinal effects, such as stimulation of secretion of gastric and intestinal enzymes and inhibition of intestinal motility. These cells have small, dark granules and are not only present in islets but also are scattered in the exocrine pancreas.
The two rare cell types are D1 cells and enterochromaffin cells. D1 cells elaborate vasoactive intestinal polypeptide (VIP), a hormone that induces glycogenolysis and hyperglycemia; it also stimulates gastrointestinal fluid secretion and causes secretory diarrhea. Enterochromaffin cells synthesize serotonin and are the source of pancreatic tumors that cause the carcinoid syndrome (Chapter 18) . We now turn to the two main disorders of islet cells: diabetes mellitus and islet cell tumors. DIABETES MELLITUS Diabetes mellitus is a chronic disorder of carbohydrate, fat, and protein metabolism. A defective or deficient insulin secretory response, which translates into impaired carbohydrate (glucose) use, is a characteristic feature of diabetes mellitus, as is the resultant hyperglycemia. About 3% of the world population, approximately 100 million people, suffer from diabetes, making this one of the most common noncommunicable diseases. Classification and Incidence
Diabetes mellitus represents a heterogeneous group of disorders that have hyperglycemia as a common feature. It may occasionally arise secondarily from any disease causing extensive destruction of pancreatic islets, including pancreatitis, tumors, certain drugs, iron overload (hemochromatosis), certain acquired or genetic endocrinopathies, and surgical excision (Table 20-2) . [28] However, the most common and important forms of diabetes mellitus arise from primary disorders of the islet cellinsulin signaling system. These can be divided into two common variants (type 1 and type 2) that differ in their patterns of inheritance, insulin responses, and origins, and less common specific genetic defects of beta-cell functions (Table 20-3) . Type 1 diabetes, also called insulin-dependent diabetes mellitus (IDDM) and previously referred to as juvenile-onset diabetes, accounts for about 10% of all cases of primary diabetes. Most of the remaining 80% to 90% of patients have the so-called type 2 diabetes, also called non-insulin-dependent diabetes mellitus (NIDDM) and previously referred to as adult-onset diabetes. The third group, commonly termed maturity-onset diabetes of the young (MODY), results from genetic defects of beta-cell function. This group accounts for less than 5% of cases. MODY is manifested as a mild hyperglycemia and is transmitted as an autosomal dominant trait (see also under "Pathogenesis").
TABLE 20-2 -- TYPES OF DIABETES MELLITUS Primary Diabetes Type 1 (previously insulin-dependent diabetes mellitus, IDDM)
Type 2 (previously non-insulin-dependent diabetes mellitus, NIDDM) Genetic defects of beta-cell function (including maturity-onset diabetes of the young [MODY]) Chromosome 2, HNF 4alpha (MODY1) Chromosome 7, glucokinase (MODY2) Chromosome 12, HNF 1alpha (MODY3) Mitochondrial DNA Other genetic defects Secondary Diabetes Infectious Congenital rubella Cytomegalovirus Endocrinopathies (e.g., adrenal, pituitary tumors) Drugs (corticosteroids, pentamidine, Vacor) Other genetic disorders (e.g., Down syndrome) Gestational diabetes mellitus HNF, hepatocyte nuclear factor. Modified from the Report of the Executive Committee on the Diagnosis and Classification of Diabetes Mellitus: Diabetic Care 20:1183-1197, 1997.
It should be stressed that while the major types of diabetes have different pathogenic mechanisms, the long-term complications in blood vessels, kidneys, eyes, and nerves are the same and are the major causes of morbidity and death from diabetes. Diabetes affects an estimated 13 million people in the United States, although only about half of these are clinically diagnosed. With an annual mortality rate of about TABLE 20-3 -- TYPE 1 VS. TYPE 2 DIABETES MELLITUS Type 1 (IDDM) Type 2 (NIDDM) Clinical
Onset 30 yr
Normal weight
Obese
Decreased blood insulin
Normal or increased blood insulin
Anti-islet cell antibodies
No anti-islet cell antibodies
Ketoacidosis common
Ketoacidosis rare
Genetics
50% concordance in twins
90% to 100% concordance in twins
HLA-D linked
No HLA association
Pathogenesis Autoimmunity, immunopathologic mechanisms Islet cells
Insulin resistance
Severe insulin deficiency
Relative insulin deficiency
Insulitis early
No insulitis
Marked atrophy and fibrosis
Focal atrophy and amyloid deposits
beta-cell depletion
Mild beta-cell depletion
914
54,000, diabetes is the seventh leading cause of death in the United States. [19] Diabetes increases in prevalence with age; about 50% of patients are over 55 years old. The lifetime risk of developing type 2 diabetes for the American adult population is estimated at 5% to 7%; for type 1 diabetes the lifetime risk is about 0.5%. Pathogenesis
The pathogenesis of the two types is discussed separately, but first we briefly review normal insulin metabolism, since many aspects of insulin release and action are important in the consideration of pathogenesis. NORMAL INSULIN PHYSIOLOGY
Normal glucose homeostasis is tightly regulated by three interrelated processes: glucose production in the liver, uptake and utilization of glucose by peripheral tissues, and insulin secretion. The insulin gene is expressed in the beta cells of the pancreatic islets (Fig. 20-12) . Preproinsulin is synthesized in the rough endoplasmic reticulum from insulin mRNA and delivered to the Golgi apparatus. There, a series of proteolytic cleavage steps by prohormone convertases generate the mature insulin and a cleavage peptide, C peptide. [29] Both C peptide and insulin are then stored in secretory granules and secreted together after physiologic stimulation.
Figure 20-12 Insulin synthesis and secretion. Glucose stimulates both synthesis and calcium-dependent secretion of insulin, while
other agents--amino acids and certain gastrointestinal hormones--induce only insulin secretion. GLUT-2 is an insulin-independent glucose transporter that facilitates entry of glucose into the cell.
Figure 20-13 Insulin action on a target cell. Insulin binds to the alpha subunit of the insulin receptor and activates tyrosine-specific
protein kinase autophosphorylation of the adjacent beta subunit. This activates a cascade that stimulates DNA synthesis, protein synthesis (anabolism), and translocation of glucose transport units (GLUT proteins) from the Golgi apparatus to the plasma membrane.
The most important stimulus that triggers insulin release and synthesis is glucose. A rise in blood glucose levels results in glucose uptake into beta cells, facilitated by an insulin-independent, glucose-transporting protein, GLUT-2. This calls forth an immediate release of insulin, presumably that stored in the beta-cell granules. If the secretory stimulus persists, coupled with normal cholinergic input from the autonomic nervous system, a delayed and protracted response follows that involves active synthesis of insulin. Other agents, including intestinal hormones and certain amino acids (leucine and arginine), as well as the sulfonylureas, stimulate insulin release but not synthesis. Insulin is a major anabolic hormone. It is necessary for (1) transmembrane transport of glucose and amino acids, (2) glycogen formation in the liver and skeletal muscles, (3) glucose conversion to triglycerides, (4) nucleic acid synthesis, and (5) protein synthesis. Its principal metabolic function is to increase the rate of glucose transport into certain cells in the body (Fig. 20-13) . [30] These are the striated muscle cells (including myocardial cells), fibroblasts, and fat cells, representing collectively about two thirds of the entire body weight. In addition to these metabolic effects, insulin and insulin-like growth factors initiate DNA synthesis in certain cells and stimulate their growth and differentiation.
915
Insulin interacts with its target cells by first binding to the insulin receptor; hence, the number and function are important in regulating the action of insulin. The insulin receptor is composed of two glycoprotein subunits, alpha and beta, possessing tyrosine kinase activity in the beta-subunit cytosolic domain. Receptor-bound insulin triggers a cascade of intracellular responses, including activation of DNA and protein synthesis, and activation of anabolic metabolic pathways and inhibition of catabolic pathways (Fig. 20-13) . [31] One of the important early effects of insulin in target tissues involves translocation of glucose transport proteins (or units) (GLUTs) from the Golgi apparatus to the plasma membrane, thus facilitating cellular uptake of glucose. There are several different forms of GLUTs, which differ in their tissue distribution, affinity for glucose, and sensitivity to insulin stimulation. GLUT-4, present in striated muscle and adipose tissue, is the major transporter regulated by insulin. On the other hand (as shown in Fig. 20-12) , GLUT-2, present in liver hepatocytes and beta cells of the pancreas, is insulin independent and serves to facilitate rapid equilibration of glucose between extracellular and intracellular compartments. Thus, whereas peripheral tissues utilize GLUT-4 to extract glucose from the blood, GLUT-2 serves primarily as a conduit for pancreatic and hepatic operation of the insulin-glucose feedback loop.
A singular feature of diabetes mellitus is impaired glucose tolerance. This is unmasked by a glucose challenge, such as an oral glucose tolerance test, in which blood glucose levels are sampled minutes to hours after an oral dose of glucose. In normal individuals, blood glucose levels rise only modestly, and a brisk pancreatic insulin response ensures a return to normoglycemic levels within an hour. In diabetic individuals and in those in a preclinical stage, blood glucose rises to abnormally high levels for a sustained period. As will become evident, this may result from an absolute lack of pancreatic insulin release, an impaired target tissue response to insulin, or both. Notably, screening programs using the glucose tolerance test indicate that prevalence rates for preclinical diabetes (principally type 2) are the same as those for clinically diagnosed disease-about 3%. PATHOGENSIS OF TYPE 1 DIABETES MELLITUS
This form of diabetes results from a severe, absolute lack of insulin caused by a reduction in beta-cell mass. Type 1 diabetes usually develops in childhood, becoming manifest and severe at puberty. Patients depend on insulin for survival; hence, the older term insulin-dependent diabetes mellitus (IDDM). Without insulin, they develop serious metabolic complications such as acute ketoacidosis and coma. Three interlocking mechanisms are responsible for the islet cell destruction: genetic susceptibility, autoimmunity, and an environmental insult. A postulated sequence of events involving these three mechanisms is shown in Figure 20-14 . It is thought that genetic susceptibility linked to specific alleles of the class II major histocompatibility complex (MHC) predisposes certain persons to the development of autoimmunity against beta cells of the islets. The
Figure 20-14 A simplified schema to show pathways of beta-cell destruction leading to type 1 (insulin-dependent) diabetes mellitus.
An environmental insult, possibly viral infection, is thought to provoke autoimmune attack of beta cells in genetically susceptible individuals. Environmental insults may involve either molecular mimicry, in which a viral antigen evokes autoimmune attack of a similar beta-cell antigen, or direct damage to beta cells, causing abnormal expression of beta-cell antigens.
autoimmune reaction either develops spontaneously or, more likely, is triggered by an environmental event that alters beta cells, rendering them immunogenic. Overt diabetes appears after most of the beta cells have been destroyed (Fig. 20-15) (Figure Not Available) . Let us now review the three mechanisms in the sequence. Genetic Susceptibility.
Type 1 diabetes mellitus occurs most frequently in persons of Northern European descent. The disease is much less common among other racial groups, including blacks, Native Americans, and Asians. Diabetes can aggregate in families; about 6% of children of first-order relatives with type 1 diabetes develop the disease. Among identical twins, the cumulative concordance risk (i.e., both twins affected) from birth to age 35 is 70%. [32] The fact that this number is not 100% implicates incomplete
penetrance of genetic susceptibility traits or an additional role for environmental factors. At least one of the susceptibility genes for type 1 diabetes resides in the region that encodes the class II antigens of the MHC on chromosome 6p21 (HLA-D). [33] You will recall (Chapter 7) that the HLA-D region contains three classes of genes (DP, DQ, and DR), that the class II molecules are highly polymorphic, and that each has numerous alleles. About 95% of white patients with type 1 diabetes have either HLA-DR3 or HLA-DR4 alleles or both,
916
Figure 20-15 (Figure Not Available) Stages in the development of type beta-1 diabetes mellitus. The stages are listed from left to right, and hypothetical beta-cell mass is plotted against age. (From Eisenbarth GE: Type 1 diabetes--a chronic autoimmune disease. N Engl J Med 314:1360, 1986. Copyright © 1986, Massachusetts Medical Society. All rights reserved.)
whereas in the general population the prevalence of these antigens is only 45%. There is an even stronger association with certain alleles (such as DQB1*0302), that are in linkage disequilibrium (i.e., coinherited) with HLA-DR genes. Notable is the finding that HLA-DQ beta peptide chains with amino acid differences in the region close to the antigen-binding cleft of the molecule seem to affect the risk for type 1 diabetes in whites. It is thought that genetic variations in the HLA class II molecule may alter recognition by the T-cell receptor, or may modify the presentation of the antigen because of variations in the antigen-binding cleft. Thus, class II HLA genes may affect the degree of immune responsiveness to a pancreatic beta -cell autoantigen, or a beta -cell autoantigen may be presented in a manner that promotes an abnormal immunologic reaction. In addition to the established influence of HLA-linked genes, human genome analysis has revealed about 20 other chromosomal regions independently associated with predisposition to the disease. To date, these include 11p15 (the insulin gene region) and regions encoding loci of glucokinase and T-cell receptor peptides. [35] Collectively, these account for no more than 10% of the genetic risk. [36] Evaluation of these and other genes will be a major emphasis in coming years. Autoimmunity.
Although the clinical onset of type 1 diabetes is abrupt, this disease in fact results from a chronic autoimmune attack of beta cells that usually exists for many years before the disease becomes evident. [37] The classic manifestations of the disease (hyperglycemia and ketosis) occur late in its course, after more than 90% of the beta cells have been destroyed. Evidence for the importance of autoimmunity is as follows: A lymphocyte-rich inflammatory infiltrate ("insulitis") is observed in the islets of patients in early diabetes, and in animal models of autoimmune diabetes (see Fig. 20-19 A). The infiltrate consists mostly of CD8 T lymphocytes, plus variable numbers of CD4 T cells and macrophages. CD4 T cells from animals with autoimmune diabetes can transfer diabetes to normal animals, thus establishing the primacy of
T-cell autoimmunity in type 1 diabetes. [38] The insulitis is associated with increased expression of class I MHC molecules and aberrant expression of class II MHC molecules on the beta cells. (However, aberrant MHC class II expression is not an absolute requisite for diabetes. [39] ) This aberrant expression is mediated in part by locally produced cytokines (e.g., interferon-gamma [IFN-gamma]) derived from activated T cells. [40] Genetic dysregulation of a cytokine that induces IFN-gamma production promotes the development of diabetes in a mouse model. [41] Whether the abnormal expression of MHC genes is a cause or consequence of insulitis is unclear. About 70% to 80% of patients with type 1 diabetes have islet cell autoantibodies against intracellular islet cell antigens such as glutamic acid decarboxylase (GAD), "islet autoantigen 2" (IA-2, a tyrosine phosphatase), insulin, and gangliosides. [43] Whether these and other autoantibodies participate in causing damage to the beta cells is unclear. Recent studies in an animal model strongly implicate GAD-reactive T cells in the pathogenesis of type 1 disease, [43] suggesting that GAD-reactive antibodies are formed after T-cell mediated injury to beta cells. Regardless of their origin, GAD autoantibodies can be detected long before the onset of clinical symptoms.[44] Moreover, the simultaneous presence of GAD, IA-2, and insulin antibodies carries close to a 100% risk of the development of clinical diabetes within 5 years. [44] Asymptomatic relatives of patients with type 1 diabetes (who are therefore at increased risk) develop islet cell autoantibodies months to years before they manifest overt diabetes. Approximately 10% of persons with type 1 diabetes also have other organ-specific autoimmune disorders such as Graves disease, Addison disease, and thyroiditis. To summarize, overwhelming evidence implicates autoimmunity and immune-mediated injury as causes of beta -cell loss in type 1 diabetes. Indeed, immunosuppressive therapies have been shown to ameliorate type 1 diabetes in experimental animals and in children with new onset of the disease. Environmental Factors.
Assuming that a genetic susceptibility predisposes to autoimmune destruction of islet cells, what triggers the autoimmune reaction? Although the answer is unknown in most cases, there is compelling evidence that environmental factors are involved. Finnish children have a 60- to 70-fold greater risk of type 1 diabetes than Korean children. In the northeastern United States there has been a tripling of type 1 diabetes incidence in
917
children under 15 years of age since the late 1960s. In three studies in Japan, Israel, and Canada, emigrants assume a risk of type 1 diabetes closer to that of their destination country than to that of their country of origin. Viruses.
Epidemiologic studies suggest the action of viruses. Seasonal trends that often correspond to the prevalence of common viral infections have long been noted in the diagnosis of new cases, as has the association between coxsackieviruses of group B and pancreatic diseases, including diabetes. [45] Other implicated viral infections include mumps, measles, cytomegalovirus, rubella, and infectious mononucleosis. Although many viruses are beta-cell tropic, direct virus-induced injury is rarely severe enough to cause diabetes mellitus. Several scenarios have been postulated for the role of viruses. One is that viruses cause mild beta -cell injury, which is followed by an autoimmune reaction against previously sequestered antigens in virally altered beta cells in persons with HLA-linked susceptibility. Type 1 diabetes would thus be a rare outcome of some relatively common viral infection, delayed by the long latency period necessary for progressive autoimmune loss of beta cells to occur and dependent on the modifying effects of the genetic background, particular that of MHC class II molecules. Another is that an immune response develops against a viral protein that shares amino acid sequences with a beta cell protein ("molecular mimicry"). For example, a 6 amino acid sequence is shared between islet cell GAD and the P2-C replicative complex of Coxsackie B4 virus. The immunologic cross-over to self could occur from virus-induced activation of preexistent autoreactive lymphocytes, or from the mounting of an immune response to a viral neoantigen. Finally, an endogenous retroviral genome has recently been identified in diabetic islets that also serves as a superantigen (Chapter 7) . [47] Whether the virus is a trigger, a precipitator, or simply a marker for diabetes is unknown. [48 ]
Others.
Antigenic exposure may also come from other sources. Although the subject is controversial, it has been reported that children who ingest cow' s milk products early in life (before age 4 months) have a 1.5-fold increased risk for type 1 diabetes relative to those who do not, raising the spectre of a cross-reacting antigen in cow's milk. [49] A number of chemical toxins, including streptozotocin, alloxan, and pentamidine, also induce islet cell destruction in animals. In humans, pentamidine, a drug used for the treatment of parasitic infections, has been occasionally associated with the development of abrupt-onset diabetes, and cases of diabetes have also been reported after accidental or suicidal ingestion of Vacor, a pharmacologic agent used as a rat exterminator. These chemicals act either directly on islet cells or indirectly by triggering a destructive autoimmune reaction. PATHOGENESIS OF TYPE 2 DIABETES MELLITUS
While much has been learned in recent years, the pathogenesis of type 2 diabetes remains enigmatic. There is no evidence that autoimmune mechanisms are involved. Life style clearly plays a role, as will become evident when obesity is considered. Nevertheless, genetic factors are even more important than in type 1 diabetes. Among identical twins, the concordance rate is 60% to 80%. In first-degree relatives with type 2
diabetes (and in nonidentical twins) the risk of developing disease is 20% to 40%, versus 5% to 7% in the population at large. Unlike type 1 diabetes, the disease is not linked to any HLA genes. Rather, epidemiologic studies indicate that type 2 diabetes appears to result from a collection of multiple genetic defects or polymorphisms, each contributing its own predisposing risk and modified by environmental factors. [50] The two metabolic defects that characterize type 2 diabetes are (1) a derangement in beta -cell secretion of insulin and (2) a decreased response of peripheral tissues to respond to insulin (insulin resistance) (Fig. 20-16) . The primacy of the secretory defect versus insulin resistance is a matter of continuing debate. Deranged beta-Cell Secretion of Insulin.
In populations at risk for developing type 2 diabetes (relatives of patients), a modest hyperinsulinemia may be observed, attributed to beta-cell hyperresponsiveness to physiologic elevations in blood glucose. With the development of overt disease, the pattern of insulin secretion exhibits a subtle change. Early in the course of type 2 diabetes, insulin secretion appears to be normal and plasma insulin levels are not reduced. However, the normal pulsatile, oscillating pattern of insulin secretion is lost and the rapid first phase of insulin secretion triggered by glucose is obtunded. Collectively, these and
Figure 20-16 Pathogenesis of type 2 diabetes mellitus. Genetic predisposition and environmental influences converge to cause
hyperglycemia and overt diabetes. The primacy of deranged beta-cell insulin secretion and peripheral insulin resistance is not established; in patients with clinical disease, both defects can be demonstrated.
918
other observations suggest derangements in beta-cell responses to hyperglycemia early in type 2 diabetes, rather than deficiencies in insulin synthesis per se. Later in the course of type 2 diabetes, a mild to moderate deficiency of insulin develops, which is less severe than that of type 1. The cause of the insulin deficiency is not entirely clear, but irreversible beta-cell damage does appear to be present. Unlike type 1 diabetes, there is no evidence of viral or immune-mediated injury to the islet cells. According to one view, all the somatic cells of predisposed individuals, including pancreatic beta cells, are genetically vulnerable to injury, leading to accelerated cell turnover and premature aging, and ultimately to a modest reduction in beta-cell mass. Chronic hyperglycemia may exhaust the ability of beta cells to function (this is unfortunately called "glucose toxicity"), as a consequence of persistent beta-cell stimulation.
Insulin Resistance.
Although insulin deficiency is present late in the course of type 2 diabetes, it is not of sufficient magnitude to explain the metabolic disturbances. Rather, reduced responsiveness of peripheral tissues (insulin resistance) is a major factor in the development of type 2 diabetes. At the outset, it should be noted that insulin resistance is a complex phenomenon that is not restricted to the diabetes syndrome. In both obesity and pregnancy (gestational diabetes), insulin sensitivity of target tissues decreases (even in the absence of diabetes), and serum levels of insulin may be elevated to compensate for insulin resistance. The molecular bases of insulin resistance are not clear. There may be a decrease in the number of insulin receptors, and more important, postreceptor signaling by insulin is impaired. You may recall from our earlier discussion that binding of insulin to its receptors leads to translocation of GLUTs to the cell membrane, which in turn facilitates cellular uptake of glucose. It is suspected that reduced synthesis and translocation of GLUTs in muscle and fat cells underlies the insulin resistance noted in obesity as well as in type 2 diabetes. Other postreceptor signaling defects have also been described. From a physiologic standpoint, insulin resistance, regardless of its mechanism, results in (1) the inability of circulating insulin to properly direct the disposition of glucose (and other metabolic fuels), (2) a more persistent hyperglycemia, and therefore (3) more prolonged stimulation of the pancreatic beta cell. Obesity.
Regardless of which initiating event is proposed for type 2 diabetes, obesity is an extremely important environmental influence. Approximately 80% of type 2 diabetics are obese, with abdominal obesity (as opposed to obesity in subcutaneous depots) having a greater impact. Intra-abdominal fat catabolism delivers free fatty acids to the liver, yet is relatively resistant to the modulating effects of insulin (neither of which is true for subcutaneous fat). Although abdominal obesity and insulin resistance could be coincidental expressions of a third unknown factor, the possibility that they are causally related must be considered. [51] Nondiabetic obese individuals can also exhibit insulin resistance and hyperinsulinemia, and a small proportion develop type 2 diabetes. However, when obese type 2 diabetics are compared with weight-matched nondiabetics, it appears that the insulin levels of obese diabetics are below those observed in obese nondiabetics, suggesting a relative insulin deficiency. Fortunately, for many obese diabetics, weight loss (and physical exercise) can reverse impaired glucose tolerance, especially early in the course of the disease. Amylin.
Current interest is also focused on the role of amylin in the pathogenesis of type 2 diabetes. This 37 amino acid peptide is normally produced by the beta cells,
copackaged with insulin and cosecreted with insulin in response to food ingestion. In patients with type 2 diabetes, amylin tends to accumulate in the sinusoidal space outside the beta cells, in close contact with their cell membranes, eventually acquiring the tinctorial characteristics of amyloid. [52] It is unknown whether amylin deposition contributes to the disturbance in glucose sensing by the beta cells, noted early in the course of type 2 diabetes, or is instead a result of disordered beta-cell function. To summarize, type 2 diabetes is a complex, multifactorial disorder involving both impaired insulin release leading to relative insulin deficiency and end-organ insensitivity. Insulin resistance, frequently associated with obesity, produces excessive stress on beta cells, which may fail in the face of sustained need for a state of hyperinsulinism. Genetic factors are definitely involved, but how they fit into this puzzle remains mysterious. GENETIC DEFECTS OF beta-CELL FUNCTION
Maturity-Onset Diabetes of the Young (MODY).
About 2% to 5% of diabetic patients do not fall clearly into either the type 1 or type 2 diabetes phenotype, yet may be confused clinically with either. However, because an insulin secretory defect occurs without beta -cell loss, affected families have been intensively studied in the hope of gaining insights into type 2 diabetes. It now appears that MODY is the outcome of a heterogeneous group of genetic defects in beta-cell function characterized by Autosomal dominant inheritance as a monogenic defect, with high penetrance. Early onset, usually before age 25, as opposed to after age 40 for most patients with type 2 diabetes. Impaired beta-cell function, normal weight, lack of GAD antibodies, and lack of the insulin resistance syndrome. Four distinct genetic defects have so far been identified. Some are characterized by severe beta-cell insulin secretory defects (MODY1 and MODY3), while others (MODY2) feature mild chronic hyperglycemia due to reduced pancreatic beta-cell responsiveness to glucose. One form (MODY1) is caused by mutations in the gene for hepatocyte nuclear transcription factor-4a (HNF-4alpha ) on chromosome 20, a member of the steroid/thyroid hormone receptor superfamily and an upstream regulator of HNF-1alpha expression. [53] MODY2 is caused by mutations in the glucokinase gene on chromosome 7. Mutations in the gene for hepatocyte nuclear factor-1alpha (HNF-1alpha ) on chromosome 12q are associated with 919
MODY3.
[54 ]
HNF-1alpha is a transcription factor that functions as a weak
transactivator of the insulin-I gene. Point mutations in mitochondrial DNA have been found to be associated with diabetes mellitus and deafness. The mechanisms by which mutations in these genes result in an autosomal dominant form of diabetes mellitus are not yet known but presumably involve abnormal insulin metabolism. PATHOGENESIS OF THE COMPLICATIONS OF DIABETES
The morbidity associated with long-standing diabetes of either type results from a number of serious complications, namely microangiopathy, retinopathy, nephropathy, and neuropathy. Hence, the basis of these complications is the subject of a great deal of research. [55] Most of the available experimental and clinical evidence suggests that the complications are a consequence of the metabolic derangements, mainly hyperglycemia. For example, when kidneys are transplanted into diabetics from nondiabetic donors, the lesions of diabetic nephropathy develop within 3 to 5 years after transplantation. Conversely, kidneys with lesions of diabetic nephropathy demonstrate a reversal of the lesion when transplanted into normal recipients. Multicenter clinical trials clearly show delayed progression of microvasculature diabetic complications by strict control of the hyperglycemia. Two metabolic events appear to be involved in the genesis of these complications (Fig. 20-17) . [56] Nonenzymatic Glycosylation.
This refers to the process by which glucose chemically attaches to the amino group of proteins without the aid of enzymes. Glucose forms chemically reversible glycosylation products with protein (named Schiff bases) that may rearrange to form more stable Amadori-type early glycosylation products, which are also chemically reversible (Fig. 20-17 A). The degree of enzymatic glycosylation is directly related to the level of blood glucose. Indeed, the measurement of glycosylated hemoglobin (HbA1c ) levels in the blood is a useful adjunct in the management of diabetes mellitus. The early glycosylation products on collagen and other long-lived proteins in interstitial tissues and blood vessel walls, rather than dissociating, undergo a slow series of chemical rearrangements to form irreversible advanced glycosylation
Figure 20-17 Chemical effects of diabetic hyperglycemia. A , Nonenzymatic glycosylation of proteins. The advanced glycosylation
product involves protein-protein cross-linking. Note that whereas the early glycosylation products are reversible, advanced end products are irreversible. (Modified from Brownlee M, et al: Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 318:1315, 1988.) B , Intracellular hyperglycemia, the sorbitol pathway, and effects on myo-inositol. (Modified from Greene DA, et al: Sorbitol, phosphoinositides, and sodium potassium ATPase in the pathogenesis of diabetic complications. N Engl J Med 316:599, 1987.)
920
TABLE 20-4 -- RELEVANT CHEMICAL AND BIOLOGIC PROPERTIES OF ADVANCED GLYCOSYLATION END PRODUCTS Chemical Cross-link polypeptides of same protein (e.g., collagen) Trap nonglycosylated proteins (e.g., LDL, Ig, complement) Confer resistance to proteolytic digestion Induce lipid oxidation Inactivate nitric oxide Bind nucleic acids Biologic Bind to AGE receptors on monocytes and mesenchymal cells Induce: Monocyte emigration Cytokines and growth factor secretion Increased vascular permeability Procoagulant activity Enhanced cellular proliferation Enhanced ECM production ECM, extracellular matrix; LDL, low-density lipoprotein. Adapted from Vlassara H, et al: Pathogenic effects of advanced glycosylation: biochemical, biological, and clinical indications. Lab Invest 70:138, 1994. ©United States and Canadian Academy of Pathology, Inc., 1994. end products (AGE), which accumulate over the lifetime of the vessel wall. AGEs have a number of chemical and biologic properties that are potentially pathogenic (Table 20-4) . [56A ]
AGE formation occurs on proteins, lipids, and nucleic acids. On proteins, such as collagen, they cause cross-links between polypeptides of the collagen molecule and also trap nonglycosylated plasma or interstitial proteins. In large vessels, trapping low-density lipoprotein (LDL), for example, retards its efflux from the vessel wall and enhances the deposition of cholesterol in the intima, thus accelerating atherogenesis (Chapter 12) . In capillaries, including those of renal glomeruli, plasma proteins such as albumin bind to the glycosylated basement membrane, accounting in part for the increased basement membrane thickening characteristic of diabetic microangiopathy. AGE cross-linked proteins are resistant to proteolytic digestion. Thus, cross-linking decreases protein removal while enhancing protein deposition. AGE-induced cross-linking in collagen type IV in basement membrane may also
impair the interaction of collagen with other matrix components (laminin, proteoglycans), resulting in structural and functional defects in the basement membranes. AGEs bind to receptors on many cell types--endothelium, monocytes, macrophages, lymphocytes, and mesangial cells. Binding induces a variety of biologic activities, including monocyte emigration; release of cytokines and growth factors from macrophages; increased endothelial permeability; increased procoagulant activity on endothelial cells and macrophages; and enhanced proliferation of and synthesis of extracellular matrix by fibroblasts and smooth muscle cells. All these effects can potentially contribute to diabetic complications. The importance of AGEs is supported by studies in which inhibition of their accumulation by pharmacologic agents abrogates the morphologic and functional defects in experimental models of diabetes. [56A ] Intracellular Hyperglycemia with Disturbances in Polyol Pathways.
In some tissues that do not require insulin for glucose transport (e.g., nerves, lens, kidneys, blood vessels), hyperglycemia leads to an increase in intracellular glucose that is then metabolized by aldose reductase to sorbitol, a polyol, and eventually to fructose. These changes have several untoward effects. The accumulated levels of sorbitol and fructose lead to increased intracellular osmolarity and influx of water, and eventually to osmotic cell injury. In the lens, osmotically imbibed water causes swelling and opacity. Sorbitol accumulation also impairs ion pumps and is believed to promote injury of Schwann cells and pericytes of retinal capillaries, with resultant peripheral neuropathy and retinal microaneurysms. In keeping with this hypothesis, experimental inhibition of aldose reductase may ameliorate the development of cataracts and neuropathy. Finally, metabolic disposition of these polyols diverts the cellular machinery from processing of normal intermediary metabolites, thereby altering the complex balance between intracellular signaling networks and target enzymes. [57] Morphology of Diabetes and its Late Complications
Pathologic findings in the pancreas are variable and not necessarily dramatic. The important morphologic changes are related to the many late systemic complications of diabetes. There is extreme variability among patients in the time of onset of these complications, their severity, and the particular organ or organs involved. In individuals with tight control of diabetes the onset may be delayed. In most patients, however, morphologic changes are likely to be found in arteries ( atherosclerosis), basement membranes of small vessels ( microangiopathy), kidneys ( diabetic nephropathy), retina ( retinopathy), nerves ( neuropathy), and other tissues. These changes are seen in both type 1 and type 2 diabetes. A schematic overview is provided in Figure 20-18 . MORPHOLOGY
Pancreas.
Lesions in the pancreas are inconstant and rarely of diagnostic value. Distinctive
changes are more commonly associated with type 1 than with type 2 diabetes. One or more of the following alterations may be present. Reduction in the number and size of islets. This is most often seen in type 1 diabetes, particularly with rapidly advancing disease. Most of the islets are small, inconspicuous, and not easily detected. Leukocytic infiltration of the islets (insulitis) principally composed of T lymphocytes similar to that in models of autoimmune diabetes (Fig. 20-19 A). This may be seen in type 1 diabetics 921
922
at the time of clinical presentation. The distribution of insulitis may be strikingly uneven. Eosinophilic infiltrates may also be found, particularly in diabetic infants who fail to survive the immediate postnatal period. By electron microscopy, beta -cell degranulation may be observed, reflecting depletion of stored insulin in already damaged beta cells. This is more commonly seen in patients with newly-diagnosed type 1 disease, when some beta cells are still present. In type 2 diabetes, there may be a subtle reduction in islet cell mass, demonstrated only by special morphometric studies. Amyloid replacement of islets in type 2 diabetes appears as deposition of pink, amorphous material beginning in and around capillaries and between cells. At advanced stages the islets may be virtually obliterated (Fig. 20-19 B); fibrosis may also be observed. This change is often seen in long-standing cases of type 2 diabetes. As mentioned earlier, the amyloid is composed of amylin fibrils derived from the beta cells. Similar lesions may be found in elderly nondiabetics, apparently as part of normal aging. An increase in the number and size of islets is especially characteristic of nondiabetic newborns of diabetic mothers. Presumably, fetal islets undergo hyperplasia in response to the maternal hyperglycemia.
Figure 20-18 Long-term complications of diabetes.
Figure 20-19 A , Insulitis, shown here from a rat (BB) model of autoimmune diabetes, and seen in type 1 human diabetes. (Courtesy of Dr. Arthur Like, University of Massachusetts, Worchester, MA.) B , Amyloidosis of a pancreatic islet in type 2 diabetes.
Vascular System.
Accelerated atherosclerosis: Diabetes exacts a heavy toll on the vascular system. Vessels of all sizes are affected, from the aorta down to the smallest arterioles and capillaries. The aorta and large- and medium-sized arteries suffer from accelerated severe atherosclerosis. Except for its greater severity and earlier age of onset, atherosclerosis in diabetics is indistinguishable from that in nondiabetics (Chapter 12) . Myocardial infarction, caused by atherosclerosis of the coronary arteries, is the most common cause of death in diabetics. Significantly, it is almost as common in diabetic women as in diabetic men. In contrast, myocardial infarction is uncommon in nondiabetic women of reproductive age. Gangrene of the lower extremities, as a result of advanced vascular disease, is about 100 times more common in diabetics than in the general population. The larger renal arteries are also subject to severe atherosclerosis, but the most damaging effect of diabetes on the kidneys is exerted at the level of the glomeruli and the microcirculation. This is discussed later. The pathogenesis of accelerated atherosclerosis is not well understood, and in all likelihood multiple factors are involved. [58] [59] About one third to one half of the patients have elevated blood lipid levels, known to predispose to atherosclerosis, but the remainder also have an increased predisposition to atherosclerosis. Qualitative changes in the lipoproteins brought about by excessive nonenzymatic glycosylation may affect their turnover and tissue deposition. Low levels of high-density lipoproteins (HDL) have been demonstrated in type 2 diabetes. Since HDL is a "protective molecule" against atherosclerosis (Chapter 12) , this could contribute to increased susceptibility to atherosclerosis. Diabetics have increased platelet adhesiveness to the vessel wall, possibly owing to increased thromboxane A2 synthesis and reduced prostacyclin. In addition to all these factors, diabetics tend to have an increased incidence of hypertension, which is a well-known risk factor for atherosclerosis. [60] Hyaline arteriolosclerosis, the vascular lesion associated with hypertension (Chapters 12 and 21) , is both more prevalent and more severe in diabetics than in nondiabetics, but it is not specific for diabetes and may be seen in elderly nondiabetics without hypertension. It takes the form of an amorphous, hyaline thickening of the wall of the arterioles, which causes narrowing of the lumen (Fig. 20-20) . Not surprisingly, in diabetics it is related not only to the duration of the disease but also to the level of blood pressure. Diabetic Microangiopathy.
One of the most consistent morphologic features of diabetes is diffuse thickening of basement membranes. The thickening is most evident in the capillaries of the skin, skeletal muscle, retina, renal glomeruli, and renal medulla. However, it may also be seen in such nonvascular structures as renal tubules, the Bowman capsule, peripheral nerves, and placenta. By both light and electron microscopy, the basal lamina separating parenchymal or endothelial
Figure 20-20 Severe renal hyaline arteriolosclerosis. Note a markedly thickened, tortuous afferent arteriole. The amorphous nature of the thickened vascular wall is evident. (Periodic acid-Schiff [PAS] stain; courtesy of M.A. Venkatachalam, MD, Department of Pathology, University of Texas Health Science Center at San Antonio, TX.)
923
Figure 20-21 Renal cortex showing thickening of tubular basement membranes in a diabetic patient. (PAS stain.)
cells from the surrounding tissue is markedly thickened by concentric layers of hyaline material composed predominantly of type IV collagen (Fig. 20-21 and 20-22) . It should be noted that despite the increase in the thickness of basement membranes, diabetic capillaries are more leaky than normal to plasma proteins. The microangiopathy underlies the development of diabetic nephropathy and some forms of neuropathy. An indistinguishable microangiopathy can be found in aged nondiabetic patients, but rarely to the extent seen in patients with long-standing diabetes. The microangiopathy is clearly related to the hyperglycemia. Diabetic Nephropathy
(See also Chapter 21) . The kidneys are prime targets of diabetes. [61] Renal failure is second only to myocardial infarction as a cause of death from this disease. Three lesions are encountered: (1) glomerular lesions; (2) renal vascular lesions, principally arteriolosclerosis; and (3) pyelonephritis, including necrotizing papillitis. The most important glomerular lesions are capillary basement membrane thickening, diffuse glomerulosclerosis, and nodular glomerulosclerosis. These are described in detail in Chapter 21 . The glomerular capillary basement membranes are thickened throughout their entire length. This change can be detected by electron microscopy within a few years of the onset of diabetes, sometimes without any associated change in renal function. Diffuse glomerulosclerosis consists of a diffuse increase in mesangial matrix along with mesangial cell proliferation and is always associated with basement membrane thickening. It is found in most patients with disease of more than 10 years' duration. When glomerulosclerosis becomes marked, patients manifest the nephrotic
Figure 20-22 Renal glomerulus showing markedly thickened glomerular basement membrane (B) in a diabetic. L, glomerular capillary lumen; U, urinary space. (Courtesy of Michael Kashgarian, MD, Department of Pathology, Yale University School of Medicine.)
syndrome (Chapter 21) , characterized by proteinuria, hypoalbuminemia, and edema. Nodular glomerulosclerosis describes a glomerular lesion made distinctive by ball-like deposits of a laminated matrix within the mesangial core of the lobule (see Fig. 21-32) . These nodules tend to develop in the periphery of the glomerulus, and since they arise within the mesangium, they push the glomerular capillary loops even more to the periphery. Often these capillary loops create halos about the nodule. This distinctive change has been called the Kimmelstiel-Wilson lesion, after the pioneers who described it. They usually contain trapped mesangial cells. Diffuse glomerulosclerosis is present in glomeruli not affected by nodular glomerulosclerosis. Advanced glomerulosclerosis is associated with tubular ischemia and interstitial fibrosis. In addition, patients with uncontrolled glycosuria may reabsorb glucose and store it as glycogen in the tubular epithelium. This change does not affect tubular function. Nodular glomerulosclerosis is encountered in perhaps 10% to 35% of diabetics and is a major cause of morbidity and mortality. Unlike the diffuse form, which may also be seen in association with old age and hypertension, the nodular form of glomerulosclerosis, for all practical purposes, implicates diabetes. Both the diffuse and the nodular forms of glomerulosclerosis induce sufficient ischemia to cause overall fine scarring of the kidneys, marked by a finely granular cortical surface (Fig. 20-23) .
924
Figure 20-23 Nephrosclerosis in a patient with long-standing diabetes. The kidney has been bisected to demonstrate both diffuse granular transformation of the surface ( left) and marked thinning of the cortical tissue ( right ). Additional features include some irregular depressions, the result of pyelonephritis, and an incidental cortical cyst ( far right ).
Renal atherosclerosis and arteriolosclerosis constitute part of the systemic involvement of blood vessels in diabetics. The kidney is one of the most frequently and severely affected organs; however, the changes in the arteries and arterioles are similar to those found throughout the body. Hyaline arteriolosclerosis affects not only the afferent but also the efferent arteriole. Such efferent arteriolosclerosis is rarely if ever encountered in persons who do not have diabetes. Pyelonephritis is an acute or chronic inflammation of the kidneys that usually begins in the interstitial tissue and then spreads to affect the tubules. Both the acute and chronic forms of this disease occur in nondiabetics as well as in diabetics but are more common in diabetics than in the general population, and once affected, diabetics tend to have more severe involvement. One special pattern of acute
pyelonephritis, necrotizing papillitis (or papillary necrosis), is much more prevalent in diabetics than in nondiabetics. These lesions are described more fully in Chapter 21 . Diabetic Ocular Complications.
Visual impairment, sometimes even total blindness, is one of the more feared consequences of long-standing diabetes. This disease is currently the fourth leading cause of acquired blindness in the United States. The ocular involvement may take the form of retinopathy, cataract formation, or glaucoma and is discussed in Chapter 31 . Diabetic Neuropathy.
The central and peripheral nervous systems are not spared by diabetes. [62] The neurologic manifestations are described in Chapters 29 and 30 . The most frequent pattern of involvement is a peripheral, symmetric neuropathy of the lower extremities that affects both motor and sensory function but particularly the latter. Clinical Features
It is difficult to sketch with brevity the diverse clinical presentations of diabetes mellitus. Only a few characteristic patterns will be presented. Type 1 diabetes, which begins by age 20 years in most patients, is dominated by polyuria, polydipsia, polyphagia, and ketoacidosis--all resulting from metabolic derangements. As insulin is a major anabolic hormone in the body, derangement of insulin function affects not only glucose metabolism but also fat and protein metabolism. Unopposed secretion of counter-regulatory hormones (glucagon, growth hormone, epinephrine) also plays a role in these metabolic derangements. The assimilation of glucose into muscle and adipose tissue is sharply diminished or abolished. Not only does storage of glycogen in liver and muscle cease, but also reserves are depleted by glycogenolysis. Severe fasting hyperglycemia and glycosuria ensues. The glycosuria induces an osmotic diuresis and thus polyuria, causing a profound loss of water and electrolytes (Fig. 20-24) . The obligatory renal water loss combined with the hyperosmolarity resulting from the increased levels of glucose in the blood tends to deplete intracellular water, triggering the osmoreceptors of the thirst centers of the brain. In this manner, intense thirst ( polydipsia) appears. With a deficiency of insulin, the scales swing from insulin-promoted anabolism to catabolism of proteins and fats. Proteolysis follows, and the gluconeogenic amino acids are removed by the liver and used as building blocks for glucose. The catabolism of proteins and fats tends to induce a negative energy balance, which in turn leads to increasing appetite ( polyphagia), thus completing the classic triad of diabetes: polyuria, polydipsia, and polyphagia. Despite the increased appetite, catabolic effects prevail, resulting in weight loss and muscle weakness. The combination of polyphagia and weight loss is paradoxical and should always raise
the suspicion of diabetes. Plasma insulin is low or absent and the glucagon level is increased. Glucose intolerance is of the unstable or brittle type, in that blood glucose levels are quite sensitive to administered exogenous insulin, deviations from normal dietary intake, unusual physical activity, infection, or other forms of stress. Inadequate fluid intake or vomiting may rapidly lead to significant disturbances in fluid and electrolyte balance. Thus, these patients are vulnerable, on the one hand, to hypoglycemic episodes (due to treatment with insulin), and on the other, to ketoacidosis. This latter complication occurs almost exclusively in type 1 diabetes and is stimulated by severe insulin deficiency coupled with absolute or relative
925
Figure 20-24 Sequence of metabolic derangements leading to diabetic coma in type 1 diabetes mellitus. An absolute insulin
deficiency leads to a catabolic state, eventuating in ketoacidosis and severe volume depletion. These cause sufficient central nervous system compromise to cause coma, and eventual death if left untreated.
926
increases of glucagon (Fig. 20-24) . [63] The insulin deficiency causes excessive breakdown of adipose stores, resulting in increased levels of free fatty acids. Oxidation of such free fatty acids within the liver through acetyl CoA produces ketone bodies (acetoacetic acid and beta-hydroxybutyric acid). Glucagon is the hormone that accelerates such fatty acid oxidation. The rate at which ketone bodies are formed may exceed the rate at which acetoacetic acid and beta-hydroxybutyric acid can be utilized by muscles and other tissues, thus leading to ketonemia and ketonuria. If the urinary excretion of ketones is compromised by dehydration, the plasma hydrogen ion concentration increases and systemic metabolic ketoacidosis results. Release of ketogenic amino acids by protein catabolism aggravates the ketotic state. Diabetics have increased susceptibility to infections. Because the stress of infection increases insulin requirements, infections often precipitate diabetic ketoacidosis. Type 2 diabetes mellitus may also present with polyuria and polydipsia, but unlike type 1 diabetes, patients are often older (over 40 years) and frequently obese. In some cases medical attention is sought because of unexplained weakness or weight loss. Frequently, however, the diagnosis is made after routine blood or urine testing in asymptomatic persons. Although patients with type 2 diabetes also have metabolic derangements, these are easier to control and less severe. In the decompensated state, these patients develop hyperosmolar nonketotic coma, a syndrome engendered by the severe dehydration resulting from sustained hyperglycemic diuresis in patients who do not drink enough water to compensate for urinary losses. Typically, the patient is an elderly diabetic who is disabled by a stroke or an infection who is unable to maintain adequate water intake. Furthermore, the absence of ketoacidosis and its symptoms
(nausea, vomiting, respiratory difficulties) delays the seeking of medical attention in these patients until severe dehydration and coma occur. In both forms of long-standing diabetes, atherosclerotic events such as myocardial infarction, cerebrovascular accidents, gangrene of the leg, and renal insufficiency are the most threatening and most frequent concomitants. [64] Diabetics are also plagued by enhanced susceptibility to infections of the skin and to tuberculosis, pneumonia, and pyelonephritis. Such infections cause the deaths of about 5% of diabetic patients. A trivial infection in a toe may be the first event in a long succession of complications (gangrene, bacteremia, pneumonia) that ultimately lead to death. Patients with type 1 diabetes are more likely to die from their disease than those with type 2. The causes of death, in descending order of importance, are myocardial infarction, renal failure, cerebrovascular disease, atherosclerotic heart disease, and infections, followed by a large number of other complications more common in diabetics than in nondiabetics (e.g., gangrene of an extremity). Fortunately, hypoglycemia and ketoacidosis are rare causes of death today. As mentioned, this disease continues to be one of the top ten "killers" in the United States. It is hoped that islet cell transplantation, which is still in the experimental stage, or insights gained from new molecular studies will lead to a cure for diabetes mellitus. Until then, strict glycemic control offers the only hope for preventing the deadly complications of diabetes. ISLET CELL TUMORS Tumors of pancreatic islet cells are rare in comparison with tumors of the exocrine pancreas. They are most common in adults and can occur anywhere along the length of the pancreas, embedded in the substance of the pancreas or arising in the immediate peripancreatic tissues. They resemble in appearance their counterparts, carcinoid tumors, found elsewhere in the alimentary tract (Chapter 18) . [65] Islet cell tumors may be single or multiple and benign or malignant, the latter metastasizing to lymph nodes and liver. When multiple, each tumor may be composed of a different cell type. Islet cell tumors have a propensity to elaborate pancreatic hormones, but some islet cell tumors may be totally nonfunctional. The three most common and distinctive clinical syndromes associated with functional islet cell tumors are (1) hyperinsulinism, (2) hypergastrinemia and the Zollinger-Ellison syndrome, and (3) multiple endocrine neoplasia. The last of these is characterized by the occurrence of tumors in several endocrine glands, and so is described in Chapter 26 . Hyperinsulinism (Insulinoma)
beta-Cell tumors (insulinomas) are the most common of islet cell tumors and may be responsible for the elaboration of sufficient insulin to induce clinically significant hypoglycemia. There is a characteristic clinical triad resulting from these pancreatic
lesions: (1) attacks of hypglycemia occur with blood glucose levels below 50 mg/dl of serum; (2) the attacks consist principally of such central nervous system manifestations as confusion, stupor, and loss of consciousness; and (3) the attacks are precipitated by fasting or exercise and are promptly relieved by feeding or parenteral administration of glucose. MORPHOLOGY.
Insulinomas are most often found within the pancreas and are generally benign. Most are solitary lesions, although multiple tumors or tumors ectopic to the pancreas may be encountered. Bona fide carcinomas, making up only about 10% of cases, are diagnosed on the basis of local invasion and distant metastases. On rare occasions, an islet cell tumor may arise in ectopic pancreatic tissue. Solitary tumors are usually small (often less than 2 cm in diameter) and are encapsulated, pale to red-brown nodules located anywhere in the pancreas. Histologically, these benign tumors look remarkably like giant islets, with preservation of the
927
Figure 20-25 Pancreatic islet cell tumor less than 1 cm in diameter in a focal area of pancreatic fibrosis. Despite the small size of the
tumor, clinical hypoglycemia was present.
regular cords of monotonous cells and their orientation to the vasculature (Fig. 20-25) . Not even the malignant lesions present much evidence of anaplasia, and they may be deceptively encapsulated. By immunocytochemistry, insulin can be localized in the tumor cells. Under the electron microscope, neoplastic beta cells, like their normal counterparts, display distinctive round granules that contain polygonal or rectangular dense crystals separated from the enclosing membrane by a distinct halo. It should be cautioned that granules may be present in the absence of clinically significant hormone activity. Hyperinsulinism may also be caused by diffuse hyperplasia of the islets. This change is found occasionally in adults but is usually encountered in infants born of diabetic mothers. Long exposed to the hyperglycemia of maternal blood, the fetus responds by an increase in the size and number of its islets. In the postnatal period, these hyperactive islets may be responsible for serious episodes of hypoglycemia. While up to 80% of islet cell tumors may demonstrate excessive insulin secretion, the hypoglycemia is mild in all but 20%, and many cases never become clinically symptomatic. The critical laboratory findings in insulinomas are high circulating levels of insulin and a high insulin-glucose ratio. Surgical removal of the tumor is usually followed
by prompt reversal of the hypoglycemia. It is important to note that there are many other causes of hypoglycemia besides islet cell tumors. The differential diagnosis of this frequently obscure metabolic abnormality includes such conditions as insulin sensitivity, diffuse liver disease, inherited glycogenoses, and ectopic formation of insulin by certain retroperitoneal fibromas and fibrosarcomas. Zollinger-Ellison Syndrome (Gastrinomas)
Marked hypersecretion of gastrin usually has its origin in gastrin-producing tumors ( gastrinomas), which are just as likely to arise in the duodenum and peripancreatic soft tissues as in the pancreas. There has been lack of agreement regarding the cell of origin for these tumors, save that endocrine cells of both the gut and pancreas can undergo dedifferentiation and express a broad array of gene products. [66] Zollinger and Ellison first called attention to the association of pancreatic islet cell lesions with hypersecretion of gastric acid and severe peptic ulceration. Ulcers are present in 90% to 95% of patients; the ratio of duodenal to gastric ulcers is 6:1 (Chapter 18) . MORPHOLOGY.
Gastrinomas may arise in the pancreas, the peripancreatic region, or the wall of the duodenum. Over half of gastrin-producing tumors are locally invasive or have already metastasized at the time of diagnosis. In some instances, multiple gastrin-producing tumors are encountered in patients who have other endocrine tumors, thus conforming to multiple endocrine neoplasia type I (Chapter 26) . As with insulin-secreting tumors of the pancreas, gastrin-producing tumors are histologically bland and rarely exhibit marked anaplasia. In the classic case of the Zollinger-Ellison syndrome, hypergastrinemia from an islet cell tumor stimulates extreme gastric acid secretion, which in turn causes peptic ulceration. The duodenal and gastric ulcers, sometimes multiple, are identical to those found in the general population; they differ only in their intractability to usual modalities of therapy. In addition, ulcers may also occur in unusual locations such as the jejunum; when intractable jejunal ulcers are found, Zollinger-Ellison syndrome should be considered. More than 50% of the patients have diarrhea; in 30% it is the presenting symptom. Treatment of the Zollinger-Ellison syndrome involves control of gastric acid secretion by use of histamine (H2 ) receptor blockers and excision of the neoplasm. Total resection of the neoplasm, when possible, eliminates the syndrome. Patients with hepatic metastases have a significantly shortened life expectancy, with progressive tumor growth leading to liver failure usually within 10 years. Other Rare Islet Cell Tumors
alpha -Cell tumors (glucagonomas) are associated with increased serum levels of glucagon and a syndrome consisting of mild diabetes mellitus; a characteristic
migratory, necrotizing skin erythema; and anemia. They occur most frequently in periand postmenopausal women and are characterized by extremely high plasma glucagon levels.
928
delta -Cell tumors (somatostatinomas) are associated with diabetes mellitus, cholelithiasis, steatorrhea, and hypochlorhydria. They are exceedingly difficult to localize preoperatively. High plasma somatostatin levels are required for diagnosis. VIPoma (diarrheogenic islet cell tumor) is an islet cell tumor that induces a characteristic syndrome of watery diarrhea, hypokalemia, and achlorhydria, caused by release of VIP from the tumor. Some of these tumors are locally invasive and metastatic. Neural crest tumors, such as ganglioneuroma, neuroblastoma, neurofibroma, and pheochromocytomas, can also be associated with the VIPoma syndrome. Pancreatic carcinoid tumors producing serotonin and an atypical carcinoid syndrome are exceedingly rare. Pancreatic polypeptide-secreting islet cell tumors are endocrinologically asymptomatic, despite the presence of high levels of the hormone in plasma. Some pancreatic and extrapancreatic tumors produce two or more hormones, usually simultaneously, and occasionally in sequence. In addition to insulin, glucagon, and gastrin, islet cell tumors may produce adrenocorticotropic hormone, melanocyte-stimulating hormone, vasopressin, serotonin, and norepinephrine. These multihormonal tumors are to be distinguished from the multiple endocrine neoplasias described in Chapter 26 , in which a multiplicity of hormones are produced by tumors in several different glands.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
REFERENCES 1.
Beger HG, et al: Natural course of acute pancreatitis. World J Surg 21:130, 1997.
2.
Ranson JHC: Risk factors in acute pancreatitis. Hosp Pract 20:69, 1985.
Steer ML: Etiology and pathophysiology of acute pancreatitis. In Go VLW, et al (eds): The Pancreas: Biology, Pathobiology, and Disease, 2nd ed. New York, Raven Press, 1993, pp 581-591. 3.
4.
Scarpelli DG: Toxicology of the pancreas. Toxicol Appl Pharmacol 101:543, 1989.
5.
Norman J: Role of cytokines in the pathogenesis of acute pancreatitis. Am J Surg 175:76, 1998.
Blackstone MO: Hypothesis: vascular compromise is the central pathogenic mechanism for acute hemorrhagic pancreatitis. Perspect Biol Med 39:56, 1995. 6.
Pitchumoni CS, Bordalo O: Evaluation of hypotheses on pathogenesis of alcoholic pancreatitis. Am Gastroenterol 91:637, 1996. 7.
8.
Steer ML: Pathogenesis of acute pancreatitis. Digestion 58 (suppl 1):46, 1997.
9.
Watanabe S: Acute pancreatitis: overview of medical aspects. Pancreas 16:307, 1998.
10.
Friess H, et al: Acute pancreatitis: the role of infection. Dig Surg 13:357, 1996.
11.
Steer ML, et al: Chronic pancreatitis. N Engl J Med 332:1482, 1995.
Bertrand JA, et al: Crystal structure of human lithostathine, the pancreatic inhibitor of stone formation. EMBO J 15:2678, 1996. 12.
13.
Sarles H, et al: Pathogenesis and epidemiology of chronic pancreatitis. Annu Rev Med 40:453, 1989.
Amman RW, et al: Course of alcoholic chronic pancreatitis: a prospective clinicomorphologic long-term study. Gastroenterology 111:224, 1996. 14.
15.
Adler G, Schmid RM: Chronic pancreatitis: still puzzling? Gastroenterology 112:1762, 1997.
Karlson B-M, et al: The risk of pancreatic cancer following pancreatitis: an association due to confounding? Gastroenterology 113:587, 1997. 16.
Armed Forces Institute of Pathology: Atlas of Tumor Pathology; Tumors of the Pancreas. Bethesda, MD, Universities Associated for Research and Education in Pathology, 1997. 17.
18.
Nishihara K, et al: Papillary cystic tumors of the pancreas assessment of their malignant potential.
Cancer 71:82, 1993. 19.
Parker SL, et al: Cancer Statistics, 1997. Ca Cancer J Clin 47:5, 1997.
20.
Ahlgren JD: Epidemiology and risk factors in pancreatic cancer. Semin Oncol 23:241, 1996.
Andren-Sandberg A, et al: Etiologic links between chronic pancreatitis and pancreatic cancer. Scand J Gastroenterol 32:97, 1997. 21.
Weyrer K, et al: p53, Ki- ras, a DNA ploidy in human pancreatic ductal adenocarcinomas. Lab Invest 74:279, 1996. 22.
Pinto M. M., et al: Ki- ras mutations and the carcinoembryonic antigen level in fine needle aspirates of the pancreas. Acta Cytol 41:427, 1997. 23.
Furuya N, et al: Long-term follow-up of patients with chronic pancreatitis and ras gene mutations detected in pancreatic juice. Gastroenterology 113:593, 1997. 24.
25.
Schmielau J, et al: The role of cytokines in pancreatic cancer. Int J Pancreatol 19:157, 1996.
Urrutia R, DiMagno EP: Genetic markers: the key to early diagnosis and improved survival in pancreatic cancer? Gastroenterology 110:306, 1996. 26.
Falkmer S: Origin of the parenchymal cells of the endocrine pancreas: some phylogenic and ontogenetic aspects. Front Gastrointest Res 23:2, 1995. 27.
American Diabetes Association, Alexandria, VA: Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20:1183, 1997. 28.
Matthews DR, Clark A: Insulin secretion and the aetiology of non-insulin-dependent diabetes. Front Horm Res 22:179, 1997. 29.
Kruszynska YT, Olefsky JM: Cellular and molecular mechanisms of non-insulin dependent diabetes mellitus. Invest Med 44:413, 1996. 30.
Prentki M, et al: Signal transduction mechanisms in nutrient-induced insulin secretion. Diabetologia 40 suppl.2:S32, 1997. 31.
Kyvik KO, et al: H. Concordance rates of insulin dependent diabetes mellitus: a population based study of young Danish twins. Br Med J 311:913, 1995. 32.
Bain SC, et al: Genetic factors associated with insulin-dependent diabetes. Front Horm Res 22:23, 1997. 33.
Reijonen H, Nepom GT: Role of HLA susceptibility in predisposing to insulin-dependent diabetes mellitus. Front Horm Res 22:46, 1997. 34.
Reed P, et al: Evidence for a type 1 diabetes susceptibility locus (IDDM10) on human chromosome 10p11-q11. Hum Mol Genet 6:1011, 1997. 35.
Buhler J, et al: Linkage analyses in type 1 diabetes mellitus using CASPAR, a software and statistical program for conditional analysis of polygenic diseases. Hum Hered 47:211, 1997. 36.
37.
Bach J-F: Insulin-dependent diabetes mellitus as an autoimmune disease. Endocr Rev 15:516, 1994.
Grewal IS, Flavell RA: New insights into insulin dependent diabetes mellitus from studies with transgenic mouse models. Lab Invest 76:3, 1997. 38.
Laufer TM, et al: Autoimmune diabetes can be induced in transgenic major histocompatibility complex class II-deficient mice. J Exp Med 178:589, 1993. 39.
Rabinovitch A: Immunoregulatory and cytokine imbalances in the pathogenesis of IDDM: therapeutic intervention by immunostimulation? Diabetes 43:613, 1994. 40.
Rothe H, et al: Active stage of autoimmune diabetes is associated with the expression of a novel cytokine IGIF, which is located near Idd2. J Clin Invest 99:469, 1997. 41.
Sepe V, et al: Islet-related autoantigens and the pathogenesis of insulin-dependent diabetes mellitus. Front Horm Res 22:68, 1997. 42.
Zekzer D, et al: GAD-reactive CD4+ Th 1 cells induce diabetes in NOD/SCJD mice. J Clin Invest 101:68, 1998. 43.
Kulmala P, et al: Prediction of insulin-dependent diabetes mellitus in siblings of children with diabetes: a population-based study. J Clin Invest 101:327, 1998. 44.
Verge CF, et al. Number of autoantibodies (against insulin, GAD or ICA512/IA) rather than particular autoantibody determines risk of type 1 diabetes. J Autoimmun 1997, 9:379, 1996. 45.
929
Andreoletti L, et al: Detection of Coxsackie B virus RNA sequences in whole blood samples from adult patients at the onset of type 1 diabetes mellitus. J Med Virol 52:121, 1997. 46.
Atkinson MA: Molecular mimicry and the pathogenesis of insulin dependent diabetes mellitus--still just an attractive hypothesis. Ann Med 5:393, 1997. 46A.
Conrad B, et al: A human endogenous retroviral superantigen as candidate autoimmune gene in type I diabetes. Cell 90:303, 1997. 47.
48.
Benoist C, Mathis D: Retrovirus as trigger, precipitator or marker? Nature 388:833, 1997.
49.
Gerstein H: Cow's milk exposure and type 1 diabetes. Diabetes Care 17:13, 1994.
Hattersley A: Genetic factors in the aetiology of non-insulin-dependent diabetes. Front Horm Res 22:157, 1997. 50.
51.
Groop LC: Etiology of non-insulin-dependent diabetes mellitus. Front Horm Res 22:131, 1997.
Sacks DB: Amylin--a glucoregulatory hormone involved in the pathogenesis of diabetes mellitus? Clin Chem 42:494, 1996. 52.
Yamagata K, et al. Mutations in the hepatocyte nucleus factor-4alpha gene in maturity onset diabetes of the young (MODY1). Nature 384:458, 1996. 53.
Frayling TM, et al: Mutations in the hepatocyte nuclear factor-1alpha gene are a common cause of maturity-onset diabetes of the young in the U.K. Diabetes 46:720, 1997. 54.
Semenkovich CF, Heinecke JW: The mystery of diabetes and atherosclerosis: time for a new plot. Diabetes 46:327, 1997. 55.
Nathan DM: The pathophysiology of diabetic complications: how much does the glucose hypothesis explain? Ann Intern Med 124:86, 1996. 56.
Vlassara H: Recent progress in advanced glycation end products and diabetic complications. Diabetes 46(Suppl 2): S19, 1997. 56A.
Stehouwer CDA, et al: Endothelial dysfunction and pathogenesis of diabetic angiopathy. Cardiovasc Res 34:55, 1997. 57.
Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977, 1993. 58.
Sowers JR, Epstein M: Diabetes mellitus and associated hypertension, vascular disease, and nephropathy: an update. Hypertension 26:869, 1995. 59.
60.
Epstein M: Diabetes and hypertension: the bad companions. J Hypertens 15 (suppl 2):S55, 1997.
61.
Cooper ME, et al: Diabetic vascular complications. Clin Exp Pharmacol Physiol 24:770, 1997.
Mooradian AD: Central nervous system complications of diabetes mellitus--a perspective from the blood-brain barrier. Brain Res Rev 23:210, 1997. 62.
Genuth SM: Diabetic ketoacidosis and hyperglycemic hyperosmolar coma. Curr Ther Endocrinol Metab 6:438, 1997. 63.
64.
Tooke JE: Microvasculature in diabetes. Cardiovasc Res 32:764, 1996.
Capella C, et al: Revised classification of neuroendocrine tumours of the lung, pancreas and gut. Virchows Arch 425:547, 1995. 65.
Vassilopoulou-Sellin R, Ajani J: Islet cell tumors of the pancreas. Endocrinol Metab Clin North Am 23:53, 1994. 66.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-2 Pancreatic acini, showing the radial orientation of the pyramidal exocrine acinar cells. The cytoplasm is devoted to the synthesis and packaging of digestive enzymes for secretion into a central lumen.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-3 Acute pancreatitis. The microscopic field shows an advancing region of fat necrosis at the upper left, impinging upon preserved adipose tissue ( lower left) and with accompanying local hemorrhage ( right). (H&E.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-4 Acute pancreatitis. The pancreas has been sectioned across to reveal dark areas of hemorrhage in the head of the pancreas and a focal area of pale fat necrosis in the peripancreatic fat ( upper left).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-5 Three proposed pathways in the pathogenesis of acute pancreatitis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-6 Comparison of the sequelae of acute and chronic pancreatitis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-7 Chronic pancreatitis. A, Extensive fibrosis and atrophy has left only residual islets and ducts, with a sprinkling of chronic inflammatory cells and acinar tissue. B, A higher power demonstrating dilated ducts with inspissated eosinophilic ductal concretions.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-8 Pancreatic pseudocyst. In this computed tomographic scan of the upper abdomen, a percutaneous needle has been placed into a large cystic lesion in the body of the pancreas. (Courtesy of Peter A. Banks, MD, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-9 Pancreatic mucinous cystadenocarcinoma. Cross-section through a mucinous multiloculated cystic tumor in the body of the pancreas. The normal pancreatic tissue has been obliterated.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-10 Carcinoma of the pancreas. A, A cross-section through the head of the pancreas and adjacent common bile duct shows both an ill-defined tumorous mass in the pancreatic substance ( arrowheads) and the green discoloration of the duct resulting from total obstruction of bile flow. B, Poorly formed glands are present in densely fibrotic stroma within the pancreatic substance; there are some inflammatory cells. (H&E.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 21 - The Kidney NORMAL Blood Vessels Glomeruli Tubules Interstitium Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 21 - The Kidney PATHOLOGY - Part 1 CLINICAL MANIFESTATIONS OF RENAL DISEASES Renal Failure Diminished Renal Reserve Renal Insufficiency Renal Failure End-Stage Renal Disease CONGENITAL ANOMALIES Agenesis of the Kidney Hypoplasia Ectopic Kidneys Horseshoe Kidney Cystic Diseases of the Kidney CYSTIC RENAL DYSPLASIA AUTOSOMAL DOMINANT (ADULT) POLYCYSTIC KIDNEY DISEASE Genetics and Pathogenesis MORPHOLOGY Clinical Features AUTOSOMAL RECESSIVE (CHILDHOOD) POLYCYSTIC KIDNEY DISEASE MORPHOLOGY CYSTIC DISEASES OF RENAL MEDULLA Medullary Sponge Kidney Nephronophthisis-Uremic Medullary Cystic Disease Complex Pathogenesis MORPHOLOGY ACQUIRED (DIALYSIS-ASSOCIATED) CYSTIC DISEASE SIMPLE CYSTS GLOMERULAR DISEASES Clinical Manifestations Histologic Alterations Hypercellularity Basement Membrane Thickening
Hyalinization and Sclerosis Pathogenesis of Glomerular Injury IN SITU IMMUNE COMPLEX DEPOSITION Anti-GBM Nephritis Heymann Nephritis Antibodies Against Planted Antigens CIRCULATING IMMUNE COMPLEX NEPHRITIS ANTIBODIES TO GLOMERULAR CELLS CELL-MEDIATED IMMUNITY IN GLOMERULONEPHRITIS ACTIVATION OF ALTERNATIVE COMPLEMENT PATHWAY EPITHELIAL CELL INJURY MEDIATORS OF GLOMERULAR INJURY Cells Soluble Mediators Mechanisms of Progression in Glomerular Diseases Focal Segmental Glomerulosclerosis Tubulointerstitial Damage Acute Glomerulonephritis ACUTE PROLIFERATIVE (POSTSTREPTOCOCCAL, POSTINFECTIOUS) GLOMERULONEPHRITIS Poststreptococcal Glomerulonephritis Etiology and Pathogenesis MORPHOLOGY Clinical Course Nonstreptococcal Acute Glomerulonephritis Rapidly Progressive (Crescentic) Glomerulonephritis Classification and Pathogenesis MORPHOLOGY Clinical Course Nephrotic Syndrome Pathophysiology Causes Membranous Glomerulonephritis (Membranous Nephropathy) Etiology and Pathogenesis MORPHOLOGY Clinical Course Minimal Change Disease (Lipoid Nephrosis) Etiology and Pathogenesis
MORPHOLOGY Clinical Course Focal Segmental Glomerulosclerosis Classification and Types MORPHOLOGY Pathogenesis Clinical Course HIV-Associated Nephropathy Membranoproliferative Glomerulonephritis MORPHOLOGY Pathogenesis Clinical Course Secondary MPGN IgA Nephropathy (Berger Disease) Pathogenesis MORPHOLOGY Clinical Course Focal Proliferative and Necrotizing Glomerulonephritis (Focal Glomerulonephritis) Hereditary Nephritis ALPORT SYNDROME MORPHOLOGY Pathogenesis Clinical Picture THIN MEMBRANE DISEASE (BENIGN FAMILIAL HEMATURIA) Chronic Glomerulonephritis MORPHOLOGY Dialysis Changes Uremic Complications Clinical Course Glomerular Lesions Associated With Systemic Disease SYSTEMIC LUPUS ERYTHEMATOSUS HENOCH-SCHONLEIN PURPURA MORPHOLOGY BACTERIAL ENDOCARDITIS DIABETIC GLOMERULOSCLEROSIS Pathogenesis MORPHOLOGY
Capillary Basement Membrane Thickening Diffuse Glomerulosclerosis Nodular Glomerulosclerosis Clinical Course AMYLOIDOSIS FIBRILLARY AND IMMUNOTACTOID GLOMERULONEPHRITIS OTHER SYSTEMIC DISORDERS Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
PATHOLOGY - Part 1 Renal diseases are responsible for a great deal of morbidity but, fortunately, are not major causes of mortality. To place the problem in some perspective, approximately 35,000 deaths are attributed yearly to renal disease in the United States, in contrast to about 750,000 to heart disease, 400,000 to cancer, and 200,000 to stroke. Morbidity, however, is by no means insignificant. Millions of persons are affected annually by nonfatal kidney diseases, most notably infections of the kidney or lower urinary tract, kidney stones, and urinary obstruction. Twenty per cent of all women suffer from infection of the urinary tract or kidney at some time in their lives, and at least 1% of the United States population develop renal stones. Similarly, dialysis and transplantation keep many patients alive who would formerly have died of renal failure, adding to the pool of renal morbidity. The cost of such programs now exceeds several billion dollars annually. Renal disease also has special importance to the clinician because so many of the deaths occur in young people. Diseases of the kidney are as complex as its structure, but their study is facilitated by dividing them into those that affect the four basic morphologic components: glomeruli, tubules, interstitium, and blood vessels. This traditional approach is useful, since the early manifestations of disease affecting each of these components tend to be distinct. Further, some components appear to be more vulnerable to specific forms of renal injury; for example, most glomerular diseases are immunologically mediated, whereas tubular and interstitial disorders are frequently caused by toxic or infectious agents. Nevertheless, some agents affect more than one structure. In addition, the anatomic interdependence of structure in the kidney implies that damage to one almost always secondarily affects the others. Disease primarily in the blood vessels, for example, inevitably affects all the structures dependent on this blood supply. Severe glomerular damage impairs the flow through the peritubular vascular system and also delivers potentially toxic products to tubules; conversely, tubular destruction, by increasing intraglomerular pressure, may induce glomerular atrophy. Thus, whatever the origin, there is a tendency for all forms of chronic renal disease ultimately to destroy all four components of the kidney, culminating in chronic renal failure and what has been called end-stage kidneys. The functional reserve of the kidney is large, and much damage may occur before there is evident functional impairment. For these reasons, the early signs and symptoms are particularly important clinically. In this chapter, we briefly review the clinical manifestations, pathogenesis, and pathology of the major renal diseases. These are dealt with in great detail in two comprehensive texts of pathology [5] [6] and renal medicine [7] [8] and in electronic updates of nephrology. [9]
CLINICAL MANIFESTATIONS OF RENAL DISEASES The clinical manifestations of renal disease can be grouped into reasonably well defined syndromes. Some are peculiar to glomerular diseases; others are present in diseases that affect any one of the components. Before we list the syndromes, a few terms must be clarified. Azotemia is a biochemical abnormality that refers to an elevation of the blood urea nitrogen (BUN) and creatinine levels and is related largely to a decreased glomerular filtration rate (GFR). Azotemia is produced by many renal disorders, but it also arises from extrarenal disorders. Prerenal azotemia is encountered when there is hypoperfusion of the kidneys (e.g., in hemorrhage, shock, volume depletion, and congestive heart failure) that impairs renal function in the absence of parenchymal damage. Similarly, postrenal azotemia is seen whenever urine flow is obstructed below the level of the kidney. Relief of the obstruction is followed by correction of the azotemia. When azotemia becomes associated with a constellation of clinical signs and symptoms and biochemical abnormalities, it is termed uremia. Uremia is characterized not only by failure of renal excretory function but also by a host of metabolic and endocrine alterations incident to renal damage. There is, in addition, secondary gastrointestinal (e.g., uremic gastroenteritis), neuromuscular (e.g., peripheral neuropathy), and cardiovascular (e.g., uremic fibrinous pericarditis) involvement, which is usually necessary for the diagnosis of uremia. We can now turn to a brief description of the clinical presentations of renal disease, some of which cluster into relatively distinct syndromes. Acute nephritic syndrome is a glomerular syndrome dominated by the acute onset of usually grossly visible hematuria (red blood cells in urine), mild to moderate proteinuria, and hypertension; it is the classic presentation of acute poststreptococcal glomerulonephritis. The nephrotic syndrome is characterized by heavy proteinuria (more than 3.5 gm/day), hypoalbuminemia, severe edema, hyperlipidemia, and lipiduria (lipid in the urine). Asymptomatic hematuria or proteinuria, or a combination of these two, is usually a manifestation of subtle or mild glomerular abnormalities. Acute renal failure is dominated by oliguria or anuria (no urine flow), with recent onset of azotemia. It can result from glomerular (e.g., crescentic glomerulonephritis), interstitial, and vascular injury or acute tubular necrosis. Chronic renal failure, characterized by prolonged symptoms and signs of uremia, is the end result of all chronic renal diseases. Renal tubular defects are dominated by polyuria (excessive urine formation), nocturia, and electrolyte disorders
936
(e.g., metabolic acidosis). They are the result of either diseases directly affecting tubular structure (e.g., medullary cystic disease) or defects in specific tubular functions. The latter can be inherited (e.g., familial nephrogenic diabetes, cystinuria, renal tubular acidosis) or acquired (e.g., lead nephropathy). Urinary tract infection is characterized by bacteriuria and pyuria (bacteria and leukocytes in the urine). The infection may be symptomatic or asymptomatic, and it may affect the kidney (pyelonephritis) or the bladder (cystitis) only. Nephrolithiasis (renal stone) is manifested by renal colic, hematuria, and recurrent stone formation. Urinary tract obstruction and renal tumors represent specific anatomic lesions with often varied clinical manifestations. Renal Failure.
Acute renal failure implies a rapid and frequently reversible deterioration of renal function. As a characteristic syndrome with a complex pathogenesis, it is discussed separately. Here the discussion is limited to chronic renal failure, which is the end result of a variety of renal diseases and is the major cause of death from renal disease. Although exceptions abound, the evolution from normal renal function to symptomatic chronic renal failure progresses through four stages that merge into one another. TABLE 21-1 -- PRINCIPAL SYSTEMIC MANIFESTATIONS OF CHRONIC RENAL FAILURE AND UREMIA Fluid and Electrolytes Dehydration Edema Hyperkalemia Metabolic acidosis Calcium Phosphate and Bone Hyperphosphatemia Hypocalcemia Secondary hyperparathyroidism Renal osteodystrophy Hematologic Anemia Bleeding diathesis Cardiopulmonary
Hypertension Congestive heart failure Pulmonary edema Uremic pericarditis Gastrointestinal Nausea and vomiting Bleeding Esophagitis, gastritis, colitis Neuromuscular Myopathy Peripheral neuropathy Encephalopathy Dermatologic Sallow color Pruritus Dermatitis
Diminished Renal Reserve.
In this situation, the GFR is about 50% of normal. Serum BUN and creatinine values are normal, and the patients are asymptomatic. However, they are more susceptible to developing azotemia with an additional renal insult. Renal Insufficiency.
The GFR is 20% to 50% of normal. Azotemia appears, usually associated with anemia and hypertension. Polyuria and nocturia occur as a result of decreased concentrating ability. Sudden stress (e.g., with nephrotoxins) may precipitate uremia. Renal Failure.
The GFR is less than 20% to 25% of normal. The kidneys cannot regulate volume and solute composition, and patients develop edema, metabolic acidosis, and hypocalcemia. Overt uremia may ensue, with neurologic, gastrointestinal, and cardiovascular complications. End-Stage Renal Disease.
The GFR is less than 5% of normal; this is the terminal stage of uremia. The details of the pathophysiology of chronic renal failure are beyond the scope of this book and are well covered in various nephrology texts. [8] [9] Table 21-1 lists the major systemic abnormalities in uremic renal failure. CONGENITAL ANOMALIES About 10% of all persons are born with potentially significant malformations of the urinary system. Renal dysplasias and hypoplasias account for 20% of chronic renal failure in children. Polycystic kidney disease (a congenital anomaly that becomes apparent in adults) is responsible for about 10% of chronic renal failure in humans. Congenital renal disease can be hereditary but is most often the result of an acquired developmental defect that arises during gestation. As discussed in Chapter 11 , defects in developmental genes, including the Wilms' tumor (WT1)-associated genes, cause urogenital anomalies. As a rule, developmental abnormalities involve structural components of the kidney and urinary tract. However, enzymatic or metabolic defects in tubular transport, such as cystinuria and renal tubular acidosis, also occur. Here we restrict the discussion to structural anomalies involving primarily the kidney. Anomalies of the lower urinary tract are discussed in Chapter 22 . Agenesis of the Kidney.
Total bilateral agenesis, which is incompatible with life, is usually encountered in stillborn infants. It is often associated with many other congenital disorders (limb defects, hypoplastic lungs) and leads to early death. Unilateral agenesis is an uncommon anomaly that is compatible with normal life, if no other abnormalities exist. The opposite kidney is usually enlarged as a result of compensatory hypertrophy. Some patients eventually develop progressive glomerular sclerosis in the remaining kidney as a result of the adaptive changes in hypertrophied nephrons, discussed later in the chapter, and in time chronic renal failure. Hypoplasia.
Renal hypoplasia refers to failure of the kidneys to develop to a normal size. This anomaly may occur bilaterally, resulting in renal failure in early childhood, but it is more commonly encountered as a unilateral defect. True renal hypoplasia is extremely rare; most cases
937
reported probably represent acquired scarring due to vascular, infectious, or other parenchymal diseases rather than an underlying developmental failure. Differentiation
between congenital and acquired atrophic kidneys may be impossible, but a truly hypoplastic kidney should show no scars and should possess a reduced number of renal lobes and pyramids: six or fewer. In one form of hypoplastic kidney, oligomeganephronia, the kidney is small but the nephrons are markedly hypertrophied. Ectopic Kidneys.
The development of the definitive metanephros may occur in ectopic foci, usually at abnormally low levels. These kidneys lie either just above the pelvic brim or sometimes within the pelvis. They are usually normal or slightly smaller in size but otherwise are not remarkable. Because of their abnormal position, kinking or tortuosity of the ureters may cause some obstruction to urinary flow, which predisposes to bacterial infections. Horseshoe Kidney.
Fusion of the upper or lower poles of the kidneys produces a horseshoe-shaped structure continuous across the midline anterior to the great vessels. This anomaly is common and is found in about 1 in 500 to 1000 autopsies. Ninety per cent of such kidneys are fused at the lower pole, and 10% are fused at the upper pole. Cystic Diseases of the Kidney
Although not all cysts of the kidney are congenital, all types of cysts are discussed here for convenience. Cystic diseases of the kidney are a heterogeneous group comprising hereditary, developmental but nonhereditary, and acquired disorders. As a group, they are important for several reasons: (1) they are reasonably common and often represent diagnostic problems for clinicians, radiologists, and pathologists; (2) some forms, such as adult polycystic disease, are major causes of chronic renal failure; and (3) they can occasionally be confused with malignant tumors. A useful classification of renal cysts is as follows [10] : 1. Cystic renal dysplasia 2. Polycystic kidney disease a. Autosomal dominant (adult) polycystic diseaseb. b. Autosomal recessive (childhood) polycystic disease 3. Medullary cystic disease a. Medullary sponge kidney b. Nephronophthisis-uremic medullary cystic disease complex 4. Acquired (dialysis-associated) cystic disease 5. Localized (simple) renal cysts 6. Renal cysts in hereditary malformation syndromes (e.g., tuberous sclerosis) 7. Glomerulocystic disease 8. Extraparenchymal renal cysts (pyelocalyceal cysts, hilar lymphangitic cysts)
Only the more important of the cystic diseases are discussed. CYSTIC RENAL DYSPLASIA
This disorder is due to an abnormality in metanephric differentiation characterized histologically by the persistence in the kidney of abnormal structures-- cartilage, undifferentiated mesenchyme, and immature collecting ductules-- and by abnormal lobar organization. Most cases are also associated with ureteropelvic obstruction, ureteral agenesis or atresia, and other anomalies of the lower urinary tract. Renal dysplasia occurs as a sporadic disorder, without familial clustering. Dysplasia can be unilateral or bilateral and is almost always cystic. In gross appearance, the kidney is usually enlarged, extremely irregular, and multicystic (Fig. 21-5 A). The cysts vary in size from small microscopic structures to some that are several centimeters in diameter. They are lined by flattened epithelium. On histologic examination, although normal nephrons are present, many have immature ducts. The characteristic feature is the presence of islands of undifferentiated mesenchyme, often with cartilage, and immature collecting ducts (Fig. 21-5 B). When unilateral, the dysplasia is discovered by the appearance of a flank mass that leads to surgical exploration and nephrectomy. Function in the opposite kidney is normal, and such patients have an excellent prognosis after surgical removal of the affected kidney. In bilateral renal dysplasia, renal failure may ultimately result. AUTOSOMAL DOMINANT (ADULT) POLYCYSTIC KIDNEY DISEASE
Adult polycystic kidney disease is a hereditary disorder characterized by multiple expanding cysts of both kidneys that ultimately destroy the renal parenchyma and cause renal failure. [11] [12] It is a common condition affecting roughly 1 of every 400 to 1000 live births and accounting for about 10% of cases of chronic renal failure requiring transplantation or dialysis. The pattern of inheritance is autosomal dominant, with high penetrance. The disease is universally bilateral; reported unilateral cases probably represent multicystic dysplasia. The cysts initially involve only portions of the nephrons, so that renal function is retained until about the fourth or fifth decade of life. The likelihood of developing renal failure is less than 2% in affected individuals younger than 40 years but rises to 25% by age 50 years, 40% at age 60 years, and 75% by age 70 to 75 years. Although the major pathologic process is in the kidneys, adult polycystic kidney disease is a systemic disorder in which cysts and other anomalies also arise in other organs (see later). Genetics and Pathogenesis.
The disease is genetically heterogeneous, caused by mutations of three separate genes. The PKD1 gene, located on chromosome 16p13.3, accounts for about 85% of
cases and encodes a large (460 kD) protein named polycystin 1.[13] Polycystin is a complex cell membrane-associated protein with a long extracellular portion, a transmembrane domain, and a short cytoplasmic tail [13A ] (Fig. 21-6) . Although its precise 938
function is unknown, it has domains with homology to proteins involved in cell-cell and cell-matrix interactions, as well as specific repeated so-called polycystic kidney disease (PKD) domains that may assume an immunoglobulin-like fold (Fig. 21-6) . The PKD2 gene is on chromosome 4q13-23, and mutations in the gene are present in about 10% of families. The PKD2 gene product, polycystin 2, is an integral membrane protein with homologies to certain calcium and sodium channel proteins as well as to a portion of polycystin 1. [14] A PKD3 gene, responsible for a minority of cases, has yet to be mapped.
Figure 21-5 Renal dysplasia. A , Gross appearance, B , Histologic section showing disorganized architecture, dilated tubules, and islands of immature cartilage, PAS stain. (Courtesy of Dr. D. Schofield, Children's Hospital, Los Angeles, CA.)
Figure 21-6 A schematic of human polycystin molecule, with various domains drawn approximately to scale. The long extracellular
region consists primarily of the following domains: two leucine-rich repeats (LRRs); a C type lectin domain; a low-density lipoprotein (LDL-A) type module; 16 PKD repeats, each of which may assume an immunoglobulin-like fold; and an egg jelly type module (EJD). Eleven membrane-spanning segments are predicted, followed by a short cytoplasmic tail. (Courtesy of Dr. Amin Arnaout, Massachusetts General Hospital, Boston, MA.)
But how do defects in these proteins cause cyst formation, cyst expansion, and renal damage? Here speculations abound, since the normal function of the proteins is still unclear. Nevertheless, it is currently thought that the link may be in the role of the proteins in cell-cell matrix interactions important in tubular epithelial cell growth and differentiation. It has long been known that epithelial cells lining cysts have a high proliferation rate, and that the nonproliferating cells in cysts exhibit abnormally simplified structure, with a relatively immature phenotype. Cysts are frequently detached from adjacent tubules and enlarge by active fluid secretion from the lining epithelial cells. In addition, the extracellular matrix (ECM) produced by cyst-lining cells is abnormal. These findings have led to the hypothetical scenario (Fig. 21-7) that cysts develop as a result of an abnormality in cell differentiation, associated with sustained cellular proliferation, transepithelial fluid secretion, remodeling of the ECM, and cyst formation. [12] In addition, cyst fluids have been shown to harbor mediators derived from epithelial cells that enhance fluid secretion and induce inflammation. This could potentially result in further enlargement of cysts and the interstitial fibrosis characteristic of progressive polycystic kidney disease. [15]
The distribution of polycystin 1 in developing renal tubules in fetal life and the structural homologies of some of its domains (see Fig. 21-6) are consistent with a role in the cell-cell and cell-matrix interactions critical to cell growth and differentiation. Indeed, targeted PKD1 mutations in transgenic mice interfere with nephrogenesis and result in cyst formation. [16] Recent molecular analyses of PKD gene alleles in single cysts suggest that the PKD1
939
Figure 21-7 Possible mechanisms of cyst formation in polycystic kidney disease (see text).
gene serves a suppressor function--its loss leads to hyperplasia of epithelial cells. [17] Akin to tumor-suppressor genes (Chapter 8) , a second somatic mutation is necessary for full expression of the defect. This intriguing speculation is thought to explain the variable phenotypic expression and focal nature of the initial cyst formation. There is also some evidence that normal PKD1 and PKD2 gene products interact (bind together) along some of their domains, thus influencing each other's function, probably accounting for the similar phenotype in the disease induced by two different genes. [18] MORPHOLOGY.
In gross appearance, the kidneys are usually bilaterally enlarged and may achieve enormous sizes; weights up to 4 kg for each kidney have been reported. The external surface appears to be composed solely of a mass of cysts, up to 3 to 4 cm in diameter, with no intervening parenchyma (Fig. 21-8) . However, microscopic examination reveals functioning nephrons dispersed between the cysts. The cysts may be filled with a clear serous fluid or, more usually, with turbid, red to brown, sometimes hemorrhagic fluid. As these cysts enlarge, they may encroach on the calyces and pelvis to produce pressure defects. The cysts arise from the tubules throughout the nephron and therefore have variable lining epithelia. On occasion, papillary epithelial formations and polyps project into the lumen. Bowman capsules are occasionally involved in cyst formation, and glomerular tufts may be seen within the cystic space. Clinical Features.
Many of these patients remain asymptomatic until indications of renal insufficiency announce the presence of the underlying kidney disease. In others, hemorrhage or progressive dilation of cysts may produce pain. Excretion of blood clots causes renal colic. The larger masses usually apparent on abdominal palpation may induce a dragging sensation. The disease occasionally begins with the insidious onset of hematuria, followed by
Figure 21-8 A and B , Autosomal dominant adult polycystic kidney, viewed from external surface and bisected. The kidney is markedly enlarged with numerous dilated cysts. C, Autosomal recessive childhood polycystic kidney disease, showing smaller cysts and dilated channels at right angles to the cortical surface. D, Liver with cysts in adult PKD.
940
other features of progressive chronic renal disease, such as proteinuria (rarely more than 2 gm/day), polyuria, and hypertension. Families with PKD2 genotype tend to have an older age at onset and later development of renal failure. Progression is accelerated in blacks (largely correlated with sickle cell trait), in males compared with females, and in the presence of hypertension. Patients with polycystic kidney disease also tend to have extrarenal congenital anomalies [19] : about 40% have one to several cysts in the liver (polycystic liver disease) that are usually asymptomatic. The cysts are derived from biliary epithelium. Cysts occur much less frequently in the spleen, pancreas, and lungs. Intracranial berry aneurysms, presumably from altered expression of polycystin in vascular smooth muscle, arise in the circle of Willis, and subarachnoid hemorrhages from these [20] account for death in about 4% to 10% of patients with polycystic kidney disease. Mitral valve prolapse and other valvular anomalies occur in 20% to 25% of patients, but most are asymptomatic. The clinical diagnosis is made by radiologic imaging techniques. Computed tomographic scanning is highly sensitive and can detect cysts a few millimeters in diameter. Ultrasound examination is the least invasive and can confirm the diagnosis. This form of chronic renal failure is remarkable in that patients may survive for many years with azotemia slowly progressing to uremia. Dialysis prolongs life further. Ultimately, about 40% of adult patients die of coronary or hypertensive heart disease, 25% of infection, 15% of a ruptured berry aneurysm or hypertensive intracerebral hemorrhage, and the rest of other causes. AUTOSOMAL RECESSIVE (CHILDHOOD) POLYCYSTIC KIDNEY DISEASE
This rare developmental anomaly is genetically distinct from adult polycystic kidney disease, having an autosomal recessive type of inheritance. Perinatal, neonatal, infantile, and juvenile subcategories have been defined, depending on time of presentation and presence of associated hepatic lesions. The first two are most common; serious manifestations are usually present at birth, and the young infant may succumb rapidly to renal failure. MORPHOLOGY.
Kidneys are enlarged and have a smooth external appearance. On cut section,
numerous small cysts in the cortex and medulla give the kidney a spongelike appearance. Dilated elongated channels are present at right angles to the cortical surface, completely replacing the medulla and cortex (Fig. 21-8 C). On microscopic examination, there is saccular or, more commonly, cylindrical dilation of all collecting tubules. The cysts have a uniform lining of cuboidal cells, reflecting their origin from the collecting tubules. The disease is invariably bilateral. In almost all cases, there are multiple epithelium-lined cysts in the liver (Fig. 21-8 D) as well as proliferation of portal bile ducts. Patients who survive infancy (infantile and juvenile form) may develop a peculiar type of hepatic fibrosis characterized by bland periportal fibrosis and proliferation of well-differentiated biliary ductules, a condition now termed congenital hepatic fibrosis. In older children, the hepatic picture in fact predominates. Such patients may develop portal hypertension with splenomegaly. Curiously, congenital hepatic fibrosis sometimes occurs in the absence of polycystic kidneys and has been reported occasionally in the presence of adult polycystic kidney disease. CYSTIC DISEASES OF RENAL MEDULLA
The two major types of medullary cystic disease are medullary sponge kidney, a relatively common and usually innocuous structural change, and nephronophthisisuremic medullary cystic disease complex, almost always associated with renal dysfunction. Medullary Sponge Kidney
The term medullary sponge kidney should be restricted to lesions consisting of multiple cystic dilations of the collecting ducts in the medulla. The condition occurs in adults and is usually discovered radiographically, either as an incidental finding or sometimes in relation to secondary complications. The latter include calcifications within the dilated ducts, hematuria, infection, and urinary calculi. Renal function is usually normal. On gross inspection, the papillary ducts in the medulla are dilated, and small cysts may be present. The cysts are lined by cuboidal epithelium or occasionally by transitional epithelium. Unless there is superimposed pyelonephritis, cortical scarring is absent. The pathogenesis is unknown. Nephronophthisis-Uremic Medullary Cystic Disease Complex
This is a group of progressive renal disorders that usually have their onset in childhood. The common characteristic is the presence of a variable number of cysts in the medulla associated with significant cortical tubular atrophy and interstitial fibrosis. Although the presence of medullary cysts is important, the cortical tubulointerstitial damage is the cause of the eventual renal insufficiency, and some prefer the term hereditary tubulointerstitial nephritis for this group.[10] Four variants are recognized: (1) sporadic, nonfamilial (20%); (2) familial juvenile nephronophthisis, (FJN), inherited as an autosomal recessive disease; (3) renal-retinal dysplasia (15%), recessively inherited and associated with retinitis pigmentosa; and (4) adult-onset medullary cystic disease,
dominantly inherited (15%). As a group, this complex accounts for about 20% of cases of chronic renal failure in children and adolescents. Affected children present first with polyuria and polydipsia, which reflect a marked tubular defect in concentrating ability. Sodium wasting and tubular acidosis are also prominent, findings consistent with initial injury to the distal tubules and collecting ducts. The expected course is progression to terminal renal failure during a period of 5 to 10 years. Pathogenesis.
The gene for many of the FJN pedigrees, on 2q13, encodes a protein with an SH3 domain, probably
941
Figure 21-9 Uremic medullary cystic disease. Cut section of kidney showing cysts at the corticomedullary junction and in the medulla.
involved in protein-protein interactions and intracellular signaling. [21] MORPHOLOGY.
In gross appearance, the kidneys are small, have contracted granular surfaces, and show cysts in the medulla, most prominently at the corticomedullary junction (Fig. 21-9) . Small cysts are also seen in the cortices. The cysts are lined by flattened or cuboidal epithelium and are usually surrounded by either inflammatory cells or fibrous tissue. In the cortex, there is widespread atrophy and thickening of the basement membranes of proximal and distal tubules together with interstitial fibrosis. Some glomeruli may be hyalinized, but in general, glomerular structure is preserved. There are few specific clues to diagnosis, because the medullary cysts may be too small to be visualized radiographically. The disease should be strongly considered in children or adolescents with otherwise unexplained chronic renal failure, a positive family history, and chronic tubulointerstitial nephritis on biopsy. ACQUIRED (DIALYSIS-ASSOCIATED) CYSTIC DISEASE
The kidneys from patients with end-stage renal disease who have undergone prolonged dialysis sometimes exhibit numerous cortical and medullary cysts. The cysts measure 0.5 to 2 cm in diameter, contain clear fluid, are lined by either hyperplastic or flattened tubular epithelium, and often contain calcium oxalate crystals. They probably form as a result of obstruction of tubules by interstitial fibrosis or by oxalate crystals.
Most are asymptomatic, but sometimes the cysts bleed, causing hematuria. The most ominous complication is the development of renal cell carcinoma in the walls of these cysts, occurring in 7% of dialyzed patients observed for 10 years. TABLE 21-2 -- SUMMARY OF RENAL CYSTIC DISEASES Inheritance Pathologic Clinical Typical Features Features or Outcome Complications Adult polycystic kidney disease
Autosomal dominant
Large multicystic kidneys, liver cysts, berry aneurysms
Hematuria, flank pain, urinary tract infection, renal stones, hypertension
Childhood Autosomal polycystic kidney recessive disease
Enlarged, cystic kidneys at birth
Hepatic fibrosis Variable, death in infancy or childhood
Medullary sponge kidney
Medullary cysts on excretory urography
Hematuria, Benign urinary tract infection, recurrent renal stones
None
Chronic renal failure beginning at age 40-60 yr
Familial juvenile Autosomal nephronophthisis recessive
Corticomedullary Salt wasting, cysts, shrunken polyuria, kidneys growth retardation, anemia
Progressive renal failure beginning in childhood
Adult-onset medullary cystic disease
Autosomal dominant
Corticomedullary Salt wasting, cysts, shrunken polyuria kidneys
Chronic renal failure beginning in adulthood
Simple cysts
None
Single or multiple cysts in normal-sized kidneys
Microscopic hematuria
Benign
Acquired renal cystic disease
None
Cystic degeneration in end-stage kidney disease
Hemorrhage, erythrocytosis, neoplasia
Dependence on dialysis
Diagrammatic Representation
942
SIMPLE CYSTS
These occur as multiple or single, usually cortical cystic spaces that vary in diameter over wide limits. They are commonly 1 to 5 cm but may reach 10 cm or more in size. They are translucent, lined by a gray, glistening, smooth membrane, and filled with clear fluid. On microscopic examination, these membranes are composed of a single layer of cuboidal or flattened cuboidal epithelium, which in many instances may be completely atrophic. Simple cysts are common postmortem findings without clinical significance. On occasion, hemorrhage into them may cause sudden distention and pain, and calcification of the hemorrhage may give rise to bizarre radiographic shadows. The main importance of cysts lies in their differentiation from kidney tumors, when they are discovered either incidentally or because of hemorrhage and pain during life. Radiologic studies show that in contrast to renal tumors, renal cysts have smooth contours, are almost always avascular, and give fluid rather than solid signals on ultrasonography. Table 21-2 summarizes the characteristic features of the principal renal cystic diseases. GLOMERULAR DISEASES Glomerular diseases constitute some of the major problems in nephrology; indeed, chronic glomerulonephritis is one of the most common causes of chronic renal failure in humans. Glomeruli may be injured by a variety of factors and in the course of a number of systemic diseases. Immunologic diseases such as systemic lupus erythematosus (SLE), vascular disorders such as hypertension and polyarteritis nodosa, metabolic diseases such as diabetes mellitus, and some purely hereditary conditions such as Fabry disease often affect the glomerulus. These are termed secondary glomerular diseases to differentiate them from those in which the kidney is the only or predominant organ involved. The latter constitute the various types of primary glomerulonephritis or, because some do not have a cellular inflammatory component, glomerulopathy. However, both the clinical manifestations and glomerular histologic changes in primary and secondary forms can be similar. Here we discuss the various types of primary glomerulonephritis and briefly review the secondary forms covered in other parts of this book. Table 21-3 lists the most common forms of glomerulonephritis that have reasonably well defined morphologic and clinical characteristics. In reviewing the specific types of glomerulonephritis, it is useful to consider each in terms of (1) clinical presentation, (2) the morphology of the glomerular lesion, and (3) the cause and pathogenesis. Clinical Manifestations
The clinical manifestations of glomerular disease are clustered into the five major glomerular syndromes described TABLE 21-3 -- GLOMERULAR DISEASES Primary Glomerulopathies Acute diffuse proliferative glomerulonephritis Poststreptococcal Non-poststreptococcal Rapidly progressive (crescentic) glomerulonephritis Membranous glomerulopathy Lipoid nephrosis (minimal change disease) Focal segmental glomerulosclerosis Membranoproliferative glomerulonephritis IgA nephropathy Focal proliferative glomerulonephritis Chronic glomerulonephritis Systemic Diseases Systemic lupus erythematosus Diabetes mellitus Amyloidosis Goodpasture syndrome Polyarteritis nodosa Wegener granulomatosis Henoch-Schonlein purpura Bacterial endocarditis Hereditary Disorders Alport syndrome Thin membrane disease Fabry disease earlier and summarized in Table 21-4 . Both the primary glomerulonephritides and the systemic diseases affecting the glomerulus can result in these syndromes. Thus, a critical point in the clinical differential diagnosis is first to exclude the major systemic disorders, of which the major four are diabetes mellitus, SLE, vasculitis, and amyloidosis.
Histologic Alterations
Various types of glomerulonephritis are characterized by one or more of four basic tissue reactions. Hypercellularity.
So-called inflammatory diseases of the glomerulus are associated with an increase in the number of cells in the glomerular tufts. This hypercellularity is associated with one or combinations of three of the following: TABLE 21-4 -- THE GLOMERULAR SYNDROMES Acute nephritic syndrome Hematuria, azotemia, variable proteinuria, oliguria, edema, and hypertension Rapidly progressive glomerulonephritis Nephrotic syndrome Chronic renal failure Asymptomatic hematuria or proteinuria
Acute nephritis, proteinuria, and acute renal failure >3.5 gm proteinuria, hypoalbuminemia, hyperlipidemia, lipiduria Azotemia
uremia progressing for years
Glomerular hematuria; subnephrotic proteinuria
943
Cellular proliferation of mesangial, endothelial, or, in certain cases, parietal epithelial cells Leukocytic infiltration, consisting of neutrophils, monocytes, and, in some diseases, lymphocytes Formation of crescents. These are accumulations of cells composed of proliferating epithelial cells and infiltrating leukocytes. Basement Membrane Thickening.
By light microscopy, this change appears as thickening of the capillary walls, best seen in sections stained with periodic acid-Schiff (PAS). On electron microscopy, such thickening can be resolved as either (1) thickening of the basement membrane proper, as occurs in diabetic glomerulosclerosis, or more commonly (2) deposition of amorphous electron-dense material representing precipitated proteins on the endothelial or epithelial side of the basement membrane or within the GBM itself. The most common type of thickening is due to extensive subepithelial deposition, as occurs in membranous glomerulonephritis, discussed later. In most instances, the material is
thought to be immune complexes, although fibrin, amyloid, cryoglobulins, and abnormal fibrillary proteins may also deposit in the GBM. Hyalinization and Sclerosis.
Hyalinization or hyalinosis, as applied to the glomerulus, denotes the accumulation of material that is homogeneous and eosinophilic by light microscopy. By electron microscopy, the hyalin is extracellular and consists of amorphous substance, made up of precipitated plasma protein as well as increased amounts of basement membrane or mesangial matrix. This change results in obliteration of structural detail of the glomerular tuft (sclerosis) and usually denotes the end result of various forms of glomerular damage. Additional alterations include intraglomerular thrombosis, fibrin deposition, or accumulation of lipid and other metabolic materials. Because many of the primary glomerulonephritides are of unknown cause, they are often classified by their histology, as can be seen in Table 21-3 . The histologic changes can be further subdivided into diffuse, involving all glomeruli; global, involving the entire glomerulus; focal, involving only a certain proportion of the glomeruli; segmental, affecting a part of each glomerulus; and mesangial, affecting predominantly the mesangial region. These terms are sometimes appended to the histologic classifications. Pathogenesis of Glomerular Injury
Although we know little of etiologic agents or triggering events, it is clear that immune mechanisms underlie most cases of primary glomerulonephritis and many of the secondary glomerular involvements [22] [23] (Table 21-5) . Glomerulonephritis can be readily induced experimentally by antigen-antibody reactions, and glomerular deposits of immunoglobulins, often with various components of complement, are found in more than 70% of patients with glomerulonephritis. Cell-mediated immune reactions also clearly play a role, usually in concert with antibody-mediated TABLE 21-5 -- IMMUNE MECHANISMS OF GLOMERULAR INJURY Antibody-Mediated Injury In situ immune complex deposition Fixed intrinsic tissue antigens Goodpasture antigen (anti-GBM nephritis) Heymann antigen (membranous glomerulonephritis) Mesangial antigens Others Planted antigens Exogenous (infectious agents, drugs) Endogenous (DNA, immunoglobulins, immune complexes, IgA)
Circulating immune complex deposition Endogenous antigens (e.g., DNA, tumor antigens) Exogenous antigens (e.g., infectious products) Cytotoxic antibodies Cell-Mediated Immune Injury Activation of Alternative Complement Pathway events. We therefore begin this discussion with a review of antibody-instigated injury. Two forms of antibody-associated injury have been established: (1) injury by antibodies reacting in situ within the glomerulus, either with insoluble fixed (intrinsic) glomerular antigens or with molecules planted within the glomerulus, and (2) injury resulting from deposition of soluble circulating antigen-antibody complexes in the glomerulus. In addition, there is experimental evidence that cytotoxic antibodies directed against glomerular cell components may cause glomerular injury. These pathways are not mutually exclusive, and in humans all may contribute to injury. IN SITU IMMUNE COMPLEX DEPOSITION
In this form of injury, antibodies react directly with intrinsic tissue antigen, or antigens "planted" in the glomerulus from the circulation. There are two well-established experimental models for anti-tissue-mediated glomerular injury, for which there are counterparts in human disease: anti-glomerular basement membrane (anti-GBM) and Heymann nephritis. Anti-GBM Nephritis
In this type of injury, antibodies are directed against intrinsic fixed antigens that are normal components of the GBM proper. It has its experimental counterpart in so-called Masugi or nephrotoxic nephritis, produced in rats by injections of anti-rat kidney antibodies prepared in rabbits by immunization with rat kidney tissue. The injected antibodies bind along the entire length of the GBM, resulting in a homogeneous, diffuse linear pattern of staining for the antibodies by immunofluorescent techniques (Fig. 21-10 B and E). This is contrasted with the granular lumpy pattern seen in other in situ models or after deposition of circulating immune complexes. In the Masugi model, the deposited immunoglobulin of the rabbit is foreign to the host and thus acts as an antigen eliciting antibodies in the rat. This rat antibody then reacts
944
Figure 21-10 Antibody-mediated glomerular injury can result either from the deposition of circulating immune complexes ( A ) or more commonly from in situ formation of complexes exemplified by anti-GBM disease ( B ) or Heymann nephritis ( C). D and E , Two patterns of deposition of immune complexes as seen by immunofluorescence microscopy: D, granular, characteristic of circulating and in situ immune complex nephritis; E , linear, characteristic of classic anti-GBM disease.
945
with the rabbit immunoglobulin within the basement membrane, leading to further glomerular injury. This is referred to as the autologous phase of nephrotoxic nephritis, to distinguish it from the initial heterologous phase caused by the anti-GBM antibody. Often the anti-GBM antibodies cross-react with other basement membranes, especially those in the lung alveoli, resulting in simultaneous lung and kidney lesions (Goodpasture syndrome). The GBM antigen responsible for classic anti-GBM nephritis and Goodpasture syndrome is a component of the noncollagenous domain (NC1) of the alpha3 chain of collagen type IV, which, as discussed earlier (see Fig. 21-3) , is critical for maintenance of GBM superstructure. [3] Anti-GBM nephritis accounts for less than 5% of cases of human glomerulonephritis. It is solidly established as the cause of injury in Goodpasture syndrome, discussed later. Most instances of anti-GBM nephritis are characterized by severe glomerular damage and the development of rapidly progressive renal failure. Heymann Nephritis
The Heymann model of rat glomerulonephritis is induced by immunizing animals with an antigen originally made up of preparations of proximal tubular brush border (Fig. 21-10 C). The rats develop antibodies to this antigen, and a membranous glomerulonephritis, resembling human membranous glomerulonephritis, develops (discussed later; see also Fig. 21-19) . On electron microscopy, the nephritis is characterized by the presence of numerous electron-dense deposits (made up largely of immune reactants) along the subepithelial aspect of the basement membrane. The pattern of immune deposition by fluorescence microscopy is granular and interrupted, rather than linear (Fig. 21-10) . It is now clear that this type of nephritis results largely from the reaction of antibody with an antigen complex located on the basal surface of visceral epithelial cells and cross-reacting with the brush border antigen used in the original experiments. This so-called Heymann antigen is a large 330-kD protein called megalin, having homology to the low-density lipoprotein receptor (Chapter 6) , complexed to a smaller 44-kD protein, called receptor-associated protein (RAP). Antibody binding to cell membrane is followed by complement activation and then by patching, capping, and subsequent shedding of the immune aggregates from the cell surface to form the characteristic subepithelial deposits (Fig. 21-10 C). Heymann nephritis most closely resembles human membranous glomerulonephritis, in which the epithelial cell antigen appears to be a homolog of the megalin complex. It must be apparent that, in humans, anti-GBM disease and membranous
glomerulonephritis are autoimmune diseases, caused by antibodies to endogenous tissue components. What triggers these autoantibodies is unclear, but any one of the several mechanisms responsible for autoimmunity, discussed in Chapter 7 , may be involved. Several forms of autoimmune glomerulonephritis can be experimentally induced by drugs (e.g., mercuric chloride), infectious products (endotoxin), and the graft-versus-host reaction (Chapter 7) . In such models, there is an induced alteration of immune regulation associated with polyclonal B-cell activation and the induction of an array of autoantibodies that react with renal antigens. Antibodies Against Planted Antigens
Antibodies can react in situ with previously "planted" nonglomerular antigens. Such antigens may localize in the kidney by interacting with various intrinsic components of the glomerulus. There is increasing experimental support for such a mechanism. Planted antigens include cationic molecules that bind to glomerular capillary anionic sites; DNA, which has an affinity for GBM components; bacterial products; large aggregated proteins (e.g., aggregated immunoglobulin [Ig] G), which deposit in the mesangium because of their size; and immune complexes themselves, since they continue to have reactive sites for further interactions with free antibody, free antigen, or complement. There is no dearth of other possible planted antigens, including viral, bacterial, and parasitic products and drugs. Most of these planted antigens induce a granular or heterogeneous pattern of immunoglobulin deposition by fluorescence microscopy, the pattern found also in circulating immune complex nephritis, discussed next. CIRCULATING IMMUNE COMPLEX NEPHRITIS
In this type of nephritis, glomerular injury is caused by the trapping of circulating antigen-antibody complexes within glomeruli. The antibodies have no immunologic specificity for glomerular constituents, and the complexes localize within the glomeruli because of their physicochemical properties and the hemodynamic factors peculiar to the glomerulus (Fig. 21-10 A). The pathogenesis of immune complex diseases (type III hypersensitivity reactions) is discussed in Chapter 7 . Here we briefly review the salient features that relate to glomerular injury. The evocative antigens may be of endogenous origin, as in the case of the glomerulopathy associated with SLE, or they may be exogenous, as is likely in the glomerulonephritis that follows certain infections. Antigens implicated include bacterial products (streptococci), the surface antigen of hepatitis B virus (HBsAg), hepatitis C virus antigen or RNA, various tumor antigens, Treponema pallidum, Plasmodium falciparum, and several viruses. The inciting antigen is frequently unknown. Whatever the antigen may be, antigen-antibody complexes are formed in the circulation and then trapped in the glomeruli, where they produce injury, in large part through the binding of complement. The glomerular lesions usually consist of leukocytic infiltration in
glomeruli and proliferation of mesangial and endothelial cells. Electron microscopy reveals the immune complexes as electron-dense deposits or clumps that lie in the mesangium, or between the endothelial cells and the GBM (subendothelial deposits), or rarely between the outer surface of the GBM and the podocytes (subepithelial deposits). Deposits may be located at more than one site in a given case. By immunofluorescence microscopy, the immune complexes are seen as granular deposits either along the basement membrane or in the
946
mesangium, or in both locations. Once deposited in the kidney, immune complexes may eventually be degraded, mostly by phagocytic infiltrating monocytes and by mesangial cells, and the inflammatory changes may then subside. Such a course occurs when the exposure to the inciting antigen is short-lived and limited, as in most cases of poststreptococcal glomerulonephritis. However, if a continuous shower of antigens is provided, as may be seen in SLE or viral hepatitis B and C, repeated cycles of immune complex formation, deposition, and injury may occur, leading to a more chronic membranoproliferative type of glomerulonephritis. Several factors affect glomerular localization of antigen, antibody, or complexes. The molecular charge and size of these reactants are clearly important. Highly cationic immunogens tend to cross the GBM, and the resultant complexes eventually achieve a subepithelial location. Highly anionic macromolecules are excluded from the GBM and either are trapped subendothelially or may, in fact, not be nephritogenic at all. Molecules with more neutral charge and their complexes tend to accumulate in the mesangium. Large circulating complexes are not usually nephritogenic because they are cleared by the mononuclear-phagocyte system and do not enter the GBM in sufficient quantities. The pattern of localization is also affected by changes in glomerular hemodynamics, mesangial function, and integrity of the charge-selective barrier in the glomerulus. These influences may underlie the variable pattern of immune reactant deposition and histologic change in various forms of glomerulonephritis, as shown in Figure 21-11 (Figure Not Available) . ANTIBODIES TO GLOMERULAR CELLS
In addition to causing immune deposits, antibodies directed to glomerular cell antigens may react with cellular components and cause injury by cytotoxic or other mechanisms. Antibodies to mesangial cell antigens, for example, cause mesangiolysis followed by mesangial cell proliferation; antibodies to endothelial cell antigens cause endothelial injury and intravascular thrombosis; and antibodies to certain visceral epithelial cell glycoproteins cause proteinuria in experimental animals. This mechanism may well play a role in certain human immune disorders not associated with demonstrable immune deposits. To conclude the discussion of antibody-mediated injury, it must be stated that in the largest proportion of cases of human glomerulonephritis, the pattern of immune deposition is granular and along the basement membrane or in the mesangium.
However, it may be difficult to determine whether the deposition has occurred in situ or by circulating complexes, or by both mechanisms--because, as discussed earlier, immune complex trapping can initiate in situ formation. Single etiologic agents, such as hepatitis B and C viruses, can cause either a membranous pattern of glomerulonephritis, suggesting in situ deposition, or a membranoproliferative pattern, more indicative of circulating complexes. It is best then to consider that antigen-antibody deposition in the glomerulus is a major pathway of glomerular injury and that in situ immune reactions, trapping of Figure 21-11 (Figure Not Available) Localization of immune complexes in the glomerulus: (1) subepithelial humps, as in acute
glomerulonephritis; (2) epimembranous deposits, as in membranous and Heymann glomerulonephritis; (3) subendothelial deposits, as in systemic lupus erythematosus and membranoproliferative glomerulonephritis; (4) mesangial deposits, as in IgA nephropathy; (5) basement membrane. LRE, lamina rara externa; LRI, lamina rara interna; LD, lamina densa; EP, epithelium; EN, endothelium; MC, mesangial cell; MM, mesangial matrix. (Modified from Couser WG: Mediation of immune glomerular injury. J Am Soc Nephrol 1:13, 1990.)
circulating complexes, interactions between these two events, and local hemodynamic and structural determinants in the glomerulus all contribute to the diverse morphologic and functional alterations in glomerulonephritis. CELL-MEDIATED IMMUNITY IN GLOMERULONEPHRITIS
Although antibody-mediated mechanisms may initiate many forms of glomerulonephritis, there is now considerable evidence that sensitized nephritogenic T cells, as a reflection of cell-mediated immune reactions, cause some forms of glomerular injury and are involved in the progression of many glomerulonephritides. [25] Clues to its occurrence include the presence of activated macrophages and T cells and their products in the glomerulus in some forms of human and experimental glomerulonephritis; in vitro and in vivo evidence of lymphocyte activation on exposure to antigen in human and experimental glomerulonephritis; abrogation of glomerular injury by lymphocyte depletion; and successful attempts in which glomerular histologic alterations are transferred by T cells in experimental glomerulonephritis. The evidence is most compelling for certain types of experimental crescentic glomerulonephritis in which antibodies to GBM may initiate or facilitate glomerular injury by subsets of activated lymphocytes. [26]
947
ACTIVATION OF ALTERNATIVE COMPLEMENT PATHWAY
Alternative complement pathway activation occurs in the clinicopathologic entity called membranoproliferative glomerulonephritis (MPGN type II), sometimes independently of immune complex deposition, and also in some forms of proliferative glomerulonephritis. This mechanism is discussed later in the discussion of MPGN. EPITHELIAL CELL INJURY
This can be induced by antibodies to visceral epithelial cell antigens; by toxins, as in an
experimental model of proteinuria induced by puromycin aminonucleoside; conceivably by certain cytokines; or by still poorly characterized factors, as in the case of human lipoid nephrosis and focal glomerulosclerosis, discussed later. Such injury is reflected by morphologic changes in the visceral epithelial cells, which include loss of foot processes, vacuolization, retraction, and detachment of cells from the GBM, and functionally by proteinuria. It is hypothesized that the detachment of visceral epithelial cells is caused by loss of adhesive interactions with the basement membrane and that this detachment leads to protein leakage (Fig. 21-12) (Figure Not Available) . MEDIATORS OF GLOMERULAR INJURY
Once immune reactants or sensitized T cells have localized in the glomerulus, how does the glomerular damage ensue? The mediators--both cells and molecules--are the usual suspects involved in acute and chronic inflammation, described in Chapter 3 , and only a few are highlighted [27] [28] (Fig. 21-13) (Figure Not Available) . Figure 21-12 (Figure Not Available) Epithelial cell injury. The postulated sequence is a consequence of antibodies against epithelial
cell antigens, or toxins, or cytokines or other factors causing injury and detachment of epithelial cells, and protein leakage through defective GBM and filtration slits. (Adapted from Couser WG: Mediation of immune glomerular injury. Am Soc Nephrol 1:13, 1990.) Figure 21-13 (Figure Not Available) Mediators of immune glomerular injury including cells and soluble mediators (see text).
Cells
Neutrophils infiltrate the glomerulus in certain types of glomerulonephritis, largely owing to activation of complement, resulting in generation of chemotactic agents (mainly C5a), but also by Fc-mediated immune adherence and by other mechanisms. Neutrophils release proteases, which cause GBM degradation; oxygen-derived free radicals, which cause cell damage; and arachidonic acid metabolites, which contribute to the reductions in GFR. Macrophages, lymphocytes, and NK cells, which infiltrate the glomerulus in antibody- and cell-mediated reactions, when activated release a vast number of biologically active molecules (described in Chapter 3) . Platelets aggregate in the glomerulus during immune-mediated injury. Their release of eicosanoids and growth factors may contribute to the manifestations of glomerulonephritis. Antiplatelet agents have beneficial effects in both human and experimental glomerulonephritis. Resident glomerular cells, particularly mesangial cells, can be stimulated to produce several inflammatory mediators, including oxygen free radicals, cytokines, growth factors, eicosanoids, nitric oxide, and endothelin. In the absence of leukocytic infiltration, they may initiate inflammatory responses in the glomerulus. Soluble Mediators
Virtually all the inflammatory chemical mediators have been implicated in glomerular injury. The chemotactic complement components induce leukocyte influx
(complement-neutrophil-dependent injury) and C5b-C9, the lytic component. C5b-C9 causes cell lysis but in addition stimulates mesangial cells to produce oxidants, proteases, and other mediators. Thus, even in the absence of neutrophils, C5b-C9 can cause proteinuria, as has been postulated in membranous glomerulonephritis. 948
Eicosanoids, nitric oxide, and endothelin are involved in the hemodynamic changes. Cytokines, particularly interleukin-1 and tumor necrosis factor, induce leukocyte adhesion and a variety of other effects. Chemokines such as monocyte chemoattractant protein 1 (MCP-1) and RANTES promote monocytes and lymphocyte influx. Of the growth factors, platelet-derived growth factor is involved in mesangial cell proliferation, [22] and transforming growth factor (TGF)-beta appears to be critical in the ECM deposition and hyalinization leading to glomerulosclerosis in chronic injury. [29] The coagulation system is also a mediator of glomerular damage. Fibrin is frequently present in the glomeruli in glomerulonephritis, and fibrinogen may leak into Bowman space, serving as a stimulus to cell proliferation. Fibrin deposition is mediated largely by stimulation of macrophage procoagulant activity. Mechanisms of Progression in Glomerular Diseases
Thus far we have discussed the immunologic mechanisms and mediators that initiate glomerular injury. The outcome of such injury depends on several factors, including the initial severity of renal damage, the nature and persistence of the antigens, the immune status of the host, and a variety of other factors. But it has long been known that once any renal disease, glomerular or otherwise, destroys functioning nephrons and reduces the GFR to about 30% to 50% of normal, progression to end-stage renal failure proceeds at a relatively constant rate, independent of the original stimulus or activity of the underlying disease. The secondary factors that lead to progression are of great clinical interest since they can be targets of therapy that delays the inexorable journey to dialysis or transplantation. The two major histologic characteristics of such progressive renal damage are focal segmental glomerulosclerosis and tubulointerstitial inflammation and fibrosis, and we discuss these separately. [30] [31] Focal Segmental Glomerulosclerosis.
Patients with this secondary change develop proteinuria, even if the primary disease was nonglomerular. The glomerulosclerosis appears to be initiated by the adaptive change that occurs in the relatively unaffected glomeruli of diseased kidneys. [32] Such a mechanism is suggested by experiments in rats subjected to ablation of renal mass by subtotal nephrectomy. Compensatory hypertrophy of the remaining glomeruli serves to maintain renal function in these animals, but proteinuria and glomerulosclerosis soon
develop, leading eventually to total glomerular sclerosis and uremia. The glomerular hypertrophy is associated with hemodynamic changes, including increases in single-nephron GFR, blood flow, and transcapillary pressure (capillary hypertension), and often with systemic hypertension. The sequence of events (Fig. 21-14) thought to lead to sclerosis in this setting entails endothelial and epithelial cell injury, increased glomerular
Figure 21-14 Renal ablation glomerulosclerosis. The adaptive changes in glomeruli (hypertrophy and glomerular capillary
hypertension), as well as systemic hypertension, cause epithelial and endothelial injury and resultant proteinuria. The mesangial response, involving mesangial cell proliferation and extracellular matrix (ECM) production together with intraglomerular coagulation, causes the glomerulosclerosis. This results in further loss of functioning nephrons and a vicious circle of progressive glomerulosclerosis.
permeability to proteins, accumulation of proteins in the mesangial matrix, and fibrin deposition. This is followed by proliferation of mesangial cells, infiltration by leukocytes, increased deposition of ECM, and sclerosis of glomeruli. This results in further reductions in nephron mass and a vicious circle of continuing glomerulosclerosis. Most of the mediators of chronic inflammation and fibrosis, and particularly TGF-beta, play a role in the induction of sclerosis. The role of this so-called renal ablation glomerulosclerosis in progression is supported by the protective effect of treatment with angiotensin-converting enzyme inhibitors, which reduces intraglomerular hypertension and actual progression in both animal and human studies. Tubulointerstitial Damage.
Tubulointerstitial injury, manifested by tubular damage and interstitial inflammation, is a component of many acute and chronic glomerulonephritides. In some instances, as in anti-GBM disease, the infiltrate may be related to cross-reacting antibodies with tubular basement membranes or to an interstitial delayed hypersensitivity reaction. But tubulointerstitial injury is also a cause of progression in nonimmune glomerular disease, for example, diabetic nephropathy. Indeed, there is often a much better correlation of decline in renal function with the extent of tubulointerstitial damage than with the severity of glomerular injury. Many factors may lead to such tubulointerstitial injury, including ischemia distal to sclerotic glomeruli, concomitant immune reactions to shared antigens, and phosphate or ammonia retention leading to interstitial fibrosis. However, current work points to the effects of proteinuria on tubular cell structure and function [30] [31 ] (Fig. 21-15) (Figure Not Available) . On the basis of in vitro and animal studies, proteinuria is thought to cause direct injury to and activation of tubular cells. Activated tubular cells in turn express adhesion molecules and elaborate proinflammatory cytokines and growth factors that contribute to interstitial fibrosis. Components of the filtered protein that produce these tubular effects include cytokines, complement products,
949
Figure 21-15 (Figure Not Available) Mechanisms of chronic tubulointerstitial injury in glomerulonephritis (see text). Various
components of the protein-rich filtrate and cytokines derived from leukocytes cause tubular cell activation and secretion of cytokines, growth factors, and other mediators. These, together with products of macrophages, incite interstitial inflammation and fibrosis. ET-1, endothelin-1; TIMP-1, tissue inhibitor of metalloproteinases. (Adapted and modified from references [ ] and [ ] ) 30
31
the iron in transferrin, immunoglobulins, and lipid moieties. Having discussed factors in the initiation and progression of glomerular injury, we now turn to a review of individual glomerular diseases. Acute Glomerulonephritis
This group of glomerular diseases is characterized anatomically by inflammatory alterations in the glomeruli and clinically by the syndrome of acute nephritis. The nephritic patient usually presents with hematuria, red cell casts in the urine, azotemia, oliguria, and mild to moderate hypertension. The patient also commonly has proteinuria and edema, but these are not as severe as those encountered in the nephrotic syndrome, discussed later. The acute nephritic syndrome may occur in such multisystem diseases as SLE and polyarteritis nodosa. Typically, however, it is characteristic of acute proliferative glomerulonephritis and is an important component of crescentic glomerulonephritis, which is described later. ACUTE PROLIFERATIVE (POSTSTREPTOCOCCAL, POSTINFECTIOUS) GLOMERULONEPHRITIS
As the name implies, this cluster of diseases is characterized histologically by diffuse proliferation of glomerular cells, associated with influx of leukocytes. These lesions are typically caused by immune complexes. The inciting antigen may be exogenous or endogenous. The prototype exogenous pattern is postinfectious glomerulonephritis, whereas that produced by an endogenous antigen is lupus erythematosus, described in Chapter 7 . The most common infections are streptococcal, but the disorder has also been associated with other infections (see later). Poststreptococcal Glomerulonephritis
This glomerular disease is decreasing in frequency in the United States but continues to be a fairly common disorder worldwide. [33] It usually appears 1 to 4 weeks after a streptococcal infection of the pharynx or skin (impetigo). It occurs most frequently in children 6 to 10 years of age, but adults of any age can be affected. Etiology and Pathogenesis.
Only certain strains of group A beta-hemolytic streptococci are nephritogenic, more than 90% of cases being traced to types 12, 4, and 1, which can be identified by typing of M protein of the cell wall. Skin infections are commonly associated with overcrowding and poor hygiene. Poststreptococcal glomerulonephritis is an immunologically mediated disease. The latent period between infection and onset of nephritis is compatible with the time
required for the building up of antibodies. Elevated titers to one or more of the streptococcal products are present in a great majority of patients. Serum complement levels are low, compatible with involvement of the complement system. The presence of granular immune deposits in the glomeruli suggests an immune complex-mediated mechanism, and so does the finding of electron-dense deposits. The streptococcal antigenic component responsible for the immune reaction has eluded identification for years. A cytoplasmic antigen called endostreptosin and several cationic antigens, including a proteinase related to the streptococcal erythrogenic toxin, are present in affected glomeruli, but whether these represent planted antigens or part of circulating immune complexes, or both, is unknown. GBM and immunoglobulins
950
altered by streptococcal enzymes have also been implicated as antigens at one time or another. MORPHOLOGY.
The classic diagnostic picture is one of enlarged, hypercellular glomeruli (Fig. 21-16) . The hypercellularity is caused by (1) infiltration by leukocytes, both neutrophils and monocytes, and (2) proliferation of endothelial and mesangial cells and, in many cases, epithelial cells. The proliferation and leukocyte infiltration are diffuse, that is, involving all lobules of all glomeruli. There is also swelling of endothelial cells, and the combination of proliferation, swelling, and leukocyte infiltration obliterates the capillary lumens. Small deposits of fibrin within capillary lumens and mesangium can be demonstrated in most cases. There may be interstitial edema and inflammation, and the tubules often contain red cell casts. By immunofluorescence microscopy, there are granular deposits of IgG, IgM, and C3 in the mesangium and along the basement membrane. Although universally present, they are often focal and sparse. The characteristic electron microscopic findings are the discrete, amorphous, electron-dense deposits on the epithelial side of the membrane, often having the appearance of "humps" (Fig. 21-16 B), presumably representing the antigen-antibody complexes at the epithelial cell surface. Subendothelial and intramembranous deposits are also seen, and there is often swelling of endothelial and mesangial cells. Clinical Course.
In the classic case, a young child abruptly develops malaise, fever, nausea, oliguria, and hematuria (smoky or cocoa-colored urine) 1 to 2 weeks after recovery from a sore throat. The patients exhibit red cell casts in the urine, mild proteinuria (usually less than 1 gm/day), periorbital edema, and mild to moderate hypertension. In adults, the onset is more likely to be atypical, with the sudden appearance of hypertension or edema, frequently with elevation of BUN. During epidemics caused by nephritogenic streptococcal infections, glomerulonephritis may be asymptomatic, discovered only on
screening for microscopic hematuria. Important laboratory findings include elevations of antistreptococcal antibody titers (anticationic proteinase and anti-DNase B), a decline in the serum concentration of C3, and the presence of cryoglobulins in the serum.
Figure 21-16 Acute proliferative glomerulonephritis. A , Normal glomerulus. B , Glomerular hypercellularity is due to intracapillary leukocytes and proliferation of intrinsic glomerular cells. C, Typical electron-dense subepithelial "hump" and a neutrophil in the lumen. (Courtesy of Dr. H. Rennke, Brigham and Women's Hospital, Boston, MA.)
951
More than 95% of affected children eventually recover totally with conservative therapy aimed at maintaining sodium and water balance. A small minority of children (perhaps less than 1%) do not improve, become severely oliguric, and develop a rapidly progressive form of glomerulonephritis (described later). Another 1% to 2% may undergo slow progression to chronic glomerulonephritis with or without recurrence of an active nephritic picture. Prolonged and persistent heavy proteinuria and abnormal GFR mark patients with an unfavorable prognosis. In adults, the disease is less benign. Although the overall prognosis in epidemics is good, in only about 60% of sporadic cases do the patients recover promptly. Some patients develop rapidly progressive glomerulonephritis. In the remainder, the glomerular lesions fail to resolve quickly, as manifested by persistent proteinuria, hematuria, and hypertension. In some of these patients, the lesions eventually clear totally, but others develop chronic glomerulonephritis. Nonstreptococcal Acute Glomerulonephritis
A similar form of glomerulonephritis occurs sporadically in association with other bacterial infections (e.g., staphylococcal endocarditis, pneumococcal pneumonia, and meningococcemia), viral disease (e.g., hepatitis B, hepatitis C, mumps, human immunodeficiency virus [HIV] infection, varicella, and infectious mononucleosis), and parasitic infections (malaria, toxoplasmosis). In all these, granular immunofluorescent deposits and subepithelial humps characteristic of immune complex nephritis are present. Rapidly Progressive (Crescentic) Glomerulonephritis
Rapidly progressive glomerulonephritis (RPGN) is a syndrome associated with severe glomerular injury and does not denote a specific etiologic form of glomerulonephritis. It is characterized clinically by rapid and progressive loss of renal function associated with severe oliguria and (if untreated) death from renal failure within weeks to months. Regardless of the cause, the histologic picture is characterized by the presence of crescents in most of the glomeruli (crescentic glomerulonephritis). These are produced in part by proliferation of the parietal epithelial cells and Bowman capsule and in part by
infiltration of monocytes and macrophages. Classification and Pathogenesis.
RPGN may be caused by a number of different diseases, some restricted to the kidney and others systemic. [34] Although no single mechanism can explain all cases, there is little doubt that in most cases the glomerular injury is immunologically mediated. Thus, a practical classification divides RPGN into three groups on the basis of immunologic findings (Table 21-6) . In each group, the disease may be associated with a known disorder or it may be idiopathic. Type I RPGN is best remembered as anti-GBM disease and hence is characterized by linear deposits of IgG and, in many cases, C3 in the GBM, as previously described. In some of these patients, the anti-GBM antibodies cross-react with pulmonary alveolar basement membranes to produce TABLE 21-6 -- RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (RPGN) TYPE 1 RPGN Idiopathic Goodpasture syndrome TYPE II RPGN (immune complex) Idiopathic Postinfectious Systemic lupus erythematosus Henoch-Schonlein purpura (IgA) Others TYPE III RPGN (pauci-immune) (ANCA associated) Idiopathic Wegener granulomatosis Microscopic polyarteritis nodosa the clinical picture of pulmonary hemorrhages associated with renal failure ( Goodpasture syndrome). The Goodpasture antigen, as noted, resides in the noncollagenous portion of the alpha3 chain of collagen type IV. What triggers the formation of these antibodies is unclear in most patients. Exposure to viruses or hydrocarbon solvents (found in paints and dyes) has been implicated in some patients, as have various drugs and cancers. Cigarette
smoking appears to play a permissive role, since most patients who develop pulmonary hemorrhage are smokers. There is a high prevalence of certain HLA subtypes and haplotypes (e.g., HLA-DRB1), a finding consistent with the genetic predisposition to autoimmunity. [34] Type II RPGN is an immune complex- mediated disease. It can be a complication of any of the immune complex nephritides, including postinfectious glomerulonephritis, SLE, IgA nephropathy, and Henoch-Schonlein purpura. In some cases, immune complexes can be demonstrated, but the underlying cause is undetermined. In all of these cases, immunofluorescence studies reveal the characteristic ("lumpy bumpy") granular pattern of staining. These patients cannot usually be helped by plasmapheresis, and they require treatment for the underlying disease. Type III RPGN, also called pauci-immune type, is defined by the lack of anti-GBM antibodies or immune complexes by immunofluorescence and electron microscopy. Most of these patients have antineutrophil cytoplasmic antibody (ANCA) in the serum, which, as we have seen (Chapter 12) , plays a role in some vasculitides. Hence, in some cases, type III RPGN is a component of a systemic vasculitis such as Wegener granulomatosis or microscopic polyarteritis. In many cases, however, pauci-immune crescentic glomerulonephritis is isolated and hence idiopathic. More than 90% of such idiopathic cases have C-ANCA or P-ANCA in the sera. To summarize, all three types of RPGN may be associated with a well-defined renal or extrarenal disease, but in many cases (approximately 50%) the disorder is idiopathic. Of the idiopathic cases, about one fourth have anti-GBM disease (RPGN type I) without lung involvement; another one fourth have type II RPGN; and the remainder are pauci-immune or type III RPGN. The common denominator in all types of RPGN is severe glomerular injury.
952
MORPHOLOGY.
The kidneys are enlarged and pale, often with petechial hemorrhages on the cortical surfaces. Depending on the underlying cause, the glomeruli may show focal necrosis, diffuse or focal endothelial proliferation, and mesangial proliferation. The histologic picture, however, is dominated by the formation of distinctive crescents (Fig. 21-17) . Crescents are formed by proliferation of parietal cells and by migration of monocytes and macrophages into Bowman space. Neutrophils and lymphocytes may be present. The crescents eventually obliterate Bowman space and compress the glomerular tuft. Fibrin strands are prominent between the cellular layers in the crescents, and indeed the escape of fibrin into Bowman space is an important contributor to crescent formation. Electron microscopy may, as expected, disclose subepithelial deposits in some cases but in all cases shows distinct ruptures in the GBM (Fig. 21-18) . In time, most crescents undergo sclerosis.
By immunofluorescence microscopy, postinfectious cases exhibit granular immune deposits; Goodpasture syndrome cases show linear fluorescence; and idiopathic cases may have granular, linear, or little deposition (pauci-immune). Clinical Course.
The renal manifestations of all forms include hematuria with red cell casts in the urine, moderate proteinuria occasionally reaching the nephrotic range, and variable hypertension and edema. In Goodpasture syndrome, the course may be dominated by recurrent hemoptysis or even life-threatening pulmonary hemorrhage. Serum analyses for anti-GBM, antinuclear antibodies, and ANCA are helpful in the diagnosis of specific subtypes. Although milder forms of glomerular injury may subside,
Figure 21-17 Crescentic glomerulonephritis (PAS stain). Note the collapsed glomerular tufts and the crescent-shaped mass of proliferating cells and leukocytes internal to Bowman capsule. (Courtesy of Dr. M.A. Venkatachalam, Department of Pathology, University of Texas Health Sciences Center, San Antonio, TX.)
Figure 21-18 Rapidly progressive glomerulonephritis. Electron micrograph showing characteristic wrinkling of GBM with focal disruptions in its continuity ( arrows).
the renal involvement is usually progressive during a matter of weeks, culminating in severe oliguria. Recovery of renal function may follow early intensive plasmapheresis (plasma exchange) combined with steroids and cytotoxic agents in Goodpasture syndrome. This therapy appears to reverse both pulmonary hemorrhage and renal failure. Other forms of RPGN also respond well to steroids and cytotoxic agents. Despite therapy, patients may eventually require chronic dialysis or transplantation. Nephrotic Syndrome
Certain glomerular diseases virtually always produce the nephrotic syndrome. In addition, many other forms of primary and secondary glomerulonephritis discussed in this chapter may evoke it. Before the major diseases associated with nephrotic syndrome are presented, the pathophysiology of this clinical complex is briefly discussed and the causes are listed. [35] Pathophysiology.
The manifestations of the nephrotic syndrome include 1. massive proteinuria, with the daily loss of 3.5 gm or more of protein (less in children); 2. hypoalbuminemia, with plasma albumin levels less than 3 gm/dl;
3. generalized edema; and 4. hyperlipidemia and lipiduria. The various components of nephrotic syndrome bear a logical relationship to one another. The initial event is a derangement in glomerular capillary walls resulting in increased permeability to the plasma proteins. It will be
953
remembered that the glomerular capillary wall, with its endothelium, GBM, and visceral epithelial cells, acts as a size and charge barrier through which the glomerular filtrate must pass. Increased permeability resulting from either structural or physicochemical alterations allows protein to escape from the plasma into the glomerular filtrate. Massive proteinuria results. The heavy proteinuria leads to depletion of serum albumin levels below the compensatory synthetic abilities of the liver, with consequent hypoalbuminemia and a reversed albumin-globulin ratio. Increased renal catabolism of filtered albumin also contributes to the hypoalbuminemia. The generalized edema is, in turn, the consequence of the loss of colloid osmotic pressure of the blood and the accumulation of fluid in the interstitial tissues. There is also sodium and water retention, which aggravates the edema (Chapter 5) . This appears to be due to several factors, including compensatory secretion of aldosterone, mediated by the hypovolemia-enhanced antidiuretic hormone secretion; stimulation of the sympathetic system; and a reduction in the secretion of natriuretic factors, such as atrial peptides. Edema is characteristically soft and pitting, most marked in the periorbital regions and dependent portions of the body. It may be massive with pleural effusions and ascites. The largest proportion of protein lost in the urine is albumin, but globulins are also excreted in some diseases. The ratio of low- to high-molecular-weight proteins in the urine in various cases of nephrotic syndrome determines the so-called selectivity of proteinuria. A highly selective proteinuria consists mostly of low-molecular-weight proteins (albumin 70,000; transferrin 76,000), whereas a poorly selective proteinuria consists of higher molecular weight globulins in addition to albumin. The genesis of the hyperlipidemia is complex. Most patients have increased cholesterol, triglyceride, very-low-density lipoprotein, low-density lipoprotein, Lp(a) lipoprotein, and apoprotein concentrations, and there is a decrease in high-density lipoprotein concentration in some patients. These defects seem to be due, in part, to increased synthesis of lipoproteins in the liver, abnormal transport of circulating lipid particles, and decreased catabolism. Lipiduria follows the hyperlipidemia, because not only albumin molecules but also lipoproteins leak across the glomerular capillary wall. The lipid appears in the urine either as free fat or as oval fat bodies, representing lipoprotein resorbed by tubular epithelial cells and then shed along with the degenerated cells. These patients are particularly vulnerable to infection, especially with staphylococci and pneumococci. The basis for this vulnerability could be related to loss of
immunoglobulins or low-molecular-weight complement components (e.g., factor B) in the urine. Thrombotic and thromboembolic complications are also common in nephrotic syndrome, owing in part to loss of anticoagulant factors (e.g., antithrombin III) and antiplasmin activity through the leaky glomerulus. Renal vein thrombosis, once thought to be a cause of nephrotic syndrome, is most often a consequence of this hypercoagulable state. Causes.
The relative frequencies of the several causes of the nephrotic syndrome vary according to age. In children younger than 15 years, for example, the nephrotic syndrome is almost always caused by a lesion primary to the kidney; whereas among adults, it may often be associated with a systemic disease. Table 21-7 represents a composite derived from several studies of the causes of the nephrotic syndrome and is therefore only approximate. As Table 21-7 indicates, the most frequent systemic causes of the nephrotic syndrome are SLE, diabetes, and amyloidosis. The most important of the primary glomerular lesions are lipoid nephrosis (minimal change disease), membranous glomerulonephritis, and focal segmental glomerulosclerosis. The first is most common in children, the second in adults, and focal segmental glomerulosclerosis occurs at all ages. [35] These three lesions, as well as a fourth less common disorder, membranoproliferative glomerulonephritis, are discussed individually in the following sections. The fifth possible primary cause, diffuse proliferative glomerulonephritis, frequently presents with the nephritic syndrome and was discussed earlier. Membranous Glomerulonephritis (Membranous Nephropathy)
Membranous glomerulonephritis is the most common cause of the nephrotic syndrome in adults. It is characterized by diffuse thickening of the glomerular capillary wall and the accumulation of electron-dense, immunoglobulin-containing deposits along the epithelial (subepithelial) side of the basement membrane.[36] Membranous glomerulonephritis occurring in association with other systemic diseases and a variety of identifiable etiologic agents is referred to as secondary membranous TABLE 21-7 -- CAUSES OF NEPHROTIC SYNDROME Prevalence (% ) Children Adults Primary Glomerular Disease Membranous glomerulonephritis
5
40
Lipoid nephrosis
65
15
Focal segmental glomerulosclerosis
10
15
Membranoproliferative glomerulonephritis
10
7
Other proliferative glomerulonephritis (focal, "pure mesangial," IgA nephropathy)
10
23
Systemic Diseases Diabetes mellitus Amyloidosis Systemic lupus erythematosus Drugs (gold, penicillamine, "street heroin") Infections (malaria, syphilis, hepatitis B, acquired immunodeficiency syndrome) Malignant disease (carcinoma, melanoma) Miscellaneous (bee-sting allergy, hereditary nephritis) *Approximate prevalence of primary disease = 95% in children, 60% in adults. Approximate prevalence of systemic disease = 5% in children, 40% in adults.
954
glomerulonephritis. The most notable such associations are as follows: Drugs (penicillamine, captopril, gold, nonsteroidal anti-inflammatory drugs [NSAIDs]): 1% to 7% of patients with rheumatoid arthritis treated with penicillamine or gold develop membranous glomerulonephritis. In a recent report, membranous glomerulonephritis was attributable to NSAIDs in 10% of patients. NSAIDs, as we shall see, also cause minimal change disease. Underlying malignant tumors, particularly carcinoma of the lung and colon and melanoma. These are present in 5% to 10% of adults with membranous glomerulonephritis. SLE. About 15% of glomerulonephritis in SLE is of the membranous type. Infections (chronic hepatitis B, hepatitis C, syphilis, schistosomiasis, malaria) Metabolic disorders (diabetes mellitus, thyroiditis) In about 85% of patients, no associated condition can be uncovered, and the disease is truly "idiopathic." Etiology and Pathogenesis.
Membranous glomerulonephritis is a form of chronic antigen-antibody-mediated disease. In secondary membranous glomerulonephritis, specific antigens can sometimes be implicated. For example, membranous glomerulonephritis in SLE is associated with deposition of autoantigen-antibody complexes. Exogenous (hepatitis B, Treponema antigens, insulin) or endogenous (thyroglobulin) antigens have been identified within deposits in some patients. The lesions bear a striking resemblance to those of experimental Heymann nephritis, which, as you may recall, is induced by antibodies to a megalin antigenic complex, and a similar antigen is present in humans. Susceptibility to Heymann nephritis in rats and
membranous glomerulonephritis in humans is linked to the HLA locus, which influences the ability to elaborate antibodies to the nephritogenic antigen. Thus, idiopathic membranous glomerulonephritis, like Heymann nephritis, is considered an autoimmune disease linked to susceptibility genes and caused by antibodies to a renal autoantigen. How does the glomerular capillary wall become leaky in membranous glomerulonephritis? With the paucity of neutrophils, monocytes, or platelets in glomeruli and the virtually uniform presence of complement, experimental work suggests a direct action of C5b-C9, the membrane attack complex of complement. C5b-C9 causes activation of glomerular epithelial and mesangial cells, inducing them to liberate proteases and oxidants, which cause capillary wall injury and increased protein leakage. MORPHOLOGY.
By light microscopy, the glomeruli either appear normal in the early stages of the disease or exhibit uniform, diffuse thickening of the glomerular capillary wall (Fig. 21-19 A). By electron microscopy, the apparent thickening is caused by irregular dense deposits between the basement membrane and the overlying epithelial cells, the latter having lost their foot processes (Fig. 21-19 B and D). Basement membrane material is laid down between these deposits, appearing as irregular spikes protruding from the GBM. These spikes are best seen by silver stains, which color the basement membrane black. In time, these spikes thicken to produce domelike protrusions and eventually close over the immune deposits, burying them within a markedly thickened, irregular membrane. Immunofluorescence microscopy demonstrates that the granular deposits contain both immunoglobulins and various amounts of complement (Fig. 21-19 C). As the disease advances, the membrane thickening progressively encroaches on the capillary lumens, and sclerosis of the mesangium may occur; in the course of time, glomeruli become totally hyalinized. The epithelial cells of the proximal tubules contain hyaline droplets, reflecting protein reabsorption, and there may be considerable mononuclear interstitial inflammation. Clinical Course.
In a previously healthy individual, this disorder usually begins with the insidious onset of the nephrotic syndrome or, in 15% of patients, with non-nephrotic proteinuria. Hematuria and mild hypertension are present in 15% to 35% of cases. It is necessary in any patient to first rule out the secondary causes described earlier, since treatment of the underlying condition (malignant neoplasm, infection, or SLE) or discontinuance of the offending drug may reverse progression. The course is irregular but generally indolent. In contrast to minimal change disease, described later, the proteinuria is nonselective and does not usually respond well to corticosteroid therapy. Progression is associated with increasing sclerosis of glomeruli, rising BUN, relative reduction in the severity of proteinuria, and development of hypertension. Although proteinuria persists in more than 60% of patients, only about 10% die or progress to renal failure within 10 years, and no more than 40% eventually develop renal insufficiency. Spontaneous remissions and a relatively benign outcome occur more commonly in women and in those with non-nephrotic range proteinuria and
mild glomerular changes on electron microscopy. Because of the notoriously variable course of the disease, it has been difficult to evaluate the overall effectiveness of corticosteroids or other immunosuppressive therapy in controlling the proteinuria or progression. Minimal Change Disease (Lipoid Nephrosis)
This relatively benign disorder is the most frequent cause of nephrotic syndrome in children. It is characterized by diffuse loss of foot processes of epithelial cells in glomeruli that appear virtually normal by light microscopy. The peak incidence is between 2 and 6 years of age. The
955
Figure 21-19 Membranous glomerulonephritis. A , PAS stain. Note marked diffuse thickening of the capillary wall without increase in the number of cells. B , Electron micrograph showing electron-dense deposits (arrow) along the epithelial side of the basement membrane (B). Note obliteration of foot process overlying deposits. CL, capillary lumen; End, endothelium; Ep, epithelium. C, Characteristic granular immunofluorescent deposits of IgG along GBM. D, Diagrammatic representation of membranous
glomerulonephritis.
disease sometimes follows a respiratory infection or routine prophylactic immunization. Its most characteristic feature is its usually dramatic response to corticosteroid therapy.[37] Etiology and Pathogenesis.
Although the absence of immune deposits in the glomerulus excludes classic immune complex mechanisms, several features of the disease point to an immunologic basis, [38] including (1) the clinical association with respiratory infections and prophylactic immunization; (2) the response to corticosteroid and immunosuppressive therapy; (3) the association with other atopic disorders (e.g., eczema, rhinitis); (4) the increased prevalence of certain HLA haplotypes in patients with minimal change disease associated with atopy (suggesting a possible genetic predisposition); (5) the increased incidence of minimal change disease in patients with Hodgkin disease, in whom defects in T cell-mediated immunity are well recognized; (6) the recurrence of proteinuria after transplantation in patients with the related disorder focal segmental
956
glomerulosclerosis, discussed later; and (7) reports of proteinuria-inducing factors in the plasma or lymphocyte supernatants of patients with lipoid nephrosis and focal glomerulosclerosis.
The current hypothesis is that lipoid nephrosis involves some immune dysfunction, eventually resulting in the elaboration of a cytokine-like circulating substance that affects visceral epithelial cells and causes proteinuria. The ultrastructural changes point to a primary visceral epithelial cell injury, and studies in animal models suggest the loss of glomerular polyanions; thus, defects in the charge barrier contribute to the proteinuria. Detachment of epithelial cells (see Fig. 21-12) (Figure Not Available) , a consequence of diminished adhesion to GBM, may also lead to protein loss. Recent clues might come from the discovery of mutations in a renal glomerular protein, termed nephrin, in a hereditary form of congenital nephrotic syndrome with minimal change morphology (Finnish type). This protein resembles immunoglobulin-like cell adhesion receptors that participate in cell-cell and cell-matrix interactions, [38A ] thus supporting a role for epithelial adhesion defects in this disease. MORPHOLOGY.
The glomeruli are normal by light microscopy (Fig. 21-20) . By electron microscopy, the basement membrane appears morphologically normal, and no electron-dense material is deposited. The principal lesion is in the visceral epithelial cells, which show a uniform and diffuse effacement of foot processes, these being replaced by a rim of cytoplasm often showing vacuolization, swelling, and villous hyperplasia (Fig. 21-21) . This change, often incorrectly termed "fusion" of foot processes, actually represents simplification of the epithelial cell architecture with flattening, retraction, and swelling of foot processes. Such foot process loss is also present in other proteinuric
Figure 21-20 Minimal change disease. Thin section of glomerulus stained with PAS. Note thin basement membrane and absence of proliferation. Compare with membranous glomerulonephritis in Figure 21-19 A .
states (e.g., membranous glomerulonephritis, diabetes). It is only when fusion is associated with normal glomeruli that the diagnosis of minimal change disease can be made. The visceral epithelial changes are completely reversible after corticosteroid therapy and remission of the proteinuria. The cells of the proximal tubules are often laden with lipid, reflecting tubular reabsorption of lipoproteins passing through diseased glomeruli (thus, the term lipoid nephrosis). Immunofluorescence studies show no immunoglobulin or complement deposits. Clinical Course.
Despite massive proteinuria, renal function remains good, and there is commonly no hypertension or hematuria. The proteinuria usually is highly selective, most of the protein consisting of albumin. Most children (more than 90%) with minimal change disease respond rapidly to corticosteroid therapy. However, the nephrotic phase may recur, and some patients may become "steroid dependent or resistant." Nevertheless, the long-term prognosis for patients is excellent, and even steroid-dependent disease resolves when children reach puberty. Although adults are slower to respond, the
long-term prognosis is also excellent. As noted, minimal change disease in adults can be associated with Hodgkin disease and, less frequently, other lymphomas and leukemias. In addition, secondary minimal change disease may follow NSAID therapy, usually in association with acute interstitial nephritis, to be described later in this chapter. Focal Segmental Glomerulosclerosis
As the name implies, this lesion is characterized by sclerosis of some, but not all, glomeruli (thus, it is focal); and in the affected glomeruli, only a portion of the capillary tuft is involved (thus, it is segmental). Focal segmental glomerulosclerosis is frequently accompanied clinically by the nephrotic syndrome or heavy proteinuria. Classification and Types.
Focal segmental glomerulosclerosis occurs in the following settings [39] : 1. in association with other known conditions, such as HIV infection and heroin addiction (HIV nephropathy, heroin addiction nephropathy), sickle cell disease, and massive obesity; 2. as a secondary event, reflecting glomerular scarring, in other forms of focal glomerulonephritis (e.g., IgA nephropathy); 3. as a component of the adaptive response in glomerular ablation nephropathy (described earlier) in advanced stages of other renal disorders such as reflux nephropathy, or with unilateral renal agenesis; 4. in certain inherited, congenital forms of nephrotic syndrome, where the disease, in certain pedigrees, has been linked to chromosome 19q13, [39] close to the locus of nephrin, described in the discussion of lipoid nephrosis; or 957
5. as a primary disease (idiopathic focal segmental glomerulosclerosis).
Figure 21-21 A , Ultrastructural characteristics of minimal change disease: loss of foot processes (double arrows) , absence of deposits, vacuoles (V), and microvilli in visceral epithelial cells (single arrow) . B , Schematic representation of minimal change disease, showing
diffuse loss of foot processes.
Idiopathic focal segmental glomerulosclerosis accounts for 10% and 15% of cases of nephrotic syndrome in children and adults, respectively. Patients differ from the usual patients with minimal change disease in the following respects: (1) they have a higher incidence of hematuria, reduced GFR, and hypertension; (2) their proteinuria is more often nonselective; (3) they respond poorly to corticosteroid therapy; (4) many progress to chronic glomerulonephritis, and at least 50% develop end-stage renal disease within 10 years; and (5) immunofluorescence microscopy shows deposition of IgM and C3 in
the sclerotic segment. MORPHOLOGY.
By light microscopy, the segmental lesions may involve only a minority of the glomeruli and may be missed if insufficient glomeruli are present in the biopsy specimen (Fig. 21-22 A). The lesions initially tend to involve the juxtamedullary glomeruli, although they subsequently become more generalized. In the sclerotic segments, there is collapse of basement membranes, increase in matrix, and deposition of hyaline masses (hyalinosis), often with lipoid droplets and foam cells (Fig. 21-22 B). Glomeruli not exhibiting segmental lesions either appear normal on light microscopy or may show increased mesangial
Figure 21-22 Focal segmental glomerulosclerosis. PAS stain. A , Low-power view showing segmental sclerosis in one of three glomeruli (at 3 o'clock). B , High-power view showing hyaline mass and lipid (small vacuoles) in sclerotic area.
958
matrix and mesangial proliferation. On electron microscopy, both sclerotic and nonsclerotic areas show the diffuse loss of foot processes characteristic of minimal change disease, but in addition there is pronounced, focal detachment of the epithelial cells with denudation of the underlying GBM. By immunofluorescence microscopy, IgM and C3 are present within the hyaline masses in the sclerotic areas. In addition to the focal sclerosis, there is often pronounced hyaline thickening of afferent arterioles. With the progression of the disease, increased numbers of glomeruli become involved, sclerosis spreads within each glomerulus, and there is an increase in mesangial matrix. In time this leads to total sclerosis of glomeruli, with pronounced tubular atrophy and interstitial fibrosis. A morphologic variant of focal segmental glomerulosclerosis, called collapsing focal segmental glomerulosclerosis, is characterized by collapse and sclerosis of the entire glomerular tuft in addition to the usual focal segmental glomerulosclerosis lesions. Although it may be seen in idiopathic focal segmental glomerulosclerosis, it is more characteristic of the form associated with HIV infection. It has a particularly poor prognosis. [40] Pathogenesis.
Whether idiopathic focal segmental glomerulosclerosis represents a distinct disease or is simply a phase in the evolution of a subset of patients with minimal change disease is a matter of conjecture, most workers favoring the latter explanation. The characteristic degeneration and focal disruption of visceral epithelial cells are thought to represent an accentuation of the diffuse epithelial cell change typical of minimal change disease. It is
this epithelial damage that is the hallmark of focal segmental glomerulosclerosis. The hyalinosis and sclerosis represent entrapment of plasma proteins in extremely hyperpermeable foci with increased ECM deposition. The recurrence of proteinuria, sometimes within 24 hours after transplantation, suggests a circulating factor, perhaps a cytokine, as the cause of the epithelial damage, and indeed a ±50-kD nonimmunoglobulin factor causing proteinuria has been isolated from sera of such patients. [41] Renal ablation focal segmental glomerulosclerosis occurs as a complication of glomerular and nonglomerular diseases causing reduction in functioning renal tissue, particularly reflux nephropathy and unilateral agenesis. These may lead to progressive glomerulosclerosis and renal failure. The pathogenesis of focal segmental glomerulosclerosis in this setting has been detailed earlier in this chapter, under Pathogenesis. Clinical Course.
There is little tendency for spontaneous remission in idiopathic focal segmental glomerulosclerosis, and responses to corticosteroid therapy are variable. In general, children have a better prognosis than that of adults. Progression of renal failure occurs at variable rates. About 20% of patients follow an unusually rapid course (malignant focal sclerosis), with intractable massive proteinuria ending in renal failure within 2 years. Recurrences are seen in 25% to 50% of patients receiving allografts. HIV-Associated Nephropathy.
HIV infection can result in a number of renal complications, including acute renal failure induced by drugs, shock, and infection; postinfectious glomerulonephritis; membranous glomerulonephritis associated with hepatitis B infection; MPGN due to hepatitis C infection; and most commonly a severe form of focal segmental glomerulosclerosis. [42] The last occurs in 5% to 10% of HIV-infected patients, more frequently in blacks than in whites, and the nephrotic syndrome may precede the development of acquired immunodeficiency syndrome. The glomerular lesions resemble idiopathic focal segmental glomerulosclerosis, but with the following additional features: A high frequency of the collapsing variant of focal segmental glomerulosclerosis, with global involvement of the tuft A striking focal cystic dilation of tubule segments, filled with proteinaceous material, inflammation, and fibrosis The presence of large numbers of tubuloreticular inclusions in endothelial cells. Such inclusions, also present in SLE, have been shown to be induced by circulating interferon-alpha. They are not present in idiopathic focal segmental glomerulosclerosis and thus may have diagnostic value in a biopsy specimen. The pathogenesis of HIV-related focal segmental glomerulosclerosis is unclear. It may be due to infection of glomerular cells by HIV, which has been shown in animal models,
and the local release of cytokines. [43] Membranoproliferative Glomerulonephritis
This group of disorders is characterized histologically by alterations in the basement membrane, proliferation of glomerular cells, and leukocyte infiltration.[44] Because the proliferation is predominantly in the mesangium, a frequently used synonym is mesangiocapillary glomerulonephritis. MPGN accounts for 5% to 10% of cases of idiopathic nephrotic syndrome in children and young adults. Some patients present only with hematuria or proteinuria in the non-nephrotic range, and others have a combined nephrotic-nephritic picture. Like many other glomerulonephritides, histologic MPGN either can be associated with other systemic disorders and known etiologic agents (secondary MPGN) or may be primary, without known cause (idiopathic) in the kidney. Primary MPGN is divided into two major types on the basis of distinct ultrastructural, immunofluorescent, and pathogenic findings: type I and type II MPGN. MORPHOLOGY.
By light microscopy, both types are similar. The glomeruli are large and hypercellular. The hypercellularity is produced by proliferation of cells in the mesangium, although infiltrating
959
leukocytes and parietal epithelial crescents are present in many cases. The glomeruli have a "lobular" appearance accentuated by the proliferating mesangial cells and increased mesangial matrix (Fig. 21-23) . The GBM is clearly thickened, often focally, most evident in the peripheral capillary loops. The glomerular capillary wall often shows a "double-contour" or "tram-track" appearance, especially evident in silver or PAS stains. This is caused by "duplication" of the basement membrane and the inclusion within the lamina rara interna of processes of cells extending into the peripheral capillary loops, so-called mesangial and monocyte interposition. Types I and II have altogether different ultrastructural and immunofluorescent features (Fig. 21-24) . Type I MPGN (two thirds of cases) is characterized by the presence of subendothelial electron-dense deposits. Mesangial and occasional subepithelial deposits may also be present (Fig. 21-24 A). By immunofluorescence, C3 is deposited in a granular pattern, and IgG and early complement components (C1q and C4) are often also present, suggesting an immune complex pathogenesis. In type II lesions, the lamina densa of the GBM is transformed into an irregular, ribbon-like, extremely electron-dense structure because of the deposition of dense
material of unknown composition in the GBM proper, giving rise to the term dense-deposit disease. In type II, C3 is present in irregular granular-linear foci in the basement membranes on either side, but not within the dense deposits. C3 is also present in the mesangium in characteristic circular aggregates (mesangial rings). IgG is usually absent, as are the
Figure 21-23 Membranoproliferative glomerulonephritis, showing mesangial cell proliferation, increased mesangial matrix, basement membrane thickening, and accentuation of lobular architecture. (Courtesy of Dr. H. Rennke, Brigham and Women's Hospital, Boston, MA.)
early-acting complement components (C1q and C4). Rare variants (type III) segregated because they exhibit both subendothelial and subepithelial deposits are associated with GBM disruption and reduplication. Pathogenesis.
Although there are exceptions, most cases of type I MPGN present evidence of immune complexes in the glomerulus and activation of both classic and alternative complement pathways. The antigens involved in idiopathic MPGN are unknown. Conversely, most patients with dense-deposit disease (type II) have abnormalities that suggest activation of the alternative complement pathway. These patients have a consistently decreased serum C3, but normal C1 and C4, the immune complex-activated early components of complement. They also have diminished serum levels of factor B and properdin, components of the alternative complement pathway. In the glomeruli, C3 and properdin are deposited, but not IgG. Recall that in the alternative complement pathway, C3 is directly cleaved to C3b (Fig. 21-25) . The reaction depends on the initial interaction of C3 with such substances as bacterial polysaccharides, endotoxin, aggregates of IgA in the presence of factors B and D, and magnesium. This leads to the generation of C3b,Bb, the alternative pathway C3 convertase. The alternative C3 convertase is labile, being degraded by factors I and H, but it can be stabilized by properdin. More than 70% of patients with dense-deposit disease have a circulating antibody termed C3 nephritic factor (C3NeF), which is a conformational autoantibody that binds to the alternative C3 convertase (Fig. 21-25) . Binding of the antibody stabilizes the convertase, protecting it from enzymatic degradation and thus favoring persistent C3 degradation and hypocomplementemia. There is also decreased C3 synthesis by the liver, further contributing to the profound hypocomplementemia. Precisely how C3NeF is related to glomerular injury and the nature of the dense deposits are unknown. C3NeF activity also occurs in some patients with a genetically determined disease, partial lipodystrophy, some of whom develop type II MPGN. Clinical Course.
The principal mode of presentation is the nephrotic syndrome occurring in older children or young adults, but usually with nephritic component manifested by hematuria or, more insidiously, as mild proteinuria. Few remissions occur spontaneously in either type, and the disease follows a slowly progressive but unremitting course. Some patients develop numerous crescents and a clinical picture of RPGN. About 50% develop chronic renal failure within 10 years. Treatments with steroids, immunosuppressive agents, and antiplatelet drugs have not been proved to be materially effective. There is a high incidence of recurrence in transplant recipients, particularly in type II disease; dense deposits may recur in 90% of such patients, although renal failure in the allograft is much less common. Secondary MPGN.
Secondary MPGN arises in the following settings [45] :
960
Figure 21-24 A , Membranoproliferative glomerulonephritis, type I. Note large subendothelial deposit (arrow) incorporated into mesangial matrix (M). E, endothelium; EP, epithelium; CL, capillary lumen. B , Type II membranoproliferative glomerulonephritis,
dense-deposit disease. There are markedly dense homogeneous deposits within the basement membrane proper. CL, capillary lumen. C, Schematic representation of patterns in the two types of membranoproliferative GN. In type I there are subendothelial deposits; type II is characterized by intramembranous dense deposits (dense deposit disease). In both, mesangial interposition gives the appearance of split basement membranes when viewed in the light microscope.
Chronic immune complex disorders, such as SLE; hepatitis B infection; hepatitis C infection, usually with cryoglobulinemia; endocarditis; infected ventriculoatrial shunts; chronic visceral abscesses; HIV infection; and schistosomiasis. Partial lipodystrophy associated with C3NeF (type 2) alpha1 -Antitrypsin deficiency Malignant diseases (chronic lymphocytic leukemia, lymphoma, melanoma) Hereditary complement deficiency states
961
Figure 21-25 The alternative complement pathway. Note that C3NeF, present in the serum of patients with membranoproliferative
glomerulonephritis, acts at the same step as properdin, serving to stabilize the alternative pathway C3 convertase, thus enhancing C3 breakdown and causing hypocomplementemia.
IgA Nephropathy (Berger Disease)
This form of glomerulonephritis is characterized by the presence of prominent IgA
deposits in the mesangial regions, detected by immunofluorescence microscopy.[46] The disease can be suspected by light microscopic examination, but diagnosis is made only by immunocytochemical techniques (Fig. 21-26) . IgA nephropathy is a frequent cause of recurrent gross or microscopic hematuria and is probably the most common type of glomerulonephritis worldwide. Mild proteinuria is usually present, and the nephrotic syndrome may occasionally develop. A patient may rarely present with rapidly progressive crescentic glomerulonephritis. Whereas IgA nephropathy is an isolated renal disease, similar IgA deposits are present in a systemic disorder of children, Henoch-Scho nlein purpura, to be discussed later, which has many overlapping features with IgA nephropathy. In addition, secondary IgA nephropathy occurs in patients with liver and intestinal diseases, as discussed under Pathogenesis. Pathogenesis.
IgA, the main immunoglobulin in mucosal secretions, is at low levels in normal serum, where it is present mostly in monomeric form, the polymeric forms being catabolized in the liver. In patients with IgA nephropathy, serum polymeric IgA is increased, and circulating IgA immune complexes are present in some patients. A genetic influence is suggested by the occurrence of this condition in families and in HLA-identical brothers and the increased frequency of certain HLA and complement phenotypes in some populations. The prominent mesangial deposition of IgA suggests entrapment of IgA immune complexes in the mesangium, and the absence of C1q and C4 in glomeruli points to activation of the alternative complement pathway. Taken together, these clues suggest a genetic or acquired abnormality of immune regulation leading to increased mucosal IgA synthesis in response to respiratory or gastrointestinal exposure to environmental agents (e.g., viruses, bacteria, food proteins). IgA1 and IgA1-containing complexes are then entrapped in the mesangium, where they activate the alternative complement pathway and initiate glomerular injury. In support of this scenario, IgA nephropathy occurs with increased frequency in patients with gluten enteropathy (celiac disease), in whom intestinal mucosal defects are well defined, and in liver disease, in which there is defective hepatobiliary clearance of IgA complexes (secondary IgA nephropathy). The nature of the antigens is unknown, and several infectious agents and food products have been implicated. The deposited IgA appears to be polyclonal, and it may be that a variety of antigens are involved in the course of the disease. Alternatively, it has been suggested that qualitative alterations in the IgA1 molecule itself make it more likely to bind to mesangial antigens, or that IgA antibodies react with mesangial cell autoantigens.
Figure 21-26 IgA nephropathy. A , Light microscopy showing mesangial proliferation and matrix increase. B , Characteristic
immunofluorescence deposition of IgA, principally in mesangial regions.
962
MORPHOLOGY.
On histologic examination, the lesions vary considerably. The glomeruli may be normal or may show mesangial widening and proliferation (mesangioproliferative), segmental proliferation confined to some glomeruli (focal proliferative glomerulonephritis), or rarely overt crescentic glomerulonephritis. Healing of the focal proliferative lesion may lead to focal segmental sclerosis. The characteristic immunofluorescent picture is of mesangial deposition of IgA (Fig. 21-26) , often with C3 and properdin and lesser amounts of IgG or IgM. Early complement components are usually absent. Electron microscopy confirms the presence of electron-dense deposits in the mesangium in most cases. In some biopsy specimens, prominent hyaline thickening of arterioles is present, a feature associated with a greater likelihood of hypertension and progression to chronic renal failure. Clinical Course.
The disease affects children and young adults. More than half the patients present with gross hematuria after an infection of the respiratory or, less commonly, gastrointestinal or urinary tract; 30% to 40% have only microscopic hematuria, with or without proteinuria, and 5% to 10% develop a typical acute nephritic syndrome. The hematuria typically lasts for several days and then subsides, only to return every few months. The subsequent course is highly variable. [47] Many patients maintain normal renal function for decades. Slow progression to chronic renal failure occurs in 25% to 50% of cases during a period of 20 years. Onset in old age, heavy proteinuria, hypertension, and the extent of glomerulosclerosis on biopsy are clues to an increased risk of progression. Recurrence of IgA deposits in transplanted kidneys occurs in 20% to 60% of grafts; the resulting disease most frequently runs the same indolent, slowly progressive course as that of the primary IgA nephropathy. [47] Focal Proliferative and Necrotizing Glomerulonephritis (Focal Glomerulonephritis)
Focal glomerulonephritis represents a histologic entity in which glomerular proliferation is restricted to segments of individual glomeruli and commonly involves only a certain proportion of glomeruli. The lesions are predominantly proliferative and should be differentiated from those of focal sclerosis. Focal necrosis and fibrin deposition within the lesions often occur (Fig. 21-27) . Focal glomerulonephritis occurs under three circumstances: 1. It may be an early or mild manifestation of a systemic disease that sometimes involves entire glomeruli; among these are SLE, polyarteritis nodosa, Henoch-Schonlein purpura, Goodpasture syndrome, subacute bacterial
endocarditis, and Wegener granulomatosis. 2. It may be a component of a known glomerular disease, such as IgA nephropathy, as discussed earlier. 3. It can occur unrelated to any systemic or other renal disease and constitutes a form of primary idiopathic focal glomerulonephritis. It is necessary to exclude all other systemic disorders and IgA nephropathy by clinical and laboratory studies. The clinical manifestations may be mild, characterized by recurrent microscopic or gross hematuria or non-nephrotic proteinuria, but occasional cases present with a nephrotic syndrome.
Figure 21-27 Focal glomerulonephritis in lupus erythematosus. There is segmental proliferation of cells and necrosis on the right. In
the necrotic area, there are neutrophils and fragmented nuclei (nuclear dust). The remainder of the glomerulus is not involved.
Hereditary Nephritis
Hereditary nephritis refers to a group of heterogeneous hereditary-familial renal diseases associated primarily with glomerular injury. Two deserve discussion: Alport syndrome, because the lesions and genetic defects have been most well studied [48] ; and thin membrane disease, the most common cause of benign familial hematuria. ALPORT SYNDROME
Alport syndrome is the name usually given to the disease in which nephritis is accompanied by nerve deafness and various eye disorders, including lens dislocation, posterior cataracts, and corneal dystrophy.[49] Males tend to be affected more frequently and more severely than females and are more likely to progress to renal failure. Females, however, are not completely spared. The mode of inheritance is heterogeneous. Most patients have an X-linked dominant pattern, but autosomal recessive and autosomal dominant pedigrees also exist. MORPHOLOGY.
On histologic examination, the glomeruli are always involved. The most common early lesion is segmental proliferation or sclerosis, or both. There is an increase in mesangial matrix
963
and, in some patients, the persistence of fetal-like glomeruli. In some kidneys, glomerular or tubular epithelial cells acquire a foamy appearance owing to accumulation of neutral fats and mucopolysaccharides (foam cells). As the disease progresses, there is increasing glomerulosclerosis, vascular narrowing, tubular atrophy, and interstitial fibrosis.
The characteristic findings are seen with the electron microscope and are found in some (but not all) patients with hereditary nephritis. The GBM shows irregular foci of thickening or attenuation (thinning), with pronounced splitting and lamination of the lamina densa (Fig. 21-28) . Similar alterations are found in the tubular basement membranes. Although such basement membrane changes may be seen focally in diseases other than hereditary nephritis, they are most widespread and pronounced in patients with this disorder. Immunohistochemistry is helpful in cases with absent or borderline basement membrane lesions, because antibodies to alpha3 , alpha4 , and alpha5 collagen fail to stain both glomerular and tubular basement membranes. There is also absence of alpha5 staining in skin biopsy specimens. Pathogenesis.
Defective GBM synthesis underlies the renal lesions. In patients with X-linked disease, the defect is caused by mutations in the gene encoding the alpha5 chain of collagen type IV (COL4A5), a component of GBM [48] (see Fig. 21-3) . The mutations are heterogeneous and affect all domains of the alpha5 chain. This is thought to interfere with the structure and function of collagen type IV and thus the GBM suprastructure. [48] In addition, probably as a result of this defect, patients synthesize lesser amounts
Figure 21-28 Hereditary nephritis. Electron micrograph of glomerulus with irregular thickening of basement membrane, lamination of
lamina densa, and foci of rarefaction. Such changes may be present in other diseases but are most pronounced and widespread in hereditary nephritis. CL, capillary lumen; Ep, epithelium.
of other collagen components, including the alpha3 chain, which as you recall includes the Goodpasture antigen and also the alpha4 chain. Indeed, glomeruli lacking the alpha3 chain fail to react with anti-GBM antibodies from patients with Goodpasture syndrome. Certain patients with the X-linked form associated with diffuse leiomyomatosis have additional mutations in the alpha6 chain of collagen. In the autosomal recessive pedigrees, mutations in the alpha3 and alpha4 chains have been reported. Clinical Picture.
The most common presenting sign is gross or microscopic hematuria, frequently accompanied by erythrocyte casts. Proteinuria may occur and, rarely, the nephrotic syndrome develops. Symptoms appear at ages 5 to 20 years, and the onset of overt renal failure is between ages 20 and 50 years in men. The auditory defects may be subtle, requiring sensitive testing.
THIN MEMBRANE DISEASE (BENIGN FAMILIAL HEMATURIA)
This is a recently appreciated and fairly common entity manifested clinically by familial asymptomatic hematuria--usually uncovered on routine urinalysis-- and morphologically by diffuse thinning of the GBM to between 150 and 225 nm (compared with 300 to 400 nm in normal individuals). Although mild or moderate proteinuria may also be present, renal function is normal and prognosis is virtually uniformly excellent. The disorder should be differentiated from IgA nephropathy, another common cause of hematuria, and X-linked classical Alport syndrome. Unlike Alport syndrome, hearing loss, ocular abnormalities, and a family history of renal failure are absent and skin biopsy specimens show presence of the alpha5 chain of collagen type IV by immunohistochemistry. [48] The anomaly in thin membrane disease has also been traced in some families to genes encoding alpha3 and alpha4 chains type IV collagen. [50] Most asymptomatic patients are heterozygous for the defective gene. The disorder in homozygotes resembles autosomal recessive Alport disease, and may progress to renal failure, even in women. Chronic Glomerulonephritis
Chronic glomerulonephritis is best considered an end-stage pool of glomerular disease fed by a number of streams of specific types of glomerulonephritis, most of which have been described earlier in this chapter [51] (Fig. 21-29) . Poststreptococcal glomerulonephritis is a rare antecedent of chronic glomerulonephritis, except in adults. Patients with RPGN, if they survive the acute episode, usually progress to chronic glomerulonephritis. Membranous glomerulonephritis, MPGN, and IgA nephropathy progress more slowly to chronic renal failure, whereas focal sclerosis often advances rapidly into chronic glomerulonephritis. Nevertheless, in any series of patients with chronic glomerulonephritis, a variable percentage of cases arise mysteriously with no antecedent history of any of the wellrecognized forms of early glomerulonephritis. These cases must represent the end result of relatively asymptomatic
964
Figure 21-29 Primary glomerular diseases leading to chronic glomerulonephritis (GN). The thickness of the arrows reflects the
approximate proportion of patients in each group who progress to chronic glomerulonephritis: poststreptococcal (1% to 2%); rapidly progressive (crescentic) (90%); membranous (50%); focal glomerulosclerosis (50% to 80%); membranoproliferative glomerulonephritis (50%); IgA nephropathy (30% to 50%).
forms of glomerulonephritis, either known or still unrecognized, that progress to uremia. Clearly, the proportion of such unexplained cases depends on the availability of renal biopsy material from patients early in their disease.
MORPHOLOGY.
The kidneys are symmetrically contracted and have diffusely granular, cortical surfaces. On section, the cortex is thinned, and there is an increase in peripelvic fat. The glomerular histology depends on the stage of the disease. In early cases, the glomeruli may still show evidence of the primary disease (e.g., membranous glomerulonephritis or MPGN). However, there eventually ensues hyaline obliteration of glomeruli, transforming them into acellular eosinophilic masses. The hyaline represents a combination of trapped plasma proteins, increased mesangial matrix, basement membrane-like material, and collagen (Fig. 21-30) . Because hypertension is an accompaniment of chronic glomerulonephritis, arterial and arteriolar sclerosis may be conspicuous. Marked atrophy of associated tubules, irregular interstitial fibrosis, and lymphocytic infiltration also occur. Dialysis Changes.
Kidneys from patients with end-stage disease on long-term dialysis exhibit a variety of changes that are unrelated to the primary disease. These include arterial intimal thickening caused by accumulation of smooth muscle-like cells and a loose, proteoglycan-rich stroma; calcification, most obvious in glomerular tufts and tubular basement membranes; extensive deposition of calcium oxalate crystals in tubules and interstitium; acquired cystic disease, discussed earlier; and increased numbers of renal adenomas and borderline adenocarcinomas. Uremic Complications.
Patients dying with chronic glomerulonephritis also exhibit pathologic changes outside the kidney that are related to the uremic state and are also present in other forms of chronic renal failure. Often clinically important, these include uremic pericarditis, uremic gastroenteritis, secondary hyperparathyroidism with nephrocalcinosis and renal osteodystrophy, left ventricular hypertrophy due to hypertension, and pulmonary changes of diffuse alveolar damage often ascribed to uremia (uremic pneumonitis). Clinical Course.
In most patients, chronic glomerulonephritis develops insidiously and slowly progresses to death in uremia during a span of years or possibly decades (see discussion of chronic renal failure). Not infrequently, patients present with such nonspecific complaints as loss of appetite, anemia, vomiting, or weakness. In some, the renal disease is suspected with the discovery of proteinuria, hypertension, or azotemia on routine medical examination. In others, the underlying renal disorder is discovered in the course of investigation of edema. Most patients are hypertensive, and sometimes the dominant clinical manifestations are cerebral or cardiovascular. In all, the disease is relentlessly progressive, although at widely varying rates. In nephrotic patients, as
glomeruli become obliterated, the protein loss in the urine diminishes. If patients with chronic glomerulonephritis are not maintained with continued dialysis or if they do not receive a renal transplant, the outcome is invariably death. Table 21-8 summarizes the main clinical and histologic features of the major forms of primary glomerulonephritis. Glomerular Lesions Associated With Systemic Disease
Many immunologically mediated, metabolic, or hereditary systemic disorders are associated with glomerular injury; in some (e.g., SLE and diabetes mellitus), the glomerular
Figure 21-30 Chronic glomerulonephritis. A Masson trichrome preparation shows complete replacement of virtually all glomeruli by blue-staining collagen. (Courtesy of Dr. M.A. Venkatachalam, Department of Pathology, University of Texas Health Sciences Center, San Antonio, TX.)
965
TABLE 21-8 -- SUMMARY OF MAJOR PRIMARY GLOMERULONEPHRITIDES Disease Most Frequent Pathogenesis Glomerular Pathology Clinical Light Microscopy Fluorescence Presentation Microscopy Poststreptococcal glomerulonephritis
Acute nephritis
Antibody mediated; circulating or planted antigen
Diffuse proliferation; leukocytic infiltration
Granular IgG and C3 in GBM and mesangium
Goodpasture syndrome
Rapidly Anti-GBM progressive COL4-A3 antigen glomerulonephritis
Proliferation; crescents
Linear IgG and C3; fibrin in crescents
Idiopathic RPGN
Rapidly Anti-GBM Immune Proliferation; focal Linear IgG progressive complex necrosis; and C3 glomerulonephritis ANCA-associated crescents Granular Negative or equivocal
Membranous glomerulonephritis
Nephrotic syndrome
In situ Diffuse capillary antibody-mediated wall thickening antigen: megalin complex
Granular IgG and C3; diffuse
Lipoid nephrosis
Nephrotic syndrome
Unknown, loss of glomerular polyanion
Focal segmental glomerulosclerosis
Nephrotic syndrome; non-nephrotic proteinuria
Unknown Ablation Focal and nephropathy segmental ?Plasma factor sclerosis and hyalinosis
Membranoproliferative Nephrotic glomerulonephritis syndrome Type I
Type II
(I) Immune complex
Normal; lipid in tubules
Negative
Focal; IgM and C3
Mesangial (I) IgG+C3; proliferation; C1+C4 basement membrane thickening; splitting
Hematuria Chronic renal failure
(II) Autoantibody: alternative complement pathway
(II) C3±IgG; no C1 or C4
IgA nephropathy
Recurrent hematuria or proteinuria
Unknown; see text Focal proliferative IgA+IgG, IgM, glomerulonephritis; and C3 in mesangial mesangium widening
Chronic glomerulonephritis
Chronic renal failure
Variable
Hyalinized glomeruli
Granular or negative
ANCA, antineutrophil cytoplasmic antibody; GBM, glomerular basement membrane; RPGN, rapidly pr glomerulonephritis. involvement is a major clinical manifestation. Most of these diseases have been discussed elsewhere in this book. Here we briefly recall some of the lesions and discuss only those not considered in other sections. SYSTEMIC LUPUS ERYTHEMATOSUS
The various types of lupus nephritis are described and illustrated in Chapter 7 . As discussed, SLE gives rise to a heterogeneous group of lesions and clinical presentations. The clinical manifestations include recurrent microscopic or gross hematuria, acute nephritis, the nephrotic syndrome, chronic renal failure, and hypertension. Glomerular changes are classified histologically into mesangial lupus nephritis, focal glomerulonephritis, diffuse proliferative glomerulonephritis, and diffuse membranous glomerulonephritis. HENOCH-SCHONLEIN PURPURA
This syndrome consists of purpuric skin lesions characteristically involving the extensor surfaces of arms and legs as well as buttocks; abdominal manifestations including pain, vomiting, and intestinal bleeding; nonmigratory arthralgia; and renal abnormalities. The renal manifestations occur in one third of patients and include gross or microscopic
hematuria, proteinuria, and nephrotic syndrome. A small number of patients, mostly adults, develop a rapidly progressive form of glomerulonephritis with many crescents. Not all components of the syndrome need to be present, and individual patients may have purpura, abdominal pain, or urinary abnormalities as the dominant feature. The disease is most common in children 3 to 8 years old, but it also occurs in adults, in whom the renal manifestations are usually more severe. [51A] There is a strong background of atopy in about one third of patients, and onset often follows an upper respiratory infection. IgA is deposited in the glomerular mesangium in a distribution similar to that of IgA nephropathy. This has led to the notion that IgA nephropathy and Henoch-Scho nlein purpura are spectra of the same disease. MORPHOLOGY.
On histologic examination, the renal lesions vary from mild focal mesangial proliferation to diffuse mesangial proliferation to relatively typical crescentic glomerulonephritis.
966
Whatever the histologic lesions, the prominent feature by fluorescence microscopy is the deposition of IgA, sometimes with IgG and C3 in the mesangial region. The skin lesions consist of subepidermal hemorrhages and a necrotizing vasculitis involving the small vessels of the dermis. IgA is also present in such vessels. Vasculitis can also occur in other organs, such as the gastrointestinal tract, but is rare in the kidney. The course of the disease is variable, but recurrences of hematuria may persist for many years after onset. Most children have an excellent prognosis. Patients with the more diffuse lesions or with the nephrotic syndrome have a somewhat poorer prognosis, and renal failure occurs in those with the crescentic lesions. BACTERIAL ENDOCARDITIS
Glomerular lesions occurring in the course of bacterial endocarditis represent a type of immune complex nephritis initiated by bacterial antigen-antibody complexes. Hematuria and proteinuria of various degrees characterize this entity clinically, but an acute nephritic presentation is not uncommon, and even RPGN may occur in rare instances. The histologic lesions, when present, generally reflect these clinical manifestations. Milder forms have a focal and segmental necrotizing glomerulonephritis, whereas more severe ones exhibit a diffuse proliferative glomerulonephritis, and the rapidly progressive forms show large numbers of crescents. DIABETIC GLOMERULOSCLEROSIS (see also Chapter 20)
Diabetes mellitus is a major cause of renal morbidity and mortality, and diabetic nephropathy is one of the leading causes of chronic kidney failure in the United States. End-stage kidney disease occurs in as many as 30% of insulin-dependent type I diabetics and accounts for 20% of deaths in patients younger than 40 years. By far the
most common lesions involve the glomeruli and are associated clinically with three glomerular syndromes, including non-nephrotic proteinuria, nephrotic syndrome, and chronic renal failure. [52] However, diabetes also affects the arterioles, causing arteriolar sclerosis; increases susceptibility to the development of pyelonephritis, and particularly papillary necrosis; and causes a variety of tubular lesions. The term diabetic nephropathy is applied to the conglomerate of lesions that often occur concurrently in the diabetic kidney. Proteinuria, sometimes in the nephrotic range, occurs in about 50% of both type 1 and type 2 diabetics. It is usually discovered 12 to 22 years after the clinical appearance of diabetes and (particularly in type 1 diabetics) often heralds the progressive development of chronic renal failure ending in death or end-stage disease within a period of 4 to 5 years. The morphologic changes in the glomeruli include (1) capillary basement membrane thickening, (2) diffuse diabetic glomerulosclerosis, and (3) nodular glomerulosclerosis. Pathogenesis.
The pathogenesis of diabetic glomerulosclerosis is intimately linked with that of generalized diabetic microangiopathy, discussed in Chapter 20 . The principal points are as follows. [53] [54] 1. The bulk of the evidence suggests that diabetic glomerulosclerosis is caused by the metabolic defect, that is, the insulin deficiency, or the resultant hyperglycemia, or some other aspects of glucose intolerance. 2. Biochemical alterations in diabetic GBM are significant and include increased amount and synthesis of collagen type IV and fibronectin and decreased synthesis of proteoglycan heparan sulfate. 3. Nonenzymatic glycosylation of proteins, known to occur in diabetics and giving rise to advanced glycosylation end products, may contribute to the glomerulopathy. The mechanisms by which advanced glycosylation end products cause their effects are discussed in Chapter 20 (see Table 20-4) . 4. One hypothesis implicates hemodynamic changes in the initiation or progression of diabetic glomerulosclerosis. It is well known that early-onset type I diabetics have an increased GFR, increased glomerular filtration area, increased glomerular capillary pressure, and glomerular hypertrophy. Hemodynamic alterations and glomerular hypertrophy also occur in experimental streptozotocin-induced diabetes in rats, in which they are associated with proteinuria and can be reversed by diabetic control. It has been speculated that the subsequent morphologic alterations in the mesangium are somehow influenced by the glomerular hypertrophy and hemodynamic changes, akin to the adaptive responses to ablation of renal mass, discussed earlier. To sum up, two processes seem to play a role in the fully developed diabetic glomerular lesions: a metabolic defect, possibly linked to advanced glycosylation end products, that accounts for the thickened GBM and increased mesangial matrix that occur in all patients; and hemodynamic effects, associated with glomerular hypertrophy, which
leads to glomerulosclerosis in about 40% of patients. MORPHOLOGY
Capillary Basement Membrane Thickening.
Widespread thickening of the glomerular capillary basement membrane (GBM) occurs in virtually all diabetics, irrespective of the presence of proteinuria, and is part and parcel of the diabetic microangiopathy. Pure capillary basement membrane thickening can be detected only by electron microscopy. Careful morphometric studies demonstrate that this thickening begins as early as 2 years after the onset of type I diabetes and by 5 years amounts to about a 30% increase. [41] The thickening continues progressively and usually concurrently with mesangial widening (Fig. 21-31) . Simultaneously there is thickening of the tubular basement membranes. Diffuse Glomerulosclerosis.
This consists of diffuse increase in mesangial matrix, with mild proliferation
967
Figure 21-31 Electron micrograph of advanced diabetic glomerulosclerosis. Note massive increase in mesangial matrix (Mes)
encroaching on glomerular capillary lumena (CL). GBM and Bowman capsule (C) are markedly thickened. Ep, epithelium; E, endothelium.
of mesangial cells, and is always associated with the overall thickening of the GBM. The increase in mesangial volume appears to lag slightly behind basement membrane widening but becomes pronounced after 10 to 20 years of diabetes. The matrix depositions are PAS positive. The changes almost always begin in the vascular stalk and sometimes seem continuous with the invariably present hyaline thickening of arterioles (Fig. 21-32) . As the disease progresses, the mesangial areas expand further and obliterate the mesangial cells, gradually filling the entire glomerulus (obliterative diabetic glomerulosclerosis). Nodular Glomerulosclerosis.
This is also known as
Figure 21-32 Diffuse and nodular diabetic glomerulosclerosis (PAS stain). Note diffuse increase in mesangial matrix and
characteristic acellular PAS-positive nodules.
intercapillary glomerulosclerosis or Kimmelstiel-Wilson disease. The glomerular lesions take the form of ovoid or spherical, often laminated, hyaline masses situated in the periphery of the glomerulus. They lie within the mesangial core of the glomerular lobules and often are surrounded by peripheral patent capillary loops (Fig. 21-32) . Usually, not all the lobules in the individual glomerulus are involved. Uninvolved lobules and glomeruli all show striking diffuse glomerulosclerosis. The nodules are PAS positive and contain lipids and fibrin. As the disease advances, the individual nodules enlarge and eventually compress and engulf capillaries, obliterating the glomerular tuft. As a consequence of the glomerular and arteriolar lesions, the kidney suffers from ischemia, develops tubular atrophy and interstitial fibrosis, and usually undergoes overall contraction in size. Nodular glomerulosclerosis and the diffuse lesion are fundamentally similar lesions of the mesangium. The nodular lesion, however, is virtually pathognomonic of diabetes, so long as care is taken to exclude membranoproliferative (lobular) glomerulonephritis, the glomerulonephritis associated with light-chain disease, and amyloidosis. Approximately 15% to 30% of long-term patients with diabetes develop nodular glomerulosclerosis, and in most instances it is associated with renal failure. Clinical Course.
The clinical manifestations of diabetic glomerulosclerosis are linked to those of diabetes. The increased GFR typical of early-onset type 1 diabetics is associated with microalbuminuria, defined as urinary albumin excretion of 30 to 300 mg/day of albumin. Microalbuminuria
968
and increased GFR are important predictors of future overt diabetic nephropathy in these patients. Overt proteinuria then develops, which may be mild and asymptomatic initially but gradually increases to nephrotic levels in some patients. This is followed by progressive loss of GFR, leading to end-stage renal failure within a period of 5 years. Systemic hypertension may precede the development of proteinuria and renal insufficiency. Indeed, the risk of renal disease in type 1 diabetics is associated with a genetic predisposition to hypertension, possibly related to polymorphisms in the genes encoding proteins of the renin-angiotensin system (Chapter 12) . Hypertension in turn increases the susceptibility to developing diabetic nephropathy in the presence of poor hyperglycemic control. Although the prevalence of proteinuria is comparable in type 1 and type 2 diabetics, the lesions are more heterogeneous and less predictable in type 2 diabetics. [55] Indeed, 20% to 50% of type 2 patients undergoing renal biopsy have other glomerular diseases (e.g., membranous glomerulonephritis). End-stage renal disease results in only 10% to 20% of patients with type 2 diabetes.
At present, most patients with end-stage diabetic nephropathy are maintained on long-term dialysis, and a few receive renal transplantation. Diabetic lesions may recur in the renal allografts. Precise control of the blood glucose level in diabetes has now been shown by several studies to delay or prevent the progression of glomerulopathy. Similarly, inhibition of angiotensin by converting enzyme inhibitors (captopril) has a beneficial effect on progression, possibly by reversing the increased intraglomerular capillary pressure. AMYLOIDOSIS
The various forms of amyloidosis and their pathogenesis are discussed in Chapter 7 . Most types of disseminated amyloidosis may be associated with deposits of amyloid within the glomeruli. The typical Congo red amyloid-positive fibrillary deposits are present within the mesangium and subendothelium and occasionally within the subepithelial space. Eventually, they obliterate the glomerulus completely. Recall that deposits of amyloid also appear in blood vessel walls and in the kidney interstitium. Patients with glomerular amyloid may present with heavy proteinuria or the nephrotic syndrome and later, owing to destruction of the glomeruli, die in uremia. Characteristically, kidney size tends to be either normal or slightly enlarged. FIBRILLARY AND IMMUNOTACTOID GLOMERULONEPHRITIS
Fibrillary glomerulonephritis is a morphologic variant of glomerulonephritis associated with relatively characteristic fibrillar deposits in the mesangium and glomerular capillary that differ from amyloid fibrils both ultrastructurally and in that they do not stain with Congo red. The fibrils are 20 to 30 nm in diameter, rather than the 10 nm characteristic of amyloid. The glomerular lesions are membranoproliferative by light microscopy, and by immunofluorescence microscopy there is selective deposition of IgG4, with complement C3, and kappa and lambda light chains. Clinically, patients develop nephrotic syndrome, hematuria, and progressive renal insufficiency. In immunotactoid glomerulopathy, a much rarer condition, the deposits are microtubular in structure and 30 to 50 nm in width. Patients often have circulating paraproteins and monoclonal immunoglobulin deposition in glomeruli. [56] The precise nature and pathogenesis of both of these entities are unknown. OTHER SYSTEMIC DISORDERS
Goodpasture syndrome (Chapter 16) , microscopic polyarteritis and Wegener granulomatosis (Chapter 12) are commonly associated with glomerular lesions, as described in the discussion of these diseases. Suffice it to say here that the glomerular lesions in these three conditions can be similar. In the early or mild forms of involvement, there is focal and segmental, sometimes necrotizing, glomerulonephritis, and most of these patients will have hematuria with mild decline in GFR. In the more severe cases associated with RPGN, there is also extensive necrosis, fibrin deposition,
and the formation of epithelial crescents. Essential mixed cryoglobulinemia is another rare systemic condition in which deposits of cryoglobulins composed principally of IgG-IgM complexes induce cutaneous vasculitis, synovitis, and focal or diffuse proliferative glomerulonephritis. Cryoglobulinemia secondary to infection (e.g., hepatitis C) may be associated with glomerulonephritis, usually of the MPGN type. Plasma cell dyscrasias may also induce glomerular lesions. Multiple myeloma is associated with (1) amyloidosis, (2) deposition of monoclonal cryoglobulins in glomeruli, and (3) peculiar nodular glomerular lesions, ascribed to the deposition of nonfibrillar light chains. This so-called light-chain glomerulopathy sometimes occurs in the absence of overt myeloma, usually associated with deposition of kappa chains in glomeruli. The glomeruli show PAS-positive mesangial nodules, lobular accentuation, and mild mesangial hypercellularity, lesions that need to be differentiated from diabetic nodules and membranoproliferative GN. These patients usually present with proteinuria or the nephrotic syndrome, hypertension, and progressive azotemia. Other renal manifestations of multiple myeloma are discussed later.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 21 - The Kidney PATHOLOGY - Part 2 DISEASES AFFECTING TUBULES AND INTERSTITIUM Acute Tubular Necrosis Pathogenesis MORPHOLOGY Clinical Course Tubulointerstitial Nephritis PYELONEPHRITIS AND URINARY TRACT INFECTION Etiology and Pathogenesis ACUTE PYELONEPHRITIS MORPHOLOGY Clinical Course CHRONIC PYELONEPHRITIS AND REFLUX NEPHROPATHY Chronic Obstructive Pyelonephritis Reflux Nephropathy MORPHOLOGY Clinical Course TUBULOINTERSTITIAL NEPHRITIS INDUCED BY DRUGS AND TOXINS Acute Drug-Induced Interstitial Nephritis MORPHOLOGY Pathogenesis Clinical Features Analgesic Abuse Nephropathy Pathogenesis MORPHOLOGY Clinical Course Nephropathy Associated With Nonsteroidal Anti-Inflammatory Drugs OTHER TUBULOINTERSTITIAL DISEASES Urate Nephropathy Hypercalcemia and Nephrocalcinosis Multiple Myeloma MORPHOLOGY
DISEASES OF BLOOD VESSELS Benign Nephrosclerosis Pathogenesis MORPHOLOGY Clinical Features Malignant Nephrosclerosis and Accelerated Hypertension Pathogenesis MORPHOLOGY Clinical Course Renal Artery Stenosis Pathogenesis MORPHOLOGY Clinical Course Thrombotic Microangiopathies Pathogenesis Endothelial Injury Platelet Aggregation CLASSIC (CHILDHOOD) HEMOLYTIC-UREMIC SYNDROME MORPHOLOGY ADULT HEMOLYTIC-UREMIC SYNDROME/THROMBOTIC THROMBOCYTOPENIC PURPURA IDIOPATHIC HUS/TTP OTHER VASCULAR DISORDERS Atherosclerotic Ischemic Renal Disease Atheroembolic Renal Disease Sickle Cell Disease Nephropathy Diffuse Cortical Necrosis MORPHOLOGY Renal Infarcts MORPHOLOGY URINARY TRACT OBSTRUCTION (OBSTRUCTIVE UROPATHY) MORPHOLOGY Clinical Course UROLITHIASIS (RENAL CALCULI, STONES) Cause and Pathogenesis MORPHOLOGY Clinical Course TUMORS OF THE KIDNEY
Benign Tumors RENAL PAPILLARY ADENOMA MORPHOLOGY RENAL FIBROMA OR HAMARTOMA (RENOMEDULLARY INTERSTITIAL CELL TUMOR) ANGIOMYOLIPOMA ONCOCYTOMA Malignant Tumors RENAL CELL CARCINOMA (HYPERNEPHROMA, ADENOCARCINOMA OF KIDNEY) Epidemiology Classification of Renal Cell Carcinoma: Histology, Cytogenetics, and Genetics MORPHOLOGY Clinical Course UROTHELIAL CARCINOMAS OF RENAL PELVIS Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
PATHOLOGY - Part 2 DISEASES AFFECTING TUBULES AND INTERSTITIUM Most forms of tubular injury involve the interstitium as well, and thus diseases affecting these two components are discussed together. Under this heading, we consider two major groups of processes: (1) ischemic or toxic tubular injury, leading to acute tubular necrosis (ATN) and acute renal failure, and (2) inflammatory reactions of the tubules and interstitium (tubulointerstitial nephritis).
969
Acute Tubular Necrosis
ATN is a clinicopathologic entity characterized morphologically by destruction of tubular epithelial cells and clinically by acute suppression of renal function. It is the most common cause of acute renal failure, [56A] which signifies acute suppression of renal function and urine flow, falling within 24 hours to less than 400 ml. It can be caused by a variety of conditions including: 1. Organic vascular obstruction, caused by diffuse involvement of the intrarenal vessels, such as in polyarteritis nodosa and malignant hypertension, and the hemolytic-uremic syndrome 2. Severe glomerular disease, such as RPGN 3. Acute tubulointerstitial nephritis, most commonly occurring as a hypersensitivity to drugs 4. Massive infection (pyelonephritis), especially when it is accompanied by papillary necrosis 5. Disseminated intravascular coagulation 6. Urinary obstruction by tumors, prostatic hypertrophy, or blood clots (so-called postrenal acute renal failure) 7. Acute tubular necrosis (ATN) Here we discuss ATN, the major cause of acute renal failure, accounting for some 50% of cases in hospitalized patients. The other causes of acute renal failure are discussed elsewhere in this chapter. ATN is a reversible renal lesion that arises in a variety of clinical settings. Most of these, ranging from severe trauma to acute pancreatitis, have in common a period of inadequate blood flow to the peripheral organs, usually accompanied by marked
hypotension and shock. This pattern of ATN is called ischemic ATN. Mismatched blood transfusions and other hemolytic crises causing hemoglobinuria, and skeletal muscle injuries causing myoglobinuria, also produce a picture resembling ischemic ATN. The second pattern, called nephrotoxic ATN, is caused by a multitude of drugs, such as gentamicin and other antibiotics; radiographic contrast agents; poisons, including heavy metals (e.g., mercury); and organic solvents (e.g., carbon tetrachloride). In addition to its frequency, the potential reversibility of ATN adds to its clinical importance. Proper management means the difference between full recovery and death. Pathogenesis.
The critical events in both ischemic and nephrotoxic ATN are believed to be (1) tubular injury and (2) persistent and severe disturbances in blood flow [57] (Fig. 21-33) . Tubule cell injury: Tubular epithelial cells are particularly sensitive to ischemia and are also vulnerable to toxins. Several factors predispose the tubules to toxic injury, including a vast electrically charged surface for tubular reabsorption, active transport systems for ions and organic acids, and the capability for effective concentration. Ischemia causes numerous structural and functional alterations in epithelial cells, as discussed in Chapter 1 . The structural changes include those of reversible injury (such as cellular swelling, loss of brush border, blebbing, loss of polarity, and cell detachment) and those associated with lethal injury (necrosis and apoptosis). Biochemically, there is depletion of adenosine triphosphate; accumulation of intracellular calcium; activation of proteases (e.g., calpain), which cause cytoskeletal rearrangement, and phospholipases, which damage membranes; 970
generation of reactive oxygen species; and activation of caspases, which induce apoptotic cell death. One early reversible result of ischemia is loss of cell polarity due to redistribution of membrane proteins (e.g., the enzyme Na+ ,K+ -ATPase) from the basolateral to the luminal surface of the tubular cells, resulting in abnormal ion transport across the cells, and increased sodium delivery to distal tubules. The latter results in tubuloglomerular feedback, which, as will be described, incites vasoconstriction. [58] In addition, ischemic tubular cells express cytokines and adhesion molecules (such as ICAM-1), thus recruiting leukocytes that appear to participate in the subsequent injury. [59] In time, detached injured cells cause luminal tubule obstruction, increase intratubular pressure, and decrease the GFR. In addition, fluid from the damaged tubules could leak into the interstitium, resulting in increased interstitial pressure and collapse of the tubule. All these effects, as shown in Fig. 21-33 contribute to the decreased GFR. Disturbances in blood flow: Ischemic renal injury is also characterized by hemodynamic alterations that cause reduced GFR. The major one is intrarenal vasoconstriction, which results in both reduced glomerular plasma flow and reduced oxygen delivery to the functionally important tubules in the outer medulla (thick ascending limb and straight segment of the proximal tubule). A number of vasoconstrictor pathways have been implicated, including the renin-angiotensin mechanism, stimulated by increased distal sodium delivery ( glomerulotubular
feedback), and sublethal endothelial injury, leading to increased release of the endothelial vasoconstrictor endothelin and decreased production of the vasodilator nitric oxide and PGI2 . Finally, there is also some evidence of a direct effect of ischemia or toxins on the glomerulus, causing a reduced glomerular ultrafiltration coefficient, possibly due to mesangial contraction.
Figure 21-33 Possible pathogenetic mechanisms in ischemic acute renal failure (see text).
The patchiness of tubular necrosis and maintenance of the integrity of the basement membrane along many segments allow ready repair of the necrotic foci and recovery of function if the precipitating cause is removed. This repair is dependent on the capacity of reversibly injured epithelial cells to proliferate and differentiate. Re-epithelialization is mediated by a variety of growth factors and cytokines produced locally by the tubular cells themselves (autocrine stimulation) or by inflammatory cells in the vicinity of necrotic foci (paracrine stimulation). [60] Of these, epidermal growth factor (EGF), TGF-alpha, insulin-like growth factor type I, and hepatocyte growth factor have been shown to be particularly important in renal tubular repair. Growth factors, indeed, are being explored as possible therapeutic agents to enhance re-epithelialization in ATN. [60] MORPHOLOGY.
Ischemic ATN is characterized by focal tubular epithelial necrosis and apoptosis at multiple points along the nephron, with large skip areas in between, often accompanied by rupture of basement membranes (tubulorrhexis) and occlusion of tubular lumens by casts [61] (Figs. 21-34 and 21-35) . The straight portion of the proximal
Figure 21-34 Patterns of tubular damage in ischemic and toxic acute tubular necrosis. In ischemic type, tubular necrosis is patchy,
relatively short lengths of tubules are affected, and straight segments of proximal tubules (PST) and ascending limbs of Henle's loop (HL) are most vulnerable. In toxic acute tubular necrosis, extensive necrosis is present along proximal tubule segments (PCT) with many toxins (e.g., mercury), but necrosis of the distal tubule, particularly ascending Henle's loop, also occurs. In both types, lumens of distal convoluted tubules (DCT) and collecting ducts (CD) contain casts.
tubule and the ascending thick limb in the renal medulla are especially vulnerable, but focal lesions may also occur in the distal tubule, often in conjunction with casts. Eosinophilic hyaline casts, as well as pigmented granular casts, are common, particularly in distal tubules and collecting ducts. These casts consist principally of Tamm-Horsfall protein (a specific urinary glycoprotein normally secreted by the cells of ascending thick limb and distal tubules) in conjunction with hemoglobin, myoglobin, and other plasma proteins. Other findings in ischemic ATN are interstitial edema and accumulations of leukocytes within dilated vasa recta. There is also often evidence of epithelial regeneration: flattened epithelial cells with hyperchromatic nuclei and mitotic figures are often present. In the course of time, this regeneration repopulates the
tubules so that if survival occurs, no residual evidence of damage can be seen. Toxic ATN is manifested by acute tubular injury, most obvious in the proximal convoluted tubules (see Fig. 21-34) . On histologic examination, the tubular necrosis may be entirely nonspecific but is
971
Figure 21-35 Ischemic acute tubular necrosis. Some of the tubular epithelial cells in affected tubules are necrotic, whereas others are
flattened, stretched out, and regenerating.
somewhat distinctive in poisoning with certain agents. With mercuric chloride, for example, severely injured cells not yet dead may contain large acidophilic inclusions. Later, these cells become totally necrotic, are desquamated into the lumen, and may undergo calcification. Carbon tetrachloride poisoning, in contrast, is characterized by the accumulation of neutral lipids in injured cells, but again, such fatty change is followed by necrosis. Ethylene glycol produces marked ballooning and hydropic or vacuolar degeneration of proximal convoluted tubules. Calcium oxalate crystals are often found in the tubular lumens in such poisoning. Clinical Course.
The clinical course of ATN is highly variable, but the classic case may be divided into initiating, maintenance, and recovery stages. The initiating phase, lasting for about 36 hours, is dominated by the inciting medical, surgical, or obstetric event in the ischemic form of ATN. The only indication of renal involvement is a slight decline in urine output with a rise in BUN. At this point, oliguria could be explained on the basis of a transient decrease in blood flow to the kidneys. The maintenance stage is characterized by sustained decreases in urine output to between 40 and 400 ml/day (oliguria), with salt and water overload, rising BUN concentrations, hyperkalemia, metabolic acidosis, and other manifestations of uremia dominating this phase. With appropriate attention to the balance of water and blood electrolytes, including dialysis, the patient can be carried over this oliguric crisis. The recovery phase is ushered in by a steady increase in urine volume that may reach up to 3 liters/day. The tubules are still damaged, so that large amounts of water, sodium, and potassium are lost in the urinary flood. Hypokalemia, rather than hyperkalemia, becomes a clinical problem. There is a peculiar increased vulnerability to infection at this stage. Eventually, renal tubular function is restored, with improvement in concentrating ability. At the same time, BUN and creatinine levels begin to return to normal. Subtle tubular functional impairment may persist for months, but most patients who reach this phase eventually recover completely.
The prognosis of ATN depends on the clinical setting surrounding its development. Recovery is expected with nephrotoxic ATN when the toxin has not caused serious damage to other organs, such as the liver or heart. With modern methods of care, 95% of those who do not succumb to the precipitating cause have a chance of recovery. Conversely, in shock related to sepsis or extensive burns, the mortality rate may rise to more than 50%. Up to 50% of patients with ATN may not have oliguria and may in fact have increased urine volumes. This so-called nonoliguric ATN occurs particularly often with nephrotoxins, and generally it tends to follow a more benign clinical course. Tubulointerstitial Nephritis
This group of renal diseases is characterized by histologic and functional alterations that involve predominantly the tubules and interstitium. [62] [62A] We have previously seen that chronic tubulointerstitial injury may occur in primarily glomerular diseases (see Fig. 21-15) (Figure Not Available) and indeed that such injury may be an important cause of progression in these diseases. This secondary tubulointerstitial nephritis is also present in a variety of vascular, cystic (polycystic kidney disease), metabolic (diabetes), and renal disorders, in which it may also contribute to progressive damage. Here we discuss disorders in which tubulointerstitial injury appears to be a primary event. These disorders have diverse causes and different pathogenetic mechanisms (Table 21-9) . Thus, the disorders are identified by cause or by associated disease (e.g., analgesic nephritis, irradiation nephritis). Glomerular and vascular abnormalities may also be present but either are mild or occur only in advanced stages of these diseases. Tubulointerstitial nephritis can be acute or chronic. Acute tubulointerstitial nephritis has an acute clinical onset and is characterized histologically by interstitial edema, often accompanied by leukocytic infiltration and focal tubular necrosis. In chronic interstitial nephritis, there is infiltration with mononuclear cells, prominent interstitial fibrosis, and widespread tubular atrophy. These conditions are clinically distinguished from the glomerular diseases by the absence, in early stages, of such hallmarks of glomerular injury as nephritic or nephrotic syndromes and by the presence of defects in tubular function. The latter may be subtle and include impaired ability to concentrate urine, evidenced clinically by polyuria or nocturia; salt wasting; diminished ability to excrete acids (metabolic acidosis); and isolated defects in tubular reabsorption or secretion. The advanced forms, however, may be difficult to distinguish clinically from other causes of renal insufficiency. Some of the specific conditions listed in Table 21-9 are discussed elsewhere in this book. In this section, we deal
972
TABLE 21-9 -- TUBULOINTERSTITIAL NEPHRITIS Infections Acute bacterial pyelonephritis Chronic pyelonephritis (including reflux nephropathy) Other infections (e.g., viruses, parasites) Toxins Drugs Acute hypersensitivity interstitial nephritis Analgesic nephritis Heavy metals Lead, cadmium Metabolic Diseases Urate nephropathy Nephrocalcinosis (hypercalcemic nephropathy) Hypokalemic nephropathy Oxalate nephropathy Physical Factors Chronic urinary tract obstruction Radiation nephritis Neoplasms Multiple myeloma Immunologic Reactions Transplant rejection Sjogren syndrome Vascular Diseases Miscellaneous Balkan nephropathy Nephronophthisis-medullary cystic disease complex Other rare causes (sarcoidosis) "Idiopathic" interstitial nephritis principally with pyelonephritis and interstitial diseases induced by drugs.
PYELONEPHRITIS AND URINARY TRACT INFECTION
Pyelonephritis is a renal disorder affecting tubules, interstitium, and renal pelvis and is one of the most common diseases of the kidney. It occurs in two forms. Acute pyelonephritis is caused by bacterial infection and is the renal lesion associated with urinary tract infection. Chronic pyelonephritis is a more complex disorder: bacterial infection plays a dominant role, but other factors (vesicoureteral reflux, obstruction) are involved in its pathogenesis. Pyelonephritis is a serious complication of an extremely common clinical spectrum of urinary tract infections that affect the urinary bladder (cystitis) or the kidneys and their collecting systems (pyelonephritis), or both. Bacterial infection of the urinary tract may be completely asymptomatic (asymptomatic bacteriuria) and most often remains localized to the bladder without the development of renal infection. However, urinary tract infection always carries the potential of spread to the kidney. Etiology and Pathogenesis. [ 63]
The dominant etiologic agents, accounting for more than 85% of cases of urinary tract infection, are the gram-negative bacilli that are normal inhabitants of the intestinal tract. By far the most common is Escherichia coli, followed by Proteus, Klebsiella, and Enterobacter. Streptococcus faecalis, also of enteric origin, staphylococci, and virtually every other bacterial and fungal agent can also cause lower urinary tract and renal infection. In most patients with urinary tract infection, the infecting organisms are derived from the patient's own fecal flora. This is thus a form of endogenous infection. There are two routes by which bacteria can reach the kidneys: (1) through the bloodstream (hematogenous infection) and (2) from the lower urinary tract (ascending infection) (Fig. 21-36) . Although the hematogenous route is the less common of the two, acute pyelonephritis does result from seeding of the kidneys by bacteria from distant foci in the course of
Figure 21-36 Schematic representation of pathways of renal infection. Hematogenous infection results from bacteremic spread. More
common is ascending infection, which results from a combination of urinary bladder infection, vesicoureteral reflux, and intrarenal reflux.
973
Figure 21-37 Vesicoureteral reflux demonstrated by a voiding cystourethrogram. Dye injected into the bladder refluxes into both
dilated ureters, filling the pelvis and calcyes.
septicemia or infective endocarditis. Hematogenous infection is more likely to occur in the presence of ureteral obstruction, in debilitated patients, in patients receiving immunosuppressive therapy, and with nonenteric organisms, such as staphylococci and certain fungi. Ascending infection is the most common cause of clinical pyelonephritis. Normal human bladder and bladder urine are sterile, and thus a number of steps must occur for renal infection to occur. The first step in the pathogenesis of ascending infection appears to be the colonization of the distal urethra and introitus (in the female) by coliform bacteria. This colonization is influenced by the ability of bacteria to adhere to urethral mucosal cells. Such bacterial adherence, as discussed in Chapter 9 , involves adhesive molecules (adhesins) on the P-fimbriae (pili) of bacteria that interact with receptors on the surface of uroepithelial cells. Specific adhesins (e.g., the pap variant) are associated with infection. In addition, certain types of fimbriae promote renal tropism, or persistence of infection, or an enhanced inflammatory response to bacteria. [64] From the urethra to the bladder, organisms gain entrance during urethral catheterization or other instrumentation. Long-term catheterization, in particular, carries a risk of infection. In the absence of instrumentation, urinary infections are much more common in females, and this has been variously ascribed to the shorter urethra in females, the absence of antibacterial properties such as are found in prostatic fluid, hormonal changes affecting adherence of bacteria to the mucosa, and urethral trauma during sexual intercourse or a combination of these factors. [65] Multiplication in the bladder. Ordinarily, organisms introduced into the bladder are cleared by the continual flushing of voiding and by antibacterial mechanisms. However, outflow obstruction or bladder dysfunction results in incomplete emptying and increased residual volume of urine. In the presence of stasis, bacteria introduced into the bladder can multiply unhindered without being unceremoniously flushed or destroyed by the bladder wall. Accordingly, urinary tract infection is particularly frequent among patients with lower urinary tract obstruction, such as may occur with benign prostatic hypertrophy, tumors, or calculi. Vesicoureteral reflux. Although obstruction is an important predisposing factor in the pathogenesis of ascending infection, it is incompetence of the vesicoureteral valve that allows bacteria to ascend the ureter into the pelvis. The normal ureteral insertion into the bladder is a competent one-way valve that prevents retrograde flow of urine, especially during micturition, when the intravesical pressure rises. An incompetent vesicoureteral orifice allows the reflux of bladder urine into the ureters (vesicoureteral reflux)[65] (Fig. 21-37) . Reflux is most often due to a congenital, inherited absence or shortening of the intravesical portion of the ureter (Fig. 21-38) , such that the ureter is not compressed during micturition. In addition, bladder infection itself, probably as a result of the action of bacterial or inflammatory products on ureteral contractility, can cause or accentuate vesicoureteral reflux, particularly in children. Acquired vesicoureteral reflux in adults can result from persistent bladder atony caused by spinal cord injury. The effect of vesicoureteral reflux is similar to that of an obstruction in that after voiding there is residual urine in the urinary tract, which favors bacterial growth.
974
Intrarenal reflux. Vesicoureteral reflux also affords a ready mechanism by which the infected bladder urine can be propelled up to the renal pelvis and deep into the renal parenchyma through open ducts at the tips of the papillae (intrarenal reflux). Intrarenal reflux is most common in the upper and lower poles of the kidney, where papillae tend to have flattened or concave tips rather than the convex pointed type present in the midzones of the kidney (and depicted in most textbooks). Reflux can be demonstrated radiographically by a voiding cystourethrogram: the bladder is filled with a radiopaque dye, and films are taken during micturition. Vesicoureteral reflux can be demonstrated in about 50% of infants and children with urinary tract infection (see Fig. 21-37) .
Figure 21-38 The vesicoureteric junction. In normal individuals ( A ), the intravesical portion of the ureter is oblique, such that the
ureter is closed by muscle contraction during micturition. The most common cause of reflux is congenital complete or partial absence of the intravesical ureter ( B ).
In the absence of vesicoureteral reflux, infection usually remains localized in the bladder. Thus, the majority of patients with repeated or persistent bacterial colonization of the urinary tract suffer from cystitis and urethritis (lower urinary tract infection) rather than pyelonephritis. ACUTE PYELONEPHRITIS
Acute pyelonephritis is an acute suppurative inflammation of the kidney caused by bacterial infection--whether hematogenous and induced by septicemic spread or ascending and associated with vesicoureteral reflux. MORPHOLOGY.
The hallmarks of acute pyelonephritis are patchy interstitial suppurative inflammation and tubular necrosis. The suppuration may occur as discrete focal abscesses involving one or both kidneys or as large, wedge-shaped areas of coalescent suppuration (Fig. 21-39) . The distribution
Figure 21-39 Acute pyelonephritis. Cortical surface exhibits grayish white areas of inflammation and abscess formation.
Figure 21-40 Acute pyelonephritis marked by an acute neutrophilic exudate within tubules and the renal substance.
of these lesions is unpredictable and haphazard, but in pyelonephritis associated with reflux, damage occurs most commonly in the lower and upper poles. In the early stages, the neutrophilic infiltration is limited to the interstitial tissue. Soon, however, the reaction involves tubules and produces a characteristic abscess with the destruction of the engulfed tubules (Fig. 21-40) . Since the tubular lumens present a ready pathway for the extension of the infection, large masses of neutrophils frequently extend along the involved nephron into the collecting tubules. Characteristically, the glomeruli appear to be resistant to the infection. Large areas of severe necrosis, however, eventually destroy the glomeruli, and fungal pyelonephritis (e.g., Candida) often affects glomeruli. Three complications of acute pyelonephritis are encountered in special circumstances. Papillary necrosis is seen mainly in diabetics and in those with urinary tract obstruction. Papillary necrosis is usually bilateral but may be unilateral. One or all of the pyramids of the affected kidney may be involved. On cut section, the tips or distal two thirds of the pyramids have gray-white to yellow necrosis that resembles infarction (Fig. 21-41) . On microscopic examination, the necrotic tissue shows characteristic coagulative infarct necrosis, with preservation of outlines of tubules. The leukocytic response is limited to the junctions between preserved and destroyed tissue. Pyonephrosis is seen when there is total or almost complete obstruction, particularly when it is high in the urinary tract. The suppurative exudate is unable to drain and thus fills the renal pelvis, calyces, and ureter, producing pyonephrosis. Perinephric abscess implies extension of suppurative 975
inflammation through the renal capsule into the perinephric tissue.
Figure 21-41 Papillary necrosis. Areas of pale gray necrosis are limited to the papillae.
After the acute phase of pyelonephritis, healing occurs. The neutrophilic infiltrate is replaced by one that is predominantly mononuclear with macrophages, plasma cells, and (later) lymphocytes. The inflammatory foci are eventually replaced by scars that can be seen on the cortical surface as fibrous depressions. Such scars are characterized microscopically by atrophy of tubules, interstitial fibrosis, and lymphocyte infiltrate and may resemble scars produced by ischemic or other types of injury to the kidney. However, the pyelonephritic scar is almost always associated with inflammation, fibrosis, and deformation of the underlying calyx and pelvis, reflecting the role of ascending infection and vesicoureteral reflux in the pathogenesis of the disease.
Clinical Course.
Acute pyelonephritis is often associated with predisposing conditions, some of which were covered in the discussion of pathogenetic mechanisms. These include the following: Urinary obstruction, either congenital or acquired Instrumentation of the urinary tract, most commonly catheterization Vesicoureteral reflux Pregnancy. Four per cent to 6% of pregnant women develop bacteriuria sometime during pregnancy, and 20% to 40% of these eventually develop symptomatic urinary infection if not treated. Patient's sex and age. After the first year of life (when congenital anomalies in males commonly become evident) and up to around age 40 years, infections are much more frequent in females. With increasing age, the incidence in males rises owing to the development of prostatic hypertrophy and frequent instrumentation. Preexisting renal lesions, causing intrarenal scarring and obstruction Diabetes mellitus, in which acute pyelonephritis is caused by more frequent instrumentation, the general susceptibility to infection, and the neurogenic bladder dysfunction exhibited by patients Immunosuppression and immunodeficiency When acute pyelonephritis is clinically apparent, the onset is usually sudden, with pain at the costovertebral angle and systemic evidence of infection, such as fever and malaise. There are usually indications of bladder and urethral irritation, such as dysuria, frequency, and urgency. The urine contains many leukocytes (pyuria) derived from the inflammatory infiltrate, but pyuria does not differentiate upper from lower urinary tract infection. The finding of leukocyte casts (pus casts) indicates renal involvement, because casts are formed only in tubules. The diagnosis of infection is established by quantitative urine culture. Uncomplicated acute pyelonephritis usually follows a benign course, and the symptoms disappear within a few days after the institution of appropriate antibiotic therapy. Bacteria, however, may persist in the urine, or there may be recurrence of infection with new serologic types of E. coli or other organisms. Such bacteriuria then either disappears or may persist sometimes for years. In the presence of unrelieved urinary obstruction, diabetes mellitus, and immunocompromise, acute pyelonephritis may be more serious, leading to repeated septicemic episodes. The superimposition of papillary necrosis may lead to acute renal failure. CHRONIC PYELONEPHRITIS AND REFLUX NEPHROPATHY
Chronic pyelonephritis is a chronic tubulointerstitial renal disorder in which chronic tubulointerstitial inflammation and renal scarring are associated with pathologic involvement of the calyces and pelvis (Fig. 21-42) . Pelvocalyceal damage is important in that virtually all the diseases listed in Table 21-9 produce chronic tubulointerstitial
alterations, but except for chronic pyelonephritis and analgesic nephropathy, none affects the calyces. Chronic pyelonephritis is an important cause of end-stage kidney disease, being found in 10% to 20% of patients in renal transplant or dialysis units. Chronic pyelonephritis can be divided into two forms: chronic obstructive and chronic reflux-associated. Chronic Obstructive Pyelonephritis.
We have seen that obstruction predisposes the kidney to infection. Recurrent infections superimposed on diffuse or localized obstructive lesions lead to recurrent bouts of renal inflammation and scarring, resulting in a picture of chronic pyelonephritis. In this condition, the effects of obstruction contribute to the parenchymal atrophy, and indeed it is sometimes difficult to differentiate the effects of bacterial infection from those of obstruction alone. The disease can be bilateral, as with obstructive anomalies of the urinary tract (e.g., posterior urethral valves), resulting in renal insufficiency unless the anomaly is corrected; or unilateral, such as occurs with calculi and unilateral obstructive anomalies of the ureter. Reflux Nephropathy.
This is by far the more common form of chronic pyelonephritic scarring. Renal involvement in reflux nephropathy occurs early in childhood, as a result
976
Figure 21-42 Typical coarse scars of chronic pyelonephritis associated with vesicoureteral reflux. The scars are usually polar and are
associated with underlying blunted calyces.
of superimposition of a urinary infection on congenital vesicoureteral reflux and intrarenal reflux, the latter conditioned by the number of potentially refluxing papillae. Reflux may be unilateral or bilateral; thus, the resultant renal damage either may cause scarring and atrophy of one kidney or may involve both and lead to chronic renal insufficiency. Vesicoureteral reflux occasionally causes renal damage in the absence of infection (sterile reflux) but only in the presence of severe obstruction. MORPHOLOGY.
The characteristic morphologic changes of chronic pyelonephritis are seen on gross examination (Fig. 21-42) . The kidneys usually are irregularly scarred; if bilateral, the involvement is asymmetric. This contrasts with chronic glomerulonephritis, in which the kidneys are diffusely and symmetrically scarred. The hallmark of chronic pyelonephritis is the coarse, discrete, corticomedullary scar overlying a dilated, blunted, or deformed
calyx (Fig. 21-43) . The scars can vary from one to several in number and may affect one or both kidneys. Most are in upper and lower poles, consistent with the frequency of reflux in these sites. The microscopic changes involve predominantly tubules and interstitium. The tubules show atrophy in some areas and hypertrophy in others, or dilation. Dilated tubules may be filled with colloid casts (thyroidization). There are varying degrees of chronic interstitial inflammation and fibrosis in the cortex and medulla. In the presence of active infection, there may be neutrophils in the interstitium and pus casts in the tubules. Arcuate and interlobular vessels disclose obliterative endarteritis in the scarred areas; and in the presence of hypertension, hyaline arteriosclerosis is seen in the entire kidney. There is often fibrosis around the calyceal mucosa as well as marked chronic inflammatory infiltrate. Glomeruli may appear normal except for periglomerular fibrosis, but a variety of glomerular changes may be present, including ischemic fibrous obliteration as well as proliferation and necrosis ascribed to hypertension.
Figure 21-43 A , Chronic pyelonephritis. Surface (left) is irregularly scarred. Cut section (right) reveals characteristic dilation and blunting of calyces. Ureter is dilated and thickened--a finding consistent with chronic vesicoureteral reflux. B , Low-power view
showing corticomedullary renal scar with an underlying dilated deformed calyx. Note thyroidization of tubules in the cortex.
977
Patients with chronic pyelonephritis and reflux nephropathy who develop proteinuria in advanced stages exhibit secondary focal segmental glomerulosclerosis, as described later. Xanthogranulomatous pyelonephritis is an unusual and relatively rare form of chronic pyelonephritis characterized by accumulation of foamy macrophages intermingled with plasma cells, lymphocytes, polymorphonuclear leukocytes, and occasional giant cells. Often associated with Proteus infections and obstruction, the lesions sometimes produce large, yellowish orange nodules that may be confused with renal cell carcinoma. Clinical Course.
Chronic obstructive pyelonephritis may be insidious in onset or may present the clinical manifestations of acute recurrent pyelonephritis with back pain, fever, frequent pyuria, and bacteriuria. Chronic pyelonephritis associated with reflux may have a silent onset. These patients come to medical attention relatively late in the course of their disease because of the gradual onset of renal insufficiency and hypertension or because of the discovery of pyuria or bacteriuria on routine examination. Reflux nephropathy is a common cause of hypertension in children. Loss of tubular function--in particular of concentrating ability--gives rise to polyuria and nocturia. Radiographic studies show asymmetrically contracted kidneys with characteristic coarse scars and blunting and
deformity of the calyceal system. Significant bacteriuria may be present, but it is often absent in the late stages. Although proteinuria is usually mild, some patients with pyelonephritic scars develop focal segmental glomerulosclerosis with significant proteinuria, even in the nephrotic range, usually several years after the scarring has occurred and often in the absence of continued infection or persistent vesicoureteral reflux. The appearance of proteinuria and focal segmental glomerulosclerosis is a poor prognostic sign, and such patients may proceed to chronic end-stage renal failure. The glomerulosclerosis, as we have discussed, may be attributable to the adaptive glomerular alterations secondary to loss of renal mass caused by pyelonephritic scarring (renal ablation nephropathy). TUBULOINTERSTITIAL NEPHRITIS INDUCED BY DRUGS AND TOXINS
Toxins and drugs can produce renal injury in at least three ways: (1) they may trigger an interstitial immunologic reaction, exemplified by the acute hypersensitivity nephritis induced by such drugs as methicillin; (2) they may cause acute renal failure, as described earlier; and (3) they may cause subtle but cumulative injury to tubules that takes years to become manifest, resulting in chronic renal insufficiency. The last type of damage is especially treacherous because it may be clinically unrecognized until significant renal damage has occurred. Such is the case with analgesic abuse nephropathy, which is usually detected only after the onset of chronic renal insufficiency. Acute Drug-Induced Interstitial Nephritis
This is a well-recognized adverse reaction to a constantly increasing number of drugs. First reported after the use of sulfonamides, acute tubulointerstitial nephritis most frequently occurs with synthetic penicillins (methicillin, ampicillin), other synthetic antibiotics (rifampin), diuretics (thiazides), NSAIDs (phenylbutazone), and miscellaneous drugs (phenindione, cimetidine). [66] [66A ] The disease begins about 15 days (range, 2 to 40) after exposure to the drug and is characterized by fever, eosinophilia (which may be transient), a rash in about 25% of patients, and renal abnormalities. The last include hematuria, mild proteinuria, and leukocyturia (including eosinophils). A rising serum creatinine level or acute renal failure with oliguria develops in about 50% of cases, particularly in older patients. MORPHOLOGY.
On histologic examination, the abnormalities are in the interstitium, which shows pronounced edema and infiltration by mononuclear cells, principally lymphocytes and macrophages. Eosinophils and neutrophils may be present (Fig. 21-44) , often in large numbers, and plasma cells and basophils are sometimes found in small numbers. With some drugs (e.g., methicillin, thiazides), interstitial granulomas with giant cells may be seen. Variable degrees of tubular necrosis and regeneration are present. The glomeruli are normal except in some cases caused by NSAIDs when minimal change disease and
the nephrotic syndrome develop concurrently (see discussion under NSAIDs, later). Pathogenesis.
Many features of the disease suggest an immune mechanism. Clinical evidence of hypersensitivity includes the latent period, the eosinophilia and rash, the
Figure 21-44 Drug-induced interstitial nephritis, with prominent eosinophilia and mononuclear infiltrate. (Courtesy of Dr. H. Rennke, Brigham and Women's Hospital, Boston, MA.)
978
fact that the onset of nephropathy is not dose related, and the recurrence of hypersensitivity after re-exposure to the same or a cross-reactive drug. IgE serum levels are increased in some patients, and IgE-containing plasma cells and basophils are sometimes present in the lesions, suggesting that an IgE-mediated late-phase response hypersensitivity may be involved in the pathogenesis (Chapter 7) . The mononuclear or granulomatous infiltrate, together with positive results of skin tests to drug haptens, suggests a delayed hypersensitivity type reaction (type IV). The most likely sequence of events is that the drugs act as haptens, which, during secretion by tubules, covalently bind to some cytoplasmic or extracellular component of tubular cells and become immunogenic. The resultant injury is then due to IgE and cell-mediated immune reactions to tubular cells or their basement membranes. Clinical Features.
It is important to recognize drug-induced renal failure because withdrawal of the offending drug is followed by recovery, although it may take several months for renal function to return to normal and irreversible damage may occur occasionally in older subjects. Analgesic Abuse Nephropathy
This is a form of chronic renal disease caused by excessive intake of analgesic mixtures and characterized morphologically by chronic tubulointerstitial nephritis with renal papillary necrosis.[67] [68] Analgesic nephropathy is of worldwide distribution. Its incidence reflects consumption of analgesics in various populations. In some parts of Australia, it ranks as one of the most common causes of chronic renal insufficiency. Its incidence in the United States is relatively low but varies between states, being highest in the Southeast. Overall it accounts for 9%, 3%, and 1% of patients undergoing dialysis in Australia, Europe, and
the United States, respectively. The renal damage was first ascribed to phenacetin, but the analgesic mixtures consumed often contain, in addition, aspirin, caffeine, acetaminophen (a metabolite of phenacetin), and codeine. Patients who develop this disease usually ingest large quantities of mixtures of at least two antipyretic analgesics. In most countries, restriction of over-the-counter sale of phenacetin or analgesic mixtures has reduced the incidence of the disorder but has not eradicated it, presumably because non-phenacetin-containing mixtures are also available. Pathogenesis.
Papillary necrosis is readily induced experimentally by a mixture of aspirin and phenacetin, usually combined with water depletion. Most patients consume phenacetin-containing mixtures, and cases ascribed to ingestion of aspirin, phenacetin, or acetaminophen alone are uncommon. It is now clear that in the sequence of events leading to renal damage, papillary necrosis occurs first, and cortical tubulointerstitial nephritis is a secondary phenomenon. The phenacetin metabolite acetaminophen injures cells by both covalent binding and oxidative damage. Aspirin induces its potentiating effect by inhibiting the vasodilatory effects of prostaglandin, predisposing the papilla to ischemia. Thus, the papillary damage may be due to a combination of direct toxic effects of phenacetin metabolites and ischemic injury to both tubular cells and vessels. MORPHOLOGY.
In gross appearance, the kidneys are either normal or slightly reduced in size, and the cortex exhibits depressed and raised areas, the depressed areas representing cortical atrophy overlying necrotic papillae. The papillae show various stages of necrosis, calcification, fragmentation, and sloughing. This gross appearance contrasts with the papillary necrosis seen in diabetic patients, in which all papillae are at the same stage of acute necrosis. On microscopic examination, the papillary changes may take one of several forms: in early cases, there is patchy necrosis; but in the advanced form, the entire papilla is necrotic, often remaining in place as a structureless mass with ghosts of tubules and foci of dystrophic calcification (Fig. 21-45) . Segments of entire portions of the papilla may then be sloughed and excreted in the urine. The cortical changes consist of loss and atrophy of these tubules and interstitial fibrosis and inflammation. These changes are mainly due to obstructive atrophy caused by the tubular damage in the papilla, but superimposed pyelonephritic changes may be present. The cortical columns of Bertin are characteristically spared from this atrophy. The small vessels in the papilla and submucosa of the urinary tract exhibit characteristic PAS-positive basement membrane thickening (analgesic microangiopathy). Clinical Course.
Analgesic nephropathy is more common in women than in men and is particularly prevalent in individuals with recurrent headaches and muscle pain, in psychoneurotic
patients, and in factory workers. Early renal findings include inability to concentrate the urine, as would be expected with lesions in the papilla. Acquired distal renal tubular acidosis contributes to the development of renal stones. Headache, anemia, gastrointestinal symptoms, and hypertension are common accompaniments of analgesic nephropathy. The anemia in particular is out of proportion to the renal insufficiency, owing to damage to red cells by the phenacetin metabolites. Urinary tract infection complicates about 50% of cases. On occasion, entire tips of necrotic papillae are excreted, and these may cause gross hematuria or renal colic due to obstruction of the ureter by necrotic fragments. Computed tomographic imaging is helpful in detecting papillary necrosis and calcifications. Progressive impairment of renal function may lead to chronic renal failure, but with drug withdrawal and proper therapy for infection, renal function may either stabilize or actually improve. Unfortunately, a complication occurs in a small percentage of patients who have survived because of their discontinuance of the offending drugs--namely, the development of transitional papillary carcinoma of the renal pelvis. Whether the carcinogenic effect is due to a metabolite of phenacetin or to some other component of the analgesic compounds is unsettled.
979
Figure 21-45 Analgesic nephropathy. A , The brownish necrotic papilla, transformed to a necrotic, structureless mass, fills the pelvis. B , Microscopic view. Note fibrosis in the medulla. (Courtesy of Dr. F. J. Gloor, Institut fur Pathologie, Kantonsspital, St. Gallen, Switzerland.)
Papillary necrosis is not specific for analgesic nephropathy. In addition to diabetes mellitus, it can occur in urinary tract obstruction, sickle cell anemia or trait, and focally in renal tuberculosis. Table 21-10 lists certain features of papillary necrosis in these conditions. Nephropathy Associated With Nonsteroidal Anti-Inflammatory Drugs
NSAIDs are one of the most common classes of drugs currently in use and produce several forms of renal injury. Although these complications are fortunately uncommon, they need to be kept in mind, since NSAIDs are frequently administered to patients with other potential causes of renal disease. NSAID-associated renal syndromes include Hemodynamically induced acute renal failure, due to the inhibition of vasodilatory prostaglandin synthesis by NSAIDs. This is particularly likely to occur in the setting of other renal diseases or conditions causing volume depletion. Acute hypersensitivity interstitial nephritis, resulting in acute renal failure, as described earlier. Acute interstitial nephritis and lipoid nephrosis. This curious association of two diverse renal conditions, one leading to renal failure and the other to nephrotic syndrome, remains unexplained.
Membranous glomerulonephritis, with the nephrotic syndrome, is a recently appreciated association, also of unclear pathogenesis. [69] Whether prolonged use of NSAIDs by decreasing prostaglandin synthesis causes papillary necrosis and chronic interstitial disease, such as occurs with analgesics, is currently unproven. [68] OTHER TUBULOINTERSTITIAL DISEASES
Urate Nephropathy
Three types of nephropathy can occur in patients with hyperuricemic disorders. Acute uric acid nephropathy is 980
caused by the precipitation of uric acid crystals in the renal tubules, principally in collecting ducts, leading to obstruction of nephrons and the development of acute renal failure. This type is particularly likely to occur in patients with leukemias and lymphomas who are undergoing chemotherapy; the drugs increase the destruction of neoplastic nuclei and the elaboration of uric acid. Precipitation of uric acid is favored by the acidic pH in collecting tubules. Chronic urate nephropathy, or gouty nephropathy, occurs in patients with more protracted forms of hyperuricemia. The lesions are ascribed to the deposition of monosodium urate crystals in the acidic milieu of the distal tubules and collecting ducts as well as in the interstitium. These deposits have a distinct histologic appearance, in the form of birefringent, needle-like crystals present either in the tubular lumina or in the interstitium (Fig. 21-46) . The urates induce a tophus often surrounded by foreign body giant cells, other mononuclear cells, and a fibrotic reaction (Chapter 28) . Tubular obstruction by the urates causes cortical atrophy and scarring. Arterial and arteriolar thickening is common in these kidneys, owing to the relatively high frequency of hypertension in patients with gout. Clinically, urate nephropathy is a subtle disease associated with tubular defects that may progress slowly. Patients with gout who actually develop a chronic nephropathy commonly have evidence of increased exposure to lead, mostly by way of drinking "moonshine" whiskey contaminated with lead. The third renal syndrome in hyperuricemia is nephrolithiasis; uric acid stones are present in 22% of patients with gout and 42% of those with secondary hyperuricemia (see later discussion of renal stones).
TABLE 21-10 -- PAPILLARY NECROSIS Diabetes Analgesic Sickle Cell Obstruction Mellitus Nephropathy Disease Male-to-female ratio
1:3
1:5
1:1
9:1
Time course
10 years
7 years of abuse
Variable
Variable
Infection
80%
25%
±
90%
Calcification
Rare
Frequent
Rare
Frequent
Almost all; different stages of necrosis
Few
Variable
Number of papillae Several; all of affected same stage
Modified from Seshan S, et al (eds): Classification and Atlas of Tubulointerstitial and Vascular Diseases. Baltimore, Williams & Wilkins (in press).
Hypercalcemia and Nephrocalcinosis
Disorders characterized by hypercalcemia, such as hyperparathyroidism, multiple myeloma, vitamin D intoxication,
Figure 21-46 Urate crystals in the renal medulla. Note giant cells and fibrosis around the crystals.
metastatic bone disease, or excess calcium intake (milk-alkali syndrome), may induce the formation of calcium stones and deposition of calcium in the kidney (nephrocalcinosis). Extensive degrees of calcinosis, under certain conditions, may lead to a form of chronic tubulointerstitial disease and renal insufficiency. The first damage induced by the hypercalcemia is at the intracellular level, in the tubular epithelial cells, resulting in mitochondrial distortion and evidence of cell injury. Subsequently, calcium deposits can be demonstrated within the mitochondria, cytoplasm, and basement membrane. Calcified cellular debris then aids in obstruction of the tubular lumens and causes obstructive atrophy of nephrons with interstitial fibrosis and nonspecific chronic inflammation. Atrophy of entire cortical areas drained by calcified tubules may occur, and this accounts for the alternating areas of normal and scarred parenchyma seen in such kidneys. The earliest functional defect is an inability to elaborate a concentrated urine. Other tubular defects, such as tubular acidosis and salt-losing nephritis, may also occur. With further damage, a slowly progressive renal insufficiency develops. This is usually due to nephrocalcinosis, but many of these patients also have calcium stones and secondary pyelonephritis. Multiple Myeloma
Nonrenal malignant tumors, particularly those of hematopoietic origin, affect the kidneys in a number of ways (Table 21-11) . The most common involvements are tubulointerstitial, caused by complications of the tumor (hypercalcemia, hyperuricemia, obstruction of ureters) or therapy (irradiation, hyperuricemia, chemotherapy, infections in immunosuppressed patients). As the survival rate of patients with malignant neoplasms increases, so do these renal complications. We limit the discussion to the
renal lesions in multiple myeloma that sometimes dominate the clinical picture in patients with this disease. Renal involvement is a sometimes ominous manifestation of multiple myeloma; overt renal insufficiency occurs in half the patients with this disease. Several factors contribute to renal damage: Bence Jones proteinuria and cast nephropathy. The main cause of renal dysfunction is related to Bence Jones (light-chain) proteinuria, because renal failure correlates well with the presence and amount of such proteinuria and is extremely rare in its absence. Two mechanisms appear to account for the renal toxicity of Bence Jones proteins. First, some light chains are directly toxic to epithelial cells; different light chains have different nephrotoxic potential. Second, Bence Jones proteins combine with the urinary glycoprotein (Tamm-Horsfall protein) under acidic conditions to form large, histologically distinct tubular casts that obstruct the tubular lumina and also induce a peritubular inflammatory reaction (cast nephropathy). Amyloidosis, which occurs in 6% to 24% of patients with myeloma Light-chain nephropathy. In some patients, light chains deposit in glomeruli in nonfibrillar forms, causing a glomerulopathy 981
(described earlier), or around tubules, causing a tubulointerstitial nephritis. Hypercalcemia and hyperuricemia, which are often present in these patients Vascular disease in the usually elderly population affected with myeloma Urinary tract obstruction with secondary pyelonephritis
TABLE 21-11 -- RENAL INVOLVEMENT BY NONRENAL NEOPLASMS Direct tumor invasion of renal parenchyma Ureters (obstruction) Artery (renovascular hypertension) Hypercalcemia Hyperuricemia Amyloidosis Excretion of abnormal proteins (multiple myeloma) Radiotherapy Chemotherapy Infection Glomerulopathy Immune complex glomerulonephritis (carcinomas) Lipoid nephrosis (Hodgkin disease)
MORPHOLOGY.
The tubulointerstitial changes in multiple myeloma are fairly characteristic. The Bence Jones tubular casts appear as pink to blue amorphous masses, sometimes concentrically laminated, filling and distending the tubular lumens. Some of the casts are surrounded by multinucleate giant cells, derived from either reactive tubular epithelium or mononuclear phagocytes (Fig. 21-47) . The epithelium surrounding the cast is often necrotic, and the adjacent interstitial tissue usually shows a nonspecific inflammatory response. On occasion, the casts erode their way from the tubules into the interstitium and here evoke a granulomatous inflammatory reaction.
Figure 21-47 Myeloma kidney. Note tubular casts with multinucleate cells around them. (Courtesy of Dr. C. Alpers, University of Washington, Seattle, WA.)
The histologic features of amyloidosis, light-chain nephropathy, and nephrocalcinosis and infection, described elsewhere, may also be present. Clinically, the renal manifestations are of several types. In the most common form, chronic renal failure develops insidiously and usually progresses slowly during a period of several months to years. Another form occurs suddenly and is manifested by acute renal failure with oliguria. Precipitating factors in these patients include dehydration, hypercalcemia, acute infection, and treatment with nephrotoxic antibiotics. Proteinuria occurs in 70% of patients with myeloma; the presence of significant non-light-chain proteinuria (e.g., albumin) suggests secondary amyloidosis or light-chain glomerulopathy. DISEASES OF BLOOD VESSELS Nearly all diseases of the kidney involve the renal blood vessels secondarily. Systemic vascular diseases, such as various forms of vasculitis, also affect renal vessels, and often their effects on the kidney are clinically important. Hypertension, as we discussed in Chapter 12 , is intimately linked with the kidney, because kidney disease can be both the cause and consequence of increased blood pressure. [70] [70A] In this chapter, we discuss benign and malignant nephrosclerosis and renal artery stenosis, lesions associated with hypertension, and sundry lesions involving mostly smaller vessels of the kidney. Benign Nephrosclerosis
Benign nephrosclerosis is the term used for the kidney associated with sclerosis of renal arterioles and small arteries. The resultant effect is focal ischemia of parenchyma supplied by the thickened narrowed vessels. Some degree of nephrosclerosis is present at autopsy with increasing age, more in blacks than whites, preceding or in the absence
of hypertension. [71] Hypertension and diabetes mellitus, however, increase the incidence and severity of the lesions. Pathogenesis.
Two processes participate in inducing the arterial lesions: Medial and intimal thickening, as a response to hemodynamic changes, genetic defects, or both Hyaline deposition in arterioles, caused partly by extravasation of plasma proteins through injured endothelium and partly by increased deposition of basement membrane matrix MORPHOLOGY.
In gross appearance, the kidneys are either normal in size or moderately reduced to average weights between 110 and 130 gm. The cortical surfaces have a fine, even granularity
982
Figure 21-48 Close-up of gross appearance of the cortical surface in benign nephrosclerosis illustrating fine leathery granularity of the
surface.
that resembles grain leather (Fig. 21-48) . On section, the loss of mass is due mainly to cortical narrowing. On histologic examination, there is narrowing of the lumens of arterioles and small arteries, caused by thickening and hyalinization of the walls (Fig. 21-49) (hyaline arteriolosclerosis). In addition to arteriolar hyalinization, the interlobular and arcuate arteries exhibit a characteristic lesion that consists of medial hypertrophy, reduplication of the elastic lamina, and increased myofibroblastic tissue in the intima, with consequent narrowing of the lumen. This change, called fibroelastic hyperplasia, often accompanies hyaline arteriolosclerosis and increases in severity with age and in the presence of hypertension. Consequent to the vascular narrowing, there is patchy ischemic atrophy, which consists of (1) foci of tubular atrophy and interstitial fibrosis and (2) a variety of glomerular alterations. The latter include collapse of GBMs, deposition of collagen within the Bowman space, periglomerular fibrosis, and total sclerosis of glomeruli.
Clinical Features.
Uncomplicated benign nephrosclerosis alone unusually causes renal insufficiency or uremia. There are usually moderate reductions in renal plasma flow, but the GFR is normal or slightly reduced. On occasion, there is mild proteinuria. However, three groups of hypertensives with benign nephrosclerosis are at increased risk of developing renal failure: blacks; patients with more severe blood pressure elevations; and patients with a second underlying disease, especially diabetics. In these groups, renal insufficiency may supervene after prolonged benign hypertension, but more rapid renal failure results from the development of the malignant or accelerated phase of hypertension, discussed next. Malignant Nephrosclerosis and Accelerated Hypertension
Malignant nephrosclerosis is the form of renal disease associated with the malignant or accelerated phase of hypertension.[71] [71A ] This dramatic pattern of hypertension may occasionally develop in previously normotensive individuals but often is superimposed on preexisting essential benign hypertension, or secondary forms of hypertension, or an underlying chronic renal disease, particularly glomerulonephritis or reflux nephropathy (Table 21-12) . It is also a frequent cause of death from uremia in patients with scleroderma. Malignant hypertension is relatively uncommon, occurring in 1% to 5% of all patients with elevated blood pressure. In its pure form, it usually affects younger individuals, with a high preponderance in men and in blacks. Pathogenesis.
The basis for this turn for the worse in hypertensive subjects is unclear, but the following sequence of events is suggested. The initial event appears to be some form of vascular damage to the kidneys. This most commonly results from long-standing benign hypertension, with eventual injury to the arteriolar walls, or it may spring from arteritis or a coagulopathy. In either case, the result is increased permeability of the small vessels to fibrinogen and other plasma proteins, endothelial injury, and platelet deposition. This leads to the appearance of fibrinoid necrosis
Figure 21-49 Hyaline arteriolosclerosis. High-power view of two arterioles with hyaline deposition, marked thickening of the walls, and a narrowed lumen. (Courtesy of Dr. M.A. Venkatachalam, Department of Pathology, University of Texas Health Sciences Center, San Antonio, TX.)
983
TABLE 21-12 -- TYPES OF HYPERTENSION Primary or Essential Hypertension
Secondary Hypertension Renal Acute glomerulonephritis Chronic renal disease Renal artery stenosis Renal vasculitis Renin-producing tumors Endocrine Adrenocortical hyperfunction (Cushing syndrome) Oral contraceptives Pheochromocytoma Acromegaly Myxedema Thyrotoxicosis (systolic) Vascular Coarctation of aorta Polyarteritis nodosa Aortic insufficiency (systolic) Neurogenic Psychogenic Increased intracranial pressure Polyneuritis, bulbar poliomyelitis, others of arterioles and small arteries and intravascular thrombosis. Mitogenic factors from platelets (e.g., platelet-derived growth factor [PDGF]), plasma and other cells cause intimal smooth hyperplasia of vessels, resulting in the hyperplastic arteriolosclerosis typical of malignant hypertension and further narrowing of the lumens. The kidneys become markedly ischemic. With severe involvement of the renal afferent arterioles, the renin-angiotensin system receives a powerful stimulus, and indeed patients with malignant hypertension have markedly elevated levels of plasma renin. This then sets up a self-perpetuating cycle in which angiotensin II causes intrarenal vasoconstriction, and the attendant renal ischemia perpetuates renin secretion. Other vasoconstrictors (e.g., endothelin) and loss of vasodilators (nitric oxide) may also contribute to vasoconstriction. Aldosterone levels are also elevated, and salt retention undoubtedly contributes to the elevation of blood pressure. The consequences of the markedly elevated blood pressure on the blood vessels throughout the body are known as malignant arteriosclerosis, and the renal disorder is malignant nephrosclerosis.
MORPHOLOGY.
On gross inspection, the kidney size is dependent on the duration and severity of the hypertensive disease. Small, pinpoint petechial hemorrhages may appear on the cortical surface from rupture of arterioles or glomerular capillaries, giving the kidney a peculiar "flea-bitten" appearance. Two histologic alterations characterize blood vessels in malignant hypertension (Fig. 21-50) : Fibrinoid necrosis of arterioles. This appears as an eosinophilic granular change in the blood vessel wall, which stains positively for fibrin by histochemical or immunofluorescence techniques. In addition, there is often an inflammatory infiltrate within the wall, giving rise to the term necrotizing arteriolitis. In the interlobular arteries and arterioles, there is intimal thickening caused by a proliferation of elongated, concentrically arranged cells, smooth muscle cells, together with fine concentric layering of collagen. This alteration is known as hyperplastic arteriolitis, also referred to as onion-skinning. The lesion correlates well with renal failure in malignant hypertension. Sometimes the glomeruli become necrotic and infiltrated with neutrophils, and the glomerular capillaries may thrombose (necrotizing glomerulitis). The arteriolar and arterial lesions result in considerable narrowing of all vascular lumens, with ischemic atrophy and infarction distal to the abnormal vessels.
Figure 21-50 Malignant hypertension. A , Fibrinoid necrosis of afferent arteriole (PAS stain). B , Hyperplastic arteriolitis (onion-skin lesion). (Courtesy of Dr. H. Rennke, Brigham and Women's Hospital, Boston, MA.)
984
Clinical Course.
The full-blown syndrome of malignant hypertension is characterized by diastolic pressures greater than 130 mm Hg, papilledema retinopathy, encephalopathy, cardiovascular abnormalities, and renal failure. Most often, the early symptoms are related to increased intracranial pressure and include headaches, nausea, vomiting, and visual impairments, particularly the development of scotomas or spots before the eyes. "Hypertensive crises" are sometimes encountered, characterized by episodes of loss of consciousness or even convulsions. At the onset of rapidly mounting blood pressure, there is marked proteinuria and microscopic or sometimes macroscopic hematuria but no significant alteration in renal function. Soon, however, renal failure makes its appearance. The syndrome is a true medical emergency requiring the institution of aggressive and prompt antihypertensive therapy before the development of irreversible renal lesions. Before introduction of the new antihypertensive drugs, malignant
hypertension was associated with a 50% mortality rate within 3 months of onset, progressing to 90% within a year. At present, however, about 75% of patients will survive 5 years, and 50% survive with precrisis renal function. Renal Artery Stenosis
Unilateral renal artery stenosis is a relatively uncommon cause of hypertension, responsible for 2% to 5% of cases, but it is of importance because it is a potentially curable form of hypertension, surgical treatment being successful in 70% to 80% of carefully selected cases in humans. [72] Furthermore, much early knowledge of renal mechanisms in hypertension has come from studies of experimental and human renal artery stenosis. Pathogenesis.
The classic experiments of Goldblatt [73] in 1934 showed that constriction of one renal artery in dogs results in hypertension and that the magnitude of the effect is roughly proportional to the amount of constriction. Later experiments in rats confirmed these results, and in time it was shown that the hypertensive effect, at least initially, is due to stimulation of renin secretion by cells of the juxtaglomerular apparatus and the subsequent production of the vasoconstrictor angiotensin II. A large proportion of patients with renovascular hypertension have elevated plasma or renal vein renin levels, and almost all show a reduction of blood pressure when given competitive antagonists of angiotensin II. Further, unilateral renal renin hypersecretion can be normalized after renal revascularization, in association with a decrease in blood pressure. Other factors, however, contribute to the maintenance of renovascular hypertension after the renin-angiotensin system has initiated it, including sodium retention and, possibly, endothelin and loss of nitric oxide. MORPHOLOGY.
The most common cause of renal artery stenosis (70% of cases) is occlusion by an atheromatous plaque at the origin of the renal artery. This lesion occurs more frequently in men, the incidence increasing with advancing age and diabetes mellitus. The plaque is usually concentrically placed, and superimposed thrombosis often occurs. The second type of lesion leading to stenosis is so-called fibromuscular dysplasia of the renal artery. This is a heterogeneous group of lesions characterized by fibrous or fibromuscular thickening and may involve the intima, the media, or the adventitia of the artery. These lesions are thus subclassified into intimal, medial, and adventitial hyperplasia--the medial type being by far the most common (Fig. 21-51) . The stenoses, as a whole, are more common in women and tend to occur in younger age groups (i.e., in the third and fourth decades). The lesions may consist of a single well-defined constriction or a series of narrowings, usually in the middle or distal portion of the renal artery. They may also involve the segmental branches and may be bilateral. The ischemic kidney is usually reduced in size and shows signs of diffuse ischemic
atrophy, with crowded glomeruli, atrophic tubules, interstitial fibrosis, and focal inflammatory infiltrate. The arterioles in the ischemic kidney are usually protected from the effects of high pressure, thus showing only mild arteriolosclerosis, in contrast to the contralateral nonischemic kidney, which may exhibit hyaline arteriolosclerosis, depending on the severity of the preceding hypertension. Clinical Course.
Few distinctive features suggest the presence of renal artery stenosis, and in general, these patients resemble those presenting with essential hypertension. On occasion, a bruit can be heard on auscultation of the kidneys. Elevated plasma or renal vein renin, response to angiotensin-converting enzyme inhibitor, renal scans,
Figure 21-51 Fibromuscular dysplasia of the renal artery, medial type (elastic tissue stain). The medium shows marked fibrous thickening, and the lumen is stenotic. (Courtesy of Dr. Seymour Rosen, Beth Israel Hospital, Boston, MA.)
985
and intravenous pyelography may aid with diagnosis, but arteriography is required to localize the stenotic lesion. As noted, the cure rate after surgery is 70% to 80% in well-selected cases. Thrombotic Microangiopathies
As described in Chapter 14 , these represent a group of disorders with overlapping clinical manifestations that are characterized morphologically by thrombosis in capillaries and arterioles throughout the body (Fig. 21-52) and clinically by microangiopathic hemolytic anemia, thrombocytopenia, and, in certain conditions, renal failure.[74] The renal failure is associated with platelet or platelet-fibrin thrombi in the interlobular renal arteries and glomeruli, together with necrosis and thickening of the vessel walls (Fig. 21-52) . The classification of these diseases is somewhat muddied by the fact that two of the conditions, hemolytic-uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP), show considerable overlap; indeed, they are now termed the HUS/TTP syndrome. [74] A useful categorization by cause and condition is as follows: 1. Classic childhood HUS, most frequently associated with intestinal infection by verocytotoxin-releasing bacteria 2. Adult HUS, associated with a. Infectionb b. Antiphospholipid antibodiesc c. Complications of pregnancy and contraceptivesd d. Vascular renal diseases such as scleroderma and hypertensione
e. Chemotherapeutic and immunosuppressive drugs 3. Idiopathic HUS/TTP The morphologic changes may be similar to those seen in malignant hypertension; but in these conditions, they may precede development of hypertension or may be seen in its absence.
Figure 21-52 Fibrin stain showing platelet-fibrin thrombi (red) in glomerular capillaries characteristic of microangiopathic disorders.
Pathogenesis.
Although these disorders may have diverse causes, two processes dominate the pathogenetic sequence of events: (1) endothelial injury and activation, with subsequent intravascular thrombosis, and (2) platelet aggregation. Both of these events cause vascular obstruction and vasoconstriction and thus precipitate distal ischemia. [75] Endothelial Injury.
The triggers for endothelial injury and activation as described in Chapters 3 and 12 can be bacterial endotoxins and cytotoxins, cytokines, viruses, drugs, or possibly antiendothelial antibodies. In childhood HUS associated with diarrheal infections, verocytotoxin, as we shall see, is clearly the culprit. [76] Still uncharacterized factors in sera of patients with both idiopathic and secondary HUS have recently been shown to cause apoptosis of cultured endothelial cells. [76] But it must be admitted that in many cases, the proximate endothelial toxin is unknown. Endothelial injury may mediate the microangiopathy in several ways. Endothelial denudation exposes a potentially thrombogenic subendothelial ECM. Reduced production of prostaglandin I2 and nitric oxide (both of which normally cause vasodilation and inhibit platelet aggregation) enhances platelet aggregation and causes vasoconstriction. Vasoconstriction can also be induced by endothelial-derived endothelin. Endothelial cells may also be activated, increasing their adhesivity to leukocytes, which themselves contribute to thrombosis, as described in Chapter 5 . Endothelial cells elaborate abnormal multimers of von Willebrand factor, which cause platelet aggregation (Chapter 14) . Platelet Aggregation.
Because many thrombi in HUS/TTP are composed largely of aggregated platelets with scant fibrin, serum factors causing platelet aggregation, or decreased levels of factors that normally inhibit platelet aggregation, have been sought. These include unusually large von Willebrand factor multimers and certain proteases, including a cysteine
protease called calpain, of uncertain origin. Some of these factors presumably induce aggregation by activating platelet surface glycoproteins (Chapter 5) . It is not clear, however, whether the platelet defects are primary or secondary to endothelial dysfunction. As we noted, damaged endothelial cells elaborate abnormal von Willebrand factor multimers . CLASSIC (CHILDHOOD) HEMOLYTIC-UREMIC SYNDROME
This is the most well characterized of the hemolytic-uremic syndromes, since as many as 75% of cases occur in children after intestinal infection with verocytotoxin-producing E. coli (e.g., type O157:H7). [77] Verocytotoxins (so called because they cause damage to Vero cells in culture) are similar to Shiga toxins produced by Shigella and described in Chapter 9 . Some epidemics have been traced to ingestion of infected ground meat (hamburgers). The disease is one of the main causes of acute renal failure in children. It is characterized by the sudden onset,
986
usually after a gastrointestinal or influenza-like prodromal episode, of bleeding manifestations (especially hematemesis and melena), severe oliguria, hematuria, a microangiopathic hemolytic anemia, and (in some patients) prominent neurologic changes. Hypertension is present in about half the patients. The pathogenesis of this syndrome is clearly related to the Shiga-like toxin. The toxin has a variety of effects on endothelium, causing increased adhesion of leukocytes; increased endothelin production and loss of endothelial nitric oxide (both favoring vasoconstriction); and in the presence of cytokines, such as TNF, endothelial lysis. The resultant endothelial effects enhance both thrombosis and vasoconstriction, resulting in the characteristic microangiopathy. Verocytotoxin also binds to erythrocytes, activates monocytes, and affects platelet function. MORPHOLOGY.
In gross appearance, the kidneys may show patchy or widespread renal cortical necrosis (described later). On microscopic examination, the glomeruli show thickening of capillary walls, due largely to endothelial and subendothelial swelling, and deposits of fibrin-related materials in the capillary lumens, subendothelially, and in the mesangium. Interlobular and afferent arterioles show fibrinoid necrosis and intimal hyperplasia and are often occluded by thrombi. If the renal failure is managed properly with dialysis, most patients experience recovery in a matter of weeks. However, the long-term (15 to 25 years) prognosis is not uniformly favorable. In one study, only 10 of 25 patients had normal renal function, and 7 had
chronic renal failure. [78] ADULT HEMOLYTIC-UREMIC SYNDROME/THROMBOTIC THROMBOCYTOPENIC PURPURA
HUS/TTP occurs in adults under a variety of settings: 1. In association with infection, such as typhoid fever, E. coli septicemia, viral infections, and shigellosis (postinfectious HUS). Endotoxin, or Shiga toxin (from Shigella species), plays a role in the pathogenesis of such cases. 2. In the antiphospholipid syndrome, either primary or secondary to SLE (lupus anticoagulant). The syndrome is described in detail in Chapter 5 . The microangiopathic changes in the kidney tend to be more chronic--healing of the thrombotic changes in glomeruli results in changes mimicking membranoproliferative glomerulonephritis. 3. In women in relation to complications of pregnancy (placental hemorrhage) or the postpartum period. So-called postpartum renal failure usually occurs after an uneventful pregnancy, 1 day to several months after delivery, and is characterized by microangiopathic hemolytic anemia, oliguria, anuria, and initially mild hypertension. The condition has a grave prognosis, although recovery may occur in milder cases. 4. Associated with vascular renal diseases, such as scleroderma, and malignant hypertension. 5. In patients treated with chemotherapeutic and immunosuppressive drugs, such as mitomycin, cyclosporine, bleomycin, and cisplatin. IDIOPATHIC HUS/TTP
Classic idiopathic TTP, discussed earlier (Chapter 14) , is manifested by fever, neurologic symptoms, hemolytic anemia, thrombocytopenic purpura, and the presence of thrombi in glomerular capillaries and afferent arterioles. The disease is more common in women, and most patients are younger than 40 years. Idiopathic TTP and various forms of HUS overlap considerably both clinically and morphologically. In classic TTP, however, central nervous system involvement is the dominant feature, whereas renal involvement occurs in only about 50% of patients. In the kidney, eosinophilic granular thrombi are present predominantly in the terminal part of the interlobular arteries, afferent arterioles, and glomerular capillaries. The thrombi are composed largely of platelets and are found in arterioles of many organs throughout the body. Untreated, the disease was once highly fatal, but exchange transfusions and corticosteroid therapy have reduced mortality to less than 50%. OTHER VASCULAR DISORDERS
Atherosclerotic Ischemic Renal Disease
We have seen that atherosclerotic unilateral artery stenosis can lead to hypertension. Bilateral disease, usually diagnosed definitively by arteriography, now appears to be a fairly common cause of chronic ischemia, with renal insufficiency, in older individuals
sometimes in the absence of hypertension. [71] [79] The importance of recognizing this condition is that surgical revascularization is beneficial in reversing further decline in renal function. Atheroembolic Renal Disease
Embolization of fragments of atheromatous plaques from the aorta or renal artery into intraparenchymal renal vessels occurs in elderly patients with severe atherosclerosis, especially after surgery on the abdominal aorta, aortography, or intra-aortic cannulization. These emboli can be recognized in the walls of arcuate and interlobular arteries by their content of cholesterol crystals, which appear as rhomboid clefts (Fig. 21-53) . The clinical consequences of atheroemboli vary according to the number of emboli and the preexisting state of renal function. Frequently, they have no functional significance. However, acute renal failure may result in elderly patients in whom renal function is already compromised, principally after abdominal surgery on atherosclerotic aneurysms. Sickle Cell Disease Nephropathy
Sickle cell disease in both the homozygous and the heterozygous forms may lead to a variety of alterations in renal morphology and function, some of which, fortunately uncommonly, produce clinically significant abnormalities. The various manifestations are termed sickle cell nephropathy.
987
Figure 21-53 Atheroemboli with typical cholesterol clefts in the interlobar artery.
The most common clinical and functional abnormalities are hematuria and a diminished concentrating ability. These are thought to be largely due to accelerated sickling in the hypertonic hypoxic milieu of the renal medulla, which increases the viscosity of the blood during its passage through the vasa recta, leading to plugging of vessels and decreased flow. Patchy papillary necrosis may occur in both homozygotes and heterozygotes; this is sometimes associated with cortical scarring. Proteinuria is also common in sickle cell disease, occurring in about 30% of patients. It is usually mild to moderate, but on occasion the overt nephrotic syndrome arises, associated with a membranoproliferative glomerular lesion. Diffuse Cortical Necrosis
This is an uncommon condition that occurs most frequently after an obstetric emergency, such as abruptio placentae (premature separation of the placenta), septic shock, or extensive surgery. When bilateral and symmetric, it is uniformly fatal, but
patchy cortical necrosis may permit survival. The cortical destruction has all the earmarks of ischemic necrosis. Glomerular and arteriolar microthrombi are found in some but by no means all cases; if present, they clearly contribute to the necrosis and renal damage. It is thought that the disorder results from disseminated intravascular coagulation (Chapter 5) and vasoconstriction. MORPHOLOGY.
The gross alterations of the massive ischemic necrosis are sharply limited to the cortex (Fig. 21-54) . The histologic appearance is that of acute ischemic infarction. The lesions may be patchy, with areas of apparently better preserved cortex. Intravascular and intraglomerular thromboses may be prominent but are usually focal, and acute necroses of small arterioles and capillaries may occasionally be present. Hemorrhages occur into the glomeruli, together with the precipitation of fibrin in the glomerular capillaries. Massive acute cortical necrosis is of grave significance, since it gives rise to sudden anuria, terminating rapidly in uremic death. Instances of unilateral or patchy involvement are compatible with survival. Renal Infarcts
The kidneys are favored sites for the development of infarcts, as one fourth of the cardiac output passes through these organs. Although thrombosis in advanced atherosclerosis and the acute vasculitis of polyarteritis nodosa may occlude arteries, most infarcts are due to embolism. The major source of such emboli is mural thrombosis in the left atrium and ventricle as a result of myocardial infarction. Vegetative endocarditis, thrombosis in aortic aneurysms, and aortic atherosclerosis are less frequent sites for the origin of emboli. MORPHOLOGY.
Because the arterial supply to the kidney is of the "end-organ" type, most infarcts are of the "white" anemic type. They may occur as solitary lesions or may be multiple and bilateral. Within 24 hours, infarcts become sharply demarcated, pale, yellow-white areas that may contain small irregular foci of hemorrhagic discoloration. They are usually ringed by a zone of intense hyperemia. On section, they are wedge shaped, with the base against the cortical surface and the apex pointing toward the medulla. There may be a narrow rim of preserved subcortical tissue that has been spared by the collateral capsular circulation. In time, these acute areas of ischemic necrosis undergo progressive fibrous scarring, giving rise to depressed, pale, gray-white scars that
Figure 21-54 Diffuse cortical necrosis. Pale ischemic necrotic areas are confined to the cortex and columns of Bertin.
988
assume a V shape on section. The histologic changes in renal infarction are those of ischemic coagulation necrosis, described in Chapter 1 . Many renal infarcts are clinically silent. Sometimes, pain with tenderness localized to the costovertebral angle occurs, and this is associated with showers of red cells in the urine. Large infarcts of one kidney are a well-known basis for hypertension. URINARY TRACT OBSTRUCTION (OBSTRUCTIVE UROPATHY) Recognition of urinary obstruction is important because obstruction increases susceptibility to infection and to stone formation, and unrelieved obstruction almost always leads to permanent renal atrophy, termed hydronephrosis or obstructive uropathy. Fortunately, many causes of obstruction are surgically correctable or medically treatable. Obstruction may be sudden or insidious, partial or complete, unilateral or bilateral; it may occur at any level of the urinary tract from the urethra to the renal pelvis. It can be caused by lesions that are intrinsic to the urinary tract or extrinsic lesions that compress the ureter. The common causes are as follows (Fig. 21-55) : 1. Congenital anomalies: posterior urethral valves and urethral strictures, meatal stenosis, bladder neck obstruction; ureteropelvic junction narrowing or obstruction; severe vesicoureteral reflux 2. Urinary calculi 3. Benign prostatic hypertrophy 4. Tumors: carcinoma of the prostate, bladder tumors, contiguous malignant disease (retroperitoneal lymphoma), carcinoma of the cervix or uterus 5. Inflammation: prostatitis, ureteritis, urethritis, retroperitoneal fibrosis 6. Sloughed papillae or blood clots 7. Normal pregnancy 8. Uterine prolapse and cystocele 9. Functional disorders: neurogenic (spinal cord damage) and other functional abnormalities of the ureter or bladder (often termed dysfunctional obstruction) Hydronephrosis is the term used to describe dilation of the renal pelvis and calyces associated with progressive atrophy of the kidney due to obstruction to the outflow of urine. Even with complete obstruction, glomerular filtration persists for some time because the filtrate subsequently diffuses back into the renal interstitium and perirenal spaces, where it ultimately returns to the lymphatic and venous systems. Because of this continued filtration, the affected calyces and pelvis become dilated, often markedly so. The high pressure in the pelvis is transmitted back through the collecting ducts into
the cortex, causing renal atrophy, but it also compresses the renal vasculature of the medulla, causing a diminution in inner medullary plasma flow. The medullary vascular defects are reversible, but if
Figure 21-55 Obstructive lesions of the urinary tract.
protracted, obstruction will lead to medullary functional disturbances. Accordingly, the initial functional alterations are largely tubular, manifested primarily by impaired concentrating ability. Only later does the GFR begin to diminish. Obstruction also triggers an interstitial inflammatory reaction, mediated by activated tubular cells and leukocytes, leading eventually to interstitial fibrosis, by mechanisms similar to those discussed earlier (see Fig. 21-15) (Figure Not Available) . [80] MORPHOLOGY.
When the obstruction is sudden and complete, the reduction of glomerular filtration usually leads to mild dilation of the pelvis and calyces but sometimes to atrophy of the renal parenchyma. When the obstruction is subtotal or intermittent, glomerular filtration is not suppressed, and progressive dilation ensues. Depending on the level of urinary block, the dilation may affect first the bladder or ureter and then the kidney. In gross appearance, the kidney may have slight to massive enlargement. The earlier features are those of simple dilation of the pelvis and calyces,
989
but in addition there is often significant interstitial inflammation, even in the absence of infection. In chronic cases, the picture is one of cortical tubular atrophy with marked diffuse interstitial fibrosis. Progressive blunting of the apices of the pyramids occurs, and eventually these become cupped. In far-advanced cases, the kidney may become transformed into a thin-walled cystic structure having a diameter of up to 15 to 20 cm (Fig. 21-56) with striking parenchymal atrophy, total obliteration of the pyramids, and thinning of the cortex. Clinical Course.
Acute obstruction may provoke pain attributed to distention of the collecting system or renal capsule. Most of the early symptoms are produced by the basic cause of the hydronephrosis. Thus, calculi lodged in the ureters may give rise to renal colic, and prostatic enlargements to bladder symptoms. Unilateral, complete, or partial hydronephrosis may remain silent for long periods, since the unaffected kidney can maintain adequate renal function. Sometimes its existence
first becomes apparent in the course of intravenous pyelography. It is regrettable that this disease tends to remain asymptomatic, because it has been shown that in its early stages, perhaps the first few weeks, relief of such obstruction is compatible with reversion to normal function. Ultrasonography is a useful noninvasive technique in the diagnosis of obstructive uropathy. In bilateral partial obstruction, the earliest manifestation is that of inability to concentrate the urine, reflected by polyuria and nocturia. Some patients will have acquired distal tubular acidosis, renal salt wasting, secondary renal calculi, and a typical picture of tubulointerstitial nephritis
Figure 21-56 Hydronephrosis of the kidney, with marked dilation of the pelvis and calyces and thinning of the renal parenchyma.
with scarring and atrophy of the papilla and medulla. Hypertension is common in such patients. Complete bilateral obstruction results in oliguria or anuria and is incompatible with long survival unless the obstruction is relieved. Curiously, after relief of complete urinary tract obstruction, postobstructive diuresis occurs. This can often be massive, with the kidney excreting large amounts of urine rich in sodium chloride. UROLITHIASIS (RENAL CALCULI, STONES) Stones may form at any level in the urinary tract, but most arise in the kidney. Urolithiasis is a frequent clinical problem, affecting 5% to 10% of Americans in their lifetime. [81] Men are affected more often than women are, and the peak age at onset is between 20 and 30 years. Familial and hereditary predisposition to stone formation has long been known. Many of the inborn errors of metabolism, such as gout, cystinuria, and primary hyperoxaluria, provide good examples of hereditary disease characterized by excessive production and excretion of stone-forming substances. Cause and Pathogenesis.
There are four main types of calculi [81] [82] (Table 21-13) : (1) most stones (about 75% ) are calcium containing, composed largely of calcium oxalate, or calcium oxalate mixed with calcium phosphate; (2) another 15% are so-called triple stones or struvite stones, composed of magnesium ammonium phosphate; (3) 6% are uric acid stones; and (4) 1% to 2% are made up of cystine. An organic matrix of mucoprotein, making up 1% to 5% of the stone by weight, is present in all calculi. Although TABLE 21-13 -- PREVALENCE OF VARIOUS TYPES OF RENAL STONES Percentage of All Stones Calcium Oxalate (Phosphate)
75
Idiopathic hypercalciuria (50%) Hypercalciuria and hypercalcemia (10%) Hyperoxaluria (5%) Enteric (4.5%) Primary (0.5%) Hyperuricosuria (20%) Hypocitraturia No known metabolic abnormality (15%-20%) Struvite (Magnesium Ammonium Phosphate) Uric Acid
10-15 6
Associated with hyperuricemia Associated with hyperuricosuria Idiopathic (50% of uric stones) Cystine
1-2
Others or Unknown
±10
990
there are many causes for the initiation and propagation of stones, the most important determinant is an increased urinary concentration of the stones' constituents, such that it exceeds their solubility in urine (supersaturation). A low urine volume in some metabolically normal patients may also favor supersaturation. Calcium oxalate stones (Table 21-13) are associated in about 5% of patients with both hypercalcemia and hypercalciuria, occasioned by hyperparathyroidism, diffuse bone disease, sarcoidosis, and other hypercalcemic states. About 55% have hypercalciuria without hypercalcemia. This is caused by several factors, including hyperabsorption of calcium from the intestine (absorptive hypercalciuria), an intrinsic impairment in renal tubular reabsorption of calcium (renal hypercalciuria), or idiopathic fasting hypercalciuria with normal parathyroid function. As many as 20% are associated with increased uric acid secretion (hyperuricosuric calcium nephrolithiasis), with or without hypercalciuria. The mechanism of stone formation in this setting involves "nucleation" of calcium oxalate by uric acid crystals in the collecting ducts. Five per cent are associated with hyperoxaluria, either hereditary (primary oxaluria) or, more commonly, acquired by intestinal overabsorption in patients with enteric diseases. The latter, so-called enteric hyperoxaluria, also occurs in vegetarians, because much of their diet is rich in oxalates. Hypocitraturia associated with acidosis and chronic diarrhea of unknown cause may produce calcium stones. In a variable proportion of patients with calcium stones, no cause can be found (idiopathic calcium stone disease).
Magnesium ammonium phosphate stones are formed largely after infections by urea-splitting bacteria (e.g., Proteus and some staphylococci), which convert urea to ammonia. The resultant alkaline urine causes the precipitation of magnesium ammonium phosphate salts. These form some of the largest stones, as the amounts of urea excreted normally are huge. Indeed, so-called staghorn calculi are almost always associated with infection. Uric acid stones are common in patients with hyperuricemia, such as gout, and diseases involving rapid cell turnover, such as the leukemias. However, more than half of all patients with urate calculi have neither hyperuricemia nor increased urinary excretion of uric acid. In this group, it is thought that an unexplained tendency to excrete urine of pH below 5.5 may predispose to uric acid stones, because uric acid is insoluble in relatively acidic urine. In contrast to the radiopaque calcium stones, uric acid stones are radiolucent. Cystine stones are caused by genetic defects in the renal reabsorption of amino acids, including cystine, leading to cystinuria. Stones form at low urinary pH. It can thus be appreciated that increased concentration of stone constituents, changes in urinary pH, decreased urine volume, and the presence of bacteria influence the formation of calculi. However, many calculi occur in the absence of these factors, and conversely patients with hypercalciuria, hyperoxaluria, and hyperuricosuria often do not form stones. It has, therefore, been postulated that stone formation is enhanced by a deficiency in inhibitors of crystal formation in urine. The list of such inhibitors is long,
Figure 21-57 Nephrolithiasis. Large stone impacted in the renal pelvis. (Courtesy of Dr. E. Mosher, Brigham and Women's Hospital, Boston, MA.)
including pyrophosphate, diphosphonate, citrate, glycosaminoglycans, and a glycoprotein called nephrocalcin. MORPHOLOGY.
Stones are unilateral in about 80% of patients. The favored sites for their formation are within the renal calyces and pelves (Fig. 21-57) and in the bladder. If formed in the renal pelvis, they tend to remain small, having an average diameter of 2 to 3 mm. These may have smooth contours or may take the form of an irregular, jagged mass of spicules. Often, many stones are found within one kidney. On occasion, progressive accretion of salts leads to the development of branching structures known as staghorn stones, which create a cast of the pelvic and calyceal system. Clinical Course.
Stones are of importance when they obstruct urinary flow or produce ulceration and
bleeding. They may be present without producing any symptoms or significant renal damage. In general, smaller stones are most hazardous, because they may pass into the ureters, producing pain referred to as colic (one of the most intense forms of pain) as well as ureteral obstruction. Larger stones cannot enter the ureters and are more likely to remain silent within the renal pelvis. Commonly, these larger stones first manifest themselves by hematuria. Stones also predispose to superimposed infection, both by their obstructive nature and by the trauma they produce. TUMORS OF THE KIDNEY Both benign and malignant tumors occur in the kidney. [83] [84] With the exception of oncocytoma, the benign
991
tumors are incidental findings at autopsy and rarely have clinical significance. Malignant tumors, on the other hand, are of great importance clinically and deserve considerable emphasis. By far the most common of these malignant tumors is renal cell carcinoma, followed by Wilms' tumor, which is found in children and described in Chapter 11 , and finally urothelial tumors of the calyces and pelves. Benign Tumors RENAL PAPILLARY ADENOMA
Small, discrete adenomas having origin in the renal tubules are found commonly (7% to 22%) at autopsy. They are most frequently papillary and are thus called papillary adenomas in the most recent international classifications. [85] MORPHOLOGY.
These are small tumors, usually less than 5 mm in diameter. [85] They are present invariably within the cortex and appear grossly as pale yellow-gray, discrete, seemingly encapsulated nodules. On microscopic examination, they are composed of complex, branching, papillomatous structures with numerous complex fronds that project into a cystic space. Cells may also grow as tubules, glands, cords, and totally undifferentiated masses of cells. The cell type for all these growth patterns is regular and free of atypia. The cells are cuboidal to polygonal in shape, have regular small central nuclei, and have a clear cytoplasm. By histologic criteria, these tumors do not differ from low-grade papillary renal cell adenocarcinoma and indeed share some immunohistochemical and cytogenetic features (trisomies 7 and 17) with papillary cancers, to be discussed later, although less extensively. The size of the tumor was once used as a prognostic feature, with a cutoff of 3 cm separating those that metastasize from those that rarely do. However, because tumors of relatively small size, 1 to 3 cm in diameter, are increasingly being detected
during x-ray procedures performed for non-renal symptoms, the current view is to consider and treat those as early cancers, until an unequivocal marker of benignity is discovered. RENAL FIBROMA OR HAMARTOMA (RENOMEDULLARY INTERSTITIAL CELL TUMOR)
On occasion, at autopsy, small foci of gray-white firm tissue, usually less than 1 cm in diameter, are found within the pyramids of the kidneys. Microscopic examination of these discloses fibroblast-like cells and collagenous tissue. Ultrastructurally, the cells have features of renal interstitial cells. The tumors have no malignant propensities. ANGIOMYOLIPOMA
This is a benign tumor consisting of vessels, smooth muscle, and fat. Angiomyolipomas are present in 25% to 50% of patients with tuberous sclerosis, a disease characterized by lesions of the cerebral cortex that produce epilepsy and mental retardation as well as a variety of skin abnormalities (Chapter 27) . ONCOCYTOMA
This is an epithelial tumor composed of large, eosinophilic cells having small, rounded, benign-appearing nuclei. It is thought to arise from the intercalated cells of collecting ducts. It is not an uncommon tumor, accounting for 5% of surgically resected neoplasms. Ultrastructurally, the eosinophilic cells have numerous prominent mitochondria. In gross appearance, the tumors are tan or mahogany brown, relatively homogeneous, and usually well encapsulated. However, they may achieve a large size (up to 12 cm in diameter). Although anecdotal cases with metastases have been reported, the tumor is considered benign. Malignant Tumors RENAL CELL CARCINOMA (HYPERNEPHROMA, ADENOCARCINOMA OF KIDNEY)
Renal cell carcinomas represent about 1% to 3% of all visceral cancers and account for 85% of renal cancers in adults. There are 30,000 new cases per year and 12,000 deaths from the disease. [86] The tumors occur most often in older individuals, usually in the sixth and seventh decades of life, showing a male preponderance in the ratio of 2 to 3:1. Because of their gross yellow color and the resemblance of the tumor cells to clear cells of the adrenal cortex, they were at one time called hypernephroma. It is now clear that all these tumors arise from tubular epithelium and are therefore renal adenocarcinomas. Epidemiology.
Tobacco is the most prominent risk factor. Cigarette smokers have double the incidence of renal cell carcinoma, and pipe and cigar smokers are also more susceptible. An
international study has identified additional risk factors, including obesity (particularly in women); hypertension; unopposed estrogen therapy; and exposure to asbestos, petroleum products, and heavy metals. [87] There is also increased incidence in patients with chronic renal failure and acquired cystic disease (see earlier) and in tuberous sclerosis. Most renal cancer is sporadic, but unusual forms of autosomal dominant familial cancers occur, usually in younger individuals. Although they account for only 4% of renal cancers, familial variants have been enormously instructive in studying renal carcinogenesis. Von Hippel- Lindau (VHL) syndrome: Half to two thirds of patients with VHL (Chapter 30) --characterized by hemangioblastomas of the cerebellum and retina--develop renal cysts and bilateral, often multiple renal cell carcinomas (nearly all, if they live long enough). As we 992
shall see, current studies implicate the VHL gene in carcinogenesis of both familial and sporadic clear cell tumors. Hereditary (familial) clear cell carcinoma, confined to the kidney, without the other manifestations of VHL, but with abnormalities involving the same or a related gene. Hereditary papillary carcinoma. This autosomal dominant form is manifested by multiple bilateral tumors with papillary histology. These tumors exhibit a series of cytogenetic abnormalities and, as will be described, mutations in the MET protooncogene. Classification of Renal Cell Carcinoma: Histology, Cytogenetics, and Genetics
The classification of renal cell carcinoma has recently undergone revision, based on correlative cytogenetic, genetic, and histologic studies of both familial and sporadic tumors. [85] The major types of tumor are as follows (Fig. 21-58) : 1. Clear cell (nonpapillary) carcinoma. This is the most common type, accounting for 70% to 80% of renal cell cancers. On histologic examination, the tumors are made of cells with clear or granular cytoplasm and are nonpapillary. They can be familial, associated with VHL disease, or in most cases sporadic. In 98% of these tumors, whether familial, sporadic, or associated with VHL, there is a deletion or unbalanced chromosomal translocation (3;6, 3;8, 3;11) resulting in losses of the smallest overlapping region of chromosome 3--3p14 to 3p26. This region harbors the VHL gene (3p25.3). [88] A second nondeleted allele of the VHL gene shows somatic mutations, or hypermethylation-induced inactivation in about 80% of clear cell cancers, indicating that the VHL gene acts as a tumor-suppressor gene in both sporadic and familial forms. The VHL gene encodes a protein that inhibits the generation of a transcriptional elongation complex, called elongin, and presumably the rate of transcription of important distal genes. [89] How these defects contribute to renal cancer is still unclear.
2. Papillary carcinoma accounts for 10% to 15% of renal cancers. [90] It is characterized by a papillary growth pattern and also occurs in both familial and sporadic forms. These tumors are not associated with 3p deletions. The most common cytogenetic abnormalities are trisomies 7, 16, and 17 and loss of Y in male patients [t(X,1)] in the sporadic form, and trisomy 7 in the familial form. The gene for the familial form has been mapped to a locus on chromosome 7, encompassing the locus for MET, a protooncogene that serves as the tyrosine kinase receptor for hepatocyte growth factor. Described in Chapter 4 , hepatocyte growth factor (also called scatter factor) mediates growth, cell mobility, invasion, and morphogenetic differentiation. [91] Both germ line and somatic mutations in the tyrosine kinase domain of the MET gene have been identified, making mutated MET a likely candidate oncogene in the cancers. A second gene called PRCC (for papillary renal cell carcinoma) on chromosome 1 has also been implicated in sporadic tumors, largely in children, exhibiting characteristic X;1 translocations. [92] 3. Chromophobe renal carcinoma represents 5% of renal cell cancers and is manifested by cells with prominent cell membranes and pale eosinophilic cytoplasm, usually with a halo around the nucleus. On cytogenetic examination, these tumors exhibit multiple chromosome losses and extreme hypodiploidy. They are, like the benign oncocytoma, thought to grow from intercalated cells of collecting ducts and have an excellent prognosis compared with that of the clear cell and papillary cancers.
Figure 21-58 Cytogenetics (in blue) and genetics (in red) of clear cell versus papillary renal cell carcinoma. (Courtesy of Dr. Keith Ligon, Brigham and Women's Hospital, Boston, MA.)
993
MORPHOLOGY.
In its macroscopic appearance, the renal cell carcinoma tumor is characteristic. It may arise in any portion of the kidney, but more commonly it affects the poles, particularly the upper one. Clear cell neoplasms occur as solitary unilateral lesions. They are spherical masses, 3 to 15 cm in diameter, composed of bright yellow-gray-white tissue that distorts the renal outline. There are commonly large areas of ischemic, opaque, gray-white necrosis, foci of hemorrhagic discoloration, and areas of softening. The margins are usually sharply defined and confined within the renal capsule (Fig. 21-59) . Papillary tumors can be multifocal and bilateral. They are typically hemorrhagic and cystic, especially when large. The papillae may be seen grossly as golden yellow flakes. As tumors enlarge, they may bulge into the calyces and pelvis and eventually may fungate through the walls of the collecting system to extend even into the ureter. One of the striking characteristics of this tumor is its tendency to invade the renal vein (Fig. 21-59) and grow as a solid column of cells within this vessel. Further extension produces a continuous cord of tumor in the inferior vena cava and even in the right side
of the heart. In clear cell carcinoma, the growth pattern varies from solid to trabecular (cordlike) or tubular (resembling tubules). The tumor cells have a rounded or polygonal shape and abundant clear or granular cytoplasm; the latter on special stains contains glycogen and lipids (Fig. 21-60 A). The
Figure 21-59 Renal cell carcinoma. Typical cross-section of yellowish, spherical neoplasm in one pole of the kidney. Note tumor in the
dilated thrombosed renal vein.
tumors have delicate branching vasculature and may exhibit cystic as well as solid areas. Most tumors are well differentiated, but some show marked nuclear atypia with formation of bizarre nuclei and giant cells. Papillary carcinoma is composed of cuboidal or low columnar cells arranged in papillary formations. Interstitial foam cells are common in the papillary cores (Fig. 21-60 B). Psammoma bodies may be present. The stroma is usually scanty but highly vascularized. Chromophobe renal carcinoma is made up of pale eosinophilic cells, often with a perinuclear halo, arranged in solid sheets with a concentration of the largest cells around blood vessels (Fig. 21-60 C). Collecting duct carcinoma is a rare variant showing irregular channels lined by highly atypical epithelium with a hobnail pattern. Sarcomatoid changes arise infrequently in all types of renal cell carcinoma and are a decidedly ominous feature of these tumors. Clinical Course.
The three classic diagnostic features of costovertebral pain, palpable mass, and hematuria unfortunately appear in only 10% of cases. The most reliable of the three is hematuria, but it is usually intermittent and may be microscopic; thus, the tumor may remain silent until it attains a large size. At this time, it gives rise to generalized constitutional symptoms, such as fever, malaise, weakness, and weight loss. This pattern of asymptomatic growth occurs in many patients, so that the tumor may have reached a diameter of more than 10 cm when it is discovered. In current times, however, many of these tumors are being discovered in the asymptomatic state by incidental radiologic studies (e.g., computed tomographic scan or magnetic resonance imaging) usually performed for non-renal indications. Renal cell carcinoma is classified as one of the great "mimics" in medicine, because it tends to produce a diversity of systemic symptoms not related to the kidney. In addition to the fever and constitutional symptoms mentioned earlier, renal cell carcinomas produce a number of paraneoplastic syndromes (Chapter 8) , ascribed to abnormal hormone production, including polycythemia, hypercalcemia, hypertension, hepatic dysfunction, feminization or masculinization, Cushing syndrome, eosinophilia, leukemoid reactions, and amyloidosis. One of the common characteristics of this tumor is its tendency to metastasize widely before giving rise to any local symptoms or signs. In 25% of new patients with renal cell
carcinoma, there is radiologic evidence of metastases at presentation. The most common locations of metastasis are the lungs (more than 50%) and bones (33%), followed in order by the regional lymph nodes, liver and adrenals, and brain. The average 5-year survival of patients with renal cell carcinoma is about 45% and up to 70% in the absence of distant metastases. With renal vein invasion or extension into the perinephric fat, the figure is reduced to approximately 15% to 20%. Nephrectomy is the treatment of choice.
994
Figure 21-60 Renal cell carcinoma. A , Clear cell type, B , Papillary type. Note papillae and foamy macrophages in the stalk. C, Chromophobe type. (Courtesy of Dr. A. Renshaw, Brigham and Women's Hospital, Boston, MA.)
UROTHELIAL CARCINOMAS OF RENAL PELVIS
Approximately 5% to 10% of primary renal tumors occur in the renal pelvis (Fig. 21-61) . These tumors span the range from apparently benign papillomas to frank papillary carcinomas, but as with bladder tumors, the benign papillomas are difficult to differentiate from the low-grade papillary cancers. Renal pelvic tumors usually become clinically apparent within a relatively short time because they lie within the pelvis and, by fragmentation, produce noticeable hematuria. They are almost invariably small when discovered. These tumors are almost never palpable clinically; however, they may block the urinary outflow and lead to palpable hydronephrosis and flank pain. On histologic examination, pelvic tumors are the exact counterpart of those found in the urinary bladder; for further details, reference should be made to that section. Urothelial tumors may occasionally be multiple, involving the pelvis, ureters, and bladder. In 50% of renal pelvic tumors, there is a preexisting or concomitant bladder urothelial tumor. On histologic examination, there are also foci of atypia or carcinoma in situ in grossly normal urothelium remote from the pelvic tumor. There is an increased incidence of urothelial carcinomas of the renal pelvis and bladder in patients with analgesic nephropathy. Infiltration of the wall of the pelvis and calyces is common. For this reason, despite their apparently small, deceptively benign appearance, the prognosis for these tumors is not good. Five-year survival rates vary from 50% to 70% for low-grade superficial lesions to 10% with high-grade infiltrating tumors.
Figure 21-61 Urothelial carcinoma of the renal pelvis. Pelvis has been opened to expose the nodular irregular neoplasm, just proximal
to the ureter.
995
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
REFERENCES 1.
Dinesen I: Seven Gothic Tales. New York, Modern Library, 1939.
Kanwar YS, Venkatachalam MA: Morphology of the glomerulus and juxtaglomerular apparatus. In Handbook of Physiology, Section of Renal Physiology, 2nd ed. Washington, DC, American Physiological Society, 1990. 2.
Hudson BG, et al: Structure, gene organization and role in human diseases of type IV collagen. J Biol Chem 268:1, 1993. 3.
4.
Timpl R, Brown JC: Supramolecular assembly of basement membranes. Bioassays 18:123, 1997.
5.
Jennette JC, et al: Heptinstall's Pathology of the Kidney, 5th ed. Philadelphia, Lippincott-Raven, 1998.
Tisher C, Brenner BM: Renal Pathology, with Clinical and Pathological Correlations, 3rd ed. Philadelphia, JB Lippincott, 1999. 6.
7.
Schrier RW, Gottschalk CW (eds): Diseases of the Kidney, 6th ed. Boston, Little, Brown, 1997.
8.
Brenner BM, Rector F (eds): The Kidney, 5th ed. Philadelphia, WB Saunders, 1996.
9.
Rose's Up To Date in Medicine--Nephrology, Vol. 6, No. 1. Up To Date, Inc., Wellesley, MA, 1998.
10.
Gardner KD Jr, Bernstein J: The Cystic Kidney. Dordrecht, Kluwer Academic Publishers, 1990.
11.
Gabow PA: Autosomal dominant polycystic kidney disease. N Engl J Med 329:332, 1993.
Grantham JJ: The pathogenesis, etiology and treatment of autosomal dominant polycystic kidney disease. Am J Kidney Dis 28:788, 1996. 12.
The International Polycystic Kidney Disease Consortium. Polycystic kidney disease: the complete structure of the PKD1 gene and its protein. Cell 81:289, 1995. 13.
Hughes J, et al: The polycystic kidney disease 1 (PKD1) gene encodes a novel protein with multiple cell recognition domains. Nat Genet 10:151, 1995. 13A.
Mochizuki T, et al: PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272:1339, 1996. 14.
Grantham JJ, et al: Evidence for inflammatory and secretagogue lipids in cyst fluids from patients with autosomal dominant polycystic kidney disease. Proc Assoc Am Physicians 109:397, 1997. 15.
16.
Lu W, et al: Perinatal lethality with kidney and pancreas defects in mice with a targeted PKD-1 mutation.
Nat Gen 17:179, 1997. Qian F, et al: The molecular basis of focal cyst formation in human autosomal dominant polycystic kidney disease type I. Cell 87:979, 1996. 17.
18.
Qian F, et al: PKD1 interacts with PKD2 through a probable coiled-coil domain. Nat Genet 16:184, 1997.
19.
Watson MC: Complications of APKD. Kidney Int 51:353, 1997.
20.
Griffin MD, et al: Vascular expression of polycystin. J Am Soc Nephrol 8:616, 1997.
Hildebrandt F, et al: A novel gene encoding on SH-3 domain protein is mutated in juvenile nephronophthisis type 1. Nat Genet 17:149, 1997. 21.
22.
Nielsen EG, Couser WG: Immunologic Renal Diseases. New York, Lippincott-Raven, 1997.
Wilson CB: Renal response to immunological injury. In Brenner BM, Rector F (eds): The Kidney, 5th ed. Philadelphia, WB Saunders, 1996, pp 1253-1391. 23.
Farquhar M, et al: The Heymann nephritis antigenic complex: megalin (gp330) and RAP. J Am Soc Nephrol 6:35, 1996. 24.
Bolton WK, et al: New avian model of experimental glomerulonephritis consistent with mediation by cellular immunity. Nonhumorally mediated glomerulonephritis in chickens. J Clin Invest 73:1263, 1984. 25.
Kalluri R, et al: Susceptibility to anti-glomerular basement membrane disease and Goodpasture syndrome is linked to MHC class II genes and emergence of T cell-mediated immunity in mice. J Clin Invest 100:2263, 1997. 26.
27.
Couser WG: Mediation of immune glomerular injury. J Am Soc Nephrol 1:13, 1990.
28.
Johnson RJ: Cytokines, growth factors and renal injury. Kidney Int 52:S2, 1997.
Border WA, Noble NA: TGF-beta in kidney fibrosis: a target for gene therapy. Kidney Int 51:1389, 1997. 29.
Remuzzi G, Ruggenenti P, Benigni A: Understanding the nature of renal disease progression. Kidney Int 51:2, 1997. 30.
Schena FP, et al: Progression of renal damage in human glomerulonephritis. Kidney Int 52:1439, 1997. 31.
Rennke HG, et al: The progression of renal disease: structural and functional correlations. In Tisher CC, Brenner B (eds): Renal Pathology, 2nd ed. Philadelphia, JB Lippincott, 1994, pp 116-139. 32.
Rodriguez-Iturbe J: Acute post-streptococcal glomerulonephritis. In Schrier RW, Gottschalk CW (eds): Diseases of the Kidney, 5th ed. Boston, Little, Brown, 1993, pp 1715-1730. 33.
Fisher M, et al: Susceptibility to anti-glomerular basement membrane disease is strongly associated with HLA-DRB1 genes. Kidney Int 51:222, 1997. 34.
35.
Haas M, et al: Changing etiologies of unexplained adult nephrotic syndrome. Am J Kidney Dis 30:621,
1997. 36.
Wasserstein AG: Membranous glomerulonephritis. J Am Soc Nephrol 8:664, 1997.
A Report on the International Study of Kidney Disease in Children. The primary nephrotic syndrome in children: identification of patients with minimal change nephrotic syndrome from initial response to prednisone. J Pediatr 98:561, 1981. 37.
38.
D'Agati V: The many masks of focal segmental glomerulosclerosis. Kidney Int 46:1223, 1994.
Kestila M, et al: Positionally cloned gene for a novel glomerular protein--nephrin--is mutated in congenital nephrotic syndrome. Mol Cell 1:575, 1998. 38A.
Mathis BJ: A locus for inherited focal segmental glomerulosclerosis maps to chromosome 19q13. Kidney Int 53:282, 1998. 39.
40.
Humphreys MH: HIV-associated glomerulonephritis. Kidney Int 48:311, 1995.
Savin V, et al: Circulating factor associated with increased permeability to albumin in recurrent focal segmental glomerulosclerosis. N Engl J Med 334:878, 1996. 41.
42.
D'Agati V, Appel GB: HIV infection and the kidney. J Am Soc Nephrol 8:139, 1997.
Bruggerman LA, et al: Nephropathy in human HIV-1 transgenic mice is due to renal trans gene expression. J Clin Invest 46:759, 1997. 43.
White RH: Mesangiocapillary glomerulonephritis. In Edelman CM Jr (ed): Pediatric Kidney. Boston, Little, Brown, 1992, pp 1307-1324. 44.
45.
Rennke HG: Secondary MPGN. Kidney Int 47:643, 1995.
Emancipator SN: Primary and secondary forms of IgA nephritis. In Jennette JC (ed): Heptinstall's Pathology of the Kidney, 5th ed. Boston, Little, Brown, 1998. 46.
Donadio JV, Grande JP: Immunoglobulin A nephropathy: a clinical perspective. J Am Soc Nephrol 8:1324, 1997. 47.
Kashtan CE, Michael AF: Perspectives in clinical nephrology: Alport syndrome. Kidney Int 50:1445, 1996. 48.
49.
Grunfeld JP: The clinical spectrum of hereditary nephritis. Kidney Int 27:83, 1985.
Hemmink HH, et al: Benign familial hematuria due to a mutation of the type IV collagen alpha4 gene. J Clin Invest 98:1114, 1996. 50.
Cameron SJ: The long-term outcome of glomerular diseases. In Schrier RW, Gottschalk CW (eds): Diseases of the Kidney, 5th ed. Boston, Little, Brown, 1993, pp 1895-1958. 51.
Blanco R, et al: Henoch-Schonlein purpura in adulthood and childhood. Two different expressions of the same syndrome. Arthritis Rheum 40:859, 1997. 51A.
52.
Mauer M, et al: Diabetic glomerulosclerosis. In Schrier RW, Gottschalk CW (eds): Diseases of the
Kidney, 5th ed. Boston, Little, Brown, 1993, pp 2153-2189. 53.
Ibrahim H, Hostetter TH: Diabetic nephropathy. Am Soc Nephrol 8:487, 1997.
Vlassara H: Recent progress in advanced glycation end products and diabetic complications. Diabetes 46:519, 1997. 54.
Gambara V, et al: Heterogeneous nature of renal lesions in type 2 diabetes. J Am Soc Nephrol 3:1458, 1993. 55.
Fogo A, et al: Morphologic and clinical features of fibrillary versus immunotactoid glomerulonephropathy. Am J Kidney Dis 22:367, 1993. 56.
56A.
Liebenthal WL: Biology of acute renal failure. Kidney Int 52:1102, 1997.
Brezis M, Epstein FH: Cellular mechanisms of acute ischemic injury to the kidney. Annu Rev Med 44:27, 1993. 57.
58.
Edelstein CL, et al: The nature of renal cell injury. Kidney Int 51:341, 1997. 996
Rabb H, et al: Leukocytes, cell adhesion molecules and ischemic renal failure. Kidney Int 51:1463, 1997. 59.
Humes DH, et al: Acute renal failure: growth factors, cell therapy and gene therapy. Proc Am Assoc Physicians 109:547, 1997. 60.
Oliver J, et al: The pathogenesis of acute renal failure associated with traumatic and toxic injury, renal ischemia, nephrotoxic damage, and the ischemic episode. J Clin Invest 30:1307, 1951. 61.
Cavallo T: Tubulointerstitial nephritis. In Jennette JC, et al (eds): Heptinstall's Pathology of the Kidney, 5th ed. Philadelphia, Lippincott-Raven, 1998, p 667. 62.
Seshan S, et al (eds): Classification and Atlas of Tubulo-interstitial and Vascular Diseases. Baltimore, Williams & Wilkins, 1998. 62A.
Rubin RH, et al: Urinary tract infection, pyelonephritis, and reflux nephropathy. In Brenner BM (ed): Brenner and Rector's The Kidney, 5th ed. Philadelphia, WB Saunders, 1996, pp 1597-1654. 63.
Langermann S, et al: Prevention of mucosal Escherichia coli infection by FimH-adhesin-based systemic vaccination. Science 276:607, 1997. 64.
Kunin CM: Urinary Tract Infections: Detection, Prevention, and Management, 5th ed. Baltimore, Williams & Wilkins, 1997. 65.
Appel GB: Acute interstitial nephritis. In Nielsen E, Couser WG (eds): Immunologic Renal Disease. Philadelphia, Lippincott-Raven, 1997. 66.
66A.
Michel D, Kelly CJ: Acute interstitial nephritis. J Am Soc Nephrol 9:506, 1998.
Kincaid Smith P, Nanra RS: Lithium-induced and analgesic-induced renal disease. In Schrier RW, Gottschalk CW (eds): Diseases of the Kidney, 5th ed. Boston, Little, Brown, 1993, pp 1099-1130. 67.
68.
De Broe ME, Elseveirs MM: Analgesic nephropathy. N Engl J Med 338:446, 1998.
Radford MG, et al: Reversible membranous nephropathy associated with the use of nonsteroidal antiinflammatory drugs. JAMA 276:466, 1996. 69.
Kurokawa K, et al (eds): Hypertension: causes and consequences of renal injury. Kidney Int 49(Suppl 55):S1, 1997. 70.
Preston RA, et al: Renal parenchymal hypertension. Present concepts. Arch Intern Med 156:602, 1996. 70A.
71.
Meyrier A, et al: Ischemic renal diseases: new insights into old entities. Kidney Int 54:2, 1998.
Kitiyakara C, Guzman NJ: Malignant hypertension and hypertensive emergencies. J Am Soc Nephrol 9:128, 1998. 71A.
Working Group on Renovascular Hypertension: Detection, evaluation, and treatment. Ann Intern Med 147:820, 1987. 72.
Goldblatt H, et al: Studies on experimental hypertension: I. Production of persistent elevation of systolic blood pressure by means of renal ischemia. J Exp Med 59:347, 1934. 73.
Kwaan HC, et al (eds): Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome. Semin Hematol 34:81, 1997. 74.
75.
Remuzzi G, Ruggenenti P: The hemolytic uremic syndrome. Kidney Int 48:2, 1995.
Mitra D, et al: Thrombotic thrombocytopenic purpura and sporadic hemolytic-uremic syndrome plasmas induce apoptosis in restricted lineages of human microvascular endothelial cells. Blood 89:1224, 1997. 76.
Boyce TG, et al: Escherichia coli O157:H7 and the hemolytic uremic syndrome. N Engl J Med 333:364, 1995. 77.
Gagnuandou MF, et al: Long-term (15-25 years) prognosis of hemolytic-uremic syndrome. J Am Soc Nephrol 4:275, 1993. 78.
79.
Greco BA, Breyer JA: Atherosclerotic ischemic renal disease. Am J Kidney Dis 29:167, 1997.
80.
Klahr S: Obstructive nephropathy. Kidney Int 54:286, 1998.
Pak CT: Urolithiasis. In Schrier RW, Gottschalk CW (eds): Diseases of the Kidney, 5th ed. Boston, Little, Brown, 1993, pp 729-743. 81.
82.
Coe FL, et al: The pathogenesis and treatment of kidney stones. N Engl J Med 327:1141, 1993.
83.
Murphy WM, et al: Tumors of the urinary bladder, urethra, ureters, renal pelves, and kidneys. Atlas of
Tumor Pathology, 3rd Series, Fascicle 11. Washington, DC, Armed Forces Institute of Pathology, 1994. 84.
Eble JN (Ed.): Tumors of the kidney. Semin Diagn Pathol 15:1-81, 1998.
85.
Storkel S, et al: Classification of renal cell carcinoma. Cancer 80:987, 1997.
86.
Motzer RJ, et al: Medical progress: renal cell carcinoma. N Engl J Med 335:865, 1996.
87.
Savage PD: Renal cell carcinoma. Curr Opin Oncol 8:247, 1996.
Neumann HPH, Zbar B: Renal cysts, renal cancer and von Hippel-Lindau disease. Kidney Int 51:16, 1997. 88.
89.
Iliopoulos O, Kaelin WG: The molecular basis of von Hippel Lindau disease. Mol Med 3:289, 1997.
90.
Lager DJ, et al: Papillary renal tumors. Cancer 76:669, 1995.
Jeffers M, et al: Activating mutations for the Met tyrosine kinase receptor in human cancer. Proc Natl Acad Sci USA 94:11445, 1997. 91.
Sidhar SK, et al: The t(X;1)(p11.2;q21.2) translocation in papillary renal cell carcinoma fuses a novel gene PRCC to the TFE3 transcription factor gene. Hum Mol Genet 5:1333, 1996. 92.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-1 A, Low-power electron micrograph of renal glomerulus. CL, capillary lumen; MES, mesangium; END, endothelium; EP, visceral epithelial cells with foot processes. (Courtesy of Dr. Vicki Kelley, Brigham and Women's Hospital, Boston, MA.) B, Schematic representation of a glomerular lobe.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-2 Glomerular filter consisting, from bottom to top, of fenestrated endothelium, basement membrane, and foot processes of epithelial cells. Note filtration slits and diaphragm. Note also that the basement membrane consists of a central lamina densa, sandwiched between two looser layers, the lamina rara interna and lamina rara externa. (Courtesy of Dr. Helmut Rennke, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-3 The structure of type IV collagen of the glomerular basement membrane (GBM), showing the building block of the collagen network: collagen type IV monomers composed of three alpha chains (of possible six alpha chain types, alpha1 to alpha6 ) arranged in a triple helix. The most common monomer is made up of alpha1 /alpha2 chains, but alpha3 /alpha4 and alpha5 /alpha6 chains are also present in the kidney. Each monomer has an NC1 domain (carboxyl terminus), a triple-helical domain, and a 7S amino acid terminus domain. Monomers form dimers through their NC1 domains and tetramers at the 7S domain to develop a suprastructure to which other extracellular matrix components attach, as shown in Figure 21-4 . (Courtesy of Dr. B. G. Hudson, University of Kansas.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-4 A proposed model of the GBM molecular architecture in which type IV collagen monomers (gray) form a stable network through their NC1 domains (dimeric interactions, gray spheres) and 7S domains (tetrameric interactions) and intertwine along the triple-helical domains. Laminin monomers (red) separately form a reversible meshwork. Entactin (green) connects laminin to the collagen network and binds to perlecan (blue), an anionic heparan sulfate proteoglycan. This anionic suprastructure determines the charged porous nature of the GBM. (Courtesy of Dr. Peter Yurchenco, Robert W. Johnson Medical School, Piscataway, NJ.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 22 - The Lower Urinary Tract Ureters CONGENITAL ANOMALIES INFLAMMATIONS MORPHOLOGY TUMORS AND TUMOR-LIKE LESIONS OBSTRUCTIVE LESIONS Sclerosing Retroperitoneal Fibrosis Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ureters CONGENITAL ANOMALIES Congenital anomalies of the ureters occur in about 2% or 3% of all autopsies. Although most have little clinical significance, certain anomalies may contribute to obstruction to the flow of urine and thus cause clinical disease. Anomalies of the ureterovesical junction, potentiating reflux, are discussed with pyelonephritis in Chapter 21 . Double and bifid ureters. Double ureters (derived from a double or split ureteral bud) are almost invariably associated either with totally distinct double renal pelves or with the anomalous development of a large kidney having a partially bifid pelvis terminating in separate ureters. Double ureters may pursue separate courses to the bladder but commonly are joined within the bladder wall and drain through a single ureteral orifice. Ureteropelvic junction obstruction, a congenital disorder, results in hydronephrosis. It usually presents in infants or children, much more commonly in boys, usually in the left ureter. However, it is bilateral in 20% of cases and may be associated with other congenital anomalies. In adults, ureteropelvic junction obstruction is more common in women and is most often unilateral. The condition has been ascribed to abnormal organization of smooth muscle bundles at the ureteropelvic junction, to excess stromal deposition of collagen between smooth muscle bundles, or in unusual cases to congenitally extrinsic compression by polar renal vessels. There is agenesis of the kidney on the opposite side in a significant number of cases, probably resulting from obstructive lesions in utero. [3] Diverticula, saccular outpouchings of the ureteral wall, are uncommon lesions. They appear as congenital or acquired defects and are of importance as pockets of stasis and secondary infections. Dilation, elongation, and tortuosity of the ureters (hydroureter) may occur as congenital anomalies or as acquired defects. Congenital hydroureter is thought to reflect some neurogenic defect in the innervation of the ureteral musculature. Massive enlargement of the ureter is known as megaloureter and is probably due to a functional defect of ureteral muscle. These anomalies are sometimes associated with some congenital defect of the kidney. INFLAMMATIONS Ureteritis may develop as one component of urinary tract infections. The morphologic changes are entirely nonspecific. Only infrequently does such ureteritis make a significant contribution to the clinical problem. Persistence of infection or repeated acute
exacerbations may give rise to chronic inflammatory changes within the ureters. MORPHOLOGY.
In certain cases of long-standing chronic ureteritis, specialized reaction patterns are sometimes observed. The accumulation or aggregation of lymphocytes in the subepithelial region may cause slight elevations of the mucosa and produce a fine granular mucosal surface (ureteritis follicularis). At other times, the mucosa may become sprinkled with fine cysts varying in diameter from 1 to 5 mm (ureteritis cystica). These changes are also found in the bladder (they receive fuller description later, in the section on urinary bladder). The cysts may aggregate to form
999
Figure 22-1 Opened ureters showing ureteritis cystica. Note smooth cysts projecting from the mucosa.
small, grapelike clusters (Fig. 22-1) . Histologic sections through such cysts demonstrate a lining of modified transitional epithelium with some flattening of the superficial layer of cells. TUMORS AND TUMOR-LIKE LESIONS Primary neoplasia of the ureter is rare. Metastatic seeding from other primary lesions occurs much more often than primary growths. Small benign tumors of the ureter are generally of mesenchymal origin. The two most common are fibroepithelial polyps and leiomyomas. The fibroepithelial polyp is a tumor-like lesion that grossly presents as a small mass projecting into the lumen. The lesion occurs more commonly
Figure 22-2 A papillary transitional cell carcinoma arising in the ureter and virtually filling the cross-section of the ureter. (Courtesy of Dr. Christopher Corless, University of Oregon, Eugene, OR.)
in the ureters (left more often than right) but may also appear in the bladder, renal pelves, and urethra. The polyp presents as a loose, vascularized connective tissue mass lying beneath the mucosa. The primary malignant tumors of the ureter follow patterns similar to those arising in the renal pelvis, calyces, and bladder, and the majority are transitional cell carcinomas (Fig. 22-2) . They cause obstruction of the ureteral lumen and are found most frequently during the sixth and seventh decades of life. They are sometimes multiple and
occasionally occur concurrently with similar neoplasms in the bladder or renal pelvis. OBSTRUCTIVE LESIONS A great variety of pathologic lesions may obstruct the ureters and give rise to hydroureter, hydronephrosis, and sometimes pyelonephritis (Chapter 21) . Obviously, it is not the ureteral dilation that is of significance in these cases, but the consequent involvement of the kidneys. The more important causes, divided into those of intrinsic and those of extrinsic origin, are cited in Table 22-1 (see also Fig. 21-55) . Only sclerosing retroperitoneal fibrosis is discussed further. Sclerosing Retroperitoneal Fibrosis.
This refers to an uncommon cause of ureteral narrowing or obstruction characterized by a fibrous proliferative inflammatory process TABLE 22-1 -- MAJOR CAUSES OF URETERAL OBSTRUCTION Intrinsic Calculi
Of renal origin, rarely more than 5 mm in diameter Larger renal stones cannot enter ureters Impact at loci of ureteral narrowing--ureteropelvic junction, where ureters cross iliac vessels, and where they enter bladder --and cause excruciating "renal colic"
Strictures
Congenital or acquired (inflammations, sclerosing retroperitoneal fibrosis)
Tumorous masses
Transitional cell carcinomas arising in ureters Rarely, benign tumors or fibroepithelial polyps
Blood clots
Massive hematuria from renal calculi, tumors, or papillary necrosis
Neurogenic causes
Interruption of the neural pathways to the bladder
Extrinsic Pregnancy
Physiologic relaxation of smooth muscle or pressure on ureters at pelvic brim from enlarging fundus
Periureteral inflammation
Salpingitis, diverticulitis, peritonitis, sclerosing retroperitoneal fibrosis
Endometriosis
With pelvic lesions, followed by scarring
Tumors
Cancers of the rectum, bladder, prostate, ovaries, uterus, cervix, lymphomas, sarcomas. Ureteral obstruction is one of the major causes of death from cervical carcinoma
1000
encasing the retroperitoneal structures and causing hydronephrosis. The disorder occurs in middle to late age. In some cases, specific causes can be identified, such as drugs (ergot derivatives, beta-adrenergic beta-blockers), adjacent inflammatory conditions (vasculitis, diverticulitis, Crohn disease), or malignant disease (lymphomas, urinary tract carcinomas). However, 70% of cases have no obvious cause and are considered primary, or idiopathic. Several cases have been reported with similar fibrotic changes in other sites (referred to as mediastinal fibrosis, sclerosing cholangitis, and Riedel fibrosing thyroiditis), suggesting that the disorder is systemic in distribution but preferentially involves the retroperitoneum. Thus, an autoimmune reaction, sometimes triggered by drugs, has been proposed. On microscopic examination, the inflammatory fibrosis is marked by a prominent inflammatory infiltrate of lymphocytes, often with germinal centers, plasma cells, and eosinophils. Sometimes, foci of fat necrosis and granulomatous inflammation are seen in and about the fibrosis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 22 - The Lower Urinary Tract Urinary Bladder CONGENITAL ANOMALIES Diverticula Exstrophy Miscellaneous Anomalies INFLAMMATIONS Acute and Chronic Cystitis MORPHOLOGY Special Forms of Cystitis Interstitial Cystitis (Hunner Ulcer) Malacoplakia Cystitis Glandularis and Cystitis Cystica NEOPLASMS Urothelial (Transitional Cell) Tumors MORPHOLOGY Other Types of Carcinoma Epidemiology and Pathogenesis Clinical Course of Bladder Cancer Mesenchymal Tumors Benign Sarcomas Secondary Tumors OBSTRUCTION MORPHOLOGY Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Urinary Bladder Diseases of the bladder, particularly inflammation (cystitis), constitute an important source of clinical signs and symptoms. Usually, however, these disorders are more disabling than lethal. Cystitis is particularly common in young women of reproductive age and in older age groups of both sexes. Tumors of the bladder are an important source of both morbidity and mortality. CONGENITAL ANOMALIES Diverticula.
A bladder or vesical diverticulum consists of a pouchlike eversion or evagination of the bladder wall. Diverticula may arise as congenital defects but more commonly are acquired lesions from persistent urethral obstruction. The congenital form may be due to a focal failure of development of the normal musculature or to some urinary tract obstruction during fetal development. Acquired diverticula are most often seen with prostatic enlargement (hyperplasia or neoplasia), producing obstruction to urine outflow and marked muscle thickening of the bladder wall. The increased intravesical pressure causes outpouching of the bladder wall and the formation of diverticula. They are frequently multiple and have narrow necks located between the interweaving hypertrophied muscle bundles. In both the congenital and the acquired forms, the diverticulum usually consists of a round to ovoid, saclike pouch that varies from less than 1 cm to 5 to 10 cm in diameter (Fig. 22-3) . Diverticula are of clinical significance because they constitute sites of urinary stasis and predispose to infection and the formation of bladder calculi. They may also predispose to vesicoureterial reflux. Rarely, carcinomas may arise in bladder diverticuli. Exstrophy.
Exstrophy of the bladder implies the presence of a developmental failure in the anterior wall of the abdomen and the bladder, so that the bladder either communicates directly through a large defect with the surface of the body or lies as an opened sac (Fig. 22-4) . The exposed bladder mucosa may undergo colonic glandular metaplasia and is subject to the development of infections that often spread to upper levels of the urinary system. In the course of persistent chronic infections, the mucosa often becomes converted into an ulcerated surface of granulation tissue, and the preserved marginal epithelium becomes transformed into a stratified squamous type. There is an increased tendency toward the development later in life of carcinoma, mostly adenocarcinoma. These
lesions are amenable to surgical correction, and long-term survival is possible. Miscellaneous Anomalies.
Vesicoureteral reflux is the most common and serious anomaly. As a major contributor to renal infection and scarring, it was taken up earlier in Chapter 21 in the consideration of pyelonephritis. Abnormal connections between the bladder and the vagina, rectum, or uterus may create congenital vesicouterine fistulas. Rarely, the urachus may remain patent in part or in whole (persistent urachus). When it is totally patent, a fistulous urinary tract is created that connects the bladder with the umbilicus. At times, the umbilical end or the bladder end remains patent, while the central region is obliterated. A sequestered umbilical epithelial rest or bladder diverticulum is formed that may provide a site for the
Figure 22-3 Bladder diverticulum (arrow) seen here in the bladder wall. Bladder lumen (L) lined by reddened mucosa is on the top. (Courtesy of Dr. Andrew Renshaw, Brigham and Women's Hospital, Boston, MA.)
1001
Figure 22-4 Exstrophy of the bladder in a newborn boy. The clamped umbilical cord is seen above the hyperemic mucosa of the everted bladder. Below is an incompletely formed penis with marked epispadias. (Courtesy of Dr. Hardy Hendren, Surgeon-in-Chief, Children's Hospital, Boston, MA.)
development of infection. At other times, only the central region of the urachus persists, giving rise to urachal cysts, lined by either transitional or metaplastic epithelium. Carcinomas, mostly glandular tumors resembling colonic adenocarcinomas, arise in such cysts. These account for only a minority of all bladder cancers (0.1% to 0.3%) but 20% to 40% of bladder adenocarcinomas. [2] INFLAMMATIONS Acute and Chronic Cystitis
The pathogenesis of cystitis and the common bacterial etiologic agents are discussed in Chapter 21 in the consideration of urinary tract infections. As emphasized earlier, bacterial pyelonephritis is frequently preceded by infection of the urinary bladder, with retrograde spread of microorganisms into the kidneys and their collecting systems. The common etiologic agents of cystitis are the coliforms-- Escherichia coli, followed by Proteus, Klebsiella, and Enterobacter. Tuberculous cystitis is almost always a sequel to renal tuberculosis. Candida albicans (Monilia) and, much less often, cryptococcal agents cause cystitis, particularly in immunosuppressed patients or those receiving
long-term antibiotics. Schistosomiasis (Schistosoma haematobium) is rare in the United States but is common in certain Middle Eastern countries, notably Egypt. Viruses (e.g., adenovirus), Chlamydia, and Mycoplasma may also be causes of cystitis. Patients receiving cytotoxic antitumor drugs, such as cyclophosphamide, sometimes develop hemorrhagic cystitis. [4] Finally, radiation of the bladder region gives rise to radiation cystitis. MORPHOLOGY.
Most cases of cystitis take the form of nonspecific acute or chronic inflammation of the bladder. In gross appearance, there is hyperemia of the mucosa, sometimes associated with exudate. When there is a hemorrhagic component, the cystitis is designated hemorrhagic cystitis. This form of cystitis sometimes follows radiation injury or antitumor chemotherapy and is often accompanied by epithelial atypia. Adenovirus infection also causes a hemorrhagic cystitis. The accumulation of large amounts of suppurative exudate may merit the designation of suppurative cystitis. When there is ulceration of large areas of the mucosa, or sometimes the entire bladder mucosa, this is known as ulcerative cystitis. Persistence of the infection leads to chronic cystitis, which differs from the acute form only in the character of the inflammatory infiltrate (Fig. 22-5) . There is more extreme heaping up of the epithelium with the formation of a red, friable, granular, sometimes ulcerated surface. Chronicity of the infection gives rise to fibrous thickening in the tunica propria and consequent thickening and inelasticity of the bladder wall. Histologic variants include follicular cystitis, characterized by the aggregation of lymphocytes into lymphoid follicles within the bladder mucosa and underlying wall, and eosinophilic cystitis, manifested by infiltration with submucosal eosinophils together with fibrosis and occasionally giant cells.
Figure 22-5 Chronic cystitis with subepithelial edema, inflammation, and a lymphoid aggretate in the lamina propria. (Courtesy of Dr. Andrew Renshaw, Brigham and Women's Hospital, Boston, MA.)
1002
All forms of cystitis are characterized by a triad of symptoms: (1) frequency, which in acute cases may necessitate urination every 15 to 20 minutes; (2) lower abdominal pain localized over the bladder region or in the suprapubic region; and (3) dysuria--pain or burning on urination. Associated with these localized changes, there may be systemic signs of inflammation such as elevation of temperature, chills, and general malaise. In the usual case, the bladder infection does not give rise to such a constitutional reaction. The local symptoms of cystitis may be disturbing, but these infections are also important as antecedents to pyelonephritis. Cystitis is sometimes a secondary complication of
some underlying disorder such as prostatic enlargement, cystocele of the bladder, calculi, or tumors. These primary diseases must be corrected before the cystitis can be relieved. Special Forms of Cystitis
Several special variants of cystitis are distinctive by either their morphologic appearance or their causation. Interstitial Cystitis (Hunner Ulcer).
This is a persistent, painful form of chronic cystitis occurring most frequently in women and associated with inflammation and fibrosis of all layers of the bladder wall. It is characterized clinically by intermittent, often severe suprapubic pain, urinary frequency, urgency, hematuria and dysuria without evidence of bacterial infection, and cystoscopic findings of fissures in the bladder mucosa after luminal distention. Some but not all patients exhibit morphologic features of chronic mucosal ulcers (Hunner ulcers). Inflammatory cells and granulation tissue may involve the mucosa, lamina propria, and muscularis, and mast cells may be particularly prominent. The condition is of unknown etiology but is thought by some to be of autoimmune origin, particularly because it is sometimes associated with lupus erythematosus and other autoimmune disorders. Malacoplakia.
This designation refers to a peculiar pattern of vesical inflammatory reaction characterized macroscopically by soft, yellow, slightly raised mucosal plaques 3 to 4 cm in diameter (Fig. 22-6) , and histologically by infiltration with large, foamy macrophages with occasional multinucleate giant cells and interspersed lymphocytes. The macrophages have an abundant granular cytoplasm. The granularity is periodic acid-Schiff positive and due to phagosomes stuffed with particulate and membranous debris of bacterial origin. In addition, laminated mineralized concretions known as Michaelis-Gutmann bodies are typically present, both within the macrophages and between cells (Fig. 22-7) . Similar lesions have been described in the colon, lungs, bones, kidneys, prostate, and epididymis. Malacoplakia is clearly related to chronic bacterial infection, mostly by E. coli or occasionally Proteus species. It occurs with increased frequency in immunosuppressed transplant recipients. The unusual-appearing macrophages and giant phagosomes point to defects in phagocytic or degradative function of macrophages, such that phagosomes become overloaded with undigested bacterial products.
Figure 22-6 Cystitis with malacoplakia of bladder showing inflammatory exudate and broad, flat plaques.
Cystitis Glandularis and Cystitis Cystica.
These terms refer to common lesions of the urinary bladder in which nests of transitional epithelium (Brunn nests) grow downward into the lamina propria and undergo transformation of their central epithelial cells into cuboidal or columnar epithelium lining slitlike (cystitis glandularis) or cystic spaces (cystitis cystica). Typical goblet cells are sometimes present, and the epithelium resembles intestinal mucosa (intestinal metaplasia). Both variants are common microscopic incidental findings in relatively normal bladders, and
Figure 22-7 Malacoplakia, PAS stain. Note the large macrophages with granular PAS-positive cytoplasm and several dense, round
Michaelis-Gutmann bodies surrounded by artifactual cleared holes in the upper middle field.
1003
TABLE 22-2 -- TUMORS OF THE URINARY BLADDER Urothelial (transitional cell) tumors Inverted papilloma Papilloma (exophytic) Urothelial tumors of low malignant potential Urothelial carcinoma Carcinoma in situ Squamous cell carcinoma Mixed carcinoma Adenocarcinoma Small cell carcinoma Sarcomas thus some experts classify them as metaplasias rather than a form of cystitis. They are, however, more prominent in inflamed and chronically irritated bladders. Lesions exhibiting extensive intestinal metaplasia are at increased risk for the development of adenocarcinoma. In cystitis cystica, the cysts are usually 0.1 to 1 cm in diameter, filled with clear fluid, and lined by cuboidal or urothelial cells. As noted, similar cysts occur in the pelvis and ureter (ureteritis and pyelitis cystica).
NEOPLASMS Neoplasms of the bladder pose biologic and clinical challenges. Despite significant inroads into their origins and improved methods of diagnosis and treatment, they continue to exact a high toll in morbidity and mortality. The incidence of the epithelial tumors in the United States has been steadily increasing during the past years and is now more than 50,000 new cases annually. [5] Despite improvements in detection and management of these neoplasms, the death toll remains at about 10,000 annually, because the increased prevalence offsets such gains as have been made. About 95% of bladder tumors are of epithelial origin, the remainder being mesenchymal tumors (Table 22-2) . Most epithelial tumors are composed of urothelial (transitional cell) type and are thus interchangeably called urothelial or transitional tumors, but squamous and glandular carcinomas also occur. Here we discuss the transitional cell tumors in some detail and only touch on the others. Urothelial (Transitional Cell) Tumors
These represent about 90% of all bladder tumors and run the gamut from small benign lesions that may never recur, to tumors of low or indeterminate malignant potential, to lesions that invade the bladder wall and metastasize frequently. Many of these tumors are multifocal at presentation. Histologic grading of these tumors, as a means to predict behavior, has been a subject of great debate, as there is poor interobserver reproducibility and no uniformly accepted grading system. There is, however, growing consensus that the majority of tumors can be segregated, at the time of initial diagnosis, into two major categories. [6] Low-grade urothelial tumors. These are always papillary, noninvasive lesions that recapitulate normal transitional epithelium and exhibit limited cellular and nuclear pleomorphism. They are usually DNA diploid, show limited chromosome and gene abnormalities, and retain blood group antigens. Patients with these tumors may develop new lesions after excision, commonly called recurrences (although many appear to be new primaries), but they have an excellent prognosis except for the relatively few patients (2% to 10%) in whom higher grade lesions develop as recurrences. High-grade urothelial carcinoma. These tumors may be papillary, nodular, or both and exhibit considerable cellular pleomorphism and anaplasia. The lesions are nearly always aneuploid, have a high frequency of chromosome and gene abnormalities, and usually lack blood group antigens. They have metastatic potential and are lethal in about 60% of cases within 10 years of diagnosis. In Table 22-3 , we have listed two of many systems of grading these tumors. The older (1972), commonly used World Health Organization (WHO) classification (currently being revised) grades tumors into a rare totally benign papilloma and three grades of transitional cell carcinoma (grades I, II, and III). A more recent classification, based on a consensus reached at a conference by the International Society of Urological Pathology (ISUP) in 1998, is currently being prepared. [7] It recognizes a rare benign papilloma, a
group of papillary urothelial neoplasms of low malignant potential, and two grades of carcinoma (low and high grade). MORPHOLOGY.
The gross patterns of urothelial cell tumors vary from purely papillary to nodular or flat to mixed papillary and nodular. The tumors may also be invasive or noninvasive (Fig. 22-8) . The papillary lesions appear as red elevated excrescences varying in size from less than 1 cm in diameter to large masses up to 5 cm in diameter. Multicentric origins may produce separate tumors. As noted, the histologic changes encompass a spectrum from benign papilloma to highly aggressive anaplastic cancers. Overall, about half of bladder cancers are high-grade lesions. Most TABLE 22-3 -- GRADING OF UROTHELIAL (TRANSITIONAL CELL) TUMORS WHO Grading ISUP CONSENSUS* Papilloma
Urothelial papilloma
TCC Grade I
Urothelial neoplasm of low malignant potential
TCC Grade II
Urothelial carcinoma, low grade
TCC Grade III
Urothelial carcinoma, high grade
WHO, World Health Organization; ISUP, International Society of Urological Pathology; TCC, transitional cell carcinoma. *Tentative ( Grades in WHO classification do not strictly correspond to ISUP terminology).
1004
Figure 22-8 Four morphologic patterns of bladder tumors.
arise from the lateral or posterior walls at the bladder base. Papilloma. This term is used to describe a rare variant, representing 1% or less of bladder tumors, seen in younger patients. The tumors usually arise singly as small (0.5 to 2.0 cm), delicate, soft structures, superficially attached to the mucosa by a stalk. The individual finger-like papillae have a central core of loose fibrovascular tissue covered by transitional epithelial cells that are histologically identical to normal urothelium (Fig. 22-9) . True recurrences rarely if ever occur. Grade I of the WHO classification corresponds more or less to the urothelial neoplasms of low malignant potential in the ISUP consensus terminology. The gross appearance is similar to that of papilloma (Fig. 22-10) . The tumor cells display some
cytologic and architectural atypia but are well differentiated and closely resemble normal transitional cells. Mitoses are rare. There may be a significant increase in the number of layers of cells but only slight loss of polarity (see Fig. 22-11) . Most recurrences are benign, but sometimes (about 3% to 5% of cases) they are of higher grade. The line between the papilloma and grade I tumor is finely drawn, but fortunately all such well-differentiated papillary neoplasms seldom become invasive and provide a 95% to 98% 10-year survival rate. Grade II. The histologic criteria are difficult to pin down. Most of the tumors are papillary, but they may have contiguous flat regions. The tumor cells are still recognizable as of transitional origin. The number of layers of cells is increased, as is the number of mitoses, and there is greater loss of polarity. Greater variability in cell size, shape, and chromaticity is present. The lower spectrum of grade II lesions of the WHO classification is included in the low-grade urothelial carcinoma of the ISUP consensus. These tumors may be associated with invasion at the time of diagnosis but have a low risk of progression. Grade III. These tumors are part of the high-grade carcinomas of the ISUP consensus 1005
(which also include the higher spectrum of the WHO grade II lesions). These tumors can be papillary, flat, or both. They tend to be larger, to be more extensive, and to show a high preponderance for invasion of the muscularis. Many of the tumor cells show anaplastic changes. In particular, there is evident disarray of cells with loosening and fragmentation of the superficial layers of cells (Fig. 22-11 D). Occasional giant cells may be present. Sometimes the cells tend to flatten out, and the lesions come to resemble squamous cell carcinomas. Alternatively, foci of glandular differentiation may be present. The tumors have a much higher incidence of invasion into the muscular layer, a higher risk of progression than low-grade lesions, and significant metastatic potential.
Figure 22-9 Low-power view of typical papillomatous growth of bladder. Note delicate axial stromal framework. (Courtesy of Dr. Christopher Corless, University of Oregon, Eugene, OR.)
Figure 22-10 Sectioned bladder showing a papillary transitional cell carcinoma projecting into the lumen (arrow). Note delicate
arborizing structure and small stalk. Note also the small diverticulum adjacent to the attachment site of the stalk. L, lumen, diverticulum.
,
Figure 22-11 A, Normal bladder mucosa. B - D, Urothelial tumors. B, Grade I or low malignant potential; C, Grade II (low grade); D, Grade III (high grade). ( A, B, D, Courtesy of Dr. Christopher Corless, University of Oregon, Eugene, OR. C, Courtesy of Dr. Donald Antonioli, Beth
Israel Hospital, Boston, MA.)
Despite the heterogeneity of gross and microscopic appearance, a few points can be made. Papillomas and low-grade lesions are almost always papillary. Higher grades may be flat or papillary. Many high-grade III lesions may be fungating, necrotic, sometimes ulcerative tumors that have unmistakably invaded deeply (Fig. 22-12) . With the higher grade neoplasms, in areas of the bladder devoid of tumor, there may frequently be areas of mucosal hyperplasia, dysplasia, or carcinoma in situ. In most analyses, less than 10% of low-grade cancers invade, but as many as 80% of high-grade transitional cell carcinomas are invasive. Aggressive tumors may extend only into the bladder wall, but the more advanced stages invade the adjacent prostate, seminal vesicles, ureters, and retroperitoneum, and some produce fistulous communications to the vagina or rectum. About 40% of these deeply invasive tumors metastasize to regional lymph nodes. Hematogenous dissemination, principally to the liver, lungs, and bone marrow, generally occurs late, and only with highly anaplastic tumors. Carcinoma in situ is defined as a high-grade flat abnormality confined to the bladder mucosa (Fig. 22-13) . It usually appears as an area of mucosal reddening, granularity, or thickening without producing an evident intraluminal mass. It is commonly multifocal and may involve most of the
1006
Figure 22-12 Opened bladder showing a high-grade invasive transitional cell carcinoma at an advanced stage. The aggressive multinodular neoplasm has fungated into the bladder lumen and spread over a wide area. Normal bladder mucosa. (Courtesy of Dr. Andrew Renshaw, Brigham and Women's Hospital, Boston, MA.)
bladder surface and extend into the ureters and urethra. Although carcinoma in situ is most often found in bladders harboring well-defined transitional cell carcinoma, about 1% to 5% of cases occur in the absence of such tumors. In time, some of these lesions become invasive. The extent of spread at the time of initial diagnosis is the most important factor in determining the outlook for a patient. Thus, staging, in addition to grade, is critical in the assessment of bladder TABLE 22-4 -- PATHOLOGIC STAGING OF BLADDER CARCINOMA Depth of Invasion AJCC/UICC Noninvasive, papillary
Ta
Noninvasive, flat
TIS
Lamina propria
T1
Superficial muscularis propria
T2
Deep muscularis propria
T3a
Perivesical fat
T3b
Adjacent structures
T4
Lymph node metastases
N1-3 *
Distant metastases
M1
AJCC/UICC, American Joint Commission on Cancer/Union Internationale Contre le Cancer. * N1, regional lymph node 5 cm or other lymph nodes.
neoplasms. The staging system most commonly used is given in Table 22-4 . Other Types of Carcinoma
Squamous cell carcinomas represent about 3% to 7% of bladder cancers in the United States, but in countries endemic for urinary schistosomiasis, they occur much more frequently. Pure squamous cell carcinomas are nearly always associated with chronic bladder irritation and infection. Mixed transitional cell carcinomas with areas of squamous carcinoma are more frequent than pure squamous cell carcinomas. Most are invasive, fungating tumors or infiltrative and ulcerative. True papillary patterns are almost never seen. The level
Figure 22-13 A, Low-power view of bladder with focus of carcinoma in situ on the left side of the illustration. B, High-power view of carcinoma confined to the epithelium. (Courtesy of Dr. Christopher Corless, University of Oregon, Eugene, OR.)
1007
of cytologic differentiation varies widely, from the highly differentiated lesions producing abundant keratohyaline pearls to anaplastic giant cell tumors showing little evidence of squamous differentiation. They often cover large areas of the bladder and are deeply invasive by the time of discovery. Adenocarcinomas of the bladder are rare. Some arise from urachal remnants or in association with extensive intestinal metaplasia (discussed earlier). Rare variants are small cell carcinoma, the highly malignant signet-ring cell carcinoma, and mixed adenocarcinoma and transitional cell carcinomas.
Epidemiology and Pathogenesis.
The incidence of carcinoma of the bladder resembles that of bronchogenic carcinoma, being more common in men than in women, in industrialized than in developing nations, and in urban than in rural dwellers. The male to female ratio for transitional cell tumors is approximately 3:1. About 80% of patients are between the ages of 50 and 80 years. A number of factors have been implicated in the causation of transitional cell carcinoma. Some of the more important contributors include the following: Cigarette smoking is clearly the most important influence, increasing the risk threefold to sevenfold, depending on the pack-years and smoking habits. Fifty per cent to 80% of all bladder cancers among men are associated with the use of cigarettes. Cigars, pipes, and smokeless tobacco invoke a much smaller risk. Industrial exposure to arylamines, particularly 2-naphthylamine as well as related compounds, as pointed out in the earlier discussion of chemical carcinogenesis (Chapter 8) . The cancers appear 15 to 40 years after the first exposure. Schistosoma haematobium infections in areas where these are endemic (Egypt, Sudan) are an established risk. The ova are deposited in the bladder wall and incite a brisk chronic inflammatory response that induces progressive mucosal squamous metaplasia and dysplasia and, in some instances, neoplasia. Seventy per cent of the cancers are squamous, the remainder being transitional cell carcinoma. Long-term use of analgesics, implicated also in analgesic nephropathy (Chapter 21) . Heavy long-term exposure to cyclophosphamide, an immunosuppressive agent, induces as noted hemorrhagic cystitis and increases the risk of bladder cancer. How these influences induce cancer is unclear, but a number of genetic alterations have been observed in transitional cell carcinoma. The cytogenetic and molecular alterations are heterogeneous. Particularly common (occurring in 30% to 60% of tumors studied) are chromosome 9 monosomy or deletions of 9p and 9q as well as deletions of 17p, 13q, 11p, and 14q. [8] The chromosome 9 deletions are the only genetic changes present frequently in superficial papillary tumors and occasionally in noninvasive flat tumors. The 9p deletions (9p21) involve the tumor-suppressor gene p16 (MTS1, INK4a), which encodes an inhibitor of a cyclin-dependent kinase (Chapter 8) , and also the related p15.[9] [10] The 9q deletion includes numerous potential tumor-suppressor foci, but the identity of this putative second tumor-suppressor locus is not yet known. On the other hand, many invasive transitional cell carcinomas show deletions of 17p, including the region of the p53 gene, as well as mutations in the p53 gene, suggesting that alterations in p53 contribute to the progression of transitional cell carcinoma. Mutations in p53 are also found in flat in situ cancer lesions. The 13q deletion is that of the retinoblastoma gene and is also present in invasive tumors. Deletions of 14q are seen exclusively in flat lesions or invasive tumors but not in papillary tumors, and a putative tumor-suppressor gene is being pursued. Increased expression of ras, c- myc, and epidermal growth factor receptors is also seen in some bladder cancers. On the basis of these findings, two models for bladder carcinogenesis have been
proposed. In the two-pathway model, [10] the first pathway is initiated by deletions of tumor-suppressor genes on 9p and 9q leading to superficial papillary or occasionally flat tumors, a few of which may then acquire p53 mutations and progress to invasion; a second pathway, possibly initiated by p53 mutations, directly results in the induction of potentially invasive tumors. The second model is a linear model of progression, [11] beginning with inactivation of tumor-suppressor genes on chromosome 9 (or 14 for flat lesions), through loss of p53 function and a variety of other genetic alterations, as has been proposed for colonic cancer [12] (Chapter 8) . Clinical Course of Bladder Cancer.
Bladder tumors classically produce painless hematuria. This is their dominant and sometimes only clinical manifestation. Frequency, urgency, and dysuria occasionally accompany the hematuria. When the ureteral orifice is involved, pyelonephritis or hydronephrosis may follow. About 60% of neoplasms, when first discovered, are single, and 70% are localized to the bladder. Patients with urothelial tumors, whatever their grade, have a tendency to develop new tumors after excision, and recurrences may exhibit a higher grade. Overall, about 50% of papillomas and low-grade carcinomas recur, in contrast to 80% to 90% of high grade tumors. In many instances, the recurrences seen at a different site, and the question of whether these represent new primaries or are true recurrences is difficult to ascertain. The prognosis depends on the histologic grade of the tumor and on the stage when it is first diagnosed. Papillomas and grade I cancers (those of low malignant potential) yield a 98% 10-year survival rate regardless of the number of recurrences; only a few patients (15 mm in diameter) as well as for many medium-sized tumors (10 to 15 mm). Radiation delivered by proton beam or by a radioactive scleral plaque is being used increasingly in the treatment of small (90% risk for most mutations) for retinoblastoma in childhood and for other cancers (e.g., osteosarcoma) later in life. [43] Most of such cases of hereditary retinoblastoma have tumors affecting both eyes (bilateral retinoblastoma); a small percent have, in addition, independently arising tumors, also occurring in childhood, either in the pineal gland or in the suprasellar or parasellar region (trilateral retinoblastoma). [44] A small number of carriers remain unaffected. Most patients with hereditary retinoblastoma have no previous family history of the disease because they have a new germ line mutation. In nonhereditary retinoblastoma (about 60 to 70% of all patients), the initial mutation affecting one copy of the RB gene arises in a somatic retinal cell or in a somatic cell that is a precursor of the developing retina. Almost all nonhereditary cases have only one tumor in one eye; they are not at increased risk for other cancers later in life. In both hereditary and nonhereditary retinoblastoma, the retinoblastomas are clonal proliferations of sensitive retinal cells that have the initial germ line or somatic mutation affecting one RB allele and that also have lost the function of the remaining wild-type RB allele. The loss of the second RB allele can occur because of an independently arising somatic mutation, because of chromosomal nondisjunction or recombination occurring during mitosis, or because of epigenetic modification such as methylation of the promoter region. [45] [46] [47] [48] [49] The RB gene is a prototype tumor-suppressor gene (Chapter 8) . The loss of both allelic, wild-type copies of the respective cancer-suppressor gene appears to be a key step in malignant transformation. As we have seen, each tumor-suppressor gene underlies the origin of more than one tumor type, such as the RB gene causing retinoblastoma and osteosarcoma, or the neurofibromatosis type 2 gene causing acoustic neuroma or meningioma (Chapter 30) . MORPHOLOGY.
Retinoblastoma is believed to arise from a cell of neuroepithelial origin in the retina. The tumors tend to be nodular masses, often with satellite seedings (Fig. 31-16) . On light microscopic examination, undifferentiated areas of these tumors are composed of small, round cells with hyperchromatic nuclei and scanty cytoplasm. The resemblance of these cells to undifferentiated retinoblasts, which are precursors of the differentiated retinal cells, led to the use of the term retinoblastoma. Differentiated structures are found within many retinoblastomas, the most
1373
Figure 31-16 Retinoblastoma. Note poorly cohesive tumor in retina abutting optic nerve.
characteristic of these being the rosettes described by Flexner and Wintersteiner (FlexnerWintersteiner rosettes) (Fig. 31-17) . These structures consist of clusters of cuboidal or short columnar cells arranged around a central lumen. The nuclei are displaced away from the lumen, which by light microscopy appears to have a limiting membrane resembling the external limiting membrane of the retina. Photoreceptor-like elements protrude through the membrane, and some taper into fine filaments. Less common are the rosettes described by Wright; these are radial arrangements of cells around a central tangle of fibrils (Homer Wright rosettes). An additional differentiated
Figure 31-17 Higher-power view of retinoblastoma showing Flexner-Wintersteiner rosettes and numerous mitotic figures (H&E×40).
structure in a few percent of tumors is the fleurette, which represents an attempt at photoreceptor differentiation by tumor cells. Tumor cells may disseminate through the choroidal vasculature or may spread beyond the eye through the optic nerve or subarachnoid space. Bone marrow aspiration, peripheral blood smears, and cerebrospinal fluid examinations assess the extent of spread in patients with metastatic retinoblastoma. In advanced cases, the tumor may penetrate through the sclera and grow in the orbit. Metastases to the preauricular and cervical lymph nodes commonly follow overt extraocular extension. The most common sites of distant metastases are the central nervous system, skull, distal bones, and lymph nodes. Spontaneous necrosis or regression of a retinoblastoma is marked by calcification and severe inflammation. The mechanism responsible for spontaneous necrosis, which is rare, is unknown. Rarely, tumors composed of uniformly benign-appearing cells exhibiting photoreceptor differentiation and the formation of fleurettes have been reported. These have been referred to as retinocytomas and are believed to be a benign variant of retinoblastoma. [50]
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
VITREOUS The adult vitreous forms during the second month of embryonic development. It is composed of 99% water with the remainder being collagen and hyaluronic acid forming a hydrogel of high viscosity. Inflammatory cells in the vitreous can be a sign of infections of the eye (e.g., bacterial endophthalmitis), noninfectious inflammations (e.g., sarcoidosis), or tumors (e.g., ocular lymphoma). Amyloid deposits in the vitreous are almost always due to mutant forms of transthyretin [51] and are associated with familial amyloidotic polyneuropathy. [52]
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 31 - The Eye OPTIC NERVE Papilledema Optic Neuritis Optic Atrophy Tumors Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
OPTIC NERVE Papilledema Papilledema, or edema of the optic disc, classically is associated with increased intracranial pressure. There are several structural characteristics of the optic nerve that are believed to play a crucial role in the pathogenesis of papilledema. [53] The subarachnoid space surrounding the optic nerve is a direct extension of the subarachnoid space around the brain, with which it is normally in direct communication. Any increase in intracranial pressure is thus transmitted to the optic nerve. In addition, the central retinal vein draining the retina runs in the axial portion within the optic nerve for about 8 to 15 mm then exits from the nerve and crosses the meninges. At this point, it is vulnerable to occlusion from increased pressure in the subarachnoid space. The optic disc possesses a rich arterial blood
1374
supply from the central retinal artery and the choroidal arteries, supplied by the arterial circle of Zinn-Haller. The relevant differences between the arterial and venous pressure seem to be significant in the development of papilledema. Axonal swelling, however, appears to be the most important factor in the increase in tissue volume of the optic nerve head. Acutely, there is edema and vascular congestion of the nerve head (Fig. 31-18) . The physiologic cup is obliterated, and hemorrhages may be seen in the optic nerve or adjacent retinal nerve fiber layer. The sensory retina is displaced away from the edges of the optic disc by the edema, and folding of the retina and choroid are seen. With chronic papilledema, degeneration of nerve fibers, gliosis, and optic atrophy may occur. Optic Neuritis Grouped together under the term optic neuritis are many pathologic processes that are noninflammatory and are better described by the term optic neuropathy. Of major importance are the optic neuropathies of demyelinating diseases. These display similar histopathologic features to those found in the brain (Chapter 30) . [54] Classically, these consist of loss of myelin and oligodendrocytes with relative preservation of axons. Other causes of optic neuritis include systemic diseases, such as sarcoidosis, collagen diseases, diabetes mellitus, and blood disorders; ischemic diseases, including temporal arteritis and atherosclerosis; toxic conditions, such as methyl alcohol or lead poisoning;
spread of inflammation from the orbit or sinuses; and infection. Optic Atrophy The ultimate result of progressive optic nerve diseases is optic nerve atrophy. Variations in the findings depend on
Figure 31-18 Papilledema showing displacement of the sensory retina ( arrows).
Figure 31-19 Optic atrophy: note the large optic cup (H&E×10).
the pathogenic factors involved. [55] Common to all cases, however, are loss of both myelin and axis cylinders, glial proliferation (gliosis), thickening of the pial septa, and widening of the space separating the optic nerve and the meninges as a result of the loss of nerve parenchyma. In addition, the physiologic cup may appear wider or deeper than normal (Fig. 31-19) . Tumors The principal primary tumors of the optic nerve are gliomas and meningiomas. These are described in detail in Chapter 30 . Less commonly, hemangiomas, hemangiopericytomas, and tumors arising from congenital rests may occur. Secondary tumors may extend into the optic nerve from adjacent or distant sites.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Part 2 - DISEASES OF ORGAN SYSTEMS 31 - The Eye GLAUCOMA MORPHOLOGY Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
GLAUCOMA Glaucoma is often mistakenly considered by nonophthalmologists to be a discrete disease entity. It is, in fact, several different diseases, many of which are characterized by an intraocular pressure sufficiently elevated to produce ocular tissue damage. Glaucoma is one of the leading causes of blindness in the United States. The three major categories of glaucoma are (1) angle-closure glaucoma, (2) open-angle glaucoma, and (3) congenital and juvenile glaucoma. The term angle refers to the angle of the anterior chamber formed by the junction of the uveal tract with the corneoscleral coat. This is the most important region of aqueous drainage. Eyes that develop primary angle-closure glaucoma are anatomically predisposed to the condition. Most commonly, the eyes are smaller than normal and hyperopic. The surface
1375
of the peripheral iris is close to the inner surface of the trabecular meshwork, resulting in a narrow or shallow anterior chamber angle. Primary open-angle glaucoma accounts for about two thirds of all glaucoma seen in whites and has an incidence of between 0.5 and 1%. The incidence of primary open-angle glaucoma in blacks is about 1.5%. The angle appears open but does not function properly in transporting aqueous humor out of the eye. The exact nature of the obstruction has not yet been elucidated. Congenital glaucoma and juvenile glaucoma are thought to be hereditary in most cases, with both recessive and dominant forms documented, [56] although infectious causes are also possible (e.g., rubella). The incidence of congenital glaucoma is about 1:5000 to 1:10,000 live births. Genes responsible for dominant juvenile glaucoma, [57] recessive congenital glaucoma, [58] and Rieger syndrome (dysgenesis of the anterior segment of the eye with glaucoma) [59] have been identified. They belong to several classes of molecules, such as cytochromes and transcription factors. The mechanisms by which defects in these genes cause glaucoma are under investigation. It is unknown how elevated intraocular pressure causes degeneration of the retinal ganglion cells and their axons (called glaucomatous optic atrophy) (Fig. 31-20) and consequent visual loss. Some experts speculate that in certain patients the elevated pressure may actually be an epiphenomenon, and the optic atrophy may be the result of a biochemical defect inherent to the ganglion cells. The occasional patient who develops glaucomatous optic atrophy in the absence of elevated intraocular pressure is
evidence for this view. The more traditional explanation, however, is that the mechanical force of the intraocular pressure on the nerve fibers as they course around the margin of the cup of the optic nerve interferes with axoplasmic flow and produces axonal necrosis. In addition or alternatively, elevated intraocular pressure may impair the vascular supply of the optic nerve, thus leading to ischemic necrosis of nerve fibers.
Figure 31-20 Glaucomatous cup. Note the characteristic excavation of the optic disc.
MORPHOLOGY. The loss of nerve fibers results in a characteristic cupped excavation of the optic disc (Fig. 31-20) . As the nerve fibers disappear, the myelin in the retrobulbar portion of the nerve also vanishes, resulting in a decrease in the diameter of the nerve evident both on gross and on microscopic examination. The retina develops thinning of the nerve fiber layer, and the retinal ganglion cells degenerate. Additional changes in eyes with long-standing, greatly elevated pressure include intracellular and intercellular epithelial edema of the cornea, corneal stromal edema, degenerative pannus, and corneal scarring; cataracts; necrosis of the iris and the ciliary body stroma; atrophy, hyalinization, and shortening of the ciliary processes; and venous stasis in the retina, sometimes with occlusion of the central retinal vein. In infants with glaucoma, the corneoscleral coat may become stretched and thinned as a result of chronically elevated intraocular pressure, producing an enlargement of the entire eye (buphthalmos). In adult eyes, sustained elevation of pressure may lead to bulging of the cornea or sclera. These areas are often lined by atrophic uveal tissue and appear black when observed clinically (staphyloma).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
PHTHISIS BULBI AND THE END STAGE OF DIFFUSE OCULAR DISEASE With the exception of eyes enucleated because of intraocular tumors, most of the eyes sent to the pathology laboratory are removed because of blindness, pain, and disfigurement. The primary causes of the ocular changes are usually trauma, glaucoma, or intraocular inflammation. End-stage blind eyes are generally classified into one of three categories. [60] Atrophy without shrinkage refers to an eye of otherwise normal or enlarged size that has atrophy of the intraocular structures. An eye with long-standing glaucoma is an example of an eye in this category. If there is also atrophy of the globe, so that it is smaller than normal, the eye shows atrophy with shrinkage. Phthisis bulbi (Fig. 31-21) describes an eye with markedly thickened sclera and generalized disorganization of intraocular contents sufficiently severe to make them unrecognizable. The globe is small; the cornea is flattened, shrunken, and scarred. The lens, if not previously removed or extruded, may be displaced and shows cataractous changes, often with calcium deposition. Most phthisical eyes contain a dense fibrous membrane running across the ciliary body (cyclitic membrane). Intraocular bone formation is a characteristic finding in phthisis bulbi. This is a result of osseous metaplasia of the retinal pigment epithelium, and it forms without cartilage. A fatty marrow can be present
1376
Figure 31-21 Phthisis bulbi. Note the markedly thickened sclera and disorganization of the intraocular contents.
within the bone, and particularly in younger individuals, the marrow may possess hematopoietic elements. The retina is usually detached and reduced to a gliotic scar, and the optic nerve is markedly atrophic. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
REFERENCES Kupfer C, et al: Leading causes of visual impairment worldwide. In Albert D, Jakobiec F (eds): Principles and Practice of Ophthalmology: Basic Sciences. Philadelphia, WB Saunders, 1994, p 1249. 1.
2.
Albert D: The ocular melanoma story. Am J Ophthalmol 123:729-741, 1997.
Lahav M, et al: Clinical and histopathological classification of retinal dysplasia. Am J Ophthalmol 75:648, 1973. 3.
4.
Jaeger EA: Ocular findings in Down's syndrome. Trans Am Ophthalmol Soc 78:808, 1980.
5.
Robb RM, Marchevski A: A pathology of the lens in Down's syndrome. Arch Ophthalmol 96:1039, 1978.
6.
Boniuk M, Zimmerman LE: Ocular pathology in the rubella syndrome. Arch Ophthalmol 77:455, 1967.
Contreras F, Pereda J: Congenital syphilis of the eye with lens involvement. Arch Ophthalmol 96:1052, 1978. 7.
World Health Organization (ed): Global Situation: Vitamin A Deficiency. Expanded Program on Immunization Update. Geneva, World Health Organization, 1988. 8.
Austin P, et al: Elastoplasia and elastodystrophy as the pathologic basis of ocular pterygia and pingueculae. Ophthalmology 90:96, 1983. 9.
10.
McCallan AF: The epidemiology of trachoma. Br J Ophthalmol 15:369, 1931.
Spencer WH, Zimmerman LE: Conjunctiva. In Spencer WH (ed): Ophthalmic Pathology, 4th ed, Vol I. Philadelphia, WB Saunders, 1996, pp 38-125. 11.
12.
Blodi FC: Squamous cell carcinoma of the conjunctiva. Doc Ophthalmol 34:93, 1973.
Munier F, et al: Kerato-epithelin mutations in four 5q31-linked corneal dystrophies. Nat Genet 15:247-251, 1997. 13.
Vance J, et al: Linkage of macular corneal dystrophy (MCD) to 16q: evidence that MCD types I and II are due to the same locus (abstract). Am J Hum Genet 57:A230, 1995. 14.
Elliott J: Introduction to uveitis. In Albert D, Jakobiec F (eds): Principles and Practice of Ophthalmology: Clinical Practice, Vol I. Philadelphia, WB Saunders, 1994, pp 396-406. 15.
Albert D, Diaz-Rohena R: Historical review of sympathetic ophthalmia and its epidemiology. Surv Ophthalmol 34:1-14, 1989. 16.
Lubin JR, et al: Sixty-five years of sympathetic ophthalmia: a clinicopathologic review of 105 cases (1913-1978). Ophthalmology 87:109, 1980. 17.
18.
Scotto J, et al: Melanomas of the eye and other noncutaneous sites. J Natl Cancer Inst 56:489, 1976.
19.
Yanoff M, Fine B: Ocular Pathology: A Text and Atlas, 3rd ed. New York, Harper & Row, 1989.
Callender GR: Malignant melanotic tumors of the eye: a study of histologic types in 111 cases. Trans Am Acad Ophthalmol 36:131, 1931. 20.
Folberg R, et al: The prognostic value of tumor blood vessel morphology in primary uveal melanoma. Ophthalmology 100:1389-1398, 1993. 21.
Eagle RJ, Spencer W: Lens. In Spencer W (ed) Ophthalmic Pathology: A Text and Atlas, 4th ed. Philadelphia, WB Saunders, 1996, pp 372-437. 22.
Shastry B, et al: Identification of missense mutations in Norrie's disease gene associated with advanced retinopathy of prematurity. Arch Ophthalmol 115:651-655, 1997. 23.
Garner A: Vascular disorders. In Garner AC, Klintworth GK (eds): Pathobiology of Ocular Disease. New York, Marcel Dekker, 1982, pp 1479-1575. 24.
25.
D'Amico DJ: Diseases of the retina. N Engl J Med 331:95-106, 1994.
Ashton N: Vascular basement membrane changes in diabetic retinopathy. Br J Ophthalmol 58:344, 1974. 26.
27.
Cogan DG, et al: Retinal vascular patterns: IV. diabetic retinopathy. Arch Ophthalmol 66:366, 1961.
Aiello L, et al: Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 331:1480-1487, 1994. 28.
Scheie HG: Evaluation of ophthalmoscopic changes of hypertension and arteriorlar sclerosis. Arch Ophthalmol 49:117, 1953. 29.
Wagener H, Keith N: Diffuse arteriolar disease with hypertension and associated retinal lesions. Medicine 18:317, 1939. 30.
Berson E: Retinitis pigmentosa and related diseases. In Albert D, Jakobiec F (eds): Principles and Practice of Ophthalmology, Vol 2. Philadelpia, WB Saunders, 1994, pp 1214-1237. 31.
32.
Dryja T, Li T: Molecular genetics of retinitis pigmentosa. Hum Mol Genet 4:1739-1743, 1995.
Cogan D: Pathology [of retinitis pigmentosa]. Trans Am Acad Ophthalmol Otolaryngol 54:629-661, 1950. 33.
34.
Gartner S, Henkind P: Pathology of retinitis pigmentosa. Ophthalmology 89:1425, 1982.
Hyman L, et al: Senile macular degeneration: a case-control study. Am J Epidemiol 118:213-227, 1983. 35.
Eye Disease Case Control Study Group: Antioxidant states and neovascular age-related macular degeneration. Arch Ophthalmol 111:104-109, 1993. 36.
37.
Evans K, Bird A: The genetics of complex ophthalmic disorders. Br J Ophthalmol 80:763-768, 1996.
Felbor U, et al: Autosomal recessive Sorsby fundus dystrophy revisited: molecular evidence for dominant inheritance. Am J Hum Genet 60:57-62, 1997. 38.
Allikemets R, et al: A photoreceptor cell-specific ATP binding transport gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet 15:236-245, 1997. 39.
Green W, Enger C: Age-related macular degeneration: histopathologic studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology 100:1519-1535, 1993. 40.
41.
Klein R, et al: Prevalence of age-related maculopathy. Ophthalmology 99:933-943, 1992.
Machemer R, Kroll AJ: Experimental retinal detachment in the owl monkey: VII. photoreceptor protein renewal in normal and detached retina. Am J Ophthalmol 71:690, 1971. 42.
Wong F, et al: Cancer incidence after retinoblastoma: radiation dose and sarcoma risk. JAMA 278:1272-1267, 1997. 43.
Bader J, et al: Bilateral retinoblastoma with ectopic intracranial retinoblastoma: trilateral retinoblastoma. Cancer Genet Cytogenet 5:230-213, 1982. 44.
Cavenee W, et al: Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305:779-784, 1983. 45.
1377
46.
Dryja T, et al: Homozygosity of chromosome 13 in retinoblastoma. N Engl J Med 310:550-553, 1984.
47.
Dryja T: Genetics of retinoblastoma. Curr Opin Pediatr 1:413-420, 1989.
Sakai T, et al: Allele-specific hypermethylation of the retinoblastoma tumor-suppressor gene. Am J Hum Genet 48:880-888, 1991. 48.
Greger V, et al: Frequency and parental origin of hypermethylated RB1 alleles in retinoblastoma. Hum Genet 94:491-496, 1994. 49.
McLean I: Retinoblastoma, retinocytoma, and pseudoretinoblastoma. In Spencer W (ed): Ophthalmic Pathology: A Text and Atlas. Philadelphia, WB Saunders, 1996, pp 1332-1380. 50.
Murrell J, et al: Production and functional analysis of normal and variant recombinant human transthyretin proteins. B Biol Chem 267:16595-16600, 1992. 51.
Benson M, Wallace M: Amyloidosis. In Scriver C, et al (eds): The Metabolic Basis of Inherited Disease. New York, McGraw-Hill, 1989, pp 2439-2460. 52.
Heyreh MS, Heyreh SS: Optic disc edema in raised intracranial pressure: I. evolution and resolution. Arch Ophthalmol 95:1237, 1977. 53.
Arnold A, et al: Retinal periphlebitis and retinitis in multiple sclerosis: I. pathologic characteristics. Ophthalmology 91:255, 1984. 54.
Sadun A: Optic atrophy and papilledema. In Albert D, Jakobiec F (eds): Principles and Practice of Ophthalmology: Clinical Practice, Vol 4. Philadelphia, WB Saunders, 1994, pp 2529-2538. 55.
Raymond V: Molecular genetics of the glaucomas: mapping of the first five "GLC" loci. Am J Hum Genet 60:272-277, 1997. 56.
Stone E, et al: Identification of a gene that causes primary open angle glaucoma. Science 275:668-670, 1997. 57.
Stoilov I, et al: Identification of three different truncating mutations in cytochrome I 4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma (buphthalmos) in families linked to the GLC3 A locus on chromosome 2p21. Hum Mol Genet 6:641-647, 1997. 58.
Semina E, et al: Cloning and characterization of a novel bicoid-related homeobox transcription factor gene, RIEG, involved in Rieger syndrome. Nat Genet 14:392-399, 1996. 59.
Spencer W: Sclera. In Spencer W (ed): Ophthalmic Pathology: A Text and Atlas, Vol 1. Philadelphia, WB Saunders, 1996, pp 334-372. 60.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-1 Anatomic elements of the eye.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Abortion, septic, 369-370 spontaneous, 1079 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Abscess, 85, 85 amebic, 358-359, 867-868 bone, 1232-1233, 1232 brain, 1315-1316, 1316,, 1323, 1323 Brodie, 1233 cardiac, 574, 574 Chlamydia, 362 extradural, 1316 gonorrheal, 362 hepatic, 358-359, 867-868 Listeria, 378 pancreatic, 907, 909 perinephric, 974-975 periodontal, 369-370 pulmonary, 722, 723 in cystic fibrosis, 480 ring, 574, 574 staphylococcal, 366-367, 367 streptococcal, 368 subareolar, 1096-1097 subdiaphragmatic, 841 subhepatic, 841 subperiosteal, 1232, 1232 Toxoplasma, 1323, 1323 tubo-ovarian, 1039 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Acantholysis, 1172 in pemphigus, 1202, 1202,, 1203 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Acanthosis nigricans, 1180-1181 paraneoplastic, 320, 321t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Acetaminophen, adverse reactions to, 416 hepatic necrosis with, 416 in cell injury, 14-15 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Acetylsalicylic acid. See Aspirin (acetylsalicylic acid). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Acinus (acini), hepatic, 846, 846 pancreatic, 903, 903 pulmonary, 698, 708 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Acquired immunodeficiency syndrome (AIDS), 236-251. See also Human immunodeficiency virus (HIV) infection. B-cell lymphoma in, 312 candidiasis in, 247-248 cervical carcinoma in, 250 clinical features of, 247-251, 247t, 249 cryptococcal meningitis in, 1322 cryptococcosis in, 248 cytomegalovirus infection in, 248 diarrhea in, 811 diffuse large B-cell lymphoma in, 661-662 epidemiology of, 236-238 etiology of, 238-239, 238,, 239 herpes simplex virus infection in, 248 in children, 237, 1321 infectious diarrhea in, 248 Kaposi sarcoma in, 248-249, 249,, 535 lymphoma in, 249-250 Mycobacterium avium infection in, 352, 352 Mycobacterium tuberculosisinfection in, 248, 351-352, 1317 myocarditis in, 584 natural history of, 245-247, 245,, 245t nephropathy in, 958 neurosyphilis in, 1317 opportunistic infections in, 247-248, 247t oral manifestations of, 759t pathogenesis of, 239-245, 240-242,, 244,, 245t peripheral neuropathy in, 1321 Pneumocystis carinii pneumonia in, 247 pneumonia in, 247, 726, 726t thrombocytopenia in, 636 tuberculosis in, 248, 351-352, 1317 vacuolar myelopathy in, 1321 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Acute tubular necrosis (ATN), 969-971 ischemic, 970, 970,, 971 nonoliguric, 971 pathogenesis of, 969-970, 969 toxic, 970-971, 970 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Adenocarcinoma, 262 of bile ducts, 899-900 of bladder, 1007 of colon, 265,, 891, 891 of endometrium, 1061-1062, 1062 of esophagus, 786-787, 786 of fallopian tubes, 1065 of gallbladder, 899, 900 of intestine, 827 of ovary, 1072 of vagina, 1046, 1046 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Adenohypophysis. See Pituitary gland, anterior. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Adenoma, 261 adrenocortical, 1153-1155, 1153,, 1155t, 1162 aldosterone-producing, 1155-1157, 1156,, 1157 adrenocorticotropic hormone-secreting, 1126-1127, 1153-1154, 1153 aldosterone-producing, 1155-1157, 1156,, 1157 carcinoid, 747-748, 748 follicle-stimulating hormone-secreting, 1127 gastric, 798, 798 gonadotroph-secreting, 1127 growth hormone-secreting, 1126 hepatic, 887-888, 887 oral contraceptives and, 416 intestinal, 827, 827,, 829-831, 829-831 familial, 831, 831 malignant change in, 830-831 tubular, 829-830, 829 tubulovillous, 830 villous, 830, 830 luteinizing hormone-secreting, 1127 null cell, 1127 of ampulla of Vater, 827, 827 of nipple, 1104 of salivary glands, 770-771, 770 pancreatic, 910 papillary, renal, 991 thyroid, 1142 parathyroid, 1148-1150, 1149 pituitary, 1123-1127, 1124,, 1124t, 1125,, 1153-1154, 1153 pleomorphic, 262, 770-771, 770 prolactin-secreting, 1125-1126, 1125 renal, 991 sebaceous, 1183t thyroid, 265,, 1140-1142, 1141
thyroid-stimulating hormone-secreting, 1127 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Adenomyosis, of endometrium, 1057, 1057 of gallbladder, 899 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Adenosine deaminase, deficiency of, gene mutation in, 147t gene therapy in, 141 in severe combined immunodeficiency disease, 235 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Adenosis, of breast, 1099, 1101, 1101 of vagina, 1046 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Adenoviruses, 333t gastrointestinal tract infection with, 354, 807t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Adrenal cortex, 1152-1163 adenoma of, 1153-1155, 1153,, 1155t, 1162 aldosterone-producing, 1155-1157, 1156,, 1157 carcinoma of, 1153-1155, 1155t, 1162-1163, 1162 congenital hyperplasia of, 1157-1159, 1158 cyst of, 1163 metastases to, adrenocortical insufficiency with, 1161 myelolipoma of, 1163 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Adrenal gland. See also Adrenal cortex; Adrenal medulla. amyloidosis of, 256 in shock, 137 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Adrenal medulla, 1152-1153, 1163-1167 neuroblastoma of, 485-487, 486,, 487,, 1166 pheochromocytoma of, 1164-1166, 1164t, 1165 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Adrenocortical insufficiency, 1159-1162, 1159t, 1160,, 1161 acute, 1159-1160 chronic (Addison disease), 1160-1161, 1161 secondary, 1161-1162 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Adrenocorticotropic hormone, hypersecretion of, 1153-1155, 1153,, 1155t tumor production of, 1126-1127, 1153-1154, 1153 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ab -- Ad Adult respiratory distress syndrome (ARDS), 700-703, 701t clinical course of, 703 endotoxemia in, 701-702, 702 hyaline membranes in, 701, 701 pathogenesis of, 701-703, 702 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Aflatoxins, 380 hepatocellular carcinoma and, 888-889 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Aflatoxin B1, 424, 424t in carcinogenesis, 308, 309 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Age. See also Aging. cancer and, 273-275, 274t maternal, trisomy 21 and, 170 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Agenesis, definition of, 466 of corpus callosum, 1300, 1301 of kidney, 936 of pancreas, 904 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Aging, amyloidosis of, 253t, 254 atrophy with, 35 cellular, 45-48, 46,, 47,, 48 timing of, 46-47, 46,, 47 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Agranulocytosis, 200, 646-647. See also Hypersensitivity reaction(s), type II (cytotoxic). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am AIDS. See Acquired immunodeficiency syndrome. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Air pollution, bronchogenic carcinoma and, 742 indoor, 418-419, 418t outdoor, 416-418, 417t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Airway. See Respiratory tract. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Alcohol, breast cancer and, 1107 fetal effects of, 467 gastric cancer and, 799, 799t myocardial toxicity of, 579-580 oral cancer and, 760 peptic ulcer disease and, 794 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Alcohol abuse, 410-412, 410,, 411,, 411t cancer and, 273 cerebellar degeneration in, 1342, 1342 dilated cardiomyopathy and, 579-580 thiamine deficiency in, 447 vitamin B6 deficiency in, 449 Wernicke-Korsakoff syndrome in, 412, 447, 1341 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Alcoholic liver disease, 869-873 cholestasis in, 872 cirrhosis in, 870-871, 870,, 871,, 872 clinical course of, 872-873 collagen deposition in, 872 fatty liver in, 39, 39,, 869, 870,, 872 fibrosis in, 870 hepatitis in, 869-870, 870,, 871,, 872 hyaline inclusions in, 27-28, 28 iron distribution in, 874 Mallory bodies in, 869, 871 mitochondria in, 27 neutrophilic reaction in, 869 pathogenesis of, 871-872 prognosis for, 872 steatosis in, 869, 870 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Allele(s). See also Gene(s). codominance of, 144 dominant negative, 145, 148 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Allergy, 199. See also Hypersensitivity reaction(s). in asthma, 713, 714 in contact dermatitis, 1195t, 1196-1197, 1196 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Alpha (alpha) toxin, of Clostridium perfringens, 344, 368 of Staphylococcus aureus, 365 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Alpha fetoprotein, in hepatocellular carcinoma, 891 in testicular germ cell tumors, 1024 in tumor diagnosis, 325, 325t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Alveolar macrophages, 698 in pneumonia, 718 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Alzheimer disease, 1296t, 1329-1333, 1330 amyloid deposition in, 252, 1331-1332, 1332,, 1332t apolipoprotein E in, 1333 genetics of, 1332, 1332t granulovacuolar degeneration in, 1331 Hirano bodies in, 1331 neuritic plaques in, 1330, 1331 neurofibrillary tangles in, 28, 1330, 1331 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Amenorrhea, in anorexia nervosa, 439 in Turner syndrome, 175 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Amines, aromatic, in carcinogenesis, 309 vasoactive, in inflammation, 66-67, 66,, 77t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Ampulla of Vater, 892 adenoma of, 827, 827 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Amyloid, composition of, 252 Congo red-stained, 255, 255 hyaline appearance of, 45 in Alzheimer disease, 252, 1331-1332, 1332,, 1332t in medullary thyroid carcinoma, 1146, 1146 in renal osteodystrophy, 1229 structure of, 251-252, 251 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Af -- Am Amyloidosis, 251-257, 251 cardiac, 256, 256,, 586 clinical features of, 256-257 endocrine, 253t, 254 gastrointestinal, 256 hemodialysis-associated, 253, 253t hemorrhage in, 634 hepatic, 255-256 heredofamilial, 253-254, 253t in multiple myeloma, 980 localized, 253t, 254 of aging, 253t, 254 of nerves, 256 pathogenesis of, 253t, 254-255, 254 primary, 252-253, 253t, 663 protein misfolding in, 41 reactive, 253, 253t renal, 255, 255,, 968 splenic, 255 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao Anaphylaxis. See also Hypersensitivity reaction(s), type I (anaphylactic). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao Anaplasia, 265-266, 265,, 266,, 323, 323. See also Tumor(s). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao Anemia, 604-633, 605t aplastic, 630-632, 631,, 632 blood loss, 605-606 Fanconi, 169, 296 hemolytic, 200, 605t, 606-621, 607 immune-mediated, 620-621, 620t in chronic lymphocytic leukemia, 659 in disseminated intravascular coagulation, 641 in glucose-6-phosphate dehydrogenase deficiency, 610-611, 610,, 611 in hereditary spherocytosis, 607-609, 609 in paroxysmal nocturnal hemoglobinuria, 619-620, 619 in sickle cell disease, 611-615, 612-614 in alpha-thalassemia, 618-619 in beta-thalassemia, 615-618, 615,, 616,, 617t, 618 microangiopathic, 637 trauma-induced, 621, 621 in liver disease, 632-633 in renal failure, 633 in Rh isoimmunization, 473-474 iron deficiency, 118, 627-630, 627,, 627t, 628,, 630 megaloblastic, 605t, 621-627, 622,, 623t in folate deficiency, 626-627, 626 in vitamin B12 deficiency, 623-626, 623t, 624 myelophthisic, 632 of chronic disease, 630 pernicious, 623-626, 623t, 624,, 791, 793 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao Aneurysm, aortic, 524-528 abdominal, 525-526, 525 berry, 525, 1310-1313, 1311,, 1312 in polycystic kidney disease, 940 blood flow effects of, 125 Charcot-Bouchard, 1310 dissecting, 524 fusiform, 525 mycotic, 128, 525 rupture of, 526 saccular, 525 syphilitic, 526 ventricular, after myocardial infarction, 563 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao Angiogenesis, 55 angiopoietins in, 104-106, 105 growth factors in, 104-106, 105,, 105t in fibrosis, 103-106, 104,, 105,, 105t in tissue repair, 103-106, 104 tumor, 301-302 vascular endothelial growth factor in, 104-106, 105,, 105t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao Angioma, spider, in hepatic failure, 852 venous, 1313 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao Angiosarcoma, 537-538, 537 of breast, 1104 of heart, 591 of liver, 537, 888 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao Anitschkow cells, in rheumatic fever, 570 in rheumatic heart disease, 570 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao Antibody(ies), anticardiolipin, 126 anticentromere, 227 anti-DNA topoisomerase I, 227 antigliadin, 813, 1205 anti-glomerular basement membrane, 943-945, 944 anti-glutamic acid decarboxylase, 916 anti-islet cell, 915,, 916 antineutrophil, 516, 951 antinuclear, 216, 217-218, 218t, 227 antiphospholipid, 126 antireticulin, 1205 antirotavirus, 354 antiviral, 344 Donath-Landsteiner, 621 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao Anticipation, in fragile X syndrome, 178 in myotonia, 1283 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao Antidiuretic hormone, deficiency of, 1129 inappropriate secretion of, 1129 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao Antigen(s), anatomic sequestration of, 215 bacterial, 344 B-cell recognition of, 190 CALLA, 317 hypersensitivity reaction to, 195-211. See also Hypersensitivity reaction(s). molecular sequestration of, 215 nuclear, 216, 217-218, 218t ocular, 215 oncofetal, 317, 325, 325t prostate-specific, 1032-1033 self, 212-214, 213,, 215 Smith (sm), 217, 218t T-cell recognition of, 189, 190,, 194, 194 tumor, 315-317, 316 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao Antigen-antibody complex. See Immune complexes. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao Antineutrophil cytoplasmic antibodies, in rapidly progressive glomerulonephritis, 951 in vasculitis, 516 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao Antioxidants, 77 in free radical inactivation, 13 vitamin E as, 446 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao Antiphospholipid antibody syndrome, 126, 986 in systemic lupus erythematosus, 218 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao alpha1-Antitrypsin, 76 deficiency of, 148, 875-876, 876 cell injury in, 38, 38,, 41 emphysema and, 709 gene mutation in, 147t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao Aorta, abdominal, aneurysm of, 525-526, 525 aneurysm of, 524-528, 525 syphilitic, 526 coarctation of, 596-597, 597 cystic medial degeneration of, 527-528, 528 dilation of, 149 dissection of, 526-528, 527-529 in Marfan syndrome, 149 intimal tear of, 527, 527 pediatric, fatty streaks in, 503 thoracic, aneurysm of, 526 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
An -- Ao Aortic valve, 545 atresia of, 597 bicuspid, calcification of, 568 dystrophic calcifications of, 43-44, 44 Lambl excrescences of, 546, 591 sclerosis of, 568 stenosis of, calcific, 567-568, 567 congenital, 597 subaortic, 597 supravalvular, 597 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As APC gene, in cancer, 287t, 292-293 in colon cancer, 297, 297,, 832, 832 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Aphthous ulcers, 757, 757 in Crohn disease, 816 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Apoptosis, 2, 4, 18-25 after growth factor deprivation, 24-25 apoptotic bodies in, 19, 19 bcl-2 gene in, 22-23, 23,, 294-295, 295 biochemical features of, 20, 21 caspases in, 22,, 23 chromatin condensation in, 19, 19 cytoplasmic blebs in, 19 cytotoxic T-lymphocyte-stimulated, 24, 206 DNA damage-mediated, 25 DNA fragmentation in, 20, 21 dysregulation of, 25 execution phase of, 22,, 23 Fas-Fas ligand-mediated, 23, 24,, 206, 212, 213 failure of, 214 histology of, 19-20, 20 in embryogenesis, 18 in Hashimoto thyroiditis, 1134 in hormone-dependent involution, 18 in immune reactions, 19, 20 in myocardial ischemia, 556 in tumors, 19 in viral infection, 19 mechanisms of, 20-23, 22,, 23 mitochondrial function in, 21-23, 23 morphology of, 19, 19 myc gene in, 282 of cytotoxic T lymphocytes, 318-319 phagocytosis in, 19, 20, 22,, 23, 64 protein cross-linking in, 20 protein hydrolysis in, 20 Rb gene loss in, 290 regulation of, 21-22, 22,, 23,, 277, 294-295, 295 signaling pathways in, 21, 22
tumor cell resistance to, 292 tumor necrosis factor receptors in, 23-24, 24 tumor necrosis factor-induced, 23-24, 24 vs. atrophy, 36 vs. necrosis, 18 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Appendix, 838-840 inflammation of, 839-840, 839 mucinous cystadenocarcinoma of, 840, 840 mucocele of, 840 normal, 838-839 pseudomyxoma peritonei of, 840 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Arachidonic acid metabolites, in inflammation, 70-72, 71,, 71t, 77t in leukocyte activation, 62 in type I hypersensitivity reaction, 198-199, 198,, 199t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As ARDS. See Adult respiratory distress syndrome (ARDS). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Argentaffinoma. See Carcinoid tumor. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Aromatic hydrocarbons, in carcinogenesis, 309 in occupational diseases, 419t, 420 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Arrhythmias, after myocardial infarction, 562 in myocardial ischemia, 556 in sudden cardiac death, 564 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Arsenic, in carcinogenesis, 274t, 309 in occupational diseases, 421t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Arterioles, 494 hyalinization of, 45 sclerosis of, 498 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Arteriolosclerosis, 498 diabetes mellitus and, 922, 922,, 924 hypertension and, 514-515, 515 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Arteriosclerosis, after heart transplantation, 598, 598 malignant, 983 Monckeberg (medial calcific sclerosis), 498 retinopathy with, 1370 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Arteritis, giant cell (temporal), 516-518, 517t, 518 Heubner, 1317 in cerebrovascular disease, 1308 infectious, 524 Takayasu, 517t, 519-520, 519 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Artery(ies), 494-495, 494. See also specific arteries. abnormal venous communication with, 498 balloon angioplasty of, 538-539, 538 collateral, 133 elastic, 494 fenestrations of, 494 graft replacement of, 539-540, 539 inflammation of, 515-524, 515t. See also Arteritis; Vasculitis. intimal thickening of, 497, 497 lamina of, 494 Monckeberg medial calcific sclerosis of, 498 muscular, 494 sclerosis of, 498-509. See also Atherosclerosis. tumors of, 531-538, 531t. See also specific tumors. types of, 494 wall of, 494, 494 endothelial cells of, 496-497, 496,, 496t smooth muscle cells of, 495,, 497, 497 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Arthritis, 203, 203,, 1246-1257 enteropathic, 1252 gouty, 1253-1257, 1254-1256,, 1254t in Reiter syndrome, 1252 in rheumatic heart disease, 572 infectious, 1253 Lyme, 389, 1253 psoriatic, 1252-1253 rheumatoid, 1248-1251. See also Rheumatoid arthritis. suppurative, 1253 tuberculous, 1253 viral, 1253 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Arthropods, bites by, 1210-1211 in viral encephalitis, 1318 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Asbestos, amphibole, 732 bronchogenic carcinoma and, 742 in buildings, 418, 418t in carcinogenesis, 274t, 309 serpentine, 732 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Asbestosis, 729t, 732-734, 733 mesothelioma and, 751-752, 752,, 753 tumors in, 733 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Ascites, chylous, 531 in cirrhosis, 855, 855 in right-sided heart failure, 550 in thecoma-fibroma, 1077-1078 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Ascorbic acid. See Vitamin C (ascorbic acid). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Aspirin (acetylsalicylic acid), adverse reactions to, 416 antiplatelet effect of, 637 asthmatic response to, 715 in inflammation, 71-72 nephropathy and, 416, 977,, 978-979, 979,, 979t Reye syndrome with, 869 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Asthma, 707t bronchial, 712-716, 715 allergy in, 199 aspirin-related, 715 atopic, 713-714, 714 clinical course of, 716 drug-induced, 715 extrinsic, 713 intrinsic, 713 nonatopic, 715 occupational, 715 pathogenesis of, 713-715, 714 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Astrocytes, 1296-1297, 1296 Alzheimer type II, 1297 gemistocytic, 1297 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ap -- As Astrocytoma, 1343-1346, 1344-1346 platelet-derived growth factor production by, 279, 279t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
At -- Az Ataxia, Friedreich, 1337 spinocerebellar, 1296t, 1337 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
At -- Az Ataxia-telangiectasia, 47, 1337 DNA defects in, 296 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
At -- Az Atheroma, 498-499 in myocardial infarction, 553 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
At -- Az Atheromatous plaque, 40, 499-503, 509 blood flow effects of, 125, 129 calcification of, 502 components of, 500-501, 500,, 501 distribution of, 499-500, 508 fibrous cap of, 499, 500,, 501,, 509 hemorrhage into, 502 histologic features of, 501-502, 501 in myocardial ischemia, 551-553, 552,, 553t necrotic core of, 499, 500,, 501 renal, 986, 987 rupture of, 502 size of, 499, 500 thrombosis with, 502-503 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
At -- Az Atherosclerosis, 40, 79, 498-509, 551. See also Coronary artery disease; Heart, ischemic disease of; Myocardial infarction. age and, 504 atheromatous plaque in, 499-503, 500,, 501. See also Atheromatous plaque. blood flow effects of, 125, 129 Chlamydia pneumoniae and, 509 cholesterol lowering in, 505 cigarette smoking and, 506 clinical features of, 498-499, 499,, 509 diet and, 506 dyslipoproteinemias and, 505, 505t endothelial injury in, 496-497, 496,, 507,, 508 epidemiology of, 503-507, 504,, 504t, 505t fatty dots in, 503, 503 fatty streaks in, 502,, 503, 509 genetic factors in, 504 hemostatic factors and, 506 homocystinuria and, 506 hypercholesterolemia and, 508 hyperlipidemia and, 504-506, 505t hypertension and, 506 in cerebrovascular disease, 1308 in diabetes mellitus, 506, 922, 924 in sudden cardiac death, 564 in transgenic mice, 506 infection and, 509 laminar shear stresses in, 508 life-style factors in, 506 lipids in, 496,, 508 lipoprotein(a) and, 506 macrophages in, 508-509 monoclonal hypothesis of, 509 mortality from, 498, 504
natural history of, 498, 499 oligoclonality of, 509 pathogenesis of, 507-509, 507,, 510 patterns of, 498 prevention of, 509 response-to-injury hypothesis of, 507-509, 507 risk factors for, 503-507, 504,, 504t, 505t additive effects of, 504,, 506-507 sex and, 504 smooth muscle proliferation in, 509 thrombosis with, 506. See also Thrombosis. vitamin E in, 446 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
At -- Az ATN, See also Acute tubular necrosis (ATN). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
At -- Az Atopy, 199. See also Hypersensitivity reaction(s), type I (anaphylactic). in asthma, 713 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
At -- Az Atresia, definition of, 466 of aortic valve, 597 of bile ducts, 898-899, 898 of duodenum, 804 of esophagus, 777, 777 of pulmonary valve, 597 of tricuspid valve, 596 of vagina, 1045 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
At -- Az Atrial natriuretic factor (peptide), 544 in cardiac hypertrophy, 35 in hypertension, 512 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
At -- Az Atrioventricular valves, 545. See also Mitral valve; Tricuspid valve. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
At -- Az Atrophy, 31, 35-36, 36 brown, 36, 546 bulbospinal, 1338 dentorubropallidolusian, 179t gastric, 792 lobar, 1333 multiple system, 1335 muscle, 1274-1275, 1280-1281, 1281 olivopontocerebellar, 1335 optic nerve, 1374, 1374,, 1375, 1375 pathologic, 35, 36 physiologic, 35 spinal, 24, 1281, 1281,, 1338 testicular, 874, 1015, 1015,, 1016 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
At -- Az Autoantibodies. See also Antibody(ies); Autoimmune diseases. in chronic lymphocytic leukemia, 659 in rheumatoid arthritis, 1250 in systemic lupus erythematosus, 219-220, 219 in type I diabetes mellitus, 915,, 916 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
At -- Az Autoimmune diseases, 79, 211-231, 211t. See also specific diseases. apoptosis failure in, 214 epitope unmasking in, 215 genetic factors in, 215-216 microbial agents in, 216 molecular mimicry in, 215 peripheral tolerance failure in, 214-215 polyclonal lymphocyte activation in, 215 sequestered antigens in, 215 suppressor T cell failure in, 215 T-cell anergy failure in, 214 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
At -- Az Axons, 1269, 1270 degeneration of, 1270,, 1273, 1274-1275, 1274 diffuse injury of, 1304 regeneration of, 1275, 1295 segmental demyelination of, 1270,, 1273, 1274, 1274 sprouting of, 1270 unmyelinated, 1271 wallerian degeneration of, 1274, 1274 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
At -- Az Azotemia, 935 in left-sided heart failure, 549 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
B -- Be B lymphocytes. See Lymphocyte(s), B. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
B -- Be Bacteria, 332, 332t, 334t, 335, 335,, 341-344. See also Infection and specific organisms. adhesins of, 341-343, 342 antigens of, 344 carbohydrate capsule of, 344 cell injury by, 341-344, 342,, 343 endotoxin of, 343 exotoxins of, 343-344, 343 genome of, 330-331 in endocarditis, 574, 575 in gastroenteritis, 807-809, 808t, 809 in myocarditis, 583-585, 584t Lancefield classification of, 330 virulence of, 341-344, 342 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
B -- Be Barbiturates, 412 hepatic adaptation to, 26, 27 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
B -- Be Basal cell carcinoma, 1186-1187, 1187 ultraviolet radiation in, 310 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
B -- Be Basement membrane, glomerular, 931-933, 932-934 antibodies to, 943-945, 944 ruptures in, 952, 952 thickening of, 943, 954, 954 in diabetes mellitus, 923, 923,, 966, 967 in diabetes mellitus, 922-923, 923,, 966, 967 in tissue repair, 90, 91 tumor invasion of, 302-305, 303,, 304 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
B -- Be bcl-2 gene, in apoptosis, 22-23, 23,, 294-295, 295 in follicular lymphoma, 660, 661 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
B -- Be Bence Jones proteins, in amyloidosis, 252-253 in multiple myeloma, 666, 980, 981, 981 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
B -- Be Bergmann gliosis, 1297 in alcohol abuse, 1342 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
B -- Be Beriberi, 1341 dry, 448 neuropathic, 1279 wet, 447, 448 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
B -- Be Beryllium, in cancer, 274t in occupational diseases, 421t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
B -- Be Beta (beta) toxin, of Clostridium perfringens, 369 of Staphylococcus aureus, 365 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Bile, composition of, 892, 892 hepatic formation of, 848-849, 849,, 892, 892 reabsorption of, 892 secretion of, 891 storage of, 891-892 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Bile ducts, congenital dilations of, 899 extrahepatic, 898-899 atresia of, 898-899, 898 carcinoma of, 899-900 cysts of, 899 fibrosing cholangitis of, 879-880, 879 infection of, 898 lithiasis of, 898 obstruction of, 851-852 paucity of, 881 interlobular, 848 intrahepatic, 877-881, 877t anomalies of, 880-881, 880 fibrosing cholangitis of, 879-880, 879 obstruction of, 851-852 primary cirrhosis of, 878-879, 879 primary sclerosing cholangitis of, 879-880, 879 secondary cirrhosis of, 878, 878 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Biliary cirrhosis, 877t primary, 877t, 878-879, 879 secondary, 877t, 878, 878 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Biliary tract, 891-900. See also Bile ducts; Gallbladder. anatomy of, 892 congenital anomalies of, 893, 893,, 899 normal, 891-892, 892 obstruction of, 851-852, 852 tumors of, 899-900, 900 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Bilirubin, 43 conjugated, 849-850 hepatic processing of, 848-849, 849 serum, 850 unconjugated, 849 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Biopsy, bone marrow, 604 endomyocardial, 579 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Birbeck granules, in histiocytosis X, 1190,, 1191 in Langerhans histiocytosis, 685, 685 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Birth. See also Infant. infection at, 470-471, 470 injury at, 464 weight at, 460-462, 461 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Bladder, 1000-1008 adenocarcinoma of, 1007 benign tumors of, 1008 congenital anomalies of, 1000-1001, 1000,, 1001 cystocele of, 998 diverticula of, 1000, 1000 embryonal rhabdomyosarcoma of, 1008 exstrophy of, 1000, 1001 infection of, 973 inflammation of, 1001-1003, 1001,, 1002 leiomyoma of, 1008 malacoplakia of, 1002, 1002 metastatic tumors of, 1008 normal, 997-998 obstruction of, 1008, 1008 radiation injury to, 429 rhabdomyosarcoma of, 1008 sarcoma botryoides of, 1008 sarcoma of, 1008 Schistosoma haematobiuminfection of, 346, 347,, 397 squamous cell carcinoma of, 1006-1007 transitional cell carcinoma of, 1003-1008, 1003t, 1004-1006,, 1006t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Bleeding. See also Hemorrhage. uterine, dysfunctional, 1055-1056, 1056t in gestational trophoblastic disease, 1086 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Blindness, herpesvirus infection and, 360 in Leber hereditary optic neuropathy, 180 in vitamin A deficiency, 441, 442 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Blood, loss of. See also Hemorrhage. anemia with, 605-606 oxygen-carrying capacity of, 4 tumor dissemination by, 270, 270 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Blood cells, 602-604, 603. See also specific cell types. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Blood flow, in inflammation, 52,, 53 in thrombus formation, 125 laminar, 125 wound healing and, 110 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Blood pressure, elevation of, 510-515, 511t. See also Hypertension. normal, 511t regulation of, 511-512, 511 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Bone(s), 1216-1246 abscess of, 1232-1233, 1232 age-related change in, 1223, 1223 avascular necrosis of, 1231, 1231 basic multicellular unit of, 1218 caisson disease of, 436 calcification of, 44-45 cells of, 1216-1217, 1216,, 1217 congenital malformations of, 1220 creeping substitution of, 1231 developmental abnormalities of, 1220-1221 diseases of. See also specific diseases. abnormal matrix in, 1221-1224, 1221,, 1222t, 1223,, 1223t, 1224 abnormal mineral homeostasis in, 1227-1229, 1228 infectious, 1232-1233, 1232 ischemic, 1231, 1231 osteoclast dysfunction in, 1224-1227, 1224-1227 trauma-induced, 1229-1231, 1230 eburnation of, in osteoarthritis, 1247, 1248 enchondral formation of, 1219, 1219 Ewing sarcoma of, 1244, 1244 fractures of, 1229-1231, 1230 giant cell tumor of, 1244-1245, 1245 growth of, 1218-1220, 1219 disorders of, 1220-1221 growth plate of, 1219, 1219 heterotopic, 44 in collagen disorders, 1221-1222, 1221,, 1222t in hyperparathyroidism, 1150, 1228-1229, 1228 in hyperthyroidism, 1132 in mucopolysaccharidoses, 1222 in multiple myeloma, 664, 664 in myositis ossificans, 1262, 1262
in renal osteodystrophy, 1229 in scurvy, 449-450, 450 in vitamin deficiency, 1227-1228 infections of, 1232-1233, 1232 intramembranous formation of, 1219 involucrum, 1232, 1232 lamellar, 1217-1218, 1217,, 1218 in Paget disease, 1226-1227, 1226 loss of, 1222-1224. See also Osteoporosis. metaplastic, 1262, 1262 mineralization of, 1216 normal, 1216-1220, 1216-1219,, 1218t onion-skin appearance of, 1244 osteoblasts of, 1216-1217, 1216,, 1218 osteoclasts of, 1217, 1217 osteocytes of, 1217 peak mass of, 1218, 1223, 1223 proteins of, 1217-1218, 1218t remodeling of, 1218, 1219 repair of, 1229-1230, 1230 sclerosis of, 1224-1225, 1224,, 1225 slow virus infection of, 1225-1227, 1226,, 1227 Treponema infection of, 1233 tuberculous infection of, 1233 tumors of, 1233-1244, 1234t bone-forming, 1234-1237, 1235-1237 cartilage-forming, 1237-1242, 1238-1241 fibrous, 1242-1244, 1242,, 1243 in Paget disease, 1227 metastatic, 1245-1246 hypercalcemia and, 45, 1148 in prostate carcinoma, 1030, 1032 vitamin D effects on, 441-444, 443 von Recklinghausen disease of, 1228 woven, 1217, 1217 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Bone marrow, anatomy of, 604 biopsy of, 604 failure of, 632-633 in ariboflavinosis, 448 in Gaucher disease, 158, 159 in idiopathic thrombocytopenic purpura, 635-636 in kwashiorkor, 439 in systemic lupus erythematosus, 224 transplantation of, 210-211 diarrhea after, 811 hepatic complications of, 884, 884,, 885-886 veno-occlusive disease after, 884, 884 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Borrelia burgdorferi, 334t, 338, 388-389, 388,, 1253, 1317 myocarditis and, 584 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Bi -- Bo Bowen disease, of penis, 1013, 1013 of vulva, 1043, 1043 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Br -- By Brain. See also Central nervous system (CNS). abscess of, 1315-1316, 1316,, 1323, 1323 atrophy of, 35, 36 bridging veins of, 1305 contrecoup injury to, 1303-1304 contusion of, 1303-1304, 1303 copper deposition in, 875 coup injury to, 1303-1304 cytotoxic edema of, 1298 diffuse axonal injury of, 1304 edema of, 116, 1298. See also Hydrocephalus. embolism to, 1308 fungal infection of, 1316 giant cells in, 240, 240 glucose supply to, 1341-1342 hemorrhage in, 117,, 118, 1302, 1305-1306, 1306,, 1310-1313, 1311,, 1312 herniation of, 1298, 1298,, 1299 in galactosemia, 477 in human immunodeficiency virus infection, 240, 240 in left-sided heart failure, 549 in preeclampsia, 1083, 1084 in preterm infant, 463 in protein-energy malnutrition, 439 in right-sided heart failure, 550 in shock, 136 in trisomy 21, 171 infarction in, 132 laceration of, 1303, 1303 Niemann-Pick disease in, 158 perinatal injury to, 1302, 1302 subfalcine herniation of, 1298, 1298 tonsillar herniation of, 1298, 1298
Toxoplasma abscess of, 1323, 1323 transtentorial herniation of, 1298, 1298 trauma to, 1302-1306, 1303,, 1305,, 1306 sequelae of, 1305-1306 vascular malformations of, 1313 vasogenic edema of, 1298 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Br -- By BRCA genes, 292 in breast cancer, 1105, 1106, 1106t in ovarian cancer, 1067 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Br -- By Breast, 1093-1117 adenosis of, 1099 angiosarcoma of, 1104 atypical ductal hyperplasia of, 1100, 1100 atypical lobular hyperplasia of, 1100 carcinoma of, 1104-1117 angiogenesis in, 1115, 1117 atomic bomb exposure and, 310 BRCA genes in, 292, 1105, 1106t c-erb B2 gene in, 286 classification of, 1107, 1107t clinical course of, 1114-1115, 1116,, 1117 colloid, 1112, 1112 diet and, 1107 distribution of, 1107 DNA index in, 1115, 1116 ductal, 269 in situ, 1107-1109, 1107t, 1108,, 1109 invasive, 1110, 1110 environmental factors in, 1106-1107 epidemiology of, 1105-1106, 1106t estrogen and, 1106 estrogen replacement therapy and, 414 etiology of, 1106-1107 flow cytometry in, 1115, 1116 genetic factors in, 1105, 1106, 1106t, 1107 grade of, 1115 hormonal factors in, 1106 hormone receptors in, 1115 in male, 1118 in situ, 1107-1110, 1107t, 1108,, 1109 ductal, 1107-1109, 1107t, 1108,, 1109 microinvasion with, 1109 lobular, 1109-1110, 1109
incidence of, 272,, 1105 inflammatory, 1114, 1115 invasive, 1110-1112, 1110,, 1111,, 1113-1114, 1114 ductal, 1110, 1110 lobular, 1110-1111, 1111 lobular, in situ, 1109-1110, 1109 invasive, 1110-1111, 1111 lumpectomy for, 1116 lymph nodes in, 1114, 1115 mammographic appearance of, 1112-1113, 1113 medullary, 1111, 1111 metastatic, 269,, 1114, 1114,, 1115 models of, 1116 mortality with, 272,, 1105 oncogenes in, 280 oral contraceptives and, 415 papillary, 1112 peau d'orange skin change in, 1114 pesticides and, 422 prognosis for, 1115, 1116,, 1117 progression of, 1107 proliferative disease and, 1101-1102 risk factors for, 1105-1106 staging of, 1114 treatment of, lymphedema after, 115 tubular, 1112, 1112 developmental abnormalities of, 1096 duct ectasia of, 1097, 1097 epithelial hyperplasia of, 1100, 1100 epithelial tumors of, 1104, 1105 fat necrosis of, 1097-1098, 1098 fibroadenoma of, 267, 268,, 1102-1103, 1103 fibrocystic changes in, 1098-1100, 1099 fibrosis of, 1098-1100 hypertrophy of, 34-35 inflammation of, 1096-1098, 1097,, 1098 lumps in, 1095, 1096
lymphoma of, 1117 male, 1117-1118, 1118 menstrual cycle-related changes in, 1094 normal, 1093-1095, 1094,, 1095 papilloma of, 1101-1102, 1102 phyllodes tumor of, 1103-1104, 1105 postmenopausal, 1095, 1095 proliferative disease of, 1100-1102, 1100-1102 radiation damage to, 429, 429 sarcoma of, 1104 sclerosing adenosis of, 1101, 1101 silicone implants for, 1098 size of, 1096 stromal tumors of, 1102-1104, 1103,, 1104 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Br -- By Brittle bone disease, 1221-1222, 1221,, 1222t collagen in, 144-145 gene mutation in, 147t gonadal mosaicism in, 181 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Br -- By Bronchial asthma, 712-716. See also Asthma, bronchial. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Br -- By Bronchioles, 698, 708 in asthma, 715, 715 infection of, 716-717, 717 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Br -- By Bronchiolitis obliterans, 736,, 738 in bronchitis, 712 in lung transplant rejection, 741 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Br -- By Bronchogenic carcinoma, 741-747. See also Lungs, carcinoma of. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Br -- By Bronchopneumonia, 720-721. See Pneumonia. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Br -- By Brown atrophy, 36 of heart, 546 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Br -- By Bullae, 1172 pulmonary, 711, 711 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Br -- By Burkitt lymphoma, 485t, 655t, 662-663, 663 Epstein-Barr virus in, 312, 313 oncogenes in, 285, 285,, 286t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Br -- By Burns, 433-434 blister from, 84, 85 Curling ulcer in, 796 disseminated intravascular coagulation in, 641, 641 electrical, 435 Pseudomonas aeruginosain, 377 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
C -- Cap C1 inhibitor, 69 deficiency of, 236 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
C -- Cap C3, activation of, 67-68, 67,, 77t deficiency of, 236 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
C -- Cap Cachexia, in cancer, 319-320 tumor necrosis factor in, 74 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
C -- Cap Cadmium, in cancer, 274t in occupational diseases, 421, 421t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
C -- Cap Caenorhabditis elegans, clock gene of, 47 insulin receptor gene of, 47 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
C -- Cap Cafe au lait spots, in McCune-Albright syndrome, 1243 in neurofibromatosis, 164 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
C -- Cap Calcification, 43-45, 44 dystrophic, 18, 43-45, 44 in analgesic nephropathy, 879,, 978 pathogenesis of, 44-45, 44 in cell injury, 9 in mammary fibroadenoma, 1103 in pancreatitis, 908, 908 in silicosis, 731, 732 in systemic sclerosis, 228 membrane-facilitated, 44, 44 metastatic, 45 of aortic valve, 567-568, 567 of atheromatous plaque, 502 of cardiac valves, 567-568, 567 of mitral annulus, 567,, 568 on mammography, 1113, 1113,, 1113t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
C -- Cap Calcitonin, 1131 in medullary thyroid carcinoma, 1145 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
C -- Cap Calcium, in cell injury, 6, 6 in osteoporosis, 1223 metabolism of, 441-442 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
C -- Cap Calculi, gallbladder, 893-895, 894,, 895,, 904 renal, 989-990, 989t, 990,, 999t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
C -- Cap Callus, bony, 1230 soft tissue, 1229 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
C -- Cap Cancer. See Carcinogens; Carcinogenesis; Tumor(s); specific neoplasms, e.g., Lymphoma. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
C -- Cap Cancer-suppressor genes, 286-294 in retinoblastoma, 275 protein products of, 287, 289-294, 289,, 291 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
C -- Cap Candidiasis, 332t, 378-379, 379 CNS, 1322 esophageal, 782 genital, 1038t, 1039 in acquired immunodeficiency syndrome, 247-248 invasive, 379 oral, 757 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
C -- Cap Capillaries, 494-495 congestion of, 116 radiation damage to, 428 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Carbon monoxide, CNS effects of, 1342 in air pollution, 418, 418t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Carcinogenesis, 305-315, 307t. See also Tumor(s). chemical, 306-309, 306,, 307 initiation of, 306-308, 306,, 307 promotion of, 306,, 307,, 308 diet and, 455-456 molecular basis of, 276-298, 296-298, 297,, 298. See also Apoptosis; Cancer-suppressor genes; Oncogenes. radiation, 309-311, 426-427 viral, 311-315, 313,, 314 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Carcinogens, chemical, 306-309, 307t dietary, 455 immunosuppression with, 318 occupational, 273, 274t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Carcinoid tumor, 837, 837t bronchial, 747-748, 748 cardiac, 577-578, 577 gastric, 802 intestinal, 835-837, 836,, 837t pancreatic, 928 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Carcinoma, 262. See also at specific sites, e.g., Breast, carcinoma of. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Cardiac valves, 545 disease of, 566-578, 567t. See also specific diseases. prosthetic, 578, 578,, 578t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Cardiomyopathy, 578-586, 578 alcoholic, 579-580 dilated, 579-581 hypertrophic, 581-583, 582 in pheochromocytoma, 1165-1166 ischemic, 564 peripartum, 580 restrictive, 583 thyrotoxic, 1131 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Cartilage. See also Bone(s). articular, 1246 ochronosis of, 42, 162 tumor formation of, 1237-1242, 1238-1241 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Caruncle, 366-367 urethral, 1009 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Cataracts, 1367-1368 in diabetes, 1334 in galactosemia, 476, 477 in myotonic dystrophy, 1283 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Catecholamines, cardiotoxicity of, 586 in pheochromocytoma, 1165-1166 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Cavernous hemangioma, 532,, 533, 1313 of liver, 886 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Cavernous lymphangioma (cystic hygroma), 533 in Turner syndrome, 175 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Cell(s), adaptations of, 2 aging of, 4 atrophy of, 2 death of, 2-4, 3,, 4t, 18-25, 90, 90. See also Apoptosis; Necrosis. differentiation of, 90, 90 genetic clock of, 46-47, 46,, 47 hypertrophy of, 2, 3,, 34 labile (continuously dividing), 90,, 91 permanent (nondividing), 90,, 91-92 regeneration of, 90 stable (quiescent), 90,, 91 stem, 91 swelling of, vs. hypertrophy, 34 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Cell cycle, 90,, 91-92 checkpoints in, 96, 96 cyclin-dependent kinases in, 283, 283,, 284 cyclins in, 283, 283,, 284 ras gene in, 281 Rb gene in, 289-290, 289 transforming growth factor-beta in, 290, 293 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Cell growth, 90-98, 90-93,, 96,, 97t, 103 adaptation(s) in, 32-38 atrophy as, 35-36, 36 hyperplasia as, 32-35, 32,, 33 hypertrophy as, 33-35, 34 metaplasia as, 36-38, 37,, 38 cell surface receptors in, 92-93, 93 collagen in, 98-99, 99,, 99t contact inhibition of, 96 cycle of, 90,, 91-92 elastin in, 99-100 extracellular matrix in, 98-102, 99-103,, 99t fibrillin in, 100 fibronectin in, 100, 100 growth factors in, 97-98, 97t hyaluronan in, 102 inhibition of, 96-97 integrins in, 100-101, 101 intercellular signaling in, 92-95, 93-95. See also Intercellular signaling. laminin in, 100 matricellular proteins in, 101 molecular events in, 92-95, 93-95 proliferative potential for, 91-92 proteoglycans in, 101-102 regulation of, 95-96, 96. See also Protooncogenes; Tumor-suppressor genes. defects in, 162, 164 signal transduction systems in, 92-95, 93-95 syndecan in, 102, 102 transcription factors in, 95 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Cell injury, 2, 3,, 4-5. See also Ischemia; Necrosis. acetaminophen-induced, 14-15 age-induced, 45-48, 46-48 amino acid loss in, 11 ATP depletion in, 5, 9, 11 bacteria-induced, 341-344, 342,, 343 calcification in, 9, 43-45, 44 calcium in, 6, 6 carbon accumulation in, 42 carbon tetrachloride-induced, 14, 14,, 15 chemicals in, 4, 14-15, 14,, 15 cholesterol accumulation in, 40, 40 cytochrome c in, 6-7 diphtheria toxin-induced, 343, 343 DNA damage in, 12 drugs in, 14-15 energy metabolism in, 7-8 free radicals in, 5-6, 6,, 10, 12-15, 13-15,, 47, 48. See also Free radicals. genetic defects in, 4 glycogen accumulation in, 41-42 hemosiderin accumulation in, 42-43, 43 hyaline change in, 45 immunologic reactions in, 4 in alpha1-antitrypsin deficiency, 38, 38 in lysosomal storage disease, 38, 38 infectious agents in, 4 intracellular accumulations in, 38-43, 38-43 irreversible, 8-11, 8-11 morphology of, 15-18, 16-18 lipid accumulation in, 38, 38,, 39-40, 39,, 40 lipid peroxidation in, 12 lipofuscin accumulation in, 42, 42
lysosomal catabolism in, 25-26 lysosomal enzymes in, 8-9 membrane permeability in, 6, 9-11, 11 mitochondrial damage in, 6-7, 7,, 9, 11 nitric oxide in, 12 nutritional imbalances in, 4-5 oxygen deprivation in, 4 pH in, 9 phospholipid loss in, 9-10, 11 physical agents in, 4 pigment accumulation in, 38, 38,, 42-43, 42,, 43 protein accumulation in, 40-41, 41 protein fragmentation in, 12 protein synthesis in, 8 repair of, 47-48, 48 reperfusion, 11-12 reversible, 7-8, 8-10 morphology of, 9,, 10,, 15 sodium in, 7 subcellular response to, 25-28 triglyceride accumulation in, 39-40, 39 ultrastructural features of, 8, 9,, 10, 10 virus-induced, 340-341, 341 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Cell membrane, lipid peroxidation of, 12 permeability of, in cell injury, 6, 9-11, 11 phospholipid loss from, 9-10, 11 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Central nervous system (CNS). See also Brain; Spinal cord. amphetamine effects on, 413 arbovirus infection of, 1318 aspirin effects on, 416 astrocytes of, 1296-1297, 1296 astrocytoma of, 1343-1346, 1344-1346 barbiturate effects on, 412 Borrelia burgdorferi infection of, 1317 carbon monoxide injury to, 1342 cells of, 1294-1297, 1296 cytomegalovirus infection of, 1319 degenerative diseases of, 1329-1338, 1330-1332,, 1332t, 1334,, 1336,, 1339 demyelinating diseases of, 1326-1329, 1327,, 1328 ependymal cells of, 1297 ependymoma of, 1346-1348, 1347 ethanol effects on, 412 ethanol injury to, 1342, 1342 fungal infection of, 1322 germ cell tumors of, 1350 glial cells of, 1295-1297, 1296 gliomas of, 1343-1348, 1344-1347 hallucinogen effects on, 413 herpes simplex virus infection of, 1318, 1318 human immunodeficiency virus infection of, 240, 240,, 244-245, 1320-1321, 1320 in diabetes mellitus, 924 in Epstein-Barr virus infection, 373 in hypoglycemia, 1341-1342 in inborn errors of metabolism, 1338-1341, 1340 in systemic lupus erythematosus, 222-223 in vitamin B1 deficiency, 1341 in vitamin B12 deficiency, 1341 infection of, 1314-1323, 1315,, 1316,, 1323. See also specific infections.
fungal, 1322 protozoal, 1323, 1323 viral, 1317-1322, 1318,, 1320,, 1322 lead effects on, 421 lymphoma of, 1349-1350 malformations of, 1299-1302, 1301 measles virus infection of, 1321-1322 medulloblastoma of, 1348-1349, 1349 metastatic tumors of, 1351 methanol injury to, 1342 methotrexate injury to, 1342-1343 microglia of, 1297 Mycobacterium tuberculosisinfection of, 1316-1317 narcotic effects on, 413 neuronal tumors of, 1348 neurons of, 1294-1295 oligodendrocytes of, 1297 oligodendroglioma of, 1346 paraneoplastic syndromes of, 1351-1352, 1352t pilocytic astrocytoma of, 1346, 1346 pleomorphic xanthoastrocytoma of, 1346 poliovirus infection of, 1319 polyomavirus infection of, 1321, 1322 poorly differentiated tumors of, 1348-1349, 1349 prion infection of, 1323-1326, 1325 rabies infection of, 1319-1320 radiation damage to, 430 radiation injury to, 1342-1343 stimulant effects on, 412-414, 413 toxic injury to, 1342-1343, 1342 Toxoplasma infection of, 1323, 1323 trauma to, 1302-1306, 1303,, 1305,, 1306 sequelae of, 1305-1306 Treponema pallidum infection of, 1317 tumors of, 1343-1355, 1344-1347,, 1349,, 1351,, 1352t, 1353. See also specific tumors. varicella-zoster virus infection of, 1319
vitamin E deficiency effects on, 446 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Cerebrospinal fluid (CSF), in acute aseptic meningitis, 1315 in acute pyogenic meningitis, 1314, 1315 in arthropod-borne viral encephalitis, 1318 in brain abscess, 1316 in poliomyelitis, 1319 ventricular accumulation of, 1298-1299, 1299 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Cerebrovascular disease, 1306-1314 arteritis in, 1308 atherosclerosis in, 1308 berry aneurysm in, 1310-1313, 1311,, 1312 collateral flow in, 1308 focal cerebral ischemia in, 1308-1310, 1309 global cerebral ischemia in, 1307-1308 granulomatous angiitis in, 1308 hypertension in, 1313-1314, 1313 hypertensive encephalopathy in, 1314 intracranial hemorrhage in, 1310-1313, 1311,, 1312 lacunar infarcts in, 1313-1314, 1313 slit hemorrhage in, 1314 subarachnoid hemorrhage in, 1310-1313 vascular malformations in, 1313 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Ceruloplasmin, in free radical inactivation, 13 in Wilson disease, 875 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Car -- Ce Cervix, 1047-1053 adenocarcinoma of, 1053 adenosquamous carcinoma of, 1053 anatomy of, 1036,, 1037, 1037 infection of, 1038-1039, 1038t, 1047-1048, 1047,, 1048 intraepithelial neoplasia of, 1049-1051, 1051,, 1052 polyps of, 1048, 1048 squamous cell carcinoma of, 1051-1053, 1053 clinical course of, 1053 human papillomavirus and, 311, 1049, 1050 in acquired immunodeficiency syndrome, 250 oral contraceptives and, 415 Pap smear for, 322-323, 323 pathogenesis of, 1049 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Chagas disease, 393-394, 584, 585 achalasia in, 778-779 megacolon in, 805 myocarditis in, 394 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Chancre, in syphilis, 363, 363 in trypanosomiasis, 393 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Chemicals. See also Carcinogenesis, chemical; Carcinogens, chemicals. at hazardous waste sites, 404, 404t biologic effective dose of, 405 estrogenic, 422 in cell injury, 14-15, 14,, 15 in esophageal injury, 782 in type I diabetes mellitus, 917 metabolism of, 405-408, 406-408 toxicity of, 404-408, 405-408 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Chemokines, 73, 192 C, 74 C-C, 74 C-X-C, 74 CX 3C, 74 in glomerulonephritis, 948 in inflammation, 74, 74t, 77t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Chemotherapy, neutropenia with, 646-747 pulmonary effects of, 740, 740t stem cell rescue with, 211 tumor cell resistance to, 292 tumor growth fraction and, 301, 301 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Cherry-red spot, in Niemann-Pick disease, 158 in Tay-Sachs disease, 156 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Chief cells, in parathyroid adenoma, 1149-1150, 1149 of parathyroid glands, 1147 of stomach, 788 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Children. See also Infant. acquired immunodeficiency syndrome in, 237 acute lymphoblastic leukemia/lymphoma in, 654-658, 655t, 657,, 657t, 658,, 659 Bordetella pertussis infection in, 374-375, 374 congenital heart disease in, 591-597, 592t, 592-596. See also specific diseases. Corynebacterium diphtheriaeinfection in, 375, 375 cystic fibrosis in, 477-481. See also Cystic fibrosis. cytomegalovirus infection in, 376 Epstein-Barr virus infection in, 371-373, 372 fatty streaks in, 503 fibrous tumors in, 484 ganglioneuroma in, 486 idiopathic thrombocytopenic purpura in, 636 infection in, 370-375, 370,, 372,, 374,, 375 measles virus infection in, 370, 370 mortality rate for, 459-460, 460t mumps virus infection in, 370-371 neuroblastoma in, 485-487, 485t, 486,, 487 poliovirus infection in, 373 tumors in, 482-489 benign, 483-484, 483,, 484 malignant, 484-491, 485t, 486,, 487,, 488t, 489 varicella-zoster infection in, 373-374, 374 Waterhouse-Friderichsen syndrome in, 1160, 1160 Wilms' tumor in, 485t, 487-489, 488,, 489t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Chlamydia pneumoniae, 361, 361t atherosclerosis and, 509 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Chlamydia trachomatis, 332t, 360t genital, 361-362, 361t, 1038t in pelvic inflammatory disease, 357-358 ocular, 1361-1362, 1362 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Cholangitis, 898 sclerosing, 877t, 879-880, 879 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Cholelithiasis, 893-895, 894,, 895 cholesterol, 894, 895 obesity and, 454 pigment, 894-895, 895 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Cholestasis, 848, 851-852, 852 in alcoholic liver disease, 872 in pregnancy, 885 in secondary biliary cirrhosis, 878 neonatal, 876-877, 877t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Cholesterol, cellular accumulation of, 40, 40 in atherosclerosis, 504-506, 505t in gallstone formation, 893, 894, 895 metabolism of, 151-152, 151,, 152 therapeutic lowering of, 505 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Choriocarcinoma, 1021, 1021,, 1023 gestational, 1087-1089, 1088 ovarian, 1076 testicular, 1021, 1021,, 1023 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Choristoma (heterotopia), 263 bone, 44 definition of, 483 duodenal, 789 neuronal, 1300 pancreatic, 789 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Choroid, lymphoma of, 1372 melanoma of, 1365-1367, 1366 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Choroid plexus, carcinoma of, 1348 papilloma of, 1347-1348 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Chromium, in carcinogenesis, 274t, 309 in occupational diseases, 421t, 422 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Chromosome(s), analysis of, in acute lymphoblastic leukemia/lymphoma, 655, 655t in acute myelogenous leukemia, 677 in adult T-cell leukemia/lymphoma, 656t in angiocentric lymphoma, 656t in Burkitt lymphoma, 655t, 662 in chronic lymphocytic leukemia, 655t, 659 in chronic myelogenous leukemia, 680-681, 680 in diffuse large B-cell lymphoma, 655t, 661 in follicular lymphoma, 655t in hairy cell leukemia, 656t in large granular lymphocytic leukemia, 656t in lymphoplasmacytic lymphoma, 656t in mantle cell lymphoma, 656t, 668 in marginal zone lymphoma, 656t in multiple myeloma, 655t, 664 in mycosis fungoides, 656t in peripheral T-cell lymphoma unspecified, 656t in plasmacytoma, 655t in Sezary syndrome, 656t in small lymphocytic lymphoma, 655t, 659 anaphase lag of, 168 deletion of, 169, 169,, 173 disorders of, 168-176, 466, 466t fluorescence in situ hybridization analysis of, 166-168, 167 fluorescent painting of, 166, 168, 168 G banding of, 165-166, 166 inversion of, 169, 169 isochromosome formation of, 169-170, 169 karyotype of, normal, 165-168, 166-168 spectral, 168, 168 terminology for, 166, 167 mosaicism of, in intrauterine growth retardation, 461, 462
nondisjunction of, 168 number of, aneuploid, 168 disorders of, 168-169, 170-173, 171,, 172 euploid, 168 paracentric inversion of, 169, 169 pericentric inversion of, 169, 169 Philadelphia, 285, 285 postnatal evaluation of, 182 prenatal evaluation of, 182 reciprocal translocation of, 169,, 170 ring, 169, 169 robertsonian translocation of, 169,, 170 sex. See also X chromosome; Y chromosome. disorders of, 173-176, 175 spectral karyotype of, 168, 168 structure of, disorders of, 169-170, 169 translocation of, 169,, 170 in oncogene activation, 284-286, 285,, 286t, 298 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Chromosome 15, maternal, in Angelman syndrome, 180-181, 181 paternal, in Prader-Willi syndrome, 180-181, 181 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cf -- Ch Chronic obstructive pulmonary disease (COPD), 706-717, 707t. See also Asthma; Bronchiectasis; Bronchitis; Emphysema. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ci -- Com Cigarette smoking, 408-410, 409t, 712, 712 atherosclerosis and, 506 bronchogenic carcinoma and, 741-742 cancer and, 273 emphysema and, 709 gastric carcinoma and, 799, 799t oral cancer and, 760 passive exposure to, 410 peptic ulcer disease and, 794 periductal mastitis and, 1097 transitional cell carcinoma and, 1007 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ci -- Com Cirrhosis, 848, 853-855, 854 alcoholic, 411-412, 411,, 411t, 869-871. See also Alcoholic liver disease. ascites and, 855, 855 biliary, 877t primary, 877t, 878-879, 879 secondary, 877t, 878, 878 cardiac, 883 collagen deposition in, 854, 854,, 872 cryptogenic, 853 etiology of, 853 in chronic hepatitis, 866, 867 Ito cells in, 254, 854 portal hypertension and, 855-856, 855 splenomegaly and, 855,, 856 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ci -- Com Clostridium difficile, 334t, 368, 369, 807-809, 808t pseudomembranous colitis from, 809-810, 810 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ci -- Com Clostridium perfringens, 334t, 368-369, 369,, 807-809, 808t necrosis with, 346 alpha toxin of, 344, 368 beta toxin of, 369 delta toxin of, 368-369 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ci -- Com Clotting. See Coagulation. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ci -- Com CMV. See Cytomegalovirus (CMV). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ci -- Com CNS. See Central nervous system (CNS). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ci -- Com Coagulation, 121,, 122-124, 123,, 124 anticoagulation regulation of, 122-124, 124 antithrombins in, 122, 124 extrinsic pathway of, 121,, 122, 640 in inflammation, 68,, 69-70 intrinsic pathway of, 121,, 122, 640 protein C in, 122-123, 124 protein S in, 122-123, 124 vitamin K in, 446-447 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ci -- Com Colitis. See also Enterocolitis. Clostridium difficile-induced, 809-810, 810 collagenous, 810 ulcerative, 818-820, 819,, 820,, 821t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ci -- Com Collagen, deficiency of, skeletal manifestations of, 1221-1222, 1221,, 1222t genes for, 144-145, 147t, 150 in Ehlers-Danlos syndromes, 149-150 in hepatic cirrhosis, 854, 854,, 872 in osteogenesis imperfecta, 144-145 in silicosis, 731, 731,, 732 in systemic sclerosis, 226-228, 228 of bone, 1217-1218, 1217 of extracellular matrix, 98-99, 99,, 99t, 103 of glomerular basement membrane, 931, 933, 933 synthesis of, 98-99, 99,, 106, 106t in fibrosis, 106, 106t in wound healing, 108-109, 108 types of, 98, 99t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ci -- Com Collagenase, in tissue remodeling, 107, 107 type IV, in tumor invasion, 303-304, 304 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ci -- Com Colon. See Intestine. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ci -- Com Colorectal carcinoma. See Intestine, carcinoma of. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ci -- Com Complement, deficiency of, 236 in systemic lupus erythematosus, 219 immune complex activation of, 203, 203 in glomerulonephritis, 947 in inflammation, 67-69, 67,, 77t in tuberculosis, 349 in type II hypersensitivity, 199-200 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Con -- Cr Condyloma acuminatum, 1209 of penis, 1012, 1012,, 1013 of vulva, 1042, 1043 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Con -- Cr Congenital heart disease, 591-597, 592t. See also specific types. clinical features of, 592-593 etiology of, 592 incidence of, 592, 592t left-to-right shunt in, 593-595, 593,, 594 obstructive, 596-597, 596,, 597 right-to-left shunt in, 595-596, 596 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Con -- Cr Congenital malformation, 464-470, 465,, 466t, 467t, 468,, 469. See also Malformation(s), congenital. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Con -- Cr Congestion, 116-117 hepatic, 116-117, 117 pulmonary, 116 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Con -- Cr Congestive heart failure, 546-550, 547,, 548. See also Heart, failure of. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Con -- Cr Conjunctiva, carcinoma in situ of, 1362 epithelial tumors of, 1362 in vitamin A deficiency, 1361 melanoma of, 1362 mucoepidermoid carcinoma of, 1362 pingueculae of, 1361, 1361 pterygium of, 1361 squamous cell carcinoma of, 1362 trachoma of, 1361-1362, 1362 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Con -- Cr Contusion, 432-433, 432 CNS, 1303-1304, 1303 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Con -- Cr Copper, deficiency of, 452t hepatic accumulation of, 875 in Ehlers-Danlos syndromes, 150 in free radical generation, 12, 13 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Con -- Cr Cornea, Avellino dystrophy of, 1363 copper deposition in, 875 endothelial dystrophy of, 1363-1364, 1364 Fuchs dystrophy of, 1363-1364, 1364 hereditary dystrophy of, 1363-1364, 1363,, 1364 herpesvirus infection of, 361 inflammation of, 1362-1363 lattice dystrophy of, 1363 macular dystrophy of, 1363, 1363 Reis-Bucklers dystrophy of, 1363 stromal dystrophy of, 1363, 1363 ulcer of, 1362-1363 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Con -- Cr Coronary artery disease, 550-564. See also Heart, ischemic disease of; Myocardial infarction. after heart transplantation, 598, 598 epidemiology of, 551 in systemic lupus erythematosus, 223-224 pathogenesis of, 551-554, 552,, 553t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Con -- Cr Cortisol, biosynthesis of, 1152 excess of, 1153-1155, 1153,, 1155t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Con -- Cr C-reactive protein, in febrile state, 86 in myocardial infarction, 506 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Con -- Cr CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia), 226, 229 antibodies in, 218t, 227 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Con -- Cr Crohn disease, 816-818, 817,, 818,, 821t complications of, 818 extraintestinal manifestations of, 818 fissures in, 816, 817 granulomas in, 817, 818 mucosal damage in, 817 pathogenesis of, 815-816 skip lesions in, 816 ulcers in, 816, 817, 817 vs. ulcerative colitis, 819,, 821t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Con -- Cr Cryptococcosis, 379-380, 380 in acquired immunodeficiency syndrome, 248 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Con -- Cr Crystal arthropathy, 1253-1257. See also Gout. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cs -- Cy CSF. SeeCerebrospinal fluid (CSF). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cs -- Cy Cushing syndrome, 1152-1155, 1153,, 1155t diagnosis of, 1155 hemorrhage in, 634 paraneoplastic, 320, 321t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cs -- Cy Cyanosis, in left-to-right shunt, 593-595, 593,, 594 in right-to-left shunt, 595-596, 596 of Raynaud disease, 524 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cs -- Cy Cyclins, in cancer, 282-284 in cell cycle, 95-96, 96,, 283, 283,, 284 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cs -- Cy Cyclin-dependent kinases, 96, 96 in cancer, 282-284 in cell cycle, 283, 283,, 284 inhibitors of, 283 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cs -- Cy Cyclophosphamide, cardiotoxicity of, 586 transitional cell carcinoma and, 1007 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cs -- Cy CYP1A1 gene, 405 in lung cancer, 307 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cs -- Cy Cyst(s), adrenal, 1163 Baker, 1258 Bartholin, 1040 blue-dome, 1099, 1099 branchial, 767 bronchogenic, 699 choledochal, 899 colloid, of cerebral ventricle, 1348 dermoid, 1181 Echinococcus granulosus, 395-396 epithelial, 1181 Gartner duct, 1045 hepatic, 880-881, 880 in von Hippel-Lindau disease, 909 inclusion, epidermal, 1181 lymphoepithelial, 767 mammary, 1099, 1099 mesenteric, 842 odontogenic, 761 ovarian, 1066-1067, 1066 pancreatic, 909 pilar, 1181 renal, 937-942, 938,, 939,, 941,, 941t synovial, 1258 thymic, 691 thyroglossal tract, 767-768 thyroid, 1142, 1147 trichilemmal, 1181 tubal, 1065 urachal, 1001 ureteral, 998-999, 999 vaginal, 1045 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cs -- Cy Cystadenocarcinoma, ovarian, 1069-1071, 1069-1071 pancreatic, 910, 910 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cs -- Cy Cystadenoma, 261 ovarian, 1069, 1069 pancreatic, 910 papillary, 261 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cs -- Cy Cystic fibrosis, 41, 477-481, 478-481 genetic defects in, 143, 143,, 147t, 148, 478-479, 479 hepatic abnormalities in, 480 pancreatic abnormalities in, 479-480, 481 pathogenesis of, 478-479, 478,, 480 Pseudomonas infection in, 376, 377 pulmonary infection in, 479, 480, 481, 481 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cs -- Cy Cytogenetic disorders, 168-176, 169. See also Chromosome(s). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cs -- Cy Cytokines, 98 autocrine effects of, 192 classes of, 73 endocrine effects of, 192 in asthma, 713, 714,, 715 in febrile state, 86 in glomerulonephritis, 948 in hepatocyte regeneration, 33, 33 in Hodgkin disease, 674 in immune system, 191-192 in inflammation, 54, 73-74, 73,, 77t in leukocyte adhesion, 57, 57t, 58 in multiple myeloma, 664 in rheumatoid arthritis, 1250-1251 in type I diabetes mellitus, 916 in type I hypersensitivity reaction, 198 natural killer cell secretion of, 191 paracrine effects of, 192 pleiotropic effects of, 192 receptors for, 192 types of, 192 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Cs -- Cy Cytomegalovirus (CMV), 333t, 376, 376 CNS, 376, 1319 congenital, 376 esophageal, 782 fetal, 467 in acquired immunodeficiency syndrome, 248 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Da -- De Deep vein thrombosis, 129. See also Embolism; Thrombosis. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Da -- De Deformation, congenital, 464-465. See also Malformation(s), congenital. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Da -- De Degenerative joint disease, 1246-1257. See also Arthritis. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Da -- De Dementia, 1329-1333. See also Alzheimer disease. in Creutzfeldt-Jakob disease, 1324 in neurosyphilis, 1317 in progressive supranuclear palsy, 1334-1335 post-traumatic, 1305-1306 vascular (multi-infarct), 1314 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Da -- De Dendritic cells, 191 follicular, 191, 243 human immunodeficiency virus infection of, 243, 250 in transplantation, 210 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Da -- De Deoxyribonucleic acid (DNA), damage to, 310 chemical, 306, 308 repair of, 47-48, 48 fragmentation of, in apoptosis, 20, 21 mitochondrial, mutations in, 179-180 mutations in, 141-143. See also Mutation(s). nucleotide excision repair of, 310 repair of, 47-48, 48,, 310 BRCA genes in, 292 defective, cancer and, 276 genes for, 277, 295-296 p53 gene in, 291, 291 transfection of, 278, 297 ultraviolet ray effects on, 310 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Da -- De Dermatitis. See also Skin. atopic, 1195t contact, 206, 206,, 1195t, 1196-1197, 1196 drug-related, 1195t eczematous, 1194-1197, 1195,, 1195t, 1196 in ariboflavinosis, 448 in pellagra, 448, 449 in zinc deficiency, 451, 452 irritant, 1195t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Da -- De Dermis, 1171,, 1172. See also Skin. dermatofibrosarcoma protuberans of, 1188 tumors of, 1187-1189, 1188 vascular tumors of, 532-533, 532,, 534-535, 534,, 537-538, 537 xanthoma of, 1189 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Di -- Dy Diabetes mellitus, 913-926 atherosclerosis and, 506 cellular glycogen in, 42 classification of, 913-914, 913t complications of, 919-920, 919,, 921 advanced glycosylation end products and, 920, 920t intracellular hyperglycemia and, 919,, 920 neuropathic, 924 nonenzymatic protein glycosylation and, 919-920, 919,, 920t ocular, 924 renal, 922-923, 923,, 924 vascular, 921,, 922, 922 glomerulosclerosis in, 966-968, 967 glucose tolerance test in, 915 hyaline arteriolosclerosis in, 514 insulin-dependent (type I), 913, 913t autoimmunity in, 915,, 916 beta-cell loss in, 916 clinical features of, 924-926, 925 environmental factors in, 916-917 genetic factors in, 915-916, 915 HLA class II gene in, 915-916, 915 immune system in, 915,, 916 insulitis in, 916, 920, 921 ketoacidosis in, 924-926, 925 mortality from, 926 pathogenesis of, 915-917, 915,, 916 T-cell anergy in, 214 transgenic mouse model of, 214 viruses in, 917 maturity-onset of young, 913, 918-919 microangiopathy in, 922-923, 923 non-insulin-dependent (type II), 913, 913t amylin in, 918
amyloidosis in, 921,, 922 beta-cell degranulation in, 922 beta-cell insulin secretion in, 917-918, 917 clinical features of, 926 insulin resistance in, 918 mortality from, 926 obesity in, 918 pathogenesis of, 917-918, 917 pancreatic lesions in, 920, 921,, 922 peripheral nephropathy in, 966-968, 967 peripheral neuropathy in, 1279, 1279 retinopathy in, 1369-1370, 1369 secondary, 913t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Di -- Dy Dialysis, kidney, 941, 964 amyloidosis with, 253, 253t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Di -- Dy Diarrhea, 805-812, 806t. See also Enterocolitis. after bone marrow transplantation, 811 bacterial infection in, 807-809, 808t, 809 definition of, 805-806 drug-induced, 811 Entamoeba histolyticain, 811 Giardia lamblia in, 811, 811 in abetalipoproteinemia, 815 in acquired immunodeficiency syndrome, 248, 811 in celiac sprue, 813 in cholera, 357-358 in disaccharidase deficiency, 815 in graft-verus-host disease, 811 in malabsorption syndromes, 214,, 806t, 812-815, 812t, 813 in motility disorders, 806t in pellagra, 448-449 in tropical sprue, 814 in Whipple disease, 814-815, 814 infectious, 248, 806-810, 806t, 807t, 808t, 809 osmotic, 806, 806t radiation-induced, 811 rice-water, 357-358 secretory, 806, 806t traveler's, 809 viral, 354-355, 806-807, 807t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Di -- Dy DIC, 640-642. See also Disseminated intravascular coagulation (DIC). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Di -- Dy Diet, 436. See also specific minerals and vitamins. disease and, 455 in atherosclerosis, 506 in breast carcinoma, 1107 in cancer prevention, 455-456 in carcinogenesis, 309 in colorectal carcinoma, 456, 833 in esophageal squamous cell carcinoma, 784-785, 785t in gastric carcinoma, 799, 799t in phenylketonuria, 476 life span and, 47 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Di -- Dy Diffuse alveolar damage, 700-703. See also Adult respiratory distress syndrome (ARDS). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Di -- Dy Diphtheria, 343, 343 oral manifestations of, 759t peripheral nerve involvement in, 1276 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Di -- Dy Disruption, congenital, 465, 465. See also Malformation(s), congenital. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Di -- Dy Disseminated intravascular coagulation (DIC), 129, 640-642, 640t, 641 clinical course of, 642 hepatic sinusoid occlusion in, 882 in cancer, 321 in preeclampsia, 1083, 1084 prognosis for, 642 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Di -- Dy Diverticulum (diverticula), Meckel, 804-805, 805 of bladder, 1000, 1000 of esophagus, 778,, 779 of intestine, 823-825, 824 of ureter, 998 Zenker, 778,, 779 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Di -- Dy DNA. See Deoxyribonucleic acid (DNA). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Di -- Dy Down syndrome, 170-171, 171,, 172 G-banded karyotype of, 171 ocular anomalies in, 1360 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Di -- Dy Drug(s), adverse reactions to, 148, 414-416, 415t, 634 fetal effects of, 467 hepatic toxicity of, 868-869, 869t after bone marrow transplantation, 885 in cell injury, 4, 14-15 in iatrogenic lysosomal disease, 26 in warm antibody hemolytic anemia, 620 interstitial nephritis with, 977-979, 977,, 979,, 979t lupus erythematosus with, 218t, 224-225 neutropenia with, 646-647 pulmonary effects of, 740, 740t smooth endoplasmic reticulum hypertrophy with, 26, 27 thrombocytopenia with, 636 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Di -- Dy Duct(s), accessory, of Santorini, 903 bile. See Bile ducts. Gartner, cyst of, 1045 mammary, 1093, 1094 ectasia of, 1097, 1097 mullerian, 1036 of Luschka, 892 pancreatic, 903, 903 obstruction of, 906, 906,, 908 thyroglossal, 1147 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Di -- Dy Duodenum, adenoma of, 827, 827 atresia of, 804 Brunner glands of, 803 gastric heterotopia of, 789 stress ulcers of, 796-797 ulcers of, 793-796, 794,, 795 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Di -- Dy Dysentery. See also Diarrhea. amebic, 358 bacillary, 355, 355 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Di -- Dy Dysplasia, definition of, 466 epithelial, 266, 267 fibrous, 1242-1243, 1243 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Di -- Dy Dystrophin, gene for, in dilated cardiomyopathy, 580 mutations in, 147t in muscular dystrophy, 1282, 1282,, 1284 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Ear, 766-767 bone deposition in, 767 inflammation of, 766-767 tumors of, 767 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En EBV. See Epstein-Barr virus (EBV). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Ecchymoses, 118 in idiopathic thrombocytopenic purpura, 636 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Ectasia, annuloaortic, 528 of mammary duct, 1097, 1097 vascular, 534 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Edema, 113-116, 114,, 114t cerebral, 116, 1298 clinical effects of, 116 congestion and, 116 generalized, 113, 560 hydrostatic pressure in, 114-115, 115 in inflammation, 53-54 in nephrotic syndrome, 953 in right-sided heart failure, 550 in Turner syndrome, 175 lymphatic obstruction in, 115 of optic nerve, 1373-1374, 1374 pitting, 116 plasma osmotic pressure in, 115 pulmonary, 116, 700 sodium retention in, 115-116 subcutaneous, 116 vs. hypertrophy, 34 water retention in, 115-116 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Effusion, inflammatory, 84, 85 pericardial, 550, 587 pleural, 550, 749-751, 750t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Ehlers-Danlos syndrome, 149-150 copper metabolism in, 150 gene mutation in, 147t hemorrhage in, 634 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Elastin, in aortic stenosis, 597 of extracellular matrix, 99-100 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Electromagnetic radiation, 425 in carcinogenesis, 310-311 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Embolism, 127, 128,, 129-132 air, 131, 435 amniotic fluid, 131-132 cerebral, 1308 cholesterol, 130, 502 estrogen replacement therapy and, 414 fat, 130-131, 131 from endocarditis, 574 gas, 435 in coronary artery occlusion, 555 oral contraceptives and, 415-416 paradoxical, 130, 555, 592 pulmonary, 130, 130,, 703-704, 703 fibrous web from, 130 prevention of, 704 pulmonary abscess and, 722 renal, 986, 987 saddle, 130, 130 systemic, 130 with cardiac valve prostheses, 578 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Embryonal rhabdomyosarcoma, 1265, 1265 of bladder, 1008 of vagina, 1046-1047, 1046 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Emphysema, 707-711, 707t alveolar tears in, 711 alpha1-antitrypsin deficiency and, 709 bullous, 711, 711 centrilobular (centriacinar), 707-709, 708,, 710 cigarette smoking and, 709 clinical course of, 710 compensatory, 710 distal acinar (paraseptal), 709 incidence of, 709 irregular, 709, 710 panlobular (panacinar), 708,, 709, 710 pathogenesis of, 709-710, 709 protease-antiprotease theory of, 709-710, 709 senile, 710 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Empyema, 721, 750 of gallbladder, 896 of sinus, 762-763 subdural, 1316 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Encephalitis, arbovirus, 1318 cytomegalovirus, 376, 1319 hemorrhagic, necrotizing, 1328-1329 herpesvirus, 360, 1318, 1318 JC virus, 1321, 1322 limbic, 1352, 1352t Naegleria, 1323 poliovirus, 1319 rabies, 1319-1320 varicella-zoster, 1319 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Encephalomyelitis. See also Encephalitis. disseminated, acute, 1328-1329 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Encephalopathy, hepatic, 853, 1342 hypertensive, 1314 hypoxic, 1307-1310 in left-sided heart failure, 549 multicystic, 1302 spongiform, 1296t, 1323-1326, 1325 Wernicke, 1341 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Endocarditis, Candida in, 379 fungal, 574 in systemic lupus erythematosus, 127, 223,, 577, 765 infective, 572-576, 575 artificial valves and, 578 renal manifestations in, 966 Libman-Sacks (noninfective, verrucous), 575,, 576-577, 576 in systemic lupus erythematosus, 127, 223, 223 thrombotic, in cancer, 321, 321t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Endocrine cells, of intestine, 803-804 of stomach, 788 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Endocrine system. See specific glands and hormones. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Endometrium, adenocarcinoma of, 1061-1062, 1062 adenomyosis of, 1057, 1057 carcinoma of, 1061-1062, 1062 estrogen replacement therapy and, 414 mortality rates with, 272 oral contraceptives and, 415 carcinosarcoma of, 1063 complex hyperplasia of, 1060, 1060 cyclic changes in, 1037-1038, 1054,, 1055, 1055 oral contraceptives and, 1056 extrauterine, 1057-1058, 1058,, 1059 hyperplasia of, 33, 1059-1061, 1060 inflammation of, 1057, 1057 menopausal changes in, 1056 metaplasia of, 1060, 1060 mixed mullerian tumors of, 1063 myosis of, 1065 papillary serous carcinoma of, 1062, 1062 polyps of, 1058-1059, 1059 sarcoma of, 1065 stromal tumors of, 1065 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Endothelium, 496, 496t activation of, 496-497, 496 antibodies to, vasculitis and, 516 anticoagulant properties of, 119,, 120 antiplatelet properties of, 120 antithrombotic properties of, 120 dysfunction of, 496, 508 fibrinolytic properties of, 118,, 120 homocysteine effects on, 506 in atherosclerosis, 496-497, 496,, 507,, 508 in disseminated intravascular coagulation, 640 in hemostasis, 119-120, 119 in systemic sclerosis, 227, 227 in thrombosis, 124-125, 124 inflammation-related changes in, 53-55, 54,, 55 leukocyte adhesion to, 53, 57-61, 57t, 58,, 59 leukocyte pavementing of, 56-57, 56 leukocyte-mediated injury to, 55 necrosis of, in inflammation, 55 nitric oxide of, 75-76, 75,, 77t. See also Nitric oxide. permeability of, in inflammation, 53-55, 53-55 procoagulant properties of, 119-120, 119 prothrombotic properties of, 120 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Endothelium-derived relaxing factor. See Nitric oxide. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Endotoxins, bacterial, 343 in adult respiratory distress syndrome, 701-702, 702 in shock, 134-136, 134,, 136 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Enteritis. See also Gastroenteritis. bacterial, 355-356, 355 Campylobacter, 355-356 eosinophilic, 793 Shigella, 355, 355 viral, 354-355 Yersinia, 356 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Enterocolitis, 805-812, 806t after bone marrow transplantation, 811 antibiotic-associated, 809-810, 810 collagenous, 810 diversion, 812 drug-induced, 811 in acquired immunodeficiency syndrome, 811 infectious, 806-810, 807t, 808t, 809 lymphocytic, 810 necrotizing, 809 neutropenic, 811-812 parasitic, 810-811 protozoal, 810-811, 811 radiation-induced, 811 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ea -- En Enzymes, defects in, 146-148, 147,, 147t in free radical inactivation, 13-14 lysosomal (acid hydrolases), 153-154, 153 of coagulation cascade, 122, 123 pancreatic, 903-904 in acute pancreatitis, 905-907, 906 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey Eosinophils, development of, 603 in inflammation, 82, 82 in type I hypersensitivity reaction, 198-199 reactive proliferations of, 648t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey Eosinophilia, 648t in inflammation, 86 in necrosis, 16, 16 pulmonary, 738 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey Epidermal growth factor, 97 in hepatocyte regeneration, 33, 33 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey Epidermis, 1171,, 1172. See also Skin. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey Epididymis, 1014-1015 inflammation of, 1016, 1016 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey Epithelium, bacterial infection of, 343 dysplasia of, 266, 267 renal, antibody-mediated injury to, 947, 947 in minimal change disease, 954-956, 956 vitamin A effects on, 441 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey Epstein-Barr virus (EBV), 333t B lymphocyte infection by, 190 B-cell immortalization of, 312 in Burkitt lymphoma, 312, 313,, 662 in carcinogenesis, 312-313, 313 in children, 371-373, 372 in diffuse large B-cell lymphoma, 661 in Hodgkin disease, 674 in nasopharyngeal carcinoma, 313, 764 in rheumatoid arthritis, 1249 in X-linked lymphoproliferative syndrome, 318 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey c-erb B2 gene, 286, 316,, 317 in cancer, 280 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey Erythema, in systemic lupus erythematosus, 222, 223 palmar, in liver failure, 852 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey Erythrocyte(s), 604-642 aplasia of, 632 deficiency of, 604-633, 605t. See also Anemia. deformability of, 606, 607 development of, 603 in myelofibrosis with myeloid metaplasia, 685, 685 Plasmodium falciparuminfection of, 389-390, 390 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey Erythropoiesis, diminished, anemias of, 604-633, 605t. See also Anemia. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey Escherichia coli, 334t, 343-344, 807-809, 808t in hemolytic-uremic syndrome, 637 pili of, 342-343 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey Esophagus, 776-787 achalasia of, 778-779, 778 adenocarcinoma of, 786-787, 786 atresia of, 777, 777 Barrett, 37, 781-782, 781,, 782,, 786, 786 candidiasis of, 378, 379 chemical-induced inflammation of, 782 congenital anomalies of, 777-778, 777 diverticula of, 778,, 779 dysplasia of, 782 fistula of, 777, 777 functions of, 776 hernia of, 778,, 779 herpes infection of, 361 in systemic sclerosis, 228 inflammation of, 780-783, 780-782 lacerations of, 778,, 779-780 motor disorders of, 778-780, 778 mucosa of, 776 normal, 776 polyps of, 783 reflux-associated inflammation of, 780-781, 780 Schatzki rings of, 777-778 short-segment Barrett mucosa of, 781 sphincters of, 776 squamous cell carcinoma of, 783-786, 785,, 785t squamous papilloma of, 783 stenosis of, 777-778 submucosa of, 776 tumors of, benign, 783 malignant, 783-787, 785,, 785t, 786 varices of, 529-530, 783, 784 in cirrhosis, 856
webs of, 777-778 Zenker diverticulum of, 778,, 779 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey Estrogen, adverse reactions to, 414-416, 415t breast cancer and, 1106 in osteoporosis, 1223-1224 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey Ethanol, 410-412, 410,, 411,, 411t. See also Alcoholic liver disease. CNS effects of, 1342, 1342 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey Ewing sarcoma, 485t, 1244, 1244,, 1260t EWS gene in, 285-286, 286t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey Extracellular matrix. See also Basement membrane. collagen of, 98-99, 99,, 99t elastin of, 99-100 fibrillin of, 100 fibronectin of, 100, 100 hyaluronan of, 102 in angiogenesis, 106 in cell growth, 98-102, 99-103,, 99t in fibrosis, 106, 106t integrins of, 100-101, 101 laminin of, 100, 100 matricellular proteins of, 101 platelet adhesion to, 120-121, 120 proteoglycans of, 101-102, 102 tumor invasion of, 302-305, 303,, 304 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey Exudate, 53 fibrinous, 84, 85 in inflammation, 53-54, 53 purulent, 84-85, 85 serous, 84, 85 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Eo -- Ey Eye(s), anatomy of, 1359, 1360 congenital anomalies of, 1360 copper deposition in, 875 dryness of, 769 in ariboflavinosis, 448 in congenital syphilis, 1361 in diabetes mellitus, 924 in Graves disease, 1137, 1138 in hyperthyroidism, 1131, 1132 in Marfan syndrome, 149 in rubella syndrome, 1361 in trisomy 13, 1360 in trisomy 21, 1360 in vitamin A deficiency, 441 infectious embryopathy of, 1360-1361 malignant melanoma of, 1365-1367, 1366 Niemann-Pick disease in, 158 phthisical, 1375-1376, 1376 radiation damage to, 430 retrolental fibroplasia of, 472 sarcoidosis of, 735 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Factor V, gene for, Leiden mutation in, 125 mutation in, 182-183, 183 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Fallopian tubes, 1037, 1065 abscess of, 1039 cysts of, 1065 ectopic pregnancy of, 1079-1080, 1080 inflammation of, 1065 tumors of, 1065 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Familial hypercholesterolemia, atherosclerosis and, 505, 505t LDL receptor gene mutations in, 144, 147t, 148, 152-153, 153 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Farnesyl transferase, 282 inhibitors of, 282 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Fat, in carcinogenesis, 309 stain for, 39-40 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Fatty liver, 38, 38,, 39, 39,, 847 in alcoholic liver disease, 411, 869, 870,, 872 in Wilson disease, 875 of pregnancy, 884-885 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Ferritin, cellular accumulation of, 42-43, 43 in free radical inactivation, 13 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi alpha-Fetoprotein, in hepatocellular carcinoma, 891 in testicular germ cell tumors, 1024 in tumor diagnosis, 325, 325t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Fetus. See also Infant. development of, 467-468, 468 drug effects on, 467 ethanol effects on, 412 infection in, 338-339, 467, 470-471 maternal cigarette smoking and, 409 radiation effects on, 467 Toxoplasma gondii infection in, 383 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Fibrillin, gene for, 147t in Marfan syndrome, 148-149 of extracellular matrix, 100 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Fibrin, 118,, 119 in crescentic glomerulonephritis, 952 in disseminated intravascular coagulation, 641-642 in glomerulonephritis, 948 in hemostasis, 122 in pericarditis, 588 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Fibrin split products, 123-124 generation of, 122 in inflammation, 69 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Fibroblast growth factor, 97, 104, 106 in tumorigenesis, 279t, 280 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Fibroepithelial polyp, 1181 of ureter, 999 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Fibroma, 261 chondromyxoid, 1240, 1240 irritation, of buccal mucosa, 758 nonossifying, 1242, 1242 pleural, 751 renal, 991 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Fibromatoses, 110, 1262-1263 in children, 484 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Fibronectin, of extracellular matrix, 100, 100,, 103 tumor cell attachment to, 303, 304 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Fibrosis, 102-107 angiogenesis in, 103-106, 104,, 105,, 105t endomyocardial, 583-584 extracellular matrix in, 106, 106t fibroblast proliferation in, 106 hepatic, 848 congenital, 880, 881 in chronic pancreatitis, 908 in inflammation, 78, 78,, 84 in systemic sclerosis, 227, 227 macrophage in, 106, 106t pipe-stem, in Schistosoma infection, 397, 397 pulmonary, 735-736, 736 radiation-induced, 426, 429, 429 retroperitoneal, 999-1000 tissue remodeling in, 106-107, 107 transforming growth factor-beta in, 98 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Fibrous histiocytoma, 1243-1244 benign, 1187-1188, 1188 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Fingers, clubbing of, 320, 321t glomus tumor of, 533-534 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fa -- Fi Fistula, arteriovenous, 498 tracheoesophageal, 777, 777 vesicouterine, 1000 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fl -- Fu Flame cells, 665 in trypanosomiasis, 393 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fl -- Fu Fluorescence in situ hybridization, in cytogenetic analysis, 166-168, 167 in tumor diagnosis, 324 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fl -- Fu FMR-1 gene, 143, 177 mutations in, 177, 178 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fl -- Fu Foam cells, 40, 40 in Alport syndrome, 963 in Niemann-Pick disease, 158 of cholesterolosis, 40, 40 of fatty streaks, 40,, 41 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fl -- Fu Follicular dendritic cells, 191 human immunodeficiency virus infection of, 243 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fl -- Fu Fracture(s), 1229-1231 healing of, 1229-1230, 1230 in osteogenesis imperfecta, 1221, 1221,, 1222t in Paget disease, 1227 infection of, 1231 skull, 1302-1303 at birth, 464 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fl -- Fu Fragile X syndrome, 177-179, 177,, 179 trinucleotide repeat mutations in, 143 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fl -- Fu Free radicals, in cell injury, 5-6, 6,, 10, 12-15, 13-15,, 47, 48 in chronic pancreatitis, 908 in toxicant metabolism, 406, 407 inactivation of, 12-14 oxygen-derived, 76-77 radiant energy-generated, 12 reduction-oxidation reaction-generated, 12, 13 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fl -- Fu Friedreich ataxia, 1337 triplet repeat mutations in, 179, 179,, 179t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Fl -- Fu Fungus (fungi), 335, 335,, 336,, 354. See also Infection. CNS infection with, 1322 cutaneous infection with, 1210 genital infection with, 1039 respiratory infection with, 352-353, 353 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
G -- Gi Gallbladder, 893-897 adenomyosis of, 899 anatomy of, 892 carcinoma of, 899, 900 cholelithiasis of, 893-895, 894,, 895 cholesterolosis of, 40, 40 congenital anomalies of, 893, 893 disease of, oral contraceptives and, 416 empyema of, 896 hydrops of, 895 inflammation of, 895-897, 896,, 897 mucocele of, 895 phrygian cap of, 893, 893 porcelain, 897 stones of, 893-895, 894,, 895 pancreatitis with, 904 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
G -- Gi Gangliosidoses, 155t, 156. See also Tay-Sachs disease. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
G -- Gi Gangrene, 368-369, 369 in diabetes mellitus, 922 pulmonary, 722 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
G -- Gi Gardner syndrome, 831 osteoma in, 1235 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
G -- Gi Gastric glands, 787-788 atrophy of, 792 hyperplasia of, 797-798 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
G -- Gi Gastritis, 789-793 acute, 789-790, 790 autoimmune, 793 chronic, 790-793, 790t, 791,, 792 atrophy in, 792 dysplasia in, 792 Helicobacter pylori in, 790-791, 790t, 791,, 792, 792 hyperplasia in, 792 metaplasia in, 792, 792 peptic ulcer disease and, 795 regenerative changes with, 791-792 eosinophilic, 793 ethanol-induced, 412 granulomatous, 793 lymphocytic, 793 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
G -- Gi Gastroenteritis. See also Enteritis. bacterial, 807-809, 808t, 809 uremic, 964 viral, 806-807, 807t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
G -- Gi Gastroesophageal reflux, 780-781, 780 in systemic sclerosis, 228 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
G -- Gi Gastrointestinal tract. See also Intestine; Stomach. amyloidosis of, 256 ethanol effects on, 412 in kwashiorkor, 439 infection of, 353-359 adenoviruses in, 354 bacterial, 354, 355-358, 355,, 357 barriers to, 353-354 Campylobacter in, 355-356 coronaviruses in, 354 Entamoeba histolytica in, 358-359, 358 fungal, 354 Giardia lamblia in, 359, 359 helminth, 354 Norwalk-like viruses in, 354 protozoan, 354, 358-359, 358 rotavirus in, 354 Salmonella in, 356-357, 357 Shigella in, 355, 355 Vibrio cholerae in, 357-358, 357 viral, 354-355 Yersinia in, 356 radiation damage to, 429 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
G -- Gi Gene(s), clock, 47 linkage analysis of, 184-186, 185,, 186 mitochondrial, mutations in, 179-180 mutations in, 141-143, 141-143. See also Mutation(s). penetrance of, 144 pleiotropic, 144 variable expressivity of, 144 virulence, 341 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
G -- Gi Genetic disorders, 139-186. See also specific disorders. consanguineous mating in, 145 cytogenetic, 168-176, 169. See also Chromosome(s). diagnosis of, 141, 182-186 direct, 182-184, 183,, 184 indirect, 184-186, 185,, 186 multifactorial, 164-165 mutations in, 141-143, 141-143. See also Mutation(s). single-gene (mendelian), 143-164 autosomal dominant, 144-145, 145t autosomal recessive, 145, 145t nonclassic, 176-182, 177-179,, 179t, 180 X-linked, 146, 146t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
G -- Gi Genital tract, female, 1036-1089. See also specific structures. anatomy of, 1036-1038, 1037 embryology of, 1036, 1036 infections of, 1038-1040, 1038t, 1039. See also Sexually transmitted diseases. male, 1011-1033. See also specific structures. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
G -- Gi Genomic imprinting, 180-181, 181 in Beckwith-Wiedemann syndrome, 488 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
G -- Gi Germ cell tumors, mixed, 1022-1024, 1023 of brain, 1350 of ovary, 1073-1076, 1073-1076 of testis, 1018-1024, 1018t, 1019-1023 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
G -- Gi Giant cell(s), in granulomatous inflammation, 83, 83 in human immunodeficiency virus infection, 240, 240 in measles virus infection, 370, 370 in seminoma, 1020 in subacute thyroiditis, 1135-1136, 1136 in tumors, 265-266 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
G -- Gi Giant cell tumor, of bone, 1244-1245, 1245 of tendon sheath, 1258-1259 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
G -- Gi Gingiva, peripheral giant cell granuloma of, 758 pyogenic granuloma of, 758, 758 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Glands. See specific glands. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Gliadin, in celiac sprue, 813 in dermatitis herpetiformis, 1205 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Glioma, 1343-1348, 1344-1347 brain stem, 1346 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Gliosis, 1297 in metachromatic leukodystrophy, 1340, 1340 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Glomerulonephritis, acute, 949-951, 950 alternative complement pathway in, 947 anti-glomerular basement membrane, 943-945, 943t, 944 basement membrane thickening in, 943 C5b-C9 in, 947, 947 cell-mediated immune reactions in, 946 chemokines in, 948 chronic, 963-964, 964,, 965t circulating immune complexes in, 944,, 945-946, 946 clinical manifestations of, 942, 942t cytokines in, 948 endothelin in, 948 epithelial cell injury in, 947, 947 fibrillary, 968 fibrin in, 948 Heymann, 944,, 945, 954 histology of, 942-943 hyalinization in, 943 hypercellularity of, 942-943 immune complex deposition in, 943-946, 943t, 944,, 946 immunotactoid, 968 in amyloidosis, 968 in bacterial endocarditis, 966 in diabetic glomerulosclerosis, 966-968, 967 in essential mixed cryoglobulinemia, 968 in Goodpasture syndrome, 968 in Henoch-Schonlein purpura, 965-966 in multiple myeloma, 968 in plasma cell dyscrasias, 968 in polyarteritis nodosa, 968 in systemic disease, 964-968, 967 in systemic lupus erythematosus, 220, 221, 221,, 962, 962,, 965 in Wegener granulomatosis, 968
light-chain deposition in, 968 lymphocytes in, 947, 947 macrophages in, 947, 947 membranoproliferative, 947, 958-960, 959-961,, 965t membranous, 953-954, 965t in systemic lupus erythematosus, 221, 221 mesangial cells in, 947, 947 monocytes in, 947, 947 necrotizing, 962 nephrotic syndrome and, 952-953 neutrophils in, 947, 947 nonglomerular antigens in, 945 pathogenesis of, 943-948, 943t, 944,, 946,, 947 platelets in, 947, 947 poststreptococcal, 949-951, 950,, 965t progression of, 948-949, 948,, 949 proliferative, acute (postinfectious), 949-951, 950 diffuse, in systemic lupus erythematosus, 221, 221 focal, 962, 962 in systemic lupus erythematosus, 220-221, 220 rapidly progressive (crescentic), 951-952, 951t, 952,, 965t sclerosis in, 943 tubulointerstitial injury in, 948-949, 949 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Glomerulosclerosis, diffuse, 966-967, 967 in diabetes mellitus, 923, 924 intercapillary, 967 nodular, 967 segmental, focal, 956-958, 957,, 965t collapsing, 958 malignant, 958 pyelonephritic scarring and, 977 renal ablation, 958 sequential, focal, 948, 948 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Glomerulus (glomeruli), 931-934, 932-934 barrier function of, 934 basement membrane of, 931-933, 932-934 antibodies to, 943-945, 944 diffuse thinning of, 963 ruptures in, 952, 952 thickening of, 943, 954, 955 in diabetes mellitus, 966, 967 compensatory hypertrophy of, 948, 948 disease of, 942-968, 942t. See also Glomerulonephritis; Glomerulosclerosis. epithelial cells of, 947, 947 filtration function of, 934 hyalinization of, 943 hypercellularity of, 942-943 in poststreptococcal nephritis, 950, 950 sclerosis of, 943 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Glossitis, 758 in ariboflavinosis, 448 in pernicious anemia, 625 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Glucose, homeostasis of, 914-915, 914 metabolism of, life span and, 47 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Glucose-6-phosphate dehydrogenase (G6PD), deficiency of, 610-611, 610,, 611 drug reactions in, 148 gene mutation in, 146 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Glycogen, intracellular accumulation of, 41-42 metabolism of, 160, 161,, 162 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Goblet cells, in bronchitis, 711, 712 of intestine, 803 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Goiter, 1138-1140, 1140 colloid, 1138 endemic, 1138-1139 intrathoracic, 1139 multinodular, 1139-1140, 1140 nontoxic, diffuse (simple), 1138-1139 sporadic, 1139 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Gout, 1253-1257, 1254-1256,, 1254t nephropathy of, 980, 980 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Graft-versus-host disease, diarrhea with, 811 esophagus in, 782 hepatic damage in, 885-886 with bone marrow transplantation, 210-211 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Granulation tissue, 102-103, 104,, 108, 108,, 109 exuberant, 110 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Granules, alpha, 120, 121 atrial, specific, 544 azurophil, 76, 76 Birbeck, 685, 685,, 1190,, 1191 delta (dense bodies), 120, 121 giant, in Chediak-Higashi syndrome, 64 hemosiderin, 43, 43 lipofuscin, in atrophy, 36 lysosomal, 64, 76, 76 specific, 76, 76 toxic, 648 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Granuloma, 83 eosinophilic, 685 foreign body, 83 immune, 83-84 in Crohn disease, 817, 818 in Histoplasma capsulatum infection, 352, 353 in pulmonary tuberculosis, 724, 724 in sarcoidosis, 734-735, 734 in Schistosoma infection, 396-397, 397 in tuberculosis, 350-351, 351 in type IV hypersensitivity, 204, 205 of breast, 1098 of gingiva, 758, 758 pyogenic, 532,, 533 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Granulomatosis, Wegener, 517t, 522-523, 522 renal manifestations of, 968 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Gl -- Gy Growth factors, 73, 97-98, 97t deprivation of, apoptosis after, 24-25 in fibroblast proliferation, 106, 106t in signal transduction, 92-93, 93,, 94 in tumorigenesis, 279-280, 279t receptors for, in tumorigenesis, 279t, 280 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ha -- Hem Hair follicles, 1171, 1171 lichen planus of, 1200 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ha -- Hem Hamartoma, 263 definition of, 483 in neurofibromatosis, 164 in tuberous sclerosis, 1354-1355 of iris, 164 pulmonary, 748-749 renal, 991 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ha -- Hem Heart, 543-598. See also Cardiac entries; Myocardium. age-related changes in, 545-546, 546t amyloidosis of, 256, 256,, 586 aortic valve of. See Aortic valve. basophilic degeneration of, 546 blood supply to, 545 brown atrophy of, 546 carcinoid disease of, 577-578, 577 collateral circulation of, 545 in nonlethal ischemia (preconditioning), 553, 561 congenital disease of, 591-597, 592t. See also specific types. clinical features of, 592-593 etiology of, 592 incidence of, 592, 592t left-to-right shunt in, 593-595, 593,, 594 obstructive, 596-597, 596,, 597 right-to-left shunt in, 595-596, 596 dilation of, 544 ethanol effects on, 412 failure of, 546-550, 547,, 548 after myocardial infarction, 563, 563,, 564 cardiac hypertrophy in, 547-549, 547,, 548 hepatic manifestations of, 117, 882-883, 883 hydrostatic pressure in, 114 in dilated cardiomyopathy, 581 left-sided, 549 right-sided, 549-550 fatty change in, 39-40 great arteries of, transposition of, 595-596, 595 hemodynamic overload of, 34,, 35 hypertensive disease of, 564-566, 565,, 565t, 566
hypertrophy of, 34,, 35, 544, 547-549, 547,, 548. See also Cardiomyopathy, hypertrophic. apoptosis in, 548 compensatory mechanisms in, 548-549 gene expression in, 548 physiologic, 548 in hyperthyroidism, 1131 in malaria, 390 in Marfan syndrome, 149 in trisomy 21, 171 infection of, 572-576, 575. See also Endocarditis; Rheumatic fever. ischemic disease of, 550-564. See also Myocardial infarction. angina pectoris in, 554 chronic, 563, 564 epidemiology of, 551 pathogenesis of, 551-554 fixed obstructions in, 551 plaque change in, 551-553, 552 thrombus in, 553 vasoconstriction in, 553-554, 553t sudden cardiac death in, 564 left-to-right shunt of, 593-595, 593,, 594 lipoma of, 590 metastases to, 591, 591t mitral valve of. See Mitral valve. myocardium of, 544-545 myxedema, 586 myxoma of, 589-590, 590 normal, 544-546, 546t papillary fibroelastoma of, 590 pressure hypertrophy of, 547, 547 radiation damage to, 429, 429 rhabdomyoma of, 591 rheumatic disease of, 570-572, 571,, 573,, 575 blood flow alterations in, 125, 129
rheumatoid disease of, 589 right-to-left shunt of, 595-596, 596 sarcoma of, 591 tigered effect in, 40 transplantation of, 210, 598, 598 rejection of, 598, 598 tricuspid valve of. See Tricuspid valve. tumors of, 589-591, 590,, 591t valves of, 545 disease of, 566-578, 567t. See also specific diseases. prosthetic, 578, 578,, 578t vegetations of. See also Endocarditis. infected, 572-576, 575 noninfected, 576-577, 576 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ha -- Hem Heart attack. See Myocardial infarction. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ha -- Hem Heat-shock proteins, 41 in tuberculosis, 349 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ha -- Hem Helicobacter pylori, in chronic gastritis, 790-791, 790t, 791,, 792, 792 in gastric carcinoma, 315, 799 in peptic ulcer disease, 793-794, 794 lymphoma and, 686 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ha -- Hem Hemangioma, 532-533, 532 capillary, 532, 532 cavernous, 532,, 533, 886, 1313 differential diagnosis of, 1189 in infant, 483, 483 sclerosing, 1264 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ha -- Hem Hematocele, 1025 of tunica vaginalis, 1025 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ha -- Hem Hematoma, 117-118 dissecting, 526-528, 527-529 epidural, 1303, 1303,, 1304, 1305 in vitamin C deficiency, 449 pulsating, 524 subdural, 1305, 1306 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ha -- Hem Hematuria, 935 familial, 963 in sickle cell disease, 987 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ha -- Hem Hemolytic anemia. See Anemia, hemolytic. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ha -- Hem Hemolytic-uremic syndrome, 636-637 adult, 986 childhood, 985-986 idiopathic, 986 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ha -- Hem Hemorrhage, 117-118, 117,, 633-642 clotting factor abnormalities in, 637-640, 638 dot-and-blot, in hypertensive retinopathy, 1370 Duret, 1298, 1299 flame-shaped, in hypertensive retinopathy, 1370 ganglionic, 1310 in amyloidosis, 634 in Cushing syndrome, 634 in disseminated intravascular coagulation, 641, 641 in drug reactions, 634, 636 in drug-induced thrombocytopenia, 636 in Ehlers-Danlos syndrome, 634 in factor VIII deficiency, 639 in factor IX deficiency, 639-640 in Henoch-Schonlein purpura, 634 in hereditary hemorrhagic telangiectasia, 634 in HIV-associated thrombocytopenia, 636 in idiopathic thrombocytopenic purpura, 635-636 in infection, 634 in platelet disorders, 634-637, 635t in polycythemia vera, 683 in scurvy, 634 in thrombotic microangiopathy, 636-637 in vitamin C deficiency, 449 in vitamin K deficiency, 447, 637-638 in von Willebrand disease, 638-639 into atheromatous plaque, 502 intracerebral, 117,, 118 intracranial, 118, 118,, 1305, 1310-1313, 1311,, 1312 at birth, 464 hypertensive, 1310, 1311,, 1314 in infant, 1302 lobar, 1310 petechial, 117,, 118
platelet abnormalities in, 634-637, 635t pulmonary, 738-739, 738 slit, 1314 subarachnoid, 1305, 1310-1313 vessel wall abnormalities in, 634 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ha -- Hem Hemosiderin, cellular accumulation of, 42-43, 43 hepatic deposition of, 874, 874 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ha -- Hem Hemosiderosis, 43 iron overload in, 586-587 pulmonary, idiopathic, 739 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ha -- Hem Hemostasis, 118-124, 118 coagulation cascade in, 119,, 121,, 122-124, 123,, 124 dysregulation of, 124-129, 124,, 125t, 127,, 128 endothelium in, 119-120, 119 platelets in, 118,, 120-122, 120,, 121 tests of, 633-634 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Henoch-Schonlein purpura, 517t, 961 hemorrhage in, 634 renal manifestations in, 965-966 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Hepatic adenoma, 887-888, 887 oral contraceptives and, 416 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Hepatic vein, obstruction of, 883-884, 883,, 884 veno-occlusive disease of, 884, 884 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Hepatitis, 848, 856-867, 856t acute, 864, 865-866, 865,, 866 alcoholic, 411, 411,, 411t apoptosis in, 866, 866 asymptomatic, 864 autoimmune, 868 bridging necrosis in, 866 carrier state in, 864 chronic, 864-865, 865,, 866, 866,, 867 cirrhosis in, 866, 867 fatty change in, 866 fulminant, 867 ground-glass hepatocytes in, 865, 865 icteric phase of, 864 in alcoholic liver disease, 869-870, 870,, 871,, 872 in Wilson disease, 875 interface, 866 neonatal, 876-877, 877t in alpha1-antitrypsin deficiency, 876 preicteric phase of, 864 sanded nuclei in, 865 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Hepatitis A virus, 333t, 856-857, 856t, 857 serologic diagnosis of, 857, 857 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Hepatitis B virus, 333t, 340, 856t, 857-859, 858,, 859 carrier of, 857, 858,, 859, 864 hepatitis D virus infection with, 862 hepatocellular carcinoma and, 888, 889 in carcinogenesis, 309, 313-314 integration of, 858 mutant strains of, 858 proliferation of, 857-858 serologic diagnosis of, 858-859, 859 structure of, 857, 858 transmission of, 857 vaccine against, 889 vasculitis and, 516 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Hepatitis C virus, 333t, 856t, 860-861, 860,, 861,, 866 in hepatocellular carcinoma, 314, 888, 889 serologic diagnosis of, 861, 861 structure of, 860, 860 transmission of, 860 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Hepatitis D virus, 333t, 856t, 861-862, 862,, 863 serologic diagnosis of, 852, 863 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Hepatocellular carcinoma, 888-891, 889 clinical features of, 891 epidemiology of, 888 alpha-fetoprotein in, 891 fibrolamellar, 890, 890,, 891 fibrolamellar variant of, 891 hepatitis C virus in, 314 pathogenesis of, 888-889 spread of, 890-891 unifocal, 889, 889 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Hepatocytes, 846-847, 847. See also Liver. priming of, 33, 33 regeneration of, 32-33, 32,, 33 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Hepatocyte growth factor, in hepatocyte regeneration, 33, 33 in tumor invasion, 304 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Hernia, diaphragmatic, 789 hiatal, 778,, 779 intestinal, 825,, 826 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Herpesviruses, 333t CNS, 1318, 1318 corneal, 1362-1363 esophageal, 782 genital, 359-361, 360,, 360t, 1038-1039, 1038t in acquired immunodeficiency syndrome, 248 mucosal, 346, 346 oral, 757 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Heterotopia (choristoma), bone, 44 definition of, 483 duodenal, 789 neuronal, 1300 pancreatic, 789 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Hexosaminidase A, alpha subunit of, deficiency of (Tay-Sachs disease), 155-156, 156,, 157 beta subunit of, deficiency of (Sandhoff disease), 155t, 156, 156 gene for, mutations in, 142, 142,, 156, 156 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Hidradenoma papilliferum, 1182 chondroid, 1184 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Histamine, in asthma, 713 in inflammation, 66, 66,, 77t in type I hypersensitivity reaction, 197, 197,, 198, 199t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Histiocytes, foamy, in leprosy, 386 sea-blue, in chronic myelogenous leukemia, 681 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Histiocytoma, 1264 fibrous, 1243-1244 benign, 1187-1188, 1188,, 1264 malignant, 1264-1265, 1264 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi Histiocytosis, Langerhans, 685-686 sinus, 650 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hen -- Hi HIV. See Human immunodeficiency virus (HIV). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hl -- Hyd Hodgkin disease, 670-675 classification of, 672t clinical course of, 674-675, 674t Epstein-Barr virus in, 674 immunophenotype of, 672, 673 lymphocyte depletion type of, 672t lymphocyte predominance type of, 672t, 673-674, 673 mixed cellularity type of, 672t, 673, 673 nodular sclerosis type of, 672, 672t, 673 pathogenesis of, 674 staging of, 671-672, 672t vs. Epstein-Barr virus infection, 372 vs. non-Hodgkin lymphoma, 674t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hl -- Hyd Homeobox genes, 1218-1219 in congenital malformations, 469-470, 469 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hl -- Hyd Homocysteine, atherosclerosis and, 506 hereditary elevation of, 125 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hl -- Hyd Hormones. See also specific hormones. in systemic lupus erythematosus, 219 tumor expression of, 266-267, 267,, 319 wound healing and, 110 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hl -- Hyd HPV. See Human papillomavirus (HPV). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hl -- Hyd Human immunodeficiency virus (HIV), 333t CD4+ T-lymphocyte infection by, 239-243, 240-242 CNS infection with, 1320-1321, 1320 dendritic cell infection with, 243 forms of, 238 genes of, 238-239, 239 group M, 239 macrophage infection by, 240, 242-243 mother-to-infant transmission of, 237 occupational transmission of, 238 parenteral transmission of, 237 sexual transmission of, 237 structure of, 238, 238 transmission of, 237-238 types of, 239 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hl -- Hyd Human immunodeficiency virus (HIV) infection. See also Acquired immunodeficiency syndrome (AIDS). acute phase of, 245-246, 245,, 245t B lymphocytes in, 244 CD4+ cell count in, 247 CD4+ T-lymphocyte loss in, 240 chronic phase of, 245,, 245t, 246 crisis phase of, 245,, 245t, 246 giant cell formation in, 240, 240 latent, 243 nephropathy with, 958 nonprogression of, 247 thrombocytopenia with, 636 viral load during, 246 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hl -- Hyd Human leukocyte antigen (HLA) complex, 193-195, 193,, 194 class I, 193-194, 193 class II, 193,, 194 autoimmune disease and, 216 disease associations of, 195, 195t in rheumatoid arthritis, 216 in Sjogren syndrome, 193-195, 193,, 194 in systemic lupus erythematosus, 218-219 in transplantation, 210 in type I diabetes mellitus, 915-916, 915 tumor expression of, 318 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hl -- Hyd Human papillomavirus (HPV), 333t, 1208-1209, 1208 genital infection with, 1012, 1012,, 1013,, 1038t hyperplasia with, 33 in carcinogenesis, 311-312 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hl -- Hyd Huntington disease, 145, 1296t, 1335-1336, 1336 triplet repeat mutations in, 179, 179,, 179t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hl -- Hyd Hyaline arteriolosclerosis, in diabetes mellitus, 922, 922 in hypertension, 514, 515 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hl -- Hyd Hydatidiform mole, 1084-1087, 1085t, 1086,, 1087 invasive, 1087, 1087 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hl -- Hyd Hydrocarbons, in carcinogenesis, 309 in occupational diseases, 419-420, 419t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hl -- Hyd Hydrogen peroxide, 12, 13. See also Free radicals. in inflammation, 76-77 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hl -- Hyd Hydroxyl radicals, 12, 13. See also Free radicals. in inflammation, 76-77 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hl -- Hyd 5-Hydroxytryptamine (serotonin), in carcinoid syndrome, 837, 837t in inflammation, 67, 77t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hygroma, cystic, 533 in Turner syndrome, 175 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hyperaldosteronism, primary, 1155-1157, 1156,, 1157 secondary, 114 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hypercalcemia, cancer-associated, 320, 321t, 1148 in multiple myeloma, 665 metastatic calcification in, 45 nephrocalcinosis with, 980 parathyroid hormone-related protein-induced, 1148 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hypercholesterolemia, atherosclerosis and, 504-506, 505t, 508 familial, atherosclerosis and, 505, 505t LDL receptor gene mutations in, 144, 147t, 148, 152-153, 153 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hyperglycemia, CNS effects of, 1342 in diabetes mellitus, 919,, 920 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hyperlipidemia, in atherosclerosis, 504-506, 505t in nephrotic syndrome, 953 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hypernephroma, 991-993, 992-994. See also Renal cell carcinoma. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hyperparathyroidism, 1148-1151, 1149 asymptomatic, 1150 brown tumor in, 1150, 1228, 1228 metastatic calcification in, 45 primary, 1148-1150 secondary, 964, 1150-1151 skeletal manifestations of, 1228-1229, 1228 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hyperplasia, 31, 32-35 compensatory, 32-33, 32,, 33 definition of, 466 hormonal, 32, 33 pathologic, 33 physiologic, 32-33, 32,, 33 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hypersensitivity reaction(s), 195-211 drug-induced, hemorrhage with, 634 in cell injury, 4 in transplant rejection, 206-211, 208,, 209 type I (anaphylactic), 195, 196-199, 196t eosinophils in, 198-199 IgE antibodies in, 196-197, 197,, 198 in asthma, 713 local, 199 mast cells in, 196-198, 197,, 198,, 199t primary mediators of, 197-198, 199t secondary mediators of, 198, 199t systemic, 199 type II (cytotoxic), 195, 196t, 199-201 antibody-dependent, 200,, 201 antibody-mediated, 200,, 201, 201t complement-dependent, 199-200, 200 type III (immune complex-mediated), 195, 196t, 201-204, 201t local, 204, 204 systemic, 202-204, 202,, 203 type IV (cell-mediated), 195, 196t, 204-206 delayed-type, 204-206, 205,, 206 T cell-mediated cytotoxicity in, 206 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hypertension, 510-515, 511t benign, 511, 981-982, 982 encephalopathy with, 1314 environmental factors in, 513 genetic factors in, 512,, 513 heart disease with, 564-565, 565 hyaline arteriolosclerosis and, 514, 515 hyperplastic arteriolosclerosis and, 514-515, 515 in atherosclerosis, 506 in hyperaldosteronism, 1157 in pheochromocytoma, 1165 in preeclampsia, 1083, 1084 malignant, 511, 982-984, 983,, 983t oral contraceptives and, 416 pathogenesis of, 511-514, 512,, 514 portal, 855-856, 855 esophageal varices with, 783 idiopathic, 882 pulmonary, 704-706, 706 in atrial septal defect, 594 renovascular, 511, 512-513 retinopathy with, 1370 salt-sensitive, 512,, 513 sodium retention in, 513 vasoconstriction in, 513-514, 514 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hyperthermia, 434-435, 1285 malignant, 1285 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hyperthyroidism, 1131-1132, 1131t, 1132 clinical course of, 1131-1132 heart in, 587 in Graves disease, 1136, 1138 in subacute thyroiditis, 1136 with goiter, 1140 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hypertrophy, 31, 32-35, 34 definition of, 466 vs. hyperplasia, 32 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hyperuricemia, nephrolithiasis with, 980 nephropathy with, 979-980, 980 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hyperviscosity syndrome, 125 in lymphoplasmacytic lymphoma, 667 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hypocalcemia, in acute pancreatitis, 907 in renal osteodystrophy, 1229 in vitamin D deficiency, 444, 444t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hypogonadism, female, 173, 174-176, 175 male, 174, 1016 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hypophysis. See Pituitary gland. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hypoplasia, definition of, 466 renal, 936-937 thymic (DiGeorge syndrome), 173, 235, 691 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hypothyroidism, 1132-1133, 1132t in Hashimoto thyroiditis, 1135 in Turner syndrome, 175 myocardial toxicity of, 587 myopathy in, 1287 with goiter, 1140 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Hyg -- Hyp Hypoxia, in cell injury, 4 in cerebrovascular disease, 1307-1310 p53 gene activation in, 292 vs. ischemia, 4 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Immune complexes. See also Hypersensitivity reaction(s), type III (immune complex-mediated). in vasculitis, 516 renal deposition of, 943-946, 943t, 944,, 946. See also Glomerulonephritis. tissue deposition of, 202-203, 202,, 203 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Immune system, 188-195. See also Lymphocyte(s). B lymphocytes of, 190, 190 cytokines of, 191-192 deficiency syndromes of, 231-251. See also Acquired immunodeficiency syndrome (AIDS). primary, 231-236, 232,, 233t dendritic cells of, 191 histocompatibility antigens and, 193-195, 193,, 194,, 195t hypersensitivity reactions of, 195-211. See also Hypersensitivity reaction(s). in berylliosis, 734 in Epstein-Barr virus infection, 371 in filariasis, 397-398 in giardiasis, 359 in glomerulonephritis, 946 in Graves disease, 1137 in Hashimoto's thyroiditis, 1132, 1134-1135 in hepatitis, 868 in idiopathic pulmonary fibrosis, 736 in Leishmania infection, 392 in leprosy, 386 in membranous glomerulonephritis, 959-960 in minimal change disease, 955-956 in multiple sclerosis, 1326 in nephritis, 977-978, 977 in poststreptococcal (proliferative) glomerulonephritis, 949-950, 950 in rheumatic fever, 572 in rheumatoid arthritis, 216, 1249-1250, 1250 in sarcoidosis, 734 in systemic lupus erythematosus, 219-220, 219 in trisomy 21, 171 in type I diabetes mellitus, 915,, 916 in vasculitis, 203-204, 203,, 204,, 516
in vitamin A deficiency, 441 infectious agent evasion of, 344, 344t intestinal, 804 isotype switching in, 234 macrophages of, 190-191 microbe evasion of, 344, 344t natural, 191, 191,, 192 natural killer cells of, 191, 191,, 192 self-antigens in, 211-231. See also Autoimmune diseases. T lymphocytes of, 189, 189,, 190 tolerance and, 212-214, 213 vitamin A effects on, 441 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Immune tolerance, 212-214, 213 central, 212, 213 peripheral, 212, 213,, 214-215 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Immune-mediated hemolytic anemia, 620-621, 620t. See also Anemia, hemolytic, immune-mediated. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Immunodeficiency, 231-251. See also Acquired immunodeficiency syndrome (AIDS). B-cell lymphoma and, 661 pneumonia and, 726, 726t primary, 231-236, 232,, 233t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Immunoglobulins, absence of, 232-233 deficiency of, 233-234 genes for, in lymphoma, 285 in amyloidosis, 663 in heavy-chain disease, 663 in leukocyte adhesion, 57, 57t, 58 in multiple myeloma, 665-666, 665 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Immunoglobulin A (IgA), in dermatitis herpetiformis, 1205, 1205 in Henoch-Schonlein purpura, 965-966 isolated deficiency of, 234 mesangial deposition of, 961-962, 961 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Immunoglobulin E (IgE), in asthma, 713, 714 in type I hypersensitivity reaction, 196-197, 197 in urticaria, 1194 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Immunoglobulin G (IgG), deficiency of, 234-235 Fc fragment of, in phagocytosis, 62 in multiple myeloma, 665-666, 665 in pemphigus vulgaris, 1202, 1203 M component, 663 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Immunoglobulin M (IgM), antigen binding to, 190 elevated levels of, 234-235 in Waldenstrom macroglobulinemia, 663 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Immunophenotype, in acute lymphoblastic leukemia/lymphoma, 655, 655t, 657,, 657t in acute myeloblastic leukemia, 657 in adult T-cell leukemia/lymphoma, 656t in angiocentric lymphoma, 656t in Burkitt lymphoma, 655t, 662 in chronic lymphocytic leukemia, 655t, 659 in diffuse large B-cell lymphoma, 655t, 661 in follicular lymphoma, 655t, 660, 660 in hairy cell leukemia, 656t, 668 in large granular lymphocytic leukemia, 656t in lymphoplasmacytic lymphoma, 656t in mantle cell lymphoma, 656t, 668 in marginal zone lymphoma, 656t in multiple myeloma, 655t in mycosis fungoides, 656t in peripheral T-cell lymphoma unspecified, 656t, 669-670 in plasmacytoma, 655t in Sezary syndrome, 656t in small lymphocytic lymphoma, 655t, 659 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Immunosuppression. See also Acquired immunodeficiency syndrome (AIDS). carcinogen-induced, 318 in transplantation, 210 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Inclusions, cytomegalic, 376, 376 in herpesvirus infection, 360, 360 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Infant. See also Children. Apgar score in, 463-464, 463t appropriate for gestational age, 460-461, 461 birth injury in, 464 birth weight of, 460-461, 461 congenital heart disease in, 591-597, 592t, 593-597. See also specific diseases. congenital malformation in, 464-470, 465,, 466t, 467t, 468,, 469. See also Malformation(s), congenital. cystic fibrosis in, 477-481, 478-481 cytomegalovirus infection in, 376 fibrous tumors in, 484 galactosemia in, 476-477, 477 gestational age of, 460-461, 461 hemangioma in, 483, 483 hemolytic disease of, 200, 473-475, 474,, 475,, 849 inborn errors of metabolism in, 475-481. See also specific disorders. infection in, 470-471, 470 intrauterine growth retardation of, 461-462, 462 large for gestational age, 460-461, 461 Listeria infection in, 378 lymphangiectasis in, 483-484 lymphangioma in, 483-484 mortality rate for, 459-460, 460t phenylketonuria in, 475-476, 476 postterm, 460 preterm, 460, 462-463, 463 respiratory distress syndrome (hyaline membrane disease) in, 471-473, 472 sepsis in, 471 small for gestational age, 460-462, 461,, 462 sudden death syndrome in, 481-482, 482t teratoma in, 484, 484
tumors in, 482-489 benign, 483-484, 483,, 484 malignant, 484-491, 485t, 486,, 487,, 488t, 489 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Infarction, 130, 132-137. See also Ischemia. blood supply and, 133 cerebral, 1307-1310, 1309 hepatic, 881-882, 882 hypoxia and, 133 incomplete, 1310 intestinal, 820-823, 821-823 mucosal, 822, 822,, 823 mural, 822, 823 transmural, 821-822, 822,, 823 myocardial, 554-564. See also Myocardial infarction. oxygen tension and, 133 pulmonary, 133,, 703-704, 704 red, 132, 133,, 1308, 1309-1310 renal, 133,, 987-988 septic, 132 spinal, 1310 splenic, 133,, 689-690, 689 white, 132, 133,, 1308-1309, 1309 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Infection, 329-399. See also specific infection, e.g., Pneumonia. agents of, bacterial, 332, 332t, 334t, 335, 335,, 341-344, 342,, 343 anaerobic, 369-370 gram-positive, 365-370, 366-369 bacteriophage, 332 categories of, 331-338, 332t chlamydial, 332t, 335 diagnosis of, 344-345, 345t ectoparasite, 337-338, 338 emerging, 331, 331,, 331t fungal, 332t, 335, 335,, 336 helminth, 332t, 336-337 immune evasion by, 344, 344t mycoplasmal, 332t, 335 prion, 332 protozoan, 332t, 335-336, 337,, 337t rickettsial, 332t, 335 transmission of, 338-340, 339 viral, 332, 332t, 333t, 340-341, 341 atherosclerosis and, 509 bloodstream invasion by, 338 cardiac, 572-576, 575. See also Endocarditis. childhood, 370-375 Bordetella pertussis in, 374-375, 374 Corynebacterium diphtheriaein, 375, 375 Epstein-Barr virus in, 371-373, 372 measles virus in, 370, 370 mumps virus in, 370-371 poliovirus in, 373 varicella-zoster virus in, 373-374, 374 clostridial, 368-369, 369
contagious, 339 diagnosis of, 344-345, 345t dissemination of, 338-339, 339 fetal, 338-339 gastrointestinal, 344, 353-359 Ancylostoma duodenale in, 394-395 bacterial, 355-358, 355,, 357 barriers to, 353-354 Campylobacter in, 355-356 Entamoeba histolytica in, 358-359, 358 Giardia lamblia in, 359, 359 Necator americanus in, 394-395 parasitic, 358-359, 358,, 359 Salmonella in, 356-357, 357 Shigella in, 355, 355 Taenia solium in, 395-396, 395 Vibrio cholerae in, 357-358, 357 viral, 354-355 Yersinia in, 356 hemorrhage with, 634 host barriers to, 338 in acquired immunodeficiency syndrome, 247-248, 247t in adrenocortical insufficiency, 1160-1161, 1160 in bronchiectasis, 716 in bronchitis, 712, 712 in Bruton agammaglobulinemia, 233 in cell injury, 4 in common variable immunodeficiency, 234 in cystic fibrosis, 479, 480, 481, 481 in hairy cell leukemia, 669 in hyper IgM syndrome, 234 in intrauterine growth retardation, 461 in isolated IgA deficiency, 234 in lung transplant patient, 741 in multiple myeloma, 665 in nephrotic syndrome, 953 in severe combined immunodeficiency disease, 235 inflammatory response to, 345-346, 345-347.
See also Inflammation. nosocomial, 719 opportunistic, 334t, 375-383 Aspergillus in, 380, 381 Candida spp. in, 378-379, 379 Cryptococcus neoformansin, 379-380, 380 Cryptosporidium parvum in, 382, 382 cytomegalovirus in, 376, 376 Legionella pneumophila in, 377-378 Listeria monocytogenes in, 378 Mucor in, 380-381, 381 Pneumocystis carinii in, 381-382, 382 Pseudomonas aeruginosa in, 376-377, 377 Toxoplasma gondii in, 382-383 pathogenesis of, 340-344, 341-343 historical studies of, 330-331, 330t perinatal, 470-471, 470 placental-fetal transmission of, 338, 470, 470 respiratory, 347-353, 717-721. See also Pneumonia. bacterial, 348-352, 350,, 351 Coccidioides immitis in, 353, 353 fungal, 352-353, 353 Haemophilus influenzae in, 348-349 Histoplasma capsulatum in, 352, 353 influenza viruses in, 348 Mycobacterium tuberculosisin, 349-352, 350-352 viral, 347-348, 347 scar formation in, 347, 347 secondary, 341 sexually transmitted, 359-365, 360t, 1038-1040, 1038t, 1039 Calymmatobacterium donovaniin, 360t Chlamydia trachomatis in, 360t, 361-362, 361t Haemophilus ducreyi in, 360t herpesviruses in, 359-361, 360,, 360t Neisseria gonorrhoeae in, 360t, 362 Phthirus pubis in, 360t Treponema pallidum in, 360t, 362-364, 363
Trichomonas vaginalis in, 360t, 364-365, 365 sites of, 338, 339 slow virus, 341 staphylococcal, 365-367, 366,, 367 streptococcal, 367-368, 368 TORCH, 470 tropical, 383-399 Chlamydia trachomatis in, 385 dengue virus in, 383 Leishmania in, 391-393, 392 Mycobacterium leprae in, 385-386, 387 Onchocerca volvulus in, 398-399, 399 Schistosoma in, 396-397, 396,, 397 Trypanosoma in, 393-394 vector-borne, 334t, 335, 339-340 Babesia microti in, 391, 391 Borrelia in, 388-389, 388 Brugia malayi in, 397-398 Onchocerca volvulus in, 398-399, 399 Plasmodium falciparum in, 389-391, 390,, 391 Rickettsia spp. in, 383-385, 384,, 385,, 385t Taenia solium in, 395-396, 395 Trichinella spiralis in, 394, 395 Wuchereria bancrofti in, 397-398, 398 Yersinia pestis in, 387-388 viral. See also specific viruses. abortive, 340 in subacute thyroiditis, 1135-1136, 1136 latent, 340 persistent, 340 with agranulocytosis, 647 with burns, 434 wound healing and, 110 zoonotic, 340 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Infectious mononucleosis, 371-373, 372,, 759t. See also Epstein-Barr virus (EBV). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Inflammation, 50-87 acute, 52-65, 52 abscess formation in, 78, 78 angiogenesis in, 55 chemical mediators of, 65-78, 66,, 77t, 78t arachidonic acid metabolites as, 70-72, 71,, 71t, 72 chemokines as, 74, 74t cytokines as, 54, 73-74, 74 lysosomal granules as, 76, 76 neuropeptides as, 77 nitric oxide as, 75-76, 75 oxygen-derived free radicals as, 76-77 plasma proteases as, 67-70, 67,, 68 platelet-activating factor as, 72, 72 vasoactive amines as, 66-67, 66 endothelial retraction in, 54 fibrinous, 84, 85 fibrosis in, 78, 78,, 84 immediate sustained response in, 55 immediate transient response in, 54, 55 leukocyte extravasation in, 55-62, 56,, 57t, 58-61 leukocyte-induced tissue injury in, 64, 64t outcomes of, 78-79, 78,, 79 phagocytosis in, 62-64, 63 resolution of, 78, 78,, 79,, 84 serous, 84, 85 transcytosis in, 54 treatment of, 71-72 ulceration in, 85, 85 vascular changes in, 53-55, 53-55 vesiculovacuolar organelle in, 54 chronic, 79-84, 346-347, 347 definition of, 79 eosinophils in, 82, 82
etiology of, 79 granulomatous, 83-84, 83 histologic features of, 79, 80 lymphatics in, 84 lymphocytes in, 82, 82 mast cells in, 82 mononuclear infiltration in, 79-82, 80,, 81,, 81t suppurative, 84-85, 85 systemic effects of, 85-86, 86 ulcerations in, 85 cytopathic-cytoproliferative, 346, 346 general features of, 50-52, 51 granulomatous, 346 historical studies of, 52 in infarction, 132 mononuclear, 345-346, 346 necrotizing, 346 in Pseudomonas infection, 377, 377 suppurative (polymorphonuclear), 345, 345 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Inflammatory bowel disease, 815-820. See also Crohn disease; Ulcerative colitis. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Injury. See Trauma. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
I -- Ins Insulin. See also Diabetes mellitus. physiology of, 914-915, 914 receptors for, 915, 918 resistance to, in obesity, 454 in Turner syndrome, 175-176 in type II diabetes mellitus, 918 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Integrins, in leukocyte adhesion, 57, 57t, 58 of extracellular matrix, 100-101, 101,, 103 receptors for, 101 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Intelligence quotient (IQ), in fragile X syndrome, 177 in neurofibromatosis, 164 in trisomy 21, 170 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Intercellular adhesion molecule 1 (ICAM-1), 57, 57t, 59 rhinovirus binding to, 347, 347 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Intercellular signaling, 92-95, 93-95 autocrine, 91,, 92 cell surface receptors in, 92-93, 93,, 94 endocrine, 91,, 92 paracrine, 91,, 92 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Interferon-gamma (IFN-gamma), in delayed-type hypersensitivity, 205-206, 205 in inflammation, 82, 82 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Interleukin-1 (IL-1), in febrile state, 86 in inflammation, 73-74, 74,, 77t in rheumatoid arthritis, 1250-1251 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Interleukin-6 (IL-6), in febrile state, 86 in hepatocyte regeneration, 33, 33 in multiple myeloma, 664 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Interstitial pneumonitis, 721-722 desquamative, 736-737, 737 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Interstitium, pulmonary, 698 renal, 934-935 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Intestine, 802-838 adenoma of, 827, 827 adhesions of, 826 anatomy of, 802 angiodysplasia of, 823 atresia of, 804 blood supply of, 802 carcinoid tumor of, 835-837, 836,, 837t carcinoma of, 265,, 827, 827,, 831-835, 832,, 834,, 835,, 835t adenoma development in, 830-831 adenomatous precursors of, 831-833, 832 APC gene in, 287t, 292-293, 297, 297 clinical features of, 834-835 DCC gene in, 293 distribution of, 833-834, 834 epidemiology of, 833 fat intake and, 456 geographic factors in, 273, 273 hepatic metastases from, 891, 891 incidence of, 272 metastatic spread of, 835, 835,, 835t molecular genetics of, 832-833, 832 molecular model of, 297, 297 mortality rates with, 272 napkin ring constriction in, 834, 834 staging of, 835, 835t vitamin deficiencies and, 451 celiac disease of, 813, 813 congenital anomalies of, 804-805 diarrheal disease of, 805-812. See also Diarrhea. disaccharidase deficiency in, 815 diverticular disease of, 823-825, 824 duplication of, 804
endocrine cells of, 803-804 enterocolitis of, 805-812, 806t after bone marrow transplantation, 811 antibiotic-associated, 809-810, 810 collagenous, 810 diversion, 812 drug-induced, 811 in acquired immunodeficiency syndrome, 811 infectious, 806-810, 807t, 808t, 809 lymphocytic, 810 necrotizing, 809 neutropenic, 811-812 parasitic, 810-811 protozoal, 810-811, 811 radiation-induced, 811 familial adenomatous polyposis of, 831,, 845 gluten sensitivity of, 813, 813,, 961 hemorrhoids of, 530, 823 hernia of, 826 Hirschsprung disease of, 805 idiopathic inflammation of, 815-820. See also Crohn disease; Ulcerative colitis. infarction of, 820-823, 821-823 mucosal, 822, 822,, 823 mural, 822, 823 transmural, 821-822, 822,, 823 intussusception of, 804, 826 ischemic disease of, 820-823, 821-823 lymphoid tissue of, 804 lymphoma of, 837-838 malabsorption syndromes of, 812-815, 812t, 813 malrotation of, 804 Meckel diverticulum of, 804-805, 805 mesenchymal tumor of, 838 mucosa of, 802-803, 803 necrotizing inflammation of, 809 obstruction of, 825-826, 825,, 825t papilloma of, 261, 261
peristalsis of, 804 polyp of, 261, 262 polyps of, 827-831, 827-831 regenerative capacity of, 803 stenosis of, 804 stricture of, 822, 823 transplantation of, 811 tumors of, 826-838, 826t vascular disorders of, 820-823, 821-823 vasculature of, 802 villi of, 802-803, 803 volvulus of, 826 Whipple disease of, 814-815, 814 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Intima, 494, 494 thickening of, 497, 497,, 501. See also Atherosclerosis. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Intraepithelial neoplasia, of cervix, 1049-1051, 1051,, 1052 of prostate gland, 1031 of vulva, 1043, 1043 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Intrinsic factor, 788 autoantibodies to, 791 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Iodine, deficiency of, 452t in Graves disease, 1138 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Ionizing radiation. See Radiation. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Iris, hamartoma of, 164 in neurofibromatosis, 164 melanoma of, 1367 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Iron, absorption of, 628-629, 628 hepatic accumulation of, 873-875, 874 in free radical generation, 12, 13 metabolism of, 627-628, 627,, 628 myocardial toxicity of, 587 requirements for, 628, 629 systemic overload of, 43 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Ischemia, 3,, 7-12 ATP depletion in, 5 atrophy with, 35, 36 calcium imbalance in, 6, 6 cardiac, 550-564. See also Ischemic heart disease; Myocardial infarction. cerebral, 1307-1310, 1309 focal, 1308-1310, 1309 global, 1307-1308 free radicals in, 5-6, 6 intestinal, 820-823, 821-823 irreversible, 8-11, 8-11 membrane permeability defects in, 6 mitochondrial damage in, 6-7, 7 renal, 969-971, 969-971,, 986 reversible, 7-8, 8-10 vs. hypoxia, 4 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Ischemic heart disease, 3,, 550-564. See also Myocardial infarction. angina pectoris in, 554 chronic, 563, 564 epidemiology of, 551 pathogenesis of, 551-554 fixed obstructions in, 551 plaque change in, 551-553, 552 thrombus in, 553 vasoconstriction in, 553-554, 553t sudden cardiac death in, 564 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Islet cells, 911-913, 912 amyloidosis of, 921,, 922 in type I diabetes mellitus, 916 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Isoimmunization, ABO, 473 Rh, 473-475, 474,, 475 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Int -- It Ito cells, 847 in cirrhosis, 254, 854 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
J Jaundice, 848 in cholestasis, 851-852, 852 in Rh isoimmunization, 473-474 neonatal, 850 pathophysiology of, 849-851, 850t physiologic, 463, 850 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
J JC virus, 333t CNS infection with, 1321, 1322 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
J Joint(s), 1246-1259 crystal arthropathies of, 1253-1257. See also Gout. cyst of, 1258 degenerative disease of, 1246-1257. See also Arthritis. ganglion of, 1258 hemosiderin deposition in, 874 in alkaptonuria, 162 in Ehlers-Danlos syndromes, 150 in Marfan syndrome, 149 in systemic lupus erythematosus, 222 in systemic sclerosis, 228 normal, 1246 osteoarthritis of, 1246-1248, 1247,, 1248 rheumatoid arthritis of, 1248-1251. See also Rheumatoid arthritis. sarcoma of, 1266-1267, 1267 seronegative spondyloarthropathy of, 1252-1253 synovial, 1246 villonodular synovitis of, 1258-1259, 1258 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
K Kallikrein, 69 in inflammation, 68,, 69 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
K Kaposi sarcoma, 535-537, 536 in acquired immunodeficiency syndrome, 248-249, 249 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
K Kartagener syndrome, 27, 716 sinusitis in, 763 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
K Keratitis, 1362-1363 disciform, 1362-1363 epithelial, herpes, 361 stromal, herpes, 361 syphilitic, 364 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
K Keratoconjunctivitis sicca, 769. See also Sjogren syndrome. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
K Keratoses, actinic, 1184, 1185 follicular, inverted, 1180 seborrheic, 1179-1180, 1180 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
K Kidney. See also Renal entries. agenesis of, 936 amyloidosis of, 255, 255,, 256, 968 dialysis-associated, 253, 253t analgesic-induced injury to, 416, 977,, 978-979, 979,, 979t angiomyolipoma of, 991 atheroembolic disease of, 986, 987 autosomal dominant polycystic disease of, 937-940, 938,, 939,, 941t autosomal recessive polycystic disease of, 940, 941t blood supply of, 931 blood vessels of, 931. See also Renal artery(ies). calcium deposition in, 980 calyces of, 931 carcinoma of, 991-994, 992-994. See also Renal cell carcinoma. congenital anomalies of, 936-942, 941t cortex of, 931 necrosis of, 987, 987 cystic disease of, 937-942, 941t autosomal dominant, 937-940, 938,, 939,, 941t autosomal recessive, 940, 941t dialysis-associated, 941, 941t dysplastic, 937, 938 medullary, 940-941, 941 simple, 941t, 942 dialysis of, 941, 941t, 964 amyloidosis with, 253, 253t disease of, analgesic-induced, 416, 977,, 978-979, 979,, 979t clinical manifestations of, 935-936, 936t congenital, 936-942, 938,, 939 cystic, 937-942, 941t
glomerular, 942-968, 942t. See also Glomerulonephritis; Glomerulus (glomeruli). neoplastic, 990-994, 992. See also Renal cell carcinoma. obstructive, 988-990, 988-990,, 989t skeletal manifestations of, 1229 tubular, 968-981. See also Acute tubular necrosis (ATN); Tubulointerstitial nephritis. vascular, 981-988. See also Hypertension; Renal artery(ies). dysplasia of, cystic, 937, 938 ectopic, 937 failure of, acute, 935 acute tubular necrosis in, 969-971, 969-971 chronic, 935, 936, 936t hyperparathyroidism in, 636-637, 964, 1151 in thrombotic microangiopathy in, 985-988, 985,, 987 metastatic calcification in, 45 postpartum, 986 fibroma of, 991 glomeruli of, 931-934, 932-934. See also Glomerulonephritis; Glomerulus (glomeruli). hamartoma of, 991 horseshoe, 937 hyaline arteriosclerosis of, 981-982, 982 hypoplasia of, 936-937 in bacterial endocarditis, 966 in diabetes mellitus, 922-923, 923,, 924,, 966-968, 967 in essential mixed cryoglobulinemia, 968 in gout, 1256, 1257 in Henoch-Schonlein purpura, 965-966 in hypertension, 512, 512 in left-sided heart failure, 549 in multiple myeloma, 665, 968, 980-981, 981,, 981t in plasma cell dyscrasia, 968 in polyarteritis nodosa, 968 in preeclampsia, 1083, 1084
in preterm infant, 463 in right-sided heart failure, 550 in shock, 136, 137 in sickle cell disease, 986-987 in systemic lupus erythematosus, 220-222, 220,, 221,, 962, 962,, 965 in systemic sclerosis, 228-229 in vitamin D metabolism, 441-442 in Wegener granulomatosis, 523, 968 infarction of, 133,, 987-988 interstitium of, 934-935. See also Tubulointerstitial nephritis. ischemic injury to, 886, 969-971, 969-971 medulla of, 931 cystic disease of, 940-941, 940,, 941t normal, 931-935, 932-934 oncocytoma of, 991 papillary adenoma of, 991 pyelonephritis of, 972-975, 972-975. See also Pyelonephritis. radiation injury to, 429 scars of, in pyelonephritis, 976, 976 stones of, 936, 989-990, 989t, 990 in hyperparathyroidism, 1150 in hyperuricemia, 979-980, 980, 980 structure of, 931-935, 932-934 transplantation of, rejection of, acute, 209-210, 209 hyperacute, 207-208 tubules of, 934, 935-936 disease of. See Acute tubular necrosis (ATN); Tubulointerstitial nephritis. tumors of, 990-994. See also Renal cell carcinoma. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
K Knockout mice, 140 FBN1, 148-149 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
K K-ras gene, in colorectal carcinoma, 832,, 833 in pancreatic carcinoma, 910 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Lacrimal gland, lymphocytic infiltration of. See Sjogren syndrome. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Lactoferrin, in free radical inactivation, 13 in phagocytosis, 64 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Lambert-Eaton myasthenic syndrome, 1289 in bronchogenic carcinoma, 747 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Lamellar bone, 1217-1218, 1217,, 1218 in Paget disease, 1226-1227, 1226 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Laminin, of extracellular matrix, 100, 100,, 103 tumor cell attachment to, 303, 304 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Langerhans cells, 191, 1171, 1171 ultraviolet light injury to, 1185 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Laryngotracheobronchitis, 348 Bordetella, 374-375, 374 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Larynx, 765-766, 766 carcinoma of, 765, 766 inflammation of, 765 papillomatosis of, 766 reactive nodules of, 765 squamous papilloma of, 766, 766 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Legs, bowing of, in vitamin D deficiency, 445, 445 thrombophlebitis of, 530 varicose veins of, 529-530, 529 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Leiomyoma, 1266 of bladder, 1008 of esophagus, 783 of intestine, 838 of stomach, 802 of uterus, 264,, 271,, 1063-1064, 1063 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Leiomyosarcoma, 1266 of intestine, 838 of stomach, 802 of uterus, 271,, 1064-1065, 1064 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Leishmaniasis, 391-393, 392 cutaneous, 392-393 mucocutaneous, 392 visceral, 392 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Lens, cataracts of, 1367-1368 in galactosemia, 476, 477 nuclear sclerosis of, 1367 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Leukemia, c-abl gene in, 282 hairy cell, 656t, 668-669, 669 in trisomy 21, 171 incidence of, 272 lymphoblastic, acute, 485t, 654-658, 655t, 657,, 657 lymphocytic, chronic, 655t, 658-659, 658,, 659 definition of, 651 minimal residual disease monitoring of, 324 MLL gene in, 285, 286t myelogenous, acute, 657,, 675-678, 676t, 676 chronic, 680-682, 680 c-abl-bcr gene in, 285, 285,, 286t oncogenes in, 280 oral manifestations of, 759t radiation-induced, 426-427 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Leukemia/lymphoma, lymphoblastic, acute, 654-658, 655t, 657,, 657t T-cell, adult, 656t, 670 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Leukocyte(s), 645-688 activation of, 60,, 62 adhesion of, 56,, 57-61, 57t, 58 apoptosis of, 64 chemotaxis of, 60,, 61, 61 deficiency of, 646-647 development of, 603 extravasation of, 55-62, 56 hydrogen peroxide-deficient, 63-64 margination of, 53, 56-57, 56 neoplastic proliferations of, 650-686. See also Leukemia; Lymphoma. pavementing of, 56,, 57 phagocytosis by, 62-64, 63 pseudopod of, 61, 61 reactive proliferations of, 647-648, 648,, 648t, 649 rolling of, 56,, 57 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Leukocytosis, 647-648, 648,, 648t, 649 in chronic myelogenous leukemia, 681, 681 in inflammation, 86 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Leukodystrophy, 1339-1340, 1340 metachromatic, 155t, 1340, 1340 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Leukoplakia, hairy, 758-759 in squamous cell carcinoma, 1185 of oral soft tissues, 759-760, 760 vulvar, 1040-1041 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Leukotrienes, 70-71, 71,, 72 in asthma, 713 in type I hypersensitivity reaction, 198 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
La -- Le Lewy bodies, 1295 in Parkinson disease, 1334, 1334 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Li -- Lo Libman-Sacks (noninfective, verrucous) endocarditis, 575,, 576-577, 576 in systemic lupus erythematosus, 127, 223, 223 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Li -- Lo Lipofuscin, 26 cellular accumulation of, 42, 42 granules of, 36 neuronal, 1295 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Li -- Lo Lipoma, 1260-1261 cardiac, 590 esophageal, 783 intestinal, 838 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Li -- Lo Lipoprotein(s), high-density, atherosclerosis and, 504-505 intermediate-density, metabolism of, 151, 151 low-density, atherosclerosis and, 505, 505t hepatic clearance of, 151, 152 metabolism of, 151-152, 151,, 152 oxidized, 508 receptor for, defects in, atherosclerosis and, 505, 505t gene for, mutations in, 144, 147t, 152-153, 153 very low-density, metabolism of, 151, 151 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Li -- Lo Liver, 846-891 abscess of, 358-359, 867-868 acetaminophen-induced necrosis of, 416 acinus of, 846, 846 adenoma of, 887-888, 887 oral contraceptives and, 416 alcohol-induced disease of, 411-412, 411,, 411t, 869-873. See also Alcoholic liver disease. amebic abscess of, 358-359 amyloidosis of, 255-256 angiosarcoma of, 888 bacterial infection of, 867 barbiturate effects on, 26, 27 bile canaliculi of, 848 bile formation by, 848-849, 849 bilirubin processing by, 848-849, 849 carcinoma of, 888-891, 889,, 890 geographic factors in, 273, 273 hepatitis B virus and, 313-314 metastatic, 270, 270,, 891, 891 cardiac sclerosis of, 883 Caroli disease of, 881 cavernous hemangioma of, 886 cells of, 846-848 centrilobular necrosis of, 882-883, 883 circulatory disorders of, 881-884, 882-884 cirrhosis of, 853-855, 854. See also Cirrhosis. congestion of, 116-117, 117 copper accumulation in, 875 Councilman bodies of, 848 degeneration of, 847 drug-induced disease of, 868-869, 869t after bone marrow transplantation, 885
failure of, 852-856, 854,, 855 fulminant, 867 fatty, 38, 38,, 39, 39,, 847 in alcoholic liver disease, 411, 411,, 869, 870,, 872 in Wilson disease, 875 of pregnancy, 884-885 fibrosis of, 848 congenital, 880, 881 in alcoholic hepatitis, 411-412, 411 in heart failure, 117 focal nodular hyperplasia of, 886-887, 887 helminthic infection of, 867-868 hemorrhagic necrosis of, 117, 117 hemosiderin granules in, 43, 43 hobnail appearance of, 870, 871 hyaline inclusions of, 27-28, 28 hyperplasia of, 886-887, 887 immune-mediated injury to, 19-20, 20 in alpha1-antitrypsin deficiency, 875-876, 876 in bone marrow transplantation, 884, 884,, 885-886 in cardiac failure, 882-883, 883 in congenital syphilis, 364 in cystic fibrosis, 480 in Epstein-Barr virus infection, 373 in galactosemia, 476, 477 in graft-versus-host disease, 885-886 in hairy cell leukemia, 668 in hemochromatosis, 873-874, 874 in kwashiorkor, 439 in malaria, 390 in Niemann-Pick disease, 157-158, 157 in pregnancy, 884-885, 885 in preterm infant, 463 in Reye syndrome, 869 in right-sided heart failure, 550 in sarcoidosis, 735 in systemic lupus erythematosus, 224 in Wilson disease, 875
infection of, 856-868 bacterial, 867 helminthic, 867-868 parasitic, 867-868 viral. See Hepatitis. inflammation of, 848. See also Hepatitis. iron accumulation in, 873-875, 873t, 874 microarchitecture of, 846-847, 846,, 847 necrosis of, 117, 117,, 847-848, 852 apoptosis-induced, 847-848 centrilobular, 882-883, 883 ischemic, 847-848 lytic, 848 zonal distribution of, 848 nodular hyperplasia of, 886-887, 886,, 887 normal, 846-847, 846,, 847 nutmeg, 117, 117,, 883, 883 parasitic infection of, 867-868 pipe-stem fibrosis of, in Schistosoma infection, 397, 397 polycystic disease of, 880, 880,, 881, 940 pregnancy-associated disease of, 884-885, 885 pyogenic abscess of, 867-868 regeneration of, 32-33, 32,, 33,, 91, 848 sinusoids of, 846-847 occlusion of, 882 stellate cells of, 847 in cirrhosis, 854, 854 stem cells of, 33 syphilitic gumma of, 364, 364 toxin-induced disease of, 868-873, 869t transplantation of, 210 complications of, 886 vinyl chloride effects on, 420 von Meyenburg complexes of, 880, 881 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Lu -- Ly Lungs, 697-753. See also Pulmonary; Respiratory entries. abscess of, 722, 723 adenocarcinoma of, 743, 744, 744 age-related overdistention of, 710 alveolar proteinosis of, 739-740, 740 alveolar walls of, 698, 698 atelectasis of, 699-700, 699 blood supply to, 698 bronchiolitis obliterans organizing pneumonia of, 738, 738 brown induration of, 700 bullae of, 711, 711 burns of, 434 carcinoid tumor of, 747-748, 748 carcinoma of, 741-747 bronchioloalveolar, 747, 747 cigarette smoking and, 409, 409t classification of, 742-743, 743,, 743t, 744 clinical course of, 745-746, 746,, 746t etiology of, 741-742 glutathione-s-transferase in, 307 in asbestos workers, 733 incidence of, 272 Lambert-Eaton myasthenic syndrome with, 1289 large cell, 744,, 745 metastatic, 749, 749 molecular genetics of, 742 mortality rates with, 272,, 273, 745-746 non-small cell, 743 P-450 gene in, 307 paraneoplastic syndromes with, 320, 321t, 746-747 peripheral neuropathy with, 1280 small cell, 743, 744-745, 744 spread of, 743-744, 743
squamous cell, 743-744, 744 staging of, 745, 745t superior vena cava syndrome in, 745 chronic obstructive disease of, 706-717, 707t. See also specific diseases, e.g., Emphysema. collapse of, 699-700, 699 congenital anomalies of, 699 congenital overinflation of, 710 congestion of, 116 cysts of, 699 desquamative interstitial pneumonitis of, 736-737, 737 diffuse alveolar damage to, 700-703. See also Adult respiratory distress syndrome (ARDS). diffuse interstitial diseases of, 726-740, 727t. See also specific diseases, e.g., Pneumoconiosis. drug-induced disease of, 740, 740t edema of, 116, 700, 700t embolism of, 703-704, 703 fibrosis of, 735-736, 736 gangrene of, 722 hamartoma of, 748-749 hemorrhage from, 738-739, 738 hemosiderosis of, 739 honeycomb, 736 hyaline membrane disease of, 471-473, 472 hypersensitivity pneumonitis of, 613, 737 in collagen vascular disorders, 739 in congenital syphilis, 364 in cystic fibrosis, 479, 480, 481, 481 in filariasis, 398 in left-sided heart failure, 549 in preterm infant, 462-463, 463 in shock, 136-137 in systemic lupus erythematosus, 224 in systemic sclerosis, 229 in tuberculosis, 722-726. See also Tuberculosis. infarction of, 133,, 703-704, 704
infection of, 347-353, 717-721 bacterial, 348-352, 350-352,, 717-721. See also Pneumonia, bacterial. Coccidioides immitis in, 353, 353 fungal, 352-353, 353 Haemophilus influenzae in, 348-349 Histoplasma capsulatum in, 352, 353 in cystic fibrosis, 479, 480, 481, 481 influenza viruses in, 348 Mycobacterium avium in, 352, 352 Mycobacterium tuberculosisin, 349-352, 350,, 351. See also Tuberculosis. rhinoviruses in, 347-348, 347 viral, 347-348, 347 lobules of, 698 maturation of, 462, 463 metastases to, 749, 749 neonatal respiratory distress syndrome of, 471-473, 472 neuroendocrine tumors of, 747-748, 748 normal, 697-698, 698 obstructive overinflation of, 710-711 overinflation of, 710-711 oxygen-induced dysplasia of, 472-473 pneumonoconioses of, 727-734, 728,, 729t, 730 proteinosis of, 739-740, 740 radiation-induced disease of, 429, 740 sarcoidosis of, 734-735, 734 scar cancer of, 742 sequestrations of, 699 staphylococcal abscess of, 367, 367 surfactant of, 471-473, 472 terminal respiratory unit of, 698, 708 transplantation of, 740-741, 741 tuberculosis of, 722-726. See also Tuberculosis. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Lu -- Ly Lupus erythematosus, cutaneous, 224, 1200-1201, 1200,, 1201 discoid, 224 drug-induced, 218t, 224-225 pulmonary involvement in, 739 systemic, 216-225. See also Systemic lupus erythematosus (SLE). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Lu -- Ly Lyme disease, 388-389, 388,, 1253, 1317 myocarditis in, 584 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Lu -- Ly Lymph nodes, 645-646, 645 follicle of, 190 follicular hyperplasia of, 649-650, 650 in acquired immunodeficiency syndrome, 250 in Epstein-Barr virus infection, 372 in inflammation, 84 in sarcoidosis, 735 in Sjogren syndrome, 226 in systemic lupus erythematosus, 224 marginal zone B-cell hyperplasia of, 649-650 paracortical hyperplasia of, 650 reticular hyperplasia of, 650 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Lu -- Ly Lymphadenitis, 84 in Toxoplasma gondii infection, 383 nonspecific, 649-650, 650 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Lu -- Ly Lymphangioma, 533 in infant, 483-484 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Lu -- Ly Lymphatic system, 495 in inflammation, 84 obstruction of, 115, 531 tumor metastases to, 269-270, 269 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Lu -- Ly Lymphocyte(s). See also Immune system. B, 190, 190 antigen expression of, 654t antigen recognition by, 190 antigen-independent activation of, 215 clonal anergy of, 213 clonal deletion of, 212, 213 differentiation of, 653 Epstein-Barr virus infection of, 190, 312 in human immunodeficiency virus infection, 244 monocytoid, 650 receptor of, 190 deficiency of, 646 development of, 603 granular, large. See Natural killer cells. in glomerulonephritis, 947, 947 in inflammation, 82, 82 of intestinal lymphoid tissue, 804 T, 189-190, 190 activated (immunoblasts), 650 antigen expression of, 654t antigen recognition by, 189, 190,, 194, 194 antigen sensitization of, in cancer, 318 antigen-independent activation of, 215 apoptosis of, 212-213, 213 atypical, in Epstein-Barr virus infection, 371, 372 CD4+, 189, 190 activation of, 243 human immunodeficiency virus infection of, 239-243, 240-242 in delayed-type hypersensitivity, 204-205, 205 CD8+, 189, 194, 194 CD3 protein expression by, 189, 189
clonal anergy of, 212-213, 213 failure of, 214 clonal deletion of, 212, 213 cytotoxic, apoptosis of, 318-319 in apoptosis, 24, 206 in cancer, 317, 318 in type IV hypersensitivity, 206 differentiation of, 653 HTLV-I infection of, 314-315, 314 in glomerulonephritis, 946 in Graves disease, 1137 in systemic lupus erythematosus, 219, 219 in transplantation rejection, 207, 208 receptor of, 189, 189 suppressor, 214 loss of, 215 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Lu -- Ly Lymphoid neoplasms, 651-675, 685-686. See also Leukemia; Lymphoma. antigen receptor genes in, 652-653 cellular origin of, 652, 653,, 654t diagnosis of, 652 immune abnormalities with, 652 monoclonality of, 652-653 REAL classification of, 651-654, 652t, 655t, 656t tissue patterns of, 653 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Lu -- Ly Lymphokines, 73. See also Cytokines. in inflammation, 82, 82 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Lu -- Ly Lymphoma, 485t, 651-654, 652t angiocentric, 656t, 671 Burkitt, 485t, 655t, 662-663, 663 Epstein-Barr virus in, 312, 313 oncogenes in, 285, 285,, 286t definition of, 651 follicular, 285, 286t, 655t, 659-661, 660,, 661 gastric, 802 gastrointestinal, 837-838 Hodgkin, 670-675. See also Hodgkin disease. in acquired immunodeficiency syndrome, 249-250 in Sjogren syndrome, 226 incidence of, 272 large B-cell, diffuse, 655t, 661-662, 661,, 662 lymphocytic, small, 655t, 658-659, 658,, 659 lymphoplasmacytic, 656t, 666-667, 667 mantle cell, 285, 286t, 656t, 667-668, 668 marginal zone, 315, 656t, 668 Mediterranean, 837 minimal residual disease monitoring of, 324 of brain, 1349-1350 of choroid, 1372 of testes, 1024-1025 of upper airway, 763 oncogenes in, 285, 286t sprue-associated, 837 T-cell, cutaneous, 1191, 1191 peripheral, unspecified, 656t, 669-670, 669 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Lu -- Ly Lysosomal granules, in inflammation, 76, 76 release of, 64 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Lu -- Ly Lysosomes, in atrophy, 36 in cell injury, 25-26 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
M -- Mel Macrophage(s). See also Leukocyte(s). activation of, 80, 81 alveolar, 698 in diffuse interstitial disease, 727 in pneumonia, 718 antigen expression of, 654t bacterial infection of, 343 cholesterol-laden, 40, 40 foamy, 40, 40 formation of, 80, 80,, 603 hemosiderin-laden, 738,, 739 human immunodeficiency virus infection of, 240, 242-243 immobilization of, 81, 81 immune complex activation of, 203 immune functions of, 190-191 in adult respiratory distress syndrome, 702-703 in asbestosis, 732 in atherosclerosis, 508-509 in cancer, 318, 318 in fibroblast proliferation, 106, 106t in glomerulonephritis, 947, 947 in inflammation, 79-82, 80,, 81,, 81t in pulmonary hemorrhage, 738,, 739 in silicosis, 731 in type IV hypersensitivity, 205, 205 LDL receptors of, 152 Legionella pneumophilainfection of, 377-378 proliferation of, 81, 81 recruitment of, 81 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
M -- Mel Macula, cherry-red spot of, in Tay-Sachs disease, 156 degeneration of, 1371, 1371 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
M -- Mel Major histocompatibility complex. See Human leukocyte antigen (HLA) complex. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
M -- Mel Malformation(s), congenital, 464-470 definition of, 464-466 environmental etiology of, 466-467, 466t etiology of, 466-467, 466t frequency of, 467, 467t genetic etiology of, 466, 466t homeobox genes in, 469-470, 469 mechanisms of, 467-470, 468,, 469 PAX genes in, 470 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
M -- Mel Malignancy. See at Tumor(s) and specific malignancies. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
M -- Mel Malnutrition. See also specific minerals and vitamins. in cell injury, 4-5 protein-energy, 437-439, 438,, 438t in chronic pancreatitis, 908 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
M -- Mel Mast cells, cytokine production by, 198 histamine release from, 66, 66,, 77t in asthma, 713 in inflammation, 82, 82 in type I hypersensitivity reaction, 196-198, 197,, 198,, 199t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
M -- Mel Mastitis, acute, 1096 granulomatous, 1098 periductal, 1096-1097 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
M -- Mel Matricellular proteins, 101 in angiogenesis, 106 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
M -- Mel Measles virus, 333t, 370, 370,, 759t CNS infection with, 1321-1322 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
M -- Mel Mediastinopericarditis, 589 adhesive, 589 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
M -- Mel Megacolon, aganglionic, congenital, 805 toxic, 818, 819 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
M -- Mel Megakaryocytes, in essential thrombocytosis, 683, 683 in myelodysplastic syndromes, 678, 679 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
M -- Mel Megaloblastic anemia, 605t, 621-627, 622,, 623t in folate deficiency, 626-627, 626 in vitamin B12 deficiency, 623-626, 623t, 624 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
M -- Mel Melanocytes, 1171, 1171 hyperplasia of, 1174 loss of, 1173-1174, 1173 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
M -- Mel Melanoma, malignant, 263, 1177-1179, 1178,, 1179 APC-beta-catenin in, 293 dysplastic nevi and, 1177, 1178 geographic factors in, 273 growth patterns of, 1178-1179, 1179 incidence of, 272 pigmentation of, 1178, 1179 tyrosinase antigens of, 317 ultraviolet radiation in, 310 uveal, 1365-1367, 1366 vulvar, 1045 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Membranous glomerulonephritis, 953-954, 965t in systemic lupus erythematosus, 221, 221 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Mendelian disorders, 143-164 autosomal dominant, 144-145, 145t autosomal recessive, 145, 145t nonclassic, 176-182, 177-179,, 179t, 180 X-linked, 146, 146t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Meningitis, 1314-1315, 1315 aseptic, 1315 chemical, 1314 cryptococcal, 1322 herpes simplex, 1318 human immunodeficiency virus-1, 1320-1321, 1320 pyogenic, 1314-1315, 1315 tuberculous, 1316-1317 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Meningoencephalitis, 1314 Acanthamoeba, 1323 bacterial, 1316-1317 fungal, 1322 human immunodeficiency virus-1 in, 1320-1321, 1320 Mucor, 381 viral, 1317-1322, 1318,, 1320,, 1322 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Menopause, atrophy with, 35 endometrial changes with, 1056 osteoporosis after, 1222-1224, 1223,, 1224 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Menstrual cycle, 1037-1038, 1054,, 1055, 1055 breast changes with, 1094 inadequate luteal phase of, 1056 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Mental retardation, in fragile X syndrome, 177 in trisomy 21, 170 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Mesangial cells, 933-934 antibodies to, 946 in glomerulonephritis, 947 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Mesothelioma, in asbestos workers, 733 of fallopian tubes, 1065 of peritoneum, 842 of pleura, 751-752, 752,, 753 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Metabolism, inborn errors of, 475-481. See also specific disorders. wound healing and, 110 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Metal(s), in carcinogenesis, 309 in occupational diseases, 420-422, 421t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Metalloproteinases, in tissue remodeling, 106-107, 107 tumor elaboration of, 303-304 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Metaplasia, 31, 36-38, 37 myeloid, myelofibrosis with, 683-685, 684 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Metastasis, tumor. See Tumor(s), metastatic. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Methanol, CNS effects of, 1342 ingestion of, 412 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Mice, knockout, 140 FBN1, 148-149 transgenic, 140 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Microabscess, in dermatitis herpetiformis, 1204, 1205 in psoriasis, 1199, 1199 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Microangiopathy, diabetic, 922-923, 923 thrombotic, 636-637, 985-988, 985,, 987 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Microglial nodules, 1297 in human immunodeficiency virus infection, 1320, 1320 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Mitochondrion (mitochondria), alterations in, 26-27, 27 in alcoholic cirrhosis, 27 injury to, 6-7, 7,, 9, 11 number of, 26 size of, 26, 27 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mem -- Mi Mitral valve, annulus of, calcification of, 567,, 568 Lambl excrescences on, 546 myxomatous degeneration of, 568-570, 569 prolapse of, 149, 568-570, 569,, 940 in Marfan syndrome, 149 in polycystic kidney disease, 940 stenosis of, blood flow alterations in, 125, 129 in rheumatic heart disease, 572 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ml -- Mu Mole, BK (dysplastic nevi), 1176-1177, 1177,, 1178 cutaneous, 1174-1176, 1175,, 1176t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ml -- Mu Monocyte(s). See also Macrophage(s). antigen expression of, 654t development of, 603 in glomerulonephritis, 947, 947 LDL receptors of, 152 maturation of, 80, 80 reactive proliferations of, 648t recruitment of, 80-81 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ml -- Mu Monokines, 73. See also Cytokines. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ml -- Mu Mononucleosis, infectious, 371-373, 372,, 759t. See also Epstein-Barr virus (EBV). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ml -- Mu Mosaicism, cellular, 168-169 in Klinefelter syndrome, 174 in trisomy 21, 170 in Turner syndrome, 174-175 gonadal, 181-182 placental, in intrauterine growth retardation, 461, 462 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ml -- Mu Motor neurons, degenerative diseases of, 1338, 1339 lower, 1269-1270, 1270 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ml -- Mu Mouth. See Oral cavity. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ml -- Mu Mucinous cystadenocarcinoma, of appendix, 840, 840 of pancreas, 910, 910 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ml -- Mu Mucocele, of appendix, 840 of sinus, 763 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ml -- Mu Mucosa-associated lymphoid tissue (MALT), 804 tumors of, 315, 668 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ml -- Mu Mucoviscidosis, 477-481, 478-481. See also Cystic fibrosis. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ml -- Mu Multiple endocrine neoplasia (MEN) syndromes, 1166-1167, 1167t medullary thyroid carcinoma in, 1145, 1168 parathyroid disorders in, 1149 pheochromocytoma in, 1164, 1164t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ml -- Mu Multiple myeloma, 655t, 664-666, 665 renal involvement in, 968, 980-981, 981,, 981t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ml -- Mu Multiple sclerosis, 1326-1327, 1327,, 1328 Marburg form of, 1328 myelin basic protein-reactive T cell clones in, 215 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ml -- Mu Muscle(s), 1270. See also Muscle fibers. chloroquine-induced disease of, 1288-1289 congenital diseases of, 1285, 1286t, 1287 denervation atrophy of, 1274-1275, 1280-1281, 1281 disuse atrophy of, 1275 drug-induced diseases of, 1288-1289 ethanol-induced disease of, 412, 1288 fibers of, 1272-1273, 1272,, 1273,, 1273t in acquired immunodeficiency syndrome, 1321 in Charcot-Marie-Tooth disease, 1277-1278 in Dejerine-Sottas disease, 1278 inflammatory diseases of, 229-231, 230,, 1287 antinuclear antibodies in, 218t leiomyoma of, 1266 leiomyosarcoma of, 1266 lipid diseases of, 1285-1286 mitochondrial diseases of, 1286-1287, 1288 pseudohypertrophy of, 1281 regeneration of, 92 reinnervation of, 1275 rhabdomyosarcoma of, 265,, 1265-1266, 1265 smooth, tumors of, 589-591, 589,, 591t steroid-induced diseases of, 1288 thyrotoxic diseases of, 1287-1288 toxic diseases of, 1287-1289 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ml -- Mu Muscle fibers, 1272-1273, 1272,, 1273,, 1273t atrophy of, 1274-1275 group atrophy of, 1273,, 1275 hypertrophy of, 1275 regeneration of, 1275 reinnervation of, 1275 segmental fibrosis of, 1275 splitting of, 1275 type grouping of, 1273,, 1275 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ml -- Mu Muscular dystrophy, 1281-1285 autosomal, 1282-1284, 1283t, 1284t Becker, 1281-1282, 1282,, 1283 Duchenne, 1281-1282, 1282,, 1284 limb girdle, 1282-1283, 1283t, 1284t X-linked, 1281-1282, 1282,, 1283 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ml -- Mu Mutation(s), 141-143, 466. See also Mendelian disorders. chromosome, 141-142. See also Chromosome(s). frameshift, 142, 142,, 143 gain of function, 145 genome, 141 in oncogene activation, 284 loss of function, 144 missense, 142, 142 point, 141,, 142, 142 trinucleotide repeat, 143 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mya -- Myx c-myc gene, in bronchogenic carcinoma, 742 in Burkitt lymphoma, 285, 285,, 286t, 312 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mya -- Myx Mycobacterium avium-intracellulare, 334t in acquired immunodeficiency syndrome, 352, 352 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mya -- Myx Mycobacterium tuberculosis, 332t, 334t, 349-352, 350,, 351. See also Tuberculosis. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mya -- Myx Mycoplasma, 334t, 335 genital infection with, 1039 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mya -- Myx Myelin protein zero, 1270 in Charcot-Marie-Tooth disease, 1277 in Dejerine-Sottas disease, 1278 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mya -- Myx Myeloid neoplasms, 675-686. See also Leukemia, myelogenous; Myelodysplastic syndromes. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mya -- Myx Myeloma, multiple, 655t, 664-666. See also Multiple myeloma. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mya -- Myx Myeloproliferative disorders, 679-685, 680-684. See also specific disorders. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mya -- Myx Myocardial infarction, 129, 554-564 after heart transplantation, 598 apoptosis in, 556 arrhythmias with, 562 atheroma in, 553 blood flow alterations in, 125 cardiogenic shock after, 562 circadian rhythms in, 551 clinical features of, 561 complications of, 562-563, 562,, 563 contractile dysfunction with, 562 contraction bands in, 559, 561 C-reactive protein in, 506 creatine kinase in, 561 estrogen replacement therapy and, 414-415 expansion of, 563 in diabetes mellitus, 922 incidence of, 554-555 inflammatory response in, 559, 560 myocardial rupture with, 562, 562 of right ventricle, 563 oral contraceptives and, 416 papillary muscle dysfunction with, 563 pathogenesis of, 555-559 coronary arterial occlusion in, 555 myocardial response in, 555-559, 555,, 556t, 557,, 558t, 559,, 560 pericarditis with, 562-563, 563 postreperfusion changes in, 559-561, 561 prevention of, 563 prognosis for, 563 reperfusion injury in, 559, 561 risk factors for, 554-555 septic, 574 subendocardial, 554, 559
thromboembolism with, 563 thrombolytic therapy in, 559, 561 thrombus in, 126-127, 127,, 552, 553, 553t transmural, 553, 554, 556-557, 558t triphenyltetrazolium chloride dye test in, 558, 559 ventricular aneurysm with, 563, 563 ventricular remodeling after, 563 wavy fibers in, 558, 560 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mya -- Myx Myocarditis, 584-586, 584t, 585 hypersensitivity, 584-585, 585 in Chagas disease, 394 in rheumatic heart disease, 571 in systemic lupus erythematosus, 223 in trichinellosis, 394 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mya -- Myx Myocardium, 544-545. See also Heart. amyloid deposits of, 586 catecholamine-induced injury to, 586 disease of, 578-587, 578. See also Cardiomyopathy. doxorubicin-induced injury to, 586 drug-induced injury to, 586-587 in thyroid disease, 587 inflammation of, 584-586, 584t, 585 iron-induced disease of, 586-587 ischemia of, 550-564. See also Ischemic heart disease; Myocardial infarction. necrosis of, 16-17, 16,, 17 rupture of, after myocardial infarction, 562, 562 stunned, 561 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mya -- Myx Myocytes, 544-545 coagulation necrosis of, 16, 16 hypertrophy of, 34,, 35 ischemic injury to, 2, 3. See also Ischemic heart disease; Myocardial infarction. lipofuscin accumulation in, 42, 42 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mya -- Myx Myometrium. See Uterus. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mya -- Myx Myopathy. See at also Muscle(s). congenital, 1285-1286, 1285t ion channel, 1285 lipid, 1286-1287 mitochondrial, 1287 toxic, 1287-1289 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Mya -- Myx Myotonic dystrophy, 1283, 1285 triplet repeat mutations in, 179, 179,, 179t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Nasopharynx, carcinoma of, 764, 764 Epstein-Barr virus in, 313 inflammation of, 763 tumors of, 763-764, 764 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Natural killer cells, 191, 191,, 192 antigens of, 654t development of, 603 in cancer, 317-318, 318 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Neck, 767-768 branchial cyst of, 767 paraganglioma of, 768-769, 768 thyroglossal tract cyst of, 767-768 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Necrosis, 2 ATP depletion in, 5 avascular, 1231, 1231,, 1231t calcium imbalance in, 6, 6 caseous, 17, 17 centrilobular, 117, 117 coagulative, 16-17, 16,, 17 fat, 17-18, 18 free radicals in, 5-6, 6 gangrenous, 17 hemorrhagic, 116-117, 117 hepatic, 117, 117,, 847-848, 852 apoptosis-induced, 847-848 centrilobular, 882-883, 883 ischemic, 847-848 lytic, 848 zonal distribution of, 848 liquefactive, 17, 17 mechanisms of, 5-7, 6,, 7 membrane permeability defects in, 6 mitochondrial damage in, 6-7, 7 morphology of, 15-18, 16-18 myocardial, 16-17, 16,, 17 secondary, 19 vs. apoptosis, 18 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Neisseria gonorrhoeae, 334t, 362, 1038t in pelvic inflammatory disease, 1039-1040 pili of, 342, 342,, 344 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Neonate. See Infant. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Neoplasm, 261. See also Carcinogenesis; Tumor(s). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Neovascularization. See Angiogenesis. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Nephritis. See also Glomerulonephritis. anti-glomerular basement membrane antibodies in, 943-945, 944 hereditary, 933, 962-963, 963 Heymann, 944,, 945, 954 immune complex, 945-946 tubulointerstitial, 971-981, 972t drug-induced, 977-979, 977,, 979,, 979t urinary tract infection and, 972-974, 972,, 973 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Nephrolithiasis, 936, 989-990, 989t, 990 in hyperparathyroidism, 1150 in hyperuricemia, 980 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Nephropathy. See at Kidney. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Nephrosclerosis, benign, 981-982, 982 malignant, 982-984, 983,, 983t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Nerves. See Central nervous system (CNS); Peripheral nerves. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Neuroblastoma, 485-487, 485t, 486,, 487,, 1166, 1348 chromosome 1 in, 487 N-myc gene amplification in, 286, 286,, 487, 487 olfactory, 764 ploidy of, 487 staging of, 486-487 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Neurodegenerative diseases. See also Alzheimer disease; Huntington disease; Parkinson disease. protein deposition in, 1295, 1296t protein misfolding in, 41 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Neurofibrillary tangles, 1295 in Alzheimer disease, 28, 1330, 1331 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Neurofibromatosis, 1354 type 1 (von Recklinghausen disease), 147t, 162, 164, 293 type 2 (acoustic neurofibromatosis), 162, 164 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Neurohypophysis. See Pituitary gland, posterior. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Neuroma, acoustic, 1352-1353, 1353 in MEN-IIB, 1168 Morton, 1280 traumatic, 1280, 1280 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Neurons, 1294-1295 degeneration of, 1295 heterotopic, 1300 in Tay-Sachs disease, 155-156, 157 inclusions of, 1295 loss of, 91 motor, degenerative diseases of, 1338, 1339 lower, 1269-1270, 1270 nitric oxide of, 75 red, 1295 tumors of, 1348 ultrastructural features of, 1295 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Neuronophagia, 1297 in arthropod-borne viral encephalitis, 1318 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Neuropathy. See Peripheral neuropathy. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Neutropenia, 646-647 colitis with, 811-812 drug-induced, 646-647 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Neutrophils. See also Leukocyte(s). azurophil granules of, 76, 76 deficiency of, 646-647 immune complex activation of, 203, 203 in adult respiratory distress syndrome, 702, 702 in alcoholic liver disease, 869 in glomerulonephritis, 947, 947 in inflammation, 86, 345, 345 in rheumatoid arthritis, 1249 reactive proliferations of, 647-648, 648,, 648t, 649 specific granules of, 76, 76 toxic granules of, 648 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Nevus, dysplastic, 1176-1177, 1177,, 1178 nevocellular, 1174-1176, 1175,, 1176t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Nickel, in carcinogenesis, 274t, 309 in occupational diseases, 421t, 422 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Nipples, 1094 adenoma of, 1104 congenital inversion of, 1096 Paget disease of, 1108-1109 papillomatosis of, 1104 supernumerary, 1096 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Nitric oxide, antimicrobial activity of, 75-76 cytokine-inducible, 75 endothelial, 75 in cell injury, 12 in inflammation, 75-76, 75,, 77t in platelet aggregation, 118,, 122 neuronal, 75 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Nodule(s), 1172 in silicosis, 731, 732 rheumatoid, 1249, 1249 thyroid, 1140 typhoid, 357, 357 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Non-Hodgkin's lymphoma. See Lymphoma. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Nonsteroidal anti-inflammatory drugs (NSAIDs), diarrhea with, 811 in inflammation, 71-72 nephropathy with, 979 peptic ulcer disease and, 794 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Nose, 762-763 carcinoma of, 764, 764 inflammation of, 762-763, 762 necrotizing lesions of, 763 neuroblastoma of, 764 papilloma of, 763, 764 plasmacytoma of, 763-764 polyps of, 762, 762 tumors of, 763-764, 764 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N NSAIDs. See Nonsteroidal anti-inflammatory drugs (NSAIDs). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
N Nutrition, 436-452. See also specific minerals and vitamins. in wound healing, 110 with burn injury, 434 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
O Obesity, 452-455, 452,, 453 cancer and, 273 in type II diabetes mellitus, 918 tumor necrosis factor in, 74 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
O Occupational diseases, 404, 404t, 419-422, 419t, 421t, 422 aromatic halogenated hydrocarbons and, 420 cigarette smoking and, 409 herbicides and, 423-424 metals and, 420-422, 421t, 422 pesticides and, 422-423, 423t plastics and, 420 polymers and, 420 pulmonary, 727-734, 728,, 729t, 730 rubber and, 420 volatile organic compounds in, 419-420, 419t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
O Oncocytoma, mitochondria in, 27 of kidneys, 991 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
O Oncogenes, 93, 277-286 activation of, 284-286, 285,, 286,, 286t nomenclature for, 278 protein products of, 279-284, 279t, 281,, 283,, 284 recessive, 277 viral, 278 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
O Optic nerve, atrophy of, 1374, 1374 glaucomatous, 1375, 1375 edema of, 1373-1374, 1374 tumors of, 1374 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
O Optic neuritis, 1374 in multiple sclerosis, 1327 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
O Oral cavity, 756-761 aphthous ulcers of, 757, 757 candidiasis of, 378, 757 cysts of, 761 dryness of, 758, 769 erythroplakia of, 760 hairy leukoplakia of, 758-759 herpes simplex virus infection of, 757 in systemic disease, 758-759, 759t inflammation of, 756-758, 757 leukoplakia of, 759-761, 760 reactive lesions of, 758, 758 squamous cell carcinoma of, 760-761, 761 tumors of, 759-761, 760,, 761 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
O Orchitis, granulomatous, 1017 mumps, 371, 1017 postvasectomy, 215 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
O Osteoarthritis, 1246-1248, 1247,, 1248,, 1254 obesity and, 454 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
O Osteogenesis imperfecta, 1220t, 1221-1222, 1221,, 1222t collagen in, 144-145 gene mutation in, 147t gonadal mosaicism in, 181 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
O Osteomyelitis, 1232-1233, 1232 extradural abscess with, 1316 pyogenic, 1232, 1232 sclerosing, of Garre, 1233 tuberculous, 1233 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
O Osteopontin, 101 in dystrophic calcification, 45 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
O Osteoporosis, 1222-1224, 1223t, 1224 disuse, 1222 pathogenesis of, 1222-1224, 1223 vs. osteomalacia, 445-446 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
O Osteosarcoma, 1236-1237, 1236,, 1237 chondroblastic, 1237, 1241 platelet-derived growth factor production by, 279, 279t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
O Ovary(ies), 1066-1079 adenofibroma of, 1072-1073, 1072 anatomy of, 1037 androblastoma of, 1078, 1078 Brenner tumor of, 1072-1073, 1072 carcinoma of, 1069-1072 clinical course of, 1073 endometrioid, 1071-1072 incidence of, 272 mortality rates with, 272 mucinous, 1070-1071, 1071 oral contraceptives and, 415 risk factors for, 1067 serous, 1069-1070, 1069,, 1070 choriocarcinoma of, 1076 clear cell adenocarcinoma of, 1072 cystadenocarcinoma of, 1069-1070, 1069,, 1070 cystadenofibroma of, 1072 cystic follicles of, 1066 cystic teratoma (dermoid cyst) of, 262-263, 264 cysts of, 1066-1067, 1066 dysgerminoma of, 1075, 1075 endodermal sinus tumor of, 1075-1076, 1076 endometrioid tumors of, 1071-1072 germ cell tumors of, 1073-1076, 1073-1076 gonadoblastoma of, 1078 granulosa luteal cysts of, 1066 granulosa-theca cell tumor of, 1076-1077, 1077 hilus cell tumor of, 1078 in Turner syndrome, 176 Leydig cell tumor of, 1078 metastatic tumors of, 1079 mucinous tumors of, 1070-1071, 1071 polycystic disease of, 1066-1067, 1066
pregnancy luteoma of, 1078 radiation damage to, 430 serous cystadenoma of, 1069, 1069 serous tumors of, 1069-1070, 1069,, 1070 Sertoli-Leydig cell tumor of, 1078, 1078 sex cord-stromal tumor of, 1076-1079, 1077,, 1078 streak, 176 stromal hyperthecosis of, 1066-1067 teratoma of, 1073-1075, 1073,, 1074 thecoma-fibroma of, 1077-1078, 1077 transitional cell carcinoma, 1073 tumors of, 1067-1079, 1067t, 1068,, 1068t yolk sac tumor of, 1075-1076, 1076 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
O Ovulation, 1054,, 1055, 1055 failure of, 1056, 1056 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
P -- Pa p53 gene, aflatoxin B1-related mutation of, 308 in angiogenesis, 302 in bronchogenic carcinoma, 742 in cancer, 290-292, 291 in colorectal carcinoma, 832,, 833 in pancreatic carcinoma, 910 ultraviolet ray-induced mutation of, 310 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
P -- Pa Paget disease, of bone (osteitis deformans), 1225-1227, 1226,, 1227 of nipple, 1107-1109, 1107t, 1108,, 1109 of vulva, 1044-1045, 1044 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
P -- Pa Pancreas, 902-928 abscess of, 907, 909 acini of, 903, 903 adenoma of, 910 agenesis of, 904 annular, 904 carcinoid tumors of, 928 carcinoma of, 910-911, 911 hepatic metastasis from, 270 incidence of, 272 mortality rates with, 272 delta-cell tumor of, 928 alpha-cell tumors of, 927 beta-cell tumors of, 926-927, 927 congenital anomalies of, 904 cysts of, 909 cystadenoma of, 910 cystic tumors of, 909-910, 910 ectopic, 904 endocrine, 911-928. See also Diabetes mellitus. alpha cell of, 911-913, 912 beta cell of, 911, 912 delta cell of, 912,, 913 D1 cell of, 913 enterochromaffin cell of, 913 enzymes of, 903-904 in acute pancreatitis, 905-907, 906 exocrine, 902-904, 903 gastrinoma of, 927 glucagonoma of, 927 hemosiderin deposition in, 874 heterotopic, 789 in cystic fibrosis, 479-480, 481
inflammation of, 904-909, 905-908,, 905t islet cell tumors of, 926-928, 927 microcystic adenoma of, 910 mucinous cystadenocarcinoma of, 910, 910 mumps virus infection of, 371 pseudocysts of, 907, 909, 909 secretions of, 903-904 solid-cystic tumor of, 910 somatostatinoma of, 928 tumors of, 909-911, 910,, 911 VIPoma of, 928 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
P -- Pa Pancreatic duct, 903, 903 obstruction of, in acute pancreatitis, 906, 906 in chronic pancreatitis, 908 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
P -- Pa Pancreatitis, 904-909 acute, 841, 904-907, 905,, 905t clinical features of, 907, 907 fat necrosis in, 17-18, 18,, 905, 905 necrotizing, 905, 905 pathogenesis of, 905-907, 906 vs. chronic pancreatitis, 907 chronic, 907-909 clinical features of, 908-909 hereditary, 908 pathogenesis of, 907-908 vs. acute pancreatitis, 907 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
P -- Pa Pancytopenia, in hairy cell leukemia, 669 oral manifestations of, 759t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
P -- Pa Papilloma, 261, 261 large duct, of breast, 1104, 1105 of choroid plexus, 1347-1348 of nose, 763, 764 of urethra, 1009 sclerosing, of breast, 1101 small duct, of breast, 1101, 1102 squamous, 1181 of esophagus, 783 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
P -- Pa Papillomatosis, 1172 of larynx, 766 of nipple, 1104 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
P -- Pa Papillomavirus. See Human papillomavirus (HPV). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
P -- Pa Paraneoplastic syndromes, 320-321, 321t, 1351-1352, 1352t with bronchogenic carcinoma, 746-747 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
P -- Pa Parathyroid glands, 1147-1151 adenoma of, 1148-1150, 1149 carcinoma of, 1149-1150 hyperfunction of, 1148-1151. See also Hyperparathyroidism. hypofunction of, 1151 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
P -- Pa Parathyroid hormone, 1147 in renal osteodystrophy, 1229 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
P -- Pa Parathyroid hormone-related protein, 1218, 1219 in hypercalcemia, 320, 1148 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
P -- Pa Parietal cells, 787-788 autoantibodies to, 791, 793 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
P -- Pa Parotid gland. See also Salivary glands. inflammation of, 769 mixed tumor of, 262, 262 pleomorphic adenoma of, 770-771, 770 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
P -- Pa Patent ductus arteriosus, 593,, 594 coarctation with, 596-597 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pc -- Phe Penis, 1011-1014 bowenoid papulosis of, 1012, 1209 carcinoma in situ of, 1013-1014, 1013 carcinoma of, 1014, 1014 condyloma acuminatum of, 1012, 1012,, 1013 congenital anomalies of, 1011-1012 epispadias of, 1012 erythroplasia of Queyrat of, 1013-1014 fibromatosis of, 1263 hypospadias of, 1012 inflammation of, 1012 phimosis of, 1012 tumors of, 1012-1014, 1012,, 1013 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pc -- Phe Perforin, in apoptosis, 24 of cytotoxic T lymphocytes, 206 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pc -- Phe Pericarditis, 587-589, 587t, 588 after myocardial infarction, 562-563, 563 in systemic lupus erythematosus, 223 in systemic sclerosis, 229 uremic, 964 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pc -- Phe Pericardium, disease of, 587-589, 587t, 588 radiation damage to, 429, 429 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pc -- Phe Peripheral myelin protein 22, 1270 in Charcot-Marie-Tooth disease, 1277 in Dejerine-Sottas disease, 1278 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pc -- Phe Peripheral nerves, 1269-1280, 1271. See also Peripheral neuropathy. axonal degeneration of, 1274-1275, 1274 compression of, 1280 demyelination of, 1274, 1274 laceration of, 1280 regeneration of, 1275 structure of, 1270-1271, 1271 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pc -- Phe Peripheral neuropathy, diabetic, 924, 1279, 1279 hereditary, 1277-1279, 1277t, 1278t motor and sensory, 1277-1278 sensory and autonomic, 1277, 1277t in acquired immunodeficiency syndrome, 1321 in vitamin deficiencies, 1279 infectious, 1276-1277 inflammatory, 1275-1276 metabolic, 1279 nutritional, 1279 optic, 1374 paraneoplastic, 320, 321t, 1279-1280, 1352, 1352t toxic, 1280 traumatic, 1280 uremic, 1279 viral, 1276-1277 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pc -- Phe Peritoneum, 841-842 inflammation of, 841 mesothelioma of, 752 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pc -- Phe Peritonitis, 841 adhesions with, 825,, 826 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pc -- Phe Petechiae, 117,, 118 in idiopathic thrombocytopenic purpura, 636 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pc -- Phe Phagocytosis, 25, 26,, 62-64, 63 frustrated, 64 in apoptosis, 19, 20, 22,, 23 in Chediak-Higashi syndrome, 64-65 nonopsonic, 62 oxygen-dependent mechanisms of, 62-64, 63 oxygen-independent mechanisms of, 64 surface, 64 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pc -- Phe Phagolysosomes, 26 in cell injury, 25-26 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pc -- Phe Pharyngitis, 763 streptococcal, 368, 570, 572, 573 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pc -- Phe Pharynx, carcinoma of, 764, 764 inflammation of, 763 tumors of, 763-764, 764 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pc -- Phe Phenylketonuria, 475-476, 476 gene mutation in, 147, 147t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Phi -- Pla Pigmentation, disorders of, 1173-1179, 1173,, 1175,, 1176t, 1177-1179 in adrenocortical insufficiency, 1162 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Phi -- Pla Pituitary gland, 1122-1129 anterior, adenoma of, 1123-1127, 1124,, 1124t ACTH-secreting, 1126-1127, 1153-1154, 1153 FSH-secreting, 1127 gonadotroph-secreting, 1127 growth hormone-secreting, 1126 LH-secreting, 1127 null cell, 1127 prolactin-secreting, 1125-1126, 1125 TSH-secreting, 1127 carcinoma of, 1127 normal, 1122-1123, 1123 Crooke hyaline change of, 1154 empty sella syndrome of, 1128 hyperfunction of, 1123-1127, 1124,, 1124t hypofunction of, 1127-1129, 1128 posterior, 1129 Sheehan postpartum necrosis of, 642 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Phi -- Pla Placenta, abnormalities of, 1080-1081, 1082,, 1083 anatomy of, 1081 in intrauterine growth retardation, 461, 462 in preeclampsia, 1082, 1083, 1084 infection transmission by, 338, 470, 470 inflammation of, 1082, 1083 mosaicism of, in intrauterine growth retardation, 461, 462 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Phi -- Pla Plaques, 1172 atheromatous, 499-503, 500,, 501. See also Atheromatous plaque. in Alzheimer disease, 1330, 1331 in multiple sclerosis, 1326-1327, 1327,, 1328 kuru, 1324, 1325 pleural, 733, 733 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Phi -- Pla Plasma cell, development of, 603 in inflammation, 82 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Phi -- Pla Plasma cell dyscrasias, 651, 663-666, 665 renal manifestations of, 968 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Phi -- Pla Plasmacytoma, 655t, 666 of nose, 763-764 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Phi -- Pla Plasmin, in coagulation, 123, 124 in inflammation, 68,, 69 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Phi -- Pla Plasminogen activator(s), 124, 124 tissue-type (t-PA), 124, 124 urokinase-like (u-PA), 124, 124 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Phi -- Pla Plasminogen activator inhibitors, 124, 124 endothelial cell production of, 120 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Phi -- Pla Plasmodium falciparum, 337t, 389-391, 390,, 391 life cycle of, 389-390, 390 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Phi -- Pla Platelet(s), abnormalities of, bleeding with, 634-637, 635t activation of, in hemostasis, 118,, 119 adhesion of, 120-121, 120 disorders of, 637 aggregation of, 121-122, 121 disorders of, 637 in hemolytic-uremic syndrome, 985 alpha granules of, 120, 121 aspirin effects on, 637 contraction of, 121 delta granules (dense bodies) of, 120, 121 development of, 603 extracellular matrix adhesion of, 120-121, 120 giant, in essential thrombocytosis, 683, 683 immune-mediated destruction of, 635-636 in glomerulonephritis, 947, 947 in hemostasis, 118,, 119, 120-122, 120,, 121 inhibition of, 120 secretions of, 121, 637 serotonin release from, 67, 77t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Phi -- Pla Platelet-activating factor (PAF), in asthma, 713 in inflammation, 72, 72,, 77t in type I hypersensitivity reaction, 198 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Phi -- Pla Platelet-derived growth factor (PDGF), 97 in angiogenesis, 105-106, 105 in myelofibrosis with myeloid metaplasia, 684 in tumorigenesis, 279-280, 279t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ple -- Prn Pleura, 749-752 effusion of, 749-751, 750t in right-sided heart failure, 550 in systemic lupus erythematosus, 224 fibroma of, 751 gas in, 751 inflammation of, 224, 749-751, 750t mesothelioma of, 751-752, 752,, 753 metastatic carcinoma of, 751 plaques of, in asbestosis, 733, 733 tumors of, 751-752, 752,, 753 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ple -- Prn Pleuritis, 749-751, 750t in systemic lupus erythematosus, 224 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ple -- Prn Pneumoconiosis, 727-734 coal workers,' 729-730, 729t, 730 pathogenesis of, 727-729, 728,, 729t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ple -- Prn Pneumocystis carinii pneumonia, 381-382, 382 in acquired immunodeficiency syndrome, 247 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ple -- Prn Pneumonia, atypical, primary, 721-722 bacterial, 348-352, 717-721 anatomic distribution of, 717, 717,, 718 clinical course of, 721 complications of, 721 etiology of, 719-720 host defense mechanisms in, 718-719 in lung transplant patient, 741 lobar, 717-718, 718 morphology of, 720-721, 720 patchy consolidation in, 717, 718 pathogenesis of, 718-719, 719 stages of, 720, 720 Chlamydia psittaci, 362 eosinophilic, 738 etiologic agents in, 719-720 Haemophilus influenzae, 349 herpes, 361 in immunocompromised host, 247, 726 Legionella, 377-378 lipid, 721 mycoplasmal, 721-722 patchy consolidation in, 716, 717 pneumococcal, 345 Pneumocystis, 247, 381-382, 382 tuberculous, 726 viral, 348, 721-722 with burns, 434 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ple -- Prn Pneumonitis, cytomegalovirus, 376 hypersensitivity, 737, 737 interstitial, 721-722 desquamative, 736-737, 737 lupus, 739 radiation, 740 uremic, 964 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ple -- Prn Poliovirus, 333t, 373 CNS infection with, 1319 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ple -- Prn Polycystic kidney disease, autosomal dominant, 937-940, 938,, 939,, 941t autosomal recessive, 940, 941t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ple -- Prn Polymerase chain reaction (PCR), in genetic disorders, 182-184, 183,, 185 in tumor diagnosis, 324 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ple -- Prn Polyneuropathy. See also Neuropathy. amyloid, familial, 1277, 1278t infectious, 1276-1277 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ple -- Prn Polyp(s), colonic, 261, 262 endocervical, 1048, 1048 endometrial, 1058-1059, 1059 esophageal, 783 fibroepithelial, 1181 of ureter, 999 fibroid, inflammatory, 802 gastric, 798 intestinal, 827-831, 827-831 adenomatous, 827, 827,, 829-831, 829-831 hyperplastic, 827,, 828, 828 juvenile, 828, 828 non-neoplastic, 827,, 828, 828 Peutz-Jeghers, 828, 828 nasal, 762, 762 vocal cord, 765 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ple -- Prn Pregnancy, ectopic, 1079-1080, 1080 fatty liver of, 884-885 hepatic disease with, 884-885, 885 intrahepatic cholestasis of, 885 luteoma in, 1078 melasma in, 1174 oral manifestations of, 758, 758,, 759t pituitary necrosis after, 642 placental abnormalities in, 1080-1081, 1082,, 1083 preeclampsia in, 884, 885,, 1082-1084 pyogenic granuloma in, 533 renal failure after, 986 spontaneous termination of, 1079 toxemia of, 642, 1082-1084, 1084,, 1085 twin, 1081, 1082 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ple -- Prn Premature infant, intraparenchymal hemorrhage in, 1302 periventricular leukomalacia in, 1300,, 1302 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Prolymphocytes, 659 in chronic lymphocytic leukemia, 658, 658 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Promoters, in carcinogenesis, 309 in chemical carcinogenesis, 306, 307,, 308 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Propylthiouracil, in Graves disease, 1138 thyroid inhibition by, 1131 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Prostaglandin D2, 70, 71 in asthma, 713 in type I hypersensitivity reaction, 198 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Prostate, 1025-1033, 1025 carcinoma of, 1029-1033, 1030,, 1031 clinical course of, 1031-1033, 1032 etiology of, 1029-1030 geographic factors in, 273, 273 grading of, 1031, 1032 incidence of, 272,, 1029 metastases from, 1030, 1031,, 1032 morphology of, 1030-1031, 1030,, 1031 perineural invasion in, 1031, 1031 prostate-specific antigen in, 1032-1033 treatment of, 1033 inflammation of, 1025-1027, 1026 intraepithelial neoplasia of, 1031 nodular hyperplasia of, 1027-1029, 1027-1029 bladder obstruction and, 1008, 1008 clinical course of, 1028-1029 etiology of, 1027 incidence of, 1027 morphology of, 1027-1028, 1028,, 1029 pathogenesis of, 1027, 1027 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Proteases, acid, 76 in angiogenesis, 106 in cell injury, 6, 6 in inflammation, 67-70, 67,, 68,, 77t neutral, 76 tumor elaboration of, 303-304 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Protein(s), cellular accumulation of, 40-41, 41 cross-linking of, in apoptosis, 20 degradation of, 36, 41 denaturation of, in necrosis, 16, 16 folding of, defects in, 41, 41 hydrolysis of, in apoptosis, 20 matricellular, 101 nonenzymatic glycosylation of, in diabetes mellitus, 919-920, 919,, 920t of bone, 1217-1218, 1218t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Protein C, activation of, 120 in coagulation, 122-123, 124 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Protein-energy malnutrition, 437-439, 438,, 438t atrophy with, 35 in chronic pancreatitis, 908 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Proteinuria, 935 in multiple myeloma, 981 in nephrotic syndrome, 952-953 in sickle cell disease, 987 renal tubular injury and, 948-949, 949 renal tubule protein reabsorption droplets in, 40-41, 41 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Proteus, 334t in pyelonephritis, 977 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Protooncogenes, 92, 277-278 amplification of, 286, 286 antigenicity of, 317 for growth factors, 279-280, 279t for nuclear transcription proteins, 279t, 282 for signal-transducing proteins, 279t, 280-282 insertional mutagenesis of, 278 oncogene transformation of, 284-286, 285,, 286,, 286t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Protozoa, 335-336, 337,, 337t CNS infection with, 1322-1323, 1323 gastrointestinal tract infection with, 358-359, 358,, 359,, 810-811, 811 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Psammoma bodies, 43 in papillary thyroid carcinoma, 1143-1144 in renal cell carcinoma, 994 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Pseudomonas aeruginosa, 334t, 376-377, 377 in cystic fibrosis, 479, 480 virulence factors of, 377 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Pulmonary. See also Lungs. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Pulmonary embolism, 130, 130,, 703-704, 703 fibrous web from, 130 prevention of, 704 pulmonary abscess and, 722 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Pulmonary valve, 545 atresia of, 597 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Purpura, 118 Henoch-Schonlein, 517t, 961 hemorrhage in, 634 renal manifestations in, 965-966 nonthrombocytopenic, 634 thrombocytopenic, idiopathic, 635-636 thrombocytopenic, 636-637 thrombotic, 986 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Pro -- Pyo Pyelonephritis, 972-975, 972-975 acute, 974-975, 974,, 975 chronic, 975-977, 976 in diabetes mellitus, 924 obstructive, 975 papillary necrosis in, 974, 975 vesicoureteral reflex in, 973-974, 973 xanthogranulomatous, 977 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ra -- Res Radiation, biologic effects of, 425-426 carcinogenicity of, 309-311 CNS effects of, 1342-1343 fetal effects of, 467 injury from, 424t, 425-430 acute, 426, 426t, 427, 427,, 427t cardiac, 429, 429 cellular mechanisms of, 426-427, 426t central nervous system, 430 cutaneous, 429, 429 delayed, 426t, 428-430, 428,, 429 developmental abnormalities and, 428 esophageal, 782 fibrosis in, 426 gastrointestinal tract, 429 gonadal, 430 growth abnormalities and, 428 intestinal, 811 mammary, 429, 429 mutations and, 428 ocular, 430 pulmonary, 429, 740 renal, 429 tumor development and, 426-427 urinary tract, 429 vascular, 428, 428 sources of, 424-425, 424t thyroid carcinoma and, 1142 ultraviolet, in carcinogenesis, 310 in systemic lupus erythematosus, 219, 222 injury from, 430-431, 430t, 431 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ra -- Res Radon, in air, 418, 418t in cancer, 274t, 742 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ra -- Res ras genes, 280-282, 281,, 284 in chemical carcinogenesis, 308 in thyroid carcinoma, 1143 ultraviolet ray-induced mutation of, 310 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ra -- Res Rash, in measles virus infection, 370 in streptococcal infection, 368 in varicella-zoster virus infection, 374 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ra -- Res Rb gene, 147t, 286-287, 288,, 1372 in cancer, 287t, 289-290, 289 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ra -- Res Reactive oxygen species. See Free radicals. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ra -- Res Receptor(s), 92-93, 93,, 94 acetylcholine, immune-mediated loss of, 1289 angiopoietin, 105 autophosphorylation of, 92, 94 cytokine, 92, 93 dimerization of, 92, 94 G protein-linked (seven-spanning), 92-93, 95 LDL, gene for, 144, 147t, 152-153, 153 serpentine, 74 Tie2, 105 tumor necrosis factor, in apoptosis, 23-24, 24 tyrosine kinase, 92, 94 vascular endothelial growth factor, 105 vitamin D, 147t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ra -- Res Rectum, blood supply of, 802 carcinoma of. See Intestine, carcinoma of. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ra -- Res Red blood cells. See Erythrocyte(s). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ra -- Res Renal. See also Kidney. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ra -- Res Renal artery(ies), embolism from, 986, 987 fibromuscular dysplasia of, 984, 984 stenosis of, 984-985, 984,, 986 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ra -- Res Renal cell carcinoma, 991-993, 992-994 chromophobe, 992, 993 metastatic, 993 nonpapillary, 992, 992,, 994 papillary, 992, 992 pulmonary metastases from, 749, 749 venous spread of, 270 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ra -- Res Renal pelvis, 931 stone in, 990, 990 urothelial carcinoma of, 994, 994 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ra -- Res Renal tubules, 934 acute necrosis of, 969-971. See also Acute tubular necrosis (ATN). protein reabsorption droplets in, 40-41, 41 thyroidization of, 976, 976 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ra -- Res Renal vein, renal cell carcinoma of, 270 thrombosis of, in nephrotic syndrome, 953 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ra -- Res Respiratory tract. See also Lungs. burns of, 434 infection of, 347-353 bacterial, 348-352, 350-352 Coccidioides immitis in, 353, 353 fungal, 352-353, 353 Haemophilus influenzae in, 348-349 Histoplasma capsulatum in, 352, 353 influenza viruses in, 348 Mycobacterium avium in, 352, 352 Mycobacterium tuberculosisin, 349-352, 350,, 351 rhinoviruses in, 347-348, 347 viral, 347-348, 347 squamous metaplasia in, 37, 37 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ret -- Ru Retina, 1368-1373. See also Retinopathy. congenital anomalies of, 1360 fibroplasia of, 1370 in Tay-Sachs disease, 156 layers of, 1368, 1368 neovascularization of, 1370 rubella-related abnormalities of, 1361 sarcoidosis of, 1364 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ret -- Ru Retinoblastoma, 485t, 1372-1373, 1373 genetic factors in, 147t, 275 pathogenesis of, 286-287, 288,, 290 two-hit hypothesis of, 286-287, 288 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ret -- Ru Retinoic acid, 440, 440 in cancer prevention, 455 teratogenicity of, 469-470, 469 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ret -- Ru Retinoids, 439-440, 440. See also Vitamin A. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ret -- Ru Retinopathy, arteriosclerotic, 1370 hypertensive, 1370 in diabetes mellitus, 1369-1370, 1369 of prematurity, 472, 1368-1369 pigmentary, 1370-1371 proliferative, 1370 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ret -- Ru Rhabdomyosarcoma, 265,, 485t, 1265-1266, 1265 alveolar, 1265-1266, 1265 embryonal, 1265, 1265 of bladder, 1008 of vagina, 1046-1047, 1046 of bladder, 1008 pleomorphic, 1266 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ret -- Ru Rheumatoid arthritis, 1248-1251 clinical course of, 1251 diagnosis of, 1251 genetic factors in, 1249 heart in, 589 immune system in, 216, 1249-1250, 1250 joint manifestations in, 1248-1249, 1248 juvenile, 1251-1252 microbial agents in, 1249 pulmonary involvement in, 739 radiographic manifestations of, 1251, 1251 skin manifestations in, 1249, 1249 vascular manifestations in, 524, 1249 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ret -- Ru Rubeola. See Measles virus. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ret -- Ru Russell bodies, 41 in lymphoplasmacytic lymphoma, 666 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
S -- Sep Salivary glands, 769-773 acinic cell tumor of, 773 adenoid cystic carcinoma of, 772-773, 773 inflammation of, 769 lymphocytic infiltration of, in Sjogren syndrome, 225, 226 mixed tumor of, 262, 262 mucoepidermoid carcinoma of, 772, 772 pleomorphic adenoma of, 770-771, 770 sarcoidosis of, 735 tumors of, 769-773, 769t, 770-773 Warthin tumors of, 771-772, 771 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
S -- Sep Sarcoma, 261-262 cardiac, 591 clear cell, 1260t Ewing, 1244, 1244 Kaposi, 535-537, 536 of bladder, 1008 of breast, 1104 of endometrium, 1065 osteogenic, 1236-1237, 1236,, 1237 synovial, 1260t, 1266-1267, 1267 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
S -- Sep Sarcoma botryoides, of bladder, 1008 of vagina, 1046-1047, 1046 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
S -- Sep Scar, 104. See also Fibrosis. formation of, 106-107, 107,, 108-109, 108,, 111 in infection, 347, 347 hypertrophic, 110, 110 renal, in pyelonephritis, 976, 976 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
S -- Sep Schistosoma spp., infection of, 396-397, 397 life cycle of, 396, 396 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
S -- Sep Schistosoma haematobium, 346, 347,, 397 transitional cell carcinoma and, 1007 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
S -- Sep Schwann cells, 1270, 1271, 1271 in neurofibromatosis, 164 Mycobacterium leprae infection of, 1276 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
S -- Sep Schwannoma, 1352-1353, 1353 malignant, 1353-1354 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
S -- Sep SCID (severe combined immunodeficiency disease), 235-236 gene mutation in, 147t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
S -- Sep Scleroderma. See Systemic sclerosis (scleroderma). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
S -- Sep Sclerosis, calcific (Monckeberg arteriosclerosis), 498 systemic, 226-229. See also Systemic sclerosis (scleroderma). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
S -- Sep Scurvy, 449-450 hemorrhage in, 634 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
S -- Sep Self-antigens, epitope crypticity of, 215 immune reactions against. See Autoimmune diseases. molecular mimicry of, 215 tolerance to, 212-214, 213 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
S -- Sep Semilunar valves, 545. See also Aortic valve; Pulmonary valve. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
S -- Sep Seminoma, 263, 264, 1019-1020, 1019 spermatocytic, 1020 vs. nonseminomatous germ cell tumor, 1023 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
S -- Sep Sensory neuropathy, 1277, 1277t paraneoplastic, 1352, 1352t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
S -- Sep Sepsis, in infant, 471 Listeria, 378 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
S -- Sep Septum (septa), alveolar, 698, 698 ventricular, sigmoid, 546 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Seq -- Sm Serotonin (5-hydroxytryptamine), in carcinoid syndrome, 837, 837t in inflammation, 67, 77t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Seq -- Sm Severe combined immunodeficiency disease (SCID), 235-236 autosomal recessive, 235 gene mutation in, 147t X-linked, 235 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Seq -- Sm Sex, genetic, 176. See also X chromosome; Y chromosome. gonadal, 176 phenotypic (genital), 176 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Seq -- Sm Sexually transmitted diseases, 359-365, 360t, 1038-1040, 1038t, 1039 Chlamydia trachomatisin, 361-362, 361t herpesvirus in, 359-361, 360 Neisseria gonorrhoeaein, 362 Treponema pallidum in, 362-364, 363 Trichomonas vaginalisin, 364-365, 365 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Seq -- Sm Shock, 134-137, 134t anaphylactic, 134 cardiogenic, 134, 134t, 562 clinical course of, 137 endotoxic, 134-136, 134 hypovolemic, 118, 134, 134t in acute pancreatitis, 907 irreversible phase of, 136 morphology of, 136-137 multiorgan system failure in, 136 neurogenic, 134 nonprogressive phase of, 136 progressive phase of, 136 septic, 134-136, 134,, 134t, 135 stages of, 136 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Seq -- Sm Shunt, cardiac, 591-596 left-to-right, 593-595, 593,, 594 right-to-left, 595-596, 595 portosystemic, in cirrhosis, 855-856, 855 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Seq -- Sm Sicca syndrome. See Sjogren syndrome. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Seq -- Sm Sickle cell disease, 611-615, 612-614 blood flow alterations in, 125 gene mutation in, 143-144, 147t hepatic sinusoid occlusion in, 882 nephropathy in, 979t, 986-987 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Seq -- Sm Signal transduction systems, 93-95, 93-95 cyclic adenosine monophosphate pathway, 93,, 94 in tumorigenesis, 279t, 280-282 inositol-lipid pathway, 94, 95 JAK/STAT pathway, 93,, 94-95 mitogen-activated protein kinase pathway, 93, 94 phosphoinositide-3-kinase pathway, 93,, 94 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Seq -- Sm Silicosis, 729t, 730-732, 731,, 732 pathogenesis of, 728-729 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Seq -- Sm Sjogren syndrome, 225-226, 226,, 758 antinuclear antibodies in, 218t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Seq -- Sm Skeletal muscle, 35, 1272-1273, 1272,, 1273,, 1273t. See also Muscle(s). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Seq -- Sm Skin, 1170-1212 acanthosis nigricans of, 320, 321t, 1180-1181 acne vulgaris of, 1206-1207, 1207 actinic keratosis of, 1184, 1185 adnexal (appendage) tumors of, 1182-1183, 1183,, 1183t, 1184 arthropod bites of, 1210-1211, 1212 atopic dermatitis of, 1195t barrier function of, 338 basal cell carcinoma of, 1186-1187, 1187 ultraviolet radiation in, 310 benign epithelial tumors of, 1179-1183, 1180,, 1182-1184,, 1183t benign fibrous histiocytoma of, 1187-1188, 1188 blistering diseases of, 1201-1206, 1201-1206 bullous pemphigoid of, 1203-1204, 1204 burns of, 433-434 Pseudomonas infection in, 377 contact dermatitis of, 206, 206,, 1195t, 1196-1197, 1196 dermatitis herpetiformis of, 1204-1205, 1205 dermatofibroma of, 1187-1188, 1188 dermatofibrosarcoma protuberans of, 1188 drug-related atopic dermatitis of, 1195t eczema of, 1194-1197, 1195,, 1195t, 1196 epidermolysis bullosa of, 1205, 1206 epithelial cyst of, 1181 erythema chronicum migrans of, 389 erythema induratum of, 1207-1208 erythema multiforme of, 1197-1198, 1197 erythema nodosum of, 1207-1208 fibroepithelial polyp of, 1181 fungal infection of, 1210 histiocytosis X of, 1189-1191, 1190 hives of, 1194, 1194 ichthyosis of, 1193, 1193 impetigo of, 1210
in adrenocortical insufficiency, 1162 in ariboflavinosis, 448 in dermatomyositis, 229, 230 in Ehlers-Danlos syndromes, 150 in filariasis, 398, 398 in Graves disease, 1138 in hyperthyroidism, 1132 in McCune-Albright syndrome, 1243 in pellagra, 448, 449 in situ carcinoma of, 1185 in systemic lupus erythematosus, 222, 223 in systemic sclerosis, 228, 228 in zinc deficiency, 451, 452 inflammatory dermatoses of, 1193-1201 acute, 1193-1198, 1194,, 1195,, 1195t, 1196 chronic, 1198-1201, 1198,, 1199 irritant dermatitis of, 1195t Kaposi varicelliform eruption of, 361 lice infestation of, 1211-1212, 1211 lichen planus of, 1199-1200, 1199 lupus erythematosus of, 1200-1201, 1200,, 1201 mastocytosis of, 1192-1193, 1192 melanoma of, 310, 1177-1179, 1178,, 1179 Merkel cell carcinoma of, 1187 mite infestation of, 1211,, 1212 molluscum contagiosum of, 1209-1210, 1209 mycosis fungoides of, 1191, 1191 papillomavirus infection of, 1208-1209, 1208 peau d'orange change of, 1114 pemphigus of, 1201-1202, 1202,, 1203 pigmentation disorders of, 1173-1179, 1173,, 1175,, 1176t, 1177-1179 porphyria of, 1206, 1206 protective function of, 1170-1173, 1171,, 1172 psoriasis of, 1198-1199, 1198,, 1199 radiation damage to, 429, 429 sarcoidosis of, 735 seborrheic keratoses of, 1179-1180, 1180 squamous cell carcinoma of, 266, 266,, 310, 1184-1186, 1186
streptococcal erysipelas of, 368, 368 T-cell lymphoma of, 670, 1191, 1191 urticaria of, 1194, 1194 vascular tumors of, 532-533, 532,, 534-535, 534,, 537-538, 537,, 1189 verrucae of, 1208-1209, 1208 warts of, 1208-1209, 1208 xanthoma of, 1189 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Seq -- Sm Skull, fracture of, 1302-1303 at birth, 464 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Seq -- Sm SLE. See Systemic lupus erythematosus (SLE). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Seq -- Sm Small round blue cell tumor, 485, 485t. See also specific tumors. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Seq -- Sm Smooth muscle, in atherosclerosis, 509 tumors of, 589-591, 589,, 591t vascular, 497, 497 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
So -- Sta Sodium, in cell injury, 7 renal retention of, in hypertension, 513 retention of, edema and, 115-116 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
So -- Sta Soft tissue tumors, 1259-1267, 1259t, 1260t. See also specific tumors. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
So -- Sta Sphincter, esophageal, 776 pyloric, 787, 787 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
So -- Sta Spinal cord, hydromyelia of, 1301-1302 in pernicious anemia, 625 malformation of, 1300 syringomyelia of, 1301-1302 trauma to, 1306 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
So -- Sta Spleen, 686-690 absence of, 690 accessory, 690 amyloidosis of, 255 enlargement of, 688, 688t in cirrhosis, 855,, 856 in right-sided heart failure, 550 filtration function of, 687 hematopoiesis in, 688 immune function of, 687 in chronic myelogenous leukemia, 681, 681 in diffuse large B-cell lymphoma, 662, 662 in Epstein-Barr virus infection, 372-373 in follicular lymphoma, 660, 660 in Gaucher disease, 158 in hairy cell leukemia, 668 in idiopathic thrombocytopenic purpura, 635 in myelofibrosis with myeloid metaplasia, 684, 689 in polycythemia vera, 682, 682 in systemic lupus erythematosus, 224 infarction of, 133,, 689, 689 miliary tuberculosis of, 725-726, 726 normal, 686-688, 687 platelet sequestration in (hypersplenism), 635 red pulp of, 687, 687 rupture of, 690 sarcoidosis of, 735 storage function of, 688 tumors of, 690 white pulp of, 687, 687 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
So -- Sta Splenomegaly, 688-689, 688t congestive, 689 in cirrhosis, 855,, 856 in right-sided heart failure, 550 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
So -- Sta Spongiosis, 1173 in eczematous dermatitis, 1196,, 1197 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
So -- Sta Sprue, celiac, 813, 813,, 961 tropical, 814 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
So -- Sta Squamous cell carcinoma, 262 of bladder, 1006-1007 of cervix, 1051-1053, 1053 of esophagus, 783-786, 785,, 785t of penis, 1014, 1014 of skin, 266, 266,, 310, 1184-1186, 1186 of thymus, 692-693, 692 of vagina, 1045-1046 of vulva, 1043-1044, 1044 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ste -- Sy Steatosis, 38, 38,, 39, 39,, 847 in alcoholic liver disease, 869, 870,, 872 in pregnancy, 884-885 in Wilson disease, 875 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ste -- Sy Stem cells, 91, 602, 603 of liver, 33 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ste -- Sy Stenosis, aortic, 567-568, 567 esophageal, 777-778 intestinal, 804 mitral, 125, 129 in rheumatic heart disease, 572 pyloric, 789 renal, 984-985, 984 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ste -- Sy Stomach, 787-802 acid secretion of, 788 adenoma of, 798, 798 anatomy of, 787-788, 787 benign tumors of, 798, 798 carcinoma of, 798-802, 799t, 800,, 801 geographic factors in, 273, 273 in lymphoma, 315 incidence of, 272 mortality rates with, 272 chief cells of, 788 concretions of, 797, 797 congenital anomalies of, 788-789 dilation of, 797 endocrine cells of, 788 foveolar cells of, 787 glands of, 787-788 atrophy of, 792 hyperplasia of, 797-798 heterotopic, 789 hypertrophy of, 797-798, 797 inflammation of, 789-793. See also Gastritis. inflammatory fibroid polyp of, 802 leiomyoma of, 802 leiomyosarcoma of, 802 lipoma of, 802 lymphoma of, 802 mucosa of, 787 dysplasia of, 792, 799 erosion of, 789-790, 790 hyperplasia of, 792 metaplasia of, 792, 792 mucosal barrier of, 788
mucous neck cells of, 787 neuroendocrine cell tumors of, 802 normal, 787-788, 787 pancreatic heterotopia of, 789 parietal cells of, 787-788 peptic ulcer disease of, 793-796, 794,, 795,, 796t rugae of, 787, 797-798, 797 rupture of, 797 stress ulcers of, 796-797, 796 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ste -- Sy Streptococcus, 367-368, 368 fibrillae of, 341-342, 342 glomerulonephritis and, 949-951, 950,, 965t in rheumatic fever, 570, 572, 573 virulence factors of, 367 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ste -- Sy Stroke, 1306-1314. See also Cerebrovascular disease. obesity and, 454 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ste -- Sy Superoxide anion, 12, 13. See also Free radicals. in inflammation, 76-77 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ste -- Sy Superoxide dismutases, in free radical inactivation, 13 life span and, 47 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ste -- Sy Synarthroses, 1246. See also Joint(s). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ste -- Sy Synovium, in rheumatoid arthritis, 1248-1249, 1248 in systemic sclerosis, 228 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ste -- Sy Syphilis, 83t, 362-364, 363 aortic aneurysms in, 526 congenital, 338-339, 364, 1361 false-positive serology for, 126 infantile, 364 perinatal, 364 secondary, 346,, 363-364 skeletal, 1233 testicular involvement in, 1017 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ste -- Sy Systemic lupus erythematosus (SLE), 126, 216-225 antinuclear antibodies in, 217, 218t antiphospholipid antibody syndrome in, 218 cardiovascular system involvement in, 223-224, 223 clinical manifestations of, 220t, 224 CNS involvement in, 222-223 cutaneous abnormalities in, 222, 222 diagnosis of, 216, 217t drugs in, 219 endocarditis in, 127, 223, 223 genetic factors in, 218-219 glomerulonephritis in, 220-221, 220,, 221,, 962, 962,, 965 immunologic factors in, 219-220, 219,, 221, 222 joint involvement in, 222 lymph nodes in, 224 pathogenesis of, 216-220, 218t, 219 pericarditis in, 223 pleural effusion in, 224 pleuritis in, 224 renal abnormalities in, 220-222, 220-222 sex hormones in, 219 splenic enlargement in, 224 tubulointerstitial lesions in, 222 ultraviolet light in, 219, 222 vasculitis in, 224, 524, 524 wire loop lesion in, 221, 222 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ste -- Sy Systemic sclerosis (scleroderma), 226-229 alimentary tract involvement in, 228 antinuclear antibodies in, 218t clinical course of, 229 cutaneous abnormalities in, 228, 228 musculoskeletal abnormalities in, 228 pathogenesis of, 226-227, 227 pericarditis in, 229 pulmonary involvement in, 229 renal abnormalities in, 228-229 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th T lymphocytes. See Lymphocyte(s), T. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Tay-Sachs disease, 155-156, 155t, 156,, 157 gene mutation in, 142, 142,, 147t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Telangiectases, 534 capillary, 1313 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Telomeres, cancer and, 296 incomplete replication of, 46-47, 46 shortening of, 47, 47 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Teratoma, 262-263, 484, 484 benign, 1073-1074, 1074 malignant, 1074-1075, 1075 monodermal, 1074 ovarian, 1073-1075, 1073,, 1074 testicular, 1021-1022, 1022 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Testis (testes), 1014-1025 atrophy of, 1015, 1015,, 1016 in hemochromatosis, 874 choriocarcinoma of, 1021, 1021,, 1023 congenital anomalies of, 1015-1016, 1015 embryonal carcinoma of, 264, 1020-1021, 1020 germ cell tumors of, 1018-1024, 1018t, 1023 gonococcal infection of, 1017 granulomatous (autoimmune) inflammation of, 1017 hemorrhage infarction of, 1017, 1017 in fragile X syndrome, 177 inflammation of, 1016-1017 Leydig cell tumors of, 1024 lymphoma of, 1024-1025 mixed tumors of, 1022-1024, 1023 mumps infection of, 371, 1017 nonseminomatous germ cell tumors of, 1022-1024, 1023 painless enlargement of, 1022 seminoma of, 1019-1020, 1019 Sertoli cell tumors of, 1024 sex cord-stromal tumors of, 1018t, 1024 spermatocytic seminoma of, 1020 syphilitic infection of, 1017 teratoma of, 1021-1022, 1022 torsion of, 1017, 1017 tuberculosis of, 1017 undescended, 1015-1016, 1015 yolk sac tumor of, 1021 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Thiamine, 440t, 447 deficiency of, 447, 448,, 1279, 1341 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Thrombasthenia, 637 Glanzmann, 122 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Thrombin, 118,, 119 in hemostasis, 121-122, 122 in inflammation, 68,, 69 prothrombin conversion to, 122, 123 receptors for, 122 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Thrombocytopenia, 200, 634-637, 635t dilutional, 635 drug-induced, 636 heparin-induced, 125-126 HIV-associated, 636 immunodeficiency with, 236 petechiae with, 118 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Thromboembolism, 127, 128,, 129-132. See also Embolism. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Thrombophlebitis, 530 migratory, 129, 530 in cancer, 320-321, 321t in pancreatic carcinoma, 911 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Thrombosis, 118,, 119, 124-129 arterial, 127, 127,, 128,, 129 blood flow abnormalities and, 124,, 125 clinical correlation of, 129 dissolution of, 127, 128 embolization of, 127, 128,, 129-132. See also Embolism. endothelial injury and, 124-125, 124 hepatic, 883-884, 883 hypercoagulability and, 124,, 125-126, 125t in myocardial infarction, 552, 553, 553t in polycythemia vera, 683 morphology of, 126-127, 127 mural, 126-127, 127 organization of, 127, 128,, 129 pathogenesis of, 124-127, 124,, 125t portal vein, 882 propagation of, 127, 128 recanalization of, 127, 129 renal, in nephrotic syndrome, 953 venous, 127, 129 outcome of, 127-129, 128. See also Embolism. with atheromatous plaque, 502-503 with atherosclerosis, 506 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Thrombospondin, 101 in apoptosis, 20 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Thrombotic thrombocytopenic purpura, 986 idiopathic, 986 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Thrombus, 124-129. See also Thrombosis. dissolution of, 127 formation of, 124-127, 124,, 125t mural, 126-127, 127 after myocardial infarction, 563 recanalization of, 128,, 129 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Thymus, 690-693 aplasia of, 691 cysts of, 691 hyperplasia of, 691 hypoplasia of (DiGeorge syndrome), 173, 235, 691 in severe combined immunodeficiency disease, 235-236 normal, 690-691 radiation-induced injury to, 427, 427 tumors of, 691-693, 692 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Thyroid gland, 1130-1131, 1130 adenoma of, 265,, 1140-1142, 1141 atypical adenoma of, 1142 carcinoma of, 1142-1147 anaplastic, 1147 follicular, 1144-1145, 1144 ionizing radiation and, 310 medullary, 1143, 1145-1147, 1146 familial, 1167 papillary, 1143-1144, 1143 pathogenesis of, 1142-1143 congenital anomalies of, 1147 cysts of, 1142, 1147 diseases of. See Hyperthyroidism; Hypothyroidism. enlargement of, 1138-1140, 1140 Hurthle cell adenoma of, 1142 hyperfunction of, 1131-1132, 1131t, 1132. See also Hyperthyroidism. hypofunction of, 1132-1134, 1133t. See also Hypothyroidism. inflammation of, 1134-1136, 1135,, 1136 inhibition of, 1130-1131 nodules of, 1140 papillary adenoma of, 1142 radioactive iodine uptake by, in hyperthyroidism, 1132 thyroglossal duct of, 1147 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Thyroiditis, 1133-1136 granulomatous (subacute), 1135-1136, 1135 Hashimoto, 1133, 1133t, 1134-1135, 1135 infectious, 1134 lymphocytic, subacute, 1136 Reidel, 1136 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Thyroid-stimulating hormone, in hyperthyroidism, 1132 in hypothyroidism, 1133 tumor secretion of, 1127 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Thyroid-stimulating hormone receptor, antibodies to, in Graves disease, 1134, 1136-1137 in Hashimoto thyroiditis, 1134 in thyroid adenoma, 1140 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
T -- Th Thyrotoxicosis, 1131-1132, 1131t, 1132. See also Hyperthyroidism. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ti -- Tre Tissue inhibitors of metalloproteinases, in experimental cancer treatment, 304 in tissue remodeling, 107, 107 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ti -- Tre Tissue repair, 89-111, 111. See also Cell growth; Wound, healing of. angiogenesis in, 103-106, 104,, 105,, 105t fibrosis in, 106, 106t remodeling in, 106-107, 107 wound healing in, 107-111, 108,, 109 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ti -- Tre Tobacco use, 408-410, 409t. See also Cigarette smoking. oral cancer and, 760 periductal mastitis and, 1097 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ti -- Tre Tolerance, immune, 212-214, 213 central, 212, 213 peripheral, 212, 213,, 214-215 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ti -- Tre Tongue, amyloidosis of, 256 carcinoma of, 760-761, 761 hemangioma of, 532, 532 inflammation of, 758 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ti -- Tre Toxicity, chemical, 404-408, 405-408 dose-response curve for, 405, 405 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ti -- Tre Toxins, hepatic toxicity of, 868-869, 869t natural, 424 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ti -- Tre Toxoplasma gondii, 337t, 382-383 CNS infection with, 1323, 1323 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ti -- Tre Toxoplasmosis, 382-383, 1323, 1323 neonatal, 383 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ti -- Tre Transcription factors, in cancer, 279t, 282 in metaplasia, 37 structure of, 95 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ti -- Tre Transforming growth factor-alpha, 97 in hepatocyte regeneration, 33, 33 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ti -- Tre Transforming growth factor-beta, 98 in angiogenesis, 105-106, 105 in cell cycle, 290, 293 in cell growth, 96-97 in Hodgkin disease, 674 in myelofibrosis with myeloid metaplasia, 684 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ti -- Tre Transfusion reaction, 200. See also Hypersensitivity reaction(s), type II. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ti -- Tre Transitional cell carcinoma, of bladder, 1003-1008, 1003t, 1004-1006,, 1006t of ovary, 1073 of ureter, 999, 999 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ti -- Tre Translocations, chromosome, 169,, 170 in oncogene activation, 284-286, 285,, 286t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ti -- Tre Transplantation, cardiac, 597,, 598, 598 HLA matching for, 210 immunosuppressive therapy for, 210 Kaposi sarcoma after, 535 lung, 740-741, 741 rejection of, 206-211 acute, 209-210, 209 antibody-mediated, 207 chronic, 210 hyperacute, 207-208 T cell-mediated, 207, 208 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ti -- Tre Trauma, 432-433, 432,, 433 altitude-related, 435-436 electrical, 435 fat embolism after, 130-131, 131 hemolytic anemia with, 621, 621 peripheral neuropathy with, 1280 thermal, 433-435 to brain, 1302-1306, 1303,, 1305,, 1306 to spinal cord, 1306 uveitis with, 215 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Ti -- Tre Treponema pallidum, 334t, 362-364, 363. See also Syphilis. CNS infection with, 1317 skeletal infection with, 1233 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Tri -- Tz Triplet repeat mutations, in fragile X syndrome, 177-178, 178 in Friedreich ataxia, 179, 179,, 179t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Tri -- Tz Trisomy 21 (Down syndrome), 170-171, 171,, 172 G-banded karyotype of, 171 ocular anomalies in, 1360 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Tri -- Tz Trousseau sign, 530 in hypoparathyroidism, 1151 in pancreatic carcinoma, 911 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Tri -- Tz Trousseau syndrome, 129 in cancer, 320-321, 321t, 911 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Tri -- Tz Trypanosoma cruzi, 332t, 337t, 393-394 in myocarditis, 584, 585 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Tri -- Tz Tuberculosis, 83-84, 83,, 83t, 349-352, 350,, 351 caseous necrosis in, 351 disseminated, 351 granuloma formation in, 350-351, 351 in acquired immunodeficiency syndrome, 248, 351-352 in adrenocortical insufficiency, 1161 in mice, 351 inflammatory response in, 350, 350 intestinal, 807-809, 808t miliary, 351 of CNS, 1316-1317 pathogenesis of, 349-351, 350,, 351 primary, 350-351, 351 pulmonary, 722-726 clinical course of, 726 fibrocaseous, 725 miliary, 725-726, 726 primary, 723, 723,, 724 progressive, 724,, 725-726, 726 secondary, 723-724, 724 secondary, 351 skeletal, 1233 testicular involvement in, 1017 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Tri -- Tz Tuberous sclerosis, 1354-1355 angiomyolipoma in, 991 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Tri -- Tz Tubulointerstitial nephritis, 971-981, 972t drug-induced, 977-979, 977,, 979,, 979t urinary tract infection and, 972-974, 972,, 973 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Tri -- Tz Tumor(s). See also Carcinogenesis. age and, 273, 274t, 275t alcohol and, 273, 412 anaplastic, 265-266, 265,, 266,, 323, 323 APC gene in, 287t, 292-293 benign, 261, 261,, 262,, 263t encapsulation of, 267, 268 malignant transformation of, 276 cachexia with, 319-320 caretaker genes in, 297, 298 chemoprevention of, 455-456 chromosome translocation in, 284-286, 285,, 286t, 298 cigarette smoking and, 273 clinical features of, 319-325, 321t clonality of, 277, 277 cranial nerve palsy with, 1279 cyclin D in, 283, 290 desmoplasia of, 261 diagnosis of, 322-325 cytology in, 322-323, 323 flow cytometry in, 324 histology in, 322 immunocytochemistry in, 323-324, 323 molecular, 324 quick-frozen section for, 322 specimen for, 322 tumor markers in, 324-325, 325t differentiation of, 264-267, 264-267,, 270t DNA repair disorders and, 276 dysplasia and, 266, 267 E-cadherin gene in, 293 environmental factors in, 273, 274t epidemiology of, 271-276, 272,, 273,, 274t, 275t
extracellular matrix invasion by, 302-305, 303,, 304 familial, 276 fibrous capsule of, 267, 268 gatekeeper genes in, 297, 298 genetic factors in, 275-276, 275t geographic factors in, 273, 273 germ cell, of testes, 1018-1024, 1018t, 1019-1023 giant cells in, 265-266 grading of, 321-322 growth fraction of, 300-301, 301 growth of, 267, 270t, 298-305. See also Tumor growth. hematogenous dissemination of, 270, 270 heredity and, 275-276, 275t heterogeneity of, 302 homing of, 305 hormonal effects of, 266-267, 267,, 319 host defense against, 315-319, 316,, 318. See also Tumor immunity. hyperchromatic nuclei in, 265 incidence of, 271-273, 272,, 273 KAI-1 gene in, 305 KiSS-1 gene in, 305 latent period of, 301 local invasion of, 267-268, 268,, 269,, 270t, 302-305, 303,, 304 lymphatic spread of, 269-270, 269 metastatic, 268-271, 269-271,, 270t, 305 calcification with, 45 minimal residual disease monitoring of, 324 mitotic figures in, 265, 266 mixed, 262 molecular basis of, 276-298. See also Apoptosis; Cancer-suppressor genes; Oncogenes. monoclonality of, 277, 277 mortality rates with, 271-273, 272 myc oncogene in, 282 NF-1 gene in, 293 NF-2 gene in, 293
nm23 gene in, 305 nomenclature for, 261-264, 263t obesity and, 273, 455 occupation and, 244t, 273 of appendix, 840 of bladder, 1003-1008, 1003t, 1004-1006,, 1006t of bone, 1233-1244, 1234t of CNS, 1343-1355, 1344-1347,, 1349,, 1351,, 1352t, 1353 of colorectum, 827-838, 827-832,, 834-836 of ear, 767 of esophagus, 783-787, 785,, 785t, 786 of fallopian tubes, 1065 of intestine, 826-838, 826t of kidney, 990-994 of larynx, 765, 766 of liver, 887-891, 887,, 889,, 890 of lung, 741-747, 743,, 743t, 744 of mediastinum, 749, 749 of mouth, 759-761, 760,, 761 of muscle, 651-652, 1265 of neck, 768-769, 768 of nose, 763-764, 764 of optic nerve, 1374 of ovary, 1067-1079, 1067t, 1068,, 1068t of pancreas, 909-911, 910,, 911 of penis, 1012-1014, 1012,, 1013 of peritoneum, 842 of pineal gland, 1168 of pleura, 751-752, 752,, 753 of prostate, 1029-1033, 1030,, 1031 of salivary glands, 769-773, 769t, 770-773 of small intestine, 826-827, 826t, 827 of spleen, 690 of stomach, 798-802, 798,, 799t, 800,, 801 of testes, 1018-1024, 1018t, 1019,, 1022,, 1023 of thymus gland, 691-693, 692 of thyroid gland, 1142-1147, 1143,, 1145-1147 of ureters, 999, 999
of urethra, 1009, 1009 of urothelium, 994, 994 of uterus, 1061-1065, 1062 of vulva, 1042-1045, 1043,, 1044 organ tropism of, 305 p53 gene loss in, 290-292, 291 p73 gene loss in, 292 paraneoplastic syndromes with, 320-321, 321t parenchymal cells of, 261 pediatric, 482-489 benign, 483-484, 483,, 484 malignant, 484-491, 485t, 486,, 487,, 488t, 489 peripheral neuropathy with, 1279-1280 pleomorphic nuclei in, 265, 265 predisposition to, 275-276, 275t preneoplastic disorders in, 276 proteolytic enzyme secretion by, 303-304 PTEN gene in, 294 radiation and, 309-311 ras oncogene in, 280-282, 281,, 284 Rb gene in, 287t, 289-290, 289 replication error phenotype of, 295 seeding of, 269 soft tissue, 1259-1267, 1259t staging of, 322 stromal cells of, 261 telomeres and, 296 transforming growth factor-beta receptor in, 293 Trousseau syndrome in, 129, 320-321, 321t, 911 two-hit hypothesis of, 286-287 vascular, 532-533, 532,, 534-535, 534,, 537-538, 537,, 1189 VHL gene in, 293-294 viruses and, 311-315, 313,, 314 vitamin E and, 446 well-differentiated, 266, 266 WT-1 gene in, 294
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Tri -- Tz Tumor growth, 267, 270t, 298-305 angiogenesis in, 301-302 extracellular matrix invasion and, 302-305, 303,, 304 kinetics of, 299-301, 300,, 301 metastases in, 305 rate of, 267 tumor heterogeneity and, 302 vascular dissemination and, 305 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Tri -- Tz Tumor immunity, 315-319 effector mechanisms in, 317-319, 318 immunosurveillance in, 318-319 tumor antigens in, 315-317, 316 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Tri -- Tz Tumor necrosis factor (TNF), cancer cachexia and, 320 in apoptosis, 23-24, 24 in delayed-type hypersensitivity, 205,, 206 in disseminated intravascular coagulation, 640 in febrile state, 86 in hepatocyte regeneration, 33, 33 in inflammation, 73-74, 74,, 77t in rheumatoid arthritis, 1250-1251 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Tri -- Tz Tumor-suppressor genes, 286-294 in retinoblastoma, 275 protein products of, 287, 289-294, 289,, 291 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Tri -- Tz Turner syndrome, 173, 174-176, 175 mosaic variant of, 168 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Tri -- Tz Tyrosinase, as tumor antigens, 317 deficiency of, 148 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Tri -- Tz Tyrosine kinase, Bruton, 232 nonreceptor-associated, in cancer, 282 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
U Ubiquitin, in atrophy, 36 in protein degradation, 41 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
U Ulcer(s), 85 aphthous, 757, 757 corneal, 1362-1363 Curling, 796 Cushing, 796 cutaneous, 1173 gingival, with agranulocytosis, 647 in Crohn disease, 816, 817, 817 in Shigella bacillary dysentery, 355, 355 peptic, 793-796, 794,, 795,, 796t. See also Peptic ulcer disease. stress, 796-797, 796 varicose, 129, 529 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
U Ulcerative colitis, 818-820, 819,, 820,, 821t carcinoma and, 820 crypt abscess in, 819, 820 mucosal damage in, 819-820, 819 pathogenesis of, 815-816 vs. Crohn disease, 819,, 821t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
U Ultraviolet radiation, 430-431 cutaneous effects of, 430-431, 430t, 431 in carcinogenesis, 310 in systemic lupus erythematosus, 219, 222 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
U Upper airway, 761-766. See also Larynx; Nose; Pharynx. Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
U Uremia, 637, 935 systemic complications of, 964 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
U Ureter(s), 997-1000 bifid, 998 congenital anomalies of, 998 cysts of, 998-999, 999 diverticula of, 998 double, 998 enlargement of, 998 inflammation of, 998-999, 999 obstruction of, 999-1000, 999t sclerosing retroperitoneal fibrosis of, 999-1000 tumors of, 999, 999 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
U Urethra, carcinoma of, 1009, 1009 caruncle of, 1009 infection of, 973 inflammation of, 1009 papilloma of, 1009 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
U Urinary tract, 997-1009. See also Bladder; Ureter(s); Urethra. infection of, 936 pyelonephritis and, 972-974, 972,, 973 tubulointerstitial nephritis and, 972-974, 972,, 973 normal, 997-998 obstruction of, 988-989, 988,, 989 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
U Uterus, 1054-1065. See also Endometrium; Myometrium. anatomy of, 1037 dysfunctional bleeding from, 1055-1056, 1056t hypertrophy of, 34, 34 leiomyoma of, 264,, 271,, 1063-1064, 1063,, 1266 leiomyosarcoma of, 271,, 1064-1065, 1064 nodules of, 1065 prolapse of, 998 sarcoma of, 1065 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
U Uvea, inflammation of, 1364-1365, 1364,, 1365 melanoma of, 1365-1367, 1366 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
U Uveitis, 1364-1365 granulomatous, 1364-1365, 1364,, 1365 infectious, 1364 post-traumatic, 215 sympathetic, 1364-1365, 1365 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vagina, 1045-1047 adenocarcinoma of, 1046, 1046 adenosis of, 1046 Candida infection of, 378 carcinoma of, 1045-1046 congenital anomalies of, 1045 embryonal rhabdomyosarcoma of, 1046-1047, 1046 infection of, 1038-1039, 1038t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Valves, cardiac, 545 disease of, 566-578, 567t. See also specific diseases. dystrophic calcifications of, 43-44, 44 prosthetic, 578, 578,, 578t thrombi of, 127 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Varicella-zoster virus, 333t, 373-374, 374 CNS infection with, 1319 peripheral nerve effects of, 1276-1277 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Varix (varices), esophageal, 529-530, 783 in cirrhosis, 856 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vascular cell adhesion molecule 1 (VCAM-1), in leukocyte adhesion, 57, 57t in rheumatoid arthritis, 1250 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vascular endothelial growth factor, 97-98 in angiogenesis, 104-106, 105,, 105t in retinopathy of prematurity, 1369 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vasculitis, 515-524, 515t antineutrophil cytoplasmic antibodies in, 516 classification of, 515t, 516, 517t, 518 cryoglobulinemic, 517t drug-induced, 516 immune complex, 203-204, 203,, 204,, 516 in connective tissue disorders, 524, 524 in systemic lupus erythematosus, 224 pathogenesis of, 515t, 516 rejection, 209-210, 209 rheumatoid, 524, 1249 viral infections in, 516 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vasoconstriction, in hemostasis, 118,, 119 in hypertension, 513-514, 514 in myocardial infarction, 553 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vater, ampulla of, 892 adenoma of, 827, 827 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vegetations, cardiac, in Libman-Sacks endocarditis, 575,, 577 in rheumatic heart disease, 571-572, 571,, 575 infective, 572-576, 575 noninfective, 575,, 576-577, 576 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vein(s), 495. See also specific veins. abnormal arterial communication with, 498 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Ventricles, cerebral, cerebrospinal fluid accumulation in, 1298-1299, 1299 colloid cyst of, 1348 ependymal cells of, 1297 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Venules, permeability of, in inflammation, 54, 55 postcapillary, 495 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vesicoureteral reflux, 973-974, 973 congenital, 1000 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vibrio cholerae, 332t, 334t, 357-358, 357,, 807-809, 808t enterotoxin of, 343-344 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vinyl chloride, in carcinogenesis, 274t, 309 in occupational diseases, 419t, 420 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Viruses, 332, 332t, 333t antibody neutralization of, 344 antigenic variants of, 344, 344t breast cancer and, 1107 cell injury by, 340-341, 341 cell membrane penetration by, 340 cell receptor binding by, 340 hyperplasia with, 33 in autoimmune diseases, 216 in carcinogenesis, 311-315, 313,, 314 in congenital malformations, 467 in dilated cardiomyopathy, 579 in gastrointestinal tract infection, 354-355, 806-807, 807t in myocarditis, 584-585, 584t in rheumatoid arthritis, 1249 in type I diabetes mellitus, 917 nasal infection with, 762 replication of, 340 transplacental infection with, 470, 470 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vision, loss of, herpesvirus infection and, 360 in Leber hereditary optic neuropathy, 180 in vitamin A deficiency, 441, 442 vitamin A in, 441 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vitamin A, 439-441, 440,, 440t deficiency of, 441, 442,, 1361 in congenital malformations, 468-469, 468 squamous metaplasia with, 37 functions of, 440-441 in cancer prevention, 455 toxicity of, 441 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vitamin B1 (thiamine), 440t, 447 deficiency of, 447, 448,, 1279, 1341 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vitamin B12, 440t deficiency of, 1341 megaloblastic anemia with, 623-626, 623t, 624 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vitamin C (ascorbic acid), 440t, 449-450 deficiency of, 449-450, 450,, 451 in collagen synthesis, 98 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vitamin D (calciferol), 440t, 441-446 deficiency of, 443,, 444, 444t, 445 excess of, 45 functions of, 442, 444 metabolism of, 441-442, 443 receptor for, 147t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vitamin K, 440t, 446-447 deficiency of, 447, 637-638 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vocal cords, polyps of, 765 squamous papilloma of, 766, 766 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Von Hippel-Lindau disease, 1355 cysts in, 909 hemangiomas in, 533 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Von Hippel-Lindau syndrome, pheochromocytoma in, 1164t renal cell carcinoma in, 991-992 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Von Recklinghausen disease, of bone, 1228 pheochromocytoma in, 1164t Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Von Willebrand factor, deficiency of, 638, 638 endothelial cell production of, 120 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
V Vulva, 1040-1045 Bartholin cyst of, 1040 Bowen disease of, 1043, 1043 carcinoma in situ of, 1043, 1043 carcinoma of, 1042-1044, 1043,, 1044 condyloma acuminatum of, 1042, 1043 infection of, 1038-1039, 1038t inflammation of, 1040-1041, 1041 intraepithelial neoplasia of, 1043, 1043 lichen sclerosis of, 1040-1041, 1041 melanoma of, 1045 Paget disease of, 1044-1045, 1044 papillary hidradenoma of, 1042 squamous hyperplasia of, 1040-1042, 1041,, 1042 tumors of, 1042-1045, 1043,, 1044 verrucous carcinoma of, 1044 vestibular adenitis of, 1040 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
W Waardenburg syndrome, 470, 1220t PAX-3 gene in, 470 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
W Waterhouse-Friderichsen syndrome, 1160, 1160 hemorrhage in, 642 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
W Wegener granulomatosis, 517t, 522-523, 522 renal manifestations of, 968 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
W Weight, birth, 460-461, 461 excess, 452-455, 452,, 453 loss of, in hyperthyroidism, 1132 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
W Wermer syndrome (MEN-I), 46, 46,, 1166-1167, 1167t DNA helicase defect in, 47 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
W White cells. See Leukocyte(s). Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
W Wilms' tumor, 485t, 487-489, 488,, 489t in Beckwith-Wiedemann syndrome, 488 in Denys-Drash syndrome, 488 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
W Wound, contraction of, 110 dehiscence of, 110 healing of, 107-111, 111 by first intention, 107-109, 108 by second intention, 108,, 109 pathologic aspects of, 110-111, 110 strength recovery with, 109, 109 systemic factors in, 109-110 ulceration of, 110 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
W WT-1 gene, in cancer, 294 in Denys-Drash syndrome, 488 in urogenital development, 468 in WAGR syndrome, 488 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
X X chromosome, disorders of, 146, 146t, 173-176, 175 fragile, 177-179, 177,, 179 inactivation of, 173 supernumerary, 176 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
X Xanthoma, 40, 1189 in cholestasis, 851 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
X X-linked lymphoproliferative syndrome, 373 Epstein-Barr virus infection in, 318 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Y Y chromosome, sex-determining region Y gene of, 174 supernumerary, 174 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Z Zebra bodies, in mucopolysaccharidoses, 160 Niemann-Pick disease in, 158 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Z Zellballen, in carotid body tumor, 768, 768 in pheochromocytoma, 1165 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Z Zollinger-Ellison syndrome, 927 in intestinal carcinoid tumor, 836 peptic ulcers in, 794 Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-1 The relationships between normal, adapted, reversibly injured, and dead myocardial cells. The cellular adaptation depicted here is hypertrophy, and the type of cellular injury is ischemic necrosis. In reversibly injured myocardium, there are generally only functional effects, without any readily apparent gross or even microscopic changes. In the example of myocardial hypertrophy, the left ventricular wall is more than 2 cm in thickness (normal is 1 to 1.5 cm). In the specimen showing necrosis, the transmural light area in the posterolateral left ventricle represents an acute myocardial infarction. All three transverse sections have been stained with triphenyltetrazolium chloride, an enzyme substrate that colors viable myocardium magenta. Failure to stain is due to enzyme leakage after cell death.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-2 Wall of a small artery in the myocardium. Continuous endothelium (E) is separated from the smooth muscle layer (SM) by a thin internal elastic membrane (ET)--unstained. Note the peripheral bands in the medial smooth muscle cells ( arrows) and the prominent external basement membrane (B). L, lumen; H, perivascular fibroblast; N, nucleus.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-3 Endothelial activation: causes (activators) and consequences (induced genes).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-2 The critical role of oxygen in cell injury. Ischemia causes cell injury by reducing cellular oxygen supplies, whereas other stimuli, such as radiation, induce damage by toxic activated oxygen species.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-3 Sources and consequences of increased cytosolic calcium in cell injury. ATP, adenosine triphosphate.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-4 Mitochondrial dysfunction, induced by a variety of stimuli, causes mitochondrial permeability transition (MPT) and leakage of cytochrome c into the cytosol. The MPT is in the inner mitochondrial membrane.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-5 Postulated sequence of events in ischemic injury. Note that although reduced oxidative phosphorylation and ATP levels have a central role, ischemia can cause direct membrane damage. ER, endoplasmic reticulum; CK, creatine kinase; LDH, lactate dehydrogenase; RNP, ribonucleoprotein.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-6 Schematic representation of a normal cell (A) and the ultrastructural changes in reversible (B) and irreversible (C) cell injury (see text).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-7 A, Electron micrograph of a normal epithelial cell of the proximal kidney tubule. Note abundant microvilli (mv) lining the lumen (L). N, nucleus; V, apical vacuoles (which are normal structures in this cell type). B, Epithelial cell of the proximal tubule showing reversible ischemic changes. The microvilli (mv) are lost and have been incorporated in apical cytoplasm; blebs have formed and are extruded in the lumen (L). Mitochondria are slightly dilated. (Compare with A.) C, Proximal tubular cell showing irreversible ischemic injury. Note the markedly swollen mitochondria containing amorphous densities, disrupted cell membranes, and dense pyknotic nucleus. (Courtesy of Dr. M.A. Venkatachalam, University of Texas, San Antonio, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-8 Mechanisms of membrane damage in ischemia and reperfusion.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-9 Formation of reactive oxygen species and antioxidant mechanisms in biologic systems. O2 is converted to superoxide (O2 - ) by oxidative enzymes in the endoplasmic reticulum (ER), mitochondria, plasma membrane, peroxisomes, and cytosol. O2 - is converted to H2 O2 by dismutation and thence to OH by the Cu2+ /Fe2+ -catalyzed Fenton reaction. H2 O2 is also derived directly from oxidases in peroxisomes. Not shown is another potentially injurious radical, singlet oxygen. Resultant free radical damage to lipid (peroxidation), proteins, and DNA leads to various forms of cell injury. Note that superoxide catalyzes the reduction of Fe3+ to Fe2+ , thus enhancing OH generation by the Fenton reaction. The major antioxidant enzymes are superoxide dismutase, catalase, and glutathione peroxidase. GSH, reduced glutathione; GSSG, oxidized glutathione; NADPH, reduced form of nicotinamide adenine dinucleotide phosphate.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-10 Rat liver cell 4 hours after carbon tetrachloride intoxication, with swelling of endoplasmic reticulum and shedding of ribosomes. At this stage, mitochondria are unaltered. (Courtesy of Dr. O. Iseri, University of Maryland, Baltimore, MD.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-11 Sequence of events leading to fatty change and cell necrosis in carbon tetrachloride (CCl4 ) toxicity. RER, rough endoplasmic reticulum; SER, smooth endoplasmic reticulum.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-12 A, Normal myocardium. B, Myocardium with coagulation necrosis (upper two thirds of figure), showing strongly eosinophilic anucleate myocardial fibers. Leukocytes in the interstitium are an early reaction to necrotic muscle. Compare with A and with normal fibers in the lower part of the figure.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-13 Coagulative and liquefactive necrosis. A, Kidney infarct exhibiting coagulative necrosis, with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture. B, A focus of liquefactive necrosis in the kidney caused by fungal seeding. The focus is filled with white cells and cellular debris, creating a renal abscess that obliterates the normal architecture.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-14 A tuberculous lung with a large area of caseous necrosis. The caseous debris is yellow-white and cheesy.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-15 Foci of fat necrosis with saponification in the mesentery. The areas of white chalky deposits represent calcium soap formation at sites of lipid breakdown.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-17 Ultrastructural features of apoptosis. Some nuclear fragments show peripheral crescents of compacted chromatin, whereas others are uniformly dense. (From Kerr JFR, Harmon BV: Definition and incidence of apoptosis: a historical perspective. In Tomei LD, Cope FO (eds): Apoptosis: The Molecular Basis of Cell Death. Cold Spring Harbor, NY, Cold Spring Harbor Laboratory Press, 1991, pp 5-29.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-18 A, Apoptosis in the skin in an immune-mediated reaction. The apoptotic cells are visible in the epidermis with intensely eosinophilic cytoplasm and small, dense nuclei. H&E stain. (Courtesy of Dr. Scott Granter, Brigham and Women's Hospital, Boston, MA.) B, High power of apoptotic cell in liver in immune-mediated hepatic cell injury. (Courtesy of Dr. Dhanpat Jain, Yale University New Haven, CT.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-19 Agarose gel electrophoresis of DNA extracted from culture cells. Ethidium bromide stain; photographed under ultraviolet illumination. Lane A, Control culture. Lane B, Culture showing extensive apoptosis; note ladder pattern of DNA fragment induced by heat. Lane C, Culture showing massive necrosis; note diffuse smearing of DNA. These patterns are characteristic of but not specific for apoptosis and necrosis, respectively. (From Kerr JFR, Harmon BV: Definition and incidence of apoptosis: a historical perspective. In Tomei LD, Cope FO [eds]: Apoptosis: The Molecular Basis of Cell Death. Cold Spring Harbor, NY, Cold Spring Harbor Laboratory Press, 1991, p 13.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-20 Schematic representation of apoptotic events. Labeled (1) are multiple stimuli of apoptosis. These include specific death ligands (tumor necrosis factor [TNF] and Fas ligand), withdrawal of growth factors or hormones, or injurious agents (e.g., radiation). Some stimuli (such as cytotoxic cells) directly activate execution caspases (right). Others act by way of adapter proteins and initiator caspases (see Fig. 1-22) , or by mitochondrial events involving cytochrome c. (2) Control and regulation are influenced by members of the Bcl-2 family of proteins, which can either inhibit or promote the cell's death. (3) Execution caspases activate latent cytoplasmic endonuclease, and proteases that degrade cytoskeletal and nuclear proteins. This results in a cascade of intracellular degradation, including fragmentation of nuclear chromatin and breakdown of the cytoskeleton. Not shown is transglutaminase-induced cross-linking of proteins. (4) The end result is formation of apoptotic bodies containing various intracellular organelles and other cytosolic components; these bodies also express new ligands for binding and uptake by phagocytic cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-21 Mitochondrial events and the effects of Bcl-2 in apoptosis. Death agonists cause changes in the inner mitochondrial membrane, resulting in the mitochondrial permeability transition (MPT) and release of cytochrome c into the cytosol by currently unclear mechanisms. Released cytochrome c disrupts the binding between Bcl-2 and pro-apoptotic protease activating factor (Apaf). The latter activates an initiator caspase, which initiates the proteolytic events that eventually kill the cell. Bcl-2 thus suppresses apoptosis by inhibition of cytochrome c release and by binding and thus inactivating Apaf-1.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-22 A model of Fas-mediated signaling, caspase activation, and the induction of a death signal (see text). FADD, Fas-associating protein with a death domain.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-23 Apoptosis vs. survival induced by TNF. A model of TNF-receptor-mediated signaling and the induction of apoptosis ( left), or NF-kappaB activation and cell survival signals ( right).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-24 A, Schematic representation of autophagy (right) and heterophagy (left). (Redrawn from Fawcett DW: A Textbook of Histology, 11th ed. Philadelphia, WB Saunders, 1986, p 17.) B, Electron micrograph of an autophagolysosome containing a degenerating mitochondrion and amorphous material.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-25 Electron micrograph of liver from phenobarbital-treated rat showing marked increase in smooth endoplasmic reticulum. (From Jones AL, Fawcett DW: Hypertrophy of the agranular endoplasmic reticulum in hamster liver induced by phenobarbital. J Histochem Cytochem 14:215, 1966. Courtesy of Dr. Fawcett.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-26 Enlarged, abnormally shaped mitochondria from the liver of a patient with alcoholic cirrhosis. Note also crystalline formations in the mitochondria.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 1-27 A, The liver of alcohol abuse (chronic alcoholism). Hyaline inclusions in the hepatic parenchymal cell in the center appear as eosinophilic networks disposed about the nuclei. B, Electron micrograph of alcoholic hyalin. The material is composed of intermediate (prekeratin) filaments and an amorphous matrix.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 2-7 General mechanisms of intracellular accumulation: (1) abnormal metabolism, as in fatty change in the liver; (2) mutations causing alterations in protein folding and transport, as in alpha1 -antitrypsin deficiency; (3) deficiency of critical enzymes that prevent breakdown of substrates that accumulate in lysosomes, as in lysosomal storage diseases; and (4) inability to degrade phagocytosed particles, as in hemosiderosis and carbon pigment accumulation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 2-8 Fatty liver. A, Schematic diagram of the possible mechanisms leading to accumulation of triglycerides in fatty liver. Defects in any of the six numbered steps of uptake, catabolism, or secretion can result in lipid accumulation. B, High-power detail of fatty change of the liver. In most cells, the well-preserved nucleus is squeezed into the displaced rim of cytoplasm about the fat vacuole. ( B, Courtesy of Dr. James Crawford, Department of Pathology, Yale University School of Medicine.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 2-9 Cholesterolosis. Cholesterol-laden macrophages (foam cells) from a focus of gallbladder cholesterolosis. The gallbladder mucosa is in the upper left.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 2-10 A, Protein reabsorption droplets in the renal tubular epithelium. (Courtesy of Dr. Helmut Rennke, Department of Pathology, Brigham and Women's Hospital.) B, Simplified scheme of protein folding and how defects can lead to protein aggregation and abnormal cellular translocation (see text).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 2-11 Lipofuscin granules in a cardiac myocyte as shown by electron microscopy. Low magnification. Note the perinuclear, intralysosomal location.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 2-12 Hemosiderin granules in liver cells. A, H&E section showing golden-brown, finely granular pigment. B, Prussian blue reaction, specific for iron.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 2-13 View looking down onto the unopened aortic valve in a heart with calcific aortic stenosis. The semilunar cusps are thickened and fibrotic. Behind each cusp are seen irregular masses of piled-up dystrophic calcification.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 2-15 Finite population doublings of primary human fibroblasts derived from a newborn, a 100-year-old person, and a 20-year-old patient with Werner syndrome. The ability of cells to grow to a confluent monolayer decreases with increasing population-doubling levels. (From Dice JF: Cellular and molecular mechanisms of aging. Physiol Rev 73:150, 1993.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 2-16 Telomeres (bottom) and proposed mechanism of length determination by regulation of telomerase activity. Active telomerase (middle) adds repeated sequences and regulatory proteins (top), which in turn repress telomerase activity. (Modified and redrawn with permission from Shore D: Different means to common ends. Nature 385:676, 1997. Copyright 1997, Macmillan Magazines Limited.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 2-17 Telomere-telomerase hypothesis and proliferative capacity. Telomere length is plotted against the number of cell divisions. In normal somatic cells, there is no telomerase activity and telomeres progressively shorten with increasing cell divisions until growth arrest, or senescence, occurs. Germ cells and stem cells both contain telomerase activity, but only the germ cells have sufficient levels of the enzyme to stabilize telomere length completely. Telomerase activation in cancer cells inactivates the teleomeric clock that limits the proliferative capacity of normal somatic cells. (Modified and redrawn with permission from Holt SE, et al.: Refining the telomer-telomerase hypothesis of aging and cancer. Nature Biotech 14:836, 1996. Copyright 1996, Macmillan Magazines Limited.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 2-18 Oxidative stress and aging. Aerobic metabolism generates reactive oxygen metabolites such as hydrogen peroxide, superoxide anion, and nitric oxide. These reactive species can be inactivated by antioxidant defense mechanisms, or give rise to a variety of secondary reactive oxygen metabolites (e.g., peroxynitrite). Interactions between the reactive species and macromolecules may cause both reversible and irreversible oxidative modifications. The accumulation of irreversible oxidative damage may be a causal factor in aging and certain diseases. Antioxidant defense mechanisms include glutathione, vitamin E, vitamin C, and urate. SOD, superoxide dismutase. (Modified and redrawn from Weindruch R, Sohal RS: Caloric intake and aging. N Engl J Med 337:986, 1997.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-2 The major local manifestations of acute inflammation, compared to normal. (1) Vascular dilation (causing erythema and warmth), (2) extravasation of plasma fluid and proteins (edema), and (3) leukocyte emigration and accumulation in the site of injury.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-3 Blood pressure and plasma colloid osmotic forces in normal and inflamed microcirculation. A, Normal hydrostatic pressure (red arrows) is about 32 mm Hg at the arterial end of a capillary bed and 12 mm Hg at the venous end; the mean colloid osmotic pressure of tissues is approximately 25 mm Hg (green arrows), which is equal to the mean capillary pressure. Although fluid tends to leave the precapillary arteriole, it is returned in equal amounts via the postcapillary venule, so that the net flow (black arrows) in or out is zero. B, Acute inflammation. Arteriole pressure is increased to 50 mm Hg, the mean capillary pressure is increased because of arteriolar dilation, and the venous pressure increases to approximately 30 mm Hg. At the same time, osmotic pressure is reduced (averaging 20 mm Hg) because of protein leakage across the venule. The net result is an excess of extravasated fluid.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-4 Diagrammatic representation of five mechanisms of increased vascular permeability in inflammation (see text).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-5 A and B, Vascular leakage as induced by most chemical mediators. This is a laminar muscle of the rat (cremaster), fixed, cleared in glycerin, and examined unstained by transillumination. One hour before sacrifice, bradykinin was injected over this muscle and colloidal carbon was given intravenously. Plasma, loaded with carbon, escapes, but most of the carbon particles were retained by the basement membrane of the leaking vessels, with the result that these became "labeled" in black. Note that not all the vessels leak--only the venules. In B, a higher power, the capillary network is very faintly visible in the background. (Courtesy of Dr. Guido Majno.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-6 Sequence of leukocytic events in inflammation, shown here for neutrophils. The leukocytes first roll, then become activated and adhere to endothelium, then transmigrate across the endothelium, pierce the basement membrane, and migrate toward chemoattractants emanating from the source of injury. Note the roles of selectins in rolling; chemoattractants in activating the neutrophils to increase avidity of integrins (in green); ICAM-1 and VCAM-1 in firm adhesion; and PECAM-1 in transmigration.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-7 Laminar blood flow maintains leukocytes against the venular wall. (Modified and redrawn from Majno G, Joris I: Cells, Tissues, and Disease. Principles of General Pathology. Cambridge, MA, Blackwell Science, 1966.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-8 Three mechanisms of mediating leukocyte endothelial adhesion. A, Redistribution of P-selectin. B, Cytokine activation of endothelium. C, Increased binding avidity of integrins (see text).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-9 Molecules mediating various steps of neutrophil extravasation in endothelial-neutrophil interaction. Top, Endothelial activation: Inflammatory mediators have upregulated the expression of E- and P-selectins on the endothelial cell. Rolling--E- and P-selectins bind sialyl-Lewis X on specific ligands, such as PSGL-1 and ESL-1, while L-selectin on the leukocytes binds carbohydrate moieties on ligand expressed on the endothelial cell. Firm adhesion--The leukocytes become activated by chemokines and increase the avidity of their beta2 integrins for ICAM-1 expressed by endothelial cells. Bottom, Transmigration--leukocytes pass between adjacent endothelial cells, using PECAM-1 and other molecules. The colored balls represent sugar moieties and the various receptors are consistently color coded.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-10 Schematic and histologic sequence of events following acute injury. For sake of simplicity, edema is shown as the acute transient response, although secondary waves of delayed response can also occur. The photomicrographs are representative of the early (neutrophilic) (left) and later (mononuclear) cellular infiltrates (right) of infarcted myocardium.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-11 Biochemical events in leukocyte activation. The key events are (1) receptor-ligand binding, (2) phospholipase-C activation, (3) increased intracellular calcium, and (4) activation of protein kinase C. The biologic activities (5) resulting from leukocyte activation include chemotaxis, modulation of adhesion molecules, elaboration of arachidonic acid metabolites, secretion/degranulation, and the oxidative burst. PIP2 , phosphatidylinositol bisphosphate.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-12 Scanning electron micrograph of a moving leukocyte in culture showing a pseudopod (upper left) and a trailing tail. (Courtesy of Dr. Morris J. Karnovsky, Harvard Medical School, Boston.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-13 A, Phagocytosis of a particle (e.g., bacterium) involves attachment and binding of Fc and C3b to receptors on the leukocyte membrane, engulfment, and fusion of granules (in red) with phagocytic vacuoles, followed by degranulation. Note that during phagocytosis, granule contents may be released extracellularly. In innate immunity, collectins also serve as opsonins. B, Summary of oxygen-dependent bactericidal mechanisms within the phagocytic vacuole, as described in the text.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-14 Chemical mediators of inflammation. EC, endothelial cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-15 A flat spread of omentum showing mast cells around blood vessels and in the interstitial tissue. Stained with metachromatic stain to identify the mast cell granules. The red structures are fat globules stained with fat stain. (Courtesy of Dr. G. Majno.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-16 Overview of complement activation pathways. The classic pathway is initiated by C1 binding to antigen-antibody complexes, and the alternative pathway is initiated by C3b binding to various activating surfaces, such as microbial cell walls. The C3b involved in alternative pathway initiation may be generated in several ways, including spontaneously, by the classic pathway, or by the alternative pathway itself (see text). Both pathways converge and lead to the formation of inflammatory complement mediators (C3a and C5a) and the membrane attack complex. Not shown is activation by collectins (the lectin pathway, see text). In this figure, bars over the letter designations of complement components indicate enzymatically active forms, and dashed lines indicate proteolytic activities of various components. (Modified from Abbas AK, et al: Cellular and Molecular Immunology, 3rd ed. Philadelphia, WB Saunders, 1997.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-17 Interrelationships between the four plasma mediator systems triggered by activation of factor XII (Hageman factor).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-18 Generation of arachidonic acid metabolites and their roles in inflammation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-19 Biosynthesis of leukotrienes and lipoxins by cell-cell interaction. Activated neutrophils generate LTB4 from arachidonic acid-derived LTA4 by the action of 5-lipoxygenase, but they do not possess LTC4 -synthase activity and consequently do not produce LTC4 . In contrast, platelets cannot form LTC4 from endogenous substrates, but they can generate LTC4 and lipoxins from neutrophil-derived LTA4 . (Courtesy of Dr. C. Serhan, Brigham and Women's Hospital.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-20 Structure, sources, and main inflammatory actions of platelet-activating factor. LT, leukotrienes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-21 Major effects of interleukin-1 (IL-1) and tumor necrosis factor (TNF) in inflammation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-22 Two types of nitric oxide (NO) synthesis in endothelium (left) and macrophages (right). NO causes vasodilation, and NO free radicals are cytotoxic to microbial and mammalian cells. NOS, nitric oxide synthase.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-23 Ultrastructure of neutrophil granules stained for peroxidase activity and their constituents. The large peroxidase-containing granules are the azurophil granules; the smaller peroxidase-negative ones are the specific granules (SG). N, portion of nucleus; BPI, bactericidal permeability increasing protein.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-24 Outcome of acute inflammation (see text).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-26 Chronic inflammation in the lung, showing all three characteristic histologic features: (1) collection of chronic inflammatory cells (*), (2) destruction of parenchyma (normal alveoli are replaced by spaces lined by cuboidal epithelium, arrowheads), and (3) replacement by connective tissue (fibrosis, arrows).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-27 Maturation of mononuclear phagocytes. (From Abbas AK, et al: Cellular and Molecular Immunology, 3rd ed. Philadelphia, WB Saunders, 1997.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-28 Two stimuli for macrophage activation. Activation of macrophages via cytokines from immune-activated T cells (interferon gamma) or by nonimmunologic stimuli such as endotoxin. The products made by activated macrophages that also mediate tissue injury and fibrosis are indicated. AA, arachidonic acid; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; TGFbeta, transforming growth factor beta.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-29 Three mechanisms for macrophage accumulation. The most important is continued recruitment from the microcirculation. (Adapted from Ryan G, Majno G: Inflammation. Kalamazoo, MI, Upjohn, 1977.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-30 Macrophage-lymphocyte interactions in chronic inflammation. Activated lymphocytes and macrophages influence each other and also release inflammatory mediators that affect other cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-31 A focus of inflammation showing numerous eosinophils.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-32 Typical tuberculous granuloma showing an area of central necrosis, epithelioid cells, multiple Langhans-type giant cells, and lymphocytes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-33 Histologic patterns of acute inflammation. A, Serous inflammation. Low-power view of a cross-section of a skin blister showing the epidermis separated from the dermis by a focal collection of serous effusion. B, Fibrinous inflammation. A pink meshwork of fibrin exudate (F) (on the right) overlies the pericardial surface (P). C, Suppurative inflammation. A bacterial abscess in the myocardium. D, Ulceration. Low-power cross-section of a duodenal ulcer crater with an acute inflammatory exudate in the base.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 3-34 Mechanism of fever (see text).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 4-8 Steps in collagen synthesis (see text).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 4-9 The fibronectin molecule ( A) consists of a dimer held together by S-S bonds. Note the various domains that bind to extracellular matrix and the cell-binding domain containing an arginine-glycine-aspartic acid (RGD) sequence. The cross-shaped laminin ( B) molecule spans basement membranes and has extracellular matrix (ECM)- and cell-binding domains.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 4-12 Schematic showing the mechanisms by which ECM (e.g., fibronectin and laminin) and growth factors can influence cell growth, motility, differentiation, and protein synthesis. Integrins bind ECM and interact with the cytoskeleton at focal adhesion complexes (protein aggregates that include vinculin, alpha-actinin, and talin). This can initiate the production of intracellular messengers, or can directly mediate nuclear signals. Cell surface receptors for growth factors also initiate second signals. Collectively, these are integrated by the cell to yield various responses, including changes in cell growth, locomotion, and differentiation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 4-13 A, Granulation tissue showing numerous blood vessels, edema, and a loose ECM containing occasional inflammatory cells. This is a trichrome stain that stains collagen blue; minimal mature collagen can be seen at this point. B, Trichrome stain of mature scar, showing dense collagen, with only scattered vascular channels.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 4-14 Steps in the process of angiogenesis (see text). (Modified from Motamed K, Sage EH: Regulation of vascular morphogenesis by SPARC. Kidney Int 51:1383, 1997.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 4-17 Steps in wound healing by first intention (left) and second intention (right). In the latter, the resultant scar is much smaller than the original wound owing to wound contraction.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 4-19 Keloid. (From Murphy GF, Herzberg AJ: Atlas of Dermatopathology. Philadelphia, WB Saunders, 1996, p 219.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 4-20 Pathways of reparative responses after acute inflammatory injury.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-3 Liver with chronic passive congestion and hemorrhagic necrosis. A, Central areas are red and slightly depressed compared with the surrounding tan viable parenchyma, forming the so-called "nutmeg liver" pattern. B, Centrilobular necrosis with degenerating hepatocytes, hemorrhage, and acute inflammation. (Courtesy of Dr. James Crawford, Department of Pathology, Yale University Medical School, New Haven, CT.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-4 A, Punctate petechial hemorrhages of the colonic mucosa, seen here as a consequence of thrombocytopenia. B, Fatal intracerebral bleed. Even relatively inconsequential volumes of hemorrhage in a critical location, or into a closed space (such as the cranium), can have fatal outcomes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-5 Diagrammatic representation of the normal hemostatic process. A, After vascular injury, local neurohumoral factors induce a transient vasoconstriction. B, Platelets adhere to exposed extracellular matrix (ECM) via von Willebrand factor (vWF), and are activated, undergoing a shape change and granule release; released adenosine diphosphate (ADP) and thromboxane A2 (TXA2 ) lead to further platelet aggregation to form the primary hemostatic plug. C, Local activation of the coagulation cascade (involving tissue factor and platelet phospholipids) results in fibrin polymerization, "cementing" the platelets into a definitive secondary hemostatic plug. D, Counter-regulatory mechanisms, such as release of tissue type plasminogen activator (t-PA) (fibrinolytic) and thrombomodulin (interfering with the coagulation cascade), limit the hemostatic process to the site of injury.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-6 Schematic illustration of some of the pro- and anticoagulant activities of endothelial cells. Not shown are the pro- and antifibrinolytic properties. vWF, von Willebrand factor; PGI2 , prostacyclin; NO, nitric oxide.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-7 Platelet adhesion and aggregation. Von Willebrand's factor functions as an adhesion bridge between subendothelial collagen and the GpIb platelet receptor. Aggregation involves linking platelets via fibrinogen bridges bound to the platelet GpIIb-IIIa receptors.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-8 The coagulation cascade. Note the common link between the intrinsic and extrinsic pathways at the level of factor IX activation. Factors in red boxes represent inactive molecules; activated factors are indicated with a lower case "a" and a green box. PL, phospholipid surface; HMWK, high-molecular-weight kininogen. Not shown are the anticoagulant inhibitory pathways (see Figs. 5-6 and 5-11) .
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-9 The central roles of thrombin in hemostasis and cellular activation. In addition to a critical function in generating cross-linked fibrin (via cleavage of fibrinogen to fibrin and activation of factor XIII), thrombin also directly induces platelet aggregation and secretion (e.g., of TXA2 ). Thrombin also activates endothelium to generate leukocyte adhesion molecules and a variety of fibrinolytic (t-PA), vasoactive (NO, PGI2 ), or cytokine (PDGF) mediators. Likewise, mononuclear inflammatory cells may be activated by the direct actions of thrombin. ECM, extracellular matrix; NO, nitric oxide; PDGF, platelet-derived growth factor; PGI2 , prostacyclin; TXA2 , thromboxane A2 ; t-PA, tissue type plasminogen activator. See Fig. 5-6 for additional anticoagulant modulators of thrombin activity, such as antithrombin III and thrombomodulin. (Modified with permission from Shaun Coughlin, MD, PhD, Cardiovascular Research Institute, University of California at San Francisco.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-10 Schematic illustration of the conversion of factor X to factor Xa, which in turn converts factor II (prothrombin) to factor IIa (thrombin). The initial reaction complex consists of an enzyme (factor IXa), a substrate (factor X), and a reaction accelerator (factor VIIIa), which are assembled on the phospholipid surface of platelets. Calcium ions hold the assembled components together and are essential for reaction. Activated factor Xa then becomes the enzyme part of the second adjacent complex in the coagulation cascade, converting the prothrombin substrate (II) to thrombin IIa, with the cooperation of the reaction accelerator factor Va. (Modified from Mann KG: Clin Lab Med 4:217, 1984.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-11 The fibrinolytic system, illustrating the plasminogen activators and inhibitors.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-12 Virchow's triad in thrombosis. Endothelial integrity is the single most important factor. Note that injury to endothelial cells can affect local blood flow and/or coagulability; abnormal blood flow (stasis or turbulence), in turn, can cause endothelial injury. The factors may act independently or may combine to cause thrombus formation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-13 Mural thrombi. A, Thrombus in the left and right ventricular apices, overlying a white fibrous scar. B, Laminated thrombus in a dilated abdominal aortic aneurysm.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-14 Potential outcomes of venous thrombosis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-15 Low-power view of a thrombosed artery. A, H&E-stained section. B, Stain for elastic tissue. The original lumen is delineated by the internal elastic lamina ( arrows) and is totally filled with organized thrombus, now punctuated by a number of recanalized channels.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-16 Large embolus derived from a lower extremity deep venous thrombosis, and now impacted in a pulmonary artery branch.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-17 Bone marrow embolus in the pulmonary circulation. The cleared vacuoles represent marrow fat that is now impacted in a distal vessel along with the cellular hematopoietic precursors.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-18 Examples of infarcts. A, Hemorrhagic, roughly wedge-shaped pulmonary infarct. B, Sharply demarcated white infarct in the spleen.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-19 Remote kidney infarct, now replaced by a large fibrotic cortical scar.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-20 Cytokine cascade in sepsis. After release of lipopolysaccharide (LPS), there are successive waves of tumor necrosis factor (TNF), interleukin-1 (IL-1), and IL-6 secretion. (Modified from Abbas AK, et al: Cellular and Molecular Immunology, 3rd ed. Philadelphia, WB Saunders, 1997.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 5-21 Effects of lipopolysaccharide (LPS) and secondarily-induced effector molecules. LPS initiates the cytokine cascade described in Figure 5-20 ; in addition, LPS and the various factors can directly stimulate down-stream cytokine production, as indicated. Secondary effectors that become important include nitric oxide (NO) and platelet-activating factor (PAF). At low levels, only local inflammatory effects are seen. With moderate levels, more systemic events occur in addition to the local vascular effects. At high concentrations, the syndrome of septic shock is seen. DIC, disseminated intravascular coagulation; ARDS, adult respiratory distress syndrome. (Modified from Abbas AK, et al: Cellular and Molecular Immunology, 3rd ed. Philadelphia, WB Saunders, 1997.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-7 Scheme of a possible metabolic pathway in which a substrate is converted to an end product by a series of enzyme reactions. M1, M2, products of a minor pathway.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-8 Schematic illustration of low-density lipoprotein (LDL) metabolism and the role of liver in its synthesis and clearance. Lipolysis of very-low-density lipoprotein (VLDL) by lipoprotein lipase in the capillaries releases triglycerides, which are then stored in fat cells and used as a source of energy in skeletal muscles.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-9 The LDL receptor pathway and regulation of cholesterol metabolism.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-10 Classification of LDL receptor mutations based on abnormal function of the mutant protein. These mutations disrupt the receptor's synthesis in the endoplasmic reticulum transport to the Golgi complex, binding of apoprotein ligands, clustering in coated pits, and recycling in endosomes. Each class is heterogeneous at the DNA level. (Modified with permission from Hobb HH, et al: The LDL receptor locus in familial hypercholesterolemia: mutational analysis of a membrane protein. Annu Rev Genet 24:133-170, 1990. © 1990 by Annual Reviews.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-11 Synthesis and intracellular transport of lysosomal enzymes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-12 Schematic diagram illustrating the pathogenesis of lysosomal storage diseases. In the example shown, a complex substrate is normally degraded by a series of lysosomal enzymes (A, B, and C) into soluble end products. If there is a deficiency or malfunction of one of the enzymes (e.g., B), catabolism is incomplete and insoluble intermediates accumulate in the lysosomes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-14 Ganglion cells in Tay-Sachs disease. A, Under the light microscope, a large neuron has obvious lipid vacuolation. (Courtesy of Dr. Arthur Weinberg, Department of Pathology, University of Texas, Southwestern Medical Center, Dallas, TX.) B, A portion of a neuron under the electron microscope shows prominent lysosomes with whorled configurations. Part of the nucleus is shown above. (Electron micrograph courtesy of Dr. Joe Rutledge, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-15 Niemann-Pick disease in liver. The hepatocytes and Kupffer cells have a foamy, vacuolated appearance owing to deposition of lipids. (Courtesy of Dr. Arthur Weinberg, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-16 Gaucher disease involving the bone marrow. A, Gaucher cells with abundant lipid-laden granular cytoplasm. B, Electron micrograph of Gaucher cells with elongated distended lysosomes. (Courtesy of Dr. Mathew Frieze, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-18 Top, Simplified schema of normal glycogen metabolism in the liver and skeletal muscles. Middle, Effects of an inherited deficiency of hepatic enzymes involved in glycogen metabolism. Bottom, Consequences of a genetic deficiency in the enzymes that metabolize glycogen in skeletal muscles.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-19 Pompe disease (glycogen storage disease type II). A, Normal myocardium with abundant eosinophilic cytoplasm. B, Patient with Pompe disease (same magnification) showing the myocardial fibers full of glycogen seen as clear spaces. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-20 Normal male karyotype with G banding. (Courtesy of Dr. Nancy Schneider, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-21 Details of a banded karyotype of the X chromosome (also called "idiogram"). Note the nomenclature of arms, regions, bands, and sub-bands. On the right side, the approximate locations of some genes that cause disease are indicated.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-22 Fluorescent in situ hybridization (FISH). Interphase nuclei of a childhood hepatic cancer (hepatoblastoma) stained with a fluorescent DNA probe that hybridizes to chromosome 20. Under ultraviolet light, each nucleus reveals three bright yellow fluorescent dots representing three copies of chromosome 20. Normal diploid cells ( not shown) have two fluorescent dots. (Courtesy of Dr. Vijay Tonk, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-23 FISH. A metaphase spread in which two fluorescent probes, one for the terminal ends of chromosome 22 and the other for the D22S75 locus that maps to chromosome 22, have been used. The terminal ends of the two chromosomes 22 have been labeled. One of the two chromosomes does not stain with the probe for the D22S75 locus, indicating a microdeletion in this region. This deletion gives rise to the 22q11 deletion syndrome described on p. 173. (Courtesy of Dr. Nancy Schneider, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-24 Chromosome painting with a library of chromosome 22-specific DNA probes. The presence of three fluorescent chromosomes indicates that the patient has trisomy 22. (Courtesy of Dr. Charleen M. Moore, The University of Texas Health Science Center at San Antonio, San Antonio, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-25 Spectral karyotype. (Courtesy of Dr. Janet D. Rowley, University of Chicago Medical Center, Chicago, IL.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-26 Types of chromosomal rearrangements.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-27 G-banded karyotype of a male with trisomy 21. (Courtesy of Dr. Nancy Schneider, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-28 Clinical features of karyotypes of selected autosomal trisomies.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-29 Clinical features and karyotypes of Turner syndrome.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-30 Fragile X, seen as discontinuity of staining. (Courtesy of Dr. Patricia Howard-Peebles, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-31 Fragile X pedigree. Note that in the first generation all sons are normal and all females are carriers. During oogenesis in the carrier female, premutation expands to full mutation; hence in the next generation, all males who inherit the X with full mutation are affected. However, only 50% of females who inherit the full mutation are affected, and only mildly. (Courtesy of Dr. Nancy Schneider, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-32 Sites of expansion and the affected sequence in selected diseases caused by nucleotide repeat mutations. UTR, untranslated region.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-33 Pedigree of Leber optic neuropathy, a disorder caused by mutation in mitochondrial DNA. Note that all progeny of an affected male are normal, but all children, male and female, of the affected female manifest disease.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-34 Diagrammatic representation of Prader-Willi and Angelman syndromes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-35 Direct gene diagnosis: detection of coagulation factor V mutation by polymerase chain reaction (PCR) analysis. A G A substitution in an exon destroys one of the two Mnl1 restriction sites. The mutant allele therefore gives rise to two, rather than three, fragments by PCR analysis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-36 Direct gene diagnosis by using PCR and an allele-specific oligonucleotide probe. A, A G A change converts a normal alpha1 -antitrypsin allele (allele M) to a mutant (Z) allele. Two synthetic oligonucleotide probes, one corresponding in sequence to the normal allele (M probe) and the other corresponding to the mutant allele (Z probe), are lined up against normal and mutant genes, and expected patterns of hybridization are indicated on the right: the arrows indicate primers used to amplify the normal or mutant DNA. B, The PCR products from normal individuals, those heterozygous for the Z allele or homozygous for the Z allele, are applied to filter papers in duplicate, and each spot is hybridized with radiolabeled M or Z probe. A dark spot indicates that the probe is bound to the DNA.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-37 Diagnostic application of PCR and Southern blot analysis in fragile X syndrome. With PCR, the differences in the size of CGG repeat between normal and premutation give rise to products of different sizes and mobility. With a full mutation, the region between the primers is too large to be amplified by conventional PCR. In Southern blot analysis the DNA is cut by enzymes that flank the CGG repeat region, and is then probed with a complementary DNA that binds to the affected part of the gene. A single small band is seen in normal males, a higher-molecular-weight band in males with premutation, and a very large (usually diffuse) band in those with the full mutation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-38 Schematic illustration of the principles underlying restriction fragment length polymorphism analysis in the diagnosis of genetic diseases.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 6-39 Schematic diagram of DNA polymorphisms resulting from a variable number of CA repeats. The three alleles produce PCR products of different sizes, thus identifying their origins from specific chromosomes. In the example depicted, allele C is linked to a mutation responsible for autosomal dominant polycystic kidney disease (PKD). Application of this to detect progeny carrying the disease gene is illustrated in one hypothetical pedigree.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-9 Pathogenesis of type I hypersensitivity reaction. TH 2, T-helper type 2 CD4 cells. Late-phase response is dominated by leukocyte infiltration and tissue injury.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-10 Activation of mast cells in type I hypersensitivity and release of their mediators. ECF, eosinophil chemotactic factor; NCF, neutrophil chemotactic factor; PAF, platelet-activating factor.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-11 Schematic illustration of three different mechanisms of antibody-mediated injury in type II hypersensitivity. A, Complement-dependent reactions that lead to lysis of cells or render them susceptible to phagocytosis. B, Antibody-dependent cell-mediated cytotoxicity (ADCC). IgG-coated target cells are killed by cells that bear Fc receptors for IgG (e.g., NK cells, macrophages). C, Antireceptor antibodies disturb the normal function of receptors. In this example, acetylcholine receptor antibodies impair neuromuscular transmission in myasthenia gravis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-12 Schematic illustration of the three sequential phases in the induction of systemic type III (immune complex) hypersensitivity.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-13 Schematic representation of the pathogenesis of immune complex-mediated tissue injury. The morphologic consequences are depicted as boxed areas.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-14 Immune complex vasculitis. The necrotic vessel wall is replaced by smudgy, pink "fibrinoid" material. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-15 Delayed hypersensitivity in the skin. Immunoperoxidase staining reveals a predominantly perivascular cellular infiltrate that marks positively with anti-CD4 antibodies. (Courtesy of Dr. Louis Picker, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-16 A section of a lymph node shows several granulomas, each made up of an aggregate of epithelioid cells and surrounded by lymphocytes. The granuloma in the center shows several multinucleate giant cells. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-17 Schematic illustration of the events that give rise to the formation of granuloma in type IV hypersensitivity reactions. Note the role played by T cell-derived cytokines.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-18 Contact dermatitis showing an epidermal blister (vesicle) with dermal and epidermal mononuclear infiltrates. (Courtesy of Dr. Louis Picker, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-19 Schematic representation of the events that lead to the destruction of histoincompatible grafts. Donor class I and class II antigens along with B7 molecules are recognized by CD8+ cytotoxic T cells and CD4+ helper T cells, respectively, of the host. The interaction of the CD4+ cells with peptides presented by class II antigens leads to proliferation of TH 1-type CD4+ cells and the release of interleukin 2 (IL-2) from the cells. IL-2 further augments the proliferation of CD4+ cells and also provides helper signals for the differentiation of class I-specific CD8+ cytotoxic cells. In addition, activation of TH 2-type CD4+ cells generates a variety of other soluble mediators (lymphokines) that promote B-cell differentiation. The TH 1 cells also participate in the induction of a local delayed hypersensitivity reaction. Eventually, several mechanisms converge to destroy the graft: (1) lysis of cells that bear class I antigens by CD8+ cytotoxic T cells, (2) antigraft antibodies produced by sensitized B cells, and (3) nonspecific damage inflicted by macrophages and other cells that accumulate as a result of the delayed hypersensitivity reaction.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-20 Acute cellular rejection of a renal allograft. A, An intense mononuclear cell infiltrate occupies the space between the glomerulus (bottom left) and the tubules. B, Tubules, highlighted by the basement membrane, undergoing destruction by invading lymphocytes. (Courtesy of Dr. Ihsan Housini, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-21 Antibody-mediated damage to the blood vessel in a renal allograft. The blood vessel is markedly thickened, and the lumen is obstructed by proliferating fibroblasts and foamy macrophages. (Courtesy of Dr. Ihsan Housini, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-22 Schematic illustration of the mechanisms involved in central and peripheral tolerance.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-23 Model for the pathogenesis of systemic lupus erythematosus. (Modified from Kotzin BL: Systemic lupus erythematosus. Cell 65:303, 1996. Copyright 1996, Cell Press.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-24 Lupus nephritis. There are two focal necrotizing lesions at 11 and 2 o'clock. (H&E stain.) (Courtesy of Dr. Helmut Rennke, Department of Pathology, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-25 Lupus nephritis, diffuse proliferative type. Note the marked increase in cellularity throughout the glomerulus. (H&E stain.) (Courtesy of Dr. Helmut Rennke, Department of Pathology, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-26 Immunofluorescence micrograph stained with fluorescent anti-IgG from a patient with diffuse proliferative lupus nephritis. One complete glomerulus and part of another one are seen. Note the mesangial and capillary wall deposits of IgG. (Courtesy of Dr. Helmut Rennke, Department of Pathology, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-27 Electron micrograph of a renal glomerular capillary loop from a patient with systemic lupus erythematosus nephritis. Subendothelial dense deposits correspond to "wire loops" seen by light microscopy. End, endothelium; Mes, mesangium; Ep, epithelial cell with foot processes; RBC, red blood cell in capillary lumen; B, basement membrane; US, urinary space; *, electron-dense deposits in subendothelial location. (Courtesy of Dr. Edwin Eigenbrodt, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-28 Lupus nephritis showing a glomerulus with several "wire loop" lesions representing extensive subendothelial deposits of immune complexes. (Periodic acid-Schiff [PAS] stain.) (Courtesy of Dr. Helmut Rennke, Department of Pathology, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-29 Systemic lupus erythematosus involving the skin. A, An H&E-stained section shows liquefactive degeneration of the basal layer of the epidermis and edema at the dermoepidermal junction. (Courtesy of Dr. Jag Bhawan, Boston University School of Medicine, Boston, MA.) B, An immunofluorescence micrograph stained for IgG reveals deposits of immunoglobulin along the dermoepidermal junction. (Courtesy of Dr. Richard Sontheimer, Department of Dermatology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-30 Libman-Sacks endocarditis of the mitral valve in lupus erythematosus. The vegetations attached to the margin of the thickened valve leaflet are easily seen. (Courtesy of Dr. Fred Schoen, Department of Pathology, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-31 Sjogren's syndrome. A, Enlargement of the salivary gland. (Courtesy of Dr. Richard Sontheimer, Department of Dermatology, University of Texas Southwestern Medical School, Dallas, TX.) B, The histologic view shows intense lymphocytic and plasma cell infiltration with ductal epithelial hyperplasia. (Courtesy of Dr. Dennis Burns, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-32 Schematic illustration of the possible mechanisms leading to systemic sclerosis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-33 Systemic sclerosis. Note the extensive deposition of dense collagen in the dermis with virtual absence of appendages and thinning of epidermis. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-34 Advanced systemic sclerosis. The extensive subcutaneous fibrosis has virtually immobilized the fingers, creating a clawlike flexion deformity. Loss of blood supply has led to cutaneous ulcerations. (Courtesy of Dr. Richard Sontheimer, Department of Dermatology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-35 A, Dermatomyositis. Note the rash affecting the eyelids. B, Dermatomyositis. The histologic appearance of muscle shows perifascicular inflammation and atrophy. C, Inclusion body myositis showing a vacuole within a myocyte. (Courtesy of Dr. Dennis Burns, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-36 Simplified scheme of lymphocyte development and sites of block in primary immunodeficiency diseases. The affected genes are indicated in parentheses for some of the disorders. ADA, adenosine deaminase; CD40L, CD40 ligand; CVID, common variable immunodeficiency; SCID, severe combined immunodeficiency.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-37 Schematic illustration of an HIV-1 virion. The viral particle is covered by a lipid bilayer that is derived from the host cell.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-38 HIV proviral genome. Several viral genes and their corresponding functions are illustrated. The genes outlined in red are unique to HIV; others are shared by all retroviruses.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-39 Molecular basis of HIV entry into host cells. Interactions with CD4 and CCR5 coreceptor are illustrated. (Adapted with permission from Wain-Hobson S: HIV. One on one meets two. Nature 384:117, 1996. Copyright 1996, Macmillam Magazines Limited.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-40 Pathogenesis of HIV-1 infection. Initially, HIV-1 infects T cells and macrophages directly or is carried to these cells by Langerhans cells. Viral replication in the regional lymph nodes leads to viremia and widespread seeding of lymphoid tissue. The viremia is controlled by the host immune response (not shown) and the patient then enters a phase of clinical latency. During this phase, viral replication in both T cells and macrophages continues unabated, but there is some immune containment of virus (not illustrated). There continues a gradual erosion of CD4+ cells by productive infection (or other mechanisms, not shown). When the numbers of CD4+ cells that are destroyed cannot be replenished, CD4+ cell numbers decline and the patient develops clinical symptoms of full-blown AIDS. Macrophages are also parasitized by the virus early; they are not lysed by HIV-1 and they transport the virus to tissues, particularly the brain.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-41 HIV infection showing the formation of giant cells in the brain. (Courtesy of Dr. Dennis Burns, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-42 The multiple effects of loss of CD4+ T cells as a result of HIV infection.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-44 Proposed role of HIV, KSHV (HHV-8), and cytokines in the pathogenesis of Kaposi sarcoma. Cytokines are produced by the mesenchymal cells infected by KSHV, by B cells infected by KSHV, or by HIV-infected CD4+ cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-45 Amyloidosis. A, A section of the liver stained with Congo red reveals pink-red deposits of amyloid in the walls of blood vessels and along sinusoids. B, Note the yellow-green birefringence of the deposits when observed by polarizing microscope. (Courtesy of Dr. Trace Worrell and Sandy Hinton, Department of Pathology, University of Texas Southwestern Medical School, Dallas TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-46 Structure of an amyloid fibril, depicting the beta-pleated sheet structure and binding sites for the Congo red dye, which is used for diagnosis of amyloidosis. (Modified from Glenner GG: Amyloid deposit and amyloidosis. The beta-fibrilloses. N Engl J Med 52:148, 1980. By permission of The New England Journal of Medicine.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-47 Proposed schema of the pathogenesis of two major forms of amyloid fibrils.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-48 Amyloidosis of the kidney. The glomerular architecture is almost totally obliterated by the massive accumulation of amyloid.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 7-49 Cardiac amyloidosis. The atrophic myocardial fibers are separated by structureless, pink-staining amyloid.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-1 Papilloma of the colon with finger-like projections into the lumen. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-2 Colonic polyp. A, This benign glandular tumor (adenoma) is projecting into the colonic lumen and is attached to the mucosa by a distinct stalk. B, Gross appearance of several colonic polyps.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-4 A, Gross appearance of an opened cystic teratoma of the ovary. Note the presence of hair, sebaceous material, and tooth. B, A microscopic view of a similar tumor shows skin, sebaceous glands, fat cells, and a tract of neural tissue (arrow).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-5 Leiomyoma of the uterus. This benign, well-differentiated tumor contains interlacing bundles of neoplastic smooth muscle cells that are virtually identical in appearance to normal smooth muscle cells in the myometrium.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-6 Benign tumor (adenoma) of the thyroid. Note the normal-looking (well-differentiated), colloid-filled thyroid follicles. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-7 Malignant tumor (adenocarcinoma) of the colon. Note that compared with the well-formed and normal-looking glands characteristic of a benign tumor (see Fig. 8-6) , the cancerous glands are irregular in shape and size and do not resemble the normal colonic glands. This tumor is considered differentiated because gland formation can be seen. The malignant glands have invaded the muscular layer of the colon. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-8 Anaplastic tumor of the skeletal muscle (rhabdomyosarcoma). Note the marked cellular and nuclear pleomorphism, hyperchromatic nuclei, and tumor giant cells. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-9 High-power detail of anaplastic tumor cells to show cellular and nuclear variation in size and shape. The prominent cell in the center field has an abnormal tripolar spindle.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-10 Well-differentiated squamous cell carcinoma of the skin. The tumor cells are strikingly similar to normal squamous epithelial cells, with intercellular bridges and nests of keratin pearls (arrow). (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-11 A, Carcinoma in situ. This low-power view shows that the entire thickness of the epithelium is replaced by atypical dysplastic cells. There is no orderly differentiation of squamous cells. The basement membrane is intact and there is no tumor in the subepithelial stroma. B, A high-power view of another region shows failure of normal differentiation, marked nuclear and cellular pleomorphism, and numerous mitotic figures extending toward the surface. The basement membrane (below) is not seen in this section.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-12 Fibroadenoma of the breast. The tan-colored, encapsulated small tumor is sharply demarcated from the whiter breast tissue.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-13 Microscopic view of fibroadenoma of the breast seen in Figure 8-12 . The fibrous capsule (below) sharply delimits the tumor from the surrounding tissue. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-14 Cut section of an invasive ductal carcinoma of the breast. The lesion is retracted, infiltrating the surrounding breast substance, and would be stony hard on palpation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-15 The microscopic view of breast carcinoma seen in Figure 8-14 illustrates the invasion of breast stroma and fat by nests and cords of tumor cells (compare with Fig. 8-13) . The absence of a well-defined capsule should be noted. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-16 Axillary lymph node with metastatic breast carcinoma. The subcapsular sinus (left) is distended with tumor cells. Nests of tumor cells have also invaded the subcapsular cortex. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-17 A liver studded with metastatic cancer.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-18 Microscopic view of liver metastasis. A pancreatic adenocarcinoma has formed a metastatic nodule in the liver. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-19 Comparison between a benign tumor of the myometrium (leiomyoma) and a malignant tumor of similar origin (leiomyosarcoma).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-22 The change in incidence of various cancers with migration from Japan to the United States provides evidence that the occurrence of cancers is related to components of the environment that differ in the two countries. The incidence of each kind of cancer is expressed as the ratio of the death rate in the population being considered to that in a hypothetical population of California whites with the same age distribution; the death rates for whites are thus defined as 1. The death rates among immigrants and immigrants' sons tend consistently toward California norms. (From Cairns J: The cancer problem. In Readings from Scientific American--Cancer Biology. New York, WH Freeman, 1986, p 13. © 1975 by Scientific American, Inc. All rights reserved.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-23 Diagram depicting the use of X-linked isoenzyme cell markers as evidence of the monoclonality of neoplasms. Because of random X inactivation, all females are mosaics with two cell populations (with G6PD isoenzyme A or B in this case). When neoplasms that arise in women who are heterozygous for X-linked markers are analyzed, they are made up of cells that contain the active maternal (XA ) or the paternal (XB )X chromosome but not both.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-24 Flow chart depicting a simplified scheme of the molecular basis of cancer.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-25 Model for action of ras genes. When a normal cell is stimulated through a growth factor receptor, inactive (GDP-bound) ras is activated to a GTP-bound state. Activated ras recruits raf-1 and stimulates the MAP-kinase pathway to transmit growth-promoting signals to the nucleus. The mutant ras protein is permanently activated because of inability to hydrolyze GTP, leading to continuous stimulation of cells without any external trigger. The anchoring of ras to the cell membrane by the farnesyl moiety is essential for its action.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-26 Schematic illustrating the role of cyclins and cyclin-dependent kinases (CDKs) in regulating the cell cycle. In the depicted example, inactive CDK is constitutively expressed; it is activated by binding to cyclin D, which is synthesized in G1 . The activated CDK allows the cell to cross the G1 S checkpoint by phosphorylating retinoblastoma (Rb) protein. After the cell enters the S phase, cyclin D is degraded, returning CDK to the inactive state.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-27 Schematic illustration of the role of cyclins, CDKs, and cyclin-dependent kinase inhibitors (CDKIs) in regulating the cell cycle. The shaded arrows represent the phases of cell cycle during which specific cyclin/CDK complexes are active. As illustrated, cyclin D/CDK4, cyclin D/CDK6, and cyclin E/CDK2 regulate the G1 S transition by phosphorylation of the Rb protein (pRb). Cyclin A/CDK2 and cyclin A/CDK1 are active in the S phase. Cyclin B/CDK1 is essential for the G2 M transition. Two families of CDK inhibitors, so-called INK4 inhibitors composed of p16, p15, p18, and p19, act on cyclin D/CDK4 and cyclin D/CDK6. The other family of three inhibitors, p21, p27, and p57, can inhibit all CDKs.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-28 The chromosomal translocation and associated oncogenes in Burkitt lymphoma and chronic myelogenous leukemia.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-29 Amplification of the N- myc gene in human neuroblastomas. The N- myc gene, normally present on chromosome 2p, becomes amplified and is seen either as extra chromosomal double minutes or as a chromosomally integrated, homogeneous staining region. The integration involves other autosomes, such as 4, 9, or 13. (Modified from Brodeur GM: Molecular correlates of cytogenetic abnormalities in human cancer cells: implications for oncogene activation. In Brown EB (ed): Progress in Hematology, Vol 14, Orlando, FL, Grune & Stratton, 1986, pp 229-256.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-30 Pathogenesis of retinoblastoma. Two mutations of the Rb locus on chromosome 13q14 lead to neoplastic proliferation of the retinal cells. In the familial form, all somatic cells inherit one mutant Rb gene from a carrier parent. The second mutation affects the Rb locus in one of the retinal cells after birth. In the sporadic form, on the other hand, both mutations at the Rb locus are acquired by the retinal cells after birth.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-31 The role of pRb in regulating the G1 S checkpoint of cell cycle. Hypophosphorylated pRb complexed to the E2F transcription factors binds to DNA and inhibits transcription of genes whose products are required for the S phase of the cell cycle. When pRb is phosphorylated by the cyclin D/CDK4, 6, and cyclin E/CDK2 complexes, it releases E2F. The latter then activates transcription of S-phase genes. The phosphorylation of pRb is inhibited by CDK inhibitors because they inactivate cyclin/CDK complexes. Virtually all cancer cells show dysregulation of the G1 S checkpoint owing to mutation in one of four genes that regulate the phosphorylation of pRb; these genes ( Rb, CDK4, cyclin D, and p16) are indicated by an asterisk.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-32 The role of p53 in maintaining the integrity of the genome. Activation of normal p53 by DNA-damaging agents or by hypoxia leads to cell cycle arrest in G1 and induction of DNA repair, by transcriptional up-regulation of the cyclin-dependent kinase inhibitor p21, and the GADD45 genes, respectively. Successful repair of DNA allows cells to proceed with the cell cycle; if DNA repair fails, p53-induced activation of the bax gene promotes apoptosis. In cells with loss or mutations of p53, DNA damage does not induce cell cycle arrest or DNA repair, and hence genetically damaged cells proliferate, giving rise eventually to malignant neoplasms.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-33 Regulation of cell death by bcl-2, bax, and p53. bcl-2 dimers favor cell accumulation by inhibiting apoptosis; bax dimers favor apoptosis. The apoptosis-inducing effect of normal p53 genes is mediated in part by increasing the synthesis of bax protein.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-34 Molecular model for the evolution of colorectal cancers through the adenoma-carcinoma sequence. (Based on studies of Fearon ER, Vogelstein B: A genetic model of colorectal carcinogenesis. Cell 61:759, 1990. Copyright 1990, Cell Press.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-35 Schematic illustration of the pathways of malignancy initiated by mutation of the gatekeeper genes (e.g., APC, NF-1, Rb) or caretaker genes (e.g., hMSH2, BRCA-1, BRCA-2).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-36 Subcellular localization and functions of major classes of cancer-associated genes. The protooncogenes are colored red, cancer suppressor genes blue, DNA repair genes green, and genes that regulate apoptosis purple.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-37 Biology of tumor growth. The left panel depicts minimal estimates of tumor cell doublings that precede the formation of a clinically detectable tumor mass. It is evident that by the time a solid tumor is detected, it has already completed a major portion of its life cycle as measured by cell doublings. The right panel illustrates clonal evolution of tumors and generation of tumor cell heterogeneity. New subclones arise from the descendants of the original transformed cell, and with progressive growth the tumor mass becomes enriched for those variants that are more adept at evading host defenses and are likely to be more aggressive. (Adapted from Tannock IF: Biology of tumor growth. Hosp Pract 18:81, 1983.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-38 Schematic representation of tumor growth. As the cell population expands, a progressively higher percentage of tumor cells leaves the replicative pool by reversion of G0 , differentiation, and death.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-39 The metastatic cascade. Schematic illustration of the sequential steps involved in the hematogenous spread of a tumor.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-40 A to D, Schematic illustration of the sequence of events in the invasion of epithelial basement membranes by tumor cells. Tumor cells detach from each other because of reduced adhesiveness, and cells then attach to the basement membrane via the laminin receptors and secrete proteolytic enzymes, including type IV collagenase and plasminogen activator. Degradation of the basement membrane and tumor cell migration follow.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-41 Experiments demonstrating the initiation and promotion phases of carcinogenesis in mice. Group 2: application of promoter repeated at twice-weekly intervals for several months; group 3: application of promoter delayed for several months and then applied twice weekly; group 6: promoter applied at monthly intervals.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-42 General schema of events in chemical carcinogenesis. Note that promoters cause clonal expansion of the initiated cell, thus producing a preneoplastic clone. Futher proliferation induced by the promoter or other factors causes accumulation of additional mutations and emergence of a malignant tumor.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-43 Schema depicting the possible evolution of Epstein-Barr virus (EBV)-induced Burkitt lymphoma.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-44 Pathogenesis of human T-cell leukemia virus type 1 (HTLV-1)-induced T-cell leukemia/lymphoma. HTLV-1 infects many T cells and initially causes polyclonal proliferation by autocrine and paracrine pathways. Ultimately, a monoclonal T-cell leukemia/lymphoma results when one proliferating T cell suffers additional mutations.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-45 Molecular mechanisms underlying the formation of tumor antigens recognized by CD8+ T cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-46 Cellular effectors of antitumor immunity and some cytokines that modulate antitumor activities. The nature of antigens recognized by T cells is depicted in Figure 8-45 .
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-47 A normal cervicovaginal smear shows large, flattened squamous cells and groups of metaplastic cells; interspersed are some neutrophils. There are no malignant cells. (Courtesy of Dr. P. K. Gupta, Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-48 An abnormal cervicovaginal smear shows numerous malignant cells that have pleomorphic, hyperchromatic nuclei; interspersed are some normal polymorphonuclear leukocytes. (Courtesy of Dr. P. K. Gupta, Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 8-49 Antikeratin immunoperoxidase stain of an undifferentiated tumor. The dark brown staining of keratin indicates an epithelial origin of this tumor (carcinoma).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-16 ICAM-1, a multifunctional receptor, binds to rhinovirus, Plasmodium falciparum, and integrins LFA-1 and Mac-1. D1 and D5 are Ig domains of the molecule.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-17 Tuberculosis: the dual consequences of macrophage activation and sensitization.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-18 Granuloma caused by Mycobacterium tuberculosis in the liver with central caseation and giant cells (arrow).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-19 Mycobacterium avium infection in a patient with AIDS, showing massive infection with acid-fast organisms. (Courtesy of Dr. Arlene Sharpe, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-20 Laminated Histoplasma granuloma of the lung.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-21 Histoplasma capsulatum yeast forms fill phagocytes in a lymph node of a patient with disseminated histoplasmosis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-22 Coccidioidomycosis with an intact spherule and a ruptured spherule releasing endospores.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-23 Close-up of a gross specimen showing colonic mucosa in Shigella colitis with erythema, ulceration, and pseudomembrane formation (white plaques).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-24 Typhoid nodule in the liver of a patient with systemic infection by Salmonella typhi.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-25 Mechanism of action of cholera toxin.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-26 Amebiasis of the colon with a portion of three Entamoeba histolytica trophozoites.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-27 Binucleate Giardia lamblia trophozoite in stool. (Courtesy of Dr. Anita Zaidi, Department of Infectious Diseases, Children's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-28 High-power view of cells from the blister in Fig. 9-14 showing glassy intranuclear herpes simplex inclusion bodies.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-29 Protean manifestations of syphilis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-30 Syphilitic chancre in the scrotum (see Fig. 9-13 for the histopathology of syphilis). (Courtesy of Dr. Richard Johnson, Beth Israel-Deaconess Hospital.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-31 Trichrome stain of liver shows liver gumma (scar), stained blue, which is caused by tertiary syphilis (also known as hepar lobatum). Compare with nodules of alcoholic cirrhosis (Chapter 19) .
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-32 Flagellated trophozoites of Trichomonas vaginalis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-33 The many consequences of staphylococcal infection.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-34 Staphylococcal abscess of the lung with extensive neutrophilic infiltrate and destruction of the alveoli (contrast with Fig. 9-12) .
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-35 Streptococcal erysipelas.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-36 Boxcar-shaped gram-positive Clostridium perfringens in gangrenous tissue.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-37 Measles giant cells in the lung. Note the glassy eosinophilic intranuclear inclusions.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-38 Pathways of transmission of the Epstein-Barr virus. In an individual with normal immune function, infection leads to mononucleosis. In the setting of cellular immunodeficiency (e.g., the X-linked immunodeficiency syndrome), proliferation of infected B cells is uncontrolled and may eventuate in B-cell neoplasms. One secondary genetic event that collaborates with Epstein-Barr virus (EBV) to cause B-cell transformation is a balanced 8;14 chromosomal translocation, which is seen in Burkitt's lymphoma. EBV has also been implicated in the pathogenesis of nasopharyngeal carcinoma, Hodgkin's disease, and certain other rare non-Hodgkin's lymphomas. Th , T helper cell; Tc , cytotoxic T cell.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-39 Atypical lymphocytes in infectious mononucleosis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-40 Dorsal root ganglion with varicella-zoster virus infection. Note the ganglion cell necrosis and associated inflammation. (Courtesy of Dr. James Morris, Radcliffe Infirmary, Oxford, England.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-41 Whooping cough showing bacilli (arrows) covering the cilia of bronchial columnar epithelial cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-42 Membrane of diphtheria lying within a transverse bronchus ( A) and forming a perfect cast (removed from the lung) of the branching respiratory tree ( B).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-43 Cytomegalovirus: distinct nuclear and ill-defined cytoplasmic inclusions in the lung. (Courtesy of Dr. Arlene Sharpe.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-44 Pseudomonas vasculitis in which masses of organisms form a perivascular blue haze.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-45 A, Severe candidiasis of the distal esophagus. B, Silver stain of a section of the same lesion reveals the dense mat of Candida.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-46 Mucicarmine stain of cryptococci (staining red) in a Virchow-Robin perivascular space of the brain (soap-bubble lesion).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-47 Aspergillus colony showing fruiting body and septate hyphae in the nasal septum (silver stain).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-48 PAS stain of mucormycosis showing hyphae, which have an irregular width and right-angle branching, invading an artery wall.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-49 Silver stain of cup-shaped Pneumocystis carinii organisms within a sputum sample from an AIDS patient.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-50 Blue cryptosporidia lining the edge of colonic epithelial cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-51 Typhus nodule in the brain.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-52 Rocky Mountain spotted fever with a thrombosed vessel and vasculitis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-53 Leprosy. A, Peripheral nerve. Note the inflammatory cell infiltrates in the endoneural and epineural compartments. B, A cell within the endoneurium contains acid-fast positive lepra bacilli. (Courtesy of E.P. Richardson Jr. and U. De Girolami, Harvard Medical School.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-54 Lepromatous leprosy. Acid-fast bacilli (red snappers) proliferate in the macrophages.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-55 Clinical stages of Lyme disease.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-56 Life cycle of Plasmodium falciparum. (Drawn by Dr. Jeffrey Joseph, Beth Israel-Deaconess Hospital, Boston.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-57 P. falciparum-infected red cells marginating within a vein in cerebral malaria.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-58 Babesia microti-filled erythrocytes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-59 Leishmania donovani parasites within the macrophages of a lymph node in visceral leishmaniasis (kala-azar).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-60 Coiled Trichinella spiralis larva within a skeletal muscle cell.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-61 Portion of a cysticercus cyst.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-62 Schistosomal life cycle.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-63 Schistosoma mansoni granuloma with a miracidium-containing egg (center) and numerous scattered eosinophils.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-64 Pipe-stem fibrosis of the liver due to chronic Schistosoma japonicum infection.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-65 Filariasis of the leg. (Courtesy of Dr. Willy Piessens, Harvard School of Public Health.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 9-66 Gravid female of Onchocerca volvulus in a subcutaneous fibrous nodule.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-5 Metabolism of ethanol. ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase. (From Parkinson A: Biotransformation of xenobiotics. In Klassen CD (ed): Casarett and Doull's Toxicology: The Basic Science of Poisons, 5th ed. New York, McGraw-Hill, 1996, p 128.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-6 Acute alcoholic hepatitis. The liver cells show cytoplasmic accumulation of fat and hyaline (arrow). A scattered inflammatory infiltrate is present. (MEDCOM © 1976.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-7 Micronodular cirrhosis is a late complication of chronic alcoholism (Masson trichrome stain). The liver architecture is distorted by regenerating nodules of hepatocytes surrounded by dense bands of fibrous tissue that stain blue. (Courtesy of Dr. Steve Kroft, Department of Pathology, Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-8 Effects of cocaine on neurotransmitters. Cocaine inhibits the reuptake of the neurotransmitters dopamine and norepinephrine in the central and peripheral nervous systems.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-9 Consequences of lead exposure.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-10 Atrophy of the thymus gland after exposure to ionizing radiation. The right panel shows a normal thymus with deeply staining cortex and pale staining medulla; the left panel shows depletion of lymphocytes with preservation of (pink, concentric) Hassall corpuscles. (American Registry of Pathology © 1990.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-11 Acute vascular injury with fibrinoid necrosis and edema after exposure to ionizing radiation. (American Registry of Pathology © 1990.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-12 Chronic vascular injury with subintimal fibrosis occluding the lumen. (American Registry of Pathology © 1990.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-13 Chronic radiation dermatitis with atrophy of the epidermis, dermal fibrosis, and telangiectasia of the subcutaneous blood vessels. (American Registry of Pathology © 1990.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-14 Extensive mediastinal fibrosis after radiotherapy for carcinoma of the lung. Note the markedly thickened pericardium. (From the teaching collection of the Department of Pathology, Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-15 Radiation fibrosis of the breast stroma after radiotherapy for infiltrating ductal carcinoma. The nests of remaining tumor cells are pleomorphic and multinucleated. (American Registry of Pathology © 1990.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-16 Solar elastosis with basophilic degeneration of the connective tissue in the upper layer of the dermis. (American Registry of Pathology © 1990.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-17 Abrasion. Note the superficial tears in the epidermis. There is bleeding under the skin as well. (From the teaching collection of the Department of Pathology, Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-18 Laceration of the scalp. The bridging strands of the fibrous tissue are evident. (From the teaching collection of the Department of Pathology, Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-19 Contusion resulting from blunt trauma. The skin is intact but there is hemorrhage in subcutaneous vessels, producing extensive discoloration. (From the teaching collection of the Department of Pathology, Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-20 A, Gunshot wound of entry from a long distance. (From the teaching collection of the Department of Pathology, Southwestern Medical School, Dallas, TX.) B, An entry gunshot wound at close range revealing the prominent black discoloration produced by unburned powder, heat, and smoke as well as the more peripheral stippling resulting from larger particles of unburned powder. (Courtesy of George Katsas, MD, Forensic Pathologist, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-21 Kwashiorkor. The infant shows generalized edema, seen in the form of puffiness of the face, arms, and legs.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-22 Interrelationships of retinoids and their major functions.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-23 Vitamin A deficiency: its major consequences in the eye, in the production of keratinizing metaplasia of specialized epithelial surfaces, and its possible role in potentiating neoplasia.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-24 A, Schema of normal vitamin D metabolism. B, Vitamin D deficiency. There is inadequate substrate for the renal hydroxylase (1), yielding a deficiency of 1,25 (OH)2 D (2), and deficient absorption of calcium and phosphorus from the gut (3), with consequent depressed serum levels of both (4). The hypocalcemia activates the parathyroid glands (5), causing mobilization of calcium and phosphorus from bone (6a). Simultaneously, the parathyroid hormone (PTH) induces wasting of phosphate in the urine (6b) and calcium retention. Consequently, the serum levels of calcium are normal or nearly normal but the phosphate is low; hence, mineralization is impaired (7).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-25 A, Detail of a rachitic costochondral junction. The palisade of cartilage is lost. Some of the trabeculae are old, well-formed bone, but the paler ones consist of uncalcified osteoid. B, For comparison, normal costochondral function from a young child demonstrates the orderly transition from cartilage to new bone formation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-26 Rickets. The bowing of legs in a toddler due to the formation of poorly mineralized bones is evident.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-27 A, The flabby, four-chambered, dilated heart of wet beriberi. B, The peripheral neuropathy with myelin degeneration leading to footdrop, wristdrop, and sensory changes in dry beriberi. C, Hemorrhages into the mamillary bodies in the Wernicke-Korsakoff syndrome.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-28 The sharply demarcated, characteristic scaling dermatitis of pellagra.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-29 A, Longitudinal section of a scorbutic costochondral junction with widening of the epiphyseal cartilage and projection of masses of cartilage into the adjacent bone. B, Detail of a scorbutic costochondral junction. The orderly palisade is totally destroyed. There is dense mineralization of the spicules but no evidence of newly formed osteoid.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-30 The major consequences of vitamin C deficiency.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-31 Zinc deficiency with hemorrhagic dermatitis around the mouth and eyes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-32 Mortality ratios for men and women at different levels of body mass index. (Data from Lew EA, Garfinkel L: Variations in mortality by weight among 750,000 men and women. J Chronic Dis 32:563, 1979.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 10-33 The hormonal and neural circuits that regulate body weight. Adipocytes secrete a hormone called leptin (also called ob protein) in response to nutritional status (available fat stores) and hormones such as insulin and glucocorticoids. Leptin is transported to the hypothalamus through the circulation, where it binds to the leptin receptor. This interaction regulates energy balance by affecting satiety (food intake) and energy expenditure. Leptin decreases the synthesis and secretion of the appetite stimulant neurotransmitter neuropeptide Y. In addition, through neuronal pathways, the activation of leptin receptor in the hypothalamus increases the release of norepinephrine from sympathetic nerve terminals that innervate adipose tissue. Norepinephrine binds to the beta3 -adrenergic receptors on fat cells and leads to increased metabolism of fatty acids and dissipation of the energy as heat. (Modified from Scott J: New chapter for the fat controller. Nature 379:113, 1996. Reprinted with permission from Nature. Copyright 1996 Macmillan Magazines Limited.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-4 Amniotic band syndrome. Note the placenta at the right of the diagram and the band of amnion extending from the top portion of the amniotic sac to encircle the leg of the fetus. (Courtesy of Dr. Theonia Boyd, Children's Hospital of Boston.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-5 Schematic diagram of the pathogenesis of the oligohydramnios sequence.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-6 Infant with oligohydramnios sequence. Note the flattened facial features and deformed right foot (talipes equinovarus).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-7 Critical periods of development for various organ systems and the resultant malformations. (Modified and redrawn from Moore KL: The Developing Human, 5th ed. Philadelphia, WB Saunders, 1993, p 156.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-8 Schematic representation of the postulated role of retinoic acid in normal development, the general features of its deficiency (vitamin A deficiency) ( left), and retinoic acid embryopathy ( right). 1, Retinol in the maternal circulation is bound by retinol-binding protein (RBP), which is synthesized by the placenta and enters the fetal circulation. 2, Once in fetal cells, retinol is bound by cytoplasmic retinol-binding protein (CRBP), which (3) regulates the conversion to retinoic acid and metabolites. The retinoic acid either remains in the cytoplasm (bound to cytoplasmic/cellular retinoic acid-binding protein [CRABP]) or (4) enters the nucleus, where it is bound to nuclear retinoic acid receptors (RAR, RXR). The retinoic acid-receptor complex acts as a transcriptional regulator of various patterning genes (e.g., HOX) that have the appropriate retinoic acid response element (RARE). Expression of the binding proteins and receptors in various tissues and at various times during embryogenesis may be a mechanism of selectively modulating the action of retinoic acid. This differential expression may also explain the pattern of abnormalities seen in vitamin A deficiency and retinoic acid embryopathy.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-9 Bone marrow from an infant infected with parvovirus B19. The arrows point to two erythroid precursors with large homogeneous intranuclear inclusions and a surrounding peripheral rim of residual chromatin.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-10 Schematic outline of the pathophysiology of the respiratory distress syndrome (see text).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-11 Hyaline membrane disease. There is alternating atelectasis and dilation of the alveoli. Note the eosinophilic thick hyaline membranes lining the dilated alveoli.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-12 Pathogenesis of erythroblastosis fetalis (see text).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-13 Numerous islands of extramedullary hematopoiesis (small blue cells) are scattered among mature hepatocytes in this infant with erythroblastosis fetalis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-14 The phenylalanine hydroxylase system.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-15 Pathways of galactose metabolism.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-16 Galactosemia. The liver shows extensive fatty change and a delicate fibrosis. (Courtesy of Dr. Wesley Tyson, The Children's Hospital, Denver, CO.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-17 Chloride channel defect in the sweat duct ( top) causes increased chloride and sodium concentration in sweat. In the airway ( bottom), cystic fibrosis patients have decreased chloride secretion and increased sodium and water reabsorption leading to dehydration of the mucous layer coating epithelial cells, defective mucociliary action, and mucous plugging of airways. There is also evidence that airway surface fluid in cystic fibrosis is deficient in antibacterial activity.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-18 Top, Normal cystic fibrosis transmembrane conductance regulator (CFTR) structure and activation. CFTR consists of two transmembrane domains, two nucleotide-binding domains (NBD), and a regulatory R domain. Agonists (e.g., acetylcholine) bind to epithelial cells and increase cAMP, which activates protein kinase A, the latter phosphorylating the CFTR at the R domain, resulting in opening of the chloride channel. Bottom, CFTR from gene to protein. The most common mutation in the CFTR gene results in defective protein folding in the Golgi/ER and degradation of CFTR before it reaches the cell surface. Other mutations affect synthesis of CFTR, nucleotide-binding and R domains, and membrane-spanning domains.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-20 Lungs of a patient dying of cystic fibrosis. There is extensive mucous plugging and dilation of the tracheobronchial tree. The pulmonary parenchyma is consolidated by a combination of both secretions and pneumonia--the green color associated with Pseudomonas infections. (Courtesy of Dr. Eduardo Yunis, Children's Hospital of Pittsburgh.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-21 Mild to moderate cystic fibrosis changes in the pancreas. The ducts are dilated and plugged with eosinophilic mucin, and the parenchymal glands are atrophic and replaced by fibrous tissue.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-22 Congenital capillary hemangioma at birth ( A) and at 2 years of age ( B) after spontaneous regression. (Courtesy of Dr. Eduardo Yunis, Children's Hospital of Pittsburgh.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-23 Sacrococcygeal teratoma. Note the size of the lesion compared with that of the infant.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-24 Adrenal neuroblastoma in a 6-month-old child. The hemorrhagic, partially encapsulated tumor has displaced the opened left kidney and is impinging on the aorta and left renal artery. (Courtesy of Dr. Arthur Weinberg, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-25 Adrenal neuroblastoma. This tumor is composed of small cells embedded in a finely fibrillar matrix.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-26 Fluorescence in situ hybridization using a fluorescein-labeled cosmid probe for N- myc on a tissue section. Note the neuroblastoma cells on the upper half of the photo with large areas of staining (yellow-green); this corresponds to amplified Nmyc in the form of homogeneously staining regions. Renal tubular epithelial cells in the lower half of the photograph show no nuclear staining and background (green) cytoplasmic staining. (Courtesy of Dr. Timothy Triche, Children's Hospital, Los Angeles, CA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-27 Wilms' tumor in the lower pole of the kidney with the characteristic tan to gray color and well-circumscribed margins.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 11-28 Triphasic histology of Wilms' tumor with a stromal, less cellular area on the left, spindle-shaped cells, and epithelial (one clear tubule in the center) and blastemic (tightly packed blue cells) elements. (Courtesy of Dr. Charles Timmons, Department of Pathology, University of Texas Southwestern Medical School, Dallas TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-4 Schematic mechanism for intimal thickening, emphasizing smooth muscle cell migration to, and proliferation and extracellular matrix elaboration in, the intima. (Modified and redrawn from Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, WB Saunders, 1989, p 254.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-5 Natural history of atherosclerosis. Plaques usually develop slowly and insidiously over many years, beginning in childhood or shortly thereafter. As described in the text, they may progress from a fatty streak to a fibrous plaque and then to a complicated plaque that is likely to lead to clinical effects. (Modified from McGill HC Jr, et al: Natural history of human atherosclerotic lesions. In Sandler M, Bourne GH (eds): Atherosclerosis and Its Origin. New York, Academic Press, 1963, p 42; Wissler RW. Principles of the pathogenesis of atherosclerosis. In Braunwald E (ed): Heart Disease, Philadelphia, WB Saunders, 1984, p 1183.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-6 Major components of well-developed atheromatous plaque: fibrous cap composed of proliferating smooth muscle cells, macrophages, lymphocytes, foam cells, and extracellular matrix. The necrotic core consists of cellular debris, extracellular lipid with cholesterol crystals, and foamy macrophages.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-7 Gross views of atherosclerosis in the aorta. A, Mild atherosclerosis composed of fibrous plaques, one of which is denoted by the arrow. B, Severe disease with diffuse and complicated lesions.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-8 Histologic features of atheromatous plaque in the coronary artery. A, Overall architecture demonstrating a fibrous cap (F) and a central lipid core (C) with typical cholesterol clefts. The lumen (L) has been moderately narrowed. Note the plaque-free segment of the wall ( arrow). In this section, collagen has been stained blue (Masson trichrome stain). B, Higher-power photograph of a section of the plaque shown in A, stained for elastin (black) demonstrating that the internal and external elastic membranes are destroyed and the media of the artery is thinned under the most advanced plaque ( arrow). C, Higher-magnification photomicrograph at the junction of the fibrous cap and core showing scattered inflammatory cells, calcification ( broad arrow), and neovascularization ( small arrows).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-9 Fatty streak--a collection of foam cells in the intima. A, Aorta with fatty streaks ( arrows), associated largely with the ostia of branch vessels. B, Close-up photograph of fatty streaks from the aorta of an experimental hypercholesterolemic rabbit shown after staining with Sudan red, a lipid-soluble dye, again illustrating the relationship of the lesions to the two-branch vessel ostia. C, Photomicrograph of fatty streak in an experimental hypercholesterolemic rabbit, demonstrating intimal macrophage-derived foam cells ( arrow). ( B and C courtesy of Myron I. Cybulsky, MD, University of Toronto, Canada.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-11 Estimated 10-year risk of coronary heart disease according to various combinations of risk factor levels. (From Kannel WB, et al: An update on coronary risk factors. Med Clin North Am 79:951, 1995.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-12 Processes in the response to injury hypothesis. 1, Normal. 2, Endothelial injury with adhesion of monocytes and platelets (the latter to denuded endothelium). 3, Migration of monocytes (from the lumen) and smooth muscle cells (from the media) into the intima. 4, Smooth muscle cell proliferation in the intima. 5, Well-developed plaque.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-13 Schematic diagram of a hypothetical sequence of cell-level events and cellular interactions in atherosclerosis. Hyperlipidemia and other risk factors are thought to cause endothelial injury, resulting in adhesion of platelets and monocytes and release of growth factors, including platelet-derived growth factor (PDGF), which lead to smooth muscle cell migration and proliferation. Smooth muscle cells produce large amounts of extracellular matrix, including collagen and proteoglycans. Foam cells of atheromatous plaques are derived from both macrophages and smooth muscle cells--from macrophages via the very-low-density lipoprotein (VLDL) receptor and low-density lipoprotein (LDL) modifications recognized by scavenger receptors (e.g., oxidized LDL), and from smooth muscle cells by less certain mechanisms. Extracellular lipid is derived from insudation from the vessel lumen, particularly in the presence of hypercholesterolemia, and also from degenerating foam cells. Cholesterol accumulation in the plaque should be viewed as reflecting an imbalance between influx and efflux, and it is possible that high-density lipoprotein (HDL) helps clear cholesterol from these accumulations.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-14 Blood pressure regulation. NO/EDRF, nitric oxide-endothelium-derived relaxing factor.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-16 Hypothetical scheme for the pathogenesis of essential hypertension, implicating genetic defects in renal excretion of sodium, functional regulation of vascular tone, and structural regulation of vascular caliber. Environmental factors, especially increased salt intake, potentiate the effects of genetic factors. The resultant increase in cardiac output and peripheral resistance contributes to hypertension. ECF, extracellular fluid.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-17 Vascular pathology in hypertension. A, Hyaline arteriolosclerosis. The arteriolar wall is hyalinized and the lumen is markedly narrowed. B, Hyperplastic arteriolosclerosis (onionskinning) causing luminal obliteration ( arrow), with secondary ischemic changes, manifested by wrinkling of the glomerular capillary vessels at the upper left (periodic acid-Schiff [PAS] stain). (Courtesy of Helmut Rennke, MD, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-19 Temporal (giant cell) arteritis. A, H&E stain of giant cells at the degenerated internal elastic membrane in active arteritis. B, Elastic tissue stain demonstrating focal destruction of internal elastic membrane ( arrow) and intimal thickening (IT) characteristic of long-standing or healed arteritis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-20 Takayasu arteritis. A, Aortic arch angiogram showing narrowing of brachiocephalic, carotid, and subclavian arteries ( arrows). B, Gross photograph of two cross-sections of the right carotid artery taken at the autopsy of the patient shown in A, demonstrating marked intimal thickening with minimal residual lumen. C, Histologic view of active Takayasu aortitis, illustrating destruction of the arterial media by mononuclear inflammation with giant cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-21 Polyarteritis nodosa. Polyarteritis nodosa with segmental fibrinoid necrosis and thrombotic occlusion of the lumen of this small artery. Note that part of the vessel wall at the upper right ( arrow) is uninvolved. (Courtesy of Sid Murphree, MD, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-22 Leukocytoclastic vasculitis in a skin biopsy showing fragmentation of neutrophil nuclei in and around vessel walls. (Courtesy of Scott Granter, MD, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-23 Wegener granulomatosis. There is inflammation (vasculitis) of a small artery along with adjacent granulomatous inflammation, in which epithelioid cells and giant cells ( arrows) can be seen. (Courtesy of Sid Murphree, MD, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-24 Thromboangiitis obliterans (Buerger disease). The lumen is occluded by a thrombus containing two abscesses ( arrows). The vessel wall is infiltrated with leukocytes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-25 Vasculitis with fibrinoid necrosis in a patient with active systemic lupus erythematosus.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-26 Gross photographs of an abdominal aortic aneurysm that ruptured. A, External view of the large aneurysm; the rupture site is indicated by the arrow. B, Opened view with the location of the rupture tract indicated by a probe. The wall of the aneurysm is exceedingly thin and the lumen is filled by a large quantity of layered but largely unorganized thrombus.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-27 A, Gross photograph of proximal aortic dissection demonstrating a small, oblique intimal tear (demarcated by the probe), allowing blood to enter the media, creating an intramural hematoma ( narrow arrows). Note that the intimal tear has occurred in a region largely free from atherosclerotic plaque, and that propagation of the intramural hematoma is arrested at a site more distally where atherosclerosis begins ( broad arrow). B, Histologic view of the dissection demonstrating an aortic intramural hematoma ( asterisk). Aortic elastic layers black and blood red in this section, stained with Movat stain.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-28 Cystic medial degeneration. A, Cross-section of aortic media with marked elastin fragmentation and formation of areas devoid of elastin that resemble cystic spaces, from a patient with Marfan syndrome. B, Normal aortic media for comparison, showing the regular layered pattern of elastic tissue. In both A and B the tissue section is stained to highlight elastin as black.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-29 Classification of dissection into types A and B. Type A (proximal) involves the ascending aorta, whereas type B (distal) does not.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-30 Varicose veins of the leg. (Courtesy of Magruder C. Donaldson, MD, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-31 Hemangiomas. A, Hemangioma of the tongue. B, Pyogenic granuloma of the lip. C, Juvenile capillary hemangioma. D, Cavernous hemangioma. ( A and B courtesy of John Sexton, MD, Beth Israel Hospital, Boston MA; C courtesy of Christopher D.M. Fletcher, MD, Brigham and Women's Hospital, Boston, MA; D courtesy of Thomas Rogers, MD, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-32 Bacillary angiomatosis. A, Photograph of a moist, erosive cutaneous lesion. B, Histologic appearance with acute neutrophilic inflammation and vascular (capillary) proliferation. Inset, Demonstration by modified silver (Warthin-Starry) stain of clusters of tangled bacilli (black). ( A courtesy of Richard Johnson, MD, Beth Israel Deaconess Medical Center, Boston, MA; B and inset courtesy of Scott Granter, MD, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-33 Kaposi sarcoma. A, Gross photograph illustrating coalescent red-purple macules and plaques of the skin. B, Histologic view of the nodular form demonstrating sheets of plump, proliferating spindle cells and vascular spaces. (Courtesy of Christopher D.M. Fletcher, MD, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-34 Schematic representation of the progressive gross and microscopic stages of Kaposi sarcoma.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-35 Angiosarcoma. A, Gross photograph of angiosarcoma of the heart (right ventricle). B, Photomicrograph of moderately well differentiated angiosarcoma with dense clumps of irregular, moderate anaplastic cells and distinct vascular lumens. C, Positive immunohistochemical staining of angiosarcoma for the endothelial cell marker CD31, proving the endothelial nature of the tumor cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-36 Balloon angioplasty. A, Coronary artery with recent balloon angioplasty in a low-power photomicrograph showing the split encompassing the intima and media ( arrow) and partial circumferential wall dissection. B, Gross photograph of restenosis after balloon angioplasty demonstrating a residual atherosclerotic plaque ( left arrow) and a new, glistening proliferative lesion ( right arrow).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 12-37 Anastomotic hyperplasia at the distal anastomosis of a synthetic femoropopliteal graft. A, Angiogram demonstrating constriction ( arrow). B, Photomicrograph demonstrating expanded polytetrafluoroethylene graft ( arrow) with prominent intimal proliferation and a very small residual lumen ( asterisk). ( A courtesy of Anthony D. Whittemore, MD, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-2 Schematic representation of the sequence of events in cardiac hypertrophy and its progression to heart failure, emphasizing cellular and extracellular changes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-3 Atherosclerotic plaque rupture. A, Plaque rupture without superimposed thrombus in a patient who died suddenly. B, Acute coronary thrombosis superimposed on an atherosclerotic plaque with focal disruption of the fibrous cap, triggering fatal myocardial infarction. C, Massive plaque rupture with superimposed thrombus, also triggering a fatal myocardial infarction (special stain highlighting fibrin in red). In both A and B an arrow points to the site of plaque rupture. ( B from Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, WB Saunders, 1989, p 61.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-4 Schematic representation of sequential progression of coronary artery lesion morphology, beginning with stable chronic plaque responsible for typical angina and leading to the various acute coronary syndromes. (Modified and redrawn from Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, WB Saunders, 1989, p 63.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-5 Postmortem angiogram demonstrating the posterior aspect of the heart of a patient who died during evolution of acute myocardial infarction. There is total occlusion of the distal right coronary artery by an acute thrombus (arrow) and a large zone of myocardial hypoperfusion involving the posterior left and right ventricles (arrowheads). The heart has been fixed by coronary arterial perfusion with glutaraldehyde and cleared with methyl salicylate, followed by intracoronary injection of silicone polymer. Photograph courtesy of Lewis L. Lainey. (From Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, WB Saunders, 1989, p 60. Courtesy of Lewis L. Lainey.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-6 Schematic representation of the progression of myocardial necrosis after coronary artery occlusion. Necrosis begins in a small zone of the myocardium beneath the endocardial surface in the center of the ischemic zone. This entire region of myocardium (dashed outline) depends on the occluded vessel for perfusion and is the area at risk. Note that a very narrow zone of myocardium immediately beneath the endocardium is spared from necrosis because it can be oxygenated by diffusion from the ventricle.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-7 Acute myocardial infarct, predominantly of the posterolateral left ventricle, demonstrated histochemically by a lack of staining by the triphenyltetrazolium chloride (TTC) stain in areas of necrosis. The staining defect is due to the enzyme leakage that follows cell death. Note the myocardial hemorrhage at one edge of the infarct that was associated with cardiac rupture, and the anterior scar (lower left), indicative of old infarct. (Specimen oriented with posterior wall at top.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-8 Microscopic features of myocardial infarction. A, One-day-old infarct showing coagulative necrosis, wavy fibers with elongation, and narrowing, compared with adjacent normal fibers (lower right). Widened spaces between the dead fibers contain edema fluid and scattered neutrophils. B, Dense polymorphonuclear leukocytic infiltrate in an area of acute myocardial infarction of 3 to 4 days' duration. C, Nearly complete removal of necrotic myocytes by phagocytosis (approximately 7 to 10 days). D, Granulation tissue with a rich vascular network and early collagen deposition, approximately 3 weeks after infarction. E, Well-healed myocardial infarct with replacement of the necrotic fibers by dense collagenous scar. A few residual cardiac muscle cells are present. (In D and E, collagen is highlighted as blue in this Masson trichrome stain.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-9 Gross and microscopic appearance of myocardium modified by reperfusion. A, Large, densely hemorrhagic, anterior wall acute myocardial infarction from a patient with left anterior descending (LAD) artery thrombus treated with streptokinase intracoronary thrombolysis (TTC-stained heart slice). B, Myocardial necrosis with hemorrhage and contraction bands, visible as dark bands spanning some myofibers (arrows). This is the characteristic appearance of markedly ischemic myocardium that has been reperfused. (Specimen in A oriented with posterior wall up.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-10 Cardiac rupture syndromes complicating acute myocardial infarction. A, Anterior myocardial rupture in an acute infarct (arrow). B, Rupture of the ventricular septum (arrow). C, Complete rupture of a necrotic papillary muscle.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-11 Complications of myocardial infarction. A, Fibrinous pericarditis, with a dark, roughened epicardial surface overlying an acute infarct. B, Early expansion of an anteroapical infarct with wall thinning and mural thrombus (arrow). (From Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, WB Saunders, 1989.) C, Large apical left ventricular aneurysm. The left ventricle is on the right on this apical four-chamber view of the heart. (Courtesy of William D. Edwards, MD, Mayo Clinic, Rochester, MN.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-12 Hypertensive heart disease with marked concentric thickening of the left ventricular wall causing reduction in lumen size. The left ventricle is on the right in this apical four-chamber view of the heart. A pacemaker is incidentally present (arrow) with the lead terminating in the right ventricle.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-13 Chronic cor pulmonale characterized by a markedly dilated and hypertrophied right ventricle, with thickened free wall and hypertrophied trabeculae (apical four-chamber view of the heart, right ventricle on the left). The shape of the left ventricle (to the right) has been distorted by the right ventricular enlargement. Compare with Figure 13-12 .
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-14 Valvular calcific degeneration. A, Degenerative calcific aortic stenosis of a previously normal valve having three cusps (viewed from the aortic aspect). Nodular masses of calcium are heaped up within the sinuses of Valsalva (arrow). Note that the commissures are not fused, as in postrheumatic aortic valve stenosis (see Fig. 13-16 E). B, Calcific aortic stenosis occurring on a congenitally bicuspid valve. One cusp has a partial fusion at its center, called a raphe (arrow). C and D, Mitral annular calcification with calcific nodules at the base (attachment margin) of the anterior mitral leaflet (arrows). C, Left atrial view; D, cut section of myocardium.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-15 Myxomatous degeneration of the mitral valve. A, Long axis view of the left ventricle demonstrating hooding with prolapse of the posterior mitral leaflet into the left atrium (arrow). The left ventricle is on the right. (Courtesy of William D. Edwards, MD, Mayo Clinic, Rochester, MN.) B, Opened valve showing pronounced hooding of the posterior mitral leaflet with thrombotic plaques at sites of leaflet-left atrium contact (arrows). C, Opened valve with pronounced hooding from a patient who died suddenly. Note also the mitral annular calcification.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-16 Acute and chronic rheumatic heart disease. A, Acute rheumatic mitral valvulitis superimposed on chronic rheumatic heart disease. Small vegetations (verrucae) are visible along the line of closure of the mitral valve leaflet (arrowheads). Previous episodes of rheumatic valvulitis have caused fibrous thickening and fusion of the tendinous cords. B, Microscopic appearance of an Aschoff body in a patient with acute rheumatic carditis. The myocardial interstitium has a circumscribed collection of mononuclear inflammatory cells, including some large histiocytes with prominent nucleoli, a prominent binuclear histiocyte, and central necrosis. C and D, Mitral stenosis with diffuse fibrous thickening and distortion of the valve leaflets, commissural fusion (arrow in C), and thickening and shortening of the tendinous cords. Marked dilation of the left atrium is noted in the left atrial view ( C). D, Opened valve. Note the neovascularization of the anterior mitral leaflet (arrow). E, Surgically removed specimen of rheumatic aortic stenosis demonstrating thickening and distortion of the cusps with commissural fusion ( E from Schoen FJ, St. John-Sutton M: Contemporary issues in the pathology of valvular heart disease. Hum Pathol 18:568, 1967.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-17 The pathogenetic sequence and key morphologic features of acute rheumatic heart disease.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-18 Bacterial infective endocarditis. A, Endocarditis of the mitral valve (subacute, caused by Streptococcus viridens). The irregular, large friable vegetations are denoted by arrows. B, Acute endocarditis of a congenitally bicuspid aortic valve (caused by Staphylococcus aureus) with severe cuspal destruction and ring abscess (arrow). C, Histologic appearance of vegetation of endocarditis with extensive acute inflammatory cells and fibrin. Bacterial organisms were demonstrated by tissue Gram stain. D, Gross photograph illustrating healed endocarditis with perforations on bicuspid aortic valve.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-19 Diagrammatic comparison of the lesions in the four major forms of vegetative endocarditis. The rheumatic fever phase of RHD (rheumatic heart disease) is marked by a row of warty, small vegetations along the lines of closure of the valve leaflets. IE (infective endocarditis) is characterized by large, irregular masses on the valve cusps that can extend onto the cords (see Fig. 13-18 A). NBTE (nonbacterial thrombotic endocarditis) typically exhibits small, bland vegetations, usually attached at the line of closure. One or many may be present (see Fig. 13-20) . LSE (Libman-Sacks endocarditis) has small or medium-sized vegetations on either or both sides of the valve leaflets.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-20 Nonbacterial thrombotic endocarditis (NBTE). A, Nearly complete row of thrombotic vegetations along the line of closure of the mitral valve leaflets. B, Photomicrograph of NBTE showing bland thrombus, with virtually no inflammation in the valve cusp (c) or the thrombotic deposit. The thrombus is only loosely attached to the cusp (arrow).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-21 Carcinoid heart disease. A, Characteristic endocardial fibrotic lesion involving the right ventricle and tricuspid valve. B, Microscopic appearance of carcinoid heart disease with intimal thickening. Movat staining shows underlying myocardial elastic tissue as black and acid mucopolysaccharides as blue-green.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-22 Thrombosis of a mechanical prosthetic heart valve.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-23 Representation of the three distinctive clinical-pathologic-functional forms of myocardial disease.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-24 Dilated cardiomyopathy. A, Gross photograph. Four-chamber dilation and hypertrophy are evident. There is granular mural thrombus at the apex of the left ventricle (on the right in this apical four-chamber view). The coronary arteries were unobstructed. B, Histology demonstrating variable myocyte hypertrophy and interstitial fibrosis (collagen is highlighted as blue in this Masson trichrome strain).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-25 Hypertrophic cardiomyopathy. A, There is asymmetric hypertrophy of the septal muscle, which bulges into the left ventricular outflow tract, and the left atrium is enlarged. Apical four-chamber view; left ventricle on right. The anterior mitral leaflet has been moved away from the septum to reveal a fibrous endocardial plaque (see text). (From Schoen FJ: Interventional and Surgical Cardiovascular Pathology: Clinical Correlations and Basic Principles. Philadelphia, WB Saunders, 1989, p 180.) B, Histologic appearance demonstrating disarray, extreme hypertrophy, and peculiar branching of myocytes as well as interstitial fibrosis (collagen is blue in this Masson trichrome stain). C, Structure of the sarcomere of cardiac muscle, highlighting proteins in which mutations cause defective contraction, hypertrophy, and myocyte disarray in hypertrophic cardiomyopathy. The frequency of a particular gene mutation is indicated as a percentage; most common are mutations in beta-myosin heavy chain. Normal contraction of the sarcomere involves myosin-actin interaction initiated by calcium binding to troponin C, I, and T and alpha-tropomyosin. Actin stimulates ATPase activity in the myosin head and produces force along the actin filaments. Myocyte-binding protein C modulates contraction. (From Spirito P, et al: The management of hypertrophic cardiomyopathy. N Engl J Med 336:775, 1997.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-26 Myocarditis. A, Lymphocytic myocarditis, with dense mononuclear inflammatory cell infiltrate and associated myocyte injury. B, Hypersensitivity myocarditis, characterized by interstitial inflammatory infiltrate composed largely of eosinophils and mononuclear inflammatory cells. C, Giant cell myocarditis, with mononuclear inflammatory infiltrate containing lymphocytes and macrophages, with extensive loss of muscle, and multinucleated giant cells, apparently derived from muscle. D, Myocarditis of Chagas disease. A myofiber is distended with trypanosomes (arrow). There is a surrounding inflammatory reaction and individual myofiber necrosis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-27 Acute suppurative pericarditis as an extension from pneumonia. Extensive purulent exudate is evident in this in situ photograph.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-28 Left atrial myxoma. A, Gross photograph showing a large pedunculated lesion arising from the region of the fossa ovalis and extending into the mitral valve orifice. B, Microscopic appearance, with abundant amorphous extracellular matrix in which are scattered collections of myxoma cells in various groupings, including abnormal vascular formations (arrow).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-29 Schematic diagram of congenital left-to-right shunts. A, Atrial septal defect. B, Ventricular septal defect (VSD). The shunt is left to right and the pressures are the same in both ventricles. Pressure hypertrophy of the right ventricle and volume hypertrophy of the left ventricle are present. C, Patent ductus arteriosus. D, Atrioventricular septal defect. E, Large VSD with irreversible pulmonary hypertension. In E, the shunt is right to left (shunt reversal) and there is volume and pressure hypertrophy of the right ventricle. Arrows indicate the direction of blood flow. Ao, aorta; RA, right atrium; LA, left atrium; LV, left ventricle; RV, right ventricle; PT, pulmonary trunk. (Courtesy of William D. Edwards, MD, Mayo Clinic, Rochester, MN.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-30 Gross photograph of a ventricular septal defect (arrow) (membranous type) viewed from the left ventricle. (Courtesy of William D. Edwards, MD, Mayo Clinic, Rochester, MN.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-31 Schematic diagram of the most important right-to-left shunts (cyanotic congestive heart disease). A, Tetralogy of Fallot. Diagrammatic representation of anatomic variants, indicating that the direction of shunting across the VSD depends on the severity of the subpulmonary stenosis. Arrow indicates the direction of the blood flow. B, Transposition of the great vessels with and without VSD. Ao, aorta; LA, left atrium; RA, right atrium; LV, left ventricle; RV, right ventricle; PT, pulmonary trunk (Courtesy of William D. Edwards, MD, Mayo Clinic, Rochester, MN.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-32 Gross photograph showing transposition of the great vessels. The aorta is arising from the right ventricle (at left) and the pulmonary artery from the left ventricle (at right). (Courtesy of William D. Edwards, MD, Mayo Clinic, Rochester, MN.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-33 Diagram showing coarctation of the aorta with and without persistent ductus arteriosus (PDA). Ao, aorta; LA, left atrium; RA, right atrium; LV, left ventricle; RV, right ventricle; PT, pulmonary trunk. (Courtesy of William D. Edwards, MD, Mayo Clinic, Rochester, MN.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 13-34 Complications of heart transplantation. A, Cardiac allograft rejection typified by lymphocytic infiltrate, with associated damage to cardiac myocytes. B, Graft coronary arteriosclerosis demonstrating severe diffuse concentric intimal thickening producing critical stenosis. The internal elastic lamina (arrow) and media are intact (Movat pentachrome stain, elastin black). ( B from Salomon RN, et al: Human coronary transplantation-associated arteriosclerosis. Evidence for chronic immune reaction to activated graft endothelial cells. Am J Pathol 138:791, 1991.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-2 Schematic of splenic sinus (electron micrograph). An erythrocyte is in the process of squeezing from the dead into the sinus lumen. Note the degree of deformability required for the red cells to pass through the wall of the sinus.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-3 Marrow smear from a patient with hemolytic anemia. The marrow reveals many clusters of proliferating normoblasts. (Courtesy of Dr. Steven Kroft, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-4 Schematic representation of the red cell membrane cytoskeleton and the effects of alterations in the cytoskeletal proteins on the shape of red cells. With mutations that affect the integrity of the membrane cytoskeleton, the normal biconcave erythrocyte loses membrane fragments. To accommodate the loss of surface area, the cell adopts a spherical shape. Such spherocytic cells are less deformable than normal and are therefore trapped in the splenic cords, where they are phagocytosed by macrophages.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-5 Model of the pathophysiology of hereditary spherocytosis. (Adapted from Wyngaarden JB, et al [eds]: Cecil Textbook of Medicine, 19th ed. Philadelphia, WB Saunders, 1992, p 859.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-6 Peripheral smear from a patient with hereditary spherocytosis. Note the anisocytosis and several dark-appearing spherocytes with no central pallor. (Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-7 The role of glucose-6-phosphate dehydrogenase (G6PD) in the defense against oxidant injury. The disposal of H2 O2 , a potential oxidant, is dependent on the adequacy of reduced glutathione (GSH), which in turn is generated by the action of NADPH. The synthesis of NADPH is dependent on the activity of G6PD. GSSG, oxidized glutathione.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-8 Peripheral blood smear from a patient with G6PD deficiency after exposure to an oxidant drug. Inset, Red cells with precipitates of denatured globin (Heinz bodies) revealed by supravital staining. As the splenic macrophages pluck out these inclusions, "bite cells" like the one in this smear are produced. (Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-9 Peripheral blood smear from a patient with sickle cell anemia. A, Low magnification shows sickle cells, anisocytosis, and poikilocytosis. B, Higher magnification shows an irreversibly sickled cell in the center. (Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-10 Pathophysiology and morphologic consequences of sickle cell anemia.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-11 A, Spleen in sickle cell anemia (low power). Red pulp with its cords and sinusoids is markedly congested; in between the congested areas, pale areas of fibrosis resulting from ischemic damage are also seen. B, Under high power, splenic sinusoids are dilated and filled with sickled red cells (Courtesy of Dr. Darren Wirthwein, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-12 Markedly shrunken spleen from a patient with sickle cell anemia. (Courtesy of Drs. Dennis Burns and Darren Wirthwein, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-13 Diagrammatic representation of the beta-globin gene, and some sites where point mutations giving rise to thalassemia have been localized.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-14 Pathogenesis of beta-thalassemia major. Note that aggregates of excess alpha-globin are not visible on routine blood smears. Blood transfusions, on the one hand, correct the anemia and reduce the stimulus for erythropoietin secretion and deformities induced by marrow expansion; on the other hand, they add to the systemic iron overload.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-15 Thalassemia: x-ray film of the skull showing new bone formation on the outer table, producing perpendicular radiations characterized as a "crew haircut." (Courtesy of Dr. Jack Reynolds, Department of Radiology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-16 Two kinds of membrane proteins: transmembrane and glycosyl phosphatidyl inositol (GPI) linked. The latter are anchored to the cell membrane by glycosyl phospatidyl inositol. In PNH the GPI moiety cannot be synthesized, and therefore the GPI-linked proteins cannot be expressed on the cell membrane.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-17 Microangiopathic hemolytic anemia. The peripheral blood smear from a patient with hemolytic-uremic syndrome shows several fragmented red cells. (Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-18 A peripheral blood smear from a patient with megaloblastic anemia shows a neutrophil with a six-lobed nucleus (macropolycyte). (Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-19 Marrow smear from a patient with megaloblastic anemia. A to C, Megaloblasts in various stages of differentiation. Note that the orthochromatic megaloblast ( B) is hemoglobinized (as evidenced by cytoplasmic color), but in contrast to an orthochromatic normoblast, the nucleus is not pyknotic. The granulocytic precursors are also large. (Courtesy of Dr. Jose Hernandez, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-20 Schematic illustration of vitamin B12 absorption.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-21 Diagram of the relationship between N[5] -methyl FH4 , methionine synthase, and thymidylate synthetase. In cobalamin deficiency, folate is sequestered as N[5] -methyl FH4 . This ultimately deprives thymidylate synthetase of its folate coenzyme ( N[5] [10] -methylene FH4 ) and thereby impairs DNA synthesis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-22 Schematic illustration of the role of folate derivatives in the transfer of one-carbon fragments for synthesis of biologic macromolecules. FH4 , tetrahydrofolic acid; FH2 , dihydrofolic acid; FIGlu, formiminoglutamate; dTMP, deoxythymidylate monophosphate. *Synthesis of methionine also requires vitamin B12 .
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-23 The internal iron cycle. In the plasma, iron bound to transferrin is transported to the marrow, where it is transferred to developing red blood cells and incorporated into hemoglobin. The mature red blood cells are released into the circulation and, after 120 days, are ingested by macrophages in the reticuloendothelial system (RES). Here the iron is extracted from hemoglobin and returned to the plasma, completing the cycle. (From Wyngaarden JB, et al [eds]: Cecil Textbook of Medicine, 19th ed. Philadelphia, WB Saunders, 1992, p 841.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-24 Diagrammatic representation of iron absorption. Mucosal uptake of heme and nonheme iron is depicted. Not illustrated is the iron transporter protein Nramp2 that is involved in the passage of iron across the mucosal cell membrane. When the storage sites of the body are replete with iron and erythropoietic activity is normal, most of the absorbed iron is lost into the gut by shedding of the epithelial cells. Conversely, when body iron needs to be increased or when erythropoiesis is stimulated, a greater fraction of the absorbed iron is transferred into plasma transferrin, with a concomitant decrease in iron loss through mucosal ferritin.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-25 Hypochromic microcytic anemia of iron deficiency. Note the small red cells containing a narrow rim of hemoglobin at the periphery. Contrast with the scattered fully hemoglobinized cells derived from a recent blood transfusion given to the patient. (Courtesy of Dr. Robert W. McKenna, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-26 Pathophysiology of aplastic anemia. Insults to stem cells may produce progeny with new antigens and evoke an autoimmune reaction, or the altered stem cells may give rise to a clonal population with reduced proliferative capacity. Either pathway could lead to marrow aplasia.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-27 Aplastic anemia (bone marrow). The marrow is markedly hypocellular, composed largely of fat cells. A, Low power. B, High power. (Courtesy of Dr. Steven Kroft, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-28 Structure and function of factor VIII-von Willebrand factor (vWF) complex. Factor VIII is synthesized by the liver and vWF in the endothelial cells. The two circulate as a complex in the circulation. Factor VIII takes part in the coagulation cascade by activating factor X. vWF causes adhesion of platelets to subendothelial collagen via the glycoprotein (Gp) Ib-IX platelet receptor. Ristocetin activates glycoprotein Ib-IX receptors in vitro and causes platelet aggregation if vWF is present.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 14-29 Pathophysiology of disseminated intravascular coagulation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 15-38 Schematic illustration of the normal splenic architecture. (Modified from Faller DV: Diseases of the spleen. In Wyngaarden JB, Smith LH [eds]: Cecil Textbook of Medicine, 18th ed. Philadelphia, WB Saunders, 1988, p 1036.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 15-39 Splenic infarcts. Multiple well-circumscribed infarcts are present in this spleen (2820 gm; normal, 150-200 gm) that is massively enlarged by extramedullary hematopoiesis secondary to bone marrow myelofibrosis. Recent infarcts are hemorrhagic, whereas older, more fibrotic infarcts are pale yellow-gray.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 15-40 Benign and malignant thymoma. A, Benign thymoma (medullary type). The neoplastic epithelial cells are arranged in a swirling pattern and have bland, oval to elongated nuclei with inconspicuous nucleoli. Only a few small, reactive lymphoid cells are interspersed. B, Malignant thymoma type I. The neoplastic epithelial cells are polygonal and have round to oval, bland nuclei with inconspicuous nucleoli. Numerous small, reactive lymphoid cells are interspersed. The morphologic appearance of this tumor is identical to that of benign thymomas of the cortical type. In this case, however, the tumor was locally aggressive, invading adjacent lung and pericardium. (Courtesy of Dr. David Dorfman, Department of Pathology, Brigham and Women's Hospital, Boston, MA.)Neutrophilic leukocytosis Acute bacterial infections, especially
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-2 Various forms of atelectasis in adults.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-3 Diffuse alveolar damage (adult respiratory distress syndrome) shown in a photomicrograph. Some of the alveoli are collapsed, others distended. Many contain dense proteinaceous debris, desquamated cells, and hyaline membranes (arrows).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-4 Simplified model for diffuse alveolar damage in endotoxemia. Endotoxin associated with gram-negative organisms acts on multiple targets. It induces monocytes and lung macrophages to release mediators, including tumor necrosis factor alpha (TNF-alpha) and chemotactic peptides (e.g., leukotriene B4 , interleukin 8). Endotoxin-induced activation of complement releases C5a, which together with bacterial lipopolysaccharide and TNF-alpha activates polymorphonuclear neutrophil leukocytes (PMNs) and up-regulates binding avidity of adhesion molecules. Endotoxin also activates endothelial cells to up-regulate adhesion molecules that facilitate binding of neutrophils. Activation of PMNs results in the release of oxidants, proteases, and prostaglandins. The net result is the sequestration (and extravasation) of PMNs in pulmonary capillaries, damage to endothelial and epithelial cells, and the development of interstitial edema and alveolar hyaline membranes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-5 Large saddle embolus from the femoral vein lying astride the main left and right pulmonary arteries. (From the teaching collection of the Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-6 Recent, small, roughly wedge-shaped hemorrhagic pulmonary infarct.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-7 Vascular changes in pulmonary hypertension. A, Gross photograph of atheroma formation, a finding usually limited to large vessels. B, Marked medial hypertrophy. C, Plexogenic lesion characteristic of advanced pulmonary hypertension seen in small arteries and arterioles.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-8 A, Diagram of normal structures within the acinus, the fundamental unit of the lung. A terminal bronchiole (not shown) is immediately proximal to the respiratory bronchiole. B, Centrilobular emphysema with dilation that initially affects the respiratory bronchioles. C, Panacinar emphysema with initial distention of the peripheral structures (i.e., the alveolus and alveolar duct); the disease later extends to affect the respiratory bronchioles.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-9 A, Centrilobular emphysema. Central areas show marked emphysematous damage (E), surrounded by relatively spared alveolar spaces. B, Panacinar emphysema involving the entire pulmonary architecture.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-10 Protease-antiprotease mechanism of emphysema. Smoking inhibits antielastase and favors the recruitment of leukocytes and release of elastase. PMN, polymorphonuclear leukocytes; Mac, alveolar macrophages.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-11 Bullous emphysema with large subpleural bullae (upper left).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-12 Schematic representation of evolution of chronic bronchitis (left) and emphysema (right). Although both can culminate in chronic bronchitis and emphysema, the pathways are different, and either one may predominate. The dashed arrows on the left indicate that, in the natural history of chronic bronchitis, it is not known whether there is a predictable progression from obstruction in small airways to chronic (obstructive) bronchitis. (Redrawn from Fishman AP: The spectrum of chronic obstructive disease of the airways. In Fishman AP (ed): Pulmonary Diseases and Disorders, 2nd ed. New York, McGraw-Hill, 1988, p 1164.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-13 A model for allergic asthma. A, Inhaled allergens (antigen) elicit a Th2-dominated response favoring IgE production and eosinophil recruitment (priming or sensitization). B, On reexposure to antigen (Ag), the immediate reaction is triggered by Ag-induced cross-linking of IgE bound to IgE receptors on mast cells in the airways. These cells release preformed mediators that open tight junctions between epithelial cells. Antigen can then enter the mucosa to activate mucosal mast cells and eosinophils, which in turn release additional mediators. Collectively, either directly or via neuronal reflexes, the mediators induce bronchospasm, increased vascular permeability, and mucus production and recruit additional mediator-releasing cells from the blood. C, The arrival of recruited leukocytes (neutrophils, eosinophils, and basophils; also lymphocytes and monocytes [ not shown]) signals the initiation of the late phase of asthma and a fresh round of mediator release from leukocytes, endothelium, and epithelial cells. Factors, particularly from eosinophils (e.g., major basic protein, eosinophil cationic protein), also cause damage to the epithelium.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-14 Comparison of a normal bronchiole with that in a patient with asthma. Note the accumulation of mucus in the bronchial lumen resulting from an increase in the number of mucus-secreting goblet cells in the mucosa and hypertrophy of submucosal mucous glands. In addition, there is intense chronic inflammation due to recruitment of eosinophils, macrophages, and other inflammatory cells. Basement membrane underlying the mucosal epithelium is thickened, and there is hypertrophy and hyperplasia of smooth muscle cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-15 Bronchiectasis. Cut surface of lung showing transected, markedly distended peripheral bronchi, in this case predominantly in the upper lobes--an unusual localization.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-16 Comparison of bronchopneumonia and lobar pneumonia.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-17 Bronchopneumonia. Gross section of lung showing patches of consolidation (arrows).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-18 Lobar pneumonia--gray hepatization, gross photograph. The lower lobe is uniformly consolidated.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-19 Lung defense mechanisms. A, In the nonimmune lung, removal of microbial organisms depends on 1 entrapment in the mucous blanket (green) and removal via the mucociliary elevator, 2 phagocytosis by alveolar macrophages that can kill and degrade organisms and remove them from the airspacesby migrating onto the mucociliary elevator, or 3 phagocytosis and killing by neutrophils recruited by macrophage factors. 4 Serum complement may enter the alveoli and be activated by the alternate pathway to provide the opsonin C3b that enhances phagocytosis. 5 Organisms, including those ingested by phagocytes, may reach the draining lymph nodes to initiate immune responses. B, Additional mechanisms operate in the immune lung.1 Secreted IgA can block attachment of the microorganism to epithelium in the upper respiratory tract. 2 In the lower respiratory tract, serum antibodies (IgM, IgG) are present in the alveolar lining fluid. They activate complement more efficiently by the classic pathway, yielding C3b (not shown). In addition, IgG is opsonic. 3 The accumulation of immune T cells is important for controlling infections by viruses and other intracellular microorganisms.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-20 A, Acute pneumonia. The congested septal capillaries and extensive neutrophil exudation into alveoli corresponds to early red hepatization. Fibrin nets have not yet formed. B, Early organization of intra-alveolar exudate, seen in areas to be streaming through the pores of Kohn ( arrow). C, Advanced organizing pneumonia (corresponding to gray hepatization), featuring transformation of exudates to fibromyxoid masses richly infiltrated by macrophages and fibroblasts.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-21 Pyemic lung abscess in the center of section with complete destruction of underlying parenchyma within the focus of involvement.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-22 Primary pulmonary tuberculosis, Ghon complex. The gray-white parenchymal focus is under the pleura in the lower part of the upper lobe (topmost arrow). Hilar lymph nodes with caseation are seen (lowermost arrows).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-23 Natural history and spectrum of tuberculosis (TB). (Adapted from a sketch provided by Dr. R. K. Kumar, The University of New South Wales, School of Pathology, Sydney, Australia.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-24 Characteristic tubercle at low magnification ( A) and in detail ( B), to illustrate central granular caseation and epithelioid and multinucleated giant cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-25 Miliary tuberculosis of the spleen. The cut surface shows numerous gray-white granulomas.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-26 A possible schema of the pathogenesis of idiopathic pulmonary fibrosis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-27 Progressive massive fibrosis superimposed on coal workers' pneumoconiosis. The large, blackened scars are located principally in the upper lobe. Note the extensions of scars into surrounding parenchyma and retraction of adjacent pleura. (Courtesy of Dr. Werner Laquer, Dr. Jerome Kleinerman, and the National Institute of Occupational Safety and Health, Morgantown, WV.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-28 Advanced silicosis seen on transection of lung. Scarring has contracted the upper lobe into a small dark mass (arrow). Note the dense pleural thickening. (Courtesy of Dr. John Godleski, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-29 Several coalescent collagenous silicotic nodules. (Courtesy of Dr. John Godleski, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-30 High-power detail of an asbestos body, revealing the typical beading and knobbed ends (arrow).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-31 Asbestos exposure evidenced by severe, discrete, characteristic fibrocalcific plaques on the pleural surface of the diaphragm. (Courtesy of Dr. John Godleski, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-32 Characteristic sarcoid noncaseating granulomas in lung with many giant cells. (Courtesy of Dr. Ramon Blanco, Department of Pathology, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-33 Diffuse interstitial fibrosis. Note the marked interstitial fibrosis (highlighted blue in this Masson trichrome stain), focal chronic inflammation, and dilated spaces lined by cuboidal type II epithelial cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-34 Desquamative interstitial pneumonitis: medium-power detail of lung to demonstrate fibrous thickening of the alveolar walls and accumulation of large numbers of mononuclear cells within the alveolar spaces.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-35 Hypersensitivity pneumonitis, histologic appearance. Loosely formed interstitial granulomas and chronic inflammation are characteristic.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-36 Bronchiolitis obliterans-organizing pneumonia (BOOP). The bronchiole shows a plug of organizing exudate.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-37 Acute intra-alveolar hemorrhage and hemosiderin-laden macrophages, reflecting previous hemorrhage, are common features of the diffuse pulmonary hemorrhage syndromes (Prussian blue stain for iron).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-38 Pulmonary alveolar proteinosis, histologic appearance. The alveoli are filled with a dense, amorphous, protein-lipid granular precipitate.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-39 Acute rejection of a lung allograft is characterized by perivascular mononuclear cell infiltrates.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-40 Bronchogenic carcinoma. The gray-white tumor tissue is seen infiltrating the lung substance. Histologically, this large tumor mass was identified as a squamous cell carcinoma.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-41 Histologic appearance of bronchogenic carcinoma: A, Well-differentiated squamous cell carcinoma showing keratinization. B, Gland-forming adenocarcinoma. C, Small cell carcinoma with islands of small deeply basophilic cells and areas of necrosis. D, Large cell carcinoma, featuring pleomorphic, anaplastic tumor cells and absence of squamous or glandular differentiation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-42 Cytologic diagnosis of lung cancer is often possible. A, A sputum specimen shows an organophilic, keratinized squamous carcinoma cell with a prominent hyperchromatic nucleus (arrow). B, A fine-needle aspirate of an enlarged lymph node shows clusters of tumor cells from a small cell carcinoma, with molding and nuclear atypia characteristic of this tumor (see also Fig. 16-41 C); note the size of the tumor cells compared with normal polymorphonuclear leukocytes in the left lower corner.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-43 Terminal bronchioloalveolar carcinoma with characteristic tall, columnar cell papillary growth. Note the loose tumor cells in the alveoli, which may account for the "aerogenous" spread of tumor often observed.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-44 A, Bronchial carcinoid growing as a spherical, pale mass (arrow) protruding into the lumen of the bronchus. B, Histologic appearance of bronchial carcinoid, demonstrating small, rounded, uniform cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-45 Numerous metastases from a renal cell carcinoma. (Courtesy of Dr. Michelle Mantel, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-46 Malignant mesothelioma. Note the thick, firm, white, pleural tumor tissue that ensheathes this bisected lung.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-47 Malignant mesothelioma, epithelial type. The tumor cells are immunoperoxidase positive for keratin, as shown (brown), but would be carcinoembryonic antigen negative.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 16-48 Ultrastructural features of pulmonary adenocarcinoma ( A), characterized by short, plump microvilli, contrasted with those of mesothelioma ( B), in which microvilli are numerous, long, and slender. (Courtesy of Dr. Noel Weidner, University of California, San Francisco, School of Medicine.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 17-6 A, Nasal polyps. Low-power magnification showing edematous masses lined by epithelium. B, High-power views showing edema and eosinophil-rich inflammatory infiltrate.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 17-7 Inverted papilloma. The masses of squamous epithelium are growing inward; hence, the term inverted. (Courtesy of Dr. James Gulizia, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 17-8 Nasopharyngeal carcinoma, lymphoepithelioma-type. The syncytium-like nests of epithelium are surrounded by lymphocytes. (Courtesy of Dr. James Gulizia, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 17-9 A, Laryngeal carcinoma. Note the large, ulcerated, fungating lesion involving the vocal cord and pyriform sinus. B, Histologic appearance of laryngeal squamous cell carcinoma. Note the atypical lining epithelium and invasive keratinizing cancer cells in the submucosa.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 17-10 Diagrammatic comparison of a benign papilloma and an exophytic carcinoma of the larynx to highlight their quite different appearances.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 17-11 Carotid body tumor. A, Low-power view showing tumor clusters separated by septa (zellballen). B, High-power view of large, eosinophilic, slightly vacuolated tumor cells with elongated sustentacular cells in the septa.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 17-12 Pleomorphic adenoma of the parotid. The transected, sharply circumscribed, yellow-white tumor protrudes above the level of the surrounding glandular substance.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 17-13 Pleomorphic adenoma. A, Low-power view showing a well-demarcated tumor with normal parotid acini below. B, High-power view showing amorphous myxoid stroma resembling cartilage, with interspersed islands and strands of myoepithelial cells. (Courtesy of Dr. E. Lee, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 17-14 Warthin tumor. A, Lower-power view showing epithelial and lymphoid elements. Note the follicular germinal center beneath the epithelium. B, Cleftlike spaces separate the lobules of tumor covered by a regular double layer of eosinophilic epithelial cells based on a lymphoid stroma. (Courtesy of Dr. James Gulizia, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 17-15 A, Mucoepidermoid carcinoma showing islands having squamous cells as well as clear cells containing mucin. B, Mucicarmine stains the mucin reddish-pink. (Courtesy of Dr. James Gulizia, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 17-16 Adenoid cystic carcinoma in a salivary gland. A, Low-power view. The tumor cells have created a cribriform pattern enclosing secretions. B, High-power view showing polygonal tumor cells surrounding the cystic space filled with secretions.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-11 Anatomy of the stomach.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-12 Acute gastritis. A, Gross view showing punctate erosions in an otherwise unremarkable mucosa; adherent blood is dark owing to exposure to gastric acid. B, Low-power microscopic view of focal mucosal disruption with hemorrhage; the adjacent mucosa is normal.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-13 Schematic presentation of the presumed action of Helicobacter pylori in the development of chronic gastritis. H. pylori infection leads to exposure of the gastric mucosa to bacteria-derived urease and toxins, including lipopolysaccharide, cagA, and vacA. These, in concert with host-derived gastric acidity and peptic enzymes, produce a chronic state of gastric mucosal injury leading to chronic gastritis as depicted. Note that H. pylori do not colonize regions of intestinal metaplasia.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-14 Chronic gastritis showing partial replacement of the gastric mucosal epithelium by intestinal metaplasia (upper left) and with inflammation of the lamina propria involving (right) lymphocytes and plasma cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-15 H. pylori. A Steiner silver stain demonstrates the numerous darkly stained Helicobacter organisms along the luminal surface of the gastric epithelial cells and within adherent mucus. Note that there is no tissue invasion by bacteria.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-16 Diagram of aggravating causes of, and defense mechanisms against, peptic ulceration.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-17 Perforating peptic ulcer of the duodenum ( arrowhead). Note that the ulcer is small (2 cm) with a sharply punched-out appearance. Unlike cancerous ulcers, the margins are not elevated. The ulcer base shows a small amount of blood but is otherwise clean. Compare with the ulcerated carcinoma in Figure 18-23 .
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-18 Multiple stress ulcers of the stomach, highlighted by dark digested blood on their surface.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-19 Trichobezoar showing the agglomeration of hair, food, and mucus that occurred within the gastric lumen.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-20 Hypertrophic gastropathy showing markedly thickened gastric folds.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-21 Adenomatous polyp of the stomach. Note the large size of the polyp and its lobulated configuration. A small ulceration ( arrow) can be identified on its surface. (From Kasimer W, Dayal Y: Gastritis, gastric atrophy, and gastric neoplasia. In Chopra S, May RJ (eds): Pathophysiology of Gastrointestinal Disorders, Boston, Little, Brown, 1989.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-22 Diagram of growth patterns and spread of gastric carcinoma. In early gastric carcinoma, tumor is confined to the mucosa and submucosa and may exhibit an exophytic, flat or depressed, or excavated conformation. Advanced gastric carcinoma extends into the muscularis propria and beyond. Linitis plastica is an extreme form of flat or depressed advanced gastric carcinoma.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-23 Ulcerative gastric carcinoma. The ulcer is large and irregular.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-24 Gastric cancer. A, Poorly differentiated intestinal-type adenocarcinoma. Note small glands. B, Diffuse signet ring cell carcinoma of the stomach, surrounding a residual benign gastric gland in the mucosa. (Courtesy of Dr. Robert Odze, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-25 A, Normal small intestinal histology showing mucosal villi and crypts, lined by columnar cells. B, Normal colon histology showing a flat mucosal surface and abundant vertically oriented crypts.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-26 Meckel diverticulum. The blind pouch is on the antimesenteric side of the small bowel.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-27 Infectious enterocolitis from Shigella infection. Segment of colon showing pale, granular, inflamed mucosa with patches of coagulated exudate.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-28 Pseudomembranous colitis from Clostridium difficile infection. A, Gross photograph. Close-up of mucosal surface showing plaques of yellow fibrin and inflammatory debris adherent to a reddened colonic mucosa. B, Low-power micrograph showing superficial erosion of the mucosa and an adherent "pseudomembrane" of fibrin, mucus, and inflammatory debris.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-29 Giardia lamblia. Trophozoite (arrow) of the organism immediately adjacent to the duodenal surface of epithelium; note the double nuclei. The other luminal material is mucus (bluish) and an erythrocyte displaced by the biopsy procedure.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-30 Celiac sprue (gluten-sensitive enteropathy) (bottom) compared with normal jejunum (top). In sprue there is diffuse severe atrophy and blunting of villi, with a chronic inflammatory infiltrate of the lamina propria. (Courtesy of Dr. James Gulizia, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-31 Whipple disease. A, PAS-positive strain showing large macrophages in lamina propria with PAS-positive material. B, Electron micrograph of a lamina propria macrophage and its adjacent extracellular space (top) from a jejunal biopsy specimen. Many bacilli are seen (arrowheads) and several disintegrating organisms are present within the macrophage (arrow), contributing membranous material and intracellular granules. ( B, From Trier JS, et al: Whipple's disease: light and electron microscope correlation of jejunal mucosal histology with antibiotic treatment and clinical status. Gastroenterology 48:684-707, 1965.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-32 Crohn disease of the ileum showing narrowing of the lumen, bowel wall thickening, serosal extension of mesenteric fat ("creeping fat"), and linear ulceration of the mucosal surface (arrowheads).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-33 Crohn disease. Low power micrograph showing a deep fissure extending into the muscle wall (center); a second, shallow ulcer (upper right); and relative preservation of the intervening mucosa. Abundant lymphocyte aggregates are present, evident as dense blue patches of cells at the interface between mucosa and submucosa.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-34 Crohn disease of the colon. Noncaseating granulomas are present in the lamina propria of a mildly inflamed region of colonic mucosa.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-35 The distribution patterns of Crohn disease and ulcerative colitis are compared, as well as the different conformations of the ulcers and wall thickenings.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-36 Ulcerative colitis. Raw ulcerated hemorrhaghic surface with knobby pseudopolyps (Courtesy of Dr. Kim Bechard, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-37 Toxic megacolon. Complete cessation of colon neuromuscular activity has led to massive dilation of the colon and black-green discoloration, signifying gangrene and impending rupture.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-38 Ulcerative colitis with crypt abscess (middle of field, top). (Courtesy of Dr. James Gulizia, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-39 Chronic ulcerative colitis. Low-power micrograph showing marked chronic inflammation of the mucosa with atrophy of colonic glands, moderate submucosal fibrosis, and a normal muscle wall.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-40 Acute ischemic bowel disease. Schematic of the three levels of severity diagrammed for the small intestine (mucosal infarction, mural infarction, and transmural infarction).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-41 Infarcted small bowel secondary to acute thrombotic occlusion of the superior mesenteric artery.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-42 Mucosal infarction of the small bowel. The mucosa is hemorrhagic and there is no epithelial layer. The remaining layers of the bowel are intact.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-43 Chronic ischemia of the colon, resulting in chronic mucosal damage and a stricture of the ascending colon. The terminal ileum is in the lower portion of the photograph.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-44 Diverticulosis. A, Section through the sigmoid colon showing multiple saclike diverticula protruding through the muscle wall into the mesentery. The muscularis propria in between the diverticular protrusions is markedly thickened. B, Low-power photomicrograph of diverticulum of the colon showing protrusion of mucosa and submucosa through the muscle wall. A dilated blood vessel at the base of the diverticulum was a source of bleeding; some blood clot is present within the diverticular lumen.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-45 Schematic depicting the four major causes of intestinal obstruction: (1) herniation of a segment in the umbilical or inguinal regions; (2) adhesion between loops of intestine; (3) intussusception (see text); and (4) volvulus formation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-46 Adenoma of the ampulla of Vater showing exophytic tumor at the ampullary orifice.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-47 Diagrammatic representation of two forms of sessile polyp (hyperplastic polyp and adenoma) and of two types of adenoma (pedunculated and sessile). There is only a loose association between the tubular architecture for pedunculated adenomas and the villous architecture for sessile adenomas.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-48 Non-neoplastic colonic polyps. A, Hyperplastic polyp, high-power view showing the serrated profile of the epithelial layer. B, Peutz-Jeghers polyp, low-power view showing the splaying of smooth muscle into the superficial portion of the pedunculated polyp.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-49 A, Pedunculated adenoma showing a fibrovascular stalk lined by normal colonic mucosa, and a head that contains abundant dysplastic epithelial glands. B, A small focus of adenomatous epithelium in an otherwise normal (mucin-secreting, clear) colonic mucosa, showing how the dysplastic columnar epithelium (deeply stained) can populate a colonic crypt and create a "tubular" architecture.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-50 A, Sessile adenoma with villous architecture. Each frond is lined by dysplastic epithelium. B, Portion of a villous frond with dysplastic columnar epithelium on the left and normal colonic columnar epithelium on the right.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-51 A, Familial adenomatous polyposis. The surface is carpeted by innumerable polypoid adenomas. (Courtesy of Dr. Tad Wieczorek, Brigham and Women's Hospital, Boston, MA.) B, Possible actions of the APC gene product (see text). (Courtesy of Dr. David Ferguson, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-52 Schematic of the morphologic and molecular changes in the adenoma-carcinoma sequence. It is postulated that loss of one normal copy of the cancer suppressor "gatekeeper" gene APC and/or loss of DNA repair "caretaker" genes (e.g., MSH2) occurs early. Indeed, individuals may be born with one mutant allele of one of these genes, rendering them prone to develop colon cancer. The loss of the normal copy of the mismatch-repair gene or APC follows ("second hit"). Mutations of the oncogene K- ras seem to occur next. Additional mutations or losses of heterozygosity inactivate the tumor suppressor gene p53 and as yet unidentified loci on chromosome 18q, leading finally to the emergence of carcinoma, in which additional mutations occur. It is important to note that while there seems to be a temporal sequence of changes, as shown, the accumulation of mutations, rather than their occurrence in a specific order, is more important.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-53 Carcinoma of the cecum. The exophytic carcinoma projects into the lumen but has not caused obstruction.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-54 Carcinoma of the descending colon. This circumferential tumor has heaped-up edges and an ulcerated central portion. The arrows identify separate mucosal polyps.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-55 Invasive adenocarcinoma of the colon showing malignant glands infiltrating the muscle wall.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-56 Pathologic staging of colorectal cancer according to the Astler-Coller system. Staging is based on the extent of local invasion and the presence of lymph node metastases ( A to C) and distant visceral metastases (D).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-57 Carcinoid tumor. A, Multiple protruding tumors are present at the ileocecal junction. B, The tumor cells exhibit a monotonous morphology, with a delicate intervening fibrovascular stroma. C, Electron micrograph showing dense core bodies in the cytoplasm.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-58 Acute appendicitis. The inflamed appendix shown below is red, swollen, and covered with a fibrinous exudate. For comparison, a normal appendix is shown above.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 18-59 Mucinous cystadenocarcinoma of a markedly enlarged appendix.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-45 Typical solute composition of gallbladder and hepatic bile in health. (From Carey MC: Biliary lipids and gallstone formation. In Csomos G, Thaler H (eds): Clinical Hepatology. Berlin, Springer-Verlag, 1983, pp 52-69.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-46 Phrygian cap of the gallbladder; the fundus is folded inward.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-47 Schematic representation of the four contributing factors for cholelithiasis: supersaturation, gallbladder hypomotility, crystal nucleation, and accretion within the gallbladder mucous layer.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-48 Cholesterol gallstones. Mechanical manipulation during laparoscopic cholecystectomy has caused fragmentation of several cholesterol gallstones, revealing interiors that are pigmented because of entrapped bile pigments. The gallbladder mucosa is reddened and irregular as a result of coexistent chronic cholecystitis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-49 Pigment gallstones. Several faceted black gallstones are present in this otherwise unremarkable gallbladder from a patient with a mechanical mitral valve prosthesis, leading to chronic intravascular hemolysis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-50 Acute calculous cholecystitis; the stone was not photographed.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-51 Chronic cholecystitis demonstrating a thickened gallbladder wall and luminal stones.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-52 Biliary atresia, schematized to show the pattern of biliary tract injury.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 19-53 Gallbladder adenocarcinoma. A, The opened gallbladder contains a large, exophytic tumor that virtually fills the lumen. B, Malignant glandular structures are present within a densely fibrotic gallbladder wall.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-11 Immunoperoxidase staining shows a dark reaction product for insulin in beta cells ( A), glucagon in alpha cells ( B), and somatostatin in delta cells ( C). D, Electron micrographs of beta cells show the characteristic membrane-bound granules, each containing a dense, often rectangular core and distinct halo. E, Portions of an alpha cell ( left) and delta cell ( right) also exhibit granules, but with closely apportioned membranes. The alpha-cell granule exhibits a dense, round center. (Electron micrographs courtesy of Dr. A. Like, University of Massachusetts Medical School, Worcester, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-12 Insulin synthesis and secretion. Glucose stimulates both synthesis and calcium-dependent secretion of insulin, while other agents--amino acids and certain gastrointestinal hormones--induce only insulin secretion. GLUT-2 is an insulin-independent glucose transporter that facilitates entry of glucose into the cell.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-13 Insulin action on a target cell. Insulin binds to the alpha subunit of the insulin receptor and activates tyrosine-specific protein kinase autophosphorylation of the adjacent beta subunit. This activates a cascade that stimulates DNA synthesis, protein synthesis (anabolism), and translocation of glucose transport units (GLUT proteins) from the Golgi apparatus to the plasma membrane.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-14 A simplified schema to show pathways of beta-cell destruction leading to type 1 (insulin-dependent) diabetes mellitus. An environmental insult, possibly viral infection, is thought to provoke autoimmune attack of beta cells in genetically susceptible individuals. Environmental insults may involve either molecular mimicry, in which a viral antigen evokes autoimmune attack of a similar beta-cell antigen, or direct damage to beta cells, causing abnormal expression of beta-cell antigens.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-16 Pathogenesis of type 2 diabetes mellitus. Genetic predisposition and environmental influences converge to cause hyperglycemia and overt diabetes. The primacy of deranged beta-cell insulin secretion and peripheral insulin resistance is not established; in patients with clinical disease, both defects can be demonstrated.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-17 Chemical effects of diabetic hyperglycemia. A, Nonenzymatic glycosylation of proteins. The advanced glycosylation product involves protein-protein cross-linking. Note that whereas the early glycosylation products are reversible, advanced end products are irreversible. (Modified from Brownlee M, et al: Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 318:1315, 1988.) B, Intracellular hyperglycemia, the sorbitol pathway, and effects on myo-inositol. (Modified from Greene DA, et al: Sorbitol, phosphoinositides, and sodium potassium ATPase in the pathogenesis of diabetic complications. N Engl J Med 316:599, 1987.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-18 Long-term complications of diabetes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-19 A, Insulitis, shown here from a rat (BB) model of autoimmune diabetes, and seen in type 1 human diabetes. (Courtesy of Dr. Arthur Like, University of Massachusetts, Worchester, MA.) B, Amyloidosis of a pancreatic islet in type 2 diabetes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-20 Severe renal hyaline arteriolosclerosis. Note a markedly thickened, tortuous afferent arteriole. The amorphous nature of the thickened vascular wall is evident. (Periodic acid-Schiff [PAS] stain; courtesy of M.A. Venkatachalam, MD, Department of Pathology, University of Texas Health Science Center at San Antonio, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-21 Renal cortex showing thickening of tubular basement membranes in a diabetic patient. (PAS stain.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-22 Renal glomerulus showing markedly thickened glomerular basement membrane (B) in a diabetic. L, glomerular capillary lumen; U, urinary space. (Courtesy of Michael Kashgarian, MD, Department of Pathology, Yale University School of Medicine.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-23 Nephrosclerosis in a patient with long-standing diabetes. The kidney has been bisected to demonstrate both diffuse granular transformation of the surface ( left) and marked thinning of the cortical tissue ( right). Additional features include some irregular depressions, the result of pyelonephritis, and an incidental cortical cyst ( far right).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-24 Sequence of metabolic derangements leading to diabetic coma in type 1 diabetes mellitus. An absolute insulin deficiency leads to a catabolic state, eventuating in ketoacidosis and severe volume depletion. These cause sufficient central nervous system compromise to cause coma, and eventual death if left untreated.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 20-25 Pancreatic islet cell tumor less than 1 cm in diameter in a focal area of pancreatic fibrosis. Despite the small size of the tumor, clinical hypoglycemia was present.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-5 Renal dysplasia. A, Gross appearance, B, Histologic section showing disorganized architecture, dilated tubules, and islands of immature cartilage, PAS stain. (Courtesy of Dr. D. Schofield, Children's Hospital, Los Angeles, CA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-6 A schematic of human polycystin molecule, with various domains drawn approximately to scale. The long extracellular region consists primarily of the following domains: two leucine-rich repeats (LRRs); a C type lectin domain; a low-density lipoprotein (LDL-A) type module; 16 PKD repeats, each of which may assume an immunoglobulin-like fold; and an egg jelly type module (EJD). Eleven membrane-spanning segments are predicted, followed by a short cytoplasmic tail. (Courtesy of Dr. Amin Arnaout, Massachusetts General Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-7 Possible mechanisms of cyst formation in polycystic kidney disease (see text).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-8 A and B, Autosomal dominant adult polycystic kidney, viewed from external surface and bisected. The kidney is markedly enlarged with numerous dilated cysts. C, Autosomal recessive childhood polycystic kidney disease, showing smaller cysts and dilated channels at right angles to the cortical surface. D, Liver with cysts in adult PKD.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-9 Uremic medullary cystic disease. Cut section of kidney showing cysts at the corticomedullary junction and in the medulla.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-10 Antibody-mediated glomerular injury can result either from the deposition of circulating immune complexes ( A) or more commonly from in situ formation of complexes exemplified by anti-GBM disease ( B) or Heymann nephritis ( C). D and E, Two patterns of deposition of immune complexes as seen by immunofluorescence microscopy: D, granular, characteristic of circulating and in situ immune complex nephritis; E, linear, characteristic of classic anti-GBM disease.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-14 Renal ablation glomerulosclerosis. The adaptive changes in glomeruli (hypertrophy and glomerular capillary hypertension), as well as systemic hypertension, cause epithelial and endothelial injury and resultant proteinuria. The mesangial response, involving mesangial cell proliferation and extracellular matrix (ECM) production together with intraglomerular coagulation, causes the glomerulosclerosis. This results in further loss of functioning nephrons and a vicious circle of progressive glomerulosclerosis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-16 Acute proliferative glomerulonephritis. A, Normal glomerulus. B, Glomerular hypercellularity is due to intracapillary leukocytes and proliferation of intrinsic glomerular cells. C, Typical electron-dense subepithelial "hump" and a neutrophil in the lumen. (Courtesy of Dr. H. Rennke, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-17 Crescentic glomerulonephritis (PAS stain). Note the collapsed glomerular tufts and the crescent-shaped mass of proliferating cells and leukocytes internal to Bowman capsule. (Courtesy of Dr. M.A. Venkatachalam, Department of Pathology, University of Texas Health Sciences Center, San Antonio, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-18 Rapidly progressive glomerulonephritis. Electron micrograph showing characteristic wrinkling of GBM with focal disruptions in its continuity ( arrows).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-19 Membranous glomerulonephritis. A, PAS stain. Note marked diffuse thickening of the capillary wall without increase in the number of cells. B, Electron micrograph showing electron-dense deposits (arrow) along the epithelial side of the basement membrane (B). Note obliteration of foot process overlying deposits. CL, capillary lumen; End, endothelium; Ep, epithelium. C, Characteristic granular immunofluorescent deposits of IgG along GBM. D, Diagrammatic representation of membranous glomerulonephritis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-20 Minimal change disease. Thin section of glomerulus stained with PAS. Note thin basement membrane and absence of proliferation. Compare with membranous glomerulonephritis in Figure 21-19 A.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-21 A, Ultrastructural characteristics of minimal change disease: loss of foot processes (double arrows), absence of deposits, vacuoles (V), and microvilli in visceral epithelial cells (single arrow). B, Schematic representation of minimal change disease, showing diffuse loss of foot processes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-22 Focal segmental glomerulosclerosis. PAS stain. A, Low-power view showing segmental sclerosis in one of three glomeruli (at 3 o'clock). B, High-power view showing hyaline mass and lipid (small vacuoles) in sclerotic area.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-23 Membranoproliferative glomerulonephritis, showing mesangial cell proliferation, increased mesangial matrix, basement membrane thickening, and accentuation of lobular architecture. (Courtesy of Dr. H. Rennke, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-24 A, Membranoproliferative glomerulonephritis, type I. Note large subendothelial deposit (arrow) incorporated into mesangial matrix (M). E, endothelium; EP, epithelium; CL, capillary lumen. B, Type II membranoproliferative glomerulonephritis, dense-deposit disease. There are markedly dense homogeneous deposits within the basement membrane proper. CL, capillary lumen. C, Schematic representation of patterns in the two types of membranoproliferative GN. In type I there are subendothelial deposits; type II is characterized by intramembranous dense deposits (dense deposit disease). In both, mesangial interposition gives the appearance of split basement membranes when viewed in the light microscope.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-25 The alternative complement pathway. Note that C3NeF, present in the serum of patients with membranoproliferative glomerulonephritis, acts at the same step as properdin, serving to stabilize the alternative pathway C3 convertase, thus enhancing C3 breakdown and causing hypocomplementemia.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-26 IgA nephropathy. A, Light microscopy showing mesangial proliferation and matrix increase. B, Characteristic immunofluorescence deposition of IgA, principally in mesangial regions.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-27 Focal glomerulonephritis in lupus erythematosus. There is segmental proliferation of cells and necrosis on the right. In the necrotic area, there are neutrophils and fragmented nuclei (nuclear dust). The remainder of the glomerulus is not involved.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-28 Hereditary nephritis. Electron micrograph of glomerulus with irregular thickening of basement membrane, lamination of lamina densa, and foci of rarefaction. Such changes may be present in other diseases but are most pronounced and widespread in hereditary nephritis. CL, capillary lumen; Ep, epithelium.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-29 Primary glomerular diseases leading to chronic glomerulonephritis (GN). The thickness of the arrows reflects the approximate proportion of patients in each group who progress to chronic glomerulonephritis: poststreptococcal (1% to 2%); rapidly progressive (crescentic) (90%); membranous (50%); focal glomerulosclerosis (50% to 80%); membranoproliferative glomerulonephritis (50%); IgA nephropathy (30% to 50%).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-30 Chronic glomerulonephritis. A Masson trichrome preparation shows complete replacement of virtually all glomeruli by blue-staining collagen. (Courtesy of Dr. M.A. Venkatachalam, Department of Pathology, University of Texas Health Sciences Center, San Antonio, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-31 Electron micrograph of advanced diabetic glomerulosclerosis. Note massive increase in mesangial matrix (Mes) encroaching on glomerular capillary lumena (CL). GBM and Bowman capsule (C) are markedly thickened. Ep, epithelium; E, endothelium.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-32 Diffuse and nodular diabetic glomerulosclerosis (PAS stain). Note diffuse increase in mesangial matrix and characteristic acellular PAS-positive nodules.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-33 Possible pathogenetic mechanisms in ischemic acute renal failure (see text).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-34 Patterns of tubular damage in ischemic and toxic acute tubular necrosis. In ischemic type, tubular necrosis is patchy, relatively short lengths of tubules are affected, and straight segments of proximal tubules (PST) and ascending limbs of Henle's loop (HL) are most vulnerable. In toxic acute tubular necrosis, extensive necrosis is present along proximal tubule segments (PCT) with many toxins (e.g., mercury), but necrosis of the distal tubule, particularly ascending Henle's loop, also occurs. In both types, lumens of distal convoluted tubules (DCT) and collecting ducts (CD) contain casts.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-35 Ischemic acute tubular necrosis. Some of the tubular epithelial cells in affected tubules are necrotic, whereas others are flattened, stretched out, and regenerating.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-36 Schematic representation of pathways of renal infection. Hematogenous infection results from bacteremic spread. More common is ascending infection, which results from a combination of urinary bladder infection, vesicoureteral reflux, and intrarenal reflux.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-37 Vesicoureteral reflux demonstrated by a voiding cystourethrogram. Dye injected into the bladder refluxes into both dilated ureters, filling the pelvis and calcyes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-38 The vesicoureteric junction. In normal individuals ( A), the intravesical portion of the ureter is oblique, such that the ureter is closed by muscle contraction during micturition. The most common cause of reflux is congenital complete or partial absence of the intravesical ureter ( B).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-39 Acute pyelonephritis. Cortical surface exhibits grayish white areas of inflammation and abscess formation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-40 Acute pyelonephritis marked by an acute neutrophilic exudate within tubules and the renal substance.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-41 Papillary necrosis. Areas of pale gray necrosis are limited to the papillae.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-42 Typical coarse scars of chronic pyelonephritis associated with vesicoureteral reflux. The scars are usually polar and are associated with underlying blunted calyces.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-43 A, Chronic pyelonephritis. Surface (left) is irregularly scarred. Cut section (right) reveals characteristic dilation and blunting of calyces. Ureter is dilated and thickened--a finding consistent with chronic vesicoureteral reflux. B, Low-power view showing corticomedullary renal scar with an underlying dilated deformed calyx. Note thyroidization of tubules in the cortex.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-44 Drug-induced interstitial nephritis, with prominent eosinophilia and mononuclear infiltrate. (Courtesy of Dr. H. Rennke, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-45 Analgesic nephropathy. A, The brownish necrotic papilla, transformed to a necrotic, structureless mass, fills the pelvis. B, Microscopic view. Note fibrosis in the medulla. (Courtesy of Dr. F. J. Gloor, Institut fur Pathologie, Kantonsspital, St. Gallen, Switzerland.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-46 Urate crystals in the renal medulla. Note giant cells and fibrosis around the crystals.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-47 Myeloma kidney. Note tubular casts with multinucleate cells around them. (Courtesy of Dr. C. Alpers, University of Washington, Seattle, WA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-48 Close-up of gross appearance of the cortical surface in benign nephrosclerosis illustrating fine leathery granularity of the surface.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-49 Hyaline arteriolosclerosis. High-power view of two arterioles with hyaline deposition, marked thickening of the walls, and a narrowed lumen. (Courtesy of Dr. M.A. Venkatachalam, Department of Pathology, University of Texas Health Sciences Center, San Antonio, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-50 Malignant hypertension. A, Fibrinoid necrosis of afferent arteriole (PAS stain). B, Hyperplastic arteriolitis (onion-skin lesion). (Courtesy of Dr. H. Rennke, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-51 Fibromuscular dysplasia of the renal artery, medial type (elastic tissue stain). The medium shows marked fibrous thickening, and the lumen is stenotic. (Courtesy of Dr. Seymour Rosen, Beth Israel Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-52 Fibrin stain showing platelet-fibrin thrombi (red) in glomerular capillaries characteristic of microangiopathic disorders.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-53 Atheroemboli with typical cholesterol clefts in the interlobar artery.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-54 Diffuse cortical necrosis. Pale ischemic necrotic areas are confined to the cortex and columns of Bertin.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-55 Obstructive lesions of the urinary tract.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-56 Hydronephrosis of the kidney, with marked dilation of the pelvis and calyces and thinning of the renal parenchyma.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-57 Nephrolithiasis. Large stone impacted in the renal pelvis. (Courtesy of Dr. E. Mosher, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-58 Cytogenetics (in blue) and genetics (in red) of clear cell versus papillary renal cell carcinoma. (Courtesy of Dr. Keith Ligon, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-59 Renal cell carcinoma. Typical cross-section of yellowish, spherical neoplasm in one pole of the kidney. Note tumor in the dilated thrombosed renal vein.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-60 Renal cell carcinoma. A, Clear cell type, B, Papillary type. Note papillae and foamy macrophages in the stalk. C, Chromophobe type. (Courtesy of Dr. A. Renshaw, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 21-61 Urothelial carcinoma of the renal pelvis. Pelvis has been opened to expose the nodular irregular neoplasm, just proximal to the ureter.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 22-1 Opened ureters showing ureteritis cystica. Note smooth cysts projecting from the mucosa.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 22-2 A papillary transitional cell carcinoma arising in the ureter and virtually filling the cross-section of the ureter. (Courtesy of Dr. Christopher Corless, University of Oregon, Eugene, OR.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 22-3 Bladder diverticulum (arrow) seen here in the bladder wall. Bladder lumen (L) lined by reddened mucosa is on the top. (Courtesy of Dr. Andrew Renshaw, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 22-4 Exstrophy of the bladder in a newborn boy. The clamped umbilical cord is seen above the hyperemic mucosa of the everted bladder. Below is an incompletely formed penis with marked epispadias. (Courtesy of Dr. Hardy Hendren, Surgeon-in-Chief, Children's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 22-5 Chronic cystitis with subepithelial edema, inflammation, and a lymphoid aggretate in the lamina propria. (Courtesy of Dr. Andrew Renshaw, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 22-6 Cystitis with malacoplakia of bladder showing inflammatory exudate and broad, flat plaques.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 22-7 Malacoplakia, PAS stain. Note the large macrophages with granular PAS-positive cytoplasm and several dense, round Michaelis-Gutmann bodies surrounded by artifactual cleared holes in the upper middle field.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 22-8 Four morphologic patterns of bladder tumors.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 22-9 Low-power view of typical papillomatous growth of bladder. Note delicate axial stromal framework. (Courtesy of Dr. Christopher Corless, University of Oregon, Eugene, OR.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 22-10 Sectioned bladder showing a papillary transitional cell carcinoma projecting into the lumen (arrow). Note delicate arborizing structure and small stalk. Note also the small diverticulum adjacent to the attachment site of the stalk. L, lumen, , diverticulum.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 22-11 A, Normal bladder mucosa. B- D, Urothelial tumors. B, Grade I or low malignant potential; C, Grade II (low grade); D, Grade III (high grade). ( A, B, D, Courtesy of Dr. Christopher Corless, University of Oregon, Eugene, OR. C, Courtesy of Dr. Donald Antonioli, Beth Israel Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 22-12 Opened bladder showing a high-grade invasive transitional cell carcinoma at an advanced stage. The aggressive multinodular neoplasm has fungated into the bladder lumen and spread over a wide area. Normal bladder mucosa. (Courtesy of Dr. Andrew Renshaw, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 22-13 A, Low-power view of bladder with focus of carcinoma in situ on the left side of the illustration. B, High-power view of carcinoma confined to the epithelium. (Courtesy of Dr. Christopher Corless, University of Oregon, Eugene, OR.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 22-14 Hypertrophy and trabeculation of bladder wall secondary to polypoid hyperplasia of the prostate.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 22-15 Carcinoma of urethra with typical fungating growth.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-6 A, Normal testis shows tubules with active spermatogenesis. B, Testicular atrophy. The tubules show Sertoli cells but no spermatogenesis. There is thickening of basement membranes. (Courtesy of Dr. Arthur Weinberg, Department of Pathology, University of Texas Health Science Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-7 Acute epididymitis caused by gonococcal infection. The epididymis is replaced by an abscess. Normal testis is seen on the right.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-8 Torsion of testis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-9 Seminoma of the testis appears as a fairly well circumscribed, pale, fleshy, homogeneous mass. (Courtesy of Dr. Kyle Molberg, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-10 Seminoma. A, Low magnification shows clear seminoma cells divided into poorly demarcated lobules by delicate septa. B, Microscopic examination reveals large cells with distinct cell borders, pale nuclei, prominent nucleoli, and a sparse lymphocytic infiltrate.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-11 Embryonal carcinoma. In contrast to the seminoma illustrated in Figure 23-9 , the embryonal carcinoma is a hemorrhagic mass. (Courtesy of Dr. Kyle Molberg, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-12 Embryonal carcinoma shows sheets of undifferentiated cells as well as glandular differentiation. The nuclei are large and hyperchromatic. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-13 Choriocarcinoma shows clear cytotrophoblastic cells with central nuclei and syncytiotrophoblastic cells with multiple dark nuclei embedded in eosinophilic cytoplasm. Hemorrhage and necrosis are seen in the upper right field. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical School, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-14 Teratoma of testis. The variegated cut surface with cysts reflects the multiplicity of tissue found histologically.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-15 Mixed germ cell tumor. Three fields from the same tumor demonstrate a mixture of various cell types. A, An area with elements of choriocarcinoma: cytotrophoblasts (clear cells) surrounded by syncytiotrophoblast. B, Prominent collection of cartilage cells. C, Sheets of epithelial cells resembling liver cells. The areas B and C represent teratomatous elements. Other parts of the tumor revealed embryonal carcinoma and yolk sac tumor. (Courtesy of Dr. Kyle Molberg, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-16 Adult prostate. The normal prostate contains several distinct regions, including a central zone (CZ), a peripheral zone (PZ), a transitional zone (TZ), and a periurethral zone. Most carcinomas arise from the peripheral glands of the organ and are often palpable during digital examination of the rectum. Nodular hyperplasia, in contrast, arises from more centrally situated glands and is more likely to produce urinary obstruction early on than is carcinoma.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-17 Prostatitis, bacterial and abacterial.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-18 Simplified scheme of the pathogenesis of prostatic hyperplasia. The central role of the stromal cells in generating dihydrotestosterone should be noted.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-19 Nodular prostatic hyperplasia. A, Well-defined nodules bulge from the cut surface. The proximity of the nodules to the urethra accounts for the urinary obstruction associated with the lesion. B, A microscopic view of a whole mount of the prostate shows nodules of hyperplastic glands on both sides of the urethra. ( B courtesy of Dr. Kyle Molberg, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-20 Nodular hyperplasia of prostate. A, A low-power view shows proliferation of glands, some cystically dilated within a well-defined nodule. B, A high-power view shows hyperplastic glands with two layers of cells: an inner columnar and an outer cuboidal or flattened. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-21 Nodular hyperplasia and carcinoma of the prostate. Carcinomatous tissue is seen on the posterior aspect ( arrows). Compare the location of the cancer with that of the hyperplastic prostate on either side of the urethra. (Courtesy of Dr. Kyle Molberg, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-22 Photomicrograph of well-differentiated adenocarcinoma of the prostate demonstrating crowded, "back-to-back" glands lined by a single layer of cuboidal cells. Glandular differentiation is much less obvious in some higher-grade lesions. (Courtesy of Dr. Kyle Molberg, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-23 Carcinoma of prostate showing perineurial invasion by malignant glands. (Courtesy of Dr. Kyle Molberg, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 23-25 Metastatic osteoblastic prostatic carcinoma within vertebral bodies.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-4 A, Acute salpingo-oophoritis with tubo-ovarian abscess. The fallopian tubes and ovaries have coalesced into an inflammatory mass adherent to the uterus. Compare with Figure 24-1 . B, Chronic salpingitis with fusion of the tubal plicae and inflammatory cell infiltrates.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-5 Schematic composition of lichen sclerosus ( top) and squamous hyperplasia ( bottom) of the vulvar mucosa.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-6 Lichen sclerosus. Note the white parchment-like patches of the skin of the vulva and labial atrophy.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-7 The histologic hallmark of lichen sclerosus is a dense band of hyaline collagen beneath the epithelium.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-8 Squamous hyperplasia. Epithelial hyperplasia and dermal chronic inflammation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-9 A, Numerous condylomas of the vulva encircling the introitus. (Courtesy of Dr. Alex Ferenczy, McGill University, Montreal, Quebec.) B, Histopathology of condyloma acuminatum showing acanthosis, hyperkeratosis, and cytoplasmic vacuolation (koilocytosis, center).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-10 Histopathology of vulvar intraepithelial neoplasia with diffuse cellular atypia, nuclear crowding, and increased mitotic index.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-11 A, Poorly differentiated vulvar carcinoma associated with human papillomaviruses (HPV). B, Well-differentiated keratinizing vulvar carcinoma, typically HPV negative.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-12 Paget disease of the vulva with a cluster of large clear tumor cells within the squamous epithelium.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-13 Clear cell adenocarcinoma showing vacuolated tumor cells in clusters and forming glands.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-14 Sarcoma botryoides (embryonal rhabdomyosarcoma) of the vagina appearing as a polypoid mass protruding from the vagina. (Courtesy of Dr. Michael Donovan, Children's Hospital, Boston.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-15 A, Low-power histology of chronic cervicitis and the cervical transformation zone. Mature squamous epithelium (epidermidalization) has replaced the columnar epithelium on the surface and covers the glands (G). An inflammatory infiltrate is present in the submucosa. B, Immature squamous metaplasia developing in an endocervical gland. Layers of immature squamous cells displace columnar cells toward the gland lumen.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-16 Severe chronic cervicitis with prominent lymphoid follicles (follicular cervicitis), typically associated with chlamydial infection. The epithelium (EP) is in the upper left.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-17 Endocervical polyp composed of a dense fibrous stroma covered with endocervical columnar epithelium.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-18 A, Postulated steps in the pathogenesis of cervical neoplasia. Conditions influencing progression are listed at the lower center of the diagram. B, Approximate lifetime risks of acquiring HPV infection ( left) and dying of cervical cancer ( right). The intermediate steps include risks of infection with high-risk HPV types, development of advanced cervical intraepithelial neoplasia (CIN), and progression to invasive carcinoma.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-19 A, Histology of a cervical condyloma illustrating the prominent koilocytotic atypia in the upper epithelial cells, as evidenced by the prominent perinuclear halos. B, Nucleic acid in situ hybridization of the same lesion for HPV nucleic acids. The blue staining denotes HPV DNA, which is typically most abundant in the koilocytes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-20 Spectrum of cervical intraepithelial neoplasia: normal squamous epithelium for comparison; CIN I with koilocytotic atypia; CIN II with progressive atypia in all layers of the epithelium; CIN III, (carcinoma in situ) with diffuse atypia and loss of maturation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-21 The cytology of cervical intraepithelial neoplasia as seen on the Papanicolaou smear. A, Normal exfoliated superficial squamous epithelial cells. B, CIN I. C, CIN II. D, CIN III. Note the reduction in cytoplasm and the increase in the nucleus to cytoplasm ratio, which occurs as the grade of the lesion increases. This reflects the progressive loss of cellular differentiation on the surface of the lesions from which these cells are exfoliated (see Figure 24-20) . (Courtesy of Dr. Edmund S. Cibas, Department of Pathology, Brigham & Women's Hospital, Boston.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-22 The spectrum of invasive cervical cancer. A, Carcinoma of the cervix, well advanced. B, Early stromal invasion occurring in a cervical intraepithelial neoplasm.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-23 Approximate quantitative changes in seven morphologic criteria found to be most useful in dating human endometrium. (Modified from Noyes RW: Normal phases of the endometrium. In Norris HJ, et al (eds): The Uterus. Baltimore, Williams & Wilkins, 1973.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-24 Histopathology of the menstrual cycle, including the proliferative phase with mitoses ( A), the early secretory phase with subnuclear vacuoles ( B) followed by secretory exhaustion ( C), predecidual changes ( D), stromal granulocytes ( E), and stromal breakdown at the onset of menses ( F) (see text).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-25 Anovulatory endometrium with stromal breakdown. Note breakdown associated with proliferative glands.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-26 Chronic endometritis with inflammatory infiltrates and leukocytes in the gland lumen.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-27 Adenomyosis. An unusual variant with functional endometrial nests producing foci of hemorrhagic cysts within the uterine wall.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-28 The potential origins of endometriosis implants.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-29 Endometriosis. A, This ovary has been sectioned to reveal a large endometriotic cyst containing necrotic brown material consisting of degenerated blood (chocolate cyst). B, Lining of an endometriotic cyst from a pregnant patient. On the right is an endometrial gland; on the left is endometrial stroma with plump stromal cells characteristic of decidual changes. In the center are numerous macrophages containing hemosiderin.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-30 Endometrial polyp projecting from a think stalk at the junction of the endometrium ( left) and endocervix ( right).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-31 Low-grade hyperplasias of the endometrium: A, simple (cystic); B, complex. Both lesions contain minimal epithelial stratification or atypia. C, High-grade (atypical) hyperplasia with epithelial stratification and cellular atypia. D, Endometrial hyperplasia with squamous metaplasia.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-32 A, Endometrial adenocarcinoma presenting as a fungating mass in the fundus of the uterus. B, Well-differentiated endometrial adenocarcinoma. Discrete glands are less easily identified because the epithelium is arranged in a confluent pattern without intervening stroma. C, Papillary serous carcinoma of the endometrium.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-33 A, Leiomyomas of the myometrium. The uterus is opened to reveal the tumors bulging into the endometrial cavity and displaying a firm white appearance on sectioning. B, Leiomyoma showing well-differentiated, regular, spindle-shaped smooth muscle cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-34 Leiomyosarcoma. A, A large hemorrhagic tumor mass distends the lower corpus and is flanked by two leiomyomas. B, The tumor cells are irregular in size and have hyperchromatic nuclei.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-35 Polycystic ovarian disease. A, The ovarian cortex reveals numerous clear cysts. B, A section of the cortex reveals several subcortical cystic follicles.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-36 Derivation of various ovarian neoplasms and some data on their frequency and age distribution.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-37 A, Borderline serous cystadenoma opened to display a cyst cavity lined by delicate papillary tumor growths. B, Cystadenocarcinoma. The cyst is opened to reveal a large, bulky tumor mass.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-38 Histopathology of papillary serous cystadenoma revealing stromal papillae with a columnar epithelium.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-39 Borderline serous cystadenoma exhibiting increased architectural complexity and epithelial cell stratification.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-40 Papillary serous cystadenocarcinoma of the ovary with invasion of underlying stroma.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-41 Serous epithelial tumor growth from the surface of the ovary ( above).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-42 A, A mucinous cystadenoma with its multicystic appearance and delicate septa. Note the presence of glistening mucin within the cysts. B, Columnar cell lining of mucinous cystadenoma.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-43 Pseudomyxoma peritonei viewed at laparotomy revealing massive overgrowth of a gelatinous metastatic tumor originating from the appendix. (Courtesy of Dr. Paul H. Sugarbaker, Washington Hospital Cancer Center, Washington, DC.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-44 A, Brenner tumor ( right) associated with a benign cystic teratoma ( left). B, Histologic detail of characteristic epithelial nests within the ovarian stroma.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-45 Histogenesis and interrelationships of tumors of germ cell origin.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-46 Opened mature cystic teratoma (dermoid cyst) of the ovary. Hair (bottom) and a mixture of tissues are evident.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-47 Benign cystic teratoma. Low-power view of skin ( top), beneath which there is brain tissue ( bottom).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-48 Immature teratoma of the ovary illustrating primitive neuroepithelium.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-49 Histopathology of dysgerminoma showing polyhedral tumor cells with round nuclei and adjacent inflammation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-50 A Schiller-Duval body in yolk sac carcinoma.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-51 Granulosa cell tumor. The tumor cells are arranged in sheets punctuated by small follicle-like structures (Call-Exner bodies).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-52 A, Thecoma-fibroma composed of plump, differentiated stromal cells with thecal appearance. B, Large bisected fibroma of the ovary apparent as a white, firm mass ( right). The fallopian tube is attached.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-53 Sertoli cell tumor. A, Gross photograph illustrating characteristic golden yellow appearance of the tumor. B, Photomicrograph showing well-differentiated Sertoli cell tubules. (Courtesy of Dr. William Welch, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-54 Potential sites for ectopic pregnancy, including the fallopian tube, ovary, cornu, and abdominal viscera.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-55 A, Diagram of placental anatomy. B, Normal term placenta with umbilical cord.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-57 Twin-twin transfusion syndrome resulting in the death of both fetuses because of excessive ( left) or deficient ( right) blood volume.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-58 Acute chorioamnionitis. A, On gross examination, the placenta contains greenish opaque membranes. Compare with Figure 24-55 B. B, A photomicrograph illustrates a dense bandlike inflammatory exudate on the amniotic surface ( top).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-60 Acute atherosis of uterine vessels in eclampsia. Note fibrinoid necrosis of the vessel walls, subendothelial macrophages and perivascular lymphocytic infiltrate. (Courtesy of Dr. Drucilla J. Roberts, Massachusetts General Hospital, Boston.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-61 Patterns of fertilization to account for chromosomal origin of complete (46,XX) and triploid partial moles (XXY). In a complete mole, one or two sperm fertilize an egg that has lost its chromosomes. Partial moles are due to fertilization of an egg by one diploid, or two haploid sperm, depicted in this example as one 23,X and one 23,Y.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-62 Complete hydatidiform mole suspended in saline showing numerous swollen (hydropic) villi.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-63 A, Photomicrograph of partial hydatidiform mole revealing swollen villi and slight hyperplasia of the surface trophoblast. B, Complete hydatidiform mole with extensive cytotrophoblastic hyperplasia ( lower field).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-64 A, Invasive mole presenting as a hemorrhagic mass adherent to the uterine wall. B, On cross-section, the tumor invades into the myometrium. (Courtesy of Dr. David R. Genest, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 24-65 A, Choriocarcinoma presenting as a bulky hemorrhagic mass invading the uterine wall. B, Photomicrograph of choriocarcinoma illustrating both neoplastic cytotrophoblast and syncytiotrophoblast. (Courtesy of Dr. David R. Genest, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 25-30 Gynecomastia. Note the ducts with hyperplastic multilayered epithelium and periductal hyalinization and fibrosis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-6 Diagram of relationship between the hypothalamus, anterior pituitary, and a peripheral endocrine gland, exemplified here by the thyroid gland. Secretion of thyroid hormones (T3 and T4 ) is controlled by trophic factors secreted by both the hypothalamus and the anterior pituitary. Decreased levels of T3 and T4 stimulate the release of thyrotropin-releasing hormone (TRH) from the hypothalamus and thyroid-stimulating hormone (TSH) from the anterior pituitary, causing T3 and T4 levels to rise. Elevated T3 and T4 levels, in turn, suppress the secretion of both TRH and TSH. This relationship is termed a negative-feedback loop.(Modified from Dr. Ronald A. DeLellis, New England Medical Center, Boston.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-7 Photograph of a patient with hyperthyroidism. A wide-eyed, staring gaze, caused by overactivity of the sympathetic nervous system, is one of the features of this disorder. In Graves disease, one of the most important causes of hyperthyroidism, accumulation of loose connective tissue behind the eyeballs also adds to the protuberant appearance of the eyes.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-8 Photomicrograph of Hashimoto thyroiditis. The thyroid parenchyma contains a dense lymphocytic infiltrate with germinal centers. Residual thyroid follicles lined by deeply eosinophilic Hu rthle cells are also seen.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-9 Subacute thyroiditis. The thyroid parenchyma contains a chronic inflammatory infiltrate with a multinucleate giant cell (above left) and a colloid follicle (bottom right).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-10 Photomicrograph of a diffusely hyperplastic gland in a case of Graves disease. The follicles are lined by tall, columnar epithelium. The crowded, enlarged epithelial cells project into the lumens of the follicles. These cells actively resorb the colloid in the centers of the follicles; resulting in the scalloped appearance of the edges of the colloid.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-11 Gross photograph of nodular goiter. The gland is coarsely nodular and contains areas of fibrosis and cystic change.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-12 Follicular adenoma of the thyroid. A solitary, well-circumscribed nodule is seen.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-13 Photomicrograph of a follicular adenoma. Well-differentiated follicles resemble normal thyroid parenchyma.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-14 Photomicrograph of a Hurthle cell tumor. A high-power view showing that the tumor is composed of cells with abundant eosinophilic cytoplasm and small regular nuclei. (Courtesy of Dr. Mary Sunday, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-15 Papillary carcinoma of the thyroid. This particular example contains well-formed papillae lined by cells with characteristic empty-appearing nuclei, sometimes termed Orphan Annie eye nuclei. Inset shows cells obtained by fine-needle aspiration of a papillary carcinoma. Characteristic intranuclear inclusions ( arrows) are visible in cytologic preparations. (Courtesy of Dr. Edmund Cibas, Brigham & Women's Hospital, Boston.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-16 Follicular carcinoma. Cut surface of a follicular carcinoma with substantial replacement of the lobe of the thyroid. The tumor has a light-tan appearance and contains small foci of hemorrhage.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-17 Follicular carcinoma of the thyroid. A few of the glandular lumens contain recognizable colloid.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-18 Medullary carcinoma of thyroid. These tumors typically show a solid pattern of growth and do not have connective tissue capsules. (Courtesy of Dr. Joseph Corson, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-19 Medullary carcinoma of the thyroid. These tumors typically contain amyloid, visible here as homogeneous extracellular material, derived from calcitonin molecules secreted by the neoplastic cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-20 Electron micrograph of medullary thyroid carcinoma. These cells contain membrane-bound secretory granules that are the sites of storage of calcitonin and other peptides (30,000×).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-21 A, Solitary chief cell parathyroid adenoma (low-power view) revealing clear delineation from the residual gland below. B, High-power detail of a chief cell parathyroid adenoma. There is some slight variation in nuclear size but no anaplasia and some slight tendency to follicular formation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-22 Normal adrenal steroid biosynthesis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-23 A schematic representation of the various forms of Cushing syndrome, illustrating the three endogenous forms as well as the more common exogenous (iatrogenic) form. ACTH, adrenocorticotropic hormone.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-24 The major causes of primary hyperaldosteronism and its principal effects on the kidney.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-25 Adrenal cortical adenoma. The adenoma is distinguished from nodular hyperplasia by its solitary, circumscribed nature. The functional status of an adrenal cortical adenoma cannot be predicted from its gross or microscopic appearance.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-26 Cross-section of nodular hyperplasia contrasted with normal adrenal.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-27 Simplified flow chart demonstrating normal adrenal steroidogenesis ( A) and consequences of C-21 hydroxylase deficiency ( B). 21-Hydroxylase deficiency impairs the synthesis of both cortisol and aldosterone. The resultant decrease in feedback inhibition (dashed line) causes increased secretion of adrenocorticotropic hormone, resulting ultimately in adrenal hyperplasia and increased synthesis of testosterone.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-28 Waterhouse-Friderichsen syndrome in a child. The dark, hemorrhagic adrenal glands are distended with blood.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-29 Autoimmune adrenalitis. In addition to loss of all but a subcapsular rim of cortical cells, there is an extensive mononuclear cell infiltrate.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-30 Adrenal carcinoma. The bright yellow tumor dwarfs the kidney and compresses the upper pole. It is largely hemorrhagic and necrotic.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-31 Adrenal carcinoma (left) revealing marked anaplasia, contrasted with normal cortical cells (right).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-33 The gray-pink pheochromocytoma with areas of hemorrhage is enclosed within an attenuated cortex. The comma-shaped residual adrenal is seen below.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 26-34 Electron micrograph of pheochromocytoma. This tumor contains membrane-bound secretory granules in which catecholamines are stored (30,000×).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-3 A, Clinical appearance of vitiligo. Well-demarcated zones of pigment loss result from depletion of melanocytes that produce small melanin granules. In the hands of this darkly pigmented patient, areas of melanin loss predominate. B, Electron microscopy of the melanocyte. These cells are difficult to identify by routine light microscopy, contain characteristic melanosomes (arrows) by electron microscopy, and are lost in lesions of vitiligo. (Arrowheads indicate basement membrane zone separating epidermis and dermis.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-4 Nevocellular nevus, junctional type. A, In clinical appearance, lesions are small, relatively flat, symmetric, and uniform. B, On histologic examination, junctional nevi are characterized by rounded nests of nevus cells originating at the tips of rete ridges along the dermoepidermal junction. (From Murphy GF, Herzberg AJ: Atlas of Dermatopathology. Philadelphia, WB Saunders, 1996, p 177.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-5 Nevocellular nevus, compound type. In contrast to the junctional nevus, the compound nevus (A) is more raised and dome shaped. The symmetry and uniform pigment distribution suggest a benign process. Histologically (B), compound nevi combine the features of junctional nevi (intraepidermal nevus cell nests) with nests and cords of nevus cells in the underlying dermis. (From Murphy GF, Herzberg AJ: Atlas of Dermatopathology. Philadelphia, WB Saunders, 1996, pp 177 and 178.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-6 Dysplastic nevus. A, The lesion often has a compound nevus component (right side of scanning field) and an asymmetric "shoulder" composed of a junctional nevus component (left side of scanning field). The former correlates clinically with the more pigmented and raised central zone, and the latter with the less pigmented, flat peripheral rim (inset). B, An important feature is the presence of cytologic atypia (irregularly shaped, dark-staining nuclei) at high magnification. The dermis underlying the atypical cells characteristically shows linear, or lamellar, fibrosis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-7 Steps of tumor progression in dysplastic nevi: A, Lentiginous melanocytic hyperplasia. B, Lentiginous junctional nevus. C, Lentiginous compound nevus with abnormal architectural and cytologic features (dysplastic nevus). D, Early melanoma, or radial growth phase melanoma (large dark cells in epidermis). E, Advanced melanoma (vertical growth phase) with malignant spread into the dermis and vessels.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-8 Malignant melanoma. A, In clinical appearance, lesions are irregular in contour and pigmentation. Macular areas correlate with the radial growth phase, while raised areas usually correspond to nodular aggregates of malignant cells in the vertical phase of growth. B, Radial growth phase of malignant melanoma, showing irregular nested and single-cell growth of melanoma cells within the epidermis, and an underlying inflammatory response within the dermis. C, Photomicrograph of lesion in the vertical phase of growth demonstrating nodular aggregates of infiltrating cells. D, High-power view of malignant melanoma cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-9 Seborrheic keratoses. Multiple coinlike pigmented lesions on the back (A) are composed of well-demarcated, orderly proliferations of basaloid cells forming small, keratin-filled cysts (B).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-10 Keratoacanthoma. A, This symmetric crater-like nodule has a prominent central keratin plug. B, At low power, the crater-like architecture may be appreciated with an elastic tissue stain where the dermis is red, epithelial elements are gray, and the central keratin plug is yellow. C, Higher power view shows keratoacanthoma to be composed of large, glassy squamous cells and central islands of eosinophliic keratin. ( A and B from Murphy GF, Herzberg AJ: Atlas of Dermatopathology. Philadelphia, WB Saunders, 1996, pp 143 and 144.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-11 Adnexal tumors. The clinical appearance is often nondescript ( A shows multiple cylindromas and C shows multiple trichoepitheliomas). B, on histologic examination, the cylindroma is composed of islands of basaloid cells containing occasional ducts and seemingly fitting together like pieces of a jigsaw puzzle. D, Trichoepithelioma is composed of buds of basaloid cells that resemble primitive hair follicles. Here the small ductlike structures are actually keratin-filled microcysts. ( B, C, and D from Murphy GF, Herzberg AJ: Atlas of Dermatopathology. Philadelphia, WB Saunders, 1996, pp 162 and 165.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-12 Adnexal tumors. A, Mixed tumor (chondroid syringoma). B, Trichilemmoma. C, Hidradenoma papilliferum.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-13 Actinic keratosis. A, Excessive scale formation in this lesion has produced a "cutaneous horn." B, Basal cell layer atypia is associated with marked hyperkeratosis and parakeratosis. C, Progression to full-thickness nuclear atypia, with or without the presence of superficial epidermal maturation, heralds the development of early squamous cell carcinoma in situ.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-14 Invasive squamous cell carcinoma. A, Lesions are often nodular and ulcerated. B, Tongues of atypical squamous epithelium have transgressed the basement membrane, invading deeply into the dermis. C, Invasive tumor cells exhibit enlarged nuclei with angulated contours and prominent nucleoli.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-15 Basal cell carcinoma. Pearly, telangiectatic nodules (A) are composed of nests of basaloid cells within the dermis (B) that are often separated from the adjacent stroma by thin clefts (C).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-16 A, Benign fibrous histiocytoma (dermatofibroma). B and C, On excision, this firm, tan papule on the leg shows a localized nodular proliferation of benign-appearing fibroblasts within the dermis. Note the characteristic overlying epidermal hyperplasia and the tendency of fibroblasts to surround individual collagen bundles.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-17 Histiocytosis X. A, Lesions may appear clinically as papules and nodules or, in this case, as erythematous scaling plaques mimicking the infantile form of seborrheic dermatitis. B, Dermal infiltration by bland mononuclear cells with infolded nuclei presents a nonspecific histologic pattern. C, Immunohistochemical demonstration of CD1a antigen confirms their origin from Langerhans cells. ( A from Murphy GF, Herzberg AJ: Atlas of Dermatopathology. Philadelphia, WB Saunders, 1996, p 205.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-18 Histiocytosis X. Ultrastructural detection of Birbeck granules, as seen in normal Langerhans cells ( arrow and inset), permitted accurate diagnosis in this case.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-19 Cutaneous T-cell lymphoma. The histologic correlate of ill-defined, erythematous, often scaling, and occasionally ulcerated plaques (A) is an infiltrate of atypical lymphocytes that show a tendency to accumulate beneath the epidermal layer (B) and to invade the epidermis as small microabscesses.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-20 Mastocytosis. A, Solitary mastocytoma in a 1-year-old child. B, By routine histology, numerous ovoid cells with uniform, centrally located nuclei are observed in the dermis. C, Giemsa staining reveals purple, "metachromatic" granules within the cytoplasm of the cells. ( A from Murphy GF, Herzberg AJ: Atlas of Dermatopathology. Philadelphia, WB Saunders, 1996, p 207.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-21 Ichthyosis. Note prominent fish-like scales (A) and compacted hyperothokeratosis (B).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-22 Urticaria. Clinically, there are erythematous, edematous, often circular plaques covered by a normal epidermal surface. (From Murphy GF, Herzberg AJ: Atlas of Dermatopathology. Philadelphia, WB Saunders, 1996, p 83.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-23 Urticaria. Histologically, there is superficial dermal edema and dilated lymphatic and blood-filled vascular spaces. The edema is manifested by widening of spaces that separate the collagen bundles. (From Murphy GF, Herzberg AJ: Atlas of Dermatopathology. Philadelphia, WB Saunders, 1996, p 83.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-24 Evolutionary stages of spongiotic dermatitis. A, Initial dermal edema and perivascular infiltration by inflammatory cells is followed within 24 to 48 hours by epidermal spongiosis and microvesicle formation (B). C, Abnormal scale, including parakeratosis, follows, along with progressive epidermal hyperplasia (D) and hyperkeratosis (E) as the lesion enters into a more chronic stage.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-25 Eczematous dermatitis. A, In an acute allergic contact dermatitis, numerous vesicles appear at the site of antigen exposure (in this case, laundry detergent that persisted in clothing). B, Histologically, intercellular edema produces widened intercellular spaces within the epidermis, eventually resulting in small, fluid-filled intraepidermal vesicles.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-26 Schematic diagram of mechanisms of allergic contact dermatitis. antigen; Ln, naive T cell; Lm, memory T cell.
Contents - 1 - 2 - Index
,
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-27 Erythema multiforme. A, The target-like clinical lesions consist of a central blister or zone of epidermal necrosis surrounded by macular erythema. B, Early lesions show lymphocytes collecting along the dermal epidermal junction where basal keratinocytes have begun to become vacuolated. (From Murphy GF, Herzberg AJ: Atlas of Dermatopathology. Philadelphia, WB Saunders, 1996, p 71.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-28 Clinical evolution of psoriasis. Early and eruptive lesions may be dominated by signs of inflammation and erythema (left). Established, chronic lesions demonstrate erythema surmounted by characteristic silver-white scale (right). Rarely, the early inflammatory phase predominates throughout the course of the disease (pustular psoriasis).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-29 Psoriasis. Histologically, established lesions demonstrate marked epidermal hyperplasia, parakeratotic scale, and, importantly, minute microabscesses of neutrophils within the superficial epidermal layers.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-30 Lichen planus. A, An erythematous and hyperpigmented plaque has resulted from coalescence of multiple small papules. B, Biopsy of one of the lesions demonstrates the bandlike infiltrate of lymphocytes at the dermoepidermal junction and pointed rete ridges ("saw-toothing"; compare with Figure 27-1) . (From Murphy GF, Herzberg AJ: Atlas of Dermatopathology. Philadelphia, WB Saunders, 1996, p 75.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-31 Lupus erythematosus. A, Discoid plaques show erythema and excessive scale. The histology of a biopsy specimen taken from the center of such a plaque is depicted in B. B, There is an infiltrate of lymphocytes within the superficial and deep dermis, marked thinning of the epidermis with loss of normal rete ridges, and hyperkeratosis. (From Murphy GF, Herzberg AJ: Atlas of Dermatopathology. Philadelphia, WB Saunders, 1996, pp 74 and 75.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-32 Granular deposits of immunoglobulin (here IgG) and complement at the dermoepidermal junction constitute a positive "band test" in lupus erythematosus. (From Murphy GF, Herzberg AJ: Atlas of Dermatopathology. Philadelphia, WB Saunders, 1996, p 27.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-33 Schematic representation of sites of blister formation. A, In a subcorneal blister, the stratum corneum forms the roof of the bulla (as in impetigo or pemphigus foliaceus). B, In a suprabasal blister, a portion of the epidermis including the stratum corneum forms the roof (as in pemphigus vulgaris). C, In a subepidermal blister, the entire epidermis separates from the dermis (as in bullous pemphigoid and dermatitis herpetiformis).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-34 Pemphigus vulgaris. A, Eroded plaques are formed on rupture of confluent, thin-roofed bullae, here affecting axillary skin. B, Suprabasal acantholysis results in an intraepidermal blister in which rounded (acantholytic) epidermal cells are identified (inset). ( A from Murphy GF, Herzberg AJ: Atlas of Dermatopathology. Philadelphia, WB Saunders, 1996, p 63.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-35 Direct immunofluorescence of pemphigus vulgaris. There is deposition of immunoglobulin along the plasma membranes of epidermal keratinocytes in a fishnet-like pattern. Also note the early suprabasal separation due to loss of cell-cell adhesion (acantholysis).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-36 Electron microscopy of pemphigus vulgaris-like acantholysis in a mouse with targeted disruption of desmoglein 3 gene. There is a blister forming directly above an intact basal cell layer. Unlike normal desmosomes that bind together plasma membranes of adjacent keratinocytes (inset, upper left), desmosomes in the region of the forming blister in the desmoglein 3-deficient mouse are separated (inset, lower right).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-37 Bullous pemphigoid. Clinical bullae (A) result from basal cell layer vacuolization, producing a subepidermal blister (B). Eosinophils, as well as lymphocytes and occasional neutrophils, may be intimately associated with basal cell layer destruction, creating a subepidermal cleft.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-38 A, Linear deposition of complement along the dermal-epidermal junction in bullous pemphigoid; the pattern has been likened to "ribbon candy." B, Bullous pemphigoid antigen is located in the lowermost portion of the basal cell cytoplasm in association with hemidesmosomes (HD), with blister formation affecting the lamina lucida (LL) of the basement membrane zone. LD, lamina densa; AF, anchoring fibrils.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-39 Dermatitis herpetiformis. A, Clinical lesions consist of intact and eroded erythematous blisters that are often grouped together. B, Histologically, neutrophilic microabscesses selectively involve the dermal papilla.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-40 Dermatitis herpetiformis. A, Papillary dermal microabscesses are associated with zones of dermal-epidermal cleavage that eventually coalesce to form a clinical blister. B, By direct immunofluorescence, these abscesses are rich in IgA and fibrin deposits.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-41 Epidermolysis bullosa. A, Junctional epidermolysis bullosa showing typical erosions in flexural creases. B, A noninflammatory subepidermal blister in this case has formed at the level of the lamina lucida. ( A from Murphy GF, Herzberg AJ: Atlas of Dermatopathology. Philadelphia, WB Saunders, 1996, p 67.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-42 Porphyria. A noninflammatory blister is forming at the dermal-epidermal junction; note the seemingly rigid dermal papillae at the base that contain the altered superficial vessels.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-43 Acne. A, Inflammatory acne is characterized clinically by erythematous papules and pustules, with the possibility of eventual scarring. B, A portion of a hair shaft piercing the follicular epithelium and eliciting an inflammatory response and fibrosis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-44 Verruca vulgaris. A, Multiple papules with rough, pebble-like surfaces are present. B, Histologically, such lesions show papillomatous epidermal hyperplasia and cytopathic alterations that include nuclear pallor and prominent keratohyaline granules (inset panel at bottom). C, In situ hybridization reveals sites of viral DNA within infected epidermal cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-45 Molluscum contagiosum. A focus of verrucous epidermal hyperplasia contains numerous cells with ellipsoid cytoplasmic inclusions (molluscum bodies) within the stratum granulosum and stratum corneum.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-46 Tinea. A, Characteristic plaque of tinea corporis. Routine histology (B) shows the picture of mild eczematous (spongiotic) dermatitis, and periodic acid-Schiff stain reveals deep red hyphae and yeast forms (C) within the stratum corneum. (From Murphy GF, Herzberg AJ: Atlas of Dermatopathology. Philadelphia, WB Saunders, 1996, p 46.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 27-47 A, Pediculosis. Egg case (nit) of head louse attached to hair shaft. B, Portions of a scabies mite within a burrow involving the stratum corneum.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-39 Severe osteoarthritis with small islands of residual articular cartilage next to exposed subchondral bone. 1, Eburnated articular surface. 2, Subchondral cyst. 3, Residual articular cartilage.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-40 Severe osteoarthritis of the hip. The joint space is narrowed, and there is subchondral sclerosis with scattered oval radiolucent cysts and peripheral osteophyte lipping (arrows).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-41 Rheumatoid arthritis. A, Low magnification reveals marked synovial hypertrophy with formation of villi. B, At higher magnification, subsynovial tissue containing a dense lymphoid aggregate is seen.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-42 Subcutaneous rheumatoid nodule with an area of necrosis ( top) surrounded by a palisade of macrophages and scattered chronic inflammatory cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-43 Immunopathogenesis of rheumatoid arthritis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-44 Rheumatoid arthritis. A, Early disease, most marked in the second metacarpophalangeal joint, where there is narrowing of joint space and marginal erosions on both radial and ulnar aspects of the proximal phalanx ( see inset). B, More advanced disease with loss of articular cartilage, narrowing of joint spaces of virtually all the small joints, and ulnar deviation of the fingers. There is dislocation of the second, third, and fourth proximal phalanges produced by advanced articular disease. (Courtesy of Dr. John O'Connor, Boston University Medical Center, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-45 Purine metabolism. The conversion of PRPP to purine nucleotides is catalyzed by amido PRT in the de novo pathway and by APRT and HGPRT in the salvage pathway.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-46 Pathogenesis of acute gouty arthritis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-47 Amputated great toe with white tophi involving the joint and soft tissues.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-48 Photomicrograph of a gouty tophus. An aggregate of dissolved urate crystals is surrounded by reactive fibroblasts, mononuclear inflammatory cells, and giant cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-49 Smear preparation of calcium pyrophosphate crystals.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-50 Excised synovium with fronds and nodules typical of pigmented villonodular synovitis (PVNS), best seen at 6 o'clock.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-51 Sheets of proliferating cells in PVNS bulging the synovial lining.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-52 Myxoid liposarcoma with abundant ground substance in which are scattered adult-appearing fat cells and more primitive cells, some containing small lipid vacuoles (lipoblasts).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-53 Nodular fasciitis with plump, randomly oriented spindle cells surrounded by myxoid stroma. Note the mitotic activity and extravasated red blood cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-54 Peripherally mineralized myositis ossificans involving the posterior thigh.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-55 Fibromatosis infiltrating between skeletal muscle cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-56 Fibrosarcoma composed of malignant spindle cells arranged in a herringbone pattern.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-57 Malignant fibrous histiocytoma revealing fascicles of plump spindled cells in a swirling (storiform) pattern, typical but not pathognomonic of this neoplasm. (Courtesy of Dr. J. Corson, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-58 Rhabdomyosarcoma composed of malignant small round cells. The rhabdomyoblasts are large and round and have abundant eosinophilic cytoplasm; no cross-striations are evident.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-59 Alveolar rhabdomyosarcoma with numerous spaces lined by tumor cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 28-60 Synovial sarcoma revealing the classic biphasic spindle cell and glandular-like histologic appearance.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 29-4 A, ATPase histochemical staining, at pH 9.4, of normal muscle showing checkerboard distribution of intermingled type 1 (light) and type 2 (dark) fibers. B, In contrast, fibers of either histochemical type are grouped together after reinnervation of muscle. C, A cluster of atrophic fibers (group atrophy) in the center.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 29-5 Electron micrograph of a single, thinly myelinated axon surrounded by concentrically arranged proliferating Schwann cells, forming an onion bulb. (Courtesy of G. Richard Dickersin, MD, from Diagnostic Electron Microscopy: A Text-Atlas. New York, Igaku-Shoin Medical Publishers, 1988, p 600.) Inset, Light microscopic appearance of an onion bulb neuropathy.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 29-6 Electron micrograph of a degenerating axon (arrow) adjacent to several intact unmyelinated fibers (arrowheads). The axon is markedly distended and contains numerous degenerating organelles and dense bodies.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 29-7 Diabetic neuropathy with marked loss of myelinated fibers, a thinly myelinated fiber, and thickening of endoneurial vessel wall (arrow).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 29-8 Traumatic neuroma showing disordered orientation of nerve fiber bundles (purple) intermixed with connective tissue (blue).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 29-9 Spinal muscular atrophy with groups of atrophic muscle fibers resulting from denervation atrophy of muscle in early childhood.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 29-10 A, Duchenne muscular dystrophy (DMD) showing variation in muscle fiber size, increased endomysial connective tissue, and regenerating fibers (blue hue). B, Western blot showing absence of dystrophin in DMD and altered dystrophin size in Becker muscular dystrophy (BMD) compared with control (Con). (Courtesy of Dr. L. Kunkel, Children's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 29-11 Diagram showing the relationship between the cell membrane (sarcolemma) and the sarcolemmal-associated proteins. Dystrophin, an intracellular protein, forms an interface between the cytoskeletal proteins and groups of transmembrane proteins, the dystroglycans and the sarcoglycans. These transmembrane proteins have interactions with the extracellular matrix, including the laminin proteins. Mutations in dystrophin are associated with the X-linked muscular dystrophies, mutations in the sarcoglycan proteins with the autosomal limb girdle muscular dystrophies, and mutations in alpha2-laminin (merosin) with a form of congenital muscular dystrophy.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 29-12 A, Nemaline myopathy with numerous rod-shaped, intracytoplasmic inclusions (dark purple structures). B, Electron micrograph of subsarcolemmal nemaline bodies, showing material of Z-band density.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 29-13 A, Mitochondrial myopathy showing an irregular fiber with subsarcolemmal collections of mitochondria that stain red with the modified Gomori trichrome stain (ragged red fiber). B, Electron micrograph of mitochondria from biopsy specimen in A showing "parking lot" inclusions.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-3 Duret hemorrhage involving the midline at the junction of the pons and midbrain.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-4 A, Hydrocephalus. Dilated lateral ventricles seen in a coronal section through the midthalamus. B, Midsagittal plane T1-weighted magnetic resonance image of a child with communicating hydrocephalus, involving all ventricles. ( B, Courtesy of Dr. P. Barnes, Children's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-5 Holoprosencephaly. View of the dorsal surface showing a lack of separation of cerebral hemispheres, a single ventricle, and fused basal ganglia.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-6 Agenesis of the corpus callosum. The sagittal section shows the lack of a corpus callosum above the third ventricle.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-7 Arnold-Chiari malformation. Midsagittal section showing small posterior fossa contents, downward displacement of the cerebellar vermis, and deformity of the medulla (arrows indicate the approximate level of the foramen magnum).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-8 Periventricular leukomalacia. Central focus of white matter necrosis with a peripheral rim of mineralized axonal processes (staining blue).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-9 Multiple contusions involving the cerebellum, inferior surfaces of frontal lobes, and temporal tips.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-10 Epidural hematoma covering a portion of the dura. Multiple small contusions are seen in the temporal lobe. (Courtesy of Dr. Raymond D. Adams, Massachusetts General Hospital, Boston, MA).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-11 Epidural hematoma ( left) in which rupture of a meningeal artery, usually associated with a skull fracture, leads to accumulation of arterial blood between the dura and the skull. In a subdural hematoma ( right), damage to bridging veins between the brain and the superior sagittal sinus leads to the accumulation of blood between the dura and the arachnoid.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-12 A, Large organizing subdural hematoma attached to the dura. B, Coronal section of the brain showing compression of the hemisphere underlying the hematoma.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-13 Sections of the brain showing a large, discolored, focally hemorrhagic region in the left middle cerebral artery distribution.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-14 Old cystic infarct. Destruction of cortex and surrounding gliosis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-15 A, Massive hypertensive hemorrhage rupturing into a lateral ventricle. B, Hypertensive hemorrhage in the pons, with extension to fill the fourth ventricle.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-16 Common sites of berry aneurysms in the circle of Willis.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-17 A, View of the base of the brain, dissected to show the circle of Willis with an aneurysm of the anterior cerebral artery ( arrow). B, Dissected circle of Willis to show large aneurysm. C, Section through a berry aneurysm showing the hyalinized fibrous vessel wall (H&E).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-18 Lacunar infarcts in the caudate and putamen.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-20 Frontal abscesses ( arrows).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-21 Herpes encephalitis showing extensive destruction of inferior frontal and anterior temporal lobes. (Courtesy of Dr. T.W. Smith, University of Massachusetts Medical School, Worcester, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-22 HIV-1 encephalitis. Note the microglial nodule and multinucleated giant cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-23 Progressive multifocal leukoencephalopathy. Section stained for myelin showing irregular, poorly defined areas of demyelination, which become confluent in places. Inset, Enlarged oligodendrocyte nuclei stained for viral antigens.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-24 Toxoplasma abscesses in the putamen and thalamus. Inset, Toxoplasma pseudocyst with bradyzoites and free tachyzoites.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-25 A, Proposed mechanism for the conversion of PrPc through protein-protein interactions. The initiating molecules of PrPsc may arise through inoculation (as in directly transmitted cases) or through an extremely low-rate spontaneous conformational change. The effect of the mutations in PrP (see B) is to increase the rate of the conformational change once PrPsc is able to recruit and convert other molecules of PrPc into the abnormal form of the protein. Although the model is drawn with no other proteins involved, it is possible that various other proteins play critical roles in the conversion of Prpc to PrPsc .B, The basic structure of the PrP protein with important sites of mutation (codon 178) and disease-associated polymorphism (codon 129). In normal individuals, codon 178 encodes Asp (D) and codon 129 encodes either Met (M) or Val (V). In some familial forms of disease, the mutation changes codon 178 to Asn (D178N). When the allele containing the D178N mutation also has a Val at codon 129, the patient develops Creutzfeldt-Jakob disease (CJD). In contrast, when the D178N allele has Met at codon 129, the clinical disorder is fatal familial insomnia.C, Histology of CJD showing spongiform change in the cerebral cortex. Inset, High magnification of neuron with vacuoles.D, Cerebellar cortex showing kuru plaques (periodic acid-Schiff [PAS] stain) representing aggregated PrPsc .
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-26 Multiple sclerosis. Section of fresh brain showing brown plaque around occipital horn of the lateral ventricle.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-27 Multiple sclerosis. A, Unstained regions of demyelination (MS plaques) around the fourth ventricle. (Luxol fast blue PAS stain for myelin). B, Myelin-stained section shows the sharp edge of a demyelinated plaque and perivascular lymphocytic cuffs. C, The same lesion stained for axons shows relative preservation.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-28 Alzheimer disease with cortical atrophy most evident on the right, where meninges have been removed. (Courtesy of Dr. E.P. Richardson, Jr, Massachusetts General Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-29 Alzheimer disease. A, Neurofibrillary tangles ( arrowheads) are present within the neurons (H&E). B, Silver stain showing a neurofibrillary tangle within the neuronal cytoplasm. C, Neuritic plaque with a rim of dystrophic neurites surrounding an amyloid core. D, Congo red staining of the cerebral cortex showing amyloid deposition in the blood vessels and the amyloid core of the neuritic plaque ( arrow).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-30 Amyloid precursor protein (APP) is a transmembrane protein: cellular trafficking of APP involves synthesis and maturation of APP through the endoplasmic reticulum (ER) and Golgi apparatus, with eventual expression in the cell surface. Surface APP can be processed to generate soluble secreted APPs through alpha-secretase cleavage, or reinternalized into an endosomal compartment. Generation of Abeta by beta- and gamma-secretases may occur in the endosomal and other compartments. Abeta fragments form amyloid fibrils.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-31 Parkinson disease (PD). A, Normal substantia nigra. B, Depigmented substantia nigra in idiopathic PD. C, Lewy bodies in a substantia nigra neuron stain bright pink. ( C, Courtesy of Dr. R. Kim, V.A. Medical Center, Long Beach, CA)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-32 Huntington disease (HD). Normal hemisphere on the left compared with the hemisphere with HD on the right showing atrophy of the striatum and ventricular dilation. (Courtesy of Dr. J.-P. Vonsattel, Massachusetts General Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-33 Amyotrophic lateral sclerosis. Spinal cord showing loss of myelinated fibers (lack of stain) in corticospinal tracts. The anterior roots are smaller than the posterior; at higher magnification, loss of anterior horn neurons can also be seen (Woelcke stain for myelin).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-34 Metachromatic leukodystrophy. Demyelination is extensive. The subcortical fibers in the cerebral hemisphere are spared (Luxol fast blue PAS stain for myelin).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-35 Alcoholic cerebellar degeneration. The anterior portion of the vermis ( upper portion of figure) is atrophic with widened spaces between the folia.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-36 Well-differentiated astrocytoma. A, The right frontal tumor has expanded gyri, which led to flattening ( arrows). B, Expanded white matter of the left cerebral hemisphere and thickened corpus callosum and fornices.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-37 A, Computed tomographic (CT) scan of a large tumor in the cerebral hemisphere showing signal enhancement with contrast material and pronounced peritumoral edema. B, Glioblastoma multiforme appearing as a necrotic, hemorrhagic, infiltrating mass.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-38 Glioblastoma multiforme. Foci of necrosis with pseudopalisading of malignant nuclei and endothelial cell proliferation, leading to a structure ( arrows).
Contents - 1 - 2 - Index
glomeruloid
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-39 Pilocytic astrocytoma in the cerebellum with a nodule of tumor in a cyst.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-40 Ependymoma. A, Tumor growing into the fourth ventricle, distorting, compressing, and infiltrating surrounding structures. B, Microscopic appearance of ependymoma.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-41 Medulloblastoma. A, CT scan showing a contrast-enhancing midline lesion in the posterior fossa. B, Sagittal section of brain showing medulloblastoma destroying the superior midline cerebellum. C, Microscopic appearance of medulloblastoma.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-42 A, Parasagittal multilobular meningioma attached to the dura with compression of underlying brain. B, Meningioma with a whorled pattern of cell growth and psammoma bodies.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 30-43 Schwannoma. A, Bilateral eighth nerve schwannomas. (Courtesy of Dr. K.M. Earle.) B, Tumor showing cellular areas (Antoni A), including Verocay bodies ( far right), as well as looser, myxoid regions (Antoni B).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-2 Pinguecula ( arrows) at the nasal limbus of the cornea.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-3 Trachoma. Corneal epithelial cells show cytoplasmic inclusion bodies (see text).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-4 Granular dystrophy of the cornea (Masson trichrome stain).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-5 Macular dystrophy of the cornea. Alcian blue stains mucopolysaccharide deposits under the epithelium.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-6 Fuchs dystrophy (H&E). Note the focal thickening of the basement membranes under the endothelium ( bottom) and detachments of epithelium ( above) from Bowman layer.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-7 Sarcoidosis of the uvea (H&E). Note the granulomas with giant cells.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-8 Sympathetic ophthalmia showing thickening of the choroid with inflammatory cells ( arrows).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-9 Malignant melanoma of the choroid. Note the collar button-shaped dark tumor on the left with adjacent pink proteinaceous exudate and detached retina. Optic nerve is at 6 o'clock, and the lens is at 12 o'clock.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-10 A, Spindle cell malignant melanoma. The cells have a spindle-shaped nucleus with nuclear fold, indistinct nuclei, and scant cytoplasm: the cell borders are difficult to discern. B, Epithelioid cell malignant melanoma. Large cells with round nuclei are seen. Tumors are poorly cohesive, with well-demarcated cell borders and eosinophilic cytoplasm. (H&E×40.) C, Mixed cell malignant melanoma. Spindle cells and epithelioid cells are seen in the most common cell type of ocular melanoma.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-11 Normal retina. Layers from top down are A, nerve fiber layer, B, ganglion cell layer, C, inner nuclear layer, D, outer nuclear layer, and E, rods and cones. (Courtesy of Dr. Umberto De Girolami, Department of Pathology, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-12 Diabetic retinopathy. Human retina from a case of advanced diabetic microangiopathy, after trypsin digestion. Note the several microaneurysms.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-13 Funduscopic picture of fluffy, superficial, yellowish cotton-wool spots.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-14 Retina showing macular degeneration. Compare with normal retina in Figure 31-12 .
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-15 Retinal detachment caused by choroidal lymphoma. Note the infiltrate of lymphoma (L) in the choroid and the fluid collection (F) between the pigment epithelium and detached retina. (Courtesy of Dr. Umberto De Girolami, Department of Pathology, Brigham and Women's Hospital, Boston, MA.)
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-16 Retinoblastoma. Note poorly cohesive tumor in retina abutting optic nerve.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-17 Higher-power view of retinoblastoma showing Flexner-Wintersteiner rosettes and numerous mitotic figures (H&E×40).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-18 Papilledema showing displacement of the sensory retina ( arrows).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-19 Optic atrophy: note the large optic cup (H&E×10).
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-20 Glaucomatous cup. Note the characteristic excavation of the optic disc.
Contents - 1 - 2 - Index
Robbins Pathologic Basis of Disease Contents - 1 - 2 - Index
Figure 31-21 Phthisis bulbi. Note the markedly thickened sclera and disorganization of the intraocular contents.
Contents - 1 - 2 - Index