Pathology: A Color Atlas

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Author: Ivan Damjanov MD PhD | James Linder MD

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PATHOLOGY A Color Atlas



THE HEART,1 CONGENITAL HEART DISEASE, 2 Cardiovascular shunts and septal defects, 2 Conotruncal anomalies, 4 Cardiovascular obstructions, 6 VALVULAR LESIONS, 9 Rheumatic heart disease, 9 Infective endocarditis, 11 Other valvular lesions, 13 MYOCARDIAL DISEASES, 14 Myocarditis, 14 Cardiomyopathy, 17 CORONARY ARTERY DISEASES, 20 Coronary atherosclerosis, 20 Myocardial infarction, 22 Complications of myocardial infarction, 22 PERICARDIAL DISEASES, 25 CARDIAC TUMORS, 27

BLOOD VESSELS, 30 ARTERIOSCLEROSIS, 32 ANEURYSMS, 35 VASCULITIS, 36 Immune-mediated vasculitis, 38

UPPER RESPIRATORY TRACT, 40 INFLAMMATORY LESIONS, 42 BENIGN TUMORS AND RELATED CONDITIONS, 44 MALIGNANT TUMORS, 45

LUNGS, 48 DEVELOPMENTAL ANOMALIES, 50 PERINATAL LUNG DISEASES, 52 PULMONARY INFECTIONS, 54 PULMONARY CIRCULATORY DISORDERS, 57 Pulmonary emboli, 57 Pulmonary hypertension, 58 IMMUNE-MEDIATED LUNG DISEASES, 58 CHRONIC INFECTIONS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (CORD), 60 Bronchiectasis, 60

Chronic obstructive pulmonary disease, 60 PNEUMOCONIOSES, 62 IDIOPATHIC INTERSTITIAL LUNG DISEASES, 66 PULMONARY NEOPLASMS, 68

THE HEMATOPOIETIC AND LYMPHOID SYSTEM, 72 ANEMIAS, 74 Bone marrow changes, 74 Peripheral blood smears, 74 Tissue changes in anemia, 77 LEUKEMIAS, 78 Acute leukemias, 78 Chronic leukemias, 80 PLASMA CELL DYSCRASIAS, 82 REACTIVE LYMPHADENOPATHIES, 84 HODGKIN DISEASE, 87 Histopathologic subtypes of Hodgkin disease, 87 NON-HODGKIN LYMPHOMA, 89 OTHER HEMATOPOIETIC PROLIFERATIONS IN LYMPH NODES, 95 NEOPLASMS INVOLVING THE SPLEEN, 96 DISEASES OF THE THYMUS, 98

UPPER DIGESTIVE TRACT, loo DEVELOPMENTAL ANOMALIES, 102 INFLAMMATORY LESIONS, 103 ORGAN-SPECIFIC LESIONS, 105 Dental cysts, 105 Oral and salivary gland lesions, 108 Esophageal lesions, 110 TUMORS, 112 Oral tumors, 112 Salivary gland tumors, 112 Esophageal tumors, 118

GASTROINTESTINAL TRACT, 120 DEVELOPMENTAL DISORDERS, 122 CIRCULATORY DISTURBANCES, 124 OBSTRUCTIONS AND DILATATIONS OF INTESTINAL LUMEN, 125


ORGAN-SPECIFIC DISEASES, 126 Gastritis and peptic ulcer, 126 Small intestinal diseases that cause malabsorption, 129 Inflammation of the appendix and the large intestine, 130 Inflammatory bowel disease (IBD), 132 TUMORS, 134 Gastric tumors, 134 Tumors of the small intestine, 136 Tumors of the appendix, 136 Intestinal polyps, 136 Carcinoma of the large intestine, 139 Anal tumors and related lesions, 140

HEPATOBILIARY TRACT, 142 HEREDITARY METABOLIC DISEASES, 144 CIRCULATORY DISORDERS, 146 INFECTIOUS HEPATITIS, 147 Viral hepatitis, 147 Hepatitis caused by pathogens other than hepatitis viruses, 149 Biliary infections, 150 DRUG-INDUCED LIVER DISEASES, 152 ALCOHOLIC LIVER DISEASES, 153 AUTOIMMUNE LIVER DISEASES, 155 BILIARY OBSTRUCTION, 156 CIRRHOSIS, 158 TUMOR-LIKE CONDITIONS AND TUMORS, 159 Tumor-like conditions, 159 Epithelial tumors, 161 Mesenchymal tumors, 163 Metastatic tumors, 163 DISEASES OF THE GALLBLADDER, 164

PANCREAS, 166 DEVELOPMENTAL AND GENETIC DISORDERS, 168 PANCREATITIS, 169 TUMORS OF THE EXOCRINE PANCREAS, 172 Benign tumors and tumors of borderline malignancy, 172 Carcinoma of the pancreas, 174 TUMORS OFTHE ENDOCRINE PANCREAS, 176 DIABETES MELLITUS, 177

ENDOCRINE GLANDS, 180 DISEASES OF THE PITUITARY GLAND, 182 Hypopituitarism, 182 Reactive changes, 183 Tumors, 183

DISEASES OF THE THYROID GLAND, 185 Thyroid hyperplasia, 185 Thyroiditis, 186 Benign thyroid tumors, 188 Malignant thyroid tumors, 190 DISEASES OF THE PARATHYROID GLANDS, 195 DISEASES OF THE ADRENAL CORTEX, 198 Adrenocortical insufficiency, 198 Adrenocortical hyperplasia and hyperfunction, 199 Adrenocortical tumors, 201 DISEASES OFTHE ADRENAL MEDULLA, 203

KIDNEY AND URINARY TRACT, 208 DEVELOPMENTAL AND GENETIC DISORDERS, 210 Agenesis, malposition, exstrophy, and related defects, 210 Polycystic kidney disease, 212 Hereditary glomerular and tubular diseases, 213 VASCULAR DISORDERS, 216 IMMUNE-MEDIATED GLOMERULAR DISEASES, 217 Membranoproliferative glomerulonephritis, 219 Membranous glomerulonephritis, 220 IgA nephropathy and Henoch-Schonlein purpura, 222 Postinfectious glomerulonephritis, 223 Crescentic glomerulonephritis, 224 Systemic lupus erythematosus (SLE), 225 TUBULOINTERSTITIAL DISEASES, 227 LOWER URINARY TRACT INFECTIONS, 232 TUMORS, 234 Tumors of the kidney and renal pelvis, 234 Tumors of the urinary bladder, 235

MALE REPRODUCTIVE SYSTEM, 238 GENETIC AND DEVELOPMENTAL DISORDERS, 240 INFECTIONS, 241 TUMORS OF THE TESTIS, 242 Germ cell tumors, 242 Sex cord stromal tumors, 246 Mixed germ cell stromal tumors, 247 Tumors of rete testis, epididymis, and tunica vaginalis testis, 248 TUMORS AND TUMOR-LIKE LESIONS OF THE PROSTATE, 248 Benign prostatic hyperplasia, 248 Carcinoma of the prostate, 250

FEMALE REPRODUCTIVE SYSTEM, 256 DEVELOPMENTAL DISORDERS, 258 INFECTIONS, 260


HORMONALLY INDUCED CHANGES, 261 TUMORS OF THE VULVA, 263 TUMORS OF THE VAGINA, 265 TUMORS OF THE CERVIX, 266 TUMORS OF THE UTERUS, 268 Endometrial adenocarcinoma, 268 Endometrial stromal tumor,s 270 Tumors of the myometrium, 271 TUMORS OF THE OVARY, 273 Serous tumors, 273 Mucinous tumors, 275 Endometrioid carcinoma, 277 Clear cell carcinoma, 278 Transitional cell tumors, 278 Sex cord stromal tumors, 278 Germ cell tumors, 282 Unclassified and metastatic tumors of the ovary, 284 DISORDERS OF THE PLACENTA, 287 Abnormal implantation and separation of the placenta and rupture of membranes, 289 Infections, 289 Gestational trophoblastic disease, 290

BREAST, 294 FIBROCYSTIC CHANGE, 296 TUMORS, 298 Fibroadenoma, 298 Adenoma, 298 Phyllodes tumor, 299 Intraductal papilloma, 300 Atypical hyperplasia, 301 Noninvasive carcinoma, 302 Invasive breast carcinoma, 303 Variants of invasive carcinoma 306 I mmunohistochemistry of breast carcinoma, 308

SKIN, 310 HEREDITARY SKIN DISEASES, 312 INFECTIONS, 312 Bacterial infections, 313 Fungal infections, 314 Viral infections, 314 INFLAMMATORY DERMATOSES, 316 I mmune-mediated dermatoses, 316 Granulomatous diseases, 319 Idiopathic skin disease, 321 NEOPLASMS AND RELATED DISORDERS, 323 Pigmentary lesions, 323 Epidermal tumors, 328 Adnexal tumors, 331 Mesenchymal tumors, 333

SOFT TISSUE, 334 FIBROBLASTIC LESIONS, 336 Benign fibroblastic tumors and tumor-like lesions, 336 Fibromatoses, 337 FIBROHISTIOCYTIC TUMORS, 338 LIPOMATOUS TUMORS, 339 VASCULAR TUMORS, 341 PERIVASCULAR TUMORS, 343 SMOOTH MUSCLE CELL TUMORS, 344 TUMORS OF STRIATED MUSCLE, 345 NEURAL TUMORS, 347 Benign neural tumors, 347 Malignant neural tumors, 348 CARTILAGE AND BONE-FORMING TUMORS, 349 MISCELLANEOUS SOFT-TISSUE TUMORS, 350

BONES AND JOINTS, 354 DEVELOPMENTAL AND GENETIC DISORDERS, 356 METABOLIC AND DEGENERATIVE DISEASES, 357 Metabolic bone diseases, 357 Hyperparathyroidism, 359 Paget disease of bone, 359 Crystal-induced arthritis, 360 Osteonecrosis, 361 Degenerative joint disease, 361 I NFLAMMATORY DISEASES, 363 Infections of bones and joints, 363 Noninfectious arthropathies, 364 NEOPLASMS, 367 Benign bone-forming tumors, 367 Malignant bone-forming tumors, 369 Fibrous lesions of bone, 377 Giant cell tumor of bone, 378 Marrow tumors, 379 Vascular tumors, 380 Miscellaneous tumors and tumor-like conditions, 380 Tumors and tumor-like lesions of joints, 383

SKELETAL MUSCLES, 384 CONGENITAL MYOPATHIES, 386 MUSCULAR DYSTROPHIES, 386 I NFLAMMATORY MYOPATHIES, 389 GENETIC-METABOLIC MYOPATHIES, 392 Carbohydrate storage diseases, 392 Lipid storage myopathies, 393 Mitochondrial myopathies, 394 DENERVATION-RELATED MUSCLE DISEASES, 395


NERVOUS SYSTEM, 398 DEVELOPMENTAL AND GENETIC DISORDERS, 400 PERINATAL BRAIN LESIONS, 401 TRAUMA OFTHE BRAIN AND THE SPINAL CORD, 403 CIRCULATORY DISTURBANCES, 405 Intracranial hemorrhages, 405 Cerebral ischemia, 408 INFECTIONS, 409 METABOLIC AND TOXIC DISEASES, 413 Inborn errors of metabolism, 414 DEMYELINATING DISEASES, 416 DEGENERATIVE DISEASES OF THE CENTRAL NERVOUS SYSTEM, 417 NEOPLASMS, 420 Astrocytic tumors, 422 Oligodendroglioma, 422 Ependymoma, 422 Neuronal, mixed neuronal-glial, and neuroendocrine neoplasms, 424 Pineal tumors, 424 Meningioma, 425 Vascular neoplasms, 425 Malformative and nonneoplastic mass lesions, 426 DISEASES OF PERIPHERAL NERVES, 426 Peripheral neuropathies, 426 Hereditary neuropathies, 428 Ischemic neuropathies, 430 Inflammatory neuropathies, 430 Neoplasms of peripheral nerves, 432

THE EYE AND OCULAR ADNEXA, 434 INFLAMMATION OFTHE EYE AND OCULAR ADNEXA, 436 EYE CHANGES IN SYSTEMIC DISEASES, 437 SPECIFIC OCULAR DISORDERS, 438 Glaucoma, 438 Diseases of the cornea, 440 Retinal degenerative diseases, 441 Cataracts, 442 TUMORS, 443 Melanoma, 443 Retinoblastoma, 445 Medulloepithelioma, 446

EAR, 448 INFLAMMATORY LESIONS OF THE EXTERNAL AND MIDDLE EAR, 450 PATHOLOGIC CHANGES OFTHE INNER EAR, 453 NEOPLASMS, 455 Tumors of the outer ear, 455 Tumors of the middle ear, 455 Tumors of the inner ear, 455


PATHOLOGY A

Color Atlas




CONGENITAL HEART DISEASE

Cardiovascular Shunts and Septa! Defects

Congenital heart disease encompasses disorders of the cardiovascular system that result from faulty embryogenesis and are present at birth. The most common cardiac malformations in descending order of frequency are 1.Ventricular septal defect (VSD) 2. Atrial septal defect 3. Pulmonary stenosis 4. Tetralogy of Fallot (including pulmonary atresia) 5. Patent ductal artery (ductus arteriosus) 6. Aortic stenosis 7. Coarctation of the aorta 8. Complete transposition of the great arteries 9. Atrioventricular septal defect 10.Tricuspid atresia 11.Aortic atresia (hypoplastic left ventricular syndrome) 12.Total anomalous pulmonary venous connection 13.Persistent truncal artery (truncus arteriosus)

Shunts result either from patency of normal fetal structures that fail to close postnatally or from incomplete formation of one or more septa during cardiac embryogenesis. Persistent fetal structures include a patent oval foramen and a patent ductal artery (Fig. 1-1). In contrast, shunts that result from faulty embryogenesis involve defects at the level of the atrial, atrioventricular, ventricular, ventriculoarterial, or aortopulmonary septa (Diagram 1-1). Atrial septal defects occur at the oval fossa in 85% of cases and are known as fossa or secundum atrial septal defects (Fig. 1-2). Ventricular septal defects involve the membranous part of the septum in 75% to 80% of cases seen at operation or autopsy (Fig. 1-3). Outlet defects located beneath the right and left cusps of both semilunar valves account for 5% to 10% of all VSD. Inlet defects that involve the inlet septum beneath the septal tricuspid leaflet account for 5% of all VSD. Defects of the muscular part of the septum account for only 10% to 20% of cases at operation or autopsy, even though they actually represent the most common form of VSD. Most of them are small and close spontaneously.

Diagram I-I. Cardiac and vascular shunts. Upper panel shows various levels of intracardiac shunts. Lower panel shows various levels of shunts involving the great arteries.


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Fig. I -I. Patent ductal artery (*), connecting the aorta with the pulmonary artery, in adult with plexogenic pulmonary hypertension.

Fig. 1-2. Atrial septal defect, fossa (secundum) type, as seen in an adult (*).

A

B

C

D

Fig. 1-3. Ventricular septal defects (*). A, Membranous defect; B, Outlet defect; C, Muscular defect; D, Muscular defect that has undergone spontaneous closure (arrows).


Conotruncal Anomalies Conotruncal anomalies are related to abnormal development of ventricular outflow tracts (Diagram 1-2). Most are associated with an overriding great artery; in some cases one or both arteries arise from the contralateral ventricle. Many patients have a VSD of the membranous or outlet type, as well as valvular or subvalvular pulmonary stenosis. Clinically these defects are associated with right-to-left shunts and peripheral cyanosis.

Tetralogy of Fallot is the most common conotruncal anomaly, accounting for 8% to 10% of all congenital heart defects. It comprises subpulmonary stenosis, a VSD, an overriding aorta, and right ventricular hypertrophy (Fig. 1-4). Pulmonary atresia with a VSD is considered the most severe form of tetralogy of Fallot (Fig. 1-5). The persistent truncal artery (Fig. 1-6) accounts for 1% of all congenital heart defects and complete transposition ofgreat vessels (Fig. 1-7) accounts for 5%.

Diagram 1-2. Conotruncal anomalies.


A

B

Fig. 1-4. Tetralogy of Fallot. A, Hypoplastic pulmonary trunk and enlarged ascending aorta (anterior view); B, Displaced outlet septum (*) with pulmonary stenosis (probe), a ventricular septal defect (arrow probe), and an overriding aorta (opened, hypertrophied right ventricle).

A

B

Fig. I-S. Pulmonary atresia with ventricular septal defect. A, Atretic cordlike pulmonary trunk (arrow) and dilated ascending aorta (anterior view). B, Ventricular septal defect, overriding aorta, and ductal origin of the left pulmonary artery (arrow).


Cardiovascular Obstructions Cardiovascular obstructions can occur congenitally at the level of cardiac chambers (e.g., hypoplastic ventricle), valves (e.g., bicuspid semilunar valves), or great vessels (e.g., coarctation of aorta) (Diagram 1-3). Aortic stenosis may be valvular, subvalvular, or supravalvular. Bicuspid aortic valves occur in 1% to 2% of the general population. Such abnormal valves usually remain asymptomatic until late in adult life. In approximately 80% of patients bicuspid valves undergo calcification, causing aortic stenosis (Fig. 1-8). Pure regurgitation occurs in 20% of patients and is the result of annular dilatation, prolapse of the conjoined cusp, or infective endocarditis. Congenital hypoplasia or nodular thickening of a unicommissural valve, or less commonly a bicuspid valve, may cause critical aortic stenosis in the neonate (Fig. 1-9).

Fig. 1-6. Persistent truncal artery is located over a ventricular septa) defect (*). The overriding truncal artery gives rise to ascending aorta and both pulmonary arteries (opened right ventricle).

A

B

Fig. 1-7. Complete transposition of great arteries. A, Anterior view. B, Long axis view showing ventriculoarterial discordance.


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Diagram 1-3. Valvular and arterial stenosis. Upper panel shows aortic stenosis. Lower panel shows pulmonary stenosis and aortic coarctation. A

B

C

Fig. 1-8. Congenitally bicuspid aortic valves (surgical specimens). A, The valve is calcified and stenotic. B, Regurgitation resulting from cuspid prolapse and annular dilatation. C, Regurgitation resulting from healed infective endocarditis with cusp perforation.


A

B

C

Fig. 1-9. Congenital aortic stenosis. A, Critical stenosis of a unicommissural valve in an infant. B, and C, represent mild stenosis of a unicommissural valve in a young adult (opened and closed positions).

A

B

C

Fig. 1-10. Pulmonary stenosis. A, Poststenotic dilatation of the pulmonary trunk (anterior view). B, Dome-shaped acommissural valve. C, Pronounced right ventricular hypertrophy (four-chamber view).


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Pulmonary stenosis, like its left-sided counterpart, may be valvular, subvalvular, or supravalvular. It often is associated with other cardiac anomalies. Isolated pulmonary stenosis is associated with a dome-shaped acommissural valve in approximately 45%, a dysplastic tricuspid pulmonary valve in 25%, unicommissural valve in 15%, a bicuspid valve in 10%, and a hypoplastic annulus in 5% of patients (Fig. 1-10). Coarctation of the aorta is the most common form of congenital vascular obstruction (Fig. 1-11). It is associated with a V-shaped invagination of the aorta, just opposite the ductal artery. It is associated with a patent ductal artery in 50%, a biscuspid aortic valve in 50%, a membranous VSD in 30%, subaortic stenosis in 25%, and mitral valve anomalies in 25% of cases.

VALVULAR LESIONS Cardiac valves may be congenitally deformed or they may undergo secondary changes due to infections, hemodynamic stress, or age-related degeneration accompanied by calcifications.

Rheumatic Heart Disease Rheumatic fever is an immune-mediated systemic inflammatory disease related to sensitization of the body to beta hemolytic group A streptococci. Even though rheumatic heart disease may involve all parts of the heart and is thus a pancarditis, endocarditis accounts for most important pathologic changes and most of the morbidity. Rheumatic carditis is less common today than it was in the preantibiotic era. An active rheumatic fever causes typical lesions, the most pathognomonic of which are the Aschoff bodies (Fig 1-12). In the granulomatous stage, which is reached three to four weeks after the infection, these bodies consist of macrophages, giant cells (Aschoff cells), lymphocytes, and occasional neutrophils. Aschoff bodies heal by scarring. They most often are found in the myocardium and the subendocardial connective tissue, and only rarely in the valves.

Fig. I-I I. Coarctation of the aorta, with a typical indentation of the aortic wall (arrow) opposite the ductal arterial ligament (*).

A

B

Fig. I-12. Rheumatic carditis in an active phase. A, Aschoff body composed of macrophages and lymphocytes is found in the interstitial plane of the myocardium. B, At higher magnification one can see that the Aschoff body is composed of macrophages, which have caterpillar (arrow) or owl's eye-shaped nuclei (curved arrow).


Rheumatic valvulitis presents in the form of verrucous endocarditis characterized by the formation of tiny translucent nodules on the atrial side of atrioventricular valves and on the ventricular surfaces of semilunar valves (Fig. 1-13). Deposits of fibrin and underlying inflammation may extend onto the left atrial parietal endocardium and less often onto the chordae tendineae or papillary muscles. Histologically the vegetations are composed of fibrin covering the valve, which are focally infiltrated with lymphocytes. The valves, which are normally avascular, become vascularized soon after the onset of inflammation. Within 6 to 8 weeks the valves contain relatively thick-walled blood vessels, which may persist indefinitely. Resolution of this inflammation results in scarring, thickening of the cusps, and obliteration of valve commisures. The chordae tendineae become shortened, thickened, and fused to each other. Mitral valves (Fig. 1-14) and aortic valves (Fig. 1-15) are involved more often than the valves of the right heart. The deformed valves tend to calcify and become infected. Clinically chronic valvular changes present as stenosis or insufficiency.

B

C

A

Fig. 1-13. Acute rheumatic endocarditis. A, Acute endocarditis presents with small translucent vegetations. B, Histologically the lesion is composed of fibrin covering a valve that is infiltrated with mononuclear inflammatory cells. C, Higher magnification of the vegetation and the inflamed value.


II

A

B

Fig. 1-14. Chronic rheumatic endocarditis of mitral valve. A, View from the opened left heart. B, Stenotic orifice seen from the left atrium.

Infective Endocarditis Inflammation may involve the valves or mural endocardium. Accordingly, infective endocarditis is classified as either valvular or mural. It most often is caused by gram-positive bacteria such as Streptococcus pneumoniae and Staphylococcus aureus. Valvular infection is more common and clinically more important. The infected valves are covered with luscious, friable vegetations and are composed of fibrin, bacterial colonies, and inflammatory cells (Figs. 1-16 and 1-17).

Fig. I-15. Chronic rheumatic endocarditis of aortic valve. The valves are deformed fused and the orifice is stenosed.

Fig. 1-16. Acute bacterial endocarditis. The valve is covered with large, friable, irregular vegetations (arrow).

Fig. I-17. Acute bacterial endocarditis. The vegetation consists of fibrin and bacteria.


Infective endocarditis affects valves of the left heart more often than those of the right heart. Factors that predispose to infection include congenitally deformed valves and preexisting valvular lesions such as those caused by rheumatic fever (Figs. 1-18 and 1-19). Sepsis, intravenous drug abuse, cardiovascular surgery, and insertion of prosthetic valves also are associated with an increased risk for infective endocarditis. Infective endocarditis of immunosuppressed persons may be caused by uncommon bacteria and even fungi (Fig. 1-20), which may cause extensive local destructive lesions (Fig. 1-21). Other complications of infective endocarditis are listed in Table 1-1.

Potential Complications of Infective Endocarditis

Fig. 1-18. Acute bacterial endocarditis superimposed on chronic rheumatic endocarditis. Valvular deformities and thickened chordae tendineae are evidence of the chronic process.

Direct Damage to Heart Perforation of valve cusps and/or leaflet causing insufficiency Valve ring or myocardial abscess and fistula formation Suppurative and obliterative pericarditis Dehiscence of prosthetic valves, conduits, and patch components Late valve fibrosis causing stenosis (accompanied by insufficiency) Septic Embolization with Abscess Formation Cerebral abscess Osteomyelitis Mycotic aneurysm Lung abscess Sepsis Infectious Arteritis with Thrombotic Occlusion Infarcts—brain, myocardium, spleen, kidneys, other viscera Ischemia in distribution of ileofemoral or other major arteries Circulating Immune Complexes Focal or diffuse glomerulonephritis Fig. 1-19. Acute bacterial endocarditis superimposed on chronic healing endocarditis. The arrow points to a microabscess formed in the central part of the vegetation.

Fig. 1-20. Fungal endocarditis. Fungal hyphae can be demonstrated in the vegetation by Gomori methenamine-silver stain.

Fig. 1-21. Infective endocarditis with extensive destruction of the valve.


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Other Valvular Lesions Nonbacterial thrombotic endocarditis, which is also known as marantic endocarditis, typically occurs in terminally ill, emaciated patients who have cancer or other chronic diseases. Small vegetations typically are found along the line of closure on otherwise normal valves (Fig. 1-22). Histologically such vegetations resemble bland fibrin thrombi (Fig. 1-23). Floppy mitral valves are common but they rarely cause clinically significant changes unless they are associated with myxomatous transformation. In floppy valve syndrome the valve cusps expand, chordae lengthen, and one or both cusps " billow " or prolapse into the atrium during systole (Fig. 1-24).

Carcinoid heart disease is a complication of intestinal carcinoids metastatic to the liver. It is characterized by fibrotic

changes in the endocardium of the right ventricle. The tricuspid and pulmonary valves have focal or diffuse plaques of glycosaminoglycan-rich, elastin-free connective tissue (Fig. 1-25). The left ventricle also is involved in one third of patients examined at autopsy, but the changes are mild and cause no clinically significant hemodynamic abnormalities. Degenerative calcific aortic stenosis represents an agerelated lesion that typically is found in the elderly. The valves are deformed by nodular calcifications within the cusps (Fig. 1-26). Aortic insufficiency may result from the dilatation of the aortic valve annulus caused by a variety of diseases such as rheumatic fever, syphilis, or atherosclerosis, which is the most common cause of this disease in the elderly (Fig. 1-27).

Fig. 1-22. Nonbacterial thrombotic endocarditis. The line of closure is covered with fine uniform vegetations.

Fig. 1-23. Nonbacterial thrombotic endocarditis. Histologically the vegetations are composed of fibrin attached to a normal valve.

Fig. 1-24. Floppy mitral valve. The valve appears irregularly thickened and deformed. The greatest redundancy and gelatinous change are noted in the posterior leaflet (to the right), but there also is localized thickening along the free margin of the anterior mitral leaflet. Chordae tendineae are variably thickened and focally fused.

Fig. 1-25. Carcinoid heart syndrome. Greatly thickened tricuspid valve and chordae show a whitish "onlay." The right upper portion of the valve is relatively spared and appears translucent.


A

B

Fig. I -26. Degenerative calcific aortic stenosis. A, Superior view of tricuspid, fibrocalcific, stenotic valve. The calcific nodules are most prominent inside the cusps (arrow). The commissures are focally fused, most prominently on the posterior side. B, Similar case with more prominent calcification.

A

B

Fig. 1-27. Aortic insufficiency due to dilatation of the aortic root. The aorta has a thickened wall and its luminal surface is covered with fibrous plaques and focal ulcerative calcific changes, most consistent with healed aortitis. Focal endocardial thickening below the aortic valve is indicative of regurgitation. B, Close-up view. Causes of Myocarditis

MYOCARDIAL DISEASES The most important myocardial diseases are myocarditis and cardiomyopathies.

Myocarditis Inflammations of the myocardium are classified as (1) infectious, (2) immune-mediated, or (3) idiopathic (Table 1-2). Pathologically myocarditis is classified as acute or chronic, focal or diffuse. Histologically it is classified descriptively according to the predominant cell type infiltrating the myocardium or the pattern of reaction, such as lymphocytic, eosinophilic, or giant cell (Fig. 1-28). Pathogens rarely


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A

B

C

D

E

F

Fig. 1-28. Microscopic appearances of myocarditis. A, Active myocarditis of the predominantly lymphocytic type. Isolated myocytes are surrounded by the infiltrate in a background of what appears to be edema. B, Ventricular myocardium with myocarditis and clusters of cells immunoreactively identified as macrophages. C, Ventricular myocardium with active myocarditis and myocytolysis (arrows). The cytolysis is associated with an infiltrate of activated immune cells in a child with suspected viral myocarditis. D, Ventricular myocardium with influenza A-related myocarditis in a young child. The "punched-out" lesions of myocyte necrosis are best defined by lack of positive staining (arrows) with monoclonal antibody to muscle-specific a-actin. E, Giant cell myocarditis with multinucleated giant cells positive for muscle-specific a-actin monoclonal antibody staining. Some of the giant cells in the same heart were derived from muscle cells, whereas others expressed macrophage markers. F, Giant cell myocarditis with multinucleated giant cell and neighboring macrophages stained brown with an antibody CD68. Although this multinucleated cell is immunonegative, others in this case were immunopositive with the same antibody.


if ever are identified by routine histologic examination of the myocardium with a few exceptions such as Chagas disease, in which the myocytes typically contain Trypanosoma cruzi (Fig. 1-29). Myocardial abscess caused by sepsis rarely contains identifiable bacteria (Fig. 1-30). Myocardial cell necrosis with myophagocytosis in a patient with diphtherial pharyngitis is by inference classified as diphtherial; the cardiac lesions actually are caused by a toxin released by C. diphtheriae, which hematogenously reaches the myocardium (Fig. 1-31).

Transplant rejection is accompanied by an immunemediated myocarditis (Fig. 1-32). The type of rejection may be classified by endocardial biopsy as: la—focal mild; lb— diffuse mild; 2—focal moderate; 3a—multifocal moderate; 3b—diffuse moderate or severe; or 4—severe (Figs. 1-32 and 1-33). Idiopathic myocarditis is the most common type of myocardial inflammation identified at autopsy. It may present histologically as lymphocytic, eosinophilic, giant cell, or granulomatous inflammation (Fig. 1-34).

Fig. 1-29. Chagas disease. Myocytes contain Trypanosoma cruzi.

Fig. 1-30. Myocardial abscess. Myocardium contains aggregates of neutrophils.

Fig. 1-31. Diphtherial myocarditis. Necrosis of cardiac myocytes is more prominent than the inflammatory infiltrate.

Fig. 1-32. Cardiac transplant rejection. Focal, moderate (grade 2).


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Fig. 1-33. Cardiac transplant rejection. Multifocal, moderate (grade 3a).

Fig. 1-34. Eosinophilic myocarditis. The interstitium contains infiltrates of lymphocyte and eosinophils.

Cardiomyopathy Cardiomyopathies are diseases characterized by cardiac dysfunction in which the main abnormality lies in the working myocardium. Cardiomyopathies are divided into two groups: primary (idiopathic, due to unknown causes) and secondary (due to known causes). Both the primary and the secondary categories have three possible functional states: (1) dilated, congestive; (2) hypertrophic, hyperdynamic; and (3) restrictive, constrictive (Diagram 1-4, p. 18).

Dilated cardiomyopathy (systolic disorder) is found in patients with hemochromatosis, chronic anemia, alcoholic cardiomyopathy, sarcoidosis, and many other diseases. Typically it is found in the end stages of ischemic heart disease and in hypertensive heart disease, in which it is accompanied by hypertrophy of all four cardiac chambers (Fig. 1-35). The dilated heart shows foci of scarring ( "replacement fibrosis" ) (Fig. 1-36). Thrombi tend to form in the dilated ventricle and there typically is functional mitral insufficiency.

Fig. 1-35. Dilated cardiomyopathy. Ventricles and atria are dilated. There is a mural thrombus in the left ventricle.

Fig. 1-36. Dilated cardiomyopathy. There is replacement fibrosis in the myocardium.


Diagram 1-4. Specific and less specific causes of dilated, hypertrophic, and restrictive cardiomyopathy.

Hypertrophic cardiomyopathy (diastolic disorder) is found in patients with Friedreich ataxia, glycogen storage disease, congenital cardiomyopathies such as those related to mutations of gene for beta-myosin heavy chain, and in infants of diabetic mothers (Figs. 1-37 and 1-38). The most common cause of left ventricular hypertrophy is arterial hypertension. Cor pulmonale causes right ventricular hypertrophy. In all these diseases there is marked hypertrophy of the cardiac myocytes, often accompanied by interstitial fibrosis. Restrictive cardiomyopathy (diastolic and systolic disorder) may be caused by pathologic processes involving the endocardium (e.g., endomyocardial fibrosis), myocardium (e.g., cardiac amyloidosis), or pericardium (e.g., constrictive pericarditis). These diseases typically impede the diastolic filling of the cardiac chambers and reduce systolic ejection of blood. The pathologic changes depend on the process that has caused the disturbance, so the ventricles can be of normal size (as in pericarditis) or markedly thickened (as in amyloidosis) (Figs. 1-39 and 1-40).

Fig. 1-37. Congenital hypertrophic cardiomyopathy with asymmetric septa) hypertrophy.


I9

Fig. 1-38. Congenital hypertrophic cardiomyopathy. Histologically the cardiac myocytes are hypertrophied and show branching and disarray. There also is considerable interstitial fibrosis.

Fig. 1-39. Amyloidosis of the heart. The ventricular myocardium appears thickened but pale.

A

B

Fig. 1-40. Amyloidosis. A, The cardiac myocytes are surrounded by hyalinized material. B, Electron microscopy shows pericellular amyloid fibers.


CORONARY ARTERY DISEASES Atherosclerosis of coronary arteries is clinically the most important heart disease. Narrowing or occlusion of coronary arteries typically causes myocardial ischemia, which clinically presents as angina pectoris, myocardial infarction, or chronic ischemic heart disease.

Coronary Atherosclerosis Atherosclerotic plaques of coronary arteries have the same morphologic features as plaques in other sites, that is, they have an atheromatous, cholesterol-rich core surrounded by a fibrous cap (Fig. 1-41). Some lesions are composed only of

fibrous tissue and are calcified. Plaques may be eccentric (Fig. 1-42) or may concentrically narrow the lumen of the coronaries (Fig. 1-43). Soft lipid-rich atherosclerotic plaques tend to rupture and provoke thrombus formation in the lumen of the coronary (Fig. 1-44). Rupture of atheroma also may cause microemboli and fibrin thrombi in the distal small branches of the coronary artery system (Fig. 1-45). Coronary thrombi may be lysed through the action of fibrinolytic enzymes. The presence of multiple vascular channels inside a coronary artery indicates recanalization (Fig. 1-46). Consequences and potential outcomes of coronary atherosclerotic plaque rupture are outlined in Diagram 1-5.

Fig. 1-41. Coronary artery with a fibrolipid plaque. In cross section the plaque, which was stained by Sudan red, had a core of lipid separated from the lumen by a white fibrous cap. The plaque projects outward rather than inward, so the artery appeared normal on angiography.

Fig. 1-42. Eccentric plaque causing narrowing of the coronary artery, estimated to be over 95 percent.

Fig. 1-43. Concentric plaque causing narrowing of the coronary artery, estimated to be over 70 percent.


21

Fig. 1-44. Coronary thrombus. In this picro-Mallory trichome—stained slide, collagen is blue and the thrombus is red. There is a small tissue in the plaque, which provoked the intraluminal thrombosis.

Fig. 1-45. Microemboli in small intramyocardial vessels. This small artery is occluded by a mass composed of platelets (blue), red cells (yellow), and cholesterol (clefts).

Fig. 1-46. Coronary artery recanalization. The lumen of the coronary artery has been subdivided into several channels by fibrous strands.

Diagram 1-5. Potential outcomes of coronary plaque rupture.


Myocardial Infarction Myocardial infarction represents the major consequence of coronary artery occlusion; it frequently is fatal. Myocardial infarcts can be localized or diffuse, transmural or subendocardial (Figs. 1-47 to 1-49). On gross examination the infarcted myocardium initially is redder than the surviving adjacent tissue at 12 hours after occlusion of the coronary and then becomes paler; by day 3 it is yellow (Fig. 1-47). The pattern of infarction is best appreciated at autopsy by staining slices of cross-sectioned heart enzyme histochemically to demonstrate dehydrogenase activity. Infarcted areas appear pale 12 hours after the onset of necrosis due to loss of enzyme activity in necrotic cells (Figs. 1-48 and 1-49). Histologic changes indicative of myocardial infarction appear approximately 6 to 12 hours after occlusion but the definite signs of necrosis can be identified only after 24 hours. The myocardial cells become hypereosinophilic, lose their cross-striations, and show coalescence of myofibrils (Fig.

Fig. 1-47. Myocardial infarct. By clinical history this infarct was six days old. The yellow necrotic area is surrounded by a hemorrhagic red rim.

1-50). Contraction band necrosis in which the cytoplasm of myocardial cells contains densely eosinophilic bands also may be seen but it is more typical of reperfusion injury (Fig. 1-51). The infarcted area is invaded by neutrophils two to three days after the coronary occlusion (Fig. 1-52). Macrophages appear three to five days after the onset of ischemia and a fully established granulation tissue develops over a few days. Granulation tissue gives rise to fibrotic scars, which form three to six weeks thereafter.

Complications of Myocardial Infarction The outcome of myocardial infarction depends on many variables and includes a spectrum of clinical pictures from sudden death to complete recovery. External cardiac rupture, a complication of transmural infarcts, occurs during the first 10 days and typically is accompanied by hematopericardium (Figs. 1-53 and 1-54). Rupture of the septum can cause an acute left-to-right shunt and the rupture of papillary muscle

Fig. 1-48. Transmural myocardial infarct. The transverse section of ventricles was stained to demonstrate succinic dehydrogenase activity. Normal myocardium is blue. The pale areas involving the anterior and septal wall of the left ventricle represent the infarct caused by occlusion of the anterior branch of the left coronary artery.

Fig. 1-49. Subendocardial infarct. The tissue was stained to demonstrate succinic dehydrogenase activity. The subendocardial pale areas correspond to the infarct, which extends across the areas supplied by at least three coronary arteries.


23

Fig. 1-50. Myocardial infarct 24 hours after occlusion of the coronary artery. The necrotic myocytes have deeply eosinophilic amorphous cytoplasm. Adjacent surviving cells appear pale and vacuolated.

Fig. I-5I. Contraction band necrosis. The cytoplasm of myocytes contains deeply eosinophilic bands.

Fig. 1-52. Myocardial infarct. In this three-day-old infarct the necrotic myocardial cells are surrounded by neutrophils.

Fig. 1-53. Rupture of a transmural infarct.

Fig. 1-54. Hematopericardium. Pericardium is filled with blood as a complication of cardiac rupture.


may cause acute mitral insufficiency (Figs. 1-55 and 1-56). Mural thrombi form over the infarcted areas (Fig.1-57). Ventricular aneurysms form at the site of large scars replacing infarcted myocardium of the left ventricle (Fig. 1-58).

Fig. 1-55. Rupture of the interventricular septum.

Fig. 1-57. Mural thrombus overlying a massive myocardial infarct.

Fig. 1-56. Papillary muscle rupture. (Courtesy of Dr. Fred Bosman, Lausanne, Switzerland.)

Fig. 1-58. Ventricular aneurysm. The bulging aneurysm has a thin fibrotic wall.


25

PERICARDIAL DISEASES The pericardium may be affected by a variety of infectious, i mmune-mediated, and metabolic diseases, as well as by adverse external influences such as -y-radiation, all of which can cause pericarditis and pericardial fibrosis or both (Table 1-3). Hydropericardium is a common complication of congestive heart failure and generalized edema. Hematopericardium is a complication of heart rupture. The pericardium often is involved, together with myocardium in myocarditis of viral origin or in any form of pancarditis such as rheumatic fever. Pericarditis also is a common complication of myocardial infarction. Pericardial diseases present in several pathologic forms: (1) serous effusion; (2) hematopericardium; (3) fibrinohemorrhagic or fibrinopurulent pericarditis; or (4) constrictive fibrosing pericarditis, which can be accompanied by calcifications or adhesive mediastinitis (Figs. 1-59 to 1-64).

Fig. 1-59. Fibrinous pericarditis. The surface of the heart is covered with a layer of fibrin.

Causes of Pericarditis TYPE

CAUSE

Infectious Viral Pyogenic Tuberculous Fungal

Coxsackievirus B Staphylococcus aureus Mycobacterium tuberculosis Histoplasma capsulatum

I mmune-mediated Rheumatic fever Sarcoidosis Systemic lupus erythematosus Dressler syndrome

— — — Myocardial infarction

Idiopathic Irradiation Surgery

Radiotherapy Open heart surgery

Metabolic Uremic

Chronic renal failure

Fig. 1-60. Fibrinous pericarditis. The surface of the epicardium is covered with fibrin. There is granulation tissue under the layer of fibrin.


26

Fig. 1-6 I. Fibrinohemorrhagic pericarditis. The heart is covered with blood-tinged fibrin.

Fig. 1-62. Fibrinohemorrhagic pericarditis. The layer on the surface of the epicardium consists of fibrin and granulation tissue.

Fig. 1-63. Tuberculous pericarditis. The inflammatory infiltrate is composed of macrophages, lymphocytes, and multinucleated giant cells.

Fig. 1-64. Constrictive pericarditis. The heart is encased in a thick layer of white fibrous tissue.


27

CARDIAC TUMORS Primary tumors of the heart are rare. The most common tumor is myxoma (Fig. 1-65). Typically myxomas are benign tumors, located in the left atrium. Less often they occur in the right atrium or attached to the valves. Rhabdomyomas are cardiac tumors of infancy and childhood (Fig. 1-66). Primary tumors of the pericardium are histologically classified

as benign or malignant mesotheliomas or hemangiosarcomas (Fig. 1-67). Metastases to the heart are more common than primary tumors. They may be found on the epicardial surface, within the cardiac chambers, or invading the myocardium (Fig. 1-68).

A

B

C

D

Fig. 1-65. Cardiac myxoma in the left atrium. A, The tumor may occlude the mitral orifice as a "ball valve." B, The external surface is smooth and the tumor appears lobulated and myxomatous. C, The tumor is composed of elongated cells surround by myxomatous matrix that stains pink. There also are thin-walled blood vessels. D, High-power view of stellate and elongated (lepidic) cells and hemosiderin laden macrophages.


A B

Fig. 1-66. Rhabdomyoma. A, The tumor presents as a myocardial mass. B, The tumor is composed of glycogen-rich cells that have clear cytoplasm.

Fig. 1-67. Hemangiosarcoma of the pericardium. This hemorrhagic tumor was found encasing the heart.

Fig. 1-68. Metastatic melanoma of the epicardium.


29

Further Reading Adenle AD, Edwards JE: Clinical and pathologic features of metastatic neoplasms of the pericardium. Chest 81:166-169, 1982. Altrichter PM, Olson LJ, Edwards WD et al: Surgical pathology of the pulmonary valve. A study of 116 cases spanning 15 years. Mayo Clin Prot 64:1352-1360, 1989. Aretz HT: Myocarditis. The Dallas criteria. Hum Pathol 18:619-624, 1987. Burke AP, Cowan D, Virmani R: Primary sarcomas of the heart. Cancer 69:387-395,1992. Burke AP, Virmani R: Cardiac myxoma. A clinicopathologic study. Am J Clin Pathol 100:671-680, 1993. Burke AP, Virmani R: Cardiac rhabdomyoma. A clinicopathologic study. Mod Pathol 4:70-74, 1991. Davies MJ: Coronary artery remodeling and the assessment of stenosis by pathologists. Histopathology 33:497-500, 1998.

Davies MJ: Review: the investigation of sudden cardiac death. Histopathology 34:93-98, 1999. Klacsmann PG, Bulkley BH, Hutchins GM: The changed spectrum of purulent pericarditis. An 86 year autopsy experience in 200 patients. Am J Med 63:666-673, 1977. Lam KY, Dickens P, Chan AC: Tumors of the heart. A 20-year experience with a review of 12,485 consecutive autopsies. Arch Pathol Lab Med 117:1027-31, 1993. Maron BJ: Hypertrophic cardiomyopathies. Lancet 350:127-133, 1997. Pardo-Mindan FJ, Lazano MD, Contreras-Mejuto F, de Alava E: Pathology of heart transplant through endomyocardial biopsy. Semin Diagn Pathol 9:238-48, 1992. Silver MD: Cardiac pathology. A look at the last five years. II. The pathology of cardiovascular prostheses. Hum Pathol 5:127-38, 1974. Winters GL: The challenge of endomyocardial biopsy interpretation in assessing allograft rejection. Curr Opin Cardiol 12:146-152, 1997.




ARTERIOSCLEROSIS Arteriosclerosis is an inclusive generic term that is used to describe thickening and hardening of arteries. Included under this term are four pathologic entities: (1) arteriosclerosis, (2) hypertensive arteriosclerosis, (3) Monckeberg medial calcific sclerosis, and (4) atherosclerosis. Arteriolosclerosis, or thickening of the wall of arterioles, occurs in two forms: hyaline arteriolosclerosis (arteriolar hyalinosis) and hyperplastic (proliferative) arteriosclerosis. In hyaline arteriolosclerosis the wall of arterioles appears thickened by homogeneously glassy pink material ( " hyaline" ) (Fig. 2-1). It may accompany hypertension or diabetes and is a common feature of involutional atrophy (e.g., postmenopausal ovaries) and aging. It often is prominent in the spleen. Hyperplastic arteriolosclerosis is characterized by narrowing of the lumen of arterioles due to the concentric proliferation of smooth muscle cells in the vessel wall (Fig. 2-2). It typically is found in malignant hypertension, progressive

systemic sclerosis (scleroderma), chronic transplant rejection, and after radiotherapy (Fig. 2-3). Hypertensive arteriosclerosis may be divided clinically and to some extent pathologically into chronic (benign) and accelerated (malignant) types. Chronic (benign) hypertension affects all arteries and arterioles. In the large elastic arteries it causes changes indistinguishable from those of atherosclerosis; in arterioles it causes hyaline arteriolosclerosis; in muscular arteries it causes thickening of the media due to increased amounts of collagen, elastic tissue, smooth muscle cells, and fibroblasts (Fig. 2-4). Malignant hypertension is characterized by hyperplastic arteriolar changes that often are accompanied by fibrinoid necrosis of the vessel wall (Fig. 2-5). Monckeberg medial calcific sclerosis is an age-related degenerative process in which the media of large and mediumsized muscular arteries undergoes calcification (Fig. 2-6). It has little or no clinical significance.

A A

B

B

Fig. 2-I. Hyaline arteriolosclerosis. A, Thickened arterioles in kidney of a diabetic man appear homogeneously pink. B, Splenic arterioles in an elderly nondiabetic man.

Fig. 2-2. Hyperplastic arteriolosclerosis. A, The lumen of the arteriole is narrowed due to concentric proliferation of smooth muscle cells in the vessel wall ("onionskin lesion"). B, Arterioles have narrow lumen due to layers of fibrous tissue.


33

Fig. 2-3. Systemic sclerosis. The vessels show hyperplastic changes and narrowing of the lumen.

Fig. 2-4. Hypertensive change in muscular arteries. The arterial wall is thickened and contains increased amounts of collagen and elastic tissue.

A

B

Fig. 2-S. Fibrinoid necrosis. A, The wall of the arteriole is infiltrated with fibrin and appears magenta red. B, Immunofluorescence microscopy shows deposits of fibrin in the vessel wall.

Fig. 2-6. Monckeberg medial calcific sclerosis. Media of this elastic artery shows a discrete area of calcification.


Fig. 2-7. Fatty streaks in the aorta of an adolescent boy.

Fig. 2-8. Fatty streak. The intima contains fat-laden foam cells that stain with oil red O.

Fig. 2-9. Severe atherosclerosis of aorta.

Fig. 2-I I. Atherosclerosis. Atheroma consists of amorphous cellular debris and cholesterol crystals walled off by fibrous tissue.

Fig. 2-10. Atheroma. It contains yellow, porridge-like material.

Fig. 2-12. Atherosclerotic aneurysm. Ulcerated atheromas are seen in the aorta above the renal arteries, whereas the lower aneurysm contains thrombi.


35

ANEURYSMS

Atherosclerosis is a multifactorial disease involving primarily the aorta and its major branches. The earliest changes, which are considered to be reversible, are fatty dots and fatty streaks of the intima (Figs. 2-7 and 2-8). These changes lead to diffuse intimal thickening followed by eccentric intimal thickening and ultimately to formation of fibrous plaques. Atheromatous plaques, the typical lesions of atherosclerosis, consist of an irreversibly altered softened central area filled with cholesterol crystals and cell debris ( "atheroma") surrounded by collagenous fibrous tissue (Figs. 2-9, 2-10, and 2-11). Weakening of the arterial wall may lead to aneurysm formation, often complicated by thrombosis (Fig. 2-12).

An aneurysm is a dilatation of the aorta or any other major artery. Atherosclerotic aneurysms most often are located in the abdominal aorta. Atherosclerosis, especially if it is combined with hypertension, predisposes to the formation of dissecting aneurysms of the aorta (Fig. 2-13). Hypertension combined with cystic medial necrosis may lead to the formation of dissecting aneurysms even in the absence of atherosclerosis (Fig. 2-14). Atherosclerosis of the splenic artery leads to formation of cirsoid aneurysms (Fig. 2-15). Berry aneurysms are related to a defect in the muscle layer of cerebral arteries (Fig. 2-16). Syphilitic aneurysms are a consequence of infection with Treponema pallidum. They typically occur in the thoracic aorta (Fig. 2-17).

Fig. 2-13. Dissecting aneurysm of the thoracic aorta. The blood has filled the space formed by the forcible separation of intima and media of the aorta.

Fig. 2-14. Dissecting aneurysm of the aorta. Layers of the aortic wall are loose and have been separated by blood.

Fig. 2-I5. Cirsoid aneurysm of splenic artery. The calcified blood vessels appear serpentine.

Fig. 2-16. Berry aneurysm of the circle of Willis (arrow).


Fig. 2-17. Syphilitic aneurysm. A, The aortic arch is dilated. B, Intima has a "tree-bark" appearance.

A

B

VASCULITIS Vasculitis, or inflammation of blood vessels, may be caused by infections or may be immune mediated (Table 2-1). Infection-induced vasculitis is an inflammation caused by invasion of the vessel wall by pathogens. Pathogens can gain entry into the vessel wall from outside (i.e., through extension of infection from the perivascular tissue) or from inside (i.e., from the blood). Fungal vasculitis is a common complication of pneumonia caused by Aspergillus or Rhizopus in which these fungi invade the pulmonary arteries and veins from outside. Fungal meningitis can spread to the cerebral vessels (Fig. 2-18).

Hematogenous dissemination of viruses, bacteria, or fungi during sepsis or by means of infected thromboemboli is a common cause of infectious vasculitis. Viruses are considered to cause granulomatous vasculitis of the central nervous system (Fig 2-19). Rickettsia have a predilection for the endothelial cells of capillaries, postcapillary venules, arterioles, and to a lesser extent small arteries (Figs. 2-20 and 2-21). Aortic lesions typical of tertiary syphilis are caused by a tendency of Treponema pallidum to cause inflammation of vasa vasorum of the aorta (Fig. 2-22). Injury of these small nutrient vessels of the aorta results in scarring of media, weakening of vessel wall, and aneurysm formation (see Fig. 2-17).

Fig. 2-18. Fungal vasculitis. Histoplasma capsulatum has invaded the meningeal arteries.

Fig. 2-19. Granulomatous giant cell vasculitis of cerebral arteries. This patient had a herpes zoster virus infection.


37

Types of Vasculitis Categorized on the Basis of Proposed Pathogenic Mechanisms Direct Infection of Vessels Bacterial vasculitis (such as neisserial) Mycobacterial vasculitis (such as tuberculous) Spirochetal vasculitis (such as syphilitic) Rickettsia) vasculitis (such as Rocky Mountain spotted fever) Fungal vasculitis (such as aspergillosis) Viral vasculitis (such as herpes zoster)

I mmunologic Injury Immune complex-mediated vasculitis Henoch-Schonlein purpura Cryoglobulinemic vasculitis Lupus vasculitis Rheumatoid vasculitis Serum sickness vasculitis Infection-induced immune-complex vasculitis Viral (such as hepatitis B and C) Bacterial (such as group A streptococci) Paraneoplastic vasculitis

Behcet disease Some drug-induced vasculitides (e.g., sulfonamide-induced vasculitis) Direct antibody attack-mediated vasculitis Goodpasture syndrome (anti-collagen IV) Kawasaki disease (possibly mediated by antiendothelial antibodies) Antineutrophil cytoplasmic autoantibody-mediated vasculitis Wegener granulomatosis Microscopic polyangiitis (microscopic polyarteritis) Churg-Strauss syndrome Some drug-induced vasculitides (such as thiouracil-induced vasculitis) Cell-mediated vasculitis Allograft cellular vascular rejection Unknown Giant cell (temporal arteritis) Takayasu arteritis Polyarteritis nodosa Behcet disease

Fig. 2-20. Rocky Mountain spotted fever. Infection with

Fig. 2-21. Rocky Mountain spotted fever. Immunofluorescence

Rickettsia ricketsii causes segmental necrosis, inflammation, and thrombosis in small blood vessels.

microscopy performed on this skin biopsy specimen demonstrates dotlike Rickettsia ricketsii in the wall of small dermal vessels.

A

B

pallidum infection caused infiltrate around vasa vasorum composed of lymphocytes and plasma cells. B, The media of the aorta shows focal loss of elastic fibers and scarring caused by ischemia. Fig. 2-22. Syphilitic aortitis. A, Treponema


Immune-mediated Vasculitis Vasculitis may be caused by antibody-mediated and cellmediated mechanisms elicited by a variety of antigens. The causative antigens cannot be identified in many cases and the exact pathogenesis of many lesions is only partially understood. For practical reasons it is best to classify vasculitides in three groups according to the type of blood vessel involved:

(1) large vessel vasculitis, (2) medium-sized vessel vasculitis, and (3) small vessel vasculitis (Diagram 2-1). Takayasu arteritis involves the aorta and its major branches. Histologically it presents as a granulomatous inflammation, causing necrosis and disruption of the media (Fig. 2-23). The infiltrate typically contains multinucleated giant cells.

Diagram 2-I. Vasculitis clinical syndromes. (Modified from Jennette JC et al: Arthritis Rheum 37:187, 1994.)

Fig. 2-23. Takayasu arteritis. Destruction of the media of the aorta is a consequence of a granulomatous inflammation. The infiltrate contains multinucleated giant cells.

Fig. 2-24. Kawasaki disease. Right lateral view of the heart of an infant who died of Kawasaki disease. There is pronounced thickening and immense prominence of all coronary arteries due to a combination of ectasia and intimal thickening, as well as adventitial fibrosis.


39

Fig. 2-25. Polyarteritis nodosa. A small subcutaneous artery shows focal fibrinoid necrosis and transmural inflammation extending into the perivascular tissue.

Fig. 2-26. Polyarteritis nodosa. The pancreatic artery forms an aneurysm that is filled with a thrombus.

Fig. 2-28. Henoch-Schinlein purpura. Small dermal vessels are infiltrated with IgA as demonstrated by immunofluorescence microscopy in this slide stained with antibodies to IgA.

Fig. 2-27. Small vessel vasculitis. Dermal venules show signs of leukocytoclastic vasculitis.

Kawasaki disease often involves coronary arteries, causing segmental mural necrosis and acute inflammation. Such lesions predispose to thrombosis, vascular ectasia, and aneurysm formation (Fig. 2-24). Polyarteritis nodosa is a necrotizing inflammation of medium-sized or small arteries (Fig. 2-25). Destruction of the vessel wall often leads to formation of microaneurysms (Fig. 2-26). Henoch-Schonlein purpura ( HSP) and drug-induced vasculitis are examples of small vessel vasculitis, typically involving postcapillary venules, capillaries, and arterioles (Fig. 2-27). In HSP this leukocytoclastic vasculitis typically is associated with a deposition of immunoglobulin A (IgA) in the wall of small vessels (Fig. 2-28).

Further Reading Jennette JC, Falk RJ, Andrassy K et al: Nomenclature of systemic vasculitides: proposal of an international consensus conference. Arthritis Rheum 37:187-201, 1994. Klima T, Spjut HJ, Coelho A et al: The morphology of ascending aortic aneurysms. Hum Pathol 14:810-817, 1983. Ledford DK: Immunologic aspects of vasculitis and cardiovascular disease. JAMA 278:1962-1971, 1997. Lie JT: Histopathologic specificity of systemic vasculitis. Rheum Dis Clin NAm 21:883-909, 1995. Parums DV: The arteritides. Histopathology 25:1-20, 1994. Pretre R, von Segesser LK: Aortic dissection. Lancet 349:1461-1464, 1997. Ross R: Rous-Whipple Award Lecture. Atherosclerosis. A defense mechanism gone awry. Am J Pathol 143:987-1002, 1993. Stary HC, Chandler AB, Dinsmore RE et al: A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report of the Committee on Vascular Lesions of the Council on Atherosclerosis, American Heart Association. Circulation 92:1355-1374, 1995.




I NFLAMMATORY LESIONS Inflammation of the upper respiratory tract may present as isolated rhinitis, sinusitis, pharyngitis, or laryngitis, or as a combined upper respiratory tract inflammation. These pathologic processes can be caused by infectious agents, most often by common respiratory viruses, and by bacteria or allergies. The pathologic findings in such conditions are banal and nondiagnostic. Uncommon infections such as nasal infection caused byKlebsiella rhinoscleromatis (Fig. 3-1) or Rhinosporidium seeberi (Fig. 3-2) produce more distinct tissue changes, which can be recognized in biopsy specimens. Allergy is a common cause of rhinitis, which usually presents as " hay fever " or rhinorrhea ( " runny nose " ). Chronic inflammation may result in the formation of nasal polyps.

Histologically nasal polyps represent edematous mucosa infiltrated with inflammatory cells, especially eosinophils and plasma cells, and dilated vessels (Fig. 3-3). Occasionally the stroma of nasal polyps may contain atypical stromal cells with dysplastic or bizarre nuclei. Such changes usually are found in polyps with ulcerated surface epithelium, and it is i mportant not to mistake them for malignancy. Inflammation may be caused by chronic strain or irritation, or by foreign material. For example, chronic laryngitis may be seen in professional speakers or singers (Fig. 3-4). Myospherulosis is a form of inflammation related to packing of nasal cavities with gauze that contains petroleum jelly (Fig. 3-5).

B

A

C

D

Fig. 3-1. Rhinoscleroma. A, Granulation tissue is seen in the nasal cavity. (Courtesy of Dr. M. Fred, Houston, Texas.) B, CT scan of paranasal sinus in 43-year-old man with rhinoscleroma. Right nasal cavity and posterior wall of left maxillary sinus are involved. C, Nasal biopsy showing numerous foamy histiocytes (Mikulicz cells). D, Slides stained with Warthin-Starry stain show numerous intracellular coccobacilli corresponding to Klebsiella rhinoscleromatis.


43

A

B

Fig. 3-2. Rhinosporidiosis. A, The inflamed nasal mucosa contains round sporangia of RhinoSporangium filled with spores and surrounded by multinucleated giant cells.

sporidium seeberi. B,

Fig. 3-3. Nasal polyp. The edematous stroma contains scattered bizarre cells between the dilated blood vessels.

Fig. 3-4. Chronic laryngitis. As seen through the laryngoscope, the lesion appears as thickening of vocal cords. (Courtesy of Dr. V. Kambic, Ljubljana, Slovenia.)

Fig. 3-5. Myospherulosis. The central sac, containing a multinucleated foreign body giant cell and a cluster of sporelike bodies representing altered erythrocytes, is surrounded by chronic inflammatory cells and fibrous tissue.


BENIGN TUMORS AND RELATED CONDITIONS Benign tumors of the upper respiratory tract are mostly of epithelial origin and present as papillomas or nodules projecting into the lumen. They also may be located inside the wall of each organ or may cause focal thickening, which cannot be distinguished with certainty without biopsy from nonneoplastic nodules inflammatory lesions, cysts, and masses such as amyloidoma. Nonepithelial tumors are less common. Papillomas most often originate from nasal or laryngeal epithelium. Nasal papillomas, which are also known as schneiderian papillomas, are of three histologic types: (1) exophytic (fungiform), (2) endophytic (inverted), and (3) oncocytic (cylindrical cells). Exophytic and endophytic papillomas together account for 95 percent of all nasal lesions (Fig. 3-6). These papillomas are lined by basaloid cells that occasionally show squamous differentiation, which may spare isolated mucin-containing respiratory cells as "microcysts " (Fig. 3-7). There is no reliable way to histologically predict recurrence, which occurs in 30 percent to 60 percent of surgically treated patients. Laryngeal papillomas are lined by nonkeratinizing squamous epithelium. Multiple papillomas are usually found in preschool children. These lesions typically contain human papilloma virus type 6 and 11. Juvenile nasopharyngeal angiofibroma is a benign mesenchymal tumor restricted to adolescent boys and young

men (Fig. 3-8). Histologically these tumors are composed of gaping, irregular vessels surrounded by fibrous stroma (Fig. 3-9). Vocal cord nodules and solitary laryngeal polyps of adults are common nonneoplastic tumefactions related to strain and abuse of voice (Fig. 3-10). These lesions represent edema of connective tissue, which often contains hyaline material that should not be confused with amyloid (Fig. 3-11).

Fig. 3-6. Schneiderian papilloma. The tumor involves the nasal cavity extending onto the septum and lateral wall. (Courtesy of Dr. R. Sirota, Oak Park, IL.)

A

B

Fig. 3-7. Schneiderian papilloma. A, The tumor is exophytic but focally it shows features of an inverted papilloma. B, Proliferation of monotonous, bland, basaloid cells with a few clear spaces ("microcysts") representing mutinous cell remnants.


45

Fig. 3-9. Juvenile nasopharyngeal angiofibroma. The irregularly shaped, dilated, thin-walled vessels are surrounded by fibroblastic cells.

Fig. 3-8. Juvenile nasopharyngeal angiofibroma. As viewed through the nasal speculum, the mass filling the nasal cavity shows prominent surface vascularity.

Fig. 3-10. Bilateral polypoid nodules of vocal cords. (Courtesy of Dr. V. Kambic, Ljubljana, Slovenia.)

Fig. 3-I I. Vocal cord nodule ("singer's node"). The polypoid mass consists of edematous, hyalinized stroma covered by an intact epithelium.

MALIGNANT TUMORS

Olfactory neuroblastoma is a rare but important nasal tumor. It may show typical features of neuroblastoma of other sites such as fibrillary stroma; alternatively, it may present as a poorly differentiated small cell tumor (Fig. 3-13). Both variants stain with antibodies to neurofila:nents and S-100 protein, and also paradoxically with antibodies to keratin. Nasopharyngeal carcinoma accounts for 85 percent of all malignant tumors of this site. Three histologic subtypes are

Malignant tumors of the upper respiratory tract are mostly of epithelial origin and histologically represent squamous cell carcinomas. Nasal tumors, which are usually found in elderly men, typically present as mass lesions or nonbleeding ulcers, which may require radical surgery such as nasal amputation (Fig. 3-12). Histologically these tumors show prominent keratinizations and tend to invade the underlying tissues.


A

B

Fig. 3-12. Squamous cell carcinoma of the nasal vestibule. A, The friable exophytic and invasive tumor. B, Invasive squamous cell carcinoma of the nasal vestibule encroaching on the hyaline cartilage of the septum.

A

B

Fig. 3-13. Olfactory neuroblaStoma. A, Nests of tumor cells beneath the epithelium. B, The tumor is composed of small cells surrounded focally by fibrillar stroma.

WHO Histologic Classification of Nasopharyngeal Carcinoma Squamous cell carcinoma Keratinization or intercellular bridges or both

Nonkeratinizing carcinoma Defined cell borders, pavement like pattern

Undifferentiated carcinoma Syncytial growth, large polygonal cells or spindle-shaped cells, prominent nucleoli, lymphoid stroma

Fig. 3-14. Nasopharyngeal carcinoma. The tumor is composed of polygonal cells with vesicular nuclei enclosed in a sea of lymphocytes.


47

Fig. 3-I5. Keratinizing intraepithelial dysplasia of larynx.. Such lesions are often aneuploid even though they show some degree of "surface maturation" into keratinized squamous cells.

A

B

Fig. 3-16. Squamous cell carcinoma of the larynx. Laryngectomy specimen showirig recurrent carcinoma of the right vocal cord.

Carcinoma of the larynx is a squamous cell carcinoma in 95 percent of patients. It may begin as squamous cell dysplasia or carcinoma in situ (Fig. 3-15). Invasive carcinomas show variable degrees of keratinization (Figs. 3-16 and 3-17).

Further Reading

Fig. 3-17. A, Vertical section through a carcinoma localized to the true vocal cord. False cord and ventricle are free of tumor. B, Vertical section through a supraglottic squamous carcinoma. The true cord is involved.

recognized (Table 3-1). The undifferentiated carcinoma, which occurs as a large polygonal cell tumor or as a spindleshaped cell tumor, accounts for 60 percent to 80 percent of all tumors (Fig. 3-14). Tumor cells are surrounded by lymphocytes, which accounts for the fact that these tumors previously were called lymphoepitheliomas.

Abbondanzo SL, Wenig BM: Non-Hodgkin's lymphoma of the sinonasal tract. A clinicopathologic and immunophenotypic study of 120 cases. Cancer 75:1281-1291, 1995. Compagno J, Hyams VJ: Hemangiopericytoma-like intranasal tumors. A clinicopathologic study of 23 cases. Am J Clin Pathol 66:672-683, 1976. Devaney K, Wenig BM, Abbondanzo SL: Olfactory neuroblastoma and other round cell lesions of the sinonasal region. Mod Pathol 9:658663, 1996. Franquemont DW, Mills SE: Sinonasal malignant melanoma. A clinicopathologic and immunohistochemical study of 14 cases. Am J Clin Pathol 96:689-697, 1991. Heffner DK, Gnepp DR: Sinonasal fibrosarcomas, malignant schwannomas, and "Triton" tumors. A clinicopathologic study of 67 cases. Cancer 70:1089-1101, 1992. Helliwell TR: "Risky" epithelium of the larynx-a practical diagnosis? Histopathology 34:262-265, 1999. Helquist H, Cardesa A, Gale Net al: Criteria for grading in the Ljubljana classification of epithelial hyperplastic laryngeal lesions. A study by members of the Working Group on Epithelial Hyperplastic Laryngeal Lesions of the European Society of Pathology. Histopathology 34:226-233, 1999. Lloreta-Trull J, Mackay B, Troncoso Petal: Neuroendocrine tumors of the nasal cavity. An ultrastructural and morphometric study of 24 cases. Ultrastruct Pathol 16:165-175, 1992. Michaels L: Benign mucosal tumors of the nose and paranasal sinuses. Sem Ding Pathol 13:113-117, 1996. Slavin RG: Nasal polyps and sinusitis. JAMA 278:1849-1854, 1997.




DEVELOPMENTAL ANOMALIES The respiratory system develops as a derivative of the primitive foregut. It is therefore not surprising that developmental anomalies involving one system are accompanied by abnormalities in the other. The most important of these conjoined anomalies is tracheoesophageal fistula ( Diagram 4-1), which may be associated with abnormal or incomplete development of trachea or tracheal agenesis. Bronchial anomalies include abnormal branching patterns, abnormalities in size, abnormal connections with other structures, and cartilage plate abnormalities. Bronchogenic cyst develops from an accessory fetal lung bud that becomes isolated from the rest of the tracheobronchial tree, producing a solitary midline cyst lined by bronchial epithelium (Figs. 4-1 and 4-2). Pulmonary anomalies range from minor variations in the lobar configuration to major developmental defects such as unilateral pulmonary agenesis or hypoplasia (Fig. 4-3). Pulmonary hypoplasia has been identified in 10 percent to 15 percent of all neonatal autopsies and in 50 percent of neonates who have other significant congenital anomalies. Anomalies limited to parts of a lung may remain asymptomatic until adult life. The most important of these anomalies are congenital cystic adenomatoid malformation and extralobar bronchopulmonary sequestration or accessory lobe (Figs. 4-4 and 4-5). So-called intralobar sequestration, which is mentioned here for the sake of completeness and differential diagnosis, is considered to be an acquired abnormality that is caused by recurrent pulmonary inflammation and scarring (Fig. 4-6).

Fig. 4-I. Bronchogenic cyst. This posterior midline subpleural cyst was compressing the esophagus, causing only minor dysphagia.

Fig. 4-2. Bronchogenic cyst. This resected cyst has a rugged internal surface.

A

B

C

D

E

Diagram 4-I. Tracheoesophageal fistulas. Type C malformations account for 85 percent of all cases.


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Fig. 4-3. Pulmonary hypoplasia in a neonate.

Fig. 4-4. Congenital cystic adenomatoid malformation. This mass, which is composed of abnormal bronchiolar structures, consists of a large cyst with several smaller cysts in the background.

A

B

Fig. 4-5. Congenital cystic adenomatoid malformation. A, The lung is composed of cystic bronchi and air spaces. B, The wall of the cyst is lined by pseudostratified or tall columnar epithelium resembling the lining of proximal bronchioli or small bronchi.

A

B

Fig. 4-6. Intralobar sequestration. A, The mass consists of markedly dilated bronchi filled with mucus and surrounded by fibrous tissue. B, Histologically, the mass consists of bronchi and air spaces lined by cuboidal cells. The interstitium is fibrosed and contains inflammatory cells.


PERINATAL LUNG DISEASES Failure of the lungs to fully expand and remain expanded is a common complication of pulmonary immaturity encountered in neonates who are born preterm. Clinically it presents as neonatal respiratory distress syndrome or hyaline membrane disease. The lungs show patchy atelectasis (Fig. 4-7). Histologically pulmonary alveoli are collapsed and atelectatic, whereas the alveolar ducts are dilated and lined by fibrin-rich hyaline membranes (Fig. 4-8). Secondary changes such as intraalveolar hemorrhage, dilatation of bronchioles proximal to atelectatic parenchyma, and dilatation of lymphatics are common. Resorption of hyaline membranes, i.e., cleanup by macrophages, begins 48 to 72 hours after birth and is associated with proliferation of bronchiolar reserve cells. Oxygen therapy and mechanical ventilation cause additional changes that cannot be separated from those caused by the disease itself. Severe hyaline membrane disease that is treated aggressively may result in development of chronic lung changes known as bronchopulmonary dysplasia (Fig. 4-9). Histologically it can be divided sequentially into three overlapping phases: (1) early reparative phase, (2) subacute fibro -

proliferative phase, and (3) chronic fibroproliferative phase. The process is dominated by organization of hyaline membranes by granulation tissue, ongoing peribronchial fibrosis and luminal obliteration (bronchiolitis obliterans), and interstitial fibrosis (Fig. 4-10). Pulmonary interstitial air, or pulmonary interstitial emphysema, which is characterized by the presence of air in the connective tissue planes of the lungs, is yet another complication of treatment of hyaline membrane disease with ventilatory support (Fig. 4-11). Neonatal pneumonia typically is a complication of: (1) transplacental spread of maternal infection, (2) intrauterine ascending amniotic fluid infection, (3) intrapartum infection with microorganisms in the birth canal, or (4) postnatal airborne infection. Most neonatal pneumonias are acquired during labor and delivery. Aspiration of infected amniotic fluid by the fetus accounts for 20 percent to 40 percent of early-onset neonatal sepsis and pneumonia. The lungs of such neonates contain amniotic fluid with squamous and inflammatory cells (Fig. 4-12).

Fig. 4-7. Neonatal atelectasis. The atelectatic parenchyma appears dark red in contrast to the paler areas of normally aerated lung (right upper corner).

A

B

Fig. 4-8. Neonatal respiratory distress syndrome. A, Alveoli are collapsed and the alveolar ducts and respiratory bronchioli are dilated and lined by hyaline membranes. B, Hyaline membranes are brown due to staining with meconium.


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Fig. 4-9. Bronchopulmonary dysplasia. Lungs are in part consolidated and in part cystic.

A

B

Fig. 4-10. A, Bronchopulmonary dysplasia. The alveoli are partially obliterated by ingrown granulation tissue. B, The lungs are consolidated except for a few cystic and slit-like spaces.

Fig. 4-I I. Pulmonary interstitial air. Air-filled spaces extending the interlobular septa are seen through the pleura.

Fig. 4-I2. Amniotic fluid aspiration with early pneumonia. The alveoli contain nucleated squamous cells and scattered inflammatory cells.


PULMONARY INFECTIONS Pneumonia, or pulmonary infection, can be classified (1) etiologically, as viral, bacterial, fungal, and so forth; (2) topologically, depending on the gross distribution, as lobar or lobular, focal or diffuse, one-sided or bilateral; (3) histologically, depending on the distribution of the inflammatory cells, as intraalveolar or interstitial and characterized by a neutrophilic, lymphocytic or mixed inflammatory infiltrate. Bacterial infection presents as lobar or lobular pneumonia (also known as bronchopneumonia). In lobar pneumonia entire lobes of one or both lungs are involved (Fig. 4-13). Bronchopneumonia presents in the form of more circumscribed infiltrates (Fig. 4-14). These infiltrates are initially composed of neutrophils and are predominantly inside the alveoli (Fig. 4-15). Without treatment, consolidation of the lungs progresses through several phases known as: (1) red hepatization, in which the lungs appear red due to congestion; (2) gray hepatization, in which the exudate of neutrophils and fibrin, combined with reduced blood flow through the compressed capillaries, imparts a gray color to the lungs; and (3) resolution phase, in which the exudate is removed and the air spaces become patent again. In severe cases the abundant fibrin cannot be removed and it stimulates the ingrowth of granulation tissue into the alveoli (organizing pneumonia) (Fig. 4-16). Pneumonia caused by Staphylococcus aureus may result in massive tissue breakdown (Fig. 4-17) and suppuration resulting in abscess formation (Fig. 4-18). Pulmonary tuberculosis presents with a spectrum of changes. Primary tuberculosis, which is characterized by a solitary parenchymal nodule and hilar lymph node involvement, usually heals spontaneously by undergoing fibrosis and calcification (Fig. 4-19). Secondary tuberculosis results in widespread dissemination of mycobacteria and the formation of multiple small nodules (miliary tuberculosis), consolidation of parenchyma (tuberculous pneumonia), or extensive destructive lung lesions (cavitary tuberculosis) (Fig. 4-20). Histologically all tuberculous lesions contain granulomas (Fig. 4-21). Similar changes can be caused by fungi such as Histoplasma capsulatum.

Fig. 4-13. Lobar pneumonia. The entire lung appears consolidated and the parenchyma is bulging on cross section.

Fig. 4-14. Bronchopneumonia. The lungs appear only focally consolidated. The infiltrates are peribronchial and appear distinct from the surrounding parenchyma.

Fig. 4-15. Lobar pneumonia in the stage of gray hepatization. The alveoli are filled with neutrophils. The alveolar walls are of normal thickness and do not contain red blood cells.


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Fig. 4-16. Organizing pneumonia. The alveoli contain abundant fibrin, which is being organized by inflammatory cells and an ingrowth of fibroblasts.

Fig. 4-17. Necrotizing pneumonia. The exudate is accompanied by necrosis of alveolar septa. The bluish material represents bacterial colonies.

Fig. 4-18. Lung abscess. The large subpleural abscess contains brownish-yellow pus. The surrounding parenchyma appears consolidated and contains scattered smaller whitish-yellow abscesses.

Fig. 4-19. Pulmonary tuberculosis. The primary lesion appears as a sharply demarcated subpleural nodule.

Fig. 4-20. Secondary pulmonary tuberculosis. The parenchyma and hilar lymph nodes contain numerous, often confluent tubercles. (Courtesy of Cathy Looby, M.D., Philadelphia, PA. From Woods CL, Gutierrez Y: Diagnostic pathology of infectious diseases, Philadelphia, 1993, Lea & Febiger.)

Fig. 4-21. Pulmonary tuberculosis. Granulomas of tuberculosis consist of lymphocytes, epithelioid macrophages, and multinucleated giant cells arranged around a central area of caseating necrosis.


Pneumocystis carinii pneumonia, an opportunistic fungal infection that occurs in immunocompromised persons, presents histologically with an acellular intraalveolar exudate (Fig 4-22). Fungal cysts can be seen in slides impregnated with silver according to Gomori. Viral infections cause alveolar cell injury, which is usually accompanied by a predominantly interstitial mononuclear cell infiltrate (Fig. 4-23). The alveoli contain well-developed fibrin-rich hyaline membranes and some edema fluid. In

most instances the causative virus is not visible except in some infections that are caused by herpes simplex virus 1 ( HSV- 1) or cytomegalovirus (CMV). CMV inclusions appear as basophilic (blue) material in the nucleus and the cytoplasm, and are accompanied by enlargement of the infected cells (Fig. 4-24). Alveolar cell injury caused by viruses such as influenza or adenovirus produce histologically nonspecific changes. Such changes are indistinguishable from other forms of diffuse alveolar damage ( DAD).

A

B

Fig. 4-22. Pneumocystis carinii pneumonia. A, The alveoli contain proteinaceous acellular floccular material. B, Pneumocystis carinii cysts are seen in silver-impregnated cytologic smear prepared . from bronchial brushings.

Fig. 4-23. Viral pneumonia. The alveolar septa are widened. The alveoli contain edema fluid, fibrin-rich hyaline membranes, and a few scattered mononuclear cells.

Fig. 4-24. Viral pneumonia caused by the cytomegalovirus (CMV). Typical intranuclear inclusions are seen in desquamated pneumocytes, which appear enlarged.


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PULMONARY CIRCULATORY DISORDERS Blood flow through the lungs depends on proper cardiac function. Acute left heart failure results in passive pulmonary congestion and intraalveolar hemorrhage. Chronic heart failure results in brown induration of the lungs. Circulatory collapse that occurs in shock and multiple organ failure often is clinically associated with adult respiratory distress syndrome (ARDS). Lungs . show signs of diffuse alveolar damage accompanied by focal atelectasis, intraalveolar hemorrhage, and hyaline membrane formation (Fig. 4-25). Pulmonary Emboli Pulmonary thromboembolism is one of the leading causes of

death, although it often is clinically unrecognized. Pulmonary emboli may involve the main pulmonary artery, its major branches, or small intrparenchymal vessels. Clinically they may cause sudden death, episodes of dyspnea and hemoptysis, or only minor discomfort and thoracic pain. Saddle emboli of the main pulmonary artery and the emboli occluding the major branches of the pulmonary artery usually cause sudden death (Fig. 4-26). In patients who survive, the thromboemboli become lysed, organized, or recanalized. Thromboemboli that lodge in peripheral pulmonary arteries cause infarcts, but only in patients whose pulmonary circulation is compromised by heart failure or atherosclerotic obstruction of the nutrient pulmonary circulation through the bronchial arteries. On gross examination pulmonary infarcts appear red, as they do in other organs with dual circulation (Fig. 4-27). Histologically, the alveoli of the infarcted area have necrotic septa and are filled with blood (Fig 4-28).

Fig. 4-25. Diffuse alveolar damage. Air spaces contain hyaline membranes, red blood cells, and desquamated cells.

Fig. 4-26. Pulmonary thromboembolism. The main branches of the pulmonary artery are occluded with thromboemboli.

Fig. 4-27. Pulmonary infarct. Infarct is triangular and hemorrhagic.

Fig. 4-28. Pulmonary infarct. The septa are necrotic and the alveoli contain blood.


Pulmonary Hypertension

episodes of wheezing and increased resistance to expiratory air flow. The principal pathologic changes occur in the bronchi and bronchioli, which show hyperplasia of mucussecreting cells, hypertrophy and hyperplasia of smooth muscle cells, and signs of chronic inflammation (Fig. 4-30). The mucus inthelumen o f thebronchi may contain CharcotLeyden crystals derived from the granules of eosinophils and Curshman spirals. Hypersensitivity pneumonia (extrinsic allergic alveolitis) can be induced by a number of allergens or drugs (Fig. 4-31). Clinically it may present under several conditions such as farmer's lung, mushroom worker 's lung disease, bagassosis, and suberosis. Foreign antigens usually induce a cellmediated reaction in the form of granulomas (Fig. 4-32). Focal cellular infiltrates composed of lymphocytes and a few plasma cells are less common. In advanced cases buds of organizing fibrovascular tissue (Masson bodies) fill the respiratory bronchioli and alveolar ducts (Fig. 4-33). Ultimately the disease may progress to diffuse pulmonary fibrosis. Pulmonary infiltration and eosinophilia (PIE) is a syndrome that could have many causes, such as visceral larva migrans syndrome related to infestation with nematodes, cestodes, or filarial worms. Many drugs may induce the same syndrome. Eosinophilic pneumonia often is found in such cases by lung biopsy (Fig. 4-34).

Pulmonary hypertension can be classified as primary or secondary. The causes of primary or idiopathic hypertension are not known. Secondary pulmonary hypertension is a consequence of left heart failure, mitral valve lesions, or chronic thromboembolism of the pulmonary vascular system. Congenital heart disease with left-to-right shunting of blood also causes pulmonary hypertension, which can be graded on a scale from 1 to 6 according to the Heath-Edwards classification (Fig. 4-29).

I MMUNE-MEDIATED LUNG DISEASES The lungs are exposed to numerous potential allergens inhaled daily and are thus a common site for a variety of i mmune-mediated diseases. The most important in this group of diseases are asthma, hypersensitivity pneumonia, eosinophilic pneumonia, sarcoidosis, and Wegener granulomatosis. The lungs also may be affected by systemic autoi mmune diseases such as systemic lupus erythematosus, Sjogren syndrome, and systemic sclerosis (scleroderma). Other immune-mediated diseases such as Goodpasture syndrome and Churg-Strauss syndrome are less common. Asthma is a disorder characterized by increased responsiveness of the airways to various stimuli as manifested by

A

B

C

D

E

F

Fig. 4-29. Plexogenic pulmonary arteriopathy. A, Medial hypertrophy and muscularization of an arteriole (grade I). B, Concentric intimal proliferation (grade 2). C, Concentric laminar intimal fibroelastosis (grade 3). D, Fibrinoid degeneration (grade 6). E, Necrotizing arteritis (grade 6). F, Plexiform lesion (grade 4). (A, C, and E, Elastica–van Gieson stain.)


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B

C

A

Fig. 4-30. Asthma. A, The bronchiole has a hy erplastic epithelium, a thick basement membrane, and prominent smooth muscle cells in its wall. The lumen contains mucus. Inflammatory cells are present in variable amounts and often are not prominent. B, Charcot-Leyden crystals. C, Curshman spiral.

Fig. 4-31. Allergic drug reaction. The alveolar septa are thickened and infiltrated with mononuclear cells, which are also found in the alveolar spaces.

Fig. 4-32. Hypersensitivity pneumonia. The air spaces contain loosely structured granulomas with multinucleated giant cells.

Fig. 4-33. Hypersensitivity pneumonia. In later stages of the disease the airways are obliterated by fibroblastic granulation tissue.

Fig. 4-34. Eosinophilic pneumonia. The alveoli and thickened septa are infiltrated by eosinophils and lymphocytes.


A B

Fig. 4-35. Wegener granulomatosis. A, The lung parenchyma contains two nodules showing central necrosis. B, The section shows areas of vasculitis, inflammation, and necrosis.

Wegener granulomatosis is an immune-mediated disease that involves the upper and lower respiratory tracts and kidneys. The lung lesions may present as pale infarcts or bulky necrotic nodules (Fig 4-35). Histologic features include vasculitis accompanied by thrombosis and pulmonary infarcts, and granulomas often superimposed on a background of nonspecific chronic inflammation. These changes contribute to a variegated ( " geographic map-like" ) appearance of tissues in histologic sections.

CHRONIC INFECTIONS AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) Chronic and recurrent pulmonary infections typically occur in persons who have congenitally reduced pulmonary defense (e.g., Kartagener syndrome, agammaglobulinemia) or acquired immunodeficiency (e.g., AIDS or cancer therapy). People who are exposed to chronic irritants such as cigarette smoke also suffer from chronic pulmonary infections.

Bronchiectasis Bronchiectasis is an irreversible dilatation of bronchi accompanied by an infection of the bronchial wall and obliteration of distal airways. It may occur in several clinical settings such as: (1) damage of bronchi by an infection in early life; (2) recurrent infections in patients with congenital disorders such as cystic fibrosis, immotile cilia syndrome, or agammaglobulinemia; (3) allergy to molds; (4) inhalation of toxic gases; and (5) in a localized form distal to a tumor or other lesions causing bronchial obstruction. The involved bronchi and bronchioli are markedly dilated, filled with mucous or mucopurulent plugs, and surrounded by peribronchial fibrosis. In cystic fibrosis, a common cause of bronchiectasis, purulent bronchitis and pulmonary insufficiency are the leading cause of death (Figs. 4-36 and 4-37).

Chronic Obstructive Pulmonary Disease COPD is a clinical diagnosis that includes two closely related entities that typically cause dyspnea and other respiratory problems in chronic cigarette smokers: chronic bronchitis and emphysema. Chronic bronchitis is defined clinically as chronic lung disease presenting as cough with expectoration and lasting at least three months during two consecutive years. The bronchi show histologic signs of chronic inflammation and contain mucus admixed with pus (Fig. 4-38). The bronchi typically have thickened walls. The enlarged bronchial mucous glands occupy more than 40 percent of the thickness of the wall, as found under normal circumstances (Reid index). Emphysema is a permanent loss of pulmonary parenchyma that leads to an enlargement of air space distal to the terminal bronchioles, without evidence of fibrosis. It occurs in two main forms: centriacinar (centrilobular) emphysema, which involves the respiratory bronchioles and destroys the alveolar septa around it (Fig. 4-39); and panacinar (panlobular) emphysema, which involves the entire acinus ( "cotton candy lung" ) (Fig. 4-40). Centriacinar emphysema most often is found in cigarette smokers and typically shows centriacinar deposition of black pigment (anthracosis). Panacinar (panlobular) emphysema typically is encountered in persons with a i -antitrypsin deficiency. Other forms of emphysema such as paraseptal or irregular emphysema (usually associated with scarring) are less important clinically. All forms of emphysema can give rise to pulmonary subpleural bullae. Similar air-filled bullae, which often are unrelated to emphysema, are a common cause of lung rupture and spontaneous pneumothorax (Fig. 4-41).


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Fig. 4-36. Cystic fibrosis. This lung from a 20-year-old man shows diffuse bronchiectasis.

Fig. 4-37. Cystic fibrosis. The bronchiole is filled with an exudate composed of neutrophils.

Fig. 4-38. Chronic bronchitis. The wall of the bronchus is thickened and inflamed.

Fig. 4-39. Centriacinar emphysema. Note that the large air spaces are surrounded by a normal alveolar network. Also note the pigmentation inside the cystic central spaces.

Fig. 4-40. Panacinar emphysema. The entire pulmonary parenchyma has a delicate cotton candy—like texture.

Fig. 4-41. Subpleural bullae.


PNEUMOCONIOSES The term pneumoconiosis was coined by the German pathologist Friedrich Zenker in 1866 for all diseases of the lung parenchyma that are attributable to the inhalation of inorganic mineral dust. The most important pneumoconioses are silicosis, silicatosis, asbestosis, coal workers' pneumoconiosis, hard metal disease, and berylliosis. Silicosis is an inflammatory and fibrotic lung disease that is caused by the inhalation of silica crystals, also known as alpha quartz. Several clinical and pathologic forms of silicosis are known, such as acute silicosis, accelerated silicosis, chronic silicosis, and progressive massive fibrosis. Typical lesions, silicotic nodules, are found in the latter two entities (Fig. 4-42). Silica crystals can be seen in these lesions by polarization microscopy.

A

Silicatosis is caused by inhalation of particulate nonfibrous silicate minerals in the absence of silica dust. Silicates account for one third of all known mineral species and are ubiquitous. Inhalation of silicates such as talc or kaolin produces peribronchial and perivascular aggregates of macrophages that are heavily laden with dust and associated with fibrosis (Fig. 4-43). Polarization microscopy reveals birefringent particulate matter that appears granular, platy, or lancetshaped. Multinucleated giant cells are especially prominent in talcosis. Coal workers ' pneumoconiosis is a fibrosing lung disease of coal workers. The lungs show grossly visible black pigmentation (Fig. 4-44). Typical histologic findings include macules (primary dust foci), which represent carbon particles containing fibrotic patches of damaged alveolar septa; and nodules (secondary dust foci), which represent larger stellate anthracotic connective tissue scars measuring 0.5 to 3 mm in diameter (Fig. 4-45). Larger nodules seen on radiographic examination of the lungs of coal workers with rheumatoid arthritis (Caplan lesion) show central necrosis surrounded by palisading macrophages that are reminiscent of subcutaneous rheumatoid nodules (Fig. 4-46). Siderosis applies to the deposition of iron oxide in the lungs, as is seen in welders, iron and steel workers, and those who work in iron mines. Reddish-brown macules composed of hemosiderin-laden macrophages gradually develop in the lungs (Fig. 4-47). Numerous nonfibrous ferruginous bodies that have round or irregularly shaped black cores also are present. Hard metal disease sporadically develops in workers who are employed in industries in which synthetic hard metals are produced or are used in cuttings and fabrication of metal parts. The disease becomes evident within days or weeks after exposure. Histologically the lungs show variable degrees of fibrosis accompanied by infiltrates composed of macrophages and giant cells (Fig. 4-48).

B

Fig. 4-42. Silicosis. A, It is composed of concentrically layered whorled collagen bands. Black pigment is evidence of anthracosis. The monocular cell infiltrate at the periphery represents a response to nonquartz silicate particles. B, Progressive massive fibrosis. The lung of a coal worker shows anthracosilicotic lesions more prominent in the upper lobes.

Fig. 4-43. Silicatosis. This lung of a slate worker shows perivascular inflammation and fibrosis. The silicates not evident in this slide could be seen by polarization microscopy.


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Fig. 4-44. Coal workers' pneumoconiosis. The lungs show increased black pigmentation.

A

B

Fig. 4-45. Coal workers' pneumoconiosis. A, Macule consists of fibrous tissue impregnated with carbon particles. B, Nodule represents a stellate heavily pigmented scar.

Fig. 4-46. Caplan lesion in coal workers' pneumoconiosis. The nodule has a variegated appearance and contains zones of necrosis, lamellar concentric fibrosis, and anthracosis.

Fig. 4-47. Siderosis. The lungs of this iron ore miner contain aggregates of hemosiderin-laden macrophages.

Fig. 4-48. Hard metal disease. The lung parenchyma contains aggregates of macrophages and multinucleated giant cells. Variable degrees of fibrosis may be found.


Berylliosis is a granulomatous lung disease that develops after exposure to aerosolized beryllium particles. Beryllium has been used for the production of lamps, for the production of atomic energy, and in space exploration programs. Histologically the disease is indistinguishable from sarcoidosis and presents in the form of noncaseating pulmonary granulomas (Fig. 4-49 and Fig. 4-50). Asbestosis is a fibrotic lung disease consequent to longterm exposure to all types of asbestos (Diagram 4-2). Asbestos bodies found in or adjacent to the walls of fibrotic res-

piratory bronchioles are the hallmark of this disease (Fig. 451). In addition to pulmonary fibrosis, exposure to asbestos leads to the formation of fibrous plaques on visceral or parietal pleura (Fig. 4-52). The most serious consequence of asbestos exposure is mesothelioma, a malignant tumor of serosal surfaces (Fig. 4-53). Histologically mesotheliomas may be classified as epithelial, sarcomatous, or mixed including both epithelial and sarcomatous elements (Fig. 4-54). The incidence of bronchial carcinoma also is increased after chronic exposure to asbestos.

Fig. 4-49. Berylliosis. The lung contains numerous noncaseating granulomas composed of epithelioid macrophages and giant cells.

Fig. 4-50. Sarcoidosis. Noncaseating granulomas are found in the peribronchiolar parencyma.

Diagram 4-2. Commercial and noncommercial asbestos.


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A

B

Fig. 4-51. Asbestosis. A, Air spaces contain beaded iron-encrusted brown asbestos bodies. B, Asbestos body.

Fig. 4-52. Asbestosis. White plaques cover the parietal pleura.

Fig. 4-53. Malignant mesothelioma. This pleural tumor has invaded the pericardial cavity encasing the heart.

A

B

Fig. 4-54. Malignant mesothelioma. A, This epithelial variant shows a glandulopapillary growth pattern. B, Fibrosarcomatous mesothelioma is composed of spindle shaped cells.


I DIOPATHIC INTERSTITIAL LUNG DISEASES Lungs may be affected by a number of chronic diseases of unknown etiology, which show common and overlapping clinical features but nevertheless have distinctive histologic characteristics. Dyspnea and deterioration of pulmonary function is invariably related to a loss of pulmonary parenchyma and pulmonary fibrosis. The most important of these diseases are listed in Table 4-1. Idiopathic organizing pneumonia, which is also known as bronchiolitis obliterans with organizing pneumonia (BOOP), is a restrictive lung disease that begins with symptoms that are suggestive of viral pneumonitis. The symptoms fail to resolve and the lung parenchyma undergoes patchy consolidation (Fig. 4-55). Microscopic sections show numerous fibroblastic polypoid protrusions (Masson bodies) obliterating the respiratory bronchioles, the alveolar ducts, and even the alveoli. The epithelium of terminal bronchioles proliferates, covering the surface of Masson bodies and lining the restructured air spaces. These findings are, however, non-

specific and also can be found in other forms of chronic pneumonia. Chronic idiopathic pulmonary fibrosis begins insidiously and progresses to end-stage lung disease over a variable period. The lungs are firm and fibrotic and the normal areas alternate with foci of scarring (Fig. 4-56). Microscopic features include prominent fibrosis replacing focally the normal lung parenchyma. The remaining air spaces are abnormal, dilated, and often lined by cuboidal cells (Fig. 4-57). Most cases of so-called usual interstitial pneumonia (UIP) show this histologic pattern. Some cases, however, are classified as desquamative interstitial pneumonia (DIP). In this variant the thick-walled alveoli are filled with numerous macrophages (Fig. 4-58). Pulmonary alveolar proteinosis is a disease of unknown etiology. It presents as progressive dyspnea and respiratory insufficiency. Parts of the lungs become consolidated due to the accumulation of lipid-rich proteinaceous material in the alveoli (Fig. 4-59).

A

B

C

Fig. 4-55. Bronchiolitis obliterans. A, The obliterated bronchioli surrounded with consolidated parenchyma impart a micronodular pattern to the cross section of the lung parenchyma. B, Masson bodies obliterate the lumen of bronchioli. C, Masson bodies in the alveolar ducts appear as oval shaped structures composed of fibroblasts and collagen.


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Clinicopathologic forms of pulmonary fibrosis Form (alternative name) Acute interstitial pneumonia (Hamman-Rich syndrome) Idiopathic organizing pneumonia (BOOP, COP) Usual interstitial pneumonia Desquamative interstitial pneumonia Nonspecific interstitial pneumonia (CIP)

Duration Weeks Weeks to months Years Years Months

Histologic appearance Uniform Uniform Heterogeneous Uniform Uniform

Distribution Diffuse Patchy Patchy Diffuse Patchy

BOOP, bronchiolitis obliterans—organizing pneumonia; CIP, cellular.interstitial pneumonia; COP, cryptogenic organizing pneumonitis.

Fig. 4-56. Idiopathic pulmonary fibrosis. Cross section of the lung shows fibrosis with microcystic dilatation of air spaces.

Fig. 4-57. Idiopathic pulmonary fibrosis. The lung parenchyma has a simplified structure because of a loss of alveoli, which have been replaced by fibrous tissue.

Fig. 4-58. Desquamative interstitial pneumonia. The alveoli have thick walls and are filled with numerous macrophages.

Fig. 4-59. Pulmonary alveolar proteinosis. The alveoli are filled with granular, eosinophilic, lipid-rich, proteinaceous material.


PULMONARY NEOPLASMS Tumors of the lungs can be classified as central (hilar) or peripheral. Several microscopic categories are recognized (Table 4-2). Hilar tumors originate from the epithelium of the main bronchi (Fig. 4-60). Histologically they present as squamous cell, small (oat) cell, large cell carcinoma, or adenocarcinoma (Figs. 4-61 and 4-62). Peripheral subpleural tumors, which often arise in anthracotic fibrous scars, have his -

tologic features of adenocarcinoma (Fig. 4-63). Bronchioloalveolar carcinoma is a form of peripheral adenocarcinoma that grows along the alveolar septa, filling the alveoli and causing pneumonia-like consolidation of the lung parenchyma (Figs. 4-64 and 4-65). Carcinoids are low-grade malignant tumors of endocrine cells (Figs. 4-66 and 4-67). Other primary malignant tumors are less common.

Fig. 4-60. Hilar squamous cell carcinoma. The tumor originates from the main bronchus. Fig. 4-61. Squamous cell carcinoma of the bronchus. A focus of carcinoma (left) is seen adjacent to an area of squamous metaplasia.

A

B

Fig. 4-62. Small cell carcinoma. A, The tumor is composed of small blue cells that have elongated or round nuclei, depending on the plane of sectioning. The tumor contains areas of necrosis (right upper corner). B, Neuroendocrine granules can be seen by electron microscopy.

Fig. 4-63. Peripheral adenocarcinoma. The tumor contains areas of black discoloration, which suggest that it originated in an anthracotic scar.


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Fig. 4-64. Bronchioloalveolar carcinoma. The tumor infiltrates the parenchyma and produces lesions that resemble pneumonia. Fig. 4-65. Bronchioloalveolar carcinoma. The cuboidal mucussecreting tumor cells grow along the alveolar septa. Lung neoplasms I. Epithelial tumors A. Benign tumors I. Papillomas 2. Adenomas a. Pleomorphic adenoma b. Monomorphic adenoma B. Dysplasia/carcinoma in situ C. Malignant tumors I. Squamous cell carcinoma (epidermoid carcinoma) 2. Small cell carcinoma a. Oat cell carcinoma b. Intermediate cell type c. Combined oat cell carcinoma 3. Adenocarcinomas a. Acinar adenocarcinoma b. Papillary adenocarcinoma c. Bronchioloalveolar carcinoma d. Solid carcinoma with mucus formation 4. Large cell carcinoma variants a. Giant cell carcinoma b. Clear cell carcinoma 5. Adenosquamous carcinoma 6. Carcinoid tumor 7. Bronchial gland carcinoma 8. Others II. Soft tissue tumors primary in the lung III. Pleural tumors A. Benign mesothelioma B. Malignant mesothelioma IV. Miscellaneous tumors A. Benign tumors B. Malignant tumors I. Carcinosarcoma 2. Pulmonary blastoma 3. Malignant melanoma 4. Malignant lymphoma 5. Others V. Unclassified tumors VI. Tumor-like lesions Modified from Colby TV, Koss MN, Travis WD: Tumors of the lower respiratory tract. Atlas of tumor pathology, series 3, fasc. 13, Washington, D.C., 1995, Armed Forces Institute of Pathology; and the World Health Organization Histological Typing of Lung Tumors, Am J Clin Pothol 77:I23126, 1982.

Fig. 4-66. Bronchial carcinoid. The tumor presented as a small nodule in the wall of the bronchus.

Fig. 4-67. Carcinoid tumor. The tumor is composed of uniform cells that have round nuclei.


Sarcomas of the lung present as bulky solid masses (Fig. 4-68). Histologically they resemble sarcomas of soft tissues. Pulmonary blastoma is an organ-specific malignant tumor composed of cuboidal epithelial cells that form branching ducts surrounded by mesenchymal stroma that resemble fetal lungs (Fig. 4-69). Benign tumors and tumor-like conditions present as coin lesions on radiographic examination. Pulmonary hamartomas are composed of cartilage, bronchial epithelium, and

smooth muscle cells. On gross examination hamartomas appear as clefted cartilaginous nodules (Fig. 4-70). Sclerosing hemangioma, also called papillary pneumocytoma, is a benign tumor of controversial histogenesis (Fig. 4-71). Inflammatory pseudotumor is an inflammatory lesion that may resemble tumors (Fig. 4-72). Metastatic tumors appear on radiographic examination as sharply demarcated multiple round nodules ( " cannonball" lesions). Equivalent autopsy findings are typical (Fig. 4-73).

Fig. 4-68. Sarcoma of the lung. The tumor forms a bulky mass.

Fig. 4-69. Pulmonary blastoma. The tumor is composed of branching epithelium-lined ducts surrounded by spindle-shaped stromal cells.

A

B

Fig. 4-70. Pulmonary hamartoma. A, The nodule has a prominently clefted appearance on cross section. B, It is composed of cartilage and cleft-like spaces lined by cuboidal cells.


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Fig. 4-71. Sclerosing hemangioma. Vascular papillae are lined by cuboidal cells. -

Fig. 4-73. Metastatic carcinoma. The parenchyma contains several round nodules.

Further Reading Bjornsson J, Edwards WD: Primary pulmonary hypertension. A histopathologic study of 80 cases. Mayo Clin Proc 60:16-25, 1985. Blumenfeld W. McCook 0, Grississ JM: Detection of antibodies to Pneumocystic carinii in bronchoalveolar lavage fluid by immunoreactivity to Pneumocystis carinii within alveoli, granulomas, and disseminated sites. Mod Pathol 5:107-113, 1992. Colby TV: Bronchiolitis: pathologic considerations. Am J Clin Pathol 109:101-109, 1998. Dunnill MS: Pulmonary fibrosis. Histopathology 16:321-329, 1990. Hagan JL, Hardy JD: Lung abscess revisited. A survey of 184 cases. Ann Surg 197:755-762, 1983.

Fig. 4-72. Inflammatory pseudotumor. The lesion is composed of a variety of cell types. Plasma cells and fibrosis predominate.

Hasleton PS, Roberts TE: Review: adult respiratory distress syndrome —an update. Histopathology 34:285-294, 1999. Jeffery PK: Structural and inflammatory changes in COPD: a comparison with asthma. Thorax 53:129-136, 1998. Marchevsky A, Rosen MJ, Chrystal G, Kleinerman J: Pulmonary complications of the acquired immunodeficiency syndrome. A clinicopathologic study of 70 cases. Hum Pathol 16:659-670, 1985. Mark EJ, Ramirez JF: Peripheral small-cell carcinoma of the lung resembling carcinoid tumor. A clinical and pathologic study of 14 cases. Arch Pathol Lab Med 109:263-269, 1985. Porter HJ: Pulmonary hypoplasia-size is not everything. Virchow Arch 432:3-6, 1998. Takemura T and others: Pulmonary vascular involvement in sarcoidosis. A report of 40 autopsy cases. Hum Pathol 23:1216-23, 1992. Travis WD, Gal AA, Colby TV et al: Reproducibility of neuroendocrine lung tumor classification. Hum Pathol 29:272-279, 1998. Travis WD, Rush W, Flieder DB et al: Survivial analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoids and its separation from typical carcinoid. Am J SurgPathol22:934-944, 1998. Uner AL, Rozum-Slota B, Katzenstein AA: Bronchiolitis obliteransorganizing pneumonia (BOOP)-like variant of Wegener's granulomatosis. A clinicopathologic study of 16 cases. Am J Surg Pathol 20:794-801, 1996. Winn WC Jr, Myerowitz RL: The pathology of the Legionella pneumonias. A review of 74 cases and the literature. Hum Pathol 12:40142, 1981. Yousem SA, Lohr RH, Colby TV: Idiopathic bronchiolitis obliterans organizing pneumonia/cryptogenic organizing pneumonia with unfavorable outcome: pathologic predictors. Mod Pathol 10:864-871, 1997.ganizing pneumonia/cryptogenic organizing pneumonia with unfavorable outcome: pathologic predictors. Mod Pathol 10:864-871, 1997.




ANEMIAS Anemia is a reduction in the hemoglobin concentration in the blood, which decreases its oxygen-carrying capacity. The pathologic changes related to anemias can be seen primarily in the bone marrow, which is the site of red blood cell (RBC) production; the circulating blood; and the spleen, which is the primary site of RBC destruction. Pathophysiologically anemias can be classified into those attributable to (1) impaired production of erythrocytes; (2) inherited quantitative and structural abnormalities of hemoglobin synthesis; (3) increased rate of erythrocyte destruction, that is, hemolytic anemias; and (4) acute blood loss. On the basis of RBC morphology, anemias are classified as (1) microcytic, (2) normocytic, or (3) macrocytic (Table 5-1).

Morphologic Classification of Anemias Microcytic hypochromic anemias Iron deficiency Chronic disease Thalassemia Sideroblastic anemia Normocytic normochromic anemias Aplastic anemia Chronic disease Myelophthisic conditions Hemolytic anemia Macrocytic anemias Vitamin B12 deficiency Folic acid deficiency Chronic liver disease Myelodysplastic syndrome

Bone Marrow Changes Hematopoietic cells constitute 40 percent of normal bone marrow (Fig. 5-1). Hemolytic anemia results in compensatory erythroid hyperplasia (Fig. 5-2). In aplastic anemia the bone marrow is acellular and contains few or no hematopoietic cells (Fig. 5-3). Anemia can result from the replacement of the normal hematopoietic cells as a result of sarcoidosis or other inflammatory conditions and tumors (Fig. 5-4). Specific causes of anemia such as parvovirus B19 occasionally may be identified by bone marrow biopsy (Fig. 5-5). Many other forms of anemia are characterized by specific bone marrow findings. For example, pernicious anemia shows megaloblastic changes (Fig. 5-6).

Peripheral Blood Smears Peripheral blood smears are important for assessing anemia. Morphology of red blood cells may be used to classify anemias into general categories (e.g., microcytic versus macrocytic) or to obtain specific information about the nature of the underlying defect, as in spherocytosis,.elliptocytosis, pyropoikilocytosis, or acanthocytosis (Figs. 5-7 to 5-9).

Fig. 5-I. Normal bone marrow of an adult. Hematopoietic cells account for approximately 40 percent of marrow's cellularity.

Fig. 5-2. Erythroid hyperplasia. Markedly hypercellular bone marrow from a patient with hemolytic anemia contains an increased number of erythroid precursors. Megakaryocytes and granulocyte at all stages of maturation are present.

Fig. 5-3. Aplastic anemia. There is a marked reduction in hematopoietic cells with expansion of fat cells.


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Fig. 5-4. Parvovirus BI9—induced erythroid hypoplasia. The bone marrow smear shows a reduced number of erythroid precursors. A giant proerythroblast with a prominent intranuclear inclusion is seen in the middle of the field.

Fig. 5-5. Sarcoidosis. The bone marrow contains several confluent noncaseating granulomas.

Fig. 5-6. Pernicious anemia. Bone marrow aspirate smear contains megaloblastic red cell precursors and giant metamyelocytes.

Fig. 5-7. Spherocytosis. Spherical RBCs may be seen in peripheral blood smears of patients who have hereditary spherocytosis or immune hemolytic anemia, or after RBC transfusion.

A

B

Fig. 5-8. Elliptocytosis and pyropoikilocytosis. A, In hereditary elliptocytosis, elliptocytes constitute more than 25 percent of all cells in peripheral blood smears. Elliptocytes also are seen in iron deficiency anemia and various myeloproliferative and/or myelodysplastic disorders. B, Pyropoikilocytosis may be hereditary, but similar morphology of RBCs can be seen in severe burns, clostridial sepsis, and snake venom poisoning.


Fig. 5-9. Acanthocytosis. Acanthocytes, or RBCs with numerous irregular surface spikes, are seen in peripheral blood smears of patients with severe liver disease, but also in abetalipoproteinemia, McLeod phenotype, and several other conditions.

A

B

Fig. 5-10. Hemolytic anemia with Heinz bodies. A, The peripheral blood smear of this patient with low glucose-6phosphate dehydrogenase activity treated with dapsone contains numerous "bite cells." B, Neutral red–brilliant green shows Heinz bodies inclusions. Reticulocytes contain red, delicate, granular deposits of ribonucleic acid.

Fig. 5-1 I. Sickle cell anemia. The red blood cells vary in size and shape and are often deformed, that is, sickle-shaped.

A

B

Fig. 5-12. Thalassemia. The peripheral blood smear contains numerous target cells. A, Thalassemia minor. B, Thalassemia major.


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Certain forms of hemolytic anemia such as sickle cell anemia or thalassemia also have typical morphologic features (Figs. 5-10 to 5-12).

Tissue Changes in Anemia Anemias produce a variety of tissue changes, which vary depending on the severity and duration of the disease and its pathogenesis. Some tissue changes such as atrophic gastritis in pernicious anemia reflect the causes of anemia. Replacement of blood cell precursors in the marrow by fibrous tissue is seen in anemia of myelofibrosis (Fig. 5-13). It may be as -

Fig. 5-13. Myelofibrosis. The hematopoietic bone marrow has been replaced with fibroblastic tissue.

sociated with extramedullary hematopoiesis, usually in the spleen and the liver (Fig. 5-14). Intrasplenic hemolysis of hereditary spherocytosis is accompanied by splenomegaly (Fig. 5-15). Histologically such enlarged spleens have dilated sinuses filled with blood (Fig. 5-16). In sickle cell anemia prolonged pooling of red blood cells and obstruction of the blood flow may cause infarcts, which ultimately lead to fibrotic shrinkage of the spleen ( " autosplenectomy " ) (Fig. 5-17). The fibrous scars in these abnormally small spleens often are i mpregnated with iron and calcium salts and thus appear black (Fig. 5-18).

Fig. 5-14. Extramedullary hematopoiesis. Erythroid and myeloid cells in various stages of maturation and megakaryocytes are seen in the liver and spleen.

Fig. 5-15. Hereditary spherocytosis. Spleen is markedly enlarged. The cut surface is homogeneously red. Fig. 5-16. Hereditary spherocytosis. Spleen shows prominent congestion of the red pulp sinuses.


Fig. 5-17. Sickle cell anemia. Spleen is shrunken and has a gray, nodular external surface.

Fig. 5-18. Sickle cell anemia. The spleen contains fibrotic scars, which are impregnated with iron and calcium salts and therefore appear black.

LEUKEMIAS Leukemias are neoplastic diseases of hematopoietic cells presenting primarily with changes in the blood and bone marrow. They are classified as two major cytologic types, myeloid and lymphocytic, based on the primary cell of origin. Within each cytologic type, the leukemias are further classified as acute or chronic, based on the degree of maturation of the major cell population.

Acute Leukemias Acute myeloid leukemias (AML) are classified into eight subgroups (Table 5-2). AML is characterized by the appearance of blast cells in the bone marrow; the diagnosis of AML is made if the bone marrow contains 30 percent or more blasts. The major blast populations include myeloblasts, monoblasts, erythroblasts, and megakaryoblasts. Two types of myeloblasts generally are recognized: type I and type II (Fig. 5-19). The monoblasts and promonocytes are the major immature cells in acute monocytic leukemia (Fig. 5-20). The promyelocyte is the predominant abnormal cell in acute promyelocytic leukemia (Fig. 5-21). In approximately 60

percent of cases of AML, myeloblasts contain linear azurophilic structures known as Auer rods (Fig. 5-22). Acute lymphoblastic leukemia is classified as L1, L2, or L3, depending on the blast morphology. The L1 lymphoblast is a small cell, approximately twice the size of a normal lymphocyte, with a high nuclear-cytoplasmic ratio, a homogeneous smooth nuclear chromatin, and inconspicuous or no identifiable nucleoli (Fig. 5-23). L2 lymphoblasts are larger than L 1 lymphoblasts and have moderate amounts of lightly basophilic cytoplasm and fine nuclear chromatin with distinct and sometimes prominent multiple nucleoli (Fig. 5-23). L3 lymphoblasts have a moderate amount of intensely basophilic cytoplasm that contains sharply defined, clear vacuoles, which usually stain with oil red O and are periodic acid–Schiff (PAS) negative (Fig. 5-24).

11

Pro

Classification of Acute Myeloid Leukemias Acute myeloblastic leukemia, minimally differentiated' (AML-MO) Acute myeloblastic leukemia without maturation (AML-M I) Acute myeloblastic leukemia with maturation (AML-M2) Acute promyelocytic leukemia (AML-M3) Hypergranular type Microgranular variant Acute myelomonocytic leukemia (AML-M4) Increased marrow eosinophils (AML-M4-EO) Acute monocytic leukemia (AML) Acute monoblastic leukemia (AML-M5A) Acute monocytic leukemia, differentiated (AML-M5B) Erythroleukemia (AML-M6) Acute megakaryoblastic leukemia (AML-M7)

Fig. 5-19. Acute myeloid leukemia. The type I myeloblast (I) is agranular. The type II myeloblast (II) has a few azurophilic granules in the cytoplasm at the lower right. The promyelocyte (Pro) has numerous azurophilic granules in the cytoplasm.


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Fig. 5-20. Acute monoblastic leukemia (M5A). The bone marrow contains monoblasts, which are larger than normal myeloblasts and usually have abundant cytoplasm, frequently with delicate, scattered, azurophilic granules.

Fig. 5-22. Acute myeloblastic leukemia with maturation (M2). Variation in size and amount of cytoplasm is shown in this bone marrow smear. The blast at the upper right is small with sparse cytoplasm and coarser nuclear chromatin and inconspicuous nucleoli. All of the blasts contain Auer rods.

Fig. 5-21. Promyelocytic leukemia. Cells with multiple intertwining Auer rods ("faggot" cells) are characteristic of hypergranular promyelocytic leukemia.

Fig. 5-23. Acute lymphoblastic leukemia. LI and L2 lymphoblasts show characteristic morphology in marrow aspirates.

Fig. 5-24. Acute lymphoblastic leukemia. The cytoplasm of L3 lymphoblasts in a marrow aspirate contains sharply outlined cytoplasmic vacuoles.


Chronic Leukemias Chronic myeloid leukemia (CML) is a myeloid stem cell disorder. Together with several other closely related diseases of the bone marrow, it forms a group if disorders known as primary myelodysplastic syndromes (Table 5-3). In CML the bone marrow is markedly hypercellular and contains an increased number of neutrophils and megakaryocytes and their precursors (Fig. 5-25). The peripheral blood leukocytosis exceeds 100 X 10 9/L in 70 percent to 90 percent of patients. Neutrophils at the myelocyte and segmented stages predominate; myeloblasts do not exceed 2 percent to 3 percent of all cells (Fig. 5-26). Chronic lymphoproliferative disorders are a heterogeneous group of diseases that are characterized by a proliferation of small well-differentiated lymphocytes. On the basis of immunohistochemical markers these disorders represent either B-cell or T-cell neoplasms (Table 5-4). Chronic B-cell lymphocytic leukemia is characterized by lymphocytosis that varies from 4 X 10 9 /L to more than 400 X 109 /L. Peripheral blood smears contain numerous relatively uniform lymphocytes that have condensed nuclear chromatin and sparse cytoplasm (Fig. 5-27). In hairy cell leukemia the peripheral blood contains medium-sized lymphocytes with an oval or lobated nucleus and shaggy cytoplasm extending into surface projections (Fig. 5-28). In adult T-cell leukemia, a disease associated with human T-cell leukemia/lymphoma virus (HTLV-1) infection, peripheral blood smears contain abnormal lymphocytes, which are described as having " flower-shaped," markedly convoluted nuclei (Fig. 5-29). In granulated cell lymphocytic leukemia peripheral blood smears contain medium-sized to large lymphocytes with abundant cytoplasm that is rich in coarse azurophilic granules (Fig. 5-30).

Fig. 5-25. Chronic myeloid leukemia. Bone marrow is markedly hypercellular and infiltrated with numerous myeloid cells.

Fig. 5-26. Chronic myeloid leukemia. The peripheral blood smear shows marked leukocytosis and basophilia.

Classification of Primary Myelodysplastic Syndromes Refractory anemia (RA)

Anemia refractory to hematinic therapy; dyserythropoiesis 6; granulocytes and megakaryocytes usually normal; marrow blasts less than 5%; no blasts in blood

Refractory anemia with ringed sideroblasts (BARS)

More than 15% of red cell precursors in marrow "ringed" sideroblasts; less than 5% blasts in marrow

Refractory anemia with excess blasts (RAEB)

5% to 20% blasts in marrow; less than 5% blasts in blood

Refractory anemia with excess blasts in transformation (RAEB-T)

I. 20% to 29% blasts in marrow; 2. 5% to 29% blasts in blood 3. Auer rods (any one criterion suffices)

Chronic myelomonocytic leukemia (CMML)

> I X I09/L monocytes in blood; I X I09/L monocytes in blood and one of the criteria listed for RAEB-T

transformation (CMML-T) Myelodysplastic syndrome, unclassified

Less than 5% blasts in marrow; significant dysplasia in two or more myeloid cell lines


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Chronic Lymphoproliferative Disorders B-cell lymphoproliferative disorders Chronic lymphocytic leukemia Typical Mixed cell type Prolymphocytic leukemia Chronic lymphocytic leukemia/prolymphocytic leukemia Hairy cell leukemia Splenic lymphoma with villous lymphocytes T-cell chronic lymphoproliferative disorders T prolymphocytic leukemia Granulated T-lymphocyte leukemia Sezary syndrome Adult T-cell leukemia

Fig. 5-27. Chronic lymphocytic leukemia. The smear contains numerous well-differentiated lymphocytes with a high nuclearcytoplasmic ratio and condensed nuclear chromatin.

A

B

Fig. 5-28. Hairy cell leukemia. A, The blood smear contains lymphoid cells that have a shaggy cytoplasm. B, Electron microscopy shows slender surface villi.

Fig. 5-29. Adult T-cell leukemia/lymphoma. The smear contains lymphoid cells with lobulated ("flower-shaped") nuclei.

Fig. 5-30. Granulated lymphocyte leukemic CD8+ lymphocytes have abundant cytoplasm filled with coarse azurophilic granules.


82

PLASMA CELL DYSCRASIAS Plasma cell dyscrasias are proliferations of B immunocytes accompanied by the production of monoclonal immunoglobulin. This group of diseases includes several closely related entities (Table 5-5). Multiple myeloma is a neoplastic proliferation of plasma cells associated with a monoclonal gammopathy. The criteria for the diagnosis are summarized in Table 5-6. Plasma cell Plasma Cell Dyscrasias and Related Disorders Monoclonal gammopathy of undetermined significance (MGUS) Solitary plasmacytoma Multiple myeloma Waldenstrom macroglobulinemia Heavy chain disease Primary amyloidosis

infiltrates cause lytic punched-out lesions in the bones (Fig. 5-31). Bone marrow aspirates of these lesions contain plasma cells, which can be classified as mature, immature, or plasmablastic (Fig. 5-32). The neoplastic infiltration of the bone marrow seen in trephine biopsies may be diffuse, focal, interstitial, or a combination of these patterns (Fig. 5-33). Immunohistochemistry typically shows that the cells are light chain restricted (i.e., monoclonal), expressing either kappa (K) or lambda (K) light chains (Fig. 5-34). Light chains of immunoglobulin are excreted in urine as Bence Jones protein. Renal amyloidosis is a common complication (Fig. 5-35). Waldenstrom macroglobulinemia is a monoclonal gammopathy of the immunoglobulin M class. It is associated with plasmacytoid lymphoma cells infiltrating the bone marrow or the lymph nodes (Fig. 5-36). The bone marrow is involved focally or diffusely in 85 percent of patients. Tumor cells appear as either small or plasmacytoid lymphocytes.

A

B

Fig. 5-3 I. Multiple myeloma. A, The radiograph shows lytic lesions. B, The skull contains lytic ("punched-out") lesions.

Fig. 5-32. Multiple myeloma. Bone marrow aspirate contains mostly plasma cells.

Fig. 5-33. Multiple myeloma. Bone marrow is infiltrated with atypical plasma cells.


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Diagnostic Criteria for Multiple Myeloma

Modified from Durie BG: Staging and kinetics of multiple myeloma, Semin Oncol 13:300, 1986.

Fig. 5-34. Multiple myeloma. The bone marrow biopsy was stained immunohistochemically with antibodies to kappa (K) and lambda (X) light chains. The plasma cells are kappa light chain restricted.

A

B

Fig. 5-35. Amyloidosis. A, Renal amyloidosis affecting the glomeruli and blood vessels is a common complication of monoclonal gammopathies. B, Congo red stained amyloid examined under polarized light appears green.

Fig. 5-36. Waldenstrom macroglobulinemia. The infiltrate consists of small lymphocytes, lymphoplasmacytic cells, and plasma cells. Arrow shows intranuclear inclusions (Dutcher bodies), which are known to be composed of immunoglobulin.


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REACTIVE LYMPHADENOPATHIES The term lymphadenopathy is used to describe nonneoplastic enlargement of lymph nodes caused either by infection or by any other antigenic stimulation. Five histologic patterns are recognized: (1) follicular, (2) interfollicular, (3) mixed follicular and interfollicular, (4) diffuse, and (5) sinusoidal (Table 5-7). Follicular hyperplasia, the most common form of reactive lymphoid proliferation, is characterized by an increased number and size of follicles. Fusion of adjacent germinal clusters may take place, resulting in a histologically bizarre " geographic pattern" (Fig. 5-37). The hyperplastic follicles contain expanded germinal centers composed of small and large cleaved and noncleaved cells (Fig. 5-38). Castleman disease, or angiofollicular lymph node hyperplasia, occurs in two forms: the more common hyaline vascular type (Fig. 5-39) and plasma cell variant (Fig. 5-40). The histologic findings are diagnostic. Histiocytic necrotizing lymphadenitis, or Kikuchi disease, is a benign self-limited disease that predominantly affects young women. Histologically the enlarged lymph nodes contain patchy areas of necrosis confined to paracortical and cortical areas, surrounded by macrophages, immunoblasts, and plasma cells (Figs. 5-41 and 5-42). Human immunodeficiency virus (HIV) infection leads to lymph node enlargement, a condition known as persistent generalized lymphadenopathy (Fig. 5-42). The enlarged lymph nodes contain hyperplastic germinal centers with little intervening interfollicular tissue. In other cases the sinuses are distended by monocytoid B-cells and scattered neutrophiles.

Fig. 5-37. Follicular lymph node hyperplasia. Fusion of adjacent germinal centers results in bizarre structures.

Patterns of Reactive Lymphadenopathies Follicular pattern Nonspecific follicular hyperplasia Rheumatoid arthritis/Sjogren syndrome Syphilis Angiofollicular hyperplasia (Castleman disease) HIV-related Progressive transformation of germinal centers Interfollicular pattern Nonspecific interfollicular hyperplasia Dermatopathic lymphadenitis Histiocytic necrotizing lymphadenitis (Kikuchi disease) Granulomatous lymphadenitis Mixed follicular and interfollicular pattern Toxoplasmosis lymphadenitis Cat-scratch disease Lymphogranuloma venereum Mesenteric lymphadenitis Kimura disease Diffuse pattern Infectious mononucleosis and other viral lymphadenitis Abnormal immune response/angioimmunoblastic lymphadenopathy Drug-induced hypersensitivity reactions Systemic lupus erythematosus Mucocutaneous lymph node syndrome (Kawasaki disease) Sinus pattern Sinus histiocytosis Hemophagocytic syndrome Sinus histiocytosis with massive lymphadenopathy Lymphangiography effect Whipple disease HIV, Human immunodeficiency virus.

Fig. 5-38. Follicular hyperplasia. The hyperplastic germinal center contains small and large cleaved and noncleaved germinal center cells, tingible body macrophages, and scattered plasma cells.


85

Fig. 5-39. Castleman disease, hyaline vascular type. Two follicles with progressively transformed germinal centers are surrounded by concentrically arranged mantle zone lymphocytes. "Lollipop" appearance of a follicle (right) is evident. Interfollicular vascularity is prominent.

Fig. 5-40. Castleman disease, plasma cell variant. Part of a follicle is seen adjacent to a dense interfollicular plasma cell infiltrate.

A

B

Fig. 5-41. Kikuchi disease. A, An irregular patchy focus of paracortical necrosis devoid of neutrophils is characteristic of this disease. B, Higher magnification shows that the necrotic area is surrounded by a mixture of large cells, such as macrophages, immunoblasts, and plasmacytoid monocytes.

A

B

Fig. 5-42. A, HIV-related lymphoadenopathy. Most of the node is replaced by large germinal centers in which there is a prominent starry sky appearance. B, Monocytoid B-cells occupy the paracortex between two large germinal centers.


86

A

B

C

D

E

F

Fig. 5-43. Diagnostic Reed-Sternberg cells and variants. A, Diagnostic Reed-Sternberg cell: a large multinucleated or multilobated cell with inclusion body–like nucleoli surrounded by a halo of clear nucleoplasm. There is a moderate amount of amphophilic cytoplasm. B, L&H variant. A large cell with a polyploid nucleus and high nuclear-cytoplasmic ratio. The nucleolus is not large and prominent. C, Lacunar variant: the cell has a lobated nucleus with small-to moderately prominent nucleoli in a clear lacuna produced by the retraction of cytoplasm from the plasm membrane. A small amount of cytoplasm often is observed around the nucleus. D, Mononuclear variant. This cell has the characteristics of a diagnostic Reed-Sternberg cell but with a single round or oval nucleus. E, Mummified (necrobiotic) cells frequently seen in nodular sclerosis type HD with pyknotic nucleus and darkly eosinophilic cytoplasm. F, Electron microscopy of a typical ReedSternberg cell.


87

HODGKIN DISEASE

Histopathologic Subtypes of Hodgkin Disease

Hodgkin disease (HD) is a neoplastic disease of lymph nodes. Current evidence suggests that HD may be a syndrome that comprises several entities, which nevertheless show some common pathologic and clinical features that distinguish them from non-Hodgkin lymphomas. Histologically the tumor consists of neoplastic Reed-Sternberg (R-S) cells that typically are found in a background of reactive cells such as small lymphocytes, macrophages, eosinophils, neutrophils, and plasma cells. R-S cells have characteristic features and are pathognomonic of HD (Fig. 5-43). In addition to classic R-S cells the tumors contain varying numbers of large pleomorphic neoplastic cells known as R-S variants (Fig. 5-43). Hodgkin disease tends to involve cervical and axillary lymph nodes in a contiguous manner (Fig. 5-44). The spleen, thymus, bone marrow, and liver also may be involved (Fig.

The pathologic classification of Hodgkin disease (HD) in current use continues to be the one proposed by Lukes and Butler in 1966. The relationship of this classification to the older classification by Jackson and Parker and the simplified version adopted at the Rye conference is shown in Table 5-8 Lymphocyte predominance type HD is characterized by a dense lymphocytic infiltrate with some histiocytes, which occasionally may be abundant. It occurs in a diffuse and a nodular form (Fig. 5-45). The L&H variants of R-S cells are scattered in this infiltrate, occasionally even in the form of small aggregates. Diagnostic R-S cells are very difficult to find. Nodular sclerosis type HD is characterized by a thickened lymph node capsule. Bands of collagen extend inward from

5-45).

The Pathologic Classification of Hodgkin Disease Jackson & Parker Paragranuloma

Granuloma

Lukes & Butler I. Lymphocytic and histiocytic a. Nodular b. Diffuse 2. Nodular sclerosis

Rye Conference Lymphocytic predominance

Frequency (%)* 5

Nodular sclerosis

70

3. Mixed cellularity 4. Diffuse fibrosis 5. Radicular

Mixed cellularity

22

Lymphocytic depletion

From Colby TV, Hoppe RT, Warnke RA Cancer 49:1848-1856, 1981. Copyright 1981 American Cancer Society. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Son, Inc. *Two percent of the cases were considered unclassifiable.

Fig. 5-44. Hodgkin disease. Axillary lymph nodes are enlarged.

Fig. 5-45. L&H Hodgkin disease, nodular type. Large nodules with small round lymphocytes, macrophages, and scattered L&H cells are seen.


88

the capsule and separate the tumor into nodules composed of a variety of reactive cells and R-S variants called lacunar cells (Fig. 5-46). Areas of necrosis or microabscess formation may be prominent (Fig. 5-47). Mixed cellularity type HD is characterized by a mixed cellular background of lymphocytes, histiocytes, eosinophils, and plasma cells (Fig. 5-48). Typical R-S cells and mononuclear variant R-S cells are readily identified. Lymphocyte depletion type HD occurs as diffuse fibrosis type (Fig. 5-49) or reticular type (Fig. 5-50). In the former R-S cells are not necessarily numerous. In the latter there is marked proliferation of R-S cells, which may be pleomorphic and bizarre.

Fig. 5-46. Nodular sclerosis type HD. Bands of thick collagen extend from the thickened capsule to divide the lymph node into smaller nodules.

Fig. 5-47. Nodular sclerosis type HD. Microabscess is surrounded by a ri m of R-S variant cells.

Fig. 5-48. Mixed cellularity type HD. Mononuclear R-S variant cells are scattered in a mixed cellular background.

Fig. 5-49. Lymphocyte depletion type HD. Diffuse fibrosis type. Much of the lymph node has been replaced by a pink, eosinophilic, amorphous material with depletion of lymphocytes. Scattered R-S variant cells are seen.

Fig. 5-50. Reticular type. The lymph node is largely replaced by a proliferation of R-S cells and R-S variant cells.


89

NON-HODGKIN LYMPHOMA The term non-Hodgkin lymphoma includes all malignant lymphomas other than Hodgkin disease. Non-Hodgkin lymphomas can be classified according to the Working Formulation developed by the National Cancer Institute; a German system, called the Kiel classification, which is widely used in Europe; or the new classification developed by the

International Lymphoma Study Group, which is referred to as REAL (Revised European-American Lymphoma; Table 5-9). Small lymphocytic lymphoma is a low-grade B-cell neoplasia that diffusely infiltrates the lymph nodes (Fig. 5-51). Morphologically the tumor cells resemble small mature lymphocytes (Fig. 5-52).

Comparison of Working Formulation (WF) and Revised European-American Lymphoma (REAL) Classification WF Category* A. Small lymphocytic consistent with CLL

Frequency (%) 4

Plasmacytoid B. Follicular, predominantly small cleaved cell

B-cell Neoplasms

REAL Classification T-cell Neoplasms

B-cell CLUSLUPLL Marginal zone/MALT Mantle cell

T-cell CLUPLL LGL

Lymphoplasmacytoid 26

Follicle center, follicular, grade I Mantle zone Marginal zone

C. Follicular, mixed small cleaved and large cell

9

Follicle center, follicular, grade II Marginal zone/MALT

D. Follicular, large cell

4

Follicle center, follicular, grade III

E. Diffuse, small cleaved cell

8

Mantle cell Follicle center, diffuse small cell Marginal zone/MALT

T-cell CLUPLL LGL Peripheral T-cell, unspecified ATUL Angioimmunoblastic Angiocentric

F. Diffuse, mixed small and large cell

7

Large B-cell lymphoma (rich in T-cells) Follicle center, diffuse small cell Lymphoplasmacytoid Marginal zone/MALT Mantle cell

Peripheral T-cell, unspecified ATUL Angioimmunoblastic Angiocentric

22

Diffuse large B-cell lymphoma ATUL Angioimmunoblastic Angiocentric

Peripheral T-cell, unspecified

H. Large cell Immunoblastic

9

Diffuse large B-cell lymphoma

Peripheral T-cell, unspecified ATUL Angioimmunoblastic Angiocentric Anaplastic large-cell

I.

Lymphoblastic

5

Precursor B-lymphoblastic

Precursor T-lymphoblastic

Small noncleaved cell Burkitt Non-Burkitt

6 Burkitt High-grade B-cell, Burkitt-like

Peripheral T-cell, unspecified

G. Diffuse, large cell

J

.

From Skarin AT, Dorfman DM: Non-Hodgkin's lymphoma: current classification and management, CA Cancer /. permission.

Clin

47:351-372, 1997. Reproduced with

*Categories A–C = low-grade (survival 5 to 10 or more years untreated); D–G = intermediate grade (survival 2 to 5 years untreated); H –J = high grade (survival 0.5 to 2.0 years untreated). Categories D–H are also called aggressive lymphomas. ATUL, Adult T-cell lymphoma/leukemia; CLL, chronic lymphocytic leukemia; LGL, large granular lymphocyte leukemia; MALT, mucosa-associated lymphoid tissue; PLL, prolymphocytic leukemia; SLL, small lymphocytic lymphoma.


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Fig. 5-5I. Small lymphocytic lymphoma. The normal lymph node architecture has been completely effaced.

Marginal zone lymphoma is a low-grade lymphoma composed of cells that resemble normal B cells of the marginal zones. These B cells are normally present external to follicular mantle cells and are particularly prominent in the spleen. They are thought to be capable of differentiating into reactive monocytoid B cells and plasma cells. Cases involving lymph nodes are often referred to as monocytoid lymphoma, whereas those arising in mucosa-associated lymphoid tissue are called maltomas. Involved lymph nodes show a variety of architectural patterns. In early stages lymphoma cells infiltrate the marginal zone surrounding reactive germinal centers, with occasional colonization of the germinal center (Fig. 5-53). In later stages lymphoma cells diffusely infiltrate the lymph nodes or the mucosa (Fig. 5-53). The infiltrate typically is composed of intermediate-sized monocytoid B cells (Fig. 5-54). Lymphoma cells tend to invade epithelia, forming " lymphoepithelial lesions " (Figs. 5-55 and 5-56). In approximately 40 percent of cases monoclonal plasma cells or plasmacytoid cells also are found in the infiltrate. Mantle cell lymphoma is a low- to intermediate-grade lymphoma. There are several architectural patterns. The normal architecture of the lymph node may be completely effaced or a vaguely vascular pattern may be retained. Mantle zone pattern results from a broad infiltrate around the reactive germinal centers (Fig. 5-57). The infiltrate is composed of small to medium-sized lymphocytes with a mature chromatin pattern and slightly irregular nuclear membranes. Nucleoli are inconspicuous and the cytoplasm is scant (Fig. 5-58). Follicular lymphoma is a low- to intermediate-grade lymphoma that grows in a follicular pattern. It represents the neoplastic counterpart of germinal center B lymphocytes (Fig. 5-59). Cytologically several variants have been recognized: small cleaved cell (Fig. 5-60), mixed small cleaved and large cell (Fig. 5-61), and predominantly large cell (Fig. 5-62). Occasionally the neoplastic cells take unusual forms, such as signet ring—like cells, or they may show plasmacytoid differentiation.

Fig. 5-52. Small lymphocytic lymphoma. The lymph node is composed of loosely packed cells of intermediate size with discernible nucleoli.

Fig. 5-53. Marginal zone lymphoma. There is preferential infiltration of the marginal zone of splenic white pulp.

Fig. 5-54. Marginal zone lymphoma. The lymph node is infiltrated by a uniform population of small to intermediate-sized lymphocytes with bland nuclei and a moderate rim of clear cytoplasm. Note the presence of scattered neutrophils.


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Fig. 5-55. Marginal zone lymphoma of salivary gland. The epithelial gland is infiltrated with lymphocytes, forming a socalled "lymphoepithelial lesion."

Fig. 5-56. Marginal zone lymphoma of the stomach ("maltoma"). Small to medium-sized lymphocytes, many of which have a clear perinuclear halo, invade gastric glands.

Fig. 5-57. Mantle cell lymphoma. Germinal center is surrounded by a broad zone ("mantle").

Fig. 5-58. Mantle cell lymphoma. The infiltrate consists of a monotonous population of small lymphocytes. The nuclei of these cells have a mature chromatin pattern and slightly irregular outlines.

Fig. 5-59. Follicular lymphoma. Many crowded nodules of relatively even size and lacking well-defined mantle zones are present.

Fig. 5-60. Follicular, predominantly small cleaved cell lymphoma. The infiltrate is composed of a monotonous population of small cells with contorted nuclei (cleaved cells).


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Fig. 5-61. Follicular, mixed small cleaved and large cell lymphoma. Two cell populations are clearly seen.

Fig. 5-62. Follicular, predominantly large cell lymphoma. The infiltrate is composed predominantly of large noncleaved cells.

Fig. 5-63. Diffuse large cell lymphoma. Large tumor cells have vesicular nuclei in contrast to occasional normal lymphocytes that have condensed chromatin.

Fig. 5-64. Large cell immunoblastic lymphoma. The tumor cells are large, with vesicular nuclei containing a single prominent nucleolus. The cytoplasm is abundant and shows plasmacytoid features.

Diffuse, mixed large cell and large cell immunoblastic lymphomas of B-cell lineage are classified according to the Working Formulation as intermediate- or high-grade lymphomas, respectively. The neoplastic cells infiltrate the lymph node, causing partial or complete effacement of the lymph node architecture. The hallmark of these lymphomas is the presence of a significant number of large lymphoid cells (Fig. 5-63) or immunoblasts (Fig. 5-64). In diffuse mixed lymphomas there is a significant admixture of small lymphoid cells, such that neither element dominates (Fig. 5-65). In other cases the small round cells represent reactive T cells that are not part of the neoplastic process. These tumors usually are designated T-cell rich B-cell lymphomas (Figs. 5-66 and 5-67). Necrosis or sclerosis may be prominent in large cell lymphomas (Fig. 5-68). Typically there is an admixture of reactive cells, such as epithelioid and nonepithelioid histio -

cytes, small lymphocytes, eosinophils, and plasma cells. Peripheral T-cell lymphomas (PTCL), also known as postthymic T-cell lymphomas, are intermediate- or high-grade malignancies composed of T cells, morphologically and immunophenotypically equivalent to mature T cells. The term PTCL encompasses several clinicopathologic entities, includipg mycosis fungoides/Sezary syndrome, adult T-cell leukemia/lymphoma; angioimmunoblastic lymphadenopathy with dysproteinemia-like (AILD-like) T-cell lymphoma, lymphoepithelioid T-cell lymphoma, angiocentric T-cell lymphoma, intestinal T-cell lymphoma, T-cell lymphoma associated with erythrophagocytosis, hepatosplenic T-cell lymphoma, erythrophagocytic T- y lymphoma, and many cases of CD30+ lymphoma. Peripheral T-cell lymphomas are difficult to recognize morphologically because they can assume a variety of histologic appearances. They


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Fig. 5-65. Diffuse mixed small and large cell lymphoma. A relatively even admixture of small and large atypical lymphoid cells is seen.

Fig. 5-66. T-cell rich B-cell lymphoma. The large tumor cells are embedded in a background of smaller T cells.

Fig. 5-67. T-cell rich B-cell lymphoma. The large cells stain with antibodies to CD20, a B cell marker.

Fig. 5-68. Large cell lymphoma. The tumor contains prominent areas of sclerosis.

never show a follicular architecture but may show effacement, preferential paracortical infiltration, or preferential sinusoidal involvement. The cell infiltrate usually is composed of a mixture of atypical intermediate-sized to large lymphoid cells (Fig. 5-69). The atypical cells often have irregular nuclear contours, which may vary from one cell to another and may include highly pleomorphic forms, some of which have multilobated nuclei (Fig. 5-70). AILD-like T-cell lymphoma is characterized by cell-poor diffuse effacement of lymph node architecture, numerous arborizing vessels, and absence or repression of germinal centers. Deposits of intercellular PAS-positive amorphous material may be prominent. In early stages of the disease the definitive diagnosis of this lymphoma cannot be made easily. When the neoplastic cells increase in number and cells with clear cytoplasm appear, often forming clusters around the

Fig. 5-69. Peripheral T-cell lymphoma. The perivascular infiltrate is composed of both large and intermediate-sized atypical lymphoid cells. Scattered eosinophils are present.


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Fig. 5-70. Peripheral T-cell lymphoma. The tumor consists of a mixed population of small, intermediate-sized, and large lymphoid cells. Many of the large lymphoid cells have hyperlobated nuclei.

Fig. 5-71. AILD-like T-cell lymphoma. The infiltrate contains prominent intermediate-sized atypical lymphoid cells with pale cytoplasm. These cells often form small groups.

Fig. 5-72. Lymphoepithelioid T-cell (Lennert) lymphoma. Atypical lymphoid cells are admixed to epithelioid histiocytes, which represent the most abundant cells in the tissue. Eosinophils and plasma cells also may be present.

Fig. 5-73. Angiocentric lymphoma. A small artery in the center is infiltrated with atypical lymphoid cells that occlude its lumen.

vessels, the diagnosis of AILD-like T-cell lymphoma can be made readily (Fig. 5-71). Lymphoepithelioid T-cell lymphoma, or Lennert lymphoma, is characterized by a proliferation of atypical T lymphocytes surrounded by epithelioid histiocytes (Fig. 5-72). Plasma cells and eosinophils usually are present. Angiocentric T-cell lymphoma is a term that encompasses a group of previously poorly characterized entities, such as lymphomatoid granulomatosis and polymorphic reticulosis. It occurs in extranodal sites, particularly the upper and lower respiratory tracts and the skin. The unifying feature of the various forms of this lymphoma is the infiltration of small arteries and veins (Fig. 5-73). The infiltrates consist of atypical T cells, small lymphocytes, plasma cells, macrophages, and eosinophils.

Lymphoblastic lymphoma is a high-grade malignant lymphoma; it represents the tissue equivalent of acute lymphoblastic leukemia. A lymphoblastic lymphoma typically presents as a mediastinal mass, often with pleural or pericardial effusion. The atypical small to medium-sized lymphoid cells tend to efface the lymph node architecture and spread into the pericapsular tissue, evoking a fibrous response (Fig. 5-74). The mitotic rate is high and extensive single cell necrosis may be present. The tumor cells have round or highly irregular nuclear contours with finely dispersed chromatin and inconspicuous nucleoli. Small noncleaved cell lymphoma (SNCL) is a high-grade malignancy of two subtypes: Burkitt type and non-Burkitt type. In Burkitt lymphoma the infiltrate begins in the germinal centers, subsequently leading to an effacement of the


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Fig. 5-74. Lymphoblastic lymphoma. A single cell file pattern of infiltration is seen in the perinodal tissue.

Fig. 5-75. Burkitt lymphoma. A starry sky pattern is seen at low magnification.

Fig. 5-76. Burkitt lymphoma. The tumor is composed of a uniform population of medium-sized lymphoid cells. The chromatin is not dispersed as finely as it is in lymphoblastic lymphoma. Each nucleus contains several nucleoli.

Fig. 5-77. Small noncleaved cell lymphoma, non-Burkitt type. A population of intermediate-sized lymphoid cells with a high mitotic rate is present. The cells are somewhat more pleomorphic than those typically seen in Burkitt lymphoma.

lymph node architecture (Fig. 5-75). There are numerous mitoses and tangible body macrophages, which impart to the lymph node a starry sky appearance. The neoplastic cells are B lymphocytes of intermediate size with round nuclei, coarse chromatin, and multiple nucleoli (Fig. 5-76). The neoplastic cells of the non-Burkitt subtype are similar to those in Burkitt lymphoma except that the cells show more pleomorphism and fewer but often more prominent nucleoli (Fig. 5-77).

OTHER HEMATOPOIETIC PROLIFERATIONS IN LYMPH NODES

Neoplasms that originate from other cellular components of lymph nodes are much less common than lymphomas. Langerhans cell histiocytosis presents with neoplastic infiltrates in lymph node sinuses (Fig. 5-78). The neoplastic

Fig. 5-78. Langerhans cell histiocytosis. The sinusoid of the lymph node is distended by sheets of Langerhans cells and an aggregate of eosinophils.


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Fig. 5-79. Follicular dendritic cell sarcoma. The infiltrate consists of spindle cells. A few scattered lymphocytes are still present.

Langerhans cells have grooved nuclei with complex, folded delicate nuclear membranes, which give them a coffee bean—like appearance. Dendritic cell sarcomas include follicular dendritic cell sarcoma and interdigitating cell sarcoma. The neoplastic cells have elongated nuclei and pale eosinophilic cytoplasm (Fig. 5-79). There are numerous small lymphocytes between the tumor cells. Myeloid leukemia may involve the lymph nodes or may present as a soft tissue mass ( "chloroma " ). Tumors are composed of a uniform population of cells with vesicular nuclei (Fig. 5-80). The mitotic rate is high and occasionally there is a starry sky appearance.

NEOPLASMS INVOLVING THE SPLEEN Splenomegaly may be caused by a variety of neoplastic and nonneoplastic diseases, which are listed in Table 5-10. All leukemias, myeloproliferative diseases, and lymphomas may involve the spleen and cause splenomegaly (Fig. 5-81). The pattern of splenic involvement depends on the type of the disease. In acute myeloid leukemia the cords and sinuses are filled with blast cells (Fig. 5-82). In hairy cell leukemia the neoplastic cells infiltrate the red pulp and surround the trabecular vessels of the white pulp (Fig. 5-83). Lowand intermediate-grade lymphomas involve the white pulp and produce a "miliary" pattern (Fig. 5-84). High-grade B-cell lymphomas, on the other hand, produce one or more solid tumors or masses (Fig. 5-85). T-cell lymphomas are less common in the spleen, where they usually involve the T zones and the red pulp (Fig. 5-86). Splenic involvement is found in approximately one third of cases of Hodgkin disease. The infiltrates are always in the white pulp.

Fig. 5-80. Acute myeloid leukemia involving a lymph node. A diagnosis of "atypical" lymphoblastic lymphoma was favored histologically because this patient did not have a history of leukemia.

Causes of Splenomegaly Neoplasia Myeloproliferative and myelodysplastic disorders, leukemia, and lymphoma Hemolytic anemias Hereditary spherocytosis, elliptocytosis Thalassemias, sickle cell anemia Autoimmune disorders Autoimmune hemolytic anemia Thrombocytopenia, essential neutropenia Systemic lupus erythematosus Rheumatoid arthritis Sarcoidosis Infections Infectious mononucleosis, brucellosis, etc. Malaria, toxoplasmosis, etc. Sepsis Congestion Cirrhosis of the liver Budd-Chiari syndrome Chronic congestive heart disease Storage diseases Gaucher disease, Niemann-Pick disease Amyloidosis


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Fig. 5-81. Chronic myeloid leukemia. Splenomegaly is a common finding. Spleen also shows infarcts.

Fig. 5-82. Acute myeloid leukemia. The cords and sinuses are filled with blast cells.

Fig. 5-83. Hairy cell leukemia. The tumor cells diffusely infiltrate the red pulp. Replacement of normal sinus-lining cells by hairy lymphocytes leads to pooling of blood and the formation of "blood lakes," which are typical of this disease.

Fig. 5-84. Mantle cell lymphoma. The enlarged follicles of the white pulp infiltrated with tumor cells impart a "miliary" pattern to the cross section of the spleen.

Fig. 5-85. Lymphoblastic lymphoma. Tumor cells form a discrete mass in the spleen.

Fig. 5-86. T-cell lymphoma, high-grade. The tumor involves the sinusoids of the red pulp, simulating malignant histiocytosis.


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DISEASES OF THE THYMUS The most important pathologic changes involving the thymus are (1) developmental disorders such as thymic aplasia, hypoplasia, or dysplasia; (2) accelerated involution of the thymus; (3) thymitis and hyperplasia; and (4) thymic neoplasia. In primary immunodeficiency states the thymus is very small (Fig. 5-87). Histologically the thymus shows either simple dysplasia (Fig. 5-88), dysplasia with stromal corticomedullary differentiation (Fig. 5-89), dysplasia with pseudoglandular appearance, or severe atrophy. Lymphofollicular thymitis, also known as lymphoid follicular hyperplasia, is found in 50 percent to 70 percent of cases of myasthenia gravis. The enlargement of the thymus is as-

sociated with an increased number of lymphoid follicles with germinal centers (Fig. 5-90). Tumors of the thymus originate from the thymic epithelium or lymphocytes. Thymomas are classified as benign or malignant. Benign thymomas are well encapsulated (Fig. 5-91). They are composed of spindle-shaped epithelial cells admixed to mature lymphocytes (Fig. 5-92). There are three forms of thymic carcinomas: (1) low-grade, predominantly cortical (organoid), malignant thymoma; (2) welldifferentiated thymic carcinoma, which includes squamous cell carcinoma, clear cell carcinoma, or carcinoid; and (3) anaplastic carcinoma (Fig. 5-93). Lymphomas are of B-cell or T-cell type. Hodgkin disease also may involve the thymus.

A

B

Fig. 5-87. Thymic hypoplasia. A, A severely hypoplastic thymus (arrowheads) was found close to the aortic arch at the autopsy of a six-month-old infant who died of sepsis superimposed on severe combined immunodeficiency (SCID). B, Incomplete DiGeorge syndrome shows incompletely descended hypoplastic thymus. T, Thymus. L, Larnyx.

Fig. 5-88. Simple thymic dysplasia. Epithelial thymic lobules are almost devoid of lymphoid cells, without corticomedullary demarcation and with a lack of Hassall corpuscles.

Fig. 5-89. Thymic dysplasia with stromal corticomedullary differentiation. Rudimentary cortical medullary demarcation is evident, but no Hassall corpuscles are seen. Patient had SCID caused by purine nucleoside phosphorylase (PNP) deficiency.


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Fig. 5-90. Follicular thymitis in myasthenia gravis. The thymus contains numerous lymphoid follicles in the perivascular spaces and the medulla.

Fig. 5-91. Thymoma. The tumor is encapsulated and appears lobulated on cross section.

Fig. 5-92. Medullary thymoma. The tumor is composed of spindle-shaped epithelial cells in a background of mature lymphocytes.

Fig. 5-93. Thymic carcinoma. Epithelial tumor cells form solid nests that contain only a few scattered lymphocytes. The borders of the tumor nests may be scalloped or infiltrating.

Further Reading Baddoura FK, Chan WC, Masih AS et al: T-cell—rich B-cell lymphoma. A clinicopathologic study of eight cases. Am J Clin Pathol 103:6575, 1995. Burke JS: Splenic lymphoid hyperplasias versus lymphomas/leukemias. A diagnostic guide. Am J Clin Pathol 99:486-493, 1993. Chang KL, Kamel OW, Arber DA et al: Pathologic features of nodular lymphocyte predominance Hodgkin's disease in extranodal sites. Am J Surg Pathol 19:1313-1324, 1995. Hammer RD, Glick AD, Greer et al: Splenic marginal zone lymphoma. A distinct B cell neoplasm. Am J Surg Pathol 20:613-626, 1996. Harris NL, Jaffe ES, Stein H et al: A revised European-American classification of lymphoid neoplasm: A proposal from the International Lymphoma Study Group. Blood 84:1361-1392, 1994. Isaacson PG: Recent developments in our understanding of gastric lymphomas. Am JSurg Pathol 20(suppl 1):S1-S7, 1996. Kuo Ti': Kikuchi's disease (histiocytic necrotizing lymphadenitis). A clinicopathologic study of 79 cases with an analysis of histologic subtypes, immunohistology, and DNA ploidy. Am J Surg Pathol 19:798-809, 1995.

Lieberman PH, Jones CR, Steinman RM et al: Langerhans cell (eosinophilic) granulomatosis. A clinicopathologic study encompassing 50 years. Am J Surg Pathol 20:519-552, 1996. Ree HJ, Kadin ME, Kikuchi M et al: Angioimmunoblastic lymphoma (AILD-type T-cell lymphoma) with hyperplastic germinal centers. Am J Surg Pathol 22:643-655, 1998. Siebert JM, Stuckey JH, Kurtin P1, Bank PM: Extranodal lymphocyte predominance Hodgkin's disease. Clinical and pathologic features. Am J Clin Pathol 103:485-491, 1995. Skarin AT, Dorfman DM: Non-Hodgkin's lymphoma: Current classification and management. CA Cancer J Clin 47:351-372, 1997. Suster S, Moran C: Primary thymic epithelial neoplasms showing combined features of thymona and thymic carcinoma. Am J SurgPathol 20:1469-1480, 1996. Zarate-Osorno A, Madeiros LJ, Kingma DW et al: Hodgkin's disease following non-Hodgkin's lymphoma. A clinicopathologic and immunophenotypic study of nine cases. Am' SurgPathol 17:123-132, 1993.




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DEVELOPMENTAL ANOMALIES The upper digestive system develops from the embryonic foregut through a sequence of highly regulated events. The morphogenesis of the mouth and especially the lips, the maxilla, and the mandible is even more complex because it involves the fusion of anlagen that are symmetrically formed on each side. The teeth primordia develop through an intricate interaction of epithelial-mesenchymal precursors of the various layers of the teeth, the periodontal ligaments, and the gingiva. Cleft lip and cleft palate are dysraphic malformations of polygenic origin that result from incomplete fusion of the facial embryonic structures (Fig. 6-1). Complex facial malfor-

mations maybe associated with incomplete formation of the mouth, nose, and other parts of the face (Fig. 6-2). Micrognathia, with recessed mandible and low-set ears, is a feature of Potter syndrome, in which the kidneys are not formed or the fetal urinary tract is obstructed (Fig. 6-3). Prognathia is abnormal protrusion of the mandible beyond the maxilla (Fig. 6-4). Anomalies of tongue include macroglossia (a common feature of Down syndrome, congenital hypothyroidism, and several other conditions), fissured tongue, congenital tumors, and hamartomas such as giant hemangioma (Figs. 6-5 and 6-6).

Fig. 6-1. Cleft palate.

Fig. 6-2. Complex facial malformation in a stillborn infant.

Fig. 6-3. Potter syndrome. The receding chin is associated with a hypoplastic mandible. The pregnancy was marked by oligohydramnios related to renal agenesis.

Fig. 6-4. Prognathia.


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Fig. 6-5. Macroglossia. It could have many causes.

Anomalies of teeth may be numerical or may involve positioning, eruption, size, shape, enamel, formation, dentinogenesis, and coloration. Anomalies of the esophagus include congenital atresia, stenosis, and tracheoesophageal fistula.

I NFLAMMATORY LESIONS Stomatitis (inflammation of the mouth), sialadenitis (inflammation of the salivary glands), pharyngitis, and esophagitis may occur as isolated diseases or as a manifestation of generalized infection and/or various systemic diseases. Because the upper digestive tract is lined by squamous epithelium from the oral orifice to the lower end of the esophagus, all of these infections show a predictable, stereotypic pathol -

Fig. 6-7. Aphthous ulcer. Grayish fibrinous material covers the ulcer on the ventral surface of the tongue.

Fig. 6-6. Giant congenital cavernous hemangioma of the tongue.

ogy, and typically are prone to ulceration, vesiculation, or acanthosis. Stomatitis may be classified as acute or chronic and according to its etiology as viral, bacterial, or fungal. Acute stomatitis presents in many forms such as erythematous, vesicular, aphthous, suppurative, or pseudomembranous inflammation (Fig. 6-7). Chronic stomatitis often is seen in smokers or may be caused by chronic irritation from illfitting dentures. Ill-fitting dentures may cause fibrous hyperplasia or inflammatory papillary hyperplasia, which typically occurs on the mucosa of the hard palate (Fig. 6-8). Hyperplastic granulation tissue on the gingiva, presumably caused by infection or trauma, may present in the form of nodular masses known as pyogenicgranuloma or epulis (Fig.

Fig. 6-8. Inflammatory papillary hyperplasia. This hard palate lesion, caused by ill-fitting denture, shows papillary hyperplasia with numerous downward projections of epithelium and a chronic submucosal inflammation.


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6-9). In most instances oral infections can be treated effectively or may heal spontaneously. Severe bacterial infection occasionally may spread to the neck and cause necrotizing neck gangrene known as Ludwig angina (Fig. 6-10). Oral lesions are common features of acquired immunodeficiency syndrome (AIDS) (Table 6-1). Pharyngitis is a common manifestation of numerous viral and bacterial infections ( " strep throat " ). Presenting symptoms include erythema, swelling or suppuration, and pseudomembrane formation. Sialadenitis may be caused by bacteria or viruses, such as mumps virus. Bacterial infections typically ascend through Stensen's excretory duct from the mouth, whereas viral infections are hematogenous. Sialadenitis also may be immune mediated (Fig. 6-11).

Esophagitis usually is found in immunosuppressed persons who have AIDS, those who are receiving treatment for cancer, or those who are debilitated. In most instances esophagitis is caused by viruses, such as herpes simplex and cytomegalovirus (CMV), or fungi, such as Candida and Aspergillus (Fig 6-12). Oral Manifestation of AIDS Chronic thrush Hyperplastic stomatitis Recurrent apthae Condyloma acuminatum Necrotizing ulcerative gingivitis Kaposi sarcoma

Angular cheilitis Erythematosus stomatitis Herpangina Hairy leukoplakia Submandibular cellulitis

Fig. 6-9. Pyogenic granuloma of gingiva. The lesion presents as a sharply demarcated nodule.

Fig. 6-10. Ludwig angina. Necrosis and ulceration are accompanied by marked inflammation and edema of underlying neck tissue.

Fig. 6-11. Chronic sialaderiitis. The salivary gland is infiltrated focally by mononuclear cells. The infiltrates are most prominent around the small ducts.


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B

Fig. 6-12. Esophagitis. A, Herpes simplex—infected cells have multinucleated "ground glass" nuclei. B, Viral particles can be demonstrated by immunohistochemistry.

ORGAN-SPECIFIC LESIONS Dental Cysts

keratinizing squamous epithelium that resembles the enamel epithelium. Mucous or ciliated cells may be present and the wall of dentigerous cysts may contain foci of ameloblastoma (Fig. 6-13). Such unicysticameloblastomas occur in teenagers and are readily cured by enucleation. Odontogenic keratocyst ( OKC) accounts for 5 percent to 10 percent of all jaw cysts. It occurs in two types: the more common parakeratotic OKC and the orthokeratotic OKC. The parakeratotic OKC is lined by a layer of squamous epith-

Dental cysts are classified as developmental or inflammatory (Table 6-2, Diagram 6-1). True cysts are lined by epithelium, in contrast to pseudocysts, which are cavities in bone that are surrounded by granulation tissue or fibroosseous tissue. Dentigerous cyst is the most common developmental odontogenic cyst. It usually is associated with the crown of an impacted or unerupted tooth. It is lined by a thin non-

A

B

C

Fig. 6-13. Dentigerous cyst. A, The cyst usually is lined by nonkeratinizing, stratified squamous epithelium. B, The stratified squamous epithelium lining the cyst shows mucous metaplasia. C, The wall of this dentigerous cyst contains foci of ameloblastoma penetrating into the connective tissue wall of the cyst.


10 6

WHO Classification of Cysts of the Jaws NonodontogeniC

Developmental Odontogenic Gingival cysts of infants (Epstein pearls) Odontogenic keratocyst (primordial cyst) Dentigerous (follicular cyst) Eruption cyst lateral periodontal cyst Gingival cyst of adults Glandular odontogenic cyst; sialood

Nasopalatine duct (incisive canal) cyst Nasolabial (nasoalveolar) cyst Inflammatory Radicular cyst Apical and lateral cysts Residual cyst Paradental (inflammatory collateral, mandibular infected buccal) cyst

From Kramer IRH, Pindborg JJ, Shear M: Histological typing of odontogenic tumors, ed 2, Berlin, 1992, Springer-Verlag.

A

B

Diagram 6-I. Diagrams of the site of odontogenic, A, and fissural (nonodontogenic) cysts, B, in the mandible and maxilla respectively. A: I, gingival; 2, eruption; 3, lateral periodontal; 4, residual; 5, periapical (radicular); 6, dentigerous; 7, primordial. B: I, nasolabial cyst; 2, nasoalveolar cyst, 3, globulomaxillary cyst; 4, nasopalatine cyst; 5, cyst of palatine papilla; 6, median palatal cyst. (From Batsakis JG: Tumors of the head and neck: clinical and pathological considerations, ed 2, Baltimore, 1979, Williams & Wilkins.) A

B

C

Fig. 6-14. Parakeratotic cyst. A, The cyst is lined by partially detached, corrugated, squamous epithelium. Daughter cysts are present in the connective tissue capsule. B, The squamous epithelium shows palisaded basal cell proliferation and surface parakeratosis. C, Higher power view shows typical parakeratosis.


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A

B Fig. 6-I S. Orthokeratotic cyst. A, The cyst is lined by keratinizing epithelium covered with a keratin layer. B, The wall of the cyst is lined by keratinizing epithelium, with flattened basal layer, prominent granular layer, and surface orthokeratin.

A

B

C

Fig. 6-16. Radicular cyst. A, Radioluscent area is seen in association with the remaining roots of the right maxillary bicuspid and first molar. B, Cyst wall contains inflammatory cells, extravasated blood, hemosiderin pigment, and cholesterol clefts. C, Rushton bodies and remnants of squamous epithelium are found in the inflamed cyst wall.

elium that is five to eight cells thick and shows maturation from the palisading basal layer toward the lumen (Fig. 6-14). The luminal surface is corrugated and is at least partially lined by parakeratotic cells. The connective tissue capsule may contain daughter cysts. The orthokeratotic OKC does not have a palisading basal layer, and the epithelial lining appears flattened. The surface keratin layer lies on a prominent granular cell layer but without surface corrugation (Fig. 6-15). The lumen is filled with keratin.

Radicular cyst is the most common cyst of the jaws. It develops from a periapical abscess or granuloma. The persistent inflammation stimulates the proliferation of the epithelium derived from odontogenic residues in the periodontal ligament, the rests of Malassez, which provide partial lining of the cavity (Fig. 6-16). The epithelium lining the radicular cysts is squamous but it shows no tendency toward keratinization. The surrounding connective tissue is heavily inflamed and may be hyalinized.


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Fig. 6-19. Mucocele. Mucus is infiltrated with inflammatory cells.

Fig. 6-20. Mucous retention cyst. The cyst is lined by squamous epithelium.

Fig. 6-21. Sjogren syndrome. A, Focal chronic sialoadenitis. B, Myoepithelial sialoadenitis of Sjogren syndrome. The myoepithelial nests are surrounded by lymphoid cells in a follicular arrangement.

Fig. 6-22. Necrotizing sialometaplasia. The epithelial nests represent ducts that have undergone squamous metaplasia. The nests are surrounded by loose connective tissue.

A

B


11 0

Diagram 6-2. Diverticula and hernia. A, Outpouchings of the esophagus may occur in the upper, middle, or lower esophagus and are either of traction or pulsion type. B, Sliding hernia. C, Rolling hernia.

Esophageal Lesions Dysphagia, the most common esophageal symptom, usually is caused by dysmotility syndromes related to spasms (e.g., "nutcracker esophagus" ). These syndromes do not have a distinct anatomic substrate and show no pathologic changes except in rare instances, such as in systemic sclerosis, in muscle diseases such as myotonic dystrophy, or in Chagas disease involving autonomic ganglia. Diaphragmatic hernia and esophageal diverticula can be diagnosed best by radiograph (Diagram 6-2). The wall of these lesions may show nonspecific inflammation. Esophageal varices are a complication of portal hypertension, which typically is caused by cirrhosis. The dilated veins are located in the lower third of the esophagus (Fig. 6-23). Lacerations at the level of the gastroesophageal junction, which typically are caused by prolonged vomiting in alcoholics, is a cause of bleeding in Mallory-Weiss syndrome (Fig. 6-24). Reflux esophagitis is an inflammatory disease that is caused by the reflux of acidic gastric juice into the esophagus. The epithelium shows basal cell hyperplasia, elongation of the papillae beyond the normal 50 percent extension into the epithelium, capillary proliferation in the papillae, and congestion (Fig. 6-25). Eosinophils have been described as characteristic but they rarely are actually seen. Prolonged reflux leads to ulceration and glandular metaplasia (Barrett esophagus) (Fig. 6-26). Mucosal ulceration maybe extensive in terminally ill patients, even in those who have not previously had reflux esophagitis (Fig. 6-27).

Erosive or corrosive esophagitis may be caused by accidental or suicidal ingestion of lye, strong acids, and corrosive chemicals. The mucosa typically is eroded, hemorrhagic, or blackened (Fig. 6-28). Rupture of the esophagus, fistulas, and stenosis are common complications.

A

B

Fig. 6-23. Esophageal varices. A, Dilated tortuous veins are seen bulging underneath the intact epithelium of the lower esophagus. B, Dilated veins filled with blood are seen in the wall of the esophagus.


Fig. 6-25. Reflux esophagitis. The papillae are elongated and congested. There also is basal cell hyperplasia.

Fig. 6-24. Mallory-Weiss syndrome. Hematemesis in this chronic alcoholic was caused by deep mucosal tears at the gastroesophageal junction.

Fig. 6-27. Ulcerative esophagitis. The normal squamous epithelium (white) is missing over broad areas.

Fig. 6-26. Barrett esophagus. The mucosa replacing the normal squamous epithelium is composed of glands rich in goblet cells.

Fig. 6-28. Corrosive esophagitis and gastritis caused by ingestion of hydrochloric acid. Mucosa appears black.


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TUMORS Oral Tumors Most tumors of the mouth originate from the squamous epithelium lining the oral cavity. Tumors also can originate from the tooth-related structures and primordia and from minor salivary glands. Histologically tumors that originate from minor salivary glands are identical to those seen in major salivary glands. Tumors of the squamous epithelium present clinically as white or red plaques (leukoplakia and erythroplakia), indurations, or ulcerations (Fig. 6-29). Histologically the tumors have the usual features of squamous cell carcinoma (SCC), beginning as carcinoma in situ and progressing to invasive carcinoma that shows varying degrees of keratinization. Important variants are (1) poorly differentiated nonkeratinizing SCC, (2) basaloid SCC, (3) papillary SCC, and (4) verrucous SCC (Fig. 6-30). Dental tumors occur in several forms (Table 6-3). Benign tumors are more common than malignant tumors.

Fig. 6-29. Erythroplakia of the hard palate.

Fig. 6-3 I. Ameloblastoma. The interdigitating cords of palisading epithelial cells surround areas composed of stellate reticulum cells.

Ameloblastoma is the most common odontogenic tumor. Ameloblastomas originate mostly in the mandible from the rests of enamel organ epithelium, epithelial lining of dentigerous cysts, or occasionally from the basal layer of the oral mucosa. Most patients are in the third to fifth decade of life. Most ameloblastomas present in a follicular or plexiform histologic pattern; other patterns are less common (Fig. 6-31). Other odontogenic tumors such as odontogenic adenomatoid tumor (Fig. 6-32), calcifying epithelial odontogenic tumor (Fig. 6-33), and ameloblastic fibroma (Fig. 6-34) are less common. Salivary Gland Tumors Salivary gland tumors occur in several histologic forms (Table 6-4). They can occur in the major or minor salivary glands. The parotid gland is the most commonly involved site, mostly because of its size . Benign tumors are more common than malignant tumors. Pleomorphic adenoma is the most

Fig. 6-30. Verrucous carcinoma. The neoplastic epithelium forms rounded nests extending into the underlying stroma.

Fig. 6-32. Odontogenic adenomatoid tumor. Cuboidal or columnar tumor cells form ductlike structures.


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Fig. 6-33. Calcifying epithelial odontogenic tumor. The islands of polyhedral epithelial cells are surrounded by extracellular eosinophilic material with foci of calcification.

Fig. 6-34. Ameloblastic fibroma. Odontogenic epithelium forms islands surrounded by highly cellular stroma.

Odontogenic Tumors Benign ;" ' Epithelial Ameloblastoma Odontogenic adenomatoid tumor Calcifying epithelial odontogenic tumor Mesenchymal Myxoma Odontogenic fibroma Cemental tumors Mixed epithelial and mesenchymal origin Ameloblastic fibroma Ameloblastic fibroodontoma Complex and compound odontomas

Malignant Epithelial Malignant ameloblastoma Ameloblastic carcinoma Mesenchymal Ameloblastic fibrosarcoma

Classification of Epithelial Salivary Gland Tumors Benign Pleomorphic adenoma (mixed tumor) Papillary cystadenoma lymphomatosum (Warthin tumor) Monomorphic adenoma • Basal cell • Ductal • Oncocytic Myoepithelioma Ductal papilloma • Intraductal • Sialadenoma papilliferum • Inverted Cystadenoma Sebaceous adenoma Sebaceous lymphadenoma Malignant Arising from Preexisting Benign Tumor Carcinoma • Ex pleomorphic adenoma • Ex monomorphic adenon cell a oma.

NNW

Ex Warthin tumor Ex myoepithelioma Malignant Mucoepidermoid carcinoma Adenoid cystic carcinoma Acinic cell carcinoma Epimyoepithelial (clear cell) carcinoma Salivary duct carcinoma Papillary and nonpapillary adenocarcinoma Mucinous adenocarcinoma Cystadenocarcinoma Adenocarcinoma, NOS Epidermoid (squamous cell) carcinoma Sebaceous carcinoma Basal cell adenocarcinoma Undifferentiated carcinoma • Large cell lymphoepithelial • Small cell lymphoepithelial Carcinosarcoma

NOS, Not otherwise specified.


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common tumor, accounting for 60 percent to 70 percent of all parotid tumors and for 40 percent to 70 percent of tumors in other glands. Pleomorphic adenoma is a benign tumor that presents as a sharply demarcated mass. Histologically it consists of an epithelial component forming ducts, nests, sheets, or interlocking cords (Fig. 6-35). Epithelial cells are intermixed or surrounded by mesenchymal stroma that may be myxoid, chondroid, or fibrous, and may even show ossification. In approximately 5 percent of patients mixed tumors give rise to adenocarcinomas (Fig. 6-36). Myoepithelioma is a benign tumor composed of myoepithelial cells (Fig. 6-37). Papillary cystadenoma lympho-

matosum is a benign slow-growing tumor of older adults. It is composed of columnar and cuboidal cells covering papillae embedded in a lymphocyte-rich stroma. Basal cell adenoma is a benign tumor composed of bluish basaloid cells that form solid sheets or nests that have a palisaded outer layer (Fig. 6-38). Oncocytoma is an uncommon benign tumor composed of mitochondria-rich cells with eosinophilic or clear cytoplasm, (Fig. 6-39). Sialadenoma papilliferum is a benign tumor composed of an exophytic and an endophytic component. Neoplastic papillae, which are typical of the tumor, can be lined by oncocytic cuboidal or squamous cells (Fig. 6-40).

Fig. 6-35. Pleomorphic adenoma of the parotid gland. The interlacing epithelial nests form occasional lumina and are surrounded by fibrous stroma.

A

B

Fig. 6-36. Adenocarcinoma arising in pleomorphic adenoma. A, The tumor has an invasive growth pattern. B, Histologically it is an adenocarcinoma.


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Fig. 6-37. Myoepithelioma: Tumor is composed of spindleshaped myoepithelial cells.

Fig. 6-38. Basal cell adenoma. The tumor nests are composed of small basaloid cells. The cells at the periphery of these nests are cuboidal and palisaded.

A

B

Fig. 6-39. Oncocytoma. A, Eosinophilic cells form solid nests. B, Clear cells are arranged in an alveolar pattern.

Fig. 6-40. Sialadenoma papilliferum. The papillae are lined by a double layer of oncocytic cells.


11 6

A

B

Fig. 6-41. Acinic cell adenocarcinoma. A, Well-differentiated serous acinar cells form solid sheets (solid pattern). B, Cells form follicles that vary in size and shape (follicular pattern).

A

B

C

Fig. 6-42. Adenoid cystic carcinoma. A, Cribriform pattern. B, Solid pattern. C, Tubular pattern.


Malignant tumors of salivary glands are less common. The ratio of benign to malignant tumors is 4:1. Mucoepidermoid carcinoma is the most common malignancy, accounting for 10 percent of major salivary gland tumors and 90 percent of minor salivary gland tumors. This tumor has the general features of squamous cell carcinoma but it also contains mucous cells, usually in the center of epithelial nests. Acinic cell carcinoma accounts for 2 percent to 3 percent of salivary gland tumors. The tumor may be composed of several cell types including serous, vacuolated, clear or-granular, acinar, and intercalated ductlike cells arranged in a solid, cystic, papillary, or follicular pattern (Fig. 6-41).

Adenoid cystic carcinoma accounts for 3 percent to 10 percent of all salivary gland tumors, more often arising in minor than major glands. Microscopically these tumors are composed of rather uniform populations of basaloid tumor cells with little cytoplasm. The cells grow in three patterns: cribriform, solid, and tubular (Fig. 6-42). Other malignant tumors, such as epithelial-myoepithelial carcinoma (Fig. 6-43), polymorphous low-grade adenocarcinoma (Fig. 6-44), sebaceous carcinoma (Fig. 6-45), and salivary duct carcinoma (Fig. 6-46), are less common.

Fig. 6-43. Epithelial-myoepithelial carcinoma. Numerous ductlike structures are lined by eosinophilic and clear cells.

Fig. 6-44. Polymorphous low-grade carcinoma. Cytologically bland and uniform basaloid cells grow in an infiltrating manner.

Fig. 6-45. Sebaceous carcinoma. Atypical basaloid cells show central sebaceous differentiation . Such cells have clear cytoplasm.

Fig. 6-46. Salivary duct carcinoma. Tumor nests are composed of cells arranged in a cribriform pattern that resembles breast carcinoma.


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Esophageal Tumors Carcinoma of the esophagus is the most important tumor in this anatomic site (see Diagram 6-2). Squamous cell carcinoma is the predominant form of esophageal tumor. It usually presents as ulcerated or indurated lesions (Figs. 6-47 and 6-48).

Fig. 6-47. Carcinoma of the esophagus. The tumor appears ulcerated.

Fig. 6-49. Barrett esophagus with early carcinoma.

Adenocarcinomas arise from the glandular epithelium of Barrett esophagus and often are located at the gastroesophageal junction (Figs. 6-49 and 6-50) and are preceded by dysplasia (Fig. 6-50). Such adenocarcinomas do not differ from those in the stomach (Figs. 6-51 and 6-52). Other malignant tumors of the esophagus, such as small cell carcinoma, sarcoma, or melanoma, are extremely rare (Fig. 6-53). Benign tumors of the esophagus are less common than malignant tumors. The most common are leiomyomas, which typically present as intramural subepithelial masses, sharply demarcated from the surrounding tissues.

Fig. 6-48. Carcinoma of the esophagus. Squamous tumor cells form solid nests.

Fig. 6-50. Barrett's esophagus with dysplasia. Nuclei in dysplastic glands appear crowded and are not restricted to the basal parts of the cells.


I19

Fig. 6-5I. Adenocarcinoma of the esophagus. The tumor at the gastroesophageal junction appears bulky and ulcerated.

Fig. 6-52. Adenocarcinoma. Some squamous epithelium remains between the neoplastic gland-like structures.

A

B

Fig. 6-53. Melanoma of esophagus. A, A black mass is seen protruding into the lumen. B, Tumor is composed of polygonal cell with a large nuclei. Brown pigment is seen focally. Further Reading Brandwein MS, Huvos AG: Oncocytic tumors of the major salivary glands. Amer J Surg Pathol 15:514-528, 1991. Cameron AJ, Carpenter HA: Barrett's esophagus, high-grade dysplasia, and early adenocarcinoma: A pathologic study. Am J Gastroenterol 92:586-591, 1997. Dawsey SM, Lewin KJ: Histologic precursors of squamous esophageal cancer. Pathol Annu 30:209-226, 1995. Delgado R, Vuitch F, Albores-Saavedra J: Salivary duct carcinoma. Cancer 72:1503-1512, 1993. Ellis GL: Clear cell neoplasms in salivary glands: clearly a diagnostic challenge. Ann Diag Pathol 2:61-78, 1998. Eveson JW: Granulomatous disorders of the oral mucosa. Semin Diagn Pathol 13:118-127, 1996. Haggitt RC: Barrett's esophagus, dysplasia and adenocarcinoma. Hum Pathol 25:982-993, 1994.

Klimstra D: Pathologic prognostic factors in esophageal carcinoma. Semin Oncol21:425-430, 1994. Lieberman MD, Shriver CD, Bleckner Set al: Carcinoma of the esophagus; prognostic significance of histologic type. J Thor Cardiovasc Surg 109:130-138, 1995. Paraf F, Fl@jou J-F, Pignon J-P et al: Surgical pathology of adenocarcinoma arising in Barrett's esophagus: Analysis of 67 cases. Am J Surg Pathol 19:183-191, 1995. Sarbia M, Bittinger F, Porschen R et al: Prognostic factors in esophageal squamous carcinoma: A study of histologic parameters of esophageal squamous cell carcinoma. Cancer 76:922-927, 1995. Simpson RH: Classification of salivary gland tumors—a brief histopathological review. Histol Histopathol 10:737-746, 1995. Wenig BM, Hitchcock CL, Ellis GL, Gnepp DR: Metastasizing mixed tumor of salivary glands. A clinicopathologic and flow cytometric analysis. Am J Surg Pathol 16:845-858, 1992.




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DEVELOPMENTAL DISORDERS Developmental disorders of the gastrointestinal tract include positional anomalies, persistent embryonic rests, duplications, congenital atresias, stenoses, dilatations, diverticula, and malrotations. Positional anomalies include conditions, such as diaphragmatic hernia or omphalocele, in which the normal body compartments have not been formed and parts of the gastrointestinal system are located outside their normal abdominal location (Fig. 7-1). Meckel diverticulum is an example of a persistent embryonic structure. It represents a remnant of the fetal vitelline duct (Fig. 7-2). Intestinal duplications are cystic structures included in the intestinal wall or attached to it (Fig. 7-3). The cysts are lined by intestinal epithelium.

Pyloric stenosis is the most common form of congenital gastrointestinal stenosis (Fig. 7-4). Projectile vomiting in the first weeks of life is the presenting symptom. Males are affected four times more often than females. Inappropriate development of innervation in the distal colon is the main cause of proximal dilatation of the large intestine in Hirschsprung disease. Microscopically the intestinal wall is devoid of ganglion cells (aganglionosis) but it contains numerous hypertrophic nerves. Proliferation of small nerves may be demonstrated immunohistochemically using antibodies to acetylcholinesterase (Fig. 7-5). Intestinal lymphangiectasia is a rare developmental disorder that is associated with protein-losing enteropathy. It may be limited to the bowel or it may be part of generalized familial lymphedema (Milroy disease). The dilated lymphatics may be seen by the naked eye as cystic spaces that distort segments of the intestine (Fig. 7-6).

Fig. 7-I. Omphalocele. As a result of incomplete formation of the anterior abdominal wall, a sac forms at the site of the insertion of the umbilical cord. It contains intestinal loops, which protrude through the defect of the abdominal wall.

Fig. 7-2. Meckel diverticulum. This blind intestinal loop of the il eus is found in 2 percent of the population, two feet proximal to the cecum. It usually is two inches long and causes clinical symptoms in 2 percent of those who have it.

Fig. 7-3. Intestinal duplication. It forms a cystic mass protruding into the intestinal lumen.


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Fig. 7-4. Pyloric stenosis. The pylorus of this adult who was operated on for congenital pyloric stenosis still shows muscular hypertrophy. (Courtesy of Dr. Fred Bosman, Lausanne, Switzerland.)

A

B

Fig. 7-5. Hirschsprung disease. A, Dilated sigmoid colon tapers off toward the lower stenotic part. B, The lamina propria of the colon contains numerous proliferated fine nerve fibers visualized immunohistochemically with the antibody to acetylcholinesterase. (Courtesy of Dr. James Dimmick, Vancouver, Canada.)

Fig. 7-6. Congenital lymphangiectasia. Cystic spaces distorting the wall of the resected intestinal loop represent dilated lymphatics. (Courtesy of Dr. W.V. Harrer, Camden, NJ.)


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CIRCULATORY DISTURBANCES Circulatory disturbances are common in the gastrointestinal tract. Acute systemic circulatory collapse as typically seen in shock is commonly associated with gastrointestinal mucosal bleeding ulcerations. Acute stress erosions and ulcers found in the proximal duodenum or stomach following burns or trauma traditionally are called Curling ulcers, and those found in the stomach and associated with brain lesions are called Cushing ulcers (Fig. 7-7). Occlusion of the mesenteric arteries or veins by thrombi or thromboemboli causes intestinal infarcts, which typically are hemorrhagic (Figs. 7-8 and 7-9). Chronic intestinal ischemia,which typically is related to the progressive stenosis

Fig. 7-7. Curling ulcers. Surface ulcerations of gastric mucosa appear as dark red defects.

Fig. 7-9. Acute ischemia of large bowel. The mucosa shows hemorrhagic discoloration.

and gradual occlusion of smaller branches of the arterial system, causes focal ischemic necrosis and ulceration of intestinal mucosa. Hypoperfusion of intestinal mucosa in shock causes similar ischemic mucosal ulcers (Fig. 7-10). Vascular anomalies, both congenital and acquired, are important causes of gastrointestinal hemorrhage. Typically seen in Osler-Weber-Rendu disease, they include mucosal aneurysmal dilatations of small vessels (congenital hemorrhagic telangiectasia) and multiple congenital hemangiomas (Fig. 7-11). Dieulafoy ulcer, a bleeding ulcer of the stomach, forms over an arteriovenous malformation (Fig. 7-12). Intestinal angiodysplasia is another important cause of gastrointestinal blood loss.

Fig. 7-8. Mesenteric artery thrombosis. The intestinal loops have undergone hemorrhagic infarction. Thrombosed artery attached to the aorta (arrow).

Fig. 7-10. Ischemic colitis. Necrotic epithelium has been sloughed off and only a few crypts remain.


125

Fig.7 - 1I . Intestinal hemangiomas.

Fig. 7-12. Dieulafoy ulcer. The ulcer contains ruptured superficial tortuous arteries.

OBSTRUCTIONS AND DILATATIONS OF INTESTINAL LUMEN The gastrointestinal tract may be obstructed by a number of intraluminal foreign bodies, such as trichobezoars, gallstones, or fecaliths (Fig. 7-13). Inspissated meconium, which is found in children who have cystic fibrosis, also may cause intestinal obstruction (Fig. 7-14). Histologically viscous mucus may be seen filling the crypts. Rupture of the obstructed intestine leads to meconium peritonitis. Protrusions of the intestines or any other abdominal organ into another body cavity, or new cavities formed by defects or weakening of the abdominal wall, are called hernias. Herniated intestinal loops may become obstructed and may require surgery. Other causes of intestinal obstruction are volvulus, intussusception, peritoneal adhesions, tumors, and tumor-like lesions such as endometriosis (Figs. 7-15 to

Fig. 7-13. Trichobezoar. This large mass removed from the stomach was composed of hair.

7-17).

A

B

Fig. 7-14. Meconium ileus. A, The dilated intestine of this neonate is obstructed by thick meconium, which appears as a black intestinal plug. B, Intestinal crypts contain viscid mucus.


1 26

Fig. 7-15. Volvulus. Intestinal loops twisted around mesocolon have undergone hemorrhagic necrosis.

Fig. 7-16. Intussusception. Loops of bowel invaginating one into another.

A

B

Fig. 7-17. Endometriosis. The serosa of this intestinal loop is covered with hemorrhagic tissue specks.

Diverticula are outpouchings of the mucosa through weakened muscularis propria. Diverticula may occur in any part of the intestine but are most common in the sigmoid colon. The outpouchings typically occur between the anti mesenteric taeniae (Fig. 7-18).

ORGAN-SPECIFIC DISEASES Each of the anatomic parts of the gastrointestinal tract may be affected by a site-specific type of inflammation or other organ-specific diseases.

Gastritis and Peptic Ulcer Inflammation of the gastric mucosa is classified as acute or chronic. Acute gastritis is subclassified as infectious (e.g., bacterial, viral, or fungal) or chemical, which most often is caused by nonsteroidal antiinflammatory drugs, irritants in food, or alcohol (Figs. 7-19 and 7-20).

Fig. 7-18. Diverticulosis. A, Subserosal protrusions. B, The mucosa protrudes through a defect of the muscle layer, as seen on cross section blackened.

Chronic gastritis is classified as autoimmune atrophic (type A) gastritis or chronic nonatrophic (type B) gastritis (Table-7-1). Type A gastritis preferentially involves the fundus and oxyntic corpus and is characterized by inflammatory cell infiltrates and progressive replacement of the normal mucosa by patches of antral, pseudoantral, or intestinal epithelium (Fig. 7-21). Type B gastritis is associated with Helicobacter pylori infection and is characterized by pronounced inflammatory infiltrates. The normal mucosal architecture is preserved and there is no atrophy (Fig. 7-22). Neutrophils and H. pylori may


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Fig. 7-19. Chemical gastritis caused by aspirin. The mucosa shows multiple hemorrhagFc erosions.

Fig. 7-20. Fungal gastritis. The fungi form slightly raised mucosal plaques.

Fig. 7-21. Gastritis type A (autoimmune), associated with pernicious anemia. The oxyntic mucosa shows atrophy and is replaced to a large extent by pseudoantral metaplasia. There also is mild edema and chronic inflammation.

A

B

Fig. 7-22. Gastritis type B (nonatrophic). A, The lamina propria is expanded by inflammatory cells. The foveolae show mild reactive changes. B, The inflammatory cells are prominent in the lamina propria and the lumen contains H. pylori organisms, which are stained black. Neutrophils are invading the epithelium of gastric pits.


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Fig. 7-23. Peptic ulcer. Two ulcers appear as sharp, deep hemorrhagic defects of gastric mucosa.

Comparison of Type A and Type B Gastritis ?~'? Location Distribution Cause Autoantibodies Gastric acidity Cancer risk Prevalence

ype A (atrophic) Fundus Diffuses Autoimmune + —

Type B (nonatrophic) Antrum Focal Helicobacter pylori

— +

+/—

+

Uncommon

Common

Fig. 7-24. Menetrier disease. The gastric mucosal folds are markedly thickened.

be seen in the mucosal pits. Infection with H. pylori also is associated with gastric and duodenal peptic ulcers (Fig. 7-23). Other less common forms of gastritis include eosinophilic, granulomatous, lymphocytic, and xanthomatous gastritis. Hypertrophic gastritis (gastropathy) includes so-called Menetrier disease and gastric mucosal hyperplasia/hypertrophy resulting from an excess of gastrin in Zollinger-Ellison syndrome. It is associated with marked rugal thickening and histologically characterized by variable degrees of hyperplasia of foveolar or glandular compartments (Fig. 7-24).

B

A

Fig. 7-25. Celiac disease A, Intestinal biopsy specimen shows atrophy of the villi and lengthening of the crypts. B, Biopsy specimen of the same patient shows that the mucosa has recovered almost completely after 6 months of gluten-free diet.


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Small Intestinal Diseases That Cause Malabsorption According to small intestinal mucosal biopsy findings the diseases that cause malabsorption syndrome are classified into four major groups (Table 7-2). Celiac disease is a multifactorial disease of uncertain pathogenesis; it is related to hypersensitivity to gluten. Small intestinal mucosa shows atrophy of the villi and lengthening of the crypts (Fig. 7-25). These changes are reversible. Complete recovery is possible if a patient follows a gluten-free diet, and the intestinal mucosa resumes its normal morphology. Infectious enteritis caused by bacteria, viruses, or fungi may cause diarrhea and malabsorption (Fig. 7-26). In many instances the causative pathogens are recognized by biopsy of the small intestine. The best examples are infections caused by Mycobacterium avium-intracellulare and Tropheryma whippelii (Figs. 7-27 and 7-28). Several diseases of neoplastic or unknown etiology such as Waldenstrom macroglobulinemia, amyloidosis, or lipoid

Classification of Malabsorption Syndromes According to the Small Intestinal Biopsy Findings Normal histologic features Gastric, pancreatic biliary disease Inborn errors of metabolism (disaccharidase deficiency) Short bowel syndrome Alcohol abuse Drug induced enteropathy

Nonspecific inflammatory mucosal changes Celiac disease (sprue) Tropical sprue Graft versus host disease Intraluminal bacterial overgrowth

Identifiable pathogens Viruses (e.g., rota virus) Bacteria (e.g., MAI, Whipple disease) Fungi (e.g., Cryptococcus neoformans) Protozoa (e.g., Giardia lamblia) Metazoa (e.g., Strongyloides stercoralis) Diagnostic tissue changes Abetalipoproteinemia Amyloidosis Lymphangiectasia Waldenstr6m macroglobulinemia Lipoid proteinosis

MAI, Mycobacterium avium-intracellulare.

Fig. 7-26. Fungal enteritis in an immunosuppressed person. Patches of mucosa infiltrated with fungi appear raised and necrotic.

A

B

Fig. 7-27. Intestinal infection with Mycobacterium avium-intracellulare ( MAI). A, The lamina propria contains numerous foamy macrophages. B, Macrophages are filled with MAI, which are acid fast in this Ziehl-Neelsen–stained slide.


13 0

B

A

C

Fig. 7-28. Whipple disease. A, Light microscopy shows prominent macrophages and dilatation of lacteals in the lamina propria. B, Detail of lamina propria with macrophages. C, Electron microscopy shows the pathogenic bacteria in the cytoplasm of these macrophages. (Courtesy of Dr. N. Ectors, Leuven, Belgium.)

proteinosis are characterized by deposition of proteinaceous extracellular material, which maybe recognized on histologic examination of the intestines (Fig. 7-29).

Inflammation of the Appendix and the Large Intestine

Fig. 7-29. Lipoid proteinosis. The lamina propria contains deposits of fibrillar proteinaceous material. (Courtesy of Dr. D. Caccamo, Detroit, MI.)

Acute appendicitis is one of the most common infections of the gastrointestinal tract that requires surgical intervention. The appendix appears swollen and congested and histologically shows signs of transmural inflammation (Fig. 7-30). The lumen of the appendix may be obstructed with inspissated feces or worms such as Enterobius vermicularis (Fig. 7-31). Infectious colitis presents as localized or diffuse inflammation and often is associated with ulceration or pseudomembrane formation. Pseudomembranous colitis typically is a complication of Clostridium difficile infection. Segments of the intestine are covered with yellow or brown flat-topped plaques (Fig. 7-32). Histologically the pseudomembranes consist of fibrin, mucin, neutrophils, and cellular debris covering the surface of the damaged mucosa (Fig. 7-33). Amebic colitis typically produces ulcers in the cecum. The necrotic cell debris in the bottom of ulcers contains pathogenic Entamoeba histolytica (Fig. 7-34).


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A

B

Fig. 7-30. Acute appendicitis. A, Inflammation extends to the serosa, which appears hyperemic. B, Cross section shows transmural inflammation (blue) and foci of hemorrhange (red).

Fig. 7-3I. Acute appendicitis. The lumen of the appendix contains Enterobius vermicularis in cross section.

Fig. 7-32. Pseudomembranous colitis. The surface of the large intestine is covered with yellow, flat-topped plaques.


13 2

A

B

Fig. 7-33. Pseudomembranous colitis. A, Volcano-like appearance of early lesions. B, The exudate covering the damaged mucosa consists of mucus, fibrin, inflammatory cells, and cell debris. The pseudomembrane has a layered appearance.

Fig. 7-34. Amebiasis. The trophozoites of Entamoeba histolytica are found in the area of "dirty necrosis" scraped from the bottom of a colonic ulcer.

Fig. 7-35. Collagenous colitis. Broad bands of collagen are seen underlying the surface epithelium in this trichrome-stained slide.

There are several histologic forms of noninfectious colitis of uncertain etiology. Eosinophilic colitis is an occasional manifestation of food allergy that presents with mucosal eosinophilia. Collagenous colitis, which is characterized by intermittent diarrhea unrelated to a known pathogen, appears on colonic biopsy specimen as typical subepithelial collagen bands (Fig. 7-35). Lymphocytic colitis is characterized by lymphocytic infiltration of colonic mucosa.

itis and Crohn disease. The morphologic features that distinguish ulcerative colitis from Crohn disease are listed in Table 7-3. Ulcerative colitis begins as acute inflammation of the mucosa, producing crypt abscesses (Fig. 7-36). As the disease progresses the inflammation spreads over the surface of the entire large intestine (Fig. 7-37). In chronic colitis the luminal surface may be flat and featureless, or it may be ulcerated, alternating with pseudopolypous transformation of the intervening mucosa that has not been destroyed (Fig. 7-38). Ulcerative colitis is characterized by superficial inflammation that is limited to colonic mucosa and does not extend

Inflammatory Bowel Disease (IBD) The term inflammatory bowel disease (IBD) includes two closely related entities of unknown etiology: ulcerative col -


133

Fig. 7-36. Ulcerative colitis. Crypt abscesses (aggregates of neutrophils in the intestinal crypts) are early signs of the disease.

Fig. 7-37. Ulcerative colitis. The entire colon is involved; there are no skip areas.

Comparison of Ulcerative Colitis and Crohn Disease Feature Macroscopic Location Pattern Wall Mucosa in chronic stages Complications

Ulcerative colitis

Crohn disease

Colon Diffuse Thin Flat or pseudopolyposis

Ileum and colon Patchy with skip areas Thick Cobblestone-like

Megacolon

Adhesions Fistulas

Mucosal Deep

Transmural Superficial

Microscopic Inflammation Ulcerations Pseudopolyps Granulomas Fibrosis Peritonitis

+(50%) + +

into the deeper layers of the intestinal wall. The weakened intestine may undergo massive dilatation ( "toxic megacolon " ). The small intestine is not involved, although the terminal ileum may show signs of " backwash ileitis." Crohn disease is a transmural inflammation of the terminal ileus and segments of the colon. Because of the segmental nature of the disease the inflamed areas alternate with uninvolved " skip areas." The intestinal wall is thickened (Fig. 7-39). The thickened ulcerated mucosa has a "cobblestone " appearance (Fig. 7-40). The inflammation extends into the deeper layers of the intestine up to the serosa and in approximately 50 percent of cases there are granulomas (Fig. 7-41).

Fig. 7-38. Ulcerative colitis. In the chronic stages of the disease there is inflammatory polyposis. Pseudopolyps represent hyperplastic mucosa surrounded by ulcers.

Fig. 7-39. Crohn disease. The intestine has a thick wall and narrowed lumen. Fat tissue covers the antimesometrial serosal surface.


134

Fig. 7-40. Crohn disease. The ulcerated thickened inflamed mucosa has a "cobblestone" appearance.

TUMORS Tumors of the gastrointestinal tract are clinically classified as benign or malignant. These tumors most often arise from the epithelium but also may be derived from the smooth muscle and other stromal cells, and from the mucosa-associated lymphoid tissue (MALT).

Gastric Tumors Carcinoma of the stomach is the most important gastric neoplasm. Several types are recognized on gross examination

Fig. 7-41. Crohn disease. Foci of chronic inflammation are seen in the muscle layers of the large intestine.

( Diagram 7-1, Fig. 7-42). Histologically these tumors are adenocarcinomas of two types: intestinal or diffuse (Fig. 7-43). The stomach is the site of origin of approximately 50 percent of all gastrointestinal stromal tumors. These submucosal tumors may be benign, of borderline malignancy, or malignant, and are composed of either smooth muscle cells, Schwann cells, or nondescript stromal cells (Figs. 7-44 and 7-45). Carcinoids and lymphomas are less common but nevertheless important tumors of the stomach.

B A

Fig. 7-42. Carcinoma of the stomach. A, Fungating tumor has a cauliflower-like appearance. B, Ulcerated tumor. The irregularly shaped ulcerated area appears indurated and shows areas of necrosis.


135

TYPE I A

TYPE Ila TYPE Ilb TYPE Ilc B

TYPE III Diagram 7-I. Gastric carcinoma. Type I, protruding; Type Ila, superficial elevated; Type Ilb, superficial flat; Type IIc, superficial depressed; Type III, excavated.

Fig. 7-44. Leiomyoma of the stomach. The tumor forms a submucosal mass.

Fig. 7-43. Adenocarcinoma of the stomach. A, Intestinal type. The neoplastic glands are composed of stratified pleomorphic cells. B, Diffuse type. The tumor is composed of scattered individual cells that have a clear and sometimes vacuolated cytoplasm and appear signet ring—like.

Fig. 7-45. Spindle cell leiomyoma. The tumor cells have elongated nuclei with round tips and eosinophilic cytoplasm.


136

Tumors of the Small Intestine Overall, tumors of the small intestine are rare. Approximately 60 percent to 75 percent of all tumors are thought to be benign and are classified as epithelial (adenomas) or mesenchymal neoplasms such as leiomyoma, lipoma, hemangioma, and so forth. (Fig. 7-46). Malignant tumors include adenocarcinomas, carcinoids, malignant stromal tumors (sarcomas), and lymphomas (Figs. 7-47 to 7-49). Histologically these tumors have the same features as the more common colonic neoplasms of the same type.

Tumors of the Appendix The most important tumors of the appendix are (1) adenoma, colonic-type, noncystic; (2) cystadenoma or circumferential adenoma; (3) adenocarcinoma, which may be colonic, mucinous, or signet ring-type; and (4) carcinoid and its most important variant, the goblet cell carcinoid (Figs. 7-50 and 7-51).

Fig. 7-47. Carcinoid tumors. Most tumors are small and appear as I to 2 cm submucosal nodules.

Intestinal Polyps Polyp is a term used to describe any mass that projects into

the lumen of the intestine. Polyps are classified as nonneoplastic or neoplastic (Table 7-4).

Fig. 7-48. Carcinoid. The tumor is composed of uniform cells with round nuclei forming nests and strands.

Fig. 7-46. Lipoma of the small intestine. The submucosal tumor appears yellow, resembling normal fat tissue. (Courtesy of Dr. W.V. Harrer, Camden, NJ.)

Fig. 7-49. Mantle cell lymphoma of the intestine. The tumor presented in the form of multiple small mucosal nodules (lymphomatous polyposis). (Courtesy of Dr. Rachel Cherian, Kansas City, MO.)


137

B

Fig. 7-50. Mutinous cystadenoma of the appendix. A, The cystic tumor is filled with mucus. B, Villi lined by mucous cells protrude into the lumen.

Fig. 7-51. Goblet cell carcinoid. The tumor is composed of uniform mucin-rich cells that form small nests.

Intestinal Polyps Neoplastic polyps

Nonneoplastic polyps Hyperplastic polyp Hamartomatous polyp Juvenile polyp Peutz-Jeghers polyp Inflammatory polyps IBD-related pseudopolyps Inflammatory fibroid polyp IBD,

.>

.

Lymphoid hyperplasia Mucosal prolapse Solitary rectal ulcer syndrome Diverticular disease Pneumatosis intestinalis

Adenoma Tubular Villous Tubulovillous Carcinoma _ cinoid

Stromal tumor Leiomyoma Lipoma GIST Lymphoma

Inflammatory bowel disease; GIST, gastrointestinal stromal tumor.


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Fig. 7-52. Hyperplastic polyp. The polyp is lined by glands that have a serrated lumen.

Fig. 7-53. Juvenile polyp. The surface is ulcerated and the stroma is congested and inflamed. The glands, which are lined by normal epithelium, are focally dilated.

Fig. 7-54. Peutz-Jeghers polyp. The polyp is composed of normal glands and strands of smooth muscle.

Fig. 7-55. Tubular adenoma. The tumor protrudes into the lumen of the large intestine.

Fig. 7-56. Tubular adenoma. Histologically the tumor is composed of dysplastic but nevertheless uniform glands.

Fig. 7-57. Villous adenoma. The finger-like villi are lined by mucin-secreting columnar cells.


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Hyperplastic polyps are minute dewdrop-like lesions, approximately 5 mm in diameter and composed of glands that have a serrated luminal surface (Fig. 7-52). Juvenile polyps are hamartomas, which usually are diagnosed during the first five years of life. Histologically they consist of stroma that contains dilated crypts lined by normal intestinal epithelium (Fig. 7-53). Peutz-Jeghers polyps are sessile arborizing lesions that most commonly are found in the small intestine. The polyps have a smooth muscle core covered with normal mucosal epithelium (Fig. 7-54). Tubular adenomas are the most common neoplastic polyps. They typically are pedunculated and often are multiple (Fig. 7-55). Polyps are composed of dysplastic columnar epithelium forming tubular glands (Fig. 7-56). Villous adenomas are sessile lesions composed of finger-like villous projections lined by columnar mucin-secreting cells (Fig. 7-57). Mixed tubulovillous polyps show both growth patterns.

Carcinoma of the Large Intestine Carcinoma of the large intestine may arise in preexisting tubular or villous adenomas or may appear de novo. Familial adenomatous polyposis coli, an autosomal dominant disorder, is the best defined premalignant condition; it invariably leads to colon cancer. Patients with this condition have multiple neoplastic colonic polyps (Figs. 7-58). Adenocarcinomas of the colon that arise in tubular adenomas invade the stalk and thereafter the submucosa of the underlying bowel (Fig. 7-59). On gross examination adenocarcinomas of the cecum and the right colon have the appearance of endophytic fungating or ulcerated masses, whereas the carcinomas of the sigmoid colon and rectum tend to produce circumferential narrowing ( "napkin ringlike lesions " ) (Figs. 7-60 and 61). Histologically the tumors are adenocarcinomas; they may be well differentiated or poorly differentiated. Many colorectal carcinomas have a mucinous component but the designation mucinous carci-

Fig. 7-58. Familial adenomatous polyposis coli. Numerous polyps cover the luminal surface of the colon.

Fig. 7-59. Adenocarcinoma arising in a tubular adenoma. The malignant glands have more irregular contours and are lined by cells that show marked nuclear irregularities and pleomorphism.

Fig. 7-60. Adenocarcinoma of the right colon. The fungating endophytic mass shows central ulceration.

Fig. 7-61. Adenocarcinoma of the sigmoid colon. The tumor forms a circumferential mass narrowing the intestinal lumen.


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noma is reserved for those neoplasms that have at least a 60 percent mucinous component. Other forms of carcinoma such as adenosquamous, pure squamous, spindle cell, clear cell, and choriocarcinomatous are less common. Neuroendocrine tumors include hindgut carcinoids, goblet cell carcinoids, combined adenocarcinoma-carcinoids, and neuroendocrine cell carcinomas (Fig. 7-62).

Anal Tumors and Related Lesions Condyloma acuminatum, which may present clinically as a

wartlike intraluminal mass, is a human papillomavirusinduced tumor-like epithelial lesion that occurs in the anus (Fig. 7-63). Benign tumors are rare. Malignant tumors originate from the epithelium and represent mostly as squamous cell neoplasms. The earliest lesions are intraepithelial and re-

semble the more common cervical lesions (Fig. 7-64). Two thirds of anal invasive cancers are keratinizing squamous cell carcinomas. The remaining one third are nonkeratinizing and are classified as basaloid (cloacogenic) (Fig. 7-65). An important variant is the so-called verrucous carcinoma, which macroscopically resembles condyloma acuminatum. Histologically the tumor is composed of well-differentiated squamous epithelial cells (Fig. 7-66). Anal gland carcinomas are of three histologic types: (1) welldifferentiated adenocarcinoma, (2) mucinous carcinoma, and (3) mucoepidermoid carcinoma (Fig. 7-67). Paget disease associated with carcinoma of the anal glands or rectum may affect the anus or the perianal skin (Fig. 7-68). It resembles genital extramammary Paget disease.

A

B

Fig. 7-62. Neuroendocrine tumors of the colon. A, Carcinoid is composed of groups of cells with uniform round nuclei. B, Small cell neuroendocrine carcinoma is composed of undifferentiated small blue cells that have oval nuclei and very little cytoplasm.

Fig. 7-63. Anal condyloma acuminatum. The lesion is composed of finger-like protrusions of keratinizing squamous epithelium covering fibrovascular cores.

Fig. 7-64. Anal intraepithelial neoplasia. The entire thickness of the disorganized epithelium contains dysplastic atypical epithelial cells.


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Fig. 7-65. Anal carcinoma of the basaloid type. The small hyperchromatic tumor cells form - nests that show peripheral palisading.

Fig. 7-66. Verrucous carcinoma. The tumor is composed of well-differentiated, relatively uniform squamous cells.

Fig. 7-67. Anal gland carcinoma. Adenocarcinoma cells surround an obstructed anal duct.

Further Reading Antonioli DA: Precursors of gastric carcinoma. A critical review with a brief description of early (curable) gastric cancer. Hum Pathol 25:994-1005, 1994. Carr NJ, McCarthy WF, Sobin LH: Epithelial noncarcinoid tumors and tumor-like lesions of the appendix. A clinicopathologic study of 184 patients with a multivariate analysis of prognostic factors. Cancer 75:757-768, 1995. Correa P: Helicobacter pylori and gastric carcinogenesis. Am J Surg Pathol 19:S37-S43, 1995. Dixon MF, Genta RM, Yardley JH et al: Classification and grading of gastritis. The updated Sidney system. Am J Surg Pathol 20:11611181, 1996. Franquemont DW: Differentiation and risk assessment of gastrointestinal stromal tumors. Am I Clin Pathol 103:41-47, 1995. Galperin C, Gershwin ME: Immunopathogenesis of gastrointestinal and hepatobiliary diseases. JAMA 278:1946-1955, 1997. Ghadially FN, Walley VM: Pigments of the gastrointestinal tract. A comparison of light microscopic and electron microscopic findings. Ultrastruct Pathol 19:213-220, 1995. Goldstein NS, Lewin KJ: Gastric epithelial dysplasia and adenoma: historical review and histological criteria for grading. Hum Pathol 28:127-133, 1997. Isaacson PG: Recent developments in our understanding of gastric lymphomas. Am J Surg Pathol 20(suppl)S1-S7, 1996.

Fig. 7-68. Paget disease of the anus. The basal portion of the squamous epithelium contains nests of mucin-rich carcinoma cells.

Kleer CG, Appelman HD: Ulcerative colitis. Patterns of involvement in colorectal biopsies and changes with time. Am J Surg Pathol 22:983-989, 1998. Lewin KJ: Nomenclature problems of gastrointestinal epithelial neoplasia. Am J Surg 22:1043-1047, 1998. Offner FA, Jao RV, Lewin KJ: Collagenous colitis: A study of the distribution of morphological abnormalities and their histologic detection. Hum Pathol 30:451-457, 1999. Pascal RR: Dysplasia and early carcinoma in inflammatory bowel disease and colorectal adenomas. Hum Pathol 25:1160-1171, 1994. Riddell RH: Premalignant and early malignant lesions in the gastrointestinal tract: definitions, terminology, and problems. Am J Gastroenterol 91:864-872, 1996. Stemmermann GN: Intestinal metaplasia of the stomach. A status report. Cancer 74:556-564, 1994. Suster S: Gastrointestinal stromal tumors. Sem Diagn Pathol 13:297313, 1996. Torres C, Antonioli D, Odze RD: Polypoid dysplasia and adenomas in inflammatory bowel disease. A clinical, pathologic and follow-up study of 89 polyps from 59 patients. Am J Surg Pathol 22:275-284, 1998. Willenbucher RF: Inflammatory bowel disease. Semin Gastrointest Dis 7:94-104, 1996.




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HEREDITARY METABOLIC DISEASES Numerous hereditary diseases of carbohydrate, lipid, or protein metabolism affect the liver. Liver changes are prominent in diseases that involve the metabolism of heavy metals such as copper or iron. Diseases of bilirubin conjugation and the excretion of bile also may be hereditary. All of these diseases may become clinically evident in infancy and childhood or may present clinically in adult life. Glycogen and lipid storage diseases typically are accompanied by hepatomegaly and intrahepatic accumulation of intermediate metabolites. Glycogen-rich hepatocytes have clear cytoplasm (Fig. 8-1). Hereditary tyrosinemia is associated with steatosis and cholestasis. Pseudoglandular transformation of hepatocytes, intraacinar and periportal fibrosis, and nodular regeneration develop early in childhood (Fig. 8-2). Hereditary hyperbilirubinemias reflect defects in bilirubin conjugation or excretion, or both (Table 8-1). Hepatocellular changes are most pronounced in the Dubin-Johnson syndrome. The liver appears brown-black on gross examination and the hepatocytes contain large amounts of cytoplasmic brown pigment (Fig. 8-3). Alpha j -antitrypsin deficiency is characterized by the presence of cytoplasmic globules, mostly in the periportal hepatocytes. These globules are round, eosinophilic, and periodic acid-Schiff (PAS) positive. They contain a l -antitrypsin, which may be demonstrated immunohistochemically (Fig. 8-4). Wilson disease is characterized by an accumulation of copper in liver cells. Liver changes include steatosis, glycogenated nuclei, and rare foci of necrosis or apoptotic bodies. Like many other storage diseases such as a,-antitrypsin deficiency or hemochromatosis, Wilson disease may progress to cirrhosis (Fig. 8-5). Genetic hemochromatosis is characterized by an accumulation of hemosiderin, the iron-rich, Prussian blue-positive, brown pigment in hepatocytes, Kupffer cells, and bile duct cells (Fig. 8-6).

Fig. 8-1. Glycogen storage disease. Glycogenosis type I (von Gierke disease) is characterized by an accumulation of glycogen in liver cells. Liver cells have clear cytoplasm.

Fig. 8-2. Hereditary tyrosinemia. The liver shows steatosis, cholestasis, lobular disorganization, and giant cell transformation of hepatocytes.

A

B

Fig. 8-3. Dubin Johnson syndrome. Hepatocytes contain coarse brown granules in their cytoplasm, which give the liver a black or dark brown appearance. A, Gross. B, Microscopic.


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Histopathology of Viral Hepatitides Disease Crigler-Najjar, type I Crigler-Najjar, type II Gilbert Rotor Dubin Johnson

Principal Defect in Bilirubin Metabolism Conjugation Conjugation Conjugation and/or uptake Unknown but may include uptake, conjugation, or excretion Excretion

Fig. 8-4. a i -Antitrypsin deficiency. The liver cells contain typical PAS-positive round cytoplasmic bodies.

Histopathologic Changes in the Liver Canalicular cholestasis None None or excess lipofuscin in zone 3 and 2 hepatocytes None Pigmented brown granules in hepatocytes

Fig. 8-5. Wilson disease. Hepatocytes of this cirrhotic liver have glycogenated nuclei, which appear clear. Some hepatocytes have clear cytoplasm, whereas cytoplasm in other hepatocytes is eosinophilic.

A B

Fig. 8-6. Hemochromatosis. A, Brown pigment (hemosiderin) accumulates in hepatocytes, Kupffer cells, and bile ductular cells. B, Hemosiderin granules in bile ductular cells appear blue after the Prussian blue reaction.


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CIRCULATORY DISORDERS The liver, which has a dual blood supply in that it receives blood from both the hepatic artery and the portal vein, often is affected by circulatory disorders. Sudden heart failure causes acute passive congestion with or without centrilobular (zone 3) hepatocellular necrosis (Fig. 8-7). Chronic passive congestion leads to zone 3 liver cell atrophy and loss, and replacement of liver cells by fibrous tissue. On gross examination such livers have a nutmeg-like appearance (Fig. 8-8). Venous outflow obstruction of Budd-Chiari syndrome is reminiscent of changes produced by congestive heart disease, but the liver typically shows a spectrum of changes. Those acini with acute changes show severe sinusoidal dilatation and congestion, which is most pronounced in zone 3 but sometimes extends to the portal tracts. Coagulative necrosis

commonly is seen. Progressive sinusoidal dilatation is accompanied by atrophy of hepatocytes and zone 3 fibrosis. In other areas the central hepatic venules and intercalated veins may contain thrombi or recanalized thrombi, or may show fibrous mural thickening (Fig. 8-9). These thrombotic changes are not seen in congestive heart failure. Venoocclusive disease maybe a consequence of irradiation, cytotoxic drug therapy, or drinking bush tea produced from Senecio or Crotalaria alkaloids. The changes resemble those seen in Budd-Chiari syndrome but are limited to the intrahepatic veins. In typical cases intimal edema of the terminal hepatic venules is followed by the subendothelial deposition of reticulin and collagen fibers, and progressive narrowing and complete obliteration of their lumen (Fig. 8-10). Inflammation is sparse and thrombi are not seen.

Fig. 8-7. Acute passive congestion. The terminal hepatic venule and the sinusoids of zone 3 are filled with blood. Many hepatocytes have been lost from those areas or are ischemic and are undergoing necrosis.

Fig. 8-8. Chronic passive congestion. The fixed liver has a nutmeg-like appearance. A nutmeg is included for comparison.

Fig. 8-9. Budd-Chiari syndrome. The vein containing an organized thrombus is surrounded by areas of necrosis of zone 3 hepatocytes.

Fig. 8-10. Venoocclusive disease caused by Senecio alkaloids. Terminal hepatic venule (center) is almost completely occluded and is surrounded by areas devoid of hepatocytes, which have undergone necrosis.


1 47

Peliosis hepatis is a consequence of endothelial cell injury leading to an accumulation of blood in the spaces of Disse and sinusoids that become transformed into blood-filled cavities (Fig. 8-11). Peliosis most often is induced by drugs or steroid hormones, but it also may be a complication of infection with Rochalimaea henselae in acquired immunodeficiency syndrome (AIDS) or chronic debilitating infections such as tuberculosis. Fibrin thrombi in sinusoids typically are found in toxemia of pregnancy and severe disseminated intravascular coagulation (DIC) syndromes. Deposits of fibrin may be accompanied by spotty hepatocellular necrosis and liver cell dropout, most prominently in the periportal areas. Portal vein thrombosis is a common complication of hepatocellular carcinoma (Fig. 8-12).

I NFECTIOUS HEPATITIS Hepatitis most often is caused by hepatotropic viruses, but it also may be found in patients infected with other pleiotropic viruses such as herpes simplex virus, cytomegalovirus (CMV), and others. Bacterial hepatitis is a feature of biliary tract infection or sepsis. Infections with protozoa and parasites occur in tropical countries.

Viral Hepatitis Unless otherwise specified, the term viral hepatitis denotes an infection caused by one of the hepatotropic viruses—hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), hepatitis E virus ( HEV ), or hepatitis G virus (HGV). The severity of the acute disease and its histology vary from case to case. In acute viral hepatitis the liver shows acinar disarray, variable degrees of ballooning of hepatocytes, scattered apoptotic bodies, and prominence of Kupffer cells (Figs. 8-13 and 8-14). Various viruses induce different changes, which are not always predictable. The comparative histopathologic features of the major forms of acute viral hepatitis are listed in Table 8-2.

Fig. 8-11. Peliosis hepatis. Blood-filled cavities do not have endothelial lining. Blood also contains leukemia cells.

Fig. 8-12. Portal vein thrombosis. The cirrhotic liver contains hepatocellular carcinoma (left).

Fig. 8-13. Viral hepatitis. The liver shows marked lobular disarray, focal necrosis of hepatocytes, and prominence of Kupffer cells.

Fig. 8-14. Viral hepatitis. Prominent apoptotic cells are being pushed into the sinusoids. Hepatocytes appear swollen and the Kupffer cells are prominent. Sinusoids appear narrow.


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Histopathology of Viral Hepatitides

*Includes apoptosis, unicellular acidophilic and ballooning degeneration, and focal necrosis. tMicrovesicular steatosis; seen only in posttransplantation "reinfection." $E, Eosinophils; L, lymphocytes; N, neutrophils; P, plasma cells.

Fig. 8-15. Massive hepatic necrosis caused by HBV. Only some periportal hepatocytes have survived the infection.

Fig. 8-16. Chronic HBV infection. Fibrous bands bridge the space between neighboring portal tracts. There also is considerable chronic inflammation and piecemeal necrosis.

Fig. 8-17. Chronic HCV infection. The bile ducts are inflamed and surrounded by a dense lymphocytic infiltrate.

Fig. 8-18. HBV carrier state. The cytoplasm of hepatocytes has a "ground glass " appearance.


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Hepatitis Caused by Pathogens Other Than Hepatitis Viruses

Complications of acute viral hepatitis include massive necrosis, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Severe viral infection may cause massive hepatic necrosis (Fig. 8-15). Chronic hepatitis, a complication of all viral hepatitides except those caused by HAV, is characterized by portal and/or lobular inflammation and fibrosis (Fig. 8-16). Entrapment of isolated hepatocytes or small groups of liver cells by the expanding portal fibrous tissue is highly typical of chronic hepatitis. Extension of strands of fibrous tissue and inflammatory cells from portal tracts into the acini with focal liver cell necrosis and dropout ("piecemeal necrosis") commonly is present. HCV causes steatosis and bile duct inflammation and destruction (Fig. 8-17). Hepatocytes with a finely granular "ground glass " cytoplasm (Fig. 8-18) are the hallmark of the chronic carrier state of hepatitis B. Serology is the best way to diagnose specific forms of hepatitis virus infection.

Herpesvirus hepatitis is characterized by foci of necrosis with a relatively sparse inflammatory response (Fig. 8-19). Cowdry type A intranuclear inclusions typically are present (Fig. 8-20). CMV infection causes enlargement of bile ductal cells, which typically contain basophilic intranuclear inclusions. Infectious mononucleosis is characterized by sinusoidal lymphocytic infiltrates and prominence of Kupffer cells (Fig. 8-21). The hepatocellular changes are relatively mild and include focal apoptosis and only mild ballooning. Q fever hepatitis is characterized by noncaseating granulomas with a fibrin ring often surrounding a centrally located fat vacuole (Fig. 8-22). Hematogenous hepatic infection occurs in many acute bacterial diseases, such as typhoid, brucellosis, tularemia, and

Fig. 8-19. Herpesvirus hepatitis. Coagulative liver cell necrosis with almost no inflammation.

Fig. 8-20. Herpesvirus hepatitis. The hepatocytes contain Cowdry type A intranuclear inclusions.

Fig. 8-21. Infectious mononucleosis. The liver shows sinusoidal Iymphocytosis and prominence of Kupffer cells.

Fig. 8-22. Q fever. Fibrin rings are typical, albeit not diagnostic of this disease.


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so forth, and causes foci of hepatic necrosis and inflammation (Fig 8-23). Mycobacterium avium-intracellulare ( MAI) infection presents in the form of granulomas composed of MAI-filled macrophages (Fig. 8-24).

Fig. 8-23. Typhoid fever. Liver contains sharply demarcated foci of necrosis.

Biliary Infections Ascending biliary infection is a common complication of bile stone impaction in the common bile duct and other diseases of the biliary system. Hematogenous infections may reach the liver through arteries, usually in sepsis, or through portal veins from the intestines. Acute bacterial cholangitis often is a suppurative infection (Fig. 8-25). Histologically there is bile ductal dilatation with infiltrates of neutrophils. Biliary hepatic abscesses may persist as encapsulated pus-filled cavities inside the liver (Fig. 8-26).

A

B

Fig. 8-24. MAI infection. A, Macrophagic granulomas. B, Ziehl-Neelsen stain shows numerous acid-fast bacilli inside macrophages.

Fig. 8-25. Bacterial cholangitis. Pus is oozing from bile ducts on a cross-sectioned liver.

Fig. 8-26. Cholangitic abscesses. Abscesses contain bile-tinged pus.


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Hepatic amebiasis, a complication of amebic colitis, is characterized by hepatic lesions called amebomas. Although these lesions are also known as amebic abscesses, they do not contain pus but are filled with putty-like material formed from necrotic liver cells (Fig. 8-27). Infections with parasites such as Echinococcus granulosus lead to the formation of hep-

atic cysts (Fig. 8-28). Infections with Schistosoma haematobium and Opisthorchis sinensis are accompanied by granulomas and periportal hepatic fibrosis of "pipe stem " type (Fig. 8-29). Malaria is accompanied by pronounced hypertrophy of Kupffer cells, which contain black hemozoic pigment (Fig. 8-30).

A B

Fig. 8-27. Amebic abscess. A, The cavitary lesion is filled with yellow putty-like material. It does not contain pus and thus is not a true abscess but rather a localized area of hepatic necrosis. (From Damjanov I: Pathology for the health related professions, Philadelphia, 1996, WB Saunders; with permission.) B, Necrotic material occupies space surrounded by fibrous tissue.

A

B

Fig. 8-28. Echinococcus granulosus cyst. A, Cyst has a hyaline fibrotic wall. B, Cyst contains cross-sectioned scolices of the parasite.


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Fig. 8-29. Schistosomiasis. The parasite in tissue is surrounded by chronic inflammation and fibrosis.

DRUG-INDUCED LIVER DISEASES Most drugs absorbed into the portal or systemic circulation are metabolized in the liver. During this metabolic process the liver cells may be injured as a result of the direct toxicity of the drug or its metabolites. These substances also may produce an immune response, and such a hypersensitivity reaction also may indirectly affect the liver. Some drugs may induce an unpredictable idiosyncratic adverse response in

Fig. 8-30. Falciparum malaria. The enlarged Kupffer cells contain black hemozoic pigment.

the liver. In general, the morphologic features of drug-induced liver injury parallel those of viral hepatitis but also include fatty change, pure cholestasis, vascular changes, and hyperplastic and/or neoplastic lesions (Table 8-3, Figs. 8-31 to 8-36).

Drug-induced Liver Diseases Ps„,-

Drug Examples Isoniazid = `ds-like Spotty necrosis Methyldopa Submassive Halothane, acetaminophen necrosis, zone 3 • Submassive Paraaminosalicylic acid, necrosis, zone I halothane • Massive necrosis Isoniazid, halothane, chlorinated naphthalenes Granulomas Methyldopa, sulfonamides phenylbutazone Cholestasis Chlorpromazine, oral contraceptives Fatty change Tetracycline, salicylates

• Microvesicular • Macrovesicular Vascular changes • Venoocclusive disease

Amiodarone Methotrexate

▪ Peliosis hepatis Hyperplastic changes

Anabolic steroids, tamoxifen Oral contraceptives

Cytotoxic drugs

Toxins

Mushrooms, copper sulfate Phosphorus, ferrous sulfate CCI4

Fig. 8-31. Drug-induced hepatitis. This patient developed a hepatitis-like disease after treatment for tuberculosis with isoniazid.

CCII , mushrooms, phosphorus

Senecio or Crotalaria alkaloids

Fig. 8-32. Massive hepatic necrosis induced by acetaminophen.


153

Fig. 8-33. Drug-induced chronic hepatitis. Liver changes in this patient treated with methyldopa resemble those of chronic hepatitis.

Fig. 8-35. Hepatic granulomas. These granulomas were found in a patient treated with phenylbutazone.

Fig. 8-34. Drug-induced fatty change.

Fig. 8-36. Cholestasis. Androgen-related jaundice was associated with bile plugs and cholestatic rosettes.

ALCOHOLIC LIVER DISEASES

Fig. 8-37. Fatty liver. The liver appears yellow.

Chronic abuse of alcohol may produce a spectrum of overlapping hepatic changes, which are classified morphologically as (1) fatty change, (2) alcoholic hepatitis, and (3) alcoholic cirrhosis. Fatty change often is associated with hepatomegaly, but in essence it causes no clinical symptoms and is reversible. Microscopically it presents with macrovesicular steatosis (Fig. 8-37). In a minority of chronic alcoholics the liver injury presents as alcoholic hepatitis. The most prominent changes are seen in zone 3, which shows pronounced unrest (pleomorphism) of hepatocytes. Many hepatocytes show cytoplasmic dissociation (clumping of part of the cytoplasm around the nucleus with rarefaction of the remainder) and Mallory body formation (Fig. 8-38). Mallory


154

Fig. 8-38. Alcoholic hepatitis. There is noticeable unrest of hepatocytes, some of which contain Mallory bodies (arrows).

bodies may be demonstrated immunohistochemically with antibodies to ubiquitin (Fig. 8-39). Groups of neutrophils tend to surround hepatocytes with Mallory bodies ( "neutrophilic satellitosis " ). Steatosis usually is mild to moderate but may even be absent. Fibrosis tends to occur around the terminal hepatic venules extending into the spaces of Disse and sinusoids enveloping individual hepatocytes or groups of hepatocytes ( "chicken wire " fibrosis) (Fig. 8-40). The connective tissue may become confluent, replacing zone 3 hepatocytes and obliterating efferent veins ( " sclerosing hyaline necrosis " ). Venoocclusive lesions may be associated with variable degrees of periportal fibrosis. In some biopsy specimens of patients with portal hypertension, perivenular fibrosis of zone 3 and steatosis may be the only findings (Fig. 8-41). Fibrosis may progress, dissecting acini into small segments, which ultimately leads to cirrhosis (Fig. 8-42). In typical cases alcoholic cirrhosis is micronodular and the liver is yellow and fatty. However, in many cases the liver is devoid of fat and appears macronodular or mixed micro- and macronodular.

Fig. 8-39. Mallory bodies. In this immunohistochemical preparation Mallory bodies stain brown with antibodies to ubiquitin.

Fig. 8-40. Alcoholic hepatitis. In this Mallory trichrome—stained slide zone 3 shows periventricular fibrosis extending between hepatocytes.

Fig. 8-41. Alcoholic liver disease. The liver shows steatosis and fibrosis of zone 3 in the center of the field.

Fig. 8-42. Alcoholic cirrhosis. Cirrhosis typically is micronodular and the liver appears yellow because of a high fat content.


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AUTOIMMUNE LIVER DISEASES Autoimmune hepatitis and primary biliary cirrhosis are the best known autoimmune diseases of the liver. It should be noted that some drug reactions also are immune mediated. Primary sclerosing cholangitis, a disease of unknown pathogenesis, is mentioned here only because many patients with this disease have perinuclear antineutrophil cytoplasmic antibodies (pANCA) and may have an altered immune system. Autoimmune chronic hepatitis includes three subgroups: (l a) lupoid hepatitis (antinuclear antibody-positive, with or without actin antibody) and (lb) which is only actin antibody—positive; (2) liver-kidney microsomal antibody—positive; and (3) liver-pancreas antibody—positive (with or without other antibodies). There are no histologic findings that reliably distinguish autoimmune chronic hepatitis from chronic hepatitis B or drug-induced chronic hepatitis. Some authors believe that hypocellular areas of collapse, severe intraacinar necrosis, and inflammation with rosettes and multinucleated hepatocytes are more suggestive of autoi mmune hepatitis than other forms of chronic hepatitis; many other investigators do not find any specificity in these findings. The presence of plasma cells is considered to be

useful for distinguishing autoimmune chronic hepatitis from chronic hepatitis C, in which the portal infiltrates consist predominantly of lymphocytes (Fig. 8-43). However, plasma cells may be abundant in viral hepatitis B and in some druginduced lesions. Primary biliary cirrhosis is an autoimmune disease that is characterized by destruction of intrahepatic bile ducts, which leads to biliary cirrhosis. An increased titer of antimitochondrial antibodies is seen in 90 percent of patients, and the disease often is associated with other autoimmune disorders such as Hashimoto thyroiditis or atrophic gastritis. Histologically, in early stages of the disease, the chronic inflammatory cells in the portal tracts infiltrate and destroy the bile ducts ( "chronic nonsuppurative destructive cholangitis") (Fig. 8-44). As the disease progresses the bile ducts are replaced by fibrosis, which extends from one portal area to another (Fig. 8-45). In liver biopsy specimens more than half the portal tracts lack bile ducts, in contrast to the normal liver in which 87 percent or more portal tracts have bile ducts. The presence of lteriportal cholestasis and foci of pseudoxanthomatous cells is useful for diagnosis but is not pathognomonic of primary biliary cirrhosis (Fig. 8-46). Cholangi-

Fig. 8-43. Autoimmune hepatitis. The inflammatory infiltrate in this chronic hepatitis contains numerous plasma cells.

Fig. 8-44. Primary biliary cirrhosis. The bile duct is distorted by inflammatory cells, which surround and invade it.

Fig. 8-45. Primary biliary cirrhosis. Connective tissue bridges connect portal areas, which typically are devoid of bile ducts in advanced stages of the disease.

Fig. 8-46. Primary biliary cirrhosis. Clusters of xanthomatous cells are found in the dilated sinusoids.


156

A

Fig. 8-47. Primary sclerosing cholangitis. A, The medium-sized bile ducts are surrounded by collagenous fibrous tissue. B, Bile ducts have been replaced by round scars. Ductopenia is accompanied by residual chronic inflammation.

olar proliferation may be prominent. Hepatocytes are relatively spared except in advanced cirrhotic stages of the disease, which are characterized by prominent piecemeal necrosis and nodular regeneration. Periportal Mallory bodies are found in approximately one fourth of all cases. Cirrhosis usually is micronodular and maybe associated with marked cholestasis. Primary sclerosing cholangitis usually is idiopathic and occurs sporadically. In some cases it may be associated with ulcerative colitis or retroperitoneal fibrosis. The disease affects the intrahepatic bile ducts, which show focal stenosis alternating with dilatation ( " beading" on cholangiography). Histologic changes in the liver resemble those caused by other forms of extrahepatic biliary obstruction and include periductal fibrosis and variable cholestasis (Fig. 8-47). Intrahepatic bile ducts compressed by concentric.(` onionskin " ) fibrosis ultimately disappear and are replaced by round fibrotic scars (Fig. 8-48). Extrahepatic ducts also are narrowed and fibrotic and ultimately are transformed into fibrous strands devoid of any lumen. Biliary cirrhosis develops terminally in most patients.

BILIARY OBSTRUCTION Obstruction of extrahepatic biliary ducts causes jaundice and is associated with typical hepatic changes. Possible causes of biliary obstruction such as bile stones are readily identified clinically (Fig. 8-49). Other causes of obstruction are listed in Table 8-4. In acute biliary obstruction the first changes are seen in acinar zone 3 and sometimes in zone 2. Zone 3 hepatocytes show slight unrest (Fig. 8-50). Portal tract infiltrates of neutrophils and acute cholangiolitis, edema, and cholangiolar proliferation are typical but not diagnostic (Fig. 8-51). The epithelium of the intraacinar bile ducts may show irregularity, hyperplasia, or edema. Bile plugs sometimes are present in the bile ducts. In severe cases the bile ducts rupture and cholangitic abscesses form (Fig. 8-52). These abscesses contain remnants of disrupted biliary epithelium, and bile mucin admixed with neutrophils in various stage of disintegration. Xanthomatous cells and foreign body giant cells with phagocytosed bile may be present. Extravasated bile ("bile lakes " ) and dissolution of liver cells resulting from the detergent action of bile ( " bile infarcts" ) are seen only in advanced cases, usually at autopsy, and are of limited diagnostic value in liver biopsies (Figs. 8-53 and 8-54).

Causes of Biliary Obstruction

Fig. 8-48. Biliary cirrhosis. The liver is nodular and shows greenish nodular discoloration.

Congenital • Atresia • Agenesis Gallstones Inflammation/Fibrosis • Primary sclerosing cholangitis • Bacterial cholangitis • Surgical stricture

Tumors • Carcinoma of head of pancreas • Carcinoma of ampulla of Vater • Carcinoma of common bile ducts • Lymphoma of hilar lymph nodes


157

Fig. 8-49. Gallstones in the hepatic ducts. Pigmented stones were found in dilated ducts.

Fig. 8-50. Extrahepatic biliary obstruction. The acinar zone 3 shows unrest and canalicular cholestasis.

Fig. 8-5 I. Extrahepatic biliary obstruction. The portal tract is inflamed and there is cholangiolar proliferation.

Fig. 8-52. Cholangitic abscess. The dilated and ruptured bile duct is filled with neutrophils and bile.

Fig. 8-53. Bile lake. Darkly stained extravasated bile surrounded by xanthomatous cells is found in late stages of biliary obstruction.

Fig. 8-54. Bile infarct. Dissolution of liver cells is a late consequence of chronic biliary obstruction.


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CIRRHOSIS Cirrhosis, a term used as a synonym for advanced liver disease or end-stage liver disease, is characterized by replacement of normal liver parenchyma by abnormal liver cell nodules and fibrosis. Morphologically it is classified as (1) micronodular if the nodules are smaller than 3 mm in diameter; (2) macronodular if the nodules are larger than 3 mm in diameter; and (3) mixed if the liver contains an equal number of large and small nodules (Figs. 8-55 and 8-56). The most important causes of cirrhosis are listed in Table 8-5. Histologic features of cirrhosis are typical and usually reflect the gross findings. In all instances groups of liver cells are arranged into nodules surrounded by fibrous septa (Fig 8-57). These septa may contain proliferating bile ducts and chronic inflammatory cells. Dilated branches of portal veins, which reflect intrahepatic vascular obstruction and portal hypertension, are found in most cases (Fig. 8-58). Septa contain reticulin fibers that extend between the liver cells, accentuating their abnormal structure (Fig. 8-59). The hepatocellular nodules are composed of pleomorphic liver cells arranged into groups, strands, and nests that lack normal sinusoidal blood supply (Fig. 8-60).

Fig. 8-55. Micronodular cirrhosis. The nodules are small and of approximately even size.

Causes of Cirrhosis

Viral hepatitis Alcohol abuse Metabolic diseases Hemochromatosis Wilson disease a,-antitrypsin deficiency Galactosemia Immune-mediated hepatic diseases Primary biliary cirrhosis Primary sclerosing cholangitis Autoimmune ("lupoid") hepatitis Toxic and drug-induced hepatitis Biliary obstruction Cryptogenic cirrhosis

Fig. 8-57. Cirrhosis. Nodules of liver cells are surrounded by fibrous septa.

Fig. 8-56. Macronodular cirrhosis. Large nodules, which vary in size and shape, are surrounded by broad areas of fibrosis.

Fig. 8-58. Cirrhosis. The fibrous septa contain proliferating bile ducts, chronic inflammatory cells, and dilated veins.


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Fig. 8-59. Cirrhosis. Reticulin stain highlights broad septa giving rise to fine fibers that extend into the hepatocellular nodules. Reticulin fibers of this kind are not seen in hepatocellular carcinoma.

TUMOR-LIKE CONDITIONS AND TUMORS Tumor-Like Conditions Extensive cystic changes in the liver are uncommon. Cysts usually occupy only part of the liver, but occasionally the change may be widespread (Fig. 8-61). Cysts of the liver are found in several hereditary conditions such as Caroli disease,

Fig. 8-60. Cirrhosis. Hepatocellular nodules lack normal sinusoidal blood supply and are composed of pleomorphic liver cells arranged into groups rather than plates.

autosomal recessive polycystic kidney disease (ARPKD), or autosomal dominant polycystic kidney disease (ADPKD). The hepatic changes vary from mild to severe. The most common finding in mild hepatic forms of ADPKD are minute nodules, measuring 1 to 3 mm in diameter, composed of small bile ductules embedded in collagenous stroma (von Meyenburgcomplexes) (Fig. 8-62).

A

B

Fig. 8-61. Polycystic liver disease. A, The liver contains numerous large cysts. B, The cyst wall contains small bile ducts surrounded by fibrous tissue. (Courtesy of Dr. Paramjit Bhatia, Kansas City, Kansas.)


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Fig. 8-62. von Meyenburg complex. Groups of small bile ducts are enclosed in connective tissue stroma.

Fig. 8-63. Focal nodular hyperplasia. The lobular mass has a central fibrotic scar.

Fig. 8-64. Focal nodular hyperplasia. The central scar extends peripherally into thinner septa.

Fig. 8-65. Nodular transformation. The nodules are composed of hepatocytes that are larger and paler than those of the surrounding normal liver.

Fig. 8-66. Nodular transformation. Reticulin stain shows the difference between the nodule composed of two cell—thick plates and the compressed normal liver to the right.

Focal nodular hyperplasia may present as solitary or multiple nodules in noncirrhotic livers of adults: It is twice as common in women as in men, and it most often is asymptomatic and is discovered accidentally. The average mass measures 5 cm in diameter. On cross section it appears lobulated and is well demarcated from the rest of the liver (Fig. 8-63). The nodule typically has a central fibrous scar radiating toward the periphery ("wagon wheel" pattern). Histologically, focal nodular hyperplasia is composed of normalappeanng hepatocytes arranged into two cell-thick plates between septa of fibrous tissue (Fig. 8-64). Nodular transformation, also known as nodular regenerative hyperplasia, represents diffuse hepatic nodularity without fibrosis or cirrhosis. It has been associated with a number of diseases such as autoimmune diseases, including CREST (calcinosis, Raynaud 's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia) syndrome and polyarteritis nodosa; inflammatory bowel disease; lymphoma and myeloproliferative diseases; or bacterial endo -


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carditis. Some cases have been related to prolonged intake of anabolic steroids or oral contraceptives. It usually is asymptomatic, but morphologically it may be confused with cirrhosis. The nodules are composed of hyperplastic hepatocytes arranged into two cell–thick plates compressing the adjacent liver without any intervening fibrous tissue (Fig. 8-65). Reticulin stain clearly shows the differences between the nodule and the compressed atrophic normal liver cells (Fig. 8-66).

Epithelial Tumors Hepatocellular adenoma is the most important benign liver

tumor. It occurs as a yellow, congested or hemorrhagic nodule in an otherwise normal liver (Fig. 8-67). The tumor is composed of hepatocytes resembling those of the normal liver. Tumor cells usually are larger, are arranged into two cell–thick plates, and contain glycogen, which makes their cytoplasm appear clear (Fig. 8-68). Hepatocellular carcinoma is a malignant liver cell tumor that most often originates in a cirrhotic liver. It maybe pathogenetically related to hepatitis B or hepatitis C virus infection. The tumor may be classified on gross examination as solitary, multinodular, massive, or diffuse (Figs. 8-69 and 8-70). Histologically, hepatocellular carcinoma occurs in several patterns such as trabecular, compact, pseudoglandular

Fig. 8-67. Hepatocellular adenoma. The tumor appears as a partially hemorrhagic yellow mass.

Fig. 8-68. Hepatocellular adenoma. The tumor is composed of clear cells arranged into two cell—thick plate. The cells have a low nuclear-cytoplasmic ratio, and the nuclei appear uniform.

Fig. 8-69. Hepatocellular carcinoma. This cirrhotic liver contains a solitary malignant nodule, which appears yellow. Smaller satellite nodules are seen left of the main mass. (Courtesy of Dr. James Fishback, Kansas City, Kansas.)

Fig. 8-70. Hepatocellular carcinoma. The massive tumor is poorly demarcated from the remaining liver.


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(acinar), and scirrhous (Figs. 8-71 and 8-72). Irrespective of its growth pattern, hepatocellular carcinoma has a poor prognosis. Fibrolamellar hepatocellular carcinoma is a distinct subtype of hepatocellular carcinoma that occurs in adolescents and young adults. It is not associated with hepatitis virus infection and occurs in normal rather than cirrhotic livers. The five-year survival rate is in the range of 60 percent to 80 percent. On gross examination the tumor presents as a mass that is demarcated from the remaining liver and crisscrossed with fibrous scars. Histologically the tumor is composed of large polygonal cells with intensely eosinophilic cytoplasm (Fig. 8-73). The cytoplasm of tumor cells appears granular because the cells contain numerous mitochondria. Tumor cells also may contain globular PAS-positive inclusions and socalled pale bodies. Hepatoblastoma is a tumor of childhood. It often is associated with a variety of congenital anomalies such as

Fig. 8-71. Hepatocellular carcinoma. The tumor has a trabecular pattern.

Fig. 8-72. Hepatocellular carcinoma. The tumor has a pseudoglandular pattern.

Fig. 8-73. Fibrolamellar hepatocellular carcinoma. The tumor is composed of large cells with well-developed eosinophilic cytoplasm. Connective tissue scars also are seen.

Fig. 8-74. Hepatoblastoma. The tumor has a lobular appearance with areas of necrosis.

Fig. 8-75. Hepatoblastoma. The tumor is composed of cuboidal cells that resemble fetal hepatocytes.


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B

Fig. 8-76. Cholangiocellular carcinoma. A, The tumor appears grayish-white. B, Histologically the tumor has a tubular pattern.

hemihypertrophy, congenital absence of the portal vein, Beckwith-Wiedemann syndrome, or familial adenomatous polyposis coli. On gross examination the tumor usually is well circumscribed with foci of cystic degeneration, necrosis, or hemorrhage (Fig. 8-74). Histologically it consists of cells that resemble embryonic fetal hepatocytes embedded in a mesenchymal matrix. Embryonal type cells are small fusiform cells with hyperchromatic nuclei. Fetal type cells are larger and have more eosinophilic or clear cytoplasm filled with fat and glycogen (Figs. 8-75). Cholangiocellular carcinoma is a malignant epithelial tumor derived from the intrahepatic bile ducts. Two thirds of these tumors are solitary and one third are multifocal. In Southeast Asia this tumor has been associated with liver fluke infestation, but in the rest of the world it seems to be sporadic. Histologically the tumors are adenocarcinomas, often of a tubular pattern evoking a strong desmoplastic reaction. (Fig. 8-76).

Fig. 8-77. Epithelioid hemangioendothelioma. Tumor cells, which typically show cytoplasmic vacuoles (lumens), are supported by delicate stroma. Sinusoidal vascular spaces are seen as clefts between tumor cells.

Mesenchymal Tumors Hemangioma is the most common benign mesenchymal tumor. It usually is asymptomatic and clinically insignificant. Other benign tumors such as lipoma and fibroma are rare. Malignant mesenchymal tumors are rare. They most often originate from vascular cells. The most important are epithelioid hemangioendothelioma, angiosarcoma, and undifferentiated sarcoma (Fig. 8-77).

Metastatic Tumors Metastases to the liver are the most common malignancy in this organ. On gross examination metastases appear as multiple spherical nodules with a central indentation ("umbilication") (Fig. 7-78). They most often originate from primary tumors in the colon, lung, or breast.


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Fig. 8-78. Metastatic carcinoma. The liver contains numerous spherical nodules, many of which show central indentation ("umbilication") corresponding to the areas of necrosis.

Fig. 8-79. Gallstones. The gallbladder is filled with multifaceted stones.

DISEASES OF THE GALLBLADDER The most important diseases of the gallbladder and biliary ducts are biliary stones (cholelithiasis), inflammation of the gallbladder (cholecystitis), and tumors. Gallstones are predominantly composed of cholesterol and bile pigment. They may be solitary or multiple, firm or soft, and radiographically opaque or translucent (Fig. 8-79). Gallstones often are accompanied by inflammation, which may be related to mechanical or chemical irritation of the mucosa or to bacterial infection. Cholecystitis may be classified as acute or chronic (Figs. 880 and 8-81). Histologically the wall of the gallbladder shows signs of inflammation, which in chronic cholecystitis may be accompanied by fibrosis and epithelial metaplasia. If extensive lymphoid hyperplasia is found, the term follicular cholecystitis is used. If infiltrates of neutrophils are found in chronic cholecystitis, the term chronic active cholecystitis is used (Fig. 8-82). Porcelain gallbladder is a term that is used for fibrosed and/or calcified gallbladders in chronic states of disease. Hydrops of the gallbladder typically is caused by impacted gallstones. The gallbladder is distended and filled with clear fluid. Its wall may be fibrosed (Fig. 8-83). Carcinoma of the gallbladder is clinically the most important tumor of the gallbladder. It often is found in association with gallstones even though there is no pathogenetic link between these two diseases. It is more common in women than in men and is especially common in Native Americans. The tumor grows into the lumen or through the wall and infiltrates the liver (Fig. 8-84). Histologically most tumors are adenocarcinomas, but some appear as mixed adenosquamous or squamous cell carcinomas. Carcinoids, endocrine carcinoma, or carcinosarcomas are rare. Sarcomas are extremely rare.

Fig. 8-80. Acute cholecystitis. The mucosa appears red and swollen. The gallbladder contained stones, which were removed after surgery.

Fig. 8-81. Chronic cholecystitis. Transmural Iymphocytic infiltrates in a follicular pattern account for the term follicular cholecystitis.


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Fig. 8-82. Chronic active cholecystitis. The wall of the gallbladder is infiltrated with chronic inflammatory cells, whereas the surface mucosa is infiltrated with neutrophils.

Fig. 8-84. Carcinoma of the gallbladder. The gallbladder is partially filled and infiltrated with neoplastic tissue Further Reading Albores-Saavedra J, Nolberg K, Henson DE: Unusual malignant epithelial tumors of the gallbladder. Sem Diag Pathol 13:326-338, 1996. Batts KP, Ludwig J: Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol 19:1409-1417, 1995. Brewer GJ, Yuzbasiyan-Gurkan V: Wilson disease. Medicine (Baltimore) 71:139-164, 1992. Carriaga MT, Henson DE: Liver, gallbladder, extrahepatic bile ducts, and pancreas. Cancer 75:175-190, 1995. Chevallier M, Guerret S, Chossegross P et al: A histological semiquantitative scoring system for evaluation of hepatic fibrosis in needle liver biopsy specimens. Comparison with morpholometric studies. Hepatology 20:349-355, 1994.

Fig. 8-83. Hydrops of the gallbladder. Dilated gallbladder contains an impacted stone in its neck region.

Desmet VI, Gerber M, Hoofnagle JH et al: Classification of chronic hepatitis: Diagnosis, grading and staging. Hepatology 19:1513-1520, 1994. Edmonson HA, Steiner PE: Primary carcinoma of the liver. A study of 100 cases among 48,900 necropsies. Cancer 7:462-503, 1954. Gold JH, Guzman IJ, Rosai J: Benign tumors of the liver. Pathologic examination of 45 cases. Am J Clin Pathol 70:6-17, 1978. Heintges T, Wands JR: Hepatitis C virus: epidemiology and transmission. Hepatology 3:521-526, 1997. Hoofnagle JH, Carithers RL Jr, Shapiro C et al: Fulminant hepatic failure. Summary of a workshop. Hepatology 21:240-252, 1995. International Working Party. Terminology of nodular hepatocellular lesions. Hepatology 22:983-993, 1995. Ishak KG: Chronic hepatitis. Morphology and nomenclature. Mod Pathol 7:690-713, 1994. James 0, Day C: Non-alcoholic steatohepatitis: another disease of affluence. Lancet 353:1634-1636, 1999. Lee WM: Hepatitis B virus infection. NEngl JMed 337:1733-1745, 1997. Maeda T, Adachi E, Kajiyama K et al: Combined hepatocellular and cholangiocarcinoma. Proposed criteria according to cytokeratin expression and analysis of clinicopathologic features. Hum Pathol 26:956-964, 1995. Meyer zum Buschenfelde K-H, Dienes H-P: Autoimmune hepatitis. Definition—classification—histopathology—immunopathogenesis. Virchows Arch 429:1-12, 1996. Ojeda VJ, Shilken KB, Walters MNI: Premalignant epithelial lesions of the gallbladder. A prospective study of 120 cholecystectomy specimens. Pathology 17:451-454, 1985. Seeff LB: Natural history of viral hepatitis, type C. Semin Gastrointest Dis 6:20-27, 1995. Weiss JB Jr, Persing DH: Hepatitis C. Advances in diagnosis. Mayo Clin Proc 70:296-297, 1995. West AB, Chatila R: Differential diagnosis of bile duct injury and ductopenia. Sem Diag Pathol 15:270-284, 1998.




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DEVELOPMENTAL AND GENETIC DISORDERS Developmental disorders of the exocrine pancreas include (1) anatomic anomalies such as annular pancreas, pancreas divisum, and ectopic pancreas (e.g., in the stomach, small intestine, or Meckel diverticulum); and (2) hamartomas, cysts, and heterotopic inclusions or choristomas, which most often are composed of splenic or intestinal tissue (Figs. 9-1 and 9-2). These abnormalities occur sporadically and usually are asymptomatic, but an annular pancreas occasionally causes intestinal obstruction. Nesidioblastosis is an anomaly of the endocrine pancreas that is characterized by persistent neonatal hyperinsulinemic hypoglycemia. It occurs in both focal and diffuse forms. In the focal form islet cells form small nodules. In the diffuse form there are distinct insular changes, which are widespread. Histologically the main criteria for establishing the diagnosis are (1) distinct 13-cell hypertrophy with nuclear enlargement, often resulting in giant and bizarre nuclei; (2) the presence of islets of variable size, often of somewhat irregular outline; (3) irregularly sized and poorly defined endocrine cell clusters scattered in the acinar parenchyma; and (4) endocrine cell complexes, often intimately connected with small or larger ducts (ductuloinsular complexes) (Figs. 9-3 and 9-4). Cystic fibrosis is one of the most common autosomal recessive diseases of man and it always involves the pancreas. The disease is related to mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Dysfunction of the CFTR is associated with increased viscosity of the mucus of many exocrine glands, including the pancreas. The viscous mucus stagnates and accumulates in the pancreatic ducts (Fig. 9-5). In advanced stages of the disease chronic obstruction of the pancreas is associated with compression and atrophy of acini, which then are replaced by fibrous tissue (Fig. 9-6).

Fig. 9-3. Diffuse nesidioblastosis. Many cells in this enlarged islet have hypertrophic nuclei.

Fig. 9-I. Annular pancreas. The narrowed duodenum is only probe patent.

A

B

Fig. 9-2. Cyst of the pancreas. A, These cysts, which may be multiple, usually are asymptomatic. B, Cyst is lined by cuboidal epithelium.

Fig. 9-4. Diffuse nesidioblastosis. The irregularly shaped islet is attached to a small duct, forming a ductuloinsular complex.


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Fig. 9-5. Cystic fibrosis. Dilated ducts contain inspissated proteinaceous material.

Fig. 9-6. Cystic fibrosis. In later stages of the disease the dilated ducts filled with eosinophilic material are surrounded by fibrotic parenchyma and atrophic acini.

PANCREATITIS Acute interstitial pancreatitis occurs in the course of many systemic diseases. It may be associated with elevated blood amylase or lipase but usually causes no symptoms. Histologically it presents as interstitial edema accompanied by a sparse inflammatory infiltrate (Fig. 9-7). Viral pancreatitis may be caused by the mumps virus, cytomegalovirus (CMV), and some other viruses (Fig. 9-8). Acute hemorrhagic pancreatitis, which is the most important clinical form of pancreatitis, results from acinar cell injury and intrapancreatic activation of pancreatic lytic enzymes (Diagram 9-1). Proteolytic enzymes digest the walls of blood vessels, which leads to massive hemorrhagic necrosis of the pancreas and adjacent tissues (Fig. 9-9). Blood-filled cavities (pseudocysts) form in the pancreas (Fig. 9-10). Fat necrosis characterized by saponification of fatty acids re -

Fig. 9-8. Viral pancreatitis. The pancreas appears disorganized, and some pancreatic cells contain CMV nuclear inclusions. The loose connective tissue stroma contains scattered inflammatory cells.

Fig. 9-7. Interstitial pancreatitis. The interstitial spaces, which appear dilated because of edema, contain a few inflammatory cells.

Fig. 9-9. Acute hemorrhagic pancreatitis. The pancreas has been completely obliterated by blood.


17 0

Diagram 9-I. A, Pathogenetic relationships of acinar cell injury and duct obstruction to pancreatitis. B, Intrapancreatic mechanisms of enzyme activation in pancreatitis

Fig. 9-10. Acute hemorrhagic pancreatitis. Hemorrhage, fat necrosis, and a pseudocyst filled with blood are seen on cross section.

Fig. 9-1 I. Acute pancreatitis. Foci of fat necrosis appear as white opaque patches.

Fig. 9-12. Acute pancreatitis. In the areas of fat necrosis the fat cells have left their normal outlines and appear eosinophilic. The necrotic pancreatic acinar cells have been transformed into amorphous bluish granular material.

Fig. 9-13. Peritonitis complicating acute pancreatitis. The mesentery shows foci of fat necrosis and hemorrhage. The bloody ascites has been removed.


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leased from damaged fat cells through the action of pancreatic lipase is a typical finding (Figs. 9-11 and 9-12). Complications of acute pancreatitis are massive bloody peritonitis, which typically is accompanied by shock and massive necrosis of mesenteric and omental fat tissue (Fig. 9-13). Large pseudocysts may form at the site of pancreatic tissue destruction (Fig. 9-14). These pseudocysts typically are filled with pancreatic enzymes, which act on the adjacent tissue, continuously promoting necrosis and inflammation (Fig. 9-15). Treatment by marsupialization (i.e., exteriorization of the cyst, allowing its drainage to the outside of the body) may eliminate the enzymes, but the fibrous capsule remains (Fig. 9-16). Chronic pancreatitis may be a late consequence of acute pancreatitis, but more often it is the end result of clinically undetected bouts of recurrent pancreatitis. The disease is a well-known complication of chronic alcoholism. Clinically it is marked by chronic pancreatic insufficiency and malabsorption. The pancreas usually is firm, fibrotic, and focally

calcified. Its obstructed and dilated ducts contain calculi (Fig. 9-17). Histologically the acini are replaced by fibrous tissue and chronic inflammatory cells, which surround the few remaining ducts and islets of Langerhans (Fig. 9-18). Diabetes is seen in approximately 25 percent to 35 percent of cases.

Fig. 9-14. Pancreatic pseudocyst. Cyst filled with hemorrhagic fluid in the tail is extending into the hilum of spleen.

Fig. 9-I5. Pancreatic pseudocyst. The lumen is lined by necrotic material that lacks an epithelial layer.

Fig. 9-16. Pancreatic pseudocyst. After drainage of its content, the pseudocyst appears as a fibrous sac.

Fig. 9-17. Chronic pancreatitis. The main pancreatic duct is dilated and contains calculi. The normal lobular architecture of the pancreas has been lost because most acini have been replaced by fibrous tissue.

Fig. 9-18. Chronic pancreatitis. Connective tissue and foci of chronic inflammatory cells are found surrounding a few scattered ducts and remnants of acini and islets.


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TUMORS OF THE EXOCRINE PANCREAS Benign or malignant neoplasms of the exocrine pancreas may arise from ductal, acinar, and stromal cells. Malignant tumors predominate; ductal adenocarcinoma accounts for 80 percent to 85 percent of pancreatic neoplasms. The World Health Organization histologic classification of tumors of the exocrine pancreas is presented in Table 9-1.

Benign Tumors and Tumors of Borderline Malignancy

Cystadenomas of the pancreas are multicystic tumors that are classified as serous or mucinous (Fig. 9-19). The cystic spaces in serous cystadenoma are filled with clear fluid and lined by flattened cuboidal epithelium (Fig. 9-20). Mucinous cystadenomas are lined by cuboidal mucin—rich epithelium. These tumors are either benign or borderline malignant, and some from the latter group may give rise to invasive cancer. Intraductal papillary mucinous neoplasms represent a group of closely related neoplasms, including benign, borderline malignant, and malignant neoplasms. Overall, they grow slowly and measure from 2 to 4 cm in diameter at di-

agnosis. The benign variant, also called intraductal papilloma, papillary adenoma, or villous adenoma of the pancreatic ducts, is composed of papillae lined by well-differentiated mucin-rich epithelium (Fig. 9-21). Intraductal papillary mucinous tumors of borderline malignancy have complex papillae lined by tall columnar epithelium with moderate nuclear dysplasia (Fig. 9-22). Malignant tumors of this group are indistinguishable from other mucinous adenocarcinomas (Fig. 9-23). Some of these tumors contain foci of borderline and even benign mucinous epithelium, indicating that the malignancy arose through an adenoma-carcinoma sequence similar to the histogenesis of carcinoma of the colon in familial adenomatous polyposis coli. Solid pseudopapillary tumor, also known as solid cystic tumor, refers to a group of tumors that may be benign, borderline, or malignant. These tumors typically occur in young women and present in the form of a solid or partially cystic mass. They measure from 2 to 20 cm in diameter. Histologically they are composed of solid nests of cuboidal cells that have clear or eosinophilic cytoplasm and round to oval nuclei (Fig. 9-24). Tumor cells contain both zymogen and neuroendocrine granules. The tumor is traversed by fibro-

Histologic Classification of Tumors of the Exocrine Pancreas Proposed by the World Health Organization

A B

Fig. 9-19. Serous cystadenoma. A, The tumor is well circumscribed. B, On cross section it appears microcystic.


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Fig. 9-20. Serous cystadenoma. Small cystic spaces are lined by flattened cuboidal epithelium.

Fig. 9-22. Intraductal papillary-mucinous tumor of borderline malignancy. The long papillary folds are lined by tall columnar epithelium showing nuclear crowding, hyperchromasia, and mild to moderate atypia.

Fig. 9-21. Intraductal papillary mucinous adenoma. The duct epithelium forms intraluminal folds lined by well-differentiated mucin-rich epithelium.

Fig. 9-23. Intraductal papillary-mucinous carcinoma.

A

B

Fig. 9-24. Solid pseudopapillary tumor. A, Solid areas are composed of uniform cuboidal cells. B, In the pseudopapillary part of the tumor, cells line or are attached to fibrovascular cores that project into the cystic space.


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vascular septa. Necrosis occurs in more than half of all tumors. In this process only the cells close to the vasculature remain viable, which gives the tumor a pseudopapillary histologic appearance. Invasion and metastases are found in 10 percent to 20 percent of cases, most of which also show a high degree of nuclear atypia.

classified as mucinous (Fig. 9-28), adenosquamous (Fig. 9-29), undifferentiated (Fig. 9-30), or undifferentiated with osteoclast-like multinucleated giant cells (Fig. 9-31). Acinar cell carcinomas are rare tumors composed of cells that resemble acinar cells. Acinar cells may form acini and lobules or solid sheets (Fig. 9-32). Pancreatoblastoma is a tumor of children and adolescents. It is composed of primitive undifferentiated cells that differentiate into epithelial and neuroendocrine cells, occasionally arranged into organoid structures (Fig. 9-33). Other tumors are extremely rare.

Carcinoma of the Pancreas Carcinoma of the pancreas not otherwise specified is a term that usually is reserved for malignant tumors that originate from ductal epithelium. Approximately 60 percent of these tumors are located in the head of the pancreas, 10 percent are in the tail, and the remaining 30 percent are in the body or are diffuse (Figs. 9-25 and 9-26). Histologically most tumors are adenocarcinomas that are graded on a scale from Ito III or are described as well-differentiated, moderately differentiated, or poorly differentiated (Fig. 9-27). Some tumors are

Fig. 9-25. Carcinoma of the body of the pancreas. The tumor has metastasized to the liver.

A

Fig. 9-26. Carcinoma of the tail of the pancreas. The tumor invades the spleen.

B

C

Fig. 9-27. Adenocarcinoma of ductal origin. A, Well-differentiated carcinoma (grade I). Columnar hyperchromatic cells form irregular glands with a "gland within gland" and "back to back " growth pattern. B, Moderately differentiated carcinoma. (grade II). Cuboidal cells form irregular glands that vary in size and shape, eliciting a strong desmoplastic reaction. C, Poorly differentiated carcinoma (grade III). It is composed of a few poorly formed ducts and scattered anaplastic or signet ring—like cells in small clusters. There is a moderate desmoplastic reaction.


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Fig. 9-28. Mucinous (noncystic) carcinoma. Mucin-filled spaces are partially lined by columnar mucin-secreting epithelium.

Fig. 9-29. Adenosquamous carcinoma. Both glandular and squamous elements are evident.

Fig. 9-30. Undifferentiated carcinoma. The tumor is composed of pleomorphic and spindle-shaped cells.

Fig. 9-3I. Undifferentiated carcinoma. The tumor contains numerous osteoclast-like multinucleated giant cells.

A

B

Fig. 9-32. Acinar cell carcinoma. A, Well-differentiated acinar carcinoma is composed of uniform cells with well-developed eosinophilic cytoplasm arranged into acini or acinar tubules. B, Solid acinar carcinoma. The tumor is composed of uniform cells that have round nuclei and welldeveloped eosinophilic cytoplasm. The cells form solid sheets.


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A

B

Fig. 9-33. Pancreatoblastoma. A, The tumor is composed predominantly of primitive cells and only occasional ductlike structures. B, The tumor is composed of duct-like and endocrine cells.

TUMORS OF THE ENDOCRINE PANCREAS Islet cell tumors are rare neoplasms that are found in the general population at a rate of 1 per 100,000. Because the tumors have the features of neuroendocrine cells and presumably have the same origin as islets of Langerhans, they are referred to as neuroendocrine tumors of the pancreas. Clinically they are either benign or malignant. It is not possible to determine on the basis of histology whether a particular tumor is benign or malignant, and the presence of metastases is the only definitive sign that a tumor is malignant. On gross examination neuroendocrine tumors appear as well-circumscribed nodules (Fig 9-34). Some tumors are multiple, and malignant tumors may have local metastases

Fig. 9-34. Islet cell tumor. The tumor presented as a small mass, which was sharply demarcated from the remainder of the pancreas.

in the lymph nodes or liver. Histologically, islet cell tumors resemble neuroendocrine tumors (carcinoids) of the intestine or the bronchi and present in several patterns such as trabecular, insular, glandular, or solid (Fig. 9-35). Some tumors are composed of endocrine and exocrine cells. In some patients with multiple endocrine neoplasia type 1 (MEN 1), islet cell tumors are seen only on microscopic examination and are classified as microadenomas (Fig. 9-36). Islet cell tumors are classified functionally according to which hormone they produce as: (1) insulinoma; (2) glucagonoma; (3) somatostatinoma; (4) PPoma (pancreatic polypeptide—secreting tumor); (5) gastrinoma; (6) VIPoma (vasoactive intestinal polypeptide-secreting tumor); (7) nonfunctioning tumors; and (8) ectopic hormone—secreting tumors. By light microscopy all of these tumors have the same features and cannot be distinguished one from another. Somatostatinomas may contain calcifications (Fig. 9-37), but

Fig. 9-35. Islet cell tumor. Uniform tumor cells with round nuclei are arranged in solid sheets.


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Fig. 9-36. Microadenoma in MEN I. The tumor cells are arranged in a trabecular pattern.

Fig. 9-37. Somatostatinoma. The tumor has a trabecular pattern with focal calcifications.

Fig. 9-38. Islet cell tumor. Immunohistochemically this insulinoma reacted strongly with antibodies to insulin.

this finding does not have enough specificity to allow one to make a definitive diagnosis. Immunohistochemistry and electron microscopy are essential for diagnosis and in most cases provide morphologic confirmation and correlation with the clinical and biochemical laboratory data (Figs. 9-38 and 9-39). Many neuroendocrine tumors of the pancreas are, however, composed of more than one cell population and are i mmunohistochemically polyhormonal.

Fig. 9-39. Islet cell tumor. Immunoelectron microscopy with antibodies to insulin proves that the tumor is an insulinoma.

DIABETES MELLITUS refers to a group of disorders characterized by hyperglycemia that is related to either absolute or relative insulin deficiency. On the basis of clinical, genetic, and immunologic features diabetes is classified as (1) type 1, insulindependent diabetes mellitus (IDDM); (2) type 2, non– insulin-dependent diabetes mellitus (NIDDM); (3) diabetes Diabetes mellitus

secondary to pancreatic disease; (4) diabetes related to overproduction of hormones that antagonize the action of insulin; and (5) gestational diabetes (Table 9-2). Type I diabetes is characterized by an immune-mediated injury of the islets of Langerhans. Infiltrates of T lympho -


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Features of the Main Types of Diabetes Mellitus

Fig. 9-40. Type I diabetes (IDDM). Islet of Langerhans is infiltrated with lymphocytes on the left. On the right side the islet still contains many cells that stain brown with the antibody to insulin.

A

Fig. 9-41. Type I diabetes (IDDM). The islet cells stain with fluorescein-labeled anti-islet autoantibodies typically found in patients with IDDM.

B

Fig. 9-42. Type I diabetes (IDDM). A, After 21 years of disease this patient shows few remaining 13 cells staining with antibodies to insulin (INS). B, There is hyperplasia of a cells staining with antibodies to glucogen (GLU).

Fig. 9-43. Type I diabetes (IDDM). The islets have been replaced to a great extent by fibrous tissue.


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Fig. 9-44. Type 2 diabetes-(NIDDM). Amyloid deposits are seen in the stroma of the islet.

Fig. 9-45. Chronic pancreatitis with diabetes. Fibrous tissue has replaced the acini but has spared the islets, which appear in clusters.

Diabetes of chronic pancreatitis is related to destruction of the pancreas, with fibrosis replacing the lost parenchyma (Fig. 9-45). Although fibrosis preferentially replaces acini, many islets also are destroyed and the number of f3-cells is reduced (Fig. 9-46). The remaining islets usually form irregular clusters surrounded by fibrotic tissue, which impedes the release of insulin into the circulation. Further Reading

Fig. 9-46. Pancreas in advanced chronic pancreatitis. Islets with reduced 13 cell number. (Immunostaining for insulin.)

cytes are seen in early stages of the disease (Fig. 9-40). Affected patients typically develop autoantibodies to islet cells (Fig. 9-41). In the course of the disease the islets lose R cells, an event that maybe accompanied by a hyperplasia of a cells (Fig. 9-42). In some fulminant cases islets may be destroyed (Fig. 9-43). In such cases patients survive only by receiving daily injections of insulin. Type 2 diabetes usually is not associated with specific insular changes. Some patients show hyalinization and/or amyloid deposition in islets (Fig. 9-44).

Klimstra DS: Pancreatoblastoma. A clinicopathologic study and review of the literature. Am J Surg Pathol 19:1371-1389, 1995. Kloppel G, Maillet B: Chronic pancreatitis. Evaluation of the disease. Hepatogastroenterology 38:408-412, 1991. Le Bodic M-F, Heyman M-F, Lecomte M et al: Immunohistochemical study of 100 pancreatic tumors in 28 patients with multiple endocrine neoplasia, type 1. Am J Surg Pathol 20:1378-1384, 1996. Marshall JB: Acute pancreatitis. A review with an emphasis on new developments. Arch Intern Med 153:1185-1198, 1993. Oertel JE: The pancreas. Nonneoplastic alterations. Am J Surg Pathol 13(suppl 1):50-65, 1989. Pettinato G and others: Papillary cystic tumor of the pancreas. A clinicopathologic study of 20 cases with cytologic, immunohistochemical, ultrastructural and flow cytometric observations, and a review of the literature. Am I Clin Pathol 98:478-488, 1992. Steer ML, Waxman I, Freedman S: Chronic pancreatitis. NEngl JMed 332:1482-1490, 1995. Steinberg W, Tenner S: Acute pancreatitis. NEngl JMed 330:1198-1210, 1994. Talamini MA, Pitt HA, Hruban RH et al: Spectrum of cystic tumors of the pancreas. Am )"Surg 163:117-124, 1992. Warshaw AL, Fernandez-del Castillo C: Pancreatic carcinoma. N Engl J Med 326:455-65, 1992.




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Diseases of the endocrine glands present clinically as hypofunctional or hyperfunctional states or as space-occupying lesions caused by neoplastic or nonneoplastic enlargement of the glands. The hypofunction of endocrine glands may be traced to a destruction of parenchymal cells by inflammation, circulatory disturbances, or tumors; hyperfunction may be related to hyperplasia or neoplasia. Major endocrine glands are interrelated, and changes in one gland may produce reactive changes in another gland.

DISEASES OF THE PITUITARY GLAND Hypopituitarism Hypofunction of the pituitary gland maybe related to (1) agen-

esis or congenital hypoplasia; (2) circulatory disturbances; (3) inflammatory disease caused by infections or autoimmune disorders; (4) compression or destruction of the pituitary gland or hypothalamus by space-occupying lesions such as tumors, abscesses, or hematomas; (5) trauma, irradiation, or surgical procedures (Fig. 10-1). Pathologic changes de -

Diagram 10-I. Primary empty sella syndrome. The pituitary is compressed as a result of the increased cerebrospinal fluid pressure. CSF, Cerebrospinal fluid.

Fig. 10-1. Pituitary necrosis caused by ischemia.

Fig. 10-2. Lymphocytic hypophysitis. The anterior pituitary is infiltrated with lymphocytes.

Fig. 10-3. Craniopharyngioma. The tumor is located at the base of the brain and consists of nests of epithelial cells. Calcifications are prominent.

Fig. 10-4. Histiocytosis X. The pituitary gland is infiltrated with Langerhans cells (histiocytes) and eosinophils.


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pend on the primary disease, but ultimately the entire content of the sella turcica may be destroyed, resulting in the socalled empty sella syndrome. Empty sella syndrome related to incomplete or absent sellar diaphragm is called primary empty sella syndrome (Diagram 10-1). If the cause of empty sella syndrome is traced to a destructive disease, it is classified as secondary. Lymphocytic hypophysitis is thought to be an autoimmune disease (Fig. 10-2). Granulomas may be infectious or-idiopathic, as in sarcoidosis. Tumors such as craniopharyngioma or Langerhans cell histiocytosis (histiocytosis X) may destroy the pituitary gland or the hypothalamus, causing hypopituitarism (Figs. 10-3 and 10-4).

Reactive Changes Reactive changes may be seen in the pituitary gland (1) under physiologic conditions, as in pregnancy; (2) as a result of hypofunction of other endocrine glands, as in hypothyroidism or adrenocortical hypofunction (Addison disease); (3) as a result of hypefunction of other endocrine glands, as in hyperadrenocorticism; or (4) as a consequence of a drug effect. The reactive cells enlarge or decrease in size, or show typical cytoplasmic changes such as Crooke hyaline in hyperadrenocorticism (Figs. 10-5 and 10-6). Tumors Tumors of the pituitary gland are mostly benign and are composed of cells equivalent to those normally seen in the pituitary gland. Immunohistochemically they are classified as prolactinomas, or as adrenocorticotropic hormone (ACTH), growth hormone (GH), thyroid-stimulating hormone, (TSH), or gonadotropic hormones (FSH or LH) secreting adenomas. If the immunochemical results are negative or inconclusive, pituitary adenomas are designated null cell adenomas or unclassified adenomas. Tumors composed of oncocytic cells are called oncocytomas. The frequency of various types of pituitary adenomas is listed in Table 10-1.

Fig. 10-5. Reactive hyperplasia of thyrotroph cells in hypothyroidism. The enlarged thyrotroph cells are arranged into acini.

Fig. 10-6. Crooke hyaline. In hyperadrenocorticism adrenocorticotropic cells enlarge because of an accumulation of intermediate filaments in their cytoplasm. These cytoplasmic bodies displace the secretory granules to the subplasmalemmal periphery of cell cytoplasm.

Frequency of Pituitary Adenomas Adenoma Type GH cell adenoma, densely granulated GH cell adenoma, sparsely granulated PRL cell adenoma, densely granulated PRL cell adenoma, sparsely granulated Mixed (GH cell—PRL cell) adenoma Mammosomatotroph adenoma Acidophil stem cell adenoma Corticotroph adenoma Silent "corticotroph" adenoma, subtype I Silent "corticotroph" adenoma, subtype 2 Silent adenoma, subtype 3 Thyrotroph adenoma Gonadotroph adenoma Null cell adenoma Oncocytoma Unclassified adeno

Percentage 7.2 6.4 0.4 26.5 3.7 I.3 1.7 9.9 1.5 2.1 1.4 1.0 9.3 12.7 13.1 1.8

GH, Growth hormone; PRL, prolactin. *Based on unselected surgical material involving 1910 cases.

Fig. 10-7. Pituitary adenoma. The tumor protrudes from the sella turcica.


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On the basis of their size, pituitary tumors are classified as microadenomas (if they are smaller than 10 mm in diameter) or macroadenomas (if they are larger than 10 mm in diameter) (Figs. 10-7 and 10-8). On the basis of their morphology on routine hematoxylin-eosin—stained slides, pituitary adenomas traditionally were classified as acidophilic, basophilic, or chromophobic (Fig. 10-9). This classification did not provide useful correlates with clinical or biochemical data, and it has been replaced by a functional classification based on immunohistochemical and electron microscopic typings of tumor cells (Figs. 10-10 and 10-11). Pituitary carcinomas are rare, locally invasive tumors that account for 2 percent to 3 percent of all pituitary neoplasms. Histologically it is not possible to distinguish with confidence adenomas from carcinomas, except in rare cases in which the malignant tumor is highly anaplastic. A

Fig. 10-8. Pituitary adenoma. On cross section the tumor nodule is sharply demarcated from the normal pituitary. B

C

Fig. 10-9. Pituitary adenomas A, Acidophilic. B, Basophilic. C, Chromophobic. A

B

Fig. 10-10. Prolactin cell adenoma. A, Small tumor cells are staining with antibody to prolactin. B, By electron microscopy the tumor cells show extrusion of small granules at the lateral cell membranes ("misplaced exocytosis").


185

A

B

Fig. 10-I I. Corticotroph adenoma. A, ACTH-positive tumor cells form solid nests. B, By electron microscopy the tumor cells contain 250 to 450 nm granules.

DISEASES OF THE THYROID GLAND Disorders of thyroid function are commonly diagnosed in clinical practice. Hypothyroidism or hyperthyroidism may be associated with distinct morphologic changes, but in most instances it is not possible to predict functional thyroid abnormalities from the morphologic data alone.

Thyroid Hyperplasia Hyperplasia typically causes enlargement of the thyroid gland (goiter), which may be either nodular or diffuse. Hyperplasia of the thyroid gland may result from hyperstimulation by (1) TSH, (2) antibodies to TSH receptor, (3) iodine deficiency, (4) goitrogens in food, or (5) drugs. Idiopathic nodular goiter is the most common cause of thyroid enlargement, affecting 3 percent to 5 percent of the population at large. In one form or another it is found in ap-

proximately 50 percent of autopsies in adults. It presents as a mass that causes enlargement of the thyroid gland without hormonal abnormalities. The thyroid gland is asymmetrically nodular and may compress surrounding structures (Fig. 10-12). Histologically it is composed of colloid-filled follicles that vary in size and shape. Follicles are lined by cuboidal or flattened epithelium, which may show focal papillary hyperplasia (Fig. 10-12). Secondary degenerative changes are common and include fibrosis, hyalinization, calcification, foci of hemorrhage, cholesterol crystals, and cystic degeneration. Foci of secondary proliferation composed of cells arranged in a microfollicular or solid pattern may be seen in some nodules, which otherwise are composed only of large dilated follicles. Some nodules may acquire adenoma-like properties, but in general nodular goiter is not a direct precursor of thyroid cancer.

A

B

Fig. 10-12. Nodular goiter. A, The thyroid gland is enlarged and consists of nodules that vary in size and shape. B, The thyroid gland is composed of follicles arranged into clusters, imparting a nodular appearance to the gland. Foci of hemorrhage and chronic inflammation are present.


18 6

B A

Fig. 10-13. Graves disease. A, The thyroid gland is symmetrically enlarged. B, On cut section the thyroid gland appears moist and hyperemic and lacks normal colloidal appearance.

Graves disease is an autoimmune disorder caused by stim-

ulation of the thyroid gland by antibodies to the receptor for TSH (Diagram 10-2). The thyroid gland is diffusely enlarged, and on cross section it appears hyperemic, moist, and soft (Fig. 10-13, B). Histologically the follicles are lined by hyperplastic, tall columnar, vacuolated cells with basally located nuclei. The epithelium often projects into the lumen of follicles in the form of small papillary infoldings. Oncocytic changes may be evident but usually are not prevalent. The colloid is pale and often shows peripheral scalloping (Fig. 10-14). The stroma is vascular and mildly fibrotic and may contain lymphoid cell aggregates.

Thyroiditis

Diagram I0-2. Pathophysiologic mechanism of Graves disease. A defect in suppressor T-lymphocytes is responsible for the excessive production of autoantibodies to TSH receptor causing enlargement of the thyroid gland and excessive production of triiodothyronine (T 3 ) and thyroxine (T 4). The excess of T 3 and T4 results in the suppression of thyrotropin-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) production.

Nonspecific lymphocytic thyroiditis is a disease of no clinical significance, commonly diagnosed at autopsy (Fig. 10-15). Other forms of thyroiditis that may cause clinical symptoms are less common but may be associated with specific clinical symptoms (Table 10-2). Subacute thyroiditis, also known as granulomatous or de Quervain thyroiditis, is characterized by painful enlargement of the thyroid gland, low-grade fever, and hyperthyroidism of sudden onset, usually following a viral infection. Histologically it is characterized by a granulomatous giant cell and lymphocytic reaction around the colloid released from ruptured follicles. (Fig. 10-16). Hashimoto thyroiditis is an autoimmune thyroid disease that may occur either in an isolated form or conjointly with other autoinunune diseases such as atrophic gastritis or primary biliary cirrhosis. It most often occurs in women, and the female-male ratio is 8:1. Most patients initially are euthyroid, but as destruction of the thyroid gland advances they may develop signs of hypothyroidism. Occasionally there is


187

A

B

Fig. I0-14. Graves disease. A, Follicles are lined by tall columnar epithelium. The colloid adjacent to the epithelium appears vacuolated and scalloped. Some follicles contain very little colloid. B, Marked hyperplasia of the epithelium is seen, and the follicles contain almost no colloid. The stroma contains lymphocytes.

Fig. 10-15. Nonspecific lymphocytic thyroiditis. The thyroid gland is infiltrated focally with lymphocytes and plasma cells. The follicular epithelium shows no significant changes.

hyperthyroidism ( " hashitoxicosis"). The thyroid gland typically is enlarged to three or four times its normal size (Fig. 10-17). Histologically the gland is infiltrated with lymphocytes and plasma cells, which form lymphoid follicles with germinal centers. Thyroid follicles are destroyed and replaced in part by the infiltrate. The remaining follicles are atrophic and often devoid of colloid. Widespread oncocytic change (i.e., transformation of epithelium into cuboidal cells with mitochondria-rich, eosinophilic, granular cytoplasm) is typical. Other epithelial changes such as nodular hyperplasia or squamous metaplasia are less common. Hashimoto thyroiditis is associated with an increased risk for lymphoma. Several histologic and clinical variants of Hashimoto thyroiditis have been recognized. The most common is the fibrous variant, which accounts for 10 percent of cases (Fig.

Fig. 10-16. Subacute granulomatous thyroiditis. Multinucleated giant cells surround residual colloid in a follicle.

Forms of Thyroiditis Type of Thyroi Nonspecific lymphocytic Acute bacterial Subacute (granulomatous) Hashimoto

Riedel

Clinical Features Common finding at autopsy; asymptomatic Rare; related to head and neck infections, sepsis, or surgery Rare; probably related to viral disease; sudden onset of painful swelling Clinically the most important autoimmune thyroiditis; leads to hypothyroidism but often euthyroid; "hashitoxicosis" rare Rare; fibrosing destruction of thyroid extending into adjacent tissue ("ligneous" thyroiditis)


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A

B

C

Fig. 10-17. Hashimoto thyroiditis. A, The enlarged thyroid has a multinodular, whitish appearance, which stems from lymphoid infiltrates and loss of colloid-filled follicles. B, A lymphoid follicle with a germinal center and diffuse lymphocytic infiltrates replace the thyroid follicles. The epithelium of the remaining follicles shows oncocytic transformation. C, Thyroid follicles devoid of colloid are lined by oncocytic cells that have eosinophilic granular cytoplasm and round vesicular nuclei.

10-18). It is characterized by fibrosis and prominent hypothyroidism, even though the thyroid gland is enlarged. Atrophic thyroiditis (idiopathic myxedema) is characterized by a loss of follicles and atrophy of the gland, and although its etiology is not known this disease might represent an outcome of Hashimoto disease. Juvenile thyroiditis is a variant that occurs in children and young women. In contrast to classic Hashimoto thyroiditis, the epithelium does not show oncocytic changes but may be hyperplastic. Closely related to it is the so-called painless thyroiditis, also known as silent thyroiditis or self-resolving lymphocytic thyroiditis with hyperthyroidism. Histologically it may present as lymphocytic or granulomatous inflammation but without multinucleated giant cells. The epithelium shows either oncocytic or hyperplastic changes. Riedel thyroiditis, also known as invasive fibrous thyroiditis, is a rare cause of hypothyroidism that is characterized by extensive fibrosis, which replaces most of the thyroid parenchyma and extends into adjacent neck structures. The process may be focal or diffuse. Histologically, collagenous bands are found replacing thyroid follicles. The remaining follicles are atrophic. Lymphocytes and plasma cells are found between the strands of connective tissue, around the blood vessels, and typically in the walls of small veins (Fig. 10-19).

Benign Thyroid Tumors Most thyroid tumors are of epithelial origin; a minority arise from stromal cells or lymphoid tissue. Benign tumors are more common than malignant tumors, which, however, present a more formidable challenge from both the diagnostic and the therapeutic point of view. Follicular adenoma is a benign encapsulated tumor that shows evidence of follicular differentiation (Figs. 10-20 and 10-21). It presents as a solitary " cold" nodule on isotopic scanning with radioactive iodine - and is surrounded by normal or compressed thyroid follicles. It should not be confused with nodular hyperplasia, which typically produces multiple nodules. Microscopically the tumor may present in one of several patterns and is classified as trabecular, solid (embryonal), microfollicular (fetal), normofollicular (simple), or macrofollicular (colloid) adenoma. These descriptive terms have no biologic or clinical implications. Hyperplastic changes in the form of papillary or pseudopapillary structures may occur (Fig. 10-22). Variants of follicular adenoma that deserve additional studies are (1) atypical follicular adenoma; (2) hyalinized trabecular adenoma; (3) adenoma with bizarre nuclei; and (4) oncocytic (HUrthle cell) adenoma. Atypical follicular adenomas show less regular architectural and cytologic features than typical adenomas. Hyalinized trabecular adenoma shows


189

Fig. 10-18. Fibrous variant of Hashimoto thyroiditis. Fibrous tissue infiltrated with lymphocytes is replacing the follicles, few of which remain.

Fig. 10-19. Riedel thyroiditis. Diffuse fibrosis and inflammatory cells such as lymphocytes and plasma cells have replaced the thyroid follicles. A medium-sized vein shows signs of vasculitis (arrow).

Fig. 10-20. Follicular adenoma. The well-circumscribed nodule has a fibrous capsule separating it from the normal parenchyma. On cross section the tumor appears yellow-tan with focal hemorrhage.

Fig. 10-21. Follicular adenoma, microfollicular pattern. Tumor cells form small follicles.

Fig. 10-22. Follicular adenoma with papillary hyperplasia. Short papillary projections lined by follicular cells have almost no fibrovascular cores.


190

Fig. 10-23. Follicular adenomas, hyalinizing trabecular pattern. Tumor cells are arranged into nests reminiscent of the "Zellballen" of paraganglioma.

Fig. 10-24. Follicular adenoma with bizarre nuclei. Clusters of cells with huge, irregularly shaped nuclei are admixed with smaller cells that have a solid growth pattern.

prominent perivascular hyalinization and collagenous strands that subdivide the parenchyma into trabeculae or solid nests reminiscent of " Zellballen" of paragangliomas (Fig. 10-23). Adenoma with bizarre nuclei is characterized by clusters of cells that have gigantic hyperchromatic nuclei (Fig. 10-24). Oncocytic (Hurthle cell) adenoma consists of solid nests of cuboidal cells that have round uniform nuclei and eosinophilic granular or clear cytoplasm (Fig. 10-25).

Malignant Thyroid Tumors

Fig. 10-25. Hurthle cell adenoma. Tumor cells arranged into solid sheets have abundant eosinophilic cytoplasm, large nuclei, and prominent nucleoli.

Malignant thyroid tumors include carcinomas, sarcomas, and lymphomas. The salient features of carcinomas, which account for the vast majority of tumors, are given in Table 10-3. Papillary carcinoma is the most common malignant tumor of the thyroid gland. It occurs more often in women than in men, with a ratio of 2.5:1. It may occur at any age,

Natural History of Different Types of Thyroid Carcinoma Arising from Follicular Cells


191

Fig. 10-26. Papillary carcinoma. This large tumor, which almost completely replaces one thyroid lobe, appears solid with some unevenness on cross section.

Fig. 10-27. Papillary carcinoma. Tumor cells line branching papillae. Numerous blue-stained psammoma bodies are seen in the connective tissue stroma.

Fig. 10-28. Papillary carcinoma. Tumor cell nuclei have a clear " "ground glass appearance.

but the mean age of patients at diagnosis is 35 to 40 years. The size of the tumor varies from microscopic to several centimeters in diameter, with the mean being 2.5 cm. It may be solid or cystic, and multicentric foci are seen in 20 percent of cases on gross examination (Fig. 10-26). The microscopic diagnosis of papillary carcinoma is made on the basis of architectural features, such as papillae, and nuclear features, such as optically clear nuclei ( "ground glass" or "Orphan Annie " nuclei), or nuclear pseudoinclusions and grooves (Figs. 10-27 and 10-28). In addition to papillary proliferation, almost all tumors also show a follicular component. Metastases to local lymph nodes are common.

Fig. 10-29. Papillary carcinoma, follicular variant. Cuboidal tumor cells with clear cytoplasm line colloid-filled spaces. Wide fibrous strands incompletely divide the tumor into lobules.

Variants of papillary carcinoma include (1) papillary microcarcinoma, (2) encapsulated variant, (3) follicular variant, (4) diffuse sclerosing variant, (5) tall cell variant, and (6) columnar cell variant (Figs. 10-29 to 10-31). Follicular carcinoma is a tumor composed of neoplastic cells that form follicles. It occurs more often in women than in men, and the average age at diagnosis is 10 years more than


192

Fig. 10-30. Papillary carcinoma, solid growth pattern. The tumor has a predominantly solid pattern.

Fig. 10-31. Papillary carcinoma, diffuse sclerosing variant. The tumor contains prominent connective tissue strands infiltrated with lymphocytes and psammoma bodies. Papillae lined by tumor cells project into the lumen of endothelium-lined spaces.

Fig. 10-32. Follicular carcinoma, minimally invasive type. On gross examination this tumor appears well circumscribed.

Fig. 10-33. Follicular carcinoma, minimally invasive type. The neoplastic cells extend across the full thickness of the capsule into the normal parenchyma.

Fig. 10-34. Follicular carcinoma, widely invasive type. Tumor cells form irregular, almost solid sheets.

Fig. 10-35. Follicular carcinoma. Follicles are lined by cells that have clear cytoplasm.


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Fig. 10-36. Oncocytic (Hiirthle cell) carcinoma. This encapsulated tumor has a tan color with central areas of necrosis and hemorrhage

Fig. 10-37. Oncocytic carcinoma. Tumor cells invade capsular vessels.

for papillary carcinomas (i.e., 45 to 50 years). Two subtypes are recognized: a minimally invasive or encapsulated form and a widely invasive form. Minimally invasive follicular carcinoma grows as an encapsulated nodule that usually exceeds 1 cm in diameter (Fig. 10-32). Histologically it resembles follicular adenoma, especially the embryonal, fetal, and atypical types. Tumor cells penetrate the capsule and extend into the surrounding thyroid tissue (Fig. 10-33). Widely invasive follicular carcinoma usually is not encapsulated but shows widespread invasion of the adjacent thyroid parenchyma and blood vessels. A solid or trabecular growth pattern is seen (Fig. 10-34). Nuclear atypia, hyperchromasia, numerous mitoses, and areas of necrosis are prominent. Clear cell change may occur focally but also may be widespread (Fig. 10-35). Metastases, which usually are blood borne, most often are seen in the lungs and bones.

Oncocytic carcinomas are more aggressive than classic follicular carcinomas and are thus a distinct entity. They may be encapsulated, but they also may invade the adjacent parenchyma, usually in a multinodular manner (Fig. 10-36). Histologically the tumors are composed of oncocytic cells arranged in a follicular pattern (Fig 10-37). Rarely, some tumors show a trabecular pattern, and a papillary pattern is even more rare. Medullary carcinoma is composed of cells that show differentiation into C cells. These tumors occur in sporadic and familial forms in the context of multiple endocrine neoplasia ( MEN) syndromes types 2A and 2B. They account for 10 percent of all thyroid malignancies (Table 10-4). Medullary carcinomas range in size; they may be barely visible or may replace the entire thyroid. The larger lesions are sharply circumscribed but not encapsulated (Fig. 10-38). Individual

Type 2 Multiple Endocrine Neoplasia (MEN) Syndromes*

*Rarely, familial forms of medullary carcinoma may occur in the absence of other endocrine abnormalities. tin a small number of families, type MEN 2A has occurred in association with hereditary cutaneous lichen amyloidosis.


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Fig. 10-38. Medullary carcinoma. The thyroid gland contains well-demarcated tan nodules.

Fig. 10-39. Medullary carcinoma. Groups of cells form lobules, which are surrounded by stroma containing deposits of amyloid that stain red with Congo red.

A

B

Fig. 10-40. Medullary carcinoma. A, Solid growth pattern. B, Lobular growth pattern.

tumor cells may be round, polygonal, oval, or spindleshaped. The stroma is abundant and typically contains amyloid (Fig. 10-39). Histologically the tumor may have a solid, lobular, or insular growth pattern (Figs. 10-40). Variants of medullary carcinoma include (1) follicular or tubular, (2) papillary, (3) pseudopapillary, (4) small cell, (5) giant cell, (6) oncocytic, (7) clear cell, (8) melanocytic, (9) squamous, and (10) amphicrine types (Fig. 10-41). Undifferentiated (anaplastic) carcinomas are rare, accounting for 10 percent to 25 percent of thyroid malignancies. These tumors typically occur in old age and are as common in women as in men. They present as a rapidly enlarging mass, with broad areas of necrosis that invade the surrounding neck structures. Histologically they show three distinct patterns known as spindle cell, giant cell, and squamoid. These different cell types often are intermixed (Fig. 10-42). Cellular pleomorphism, high mitotic activity, areas of necrosis, and in-

vasion into adjacent structures typically are found. These tumors grow fast, metastasize widely, and have a poor prognosis. Poorly differentiated carcinoma is a recently described type of thyroid cancer that occupies an intermediate position between well-differentiated follicular and papillary carcinomas and undifferentiated (anaplastic) carcinomas. Histologically these tumors show a solid trabecular or microfollicular pattern (Fig. 10-43). Solid nests tend to retract from the connective tissue stroma, imparting an " insular" pattern. As a result of widespread necrosis that spares only the perivascular cells, a "peritheliomatous " pattern may be prominent. In most cases these tumors represent poorly differentiated follicular carcinomas, but occasionally they may arise from papillary carcinomas. Immunohistochemically the tumors are positive for thyroglobulin and keratin and negative for calcitonin, which distinguishes them from medullary carcinoma. Metastases are common and occur hematogenously.


195

A

B

Fig. 10-41. Medullary carcinoma. A, Follicular variant. B, Small cell variant.

Fig. 10-42. Undifferentiated carcinoma. The tumor is composed of spindle-shaped and giant cells.

DISEASES OF THE PARATHYROID GLANDS Hypoparathyroidism is a rare disease that most often is related to inadvertent removal of the parathyroid glands during neck surgery or radiotherapy. Other causes include genetic diseases such as DiGeorge syndrome, metabolic disorders that destroy the parathyroid glands such as hemochromatosis, and pluriglandular endocrine autoimmune disorders. Hyperparathyroidism is classified clinically as primary if the cause lies primarily in the parathyroid glands or secondary if the cause is outside the parathyroid glands. In the latter case the glands become hyperfunctioning in response to the altered homeostasis of calcium and phosphate caused

Fig. 10-43. Poorly differentiated carcinoma. The neoplastic cells form solid nests surrounded by connective tissue stroma that shows artificial retraction from tumor nests.

by a kidney, bone, or intestinal diseases (Diagrams 10-3 and 10-4). Parathyroid hyperplasia, whether primary or secondary, shows the same morphologic changes. All four glands are enlarged, although not to the same extent (Fig. 10-44). Histologically the glands are composed of a mixture of chief, oxyphil, and transitional oxyphil cells arranged into cords, sheets, and follicles (Fig. 10-45). Hyperplastic glands composed exclusively of clear cells rarely are found but usually are associated with severe hypercalcemia. Parathyroid adenoma usually presents in the form of nodular enlargement of one parathyroid gland while the other three glands are of normal size (Fig. 10-46). Histologically most parathyroid adenomas are composed of chief cells


196

Diagram I0-3. Control of calcium metabolism. Parathyroid hormone (PTH) acts primarily on the bone and kidneys, whereas vitamin D (D) metabolites act on the intestines, bone, and parathyroid glands. Calcium-ion concentration acts on the parathyroid glands and the thyroid C cells. In humans calcitonin appears to play a relatively insignificant role in the rapid regulation of calcium metabolism. All effects of PTH and vitamin D (+) tend to elevate the ionic serum calcium, and such elevation results in a negative feedback on PTH. Calcitonin acts in opposition to PTH in most experimental conditions.

Diagram I 0-4. Human calcium balance in a young adult in calcium balance. Of the total dietary calcium 200 mg per day is actually absorbed and excreted through the kidneys and sweat glands. The bone exchange is 640 mg per day.

Fig. 10-45. Parathyroid hyperplasia. Indistinct nodules composed of chief and oxyphil cells are surrounded by loose connective tissue stroma. Only a few fat cells remain inside the parenchyma.

Parathyroid carcinoma is a rare tumor, accounting for 1 Fig. 10-44. Parathyroid hyperplasia. All four glands are enlarged, albeit not to the same extent.

that form solid sheets, nests, or acini (Fig. 10-47). Adenomas of oxyphil cells are less common. Nuclei of tumor cells usually are of normal size and uniform, but in 10 percent of adenomas there are multinucleated cells and even giant cells (Fig. 10-48).

percent to 2 percent of all cases of primary hyperparathyroidism. The tumor has an invasive growth pattern and tends to metastasize. Histologically it is composed of cells that resemble watermelon seeds arranged into solid sheets rimmed by thick ocellular fibrous bands (Fig. 10-49). Cells tend to be uniform. The presence of nuclear atypia, variation, and giant cells speaks against the diagnosis of malignancy; such cellular changes more often are found in adenomas than in carcinomas of the parathyroid glands.


197

Fig. 10-47. Parathyroid adenoma. The tumor is composed almost entirely of chief cells arranged into uniform sheets, cords, and pseudofollicles, which are best seen in the left lower portion of the photograph.

Fig. 10-46. Parathyroid adenoma. The enlarged gland (3 X 2.5 cm) is teardrop-shaped, nodular, and yellow-tan beneath its thin translucent capsule.

Fig. I 0-48. Parathyroid adenoma. Tumor cell nuclei vary in size and shape.

A

B

Fig. 10-49. Parathyroid carcinoma. A, Solid sheets of tumor cells are traversed by thick fibrous septa, as seen in this trichrome-stained specimen. B, Large watermelon-shaped cells have regular nuclei. Cells show palisading around a centrally placed vessel.


198

DISEASES OF THE ADRENAL CORTEX Adrenocortical Insufficiency Insufficiency or hypofunction of the adrenal cortex may be diagnosed in any age group and may be related to (1) congenital disorders, such as congenital adrenal hypoplasia, familial glucocorticoid deficiency, or adrenoleukodystrophy; (2) deposition of amyloid in amyloidosis or hemosiderin in hemochromatosis; (3) circulatory disorders such as massive bilateral hemorrhage in Waterhouse-Friderichsen syndrome; (4) infections, such as tuberculosis, histoplasmosis, and viral infections with cytomegalovirus (CMV), herpes simplex, or varicella-zoster virus; (5) autoimmune adrenalitis, which may be limited to the adrenal glands or may be part of a pluriglandular syndrome. Schmidt syndrome, which includes adrenocortical insufficiency and hypothyroidism, probably is such an autoimmune disease. If no obvious causes are found, adrenocortical insufficiency is designated idiopathic Addison disease.

Fig. 10-50. Adrenoleukodystrophy. The cytoplasm of large ballooned cortical cells contains cleftlike spaces caused by extraction of lipid.

Fig. 10-52. CMV infection. Adrenal cells appear enlarged and contain viral inclusions. Infection is associated with necrosis.

Adrenoleukodystrophy is an inborn defect of metabolism of fatty acids that affects peroxisomes. Three clinical forms are recognized: infantile, juvenile (childhood onset), and adult. Adrenocortical insufficiency accompanies the more prominent central nervous system symptoms. The adrenal glands are small, but the cortical cells appear enlarged and have a striated or ballooned cytoplasm (Fig. 10-50). Lipid accumulation is thought to have cytotoxic defects in both the adrenal glands and the brain. Amyloidosis is a rare cause of adrenocortical insufficiency. Amyloid deposits are found in the sinusoids and in the walls of larger blood vessels. Amyloid deposits cause atrophy of adrenal cells, and ultimately the entire gland may be replaced by amyloid (Fig. 10-51). Such deposits usually are found in secondary amyloidosis and represent AA amyloid.

Fig. 10-51. Amyloidosis. Eosinophilic hyaline material has replaced most of the cortical cells.

Fig. 10-53. Histoplasmosis. Histiocytes filled with round to oval structures are found between adrenocortical cells.


199

Infectious adrenalitis caused by bacteria, viruses, or fungi is accompanied by adrenocortical cell loss. CMV has a distinct tropism for adrenocortical cells, and adrenal involvement is found in 50 percent of patients with acquired immunodeficiency syndrome (AIDS) (Fig. 10-52). In systemic histoplasmosis the adrenal glands often are involved (Fig. 10-53). In severe cases the entire adrenal gland may be destroyed. In tuberculosis the gland is replaced to a large extent by caseating granulomas, and in advanced stages it often is accompanied by calcifications (Fig. 10-54). Immune-mediated adrenalitis is currently the most common cause of adrenal inflammation. The adrenal glands are infiltrated with lymphocytes that destroy the adrenocortical cells until no cortex remains (Fig. 10-55). In chronic stages of Addison disease the adrenal glands have almost no cortex and are reduced to only the medulla.

Fig. 10-54. Tuberculosis. Caseating granulomas are partially replacing the parenchyma of the adrenal gland.

A

B

Fig. 10-55. Autoimmune adrenalitis. A, Adrenal gland is infiltrated with lymphocytes arranged into a follicle. B, Most of the cortex has been destroyed.

Adrenocortical Hyperplasia and Hyperfunction Hyperfunction of the adrenal cortex may present as several clinical syndromes: (1) hyperaldosteronism (Conn syndrome), (2) hypercortisolism (Cushing syndrome), or (3) adrenogenital syndrome. Hypercortisolism is considered primary if it is caused by adrenocortical hyperplasia or neoplasia; secondary hyperplasia develops as a result of overstimulation of the adrenal cortex by the pituitary gland or ACTH-secreting tumors (Diagram 10-5).

Adrenocortical hyperplasia may be diffuse or nodular (Figs. 10-56 and 10-57). In typical Cushing disease caused by an ACTH-secreting pituitary adenoma, the cortex is thicker than 2 mm because of an increase in the thickness of the zona fasciculata (Fig. 10-58).Adrenocortical cells of the inner zona fasciculata have eosinophilic cytoplasm as a result of the conversion of lipid-rich cells to more compact lipid-depleted cells. Hyperplastic cells may extend into periadrenal fat, forming microscopic nodules. Macronodular hyperplasia rarely occurs. Macronodular hyperplasia more often is a sign


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Fig. 10-56. Diffuse adrenocortical hyperplasia.

Fig. I 0-57. Nodular adrenocortical hyperplasia on cross section. The adrenal gland shows several yellow nodules that measure up to I cm in diameter.

Fig. I0-58. Adrenocortical hyperplasia in Cushing disease. The cortex appears thickened. The zona fasciculata consists of clear and lipid-depleted compact cells.

Fig. I0-59. Macronodular hyperplasia of adrenal in Cushing syndrome. The nodules are composed of pale lipid-rich cells.

Fig. 10-60. Primary pigmented nodular adrenocortical disease (PPNAD). The adrenal contains darkly pigmented nodules.

Fig. 10-6I. PPNAD. Adrenal cells have eosinophilic cytoplasm that is rich in lipofuscin (brown). There also is an area of lipomatous metaplasia.


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Ectopic ACTH (or CRF) Syndrome Diagram 10-5. A, Pituitary-dependent form of hypercortisolism (Cushing disease) is usually caused by an ACTH-producing microadenoma of the pituitary gland. ACTH levels may be in the normal range or only mildly elevated. B, Autonomous secretion of cortisol by an adrenocortical neoplasm. ACTH levels tend to be very low or undetectable. C, With ectopic secretion of ACTH (or rarely corticotropin-releasing factor) levels of circulating ACTH typically are higher than in Cushing disease and sometimes are greatly elevated. Some tumors may secrete corticotropinreleasing factor (CRF)

of primary adrenal disease in which the Cushing syndrome is caused by autonomous hyperfunction of adrenocortical cells (Fig. 10-59). Primary pigmented nodular adrenocortical disease (PPNAD) is a rare ACTH-independent hypercortisolism. PPNAD is a descriptive term that has no particular reference to underlying pathogenesis. The adrenal glands are enlarged and show pigmented nodules on their surface and on cross section (Fig. 10-60). Histologically the micronodules appear to reside in the zona reticularis and may encroach slightly on the medulla (Fig. 10-61). Most of the cells in these nodules have compact eosinophilic cytoplasm and contain variable amounts of lipochrome pigment.

Adrenocortical Tumors Adrenocortical tumors are classified as benign (adenomas) or malignant (carcinomas). These tumors may secrete one or more hormones and are classified clinically as inactive or active. Hormone-producing tumors may be associated with typical adrenocortical syndrome (Cushing, Conn, or adrenogenital syndrome) or with generalized adrenocortical hyperfunction that combines some features of all three syndromes. Adenomas are benign, sharply circumscribed nodules that are attached to the adrenal gland or more often completely replace it. Tumors removed from patients with Cushing syndrome usually weigh less than 50 g and measure 3 to 4 cm in diameter (Fig. 10-62). On cross section most tumors are

Fig. 10-62. Adrenal adenoma on cross section. The tumor appears deep orange with tan-brown geographic areas composed of lipid-depleted cells that are rich in lipofuscin.

Fig. 10-63. Adrenal adenoma. The tumor is composed of pale li pid-rich cells.


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yellow, but some are brown and may have a variegated appearance. Histologically they are composed of pale lipidladen cells resembling those of normal zona fasciculata (Fig. 10-63). Aldosterone-secreting adenomas of Conn syndromes usually are small intraadrenal nodules that measure less than 3 cm in diameter (Fig. 10-64). On cross section these tumors are homogeneously yellow-orange or canary-yellow, but larger tumors may show degenerative changes. Histologically they are composed of alveolar ducts, short cords, or anastomosing trabeculae (Fig. 10-65). Cells may have clear or granular eosinophilic cytoplasm, and occasional intranuclear pseudoinclusions are seen. Nuclei are round and uniform, but sometimes there is considerable nuclear variation.

Fig. 10-65. Aldosterone-producing adrenocortical adenoma. The tumor is composed of cortical cells that have granular cytoplasm. Spironolactone bodies appear as round cytoplasmic inclusions. Inset shows spironolactone bodies stained with Luxol fast blue.

A

Fig. 10-64. Aldosterone-producing adrenocortical adenoma. The tumor is yellow-orange and sharply circumscribed.

Fig. 10-66. Adrenocortical carcinoma resected from a teenaged girl with virilization. The tumor weighs more than 1000 g, and on cross section it is coarsely nodular with extensive areas of necrosis.

B

Fig. 10-67. Adrenocortical carcinoma. A, Histologically the tumor is composed of cells arranged into broad trabeculae. B, Tumor cells have voluminous compact eosinophilic cytoplasm and large pleomorphic nuclei with prominent pseudoinclusions.


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Some tumor cells contain round cytoplasmic bodies that are known as spironolactone bodies. The histologic appearances may vary from one microscopic field to another. Adrenocortical carcinomas are rare malignant tumors that occur at a rate of 2 per million. These tumors may be found in any age group, and functionally they are either active or inactive. Tumors vary in size, typically measuring over 12 cm in diameter and weighing on average 1000 g (Fig. 10-66). Areas of necrosis, cystic degeneration, hemorrhage, and invasion of adjacent tissues are apparent in large tumors,,Histologically the cells show considerable pleomorphism, and atypical mitoses may be seen (Fig. 10-67). Growth patterns have been described as trabecular, alveolar, or diffuse. There are no reliable differences between adrenocortical adenomas and carcinomas. Empiric data indicate that in adults most tumors that weigh less than 50 g are benign, whereas those that weigh more than 95 g tend to be malignant. On microscopic examination the following features are most predictive of malignancy: (1) broad fibrous bands, (2) diffuse growth pattern, (3) vascular invasion, (4) mitotic rate greater than 5 per 50 high-power fields, and (5) atypical mitoses. In a small but significant number of cases, it is not possible to predict the biologic behavior of tumors, most of which weigh between 100 and 400 g. Adrenocortical carcinomas are highly malignant tumors that metastasize through the lymphatics or hematogenously. In most cases they cause death within 12 months of diagnosis.

DISEASES OF THE ADRENAL MEDULLA Hyperplasia of adrenal medullary cells is seen most convincingly in patients with MEN syndrome type 2 (Fig. 10-68). It also occurs in Beckwith-Wiedemann syndrome and in some patients with paroxysmal attacks of hypertension that are suggestive of pheochromocytoma. The distinction between

Fig. I0-68. Adrenal medullary hyperplasia. There is nodular expansion of the medulla.

hyperplasia and small pheochromocytomas is, however, arbitrary. By convention most nodules larger than 1 cm in diameter are considered to represent true neoplasms. Pheochromocytoma is a tumor composed of cells that resemble normal adrenal medullary cells. Pheochromocytomas occur in the general population at a rate of 8 per million. As a general rule, 90 percent of tumors are functional, causing hypertension, and 10 percent are nonfunctional; 90 percent are located in the adrenal, and 10 percent are located in sympathetic ganglia; 90 percent are unilateral and 10 percent are bilateral; 90 percent are benign and 10 percent are malignant. On gross examination the tumors are sharply circumscribed, grayish or brownish-tan nodules that may resemble adrenocortical neoplasms (Fig. 10-69). Most surgically resected tumors weigh approximately 100 g and measure 3 to 5 cm in diameter. On cross section they appear grayish or dusky red. Degenerative changes such as fibrosis, necrosis, cystic degeneration, and hemorrhage are seen in larger tumors. Invasive growth is a feature of malignant types. Histologically three major architectural patterns are seen: (1) trabecular, in which cells form anastomosing cords; (2) alveolar, in which groups of cells are surrounded by connective tissue septa; and (3) diffuse, in which cells grow in solid sheets (Fig. 10-70). A spindle cell pattern occasionally is seen. Individual tumor cells are polygonal with a lightly eosinophilic granular cytoplasm. The cytoplasm of tumor cells may be lavender, resembling normal medullary chromaffin cells. Nuclei are round and vesicular. In larger tumors there is considerable nuclear variation and pseudoinclusions, but this should not be considered a sign of malignancy. Intracytoplasmic hyaline globules are found in 45 percent of pheochromocytomas. Such globules are periodic acid–Schiff positive and diastase resistant. By electron microscopy tumor cells contain typical neurosecretory granules (Fig. 10-71).

Fig. 10-69. Pheochromocytoma. The cross-sectioned surface of this encapsulated tumor appears grayish or red because of areas of congestion and hemorrhage.


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A

B

C

Fig. 10-70. Pheochromocytoma. A, Trabecular pattern. Tumor cells form anastomosing cords partially surrounded by fibrous septa. B, Diffuse pattern. Cells form solid sheets. Their lavender cytoplasm contains fine pinpoint granules. C, A few tumor cells have unclear pseudoinclusions, which are intranuclear invaginations of the cytoplasm.

A

B

Fig. 10-71. Pheochromocytoma. A, By electron microscopy tumor cell cytoplasm contains numerous dense granules. B, Dense-core neurosecretory granules vary in size and shape. Norepinephrine is stored in granules that have an eccentric dense core surrounded by a wide halo (straight arrow). Epinephrine is stored in granules that appear more symmetric, lacking the wide halo around the dense core (curved arrow).


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Scattered neuronal or ganglion cells often are present, and approximately 5 percent of tumors have composite features of pheochromocytoma, neuroblastoma, ganglioneuroblastoma, or ganglioneuroma. Pheochromocytomas are sporadic in 90 percent of cases, but 10 percent occur in the context of MEN 2A or 2B conjointly with medullary carcinoma of the thyroid gland. Patients with MEN 2B have typical oral neuromatous nodules (Fig. 10-72). Neuroblastoma is a tumor of neural crest–derived neuroblastic precursors of adrenal medullary cells and sympathetic ganglia. It is the most common malignancy in infants under the age of one year, with an incidence of 9.6 per million. The tumor presents as a partially encapsulated, soft ("encephaloid" ) adrenal mass that often invades the surrounding tissues (Fig. 10-73). On cross section the tumor is lobulated and shows prominent areas of necrosis and hemorrhage. Metastases through the lymphatics or blood vessels are common,

Fig. 10-72. MEN 2B. The tongue is studded with neuromatous nodules.

Fig. 10-73. Neuroblastoma. The bisected tumor attached to the kidney appears lobulated and blood-stained.

Fig. 10-74. Neuroblastoma. The tumor is composed of sheets of closely packed cells that have very little cytoplasm. Pale fibrillar areas are composed of neuritic processes.


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A

B

C

Fig. 10-75. Neuroblastoma. A, Nests of small cells are enclosed by fibrous septa with foci of calcification. B, Cells appear loosely arranged. The spaces between the nuclei contain pink fibrillar material that represents neuritic processes. C, Tumor cells form Homer Wright rosettes.

Fig. 10-76. Ganglioneuroblastoma. The tumor consists of ganglion cells that have eosinophilic cytoplasm. Stroma is inconspicuous.

Fig. 10-77. Ganglioneuroma. The tumor consists of spindleshaped Schwann cells and round ganglion cells.

with a predilection for the cortex of long bones and short bones. Other sites of metastasis are the lymph nodes, liver, skin, bone marrow, and skull. The dura may be involved, but brain metastases are unusual. Histologically the tumors are composed of small blue cells that are separated focally by eosinophilic fibrillar material representing neuritic processes (Fig. 10-74). These neuritic processes extend between cells, may be arranged around vessels or connective tissue cores, and form so-called Homer Wright rosettes, which are the most characteristic feature of neuroblastomas (Fig. 10-75). As differentiation or maturation of neuroblasts proceeds, neoplastic cells develop neuronal or ganglion-like features, with more distinct cell borders and more pronounced

eosinophilia of the cytoplasm. Such tumors are called ganglioneuroblastomas (Fig. 10-76). Ultrastructurally the fibrillar matrix of neuroblastoma and ganglioneuroblastomas consisfs of a tangled Skein of neuritic process that contains arrays of microtubles and intermediate filaments. An important diagnostic feature is the presence of small, densecore, membrane-bound neurosecretory granules. Ganglioneuromas are benign tumors that are composed of ganglion cells and Schwann cells (Fig. 10-77). Approximately 10 percent to 15 percent of ganglioneuromas originate in the adrenal glands, usually in school-aged children (average age seven years). Most ganglioneuromas are, however, found in the posterior mediastinum.


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Further Reading Attie JN, Auguste LJ: Multiple parathyroid adenomas: Report of thirtythree cases. Surgery 108:1014-1019, 1990. Brodeur GM: Molecular pathology of human neuroblastomas. Semin Diagn Pathol 11:118-125, 1994. Grimelius L, Bondeson L: Histopathological diagnosis of parathyroid diseases. Path Res Pract 191:353-365, 1995. Kane LA, Leinung MC, Scheithauer BW et al: Pituitary adenomas in childhood and adolescence. A clinicopathologic study of the Mayo Clinic experience. Endocr Pathol 3:517-518, 1992. Kontogeorgos G, Kovacs K, Horvath E et al: Null cell adenomas, oncocytomas, and gonadotroph adenomas of the human pituitary. An i mmunocytochemical and ultrastructural analysis of 300 cases. Endocr Pathol 4:20-27, 1993. Lamovec J, Frkovic-Grazio S, Bracko M: Nonsporadic and unusual morphologic features in pheochromocytoma and paraganglioma. Arch Pathol Lab Med 122:63-68, 1998. Lin BT-Y, Bonsib SM, Mierau GW et al: Oncocytic adrenocortical neoplasms. A report of seven cases and review of the literature. Am J Surg Pathol 22:603-614, 1998. Mizukami Y, Michigishi T, Nonomura A et al: Autonomously functioning (hot) nodule of the thyroid gland. A clinical and histopathologic study of 17 cases. Am I Clin Pathol 101:29-35,1994.

Oelkers W: Adrenal insufficiency. NEngl J Med 335:1206-1212, 1996. Ohta TI et al: Cortico-medullary mixed tumor (pheochromocytoma and cortical adenoma) of the adrenal gland. J Urol Pathol 3:157164, 1995. Ostrowski ML, Merino MJ: Tall cell variant of papillary thyroid carcinoma. A reassessment and immunohistochemical study with comparison to the usual type of papillary carcinoma of the thyroid. Am J Surg Pathol 20:964-974, 1996. Samaan NA, Hickey RC: Pheochromocytoma. Semin Oncol 14:297-305, 1987. Schlumberger MJ: Papillary and follicular thyroid carcinoma. N Engl J Med 338:297-306, 1998. Shortell CK, Andrus CH, Phillips CE Jr, Schwartz SI: Carcinoma of the parathyroid gland. A 30-year experience. Surgery 110:704-708, 1991. Singer PA: Thyroiditis. Acute, subacute and chronic. Med Clin North Am 75:61-77, 1991. Thapar K, Kovacs K, Muller PJ: Clinical-pathological correlation of pituitary tumours. Bailliere's Clin Endocrin Metab 9:243-270, 1995. Westra WH, Pritchett DD, Udelsman R: Intraoperative confirmation of parathyroid tissue during parathyroid exploration. A retrospective evaluation of the frozen section. Am J SurgPathol 22:538-544, 1998.




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DEVELOPMENTAL AND GENETIC DISORDERS The kidneys and the urinary tract form during prenatal life in a complex sequence of interrelated morphogenetic processes. The urethra and the urinary bladder form from the cloaca, which gives rise to ureteric buds. Ureteric buds grow upward and interact with the primordium of the kidney, which has passed through three sequential stages: pronephros, mesonephros, and metanephros. Metanephric blastema establishes contact with the ureteric bud and is induced to form the definitive kidney. Developmental disorders of the kidneys and the urinary tract reflect disturbances of this complex morphogenesis.

Agenesis, Malposition, Exstrophy, and Related Defects The definitive kidney results in incomplete induction (renal hypoplasia) or aplasia (renal agenesis), which may be unilateral or bilateral (Fig. 11-1). Bilateral agenesis results in a developmental sequence called Potter syndrome, in which renal agenesis is accompanied by oligohydramnios, pulmonary hypoplasia, and a small recessed mandible and low-set ears (see also Fig. 5-4). Ectopia of one or both kidneys results from malpositioning of the kidneys (Diagram 11-1). Ectopic kidneys usually are located caudal to their normal lumbar position but may be cranial to their normal location or even in the thorax (thoracic ectopia or dystopia). Both kidneys may be on the same side of the vertebra (crossed ectopia). Ectopia also may be associated with abnormal rotation of the kidney, and in such cases the hilum may face anteriorly or posteriorly (Fig. 11-2). Horseshoe kidney results from the fusion of left and right renal anlage into a simple kidney (Fig. 11-3).

Fig. 11-1. Renal agenesis. Urinary bladder, adrenal, and testes are normally developed, but the ureters and kidneys are missing.

B

Diagram 11-1. Positional renal abnormalities. A, Pelvic kidney. B, Crossed ectopia. The right kidney has crossed the left ureter and has migrated only part of the normal distance. (From Carlson BM: Human embryology and developmental biology, St. Louis, 1994, Mosby)

Fig. 11-2. Ectopia and malrotation of the kidney. The right kidney is located lower than the left one, and its hilum is facing anteriorly.


21I

The ureters may form incompletely and may show focal stenosis or atresia. Congenital megaureters are dilated and tortuous and usually are associated with abnormal urinary conduit (Fig.l1-4) Exstrophy of the urinary bladder represents incomplete formation of the urinary bladder combined with a defect of the anterior abdominal wall (Fig. 11-5). Developmental defects of the urethra include agenesis and stenosis. In males these anomalies maybe associated with abnormal development of the penis. An abnormal opening of the urethra on the lower side of the penile shaft is called

hypospadia (Fig. 11-6). Epispadia, which is less common than hypospadia, is an opening of the urethra on the dorsum of the penis. Abnormalities of the penis such as agenesis or micropenis are rare and usually are associated with other urogenital anomalies or chromosomal changes.

Fig. I 1-4. Megaureters. The ureters are dilated and tortuous. The kidneys are multicystic and dysplastic.

Fig. 11-3. Horseshoe kidney.

Fig. I I-S. Exstrophy of the urinary bladder. Red mucosa of the urinary bladder may be seen through the defect of the anterior abdominal wall. (Courtesy of Dr. Roger D. Smith, Cincinnati, Ohio, and GRIPE.)

Fig. I 1-6. Hypospadia. The urethra opens on the lower side of the shaft of the penis rather than on the tip of the glans penis.


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Polycystic Kidney Disease Abnormal morphogenesis of nephrons, which are the basic anatomic and functional units of the kidneys, results in polycystic kidney disease. Several clinicopathologic subtypes are recognized, the most important of which are (1) autosomal dominant polycystic kidney disease; (2) autosomal recessive polycystic kidney disease; (3) familial juvenile nephronophthisis-medullary cystic disease complex; and (4) renal dysplasia (Diagram 11-2). Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease that occurs at a rate of 1 per 1000. Symptoms of renal disease appear in the third or fourth decade, and the disease therefore is known as adult polycystic kidney

disease. Both kidneys are enlarged, weighing up to 2000 to 3000 g and measuring up to 40 cm in length. Kidney parenchyma typically is replaced by fluid-filled cysts that vary in size and shape (Fig. 11-7). These cysts are lined by nondescript flattened cells derived from the epithelium of tubules, collecting ducts, or Bowman capsule (Fig. 11-8). Autosomal recessive polycystic kidney disease (ARPKD) is less common than ADPKD. Because symptoms of ARPKD appear in infancy and childhood, both infantile and childhood forms are recognized. Both kidneys are enlarged but retain their normal shape. The cysts are small and elongated, extending in the form of slits from the corticomedullary junction toward the subcapsular cortex (Fig. 11-9). The cysts

Diagram 11-2. Cystic developmental kidney diseases. A, Autosomal dominant polycystic kidney disease is characterized by widespread cystic dilatation of all parts of the nephron. B, Childhood polycystic disease is autosomal recessive, but also shows microcystic changes in all parts of the nephron. C, Medullary sponge kidney shows cystic dilatation of collecting ducts of the papillae. D, Nephronophthisis shows cystic dilatation of juxtacortical medullary tubules. E, Cystic dysplasia contains solid and cystic areas. The solid areas comprise homologous renal and heterologous (nonrenal) elements. (From Damjanov I: Histopathology. A color atlas and textbook, Baltimore, 1996, Williams & Wilkins.)

Fig. 11-7. ADPKD. The enlarged kidneys consist of cysts that have replaced the normal parenchyma.

Fig. 11-8. ADPKD. The cysts are lined by flattened epithelium and contain proteinaceous fluid.


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represent dilated collecting ducts, which compress the remaining tubules, causing either atrophy or dilatation of the remaining parts of the nephron (Fig. 11-10). Renal dysplasia is a disorder of differentiation of the metanephros, often in association with other developmental disorders. It may be bilateral, but more often it is unilateral, causing an abdominal mass in neonates and infants. The enlarged kidney consists of cysts ( " multicystic dysplasia " ) and solid tissue replacing to a variable extent the normal renal parenchyma (Fig. 11-11). Histologically the cysts varyin size and shape and are lined by cuboidal or flattened epithelium. The solid areas consist of primitive ducts lined by columnar

epithelium surrounded by concentric layers of fibromuscular stroma that often contains islands of cartilage (Fig. 11-12).

Hereditary Glomerular and Tubular Diseases Many multisystemic genetic disorders affect the kidneys, but only in certain disorders do renal symptoms represent the main clinical manifestation of such diseases. Alport syndrome is a form of hereditary nephritis that is caused by a defect in the synthesis of collagen type IV. The biochemical defect is associated with morphologic changes of the glomerular basement membrane (GBM), which show

Fig. 11-9. ARPKD. The kidneys are enlarged because of diffuse dilatation cystic transformation of tubules and collecting ducts, which appear as dilated channels crossing from the cortex to the medulla.

Fig. 11-10. ARPKD. The cortex contains numerous dilated collecting ducts lined by flattened epithelium. The remaining portions of the nephrons are either compressed or dilated.

Fig. I 1-I I. Multicystic renal dysplasia. The deformed kidney consists of several large cysts and solid tissue replacing the normal renal parenchyma.

Fig. 11-12. Renal dysplasia. The normal parenchyma has been almost completely replaced by fibromuscular tissue and cartilage. Remnants of two fetal glomeruli are seen surrounded by atrophic tubules.


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focal thinning, thickening, and layering. These changes are best appreciated by electron microscopy (EM) (Fig. 11-13). Presenting symptoms include proteinuria, hematuria, and slowly evolving but progressive renal failure. The disease is more common, has an earlier onset, and is more severe in men than in women. Thin basement membrane nephropathy may occur in familial and sporadic forms. By light microscopy the glomeruli are normal. By EM the glomeruli have membranes that measure 80 to 250 nm in width, which is much thinner than normal (340 to 360 nm) (Fig. 11-14). Thinning is caused by the reduction of the width of the lamina densa. Clinically the disease presents with mild hematuria with or without proteinuria. Renal function remains preserved, and the disease has a good prognosis. Fabry disease is an X-linked hereditary disease caused by the mutation of the gene for a-galactosidase A. The disease has renal, neurologic, and cutaneous manifestations. The en-

zyme deficiency results in accumulation of the glycosphingolipid ceramide trihexoside in plasma and many tissues. In the kidneys ceramide trihexoside accumulates in glomerular epithelial cells, which become vacuolated (Fig. 11-15). EM reveals accumulation of lipid-rich myelin figures in the cytoplasm of these cells (Fig. 11-16). Similar changes are seen in arteries and arterioles, and occasionally in interstitial cells. Damage of the glomeruli ultimately leads to proteinuria. Chronic renal failure evolves over 10 to 20 years. Nail-patella syndrome is a hereditary disease whose presenting symptoms include typical nail changes, congenital absence of the patella, and renal symptoms. Glomerular changes are prominent and are related to changes in the glomerular membrane, which contains strands of banded collagen (Fig. 11-17). Many inborn errors of metabolism affect the renal tubules. In glycogenosis type I the renal tubules are vacuolated and filled with glycogen (Fig. 11-18).

A

A

B

B

Fig. 1 I-13. Alport syndrome. A, The glomerulus appears unremarkable by light microscopy. The tubules appear atrophic and there are foam cells in the interstitium. B, By EM the thickened basement membrane consists of alternating dense and lucent segments. There also is subepithelial scalloping of the basement membrane and partial effacement of the epithelial cell foot processes.

Fig. I 1-14. Thin basement membrane nephropathy. A, The capillary wall is very thin, measuring 90 nm in width. The epithelial cell foot processes are discrete and show no effacement. B, Normal basement membrane, shown here for comparison, measures 360 nm in width.


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Fig. 11-15. Fabry disease..The visceral epithelial cells are enlarged and have vacuolated cytoplasm.

Fig. I 1-16. Fabry disease. The cytoplasm of epithelial cells is filled with dense myelin figures representing stored sphingolipid. A

B

Fig. I 1-17. Nail-patella syndrome. A, Abnormal nails. B, GBM contains banded collagen fibrils.

Fig. 11-18. Glycogenosis type I. Renal tubules have clear cytoplasm as a result of glycogen accumulation.


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VASCULAR DISORDERS The most important vascular disease that affects the kidneys is atherosclerosis. Atherosclerosis most prominently involves the main renal arteries, but it also is associated with intimal and medial fibrosis of the intrarenal arteries, arteriolosclerosis, and glomerulosclerosis. Because the entire kidney is affected, the term nephroangiosclerosis (nephrosclerosis) is used as a synonym for ischemic changes in the kidney caused by prolonged ischemia in atherosclerosis. On gross examination the kidneys are smaller than normal and show cortical atrophy and V-shaped indentations that correspond to small infarcts (Fig. 11-19). Larger cortical infarcts may cause more profound multiple scarring, which may be indistinguishable from scars caused by pyelonephritis (Fig. 11-20). Histologically the glomeruli are hyalinized, and the tubules appear atrophic and are replaced by fibrous tissue and scattered lymphocytes (Fig. 11-21). Atrophic tubules filled with colloid ( " thyroidization " ) typically are found as evidence of blocked flow of solutes through nephrons that have been dis -

rupted or obstructed by interstitial scarring (Fig. 11-22). Clinically nephrosclerosis is accompanied by a loss of renal function, which slowly progresses to renal failure. Nephrosclerosis accounts for 15 percent of end-stage kidney disease worldwide. It is especially prevalent among the elderly. Thrombotic microangiopathy is a term that encompasses several diseases, including hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, scleroderma, and malignant hypertension. All thrombotic microangiopathies are characterized by intravascular deposition of fibrin and lesions that primarily involve arterioles and glomerular capillaries (Fig. 11-23). Two types of glomerular changes are seen: those that result from fibrin deposition and those that result from ischemia (Fig. 11-24). Capillary walls are thickened because of endothelial cell swelling and widening of subendothelial spaces, which sometimes gives the capillaries a double contour. Capillary lumens may contain fibrin thrombi. Mesangial regions are widened, with increased cytoplasmic volume. Mesangiolysis (dissolution of matrix)

Fig. 11-19. Nephroangiosclerosis. Kidneys have , scarred and granular external surface. Aorta shows marked atherosclerosis. The kidney on the right contains a cyst.

Fig. 11-20. Nephroangiosclerosis. Severe surface scarring may be indistinguishable from changes caused by pyelonephritis.

Fig. 11-21. Nephroangiosclerosis. The glomeruli are hyalinized, and the atrophic tubules are surrounded by fibrous tissue.

Fig. 11-22. Nephroangiosclerosis. Atrophic tubules are filled with eosinophilic proteinaceous casts that resemble thyroid follicles ("thyroidization of the kidney").


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may produce microaneurysms. During the healing process there is sclerosis of glomeruli, which often has a lobular pattern that is reminiscent of membranoproliferative glomerulonephritis type I. Lesions of interlobar and arcuate arteries may be present and are most prominent in scleroderma. Clinically all of these disorders are characterized by diminished renal function and oliguria. Hypertension is evident in 50 percent of cases.

I MMUNE-MEDIATED GLOMERULAR DISEASES

Fig. 11-23. Thrombotic microangiopathy. The arteriole contains a thrombus that extends into the glomerulus.

Fig. 11-24. Thrombotic microangiopathy. Double contours of glomerular capillaries are seen in segments of the glomerulus. Some capillary loops have wrinkled membranes.

I mmune-mediated glomerular diseases may involve any part of the kidney but most often they present as glomerulonephritis. The pathogenesis of some glomerulopathies, such as poststreptococcal glomerulonephritis, has been elucidated to a great extent, whereas the pathogenesis of others, such as minimal change disease, remains obscure. Clinically glomerulopathies present with proteinuria, hematuria, or both, and are diagnosed as nephrotic or nephritic syndromes. Glomerular disease may occur in an isolated form or as part of a systemic disease, such as systemic lupus erythematosus (SLE). Some glomerulopathies, such as minimal change disease, respond well to treatment with corticosteroids, whereas others, such as membranous nephropathy, are slowly progressive and unresponsive to treatment. Minimal change disease, also known as nil disease, lipoid nephrosis, or visceral epithelial cell disease, is a disease of unknown etiology and poorly understood pathogenesis. It is one of the "primary" glomerulopathies responsible for nephrotic syndrome (Table 11-1). By light microscopy the glomeruli appear normal (Fig. 11-25). There are no diagnostic immunofluorescence (IF) microscopy findings. By EM the GBMs are normal, but the epithelial foot processes show complete effacement (Fig. 11-26). Focal and segmental glomerulosclerosis (FSG) is a term used to describe two entities: a glomerulopathy that causes nephrotic syndrome, and morphologic changes that may occur in association with a variety of systemic diseases that affect the kidneys (Table 11-2). The etiology and pathogenesis of FSG are not known. Segmental sclerosis (i.e., obliteration of segments of a single glomerulus) is seen affecting some glomeruli (hence called focal). The sclerotic lesions may correspond to an occluded capillary obliterated with plasma protein deposits ( " hyalinosis " ) or may represent expanded mesangium associated with collapsed capillary base-

"Primary" Glomerulopathies Responsible for Nephrotic Syndrome Minimal change disease Mesangial injury glomerulonephritis with IgM deposits Focal and segmental glomerulosclerosis Membranous glomerulonephritis Membranoproliferative glomerulonephritis Fig. 11-25. Minimal change disease. In this slide stained with PAS— methenamine silver the glomeruli appear normal.

IgM. Immunoglobulin.


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ment membrane (Figs. 11-27 and 11-28). Except for deposits of immunoglobulin (IgM) and third component of complement (C3) in the areas of hyalinosis, there are no other findings by IF microscopy. Hyaline material appears finely granular by EM and may contain lipid droplets. Human immunodeficiency virus (HIV)—associated nephropathy may present as FSG, but in many cases the glomeruli also show changes that might represent precursor lesions of typical hyalinosis. The most typical is the so-called collapsing glomerulopathy, in which there is complete collapse of the capillary loops (Fig. 11-29). The tubules contain proteinaceous casts and may undergo microcystic dilatation. Numerous tubuloreticular structures are seen by EM in the cytoplasm of endothelial cells but also in other cells (Fig. 11-30).

Focal and Segmental Glomerulosclerosis "Primary" Parts of minimal change disease spectrum Unique disease Secondary Heroin-associated nephropathy HIV-associated nephropathy Complicating Other Renal Disorders Reflux nephropathy and other sclerotic interstitial disorders Glomerulonephritis (many types) Nephrosclerosis Familial-metabolic diseases Chronic transplant rejection Variants Collapsing glomerulopathy Tip lesions HIV, Human immunodeficiency virus.

Fig. I 1-27. Focal and segmental glomerulosclerosis. The hyalinized portions of the glomerulus appear blue in this Masson trichrome—stained slide.

Fig. I 1-26. Minimal change disease. There is complete effacement of the foot processes of the visceral epithelial cell. A normal mesangial cell is seen to the right.

Fig. I 1-28. Focal and segmental glomerulosclerosis. "Hyaline" occludes the lumen of the hilar capillaries.


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Fig. 11-29. HIV-associated nephropathy. The glomerulus in the center shows collapse of capillary loops, and the tubules filled with proteinaceous casts show microcystic dilatation.

Fig. I 1-30. HIV-associated nephropathy. The cytoplasm of this endothelial cell contains a large tubuloreticular structure.

Fig. 11-31. MPGN-I. The glomerulus has a lobular configuration with mesangial widening and hypercellularity. Peripheral capillary loops have double contours.

Fig. 11-32. MPGN-I. Glomerular capillary has a narrow lumen because of peripheral extension of mesangial cell cytoplasm, which is interposed between the layers of basement membrane.

Membranoproliferative Glomerulonephritis Membranoproliferativeglomerulonephritis ( MPGN) is a renal

Fig. 11-33. MPGN-I. Granular deposits of C3 are seen along the capillary loops and in the mesangium by IF microscopy.

lesion that may represent different disease entities, which are grouped here for historical reasons. Three subtypes (I, II, and III) are recognized. MPGN-1 is an immune complex— mediated disease that is characterized by mesangial hypercellularity, lobular appearance of glomeruli, and prominent reduplication (double contours) of basement membranes (Fig. 11-31). These double contours are better seen by EM, which shows interposition of mesangial cell cytoplasm between the original basement membranes and the newly formed basement membranes (Fig. 11-32). IF microscopy shows granular deposits of C3 along the peripheral capillary loops and in the mesangium (Fig. 11-33). IgG and IgM deposits are present focally but may be missing entirely. IgA maybe found in a few patients. Immune deposits seen by EM


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are located in the basement membranes or inside the capillaries in a subendothelial location. MPGN-II, or dense deposit disease, involves activation of the alternate complement pathway, which results in consumption of complement. Circulating C3 typically is decreased. C3 nephritic factor, an IgG that enhances clearance of C3, may be demonstrated in the blood. The basement membranes of the glomeruli are biochemically abnormal, which may contribute to glomerular pathology. By light microscopy the glomeruli appear lobular and show mesangial expansion and hypercellularity. The basement membranes appear thickened and may have double contours (Fig. 11-34). Dense deposits are seen along the basement membranes by EM (Fig. 11-35). By IF microscopy deposits of C3 are seen in a finely granular pattern along the GBMs and in the mesangial areas (Fig. 11-36). MPGN-III is a heterogeneous group of diseases that produce changes similar to MPGN-I.

Fig. I 1-34. MPGN-II. The glomerular capillary basement membranes are thickened and have a ribbon-like quality. Double contours are seen segmentally. The mesangial areas are expanded and hypercellular segmentally and show some nodularity.

Membranous Glomerulonephritis Membranous glomerulonephritis (GN), also known as membranous nephropathy, is an immune complex— mediated disease that presents with proteinuria and nephrotic syndrome. It may occur as a primary kidney disease or secondary to other systemic diseases (Table 11-3). By light microscopy the glomeruli show thickening of basement membranes, which become more prominent in the course of disease progression (Fig. 11-37). Silver impregnation techniques show subepithelial projections ( " spikes ") of the basement membrane between the deposits of immune complexes, which may be seen as fuchsinophilic material in Masson trichrome—stained slides. By EM the early deposits (stage I) are epimembranous and subepithelial. In stage II the deposits are larger and are located between the spikes of the basement membrane. In stage III or IV of the disease the deposits may be completely covered with the basement membrane (Fig. 11-38). Dense

Fig. I 1-35. MPGN-II. EM shows segmental replacement of the lamina densa by electron-dense finely granular material. A resorbing subendothelial deposit is indicated by an arrow.

Common Associations with Secondary Membranous Glomerulonephritis Infections Hepatitis B Syphilis Autoimmune Diseases Systemic lupus erythematosus Rheumatoid arthritis Sjogren syndrome Thyroiditis Drugs Gold Penicillamine Captopril Malignancies Diabetes mellitus Renal transplantation

Fig. I 1-36. MPGN-II. Glomerulus shows coarse granular staining of mesangial regions, capillary walls, and tubules.


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A

B

Fig. 11-37. Membranous glomerulonephritis. A, In this slide stained with PAS—methenamine silver the thickened basement membranes have fine spikes along their subepithelial surface. B, In this Masson trichrome–stained slide immune complexes appear red ( " fuchsinophilic").

A

B

C

Fig. 11-38. Membranous glomerulonephritis. A, Early (stage I) disease shows small subepithelial electron-dense deposits (arrows). B, Stage II is characterized by larger deposits between the intervening projections of newly formed basement membrane ("spikes"). C, Stage IV disease is characterized by large lucent spaces enclosed by basement membrane. The lucent areas correspond to partially resorbed immune complexes.


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deposits may become lucent, which usually is a sign of their resorption. By IF microscopy the immune complexes appear as finely granular deposits along the basement membrane (Fig. 11-39).

IgA Nephropathy and Henoch-Schonlein Purpura IgA nephropathy (Berger disease) is an immune complex—

Fig. 11-40. IgA nephropathy. IF microscopy shows that the mesangial areas contain diffusely finely granular deposits of IgA.

mediated glomerulonephritis with IgA as the sole or dominant antibody in the complexes, which localize preferentially in the mesangium. It is the most common primary immunemediated glomerulopathy worldwide, with an exceptionally high incidence in Asia and in Mediterranean countries. Its etiology and pathogenesis are not known. The disease presents with widening of mesangial areas, increased mesangial cellularity, and mesangial or paramesangial deposits of IgA (Figs. 11-40 to 11-43). Clinically, presenting symptoms of the disease are asymptomatic proteinuria and hematuria but it also may manifest in the form of other renal syndromes and thus is considered to have a protean nature. Approximately one third of all patients develop end-stage renal disease over 20 years and require renal transplantation. IgA mesangial deposits recur in transplanted kidneys but are clinically insignificant in most cases. Henoch-Schonlein purpura ( HSP), also known as anaphylactoid or rheumatoid purpura, is a clinical syndrome that comprises renal, dermal, and gastrointestinal lesions. The primary abnormality is a small vessel vasculitis in the IgA deposits of affected vessels. The renal changes result from deposition of immune complex, which contains IgA. The glomerular changes vary from mild to severe. In mild cases there are only mesangial deposits of IgA. In severe cases the deposits also are found in the glomerular capillaries. In extreme cases the damaged capillaries rupture, and a crescentic glomerular nephritis ensues. Accordingly, on the basis of glomerular lesions, HSP glomerulonephritis is classified as

Fig. I 1-41. IgA nephropathy. Several widened mesangial and paramesangial areas contain large, round, fuchsinophilic deposits in this Masson trichrome—stained slides. The number of mesangial cells is not increased.

Fig. I 1-42. IgA nephropathy. The glomerulus shows mesangial widening and segmental mesangial hypercellularity in this slide stained with PAS—methenamine silver. A capsular adhesion and an area of sclerosis are seen at 12 o'clock.

Fig. I 1-39. Membranous glomerulonephritis. By IF microscopy the capillary loops are covered with granular, partially confluent deposits of IgG and C3.


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A

B

Fig. 11-43. IgA nephropathy. The paramesangial areas are widened by round electron-dense deposits. The capillary loops appear unremarkable.

Fig. 11-44. Henoch-Schonlein purpura. A, Some mesangial areas appear expanded and hypercellular, whereas others appear normal. The capillary loops are normal in this Masson trichromestained slide. B, EM shows electron dense deposits in the mesangial area.

(1) mesangiopathic, (2) focal and segmental, (3) diffuse proliferative (endocapillary), and (4) endocapillary/extracapillary (crescentic). If microscopy is required for diagnosis; it shows IgA predominance. By light microscopy there always is mesangial widening and hypercellularity (Fig. 11-44, A). EM demonstrates mesangial deposits, which usually are more diffuse and not as round as in IgA nephropathy (Fig. 11-44, B). In more severe cases hump-shaped subepithelial and subendothelial capillary deposits are seen, and in such cases HSP resembles SLE. Clinically, renal disease occurs in 10 percent to 25 percent of affected children and young adults. Symptoms vary, but in general the outcome of the disease correlates with the severity of glomerular changes.

Postinfectious Glomerulonephritis Postinfectious glomerulonephritis is a form of immune com-

plex—mediated acute glomerulonephritis that occurs as a sequela of certain bacterial infections. Certain strains of group A streptococci, usually belonging to types 12, 4, and 1, are the most common cause. It is believed that the antigens of these microorganisms are planted in the glomeruli, where they form immune complexes with the antibodies deposited into the glomeruli from circulation. Immune complexes attract neutrophils and evoke a proliferative response by glomerular cells. Histologically the glomeruli appear hypercellular and typically contain inflammatory cells in the capillaries (Fig. 11-45). Deposits of IgG and complement are seen in the capillaries and mesangial areas (Fig. 11-46). Large subepithelial deposits of osmiophilic material ( " lumps" ) are seen by EM.


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Clinically, poststreptococcal glomerulonephritis usually presents as a transient self-limited nephritic syndrome of childhood. Most children recover, and end-stage kidney disease occurs in less than 2 percent to 3 percent of all patients. Unfavorable outcome is more common in adults, 50 percent of whom may ultimately show signs of chronic kidney disease. In such cases the kidneys are uniformly shrunken and small (Fig. 11-47). There is extensive glomerular hyalinization and tubular atrophy accompanied by interstitial fibrosis (Fig. 11-48). These morphologic findings are, however, nonspecific and also are seen in a variety of other kidney diseases that progress to end-stage renal disease.

Crescentic Glomerulonephritis Fig. 1 I-45. Acute poststreptococcal glomerulonephritis. The glomerulus appears hypercellular and contains numerous intracapillary neutrophils.

Glomerular crescents are a sign of severe glomerular injury associated with rupture of GBMs and exudation of fibrin and macrophages into the glomerular urinary space. Crescents may be seen in several diseases (Table 11-4). Anti glomerular basement membrane disease is an i mmune-mediated disease that is characterized by destructive glomerular lesions caused by antibodies to GBM antigens, such as the globular noncollagenous domain of type IV collagen. The disease may be limited to the kidneys or may

Diseases That May Present as Crescentic Glomerulonephritis

Fig. I 1-46. Acute postinfectious glomerulonephritis. IF microscopy shows irregular deposits of C3 in the mesangium and the capillaries.

Fig. 11-47. Chronic glomerulonephritis. Symmetrically shrunken kidneys have a uniformly granular surface.

Anti-GBM disease Idiopathic glomerulonephritis with anti-GBM antibodies Goodpasture disease Wegener granulomatosis Polyarteritis nodosa Systemic lupus erythematosus Henoch-Schonlein purpura Essential cryoglobulinemia Postinfectious glomerulonephritis

Fig. 11-48. Chronic glomerulonephritis. Glomeruli are hyalinized and surrounded by atrophic tubules, interstitial fibrosis, and scattered mononuclear cells.


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be part of a renal-pulmonary syndrome (Goodpasture disease). The glomeruli show typical extracapillary exudation of fibrin into the urinary space between the Bowman capsule and the capillary loops (Fig. 11-49). In addition to fibrin, such "crescents " also contain exudated macrophages and proliferated epithelial cells compressing the collapsed capillary loops. IF microscopy shows linear staining of the capillaries with antibodies to IgG or IgM . (Fig. 11-50). Fibrin is seen in the crescents. Damaged glomeruli undergo scarring, and end-stage kidney disease may evolve over a few weeks or months. Clinically this is recognized as rapidly progressive glomerulonephritis (RPGN) characterized by relentless loss of renal function. Typical Goodpasture disease, presenting with pulmonary hemorrhage and RPGN, is rare. Crescentic glomerulonephritis of the type found in Goodpasture disease may be found in other kidney diseases that present as RPGN, which are

World Health Organization Classification of Lupus Nephritis Class

II A B III IV V A B C D

Lesion No abnormalities by light, electron, and immunofluorescence microscopies Mesangial (injury, proliferative glomerulonephritis) No increased cellularity Mild increases in mesangial cellularity Focal and segmental glomerulonephritis Diffuse proliferative glomerulonephritis Membranous glomerulonephritis "Pure" membranous glomerulonephritis With mesangial glomerulonephritis With focal proliferative glomerulonephritis With diffuse proliferative glomerulonephritis

listed in Table 11-4. Wegener granulomatosis probably is the most common cause of crescentic glomerulonephritis. Because all of these diseases produce the same morphologic changes, additional immunologic data, such as tests for antinuclear antibody (ANA) and antineutrophil cytoplasmic antibody (ANCA), are essential for proper diagnosis.

Systemic Lupus Erythematosus (SLE) SLE glomerulonephritis is an immune complex–mediated renal disease that occurs in more than 75 percent of patients who have this systemic autoimmune disease. According to the World Health Organization classification, the renal lesions are graded on a scale from mild to severe and are classified into five categories (Tables 11-5 and 11-6). In mesangial lupus glomerulonephritis there is mild mesangial widening accompanied by mild mesangial hypercellularity (Fig. 11-51). In focal and segmental proliferative

Lupus Nephritis Scoring System of Renal Pathology GLOMERULAR

Active Lesions Hypercellularity Leukocytic infiltration Necrosis, karyorrhexis* Crescents—cellular* "Wire loops" "Hyaline thrombi"

Chronic Lesions Sclerosis Fibrous crescents

TUBULOINTERSTITIAL

Active Lesions Mononuclear leukocyte infiltration

Chronic Lesions Interstitial fibrosis Tubular atrophy

Each lesion is assigned a grade of 0, I, 2, or 3; those with an asterisk are doubled. Add all active lesions for activity index (maximum number 27) and chronic lesions for chronicity index (maximum number 12).

Fig. 11-49. Anti–glomerular basement membrane nephritis. In this slide stained with PAS–methenamine silver the collapsed capillary loops are compressed by a crescent composed of fibrin and macrophages. Some tubules contain red blood cells as evidence of severe glomerular injury and glomerular hematuria.

Fig. 11-50. Anti–glomerular basement membrane nephritis. The capillary loops stain in a linear manner with antibodies to IgG.


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GN and diffuse proliferative GN, deposits of immune complexes are accompanied by proliferation of mesangial cells, expansion of mesangial areas, and obliteration of capillary lumina (Figs. 11-52 and 11-53). Deposits of immune complexes may be found by IF microscopy in the mesangial areas, along the GBM, and in capillaries (Figs. 11-54 and 11-55). Capillary deposits are classified by EM as subendothelial,

intramembranous, or subepithelial. Endothelial cells typically contain tubuloreticular structures (Fig. 11-54). Deposits of immune complexes also may be seen in the interstitial peritubular spaces (Fig. 11-55). In membranous GN the glomeruli show subepithelial deposits like in any other membranous GN, but they also contain mesangial deposits (Fig. 11-56).

Fig. I 1-51. Lupus nephritis, mesangial proliferative. Mesangial areas are widened and contain an increased number of mesangial cells in this slide stained with PAS–methenamine silver.

Fig. I 1-52. Lupus nephritis, focal proliferative. Glomerulus shows segmental loss of normal architecture of the tufts because of deposition of eosinophilic material and cell proliferation. The lower part of the glomerulus is relatively spared.

Fig. I 1-53. Lupus nephritis, diffuse proliferative. The glomerulus is hypercellular and has expanded mesangial areas and partially obliterated capillary lumens. Intracapillary eosinophilic hyaline thrombi and wire loops are seen segmentally.

Fig. 11-54. Lupus nephritis, diffuse proliferative. EM shows a large subendothelial electron-dense deposits and "hyaline capillary thrombus."


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Fig. 11-55. Lupus nephritis. Numerous interstitial deposits are located around a peritubular capillary.

Fig. 11-56. Lupus nephritis, membranous. Deposits of dense material corresponding to immune complexes are seen in a subepithelial location along the capillaries and in the mesangium.

TUBULOINTERSTITIAL DISEASES

Acute interstitial nephritis, also known as acute tubulointerstitial nephritis, may have many causes (Table 11-7). The kidneys typically are enlarged and edematous and show extensive interstitial infiltrates composed of lymphocytes, macrophages, plasma cells, or eosinophils (Fig. 11-57). Interstitial nephritis also may present as a granulomatous reaction (Fig. 11-58).

Tubulointerstitial diseases are classified etiologically as (1) immune-mediated, (2) infectious, (3) metabolic and/or toxic, and (4) ischemic. These diseases have many common morphologic features, and their etiology is not always apparent. Clinically and pathologically they are classified as acute or chronic.

B

A

Fig. 11-57. Acute interstitial nephritis. A, In this Masson trichrome–stained slide the edematous interstitium is infiltrated with mononuclear cells. Tubules show focal signs of injury. B, The interstitium contains a dense infiltrate of lymphocytes, macrophages, and eosinophils.


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Pyelonephritis is a term that refers to bacterial tubulointerstitial infections. Infections may be caused by hematogenous spread of bacteria or reflux of infected urine. In acute pyelonephritis the kidney is infiltrated with neutrophils, which may fill the tubules or form interstitial abscesses (Fig 11-59). The kidneys are enlarged and swollen and may contain abscesses. In chronic pyelonephritis, which often is associated with urinary obstruction, the loss of renal parenchyma typically results in shrinkage of the kidneys and hydronephrosis (Fig. 11-60). Histologically the kidneys are infiltrated with lymphocytes, macrophages, and plasma cells, which tend to replace the tubules (Fig. 11-61). Pyelonephritis may be unilateral or bilateral. Bilateral chronic pyelonephritis is associated with end-stage kidney disease. Metabolic and/or toxic disorders that affect the kidneys cause tubular injury, which may or may not be associated with glomerular and vascular changes. Acute tubular necrosis (ATN) is a reversible lesion of the tubular epithelium that is associated clinically with acute renal failure. It may be caused

Etiologies of Acute Interstitial Nephritis Drug-induced Allergic (hypersensitivity) Toxic Idiopathic Immune-mediated Antitubular basement membrane disease Immune complex deposition T cell–mediated (sarcoid, idiopathic) Infection-associated Reactive (viral, bacterial) Direct (viral, leptospiral, rickettsial, mycobacterial) Hereditary and metabolic Crystal formation Paraprotein-mediated Toxins Hereditary Irradiation Idiopathic

Fig. 11-58. Granulomatous interstitial nephritis. The interstitium contains epithelioid granulomas.

Fig. 11-59. Acute pyelonephritis. Neutrophils are found in the tubules and the edematous interstitium.

Fig. 11-60. Chronic pyelonephritis. This kidney from a patient with urinary obstruction shows dilatation of calices and pelvis and loss of renal parenchyma.

Fig. 1 1-61. Chronic pyelonephritis. Extensive mononuclear infiltrates have replaced most of the tubules, but the glomeruli appear preserved in this Masson trichrome–stained slide.


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Causes of Toxic Acute Tubular Necrosis

Fig. 11-62. ATN. The tubules are lined by flattened epithelium, which is focally missing altogether. Some tubules contain granular casts.

Fig. 11-63. ATN. The medullary tubules contain casts, and the congested vasa recta contain nucleated red blood cells.

by a variety of toxins (Table 11-8). Ischemia may also cause ATN, which typically is found in various forms of shock, in multiple organ failure, and in essentially all conditions that are associated with anoxia or hypoperfusion of the kidneys. The kidneys are enlarged and have a pale cortex and congested medulla. Histologically the earliest changes are those in which the proximal tubules lose their brush borders, which is best seen in slides stained with period acid–Schiff reagent. Necrosis of tubular cells leads to widening of the tubules, which contain cellular debris in the form of granular proteinaceous material. The epithelium of the tubules is flattened, and focally cells are missing altogether (Fig. 11-62). The desquamated cells fragment and form granular casts that are most prominent in the medullary tubules, accounting for the term lower nephron nephrosis, which previously was used to describe ATN in autopsy specimens. The vasa recta of the medulla typically are congested and contain nucleated blood cell precursors (Fig. 11-63). Renal tubular epithelium may regenerate, and in the recovery phase of ATN the tubules are lined by cells that have basophilic cytoplasm. Recovery is associated with normalization of renal function. Diabetes mellitus is a major cause of kidney disease. Typical renal lesions include (1) diabetic glomerulosclerosis, (2) hyalinization of arterioles (hyaline arteriolosclerosis), (3) pyelonephritis, and (4) papillary necrosis. Diabetic glomerulosclerosis occurs in diffuse and nodular forms (Figs. 11-64 and 11-65). In diffuse glomerulosclerosis the GBMs are uniformly thickened and the amount of mesangial matrix is increased. In nodular glomerulosclerosis there is nodular expansion of the mesangial regions. By microscopy the basement membranes and mesangial areas appear to be impregnated with IgG and albumin, which imparts to them a " pseudolinear " staining pattern (Fig. 11-66). By EM the basement membranes of the capillary loops appear uniformly thickened. The expanded mesangial areas and the nodular material also consist of basement membrane–like material.

Fig. 11-64. Diabetic glomerulosclerosis. The glomerulus contains a mesangial nodule composed of basement membrane–like material.


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Fig. I 1-65. Diffuse diabetic glomerulosclerosis. The basement membranes are diffusely thickened, and the mesangial areas appear widened. Bowman capsule thickening ("hyaline drop") also is seen. The arterioles show hyalinization.

Fig. 11-66. Diabetic glomerulosclerosis. Antibody to IgG stains the GBM and Bowman capsule in a linear way.

Fig. 11-67. Papillary necrosis. Papillae missing their tips appear blunted and partially calcified (arrows).

Fig. 11-68. Urinary stone. The dilated pelvis contains irregular stones.

Papillary necrosis is characterized by an infarction of the renal papillae, which may slough off into the pelvis (Fig. 11-67). This complication is not unique to diabetes. It is especially common in diabetic patients who have obstruction of urine flow or pyelonephritis. Papillary necrosis also occurs in women who abuse aspirin and phenacetin ( " analgesic abuse nephropathy " ). Metabolic changes associated with the excretion of calcium and phosphates often result in the formation of urinary stones. Urolithiasis (urinary stones) also occurs in gout, in several other metabolic diseases such as hyperoxaluria and cystinosis, and in urinary tract infections. Biochemically, uri-

nary stones are composed of (1) calcium (oxalate or phosphate,, (2) magnesium ammonium phosphate, (3) uric acid, and (4) cysteine. The stones may be small or large, and clinical symptoms depend on their size and location. Small stones that obstruct the ureter cause colic. Large stones that are impacted in the pelvis cause obstructive hydronephrosis and progressive renal failure (Fig. 11-68). Calcium phosphate crystals may precipitate in renal tubules or renal interstitium, especially in end-stage kidney disease (nephrocalcinosis). Deposits of other metabolites that may be found in the kidneys include uric acid crystals in gout and oxalate crystals in oxalosis or ethylene glycol poisoning (Figs 11-69 and 11-70).


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A

B

Fig. I 1-69. Gout. A, Deposits of uric acid crystals have caused yellowish discoloration of the papilla. B, Uric acid crystals appear as birefringent deposits in the medulla.

Fig. 11-70. Oxalosis. Birefringent crystals in the tubules are seen under polarized light.

Fig. 11-71. Amyloid. Amyloid fibrils have a typical appearance by EM.


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Fig. 11-72. Multiple myeloma. Tubular proteinaceous casts elicit a giant cell reaction.

Renal deposits of amyloid are found in both primary and secondary amyloidosis. These deposits are seen in the glomeruli, blood vessels, and tubular basement membranes (Fig. 11-71). Besides amyloid, multiple myeloma kidney disease is characterized by tubular casts of immunoglobulin light chains, which may cause urinary obstruction (Fig. 11-72). Deposition of cryoglobulins, plasma proteins that precipitate at low temperature, predominantly occurs in renal vessels. Cryoglobulinemia typically is associated with glomerulonephritis, which usually leads to lobular transformation of the hypercellular glomerular tufts reminiscent of MPGN (Fig. 11-73).

Fig. 11-74. Acute cystitis. The mucosa of the urinary bladder is congested and shows foci of hemorrhage.

Fig. 11-73. Cryoglobulinemia. The glomerulus shows lobular expansion and hypercellularity. Many capillary loops have double contours, and some contain pink-staining plasma protein casts in their lumen.

LOWER URINARY TRACT I NFECTIONS Infections of the lower urinary tract may occur as an isolated form, such as urethritis or cystitis, but most often the pathogens do not respect the anatomic boundaries and the inflammation involves the major part of the lower urinary tract. In males it may spread to the prostate, vas deferens, or epididymis.

Fig. 11-75. Chronic cystitis caused by prostatic hyperplasia. The wall of the bladder is thickened. The mucosa is focally hemorrhagic.


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Cystitis is a very common disease. Acute cystitis usually is caused by coliform bacteria. It is less common in men than in women, who have shorter urethra and are more likely to develop an ascending urinary tract infection. The urinary bladder appears congested and may show shallow bleeding ulcerations that result in hematuria (Fig 11-74). Chronic cystitis may result from recurrent bouts of acute infection. It often is associated with predisposing conditions such as urinary stones or prostatic hyperplasia. The urinary bladder has a thick wall and may show trabeculation as a result of smooth muscle hypertrophy and hyperplasia (Fig. 11-75). Several pathologic variants of chronic cystitis are recognized, and they do not necessarily have distinct clinical symptoms. Interstitial cystitis is a persistent form of cystitis of unknown etiology that typically affects women. It presents with thickening of the wall of the urinary bladder and mucosal ulceration (Hunner ulcer) (Fig. 11-76). Pseudomembranous cystitis may be a complication of chemotherapy. In this disease the urinary bladder undergoes necrosis of the epithelium, and the surface of the bladder subsequently is covered with a pseudomembrane that is composed of fibrin and cell debris. The mucosa of the urinary bladder of patients receiving chemotherapy may necrotize and the urinary bladder may fill with blood and necrotic debris (Fig. 11-77). Histologic features of chronic cystitis generally are nonspecific and provide few if any clues to the etiology of the disease. In interstitial cystitis the chronic inflammatory infil-

trate contains an increased number of mast cells, but these cells also may occur in other forms of cystitis. Histologically pseudomembranes may be recognized by their content of fibrin and amorphous cell debris. Granulomatous cystitis has been observed in patients treated by intravesical instillation of bacille Calmette-Guerin (BCG) vaccine. Malacoplakia (see Chapter 12) is characterized by the presence of Michaelis-Gutmann bodies and von Hansemann histiocytes. Chronically inflamed epithelium of the lower urinary tract may show hyperplastic and metaplastic changes, which are known in the urinary bladder as (1) von Brunn nests, (2) cystitis cystica, (3) cystitis glandularis, (4) nephrogenic metaplasia, and (5) squamous metaplasia (Figs. 11-78).

Fig. 11-76. Interstitial cystitis. The wall of the contracted bladder is edematous and thickened and the mucosa shows hemorrhagic ulceration.

Fig. I 1-77. Massive hemorrhagic cystitis. Urinary bladder of this patient treated for Burkitt lymphoma is filled with clotted blood and necrotic detritus.

Fig. I 1-78. Chronic cystitis. Inflammation and glandular metaplasia are seen.


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TUMORS The most important tumors of the kidney and the urinary tract are (1) renal cell carcinoma, (2) Wilms tumor, and (3) urothelial carcinoma. In comparison with these tumors, which account for most neoplasms at this site, all other benign and malignant tumors are rare.

Tumors of the Kidney and Renal Pelvis the most common renal tumor. It occurs in several histologic subtypes (Table 11-9). Most tumors are of clear cell type. On gross examination tumors appear as well-circumscribed, solid lobulated masses, of yellow color, and with areas of necrosis or hemorrhage (Fig. 11-79). Histologically the tumors are composed of clear cells arranged in an alveolar or diffuse pattern (Fig. 11-80). The tuRenal cell carcinoma is

Classification of Renal Cell Tumors Benign Neoplasms Renal oncocytoma Carcinomas Renal cell carcinoma Clear cell Chromophil Eosinophil Basophil Chromophobe Typical Eosinophil Collecting duct carcinoma Neuroendocrine tumors Carcinoid Small cell carcinoma

mors are graded on a scale from 1 to 4 according to size, the contour of nuclei, and the appearance of nucleoli (Table 11-10). Wilms tumor, or nephroblastoma, is a tumor of infancy and childhood that arises from nephrogenic nests. The tumors may be unilateral or bilateral. On gross examination nephroblastomas may replace the whole kidney, but often they appear as circumscribed multinodular masses. On cross section they are solid, soft, and grayish-white (Fig. 11-81). Areas of hemorrhage, necrosis, or cystic degeneration are common. Histologically they are composed of a mixture of blastema-like epithelial and stromal cells and cells forming tubules and cords (Fig. 11-82). The stroma component is composed of loose connective tissue that occasionally may show differentiation into skeletal muscle or cartilage. On the basis of histologic features and the presence or absence of anaplasia, nephroblastomas are classified as tumors of a favorable or an unfavorable nature. Unfavorable features are large hyperchromatic nuclei and multipolar mitotic figures. Nephroblastomas, which account for 80 percent of the renal tumors of childhood, must be differentiated from mesoblastic nephroma, clear cell sarcoma, rhabdoid tumor, and cystic nephroma.

Grading of Nuclei of Renal Cell Tumors Grade I Rund, uniform nuclei approximately 10 p.m in diameter with minute or absent nucleoli Grade 2 Slightly irregular contours and diameters of approximately I5 p.m with nucleoli visible at 400x Grade 3 Moderately to greatly irregular nuclear contours and diameters of approximately 20 p.m with large nucleoli visible at IOOx Grade 4 Nuclei similar to those of grade 3 but also multilobular or multiple nuclei or bizarre nuclei and heavy clumps of chromatin

Fig. 11-80. Renal cell carcinoma. The tumor is composed of Fig. I 1-79. Renal cell carcinoma. A relatively well demarcated yellow tumor occupies the upper pole of the kidney.

clear cells arranged into alveoli surrounded by thin fibrovascular strands.


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Fig. 11-81. Wilms tumor. The multinodular tumor is replacing a large portion of the renal parenchyma.

Fig. I 1-82. Wilms tumor. The tumor is composed of blastema, primitive tubules, and loose stroma.

Fig. I 1-83. TCC of the renal pelvis. Wartlike tumor masses protrude into the lumen of the pelvis. Fig. I 1-84. TCC of the renal pelvis. The tumor is composed of papillary and solid components. Classification of Urinary Bladder Tumors (Epithelial Neoplasms) Transitional cell (urothelial) neoplasms Papilloma Inverted Everted Carcinoma Papillary Nonpapillary (solid) Carcinoma in situ and possible precursor lesions Variants of TCC TCC, nested type TCC with glandlike lumens Lymphoepithelial carcinoma Squamous cell carcinoma, conventional type Verrucous squamous cell carcinoma Villous adenoma Adenocarcinoma Papillary, glandular, mucinous, signet-ring cell, and clear cell Small cell carcinoma (neuroendocrine carcinoma) Mixed carcinoma Other epithelial neoplasms Carcinosarcoma Carcinoid tumor

Urothelial carcinomas of the renal pelvis and ureter present as exophytic and papillary masses that often fill the pelvis and obstruct the ureter (Fig. 11-83). Histologically most tumors are transitional cell carcinomas (TCC) (Fig. 11-84). Approximately 10 percent of tumors are squamous cell carcinomas, and 1 percent to 2 percent of tumors show glandular differentiation and are classified as adenocarcinomas. In all respects these tumors resemble the more common urinary bladder tumors.

Tumors of the Urinary Bladder Most tumors of the urinary bladder arise from the urothelium; only a small fraction of all bladder tumors are of mesenchymal origin, arising from the smooth muscle or stromal cells. A histologic classification of epithelial bladder tumors is given in Table 11-11.


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Fig. I 1-85. Carcinoma of the urinary bladder. This exophytic tumor protrudes into the lumen of the bladder.

Fig. 11-86. Transitional cell papilloma, everted type. The central fibrovascular core is lined by transitional epithelium that has a surface umbrella cell layer.

A

B

C

Fig. I 1-87. TCC. A, Grade I TCC is composed of slightly atypical cells forming a thickened transitional epithelium-like layer. B, Grade II TCC is composed of cells showing mild nuclear pleomorphism, hyperchromasia, and loss of polarity. C, Grade III TCC is composed of pleomorphic cells showing variation in the size and shape of their nuclei and a complete loss of polarity.


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Fig. 11-88. Carcinoma in situ of the urinary bladder. Pleomorphic cells have completely lost polarity, and the epithelium appears disorganized throughout its entire thickness.

Fig. 1 1-89. Small cell carcinoma of the urinary bladder with foci of TCC.

Bladder tumors appear on gross examination as polyps or exophytic cauliflower-like masses that protrude into the lumen of the bladder (Fig. 11-85). Some tumors appear as flat plaquelike lesions, whereas others show both an exophytic and an endophytic invasive component. Approximately 25 percent of bladder tumors are multifocal. Papillomas are benign lesions of transitional epithelium that occur in two forms: everted and inverted papillomas. Everted papillomas have a connective tissue core lined by seemingly normal transitional epithelium that is less than seven cells thick and a surface umbrella cell layer (Fig. 11-86). Inverted papillomas are composed of similar cells that form solid nests. They are rare and represent less than 1 percent of all bladder tumors. Transitional cell carcinomas (TCC) occur in three grades (Fig. 11-87). Grade I tumors are papillary lesions that are lined by slightly disorganized epithelium showing minimal nuclear abnormalities and measuring more than seven layers in thickness. Grade II lesions are multilayered, and to a large extent the cells have lost their polarity. Grade III tumors are composed of nests of disorganized cells that show marked nuclear polymorphism. Adjacent epithelium may contain carcinoma in situ (Fig. 11-88). Pathologic findings are of prognostic significance. In addition to the stage of the tumor, which is determined by its size and the extent of local and metastatic spread, the recurrence or progression and a clinically unfavorable outcome are related to (1) high tumor grade, (2) interruption of basement membrane, (3) invasion into or below the muscularis mucosae, (4) detrusor muscle involvement, (5) invasion of blood vessels or lymphatics, (6) tentacular invasion, (7) associated carcinoma in situ in adjacent epithelium, and (8) multiple tumors.

Approximately 90 percent of urinary bladder tumors are TCC, 9 percent are squamous cell carcinomas, and the remaining 1 percent are adenocarcinomas and small cell carcinomas. Sarcomas, most of which are leiomyosarcomas, are rare. Rhabdomyosarcoma is the most common malignancy of the urinary bladder in children. The tumor presents in the form of multiple, glistening, polypoid masses or a solitary large mass that replaces the wall of the bladder. Histologically it shows features of embryonal rhabdomyosarcoma (Fig. 11-89). Further Reading Berden JHM: Lupus nephritis. Kidney hit 52:538-558, 1997. Bostwick DG, Eble IN, Murphy GP: Conference summary: Diagnosis and progression of renal cell carcinoma: 1997 workshop, Rochester, Minnesota. Cancer 80:975-976, 1997. Couser WG: Glomerulonephritis. Lancet 353:1509-1515, 1999. Emancipator SN: IgA nephropathy: Morphologic expression and pathogenesis. Am J Kidney Dis 23:451-460, 1994. Epstein JI, Amin MB, Reuter VR et al: The World Health Organization/ International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of urinary bladder. Am J Surg Pathol 22:1435-1448, 1998. Lynch CF, Cohen MB: Urinary system. Cancer 75:316-329, 1995. Pearson JM, McWilliams LJ, Coyne JD, Curry A: Value of electron microscopy in diagnosis of renal disease. J Clin Pathol 47:126-132, 1994. Rennke HG: Secondary membranoproliferative glomerulonephritis. Kidneylnt 47:643-651, 1995. Reichert LJM, Koene RAP, Wetzels JFM: Prognostic factors in idiopathic membranous nephropathy. Am 'Kidney Dis 31:1-11, 1998.




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GENETIC AND DEVELOPMENTAL DISORDERS The abnormal development of the testis may result in (1) abnormal positioning of one or both testes, including cryptorchidism, testicular ectopia, or dystopia; (2) numeric aberrations, including anorchia, monorchidism, or polyorchidism; (3) structural malformations of the testes or epididymis; (4) gonadal dysgenesis, which almost always is associated with sex chromosome abnormalities and intersexuality; and (5) abnormal spermatogenesis, including germ cell aplasia, hypospermatogenesis, and various forms of maturation arrest associated with oligospermia or azoospermia. Klinefelter syndrome is a chromosomal anomaly that usually is associated with a 47,XXY karyotype. The testes are atrophic and show no signs of spermatogenesis (Fig. 12-1). Cryptorchidism, a term derived from Greek words meaning "hidden testis, " is generally used as a synonym for undescended testes, which may be unilateral or bilateral. Undescended testes are smaller than normal and remain small even after orchidopexy. The histologic features vary depending on the age of the patient, the location of the testis, and the treatment that has been carried out. Histologic changes are minimal in 26 percent of patients. Marked germinal hypoplasia is found in 24 percent, diffuse tubular hypoplasia in 33 percent, and severe atrophy in 17 percent of patients (Fig. 12-2). Approximately 25 percent of contralateral descended testes show similar changes, and in many cases there also are epididymal abnormalities.

Fig. 12-1. Klinefelter syndrome. The seminiferous tubules have been replaced by fibrous tissue. The remaining tubules have thick hyalinized basement membranes and contain no spermatogenetic cells (Courtesy of Drs. N. Skakkebaek and A. Giwercman, Copenhagen, Denmark.)

Fig. 12-2. Cryptorchidism. The tubules appear dilated and show hypospermatogenesis.

Fig. 12-3. Germ cell aplasia. The tubules contain only Sertoli cells.

Fig. 12-4. Maturation arrest of spermatogenesis. Spermatogenesis has not progressed beyond the stage of spermatocytes. (Courtesy of Drs N. Skakkebaek and A. Giwercman, Copenhagen, Denmark.)


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Fig. 12-6. Hypogonadotropic hypogonadism. The small seminiferous tubules contain immature (fetal) Sertoli cells and a few spermatognia.

Fig. 12-5. Hypospermatogenesis. Only one seminiferous tubule contains spermatozoa.

Disturbances of spermatogenesis occur in several forms. The most severe form is aplasia of germ cells, in which the seminiferous tubules contain only Sertoli cells (Fig. 12-3). Maturation arrest may occur at any stage of spermatogenesis. The arrest typically is at the level of spermatocytes or round spermatids (Fig. 12-4). Hypospermatogenesis is associated with hypoplasia of germinal epithelium, dilatation of seminiferous tubules, and reduced sperm counts (Fig. 12-5). Spermatogenesis also may be reduced as a result of hypothalamic or pituitary disorders that are characterized by a lack of gonadotropin and hypogonadotropic hypogonadism. This form of hypogonadism is typical of Prader-Willi prepubertal syndrome, Kallmann syndrome, pituitary apoplexy, or hypothalamic tumors. Follicle-stimulating hormone and luteinizing hormone deficiencies result in incomplete maturation of the testes. The testes are small and never attain normal adult size. The seminiferous tubules are small and are lined by immature Sertoli cells that have round nuclei and inconspicuous nucleoli (Fig. 12-6). The germ cells are sparse, and there is no evidence of spermatogenesis.

INFECTIONS Infections of the male genital organs may occur in a localized form as orchitis, epididymitis, prostatitis, urethritis, or

Fig. 12-7. Suppurative epididymoorchitis. The testis contains abscesses.

balanoposthitis, or in a diffuse form that involves all of the genital organs and the lower urinary tract. Infections most often are acquired through sexual transmission or from ascending urinary tract infections. Pathogens may reach the genital organs hematogenously. Gonorrhea, syphilis, and herpesvirus infection are typical sexually transmitted diseases. Mixed infections with uropathogens such as Escherichia coli or Pseudomonas aeruginosa are common causes of infection in older men over the age of 60 years. Viruses such as the mumps virus reach the testes hematogenously. Ascending bacterial infections that reach the testes usually also affect the epididymis and cause a suppurative epididymoorchitis (Fig. 12-7). In contrast to bacterial infections, viral infections cause an interstitial orchitis, which usually is associated with spermatogenetic arrest (Fig. 12-8). Chronic infections cause severe testicular destruction. The best known example of such chronic infection is malacoplakia, also known as granulomatous orchitis. In this disease the seminiferous tubules are infiltrated with numerous macro -


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phages, lymphocytes, and plasma cells (Fig. 12-9). The macrophages have a prominent cytoplasm filled with residues of phagocytosed bacteria and concentrically calcified round inclusions called Michaelis-Gutmann bodies. These bodies have a characteristic targetoid appearance by electron microscopy (EM). The testes may be damaged by a variety of systemic infections even if there is no direct invasion of testicular tissue by pathogens. In acquired immunodeficiency syndrome (AIDS) the testes show atrophy of germinal epithelium, tubular hyalinization, interstitial fibrosis, a reduced number of Leydig cells, and focal lymphocytic infiltrates (Fig. 12-10).

In most patients who histologically show extensive tubular atrophy, hyalinization and loss (so-called end-stage testis disease), the cause of testicular injury usually cannot be determined (Fig. 12-11).

TUMORS OF THE TESTIS Testicular tumors account for approximately 1 percent of all tumors of the internal organs in men. Germ cell tumors account for 92 percent to 95 percent of all neoplasms. Sex cord cell tumors such as Leydig cell and sertoli cell tumors account for 2 percent to 5 percent of all tumors, whereas the remainder are tumors of nonspecific stromal cells and metastases. Malignant tumors are more common than benign tumors. All age groups may be affected, but the peak incidence for germ cell tumors typically is in the range of 25 to 40 age years (Table 12-1).

Germ Cell Tumors

Fig. 12-8. Mumps orchitis. Mononuclear infiltrate is associated with spermatogenic arrest.

The histogenesis of germ cell tumors has not been entirely clarified, which reflects our ignorance about the initiation and promotion of malignancy in this cell system. With an exception of some tumor types, such as spermatocytic seminoma and yolk sac tumor of infancy and childhood, all other germ cell tumors pass through a preinvasive carcinoma in situ (CIS) stage (Diagram 12-1). CIS, also known as intratubular testicular neoplasia (ITTN), appears in the form of large atypical cells inside the tubules, which are devoid of spermatogenesis (Fig. 12-12). CIS cells give rise to seminoma or embryonal carcinoma (EC), cells, which are developmentally pluripotent cells that resemble early embryonic cells. EC cells may mimic normal embryonic cells and form embryo-

B

A

Fig. 12-9. Malacoplakia A, The tubules are obliterated by a mononuclear infiltrate. B, By EM this typical Michaelis-Gutmann body has a dark calcified center surrounded by a halo and a distinct rim.


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Fig. 12-I I. End-stage testis disease. Most tubules are hyalinized, and the interstitial spaces are dilated and fibrotic.

Fig. 12-10. AIDS. The seminiferous tubules are dilated hypocellular and show reduced spermatogenesis.

Fig. 12-12. CIS. Large neoplastic cells with centrally located nuclei and clear cytoplasm are located along the basement membrane.

Classification of Testicular and Epididymal Neoplasms Germ cell tumors Tumors of sex cord cells Leydig cell tumors Sertoli cell tumors Mixed germ cell–sex cord cell tumors Tumors of the rete testis Tumors of the epididymal epithelium Tumors of mesothelial origin Tumors of nonspecific stromal cells Tumors derived from epithelial rests and choristomas Tumors of hematopoietic cells

Diagram 12-1. Pathogenesis of germ cell tumors.


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like structures, which are called embryoid bodies (Fig. 12-13). EC cells also may differentiate into various somatic tissues, such as nerve, muscle, or glands, or into extraembryonic tissues, such as trophoblast or yolk sac epithelium. Tumors composed of EC cells and their derivatives are called teratocarcinomas. For clinical purposes germ cells are divided into two groups: seminomas and nonseminomatous germ cell tumors (NSGCT). The latter is a heterogeneous group that encompasses embryonal carcinoma, teratocarcinoma, i mmature and mature teratomas, choriocarcinoma, and yolk sac carcinomas. The histologic components of these tumors most often are intermixed, and after a diagnosis of malignant

NSGCT has been established, it is only of academic interest to enumerate all elements identified in the tumor. It is, however, important to note that the malignancy of NSGCT tumors resides primarily with EC cells. An abundance of EC cells in a given tumor and extensive invasion of EC cell into the blood vessels and lymphatics are related to an unfavorable prognosis. Seminoma is the most common germ cell tumor. The tumor appears lobulated and homogeneously yellowish on cross section (Fig. 12-14). Histologically it is composed of clear glycogen-rich cells arranged into nests that are surrounded by fibrous septa (Fig. 12-15). Fibrous septa are infiltrated with lymphocytes, macrophages, plasma cells, and occasionally multinucleated giant cells. The tumor cells are positive for placental alkaline phosphatase (PLAP) and negative for keratin, which distinguishes them from EC cells, which are PLAP-negative and keratin-positive. In approximately 20 percent to 30 percent of tumors there are scattered trophoblastic giant cells. Seminomas are radiosensitive and have a good prognosis. Embryonal carcinoma is a tumor that grows much faster than a seminoma. On gross examination it has a variegated appearance because of broad areas of necrosis and hemorrhage (Fig. 12-16). Histologically it is composed of a single population of undifferentiated cells, which have vesicular, irregularly shaped nuclei, and scant cytoplasm with indistinct borders (Fig. 12-17).

Fig. 12-13. Embryoid body. It consists of an embryonic shield and primitive amniotic and yolk sac cavities, and resembles early human embryo. A

B

Fig. 12-14. Seminoma. The tumor is homogeneously yellow and lobulated.

Fig. 12-15. Seminoma. A, Clear tumor cells form nests surrounded by fibrous strands infiltrated with lymphocytes. B, Placental alkaline phosphatase is demonstrated in tumor cells.


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Teratocarcinoma is a tumor that is composed of EC cells and their somatic and extraembryonic derivatives (Figs. 12-18 to 12-20). Extraembryonic tissues include trophoblastic and yolk sac elements. Trophoblastic cells secrete human chorionic gonadotropin (hCG), and yolk sac carcinoma cells secrete alpha-fetoprotein (AFP). Antibodies to hCG and AFP are used to demonstrate these tumor components immunohistochemically in tissue sections. In some tumors these cells may proliferate and overshadow all others. Pure yolk sac carcinomas and choriocarcinoma are rare in the testis (Fig. 12-21). Teratoma of adult testis ostensibly is a histologically benign tumor composed of somatic tissues that are devoid of EC cells. Such teratomas develop from teratocarcinomas in which all EC cells have differentiated into histologically benign somatic tissues (Fig. 12-20). However, one can never be sure that all malignant cells have disappeared from such tumors, many of which actually are capable

Fig. 12-16. Embryonal carcinoma. On cross section the tumor has an inhomogeneous texture.

Fig. 12-17. Embryonal carcinoma. The tumor is composed of undifferentiated cells with scant cytoplasm. The nuclei appear crowded and overlap.

Fig. 12-18. Teratocarcinoma. On cross section the tumor shows irregular nodularity and appears to be composed of heterogeneous elements.

Fig. 12-19. Teratocarcinoma. The tumor is composed of hyperchromatic EC cells and other loosely arranged elements.

Fig. 12-20. Teratoma. The tumor is composed of neural tissue, squamous epithelium, and connective tissue stroma.


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Fig. 12-21. Choriocarcinoma. Clear cytotrophoblastic and multinucleated syncytiotrophoblastic cells are surrounded by extravasated blood.

Fig. 12-22. Yolk sac tumor. The tumor is composed of epithelial cells forming solid nests and strands lining irregular cavities.

ranged into dense sheets. Medium-sized principal cells with round nuclei and scant cytoplasm predominate. Small cells that resemble lymphocytes are scattered at random or form small clusters. Giant cells, which measure up to 100 pm in diameter, are the least common (Fig. 12-23). Spermatocytic seminoma generally is a benign tumor, although a few malignant ones have been described.

Sex Cord Stromal Tumors

Fig. 12-23. Spermatocytic seminoma. The tumor consists of three types of cells: medium-sized principal cells, small cells, and giant cells.

of progressive growth and metastasis. Teratomas of infancy and childhood are benign tumors, which probably have a histogenesis entirely different from that of tumors of adult testis. Yolk sac tumor, a neoplasm composed of pure yolk sac elements, is the most common tumor of infancy. Histologically it consists of yolk sac—like tissue that is similar to the yolk sac components of teratocarcinoma (Fig. 12-22). Yolk sac tumors of infancy have a good prognosis. Spermatocytic seminoma is a germ cell tumor of older adults. It apparently is unrelated to NSGCT tumors and is not associated with CIS. It is composed of three cell types ar-

Tumors of specialized gonadal stroma include Leydig cell tumors, Sertoli cell tumors, and granulosa cell tumors. Leydig cell tumors are composed of cells that resemble normal Leydig cells and therefore may be hormonally active. These tumors account for 2 percent to 3 percent of testicular neoplasms. They most often occur in the 30- to 60-year age group, but approximately 20 percent of Leydig cell tumors are found in children. Most Leydig cell tumors are benign, but 10 percent are malignant. On gross examination they appear as well-circumscribed brown nodules. Histologically they are composed of polyhedral cells that have welldeveloped eosinophilic cytoplasm and vesicular round nuclei (Fig. 12-24). The cytoplasm may be vacuolated because of fat droplets or may contain brown pigment (lipofuscin). Typical Reinke crystals are sparse and are found in only one third of tumors. There are few mitoses, even in those tumors that are clinically malignant and metastasize. Hormonally inactive tumors do not differ from those that are hormonally active; androgen-secreting tumors are not different from estrogen-secreting tumors. Benign Leydig cells cannot be histologically distinguished from malignant Leydig cells, and the presence of metastases is the only reliable sign of malignancy.


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Fig. 12-24. Leydig cell tumor. The tumor is composed of solid nests of uniform cells that have vesicular round nuclei, prominent nucleoli, and well-developed eosinophilic cytoplasm.

Fig. 12-25. Sertoli cell tumor. Tumors form cords and groups that resemble tubules.

Fig. 12-26. Sertoli cell, large cell calcifying type. Tumor is composed of tubules lined by Sertoli cells. It contains prominent foci of calcification.

Fig. 12-27. Gonadoblastoma. Tumor nests composed of germ cells and sex cord cells are surrounded by dense stroma that contains lymphocytes. Foci of calcification may be seen in epithelial nests, often replacing them.

Sertoli cell tumors are composed of cells that resemble adult or fetal Sertoli cells. Sertoli cells account for 1 percent of all testicular tumors. They occur in all age groups. Clinically they are benign or malignant. Histologically Sertoli cell tumors are composed of cells that form nests and cords reminiscent of seminiferous tubules (Fig. 12-25). Other variants are (1) tubular, which are known as tubular adenoma of Pick; (2) large cell calcifying; (3) sclerosing; (4) sex cord tumor with annular tubules; and (5) anaplastic, which may invade and metastasize (Fig. 12-26).

tumor of the adult testes. The latter tumor is benign and resembles such tumors in the dysgenetic ovary, the most common site of their occurrence. Gonadoblastomas are tumors of dysgenetic gonads and are found in infants, children, and adolescents. Almost all gonadoblastomas described so far were found in persons who have a Y chromosome. Histologically they are composed of nests of germ cells and sex cord cells surrounding round bodies composed of basement membrane–like material (Fig. 12-27). Areas of calcification are common. The abundant stroma surrounding these nests may contain lymphocytes. Invasive germ cell tumors may evolve from gonadoblastomas.

Mixed Germ Cell Stromal Tumors Tumors composed of germ cells and sex cord stromal cells occur in two forms: gonadoblastoma and mixed germ cell


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Fig. 12-29. Adenomatoid tumor. Tissue spaces are lined by flattened epithelial cells surrounded by cords of cuboidal cells in connective tissue stroma. Fig. 12-28. Adenocarcinoma of rete testis. Cuboidal tumor cells form tubules and papillae that project into their lumen.

Tumors of Bete Testis, Epididymis, and Tunica Vaginalis Testis Tumors of rete testis are very rare. These lesions may be benign or malignant. Carcinoma of rete testis is a tumor that occurs in men over the age of 40 years. Histologically it appears as adenocarcinoma with papillary and tubular features (Fig. 12-28). Epithelial tumors of the epididymus resemble miillerian serous or mucinous adenomas and adenocarcinomas of the female genital system. The mesothelium of the tunica vaginalis may give rise to benign and malignant tumors. Benign tumors are called adenomatoid tumors; malignant tumors are called malignant mesotheliomas and are similar to peritoneal or pleural mesotheliomas. Adenomatoid tumors are small nodules that measure from a few millimeters to 5 to 6 cm in diameter. Histologically these tumors are composed of epithelial cells arranged into cords or strands in dense connective stroma, lining glandlike or cystic spaces (Fig. 12-29).

TUMORS AND TUMOR-LIKE LESIONS OF THE PROSTATE The two most important diseases of the prostate are benign prostatic hyperplasia (BPH) and carcinoma of the prostate.

Benign Prostatic Hyperplasia BPH is a disease of old age that results from proliferation of epithelial and stromal cells of the periurethral and transitional zone of the prostate. BPH is a common disorder, accounting for approximately 400,000 partial prostatectomies per year in the United States. The pathogenesis of BPH is not understood, but it is apparent that it is hormonally mediated and that androgens play an important role in its development. The enlarged prostate contains rubbery, yellow-gray

Fig. 12-30. Benign prostatic hyperplasia (BPH). Shelled-out prostate contains numerous nodules.

nodules that bulge from the surface (Fig. 12-30). The prostate nodules may compress and deform the urethra (Fig. 12-31). The enlarged median bar may protrude into the urinary bladder, acting as a ball valve. Microscopically BPH typically is nodular and is composed of varying proportions of epithelium and stroma comprising fibrous connective tissue and smooth muscle (Fig. 12-32). In addition to this most prevalent form of hyperplasia, several histologic variants are recognized (Figs. 12-33 to 12-35). The most important histologic variants are 1. Atrophy, which is characterized by small distorted glands.lined by flattened epithelium, hyperchromatic nuclei, and stromal fibrosis. The incidence of atrophy increases with age. 2. Postatrophic hyperplasia, in which clear cells proliferate in an atrophic background. Such cells often show nuclear atypia, and the glands contain mucin. 3. Basal cell hyperplasia, which is characterized by several layers of basal cells at the periphery of the prostatic glands and acini. The hyperplastic basal cells usually are larger than normal, elongated or spindled basal cells; they often show nuclear enlargement.


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Fig. 12-3I. BPH. Periurethral prostate appears nodular.

Fig. 12-32. BPH. The lesions typically are composed of hyperplastic glands and stroma.

Fig. 12-33. BPH, atrophic variant. The distorted glands are lined by flattened epithelium. Fig. 12-34. Cribriform hyperplasia. The glands have a cribriform appearance.

4. Atypical basal cell hyperplasia, which is composed of large basal cells with prominent nucleoli. 5. Basal cell adenoma, which consists of large, circumscribed nodules composed of basal cells arranged into solid nests or cystically dilated glands. Stromal connective tissue often traverses the adenomatous nodule, creating incomplete lobulation. 6. Adenoid cystic–like tumor (adenoid basal cell tumor), which is composed of nests of basaloid cells that infiltrate the stroma. In contrast to basal cell adenoma, this lesion is not circumscribed. The cell nests frequently are large and round to angular. Peripheral basaloid cells have elongated nuclei and often show palisading. Cell crowding is prominent, and the lumina surrounded by such cells vary in size and shape. Peripheral invasion may be seen, but there are no metastases. 7. Cribriform hyperplasia, including clear cell cribriform hyperplasia, which usually presents as a nodule composed of glands that have a distinctive cribriform pattern. The cells from such glands usually have pale to clear cytoplasm and small uniform nuclei with inconspicuous nucleoli.

Fig. 12-35. Stromal hyperplasia with atypia. Stromal cell nuclei vary in size and shape and appear hyperchromatic.


25 0

8. Atypical adenomatous hyperplasia (adenosis), in which a localized but circumscribed proliferation of small glands within the prostate may be mistaken for carcinoma. 9. Sclerosing adenosis, in which there is striking myoepithelial metaplasia of the basal cell compartment, and the stroma is exuberant and contains loose ground substance surrounding fibroblasts. The basal cells react positively with antibodies to S-100 protein and smooth muscle–specific actin, as evidence of myoepithelial metaplasia. 10. Stromal hyperplasia with atypia composed of hypercellular nodules that show crowding of cells, hyperchromasia, and nuclear enlargement with atypia. There are, however, no mitoses or necrosis, and such stromal nodules should not be considered malignant. Solid stromal nodules composed of smooth muscle cells are referred to as atypical leiomyomas. 11.Phyllodes tumor, which is a rare benign tumor that has the features of a fibroadenoma and resembles the more common breast tumors. The glandular epithelium is distorted, lining slitlike spaces. The stroma, which is composed

A

B

of fibroblasts and smooth muscle cells, appears proliferative. Benign and malignant phyllodes tumors are differentiated on the basis of a number of factors, including the ratio of stroma to epithelium and the degree of stromal cellularity, mitotic activity, and cytologic atypia.

Carcinoma of the Prostate Prostatic intraepithelial neoplasia (PIN) represents the putative precancerous end of the morphologic continuum of cellular proliferations that occur within prostatic ducts, ductules, and acini (Diagrams 12-2 and 12-3). The cells show nuclear atypia but are enclosed by a basement membrane (Fig. 12-36). Several architectural patterns, such as flat, tufting, micropapillary, or cribriform, are recognized. Adenomatous hyperplasia, a localized proliferation of small glands with varying degrees of nuclear atypia, is another possible preinvasive lesion (Fig. 12-37). Carcinoma of the prostate is the most common form of cancer among men in the United States. Estimates are that in 1998 more than 45,000 men will die of prostate cancer and

C

D

Diagram 12-2. The architectural patterns assumed by high-grade PIN. A, Tufting pattern. B, Micropapillary pattern. C, Cribriform pattern. D, Flat pattern. (From Bostwick DG et al: Hum Pathol24:298, 1993.)

Diagram 12-3. Morphologic continuum from normal prostatic epithelium through increasing grades of PIN to early invasive carcinoma, according to the disease continuum concept. Low-grade PIN (formerly grade I) corresponds to very mild to mild dysplasia. High-grade PIN (formerly grades 2 and 3) corresponds to moderate to severe dysplasia and CIS. The precursor state ends when malignant cells invade the stroma; this invasion occurs where the basal cell layer is disrupted. Notice that the dysplastic changes occur in the superficial (luminal) secretory cell layer, perhaps in response to lumina) carcinogens. Disruption of the basal cell layer accompanies the appearance of the architectural and cytologic features of high-grade PIN and appears to be a necessary prerequisite for stromal invasion. (From Bostwick DG, Brawer MK: Cancer 59:788, 1987.)


Fig. 12-36. PIN. This high-grade lesion has a flat pattern.

Fig. 12-37. Atypical adenomatous hyperplasia. Small proliferating atypical glands form a cluster adjacent to the normal prostatic glands.

B A

Fig. 12-38. Carcinoma of the prostate. A, The main tumor appears as a circumscribed, yellowwhite mass in the lateral peripheral zone of the prostate. Additional microscopic foci were found bilaterally in the periphery. B, Transition zone cancer is characterized by a bulging asymmetric mass that is present in association with BPH (arrow).

Fig. 12-39. Carcinoma of the prostate. Cross section of tumor

Fig. 12-40. Carcinoma of the prostate. It extends into the

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more than 250,000 cases will be diagnosed. Approximately 80 percent of all 80-year-old men have been found to have prostate cancer at autopsy, indicating that only a fraction of these tumors become clinically apparent. Carcinoma of the prostate tends to occur in peripheral parts of the gland (Figs. 12-38 and 12-39) but also may occur in the transition zone. Carcinoma invades the seminal vesicles (Fig. 12-39) and may extend into other pelvic organs (Fig. 12-40).

Microscopically, prostatic carcinoma most often consists of small glands that exhibit a myriad of patterns. The diagnosis is dependent on confirmation of architectural and cytologic findings (Fig. 12-41). Several histologic variants of prostatic carcinoma are recognized. The clinical and pathologic features of these variants are summarized in Table 12-2, and the salient features are shown in Fig. 12-42.

A

B

C

D

E

F

Fig. 12-41. Carcinoma of the prostate. A, Gleason pattern I. B, Gleason pattern 2. C, Gleason pattern 3, small gland subtype. D, Gleason pattern 3, cribriform subtype. E, Gleason pattern 4, with fused glands. F, Gleason pattern 5, with little or no glandular differentiation.


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Carcinoma of the prostate is graded according to the system developed by Gleason (Table 12-3, Diagram 12-4). The Gleason system takes into account the degree of glandular differentiation, accommodating tumor heterogeneity by assigning a primary pattern for the dominant

grade and a secondary pattern for the nondominant grade; the composite histologic score is derived by including the scores for the dominant and secondary patterns. Typical histologic patterns used for Gleason grading are shown in Fig. 12-41.

A

B

C

D

E

F

Fig. 12-42. Variants of prostatic carcinoma. A, Ductal (endometrioid) carcinoma. B, Small cell carcinoma. C, Mucinous (colloid) adenocarcinoma. D, Signet-ring cell carcinoma. E, Urothelial carcinoma of the prostate. F, Adenocarcinoma after androgen deprivation therapy.


25 4

Variants of Prostate Adenocarcinoma Ductal (endometrioid) adenocarcinoma Histologic features: Florid papillary, cribriform, or solid epithelial proliferation in large periurethral prostatic ducts Clinical features: Often presents at an advanced stage without elevation of serum PSA level

Carcinosarcoma Histologic features: Adenocarcinoma with sarcomatous elements (for example, cartilage, bone, and smooth muscle) Clinical features: Poor prognosis, apparently the same as sarcomatoid carcinoma

Small cell, undifferentiated carcinoma (high-grade neuroendocrine carcinoma) Histologic features: Identical to counterpart in lung and other sites Clinical features: Very poor prognosis, with mean survival less than 2 years; may be associated with paraneoplastic syndromes such as Cushing syndrome, inappropriate antidiuretic hormone secretion, and others

Transitional cell carcinoma of the prostate Histologic features: May be primary in the prostate or prostatic urethra but usually is secondary to bladder involvement. Tumor may be in situ or invasive within the prostate; look for pagetoid spread, which rarely may extend along the ejaculatory ducts through the prostate to the seminal vesicles Clinical features: Unfavorable prognosis; important to distinguish from adenocarcinoma because tumor is refractory to androgen deprivation therapy

Mutinous (colloid) carcinoma Histologic features: At least 25 percent of tumor is composed of extracellular mucin, some with extraglandular mucin and mucin lakes. Rare variant includes colonic-type carcinoma of the prostate, but this pattern usually is a result of contiguous spread from rectal cancer Clinical features: Similar or slightly worse than those of conventional adenocarcinoma Signet-ring cell carcinoma Histologic features: Typical signet-ring cell features, with tumor cells showing PAP and PSA immunoreactivity; mucin may or may not be present; usually mixed with typical acinar adenocarcinoma Clinical features: Very rare in pure form; very poor prognosis Squamous cell carcinoma of the prostate Histologic features: Most commonly seen as mixed adenosquamous carcinoma but may be pure squamous cell carcinoma with typical malignant features Clinical features: Mixed adenosquamous and pure squamous cell carcinoma pattern may appear after irradiation or hormonal therapy for typical acinar adenocarcinoma. Pure squamous cell carcinoma is rare and carries a very poor prognosis; it is refractory to androgen deprivation therapy

Adenoid basal cell tumor (adenoid cystic carcinoma or basal cell carcinoma) Histologic features: Nests of basaloid round to oval cells, often with a cribriform pattern; look for luminal mucin and eosinophilic basement membrane–like material Clinical features: Very rare, with no definite metastatic tumors or deaths Lymphoepithelioma-like carcinoma Histologic features: Islands of closely packed glands set in a dense lymphocytic stroma Clinical features: Only one reported case; unknown prognostic significance Adenocarcinoma after androgen deprivation therapy Histologic features: Shrunken, closely packed glands with optically clear cytoplasm and inconspicuous nucleoli Clinical features: Unknown; no long-term follow-up studies of this histologic pattern

Sarcomatoid carcinoma of the prostate Histologic features: Spindle cell carcinoma, usually with typical acinar carcinoma; immunohistochemical results may be positive for PSA, keratin proteins, and other epithelial markers; main differential diagnosis is carcinosarcoma, and some authors do not make this distinction Clinical features: Poor prognosis, death in less than 48 months PAP, Prostatic acid phosphatase; PSA, prostate-specific antigen.

Further Reading Blute ML, Bostwick DG, SeayTM et al: Pathologic classification of prostate carcinoma. The impact of margin status. Cancer 82:902-908, 1998. Bostwick DG, Amin MB, Dundore Petal: Architectural patterns of highgrade prostatic intraepithelial neoplasia. Hum Pathol 24:298-310, 1993. Bostwick DG, Dousa MK, Crawford BG, Wollan PC: Neuroendocrine differentiation in prostatic intraepithelial neoplasia and adenocarcinoma. Am J Surg Pathol 18:1240-1246, 1994. Bostwick DG: Grading prostate cancer. Am J Clin Pathol 102:S38-S56, 1994.

Cheville JC, Dundore PA, Bostwick DG et al: Transitional cell carcinoma of the prostate. Clinicopathologic study of 50 cases. Cancer 82:703-707, 1998. Cubilla AL, Barreto JE, Ayala G, Riveros M: Pathologic features of epidermoid carcinoma of the penis. Am J Surg Pathol 17:753-776, 1993. Cubilla AL, Reuter VE, Gregoire L et al: Basaloid squamous cell carcinoma: a distinctive human papilloma virus-related penile neoplasm: a report of 20 cases. Am J Surg Pathol 22:755-761, 1998. Eble JN: Spermatocytic seminoma. Hum Pathol 25:1035-1042, 1994. Eble JN: Variants of prostatic hyperplasia that resemble carinoma. J Urol Pathol 8:3-20, 1998.


25S

Gleason Grading System for Prostatic Adenocarcinoma: Histologic Patterns

Diagram 12-4. Gleason grading system of prostatic adenocarcinoma

Epstein JI: Diagnostic criteria of limited adenocarcinoma of the prostate on needle biopsy. Hum Pathol 26:223-229, 1995. Epstein JI: Pathology of prostatic intraepithelial neoplasm and adenocarcinoma of the prostate. Prognostic influences of stage, tumor, volume, grade, and margins of resection. Semin Oncol 21:527-541, 1994. Grignon DJ: Minimal diagnostic criteria for adenocarcinoma of prostate. J Urol Pathol 8:31-44, 1998. Heidenreich A, Sesterhenn IA, Mostofi FK, Moul JW: Prognostic risk factors that identify patients with clinical stage I nonseminomatous germ cell tumors at low risk and high risk for metastasis. Cancer 83:1002-1011, 1998. Jones MA, Young RH, Scully RE: Malignant mesothelioma of the tunica vaginalis. A clinicopathologic analysis of 11 cases with review of the literature. Am J Surg Pathol 19:815-825, 1995. Murphy WM: Prognostic factors in the pathological assessment of prostate cancer. Hum Pathol 29:427-430, 1998. Ohori M, Egawa S, Wheeler TM: Nodules resembling nodular hyperplasia in the peripheral zone of the prostate gland. J Urol Pathol 2:223-234, 1994. Piaton E, Fendler J-P, Berger Net al: Clinical value of fine-needle aspiration cytology and biopsy in the evaluation of male infertility. A comparative study of 48 infertile patients. Arch Pathol Lab Med 119:722-726, 1995. Randolph TL, Amin MB, Ro JY, Ayala AG: Histologic variants of adenocarcinoma and other carcinomas of prostate: pathologic criteria and clinical significance. Mod Pathol 10:612-629, 1998. Ulbright TM: Germ cell neoplasm of the testis. Am J Surg Pathol 17:1075-1098, 1993. van de Voorde W, Baldewijns M, Lauweryns J: Florid basal cell hyperplasia of the prostate. Histopathology 24:341-348, 1994. Young RH, Koelliker DD, Scully RE: Sertoli cell tumors of the testis, not otherwise specified. A clinicopathologic analysis of 60 cases. Am J Surg Pathol 22:709-721, 1998.




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DEVELOPMENTAL DISORDERS The development of the female genital organs is complex for two main reasons: various parts of the system develop from distinct embryonic primordia such as genital ridges, mullerian ducts, and cloaca; and proper development de -

pends on genetic and hormonal regulation. Clinically important conditions that involve abnormal sexual development are listed in Table 13-1, and some of these conditions are illustrated in Figs. 13-1 to Fig. 13-6.

Intersex Syndromes Affecting Females, Apparent Females, or Female Genitalia

Courtesy of Dr. Robert H. Shikes, Denver, Colorado.


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A

B

Fig. 13-2. Turner syndrome. Streak gonad consists of ovarian type of stroma without follicles. Hilar vessels and rete ovarii are seen in the lower portion of the figure. Fig. I3-I. Turner syndrome and gonadal dysgenesis. A, Streak gonad is attached to a hypoplastic uterus. B, The dysgenic gonad contains a gonadoblastoma that appears like a small nodule.

Fig. 13-3. External genitalia in mixed gonadal dysgenesis. Left testis has descended into the scrotum; the right gonad was a streak in the abdomen.

Fig. 13-4. Androgen insensitivity (testicular feminization) syndrome. Bisected testis appears dark brown and contains hamartomatous nodules.

Fig. 13-5. Androgen insensitivity (testicular feminization) syndrome. Histologically the testis consists of immature solid tubules lined by Sertoli cells.

Fig. 13-6. Persistent miillerian duct syndrome (hernia uteri inguinalis) secondary to deficiency of miillerian inhibitory substance ( MIS). The hernia sac of this phenotypic male contains endomyometrium.


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INFECTIONS Infections of the female reproductive system may be localized to external or internal genital organs and occur in an isolated form such as vulvitis, vaginitis, cervicitis, endometritis, salpingitis, or oophoritis; or they may involve the entire reproductive system as a chronic inflammation known as pelvic inflammatory disease (PID). The infections may be acute or chronic and are caused by various pathogens. Most of these infections are sexually transmitted or are related to infections in other parts of the body. Herpes simplex virus 2 is a very common cause of infection of the vulva. Infection tends to occur in the form of vesicles, which ulcerate and then heal spontaneously (Fig. 13-7). Condyloma acuminatum, or giant genital warts, are found on the vulva but also may occur on the cervix. These lesions are caused by several types of human papillomavirus (HPV) and present as whitish-gray, wartlike excrescences (Fig. 13-8). Histologically these lesions are squamous cell papillomas composed of cells that show typical nuclear and cytoplasmic changes (koilocytosis), which may be recognized in histologic sections and Papanicolaou (Pap) smears (Fig. 13-9). Trichomas vaginalis is the most common cause ofvaginitis in sexually active women. The flagellate protozoan resides in the lumen of the vagina and maybe recognized in Pap smears (Fig. 13-10, A). Infection with the bacterium Gardnerella vaginalis is yet another cause of vaginitis and leukorrhea. In Pap smears the bacteria tend to adhere to squamous cells, which assume a peculiar appearance and are known as "clue cells " (Fig. 13-10, B). PID, which is an infection of the internal genital organs, may occur in the form of a recurrent acute infection or as a chronic infection. Infections tend to center on the fallopian tubes, and salpingitis is almost a sine qua non for the diagnosis of PID. The fallopian tubes are distorted, swollen, and thick-walled (Fig. 13-11). These infections, which are caused

Fig. 13-8. Condyloma acuminatum. Exuberant keratotic papillary processes cover and obliterate large areas of the vulva.

by a mixed flora, including gram-negative coliform bacteria, gram-positive bacteria, Chlamydia, and Ureaplasma, may cause tumor-like periovarian and peritubal abscesses or may spread to the peritoneal cavity. Intraluminal fibrosis and adhesions impart the tube's complex and multiglandular appearance on cross section (Fig. 13-12).

Fig. 13-7. Herpesvirus infection of the vulva. Mucosa shows numerous vesicles, some of which have ruptured. (Courtesy of Dr. Cynthia Caputo, Kansas City, Missouri.)

Fig. 13-9. Condyloma acuminatum. Papillary processes are covered by orderly squamous epithelium, each supported by a fibrovascular connective tissue stalk.


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B

A

Fig. I3-I0. Vaginal infections. A, A Trichomonas vaginalis infection. Protozoans are seen between the epithelial cells. B, Gardnerella vaginalis showing "clue cells."

Fig. 13-I I. Chronic salpingitis. Both fallopian tubes are retortshaped and swollen and show adhesions to the ovaries.

Fig. 13-12. Chronic follicular salpingitis. The lumen of the fallopian tube is partially obliterated by deformed, swollen villi infiltrated with mononuclear cells. Epithelial hyperplasia may be prominent and may simulate adenocarcinoma.

HORMONALLY INDUCED CHANGES

Fig. 13-13. Anovulatory cycle. Endometrium has failed to enter the secretory phase and shows ischemic stromal necrosis.

The entire female reproductive system normally is under the influence of female sex hormones, but it also may respond to male hormones, hormone-like drugs, and hormone antagonists. During the reproductive life of a woman, estrogen and progesterone act in a cyclic manner. This cycle ends at the time of menopause but also is interrupted by pregnancy and lactation and may be perturbed by exogenous hormones, contraceptive pills, and various drugs. Lack of sex hormones or their excess may cause typical changes, most prominently in the uterus. Anovulatory cycles result in prolonged estrogenic stimulation, and when the endometrial mucosa exceeds its capacity to respond, it undergoes necrosis and a hemorrhage ensues (Fig. 13-13). Excess of endogenous or exogenous estrogens leads to endometrial hyperplasia, which is classified histologically as simple, corn -


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Fig. 13-14. Simple (cystic) hyperplasia. Endometrial glands are dilated and cystic. There are thrombosed vessels in the abundant stroma between the glands.

Fig. 13-15. Complex hyperplasia (adenomatous hyperplasia). Glands are fairly widely separated by stroma but exhibit architectural complexity. Cytologic atypia is absent.

A

Fig. 13-16. Complex hyperplasia with atypia. Cells within these closely packed glands lack polarity and show stratification and nuclear atypia resembling to some extent well-differentiated adenocarcinoma.

B

Fig. 13-17. Polycystic ovarian disease (PCOD). A, On cross section the enlarged ovary has abundant central stroma and subcapsular follicles. B, Prominent stroma and follicles are seen in the histology section. The follicles show theca cell hyperplasia and atrophy of the granulosa cells.


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plex, or complex with atypia (Figs. 13-14 to 13-16). Endometrial hyperplasia is a reversible benign lesion, but in some cases, especially if it is associated with atypia, it may progress to endometrial carcinoma. The ovaries function as part of the hypothalamicpituitary-ovarian and adrenal system. Disturbances of this system are considered to be the major cause of polycystic ovarian disease (PCOD). In this relatively common hor-

A

monal disorder, which is associated with menstrual irregularities and infertility, the dysfunctioning ovaries are enlarged and contain numerous follicular cysts (Fig. 13-17). The follicles, which are composed of nonluteinized granulosa cells and an outer layer of luteinized theca cells, are surrounded by dense cortical stroma that may form an external fibrous capsule. Hyperthecosis may be seen in deeper parts of the cortex. PCOD may be treated hormonally, albeit with varying results. Endometriosis is a disease of unknown etiology. It is characterized by the appearance of ectopic endometrial tissue on the serosal surface of the fallopian tube, ovary, pelvic peritoneum, and less often on other sites. Most foci of endometriosis are small, measuring only a few millimeters in diameter. Larger nodules (endometriomas), which usually are found on the ovary, are filled with old blood and are colloquially called " chocolate cysts " (Fig. 13-18). Histologically endometriosis consists of endometrial glands and stroma, which respond to hormonal stimulation and tend to become hemorrhagic at the time of normal menstruation. Endometriosis may be treated hormonally, but large endometriomas and some complications (e.g., intestinal adhesions) may require surgery.

TUMORS OF THE VULVA Squamous cell carcinoma and its precursor lesions, vulvar in-

B

Fig. 13-18. Ovarian endometriosis. A, "Chocolate cyst." B, Histologically the nests are composed of endometrial glands and stroma.

Fig. 13-19. VIN. Lesion is white and well circumscribed. It involves the left labium minus.

traepithelial neoplasia (VIN), represent the most important neoplastic vulvar lesions. These lesions must be distinguished clinically and pathologically from viral warts (condyloma acuminatum) and nonneoplastic vulvar dystrophies, such as lichen plan us et acuminatus atrophicans, which may present clinically as leukoplakia or kraurosis vulvae. Carcinoma of the vulva is believed to begin as an intraepithelial malignancy that progresses over time to invasive cancer (Fig. 13-19). VIN, a term that has replaced older terms such as carcinoma in situ, Bowen disease, and erythroplasia of

Fig. 13-20. VIN with anal interepithelial neoplasia (VIN-AIN). Many atypical cells are scattered through all layers of the epidermis.


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Queyrat, may be graded histologically on the basis of the extent of cytologic atypia. The neoplastic process tends to spread horizontally. It may involve large portions of the vulva and may even extend to the anus (Fig. 13-20). Vertical growth with invasion of the underlying stroma ensues in untreated cases (Fig. 13-21). Invasive cancer usually presents as indurated ulcers (Fig. 13-22). Metastases are found first in inguinal lymph nodes, but they also occur in the pelvic and abdominal lymph nodes and hematogenously may reach distant organs. Extramammary Paget disease is an intraepidermal neoplasm that has features of adenocarcinoma. Grossly it appears as an eczematoid patch with discrete borders and white keratotic areas and typically begins on the labia majora. Histologically the epidermis contains pale vacuolated adenocarcinoma cells scattered between the compressed but otherwise normal squamous cells (Fig. 13-23). The epithelium of hair follicles and apocrine glands also is typically involved. An underlying adenocarcinoma is found in approximately one third of all cases. In the presence of invasive growth and metastasis the tumor has a poor prognosis. Other tumors of the vulva, such as melanoma, adenocarcinoma of Bartholin glands, and stromal neoplasms, are rare. Locally invasive aggressive angiomyxoma is a rare but i mportant lesion of the labia. It usually affects women under the age of 40 years. The lesion appears as a soft, circumscribed, myxoid mass that is composed of hypocellular myxoid tissue with numerous muscular medium-sized arteries (Fig. 13-24). The tumor cells are fibroblasts and myofibroblasts that lack significant nuclear atypia but nevertheless have a propensity to invade local tissues. The tumor may recur locally but metastases have not been reported.

Fig. 13-22. Invasive squamous cell carcinoma of vulva. The tumor appears ulcerated.

Fig. 13-21. Carcinoma of the vulva. Radical vulvectomy and bilateral inguinal lymphadenectomy were performed for this squamous cell carcinoma of the left labia.

Fig. 13-23. Vulvar Paget disease. Neoplastic cells infiltrate the epidermis in small clumps. Squamous cells of the epidermis itself are histologically benign and compressed by tumor, and the underlying dermis is not involved by cancer cells.


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A

TUMORS OF THE VAGINA The most common malignant tumor of the vagina is squamous cell carcinoma, which has the same features as the more common carcinomas of the vulva and the cervix. Other tumors are less common but deserve to be mentioned because of their unique features. Vaginal adenosis is a benign condition that has been reported in young women who were exposed to diethylstilbestrol (DES) during fetal life. On gross examination foci of vaginal adenosis appear red and velvety, in contrast to the more opaque, pale pink normal vagina. Histologically the lesions are composed of glands lined by mucinous columnar epithelium (Fig. 13-25). Invasive adenocarcinoma may evolve from some of these lesions (Fig. 13-26). Histologically these tumors are clear cell adenocarcinomas and are similar to those in the ovary or uterus (Fig. 13-27). Tumor cells are rich in glycogen, and electron microscopy (EM) shows that they have prominent apical microvilli. Benign mixed tumor of the vagina is a rare tumor that may be confused with sarcoma. The tumor occurs in young women (median age 30 years) and is located in or just above the hymenal ring. Histologically this small (1 to 5 cm in di-

B

Fig. 13-24. Aggressive angiomyxoma. A, The tumor presented as a large, soft, myxoid, well-circumscribed mass. B, Hypocellular myxoid tissue surrounds numerous medium-sized blood vessels.

Fig. 13-25. Vaginal adenosis. Mucosa of the exocervix and adjacent vagina contains mucinous glands in place of normal squamous epithelium. Mucus is PAS-positive (red).

Fig. 13-26. Clear cell adenocarcinoma of the vagina subsequent to in utero exposure to diethylstilbestrol. Carcinoma appears as an ulcerated nodule (right). The cervix (left) shows an abnormal configuration.


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ameter) tumor is composed of bland spindle-shaped " stromal" elements admixed with epithelial foci (Fig. 13-28). Both the spindle-shaped cells and the epithelial cells appear to be of epithelial origin. Embryonal rhabdomyosarcoma (botryoid sarcoma) is the most common malignant vaginal tumor in girls under the age of five years. The tumor presents as a grapelike polypoid mass protruding from the vagina (Fig. 13-29). Histologically it is composed of malignant spindle-shaped cells that forming dense aggregates that are separated from the surface squamous epithelium by a lucent loosely textured zone ( "cambium layer " ) (Fig. 13-30). Tumor cells may show crossstriations and react with antibodies to desmins, indicating that they represent rhabdomyoblasts.

TUMORS OF THE CERVIX

Fig. 13-27. Clear cell adenocarcinoma arising in vaginal adenosis from a young women exposed in utero to diethylstilbestrol. The tumor is composed of tubulocystic glands.

Fig. 13-28. Benign mixed tumor of the vagina. A mixture of stromal and squamous cells is seen in the submucosa. Cells show no significant atypia.

Fig. 13-29. Embryonal rhabdomyosarcoma of the vagina (botryoid sarcoma). A fleshy mass protrudes into the lumen of the vagina.

Fig. 13-30. Embryonal rhabdomyosarcoma of vagina (botryoid sarcoma). The tumor is composed of embryonic rhabdomyoblasts.

Most tumors of the cervix originate from the squamocolumnar junction between the squamous epithelium of the exocervix and the glandular epithelium of the endocervix (transitional zone). Tumors also originate from the squamous epithelium itself, but the neoplastic transformation of the glandular epithelium of the endocervix is less common. Most tumors are classified as squamous cell carcinomas; adenocarcinomas are considerably less common. Carcinoma of the cervix begins as an intraepithelial neoplasm that is termed cervical intraepithelial neoplasia (CIN). It is graded on the basis of cellular and architectural atypia as CIN I, CIN II, or CIN III. These lesions maybe recognized by colposcopy (Fig. 13-31).


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The National Cancer Institute recently proposed a new terminology (Bethesda System) according to which the three-grade CIN scheme was reduced to two grades of squamous intraepithelial lesion (SIL). The lesions that formerly were designated CIN I, mild koilocytic dysplasia, and simple koilocytotis now are grouped under one heading, low-grade squamous intraepithelial lesion (LSIL) (Fig. 13-32). Lesions that previously were classified as CIN II and CIN III are called high-grade squamous intraepithelial lesion (HSIL) (Figs. 13-33 and 13-34). The main reason for the change in terminology is the apparent differential distribution of HPV in these lesions. HPV 6 and HPV 11 account for 70 percent to 90 percent of HPV associated with flat and exophytic condy-

lomas; HPV 16 is found in nearly one half of CIN III and invasive carcinomas. Low-grade lesions usually are diploid or polyploid and tend to regress. High-grade lesions are aneuploid and are more likely to progress. It is becoming increasingly obvious that LSIL represents a productive viral infection, whereas HSIL is a true neoplastic intraepithelial lesion, and the two entities do not appear to be related. Invasive carcinoma of the cervix may appear as an ulcer, an indurated mass, or a polypoid cauliflower-like lesion (Fig. 13-35). Staging and grading of cervical cancer are important for clinical assessment, therapy, and prognosis. Carcinoma of the cervix spreads by direct invasion of contiguous tissues and lymphogenously to local lymph nodes. Distant metastases are found at autopsy in the lungs and liver in 25 percent of patients. Adenocarcinoma of the cervix occurs in several histologic patterns. Clear cell carcinoma of the cervix may be similar to

Fig. 13-31. HSIL. Colposcopy shows a mosaic pattern and accentuated punctate vessels against a background of white-red opaque epithelium.

Fig. 13-32. LSIL (CIN I) of the cervix. This lesion, also known as flat condyloma, is characterized by koilocytotic atypia and usually is related to HPV 6 or HPV I I infection.

Fig. 13-33. HSIL (CIN II) of the cervix. Abnormal squamous epithelial cells appear atypical, but they vary considerably in size and shape and have a relative abundance of cytoplasm. Maturation is evident at the surface.

Fig. 13-34. HSIL (CIN III) of the cervix. Abnormal cells have uniform size and shape and relatively scant cytoplasm. There is no evidence of maturation.


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Fig. 13-35. Invasive squamous cell carcinoma of the cervix. Ulcerated invasive lesion extends into the endocervix.

Fig. 13-36. Villoglandular adenocarcinoma of the cervix. The tumor resembles a colonic polyp. No stromal invasion is seen.

the clear cell carcinoma of the vagina or endometrium. A well-differentiated mucinous adenocarcinoma may be difficult to distinguish from reactive changes in the normal endocervix. Villoglandular papillary adenocarcinoma is a newly recognized variant. It is characterized by exophytic growth, elongated fibrovascular papillae that are lined by well-differentiated, slightly atypical cuboidal cells (Fig. 13-36). Malignant mixed miillerian tumors, carcinosarcomas, and smooth muscle tumors similar to those in the body of the uterus rarely are found in the cervix.

velop endometrial cancer during her life span. Estrogenic stimulation plays an important pathogenetic role in lowgrade ( "endometrioid") cancer of post menopausal women and cancer that is associated with endometrioid hyperplasia. The more aggressive forms of endometrial cancer (serous, adenosquamous, and clear cell carcinoma) that occur in women of reproductive age do not seem to be related to hyperestrinism. Endometrial carcinoma presents as an intrauterine lesion that invades the myometrium and extends into the cervix (Fig. 13-37). Several histologic patterns are recognized (Table 13-2). Endometrioid carcinoma, the most common subtype, is graded histologically according to the scheme adopted by the International Federation of Gynecology and Obstetrics (FIGO) (Figs. 13-38 and 13-39). Other variants, such as serous papillary carcinoma, clear cell carcinoma, and adenocarcinoma with squamous differentiation, have typical histologic features (Figs. 13-40 to 13-42). Histologic features have prognostic implications, but the stage of the tumor is the most important prognostic parameter (Table 13-3).

TUMORS .OF THE UTERUS Tumors of the body of the uterus may arise from endometrial glands, endometrial stroma, or the myometrium.

Endometrial Adenocarcinoma Adenocarcinoma of the uterus occurs in menopausal and postmenopausal women. In industrialized countries its incidence has surpassed the incidence of cervical cancer, and in the United States it is estimated that 1 in 100 women will de -

Classification of Endometrial Carcinoma* Endometrioid Typical Variants With squamous differentiation Secretory carcinoma Ciliated carcinoma Serous papillary adenocarcinoma Clear cell adenocarcinoma Mucinous adenocarcinoma Squamous cell carcinoma Mixed carcinomat Un_ i _;tiated carcinoma

Fig. 13-37. Adenocarcinoma of the endometrium. The tumor

*Modified from the World Health Organization and International Society of Gynecological Pathologists classifications of endometrial carcinoma.

fills the endometrial cavity. Obvious myometrial invasion in seen.

t o carcinoma containing more than 10 percent of a second cell type.


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Fig. 13-38. Endometrial adenocarcinoma, FIGO grade I. Glands show back to back and gland within gland arrangement.

Fig. 13-39. Endometrial adenocarcinoma, FIGO grade I, secretory type. Tumor cells have cytoplasmic vacuoles.

Fig. 13-40. Serous papillary adenocarcinoma of the endometrium. Thick connective strands forming papillae are lined by stratified anaplastic cells.

Fig. 13-41. Clear cell carcinoma. Glands are lined by clear hobnail-like cells.

International Federation of Gynecology and Obstetrics (FIGO) Staging of Endometrial Adenocarcinoma (1988)

Fig. 13-42. Adenocarcinoma with squamous differentiation (adenoacanthoma). The glands are malignant but the squamous epithelium appears benign.


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Endometrial Stromal Tumors Tumors that originate from the endometrial stromal cells include benign endometrial stromal nodules, low-grade endometrial stromal sarcomas (ESS), and high-grade ESS. Benign endometrial stromal nodules form single, well-circumscribed masses that often resemble leiomyomas but differ from them by their yellow color and softer consistency. They most often are located in the myometrium, but some nodules protrude into the endometrial cavity (Fig. 13-43). Histologically these nodules resemble endometrial stroma, with numerous evenly distributed small vessels. Stromal lesions of distinct trabecular architecture may form a variety of glandlike structures and may mimic sex cord stromal ovarian tumors. The lesions often are found under the serosa of the uterus and are called plexiform tumorlets. Similar his-

tologic elements may be found in typical endometrial stromal nodules and ESS. Low-grade ESS occur as grossly circumscribed nodules with or without extensive intravascular extension (endolymphatic stromal myosis). The most characteristic feature is the presence of numerous wormlike masses that protrude from the vascular spaces on cut surface. Microscopically these tumors also are composed of endometrial stromal cells that resemble the stroma of proliferative stage endometrium or that of benign endometrial stromal nodules. In contrast to these benign lesions, the cells of ESS infiltrate the adjacent myometrium (Fig. 13-44). Mitotic figures may be prominent. High-grade ESS are malignant tumors that form one or more nodules and polypoid masses that protrude into the lumen and invade the myometrium. These tumors are composed of cells that resemble endometrial stromal cells even less than those of the low-grade ESS (Fig. 13-45). There are

Fig. 13-43. Endometrial stromal nodule. A well-circumscribed nodule protrudes into the endometrial cavity. The tumor was limited to the endometrium. (From Lloreta J, Prat J: Int J Pathol 11:293, 1992)

Fig. 13-44. Low-grade ESS. The myometrium appears infiltrated with irregularly contoured aggregates of tumor cells that resemble endometrial stromal cells.

Fig. 13-45. Low-grade ESS. Tumor cells resemble endometrial cells of proliferative endometrium and are separated by a network of small blood vessels.

Fig. 13-46. Malignant mixed miillerian tumor. The large multinodular tumor has a variegated cross section with areas of hemorrhage and necrosis.


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prominent small blood vessels between the cells, and mitotic figures are prominent; usually there are more than 10 mitotic figures per 10 high-power fields (HPFs). The histologic appearance of the tumor is, however, more reliable than its mitotic rate as a predictor of the biologic behavior of ESS. Mixed mullerian tumors are composed of both epithelial and mesenchymal cells and are classified as carcinosarcomas. Typical lesions protrude into the endometrial cavity as large irregular polypoid masses (Fig. 13-46). Histologically they are composed of poorly differentiated, often papillary endometrial adenocarcinoma and homologous or heterologous malignant stromal cells (Fig. 13-47). Homologous stromal cells resemble endometrial stroma, whereas the heterologous elements include cells that resemble chondrosarcoma, rhabdomyosarcoma, or osteosarcoma cells. These tumors have a poor prognosis. .

Fig. 13-47. Malignant mixed miillerian tumor. Carcinomatous component is of the papillary serous type, and the stroma consists of large pleomorphic spindle cells.

Fig. 13-48. Adenosarcoma. Apparently benign glands are surrounded by neoplastic stromal cells.

Miillerian adenosarcoma is a variant in which the homologous stromal elements form a sarcomatous stroma and the glandular epithelium is benign (Fig. 13-48).

Tumors of the Myometrium Tumors of the myometrium originate from smooth muscle cells and thus are classified as leiomyomas or leiomyosarcomas. Leiomyoma is the most common benign tumor of the uterus. It presents in the form of well-circumscribed, firm nodules that appear gray-white and have a characteristic whorled appearance on cross section. These nodules often are multiple and vary considerably in size and shape (Fig. 13-49). By location they may be submucosal, intramural, or subserosal. Histologically they are composed of smooth muscle cells that have typically elongated "cigar-shaped" nuclei and eosinophilic cytoplasm that has no distinct borders (Fig. 13-50). Several histologic variants are recognized. Lipoleiomyomas contain a sizable adipose tissue component. Cellular leiomyomas are highly cellular and may resemble endometrial stromal nodules. Nevertheless, the fusiform nuclei, fascicular growth pattern, and lack of extensive vascular network provide clues to the leiomyomatous nature of these lesions. Bizarre (symplastic) leiomyomas have a frightening appearance on microscopy because of many giant cells with very large, cytologically malignant-looking nuclei, which may be multiple. Mitotic figures are sparse. This lesion occurs in premenopausal women and occasionally is associated with exogenous progestin intake. Epithelioid leiomyoma (leiomyoblastoma) is composed of cells that have clear glycogen-rich cytoplasm and resemble leiomyoblastomas of the gastrointestinal tract. They show low mitotic activity and generally are benign. A few more aggressive tumors of this type have been reported, but they contained more numerous mitoses.

Fig. 13-49. Multiple leiomyomas. In sagittal section there are numerous, well- circumscribed, solid, light gray nodules distorting the uterus.


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A

Fig. 13-5 I . Intravenous leiomyomatosis. Intravascular cast of smooth muscle cells contains prominent blood vessels.

B

Fig. 13-50. Leiomyoma. A, Spindle cells are arranged in a typical interlacing pattern. B, Elongated nuclei have rounded ends and are described as "cigar-shaped."

Fig. 13-52. Leiomyomatosis peritonealis disseminata. Omentum contains multiple nodules of smooth muscular tissue, grossly simulating metastatic leiomyosarcoma.

Fig. 13-53. Leiomyosarcoma of the uterus. Intramural, solitary mass shows foci of necrosis.

Fig. 13-54. Leiomyosarcoma. Spindle-shaped nuclei show marked hyperchromasia. Mitotic figures are present.


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Some smooth muscle cell tumors may behave aggressively, belying their benign microscopic appearance. These variants include intravenous leiomyomatosis, metastasizing leiomyomatosis, and peritoneal leiomyomatosis. Intravenous leiomyomatosis is characterized by the presence of grossly visible intravenous proliferation of benign smooth muscle cells, usually found in the pelvic veins. Such intravascular masses usually consist of benign smooth muscle cells and prominent blood vessels (Fig. 13-51). Peritoneal leiomyomatosis refers to extensive proliferation of histologically benign smooth muscle cells, typically limited to peritoneal cavity. Such intravascular masses usually consist of benign smooth muscle cells that form microscopic or macroscopic nodules on the peritoneal surfaces (Fig. 13-52). These lesions most often occur in pregnancy or under hormonal stimulation and tend to regress after the hormonal stimulus is withdrawn. Metastasizing leiomyoma is a term used to describe a benign uterine leiomyoma that is associated with secondary nodules in the lymph nodes or the lungs. These lesions are composed of benign smooth muscle cells and have no mitotic activity. Some of them are related to hormonal stimulation or pregnancy and may regress following cessation of hormonal stimulation or termination of pregnancy. Leiomyosarcomas are rare malignant tumors of smooth muscle cells. They account for one third of all uterine sarcomas. Estimates are that 1 in 800 smooth muscle cell tumors of the uterus is malignant. On gross examination they usually appear as solitary, soft, intramural masses that distort the

uterus. On cross section they appear yellow or brown and show numerous areas of hemorrhage and necrosis (Fig. 13-53). Histologically they are composed of spindle-shaped cells arranged into fascicles (Fig. 13-54). There typically is focal or diffuse hypercellularity and marked nuclear atypia. Mitotic figures are found at a rate of more than 10 per 10 HPFs. Tumors that are mitotically less active may pose diagnostic problems. It has been recommended that tumors that have more than 5 mitotic figures per 10 HPFs and show nuclear atypia should be designated leiomyosarcoma; those that have the same mitotic rate but show no nuclear atypia are designated mitotically active leiomyomas.

TUMORS OF THE OVARY Ovarian tumors occur in many forms and generally are classified as originating from the surface epithelium, sex cord stromal cells, and germ cells (Table 13-4). Serous Tumors Serous tumors are classified as benign, borderline malignant, and malignant. Serous cystadenoma is a benign cystic mass that has one or multiple cavities filled with clear serous fluid (Fig. 13-55). Histologically the cavities are lined by cuboidal or low columnar uniform epithelium, which may be ciliated or pseudostratified as in the fallopian tube (Fig. 13-56). Papillary processes are common and may be complex. Similar epithelium may cover the external surface of the cysts. Borderline malignant tumors more often are multilocular and

World Health Organization Classification of Ovarian Tumors


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Fig. 13-55. Serous cystadenoma. The cystic mass has a smooth surface. It is filled with clear serous fluid and appears translucent.

A

B

Fig. 13-56. Serous cystadenoma. A, Fluid has flowed out from the main cyst. There still are several smaller unopened cysts. B, Cyst is lined by cuboidal cells that have round or elongated regular nuclei with evenly distributed chromatin.

Fig. 13-57. Borderline serous tumor of ovary, a multilocular cystic mass with spaces lined by papillary epithelial masses.

Fig. 13-58. Serous borderline tumor of the ovary. Prominent papillae lined by cuboidal epithelium project into the lumen of the cystic tumor.


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form complex papillae on their internal surface (Fig. 13-57). Papillae are lined by cells that show atypia, mitotic activity, and stratification (Fig. 13-58). Microinvasion of the stroma may be present, and in approximately 30 percent of cases there are peritoneal implants. Peritoneal implants are classified as invasive or noninvasive; the former are further divided into epithelial and desmoplastic subtypes (Fig 13-59). The cells of these implants resemble the original tumor and may show mild to moderate atypia. Similar.tumors may arise from the peritoneum without ovarian neoplasia. Malignant serous tumors (serous cystadenocarcinomas) form papillae, invade stroma, and contain many solid areas (Fig. 13-60). Peritoneal seeding and ascites often are present.

Mutinous Tumors Mucinous tumors typically are large, cystic, mucus-filled

masses, which on cross section may be classified as unilocular or multilocular (Fig. 13-61). The cavities are lined by tall columnar epithelium that resembles endocervical glands. Such cells have basally located nuclei and apical cytoplasm filled with mucus (Fig. 13-62). More often the epithelium may contain goblet cells, interspersed with neuroendocrine and even Paneth cells, and resembles intestinal epithelium. Borderline mucinous tumors account for 40 percent to 50 percent of all mucinous malignant tumors. Such tumors differ from benign cystadenomas in that they show more nuclear unrest, atypia, and focal invasion (Figs. 13-63 and

Fig. 13-59. Serous borderline tumor of the ovary. A, Paratubal implant of serous borderline tumor of noninvasive epithelial type. Papillae fill submesothelial invaginations. B, Invasive implant of serous borderline tumor. Tumor nests resemble low-grade serous carcinoma but are composed of cells that show no atypia and are devoid of mitotic figures.

Fig. 13-60. Serous carcinoma of the ovary. This carcinoma is composed of glands that contain papillary projections lined by cuboidal cells.

Fig. 13-61. Mucinous cystadenoma of the intestinal type. Mucus was removed from the main cavity, but it still shines through the wall of smaller cysts.


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Fig. 13-62. Mucinous cystadenoma of the intestinal type. Mucinrich goblet cells line the central cavity of this cystic tumor. Fig. 13-63. Mucinous intestinal cystadenoma of borderline malignancy. Irregular glands are lined by relatively uniform mucus-rich cells. There is no stromal invasion.

Fig. 13-64. Mucinous endocervical (miillerian) cystadenoma of borderline malignancy. Mucin-rich tumor cells line edematous papillae that are infiltrated with neutrophils.

Fig. 13-65. Mucinous intestinal cystadenocarcinoma. The tumor appears as a solid mass.

Fig. 13-66. Mucinous intestinal cystadenocarcinoma, FIGO grade II. Mucin-rich cells pile up within atypical glands invading the stroma.

Fig. 13-67. Endometrioid adenocarcinoma. The tumor is a solid mass.


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13-64). In 85 percent of cases cysts are lined by intestinal-like epithelium. Borderline tumors of the endocervical type have a better prognosis than those of the intestinal type. Mucinous cystadenocarcinomas are obviously malignant tumors that contain large solid parts or may be composed entirely of solid tissue (Fig. 13-65). Histologically such tumors are adenocarcinomas lined by mucus-producing cells. The solid area may contain anaplastic carcinoma or rarely sarcoma. Sarcoma-like stromal reaction occasionally is seen, but it is inconsequential from the clinical point of view. The distinction between borderline malignant and low-grade malignant mucinous tumors may be difficult. The main reason for this diagnostic dilemma lies in the nature of stromal reaction to the tumor. Instead of being desmoplastic, the stroma of the tumor may be luteinized and may resemble ovarian stroma, which.makes it almost impossible to determine whether there is any true invasion (Fig. 13-66). Empiric criteria have been proposed, and carcinoma is diagnosed if the tumor forms layers that are four or more cells thick; if it

forms finger-like projections of solid cellular masses without connective tissue support; or if the neoplastic glands have a cribriform growth pattern. Recently it was proposed that intestinal mucinous borderline tumors may be separated from well-differentiated carcinomas by quantitative nuclear morphologic analysis. Extraovarian spread of mucinous tumors results in peritoneal seeding and mucinous ascites known as pseudomyxoma peritonei. There often is a simultaneous mucinous tumor of the appendix, and there is controversy over whether these represent two independent primary tumors, that is, multifocal primaries, a metastasis of the ovarian tumor to the appendix, or vice versa. Endometrioid Carcinoma

Fig. 13-68. Well-differentiated endometrioid adenocarcinoma of the ovary. Histologically it is identical with uterine endometrial adenocarcinoma.

Endometrioid carcinomas account for 20 percent to 30 percent of all ovarian cancers. They are so named because of their histologic resemblance to uterine adenocarcinomas. The similarity is most evident in well-differentiated tumors. Less-differentiated lesions may have a typical endometrioid appearance only focally, which together with additional foci of squamous differentiation may be the only clue to the true nature of such tumors. Endometrioid adenocarcinomas present as solid or partially cystic ovarian masses (Fig. 13-67). Histologically they resemble endometrioid adenocarcinomas of the uterus and are graded the same way (Fig. 13-68). The criteria for borderline malignant endometrioid tumors are not well established. Such criteria are most easily applied to endometrioid tumors that have a prominent stromal component. These tumors are called adenofibromas and may be classified as benign, borderline malignant, or malignant (Fig. 13-69). Endometrioid tumors that have a malignant stromal component are classified as carcinosarcomas and are equivalent to uterine malignant mixed mullerian tumors. Adenosarcomas and endometrial stromal sarcomas also occur in the ovary, but they are rare.

Fig. 13-69. Endometrioid adenofibroma of borderline malignancy. The tumor contains glands and squamous morules with central necrosis.

Fig. 13-70. Clear cell adenocarcinoma. Tubulocystic pattern is identical to that found in clear cell carcinomas of the vagina, cervix, and endometrium.


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Clear Cell Carcinoma Clear cell carcinomas account for approximately 10 percent of all ovarian cancer. On gross examination they appear as solid or partially cystic masses. Microscopically they are characterized by masses of large epithelial cells with clear cytoplasm arranged into glands or solid nests. The most common pattern is that of small tubules and cysts lined by a single layer of cuboidal hobnailed cells (Fig. 13-70). Benign and borderline clear cell tumors rarely occur, usually as adenofibromas. The association between clear cell carcinoma and endometriosis is six times greater than that of ovarian carcinomas in general.

Transitional Cell Tumors Transitional cell tumors include benign Brenner tumors, transitional cell carcinomas that originate from Brenner tumors (malignant Brenner tumor), and transitional cell carcinomas that are of surface epithelial origin and are unrelated to a preexisting Brenner tumor.

Brenner tumor is a benign lesion that accounts for 2 percent to 3 percent of all ovarian tumors. In 25 percent of cases Brenner tumors are found within mutinous ovarian tumors. Tumors typically appear as small, fibrotic nodules, which histologically are composed of nests of transitional epithelium surrounded by dense fibrous stroma (Fig. 13-71). The epithelial nests may be solid or may have a central lumen that contains dense eosinophilic material or mucus. The tumor cells are polygonal and have grooved nuclei and clear cytoplasm. The cells lining the central lumen may be filled with mucin. The surrounding stroma often is hyalinized and may contain foci of calcification. Less than 2 percent of all Brenner tumors are classified as borderline malignant or overtly malignant. The epithelial component of borderline malignant Brenner tumors resembles grade I papillary carcinomas of the urinary bladder, and no invasion of the stroma is seen. In malignant Brenner tumors the nests have features of higher grade transitional cell malignancy (Fig. 13-72). Similar tumors may originate from the surface epithelium unrelated to Brenner tumors, but such transitional carcinomas of the ovary are rare.

Sex Cord Stromal Tumors

Fig. 13-71. Brenner tumor. Solid tumor nests are enclosed by fibroblastic stroma.

Fig. 13-72. Malignant Brenner tumor. Cells in the nest to the left show significant atypia.

Sex cord stromal tumors originate from specialized and nonspecific stroma of the ovary. Accordingly, the tumors are composed of cells that resemble granulosa cells, theca cells, luteinized and nonluteinized fibroblastic stromal cells, and hilar luteinized cells. Sex cord stromal tumors account for most hormonally active ovarian tumors. Granulosa cell tumors usually present as solid masses with some cystic parts. On cross section solid areas appear brown or grayish-yellow and typically contain blood clots. Approximately 75 percent of all granulosa cell tumors are estrogenic, whereas others are either nonfunctioning or androgenic. Less than 5 percent are bilateral. Granulosa cell tumors are composed of cells that resemble normal granulosa cells. Tumor cells have oval nuclei with prominent clefts (coffee bean– shaped nuclei) and often are arranged into rosette-like structures, known as Call-Exner bodies, which are reminiscent of those found in normal graafian follicles (Fig. 13-73). Several microscopic patterns are recognized. Microfollicular and macrofollicular patterns recapitulate the histologic features of graafian follicles. Tumors may have a trabecular, insular, or gyriform pattern, but these descriptive terms do not have significant clinical implications. Diffuse or sarcomtoid tumors may behave more aggressively. Juvenile granulosa tell tumor, a variant that is found in girls, has a distinct histologic appearance. It consists of cells that often are luteinized and form rudimentary follicles or solid masses (Fig. 13-74). All granulosa cell tumors should be considered potentially malignant, although 90 percent of patients survive 10 years after surgery. Late recurrences may occur even beyond that period. The most consistent indicator of aggressive behavior is the presence of metastases or invasion of surrounding tissues outside the ovary. Other unfavorable signs, which are not consistently reliable predictors


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A

B

Fig. 13-73. Granulosa cell tumor. A, Microfollicular pattern. B, Tumor cells have clefted, coffee bean—shaped nuclei.

Fig. 13-74. Juvenile granulosa cell tumor. Cells form rudimentary follicles. Tumor cell nuclei show some atypia, and their cytoplasm appears luteinized and clear.

of malignancy, are large tumor size, tumor rupture, and high mitotic rate. Tumors of older patients appear to be more aggressive than those of younger women. Fibromas of the ovary account for 6 percent of all ovarian tumors. These hormonally nonfunctioning tumors are composed of fibroblasts that form solid masses. On cross section the masses are white and have a whorled appearance (Fig. 13-75). Fibromas are benign, even if they are classified as cellular and mitotically active. Fibrosarcomas are rare and resemble equivalent soft-tissue tumors. Thecomas are similar to fibromas, but they are hormonally active and are composed of luteinized stromal cells. Because of the luteinization of tumor cells, theca cell tumors appear yellow on cross section (Fig. 13-76). Histologically they consist of fibroblast-like tumor cells, which may have a somewhat more abundant cy -

Fig. 13-75. Fibroma. On cross section this lipid-rich tumor appears white and fibrotic.

Fig. 13-76. Thecoma. On cross section this lipid-rich tumor appears yellow.


28 0

A B

Fig. 13-77. Thecoma. A, The tumor is composed of spindle-shaped cells. B, Fat stain (oil red 0) shows lipid droplets in the cytoplasm of tumor cells.

Fig. 13-78. Sclerosing stromal tumor of the ovary'. Spindleshaped and clear cells form nests surrounded by loosely structured stroma and thin-walled vessels.

Fig. 13-79. Sertoli-Leydig cell tumor. The tumor is yellow on cross section.

Fig. 13-80. Sertoli-Leydig cell tumor. The well-differentiated tumor consists of tubules and groups of Leydig cells.

Fig. 13-81. Sertoli-Leydig cell tumor. This tumor shows intermediate differentiation, and its cells form cords.


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toplasm than the cells of fibromas. Such cells typically contain fat droplets that may be demonstrated by special stains (Fig. 13-77). Thecomas are benign tumors of older women (80 percent are postmenopausal), and malignant variants are extremely rare. Sclerosing stromal tumor of the ovary belongs to the general category of fibroblastic stromal tumors, but it differs from fibromas and thecomas both clinically and morphologically. These tumors occur in women under the age of 30 years and are composed of distinct nests of spindle-shaped stromal and clear cells separated from other similar nests by loosely structured stroma (Fig. 13-78). The tumor typically contains thin-walled vessels. Luteinization of cells occurs at a variable rate, and occasional tumors may be hormonally active. Sertoli-Leydig cell tumors occur in all age groups, but their peak incidence is in younger women (average age 25 years). These tumors typically are solid, yellow, and often lobulated N(Fig. 13-79). They secrete androgenic hormones and cause virilization. Histologically Sertoli-Leydig cell tumors have features of a developing testis and are composed of cells that resemble Sertoli cells and Leydig cells. Five histologic patterns are recognized: 1. Well-differentiated tumors in which Sertoli cells form tubules surrounded by nests of Leydig cells 2. Tumors of intermediate differentiation, which are composed of cords, abortive tubular structures, and nests of luteinized Leydig cells and spindle-shaped stromal cells 3. Sarcomatoid variant, which is composed of spindleshaped cells with focal formation of vague tubular structures and only sparse Leydig cells, which maybe missing altogether 4. Retiform tumors, which mimic rete ovarii or rete testis 5. Sertoli-Leydig cell tumors with heterologous elements, such as neoplastic mucous glands, cartilage, or skeletal muscle cells (Figs. 13-80 to 13-82). Almost all Sertoli-Leydig cell tumors are benign. The rare malignant tumors were poorly differentiated and had mesenchymal heterologous elements. Intraabdominal spread but not extraabdominal metastases were recorded in such cases.

Fig. 13-83. Sex cord tumor with annular tubules. Eosinophilic globules are surrounded by spindle-shaped cells.

Sex cord stromal tumor with annular tubules (SCTAT) is a unique tumor composed of cells that have intermediate features of granulosa cells and Sertoli cells. These tumors occur in patients with Peutz-Jeghers syndrome. They have a favorable prognosis in most instances. Histologically they are composed of tubules lined by spindle-shaped cells arranged around centrally located globules of eosinophilic basement membrane like—material (Fig. 13-83). Gynandroblastoma is a term that is used to describe Sertoli-Leydig cell tumor cognates that also contain incontrovertible granulosa cells. Steroid lipid (cell) tumors are distinctive tumors that appear as yellow or brown nodules or larger masses. They include three entities: stromal luteomas, hilar cell tumors, and steroid cell tumors not otherwise specified (NOS). These tumors are hormonally active and usually are benign, except for steroid cell tumors NOS, which may be malignant. Histologically they are composed of polyhedral luteinized cells with round nuclei and well-developed eosinophilic, lipidrich cytoplasm (Fig. 13-84).

Fig. 13-82. Sertoli-Leydig cell tumor, sarcomatoid variant. The tumor is composed of spindle-shaped cells.

Fig. I3-84. Stromal luteoma. The tumor is composed of polyhedral cells that have round centrally located nuclei and welldeveloped eosinophilic cytoplasm.


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Germ Cell Tumors Germ cell tumors of the ovary originate from the oocytes and are histologically equivalent to testicular and extragonadal germ cell tumors. Dysgerminoma is the most common malignant germ cell tumor of the ovary. It occurs in young women and is considered to be an ovarian equivalent of testicular seminoma. Grossly it appears as a gray-white or yellowish lobulated solid mass (Fig. 13-85). Histologically it is composed of polygonal clear cells arranged into nests that are surrounded by stroma infiltrated with lymphocytes (Fig. 13-86). Dysgerminomas are extremely radiosensitive and have a good prognosis; the five-year survival rate is approximately 95 percent. Embryonal carcinoma of the ovary is rare. Choriocarcinoma is composed of cytotrophoblastic and human chorionic gonadotropin (hCG)–positive syncytiotrophoblastic cells. Yolk sac carcinoma is an alpha-fetoprotein–secreting tumor of women under the age of 20 years. Histologically the

tumor may present in several patterns, including reticular, microcytic, tubular, and so forth (Figs. 13-87 and 13-88). Glomeruloid Schiller-Duval bodies are typical. Tumors also contain periodic acid-Schiff–positive, diastase-resistant hyaline globules. Benign cystic teratoma (dermoid) is the most common germ cell tumor of the ovary. It typically occurs after puberty and early reproductive life, but in some cases it is diagnosed later in life. On gross examination it presents as a cystic structure that is filled with hair and sebaceous material (Fig. 13-89). Histologically the tumor is composed of various mature somatic tissues, including skin, glandular epithelium, neural tissue, bone, and teeth (Fig. 13-90). Teratomas are benign, although they may undergo malignant transformation if they are left inside the body. Most of these secondary malignancies are squamous cell carcinomas, but a few sarcomas also have been reported.

Fig. 13-85. Dysgerminoma. This large lobulated tumor was removed from a six-year-old girl.

Fig. 13-86. Dysgerminoma. Tumor cells have clear cytoplasm. These cells form' solid nests by septa infiltrated with lymphocytes.

Fig. 13-87. Yolk sac carcinoma. Tumor cells form glomeruloid structures, nests, and strands.

Fig. 13-88. Yolk sac carcinoma. Tumor cells are positive for alpha-fetoprotein.


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Immature teratomas are malignant tumors that present as solid masses, parts of which appear encephaloid (Fig. 13-91).

Histologically they may contain many kinds of tissues, but their malignancy derives predominantly from the immature neural tissue. Neural components of immature teratomas are graded on a scale from Ito III (Fig. 13-92 to 13-94). Tumors tend to spread throughout the peritoneum, and the histologic evaluation of metastases is important for prognostic purposes. Benign glial implants are innocuous, but those that are composed of neuroblasts are ominous. Overall five-year survival is in the range of 70 percent, mostly because of the efficient use of modern chemotherapy. Specialized teratomas may represent one-sided differentiation of an overgrowth of a specific tissue or tumor type in a previously benign teratoma. Struma ovarii is composed of thyroid tissue, which may be highlighted with antibodies to thyroglobulin (Fig. 13-95). Neuroendocrine tumors may resemble carcinoids as in other parts of the body, but they also may originate in thyroid tissue (Fig. 13-96). Fig. 13-89. Benign cystic teratoma (dermoid cyst). The cavity is filled with sebaceous material and hair.

Fig. 13-90. Benign teratoma. The tumor is composed of squamous epithelium, neural tissue, and glands.

Fig. 13-91. Immature teratoma. Solid areas appear encephaloid and bulge from the cross section.

Fig. 13-92. Immature teratoma, grade I . The tumor consists of differentiated neuropil with only occasional immature neural cells.

Fig. 13-93. Immature teratoma, grade 2. The tumor contains mature and immature neural tissue.


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Unclassified and Metastatic Tumors of the Ovary Small cell carcinoma with hypercalcemia is a highly malignant tumor of young women. It is composed of small undifferentiated cells that form solid compact sheets and nests with areas of necrosis (Fig. 13-97). Tumor cells may form abortive rosettes and follicles, but they do not show any distinct differentiation.

Fig. 13-94. Immature teratoma, grade 3. The tumor consists mostly of immature neuroblastic cells that form rosettes.

Fig. 13-95. Struma ovarii. The tumor consists of thyroid-like tissue.

Fig. 13-97. Small cell carcinoma with hypercalcemia. The tumor is composed of closely compacted small cells, focally surrounding spaces filled with proteinaceous fluid.

Fig. 13-96. Strumal carcinoid. The tumor consists of small neuroendocrine cells surrounding

Fig. 13-98. Krukenberg tumor. Metastatic carcinoma from the primary tumor in the stomach has symmetrically enlarged the ovaries, which appear lobulated and have a smooth surface.


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Krukenberg tumor represents bilateral metastases of adenocarcinoma of the gastrointestinal tract to the ovaries. The ovaries typically are enlarged and have a smooth, usually lobulated external surface (Fig. 13-98). Histologically the ovary is permeated with tumor cells, which maybe signet ring—like or cuboidal (Figs. 13-99 and 13-100). Ovarian stromal cells often are luteinized and hyperplastic. Nodular metastases on the surface of the ovary may mimic primary ovarian tumors, and mucinous adenocarcinomas of the large intestine may

produce lesions that are indistinguishable from primary ovarian tumors of the same histologic type. Nevertheless, metastases tend to be composed of more anaplastic cells, and the tumors often show extensive necrosis (Fig. 13-101). Lymphoma may involve the ovary, usually in the advanced stages of the disease. Burkitt lymphoma occasionally may present as a primary ovarian mass. Histologically such tumors are indistinguishable from equivalent lymphomas in other sites (Fig. 13-102).

Fig. 13-99. Krukenberg tumor. The ovary is infiltrated with signet-ring cancer cells.

Fig. I3-100. Krukenberg tumor. Stromal cells of the ovary infiltrated with cancer appear hyperplastic.

Fig. 13-101. Metastasis from colonic adenocarcinoma. The neoplastic glandlike structures are partially necrotic.

Fig. 13-102. Burkitt lymphoma. Ovary infiltrated by undifferentiated lymphoid cells has a starry sky appearance.


28 6

Diagram 13-I. A, B, Drawing of a frontal section of the uterus showing the elevation of the decidua capsularis caused by the expanding chorionic sac of a 4-week embryo. C-F, Drawings of sagittal sections of the gravid uterus from the fifth to twenty-second weeks, showing the changing relationship of the fetal membranes to the decidua. In F, the amnion and chorion are closely approximated but never quite fuse with each other and the decidua parietalis, thereby obliterating the uterine cavity. Note in D to F that the chorionic villi thrive only where the chorion is associated with the decidua asalis; here they form the chorion frondosum, and the chorion laeve will show persistence of ghostlike atrophic villi seen even at term on the free membranes. (Modified from Moore KL, Persaud TVN: The developing human, clinically oriented embryology, ed 5, Philadelphia, 1993, Saunders.)


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DISORDERS OF THE PLACENTA The placenta develops from embryonic trophoblastic cells at the site of implantation of the embryo, which occurs at the blastocyst stage. The fully functioning placenta, which provides the essential support to the developing fetus, develops over a period of weeks and remains in place in utero until the end of pregnancy. The mature placenta consists of the placental disk, the chorioamniotic membranes, and the'umbilical cord (Diagrams 13-1 and 13-2). The placental disk consists of trophoblastic cells, including mononuclear cytotrophoblastic and -multinucleated syncytiotrophoblastic cells arranged into chorionic villi. Villi, like the entire placenta, contain numerous blood vessels filled with fetal blood, which carries nutrients and oxygen to the fetus from the mother. In pregnancies with multiple fetuses the placenta varies from the normal in that it maybe composed of a single disk or entirely

separate disks. In twin pregnancy, which is the most common multiple pregnancy, a single-disk placenta is classified as monochorionic, diamniotic, or dichorionic diamniotic (Figs. 13-103 and 13-104). Such variations are of limited clinical significance in most cases. Placental abnormalities include (1) abnormal implantation, which may occur in the uterus (e.g., placenta previa) or outside the uterus, which results in extrauterine pregnancy; (2) abnormal separation of the placenta from the pregnant uterus, such as placenta accreta; (3) abnormal morphology of the placental disk, which may be multilobated, succenturiate, and so forth, or may show abnormal insertion of the umbilical cord and the chorioamniotic membranes (e.g., circummarginate or circumvallata placenta); (4) abnormal differentiation of trophoblastic cells, which results in gestational trophoblastic disease, such as hydatidiform mole and choriocarcinoma.

Diagram 13-2. Recommended minimum sections include a membrane roll, which included the zone of rupture and a marginal portion of the placental disk for orientation. There are two sections of umbilical cord, one from the fetal end and the other from the placental end, 2 to 3 cm from the insertion. (Computer-generated diagram by Martin E. Nau.)

Fig. 13-103. Monochorionic diamniotic placenta. The fetal surface of the placenta shows the thin dividing membrane. Fetal vessels were injected with milk-barium solution to illustrate the vascular anastomoses. (Courtesy of Dr. Milton J. Finegold, Houston, Texas.)

Fig. 13-104. Dichorionic diamniotic placenta. The fetal surface shows a very thick dividing membrane.


28 8

A B

Fig. 13-105. Ectopic pregnancy. A, The fetus was found in the fallopian tube. B, Chorionic villi and blood are found inside the fallopian tube.

Fig. 13-106. Placenta accreta. A hysterectomy was performed because the placenta could not be removed from the pregnant uterus.

A

B

C

Fig. 13-107. The early amnion rupture sequence (TEARS). Fetal abnormalities usually are related to placental changes. A, Fetus shows abnormalities of the head and extremities. B, The fetal surface of the placenta shows a dull denuded chorionic surface with thin bands of tissue extending from it. C, Microscopically the epithelial layer of the amnion is absent and the chorion is thickened and cellular. (A and B, courtesy Sherrie A. Caldwell, MD, The Children's Hospital, Denver, Colo.)


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Abnormal Implantation and Separation of the Placenta and Rupture of Membranes Extrauterine implantation results in ectopic pregnancy, usu-

ally in the fallopian tubes (Fig. 13-105). Chorionic villi of an abnormally implanted ovum tend to invade the underlying tissue. Destruction of the muscle layer of the fallopian tube typically is associated with a hematosalpinx, and tubule rup,ture may ensue. Abnormal invasion of chorionic villi at an intrauterine site results in placenta accreta. Placenta accreta is firmly anchored in the uterus, and it does not separate normally during delivery. It may be removed with difficulty, and until recently many patients with placenta accreta required hysterectomy (Fig. 13-106). Histologically placenta accreta shows invasion of chorionic villi into the myometrium, without an intervening decidua and Nitabuch fibrinoid layer. In the third trimester premature separation of the placenta from the uterus, such as abruptio placentae, or rupture of the fetal

membranes, results in premature delivery. Premature rupture of the membranes also may cause infection. The early amnion rupture sequence (TEARS), which occurs in early pregnancy, is associated with a variety of fetal malformations that usually affect the head and the extremities (Fig. 13-107).

Infections On the basis of the route of entry, fetoplacental infections are classified as secondary to (1) hematogenous spread, (2) endometrial infection, including descending infection of the fallopian tubes or the peritoneum, (3) ascending infection of the vagina, and (4) iatrogenic infection of the amniotic fluid during amniocentesis or fetal surgery. The infection may cause inflammation in the umbilical cord (funisitis), chorion, amnion (chorioamnionitis), or chorionic decidua (Figs. 13-108 and 13-109). Histologically the inflammatory response may include neutrophils, which may be sprinkled

A

B

C

D

Fig. 13-108. Acute chorioamnionitis. A, The row of membranes sectioned crosswise shows more inflammation at the center nearest the cervical os. B, Bacterial polymorphonuclear leukocytes extend from the maternal intervillous space at the subchorionic space into the chorion. C, Fusobacterium, a common cause of preterm labor, is seen "standing on end" in the amnion, which was impregnated with silver according to the Warthin-Starry method. D, A "bacterial cloud" is seen without much inflammation, a feature suggestive of inadequate maternal response.


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at random or may form abscesses. Lymphocytes and plasma cells may be found together with macrophages, which occasionally are arranged into granulomas. Histologic findings are not reliable indicators for the onset of inflammation, and often one cannot determine whether the inflammatory response was elicited by infective pathogens or by an immune response. Pathogens such as bacteria, viruses, or fungi may be demonstrated, sometimes with the use of special stains, but in most cases they are not obvious. Many cases of chronic inflammation identified histologically and interpreted without additional clinical or microbiological data often are classified as villitis of undetermined etiology ( WE) (Fig. 13-110).

Gestational Trophoblastic Disease Gestational trophoblastic disease (GTD) has been defined by the World Health Organization and International Society of

Fig. 13-109. Villitis caused by Listeria monocytogenes. An infiltrate composed of neutrophils involves microvilli,extending into the intervillous spaces.

Gynecological Pathologists as a group of closely related diseases that includes (1) complete hydatidiform mole, (2) partial hydatidiform mole, (3) invasive mole, (4) placental site trophoblastic tumor, (5) choriocarcinoma, and (6) other trophoblastic lesions. The salient features of these lesions are summarized in Table 13-5 and are compared with changes in hydropic abortus. Representative gross and microscopic aspects of GTD are shown in Figs. 13-111 to 13-115. Hydropic abortus must be included in the differential diagnosis of molar gestation. The classic features are amphophilia of the villous stroma and atrophy of the trophoblasts. Trophoblastic proliferation, if present at all, is polar, representing a normally implanting villus (Fig. 13-116). The differential diagnosis of placental site trophoblastic tumor includes the "exaggerated implantation site " and the placental nodule (Fig. 13-117).

Fig. 13-I 10. Chronic villitis. This predominantly intervillous inflammation ("intervillositis") may have been caused by infection, but it also might represent an immune response.

A

B

Fig. 13-III. Complete hydatidiform mole. A, Nearly all villi are enlarged and are interconnected by thin nonedematous cordlike structures. B. Greatly enlarged edematous villus with incompletely formed central cistern. There also is circumferential cellular obliteration of syncytiotrophoblast, cytotrophoblast, and intermediate trophoblast, some of which show eosinophilic necrosis.


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Gestational Trophoblastic Disease: Clinical, Gross, Microscopic, and Flow Cytometric Features

From Popek EJ: ASCP check sample AP 94-7 (AP-241), "Partial hydatidiform mole," American Society of Clinical Pathologists, 1994. Copyright ASCP Chicago. AB, Abortion; CHM, complete hydatidiform mole; CT, cytotrophoblast; I-I A, hydropic abortus; IT, intermediate trophoblast; n/a, not applicable; n/r, none reported; NRBC, nucleated red blood cells; PHM, partial hydatidiform mole; PSTT, placental site trophoblastic tumor; SAB, spontaneous abortion; ST, syncytiotrophoblast.


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A

B

Fig. 13-112. Partial hydatidiform mole. A, Less than 20 percent of villi are cystic. A macerated fetus is attached to the placenta. B, Enlarged villus shows pronounced scalloping, which results in pseudoinclusions (i.e., islands of trophoblast in the stroma of the villus). "Knuckles" of proliferating syncytiotrophoblast have undergone eosinophilic necrosis.

Fig. I3-1 13. Invasive CHM showing enlarged villi with trophoblastic proliferation deeply invasive into the myoretrium.

Fig. 13-1 14. Placental site trophoblastic tumor (PSTT). Uniform polygonal cells form sheets of intermediate trophoblast, with only rare multinucleated cells invading the myometrium.

A

B

Fig. 13-I 15. A, Choriocarcinoma. Cytotrophoblastic and syncytiotrophoblastic cells show foci of necrosis and are admixed with extravasated blood. B, Immunohistochemically, human chorionic gonadotrophin can be demonstrated in the syncytiotrophoblastic cells.


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Fig. 13-116. Hydropic abortus (HA) with enlarged edematous villi with amphophilic stroma, few residual blood vessels, and polar trophoblastic proliferation of anchoring villi.

A

B

Fig. 13-1 17. Lesions easily confused with PSTT. A, Exaggerated implantation site with numerous mononuclear cells within the maternal myometrium. Normal invasion of the uterus by trophoblasts is extensive in early pregnancy and may be underappreciated. B, Placental nodule is residua from a previous pregnancy; well circumscribed, it has a central acellular or sclerotic region surrounded by a few viable intermediate trophoblasts. The last documented pregnancy in this case was several years before this curettage.

Further Reading Benda JA: Pathology of cervical carcinoma and its prognostic implications. Semin Oncol 21:3-11, 1994. Clement PB: Pathology of the uterine corpus. Hum Pathol 22:776-791, 1991. Cramer SF, Patel A: Myometrial hyperplasia. Proposed criteria for a discrete morphological entity. Mod Pathol 8:71-77, 1995. Eichhorn JH, Bell DA, Young RH, Scully RE: Ovarian serous borderline tumors with micropapillary and cribriform patterns. A study of 40 cases and comparison with 44 cases without these patterns. Am J Surg Pathol 23:397-409, 1999. Gordon MD, Ireland K: Pathology of hyperplasia and carcinoma of the endometrium. Semin Oncol 21:64-70, 1994. Hoerl HD, Hart WR: Primary ovarian mucinous systadenocarcinomas. A clinicopathologic study of 49 cases with long-term follow-up. Am J Surg Pathol 22:1449-1462, 1998. Longacre TA, Hendrickson MR: Diffusely infiltrative endometrial adenocarcinoma. An adenoma malignum pattern of microinvasion. Am J Surg Pathol 23:69-78, 1999.

Manson CM, Hirsch PJ, Coyne JD: Post-operative spindle cell nodule of the vulva. Histopathology 26:571-574, 1995. Merino MJ: Vaginal cancer. The role of infectious and environmental factors. Am J Obstet Gynecol 165:1255-1262, 1995. Riopel MA, Ronnett BM, Kurman RJ: Evaluation of diagnostic criteria and behavior of ovarian intestinal-type mucinous tumors. Atypical proliferative (borderline) tumors and intraepithelial, microinvasive, invasive, and metastatic carcinoma. Am J Surg Pathol 23:617-635, 1999. Young RH: New and unusual aspects of ovarian germ cell tumors. Am J Surg Pathol 17:1210-1224, 1993. Zaino RJ, Kurman RJ, Brunetto VL et al: Villoglandular adenocarcinoma of the endometrium: a clinioopathologic study of 61 cases. A Gynecologic Oncology Group Study. Am J Surg Pathol 22:13791385, 1998.




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FIBROCYSTIC CHANGE

Epithelial proliferative lesions occur in several histologic forms, including (1) sclerosing adenosis, (2) ductal hyperplasia, (3) radial scar formation, and (4) lobular hyperplasia. Sclerosing adenosis presents as enlargement of one or more lobular units, which is caused by an increased number of alveolar ducts along with an increase in the density of interlobular fibrous tissue. Occasionally a mass is produced by aggregation of adjacent lobules or less commonly by massive enlargement of a single lobule. The normal double cell layer structure of ductules is preserved, but their lumina may be compressed or narrowed. In some cases the lumen is dilated, and this change is termed blunt duct adenosis or microglandular adenosis. Ductal hyperplasia occurs predominantly in terminal ducts and lobular units and is characterized by an increased number of cells inside the lumen of these structures. Ductal hyperplasia includes a continuum of changes that range from trivial changes to changes similar to those of ductal carcinoma in situ (CIS), which is termed atypical ductal hyperplasia. In mild hyperplasia the ducts are lined by one or two additional cell layers. If there are more cells layers, hyperplasia is considered to be moderate; if it is quite prominent, the term florid hyperplasia is used (Fig. 14-2). Irregular proliferation of ductlike epithelial structures around a centrally located focus of connective tissue is called radial scar formation. Ductal hyperplasia may be associated with lobular hyperplasia. Occasionally lobular hyperplasia may be more prominent, and the hyperplastic cells may extend into the ductules.

The mammary tissue develops from the ingrowth of epithelial strands that differentiate into ducts, ductules, and acini arranged into lobules (Diagram 14-1). Once the breasts reach their adult form, they remain sensitive to hormonal stimulation and undergo typical cyclic changes during each menstrual cycle. However, female breasts reach their full differentiation only under proper hormonal stimulation during pregnancy and lactation. The breasts involute to some extent after the cessation of lactation, but they remain capable of assuming their full functional potential again. The breasts involute after menopause. If the normal hormonal response of breasts is disrupted or partially altered, the breast tissue undergoes fibrocystic change, a complex set of changes characterized by fibrosis, epithelial proliferation, and cyst formation (Figs. 14-1 and 14-2). Cysts are the most common feature of fibrocystic disease. Cystic dilatation begins at the level of terminal ducts and lobules, but over time microscopic cysts enlarge and transform into fluid-filled macroscopic cysts. The largest cysts are associated with atrophy of the remaining lobular elements, whereas small cysts typically develop as multiple dilatations within the same lobule. Solitary cysts are lined by simple cuboidal or flattened epithelium, whereas multiple cysts are lined by apocrine type of epithelium (apocrine metaplasia). Fibrosis leads to the expansion of the dense perilobular connective tissue, which encroaches on the lobules and ultimately replaces the loose interlobular stroma. As part of the fibrocystic change, fibrosis typically occurs in younger women, and fibrotic nodules are the sole lesions in approximately 5 percent of benign breast biopsy specimens.

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Diagram 14-I. A, Development of mammary ducts and lobules. Upper, birth; middle, early adolescence; lower, adult. B, Adult breast illustrating typical variability in size and development of lobules. (A from Russo J, Russo IH: Development of the human mammary gland. In Neville MC, Daniel CW, editors: The mammary gland: development, regulation, and function, New York and London, 1987, Plenum Press.)


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Fig. 14-I. Fibrocystic change. A, Dilated terminal duct and lobules are lined by epithelium that either is flattened or shows apocrine metaplasia (evidenced as cuboidal cells with eosinophilic cytoplasm). The overall lobular structure is preserved. B, Fibrosis leads to merging of perilobular and intralobular connective tissue. C, Sclerosing adenosis involves hyperplasia of alveolar ductules, along with an increase in the density of intralobular fibrous tissue. Ductules show swirling and collapse of their lumina. D, Focal adenosis shows similarity of proliferated ductules to those in the adjacent uninvolved normal lobule.

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Fig. 14-2. Fibrocystic changes. A, Florid duct hyperplasia. The epithelial nests inside the ducts are partially solid and partially cystic but lack fibrovascular stalks. B, Radial scar. Central fibrosis is surrounded in a radiating manner by ductlike structures.


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TUMORS Tumors of the breast may be benign or malignant. Adenomas are benign epithelial tumors. However, because they also entail proliferation of stromal cells, most of them are classified as fibroadenomas. Most malignant tumors originate from the mammary epithelium and accordingly are called carcinomas. Breast tumors represent the most common malignancy in women, accounting for 30 percent of all newly diagnosed cancers in 1998. Breast cancer is responsible for 16 percent of cancer-related deaths in women.

Fibroadenoma Fibroadenoma is the most common breast mass encountered

Fig. 14-3. Fibroadenoma. This spherical tumor surgically shelled out from the breast of a young women appears myxoid, translucent, grayish white, and lobulated on cross section.

in young women, constituting the majority of lesions found at biopsy or in surgically removed specimens in women under the age of 25 years. On gross examination fibroadenomas are sharply circumscribed, rubbery nodules that are distinct from the surrounding tissue (Fig. 14-3). They may range in size from less than 1 mm to several centimeters in diameter. Histologically they are composed of proliferating ducts and stroma. Two patterns of growth, intracanalicular and pericanalicular, are recognized (Fig. 14-4). Most breast lesions show both of these growth patterns.

Adenoma

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Considering the relative frequency of fibroadenomas and mammary carcinoma, it is surprising that pure epithelial tumors , or adenomas, are so infrequent. Adenomas are benign circumscribed tumors (Fig. 14-5). Histologically classified, they are as tubular or lactating (Fig. 14-6). Both of these tumor types are composed of closely packed terminal ducts with little surrounding stroma. Myoepithelial cells surround the cuboidal ductal epithelium. In lactating adenomas the ductlike structures are dilated and show cytoplasmic vacuolization and enlargement that is typical of lactation.

B

Fig. 14-4. Fibroadenoma. A, Intracanalicular type. Myxoid stroma distorts the elongated ducts. B, Pericanalicular type. Cellular fibrous stroma shows periductal layering.

Fig. 14-5. Lactating adenoma. The lobulated tumor appears fleshy brown on cross section. Its margins are less distinct than those of typical fibroadenoma or juvenile fibroadenoma.


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Fig. 14-6. Adenoma. A, Tubular adenoma consists of tubules surrounded by stroma similar to that of normal breast. B, Lactating adenoma is composed of tubules that show lactational changes. The presence of interlobular duct suggests focal hyperplasia rather than neoplasia.

Phyllodes Tumor Phyllodes tumors are composed of proliferating epithelial and stromal cells. At presentation phyllodes tumors are on average larger than fibroadenomas or adenomas, and a history of rapid tumor growth is a common presenting symptom. The excised specimen is firm and rubbery and may separate into leaflike structures, which account for its name (Greek phyllon, meaning leaf).

Phyllodes tumors are classified clinically as low-grade or high-grade neoplasms. On gross examination low-grade tumors tend to have a variegated pale appearance, and highgrade tumors appear more fleshlike (Fig. 14-7). Stroma of low-grade tumors is composed of loosely arranged cells that have bland nuclei. High-grade tumors have a more cellular stroma, and the nuclei of these tumor cells show atypia, hyperchromasia, and mitotic figures (Fig. 14-8).

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Fig. 14-7. Phyllodes tumor. A, Low-grade tumor lacks encapsulation and shows a variegated redtan and white cut surface. B, High-grade tumor has a fleshy appearance.


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Intraductal Papilloma

Fig. 14-8. Phyllodes tumor. A, Low-grade tumor shows low cellularity, which is more pronounced around the elongated ducts. B, High-grade tumor consists of densely arranged stromal cells showing nuclear atypia.

Papillomas are benign intraductal tumors that usually reach clinical attention primarily because of nipple discharge or bleeding, although a few may present as a palpable mass. Most papillomas measure 0.5 to 2 cm in diameter and are located in the main collecting ducts, but 20 percent to 25 percent occur more peripherally and appear to be multiple. Microscopically the hallmark of papillomas is intraductal proliferation of epithelial cells arranged into fronds that have a fibrovascular core (Fig. 14-9). Large subareolar lesions may be quite cellular and are composed predominantly of glandlike structures (Fig. 14-10). Papillomas display a propensity for degeneration and necrosis and often are accompanied by periductal fibrosis and sclerosis, which may obscure their papillary nature. Epithelial elements trapped in the fibrous scar may be mistaken for invasive carcinoma, but the absence of intraductal carcinoma in adjacent ducts is a clue to their benign nature. Papillomas must be differentiated from papillary carcinoma, an indolent malignancy of older women that also is largely intraductal but displays definitive signs of malignancy, including a cribriform pattern of epithelial growth, nuclear anaplasia, and intraductal papillary proliferation without fibrovascular cores. The presence of papillary carcinoma in an intraductal papilloma may present a difficult diagnostic problem. Papillomas as a group confer a slightly elevated risk for the subsequent development of invasive mammary carcinoma. Some authors believe that the risk is largely confined to patients who have multiple papillomas. Multiple lesions more commonly are associated with atypical patterns of epithelial proliferative disease, and their biologic behavior and tendency to progress to invasive cancer should be predicted more accurately by evaluating the degree of cellular atypia rather than their architectural features.

Fig. 14-9. Ductal papilloma. Epithelial cells are arranged on fibrovascular stalks that project into the ductal lumen.

Fig. 14-10. Ductal papilloma, subareolar type. The lesion shows florid proliferation of epithelial cells with focal nuclear atypia.

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Atypical Hyperplasia Atypical hyperplasia occurs in two forms: atypical intraductal hyperplasia (ADH) and atypical intralobular hyperplasia (ALH). Atypical hyperplasia is the only finding in approximately 3 percent of breast biopsy specimens; nevertheless, it must be recognized and treated appropriately. Diagnostic criteria for ADH and ALH have been defined, but their reproducibility has been a matter of discussion. There also is controversy over whether atypical hyperplasia is only a risk factor or a definitive precursor to invasive carcinoma. Several studies have shown that atypical hyperplasia is associ -

ated with a four- to fivefold higher risk for carcinoma than that for age-matched controls. ADH usually is an incidental finding in biopsy specimens that show mostly benign changes. Microscopically ADH is characterized by intraductal proliferation of cells showing either the growth pattern or the cytologic features that are characteristic of noninvasive carcinoma, but neither in a fully developed form. ADH may mimic noncomedo type ductal CIS growing in a cribriform, partially cribriform, micropapillary, fenestrated, solid, or mixed pattern (Fig. 14-11). Regularity of the pattern, regardless of the specific cellular ar-

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Fig. 14-I I. Atypical ductal and lobular hyperplasia. The most common patterns of ADH include A, Cribriform intraductal pattern, B, Partial cribriform intraductal pattern, C, Fenestrated intraductal pattern, and D, Micropapillary intraductal pattern. E, ALH appears as distention of lobules filled with atypical cells.


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rangements, is an important theme of ADH. The cytologic features also resemble those of noncomedo type intraductal carcinoma and include relatively small, round cells with distinct borders; moderate to scant cytoplasm; and uniform, occasionally hyperchromatic, round-to-oval nuclei with delicate chromatin and small nucleoli. Mitotic figures are rare. Because of their perplexing similarity to intraductal carcinoma, these lesions represent a diagnostic problem and there is no consensus regarding therapy. ALH is found in 1 percent of breast biopsy specimens, mostly in premenopausal women. ALH has no distinguishing clinical or mammographic features and usually is an incidental finding on histologic examination. It also carries a four- to fivefold higher risk for invasive cancer. The microscopic features are distinctive and include intralobular proliferation of cells distending the lobules. The cells are uniform, small, and round to polygonal. The cells have moderate to scant cytoplasm, round regular nuclei, delicate chromatin, and small nucleoli. ALH often is multicentric. It is not always possible to distinguish ALH from intralobular carcinoma.

Noninvasive Carcinoma Noninvasive carcinoma of the breast is diagnosed in approximately 10 percent of breast biopsy specimens. Two major categories are recognized: ductal carcinoma in situ ( DCIS) and lobular carcinoma in situ (LCIS). DCIS is further divided into (1) comedo, (2) cribriform, (3) micropapillary, (4) solid, and (5) papillary subtypes. Comedo type DCIS accounts for 3 percent to 5 percent of all breast carcinomas and 35 percent to 50 percent of solitary noninvasive carcinomas. The majority of comedo DCIS present as palpable masses that are 2 to 3 cm in diameter, but some may be as large as 5 cm or more. On gross examination they are well circumscribed, and a cheesy "comedo-like " necrotic material may be expressed from the dilated ducts. Microscopically comedo DCIS grows inside the ducts, distending them to as much as 10 times their normal diameter.

The atypical neoplastic cells form solid masses that typically show central necrosis (Fig. 14-12). The cytoplasm of most tumors is well developed. Nuclear features are those of highgrade tumors, and mitoses are common. Retrograde extension of the tumor cells into the acini (cancerization of the lobules) is common. Such an extension of tumor should not be confused with invasion, which should be diagnosed only if the neoplastic cells extend across the borders of the loose intralobular connective tissue. Noncomedo DCIS accounts for 5 percent to 8 percent of all breast carcinomas and 50 percent to 70 percent of solitary noninvasive carcinomas. It is considered to be less aggressive than comedo type DCIS, with a lower short-term recurrence rate (less than 5 percent) after local excision. Other favorable biologic features, such as the presence of hormone receptors, low proliferation rates, and diploid DNA content, also are also usually found. However, the unequivocal malignant potential of these lesions is underscored by a 30 percent recurrence rate after incomplete surgical excision and the invasiveness of cancer found in 50 percent of these recurrences. Noncomedo DCIS rarely produces palpable masses and usually is diagnosed by biopsy of microcalcific breast lesions recognized by mammography. Several histologic subtypes are found, but the patterns often are intermixed and usually are present in the same lesion. On the basis of histologic growth patterns, these tumors are subtyped as (1) cribriform, (2) micropapillary, (3) solid, and (4) papillary (Fig. 14-13). Lobular carcinoma in situ (LCIS) accounts for 1 percent to 3 percent of all breast carcinomas and 10 percent to 30 percent of solitary noninvasive carcinomas. It usually is not detected by palpation but rather incidentally in breast biopsy tissue of premenopausal women. Histologically it presents as multifocal interlobular proliferation of atypical neoplastic cells (Fig. 14-13). Pagetoid spread beneath the epithelium of larger ducts is common. Tumor cells typically have round or oval nuclei with homogeneous chromatin and inconspicuous nucleoli. The risk of developing invasive carcinoma of

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Fig. 14-12. DCIS, comedo type. A, The distended ducts are lined by atypical cells that have undergone necrosis in the central portion. B, Cancerization of the lobule presents as extension of the malignant cells into the acini.


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Fig. 14-13. DCIS, noncomedo type, and LCIS. Typical growth patterns of ductal carcinoma in situ include A, Cribriform ductal, B, Solid ductal, and C, Papillary ductal pattern. D, Lobular carcinoma in situ presents in the form of distended acini filled with atypical cells. The lobular pattern is preserved.

the breast after excision of LCIS increases by approximately 1 percent per year, a rate that translates to a greater than tenfold relative risk and a 20 percent absolute risk over 20 years. The risk is bilateral, and most invasive carcinomas that develop are ductal rather than lobular. This indicates that LCIS may be a marker for the development of invasive breast cancer rather than its precursor.

Major Histologic Types of Breast Carcinoma and Their Relative Incidence for All Stages Combined

Invasive Breast Carcinoma Invasive breast carcinoma accounts for approximately 90 percent of all breast cancers. Modern taxonomic attempts to subdivide these lesions into categories with distinct morphologic, biologic, and clinical features have not produced definitive results because breast carcinomas are a heterogeneous group of tumors. The system of nomenclature used here is a compromise derived from several studies and proposed classifications (Table 14-1). Infiltrating ductal carcinoma not otherwise specified (IDCNOS) is a heterogeneous group of lesions characterized by a relative absence of histologic features that define other special forms of breast carcinoma, and in this sense it is a diagnosis of exclusion. It accounts for approximately 60 percent of all breast carcinomas and 70 percent of invasive breast can -

NOS, Not otherwise specified.


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Fig. 14-14. Infiltrating ductal carcinoma, NOS. A, Typical scirrhous tumor presents as a stellate scar in the fat tissue of the breast. B, Irregularly shaped fibrotic tumor does not have definite borders even though it seems to have been removed in toto, with adequate normal peritumoral breast tissue. The foci of hemorrhage are due to previous biopsy.

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Fig. 14-15. Infiltrating ductal carcinoma, NOS. Common growth patterns include A, Solid hypercellular, B, Solid desmoplastic, C, Acinar and tubular, and D, Acinar and solid.


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cers. It is clinically and biologically more aggressive than the special types of cancer separated from it. The median fiveyear survival rate for IDC-NOS is only approximately 60 percent, compared with 80 percent to 95 percent for the special types of cancer. IDC-NOS usually presents as a firm mass that is gritty on cross section. It may vary in size and shape and may present as a small stellate mass with indistinct borders or as larger fibrotic masses that are relatively distinct from the remainder of the breast (Fig. 14-14). Histologically IDC-NOS is ap adenocarcinoma that has no distinctive features. It may be cellular, paucicellular, or desmoplastic, or it may consist of solid strands or acini (Fig. 14-15). Several grading systems for IDC-NOS have been developed over the years. Table 14-2 shows the widely used Elston modification in which numeric scores are assigned to each of three major histologic features: the percentage of tubule formation, the degree of nuclear pleomorphism, and the number of mitoses per 10 high-power fields based on microscopic evaluation of the entire lesion. Nuclear grading is based on assessing the lesionis size and shape, chromatin pattern, and nucleoli (Fig. 14-16). Using this grading system in prospective studies, median 10-year survival rates of 90 percent, 60 percent, and 40 percent were associated with grade I, grade II, and grade III lesions, respectively. Infiltrating lobular carcinoma (ILC) accounts for approximately 15 percent of all invasive breast carcinomas. In addition to the classic type, which shows single file ( " Indian file " ) cell arrangement, the tumor may present in several histologic variants, such as (1) solid, (2) alveolar, (3) mixed, or (4) pleomorphic (Fig. 14-17). The cytologic features of these subtypes are the same as those of classic ILC. A

B

Histologic Grading of Breast Carcinoma

*The percentage of tubule formation is based on assessment of the entire tumor. However, nuclear pleomorphism is assessed in the worst area, and mitotic counts are assessed at the leading edge of tumor growth. HPF, High power field.

C

Fig. 14-16. Nuclear atypia in infiltrating ductal breast carcinoma. A, Grade I, mild atypia. B, Grade II, moderate atypia. C, Grade III, severe atypia.


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Fig. 14-17. Infiltrating lobular carcinoma. Common growth patterns include A, Classic ("Indian file"), B, Solid, C, Alveolar, and D, Pleomorphic.

Variants of Invasive Carcinoma Several variants of breast carcinoma that differ biologically from IDC-NOS and ILC have been described, the most important of which are (1) medullary carcinoma, (2) mucinous carcinoma, (3) tubular carcinoma, (4) cribriform carcinoma, (5) Paget disease, and (6) metaplastic carcinoma. For the most part these variants occur in a typical form, but they also may have subtypes. Medullary carcinoma accounts for approximately 7 percent of all breast cancers. Typical medullary carcinoma has a better prognosis than IDC-NOS, with a 10-year survival rate of 80 percent to 90 percent. It presents as a palpable mass, which usually is circumscribed and measures 2 to 3 cm in diameter. On cross section it appears lobulated, wellcircumscribed, tan-white, relatively soft, and homogeneous in consistency. Microscopically the tumor has blunt, pushing borders, and the cells are arranged into solid nests that have a syncytium-like appearance (Fig. 14-18). The tumors contain a lymphocytic infiltrate, which is most prominent in the loose connective tissue stroma and at the margins of nests of neoplastic cells. Bizarre tumor giant cells and foci of squamous metaplasia may be seen in some tumors. There may be a minor intratubular component, which usually is of the comedo type.

Mucinous carcinoma, also known as colloid carcinoma, accounts for approximately 2 percent to 3 percent of all breast cancers. Typical mucinous carcinomas have a very good prognosis with a 10-year survival rate in the range of 85 percent to 90 percent. Tumors present as soft palpable masses that produce vague, nonspecific findings on mammography. On cross section they appear circumscribed, glistening, tan, soft, and gelatinous. Histologically the tumors are composed of small islands of malignant cells in a contiguous pool of extracellular mucinous material (Fig. 14-19).An in situ component is rare. Cytologic and nuclear features are those of a low- to intermediate-grade malignant tumor. The mucinous part must constitute 90 percent of the total lesion if the tumor is to be classified as mucinous. If the mucinous parts account for only 75 percent or less, the tumor should be classified as IDC-NOS. Tubular carcinoma accounts for approximately 5 percent of all breast cancers. It has a favorable prognosis, with a fiveyear survival rate of 95 percent to 100 percent. However, concurrent or subsequent contralateral breast cancer maybe present in up to 20 percent of patients. Tubular carcinoma usually presents as a small mass, 1 cm in diameter or smaller, and usually is detected by mammography. The lesions appear firm, white, and stellate. Microscopically these tumors


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Fig. 14-18. Medullary carcinoma. Tumor cells form syncytia-like solid nests with pushing circumscribed margins surrounded by lymphocytes.

Fig. 14-19. Mucinous carcinoma. Clusters of well-differentiated cells appear suspended in pools of mucin-filled spaces between thin strands of fibrovascular stroma.

Fig. 14-20. Tubular carcinoma. Tumor cells form small angular glands evenly distributed in the dense fibrous stroma.

Fig. 14-21. Cribriform carcinoma. Low-grade tumor cells form islands that contain round lumina.

are composed of small glands or tubules that have round, oval, or angular ( " teardrop" ) shapes (Fig. 14-20). The glands are uniformly distributed in centrally dense fibrous stroma with prominent elastosis. The peripheral stroma is less dense, and in these places the glands may invade the adjacent tissue. Cribriform or micropapillary DCIS may be present in up to 65 percent of tubular carcinomas. Cribriform invasive carcinoma is a recently described histologic entity that has biologic properties similar to those of tubular carcinoma (Fig. 14-21). Paget disease of the nipple presents as an eczematous rash or as a red oozing lesion of the nipple. It represents the intraepidermal spread of malignant cells that reach the skin through ducts that are involved with DCIS or high-grade ductal carcinoma (Fig. 14-22).

Fig. 14-22. Paget disease of the nipple. Groups of tumor cells with clear cytoplasm form nests in the epidermis of the nipple.


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Figure 14-23. Invasive papillary carcinoma. The tumor grows in a micropapillary pattern.

Figure 14-24. Adenocystic carcinoma. This breast tumor is indistinguishable from equivalent carcinoma in the salivary glands.

Figure 14-26. Metaplastic carcinoma. Tumor shows chondroid differentiation. Fig. 14-25. Metaplastic carcinoma. Metaplastic bone is formed between sheets of carcinoma cells.

Rare forms of breast carcinoma account for less than 1 percent of all breast cancers. Included among these cancers are signet-ring carcinoma, invasive papillary carcinoma, salivary gland—like carcinoma, secretory carcinoma, and clear cell carcinoma (Figs. 14-23 to 14-25). . Metaplastic carcinoma is a rare cancer that may present as squamous cell carcinoma and pseudosarcomatous carcinoma. Pseudosarcomatous metaplastic carcinomas contain at least 20 percent of metaplastic elements, such as areas that resemble fibrosarcoma, chondrosarcoma, or osteogenic sarcoma (Figs. 14-25 to 14-27). Such tumors grow fast and have a poor prognosis.

I mmunohistochemistry of Breast Carcinoma

Figure 14-27. Metaplastic carcinoma. Tumor has features of fibrosarcoma.

Immunohistochemical analysis is being increasingly employed by pathologists to measure unreported prognostic factors, including estrogen and progesterone receptors (ER, PgR), pS2, Ki-67, HER-2/neu, and p53 (Fig. 14-28). Although these tests will undoubtedly play an important role in the future, they have yet to be technically and clinically validated before they become part of routine practice.


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Figure 14-28. Immunohistochemistry of breast cancer. A, Estrogen receptors; B, progesterone receptors; C, estrogen-induced protein pS2; D, Proliferation-associated marker Ki-67; E, HER-2/neu oncoprotein; and F, p53 tumor-suppressor gene product.

Further Reading Andersen JA: Lobular carcinoma in situ. A histological study of 52 cases. Acta Pathol Microbiol Scand (A) 82:735-741, 1974. Andersen JA, Gram JB: Radial scar in the female breast. A long-term follow-up study of 32 cases. Cancer 53:2557-2560, 1984. Bannayan GA, Hajdu SI: Gynecomastia. Clinicopathologic study of 351 cases. Am J Clin Pathol 54:431-437, 1972. Bobrow LG, Happerfield LC, Gregory WM et al: The classification of ductal carcinoma in situ and its associations with biological markers. Semin Diagn Pathol 11:199-207, 1994. Dawson AE, Mulford DK, Sheils LA: The cytopathology of proliferative breast disease. Am J Clin Pathol 103:438-442, 1995. Di Costanzo D, Rosen PP, Gareen I, Franklin S, Lesser M: Prognosis in infiltrating lobular carcinoma. An analysis of "classical" and variant tumors. Am J Surg Pathol 14:12-23, 1990. Elston CW: Pathological prognostic factors in breast cancer. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 19:403-411, 1991. Eusebi V, Feudale E, Foschini MP et al: Long-term follow-up of in situ carcinoma of the breast. Semin Diagn Pathol 11:223-235, 1994. Fechner RE: Frozen section examination of breast biopsies. Practice parameter. Am J Clin Pathol 103:6-7, 1995. Gaffey MJ, Mills SE, Frierson HR Jr et al: Medullary carcinoma of the breast. Interobserver variability in histopathologic diagnosis. Mod Pathol 8:31-38, 1995.

Hensen DE, Oberman HA, Hutter RVP et al: Practice protocol of the examination of specimens removed from patients with cancer of the breast. A publication of the Cancer Committee, College of American Pathologists. Arch Pathol Lab Med 121:27-33, 1997. Hertzel BF, Zaloudek C, Kempson RL: Breast adenomas. Cancer 37:2891-2905, 1976. Lefkowitz M, Lefkowitz W, Wargotz ES: Intraductal (intracystic) papillary carcinoma of the breast and its variants. A clinicopathological study of 77 cases. Hum Pathol 25:802-809, 1994. Love SM, Gelman RS, Silen W: Fibrocystic "disease" of the breast. A nondisease? N Engl J Med 307:1010-1014, 1982. Merino MJ, Carter D, Berman M: Angiosarcoma of the breast. Am J Surg Pathol 7:53-60, 1983. Moffat CJC, Pinder SE, Dixon AR, Elston CW, Blamey RW, Ellis I0: Phyllodes tumours of the breast: a clinicopathological review of thirty-two cases. Histopathology 27:205-218, 1995. Oberman HA: Hamartomas and hamartoma variants of the breast. Semin Diagn Pathol6:135-145, 1989. Rosen PP, Caicco JA: Florid papillomatosis of the nipple. A study of 51 patients, including nine with mammary carcinoma. Am J Surg Pathol 10:87-101, 1986. Tavassoli FA: Ductal carcinoma in situ: introduction of the concept of ductal intraepithelial neoplasia. Mod Pathol 11:140-154, 1998. Telesinghe PU, Anthony PP: Primary lymphoma of the breast. Histopathology 9:297-307, 1985.




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HEREDITARY SKIN DISEASES Hereditary skin diseases (genodermatoses) present in many forms, such as recurrent bullae in epidermolysis, bullosa, or diffuse or localized keratoses. Ichthyosis is a term used to describe a complex group of disorders of keratinization characterized by formation of scales on the skin surface. The diseases usually are hereditary (e.g., ichthyosis vulgaris, lamellar ichthyosis, X-linked ichthyosis) but there also is an acquired form. Ichthyosis vulgaris, a common autosomal dominant disease, involves in a symmetric manner the exterior surfaces of the limbs and the trunk (Fig. 15-1). Histologically all forms of ichthyosis are characterized by hyperkeratosis. Porokeratosis is a disease that is characterized by the formation of small papules with surface scale that progressively enlarge to form a sharply demarcated ring of hyperkeratosis, often with an atrophic center. It affects men more often than

women. Autosomal dominant transmission has been suggested for the variant known as porokeratosis of Mibelli. Histologically the ring of hyperkeratosis is represented by a discrete parakeratotic column of hyperkeratosis, known as cornoid lamella (Fig. 15-2). The dermis beneath the cornoid lamella contains a lymphocytic infiltrate. Darier disease, or keratosis follicularis, is an autosomal dominant disease whose presenting symptoms include lesions of the scalp, neck, and upper chest in a distribution resembling that of seborrheic keratosis. It may be more widespread and also may involve mucosal surfaces and nails. The basic lesion is a papule that is 1 to 3 mm in diameter, with a dirty gray-tan, keratotic surface (Fig. 15-3). These papules become confluent, forming scales. Secondary infection is common. Histologically the basic lesion consists of a broad zone of hyperkeratosis with parakeratosis, suprabasal acantholysis, and formation of rounded cells (corps ronds) and oval, individually keratinized cells (grains) (Fig. 15-4). In well-developed lesions, the basal layer forms villi that project into the clefts. Hailey-Hailey disease, or familial benign pemphigus, is an autosomal dominant disease that presents with small vesicles on an erythematous base. These lesions become confluent, forming erythematous plaques (Fig. 15-5). Plaques often are found in the axillae, neck, or intertriginous zones that are predisposed to friction and excessive moisture. Superficial bacterial infections exacerbate or trigger the development of these lesions, which become crusted and fissured. Histologically the lesions show prominent partial acantholysis of the lower stratum spinosum (Fig. 15-6). A suprabasal cleft is formed, leading to detachment of groups of cells and a few individual cells, which are found floating in the cavity. Dermal inflammation is minimal.

I NFECTIONS Fig. 15-I. Ichthyosis vulgaris. The extensor surface of the arm is covered with polygonal scales.

The skin often is infected by viruses, bacteria, fungi, protozoa, and other pathogens.

Fig. 15-2. Porokeratosis. Cornoid lamella is formed by a column of parakeratosis overlying slightly vacuolated keratinocytes that have migrated centrifugally, here from right to left.

Fig. 15-3. Darier disease. Brown scaly papules form aggregates on the lateral surface of the shoulder.


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Fig. 15-4. Darier disease. A cleft is formed as a result of acantholysis of the lower strata of epidermis. The clefts contain rounded cells (corps ronds) and oval individually keratinized cells (grains).

Fig. 15-5. Hailey-Hailey disease. The papules and vesicles have fused to form a fissured plaque with a scaly surface.

Fig. 15-7. Impetigo. The lesions are erythematous and covered with yellow-white purulent crusts.

Fig. 15-6. Hailey-Hailey disease. A suprabasal cleft is formed as a result of acantholysis of deeper parts of the epidermis.

Bacterial Infections Impetigo is a clinical diagnosis that denotes superficial bac-

terial infection of the epidermis. Impetigo contagiosa (nonbullous type) most often is caused by streptococci. The bulbous form is caused by Staphylococcus aureus. The infection begins in the form of small papules that become thin-roofed vesicles. Vesicles rupture to produce a yellow or honeycolored surface crust (Fig. 15-7). Staphylococci cause extensive cleavage of epidermis in the upper layers, which results

Fig. 15-8. Impetigo. In this bullous lesion a blister containing pus has formed below the stratum granulosum.


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in the formation of bullae or extensive exfoliation. Histologically impetigo contagiosa shows collections of neutrophils in the epidermis beneath the stratum corneum. In bullous impetigo the blister is below the level of the granular layer (Fig. 15-8). Deeper bacterial infections may involve both the epidermis and the dermis (pyoderma) and may extend into the subcutis, causing widespread cellulitis.

Fungal Infections Tinea is the name for epidermal infections caused by fungi, known as dermatophytes, which usually belong to the genera Microsporum, Trichophyton, Epidermophyton, or Malassezia. The lesions vary in appearance and may present as papules, plaques, or blisters. Lesions often are annular and show scaling with central clearing (Fig. 15-9). Histologically there usually is a superficial infestation with fungal yeast and hyphae with variable inflammation in the dermis (Fig. 15-10). Fungal infection of hair follicles may cause deep folliculitis and abscesses, which have been named kerion or Majocchi granuloma (Fig. 15-11). Histologically the skin shows acute and chronic inflammation surrounding cellular debris and fragments of hair and fungi (Fig. 15-12).

Fig. 15-9. Tinea. This superficial fungal infection (ringworm) appears as a round scaly erythema with central clearing.

Viral Infections Human papillomaviruses ( HPV) of several types may infect the skin and cause warts (verruca vulgaris or verruca plana), condyloma acuminatum, bowenoid papulosis, or epidermodysplasia verruciformis. These chronic skin lesions present as localized, often multiple papules or larger excrescences, except for verruca plana, which leads to minimal elevation of the skin (Figs. 15-13 and 5-14). Herpes simplex virus (HSV) infections of the skin may be caused by any of the several HSV viruses, but they most often are caused by HSV- 1 and HSV-2, herpes zoster virus (HZV), varicella-zoster virus (VZV), and less commonly cytomegalovirus (CMV). Clinically HSV and VZV present in the form of a vesicular exanthema on erythematous skin (Fig. 15-15). Keratinocytes infected with herpesviruses show ballooning degeneration and often become multinucleated (Fig. 15-16). Intranuclear viral particles account for their " ground glass " appearance. Vesicles formed as the result of acantholysis of epidermis are associated with a variable inflammatory response in the dermis. Secondary bacterial infections are common. Molluscum contagiosum is a DNA virus (deoxyribovirus) of the pox family. The skin infection may present as a solitary lesion or as umbilicated papular lesions, some of which are surrounded by an erythematous ring. Histologically the papule shows striking acanthosis of the epidermis with some extension into the dermis (Fig. 15-17). Viruses grow in keratinocytes, filling their cytoplasm in the form of eosinophilic inclusions. As the viral aggregates are extruded into the stratum corneum, they become basophilic. In ruptured lesions the dermis shows a strong inflammatory response. Human immunodeficiency virus ( HIV), type I and type II, may cause a psoriasiform dermatitis. This skin lesion in part is caused by the uptake of HIV into the Langerhans cells and

Fig. 15-10. Tinea versicolor. Fungal hyphae and spores are evident in the stratum corneum.

Fig. 15-11. Majocchi granuloma. This fungal infection of the hair follicles presented as a dermal abscess.


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Fig. I 5-12. Majocchi granuloma. Neutrophils surround a centrally located hair covered with fungal spores and hyphae.

Fig. 15-13. Verruca plana. Human papillomavirus type 3 has caused hyperpigmented, only slightly elevated, multiple skin lesions.

Fig. 15-14. Verruca plana. The keratinocytes in the upper spinous layer show typical vacuolization.

Fig. 15-15. Herpes simplex virus infection. Perioral skin shows grouped vesicles.

Fig. 15-16. Herpes zoster. Early changes include ballooning degeneration of midepidermal keratinocytes, which have pale nuclei and multinucleation.

Fig. 15-17. Molluscum contagiosum. Acanthotic invaginations of the epidermis contain cytoplasmic inclusions of viral particles.


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Fig. 15-18. HIV infection. This psoriasiform dermatitis of AIDS shows acanthosis of the epidermis and a scant dermal lymphocytic infiltrate. Necrotic keratinocytes and fragments of lymphocytes are seen focally.

Fig. 15-19. Pemphigus vulgaris. An acantholytic cleft separates the basal cell layer, which is still attached to the basement membrane, from the superficial layers of the epidermis.

in part is a reflection of immune, metabolic, and other changes in the body. Histologically the lesions differ from classic seborrheic dermatitis or psoriasis in that they show necrosis of keratinocytes, and leukocytoclasis of lymphocytes but lack suprapapillary thinning (Fig. 15-18).

I NFLAMMATORY DERMATOSES Acute and chronic dermatoses may be related to an immune or metabolic injury, but most often they have a complex pathogenesis. In many cases the pathogenesis of such dermatoses is not known.

Immune-mediated Dermatoses Pemphigus is a term that encompasses several diseases that are characterized by the formation of intraepidermal blisters caused by the binding of antibodies to the cell membrane of keratinocytes. In the most common form, pemphigus vulgaris, flaccid blisters form and rupture, leaving behind reddened, eroded skin. Histologically the blisters present as clefts just above the basal row of keratinocytes with minimal necrosis (Fig. 15-19). Immunoglobulin G (IgG) may be demonstrated by immunofluorescence (IF) microscopy on the surface of keratinocytes in the lower layers of the epidermis (Fig. 15-20). Bullous pemphigoid is a chronic blistering disease that occurs in several forms. It is characterized by a split in the lamina lucida portion of the basement membrane, which results in the formation of subepidermal bullae. It is the most common blistering disease of the elderly, preferentially affecting the legs, thighs, and lower trunk. The initial erythematous lesions show spongiosis and an infiltrate in the epidermis that contains many eosinophils as well as lymphocytes and neutrophils. The dermal infiltrate usually is superficial and is located around the blood vessels and diffusely in the papillary dermis. Vesicles and bullae form at the dermoepidermal junction (Fig. 15-21). The blister cavity contains

Fig. 15-20. Pemphigus vulgaris. IF microscopy shows linear deposits of IgG along the cell membrane of basal keratinocytes.

eosinophils and neutrophils. IgG deposits may be demonstrated along the dermoepidermal basement membrane by IF microscopy (Fig. 15-22). Dermatitis herpetiformis ( Duhring disease) is a rare, IgAmediated, blistering disease that often is accompanied by a sensitivity to gluten in the diet. Small pruritic vesicles that resembl.herpetic lesions appear on the extensor aspects of the legs and arms. Histologically the blisters start at the tips of dermal papillae and then become confluent, forming larger bullae. The dermal inflammatory infiltrate contains neutrophils and scattered eosinophils (Fig. 15-23). Granular deposits of IgA may be seen by IF microscopy in the tips of dermal papillae. Erythema multiforme is a common immune-mediated disease that represents a hypersensitivity response to a variety of antigens. The disease occurs at any age, although it is more common in children and young adults. There are two


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Fig. 15-21. Bullous pemphigoid. The blister is subepidermal and its cavity contains proteinaceous fluid and inflammatory cells.

Fig. 15-22. Bullous pemphigoid. A band of IgG is found along the dermoepidermal junction.

Fig. 15-23. Dermatitis herpetiformis. The subepidermal blister contains neutrophils, which show a tendency to aggregate at the tips of dermal papillae.

Fig. 15-24. Erythema multiforme. The targetoid lesions on the palms have a central, dusky gray, necrotic center.

forms: erythema multiforme minor and Stevens-Johnson syndrome, which is related to hypersensitivity to drugs. The same type of immune reaction may result from hypersensitivity to microbes or from malignant tumors. It also may be part of a systemic autoimmune disease, such as systemic lupus erythematosus. Both forms present with distinctive skin lesions, which are called iris lesions or target lesions. These skin lesions consist of a zone of erythema with a pale center or a central vesicle (Fig. 15-24). In the minor form erythema multiforme tends to occur on the extremities or on the trunk. Stevens-Johnson syndrome presents as a generalized blistering disease that involves the entire body and the oral and ocular mucosae. Histologically the disease is characterized by perivascular dermal infiltrates of lymphocytes. During the first 24 hours deposits of IgM are found in the walls of small blood vessels of dermal papillae by IF microscopy. Blisters form as a result of necrosis of basal keratinocytes, but ulti -

mately the entire epidermis becomes necrotic. The early blisters contain fragmented lymphocytes and necrotic keratinocytes, and the underlying dermis usually shows a lymphocytic infiltrate. Secondary infection is common, especially in the most severe systemic form of the disease, which is known as toxic epidermal necrolysis. In contrast to classic erythema multiforme, this disease is characterized by a rather sparse lymphocytic dermal infiltrate. By definition more than 30 percent of the skin surface is involved. Lupus erythematosus is an autoimmune disorder that may present as a systemic disease (SLE) or in a localized form as discoid lupus erythematosus (DLE). SLE is associated with arthritis, kidney disease, and many other disorders. A third, often mild form that is intermediate between SLE and DLE is called subacute lupus erythematosus. In all forms of lupus erythematosus there are autoantibodies to DNA virus and a variety of other antigens. Skin lesions appear atrophic and


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tend to occur on sun-exposed skin. Malar erythema ( " butterfly rash") is common in SLE (Fig. 15-25). Nonspecific but disease-related manifestations include urticaria, telangiectasia, necrotizing vasculitis, Raynaud phenomenon, and bullous eruptions. Histologically DLE differs from SLE, although in the beginning both diseases have many common features. Early changes include infiltrates of lymphocytes at the dermoepidermal junction with foci of necrosis of ker-

atinocytes and surface parakeratosis (Fig. 15-26). Epidermal atrophy is common. Infiltrates of lymphocytes in the deeper dermis are found around the skin appendages and blood vessels. The reticular dermis appears edematous and contains increased amounts of hyaluronic acid. Chronic discoid lupus is characterized by prominent epidermal atrophy and prominent infiltrates of lymphocytes in the superficial and deep dermis (Fig. 15-27). Infiltrates of lymphocytes center around blood vessels and skin appendages. Advanced lesions have thick basement membranes and a dermis that is sclerotic, eosinophilic, and hypocellular (Fig. 15-28). Appendages often are destroyed, and if this destruction extends into the subcutis, the disease is called lupus erythematosus profundus. If the lesions are concentrated in the subcutis, the term lupus

Fig. 15-25. SLE. This patient with acute lupus erythematosus has a classic red "butterfly rash" over her malar areas. The eroded erythematous surfaces weep fluid.

Fig. 15-26. Lupus erythematosus, acute systemic disease. Lymphocytic infiltrates are found at the dermoepidermal junction. Hydropic changes of the basal layer are accompanied by necrosis of keratinocytes.

Fig. 15-27. DLE. Atrophic epidermis covers sclerotic dermis, which contains superficial and deep perivascular appendages and infiltrates of lymphocytes around blood vessels and skin appendages. Hyperkeratosis of patulous hair follicles is prominent.

Fig. 15-28. DLE. Periodic acid—Schiff method stains a thickened basement membrane. The dermis contains scattered lymphocytes and melanophages.


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Fig. 15-29. SLE. Granular deposits of immunoglobulin and complement are seen along the dermoepidermal junction.

panniculitis is applied. Immune complexes, which form gran-

ular deposits along the epidermal basement membrane, on the hair follicles, and occasionally diffusely spread in the papillary dermis and in the blood vessels, are typical (Fig. 15-29). Early lesions contain IgM and complement, but later there also are deposits of IgG, IgA, and fibrin. Deposits of immunoglobulins without complement are found in the sunprotected skin in approximately 50 percent of patients with SLE, and sun-exposed skin shows deposits in 70 percent of these patients. Mixed connective tissue disease is an autoimmune disorder that has some features in common with SLE, scleroderma, and polymyositis. It is characterized by antibodies to nuclear riboproteins and a lack of antibodies to native DNA. Skin lesions resemble those of SLE and scleroderma. Dermatomyositis is an autoimmune disease in which the primary target organs are the skin and skeletal muscle. In both the childhood and the adult forms of dermatomyositis, patients develop symmetric erythematous skin lesions on the face (Fig. 15-30). Skin lesions are most prominent on the upper eyelids and cheeks. Lesions also appear on the elbows and knees, nail folds, and dorsal surface of the knuckles. There is slight hyperkeratosis, edema, telangiectasia, and occasional hypopigmentation. Skin atrophy develops over time. Histologically the skin lesions are subtle, with some similarity to those of acute SLE. In contrast to SLE, there are no deposits of immunoglobulin along the dermoepidermal junction.

Fig. 15-30. Dermatomyositis. Diffuse erythema symmetrically involves the cheeks and upper eyelids.

granulomatous diseases according to their clinical and histopathologic features. The most important noninfectious granulomatous diseases are (1) sarcoidosis; (2) granulomatous vasculitis, as typically found in Wegener granulomatosis, Churg-Strauss syndrome, and giant cell arteritis; (3) granuloma annulare; (4) necrobiosis lipoidica; (5) erythema nodosum; (6) erythema induratum; and (7) rheumatoid nodules. Granuloma annulare presents in the form of papules arranged in an annular manner (Fig. 15-31). The cause of this disease is not known. Histologically the lesions show foci of mucin and fibrin deposition in the superficial dermis surrounded by macrophages (Fig. 15-32).

Granulomatous Diseases Granulomatous reactions in the dermis may be elicited by mycobacteria, such as M. tuberculosis or M. leprae, or by fungi. The causative pathogen may be demonstrated by special stains. Granulomas also typically form in the skin as part of a type IV, cell-mediated hypersensitivity reaction. However, in many instances it is not possible to identify an inciting antigen, and thus it is more convenient to classify various

Fig. 15-3I. Granuloma annulare. Papules are distributed on the extremities in an annular manner.


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Fig. 15-32. Granuloma annulare. Deposits of fibrin and mucin in the upper dermis are surrounded by macrophages penetrating between the collagen bundles.

Fig. 15-35. Erythema induratum. Deep erythematous nodules are typically found on the legs. Depressed areas reflect tissue necrosis caused by the underlying vasculitis.

Fig. 15-33. Erythema nodosum. The shin, which-is the favored site for these lesions, show erythematous deep subcutaneous nodules.

Fig. 15-34. Erythema nodosum. The connective tissue septa of the subcutis are widened, fibrotic, and infiltrated at their edges with lymphocytes. Multinucleated giant cells and eosinophils may be present.

Erythema nodosum is an inflammatory lesion of the subcutis that typically presents in the form of erythematous painful nodules on the anterior shin (Fig. 15-33). The lesions may spread to other parts of the legs, the hands, and even the face. Erythema nodosum may have many causes, but most often it is a reaction to streptococcal or other infection. It may be part of generalized sarcoidosis, and in such cases it is considered to be a type IV hypersensitivity reaction. Histologically it involves the connective tissue septa of the subcutis. Initially the septa are widened by infiltrates of lymphocytes, neutrophils, and eosinophils. Focal hemorrhages are common. Later, as the lesions evolve, the-septa become infiltrated with lymphocytes and macrophages, and the amount of collagen increases (Fig. 15-34). Small compact granulomas often are present, and the infiltrates may extend into the fat tissue. Erythema induratum is one of the classic tuberculoids, that is,, it represents a hypersensitivity reaction to mycobacterial infection in some other part of the body. The skin lesions present as painful, firm, erythematous nodules, most often on the posterior calf (Fig. 15-35). The lesions may ulcerate and heal by scarring. They respond favorably to tuberculostatic therapy. Lesions of this type that develop in patients who are not infected with M. tuberculosis are called nodular vasculitis. Histologically there are signs of necrotizing vasculitis with neutrophilic infiltrates affecting arteries and veins in the fat lobules of the subcutis (Fig. 15-36). Lymphocytic infiltrates extend into the fat lobules.


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Fig. 15-37. Psoriasis. The skin shows deep erythema and is covered with silvery scales.

Fig. 15-36. Nodular vasculitis. The inflammation is centered around medium-sized arteries in the fat lobules of the subcutis. Lymphocytic infiltrates extend into the fat tissue.

Idiopathic Skin Disease Psoriasis is a common skin disease of unknown etiology. It affects 1 percent to 2 percent of the entire population in the United States. The skin lesions appear as relapsing and remitting papulosquamous plaques and silvery scales (Fig. 15-37). The skin lesions most often are found over the elbows, knees, scalp, intergluteal groove, and the nails. Psoriasis is considered to be a disorder of proliferation and differentiation of keratinocytes that results in irregular acanthosis of the epidermis. The epidermis typically has thickened rete ridges that extend into the dermis (Fig. 15-38). The intervening dermal papillae are edematous and contain dilated capillaries surrounded by scattered lymphocytes. The epidermis overlying the dermal papillae is thin. The epidermis lacks stratum granulosum and typically is covered with alternating zones of keratotic and parakeratotic scales. Parakeratotic layers may contain nuclear debris (Munro microabscesses). Foci of spongiosis of the upper epidermal layers infiltrated with neutrophils and occasional lymphocytes are known as spongiform pustules of Kogoj. Seborrheic dermatitis is a chronic scaling spongiotic and psoriasiform dermatitis of unknown etiology that affects approximately 3 percent of the total population in the United States. It ranges in severity from common minimal dandruff of the scalp to the severe but rare Leiner disease (erythro-

Fig. 15-38. Psoriasis. The acanthotic epidermis shows bridging of thickened rete ridges. It is covered with a crust of parakeratosis and many neutrophils. The dermal papillae are edematous and contain dilated vessels surrounded by scattered lymphocytes and some extravasated red blood cells.

derma desquamativum) of neonates. The disease affects skin that has prominent sebaceous follicles, such as the scalp, supraorbital region, face, and central chest. The early skin lesions present histologically with spongiosis with neutrophils and lymphocytes at the orifices of hair follicles (Fig. 15-39). With the progression of the disease the interfollicular epidermis becomes involved, and the lesions may resemble psoriasis, although they typically show much more spongiosis. Pityrosporum yeasts may be seen in the parakeratotic surface crusts. Pityriasis rosea is a rather common transient papulosquamous disease that presents in the form of erythematous papules or small plaques, often arranged in the axes of skin lines. Histologically the lesions show a surface scale of parakeratosis with slight spongiosis but without microvesicula-


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tion or neutrophilic infiltration (Fig. 15-40). The scale is focal and loosely attached, and the amount of acanthosis may be variable. Lymphocytic infiltrates and hemorrhages may be seen in the dermis extending into the epidermis. Small plaque parapsoriasis is a chronic macular to papular scaling disorder of unknown etiology. It is also known as digitate dermatosis, xanthoerythroderma perstans, or chronic superficial dermatitis. This disorder may include several disease entities that present with slightly scaly, erythematous

macules and plaques that have a fine scale and orange-red color. The histologic changes are very subtle and often do not allow for a definitive diagnosis. The dermis shows sparse lymphocytic infiltrates around the vessels of the superficial plexus, and the epidermis is spongiotic and covered with thin parakeratotic scales (Fig. 15-41). Pityriasis lichenoides et varioliformis acuta (PLEVA), or Mucha-Habermann disease, typically affects children and young adults. It is more common in males than in females,

Fig. 15-39. Seborrheic dermatitis. Spongiosis and parakeratosis of the epidermis of the orifice of the hair follicle is associated with mild inflammatory infiltrates.

Fig. 15-40. Pityriasis rosea. The unit lesion is a papule with slight spongiosis, surface parakeratosis, and a lymphocytic infiltrate with a few small hemorrhages extending from the papillary dermis into the epidermis.

Fig. 15-41. Parapsoriasis. A superficial perivascular lymphocytic infiltrate is accompanied by slight hyperkeratosis, slight spongiosis, and early fibrosis of the papillary dermis.

Fig. 15-42. Pityriasis lichenoides and varioliformis acuta (PLEVA). Foci of hemorrhage and lymphocytic infiltrates in the upper dermis extend into the epidermis, which shows hyperkeratosis and necrosis of individual keratinocytes.


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with a 3:1 ratio. It presents with small round to oval, slightly scaly macules or papules, and occasionally small plaques, which appear in crops and disappear spontaneously. These lesions typically are found on the arms, legs, buttocks, or trunk. Histologically the lesions show a superficial and deep perivascular lymphocytic infiltrate that extends into the epidermis (Fig. 15-42). The epidermis shows slight acanthosis and parakeratosis, as well as single cell necrosis associated with invading lymphocytes. Hemorrhages in the papillary dermis extend into the dermis. Ulceration may result from extensive epidermal necrosis.

ically it is characterized by elongation of rete ridges, increased pigmentation of basal keratinocytes, and an increased number of melanocytes (Fig. 15-44). Lentigo may be associated with sun damage (solar lentigo), but it also occurs in association with hypertrichosis on the shoulders of young men (Becker nevus), or with polyps of the gastrointestinal tract

NEOPLASMS AND RELATED DISORDERS Tumors of the skin are classified according to their site of origin as epidermal, dermal, or subcutaneous, and according to their biologic characteristics as benign or malignant.

Pigmentary Lesions Benign pigmentary lesions include ephelis, lentigo, and nevus; malignant pigmented lesions are called malignant melanomas (Table 15-1). Ephelis or freckle is a small, discrete, nearly round, pigmented macule that is less than 5 mm in diameter and has a uniform brown color. Freckles appear on sun-exposed skin. The tendency to form freckles is transmitted in an autosomal dominant manner. Histologically freckles are characterized by an increased amount of melanin in the basal keratinocytes. Melanocytes are not increased in number. Lentigo is a discrete, round to oval, hyperpigmented lesion that is not limited to sun-exposed skin (Fig. 15-43). Histolog-

Fig. 15-43. Lentigo. The palms show multiple pigmented lesions.

Comparison of Melanocytic Lesions*

*, Meaning of scale: —=absent; +/—=rare or uncommon; + = common; ++ = present in almost all lesions; +++ =very striking feature in almost all lesions. t , At birth, occasionally in acral nevi in young patients, and in some recurrent junctional components of nevi after surgery or trauma. t , Nodular melanomas, small melanomas, and metastatic melanomas may have symmetry. §, Melanoma in situ does not have a dermal component. I Regression of the dermal portion of a lesion can lead to fibrosis. I, Lamellar fibroplasia at the tips of rete ridges can be a residual component in melanomas that arise in disordered nevi.


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Fig. 15-44. Lentigo. The epidermis shows slight thickening of rete ridges, increased prominence of a few melanocytes, and hyperpigmentation of basal keratinocytes at the rete ridges.

Fig. 15-45. Junctional nevus with architectural disorder (dysplastic nevus). This lesion is larger than 6 mm in diameter. It is irregularly pigmented and shows inflammatory erythema at its borders.

Fig. 15-46. Lentiginous junctional nevus with minimal architectural disorder and cytologic atypia (MIN-I). Nests of nevus cells are present, as are individual melanocytes on slightly distorted rete ridges. The papillary dermis is fibrotic. The nevus cell nuclei are small, and nucleoli are not visible.

Fig. 15-47. Lentiginous junctional nevus with moderate architectural disorder and cytologic atypia (MIN-II). The nests of nevus cells distort the rete ridges more than those in MIN-I. The nuclei are larger, and a few cells have visible nucleoli.

and pigmentation of mucosae of the mouth and other body ostia (Peutz-Jeghers syndrome). When the melanocytes form rounded nests of nevus cells on the elongated rete ridges, the preferred term is lentiginous junctional melanocytic nevus. In some enlarged nevi there is grossly visible irregular pigmentation (Fig. 15-45). Histologically such lesions show architectural disorder such as elongation and distortion of rete ridges and fibrosis of the papillary dermis (Fig. 15-46). Melanocytes show atypia that may be mild, moderate, or severe. These lesions, formerly called dysplastic junctional melanocytic nevi, now are called junctional melanocytic nevus with architectural disorder and atypism of melanocytes, and are graded from mild to severe.

Numeric grades may be applied, and the lesions are designated melanocytic intraepidermal neoplasm ( MIN), grade I, II, or III (see Figs. 15-46 to 15-48). Lentiginous lesion may be static and unchanging or they may progress from simple lentigo to lentiginous nevi. However, all of these lesions involve keratinocytes, which form elongated rete ridges, in contrast to malignant melanomas, which do not show proliferation of keratinocytes. Melanomas also show upward proliferation of melanocytes. Nevertheless. histologic distinction between atypical lentiginous lesions and melanoma may be difficult. Compound melanocytic nevus is formed by the proliferation of nevus cells in the epidermis, followed by the exten -


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Fig. 15-48. Junctional melanocytic nevus with severe architectural disorder and cytologic atypia (MIN-III). The nests of nevus cells are almost confluent on the distorted rete ridges. The nuclei are enlarged, and nucleoli are prominent. There is no intraepidermal upward migration of individual atypical melanocytes.

Fig. 15-49. Congenital compound melanocytic nevus. This intermediate-sized lesion shows peripheral speckling of pigmentation.

Fig. 15-50. Compound melanocytic nevus. Each nest of melanocytic nevus cells is surrounded by a fibrillar basement membrane. The cells in the deeper reticular dermis are dispersed and smaller than those at the dermoepidermal junction.

Fig. 15-51. Compound melanocytic nevus with architectural disorder. The epidermal component extends several rete ridges beyond the dermal component. The nests of nevus cells appear irregular and distort the rete ridges.

sion of these cells, with certain cytologic modifications, into the dermis. Most compound nevi are acquired after birth, and only 1 percent of whites are born with a congenital compound melanocytic nevus. Congenital compound melanocytic nevi often have a slightly irregular outline with peripheral speckling of the pigmentation. They vary in size and occasionally may cover segments of the skin as so-called giant congenital nevi (Fig 15-49). Compound melanocytic nevi are slightly raised. They remain less that 6 mm in diameter, have a smooth outline, and are round-to-oval, symmetric, with rather uniform brown pigmentation. Histologically compound melanocytic nevi have sharply circumscribed lateral borders. Proliferated melanocytes

(nevomelanocytes) form nests at the dermoepidermal junction (Fig. 15-50). Some compound melanocytic nevi have prominent individual melanocytes on elongated rete ridges, as in lentiginous nevi. As the nevus cells extend into deeper reticular dermis, their nuclei and cytoplasm diminish in size. The size of nevus cell nests also decreases in size, and the cells tend to become dispersed in a fine collagenous matrix. Compound melanocytic nevus with architectural disorder differs from the typical compound melanocytic nevus in that the junctional component extends for many rete ridges beyond the region that contains the dermal component (Fig. 15-51). The epidermal changes of such lesions (see Fig. 15-46 to 15-48) are accompanied by dermal changes. Dermal


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changes include fibrosis at the tips of rete ridges, arranged parallel to the skin surface (lamellar fibroplasia), or condensation of eosinophilic collagen bundles around the tips of rete ridges (concentric eosinophilic fibrosis) (Fig. 15-52). Spitz nevus is a variant of compound nevi that is found in children and young adults. It has all the features of compound nevi, but in addition it contains large cells with large nuclei and finely dispersed delicate chromatin, sharp nuclear envelope, and a single large round nucleolus (Figs. 15-53 and 15-54). There usually is a mixture of spindle-shaped and epithelioid melanocytes. Mitoses are common in the upper part of the lesion but not in the deeper dermal parts. The cells become smaller as they descend into the dermis and are less cohesive. Variant Spitz nevus, which shows pigmentation and

is restricted to the epidermis and papillary dermis, is called pigmented spindle cell nevus of Reed. Spitz nevus and its variants occasionally may be difficult to distinguish from malignant melanoma. Malignant melanoma is a malignant tumor of melanocytes, estimated to affect 1 in every 70 whites in the United States. Malignant melanomas may occur in any age group, but they tend to be more common in the older age groups. Certain patterns of clinical presentation have been defined. Lentigo maligna melanoma (LMM) most often occurs on the face of elderly persons with very sun-damaged skin and accounts for approximately 15 percent of cases of malignant melanoma (Fig. 15-55). It characteristically has a long intraepidermal growth phase, and it forms a spindle cell nodule

Fig. 15-52. Compound melanocytic nevus with architectural disorder. The junctional lesion is accompanied by dermal lamellar fibroplasia in the form of collagen layers parallel to the surface of the skin.

Fig. 15-53. Spitz nevus. Epidermal hyperplasia is associated with a proliferation of large epithelioid and spindle-shaped melanocytic nevus cells that form nests at the dermoepidemal junction. Smaller groups of cells have descended into the dermis.

Fig. 15-54. Spitz nevus. At the base of the lesion, the cells decrease in size, become dispersed between the collagen bundles, and cease mitotic activity.

Fig. 15-55. Lentigo maligna, malignant melanoma.


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in the dermis (Fig. 15-56). Superficial spreading melanoma accounts for 60 percent of cases of malignant melanoma. It presents as an irregularly shaped maculopapular lesion with varied pigmentation (Fig. 15-57). Histologically it has an intraepidermal and a dermal component (Fig. 15-58). Nodular melanoma accounts for 15 percent of all cases of malignant melanoma and presents as a well-circumscribed hyperpigmented nodule. It has mostly a dermal neoplastic component with relative sparing of the adjacent epidermis. Acral lentiginous melanoma accounts for approximately 5 percent of all cases of malignant melanoma. It originates in the skin of distal extremities that often are protected from the sun. It may have a prolonged epidermal phase. Malignant melanoma cells vary in size and shape and may proliferate as individual cells or in small groups. The cytoplasm may be well developed and pigmented or scant and

Fig. 15-56. Lentigo maligna melanoma. The invasive nodule is composed of spindle-shaped atypical melanocytes.

Fig. 15-58. Malignant melanoma. This superficial spreading melanoma has invaded the dermis. Atypical melanocytes may be seen in the superficial stratum corneum and the granular layer of the epidermis.

nonpigmented. The nuclei usually contain prominent nucleoli. Desmoplastic melanoma, a distinctive histologic variant that is associated with minimal lentiginous proliferation of atypical melanocytes in the epidermis, typically presents in the form of spindle-shaped amelanotic cells in a fibrous and myxoid stroma (Fig. 15-59). It may be difficult to distinguish it from scar. When desmoplastic melanomas form structures that resemble nerves or invade nerves in the dermis, the term neurotropic melanoma is applied. Acral lentiginous melanoma has the growth pattern of lentigo maligna melanoma or a superficial spreading melanoma, but characteristically it contains highly dendritic cells and often small melanoma cells (Fig. 15-60).

A

B

Fig. 15-57. Malignant melanoma. A, Superficial spreading malignant melanoma with invasion. The lesion appears multinodular and shows pale gray scaly foci of atrophy or regression. B, Nodular melanoma. A well-circumscribed nodule is protruding above the skin surface.

Fig. 15-59. Desmoplastic melanoma. Spindle-shaped cells showing nuclear atypia are intermixed with fibroblasts and bundles of collagen. There is no pigment.


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Fig. 15-60. Acral lentiginous melanoma, invasive. This slide was stained with the antibody HMB45 to show the dendritic melanocytes in the epidermis and the nodule of tumor cells in the dermis.

B

Fig. 15-6I I. Seborrheic keratosis. A, Exophytic slightly yellowish skin lesion. B, Pigmented lesion with a corrugated surface. Such lesions may be mistaken for malignant melanoma.

The histologic diagnosis of malignant melanoma may be fraught with difficulties. The important histologic features that are useful in distinguishing malignant melanomas from other pigmented lesions are listed in Table 15-1. The prognosis of melanomas depends on the extent of tumor spread. Histologically the extent of invasion maybe expressed in millimeters, or it is designated by levels Ito IV according to the systems developed by Breslow and Clark, respectively.

Epidermal Tumors Seborrheic keratosis is a very common benign epidermal lesion that is known as verruca seborrheica. It occurs mostly in the elderly as a well-demarcated, flat to raised papule or plaque that is flesh-colored or yellow-pigmented with a rugose surface (Fig. 15-61). It occurs in several histologic patterns, all of which show acanthosis of the epidermis without cytologic atypia (Fig. 15-62). Actinic keratosis, also known as solar keratosis or senile keratosis, is one of the most common neoplasms in whites. It presents as a scaly, erythematous patch on sun-exposed skin. It may be hyperpigmented and confluent and tends to bleed or ulcerate (Fig. 15-63). Histologically the affected skin contains atypical keratinocytes with enlarged hyperchromatic nuclei arranged in an irregular pattern. According to the degree of atypia, these lesions are called squamous intraepithelial neoplasia (SIN), grade I, II, or III (Figs. 15-64 and 15-65). In SIN I cytologic atypia is restricted to the basal layer; in SIN II the entire lower half of the epidermis contains atypical cells; and in SIN III the entire thickness of the epidermis is involved. The surface of the epidermis usually is keratinized, and the suprabasal region may show acantholysis, mimicking acantholytic bullous disorders. The dermis shows signs of solar injury. Several histologic variants are recognized, including pigmented actinic keratosis, lichenoid actinic keratosis, hyperplastic actinic ker -

Fig. 15-62. Seborrheic keratosis. The epidermis is acanthotic, with interconnected rete ridges, and the dermal papillae are fibrotic. Small collections of keratin form "horn pseudocysts."

atosis, and large cell acanthoma. Actinic keratosis is a precursor of invasive squamous carcinoma. Squamous carcinoma in situ of sun-protected skin is known by several names, including Bowen disease or erythroplasia of Queyrat if it is found on the penis. As in typical Bowen disease, this neoplasia is characterized by cytologic atypia of cells, which appear in the basal layer but spread through all layers of the epidermis (Fig. 15-66). Bowen disease also is graded SIN-I, SIN-II, and SIN-III. Squamous cell carcinoma most often occurs on sunexposed skin and presents as a nodular or ulcerated lesion (Fig. 15-67). Histologically it is composed of nests and strands of squamous cells. Tumors may differ with regard to the level of differentiation and keratinization (Fig. 15-68).


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Fig. 15-63. Actinic keratosis. Confluent lesions on sun-damaged skin. Foci of ulceration and hemorrhage occur because of the increased fragility of the skin.

Fig. 15-64. Actinic keratosis (SIN-I). Atypical keratinocytes replace almost the entire basal layer. Decreased cohesiveness of the cells cause suprabasal cleavage.

Fig. 15-65. Actinic keratosis (SIN-II). The lower half of the epidermis has been replaced by atypical keratinocytes. The surface shows extensive keratosis and parakeratosis.

Fig. I5-66. Bowen disease (SIN-III). Atypical keratinocytes are found in all layers of the epidermis.

Fig. 15-67. Squamous cell carcinoma. The irregularly shaped plaque on the forehead has a hyperkeratotic and hemorrhagic crust.

Fig. 15-68. Squamous cell carcinoma. The tumor is composed of invasive nests of keratinizing squamous cells.


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Histologically this tumor resembles squamous cell carcinoma from other sites. Metastases of squamous cell carcinoma of the internal organs to the skin may be difficult to distinguish from primary tumors, especially because the metastatic tumors also may establish contact with the epidermis, and thus mimic a primary skin neoplasm. Keratoacanthoma is a solitary, round, symmetric, nodular lesion with a central keratotic plug (Fig. 15-69). It typically grows rapidly, and most lesions fully develop over several weeks or months. Histologically keratoacanthomas are symmetric, crater-like lesions that have a central keratotic plug and folds of keratinized epithelium (Fig. 15-70). Because of the expansile growth of the lesion, it compresses the adjacent epidermis, which forms a collarette around the central craterlike tumor. The keratinocytes are large and pale and remain closely adherent to one another, in contrast to acantholysis

Fig. 15-69. Keratoacanthoma. The tumor is round and symmetric and has a visible central keratotic plug.

Fig. 15-71. Basal cell carcinoma. This nodular tumor has a depressed center and is surrounded by telangiectatic blood vessels.

in squamous cell carcinoma. Intraepidermal neutrophils are present and may form abscesses. The adjacent epidermis shows no signs of atypia. The intradermal portion of the tumor is sharply demarcated, and there is no invasion or extension beyond its margins.

Fig. 15-70. Keratoacanthoma. Central area consists of a keratotic plug with papillary projections of keratinized epithelium. The lesion has a spherical contour compressing the lateral epidermis and the dermis.

Fig. 15-72. Basal cell carcinoma. The tumor is composed of basaloid cells that form compact nests. Peripheral cells show palisading. Clefts are seen between the tumor nests and the stroma. Mitoses are prominent. There also are scattered apoptotic cells.


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Basal cell carcinoma is the most common malignant tumor in whites. It typically occurs on the sun-exposed skin of the elderly and is directly related to excessive ultraviolet light exposure. Clinically there are three types of tumors: (1) nodular type, which is an opalescent gray nodule that often is associated with telangiectasia; (2) superficial type, which is a scaly, erythematous, flat lesion with distinct, sometimes pearly borders; and (3) morpheic type, which is a flat, someti mes depressed, white plaque with adjacent erythema (Fig. 15-71). Each of these types of tumor grows slowly, but. they also may enlarge quickly and ulcerate. Inexorable local lesions are common, but metastases are extremely rare. Histologically, basal cell carcinoma presents in several forms, but most of them have at least four of the following six features: (1) basaloid cells that resemble the basal layer of the epidermis; (2) peripheral palisading at the margins of cell nests; (3) mitotic figures; (4) individual cell apoptosis, balancing the proliferation; (5) cellular stroma composed of spindleshaped cells in a mucinous matrix with fine collagen fibrils and scattered mast cells; and (6) cleft formation that separates nests of neoplastic cells from the stroma (Fig. 15-72). The only exception is the morpheic basal cell carcinoma, which often lacks peripheral palisading and shows very little cleft formation. The stroma of morpheic basal cell carcinoma is dense and collagenous. Furthermore, these tumors may show foci of keratinization. Keratinization maybe seen in the typical basal cell carcinomas, which are called keratotic basal cell carcinomas. Extensive keratinization makes basal cell carcinomas resemble squamous cell carcinoma, and those tumors are termed basosquamous carcinoma. There also may be focal sebaceous differentiation and even formation of ducts that resemble sweat ducts. Pigmentation of tumor cells may be found, and this is attributed to the proliferation of dendritic, heavily pigmented melanocytes, which transfer the pigment to tumor cells. Pigmentation most often is seen in superficial basal cell carcinomas. Basal cell carcinoma—like changes occur in the epidermis overlying dermatofibromas.

Fig. 15-73. Trichoepithelioma. Multiple small papular lesions appear flesh-colored.

Fig. 15-74. Trichoepithelioma. The tumor is composed of groups of basaloid cells in a cellular stroma. They differ from basal cell carcinoma in that they lack clefts between nests of tumor cells and stroma, have low mitotic count, and show no areas of confluent necrosis.

Adnexal Tumors Many histologically distinct tumors are found in the dermis and subcutis. These tumors originate from cells that form hair follicles, sebaceous glands, apocrine glands, and many others. These tumors usually are solitary and benign, but they may be multiple and malignant. Only some tumors, which have been chosen to illustrate this heterogeneity, are presented here. Trichoepithelioma is a tumor of the hair follicles that presents in the form of solitary or multiple skin nodules (Fig. 15-73). Histologically this tumor varies with regard to the degree of its differentiation, but most tumors contain both keratotic and basaloid areas (Fig. 15-74). Syringocystadenoma papilliferum is a tumor that typically occurs on the face or the scalp as a crusty, exophytic, papillary lesion (Fig. 15-75). Histologically the tumor cells line connective tissue papillae that project into the lumen of a cystic cavity (Fig. 15-76).

Fig. 15-75. Syringocystadenoma papilliferum. The tumor presented as a solitary crusted papillary lesion.


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Fig. 15-76. Syringocystadenoma papilliferum. Papillary fronds lined by epithelial layers project into a cystic cavity.

Fig. 15-77. Sebaceous carcinoma. The tumor is composed of epithelial cells that differentiate focally into lipid-laden, sebaceous cells that have clear cytoplasm.

A

B

Fig. 15-78. Merkel cell carcinoma. Tumor cells that have round nuclei of uniform size and very little cytoplasm form compact nests in the dermis.

Fig. 15-79. Blue nevus. A, Common blue nevus appears as a black, slightly raised papule. B, Cellular blue nevus is larger and may resemble malignant melanoma.

Fig. 15-80. Cellular blue nevus. The dermis is replaced by densely packed spindle cells that contain variable amounts of brown melanin pigment.

Fig. 15-81. Juvenile xanthogranuloma. Typical lesions present as slightly orange-colored papules or nodules.


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Fig. 15-82. Juvenile xanthogranuloma. This well-developed lesion consists of Iipidized macrophages and scattered multinucleated Touton giant cells.

Fig. 15-83. Kaposi sarcoma. Purplish nodules, many of which have ulcerated, cover large parts of the body. Between the larger lesions there still are many smaller ones that resemble bruises.

Sebaceous carcinoma is a rare form of malignancy that originates from the sebaceous glands. The epithelial cells of this tumor differentiate into fat-laden sebaceous cells (Fig. 15-77). Merkel cell carcinoma is a malignant skin tumor that is composed of neuroendocrine cells. The tumor is composed of dense aggregates of uniform cells that have round nuclei and little cytoplasm (Fig. 15-78).

Mesenchymal Tumors Mesenchymal tumors of the dermis and epidermis most often are benign but may be malignant. They correspond histologically to equivalent tumors of soft tissues. Only some of these tumors are illustrated here. Blue nevus is a dermal lesion composed of dendritic and spindle-shaped highly pigmented cells that produce blueblack skin nodules (Figs. 15-79 and 15-80). In addition to the common type, there is a cellular blue nevus, which may show atypia. Juvenile xanthogranuloma is a nodular lesion composed of macrophages. It presents in the form of solitary or multiple skin nodules (Fig. 15-81). This lesion typically is found in children. Infiltrates of macrophages are found in the dermis (Fig. 15-82). In fully developed lesions these macrophages have lipid-rich cytoplasm. Scattered multinucleated cells with a wealth of nuclei also are present. Kaposi sarcoma is a low-grade, often multifocal malignant vascular tumor that involves the skin and the internal organs. It has been linked to infection with herpesvirus type 8. It occurs both in a sporadic form and epidemically in patients who are infected with HIV. Patients present with purplish macules of the skin, which evolve over time `ipto hemorrhagic nodules (Fig. 15-83). Histologically this tumor is composed of spindleshaped cells lining clefts that contain red blood cells (Fig. 15-84). Nuclear atypia is minimal, but mitoses are present.

Fig. 15-84. Kaposi sarcoma. The tumor is composed of spindleshaped cells, and the clefts between the tumor cells contain red blood cells.

Further Reading Carlson AJ, Mihm MC Jr, LeBoit PE: Cutaneous lymphocytic vasculitis: a definition, a review, and a proposed classification. Sem Diagn Pathol 13:72-90, 1996. Kohler S, Rouse RV, Smoller BR: The differential diagnosis of pagetoid cells in the epidermis. Mod Pathol 11:79-92, 1998. LeBoit PE: Minimal deviation melanoma: concept or quagmire? Adv Dermatol 13:289-304, 1997. Leung DYM, Diaz LA, DeLeo V, Soter NA: Allergic and immunologic skin disorders. ]AMA 278:1914-1923, 1998. Murphy GF, Mihm MC Jr: Recognition and evaluation of cytological dysplasia in acquired melanocytc nevi. Hum Pathol 30:506-512, 1999. Rippey JJ: Review: Why classify basal carcinomas? Histopathology 32:393-398, 1998.




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FIBROBLASTIC LESIONS Benign Fibroblastic Tumors and Tumor-Like Lesions Fibroblastic tumors encompass a variety of lesions ranging from purely reactive conditions secondary to injury and benign fibromas to fibrosarcomas that have the ability to both recur and metastasize. Fibromatoses fall midway in the spectrum in that they have the ability to recur locally but do not metastasize (Table 16-1). Nodular fasciitis is a tumor-like spindle cell proliferation that may be confused with sarcoma. It is more common in young adults, but it also occurs in older adults. Typically it first appears as a small (1 to 2 cm in diameter), rapidly enlarging, mildly painful, subcutaneous nodule in the upper extremity, especially the forearm. Although most lesions are superficial, they may extend to the fascia and form an intramuscular mass that may be confused with soft-tissue sarcoma. Histologically, nodular fasciitis is composed of enlarged spindle-shaped to round cells in a richly vascular myxoid background that contains extravasated erythrocytes, variable lymphocytic infiltration, and newly formed collagen fibers (Fig. 16-1). The cells resemble tissue culture fibroblasts in that they have enlarged but regular nuclei with prominent nucleoli. Multinucleated giant cells may be present. Mitotic figures may be numerous, but atypical forms seldom are present. The histologic appearance changes as the lesion ages. Younger lesions are cellular, whereas older lesions contain more collagen and may be hyalinized or cystic. Proliferative fasciitis and proliferative myositis are reactive fibrous lesions that have similar histologic features. The former arises at the fascial level, the latter within the muscles, typically in middle-aged persons. These lesions resemble nodular fasciitis in their proliferative spindle cell component and myxoid background, but they also contain ganglion cell–like cells with large nuclei and prominent nucleoli (Fig. 16-2).

Fig. 16-I. Nodular fasciitis. The lesion is composed of spindleshaped cells in a myxoid background.

Elastofibroma is a nonneoplastic condition that probably is degenerative. It typically and almost exclusively occurs on the thoracic wall at the lower end of the scapula. The lesion is seen in adults, most of whom are elderly women. Histologically it consists of scattered fibroblasts, collagen fibers, fat cells, and large amounts of coarse, serrated elastic fibers of variable sizes that maybe highlighted with elastin stains (Fig. 16-3). Fibrous hamartoma of infancy usually occurs in the axillary soft tissue or in the proximal parts of the extremities

Fibrous Tissue Tumors

Fig. 16-2. Proliferative fasciitis. In addition to spindle-shaped cells, there are polygonal ganglion cell—like cells that have more cytoplasm.


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during the first year of life. It is more common in boys. The lesion is poorly circumscribed and usually measures 3 to 5 cm in diameter. Histologically it consists of collections of cellular fibrous tissue traversing fibroadipose tissue and of nodules of immature-appearing fibroblasts in a myxoid stroma (Fig. 16-4).

broblastic lesions with locally infiltrative features. Fi gromatoses in adults are divided into two types: a deep form (desmoid tumor) and a superficial form (palmar and plantar fibromatoses); the two forms vary in their clinical presentation and biologic behavior. Desmoid tumor (aggressive or musculoaponeurotic fibromatosis) previously was commonly classified as low-grade fibrosarcoma. Approximately half of all cases are abdominal

desmoids, which typically occur in the rectus abdominis muscles of young women. Extraabdominal desmoids occur in both women and men, most commonly between 30 and 40 years of age. The most common locations include the shoulder girdles, chest wall, and thigh. Desmoids typically arise within muscles but extend into fat tissue and the subcutis. On sectioning they are firm graywhite masses that have a rubbery consistency and a trabeculated surface. The periphery may have an infiltrating or sharply demarcated appearance (Fig. 16-5). Histologically all desmoids are composed of long, sweeping fascicles of differentiated fibroblastic cells with ill-defined cytoplasmic borders, delicately staining nucleoli, and only rare mitoses. Broad bands of collagen, similar to those seen in keloids, may be present. The microscopic tumor infiltration beyond the margins explains the common recurrence of locally excised desmoids.

Fig. 16-3. Elastofibroma. Fibrofatty tissue contains fragmented elastic fibers.

Fig. 16-4. Fibrous hamartoma of infancy. Fibrofatty tissue contains groups of loosely arranged immature-appearing fibroblasts.

Fibromatoses Fibromatosis is the term given to a group of differentiated fi-

A

B

Fig. 16-5. Desmoid tumor. A, Abdominal wall desmoid appears as a gray-white mass measuring 4 cm in diameter. B, Broad bands of fibroblastic collagenous tissue infiltrate the space between muscle cells.


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FIBROHISTIOCYTIC TUMORS The generally accepted category of fibrohistiocytic tumors has been retained for historic reasons to facilitate the communication between clinicians and pathologists who have been using this term for more than 30 years. Immunohistochemical data indicate, however, that these tumors are composed of fibroblastic cells, which show no evidence of histiocytic differentiation. This category includes benign tumors, such as benign fibrous histiocytoma; tumors of intermediate malignancy, such as dermatofibrosarcoma protuberans; and malignant tumors, such as malignant fibrous histiocytoma (Table 16-2). Dermatofibrosarcoma protuberans ( DFSP) is a superficial tumor of intermediate (low-grade) malignancy. This tumor occurs primarily in young adults and develops as a cutaneous mass, most commonly on the chest wall or trunk (Fig. 16-6). Initially developing as a plaque or small nodule, it may become large, ulcerate, and give rise to satellite nodules. Histologically DFSP is composed of slender fibroblastic cells that often are arranged in a repetitive storiform pattern. Although most of the lesions are quite cellular, hyalinization or a myxoid change of the stroma may supervene to obscure the typical appearance. The cells seldom display significant mitotic activity. The tumors show an infiltrative pattern of growth into subcutaneous fat, a feature that accounts for the high frequency of recurrences after conservative local excision. Malignant fibrous histiocytoma ( MFH) is a malignant tumor composed of cells that resemble fibroblasts and histiocytes. Immunohistochemical data indicate that these cells are fibroblasts and that there is no evidence of differentiation into histiocytes (macrophages). The term MFH is retained for historical reasons. MFH occurs in soft tissues of extremities, in the retroperitoneum, and in other sites. On gross examination the tumor appears as a fibrotic, often multinodular, white mass with areas of necrosis and hemorrhage (Fig. 16-7). There are four histologically distinct subtypes of MFH: (1) storiformpleomorphic, (2) myxoid, (3) giant cell, and (4) inflammatory. Storiform-pleomorphic MFH is the most common

subtype. Histologically this tumor consists of large spindleshaped or polygonal cells arranged into sheets or short intersecting fascicles. The cells typically are pleomorphic. Mitoses are prominent and often atypical. Myxoid MFH is the second most common subtype. As its name implies, it has a myxoid component, which occupies more than 50 percent of the entire mass. Giant cell MFH is composed of spindle and round cells, with an abundant infiltrate of osteoclast-like multinucleated giant cells. Inflammatory MFH is the least common subtype and usually is found in the retroperitoneum. It consists of parts that resemble the conventional MFH and parts that show poor cellular cohesion and infiltrates of inflammatory cells, including neutrophils and macrophages, which often transform into xanthoma cells.

Fibrohistiocytic Tumors

B A

Fig. 16-6. Dermatofibrosarcoma protuberans. A, This 3 cm mass located in the dermis and subcutis appears grayish-white on cross section. B, Fibroblasts arranged in whorls infiltrate the subcutaneous fat.


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B

A

C

D

Fig. 16-7. Malignant fibrous histiocytoma (MFH). A, This large fleshy mass was removed from the deep soft tissue of the calf. B, Storiform-pleomorphic MFH consists of spindle-shaped and larger pleomorphic cells. C, Myxoid MFH consists of myxoid tissue surrounding prominent blood vessels. D, Giant cell MFH consists of fibroblastic and multinucleated giant cells.

LIPOMATOUS TUMORS Lipomatous tumors are composed of fat cells and their precursors (Table 16-3). Lipoma probably is the most common soft-tissue tumor. This benign tumor typically occurs in subcutaneous tissue but may be found elsewhere. It is composed of mature fat

cells that may be admixed with connective tissue, blood vessels, and other elements (Fig. 16-8). Several subtypes are recognized, including (1) angiolipoma, (2) angiomyolipoma, (3) spindle cell lipoma, (4) pleomorphic lipoma, (5) intramuscular lipoma, (6) perineural fibrolipoma, and (7) myelolipoma.

Lipomatous Tumors


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Fig. 16-8. Spindle cell lipoma. In addition to fat cells, the tumor contains spindle-shaped fibroblastic cells.

Hibernoma is a benign tumor of brown fat (Fig. 16-9). This tumor most often develops on the back or the shoulder and less often appears on the thigh. Lipoblastoma is a benign tumor of infancy and childhood that is composed of lobules of immature fat cells (Fig. 16-10). Liposarcoma is a common soft-tissue malignancy that almost exclusively occurs in adults. Approximately 50 percent of liposarcomas occur on the lower extremities; 20 percent are intraabdominal. On gross examination liposarcoma appears as a yellow mass that may be relatively circumscribed or invasive (Fig..16-11). Several histologic subtypes are recognized: (1) well-differentiated (lipoma-like and sclerosing), (2) myxoid, (3) round cell, (4) pleomorphic, and (5) dedifferentiated. The first two forms are low-grade sarcomas, whereas the latter three are high-grade sarcomas that have a tendency to metastasize. Well-differentiated liposarcomas resemble mature fat tissue or lipomas, and the only indication that the tumor is malignant stems from the hyperchromatic atypical cells in the widened connective tissue septa and the presence of scattered lipoblasts. The latter are immature fat cells that contain one or more fat vacuoles, which indent or scallop the nucleus. Lymphocytic infiltrates are common, especially in abdominal liposarcomas of this type. Myxoid liposarcoma is the most common type. Histologically it has a typical pattern with abundant branching fine capillaries surrounded by uniform small tumors cells suspended in hyaluronic acid—rich matrix (Fig. 16-11, B). Varying numbers of lipoblasts are present. Lipoblasts vary in size and shape and typically contain vacuoles of lipid in their cytoplasm. Round cell liposarcoma represents the cellular or poorly differentiated variant of myxoid liposarcoma. It may coexist as a minor component of otherwise typical myxoid liposarcoma; in such cases the tumor shows more pronounced aggressiveness. Histologically it consists of uniform, primitive round cells with a high nuclear-cytoplasmic ratio (Fig. 16-11, C).

Fig. 16-9. Hibernoma. The tumor is composed of multivacuolated cells that resemble normal brown fat cells.

Fig. 16-10. Lipoblastoma. Immature, richly vascular fat tissue has a lobular appearance.

There often is a hemangiopericytomatous pattern in which the cells surround branching blood vessels. Pleomorphic liposarcoma is a relatively rare tumor that typically is found in the elderly. Histologically it is composed of pleomorphic tumor cells, including highly atypical multinucleated giant cells, many of which have multiple cytoplasmic vacuoles (Fig. 16-11,D). Dedifferentiated liposarcoma consists of areas that resemble well-differentiated liposarcoma and areas that resemble high-grade MFH.


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A

B

C

D

Fig. 16-1 I. Liposarcoma. A, On gross examination this liposarcoma appears as a yellow, deepseated circumscribed mass. B, Myxoid liposarcoma consists of small lipoblasts in a loose myxoid stroma arranged around prominent branching blood vessels. C, Round cell liposarcoma consists of compact sheets of round cells, some with fat vacuoles. D, Pleomorphic liposarcoma consists of large pleomorphic and multinucleated cells, many of which contain lipid vacuoles in their cytoplasm.

Endothelial Tumors of Blood and Lymph Vessels

VASCULAR TUMORS Vascular tumors composed of endothelial cells of blood and lymph vessels are very common lesions of the skin and subcutaneous tissue, but they also occur in many other tissues and in internal organs. Most vascular tumors are benign. Low-grade malignant tumors such as hemangioendothelioma and highly malignant angiosarcomas are less common (Table 16-4).

Benign tumors of endothelial cells occur in all age groups and may present in many clinical and pathologic forms. Some congenital hemangiomas actually are hamartomas, whereas others, such as bacillary angiomatosis or pyogenic granuloma, maybe reactive lesions (Fig. 16-12). On the basis of histology it is difficult and often impossible to determine the true nature of such vascular lesions.


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A

B

Fig. 16-12. Pyogenic granuloma. A, The lesion is a well-circumscribed, red nodule that bleeds easily on trauma. It forms fast and tends to recur rapidly if it is incompletely excised. B, The lesion is composed of thin-walled vessels with edematous stroma that is rich in inflammatory cells and capillaries that have collapsed lumina.

Fig. 16-13. Lymphangioma. The dilated vascular spaces lined by flattened endothelial cells contain proteinaceous lymph and a few lymphocytes.

Fig. 16-14. Epithelioid hemangioendothelioma. The tumor consists of endothelial cells arranged into cords and clusters. The vacuoles represent microlumina.

A

B

Fig. 16-15. Angiosarcoma. A, The tumor forms a hemorrhagic mass in the deep soft tissue. B, The tumor is composed of endothelial cells lining irregular channels, some of which contain blood. (Gross specimen photograph courtesy of Dr. Steven I. Hajdu, Manhasset, New York.)


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Benign tumors of blood vessels are called hemangiomas, and those that originate from endothelial cells of lymphatics are called lymphangiomas (Fig. 16-13). Several clinical and pathologic variants are recognized, including (1) capillary hemangioma, (2) cavernous hemangioma, (3) intramuscular hemangioma, (4) epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia or Kimura disease), (5) angiomatosis, 6) bacillary angiomatosis, (7) pyogenic granuloma, (8) intravascular papillary endothelial cell hyperplasia (Masson hemangioma), (9) cystic lymphangioma, (10) lymphangiomyoma, and (11) lymphangiomyomatosis. Hemangioendothelioma is an endothelial cell neoplasm of intermediate (borderline) malignancy that occurs in several forms, such as (1) epithelioid hemangioendothelioma, (2) spindle cell hemangioendothelioma, and (3) Kaposiform hemangioendothelioma. Epithelioid hemangioendothelioma is composed of endothelial cells that have abundant eosinophilic cytoplasm and thus resemble histiocytes (Fig. 16-14). More than one half of all soft-tissue tumors of this type arise from the wall of identifiable vessels, which usually are thrombosed. Neoplastic endothelial cells have cytoplasmic vacuoles, representing miniature vascular lumens, which may contain erythrocytes. These cells are arranged into cords and clusters in a loose fibromyxoid stroma. Spindle cell hemangioendothelioma is a rare vascular tumor of the subcutis of young adults, usually located on the hands. Histologically it is composed of cavernous blood spaces juxtaposed with bland spindle cells, reminiscent of Kaposi sarcoma. Kaposiform hemangioendothelioma is a rare childhood tumor of superficial or deep soft tissues. Histologically it resembles Kaposi sarcoma. Angiosarcoma is a term that encompasses four clinical entities: (1) cutaneous tumors that occur without preexisting lymphedema, (2) cutaneous tumors that arise in lymphedematous extremities, (3) angiosarcomas of the breast, and (4) angiosarcomas of deep soft tissues. On gross examination tumors often are hemorrhagic and poorly demarcated from normal tissue (Fig. 16-15,A). Histologically the tumors show a wide spectrum of differentiation. The well-differentiated tumors show irregular anastomosing, blood-filled vascular channels, lined by variably atypical endothelial cells, which often show papillary intraluminal tufting. The less differentiated tumors may show solid strands and sheets, resembling carcinoma or lymphoma (Fig. 16-15, B). Immunohistochemically the cells express endothelial markers such as von Willebrand factor, CD31 and CD34, and receptors for the lectin Ulex europaeus. WeibelPalade bodies are the electron microscopy (EM) markers of endothelial cells. Angiosarcoma also must be distinguished from Kaposi sarcoma and benign vascular tumors, which may show some nuclear unrest when irritated. Because angiosarcoma-like areas occur in many hypervascular soft tissues and bone tumors, it is important not to diagnose such tumors as angiosarcomas. The same rule applies to hemangiopericytomas.

PERIVASCULAR TUMORS The new World Health Organization (WHO) classification of soft-tissue tumors assigns glomus tumors and hemangiopericytomas to a separate category of perivascular tumors (Table 16-5). Glomus tumors are small painful nodules in superficial soft tissues of adults. They recapitulate the basic features of glomus bodies, that is, specialized arteriovenous anastomoses regulating the blood flow in distal parts of the body. Most often they arise from the nailbeds or from the fingers, palms, feet, legs, and forearms. Simple excision is curative in most instances, albeit 10 percent of glomus tumors recur locally. Histologically the tumors are composed of uniform, round to polygonal cells arranged into sheets and cords surrounding thin-walled dilated blood vessels (Fig. 16-16).Variants such as glomangioma, glomangiomyoma, and rare malignant glomus tumors have been described. Hemangiopericytoma is a rare borderline malignant tumor that occurs in deep soft tissues of the extremities and the retroperitoneum of adults. Tumor cells are arranged around thin-walled blood vessels, and although they resemble pericytes, their true nature is subject to controversy; it has not been proved that they truly are derived from normal pericytes. Histologically hemangiopericytomas are composed of spindle-shaped or round cells embedded in a moderately dense stroma matrix arranged around dilated vas-

Perivascular Tumors

Fig. I6-16. Glomus tumor. Round and polygonal cells surround thin walled blood vessels in a collar-like manner.


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Fig. 16-17. Hemangiopericytoma. Thin-walled blood vessels in a "staghorn"pattern are surrounded by spindle-shaped cells in a collagenous matrix.

Fig. 16-18. Leiomyoma. This spherical nodule was shelled out from subcutaneous soft tissue. It is brownish-red on cross section because of an abundance of blood vessels in its stroma.

cular lumina (Fig. 16-17). Reticulin fibers surrounding each tumor cell and arranged radially perpendicular to the lumen of the vessel may be demonstrated with special stains. Mitotic activity usually is low, except in highly malignant tumors. There are no immunohistochemical stains that would be typical of hemangiopericytoma. Most tumors react positively with antibodies to CD34 and are negative for endothelial cell markers, smooth muscle cell actin, and desmin. However, some tumors of the same histologic appearance react with antibodies to smooth muscle actin, which suggests that some "hemangiopericytomas" are not of pericytic origin but are leiomyosarcomas. Hemangiopericytomatous patterns of growth may be seen in other soft-tissue sarcomas, most notably MFH and liposarcomas.

SMOOTH MUSCLE CELL TUMORS Smooth muscle cell tumors include leiomyomas and leiomyosarcomas, which histologically resemble the more common uterine and gastrointestinal tumors (Table 16-6). Leiomyomas are benign soft-tissue tumors that are grouped into four clinicopathologic categories: (1) piloleiomyoma arising from arrectores pilorum and presenting as small 1 to 2 cm nodules; (2) genital leiomyoma commonly found in the vulva or the scrotum; (3) angiomyoma presenting as vascular subcutaneous nodules with a predilection for the lower extremities, especially the legs and ankles; and (4) leiomyomas of deep soft tissue, which are rare tumors that show considerable regressive changes, such as hyalinization. Leiomyomas usually are well-demarcated nodules, which on cross section appear grayish-tan or brown and red, depending on the extent of vascularization (Fig. 16-18). Histologically the tumors are composed of smooth muscle cells that have uniform elongated nuclei with blunt tips and a welldeveloped eosinophilic cytoplasm (Fig. 16-19). Leiomyosarcomas are malignant tumors composed of atypical smooth muscle cells, arranged into fascicles that in -

Fig. 16-19. Leiomyoma. The tumor is composed of smooth muscle cells that have uniform elongated nuclei and welldeveloped cytoplasm.

Smooth Muscle Tumors


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A

B

Fig. 16-20. Leiomyosarcoma. A, Pleomorphic leiomyosarcoma is composed of atypical spindle-

shaped cells that vary in size and shape and often show considerable nuclear pleomorphism. B, Epithelioid leiomyosarcoma consists of polygonal cells that often have clear cytoplasm. Nuclei appear more uniform, but there are mitotic figures, which indicate that this is a malignancy.

A

B

Fig. 16-21. Adult rhabdomyoma. A, Tumor presented as a lobulated pharyngeal mass. B, Tumor

is composed of large polygonal cells that have ample eosinophilic cytoplasm and small nuclei. (Gross specimen photograph courtesy of Dr. Antonio Racela, Overland Park, Kansas.)

tersect obliquely or perpendicularly with one another. Neoplastic cells have elongated nuclei that show hyperchromasia, have irregular distribution of chromatin, and often are pleomorphic (Fig. 16-20, A). Areas of necrosis are prominent in larger tumors. The number of mitoses varies, and the prognosis is determined by taking into account the size of the tumor, its location, and the histologic findings. Epithelioid leiomyosarcoma (leiomyoblastoma, bizarre leiomyoblastoma) more often is found in the gastrointestinal tract but also may occur in soft tissues. The most common sites are the peritoneum, omentum, and mesentery. Tumors that measure more than 6 cm in diameter and have more than 3 to 5 mitoses per 10 high-power fields are malignant. Histologically the tumors are composed of polygonal cells arranged into sheets (Fig. 16-20, B). These cells have welldeveloped cytoplasm that may be clear or eosinophilic, and some cells even have a signet ring—like appearance.

TUMORS OF STRIATED MUSCLE Tumors of striated muscle include rhabdomyomas and rhabdomyosarcomas. Rhabdomyoma is a benign tumor that shows striated muscle differentiation. Four clinicopathologic entities are recognized: (1) adult rhabdomyoma, (2) rhabdomyoma of female genital organs, (3) fetal rhabdomyoma, and (4) cardiac rhabdomyoma. Strictly speaking, only adult rhabdomyoma and fetal rhabdomyoma are soft-tissue tumors. Adult rhabdomyoma is a rare tumor of adults that typically presents as a slow-growing mass in the oral cavity or nasopharynx. Grossly the tumor is a brown or red multilobular mass that measures 1 to 5 cm in diameter (Fig. 16-21,A). Histologically it is composed of large polygonal cells that resemble skeletal muscle cells. Compared with normal or hyperplastic muscle cells, rhabdomyoma cells are larger and show cytoplasmic vacuolization (Fig. 16-21, B).


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Rhabdomyosarcoma is a malignant tumor that shows striated muscle differentiation and primarily affects children. Five clinicopathologically distinct types are recognized: (1) embryonal, (2) botryoid, (3) spindle cell, (4) alveolar, and (5) pleomorphic, although some overlap exists among these types. On gross examination rhabdomyosarcoma usually appears as a gray-white myxoid mass (Fig. 16-22,A). Histologically, embryonal rhabdomyosarcoma accounts for 75 percent of all cases. It has a peak incidence in the first year of life. Urogenital and head and neck areas most often are involved. Embryonal rhabdomyosarcoma are composed of a mixture of small and large rhabdomyoblasts, which have prominent eosinophilic cytoplasm (Fig. 16-22, B). The degree of rhabdomyoblastic differentiation correlates positively with the prognosis. In some cases loose myxoid areas alternate with cellular areas in a trabecular pattern. Alveolar rhabdomyosarcoma accounts for 10 percent to 20 percent of all cases of rhabdomyosarcoma. It occurs predominantly in adolescents and preferentially involves the distal parts of the extremities and the head and neck area. Histologically the tumor is composed of small cells that are separated into groups by fibrovascular septa.

Because of poor cohesiveness of the cells and areas of necrosis, central parts of tumor nests transform into " alveolar spaces " (Fig. 16-22, C). In addition to the round undifferentiated cells, the tumor may contain larger multinucleated cells with abundant eosinophilic cytoplasm. Desmin, which is the best marker of striated differentiation, may be demonstrated even in the smaller cells (Fig. 16-22, D). EM is useful for demonstrating myofibrils, which show Zband–like condensations (Fig. 16-22, E). Pleomorphic rhabdomyosarcoma, which previously was considered to be a common soft-tissue sarcoma of the extremities in adults, now is considered to be rare. Most of these tumors actually are desmin negative and represent pleomorphic MFH. Spindle cell rhabdomyosarcoma is a rare childhood tumor that is composed of spindle-shaped rhabdomyoblasts. Botryoid rhabdomyosarcomas are myxoid, " grapelike,"exophytic tumors of the urinary bladder, cervix, and vagina of preschool-age girls (see Figs. 13-29 and 13-30). Similar tumors occasionally are found in the liver and upper respiratory tract.

A

B

C

D

E

Fig. 16-22. Rhabdomyosarcoma. A, On gross examination the tumor appears as a myxoid mass. B, Embryonal rhabdomyosarcoma consists of small and large rhabdomyoblasts. C, Alveolar rhabdomyosarcoma is composed of undifferentiated small round cells attached to fibrous septa. Alveolar spaces are formed between discohesive cells. D, Rhabdomyosarcoma stains positively with antibodies to desmin. E, EM shows thick and thin filaments and Z-band—like densities.


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NEURAL TUMORS Neural tumors include neoplasms that show nerve sheath differentiation and are composed of Schwann cells, perineurial cells, and perineurial fibroblasts; and those that display neuronal feature ganglioneuroma. Most of these neural tumors are benign, and many of them are quite common. Malignant nerve sheath tumors are rare.

Benign Neural Tumors

Benign Neural Tumors Benign neural tumors are listed in Table 16-7. Schwannoma is a benign tumor that is composed of Schwann cells. It typically originates from peripheral nerves and often is recognized as a fusiform mass that focally expands the nerve or is attached to it (Fig. 16-23, A). Histologically it is characterized by cellular Antoni A areas alternating with myxoid Antoni B areas. The cellular areas consist of sheets of spindle cells with palisaded nuclei that form columns around an amorphous matrix (Verocay bodies) (Fig. 16-23, B). Neurofibroma is a common benign nerve sheath tumor that most often appears as an unencapsulated subcutaneous nodule. It consists of haphazardly arranged fibroblasts, perineurial cells, and Schwann cells (Fig. 16-24). The spindleshaped tumor cells are intermixed with wavy collagen bundles. The stroma may be myxoid or densely collagenous. Nerve sheath myxoma (neurothekeoma) is a benign nerve sheath tumor of the subcutis that most often is found in children and young adults. Histologically it is composed of multiple lobules of spindle cells suspended in myxoid material surrounded by dense fibrous bands (Fig. 16-25).

A Fig. 16-24. Neurofibroma. Spindle-shaped cells are surrounded by wavy matrix.

B

Fig. 16-23. Schwannoma. A, Tumor has produced a bulging mass in the peripheral nerve. B, Spindle-shaped cells show palisading, which is evidenced by the alignment of nuclei at the margins of eosinophilic areas composed of cytoplasmic processes.

Fig. 16-25. Nerve sheath myxoma. Cellular myxoid lobules are found enclosed in dense connective tissue septa.


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Malignant Neural Tumors Malignant neural tumors are listed in Table 16-8. Malignant peripheral nerve sheath tumors (MPNST), which include malignant schwannoma and neurofibrosarcoma, account for less than 10 percent of all soft-tissue sarcomas. Approximately 50 percent of these tumors arise in patients with neurofibromatosis type I through malignant transformation of nerve trunk fibromas, whereas the remainder arise sporadically. Schwannomas almost never

Malignant Neural Tumors

undergo malignant transformation. Most patients are middle-aged but some are young, especially those with neurofibromatosis. Multiple malignancies occasionally are found, again mostly in the context of neurofibromatosis. MPNST originating from nerves or from preexisting neurofibromas within a nerve expand the nerve in an irregular manner and extend into the adjacent soft tissues (Fig. 16-26, A). Histologically MPNST resembles fibrosarcoma except for the fact that spindle cells tend to have an irregular buckled shape that is reminiscent of normal Schwann cells (Fig. 16-26, B). Some tumors may be pleomorphic and resemble MFH. Heterologous elements such as cartilage and bone may be present. Malignant triton tumor is the designation used to describe tumors that contain rhabdomyoblasts. Glandular malignant schwannoma is the term used for those that contain glandular elements. Clear cell sarcoma shows melanocytic differentiation. Well-differentiated malignant neural tumors stain with antibodies to S-100 protein (Fig. 16-26, C), like normal Schwann cells, but many highly malignant ones do not. Differentiation into Schwann cells may be detected by EM in better differentiated tumors. These ancillary tests are of no value in undifferentiated tumors. Precise diagnosis of such tumors often is uncertain unless the tumor arose in the context of neurofibromatosis type I or the mass was obviously attached to a peripheral nerve.

A

B

C

Fig. 16-26. Malignant peripheral nerve sheath tumor (MPNST). A, Tumor is arising from the ulnar nerve. B, Histologically MPNST is composed of nondescript spindle-shaped cells. C, Some tumor cells in the MPNST stain with the antibody to S-100 protein.


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CARTILAGE AND BONE-FORMING TUMORS Cartilage and bone-forming tumors are listed in Table 16-9. Histologically these tumors have the same features as their more common equivalents in the bones. Myositis ossificans is a pseudoneoplastic condition that is marked by the formation of reactive bone inside the muscle. It typically occurs in young adults and presents as a painful mass, most often in the anterior muscle of the thigh. or the buttocks (Fig. 16-2 7, A). The mature lesion is sharply demar-

cated from the surrounding muscle. The central part, which consists of osteoblasts, osteoid, and osteoclasts, is rimmed by mature bone at the periphery (Fig. 16-27, B and C). Osteosarcoma of soft tissues is a tumor of adulthood, and most patients are older than 40 years. Deep muscle compartments of the extremities and the retroperitoneum are the most common sites. Histologically most tumors are highgrade sarcoma and may be indistinguishable from those in MFH except that focally they show osteoblastic differentiation and produce trabecular osteoid (Fig. 16-28).

Cartilage and Bone-Forming Tumors of Soft Tissue

A

B C

Fig. 16-27. Myositis ossificans. A, Sharply demarcated intramuscular lesion shows a distinct difference between the peripheral rim of bone and the central part. B, The peripheral part consists of trabeculae of newly formed bone. C, The central part consists of osteoblasts surrounding osteoid and osteoclast-like giant cells.


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Fig. 16-28. Osteosarcoma of soft tissue. Tumor is composed of high-grade malignant spindle-shaped cells surrounded by osteoid.

Fig. 16-29. Extraskeletal myxoid chondrosarcoma. Trabeculae of spindle cells are suspended in myxoid matrix.

pended in a myxoid matrix (Fig. 16-29). Because of its resemblance to chordoma, it also is known as chordoid sarcoma. Hyaline cartilage, a typical finding in skeletal chondrosarcoma, is seen only occasionally. Mesenchymal chondrosarcoma of soft tissues is a rare malignancy that is similar to its osseous counterpart. It occurs in young patients in the thigh and the meninges and is prone to metastasis, which may be found in the lungs at the time of diagnosis. The tumor consists of primitive round cells in a collagenous stroma demarcating islands of differentiated cartilage (Fig. 16-30). These tumors usually are highly vascular and may have a hemangiopericytomatous appearance.

MISCELLANEOUS SOFT TISSUE TUMORS

Fig. 16-30. Mesenchymal chondrosarcoma of soft tissue. Primitive-appearing round cells in fibrous stroma are focally juxtaposed to differentiated cartilage. Vascularity of the tumor imparts to it a hemangiopericytomatous pattern.

Chondrosarcomas of soft tissues may present as extraskeletal myxoid chondrosarcoma or mesenchymal chondrosarcoma. Extraskeletal myxoid chondrosarcoma is a highly malignant tumor of middle-aged persons. It presents as a gray gelatinous tumor of the extremities and the retroperitoneum. Histologically it consists of spindle-shaped cells sus -

Soft tissues may give rise to a variety of tumors of unknown or incompletely known histogenesis (Table 16-10). Some of these tumors are benign, others are malignant, and in all likelihood still others are not even neoplastic. Small round cell tumors of soft tissues are grouped together because of similar morphology, even though there is no doubt that they may not be related one to another histogenetically. This group of tumors includes extraskeletal Ewing sarcoma, peripheral neuroepithelial tumors (PNET, or peripheral neuroepithelioma), Askin tumor, and intraabdominal desmoplastic small round cell tumors (Figs. 16-31 and 16-32). Neuroblastomas and metastatic tumors such as nephroblastoma or hepatoblastoma and lymphomas might have the same morphology.


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Miscellaneous Soft-Tissue Tumors

Fig. 16-3I. Peripheral neuroepithelioma (PNET). Tumor is composed of nests of small cells arranged focally into rosettes.

Fig. 16-32. Intraabdominal desmoplastic small round cell tumor. Nests of small blue cells are surrounded by dense collagenous stroma.

A

B

Fig. 16-33. Synovial sarcoma. A, Biphasic tumor consists of glandlike structures surrounded by uniform spindle-shaped cells. B, Monophasic tumor is composed of nearly uniform spindle-shaped cells with some whorling focally.


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A

A

B

B

Fig. 16-34. A, Epithelioid sarcoma. Polygonal cells form compact nests surrounded by spindle-shaped cells. B, The epitheliod sarcoma cells are uniformly positive for cytokeratin. C, The cells show membrane staining for CD34.

Fig. 16-35. A, Alveolar soft-part sarcoma. Polygonal cells are arranged into nests surrounded by connective tissue septa. The central space gives the tumor an alveolar appearance. B, Electron microscopy shows rhomboid crystals with a latticelike pattern and regular periodicity.


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Synovial sarcoma is a distinctive malignant tumor of soft tissues that often shows a dual epithelial and spindle cell mesenchymal differentiation, which previously was believed to reflect differentiation into synovium. Even though there is no evidence that the tumor is related to the synovium, its name was retained for historical reasons. Synovial sarcoma occurs in young adults (25 to 35 years) and predominantly involves the extremities. It accounts for 10 percent of softtissue sarcomas. Histologically it occurs in both biphasic and monophasic forms. The biphasic form of synovial sarcoma consists of glandlike epithelial structures and mesenchymal spindle cells (Fig. 16-33, A). The monophasic synovial cell sarcoma is composed only of spindle cells (Fig. 16-33, B). Epithelial cells and some spindle-shaped cells react immunohistochemically with antibodies to keratins and epithelial membrane antigen (EMA). Epithelioid sarcoma is a rare soft-tissue sarcoma that affects young adults (average age 30 to 35 years). It tends to arise from distal parts of the extremities and usually presents as a superficial nodule. The neoplastic nature of the lesion may elude the clinician and the pathologist alike, but during histologic examination tumor cells usually extend beyond the area that is assumed to be involved on the basis of gross impression. Histologically the tumor is composed of epithelial-like cells arranged into sheets or groups surrounded by connective tissue stroma (Fig. 16-34). Central necrosis is common in larger clusters. The nuclei of tumor cells have complex outlines, and the cytoplasm of most cells is well developed and eosinophilic. The tumor cells typically stain with antibodies to vimentin, keratin, and EMA, but they also are positive for CD34. Alveolar soft-part sarcoma is an architecturally distinct, rare soft-tissue sarcoma of unknown histogenesis. Most often it is located in the deep soft tissue of the thigh, but it may occur anywhere. Most patients are young. Histologically the tumor has a distinctive organoid appearance (Fig. 16-35). Tumor cells are polygonal and have an abundant granular eosinophilic cytoplasm. Central areas of tumor nests tend to necrotize, giving the nests an alveolar appearance. The cytoplasm contain PAS-positive crystals, which have a lattice-like appearance on EM. Although it resembles paraganglioma, there is no evidence of neuroendocrine or neural differentiation. The tumor does not contain keratin and is not epithelial. Further Reading Agamanolis DP, Dasu S, Krill CE: Tumors of skeletal muscle. Hum Pathol 17:778-795, 1986. Aiba M. Hirayama A, Kuramochi S: Glomangiosarcoma in a glomus tumor. An immunohistochemical and ultrastructural study. Cancer61:1467-471, 1988. Allen PW, Enzinger FM: Hemangioma of skeletal muscle. An analysis of 89 cases. Cancer 29:8-22, 1972. Allen PW: The fibromatoses. A clinicopathologic classification based on 140 cases. Am J Surg Pathol 1977; 1:255-270, 1977.

Azzopardi JG, Iocco J, Salm R: Pleomorphic lipoma. A tumour simulating liposarcoma. Histopathology 7:511-523, 1983. Bernstein KE, Lattes R: Nodular (pseudosarcomatous) fasciitis, a nonrecurrent lesion. Cancer 49:1668-1678, 1982. Chase DR, Enzinger FM: Epithelioid sarcoma. Diagnosis, prognostic indicators, and treatment. Am J Surg Pathol 9:241-263, 1985. Churg AM, Kahn LB: Myofibroblasts and related cells in malignant fibrous and fibrohistiocytic tumors. Hum Pathol 28:205-218, 1997. Coffin CM, Dehner LP: Vascular tumors in children and adolescents. A clinicopathologic study of 228 tumors in 222 patients. Pathol Annu 28(pt 1):97-120, 1993. Enzinger FM, Smith BH: Hemangiopericytoma. An analysis of 106 cases. Hum Pathol 7:61-82, 1976. Enzinger FM: Malignant fibrous histiocytoma 20 years after Stout. Am J Surg Pathol 10(suppl 1):43-53, 1986. Erlandson RA, Woodruff JM: Role of electron microscopy in the evaluation of soft tissue neoplasms, with emphasis on spindle and pleomorphic tumors. Hum Pathol 29:1372-1381, 1998. Evans HL: Liposarcoma. A study of 55 cases with a reassessment of its classification. Am J Surg Pathol 3:507-523, 1979. Fields JP, Helwig EB: Leiomyosarcoma of the skin and subcutaneous tissue. Cancer 47:156-169, 1981. Fletcher CDM: Benign fibrous histiocytoma of subcutaneous and deep soft tissue. A clinicopathologic analysis of 21 cases. Am JSurgPathol 14:801-809, 1990. Goodlad JR, Fletcher CDM: Recent developments in soft tissue tumours. Histopathology 27:103-120, 1995. Henricks WH, Chu YC, Goldblum JR, Weiss SW: Dedifferentiated liposarcoma: a clinicopathologic analysis of 155 cases with a proposal for an expanded definition of dedifferentiation. Am J Surg Pathol21:271-281, 1997. Hibshoosh H, Lattes R: Immunohistochemical and molecular genetic approach to soft tissue tumor diagnosis: a primer. Sem Oncol 24:515-525, 1997. Hollowood K, Fletcher CDM: Soft tissue sarcomas that mimic benign lesions. Sem Diag Pathol 12:87-97, 1995. Hollowood K, Fletcher CDM: Malignant fibrous histiocytoma: morphologic pattern or pathologic entity? Sem Diag Pathol 12:210-220, 1995. Jensen B, Schumacher B, Jesen OM et al: Extraskeletal osteosarcomas. A clinicopathologic study of 25 cases. Am J Surg Pathol 22:588-594, 1998. Lucas DR, Nascimento AG, Sanjay BK, Rock MG: Well differentiated liposarcoma. The Mayo Clinic experience with 58 cases. Am J Clin Pathol 102:677-683, 1994. Meis-Kindblom JM, Bergh P, Gunterberg B, Kindblom L-G: Extraskeletal myxoid chondrosarcoma. A reappraisal of its morphologic spectrum and prognostic factors based on 177 cases. Am JSurg Pathol 23:636-650, 1999. Middleton LP, Duray PH, Merino JM: The histological spectrum of hemangiopericytoma: application of immunohistochemical analysis including proliferative markers to facilitate diagnosis and predict prognosis. Hum Pathol 29:636-640, 1998. Miettinen M, Lehto V-P, Virtanen I: Monophasic synovial sarcoma of spindle-cell type. Virchows Arch [A] 44:187-199, 1983. Miettinen M, Soini Y: Malignant fibrous histiocytoma. Heterogeneous patterns of intermediate filament proteins by immunohistochemistry. Arch Pathol Lab Med 113:1363-1366, 1989. Smith PS, Pieterse AS, McClure J: Fibroma of tendon sheath. J Clin Pathol 35:842-848, 1982. Stemmermann GN, Stout AP: Elastofibroma dorsi. Am J Clin Pathol 37:490-506, 1962. Wolf AN, Ladany M, Paull G et al: The expanding clinical spectrum of desmoplastic small round-cell tumor: a report of two cases with molecular confirmation. Hum Pathol 30:430-435, 1999.




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DEVELOPMENTAL AND GENETIC DISORDERS Developmental disorders that affect the bones most often are based on a genetic defect that prevents the normal formation of the osteon, the basic anatomic and functional unit of the bone. Many of the genes responsible for these developmental defects have already been cloned, and the pathogenesis of many developmental bone disorders has been elucidated. The basic nature of others remains obscure. Achondroplasia is the most common cause of disproportionately short stature, affecting 1 in 40,000 newborns. It is based on the mutation of the gene encoding the receptor for the fibroblast growth factor, which is transmitted from one generation to another in an autosomal dominant manner. Nevertheless, 80 percent of cases are sporadic. The growth of the long bones of the extremities has been stunted, which accounts for dwarfism, the most prominent feature of this disease (Fig. 17-1). Histologically the long bones show abnormalities of endochondral ossification at the epiphyseal growth plate (Fig. 17-2). Osteogenesis imperfecta is a name given to several clinical syndromes, all of which are caused by mutations in the genes encoding collagen type I. Four main forms of osteogenesis imperfecta have been identified, all of which except the rare type III are transmitted in an autosomal dominant manner. The clinical and pathologic findings vary from mild to severe, depending on the type of the disease and the nature of the genetic defect. Osteopenia is the main feature, and it may be associated with dental defects and abnormalities of the skin, ligaments, and sclerae, which typically are blue. Type II osteogenesis imperfecta is lethal in infancy. Affected infants

Fig. 17-2. Achondroplasia. Epiphyseal growth plate is broad and disorganized.

show minimal calvarial mineralization ( "rubber head " ) and short compressed and fractured bones of the extremities (Fig. 17-3). Histologically bones show irregular and inefficient osteogenesis and are composed of incompletely calcified, thin, and irregular trabeculae (Fig. 17-4). Osteopetrosis, which is also called marble bone disease or Albers-Schonberg disease, is a term used to describe four clinical syndromes that are characterized by excessive thickness of bones. Despite this variability the pathogenesis of all types involves defective osteoclast function that impairs bone

Fig. 17-I. Achondroplasia. Bones of the extremities are short and have a disproportionately large cartilaginous epimetaphyseal part, as compared with short diaphysis.

Fig. 17-3. Osteogenesis imperfecta type II. The infant, who died shortly after birth, had a large, soft head, small thorax, and short extremities, which by radiograph showed numerous fractures.


357

resorption. Carbonic anhydrase II deficiency has been identified in some cases. As a result, primary spongiosa of growing bones is not removed but persists into adult life. The bones remain sclerotic forever (Fig. 17-5). In severe forms of the disease there is anemia because the thick bones do not contain enough space for hematopoiesis. Sclerotic bones tend to fracture easily despite their thickness. Sporadic nongenetic developmental anomalies of the skeleton occur without obvious causes, and they present as abnormalities of fingers and toes (syndactyly). Parts of extremities or the entire limb may be defective or missing. In most severe cases such as amelia, li mbs are not formed at all (Fig. 17-6).

METABOLIC AND DEGENERATIVE DISEASES Metabolic Bone Diseases

Fig. 17-4. Osteogenesis imperfecta type II. Neonatal long bones show irregular osteogenesis. Cortex is incompletely mineralized and the trabeculae are irregular.

In adults metabolic bone diseases are disorders of the bone remodeling system, which is responsible for the maintenance of the anatomic and functional integrity of the osteon, the basic anatomic unit of bone. In some instances a genetic defect is found to be the cause of bone disease, as in hypophosphatasia or Marfan syndrome; in other cases bone disease is secondary to a primary disease of the kidneys, endocrine glands, or gastrointestinal tract. The pathogenesis of many bone diseases such as osteoporosis remains, however, incompletely understood. Osteoporosis is defined as a loss of normally mineralized bone. Bones are structurally weak because of a loss of trabecular bone, cortical porosity, and reduced thickness of cortical bone (Fig. 17-7). In states of low bone turnover, the rate of

Fig. 17-5. Osteopetrosis. The medullary spaces of the bone do not contain fibrous tissue or hematopoietic marrow cells but are filled with bone corresponding to primary spongiosa.

Fig. 17-6. Amelia. Extremities have not formed.

Fig. 17-7. Osteoporosis. Cortical bone and trabeculae are thin.


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bone formation is normal to reduced and small amounts of osteoid are present. Osteoid surface areas are decreased, and the surface of the bone trabeculae appears smooth and " inactive" (Fig. 17-8). Bone resorption studies indicate decreased resorption surface areas and number of osteoclasts. In high-turnover osteoporosis, the osteoid surface areas covered with osteoblasts are increased but the width of the osteoid is normal (Fig. 17-9). Bone resorption indices point to an increased bone resorption. Osteomalacia and rickets are diseases that result from defective mineralization of the trabecular and cortical bone matrix. Rickets is a disease of childhood in which defective mineralization occurs at the growth plate, thus inhibiting normal bone growth. It usually is related to vitamin D defi-

ciency. Typically the epiphyseal growth plate is disorganized and widened (Fig. 17-10). Affected bones are weak and tend to become deformed (bowlegs). Other features of rickets, such as craniotabes, rachitic rosary (thickening of the costochondral junction), pigeon breast, and lumbar lordosis, also are related to basic defects in bone mineralization and growth. Osteomalacia is characterized by softening of bones, which typically contain more osteoid than normal (Fig. 17-11). Inadequate mineralization of the osteoid, accompanied by inadequate reabsorption and remodeling of the peripheral rim of the trabeculae, results in their widening and structural weakness. Such bones tend to be less resistant to stress and are prone to deformities and fractures. Osteomalacia is a major component of renal osteodystrophy, which typically is found in patients with end-stage kidney disease. The affected bones show decreased mineralization of the os-

Fig. 17-8. Osteoporosis, inactive. The surface of the bone trabeculae is smooth and covered with flattened inactive cells. Very little or no osteoid may be found.

Fig. 17-9. Osteoporosis, active. The trabeculae are rimmed with osteoid, lined by osteoblasts.

Fig. 17-10. Rickets. Epiphyseal growth plate is disorganized and widened.

Fig. 17-I I. Osteomalacia. Thick seams of osteoid cover the calcified core of bone trabeculae.


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teoid but increased osteoclastic bone resorption and fibrosis of the medullary spaces (Fig. 17-12).

Hyperparathyroidism Hyperparathyroidism is an important cause of metabolic bone changes. Parathyroid hormone stimulates both osteoblasts and osteoclasts, which leads to accelerated remodeling of the bone and loss of minerals from the osteon (Fig. 17-13). The bone marrow shows fibrosis. Focal aggregates of„multinucleated osteoclasts may result in lytic lesions (osteitis fibrosa cystica) or tumors ( " brown tumors of hyperparathyroidism"). These lesions may resemble giant cell tumors of bones (Fig. 17-14). Weakened bones tend to fracture or bleed, and these secondary changes are accompanied by additional histologic changes that reflect replacement of damaged bone and new bone formation. For unknown reasons hyperparathyroidism affects the cortical and subperiosteal bone more than the trabeculae of the cancellous bone. Early diagnosis of primary hyperparathyroidism and successful treatment of chronic renal diseases have reduced the occurrence of severe

forms of renal osteodystrophy and osteitis fibrosa cystica, and brown tumors of hyperparathyroidism rarely are seen today. Minor bone changes similar to those seen in other forms of osteomalacia are, nevertheless, often encountered. Such changes respond well to treatment of the primary disease.

Paget Disease of Bone Paget disease of bone, also known as osteitis deformans, is a chronic osteolytic and osteosclerotic bone disease of uncertain cause. It may involve one or more bones, causing pain, progressive deformities, fractures, and arthritis. It is a common disease that affects 3 percent of the white population over 40 years of age. The incidence of Paget disease increases with age. Most patients (80 percent to 90 percent) are asymptomatic. Deformities of weight-carrying bones of the extremities are the most common feature of polyostotic Paget disease, which also tends to involve the hematopoietically active flat bones. Involvement of the skull is especially common in monostotic Paget disease. Involved bones appear sclerotic and dense (Fig. 17-15).

Fig. 17- 12. Renal osteodystrophy. Trabeculae are rimmed with prominent osteoid, and the medullary spaces contain increased amounts of dense fibrous tissue and scattered osteoclasts.

Fig. 17-13. Hyperparathyroidism. Osteoblasts form an almost continuous line along the thick seams of osteoid rimming the bone trabeculae. There also is marrow fibrosis, and groups of osteoclasts are seen in lacunae of bone.

Fig. 17-14. Hyperparathyroidism. Brown tumor of hyperparathyroidism is composed of numerous multinucleated osteoclasts.

Fig. 17-I5. Paget disease of bone. The bone appears sclerotic and dense.


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A

B

C

Fig. 17-16. Paget disease of bones. A, Active resorptive phase is characterized by increased osteoclastic activity. B, Active osteogenic phase is characterized by new bone formation. C, In sclerotic phase the bone has prominent seams that impart to it a jigsaw mosaic pattern.

Paget disease may be divided into three phases: (1) active resorptive phase, (2) active osteogenic phase, and (3) quiescent sclerotic phase (Fig. 17-16). In the active resorptive phase the bone marrow is replaced by richly vascular, loose connective tissue and congregations of osteoclasts along the existing trabeculae and within the cortex. The osteoclasts are morphologically abnormal and many are very large, containing up to 100 nuclei. In the second phase osteoblastic activity is triggered. Repeated episodes of bone removal, remodeling, and new bone formation finally result in a jigsaw mosaic pattern, which is the hallmark of sclerotic Paget disease. Crystal-induced Arthritis Crystal-induced arthritis refers to a group of metabolic disorders that are characterized by deposition of crystals in and around the joints. Arthritis may result from the deposition of monosodium urate, calcium pyrophosphate, and basic calcium phosphate (hydroxyapatite) and calcium oxalate. Gout, which is caused by deposition of urate crystals, is the most important and most common of these diseases, affecting approximately 0.5 percent of the population. Urate crystals accumulate in the synovial fluid, eliciting an intraarticular inflammation. During an acute attack uric acid crystals typically are seen in the cytoplasm of polymorphonuclear leukocytes obtained from the inflamed joint. As the disease progresses deposits of urates form masses ( " tophi " ) that erode the adjacent bone and extend into the soft tissues.

In chronic tophaceous gout, tophi may be seen not only around the joints but also in the subcutaneous tissue, tendons, earlobes, and even in some internal organs such as the kidneys. Histologically tophi are characterized by deposits of uric acid crystals with a central core of proteinaceous material (Fig. 17-17). Crystal deposits are surrounded by granulation tissue that often contains foreign body multinucleated giant cells (Fig. 17-18). Because uric acid is soluble in water that contains fixatives, it is washed out during tissue processing. However, in tissues fixed in absolute alcohol, uric acid crystals appear birefringent when examined under polarized light. Pseudogout, which is caused by deposition of calcium pyrophosphate crystals in articular cartilage, synovium, ligaments, menisci, and intervertebral discs, resembles gout. In contrast to gout, most patients have a short history. In acute phases the disease evokes an acute inflammatory response followed by a chronic inflammation. Challdike deposits are seen in chronic stages of the disease. These deposits are composed of typical biaxial crystals. Ochronosis, also known as alkaptonuria, is an inborn error of metabolism that is marked by a deficiency of homogentisic acid oxidase. Polymers of homogentisic acid accumulate in connective tissue, particularly cartilage, and cause grossly visible blue-black discoloration. In histologic slides these deposits appear brown (Fig. 17-19). Homogentisic acid interferes with the normal metabolism of cartilage, which becomes brittle and easily abraded from the joint surface, which


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Fig. 17-17. Gout. Tophus appears as a soft-tissue mass.

Fig. 17-18. Gout. Tophus consists of deposits of uric acid surrounded by granulation tissue that contain foreign body giant cells.

Fig. 17-19. Ochronosis. Polymers of homogentisic acid appear as brown material in the connective tissue.

Fig. 17-20. Osteonecrosis of the head of femur. The necrotic bone appears discolored and is demarcated from surrounding normal bone.

leads to joint dysfunction. Severe spondylosis with chondrocalcinosis of intervertebral disks and degenerative arthropathy of weight-carrying joints develops at an early age.

blood vessels. In the head of the femur the necrotic area usually appears triangular, with a broad subchondral base and the apex pointing inside (Fig. 17-20). The articular cartilage may be intact because it receives nutrients from the synovial fluid.

Osteonecrosis Osteonecrosis, also known as aseptic or avascular necrosis, is

a term used to describe bone necrosis that occurs in many sites but which most often is found in the femoral head of the elderly. Many predisposing factors have been identified, including systemic, metabolic, and autoimmune diseases; drugs; and hormones. In most instances the exact cause cannot be found and the condition is considered to be idiopathic. Corticosteroids are the most common identifiable cause of osteonecrosis in younger persons. Treatment of endstage kidney disease by xenotransplantation and trauma is another common cause. Morphologically the bone shows typical signs of ischemic necrosis. The infarct usually involves the medulla and the bone marrow. The medullary bone and the bone marrow often are affected, sparing the cortex that receives blood from periosteal

Degenerative Joint Disease Degenerative joint disease, also known as osteoarthritis, is a common noninflammatory disease of movable joints that is characterized by degeneration of articular cartilage and adjacent bone and new bone formation. Osteoarthritis may be classified as primary, or as idiopathic and secondary when it is related to identifiable causes. The pathologic changes include a variety of degenerative changes, associated with destruction of the bone and joint, and reparatory changes (Diagram 17-1). These changes typically include fragmentation of cartilage, proliferation of chondrocytes, remodeling of tidemark, subchondral pseudocysts, eburnation, subchondral bone sclerosis, and focal necrosis of subchondral bone and osteophytes (Fig. 17-21).


36 2

Diagram I7-I. Possible insults to joint structure and function are numerous and result in a high cumulative prevalence of joint disorders.

B

A

Fig. 17-21. Degenerative joint disease. A, Degeneration of cartilage leads to denuded articular surface areas. B, Fragmentation of cartilage with proliferation of chondrocytes leads to remodeling of the tidemark.


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I NFLAMMATORY DISEASES Inflammatory diseases of bones and joints include infections of the bone (osteomyelitis), infections of the joints (infectious arthritis), and immune-mediated inflammatory diseases of the joints, such as rheumatoid arthritis.

Infections of Bones and Joints Infections of bone and joints may occur in an isolated form or together. Osteomyelitis may spread into the joint and cause arthritis, and the primary infection of the joint may spread into the underlying bone. Infectious arthritis may be caused by viruses, bacteria, or fungi. Viral arthritis usually is a short-lived acute infection that heals spontaneously and leaves no consequences. Arthritis is a common feature of human immunodeficiency virus (HIV) infection, and the HIV virus may be isolated readily from the affected joints. Epstein-Barr virus infection typically is associated with arthritis. The pathologic findings are nonspecific and include synovial edema, chronic infiltrates of lymphocytes, and mild hyperplasia of synovial cells. Bacterial arthritis maybe caused by a variety of pathogens, including Streptococcus and Staphylococcus species, Neisseria gonorrhoeae; spirochetes such as Treponema pallidum and Borrelia burgdorferi; and mycobacteria such as Mycobacterium tuberculosis. Depending on the causative agent, the inflammatory response may be mediated by neutrophils or macrophages and lymphocytes, which may form granulomas (Fig. 17-22). Chronic granulation tissue forms a layer, known as pannus, which also leads to destruction of the cartilage and adjacent bone and formation of intraarticular free bodies ( " mice" ) (Fig. 17-23). Destructive lesions lead to ankylosis and deformities of the joint. Osteomyelitis typically results from bacterial infections that may reach the bone by blood-borne means, from adjacent infected joints or soft tissues, or as a result of a bone fracture or bullet wound. Staphylococcus aureus is the most common pathogen, accounting for more than 80 percent of all

Fig. 17-23. Tuberculous synovitis. Articular surface is covered with grapelike bodies ("rice bodies").

cases that are unrelated to bone fracture. Mixed infections are especially common in posttraumatic osteomyelitis complicating open fractures or bullet wound. Morphologic changes in bones affected by osteomyelitis reflect its etiology and pathogenesis. Staphylococcus aureus tends to produce abscesses and cavitary lesions, which may be medullary or subperiosteal (Fig. 17-24). Deep-seated abscesses form sinus tracts lined by granulation tissue that does not heal (Fig. 17-25). The bone fragments generated in this process remain inside the cavity of the abscess and are known as "sequestrum:" Reactive bone sclerosis forms around the abscess, corresponding to the pseudocapsule of a chronic ab-

Fig. 17-22. Tuberculous arthritis. Pannus infiltrated with mononuclear cells covers the articular cartilage.

Fig. 17-24. Osteomyelitis. Infection has caused massive destruction of the bone shaft and has extended into the surrounding soft tissue.


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scess of soft tissues or parenchymal internal organs. Such a walled-off abscess is called a Brodie abscess. Sclerotic bone surrounding a sequestrum-containing abscess cavity is referred to as " involucrum." Extensive new bone formation results in complete obliteration of medullary spaces and high-density osteosclerotic lesions (Fig. 17-26). Chronic osteomyelitis leads to deformities of the skeleton. Since the advent of modern chemotherapy, deformities, such as severe gibbous kyphoscoliosis (Pott disease), that result from tuberculosis of the spine are rare (Fig. 17-27).

Fig. 17-25. Osteomyelitis. Granulation tissue forms between the bone trabeculae in response to persistent infection.

Noninfectious Arthropathies Noninfectious arthritis and spondylitis are common diseases that often are accompanied by other systemic symptoms. The most important among these diseases is rheumatoid arthritis, which is a systemic, presumably autoimmune, chronic disease that also involves the soft tissues, muscles, heart, and lungs. The disease is accompanied by a set of immunologic disturbances reflected in positive serologic tests such as the test for rheumatoid factor. The groups of chronic arthritides that do not have positive immunologic test results are, in contradistinction to rheumatoid arthritis, termed seronegative. This group includes diseases such as ankylosing spondylarthritis, Reiter syndrome, psoriatic arthritis, enteropathic arthritis, and some less common diseases. Rheumatoid arthritis begins as a slowly evolving but persistent chronic inflammation that may lead to significant deformities of joints (Fig. 17-28). The inflamed synovium is edematous and is infiltrated with lymphocytes and plasma cells (Fig. 17-29). The infiltrates are most prominent around the blood vessels, which are increased in number and often show signs of endothelial proliferation and fibrinoid necrosis. With time the synovium forms a cover over the joint surfaces ( " pannus " ). Hypertrophic synovitis typical of advanced rheumatoid arthritis leads to erosion of the joint surfaces. It may obliterate the entire cavity and cause ankylosis ( Diagram 17-2). Hyperplastic synovium forms hypervascular fronds that are infiltrated with lymphocytes, plasma cells, and macrophages. As a result of foci of necrosis and mechanical trauma, pannus tends to fragment and form loose intraarticular bodies ( " rice bodies") (Fig. 17-30). All of these changes are associated with joint deformities, reduced mobility, and often complete loss of joint function and ankylosis. Rheumatoid arthritis is a systemic disease that may affect many internal organs. Nodules form in the subcutaneous tissue. These nodules consist of a central area of fibrinoid

Fig. 17-26. Chronic osteomyelitis. The bone appears sclerotic.

Fig. 17-27. Tuberculosis of spine (Pott disease). Destructive lesion of vertebral bodies may result in kyphoscoliosis.

Fig. 17-28. Rheumatoid arthritis. Prominent deformities of hands are features of long-lasting disease.


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A

B

Fig. 17-29. Rheumatoid arthritis. A, Synovium is cellular and covered with fibrin. B, Prominent synovial vessels are surrounded by plasma cells and lymphocyte.

Diagram 17-2. Complex multifactorial pathogenesis of rheumatoid arthritis involves genetic susceptibility and environmental influences.


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A

B

C

Fig. 17-30. Rheumatoid arthritis. A, Hyperplastic synovium and a rheumatoid nodule removed from joint. B, Chronic synovitis results in the formation of fibrovascular structures lined on their surface by synovial cells. C, Pannus invading the subchondral bone.

Fig. 17-31. Rheumatoid nodule. The subcutaneous nodule is composed of a central zone of fibrinoid necrosis surrounded by palisaded histiocytes.


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necrosis surrounded by palisaded macrophages and lymphocyte or plasma cells (Fig. 17-31). Vasculitis that involves small vessels occasionally is seen in patients with a high titer of immunoglobulin M (IgM). Large vessel disease is even less common but may involve internal organs, which show signs of infarction. Rheumatoid nodules, fibrosis, and chronic inflammation also may occur in internal organs, most notably in the lungs of coal workers (Caplan lesion).

NEOPLASMS

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Neoplasms of bones are rare, accounting for only 0.2 percent of all tumors of internal sites. Nevertheless, they are an important cause of morbidity and mortality, especially in children and young adults. Although neoplasms of bone are quite heterogeneous, overall they tend to affect younger persons, with a peak incidence under the age of 20 years. Long bones more often are involved than short bones, and the long bones of legs are the most common site. Malignant neoplasms are distinctly rare in short bones. Primary tumors of joints are even less common than bone tumors. The evaluation of patients with bone tumors is based on an interdisciplinary approach that includes a clinicianorthopedic surgeon, a radiologist, and a pathologist. Clinical and radiologic data are essential for proper pathologic diagnosis, which should never be based on microscopic findings alone. Typical anatomic locations of the most common bone tumors and their radiographic features are shown in Diagram 17-3.

Benign Bone-forming Tumors Osteoma is a benign slow-growing tumor that is composed

of mature bone (Fig. 17-32). Clinical symptoms are rare except in tumors that compress nerves or cause facial deformities. Osteoid osteoma is a benign bone-producing tumor that may occur at any age but most often is seen in the second and third decades. Males are affected significantly more often than females. This tumor most often is located within the cortex of long bones or immediately beneath it (Fig. 17-33).

Fig. 17-32. Osteoma. The tumor is composed of mature bone.

Diagram 17-3. Anatomic locations of common benign and malignant bone neoplasms. Left, proximal end of tibia. Right, distal end of femur. (Modified from Madewell JE, Ragsdale ED, Sweet DE: Radio) Clin North Am 19:715, 1981.)


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It consists of a small nidus of bone-forming cells surrounded by sclerotic bone. The nidus, which by definition measures only 1 to 2 cm in diameter, is composed of osteoblasts, interlacing trabeculae of woven bone and osteoid, blood vessels, and occasional osteoclasts. Osteoblastoma is a benign bone-producing tumor that accounts for 1 percent of all bone neoplasms. It more often is found in males than in females and most often is located in

the posterior parts (transverse and spinous processes) of the vertebrae. Radiologically it is a mixed osteolytic and osteoblastic lesion that may cause cortical thinning and eventually cortical expansion (Fig. 17-34). On gross examination osteoblastoma appears as a granular, hemorrhagic, gritty mass that is sharply demarcated from the normal bone. Histologically it is indistinguishable from osteoid osteoma. The tumor contains numerous interlacing trabeculae of osteoid

A

B

C

Fig. 17-33. Osteoid osteoma.A, Radiograph shows a dense blastic reaction of cortex with a small lucent area. B, Nidus of osteoid osteoma measures approximately I cm in diameter and has a finely granular lattice-like appearance. C, Bone spicules lined by osteoblasts are formed within fibrovascular stroma.

A

B

Fig. 17-34. Osteoblastoma. A, Radiograph show an osteolytic lesion with foci of calcification. B, Osteoblasts line newly formed spicules of osteoid and bone.


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and woven bone that are lined by a nearly continuous population of osteoblasts, which may be likened to soldiers in a row or crows on a fence. The stroma is highly vascular and there are scattered osteoclasts. No other elements are seen, although recently there have been reports that small foci of cartilage occasionally are found. Osteoblastomas are benign tumors but a rare aggressive variant may appear occasionally. These tumors are considered to be low-grade osteosarcomas and are treated accordingly. .

Malignant Bone-forming Tumors Osteosarcoma is a complex family of biologically diverse

pathologic entities that share a single histologic finding: the production of bone or osteoid by malignant cells. On the basis of clinical and pathologic features, conventional ( "classic" ) osteosarcomas may be separated from several variant forms. Variant forms of osteosarcoma have a different prognosis from that of conventional osteosarcoma and need to be recognized. Conventional osteosarcomas account for 65 percent to 75 percent of all osteosarcomas. Although they may occur in any age group, most tumors are diagnosed in persons between 10 and 30 years of age. Males are affected twice as often as females. Fewer than 1000 cases of conventional osteosarcoma are diagnosed yearly. Although any bone may be involved, most tumors arise in the distal part of the femur and in the proximal parts of the tibia, fibula, femur, and radius. Approximately 90 percent of tumors arise in the metaphysis, and 10 percent arise in the diaphysis. Epiphyseal involvement

almost always represents secondary extension or metastasis from a metaphyseal primary tumor. Radiologically osteosarcoma presents as a highly aggressive and destructive lesion that has a variegated appearance on radiograph (Fig. 17-35). Most lesions contain both radiolucent and radiopaque areas, and extension into the soft tissues is common. There are, however, no specific diagnostic radiologic features or features that would have special prognostic significance. The gross and microscopic appearance of conventional osteosarcoma is highly variable and depends on its histologic composition. Lesions that are rich in osteoid and bone appear dense, granular, and sclerotic, and their color varies from yellow-brown to ivory-white. Tumors that contain significant amounts of cartilage have an overall gray-blue, lobulated, chondroid appearance. If little matrix is present, the tumors appear gray-tan; hemorrhage may account for the brownish-red mottling of some lesions. Microscopically osteosarcoma is composed of atypical spindle-shaped cells (Fig. 17-36). The production of osteoid or bone by malignant cells represents the single diagnostic criterion of conventional osteosarcoma. Osseous matrix may be the dominant histologic finding or it may be quite inconspicuous. Cartilage and collagenous stroma also may be present, and accordingly tumors may be further subclassified as osteoblastic, chondroblastic, or fibroblastic. Most osteosarcomas represent a mixture of these three patterns. Histologic subclassifications are impractical and have no clinical value. Multidisciplinary protocols used in the treatment of osteosarcoma have dramatically improved the long-term survival

B A

Fig. 17-35. Osteosarcoma, conventional. A, MRI shows a predominantly blastic lesion extending into soft tissue. B, The mass in the distal femur has destroyed the cortex, extending into the soft tissue. Whitish areas represent the sclerotic part of the tumor. Medullary cavity contains a "skip" metastasis that appears as a whitish nodule.


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A

B

C

D

Fig. 17-36. Osteosarcoma. conventional. Tumors may show several histologic patterns. A, Hypercellular tumor forms only a few bone spicules. B, Osteoblastic tumor shows extensive new bone formation. C, Chondroblastic tumor contains abundant cartilage. D, Fibroblastic osteosarcoma consists of heterogeneous spindle-shaped cells with focal bone formation.

of patients with conventional osteosarcoma from less than 20 percent in the past to approximately 80 percent as reported in most recent studies.

Osteosarcoma Variants Parosteal osteosarcoma is a low-grade malignant tumor that arises from the surface of bones. It most often occurs in the third to fifth decade of life, and women are affected twice as often as men. It is almost exclusively a disease of long bones and most often affects the posterior aspect of the distal femur (Fig. 17-37). Radiologically it appears as a radiopaque, lobulated mass that seemingly is applied to the surface of the involved bone. The tumor generally grows along the surface of the bone without involving the medullary cavity. On gross examination the tumor arises from the bone surface and tends to be large. Microscopically, parosteal osteosarcoma is composed of relatively innocuous spindle-shaped fibroblastic cells that produce well-formed lamellar bone spicules. With appropriate treatment, the long-term survival rate is over 90 percent. Periosteal osteosarcoma has a peak incidence in the second and third decades of life. Men are affected more often than women. This tumor most often arises in the diaphysis and

metadiaphysis of long bones, especially the femur and the tibia. Radiologically it may involve part of the surface or may extend into the soft tissues in a spiculated "sunburst " pattern (Fig. 17-38). Like parosteal osteosarcoma, this tumor also may circumferentially envelop tubular bones from which they have arisen. On gross examination the tumor is located in the metaphysis or metadiaphysis; it has a broad base, with fusiform elevation of the periosteum. Microscopically it has the features of high-grade chondroblastic osteosarcoma. The five-year survival rate is 50 percent. Intraosseous well-differentiated osteosarcoma is a rare variant that has a peak incidence in the third decade and affects women more often than men. The tumor has a strong predilection for the long bones of the extremities, especially the metaphysis, but it also may occur in the diaphysis. Radiologically it has no distinct features and may simulate fibrous dysplasia or desmoplastic fibroma. Grossly it contains both osteoblastic and osteolytic areas and often is confined to the medullary cavity (Fig. 17-39), although older lesions may extend beyond the cortex. The tumor shares the innocuous histologic features of parosteal osteosarcoma. Microscopically it is composed of relatively bland fibroblastic cells that form mature bone spicules, resembling parosteal osteosarcoma. It has a favorable prognosis.


371 A

B

B A

C

C

Fig. 17-37. Parosteal osteosarcoma. A, Radiopaque lobulated masses are found on the surface encircling the long bone. B, Longitudinal section of the femur shows a superficial tumor attached to the posterior side of the bone. C, Bland spindleshaped cells surround lamellar bone spicules.

Fig. 17-38. Periosteal osteosarcoma. A, Radiograph shows a spiculated surface mass that has a "sunburst" appearance. B, Surface tumor arising from the shaft of the femur has a broad base. The medullary cavity is intact. C, Tumor cells form cartilage. Nuclei show high degree of atypia.

A B

Fig. I7-39. Intraosseous well-differentiated osteosarcoma. A, The medullary cavity contains tumor tissue that is partially sclerotic. B, Bone spicules are associated with innocuous fibroblastic cells.


37 2

A

B

C

D

Fig. 17-40. Telangiectatic osteosarcoma. A, Radiograph shows an invasive tumor with prominent cystic areas. B, Multiple cystic areas involving the proximal metaphysis of the bone resected after chemotherapy. C, Large hemorrhagic mass in the distal epimetaphysis of the femur has destroyed the cortex and extended beyond the confines of the bone. D, High-grade osteoblastic cells are surrounded by cystic dilated vascular spaces and extravasated blood.

Telangiectatic osteosarcoma has the same clinical features as conventional osteosarcoma but differs in that it is cystic and hemorrhagic and may resemble aneurysmal bone cyst (Fig. 17-40). Microscopically the tumor is composed of highgrade osteoblastic cells that produce little osteoid and are surrounded by prominent dilated blood vessels.

Benign Cartilage-forming Tumors Osteochondroma is the most common benign cartilaginous tumor of bones, accounting for approximately one third of all benign bone neoplasms. Most often it is found in children and adolescents. It usually is located in the metaphysis of long bones, growing away from the nearest joint. On gross examination the tumor apparently arises from the cortex and may be sessile or pedunculated. The lesion consists predominantly of cancellous bone that is covered with a cartilaginous cap (Fig. 17-41). Histologically the lesion is composed of ma -

ture bone and cartilage and is not resected unless it causes compression, fracture, or other complications. Enchondroma is a benign cartilaginous tumor of short bones of the hand and foot of adults. When tumors are multiple and unilateral, the disorder is referred to as Oilier disease. If tumors are multiple and are associated with angiomas of soft tissues, the condition is called Maffucci syndrome. Solitary enchondroma is the most common of all tumors that occur in the short tubular bones of hands. Enchondromas typically are located, in order of decreasing frequency, in bones of the fingers, metacarpal bones, phalanges of toes, and metatarsal bones. Tumors arise from the medullary cavity, extending the bone longitudinally, expanding it, and causing cortical thinning. Histologically the tumors consist of hyaline cartilage of variable cellularity. There often are numerous binucleated chondrocytes with nuclei larger than the nuclei of mature lymphocytes (Fig. 17-42). Finely dispersed chro-


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A B

Fig. 17-41. Osteochondroma. A, The lesion is composed of cancellous bone covered with a cartilaginous cap. B, A cartilaginous cap covers the cancellous bone. .

matin and nucleoli are seen, but mitoses are not apparent. These tumors do not metastasize but may recur after curettage. Conservative treatment is recommended because only a few tumors that have metastasized have been reported. Periosteal chondroma is a rare, benign, slow-growing, cartilaginous tumor that arises from the surface of a bone under the periosteum. Like enchondromas of the hand and feet, its histologic features may be alarming, but its behavior is benign. The most common location is the metaphyseal region of long tubular bones, such as the humerus and femur, proxi mal tibia, and phalanges of fingers (Fig. 17-43). Radiologically the lesion typically is small (1 to 3 cm in diameter) and saucer-shaped on the surface of the bone with a dense rim of reactive bone tissue. The lesion usually protrudes into the soft tissue but is well delimited by the periosteum, which may form a thin eggshell ossification around it. On gross examination periosteal chondroma is a lobulated cartilaginous nodule surrounded by a rim of bone. Histologically it may appear as an innocuous proliferation of hyaline cartilage, but it is common to find binucleated cells and enlarged nuclei with finely dispersed chromatin. This histologic pattern is similar to that of a low-grade chondrosarcoma. The diagnosis is based on typical radiologic findings, and the histologic findings should not be a cause for alarm because the tumor is invariably benign. Nevertheless, it should be distinguished from periosteal chondrosarcoma and periosteal osteosarcoma, both of which show much more pronounced nuclear atypia. Chondromyxoid fibroma is a rare, locally aggressive but benign tumor of bone that accounts for less than 0.5 percent of benign bone tumors. It may occur in any age group but is more common in the second and third decades of life. The most common sites of involvement are the metaphyses of long bones, proximal tibia and fibula, and distal femur, which

Fig. 17-42. Enchondroma. The tumor is composed of cartilaginous cells that show mild nuclear variation.

is the site of origin of approximately one half of all cases. Radiographically the lesion has an eccentric radiolucent area surrounded by a sclerotic rim of dense bone, which imparts a geographic appearance (Fig. 17-44). In contrast to other cartilaginous tumors, chondromyxoid fibromas rarely contain calcifications. Tumor may destroy the cortex, but generally it is well delimited by the periosteum. On gross examination the tumor is glistening, myxoid, lobulated, and cartilage-like, and in resected specimens it is surrounded by a rim of dense bone. Microscopically the tumor contains lobules of myxoid tissue surrounded by condensation of cells at the periphery of the lobulated areas. The myxoid areas are poorly cellular, containing stellate, triangular-shaped, spindle-shaped, or round cells Hyaline cartilage differentiation is not seen even though some cells resemble chondroblasts. At the periphery of lobules there is condensation of


37 4

B

A

C

Fig. 17-43. Periosteal chondroma. A, Radiograph of the posterior surface of distal femur shows a well-delineated nodule that has a saucer-like shape at the base and a rim of peripheral calcified material. B, The tumor is composed of cartilage, which focally has lacunae with two nuclei. C, Cartilage cells show signs of atypia.

A

B

Fig. 17-44. Chondromyxoid fibroma of bone. A, Tomogram of the elbow shows a lytic lesion surrounded by a sclerotic border. B, The tumor consists of lobulated cartilaginous tissue enclosed by thick sclerotic rim of bone. C, Tumor cells are arranged into lobules that have less cellular central areas and cellular periphery. C


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A

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Fig. 17-45. Chondroblastoma. A, Epiphysis of femur contains a lucent but demarcated lesion. B, Tumor is composed of small roue chondroblasts. C, Chondroblasts are surrounded by amorphous material ("chondroid").

medium-sized cells, many of which resemble chondroblasts. Some osteoclast-like giant cells are seen, but mitoses are rare. Immunohistochemically the cells are positive for S-100 proteins, which indicates their cartilaginous nature. Tumors are treated by block resection because curettage alone is accompanied by an 80 percent recurrence rate. Chondroblastoma is a rare, benign, cartilaginous tumor that accounts for 1 percent of benign bone tumors. It may occur at any age but most often it is diagnosed in the second decade of life. It typically occurs in the epiphyses of long bones but extends into the metaphyses as it grows. Radiologically the lesion is eccentric in 75 percent of cases. It has a geographic pattern of bone destruction with a sclerotic rim of dense bone at the periphery, consistent with the slow growth of the tumor over prolonged periods (Fig. 17-45). Grossly the lesion consists of reddish-brown hemorrhagic tissue, with occasional small calcifications. Microscopically the tumor consists of chondroblasts, islands of cartilage, giant cells, and calcifications. The chondroblasts are polygonal or round cells with indented or grooved nuclei, without nucleolus and abundant light tan–pink cytoplasm. These cells stain positive for S-100 protein. Mitotic figures are found in most tumors and range from 1 to 3 per 10 high-power fields. Nuclear atypia and focal necrosis may be found, but these changes alone do not imply malignancy. Cartilage is found in the form of small islands but appears as ill-defined amorphous pink material that may resemble osteoid. It contains collagen but is depleted of proteoglycans and is referred to as " chondroid." Giant cells, which may be sparse or abundant, represent osteoclasts. Calcifications are of two types: small, irregular, and ill-defined; or lacy, " chicken wire " type, i mparting to the lesions a honeycomb appearance. Ossification that simulates osteoblastoma is found in 5 percent of lesions. Aneurysmal bone cyst formation is a common secondary phenomenon that might be associated with a higher degree of recurrences. Most tumors are benign and respond

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well to conservative management with curettage. Recurrences are expected in 15 percent of cases. Metastasizing malignant chondroblastomas are extremely rare.

Malignant Cartilage-forming Tumors Chondrosarcoma is the second most malignant bone tumor. It is classified as central (medullary) if it is located in the medullary cavity or peripheral (juxtacortical) if it is found on the surface of the bone. Microscopically it is categorized as classic chondrosarcoma or as chondrosarcoma variants . Chondrosarcomas may arise de novo or as a secondary malignancy in a preexisting cartilage lesion, such as enchondromas of Oilier disease. Chondrosarcomas occur mostly in adults, generally those between 20 and 70 years of age. The most common sites of involvement are the pelvis, femur, scapula, humerus, and ribs (Fig. 17-46). Radiographic findings are typical. Scattered calcifications, described as punctate, annular, popcorn-like, stippled, and so on, are indicative of cartilaginous tumors but do not help in distinguishing benign from malignant tumors. Classic chondrosarcoma is the most common type of this malignancy. On gross examination the tumors have a glistening, lobulated cartilaginous appearance irrespective of their intramedullary or surface location. As the tumors grow, they tend to compress tissues or invade and trap adjacent structures. Microscopically chondrosarcomas may be composed of morphologically benign cells or apparently malig-


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Fig. 17-46. Chondrosarcoma. A, Humerus shows extensive diaphyseal and metaphyseal involvement with scalloping of endosteum. B, Cartilaginous mass originates from the surface of ilium.

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nant and undifferentiated cells (Fig. 17-47). Histologic grading of lesions, which usually is done on a scale from 1 to 3, is an important part of the evaluation of all cartilaginous tumors. Low-grade lesions are made up of hyaline cartilage showing sparse cellularity and rare lacunae with binucleated cells. The nuclei of tumor cells are dark, round, and not larger than the nuclei of lymphocytes. Higher grade lesions are more cellular and are composed of tumor cells that have larger nuclei with finely dispersed chromatin and occasional nucleoli. There is increased variation in the size and shape of nuclei, some of which are spindle-shaped, vesicular, or bizarre. The number of lacunae with binucleated cells is increased. High-grade lesions show nuclear atypia, pleomorphism, and mitotic activity. Two or more mitoses per 10 highpower fields are found in grade 3 lesions. Grade 1 lesions have an excellent prognosis and may be cured by local treatment, in contrast to grade 3 lesions, which tend to metastasize and have a 10-year survival rate of 55 percent. Chondrosarcoma variants include (1) dedifferentiated chondrosarcoma, (2) mesenchymal chondrosarcoma, and (3) clear cell chondrosarcoma. Dedifferentiated chondrosarcoma is a rare tumor that accounts for 1 percent to 2 percent of malignant bone tumors. It has the worst prognosis of all chondrosarcomas and invariably is considered to be fatal. Most tumors occur in the elderly and most often are located in the pelvis and femur. Radiologically the tumors are speckled like other cartilaginous tumors, but they also have a large lytic component and extend outside the bones. On gross examination they are large infiltrative tumors, with variable foci of obvious cartilage. Histologically the diagnosis is made upon finding areas of cartilage adjacent to high-grade sarcoma, which usually appears like malignant fibrous histiocytoma or unclassified spindle cell sarcoma or osteosarcoma. Despite radical surgery survival rates are dismal. Mesenchymal chondrosarcoma is a rare tumor that accounts for 0.3 percent to 0.5 percent of primary malignant

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Fig. 17-47. Chondrosarcoma. A, Grade I tumor is composed of innocuous bland cells that have nuclei the size of those of lymphocytes. B, Grade 2 tumors have enlarged nuclei, fine chromatin, and occasional nucleoli. C, Grade 3 lesions show hypercellularity and nuclear anaplasia.


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A Fig. 17-48. Mesenchymal chondrosarcoma. The tumor consists of small undifferentiated cells and foci of cartilage.

bone tumors. It has a peak incidence in the second decade, and 80 percent of all patients are younger than 40 years old; it is rare in children. Any bone may be involved. Radiologic findings are nonspecific. On gross examination the tumor is meaty, red-brown, and hemorrhagic. Histologically it consists of two components: a primitive small cell neoplasm and hyaline cartilage that either appears benign or shows features of low-grade malignancy (Fig. 17-48). The small cell component may simulate Ewing sarcoma or hemangiopericytoma. Management is surgical, although in some cases chemotherapy has been beneficial. The prognosis is poor. Clear cell chondrosarcoma is an extremely rare tumor that has a relatively good prognosis. It occurs in the epiphysis of long bone, especially the head of the femur, which is the most common location. Grossly it appears as calcified or ossified foci alternating with cartilaginous-like material enclosed within the bone but also extending into the surrounding tissues (Fig. 17-49). Microscopically it consists of clear polygonal cells with round nuclei. The stroma is scant and usually includes only fine capillaries juxtaposed to tumor cells. Osteoclastic giant cells appear in clusters or are scattered throughout the tumor. Osteoid and bone spicules may be found, together with foci of calcification. En bloc resection cures most lesions and the five-year survival rate is 85 percent.

Fibrous Lesions of Bone Fibrous neoplasms of bone include benign lesions, locally aggressive lesions, and frank malignancies. They are classified as (1) fibrous cortical defect and nonossifying fibroma of bone, (2) fibrous histiocytoma, (3) xanthoma, (4) osteofibrous dysplasia and fibrous dysplasia, (5) desmoid tumor of bone (desmoplastic fibroma), and (6) malignant fibrous histiocytoma. Some of these lesions are unique to bones, but others have the same morphology and biologic properties as their equivalents in soft tissues. Fibrous cortical defect and nonossifying fibroma are closely related entities that differ in size but histologically are iden -

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Fig. 17-49. Clear cell chondrosarcoma. A, The tumor in the head of femur shows central calcification surrounded by darker tissue. B, Tumor cells have clear cytoplasm. The blood vessels have thin walls.

tical and have a tendency to self-heal. Both lesions are found in children. They usually are asymptomatic and are discovered incidentally during radiographic examination. Radiologically, fibrous cortical defect presents as a small radiolucent defect in the cortical part of the metaphysis of long bones. Nonossifying fibroma is larger and presents as an eccentric metaphyseal, radiolucent, loculated lesion rimmed by a zone of sclerosis. Both lesions tend to involute spontaneously. On gross examination they appear yellowish to rusty brown, depending on the amount of lipid and blood-derived pigment (Fig. 17-50). Histologically these lesions are composed of bland fibroblasts and histiocytes, which may be lipid-laden and vacuolated.


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Fig. 17-50. Nonossifying fibroma. A, Metaphyseal brown tumor is rimmed by a zone of sclerosis. B, Fibroblastic cells are arranged in a storiform pattern.

Fibrous dysplasia is a relatively common benign disorder that affects children and young adults. Considered a developmental anomaly rather than a neoplasm, it consists of fibroosseous tissue replacing the normal marrow spaces. It may present in the more common monostotic form or a less common polyostotic form. Approximately two thirds of cases of fibrous dysplasia are diagnosed in persons younger than 30 years of age. Polyostotic fibrous dysplasia may be combined with cafe au lait skin spots, and endocrine dysfunction is a component of the syndrome. Radiologically fibrous dysplasia presents with typical " ground glass" lesions in the medullary cavity (Fig. 17-51). Microscopically the lesions are composed of fibroblasts intermixed with bone spicules. The trabeculae, which are composed of woven bone, come in various shapes and have been likened to Chinese letters or alphabet soup. Fibrous dysplasia requires no treatment because most lesions stop growing after puberty. Osteofibrous dysplasia, also known as ossifying fibroma, is a rare lesion of children that typically is found in the tibia and fibula. Unlike fibrous dysplasia, it arises in the cortex. On radiograph it may be purelylytic or may have a " ground glass" appearance and a sclerotic rim. Microscopically it is composed of fibroblasts, occasionally showing a storiform pattern, and spicules of bones lined by osteoblasts. No treatment is required except in cases of pathologic fracture caused by the lesion.

Giant Cell Tumor of Bone Giant cell tumor of bone is a common benign bone lesion that accounts for 21 percent of all bone tumors and is the only one that affects the epiphysis and metaphysis of long bones. With a few exceptions, giant cell tumors of bone develop after the bones stop growing, and 80 percent of patients are in the range 20 to 40 years old. Radiologically giant cell tumors present as radiolucent lesions of the epiphysis reaching the ar-

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Fig. 17-51. Fibrous dysplasia. A, Proximal tibia contains a well-demarcated lesion that has a typical "ground glass" appearance. B, Fibrous dysplasia. Fibroblasts are in direct contact with bone spicules of variable shape.


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ticular cartilage and often extending into the metaphysis. The tumor may destroy the cortex, but usually there is no or only focal sclerosis around it. Nonepiphyseal giant cell tumors are rare. On gross examination they consist of reddish-brown soft tissue filling a cystlike space inside the bone (Fig. 17-52). Aneurysmal bone cyst components may replace most of the tumor in some cases. Microscopically two components are recognized: multinucleated giant cells and mononuclear stromal cells. Stromal cells are spindle-shaped and contain a moderate amount of cytoplasm. Mitotic activity is variable. Blood vessels, foci of hemorrhage, hemosiderin, and xanthomatous macrophages are seen in varying proportions. Immunohistochemically tumor cells display macrophagerelated markers. Giant cell tumors have a tendency to recur after curettage and are considered by some authorities to be a low-grade malignancy. Malignant giant cell tumors are rare. Some malignant tumors arise after radiotherapy of benign giant cell tumors. Marrow Tumors Tumors that originate from the bone marrow include (1) Ewing sarcoma, (2) multiple myeloma and solitary plasmacytoma, (3) non-Hodgkin lymphoma, and (4) Hodgkin lymphoma. Multiple myeloma and lymphoid neoplasms are illustrated in Chapter 5. Ewing sarcoma is a malignant tumor accounting for 6 percent to 14 percent of all bone tumors. It is composed of undifferentiated small cells, the nature and origin of which has not been determined unequivocally. It is a tumor of children and young adults, with a peak incidence in the second decade. Males are affected twice as often as females, and it is distinctly

uncommon in African-Americans. In the past it invariably was fatal, but with modern therapy the five-year survival rate is 65 percent except for patients with widespread disease and distant metastases, who have a poor prognosis. Tumors of the same morphology occur in soft tissues. Ewing sarcoma most often occurs in the medulla of long bones of the extremities and in the pelvis, but it also may occur in any other bone. Radiologically it presents as an intramedullary and extramedullary growth that imparts to the bone a mottled or moth-eaten pattern (Fig. 17-53). Generally there also is a large soft-tissue component with illdefined margins. Another important feature of Ewing sarcoma is the presence of reactive bone within the medullary cavity and the periosteum, which may produce an onionskin pattern. Magnetic resonance imaging (MRI) is most useful for evaluating the extent of bone involvement. On gross examination Ewing sarcoma appears as grayish-white, soft, glistening tissue permeating the bone and typically breaking through the cortex, distending the periosteum and usually infiltrating the soft tissues. Reactive osteosclerosis may be seen in the medullary cavity with a "sunburst" form on the periosteum as it is lifted from the bone. Histologically Ewing sarcoma is composed of a monotonous population of primitive small blue cells that have round to oval nuclei and scanty cytoplasm. The nuclei have finely dispersed chromatin and small nucleoli. The cytoplasm is clear because of its high glycogen content. Atypical Ewing sarcoma is a variant that shows nuclear variation, lacks glycogen, has an increased number of mitoses, and forms neoplastic vascular structures. All forms of Ewing sarcoma have the same chromosomal changes, which are typical of this entity.

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Fig. 17-52. Giant cell tumor of bone. A, The epimetaphysis contains a hemorrhagic meaty tumor that destroys the cortex and expands the periosteum. B, Tumor is composed of multinucleated giant cells and mononuclear cells.


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Fig. 17-53. Ewing sarcoma. A, Radiograph shows a large lytic tumor in the shaft of long bone, with reactive thickenings of the cortex and laminated periosteal reaction. A large soft-tissue component is barely visible. B, The medullary cavity of the distal end of the tibia is permeated with tumor that extends into the soft tissue even though it is still covered by periosteum. C, Tumor is composed of uniform small blue cells. D, Electron microscopy shows aggregates of glycogen in the cytoplasm of tumor cells.

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Vascular Tumors Vascular tumors include benign lesions such as hemangioma, skeletal angiomatosis and lymphangiomatosis, glomus tumor, as well as malignant tumors such as hemangioendothelioma, hemangiopericytoma, and angiosarcoma. Microscopically these tumors correspond to their soft-tissue counterparts.

Miscellaneous Tumors and Tumor-like Conditions Adamantinoma of long bones is a rare low-grade malignant

tumor that shows both epithelial and mesenchymal differentiation and microscopically resembles adamantinoma of the jaw. Most adamantinomas of long bones (90 percent) have been reported in the shaft of the tibia, but they also may occur in other bones (Fig. 17-54). Radiologically the tumors have a typical appearance, which has been described as a " soap bubble " pattern because of numerous cysts rimmed by sclerotic bone. On gross examination the tumor appears lobulated and is grayish-tan because of a high content of fibrous tissue. Multiple cystlike spaces are surrounded by thick sclerotic bone, and the cortex may be scooped out or totally destroyed. Microscopically the tumor consists of epithelial nests and stroma. The epithelial cells may resemble basal or squamous cells of the skin and often are palisaded along the periphery of these nests. A fibrous dysplasia component

often is seen. Management is surgical, and the prognosis is relatively favorable. Approximately 15 percent to 30 percent of tumors recur or metastasize. Chordoma is a tumor of notochord that typically occurs in the midline of the spinal column. In major cancer treatment reference centers it accounts for 4 percent of all bone tumors. Its peak incidence is in the sixth decade. Approximately one half of the tumors are found in the sacrococcygeal region and 37 percent are at the base of the skull in the sphenooccipital region. Radiologically it presents as a destructive lesion of bone extending into soft tissue. On gross examination the tumor is grayish-white with myxoid areas and foci of necrosis and hemorrhage. Histologically the tumor is composed of round, spindle-shaped, and polygonal cells in a loose myxomatous matrix, arranged into lobules separated by strands of connective tissue (Fig. 17-55). Most cells show numerous cytoplasmic vacuoles. The vacuolated cytoplasm of physaliphorous cells, typical of chordoma, has been likened to jellyfish. Chordoma cells are positive for keratin, epithelial membrane antigen (EMA), and S-100 protein. Management is surgical, but larger lesions also require radiotherapy. The prognosis depends on the size and location of the tumor. Most tumors recur but few metastasize. Aneurysmal bone cyst (ABC) is a relatively common bone lesion of uncertain origin. It occurs in two forms: as a primary ABC arising de novo or as a secondary ABC that de -


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Fig. 17-54. Adamantinoma of long bones. A, The shaft of tibia shows extensive lytic lesions, giving it a "soap bubble" appearance. B, Bivalved segment of the tibia shows a medullary tumor that is destroying the cortex and elevating the periosteum. C, Nests of basaloid cell infiltrates are surrounded by fibrous stroma.

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Fig. 17-55. Chordoma. Over a myxoid background there are cords of large cells with vacuolated cytoplasm.

Fig. 17-56. Aneurysmal bone cyst. A, Radiograph shows an eccentric lytic lesion in the metaphysis of the distal femur. B, Hemorrhagic cyst has a thin bone capsule. C, Fibroblastic wall of the cyst contains osteoclasts grouped around a space filled with blood.


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Fig. 17-57. Eosinophilic granuloma. A, Histiocytes with vesicular nuclei are surrounded by eosinophiles. B, Birbeck granules appear as rod-shaped structures in the ectoplasm of Langerhans cells.

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Fig. 17-58. Villonodular synovitis. A, Brown tissue removed from the joint. B, Histologically, villi are composed of spindle cells and scattered hemosiderin-laden macrophages.

Fig. 17-59. Synovial chondromatosis. Numerous cartilaginous bodies were removed from the joint cavity.


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velops on a preexisting bone lesion. Primary ABC accounts for 1 percent to 6 percent of all bone lesions. Its peak incidence is in the second decade of life. The femur, tibia, and radius most commonly are involved. Radiologically the lesion is located in the metadiaphysis and appears as a blown-out eccentric lytic lesion with a sclerotic rim on the inner side and destructive cortical edge (Fig. 17-56). Grossly ABC consists of multiple hemorrhagic cysts and a solid component, which usually is not too prominent. Histologically the wall of cysts is composed of fibroblastic stroma, macrophages, and scattered osteoclastic giant cells. Management includes curettage with bone packing, but up to 40 percent of lesions recur. Malignant transformation is rare. Eosinophilic granuloma is a form of Langerhans cell histiocytosis involving bones. Proliferation of Langerhans histiocytes is accompanied by infiltrates of eosinophiles (Fig. 17-57). These histiocytes are positive for S-100 protein and contain Birbeck granules visible by electron microscope.

Tumors and Tumor-like Lesions of Joints Theoretically any component of the joint may give rise to a neoplasm, but primary tumors of the joints are quite rare. They are classified as benign or malignant. Pigmented villonodular synovitis (xanthofibroma) is a tumor-like joint lesion that occurs in several forms: (1) diffuse pigmented villonodular synovitis, (2) localized nondestructive villonodular variant, and (3) nodular giant cell tumor of the tendon sheath. The diffuse variant most often occurs in the knee joints of young persons, but other joints also may be involved. On gross examination the lesions appear as intraarticular villous brownish-yellow tissue (Fig. 17-58). Microscopically the synovial fronds are composed of ovoid cells, spindle-shaped cells, multinucleated giant cells, macrophages, and various chronic inflammatory cells, in variable proportions. Lipid-laden macrophages and hemosiderin account for the brownish-yellow color of the tissue. Slitlike spaces lined by flattened or ovoid cells that resemble normal synovial surfaces also are seen, but in some lesions solid fibrous areas predominate. Bone invasion and recurrences are encountered in the diffuse form of villonodular synovitis. Synovial chondromatosis is a rare condition that is characterized by multiple metaplastic nodules of cartilage developing in the synovium. It most often is found in the knee joints of young persons. The altered synovial fronds detach to become loose intraarticular bodies, which may fill the joint (Fig. 17-59). Histologically the nodules are composed of mature cartilage surrounded by fibrous tissue.

Further Reading Ayala AG, Raymond AK, Jaffe N: The pathologist's role in the diagnosis and treatment of osteosarcoma in children. Hum Pathol 15:258266, 1984. Bjornsson J, McLeod RA, Unni KK et al: Primary chondrosarcoma of long bones and limb girdle. Cancer 83:2105-2119, 1998. Clough JR, Price CHG: Aneurysmal bone cyst. Pathogenesis and long term results of treatment. Clin Orthop 97:52-63, 1973. Dahlin DC, Unni KK, Matsuno T: Malignant (fibrous) histiocytoma of bone — fact or fancy? Cancer 39:1508-1516, 1977. deSantos LA, Murray JA, Ayala AG: The value of percutaneous needle biopsy in the management of primary bone tumors. Cancer43:735744, 1979. Dorfman HD, Czerniak B: Bone cancers. Cancer 75:203-210, 1995. Dosoretz DE, Raymond AK, Murphy GF et al: Primary lymphoma of bone. The relationship of morphologic diversity to clinical behavior. Cancer 50:1009-1014, 1982. Greenspan A: Benign bone-forming lesions osteoma, osteoid osteoma, and osteoblastoma. Clinical, imaging, differential considerations (review). Skel Radio/ 22:485-500, 1993. Jundt G, Remberger K, Roessner A et al: Adamantinoma of long bones. A histopathological and immunohistochemical study of 23 cases. Pathol Res Pract 191:112-120, 1995. Kahn LB, Wood RM, Ackerman LV: Malignant chondroblastoma. Report of two cases and review of the literature. Arch Pathol 88:371376, 1969. Loizaga JM, Calvo M, Lopez Barea K et al: Osteoblastoma and osteoid osteoma. Clinical and morphological features of 162 cases. Pathol Res Pract 189:33-41, 1993. Maygarden SJ, Askin FB, Siegal GP et al: Ewing sarcomas of bone in infants and toddlers. A clinicopathologic report from the Intergroup Ewing's Study. Cancer 71:2109-2118, 1993. McLeod RA, Dahlin DC, Beabout JW: The spectrum of osteoblastoma. Am J Roentgenol 126:321-335, 1976. Okada K, Unni KK, Swee RG, Sim FH: High grade surface osteosarcoma: a clinicopathologic study of 46 cases. Cancer 85:1044-1054, 1999. Reed RJ: Fibrous dysplasia of bone. A review of 25 cases. Arch Pathol 75:480-495, 1963. Schiller AL: Diagnosis of borderline cartilage lesions of bone. Semin Diagn Pathol 2:42-62, 1985. Sokoloff L: Pathology and pathogenesis of osteoarthritis. In McCarty DJ, editor: Arthritis and applied conditions, ed 9, Philadelphia, 1979, Lea & Febiger. Unni KK, Dahlin DC: Premalignant tumors and conditions of bone. Am J Surg Pathol 3:47-60, 1979. Unni KK, Ivins JC, Beabout JW, Dahlin DC: Hemangioma, hemangiopericytoma, and hemangioendothelioma (angiosarcoma) of bone. Cancer 27:1403-1414, 1971. Yaw KM: Pediatric bone tumors. Sem Surg Oncol 16:173-183, 1999.




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CONGENITAL MYOPATHIES Congenital myopathies are a diverse group of diseases. They usually present early in life in the form of the so-called floppy infant syndrome, which includes a triad of adaxial weakness, hypotonia, and decreased spontaneous muscular motor activity. Some congenital myopathies are mild and become symptomatic only in later childhood, whereas others are not diagnosed until adult life. Morphologically it is possible to identify several distinct entities, some of which are listed in Table 18-1. Pathologic findings are constantly being amplified with molecular biology findings, and many congenital myopathies have been linked to specific gene defects. Central core disease, a mild proximal muscle weakness of infants and children, is characterized by specific changes in the muscle, which may be best demonstrated by enzyme histochemistry or electron microscopy (EM). Enzyme histochemistry shows that the central portion of each muscle fiber lacks oxidative enzyme activity (Fig. 18-1). By EM the central core appears as a disorganized aggregate of myofilaments. Nemaline (rod) myopathy presents in childhood as muscle weakness that predominantly involves the proximal parts of the extremities and the facial muscles. Rods, which are

thought to be derived from Z-band material of the myofibrils, may be seen in muscle fibers stained with trichrome or by EM (Fig. 18-2). Centronuclear myopathy refers to a heterogeneous group of diseases whose presenting symptom is muscle weakness, which may appear in childhood or adulthood. Axial, extraocular, and facial muscles are involved. Muscle fibers contain centrally located nuclei, occasionally with type I muscle fiber hypotrophy (Fig. 18-3). Sarcotubular myopathy describes a heterogeneous group of diseases that may present early in life or even in adulthood. The diagnosis is established by EM, which shows typical hollow tubular structures in the cytoplasm of scattered muscle fibers (Fig. 18-4).

MUSCULAR DYSTROPHIES The unsophisticated historical term dystrophy is used clinically to refer to a variety of genetic diseases that are characterized by progressive muscular weakness. Recent genetic studies have shown that such diseases may be linked to mutations of genes encoding unique structural proteins of the muscle fiber cytoplasm, cell membrane, or perimysial basement membrane (Diagram 18-1).

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Fig. 18-I. Central core disease. A, Enzyme histochemical technique for demonstrating oxidative enzymes was used to show reduced enzyme activity in the center of each muscle fiber. B, By EM the central core consists of disorganized sarcomeres.

Fig. 18-2. Nemaline myopathy. A, Many small, dark blue–stained rods are seen in some muscle cells in this Gomori trichromestained slide. B, By EM the nemaline rods appear as condensed filaments resembling Z-band material.


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Congenital Myopathies

Fig. 18-3. Centronuclear myopathy. Type I muscle fibers, which stain lighter in this slide and react for ATPase at pH 9.4, contain a central unstained region corresponding to nuclei. Type I fibers are abnormally small, and the darker type II fibers are enlarged.

Fig. 18-4. Sarcotubular myopathy. This EM photograph shows cytoplasmic tubules derived from the sarcomeres.

Diagram 18-1. Dystrophin-sarcoglycan complex of striated muscle cells consists of several proteins that are essential for muscle contraction. Dystrophin, the best known of these proteins, is linked to several other plasma membrane proteins such as dystroglycans and sarcoglycans. Deficiency of dystrophin and related proteins has been identified as the cause of muscle diseases. (© Copyright 1997 Massachusetts Medical Society, all rights reserved. From Duggan DJ et al: N Engl J Med 1997; 336: 618-24; with permission).


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Duchenne muscular dystrophy is a severe X-linked muscle disease that affects 1 in 3500 boys. It has been linked to abnormalities of the gene for dystrophin, a structural protein that links the muscle cell membrane to the contractile elements. Abnormal muscle fibers become rounded up and are recognizable in routine sections stained with hematoxylin and eosin because of their eosinophilic cytoplasm as " hyaline fibers." Muscle fiber necrosis attracts macrophages, which phagocytize dead muscle fibers (Fig. 18-5). Regeneration ensues but is unable to compensate for the muscle fiber loss. Lost muscle fibers are replaced by fibrous and fat tissue, which may even enlarge the muscles (pseudohypertrophy). Duchenne muscular dystrophy is a lethal disease. Becker muscular dystrophy, which is caused by milder alterations of the dystrophin gene, is a progressive muscle disease that affects teenagers and young adults. It is a less severe form of dystrophy, and although it has a slower downward course, it also is invariably fatal. Immunohistochemical studies with antibodies to dystrophin show a lack of immunoreactive dystrophin in the muscle of patients with Duchenne dystrophy. The muscle from Becker dystrophy patients shows patchy staining.

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Facioscapulohumeral dystrophy is a relatively mild disease that affects the muscles of the head and neck, shoulders, upper back, and arms. The affected muscles show numerous atrophic and hypertrophic muscle fibers but little necrosis or regeneration. Enzyme histochemistry techniques for demonstrating oxidative enzymes are most useful for demonstrating the abnormal muscle fibers, which appear mottled or moth-eaten because of uneven staining of their cytoplasm (Fig. 18-6). Scattered lymphocytes, which are found during ingravescent stages of the disease, are unique features of this disease that distinguish it from other dystrophies. Limb girdle dystrophy is characterized by a declining strength of muscles of the shoulder, pelvic girdles, and proxi mal limbs. Several distinct genetic diseases have been known to present in this form. The muscle biopsy shows internalization of sarcolemmal nuclei, muscle fiber atrophy, and florid compensatory hypertrophy, associated with muscle fiber splitting (Fig. 18-7). Myotonic muscular dystrophy is a multisystemic disease with a prevalence of 1 in 8000. It is linked to a mutation of a gene on chromosome 19 that shows amplification of cytosine-thymidine-guanine triplet repeats. Symptoms begin in early adult life and slowly progress over many years. Myotonia is an early symptom. Muscle biopsy shows typical atrophy of type I fibers, a multitude of internal nuclei, and ring fiber formation (Fig. 18-8).

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Fig. 18-5. Duchenne muscular dystrophy. A, In early stages of disease dead and dying fibers are phagocytized by macrophages. B, In terminal stages of the disease muscle fibers have been replaced by fibrous and fat tissue. C, Muscle does not react with antibodies to dystrophin. D, Positive control was stained with antibodies to basement membrane laminin.


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Fig. 18-6. Facioscapulohumeral dystrophy. In this slide stained for demonstrating oxidative enzymes, the muscle fibers appear moth-eaten and contain numerous small, poorly demarcated, unreactive sarcoplasmic areas.

Fig. 18-7. Limb girdle dystrophy. The muscle contains numerous hypertrophic fibers. Hypertrophic fiber in the center has split into six smaller segments.

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Fig. 18-8. Myotonic dystrophy. A, Many fibers show centrally located nuclei. B, Ring fibers consist of a central core in which the cross-striations run in a different direction than the crossstriations of the peripheral ring.

I NFLAMMATORY MYOPATHIES Inflammatory myopathies are a diverse group of diseases that are related to infections or immune reactions and are encountered in systemic autoimmune diseases, immunemediated myositis (polymyositis or dermatomyositis), or hypersensitivity and allergy to drugs and other exogenous antigens (Table 18-2). Viral myositis probably is the most common muscle infection. In systemic viral diseases it causes muscle pain, but occasionally it may result in rhabdomyolysis. Muscle fiber injury may be accompanied by infiltrates of lymphocytes and macrophages. In the former case the changes are indistinguishable from those of polymyositis. Similar changes may be seen in some patients with acquired immunodeficiency syndrome (AIDS).

Inflammatory Myopathies

SLE, Systemic lupus erythematosus.


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The most common cause of parasitic myositis is trichinosis, which is caused by Trichinella spiralis. The encysted parasites, which often are surrounded by inflammatory cells and fibrous tissue, may be seen in the muscle (Fig. 18-9). Polymyositis is an autoimmune disease in which the muscle inflammation is mediated primarily by CD8 + T lymphocytes (Fig. 18-10). Muscle fibers undergo necrosis individually or in small groups and are surrounded or infiltrated with lymphocytes and macrophages. Dermatomyositis also is an autoimmune disease but in contrast to polymyositis, it is an antibody-mediated disease. Immune complexes have been localized to blood vessels, which usually are surrounded by inflammatory cells. These infiltrates consist predominantly of CD4 + helper T lymphocytes, B lymphocytes, and plasma cells (Fig. 18-11). Vascular changes typically are associated with perifascicular atrophy of muscle fibers (Fig. 18-12). Polyarteritis nodosa and Churg-Strauss syndrome may affect small arteries in the muscle and also cause interstitial inflammation. Drug-induced myositis usually represents a hypersensitivity reaction. Microscopically, it is characterized by inflammatory changes and muscle cell necrosis and inflammatory changes, usually with a prominent contribution of eosinophils (Fig. 18-13). Inclusion body myositis is an inflammatory myopathy of unknown origin. It affects males more often than females and has a peak incidence in the 50 to 70 year age group. It may have an indolent course or a slowly progressive course that is resistant to steroid treatment. Histologic findings are suggestive of polymyositis, but in 60 percent of patients the muscle does not show inflammation. In all cases the muscle

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fibers show vacuolar inclusions consisting of rimmed vacuoles and granules (Fig. 18-14). By EM the vacuoles contain remnants of cytoplasmic membranes and bundles of viruslike tubulofilamentous structures. Similar virus-like particles are found in the muscle cell nuclei.

Fig. 18-9. Trichinosis. The muscle contains encysted parasites.

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Fig. 18-10. Polymyositis. A, Muscle is invaded by lymphocytes. B, Immunohistochemistry shows that most lymphocytes are CD8+ cytotoxic or suppressor cells.


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A

B

Fig. 18-I I. Dermatomyositis. A, The edge of the fascicle at the top of this picture shows atrophy, which is referred to as perifascicular. B, Undulating tubular profiles are seen in endothelial cells.

A

Fig. 18-12. Dermatomyositis. The edge of the fascicle shows perifasicular atrophy.

B

Fig. 18-13. Drug-induced myositis. The infiltrate contains prominent eosinophils.

Fig. 18-14. Inclusion body myositis. A, This cryostat section stained with Gomori trichrome shows the characteristic vacuole containing numerous small red granules. B, By EM the rimmed vacuole contains numerous membranous profiles and bundles of virus-like tubulofilamentous structures.


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GENETIC-METABOLIC MYOPATHIES Genetic-metabolic myopathies may be grouped into three broad categories: (1) carbohydrate storage diseases, (2) lipid storage myopathies, and (3) mitochondrial myopathies. Carbohydrate Storage Diseases Carbohydrate storage diseases include disorders of glycogen storage and degradation. These diseases traditionally have been designated eponymically or numerically, but because the enzymatic defect is known for all of them it is more appropriate to label them according to the underlying deficiency. Symptoms usually appear only during exercise or periods of intense energy demand. Pathologic changes vary, depending on the extent of glycogen storage, the nature of the metabolic defect, and the extent of glycogen storage in the muscle. In the infantile form of acid maltase deficiency

(type II glycogenosis, or Pompe disease), the muscle fibers show extensive vacuolation caused by massive accumulation of glycogen beneath the sarcolemma and between the myofibrils, as may be seen by EM (Fig. 18-15). In addition, the muscle shows deposits of basophilic material that is periodic acid–Schiff (PAS) positive but resistant to diastase digestion. In contrast, the adult form is characterized by less prominent vacuolation, which is seen only in some muscle fibers. The basophilic mucopolysaccharide deposits are not seen (Fig. 18-16). Vacuolation and glycogen accumulation are seen in debranching enzyme deficiency (type III glycogenosis, or Forbes disease) but generally the vacuolation is more prominent (Fig. 18-17). All fibers contain subsarcolemmal vacuoles or show extensive clearing of the central and peripheral cytoplasm. Branching enzyme deficiency (type IV glycogenosis, or Andersen disease) is characterized by abnormal deposits

Fig. I8-15. Infantile form of acid maltase deficiency. There is severe vacuolation of muscle fibers combined with basophilic deposits of mucopolysaccharides in this paraffin embedded, Susa fixative–fixed tissue.

Fig. 18-16. Adult form of acid maltase deficiency. Scattered muscle fibers are vacuolated.

Fig. 18-17. Debranching enzyme deficiency in an adult. There are numerous large vacuoles in the muscle fibers. The tissue was fixed in Susa fixative, embedded in paraffin, and trichrome stained.

Fig. 18-18. Branching enzyme deficiency in a young child. The muscle fibers contain numerous bluish polyglycosan bodies.


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of polysaccharides in the peripheral cytoplasm of the affected fibers (Fig. 18-18). Carbohydrate deposits form so-called polyglycosan bodies, which ultrastructurally appear as unbounded aggregates of branched fibrils and granular material. Polyglycosan bodies are PAS positive and diastase resistant. Myophosphorylase deficiency (type V glycogenosis, or McArdle disease) is characterized by small subsarcolemmal vacuoles or blebs in most muscle fibers (Fig. 18-19). Smaller deposits may form vacuoles in the central parts of the fibers. This material is PAS positive and at least partially digestible. An enzyme histochemical assay for demonstrating myophosphorylase is used to confirm the diagnosis, and it typically gives negative results (Fig. 18-20).

Lipid Storage Myopathies Skeletal muscle cells use long-chain fatty acids as a major source of energy during fasting and sustained exercise. The long-chain fatty acids must be combined with carnitine to pass through the mitochondrial membranes to the matrix compartment, where they undergo beta-oxidation. Myopathies may result from lack of carnitine, deficiency of carnitine palmitoyltransferase, and defects of beta-oxidation. Muscle of patients with lipid storage myopathies contains increased amounts of lipids, which may be demonstrated as cytoplasmic droplets in frozen sections stained with osmium tetroxide (Fig. 18-21) or Sudan red 0, or by EM (Fig. 18-22). These fat droplets are more prominent in type I fibers, which contain more lipid even under normal circumstances. Lipid accumulation is, however, not diagnostic of lipid storage diseases and may occur in a variety of other conditions.

Fig. 18-19. Myophosphorylase deficiency. The muscle fibers

Fig. 18-20. Myophosphorylase deficiency. The control sections

have peripheral vacuoles.

stain dark, whereas the patient's tissue is unstained and light yellow (From Schochet SS Jr: Diagnostic pathology of skeletal muscle and peripheral nerve, Norwalk, Conn, 1986, Appleton-CenturyCrofts.)

Fig. 18-21. Lipid storage myopathy. In this frozen osmium tetroxide—stained section, lipid droplets are more prominent in type I fibers.

Fig. 18-22. Lipid storage myopathy. In this frozen section

stained with Sudan red 0, the lipid droplets are larger in type I fibers than in type II fibers.


394

Mitochondrial Myopathies Mitochondria are organelles that are involved in generating energy, but they also contain deoxyribonucleic acid (DNA) and are important for the transmission of maternal cytoplasmic genetic material through the cytoplasm of the oocyte. Numerous mitochondrial myopathies have been described. In some of these muscle diseases the muscle shows no distinct histologic findings, whereas in others the muscle fibers show mitochondrial abnormalities. When evident, mitochondrial abnormalities may manifest as ragged red fibers in histologic trichrome-stained sections or enzyme histochemically by a technique for demonstrating oxidative enzymes (Fig. 18-23 and 18-24). Mitochondrial abnormalities are better seen by EM when they appear in the form of an increased number of normal mitochondria or as structurally abnormal mitochondria (Figs. 18-25 and 18-26).

Fig. 18-23. Mitochondrial myopathy. Ragged red fiber has clusters of red-staining mitochondria beneath the sarcolemma in this trichrome-stained slide.

Fig. 18-24. Mitochondrial myopathy. Clustering of mitochondria in the peripheral cytoplasm leads to darker staining of the peripheral cytoplasm in this enzyme histochemical preparation for demonstrating oxidative enzymes.

Fig. 18-25. Mitochondrial myopathy. By EM the muscle fibers were found to contain increased numbers of normal mitochondria,

Fig. 18-26. Mitochondrial myopathy (Kearns-Sayre syndrome). By EM the mitochondria appear abnormal.


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DENERVATION-RELATED MUSCLE DISEASES

Denervating Diseases

The welfare of muscle fibers depends on their proper innervation. Denervation results in muscle cell atrophy (Diagram 18-2). It may occur in a number of diseases involving the central nervous system or peripheral nerves (Table 18-3).

Normal motor unit

Early denervation

B

A

Reinnervation

Late denervation

D

C

Diagram 18-2. Schema of the normal motor unit and three stages of denervation. A, Normal motor unit. Two oversimplified motor units are shown (I and II). Each motor neuron (MN) innervates only muscle fibers of the same type. By neurotrophic influences, the motor neuron determines the fiber type within the motor unit. Notice that the fibers from each motor unit are geographically dispersed and are not grouped together. B, Early denervation. Atrophic fibers in the diseased motor unit II (dark) are angular and randomly distributed. C, Reinnervation. The remaining motor neuron I (light) has reinnervated the type II, dark fibers by means of sprouting collateral axons. Notice that the previous type II, dark fibers have been converted to type I, light fibers, because the motor neuron governs the fiber type within the motor unit. This process of reinnervation leads to type grouping. D, Grouped atrophy. In chronic denervation, groups of atrophic fibers result from the process of denervation, reinnervation, and subsequent denervation of the reinnervated fibers.


39 6

Atrophy may involve single muscle fibers, groups of fibers, the entire fascicle, or the entire muscle, depending on the type and the location of nerve injury. Single atrophic denervated fibers are smaller than normal and angular (Fig. 18-27). They typically show increased activity of nonspecific esterase (Fig. 18-28). Chronic neurogenic atrophy shows group atrophy (Fig. 18-29). Enzyme histochemistry for oxidative enzymes shows that the atrophic fibers stain darkly and are surrounded by normal-sized fibers that have a targetoid appearance (Fig. 18-30). Denervation with reinnervation results in a loss of normal checkerboard distribution of type I and type II fibers and type-specific grouping of muscle fibers (Fig. 18-31). Spinal muscular atrophy tends to be more prominent and is termed fascicular because it involves entire large groups of muscles (fascicles) (Fig. 18-32).

Fig. 18-27. Denervation atrophy caused by amyotrophic lateral sclerosis. Atrophic fibers are angular and compressed between the normal fibers.

Fig. 18-28. Denervation atrophy. Denervated atrophic fibers show increased esterase activity as indicated by their brown color in this enzyme histochemical preparation for demonstrating esterase activity.

Fig. 18-29. Chronic neurogenic atrophy. Atrophic fibers are found in groups. They stain dark in this enzyme histochemical preparation for demonstrating oxidative enzymes.

Fig. 18-30. Chronic denervation. Target fibers have pale centers in this enzyme histochemical preparation for demonstrating oxidative enzymes.


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Fig. 18-3I. Denervation with reinnervation. Type-specific grouping has replaced the normal checkerboard pattern in this slide stained for demonstrating ATPase at pH 9.4.

Fig. 18-32. Infantile spinal muscular atrophy. Severe atrophy involves entire fascicles.

Further Reading

Engel AG, Hohlfeld R, Banker BQ: The polymyositis and dermatomyositis syndromes. In Engel AG, Franzini-Armstrong C, editors: Myology, ed 2, New York, 1994, McGraw-Hill. Heffner RR: Inflammatory myopathies: a review. J Neuropathol Exp Neurol 52:339-348. 1999. Kuncl RW, George EB: Toxic neuropathies and myopathies. Curr Opin Neurol 6:695-704, 1993. Mantegazza R, Bernascone P, Confalonieri P, Cornelio F: Inflammatory myopathies and systemic disorders: a review of immunopathogenetic mechanisms and clinical features. J Neurol 244:277287, 1997. Prayson RA: Granulomatous myositis. Clinicopathologic study of 12 cases. Am J Clin Pathol 112:63-68, 1999. Schmalbruch H: The muscular dystrophies. In Mastaglia FL, Walton JN, eds: Skeletal muscle pathology. London, 1992, Churchill Livingstone. Wewer UM, Engvall E: Merosin/laminin-2 and muscular dystrophy. NeuromuscDisord 6:409-418, 1996.

Amato AA, Gronseth GS, Jackson CE et al: Inclusion body myositis: clinical and pathological boundaries. Ann Neu ro140:581-586, 1996. Anderson JR: Recommendation for the biopsy procedure and assessment of skeletal muscle biopsies. Virchows Arch 431:227-233, 1997. Arahata K, Ishihara T, Kamakura K et al: Mosaic expression of dystrophin in symptomatic carriers of Duchenne's muscular dystrophy. N Engl J Med 320:138-142, 1989. Bell CD, Conen PE: Histopathological changes in Duchenne muscular dystrophy. J Neurol Sci 7:529-544, 1968. Campbell KP: Three muscular dystrophies: loss of cytoskeleton-extracellular matrix linkage. Cell 80:675-679, 1995. Dalakas M: Inflammatory and toxic myopathies. Curr Opin Neurol Neurosurg 5:645-654, 1992. Dubowitz V: The muscular dystrophies—clarity or chaos? NEngl JMed 36:650-651, 1997. Dubowitz V: Procedure of muscle biopsy: a practical approach, ed 2, London, 1985, Bailliere Tindall.




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DEVELOPMENTAL AND GENETIC DISORDERS The morphogenesis of the brain depends on the interaction of numerous genes, which must be activated and inactivated sequentially and in an orderly spatial manner to ensure normal development. Because this sequence of events may be disturbed by numerous endogenous and exogenous influences, all of which might cause developmental disturbances, it is not surprising that cerebral malformations are quite common. Many of these abnormalities are not compatible with life and are associated with intrauterine fetal demise and abortion. At the other end of the spectrum are minor defects that cause no significant clinical symptoms. Major developmental disorders are associated with distinct clinical syndromes.

Fig. 19-I. Anencephaly. The calvaria are missing, and the base of the skull is covered with a dark red tissue layer called the area cerebrovasculosa.

A

Neural tube defects are attributed to failure of fusion of lateral folds of the neural plate (dysraphism) or rupture of a previously closed tube (neuroschisis). This group of disorders includes anencephaly, craniorrhachischisis, encephalocele, meningocele, and spina bifida. Anencephaly, the most severe neural tube defect, is characterized by incomplete formation of the bony cranial vault. Calvaria is missing or is only rudimentary, and a reddish spongy mass (area cerebrovasculosa) covered by a thin membrane occupies the gap in the skull (Fig. 19-1). Holoprosencephaly is a severe disturbance of forebrain induction that results in incomplete separation of cerebral hemispheres (Fig. 19-2). Arnold-Chiari malformation and Dandy-Walker malformation result from abnormal development of the hindbrain

Fig. I9-2. Holoprosencephaly. Posterior view shows the reflected cyst wall communicating with a unicameral ventricle.

B

Fig. 19-3. Arnold-Chiari malformation. A, Severe elongation of the medulla and vermis. B, "Beaking" of the tectum (white arrow) and dilatation of the aqueduct (open arrow) caused by compression of the fourth ventricle.


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and several related posterior fossa structures (Figs. 19-3 and 19-4). Malformed and misplaced parts of the central nervous system (CNS) cause hydrocephalus. Agyria-pachygyria complex represents a severe defect in neuronal migration. The brain has a smooth surface agyria or shows a few broad convolutions with shallow sulci ( macrogyria and pachygyria) (Fig. 19-5). In polymicrogyria the brain surface exhibits numerous small irregular gyri (Fig. 19-6).

PERINATAL BRAIN LESIONS

Fig. 19-4. Dandy-Walker malformation. Hypoplastic vermis and cyst are reflected to expose a dilated fourth ventricle.

The brain is susceptible to a variety of injuries during intrauterine life and the perinatal period. The nature of these injuries is not always obvious. It is well known that premature infants are more prone to such injuries than term infants. Complicated or prolonged delivery and maternal ill health predispose to brain injuries, although their pathogenesis is conjectural. Ischemia is considered to be one of the most important causes of brain injury in this period of life. Trauma is an important contributory factor but its role often has been overstated. Subependymal and intraventricular hemorrhages are the most common major intracranial complications of prematurity. Such hemorrhages are especially common in infants born before week 34 of pregnancy or those who weigh less than 1500 g. Hemorrhages usually develop within hours of delivery and are associated with high mortality. These hemorrhages may begin anywhere in the periventricular germinal matrix but most often are located near the sulcus terminalis just posterior to the foramen of Monro (Fig. 19-7). The hemorrhages often are bilateral and vary in size from focal patchy extravasations of blood to large hematomas that rupture into the ventricles (Fig. 19-8). Blood from the largest hematomas may diffusely infiltrate the brain parenchyma.

Fig. 19-5. Agyria-pachygyria complex in Miller-Dieker syndrome. Frontal lobe is devoid of gyri (arrow), whereas the remaining brain has broad gyri and shallow sulci.

Fig. 19-6. Polymicrogyria. The brain has a puckered, "morocco leather" surface.

Fig. 19-7. Subependymal hemorrhage. The germinal matrix is bilaterally infiltrated with extravasated blood. The section was made through the ganglionic eminence at foramen of Monro (arrow).


402

Fig. 19-8. Subependymal hemorrhage extending into the ventricles. Ventricles contain coagulated blood.

Periventricular leukomalacia presents in the form of multiple, irregular, yellowish or chalky white lesions in the white matter adjacent to the lateral ventricles, particularly in the rostral frontal lobes and parietooccipital regions (Fig. 19-9). The pathogenesis of these lesions, which most often occur in premature infants, is debatable. It is thought that they represent shock lesions associated with other CNS lesions, such as subependymal hemorrhages, sepsis, or hypoxia. Histologically the lesions are composed of foamy macrophages, reactive astrocytes, and irregularly swollen axons that undergo mineralization. If the infant survives the insult, periventricular leukomalacia may transform itself into unilocular or multilocular cysts. Infarcts of the brain occur in anatomic areas that correspond to the distribution zones of major cerebral arteries. Ulegyria is a consequence of such ischemic lesions and is characterized by the appearance of mushroom-shaped gyri (Fig. 19-10). The cortex in the depth of the sulci is reduced to a glial scar, whereas the crest remains relatively intact. Ule-

Fig. 19-9. Periventricular leukomalacia. Chalky white lesions are indicated by arrows.

Fig. 19-10. Ulegyria. The affected gyri appear mushroom-shaped.

Fig. 19-1 I. Porencephaly. Porus, the funnel-shaped defect, is bordered by polymicrogyria.

Fig. 19-12. Multicystic encephalopathy. The entire brain has been transformed into numerous irregularly shaped cystic cavities.


403

gyria often is seen in arterial border zones, especially between the anterior and the middle cerebral arteries, and usually is bilateral. Porencephaly and hydranencephaly represent sequelae of major destructive brain lesions and usually occur during the first six months of fetal life, before the immature brain is able to mount sufficient glial reaction to injury. Porencephaly refers to linear or funnel-shaped defects of the cerebral hemispheres (Fig. 19-11). The defect or porus communicates with the ventricular cavity, but sometimes a thin membranous diaphragm, usually made of arachnoid cells, seals it from the ventricle. The porus may be surrounded by polymicrogyria, nodular heterotopias, or radially arranged gyri that histologically exhibit abnormal cortical lamination. In hydranencephaly the cerebral hemispheres are converted to thinwalled, fluid-filled vesicles. In multicystic encephalopathy, the cerebral hemispheres are transformed into multilocular cavities separated by gliovascular trabeculae (Fig. 19-12).

ging brain is flung back and forth against the temporarily deformed skull, resulting in major contusions on the surface of the brain diametrically opposite the site of cranial impact; these contusions are known as contrecoup lesions (Fig. 19-14, Diagram 19-1, p. 404). Laceration is a lesion that is characterized by bleeding into tissue whose integrity has been disrupted. Lacerations occur in the same locations as contusions, at sites of depressed fractures, and with penetrating or perforating head injuries (Fig. 19-15). Lacerations at the pontomedullary junction and tears in medullary peduncles have been described in severe hyperextension of the neck accompanied by basal fractures of the

TRAUMA OF THE BRAIN AND THE SPINAL CORD Trauma of the brain and the spinal cord, often related to vehicular accidents, is a major cause of morbidity and mortality in industrialized countries. In the Unites States the incidence of hospitalization for craniocerebral injuries is 2 per 1000 persons and the mortality rate for accident-related deaths is 0.3 per 1000 persons. Brain injuries often are associated with skull fractures, but many brain contusions and even lacerations occur in closed head injury without apparent fracture. Contusions are bruises in which there is extravasation of blood into tissues whose integrity is retained. A direct blow to a resting but mobile head causes deformation and bending of the skull bone and produces maximal contusions at the site of cranial impact, which are known as coup contusions (Fig. 19-13). If the head is in motion (acceleration) as in a fall and comes to an abrupt standstill (deceleration), the lag-

Fig. 19-13. Contusion of the brain. Coup lesion with hemorrhage perpendicular to the surface was caused by a direct blow to the head with a blunt object.

Fig. 19-14. Contusion. Contrecoup lesion in the frontal and temporal poles are (arrows) are located opposite to a small coup lesion over the cerebellum (small arrow).

Fig. 19-15. Laceration. Hemorrhage into brain tissue is accompanied by a loss of parenchyma.


40 4

Diagram 19-1. Comparison of impact and nonimpact injuries. A, Coup contusions at impact site. B, Contrecoup contusions diametrically opposite impact site. C, Nonimpact contreceoup contusions caused by sudden angular acceleration of the head.

Fig. 19-16. Plaque jaune. Old contusion of orbital surface of left frontal lobe is accompanied in this case by destruction of olfactory bulb and nerve.

Fig. 19- 17. Edema of the brain. The gyri appear flattened and the sulci are narrow.

Fig. 19-18. Herniation of the parahippocampal gyrus. Unilateral herniation of the parahippocampal gyrus on the left side is accompanied by brainstem hemorrhages.


405

posterior fossa. Old contusions and lacerations appear as yellow discoloration (plaque jaune), which most often is found on the orbital surfaces of the frontal lobes and olfactory bulbs in persons who have suffered repeated brain injuries, such as alcoholics (Fig. 19-16). Brain trauma often is accompanied by cerebral edema. Brain edema also accompanies most space-occupying brain lesions and infections recognizable by the flattening of gyri and narrowing of sulci (Fig. 19-17). Because of the space constriction provided by the rigid dura and skull, increased intracranial pressure leads to displacement of parts of the brain, which are known as herniations. Herniations preferentially occur down into the floor of the anterior fossa, over the sphenoid wing, under the falx cerebri, into the tentorial notch into bony orifices, into the sella turcica, down into the foramen magnum, or through the defect in the fractured calvaria. Unilateral herniation of the parahippocampal gyri leads to secondary brainstem hemorrhages (Fig. 19-18).

CIRCULATORY DISTURBANCES Circulatory disturbances of the brain present as hemorrhage or ischemia and may be classified according to location, the type of blood vessel affected (e.g., arterial or venous), or pathogenesis (e.g., traumatic, hypertensive, and so forth).

Intracranial Hemorrhages Intracranial hemorrhages may be caused by (1) trauma; (2) hypertension; (3) spontaneous rupture of congenital

Fig. 19-19. Acute subdural hematoma. Dura was removed to show the hematoma and intact Ieptomeninges.

aneurysms or arteriovenous malformations; (4) systemic diseases such as hemorrhagic diathesis or fat emboli; (5) ischemic necrosis (infarcts) caused by thrombosed atherosclerotic cerebral arteries or emboli; and (6) tumors that are either hypervascular (e.g., hemangioma) or necrotic and destructive (e.g., glioblastoma multiforme). Traumatic hemorrhages may take place in one or more of the potential spaces surrounding the brain (epidural, subdural, and subarachnoid spaces), brain parenchyma, or the ventricles. Epidural hematoma usually is located in the ternporoparietal region and is related to rupture of the middle meningeal artery caused by fracture of the temporal bone. Subdural hematoma is caused by hemorrhage between the dura and the outer surface of the arachnoid membrane (Diagram 19-2, p. 406). Acute subdural hematomas often are associated with severe head injuries and are bilateral in 20 percent of cases. The bleeding is from arteries or bridging veins that drain cortical veins into the superior sagittal sinus and often are associated with underlying cerebral contusion, hemorrhage, or both, a condition referred to as "burst lobe." Acute subdural hematomas are space-occupying lesions that require emergency intervention (Fig. 19-19). Chronic subdural hematomas is encountered in the elderly in whom cerebral atrophy causes widening of the subdural space, thus exposing the bridging veins to a greater risk of rupture when subjected to angular shearing forces. Oozing of blood usually is gradual and spreads over a large surface overlying the brain. Granulation tissue growth into the hematoma from the inner dura forming a "neomembrane" (Fig. 19-20).

Fig. 19-20. Chronic subdural hematoma. Reflected dura reveals the outer membrane and the resected anterior segment of the hematoma exposing its cavity and inner membrane.


406

A

B

Diagram 19-2. A, Epidural hemorrhage. Torn middle meningeal artery at skull fracture (arrow) with accumulation of blood in epidural space causing midline shift with uncal and incipient cingulate herniations. B, Chronic subdural hematoma. Ruptured bridging vein secondary to angular acceleration with accumulation of blood in the subdural space, midline shift with uncal and incipient cingulate herniations.


407

Subarachnoid hemorrhage occurs in any craniocerebral injury of substantial magnitude. Such traumatic hemorrhages are secondary to superficial contusions or lacerations of the brain that release blood into the subarachnoid space (Fig. 19-21). Subarachnoid hemorrhage also may result from spontaneous rupture of aneurysms of the circle of Willis (Fig. 19-22). Such hemorrhages are located at the base of the brain and may penetrate the brain or spread throughout the brain, causing death within minutes or hours after rupture of the aneurysm. Intracerebral hemorrhage usually occurs in older adults as a typical complication of long-standing hypertension. Many hypertensive hemorrhages begin in the external capsules, but often they are so massive that the exact source cannot be determined (Fig. 19-23).. Spinal cord hemorrhages usually are associated with trauma, 40 percent of which is attributable to motor vehicle accidents. Trauma may cause open injury (e.g., gunshot wound), but more often it is a closed injury in which the

spinal cord is damaged by either hyperflexion or hyperextension, tearing of spinal ligaments, and subluxation or fracturing of vertebrae. Hemorrhage is associated with contusion, laceration, or complete transection of the spinal cord (Fig. 19-24).

Fig. 19-2I. Acute subarachnoid hemorrhage. The subarachnoid space is infiltrated by blood. There are a few accentuated areas over superficial cortical contusions.

Fig. 19-22. Subarachnoid bleeding caused by rupture of berry aneurysm. The basal subarachnoid space is filled with blood. A berry aneurysm at trifurcation of the middle cerebral artery is indicated by black arrow. White arrow points to the rupture into the temporal horn.

Fig. 19-23. Acute hypertensive hemorrhage. Massive bleeding into the central part of the left hemisphere is associated with intraventricular extension.

Fig. 19-24. Spinal hemorrhage. The localized hemorrhage and contusion were caused by fracture dislocation of the spine.


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Cerebral Ischemia Cerebral ischemic lesions may be acute or chronic and localized or widespread. Ischemia usually is related to occlusion of blood vessels or hypoperfusion of the brain as a result of heart failure, systemic hypotension, or shock. Atherosclerosis is the most common cause of cerebrovascular disease. Hypertension and diabetes are major predisposing factors that accelerate or aggravate the course of the disease. Occlusion of an artery for a sufficient time results in infarction, which is referred to as encephalomalacia. Infarcts may be pale or hemorrhagic (Fig. 19-25). An infarct undergoes sequential microscopic changes reflecting its age; however, precise timing of these changes could not be reproduced from one study to another. One of the earliest changes is loss of affinity of myelin and neuropil for stains, which may be

A

seen within six to eight hours (Fig. 19-26). In the meantime, gray matter neurons undergo eosinophilic degeneration, and the neuropil becomes vacuolated, especially around the blood vessels. In embolic infarcts, neutrophils and erythrocytes permeate the blood vessels during the first 24 to 48 hours and soon are replaced by macrophages. Reactive astrocytes, macrophages, and capillaries begin to appear by the fourth day, and their numbers increase with time. Macrophages with foamy cytoplasm ( "gitter cells " ) or filled with hemosiderin are seen in later stages. Tissue lysis accompanied by phagocytosis of the debris leads to formation of pseudocysts filled with serous fluid (Fig. 19-27). Chronic cerebral ischemia produces a variety of changes, including formation of lacunae, multiinfarct state, granular atrophy of cortex, and subcortical arteriosclerotic atrophy of cortex. Vascular changes of diabetes and hypertension lead to formation of small cystic spaces. These changes may be diffuse, in which case the condition is known as etat lacunaire (Fig. 19-28). Many of these cysts represent small old infarcts,

B

Fig. 19-25. Cerebral infarcts in the middle cerebral artery distribution. A, Pale infarct (approximately two weeks in duration) with "cracks" (arrows) demarcating it from intact tissue. B, Hemorrhagic infarct consists of blood-infiltrated and necrotic tissue (arrows)

Fig. 19-27. Old infarct. Missing tissue and cysts are found at the site of an old infarct in the middle cerebral artery distribution.

Fig. 19-26. Acute cerebellar infarct. Pallor, in this case involving the gray and white matter, is an early sign of ischemia.

Fig. 19-28. Multiple lacunae. On cross section the brain shows multiple small cystic cavities (etat lacunaire), which are most prominent in the basal ganglia (arrows).


409

but others are related to resolved old hemorrhages, and some may even represent dilated perivascular spaces caused by increased tortuosity and spiraling of the perforating arteries because of hypertension. Lacunae are most prominent in the basal ganglia, internal capsule, basis pontis, and hemispheric white matter. In multiinfarct state the brain contains numerous infarcts that vary in size, shape, and distribution and usually are accompanied by dementia. Granular atrophy of cortex superficially resembles granularity of renal cortex in nephrosclerosis (Fig. 19-29). The granularity of cortex is a result of microscopic scarring of numerous wedge-shaped or stellate intracortical infarcts. The gyri in the affected regions are thinned, and the overlying blood vessels often are stenotic and thick. Granular atrophy of cortex sometimes is associated with lacunae, multiple infarcts, or both. Subcortical arteriosclerotic leukoencephalopathy (Binswanger disease) is a rare cause of vascular dementia that is characterized by multicentric or diffuse degeneration of white matter (Fig. 19-30). Microscopically myelin destruction and loss are associated with gliosis and scattered foamy macrophages. The arcuate fibers typically are spared. The intraparenchymal blood vessels have thick walls and appear hyalinized.

Fig. 19-29. Granular atrophy of cortex. Arrows point to the border zone distribution of the surface granularity of the cortex.

INFECTIONS Infections of the brain, the spinal cord, and their envelopes may be caused by a variety of pathogens, including viruses, bacteria, and fungi. These pathogens may gain entry through (1) hematogenous spread, as is the case in most viral infections and many bacterial and fungal infections related to sepsis; (2) extension from local structures, such as the paranasal sinuses or middle ear; (3) direct implantation through wounds; (4) axonal transport, which typically accounts for CNS infections with herpesvirus and rabies virus (Diagram 19-3). Such infections may result in widespread inflamma -

Fig. 19-30. Binswanger subcortical arteriosclerotic leukoencephalopathy. The matter of centrum semiovale (arrows) appears gray, granular, and shrunken.

Diagram 19-3. Major tumors of CNS by location and age.


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tion of the entire CNS or may be localized to certain structures. They are recognized as meningitis, cerebritis, encephalitis, myelitis, or abscesses, which are designated by their location as epidural, subdural (empyema), or intracerebral. Bacterial infections may be localized and present as foci of suppuration leading to abscess formation or diffuse cerebritis, meningitis, or meningoencephalitis and myelitis. Bacterial meningitis is characterized by exudation of inflammatory cells into the subarachnoid space. In acute purulent meningitis neutrophils predominate, and on gross examination the subarachnoid space appears filled with pus (Fig.

19-31). In chronic bacterial infections lymphocytes and macrophages predominate. In tuberculosis the subarachnoid space at the base of the brain is obliterated by granulomas (Fig. 19-32). Bacterial invasion of brain tissue results in cerebral abscess formation (Fig. 19-33). Over time the abscess becomes walled off by granulation tissue (Fig. 19-34). Incomplete encapsulation leads to the formation of daughter abscesses. Some abscesses may rupture into ventricles or subarachnoid space. Fungal infections of the brain most often are encountered in immunosuppressed persons. Such infections may be caused by Candida albicans, Aspergillus fumigatus, Histo-

Fig. 19-3 I. Bacterial meningitis. Streaks of purulent material (small arrows) are obscuring the sulci (large arrow).

Fig. 19-32. Tuberculous meningitis. Dense organizing exudate is obliterating the basilar subarachnoid space encasing the cranial nerves (arrows).

Fig. 19-33. Brain abscess. The abscess is accompanied by daughter abscesses (arrows). (Courtesy of Dr. L. Forno.)

Fig. 19-34. Chronic brain abscess. Central area filled with pus (white arrow) is surrounded by granulation tissue (open arrow) and edematous brain tissue (dark arrow).


41I

plasma capsulatum, and other fungi, which reach the brain hematogenously and produce multiple foci of ischemic necrosis and hemorrhage (Fig. 19-35). Histologically the fungi are found in the wall of the blood vessels and usually are associated with thrombosis, which causes ischemic infarction of the brain tissue. Fungi also invade the tissue around the blood vessels, causing direct destruction of the brain parenchyma. Mucormycosis of the brain, which typically is found in persons with diabetes, may be caused by infections that spread directly from the nasal mucosa, or it may be related to hematogenous dissemination of fungi. Rhinocerebral mucormycosis is characterized by large areas of necrosis, predominantly basilar, representing foci of hemorrhagic infarction and acute cerebritis caused by intravascular growth of fungi (Fig. 19-36).

Fig. 19-35. Cerebral aspergillosis. Multiple foci of hemorrhage, hemorrhagic and pale necrosis, and early abscess formation are seen distributed at random.

Fig. 19-37. Toxoplasmic encephalitis. The tissue is infiltrated with various inflammatory cells and contains free tachyzoites and a cyst releasing tachyzoites.

Protozoal infections usually are found in immunosuppressed persons. Toxoplasma gondii infection is the most prevalent protozoal infection of the CNS in patients with acquired immunodeficiency syndrome (AIDS). It is characterized by foci of necrotizing cerebritis that evolve into chronic abscesses, usually in the deep gray matter. Microscopically the irregular patches of necrosis are surrounded by zones of vascular congestion, intense mixed inflammatory exudate, reactive astrocytosis, and variable numbers of dormant cysts, pseudocysts, and extracellular tachyzoites (Fig. 19-37). Metazoal infections are rare in the United States but are more common in Asia, Africa, and South America. Cerebral cysticercosis is produced by larvae of the pork tapeworm, Taenia solium, and presents with space-occupying lesions corresponding to encysted parasites (Fig. 19-38).

Fig. 19-36. Rhinocerebral mucormycosis. Necrosis of the medial temporal lobe simulating a contusion or herpesvirus I infection is accompanied by necrosis of the ipsilateral optic nerve (large arrow) and occlusion of the internal carotid artery by fungus

(small arrow).

Fig. 19-38. Cysticercosis of the brain. Multiple cysts are seen, most often at the junction between the gray matter and the white matter.


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Viral infections of the CNS occur in a mild and transient form during systemic viral diseases, whereas encephalitis and meningitis caused by encephalitogenic viruses are associated with considerable morbidity and mortality. Viruses evoke a rather stereotypic response, such as diffuse or multifocal distribution, predominant involvement of neurons (gray matter), glial hyperplasia in response to neuronal injury, and perivascular cuffs of lymphocytes (Fig. 19-39). Some viruses have a predilection for certain parts of the brain. Herpesvirus type I commonly involves the limbic areas of the brain (orbitofrontal cortex, insula, cingulate gyrus, amygdala, and hippocampus). Infected areas show massive hemorrhage and

necrosis, and virions maybe demonstrated in neurons by immunohistochemistry or electron microscopy (EM) (Fig. 19-40). Slow viral infections characterized by chronic encephalitis include subacute sclerosing panencephalitis, progressive multifocal leukoencephalopathy, and progressive rubella encephalitis. Subacute sclerosing panencephalitis is attributable to the measles virus. CNS infections related to prions cause Creutzfeldt-Jakob disease, kuru, and Gerstmann-Straussler-Scheinker syndrome. All of these diseases are characterized by spongiform changes of the brain (Figs. 19-41 and 19-42).

Fig. 19-39. Acute viral encephalitis. The blood vessels are surrounded by cuffs of lymphocytes, whereas the brain tissue shows reactive changes evoked by neuronal damage.

Fig. 19-40. Herpesvirus encephalitis. Infection is accompanied by hemorrhage and necrosis. Inset shows immunoreactive infected virus cells.

Fig. 19-41. Creutzfeldt-Jakob disease. The gray matter shows extensive spongiform (vacuolar) degeneration of the neuropil between nerve cell bodies.

Fig. 19-42. Creutzfeldt-Jakob disease. EM shows swelling of neuritic processes with loss of internal organelles and formation of lacy, abnormal membranes within the vacuolated cytoplasm.


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METABOLIC AND TOXIC DISEASES

Metabolic and Toxic Diseases of the CNS

The nervous system is directly or indirectly affected by numerous congenital and acquired metabolic diseases. Central to understanding the pathophysiology and distribution of various lesions is the concept of selective vulnerability, which states that specific cell types or cell populations are more susceptible to a particular insult. An abridged classification of metabolic and toxic diseases of the CNS is given in Table 19-1. Wernicke disease, which most often is encounteretl in alcoholics, is caused by a deficiency of thiamine. It may occur in an acute form, which often produces no gross findings or only minor hemorrhages. Histologic findings include endothelial swelling and proliferation, spongiosis of the neuropil, and astrocytosis in the presence of intact neurons. These changes are most prominent in the mamillary bodies, medial dorsal nuclei of the thalamus, and other nuclei around the third and fourth ventricles. In chronic Wernicke disease mamillary bodies typically show brownish discoloration and atrophy, often associated with calcifications (Fig. 19-43). Microscopically these areas show neuronal loss and astrogliosis and often contain foci of hemosiderin deposition and calcification (Fig. 19-44). Central pontine myelinolysis is a disease that may present with coma, quadriplegia, or no symptoms at all. It is an iatrogenic demyelinating disease caused by overzealous correction of chronic hyponatremia and excessive swings in serum osmolality. It typically affects middorsal-crossing fibers of the pons (Fig. 19-45). Microscopically the affected areas show axonal loss, spheroids, lipophages, and astrocytes with atypical nuclei (Fig. 19-46). Marchiafava-Bignami disease, another rare disease that is associated with alcoholism, shares some of the demyelinating features of central pontine myelinolysis but primarily affects the corpus callosum. Subacute combined degeneration of the spinal cord is caused by deficiency of vitamin B12 (cyanocobalamin). Typically associated with atrophic gastritis and pernicious anemia, it presents with spongy changes in myelin, followed by axonal and oligodendrocytic loss, astrocytosis, and mac -

Fig. 19-43. Wernicke encephalopathy. Periventricular hemorrhages and discoloration of mamillary bodies.

Fig. 19-44. Wernicke encephalopathy. In chronic stages there is neuronal loss and fibrillary gliosis.

Fig. 19-45. Central pontine myelinolysis. The pons shows a sharply demarcated area of demyelination.


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rophagic response. The localization of these changes to the posterior and posterolateral columns, particularly in the upper thoracic cord, their asymmetry, and their transgression of tract boundaries are characteristic (Fig. 19-47). White matter changes also are detected elsewhere. Wilson disease (hepatolenticular degeneration) is a congenital metabolic disorder of the metabolism of copper. Copper accumulates in the liver and brain with cytotoxic effects. CNS lesions resulting from excess copper are most prominent in the putamen, which may show rare active spongy change progressing to cavitary necrosis (Fig. 19-48). Rarely, neocortical layers V and VI are involved.

Many genetic diseases affect the brain and produce changes in the gray matter, the white matter, or both. Each disease is characterized by a typical set of pathologic changes, which often occur preferentially in certain parts of the CNS. Lysosomal disorders refer to a diverse group of diseases that are also known as lipidoses and neuronal storage diseases. The deficiency of a catabolic enzyme in these autosomal

recessive diseases results in the accumulation or storage of substrates and intermediate metabolites that cannot be processed further. This group of diseases includes (1) sphingolipidoses (Tay-Sachs or Niemann-Pick disease); (2) glucosaminoglycanoses (mucopolysaccharidoses; Hurler, Hunter, and Sanfilippo syndromes); (3) sialidoses, mucolipidoses, and glycoproteinoses (mannosidoses and fucosidosis); and (4) glycogenoses (Pompe or Andersen disease). Tay-Sachs disease, which is caused by a deficiency of hexosaminidase A, is a prototype of sphingolipidoses. The brain contains ballooned neurons that have vacuolated cytoplasm (Fig. 19-49). By EM these vacuoles correspond to lipid-rich membranous cytoplasmic bodies (Fig. 19-50). Leigh disease (subacute necrotizing encephalomyelopathy) produces changes similar to those seen in Wernicke disease, which may lead to massive necrosis of the putamen, thalamus, brainstem, and cerebral and cerebellar white matter (Fig. 19-51). Leukodystrophies are diseases of infancy and childhood that typically demonstrate diffuse, confluent dysmyelination and atrophy of cerebral and cerebellar white matter. These

Fig. 19-46. Central pontine myelinolysis. Demyelination is accompanied by the formation of spheroids (arrows), lipophages, reactive astrocytes, and relative neuronal sparing.

Fig. 19-47. Subacute combined degeneration. Spinal cord shows loss of myelinated axons, most prominently in the posterior columns.

Fig. 19-48. Wilson disease. Cross section of the brain shows cavitary necrosis of the putamen.

Fig. 19-49. Tay-Sachs disease. Neurons have finely vacuolated cytoplasm and appear ballooned.

Inborn Errors of Metabolism


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changes are accompanied by significant axonal loss and relative sparing of arcuate (subcortical U) fibers (Fig. 19-52). In addition to common features that include loss of myelin and oligodendroglia, accumulation of myelin breakdown products, and reactive astrogliosis, each specific disease shows additional characteristic light and electron microscopic features. Globoid cell leukodystrophy (Krabbe disease) is characterized by accumulation of large uninuclear or multinuclear globoid cells that are periodic acid—Schiff-positive (Fig. 19-53). Myelinolytic diseases are characterized by widespread demyelination of axons. Spongy degeneration of the CNS in infancy (Canavan-Van Bogaert-Bertrand disease) is a prototype of congenital myelinolytic disorders that primarily affect the white matter . of the CNS, which undergoes grossly visible gelatinous to aqueous transformation (Fig. 19-54). Histologically there is spongy vacuolar myelinopathy, with a paucity of myelin breakdown products and macrophages.

Fig. 19-51. Leigh disease (subacute necrotizing encephalomyelopathy). Cross section of the brain shows necrotic lesions in the caudae and putamen.

Fig. 19-53. Globoid cell leukodystrophy (Krabbe disease). Brain contains numerous multinucleated globoid cells.

Fig. 19-50. Tay-Sachs disease. Whorls of membranes forming round cytoplasmic bodies are typical of sphingolipidoses, especially gangliosidoses.

Fig. 19-52. Leukodystrophy (globoid cell). Cross section of the brain shows confluent demyelination with relative sparing of arcuate fibers (arrows).

Fig. 19-54. Spongy degeneration of the CNS in infancy (CanavanVan Bogaert-Bertrand disease). The white matter shows gelatinous transformation, which is most noticeable at arcuate fibers.


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DEMYELINATING DISEASES Demyelinating disease are sporadic inflammatory diseases that are characterized by immune or infectious destruction of biochemically normal myelin or its supporting cells, with relative sparing of axons. This group of diseases includes multiple sclerosis, acute disseminated encephalomyelitis, and infectious diseases such as progressive multifocal leukoencephalopathy and subacute sclerosing panencephalitis. Multiple sclerosis is a relatively common neurologic disease of young adults (20 to 40 years). It has both a genetic and an environmental component, as evidenced by the predominance of disease among persons of certain human leukocyte antigen (HLA) types and its geographic distribution. Clinical and laboratory data suggest that the disease has an autoimmune pathogenesis. The pathologic hallmark of the disease, the demyelinative plaque, is a sharply demarcated lesion, which usually is focal, asymmetric if bilateral, and disrespectful of anatomic boundaries such as tracts or gray matter—white matter junctions (Figs. 19-55 and 19-56). Sites of predilection for the plaques are the pial surface of the optic

nerves and optic chiasms, basis pontis, spinal cord, and periventricular white matter, that is, white matter close to cerebrospinal fluid spaces and deep cerebral veins. Acute lesions contain CD4 + and CD8 + lymphocytes, macrophages, and scattered plasma cells (Fig. 19-57). Demyelination of oligodendroglial cells and relative sparing of axons are typical of chronic lesions (Fig. 19-58). Subacute sclerosing panencephalitis (SSPE) is a demyelinating disease attributable to infection caused by measles virus that lacks a membrane (M) protein. It typically occurs several to many years after infection and has a fatal course. The brain shows destruction and loss of white matter and also loss of neurons from the gray matter. The white matter typically is infiltrated with lymphocytes and plasma cells and shows gliosis. Demyelination and axonal loss are associated with typical intranuclear inclusions in oligodendroglial cells (Fig. 19-59).

Fig. 19-55. Multiple sclerosis. Most prominent preventricular demyelinative plaques are accompanied by others at the corticomedullary junction (arrow).

Fig. 19-56. Multiple sclerosis. In unfixed state the medulla oblongata appears grayish-pink. The lesions do not respect anatomic boundaries.

Fig. 19-57. Multiple sclerosis, acute stage. Lesions are infiltrated with lymphocytes and macrophages.

Fig. 19-58. Multiple sclerosis. Chronic lesions show extensive demyelination.


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Fig. 19-59. Subacute sclerosing panencephalitis. Demyelination of white matter is accompanied by chronic inflammation, reactive astrocytosis, and intranuclear inclusions in the oligodendroglial cells. Intranuclear inclusions have a halo separating them from the nuclear membrane.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease that is seen in immunocompromised persons and is believed to be caused by JC polyomavirus. Multifocal destructive lesions of the white matter consist microscopically of lipophages, bizarre hypertrophic astrocytes, demyelinating axons, and enlarged oligodendroglial nuclei that contain amphophilic inclusions (Fig. 19-60).

Fig. 19-60. Progressive multifocal leukoencephalopathy. Oligodendroglial cells, which show typical intranuclear inclusions, are surrounded by atypical astrocytes and lipophages.

Neurodegenerative Diseases

DEGENERATIVE DISEASES OF THE CENTRAL NERVOUS SYSTEM

Degenerative diseases constitute a heterogeneous group of idiopathic diseases that are primarily germane to the CNS. They share a gradual symmetric loss of specific neurons, groups of neurons, and nerve fiber tracts that often are functionally related (multisystem degeneration). These diseases may be classified according to whether they primarily affect the cortical or subcortical parts of the cerebrum, cerebellum, brainstem and spinal cord, or motor neurons (Table 19-2). Alzheimer disease (senile dementia of Alzheimer type) is characterized by atrophy of gyri and widening of sulci, most prominently in the frontal and temporal lobe and notably the hippocampi (Fig. 19-61). The disease is characterized by a loss of neurons and the typical appearance of senile plaques and neurofibrillary tangles (Fig. 19-62). Senile plaques, also known as neuritic, dendritic, and amyloid plaques, are argyrophilic and are best seen in silver-impregnated slides. They appear as spherical bodies often are located near capillaries. Mature plaques have an amyloid core surrounded by a ring of radiating bulbous irregular neurites and processes of microglial and astrocytes. Neurofibrillary tangles are cytoplasmic bodies composed of coarse linear fibrils. Their appearance varies, depending on their stage and the shape of the cell in which they are located. They are faintly basophilic in routine hematoxylin-eosin (H&E) sections and are best demonstrated by silver impregnation techniques.

Diseases shown in boldface type are the best characterized.


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Fig. 19-61. Alzheimer disease. Compared with an age-matched control (lower specimen), the affected brain is smaller and shows narrow gyri and widened sulci.

Fig. 19-62. Alzheimer disease. Senile plaques appear as spherical bodies in silver-impregnated slides. Neurofibrillary tangles are formed of coarse fibrils that react with silver (inset).

Fig. 19-63. Pick disease. Atrophy of gyri is most prominent in the frontal lobe ("knife edge gyri") (arrow).

Pick disease is an uncommon cause of sporadic dementia. It typically presents with severe brain atrophy (lobar sclerosis), classically involving the orbitofrontal and anterior temporal regions (Fig. 19-63). The corresponding white matter is greatly attenuated and firm, resulting in hydrocephalus ex vacuo. Atrophy of the caudate nucleus may simulate Huntington disease. Microscopically the affected gyri show considerable neuronal loss, prominent astrogliosis, ballooned neurons (Pick cells), and intracytoplasmic globular agyrophilic masses (Pick bodies) (Fig. 19-64). Huntington disease is an autosomal dominant neurodegenerative disease that becomes symptomatic in the fourth decade. It is characterized by dementia, emotional disturbances, and chorea. The most prominent change in the brain is atrophy of the caudate nucleus, which results in enlarge-

ment of the anterior horns of the lateral ventricles (Fig. 19-65). The putamen also is affected, but involvement of other nuclei and cortex is not constant. Microscopically the disease is characterized by astrocytosis and a loss of small and medium-sized neurons. Multisystem atrophy is a term that refers to three clinicopathologic entities: striatonigral degeneration, olivopontocerebellar atrophy, and Shy-Drager syndrome. The disease becomes symptomatic between the fourth and sixth decades and is characterized by parkinsonism, cerebellar atrophy, and autonomic dysfunction. Loss of neurons and myelinated fibers results in atrophy of the cerebellum and pons (Fig. 19-66). Argyrophilic cytoplasmic inclusions in oligodendroglial cells and Pick-like inclusions in neurons are a typical microscopic findings.


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Fig. 19-64. Pick disease. Pick cell has a ballooned cytoplasm and an eccentric nucleus (left). Pick body appears as a basophilic globule in the perikaryon (right).

Fig. 19-65. Huntington disease. The ventricles are dilated because of atrophy of the caudate nuclei on their lateral sides.

Fig. 19-66. Olivopontocerebellar atrophy. Cerebellar hemispheres appear disproportionately small and the pontine bulge is flattened.

Parkinson disease (idiopathic parkinsonism) is a common neurodegenerative disease that has its highest prevalence in the eighth decade. It usually is sporadic and idiopathic, but it also may be secondary to infectious disease, exposure to toxins, or drugs. Major pathologic changes are found in the substantia nigra and the locus coeruleus, which appear pale because of the destruction of neuromelanin-containing neurons (Fig. 19-67). Some of the surviving neurons are slightly enlarged and pale, whereas others display the diagnostic cytoplasmic inclusions. These inclusions, which are known as Lewy bodies, appear as spherical eosinophilic cytoplasmic bodies (Fig. 19-68). Diffuse Lewy body disease, in which such cytoplasmic inclusions are seen in cortical neurons, may be associated with dementia.

Fig. 19-67. Parkinson disease. Substantia nigra is depigmented, as evidenced in the atrophic specimen (left) compared with an age-matched control (right).

Fig. 19-68. Parkinson disease. Lewy bodies appear as round cytoplasmic masses in the pigmented neurons.


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Fig. 19-69. Friedreich ataxia. Attenuation and fattening of dorsal spinal cord caused by nerve fiber loss in ascending tracts (c, cuneate; g, gracile; psc, posterior spinocerebellar) and descending pyramidal (py) tracts.

Friedreich ataxia is the best characterized of the hereditary degenerative spinocerebellar syndromes. It is an autosomal recessive disease that becomes clinically apparent in the second decade. It has a rapid downhill course, and most patients die within five years after onset of symptoms. Mixed cerebellar and sensory ataxia caused by peripheral neuropathy dominate the clinical picture. The spinal cord is thin because of loss of ascending and descending myelinated fiber tracts and their replacement with astrocytes (Fig. 19-69). Amyotrophic lateral sclerosis and motor neuron disease are two terms that are used interchangeably to describe the same disease of unknown etiology and pathogenesis. It affects persons over the age of 55 years and occurs at a rate of 1.5 per 1,000,000. Most cases are sporadic, but 10 percent have a family history and are inherited in an autosomal dominant manner. Both upper and lower motor neurons are involved, causing progressive loss of muscle strength. The anterior spinal roots are atrophic and gray (Fig. 19-70). The spinal cord shows loss of myelinated fibers, most prominently in the lateral corticospinal tracts (Fig. 19-71). Spinal cord changes are secondary to loss of motor neurons, best appreciated in the hypoglossal nuclei and anterior horns of the cervical and lumbosacral enlargements of the spinal cord.

NEOPLASMS

Fig. 19-70. Amyotrophic lateral sclerosis. Atrophic and gray posterior roots of cauda equina (black arrow) in contrast to normal posterior roots (white arrow).

Primary neoplasms of the CNS account for 9 percent of primary cancers. These neoplasms occur at a rate of 10 to 20 per 100,000. They occur in all age groups and are an especially significant cause of morbidity and mortality in children and young adults. In the first decade of life brain tumors account for 15 to 18 percent of all malignant tumors (Diagram 19-4). Neoplasms of the CNS may be grouped into several major categories: (1) astrocytic, oligodendroglial, ependymal, and choroid plexus tumors; glial neoplasms; (2) neuronal, mixed neuronal-glial and neuroendocrine tumors including medulloepithelioma, medulloblastoma, neuroblastoma, and primitive neuroectodermal tumor (PNET); (3) meningeal tumors; (4) nerve sheath tumors; (5) vascular neoplasms; (6) hematopoietic and lymphoid cell tumors; (7) germ cell tumors; and (8) pineal tumors.

Fig. 19-71. Amyotrophic lateral sclerosis. Cross section of the spinal cord shows pale crossed (long arrow) and uncrossed (short arrow) pyramidal tracts.


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Diagram 19-4. Major tumor of CNS by location and age.


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Astrocytic Tumors Astrocytic tumors include astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme. Less common variants include astroblastoma and pleomorphic xanthoastrocytoma. Astrocytic tumors represent 70 percent of all primary CNS tumors. Astrocytomas infiltrate the normal structures of the brain, causing them to enlarge or expand (Fig. 19-72). Cerebellar astrocytomas of childhood typically are cystic (Fig. 19-73). Microscopically astrocytomas are composed of fibrillar or protoplasmic astrocytes that have slightly atypical nuclei. In anaplastic astrocytomas, which usually are more cellular, the nuclei are more anaplastic (Fig. 19-74). Glioblastoma multiforme is a highly malignant invasive neoplasm, which may extend from one hemisphere to the other (Fig. 19-75). On cross section the tumor has a variegated appearance because of large areas of necrosis and hemorrhage. Microscopically it may exhibit uniform or diverse cytologic fea-

tures and is composed of small, large, or bizarre cells (Figs. 19-76 and 19-77). The blood vessels usually are prominent and typically show endothelial cell hyperplasia, which may assume glomeruloid features.

Oligodendroglioma Oligodendrogliomas are tumors composed of oligodendrocytes. They represent 10 percent of all primary brain tumors and usually occur in middle-aged adults. On gross examination they appear relatively well demarcated from the surrounding brain tissue, with occasional cystic areas and calcifications. Microscopically oligodendrogliomas are composed of sheets of uniform cells that resemble oligodendroglial cells. These cells have closely apposed, welldefined cell borders and round nuclei (Fig. 19-78). The cytoplasm of these cells is clear, and if the tissue is not promptly fixed, a perinuclear halo forms, which gives them a " fried egg" appearance. Anaplastic oligodendroglioma is a rare variant that exhibits more pronounced nuclear atypia.

Ependymoma

Fig. 19-72. Astrocytoma of pons. Diffusely infiltrating glioma has caused irregular enlargement of the pons and middle cerebellar peduncles.

Fig. 19-73. Cystic astrocytoma of cerebellum in a child. The tumor appears cystic. It involves the cerebellar hemisphere and partly fills the fourth ventricle.

Ependymomas are composed of neoplastic ependymal cells. These tumors account for 5 percent of all primary CNS neoplasms and 10 percent of CNS tumors in children and adolescents. Ependymomas may occur anywhere in the CNS, but 60 percent to 70 percent are infratentorial. A favorite site is the fourth ventricle, where it usually arises from the floor as a globular to lobulated exophytic mass. It may protrude from the roof foramina and partially encircle the brainstem. Supratentorial ependymomas, however, tend to expand within the adjacent brain rather than grow into the ventricles (Fig. 19-79). Less common sites are the cerebellopontine angle, posterior third ventricle, and aqueduct. Ependymomas are the most common intraspinal tumor. Microscopically there are several variants. So-called cellular type is the most common variant, in which cells form sheets or align themselves around blood vessels, forming " perivascular pseudorosettes" (Fig.19-80). Nuclei of typical ependymomas display little pleomorphism. However, in anaplastic ependy-

Fig. 19-74. Anaplastic astrocytoma. Tumor cells show moderate anaplasia. Endothelial cells are prominent.


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Fig. I9-76. Glioblastoma multiforme. The tumor is composed of small cells showing primitive palisading. Endothelial cells are prominent and there are areas of necrosis. Fig. 19-75. Glioblastoma multiforme. The tumor involves the splenium of corpus callosum spreading into adjacent hemisphere.

Fig. 19-77. Glioblastoma multiforme. Tumor cells show marked pleomorphism.

Fig. 19-78. Oligodendroglioma. Tumor cells have round nuclei surrounded by clear cytoplasm in the form of a halo. Capillaries are delicate.

Fig. 19-79. Ependymoma. The tumor distorts the pons and compresses the cerebellum.

Fig. 19-80. Ependymoma. This cellular type of ependymoma is composed of uniform cells that form perivascular pseudorosettes.


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moma the cells show marked pleomorphism and nuclear atypia. Choroid plexus papillomas are rare tumors that account for 1 percent of all primary brain neoplasms. They have a predilection for the lateral ventricles in children and the fourth ventricle in adults. The tumors have a cauliflower-like granular surface expanding the cavity in which they arise. Microscopically they recapitulate the features of the choroid plexus, except that the cells lining fronds are more crowded and mildly pleomorphic (Fig. 19-81). Choroid plexus carcinomas have all the features of malignant epithelial tumors, and it may be difficult to distinguish them from metastatic adenocarcinomas.

Neuronal, Mixed Neuronal-Glial, and Neuroendocrine Neoplasms Medulloepithelioma, medulloblastoma, and neuroblastoma are designated in the World Health Organization classification as embryonal and cytologically pluripotential neoplasms. Medulloblastoma is the most common, accounting for 7 percent to 8 percent of all primary brain neoplasms. It has two peaks of incidence, one at 10 and the other at 22 years of age. After cerebellar astrocytoma it is the most common CNS neoplasm of children. Medulloblastomas typically arise in the vermis of cerebellum and usually appear as a well-demarcated grayish mass with variable zones of necrosis and hemorrhage (Fig. 19-82). They protrude into the fourth ventricle, infiltrate its floor, and extend into the cerebellar peduncles. Microscopically medulloblastomas exhibit highly variable histologic features, mostly appearing as infiltrative, highly cellular, undifferentiated neoplasms composed of small cells (Fig. 19-83). The cells have carrot-shaped ovoid nuclei with coarse dark chromatin and scant or no visible cytoplasm. Mitoses and necrosis may be found, and some cells form Homer Wright rosettes. Medulloblastomas are highly malignant neoplasms. Nevertheless, with modern surgical ablation and radiotherapy, up to 75 percent of patients may survive 5 to 10 years.

Fig. 19-81. Choroid plexus papilloma. The tumor is composed of papillae lined by cuboidal cells.

Fig. 19-82. Medulloblastoma. This cerebellar tumor appears partially necrotic, filling in part the fourth ventricle.

Pineal Tumors Most pineal tumors originate from misplaced germ cells and are similar to the more common germ cell tumors of the testis or ovary. Tumors composed of neoplastic pineal cells are called pineoblastomas or pineocytomas. Pineoblastomas are tumors of children and young adults (Fig. 19-84). Such tumors are composed of poorly differentiated cells that have the cytologic and histologic features of a medulloblastoma. Tumor cells may form Homer Wright or Flexner-Wintersteiner rosettes and even "fleurettes" indicative of photoreceptor differentiation. Although they are radiosensitive, they have a poor prognosis because they tend to recur after resection and disseminate into the subarachnoid space. Pineocytomas tend to be more localized and slower growing than pineoblastomas. Pineocytomas are formed of relatively mature uniform cells, which are arranged into sheets or lobules and intervening paucicellular fibrillated zones forming rosettes

Fig. 19-83. Medulloblastoma. The tumor is composed of primitive cells that have elongated nuclei and scant cytoplasm.


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Fig. 19-85. Pineocytoma. Pineocytes surrounded by fibrillar material form vague rosettes. Fig. 19-84. Pineoblastoma. Sagittal section reveals a large necrotic mass extending from the pineal region into the diencephalon.

(Fig. 19-85). The prognosis is variable but is considered more favorable than that of pineoblastoma.

Meningioma Meningiomas are tumors that are composed of meningothelial cells. They arise from leptomeningeal arachnoid cells, which are most concentrated in the parasagittal arachnoid granulations and dural sleeves of the spinal canal. Tumors typically are attached to the dura, are firm, and compress the adjacent brain or spinal cord (Fig. 19-86). Several histologic types are recognized, including syncytial, fibroblastic, psammomatous, angioblastic, and so forth. Tumor cells typically have ovoid pale nuclei, which are larger than those of astrocytes, with vacuoles of cytoplasmic invaginations (often exaggerated in frozen sections) and well-developed cytoplasm that shows no distinct borders. The cells often form whorls, which may contain centrally located psammoma bodies (Fig. 19-87). They are indolent in their growth but commonly invade dura, bone, or dural sinuses. Although such invasion does not herald malignancy, it is responsible for most recurrences, the rate of which is estimated to be in the range of 15 percent over the five-year period after removal. Several degenerative, reactive, or metaplastic changes may complicate the recognition of its meningeal origin: myxomatous, xanthomatous, lipoblastic, osteoblastic, chondroid, chordoid, microcystic, secretory, and inflammatory changes. Malignant meningiomas rarely occur, but the criteria for their histologic recognition are imprecise. Meninges also may give rise to sarcomas and malignant melanomas.

Fig. 19-86. Meningioma. This midline well-circumscribed tumor originated from the falx (not shown). It occupies a cavity that has formed by the tumor pushing itself into the cerebral hemisphere.

Vascular Neoplasms Hemangiopericytoma and hemangioblastoma are the most common vascular tumors in the cranial cavity. Hemangiopericytomas represent an invasive malignant tumor that has a 50 percent recurrence rate. Hemangioblastomas present as intraaxial lesions of the cerebellum or brainstem, representing 10 percent of posterior fossa tumors. They occur less

Fig. 19-87. Meningioma. Tumor cells have oval nuclei and inconspicuous cytoplasmic borders. Cell form nests, which show some whorling.


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Fig. 19-88. Hemangioblastoma. The tumor is composed of thinwalled vessels surrounded by vacuolated clear stromal cells.

Fig. 19-89. Colloid cyst. Cyst is located in the third ventricle.

often in the spinal cord. They may be multiple in patients with Lindau or von Hippel–Lindau disease, which is known to be related to a tumor suppressor gene defect. Hemangioblastomas are well demarcated, cystic, or solid; many consist of a solid yellow to red mural nodule in a cyst filled with yellow or brown fluid. Microscopically the tumors consist of small to dilated vascular channels lined by hypercellular endothelium and surrounded by pericytes and vacuolated stromal cells (Fig. 19-88). Hemangioblastomas infiltrate parenchyma to some degree and tend to recur if they are incompletely excised.

embedding it in plastic for thin sectioning and EM and by submitting it for tease preparation. Disease may begin in any of these anatomic structures. The initial lesion usually is followed by secondary changes in other compartments. Pathogenetically, peripheral neuropathies are thus classified as (1) axonal injury (axonopathy or primary axonal degeneration); (2) myelin sheath injury (primary demyelination or demyelinating diseases); (3) vascular diseases involving nerves such as ischemic neuropathy or neuropathy caused by vasculitis; and (4) diseases caused by deposition of extraneous substances in the connective tissue, such as amyloidosis. Acute axonopathy may be recognized in routine H&E–stained slides as myelin ovoids, which appear as vacuolated spaces and eosinophilic material arranged in the form of a linear chain. These changes are better appreciated in plastic-embedded thick sections (Fig. 19-90). The necrotic debris is derived from the axon and the corresponding myelin sheath enclosed within the parameter of the original nerve fiber, but later it is taken up by macrophages. In teased-fiber preparations, linear chains of myelin ovoids are readily visualized as round or fusiform bodies in the confines of individual nerve fibers. Because the interval from injury to total axonal fragmentation is generally less than two weeks, acute axonopathy is characterized by abundant degenerating fibers. Chronic axonopathy is characterized by a loss of axons. The number of axons per cross-sectional diameter is diminished, and the endorieural space is filled with collagen replacing the lost axons (Fig. 19-91). Axonal degeneration is accompanied by axonal regeneration, which appears as sprouting of axons. In plastic-embedded thin sections, regenerating axons may be recognized as thinly myelinated axons clustered closely together (Fig. 19-92). By EM they are surrounded by a band of Biangner. In teased-fiber preparations, the internodal length of regenerated axons appears uniformly shorter than normal. Demyelination refers to pathologic processes that selectively interfere with the ability of Schwann cells to maintain

Malformative and Nonneoplastic Mass Lesions This heterogeneous group includes tumors such as craniopharyngioma, dermoid cysts, arachnoid cysts, and colloid cysts. Colloid cysts usually are located in the anterior roof of the third ventricle (Fig. 19-89). They are congenital lesions that are derived from misplaced endoderm. The cysts are lined by columnar pseudostratified epithelium containing ciliated or mucus-producing cells, resting on a collagenous capsule. The lumen of the cyst is filled with colloid.

DISEASES OF PERIPHERAL NERVES Peripheral Neuropathies Peripheral neuropathies may be classified as acute or chronic; limited to one nerve (mononeuropathy) or involving several nerves at the same time (polyneuropathy or mononeuropathy multiplex); and etiologically as inflammatory, metabolic/toxic, nutritional, ischemic, or cryptogenic. Clinically they present in the form of several syndromes such as acute ascending paralysis, subacute sensorimotor neuropathy, chronic progressive sensorimotor neuropathy, chronic relapsing-remitting neuropathy, mononeuropathy, or mononeuropathy multiplex. Peripheral nerves are composed of axons, myelin sheaths, connective tissue forming the endoneurium and perineurium, and blood vessels. These components of the nerve are best evaluated in nerve biopsy specimen prepared not only for paraffin embedded routine sectioning but also by


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A

B

C

Fig. 19-90. Acute axonopathy. A, Degenerating axons with myelin debris completely replacing the axonal profile in cross section of the nerve embedded in plastic and sectioned at I micron thickness (arrow). B, Myelin ovoids (teased fiber preparation). C, Most axons are in acute stages of axonal degeneration.

Fig. 19-91. Chronic axonopathy. The nerve contains only a few myelinated axons, whereas most others have been lost and have been replaced by collagen.

myelin sheaths. Because each Schwann cell myelinates the segment of the axon between two nodes of Ranvier, injury to individual Schwann cells leads to internodal loss of myelin surrounding segments of the axon. Disintegration of myelin is accompanied by preservation of the axon, which appears segmentally denuded in teased-fiber preparations (Fig. 19-93). Segmental demyelination cannot be assessed in routinely processed paraffin-embedded tissue. In plasticembedded sections, the nerve contains normal axons and axons whose myelin sheath is too thin for their caliber (Fig. 19-94). This variability in myelin thickness in plasticembedded cross-sectioned nerves is a hallmark of a demyelinating neuropathy. Remyelinated axons appear in teased-fiber preparations thin er and have shorter internode segments. Therefore, after emyelination, the internodes are of variable length and myel' kness varies along the length of a single fiber (Fig. 19-93). Repetitive episodes of demyelination and remyelina -

Fig. 19-92. Axonal regeneration. Axonal sprouts appear as clusters of small myelinated axons (arrows).

Fig. 19-93. Segmental demyelination. In teased-fiber preparation the demyelinated segment (between arrows) had a thin myelin sheath and is shorter than adjacent internodes.


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tion are accompanied by formation of additio 1 periaxonal layers by Schwann cell processes ( " onion formation" ), which are reminiscent of changes seen in hypertrophic axonal neuropathies.

Hereditary Neuropathies

Fig. 19-94. Segmental demyelination. Axons of the same caliber have myelin sheaths that vary in thickness. This variation typically is seen in nerves that have undergone segmental demyelination.

Hereditary neuropathies occur in several clinically distinct forms, with an estimated prevalence of 1 in 2500. Two major groups are recognized: hereditary motor and sensory neuropathies (HMSN) and hereditary sensory and autonomic neuropathies (HSAN) (Table 19-3). Charcot-Marie-Tooth disease ( MCT) is the most common hereditary neuropathy. It is inherited as an autosomal dominant trait and occurs in two forms. Type I is more common

Hereditary Peripheral Neuropathies


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and presents as a demyelinating neuropathy, whereas type II presents as axonal neuropathy. Type I MCT is characterized by a moderate loss of large caliber axons and prominent onion bulb formation (Fig. 19-95). Type II MCT is characterized by axonal loss and onion bulbs are not prominent. Dejerine-Sottas disease is a hereditary neuropathy of childhood that is inherited as an autosomal recessive trait. Microscopically the nerves show prominent onion bulb formation, which is readily apparent in routine H&E—stained -sections (Fig. 19-96). Giant axonal neuropathy is an uncommon peripheral neuropathy of childhood that is inherited as an autosomal recessive trait. Microscopically it is recognized by the presence of greatly enlarged axons that appear in routine sections as homogeneous eosinophilic spheroids (Fig. 19-97). Immunohistochemistry shows that these spheroids are filled with neurofilaments. Tomaculous neuropathy is an autosomal dominant hereditary neuropathy that is characterized by a tendency to develop compression neuropathy. In plastic sections a few fibers

Fig. I9-96. Dejerine-Sottas disease. Cross section of peripheral nerve shows numerous onion bulbs.

A A

B B

Fig. 19-95. Charcot-Marie-Tooth disease, type I. A, Onion bulbs may be difficult to identify in routine histologic sections. They appear as ill-defined layers of Schwann cell processes and are accentuated by the appearance of two Schwann cell nuclei adjacent to a single fiber. B, In plastic-embedded tissue sectioned at I micron thickness, onion bulbs are composed of concentric layers of Schwann cell cytoplasm with only occasional Schwann cell nuclei identifiable.

Fig. 19-97. Giant axonal neuropathy. A, Prominent eosinophilic enlarged axons are distributed at random and are occasionally surrounded by rings of Schwann cells (Schwann cell hyperplasia). B, Immunohistochemistry shows that axonal spheroids contain neurofilaments.


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have excessively thick myelin sheaths, which in teased-fiber preparations have been likened to sausages (Latin: tomaculum) (Fig. 19-98). Hereditary amyloid neuropathy is characterized by endoneurial deposition of amyloid, most often derived from transthyretin. Although they have been described in several parts of the world, many appear to be based on mutations of the same segment of the transthyretin gene. Microscopically amyloid is found in the endoneurium and in the wall of blood vessels (Fig. 19-99).

A

Ischemic Neuropathies Microangiopathy caused by diabetes, hypertension, and atherosclerosis accounts for most ischemic neuropathies. Nerve biopsies show chronic axonal loss that involves both large caliber and small caliber myelinated axons, which are replaced by collagenous tissue (Fig. 19-100). Polyarteritis nodosa and Churg-Strauss syndrome may cause acute and chronic neuronal ischemia, which typically is segmental. The diagnosis is made by identifying foci of polyarteritis in the nerve biopsy (Fig. 19-101).

Inflammatory Neuropathies Guillain-Barre syndrome is an acute or subacute demyelinating peripheral neuropathy with an incidence of 1 to 2 per 100,000. It usually occurs after a self-limited viral disease, after immunization, in patients with AIDS, following surgery, and with infection by Campylobacter jejuni. It is considered to be an immune-mediated disorder. Nerve changes, which are most prominent in the spinal roots, include acute demyelination and foci of inflammation composed of lymphocytes and macrophages (Fig. 19-102).

B

Fig. 19-98. Tomaculous neuropathy. A, Cross section of the nerve shows scattered "hypermyelinated" axons with thickened myelin sheaths. B, In teased-fiber preparation the nerve fibers show fusiform thickening.

Fig. 19-99. Familial amyloid neuropathy. Amyloid deposits in the form of homogeneously eosinophilic material are present in the wall of blood vessels and the endoneurium.

Fig. 19-100. Ischemic neuropathy. Cross section of the nerve shows loss of axons from broad areas.


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Chronic inflammatory demyelinating polyneuropathy is similar to Guillain-Barre syndrome in its immune-mediated pathogenesis and targeted demyelination. However, it is distinguished by an insidious onset, progressive course, and variable response to therapy. Microscopically the affected nerves show chronic demyelination, with variable amounts of inflammation, which often is perivascular or not present at all (Fig. 19-103). Systemic inflammatory diseases such as sarcoid6sis may involve nerves, which typically contain granulomas (Fig. 19-104). Sensory perineuritis is a disease of unknown etiology. It is characterized by chronic granulomatous inflammation that is restricted to the perineural layers (Fig. 19-105). Infections of nerves with viruses such as herpes simplex or bacteria such as Mycobacterium leprae produce distinct morphologic changes and variable destruction of nerve tissue.

Fig. 19-102. Guillain-Barre syndrome. Scattered axons show acute demyelination (arrow). Variation in the thickness of myelin sheaths of axons of the same caliber also is evident.

Fig. 19-104. Sarcoidosis. The epineurium contains noncaseating granulomas.

Fig. 19-101. Polyarteritis nodosa. The blood vessel is infiltrated by inflammatory cells.

Fig. 19-103. Chronic inflammatory demyelinating polyradiculoneuropathy. In cross section the nerve shows marked variation in the thickness of myelin sheaths and focal axonal loss.

Fig. 19-105. Perineuritis. The perineurial layers contain chronic inflammatory cells forming granulomas.


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Neoplasms of Peripheral Nerves Peripheral nerve tumors are common but usually are small and benign and thus of limited clinical significance. Malignant tumors are uncommon. Schwannoma (neurilemoma) is the most common peripheral nerve tumor. Most schwannomas present in the form of firm, encapsulated tumors that may ostensibly be attached to a peripheral nerve (Fig. 19-106). Microscopically the tumors are composed of uniform Schwann cells that have elongated nuclei with tapering ends. In parallel alignment, they form interwoven fascicles. Densely cellular areas are termed Antoni A areas, and those that are myxomatous are called Antoni B areas (Fig. 19-107). Palisading tumor cells forming rows that alternate with acellular areas are called Verocay bodies. Neurofibroma is a benign tumor composed of nerve sheath—derived cells, some of which resemble Schwann cells, perineurial cells, or endoneurial fibroblasts. It may present as a solitary intradermal lesion or perineurial masses; or it

may cause ropelike, fusiform expansion of the involved nerve segment (plexiform neurofibroma). In neurofibromatosis type I (von Recklinghausen disease), neurofibromas may be multiple. On gross examination they appear soft and malleable with a mucoid translucent cut surface (Fig. 19-108). Microscopically they consist of elongated cells and moderately abundant matrix (Fig. 19-109). Neurofibromas tend to infiltrate nerves and ganglions and may contain entrapped neural elements. Some tumor cells stain with antibody to S-100 protein, like Schwann cells; others stain with antibodies to epithelial membrane antigen (EMA), like perineurial cells; and still others do not express any markers and are considered to be fibroblasts. Other benign tumors and tumor-like conditions of peripheral nerves that have distinct features are granular cell tumor, perineuroma, ganglioneuroma, and Morton neuroma. Perineurioma is a localized mass that occupies a single nerve and expands each of its fascicles. Each individual fas-

Fig. 19-106. Schwannoma. The tumor is grayish-yellow, encapsulated, and lobulated. Blood vessels are seen on its surface.

Fig. 19-107. Schwannoma. The tumor is composed of spindleshaped cells that show typical palisading.

Fig. 19-108. Neurofibroma. Tumor lobules follow the course of the nerve.

Fig. 19-109. Neurofibroma. Neurofibroma has infiltrated a ganglion, as evidenced by the presence of scattered ganglion cells between elongated tumor cells.


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Fig. I9-1 10. Perineurioma. Concentrically oriented cells create a hypercellular endoneurium.

Fig. 19-I 1 I . Morton neuroma. Fibrosis of the perineurial layer is accompanied by a central loss of axons.

cicle is enlarged and is hypercellular with a single cell species. The tumor cells lie concentric to the perineurial sheath or concentrically around individual nerve fibers (Fig. 19-110). The latter pattern is reminiscent of onion bulbs in the hereditary hypertrophic neuropathies and has led to the synonymous term localized hypertrophic neuropathy. Like neurofibromas, perineuriomas may occur as intraneural plexiform tumors or as solitary extraneural tumors (intramuscular perineuriomas). Morton neuroma (perineurial fibrosis) is a painful enlargement of an interdigital plantar nerve, usually between the third and fourth metatarsal bones. Females are affected more often than males. The focal segment of the affected nerve is thickened because of fibrosis of the perineurium compressing the nerve trunk showing a loss of axons (Fig.

DeArmond SJ, Prusiner SB: Etiology and pathogenesis of prion disease. Am J Pathol 146:785-811, 1995. Dyck PJ, Giannini C: Pathologic alterations in the diabetic neuropathies of humans. J Neuropathol Exp Neurol 55:1181-1193, 1996. Forno LS: Neuropathology of Parkinson's disease. J Neuropathol Exp Neurol 55:259-272, 1996. Golden JA: Holoprosencephaly: a defect in brain pattering. J Neuropathol Exp Neurol 57:991-999, 1998. Inagawa T, Hirano A: Ruptured intracranial aneurysms. An autopsy study of 133 patients. Surg Neurol 33:117-123, 1990. Jellinger K: Vascular malformations of the central nervous system. A morphological overview. Neurosurg Rev 9:177-216, 1986. Kepes JJ, Moral LA, Wilkenson SB et al: Rhabdoid transformation of tumor cells in meningiomas: a histologic indication of increased proliferative activity. Report of four cases. Am J Surg Pathol 22:231238, 1998. Kepes JJ, Scheithauer B: Pathology of selected neoplasms of central nervous system. Mod Pathol 9:579-597, 1996. Koppen AH: The hereditary ataxias. J Neuropathol Exp Neurol 57:531543, 1998. Lie JT: Primary (granulomatous) angiitis of the central nervous system. A clinicopathologic analysis of 15 new cases and review of the literature. Hum Pathol 23:164-171, 1992. Ludwig C, Smith M, Godfrey A, Armbrustmacher V: A clinicopathologic study of 323 patients with oligodendrogliomas. Ann Neurol 19:15-21, 1986. Mirra SS, Hart MN, Terry RD: Making the diagnosis of Alzheimer's disease. Arch Pathol Lab Med 117:132-144, 1993. Said G, Goulon-Goeau C, Lacroix C, Moulonguet A: Nerve biopsy findings in different patterns of proximal diabetic neuropathy. Ann Neurol 35:559-569, 1994. Said G, Lacroix-Ciaudo C, Fujimura H et al: The peripheral neuropathy of necrotizing arteritis. A clinicopathologic study. Ann Neurol 23:461-465, 1988. Tredici G, Minazzi M: Alcoholic neuropathy. An electron-microscopic study. JNeurol Sci 25:333-346, 1975. Vonsattel JPG, Difiglia M: Huntington disease. J Neuropathol Exp Neurol 57:369-384, 1998.

19-111). Further Reading Anthony DC, Crain BJ: Peripheral nerve biopsies. Arch Pathol Lab Med 120:26-34, 1996. Asbury AK, Amason BG, Adams RD: The inflammatory lesion in idiopathic polyneuritis. Its role in pathogenesis. Medicine 48:173-215, 1969. Bigner SH, Schold SC. The diagnosis of metastases to the central nervous system. Pathol Annu 19(pt 2):89-119, 1984. Bjornsson J, Scheithauer BW, Okazaki H, Leech RW: Intracranial germ cell tumors. Pathobiological and immunohistochemical aspects of 70 cases. J Neuropathol Exp Neurol 44:32-46, 1985. Burger PC, Scheithauer BW: Tumors of the central nervous system. Atlas of tumor pathology, series 3, fascicle 10, Washington, DC, 1994, Armed Forces Institute of Pathology. Chuaqui R, Tapia J. Histologic assessment of the age of recent brain infarcts in man. J Neuropathol Exp Neurol 52:481-489, 1993. Coffin CM, Wick MR, Braun JT, Dehner LP: Choroid plexus neoplasms. Clinicopathologic and immunohistochemical studies. Am J Surg Pathol 10:394-404, 1986.




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I NFLAMMATION OF THE EYE AND OCULAR ADNEXA Inflammation of the eye is common. It may be related to infections, allergies, systemic diseases, irritants, drugs and chemicals, mechanical devices, and tumors. Inflammation may be limited to the conjunctiva (conjunctivitis), cornea (keratitis), cornea and conjunctiva (keratoconjunctivitis), corneal stroma (interstitial keratitis), episclera (episcleritis), sclera (scleritis), orbital connective tissue (orbital cellulitis), uvea (uveitis), iris (iritis), ciliary body (cyclitis), choroid (choroiditis), iris and ciliary body (iridocyclitis), retina (retinitis), optic nerve (optic neuritis), eyelid (blepharitis), choroid and retina (chorioretinitis), vitreous (vitritis), pars plana of ciliary body (pars planitis), lacrimal gland (dacryoadenitis), the intraocular contents

with sparing of the sclera and orbit (endophthalmitis), or the ocular contents and cornea or sclera (panophthalmitis). Conjunctivitis is classified according to the nature of the inflammatory reaction (acute conjunctivitis, chronic conjunctivitis, granulomatous conjunctivitis, inclusion conjunctivitis, ligneous conjunctivitis, membranous conjunctivitis, pseudomembranous conjunctivitis, chronic follicular conjunctivitis, giant papillary conjunctivitis, vernal conjunctivitis), or it is classified according to the etiologic agent (bacterial conjunctivitis, viral conjunctivitis, allergic conjunctivitis, trachoma) (Fig. 20-1). Chalazion is an inflammation associated with obstruction of sebaceous glands (meibomian or Zeis glands). Histologically it presents as a chronic lipogranulomatous reaction (Fig. 20-2).

Fig. 20-I. Chronic follicular conjunctivitis. This follicle contains a germinal center. The conjunctiva's normal resident population of lymphocytes has been stimulated to proliferate.

Fig. 20-2. Chalazion. A mass of chronic inflammatory cells is seen anterior to the tarsal plate of the eyelid. Empty lipid vacuoles are necessary for the diagnosis of li pogranulomatous inflammation.

Fig. 20-3. Fungal endophthalmitis. Multiple vitreous microabscesses developed due to Fusarium infection acquired during cataract surgery. Multiple vitreous microabscesses are a characteristic finding in fungal endophthalmitis.

Fig. 20-4. Sympathetic uveitis, choroid. The choroid is massively thickened by a diffuse chronic inflammatory infiltrate composed of epithelioid histiocytes and lymphocytes. The choriocapillaris is visible ("spared"). A Dalen-Fuchs nodule of epithelioid histiocytes elevates the retinal pigment epithelium (RPE) from Bruch membrane at right. The retina is detached.


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Endophthalmitis and panophthalmitis may be classified as an endogenous or exogenous intraocular infection that results in abscesses and chronic destructive inflammatory lesions (Fig. 20-3). Sympathetic uveitis is a rare but very important bilateral granulomatous reaction that follows unilateral ocular injury or surgery, usually complicated by incarceration of uveal tissue in the wound. The condition is. thought to represent an autoimmune response to sensitization to ocular isoantigens and is characterized by chronic lymphocytic inflammation (Fig. 20-4). Keratitis caused by bacteria, viruses, or fungi is characterized by destruction of the corneal epithelium and the Bowman layer, and by prominent inflammatory infiltrates (Fig. 20-5). Histologic examination of the eye rarely provides an insight into the cause of the disease. Pathogens such as cytomegalovirus (CMV), herpesvirus, or parasites occasionally may be identified (Fig. 20-6).

EYE CHANGES IN SYSTEMIC DISEASES The eye is involved in numerous systemic diseases, some of which are listed in Table 20-1. The most important among these systemic diseases are hypertension, atherosclerosis, and diabetes mellitus. These diseases produce a variety of changes in the retina, iris, and vitroretinal part of the eye, all of which are related either to ischemia or to microvascular injury. Pathologic changes correspond to those seen on ophthalmoscopy as cotton wool spots, microaneurysms, or neovascularization of the eye background (Figs. 20-7 to 20-10). Extraocular muscles are involved in Graves disease. These thickened muscles are fibrotic and histologically show lymphocytic myositis (Fig. 20-11).

Examples of Systemic Diseases That Affect the Eyes

CMV, cytomegalovirus Fig. 20-5. Acute keratitis and scleritis caused by Pseudomonas aeruginosa. Pseudomonas infections of the cornea often extend posteriorly as an acute infectious scleritis.

Fig. 20-6. Ocular toxocariasis. Eosinophilic abscess contains fragment of nematode larva.

Fig. 20-7. Cotton wool spot and hard exudates of retina. Blockage of axoplasmic flow thickens nerve fiber layer at left. Several cytoid bodies in cotton wool spot contain darkly-staining nucleoids of dammed organelles. Hard exudates are seen as pools of proteinaceous fluid centered on outer plexiform layer at right.


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Fig. 20-8. Retinal arterial macroaneurysm with hard exudates. Fibrin surrounds dilated vessel in inner retina, which is thought to represent an arterial macroaneurysm. Hard exudates and hemorrhage are seen in outer plexiform layer.

Fig. 20-10. Diabetic microaneurysms of the retina. Whole mount of retina shows saccular dilatations (Courtesy of Dr. J.M.B. Bloodworth, Madison, Wisconsin.)

Fig. 20-9. Proliferative diabetic retinopathy. Neovascularization occurs on anterior surface of retina and extends onto the posterior face of the detached vitreous. Hemorrhage is present in the vitreous and the subhyaloid space. The vitreoretinal membrane is beginning to cause a tractional retinal detachment.

Fig. 20-11. Graves disease. Postmortem exenteration specimen showing massive enlargement of extraocular muscles. (Case reported by Hufnagel TJ et al, Ophthalmology 91:141 I, 1984).

Hereditary tumor syndromes that involve more than one organ system also may involve the eye. Eye involvement is a typical feature of neurofibromatosis type I and von HippelLindau disease (Fig. 20-12).

SPECIFIC OCULAR DISORDERS Glaucoma Glaucoma is a term that denotes a group of disorders char-

Fig. 20-12. Retinal capillary hemangioma, von Hippel-Lindau disease. Although they often are called retinal capillary hemangiomas, histopathologically the retinal tumors are identical to cerebellar hemangioblastomas. Lipidized stromal cells are found between the capillary vessels.

acterized by optic neuropathy associated with a characteristic excavation of the optic disk and a progressive loss of visual field sensitivity. In most cases the intraocular pressure is elevated. The condition may develop without an apparent antecedent underlying ocular disease (primary glaucoma), or it may follow or occur concomitantly with a known ocular disorder (secondary glaucoma). Primary and secondary glaucomas are subdivided into open-angle and closed-angle types, depending on whether the iridocorneal angle appears open


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Fig. 20-13. End-stage glaucomatous cupping of optic nerve head. This massively excavated nerve head has a bean pot configuration. The lamina cribrosa is bowed posteriorly.

Fig. 20-14. Glaucomatous retinal atrophy. Atrophy is limited to the ganglion cell and nerve fiber layers of the retina. A few glial cells are seen in the nerve fiber layer.

Fig. 20-15. Narrow angle, anterior chamber. The peripheral stroma of the iris is in close proximity to the trabecular meshwork. Patients with the narrow angle configuration are at risk for developing an acute attack of angle closure glaucoma.

Fig. 20-16. Peripheral anterior synechiae. The anterior surface of the peripheral iris is adherent to the trabecular meshwork. Uveal melanoma was the indication for enucleation.

or closed. Glaucoma also may be subdivided into congenital (developmental) or acquired types, depending on the time of onset. Primary open-angle glaucoma, the most common form, affects 1 percent to 3 percent of all persons over 40 years of age. Congenital glaucoma is the least common form. Pathologic studies on eyes with glaucoma disclose abnormalities relevant to the effects of elevated intraocular pressure, such as a loss of ganglion cells and axons in the retinal nerve fiber layer, posterior bowing of the lamina cribrosa, excavation of the optic nerve head ( "glaucomatous cupping"), and optic atrophy (Figs. 20-13 to 20-18). With long-standing glaucoma the corneal endothelium may be deficient and the cornea may have features of a bullous keratopathy. Most enucleated blind glaucomatous eyes have secondary closed-angle glaucoma. Pathologic alterations relevant to the cause of the glaucoma may also be apparent. These abnormalities include the presence of epithelium on the surface of the iris and even

Fig. 20-17. Postcontusion angle recession (recessed angle), eye with pseudoexfoliation syndrome. The iris root and first ciliary process are displaced posteriorly. The ciliary muscle has a fusiform shape caused by ischemic atrophy of its inner part after tear into face of ciliary body during contusion injury.


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in the vitreous ( "epithelial downgrowth"). Neovascularization of the iris is found in cases of neovascular glaucoma, the most common and clinically significant form of secondary closed-angle glaucoma.

Diseases of the Cornea

Fig. 20-18. Congenital glaucoma, gross photo showing enlarged cornea with healed ruptures of Descemet membrane. Corneal enlargement occurs when the intraocular pressure is elevated in childhood. Stretching may produce spontaneous tears in Descemet membrane called Haab striae. The healed ruptures are seen as radiating lucent ridges on the posterior corneal surface in the photo.

Fig. 20-19. Pseudophakic bullous keratopathy. Descemet membrane is normal. The endothelial cells are absent, and the stroma is edematous. Endothelial damage caused by cataract surgery and prosthetic intraocular lens implantation is the most common indication for corneal transplantation.

Fig. 20-21. Fuchs corneal dystrophy. Guttate excrescences of abnormal basement membrane material stud posterior surface of thickened Descemet membrane. Some residual endothelial cells contain granules of melanin pigment from iris. Stroma has edematous "cotton candy" appearance.

Diseases of the cornea often show unique features, although their nature is not fully understood. Bullous keratopathy is a common disease in which the corneal stroma and epithelium become edematous and bullae form between the epithelium and the Bowman layer. The changes are classified according to the cause of epithelial loss: cataract extraction (aphakic bullous keratopathy), cataract extraction combined with implantation of a prosthetic intraocular lens (pseudophakic bullous keratopathy), and Fuchs corneal dystrophy (Figs. 20-19 to 20-23). Corneal graft rejection may cause similar changes. Fuchs corneal dystrophy, which accounts for many corneal specimens submitted for pathologic examination in the

Fig. 20-20. Granular corneal dystrophy. Stroma contains aggregates of intensely eosinophilic crystalloids with "rock candy" appearance. Material stains intensely with Luxol fast blue and shows acid fuchsinophilia (red staining) with Masson trichrome.

Fig. 20-22. Lattice corneal dystrophy. Smudgy oval deposit of stromal amyloid stained positively with Congo red and showed apple-green birefringence and dichroism on polarization microscopy.


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United States, is characterized by multiple, centrally located, wartlike excrescences ("corneal guttae " ) on a thickened Descemet membrane in addition to features of bullous keratopathy (Fig. 20-21). The inherited lattice corneal dystrophies are characterized by irregular linear opacities caused by stromal amyloid deposits in corneas with an unremarkable Descemet membrane and endothelium (Fig. 20-22). Macular dystrophies are characterized by accumulation of keratan sulfate—related glycosaminoglycan within the fibroblasts, in the endothelium of the cornea, among the collagen lamellae, and in the Descemet membrane (Fig. 20-23). Hale colloidal iron technique and the Alcian blue stain are particularly useful in coloring the abnormal accumulations. Keratoconus is a common progressive disease that is characterized by thinning of the central corneal stroma, which causes conical distortion of the cornea, without evidence of inflammation or vascularization. This poorly understood disorder may be familial and occasionally is associated with other hereditary disorders such as Marfan syndrome. Excessive eye rubbing is common in patients with keratoconus and may precede the formation of a conical cornea. Histologically the epithelium of the cornea is ectatic and the Bowman layer contains typical dehiscences. The epithelium often contains a ring of stainable iron surrounding the cone (Fleischer ring) (Fig. 20-24).

Fig. 20-23. Macular corneal dystrophy. Deposits of lucent, finely granular storage material (abnormal nonsulfated keratan sulfate) are seen in anterior interlamellar spaces.

A

Retinal Degenerative Diseases Retinal degenerative changes may occur at any age but are more common in older people. Most important among these disorders are macular degeneration and retinal detachment (Fig. 20-25). Pigmentary retinopathy, which is better known by the generic misnomer retinitis pigmentosa, a term that encompasses a large group of progressive degenerative diseases of the retina, is characterized by a loss of retinal photoreceptors and by perivascular accumulation of pigment within the retina (Fig. 20-26).

Fig. 20-25. Age-related macular degeneration. The retina is shallowly detached by serous fluid. Detached hemorrhagic-retinal pigmentary epithelium is undergoing organization into a collagenous disciform scar.

B

Fig. 20-24. Keratoconus. A, The central corneal stroma is markedly ectatic. In this area the corneal epithelium has undergone compensatory hyperplasia. Dehiscences are seen in the Bowman membrane. B, Fleischer iron ring in corneal epithelium.

Fig. 20-26. Retinitis pigmentosa. Retinal atrophy is confined to the photoreceptors. A single row of residual cone nuclei comprises the outer nuclear layer in the posterior retina. The remaining inner segments are atrophic. The retinal pigmentary epithelium and the inner retinal layers are intact.


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Cataracts A cataract is an opacity in the lens that usually is severe enough to impair visual acuity. Cataracts may have numerous causes and are classified as genetic, metabolic, druginduced, and so forth. Most cataracts are associated with aging. Four basic types of cataract are recognized histopathologically: (1) cortical, (2) nuclear, (3) anterior subcapsular, and (4) posterior subcapsular (Figs. 20-27 to 20-30). In the nuclear sclerotic cataract the hardened central lens nucleus appears yellowish or brown, reflecting the accumulation of the photooxidation pigment urochrome. The colored lens absorbs blue light, which distorts color vision. An increase in the index of refraction of the lens causes lenticular myopia. Nuclear sclerosis is characterized microscopically by increased eosinophilia and homogeneity of the lens nucleus, which lacks the artifactitious clefts that are observed in a normal lens cortex (Fig. 20-27). Nuclear cataracts occasionally contain oval birefringent crystals of calcium oxalate. Cortical (soft) cataracts result from degeneration of the lens cells or fibers and are characterized by fractures, degen-

eration, and liquefaction of the fiber cells of the lens cortex (Fig. 20-28). There initially is formation of vacuoles or clefts in the lens cortex, but subsequently interrupted and folded lens fibers and cortical clefts are filled with morgagnian globules. The sclerotic nucleus usually resists liquefaction. The osmotic effect of the degenerated cortex causes the lens to imbibe aqueous and swell. Total cortical liquefaction eventually may ensue, leading to the formation of a so-called morgagnian cataract. Anterior subcapsular cataract is characterized by inflammation and adhesions between the iris and the lens (posterior synechiae). Other factors besides inflammation occasionally stimulate the anterior subcapsular monolayer of cuboidal lens epithelium to proliferate, undergo metaplasia, or migrate posteriorly. The proliferating lens epithelial cells synthesize a thick plaque of collagen beneath a sinuously folded anterior lens capsule (Fig. 20-29). Within the plaque the cells are surrounded by basement membrane material that is periodic acid—Schiff positive, bearing testimony to the lens epithelial lineage of the cells. Proliferation and fibrous transformation of residual lens epithelial cells is a major cause of posterior capsular fibrosis after extracapsular cataract extraction.

Fig. 20-27. Nuclear sclerotic cataract. Artifactitious cleft separates dense sclerotic nucleus from degenerated cortex. Nucleus shows intense homogeneous staining and lacks artifactitiously intercellular clefts seen in cortex.

Fig. 20-28. Cortical cataract. Morgagnian globules of degenerated lens protein fill cleft in lens cortex.

Fig. 20-29. Anterior subcapsular cataract. Collagenous plaque made by distressed lens epithelial cells is seen beneath folded anterior lens capsule. Basement membrane capsules surround residual lens epithelial cells within plaque. A fibrous papillary membrane rests on the anterior surface of this cataract.

Fig. 20-30. Posterior subcapsular cataract with Wed! cells. An aggregate of Wedl or bladder cells formed by posterior migration of the lens epithelium is seen next to thin posterior lens capsule. Wed! cells represent abortive attempts by lens epithelial cells to form new lens fibers.


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Posterior subcapsular cataract results from the migration

of lens epithelial cells posterior to the normal termination of the epithelium at the lens equator. Situated abnormally, the cells retain their nuclei and form large aberrant globular lens fibers called bladder or Wedl cells (Fig. 20-30). Globular transparent aggregates of lens cortical material called Elschnig pearls, which occasionally develop after extracapsular cataract surgery, reflect an identical proliferation of residual lens epithelial cells.

TUMORS Benign and malignant tumors of the eye and ocular adnexa may be classified as extraocular or intraocular. Extraocular tumors originate from the conjunctiva, cornea, palpebral skin, adnexal glands, and various mesenchymal cells of the orbit. These tumors are histologically similar to equivalent tumors in other sites (Fig. 20-32). Occasionally, some pigmented lesions, such as primary acquired melanosis, may pose problems. In traocular tumors are more unique, but even these neoplasms rarely exhibit features that are not seen in other locations.

Melanoma Melanoma is the most common primary intraocular tumor of adults, although it is regarded as rare. Only approximately 1500 new intraocular melanomas are diagnosed in the United States yearly. Persons of fair skin are at greater risk of developing melanoma than are those who have a dark complexion. Intraocular malignant melanomas arise from melanocytes in the iris, ciliary body, and choroid. They usually are solitary and unilateral. These tumors range from totally amelanotic white lesions to jet-black masses, and parts of individual tumors often vary greatly in pigment content. Melanomas of the choroid or ciliary body initially are ovoid, but choroidal tumors often rupture through Bruch membrane and proliferate in the subretinal space, so a characteristic mushroom or "collar button" configuration is assumed (Figs. 20-33 and 20-34). A flat, diffuse, or multinodular growth pattern occasionally occurs but is more typical of

Fig. 20-32. Primary acquired melanosis with atypia in conjunctiva. Conjunctival epithelium is massively thickened by atypical melanocytes, including epithelioid cells. Substantia propria contains lymphocytes and plasma cells. Invasive malignant melanoma was found nearby. Fig. 20-3I. Basal cell carcinoma. Tumor is composed of basaloid cells showing peripheral palisading.

Fig. 20-33. Choroidal malignant melanoma. Bruch membrane is intact overlying an almond-shaped tumor, which remains confined to the choroid. The tumor is variably pigmented.

Fig. 20-34. Choroidal malignant melanoma. This melanoma has a characteristic mushroom or collar button configuration, which results when the tumor perforates Bruch membrane and grows in the subretinal space. The overlying retina is detached by the mushrooming head of the tumor and adjacent serous fluid. The mushroom configuration is typical of uveal melanoma.


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metastatic than primary tumors. Histologically, uveal melanomas are composed of spindle-shaped or epithelioid cells. Spindle-shaped melanoma cells grow in a cohesive manner, forming a syncytium. Some spindle cells have slender nuclei (occasionally with a prominent longitudinal fold in the nuclear membrane) without nucleoli (spindle A cells) (Fig. 20-35). Other spindle-shaped cells have plumper nuclei with small distinct nucleoli (spindle B cells) (Fig. 20-36). Less differentiated epithelioid cells are larger, polygonal, and poorly cohesive, with distinct cytoplasmic margins. Epithelioid cell nuclei are round or oval, have one or more prominent nucleoli, and their chromatin clumps along the nuclear membrane.

Most primary uveal melanomas contain variable numbers of spindle A and B cells and epithelioid cells (mixed cell melanomas) (Figs. 20-37 and 20-38). Poorly differentiated melanomas sometimes contain abundant cytoplasmic lipid ( " balloon cell degeneration" ) or bizarre giant cells. Necrosis is common in all melanomas. Complications include hemorrhage, cataract, glaucoma, retinal detachment, and inflammation. The five-year survival rate is in the range of 55 percent to 85 percent, depending primarily on the size of the tumor. Other prognostic factors include the location, histologic type, and pigmentation of the tumor.

Fig. 20-35. Malignant melanoma, spindle A cell type. Spindle A cells have slender cigar-shaped nuclei, finely dispersed chromatin, indistinct nucleoli, and a chromatin stripe caused by a longitudinal fold in the nuclear membrane.

Fig. 20-36. Malignant melanoma, spindle B cell type. Spindle B cells have plumper oval-shaped nuclei with a distinct nucleolus.

Fig. 20-37. Choroidal malignant melanoma, epithelioid cell type. Nuclei are large and round and have prominent nucleoli. The chromatin is often clumped along the inside of the nuclear membrane (peripheral margination of chromatin). These cells are poorly cohesive.

Fig. 20-38. Malignant choroidal melanoma, mixed spindle and epithelioid cell type. This field contains a prominent clone of amelanotic epithelioid cells. In some mixed tumors epithelioid cells are admixed diffusely among the spindle cells.


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Retinoblastoma Retinoblastoma is the most common primary malignant eye

tumor of children. Most tumors are diagnosed before the age of two years. Approximately 90 percent of tumors are sporadic and 10 percent are familial. Bilateral tumors are found in approximately 10 percent of cases. Tumors are related to deletion or inactivation of the retinoblastoma (Rb) gene. Retinoblastoma originates from the retinal cells or their precursors. Tumors may show an exophytic, endophytic, or mixed endophytic and exophytic growth pattern. Clinically they produce leukokoria, which often is associated with strabismus (Fig. 20-39). Small tumors cause retinal detachment, whereas larger tumors fill the eye (Fig. 20-40). Tumors are

composed of primitive cells that correspond to fetal retinoblasts and their neuroblastic precursors. The degree of differentiation varies from one tumor to another. Some tumors are composed of densely packed, poorly differentiated neuroblastic cells with round, hyperchromatic nuclei, scant cytoplasm, and prominent mitoses; others contain typical Flexner-Wintersteiner rosettes consisting of a central round lumen surrounded by more differentiated cells that have a well-developed apical cytoplasm corresponding to the subretinal space (Fig. 20-41). The cells forming the rosettes are joined by a series of zonulae adherens analogous to the outer li miting membrane of the normal retina. The nuclei are

Fig. 20-39. Retinoblastoma. Leukokoria, a white papillary reflex, is a classic sign of retinoblastoma.

Fig. 20-40. Retinoblastoma. This exophytic growth arising from outer layers of the retina has caused total retinal detachment. The retina adheres to the posterior surface of lens, which is displaced anteriorly. This eye had secondary closed-angle glaucoma.

Fig. 20-41. Retinoblastoma. Flexner-Wintersteiner rosettes have a true lumen, which is analogous to the subretinal space. The apices of the cells comprising the rosette are joined by zonulae adherens like the external limiting membrane of the retina.

Fig. 20-42. Retinoblastoma. The center of a Homer VYright rosette contains a tangle of neural processes. A lumen is not present. Relatively nonspecific Homer Wright rosettes are found in other tumors such as neuroblastoma.


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Fig. 20-43. Retinoblastoma. The tumor shows photoreceptor differentiation and forms fleurettes and bouquets composed of neoplastic photoreceptor inner segments.

Fig. 20-44. Medulloepithelioma of the ciliary body. The tumor is located on the inner surface of ciliary process. The tumor consists of bands of thicker cells corresponding to primitive medullary epithelium and flat cells lining cystic spaces filled with vitreous-like fluid

placed abluminally, indicating that these cells are showing photoreceptor-like differentiation. The most differentiated tumors contain bouquet-like aggregates of relatively bland neoplastic photoreceptors called fleurettes, which are composed of bulbous eosinophilic cell processes that correspond to photoreceptor inner segments (Fig. 20-42). Less frequently the neuroblastic cells form Homer Wright rosettes that lack a central lumen and resemble those in neuroblastomas (Fig. 20-43). Extensive areas of necrosis often leave only a few perivascular cells intact, and viable tumor cells cuffing blood vessels may impart the appearance of pseudorosettes. Deoxyribonucleic acid released from the necrotic tumor cells may precipitate and impregnate intraocular blood vessels, the iris, the trabecular meshwork, the lens capsule, and other intraocular basement membranes. Neovascularization of the iris is common and may cause peripheral anterior synechiae and neovascular glaucoma. Long-term survival may be achieved with appropriate therapy, and in most developed countries the rate is in the

range of 90 percent. Favorable histologic findings include the presence of numerous fleurettes or Flexner-Wintersteiner rosettes. Ominous prognostic signs are optic nerve, choroidal, and orbital invasion. Patients with germline deletions of the Rb gene occasionally develop a benign counterpart of retinoblastoma called retinocytoma or retinoma. These tumors are almost completely composed of fleurette-forming cells, and although they may evolve into retinoblastoma, they have a favorable prognosis.

Medulloepithelioma Medulloepithelioma is a rare pediatric tumor composed of cords or sheets of polarized neuroepithelial cells that form elongated tubules and line cystic spaces in a loose mesenchymal stroma that is rich in hyaluronic acid, similar to primitive vitreous (Fig. 20-44). Parts of medulloepithelioma may resemble retinoblastoma, and such tumors may invade the cranium through the optic nerve. .


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Further Reading Albert D: The ocular melanoma story. Am J Ophthalmol 123:729-741, 1997. Akhtar S, Meek K, Ridgeway AEA et al: Deposits and proteoglycan changes in primary and recurrent granular dystrophy of the cornea. Arch Ophthalmol 117:310-321, 1999. Cunnigham ET, Seiff SR, Berger TG et al: Intraocular coccidiooidomycosis diagnosed by skin biopsy. Arch Ophthalmol 116:674677, 1998. Dunlop AAS, Cree IA, Hague S et al: Muitifocal chorioiditis. Clinicopathologic correlation. Arch Ophthalmol 116:801-803, 1998. Folberg R, Verdick R, Weingeist T, Montague P: Gross examination of eyes removed for ciliary body or choroidal melanoma. Ophthalmology 93:1643-1647, 1986. Font RL, Smith SL, Bryan RG: Malignant epithelial tumors of the lacrimal gland. A clinicopathologic study of 21 cases. Arch Ophthalmol 116:613-616, 1998. Kresloff MS, Castellarin AA, Zarbin MA: Endophthalmitis. Sur) Ophthalmol 43:193-224, 1998.

Margo CE, Mulla ZD: Malignant tumors of the eyelid. A populationbased study of non-basal cell and non-squamous cell malignant neoplasms. Arch Ophthalmol 116:195-198, 1998. Margo CE, Waltz K: Basal cell carcinoma of the eyelid and periocular skin. Sun' Ophthalmol 38:169-192, 1993. Moorthy RS, Mermoud A, Baerveldt G et al: Glaucoma associated with uveitis. Sun, Ophthalmol 41:361-394, 1997. Mooy CD, De Jong PTVM: Prognostic parameters in uveal melanoma: a review. Sun/ Ophthalmol 41:215-228, 1996. Seregard S: Conjunctival melanoma. Sur, Ophthalmol 41:321-228, 1996. Shields JA, Shields CL, Mercado G et al: Adenoma of the iris pigment epithelium: a report of 20 cases. The 1998 Pan-American lecture. Arch Ophthalmol 117:736-741, 1999. Wax MB, Tezel G, Edward PD: Clinial and ocular histopathologic findings in a patient with normal pressure glaucoma. Arch Ophthalmol 116:993-1001, 1998.




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INFLAMMATORY LESIONS OF THE EXTERNAL AND MIDDLE EAR Infections of the external and middle ear are common. Such infections may be caused by bacteria, viruses, and other pathogens. They are more common in children and in some populations that are at greater risk, such as people with acquired immunodeficiency syndrome (AIDS) and those with debilitating diseases and malnutrition. Infections may be acute or chronic. The pathologic changes they cause do not differ from those that are induced by similar infections in other anatomic sites. In some cases the inflammation is caused by foreign material, such as keratin or cholesterol crystals deposited in tissues. The cause of some inflammatory lesions, such as chondrodermatitis nodularis chronica helicis or relapsing polychondritis, is not known. Chondrodermatitis nodularis chronica helicis presents as a small painful nodule on the auricle, usually in the superior portion of the helix (Fig. 21-1). The cause of this lesion is not known. Microscopically the nodule usually shows ulceration with pronounced irregular acanthosis at its margins. The collagen in its center shows increased eosinophilia, appears degenerated, and is surrounded by granulation tissue and chronic inflammatory cells. The perichondrium of the underlying cartilage is inflamed, and the cartilage itself shows signs of degeneration. Relapsing polychondritis is a multisystemic disease that often involves the ear, the larynx, the heart, and the eye. It presents in the form of recurring bouts of inflammation that involve the cartilage of the ear. The earlobe is of normal shape but is hot and erythematous. Later the anterior surface may assume a cobblestone appearance, and the auricle may undergo atrophy. Microscopically the lesion consists of granu-

lation tissue invading the cartilage (Fig. 21-2). The ground substance of the cartilage becomes more acidophilic and stains more deeply with periodic acid-Schiff. Antibodies to type II collagen may be demonstrated in the blood but their significance remains unknown. Epithelioid hemangioma is a skin lesion that has a particular predilection for the pinna and the external auditory canal. It is also known as benign angiomatous nodule, angiolymphoid hyperplasia, or atypical pyogenic granuloma. Its nature is a subject of controversy; some clinicians consider it neoplastic, whereas others think that it is a form of chronic inflammation. Grossly it appears as small red or reddish-blue nodules or plaques that tend to coalesce and obstruct the external auditory canal. Microscopically the lesion is composed of proliferating capillaries lined by plump, occasionally multilayered endothelium, and surrounded by loose connective tissue infiltrated with lymphoid cells, eosinophils, macrophages, and mast cells (Fig. 21-3). Surgical resection is recommended because spontaneous regression may occur, albeit rarely. Keratin plugs form from cells that exfoliate from the skin of the external canal. Solid plugs may fill the external canal (keratosis obturans). Keratin deposits may form on the tympanic membrane, and occasionally keratin squames may even implant in deeper tissues and cause a keratin implantation granuloma (Fig. 21-4). Xanthomas, which are deposits of cholesterol, may occur in the ears of patients with hereditary hyperlipidemia. Deposits may occur in the subcutaneous tissue and in bone, and they usually evoke a histiocytic reaction. Clefts of cholesterol and lipid-laden macrophages are seen on microscopic examination (Fig. 21-5).

A

B

Fig. 21-I. Chondrodermatitis nodularis chronica helicis. A, A scaly ulcerated nodule is seen on the upper part of the helix. B, Histologically the ulceration of the acanthotic epidermis extends into the underlying cartilage, which shows signs of degeneration.


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Otitis media is a common disease in children but it also may occur in adults. Repeated bouts of acute otitis media may progress to chronic otitis media, which is characterized by a variety of pathologic changes. The tubotympanic region and mastoid air cells most often are involved. The mucosa of the tympanic membrane may be thickened and congested, and it may show surface irregularities and bulges (Fig. 21-6). Granulation tissue may be so extensive as to form polyps or protrude through the perforation of the tympanic membrane. The epithelium of the middle ear, which usually is devoid of tubuloalveolar glands, proliferates and gives rise to tubuloalveolar glands, which normally are not found in the middle ear (Fig. 21-7). Granulation tissue ultimately matures into dense connective tissue, and such fibrosis may replace normal middle ear elements and extend into the bone (Fig. 21-8). Cholesterol granulomas often are formed from lipids released

Fig. 21-2. Relapsing polychondritis. The cartilage is invaded by granulation tissue.

Fig. 21-3. Epithelioid hemangioma of the pinna. The lesion consists of blood vessels lined by plump endothelial cells and loose stroma infiltrated with lymphocytes, eosinophils, and macrophages.

Fig. 21-4. Keratin implantation granuloma of ear canal. Keratin has evoked a granulomatous reaction with foreign body giant cells.

Fig. 21-5. Xanthoma of mastoid bone. Cholesterol clefts are seen between bone trabeculae. The patient had type V hyperlipoproteinemia.

Fig. 21-6. Chronic otitis media. The tympanic membrane appears thickened and bulges irregularly.


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from the blood and other cells. Tympanosclerosis develops as a result of the deposition of aggregates of hyalinized collagen on the tympanic membrane. It may have a laminated appearance and may contain metaplastic bone (Fig. 21-9). Cholesteatomas are space-occupying lesions of the middle ear that are composed of keratin-forming squamous epithelium. They may be congenital or acquired. Acquired cholesteatomas often are found in ears affected by chronic inflammation. Although the precise pathogenesis of cholesteatoma is not known, it is assumed that it results from proliferation of irritated squamous epithelium within the confines of the middle ear. Squamous epithelium forms keratin-filled cysts (Fig. 21-10). Ruptured cysts may evoke a foreign body giant cell reaction and intensify the chronic inflammation. AlFig. 21-7. Chronic otitis media of the middle ear. The connective stroma contains newly formed tubuloalveolar glands (glandular metaplasia of the middle ear).

Fig. 21-8. Low-grade otitis media in an AIDS patient. The mastoid air cells contain connective tissue and tubuloalveolar glands. Fig. 21-9. Tympanosclerosis. The tympanic membrane consists of laminated hyalinized material and metaplastic bone.

Fig. 21-10. Cholesteatoma. The lesion is lined by keratinizing squamous epithelium. The adjacent middle ear stroma shows chronic inflammation and glandular metaplasia.

Fig. 21-I I. Cholesteatoma. Squamous epithelium extends downward into the stroma.


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though the squamous epithelium that lines cholesteatomas is composed of benign cells, it may extend into adjacent structures and it often infiltrates the mastoid air cells (Fig. 21-11).

PATHOLOGIC CHANGES OF THE INNER EAR Pathologic changes of the inner ear cause deafness and loss of balance. These changes may be classified as (1)-developmental malformations; (2) ototo)ic conditions; (3) infections; and (4) idiopathic conditions of unknown etiology and pathogenesis, such as Meniere disease, presbycusis, osteopetrosis, and otosclerosis. Infections of the inner ear may be caused by viruses, bacteria, or fungi. Viral infections, which reach the inner ear hemotogenously, are an important cause of hearing loss. The developing ear is especially susceptible, and in the preimmunization ear intrauterine rubella virus was a common cause of congenital deafness. The damaged inner ear shows marked cochlear hydrops (Fig. 21-12). Suppurative labyrinthitis or petrositis usually is a complication of local bacterial infections that spread by contiguity to the inner ear, but they also may be hematogenous. Fungal diseases are rare and most often are found in immunosuppressed persons, such as those who have AIDS (Fig. 21-13). Presbycusis is the hearing loss that occurs in aged persons and which cannot be ascribed to any cause other than old age. Degenerative changes in at least four different sites in the cochlea have been implicated as the pathologic basis for the hearing loss. These sites are the hair cells, spiral ganglion cells, stria vascularis, and basilar membrane. Surface preparation of perfused cochleas stained for light microscopy shows considerable losses in the outer hair cells, with lengthening and thickening of stereocilia emanating from some surviving outer hair cells (Fig. 21-14). The numbers of spiral ganglion cells are reduced, but this usually occurs in later stages of disease, possibly secondary to the primary atrophy of hair cells.

Fig. 21-13. Cryptococcal infection in AIDS. Fungi fill spaces in the basilar membrane that normally are occupied by nerve fibers.

Fig. 21-14. Presbycusis. Surface preparation of the middle coil of the cochlea show a diminished number of outer hair cells and giant stereociliary degeneration. The preparation was stained with osmic acid, Alcian blue, and phloxine.

Fig. 21-15. Paget disease. Ossification is accompanied by prominently bluish globuli ossei (calcified cartilage cells).

Fig. 21-12. Rubella infection. Cochlear hydrops is the main consequence of this fetal viral infection associated with deafness.


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Fig. 21-16. Otosclerosis. Microslice of temporal bone shows a hypervascular focus of otosclerosis adjacent to the cochlea.

Fig. 21-17. Otosclerosis. Otosclerotic foci composed of woven bone involve the footplate of the stapes.

Fig. 21-18. Basal cell carcinoma. Lobules of basal cells are found in the upper dermis. Cystic change in the deeper dermis imparts an adenoid cystic appearance to the tumor.

Fig. 21-19. Ceruminous adenoma. The tumor is composed of glands lined by a bilayered epithelium. The cells have uniformly round nuclei and show aprocrine secretion.

Fig. 21-20. Cylindroma of the external canal. Tumor nests in hyalinized stroma are arranged in a jigsaw puzzle—like pattern. Some nests contain round hyaline globules.

Paget disease is a disease of unknown origin that primarily affects bones. It is an important cause of hearing loss, which may be traced to changes in the periosteal and endochondral part of the labyrinth (Fig. 21-15). Otosclerosis is a common but poorly understood focal lesion of the otic capsule that is found principally in relation to the cochlea and footplate of the stapes. Otosclerotic deposits not associated with hearing loss have been noted at autopsy in 10 percent to 13 percent of adults and are found in the otic capsule bone anterior to the oval window. Conductive deafness occurs in a smaller number of such persons as the extension of this otosclerotic lesion to the footplate of the stapes. At autopsy the focus of otosclerosis appears well demarcated and pink because of prominent evenly distributed blood vessels (Fig. 21-16). Microscopically, otosclerotic foci are made up of trabeculae of woven bone with abundant osteoblasts (Fig. 21-17).


455

NEOPLASMS Tumors of the Outer Ear Basal cell carcinoma is the most common neoplasm of the ex-

ternal ear. It typically occurs on the sun-exposed pinna and is rare in the auditory canal. It is identical to basal cell carcinoma in other sites (Fig. 21-18). Squamous cell carcinoma of the external ear accounts for 7 percent of all squamous cell carcinomas of the head and neck. Ceruminous adenoma is a benign tumor of the ceruminous glands. Microscopically, although benign, it lacks a definite capsule and is composed of regular glands lined by a bilayered epithelium (Fig. 21-19). The luminal surface of tumor cells shows cytoplasmic projections. The cytoplasm of tumor cells contains acid-fast fluorescent pigment similar to that found in normal ceruminous glands. Malignant ceruminous gland tumors are rare. Cylindroma is a benign tumor that occurs in the external canal. Histologically it is composed of a rounded mass of small, darkly stained cells that fit together in a jigsaw puzzle—like pattern (Fig. 21-20).

Fig. 21-21. Adenoma of the middle ear. The tumor is composed of small glands arranged in a back to back pattern.

Tumors of the Middle Ear Adenoma of the middle ear is a rare benign tumor arising from

the metaplastic glands that form from the inner ear epithelium as a result of chronic inflammation. Microscopically it is composed of a small tubular gland with a back to back appearance (Fig. 21-21).A solid or trabecular arrangement may result in apparent loss of the glandular pattern. The cells are cuboidal or columnar, and the lumina may contain secretions. No myoepithelial layer is seen. Other middle ear tumors are neuroendocrine adenomas or low-grade malignancies (carcinoids) and paragangliomas. Paragangliomas have a typical lobular " Zellballen" appearance in which the main cells are surrounded by sustentacular cells (Fig. 21-22). Squamous cell carcinoma is the most common malignant neoplasm of the middle ear. Papillary adenocarcinomas, hemangiomas, meningiomas, and rhabdomyosarcomas are rare.

Fig. 21-22. Paraganglioma. Groups of epithelioid cells are surrounded by sustentacular cells in a typical "Zellballen" appearance.

Tumors of the Inner Ear Acoustic neuroma, which is bilateral in 10 percent of cases, is

the most common tumor of the inner ear. Low grade adenocarcinoma of probable endolymphatic sac origin may be associated with von Hippel-Landau disease. It is a papillary low-grade adenocarcinoma (Fig. 21-23) reminiscent of choroid plexus papilloma. Other tumors are rare.

Further Reading Kempermann G, Neumann HPH, Volk B: Endolymphatic sac tumours. Histopathology 33:2-10, 1998. Kuhel WI, Hume CR, Selesnik SH: Cancer of the external auditory canal and temporal bone. Otolaryngol Clin N Amer 29:827-852, 1996. Mills SE, Fechner RE: Middle ear adenoma. A cytologically uniform neoplasm displaying a variety of architectural patterns. Am J Surg Pathol 8:677-685, 1984. Tran LP, Grundfast KM, Selesnik SH: Benign lesions of the external auditory canal. Otolaryngol Clin N Amer 29:807-826, 1996.

Fig. 21-23. Low-grade adenocarcinoma of the endolymphatic sac. The tumor forms papillae projecting into spaces filled with proteinaceous material. Glandlike spaces are filled with the same material.


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INDEX A Abnormalities; see also Anomalies placental, 287 positional, renal, 210, 210d Abscesses biliary hepatic, 150, 150f brain, 410, 410f cerebral, 410, 410f cholangitic, 150, 150f 156, 157f lung, 54, 55f Munro microabscesses, 321 myocardial, 16, 16f pyogenic, 409, 409d Acanthocytosis, 74,76f Accessory lobe, 50, 51f Acetaminophen, 152, 152f Achondroplasia, 356, 356f Acid maltase deficiency adult form, 392, 392f infantile form, 392, 392f Acinar cell carcinoma, 174, 175f Acinic cell adenocarcinoma, 116f 117 Acoustic neuroma, 455 Acquired immunodeficiency syndrome cryptococcal infection in, 453, 453f low-grade otitis media in, 451, 452f oral manifestations of, 104, 104t psoriasiform dermatitis of, 314-316, 316f testicular, 242, 243f Acral lentiginous melanoma, 327 invasive, 327, 328f Actinic keratosis, 328, 329f Acute Iymphoblastic leukemia, 78, 79f Acute myeloid leukemia, 78, 78f classification of, 781 Acute stress erosions, 124 Acute tubular necrosis, 228-229, 229f toxic, 228-229, 229t Adamantinoma, 380, 3811 Addison disease, idiopathic, 198 Adenoacanthoma, 268, 269f Adenocarcinoma acinic cell, 116f 117 of cervix, 267-268 clear cell of ovary, 277f, 278 of vagina, 265, 265f 266f of colon, 139, 139f metastasis from, 285, 28Sf cystadenocarcinoma, mucinous, 276f 277 of ductal origin, 174, 174f endometrial, 268, 268f 269f staging of, 268, 2691 endometrioid, 276f 277 well-differentiated, 277, 277f of esophagus, 118, 118f 119f low-grade of endolymphatic sac, 455, 455f polymorphous, 117, 117f mucinous, 172, 173f peripheral, 68, 68f in pleomorphic adenoma, 114, 114f prostatic Gleason grading system of, 253, 255f 255t

Adenocarcinoma-cont ' d prostatic-cont'd variants of, 254t of rete testis, 248, 248f serous papillary, 268, 269f with squamous differentiation, 268, 269f of stomach, 134, 135f in tubular adenoma, 139, 139f of uterus, 268 villoglandular, 268, 268f villoglandular papillary, 268, 268f Adenofibroma, endometrioid, 277, 277f Adenoid basal cell tumors, 249 Adenoid cystic carcinoma, 116f 117 Adenoid cystic-like tumor, 249 Adenoma adrenal, 201-203, 201f adrenocortical, 201-203, 201f basal cell, 114, 115f 249 with bizarre nuclei, 190, I90f of breast, 298, 298f 299 ceruminous, 454f 455 corticotroph, 184, 185f follicular, 188, 189f hepatocellular, 161, 161 f hyalinized trabecular, 188-190, 190f intraductal papillary mucinous, 172, 173f lactating, 298, 298f of middle ear, 455, 455f oncocytic (Hurthle cell), 190, 190f papillary, 172, 173f parathyroid, 195-196, 197f pituitary, 183f 184, 184f frequency of, 1831 pleomorphic, 114, 114f prolactin cell, 184, 184f tubular, 138f 139 adenocarcinoma in, 139, 139f villous, 138f 139 of pancreatic ducts, 172, 173f Adenomatoid malformation, congenital cystic, 50, 51f Adenomatoid tumors, 248, 248f odontogenic, 112, 112f Adenomatous hyperplasia, 250, 251f atypical, 250, 251f endometrial, 261-263, 262f Adenosarcomas, 277 mullerian, 271, 271f Adenosis, 250 blunt duct, 296 microglandular, 296 sclerosing, 250, 296 vaginal, 265, 265f from DES exposure in utero, clear cell adenocarcinoma in, 265, 266f Adenosquamous carcinoma, of pancreas, 174, 175f ADH; see Atypical intraductal hyperplasia Adnexa, ocular, 435-446 Adnexal tumors, 331-333 ADPKD; see Autosomal dominant polycystic kidney disease Adrenal adenoma, 201-203, 201f

Adrenal cortex diseases of, 198-203 hyperfunction of, 199-201 syndromes, 199, 201d Adrenal gland, macronodular hyperplasia of, 199-201, 200f Adrenal masses, encephaloid, 205 Adrenal medulla diseases of, 203-206 hyperplasia of, 203, 203f Adrenalitis f autoimmune, 1 immune-mediated, 199, 199f infectious, 198f 199 Adrenocortical adenomas, 201-203, 201f aldosterone-producing, 202, 202f Adrenocortical carcinoma, 202f 203 Adrenocortical disease, primary pigmented nodular, 200f 201 Adrenocortical hyperplasia, 199-201, 200f in Cushing disease, 199, 200f diffuse, 199, 200f nodular, 199, 200f Adrenocortical insufficiency, 198-199 Adrenocortical tumors, 201-203 Adrenogenital syndrome, 199, 201d Adrenoleukodystrophy, 198, 198f Aganglionosis, 122, 123f Age-related macular degeneration, 441, 441f Agenesis gonadal, 258t mixed gonadal, 258t renal, 210, 210f Agyria-pachygria complex, 401, 401f AIDS; see Acquired immunodeficiency syndrome Albers-Schonberg disease, 356 Alcoholic cirrhosis, 154, 154f Alcoholic hepatitis, 153, 154f Alcoholic liver diseases, 153-154 Aldosterone-producing adrenocortical adenomas, 202, 202f ALH; see Atypical intralobular hyperplasia Allergic drug reactions, 58, 59f Allergy, 42 Alport syndrome, 213-214, 214f Alveolar damage, diffuse, 56 Alveolar proteinosis, pulmonary, 66, 67f Alveolar rhabdomyosarcoma, 346 Alveolar soft-part sarcoma, 352f 353 Alzheimer disease, 418, 418f 419f Amebiasis, 130, 132f hepatic, 151, 151f Amebic colitis, 130 Amelia, 357, 357f Ameloblastic fibroma, 112, 113f Ameloblastoma, 112, 112f unicystic, 105, 105f AML; see Acute myeloid leukemia Amnion rupture, early, 288f, 289 Amniotic fluid, aspiration of, 52, 53f Amyloid, 231f 232 Amyloid neuropathy familial, 430, 430f hereditary, 430, 430f


457

Amyloidosis, 129-130, 198, 198f 231f 232 of heart, 18, 19f renal, 82, 83f Amyotrophic lateral sclerosis, 420, 420f 421f denervation atrophy caused by, 396, 396f Anal carcinomas, basaloid type, 140, 141f Anal gland carcinoma, 140, 141f types of, 140 Anal intraepithelial neoplasia, 140, 140f vulvar intraepithelial neoplasia with, 263f 264 Anal tumors, 140 benign, 140 malignant, 140 Analgesic abuse nephropathy, 239 Anaphylactoid or rheumatoid purpura, 222 Anaplastic astrocytoma, 422, 422f Anaplastic carcinoma, of thyroid, 194, I95f Andersen disease, 392 Androgen insensitivity, 259f Anemias, 74-77 aplastic, 74, 74f bone marrow changes in, 74, 74f 75f classification of, 74, 74t hemolytic, 76f 77 peripheral blood smears in, 74-77, 75f-76f pernicious, 74, 75f refractory, 80t sickle cell, 76f 77, 78f tissue changes in, 77, 77f, 78f Anencephaly, 400, 400f Aneurysmal bone cysts, 380-383, 381f Aneurysms, 35 atherosclerotic, 34f, 35 berry, 35, 35f subarachnoid hemorrhage caused by rupture of, 407, 407f cirsoid, 35, 35f diabetic microaneurysms of retina, 437, 438f dissecting, of aorta, 35, 35f retinal arterial macroaneurysms with hard exudates, 437, 438f syphilitic, 35, 36f ventricular, 24, 24f Angina, Ludwig, 104, 104f Angiocentric lymphoma, 94, 94f Angiodysplasia, intestinal, 124, 125f Angiofibroma, juvenile nasopharyngeal, 44, 45f Angioleiomyomas, 344, 344f Angiomyxoma, aggressive, 264, 265f Angiosarcoma, 163, 342f 343 Annular tubules, sex cord stromal tumors with, 281, 281f Anomalies bronchial, 50 conotruncal, 4, 4d developmental of lungs, 50 of upper digestive tract, 102-103 of esophagus, 103 placental, 287 positional of gastrointestinal tract, 122 renal, 210, 210d pulmonary, 50, 51f of teeth, 103 of tongue, 102, 102f Anovulatory cycle, 261-263, 261f

Anti-glomerular basement membrane disease, 224-225 a 1 -Antitrypsin deficiency, 144, 145f Anus, Paget disease of, 140, 141f Aorta coarctation of, 6, 7d, 9, l if dissecting aneurysms of, 35, 35f Aortic insufficiency, due to dilatation of aortic root, 13, 14f Aortic stenosis, 6, 7d congenital, 6, 8f degenerative calcific, 13, 14f Aortic valve bicuspid, 6, 7f chronic rheumatic endocarditis of, 10, 11f Aortitis, syphilitic, 36, 37f Aphthous ulcers, 103, 103f Aplasia, germ cell, 240f 241 Apparent females, intersex syndromes affecting, 258t Appendicitis, acute, 130, 131f Appendix inflammation of, 130-132 mutinous cystadenoma of, 136, 137f tumors of, 136, 137f Architectural disorder compound melanocytic nevus with, 325-326, 325f 326f junctional melanocytic nevus with, 324, 324f minimal, 324, 324f moderate, 324, 324f severe, 324, 325f Arnold-Chiari malformation, 400-401, 400f ARPKD; see Autosomal recessive polycystic kidney disease Arteriopathy, plexogenic pulmonary, 58, 58f Arteriosclerosis, 32-35 forms of, 32 hyaline, 32, 32f hyperplastic, 32, 32f 33f hypertensive, 32 Arteriosclerotic leukoencephalopathy, subcortical, 409, 409f Arteritis, Takayasu, 38, 38f Arthritis bacterial, 363 crystal-induced, 360-361 rheumatoid, 364-366, 364f 365f 366f seronegative, 364 tuberculous, 363, 363f viral, 363 Arthropathies, noninfectious, 364-367 Asbestos, 64, 64d Asbestosis, 64, 65f Aschoff bodies, 9, 9f Aspergillosis cerebral, 410-411, 411f fungal vasculitis of, 36 Aspiration of infected amniotic fluid, 52, 53f Asthma, 58, 59f Astrocytic tumors, 422 Astrocytoma anaplastic, 422, 422f cystic, of cerebellum, in child, 422, 422f of pons, 422, 422f Atelectasis, neonatal, 52, S2f Atheroma, 34f 35 Atherosclerosis, 34f 35, 408

Atherosclerosis—cont ' d coronary, 20, 20f 21f outcomes of, 20, 21d severe, 34f Atherosclerotic aneurysms, 34f,' ATN; see Acute tubular necrosis Atrial septal defects, 2 fossa or secundum, 2, 3f Atrophic thyroiditis, 188 Atrophy denervation, 396, 396f glaucomatous retinal, 439, 439f granular, 409, 409f multisystem, 419, 419f neurogenic, chronic, 396, 396f olivopontocerebellar, 419, 419f prostatic, 248 spinal muscular fascicular, 396, 397f infantile, 396, 397f Atypia, cytologic lentiginous junctional melanocytic nevus with minimal architectural disorder and, 324, 324f lentiginous junctional melanocytic nevus with moderate architectural disorder and, 324, 324f lentiginous junctional melanocytic nevus with severe architectural disorder and, 324, 325f Atypical ductal hyperplasia, 301-302, 301f Atypical intraductal hyperplasia, 301-302, 301f Atypical intralobular hyperplasia, 301, 301f 302 Atypical lobular hyperplasia, 301, 301f 302 Auer rods, 78, 79f Autoimmune adrenalitis, 199, 199f Autoimmune chronic hepatitis, 155 Autoimmune hepatitis, 155, 155f Autoimmune liver diseases, 155-156 Autosomal dominant polycystic kidney disease, 212, 212f Autosomal recessive polycystic kidney disease, 212-213, 213f Axonal regeneration, 426, 427f Axonopathy acute, 426, 427f chronic, 426, 427f

B B-cell lymphocytic leukemia, chronic, 80, 81f B-cell lymphoma large cell immunoblastic, 92 T-cell rich, 92, 93f Backwash ileitis, 133 Bacterial arthritis, 363 Bacterial cholangitis, 150, 150f Bacterial endocarditis, acute, 11, 1lf on chronic healing endocarditis, 12, 12f on chronic rheumatic endocarditis, 12, 12f Bacterial infections acute, 149-150 of nervous system, 410 of skin, 313-314 Bacterial meningitis, 410, 410f Ball valves, 27f Balloon cell degeneration, 444 Barrett esophagus, 110, 111 f with dysplasia, 118, 118f


458

Barrett esophagus-coned with early carcinoma, 118, 118f Basal cell adenoma, 114, 115f 249 Basal cell carcinoma, 330f 331 features of, 331 of outer ear, 454f 455 types of, 331 Basal cell hyperplasia, 248 atypical, 249 Basal cell tumors, adenoid, 249 Basosquamous carcinoma, 331 Becker muscular dystrophy, 388 Becker nevus, 323 Benign prostatic hyperplasia, 248-250, 248f 249f atropic variant, 248, 249f variants, 248-250, 249f Berger disease, 222 Berry aneurysms, 35, 35f subarachnoid hemorrhage caused by rupture of, 407, 407f Berylliosis, 64, 64f Bile infarcts, 156, 157f Bile lakes, 156, 157f Biliary cirrhosis, 156, 156f primary, 155-156, 155f Biliary hepatic abscesses, 150, 150f Biliary infections, 150-151 ascending, 150 Biliary obstruction, 156, 157f causes of, 156, 156t extrahepatic, 156, 157f Biliary tract circulatory disorders of, 146-147 diseases of, 142 Binswanger disease, 409, 409f Bite cells, 76f . Bizarre leiomyoblastoma, 345, 345f Bladder; see Urinary bladder Blastoma, pulmonary, 70, 70f Blood smears, peripheral, 74-77 Blood vessels, 31-39 diseases of, 30 endothelial tumors of, 341, 341t Blue nevus, 332f 333 cellular, 332f 333 Blunt duct adenosis, 296 Bone(s), 355-383 chondromyxoid fibroma of, 373-375, 374f degenerative diseases of, 357-359 developmental disorders of, 356-357 diseases involving, 354 fibrous lesions of, 377-378 genetic disorders of, 356-357 giant cell tumor of, 378-379, 379f infections of, 363-364 inflammatory diseases of, 363-367 long, adamantinoma of, 380, 381f mastoid, xanthoma of, 450, 451f metabolic diseases of, 357-359 neoplasms of, 367-383 Paget disease of, 359-360, 359f 360f tumor-like conditions of, 380-383 Bone cysts, aneurysmal, 380-383, 381f Bone-forming tumors, 349-350, 349t benign, 367-369 malignant, 369-370 Bone marrow changes in anemia, 74, 74f 75f

Bone marrow-coned normal adult, 74f tumors, 379 Bone tumors, 380-383 locations of, 369, 369d Borrelia burgdorferi infection, 363 Botryoid rhabdomyosarcoma, 346 Botryoid sarcoma, 266, 266f Bowen disease, 263, 328, 329f BPH; see Benign prostatic hyperplasia Brain circulatory disturbances of, 405-409 edema of, 404f, 405 infarcts of, 402 infections of, 409-410 injuries to, impact vs nonimpact, 403, 404d " morocco leather" surface, 401, 401f perinatal lesions, 401-402 trauma of, 403-405 Brain abscesses, 410, 410f Branching enzyme deficiency, in young child, 392-393, 392f Breast, 295-309 development of, 296, 296d fibrocystic changes, 296, 297f lesions of, 294 tumors of, 298-308 Breast carcinoma grading of, 305, 305f 305t histologic types, 303, 303t immunohistochemistry of, 308, 309f infiltrating ductal not otherwise specified, 303-305, 304f nuclear atypia in, 305, 305f invasive, 303-305 variants of, 306-308 noninvasive, 302-303 categories of, 302 variants of, 306 Brenner tumors, 278, 278f Bronchial anomalies, 50 Bronchial carcinoid, 68, 69f Bronchiectasis, 60 Bronchiolitis obliterans, 52, 66, 66f Bronchioloalveolar carcinoma, 68, 69f Bronchitis, chronic, 60, 61f Bronchogenic cysts, 50, 50f Bronchopneumonia, 54, 54f Bronchopulmonary dysplasia, 52, 53f Bronchopulmonary sequestration, extralobar, 50, 51f Bronchus, squamous cell carcinoma of, 68, 68f Brown tumors of hyperparathyroidism, 359, 359f Budd-Chiari syndrome, 146, 146f Bullae, subpleural, 60, 61f Bullous keratopathy, pseudophakic, 440, 440f Bullous pemphigoid, 316, 317f Burkitt lymphoma, 94-95, 95f ovarian, 285, 285f " Burst lobe," 405, 405f Butterfly rash, 318, 318f

C Calcific aortic stenosis, degenerative, 13, 14f Calcific sclerosis, Monckeberg medial, 32, 33f Calcifications, "chicken wire, " 375 Calcifying epithelial odontogenic tumor, 112, 113f

Calcium balance, 195, 196d Calcium metabolism, 195, 196d Call-Exner bodies, 278, 279f Campylobacter jejuni infection, 430 Canavan-Van Bogaert-Bertrand disease, 415, 415f Cancer; see Carcinoma Candida albicans infection, 410-411 " Cannonball " lesions, 70, 71f Capillary hemangioma, retinal, 438, 438f Caplan lesions, 367 in coal workers ' pneumoconiosis, 62, 63f Carbohydrate storage diseases, 392-393 Carcinoid heart disease, 13, 13f Carcinoid heart syndrome, 13, 13f Carcinoid tumors bronchial, 68, 69f goblet cell, 136, 137f pulmonary, 68, 69f of small intestine, 136, 136f strum!, 283, 284f Carcinoma; see also Adenocarcinoma acinar cell, 174, 175f adenoid cystic, 116f 117 adenosquamous, of pancreas, 174, 175f adrenocortical, 202f 203 anal, basaloid type, 140, 141f anal gland, 140, 141f anaplastic, of thyroid, 194, 195f basal cell, 330f 331 of outer ear, 454f 455 basosquamous, 331 breast immunohistochemistry of, 308, 309f invasive, 303-305 invasive variants, 306-308 noninvasive, 302-303 variants of, 306 bronchioloalveolar, 68, 69f of cervix, 266, 267f cholangiocellular, 163, 163f choriocarcinoma, 245, 246f 282, 290, 292f features of, 291t clear cell of breast, 308, 308f of endometrium, 268, 269f of ovary, 278 colloid, 306 cribriform, 307, 307f cystic, adenoid, 116f 117 early, Barrett esophagus with, 118, 118f embryonal of ovary, 282 of testis, 244, 245f endometrial, 268, 268t endometrioid, 268, 276f 277, 277f epithelial-myoepithelial, 117, 117f of esophagus, 118, 118f follicular, 191-193, 192f of gallbladder, 164, 165f gastric, 134, 135d hepatocellular, 161-162, 16lf 162f Hiirthle cell, 193, 193f features of, 190t infiltrating ductal, not otherwise specified, 303-305, 304f infiltrating lobular, 305, 306f intraductal papillary mucinous, 172, 173f invasive


459

Carcinoma—cont'd invasive—cont ' d of breast, 303-305 of cervix, 267, 268f cribriform, 307, 307f variants of, 306-308 invasive papillary, 308, 308f of large intestine, 139-140 of larynx, 47, 47f medullary, 193-194, 194f 306, 307f variants of, 194, 195f Merkel cell, 332f 333 metaplastic, 308, 308f metastatic, 70, 71f metastatic to liver, 163, 164f mucinous (noncystic) of breast, 306, 307f of large intestine, 139-140 of pancreas, 174, 175f mucoepidermoid, 117 nasopharyngeal, 45-47, 46f oncocytic (Hiirthle cell), 193, 193f features of, 190t of pancreas, 174, 174f 175f papillary invasive, 308, 308f of thyroid gland, 190-191, 191f variants of, 191, 192f parathyroid, 196, 197f pituitary, 184 polymorphous low-grade, 117, 117f poorly differentiated of thyroid, 190t, 194, 195f of thyroid glandoncocytic (Hiirthle cell), 190t of prostate, 250-253, 251f 252f renal cell, 234, 234f of rete testis, 248, 248f salivary duct, 117, 117f salivary gland—like, 308, 308f sebaceous, 117, 117f 332f 333 secretory, 308, 308f serous, of ovary, 275, 275f signet-ring, 308, 308f small cell of esophagus, 118 with hypercalcemia, 284, 284f of lung, 68, 68f of urinary bladder, 237, 237f squamous cell of bronchus, 68, 68f esophageal, 118, 118f hilar, 68, 68f invasive of cervix, 267, 268f of vulva, 264, 264f of larynx, 47, 47f of nasal vestibule, 45, 46f of skin, 328, 329f of vagina, 265 variants of, 112 verrucous, 112, 112f of vocal cord, 47, 47f vulvar, 263 of stomach, 134, 134f 135f teratocarcinomas, 244, 245, 245f thymic, 98, 99f thyroid, 190t

Carcinoma—cont ' d transitional cell—cont'd of renal pelvis, 235, 235f of urinary bladder, 236f 237 tubular, 306-307, 307f undifferentiated of pancreas, 174, 175f of thyroid, 190r, 194, 195f of urinary bladder, 236f 237 verrucots anal, 140, 141f oral, 112, 112f of vocal cord, 47, 47f of vulva, 263-264, 263f 264, 264f yolk sac, 282, 282f Carcinoma in situ ductal comedo type, 302, 302f lobular, 302-303, 303f noncomedo type, 302, 303f testicular, 242, 243f of urinary bladder, 237, 237f vulvar, 263 Carcinosarcomas, 277 Cardiac malformations, 2 Cardiac tumors, 27 Cardiomyopathy, 17-18 dilated, 17, 17f causes of, 18d hypertrophic, 18, 18f 19f causes of, 18d congenital, 18, 18f 19f primary, 17 restrictive, 18, 19f causes of, 18d secondary, 17 types of, 17, 18d Cardiovascular diseases, that affect eyes, 437, 437t Cardiovascular obstructions, 6-9, 7d Cardiovascular shunts, 2, 2d Carditis, rheumatic, 9, 9f Cartilage-forming tumors, 349-350, 3491 benign, 372-375 malignant, 375-377 Castleman disease, 84, 85f hyaline vascular type, 84, 85f plasma cell variant, 84, 85f Cataracts, 442-443, 442f anterior subcapsular, 442-443, 442f cortical (soft), 442, 442f nuclear sclerotic, 442, 442f posterior subcapsular, 442f 443 types of, 442 Cavernous hemangioma, giant congenital, 102, 103f Cavitary tuberculosis, 54 Celiac disease, 128, 128f Cellular blue nevus, 332f 333 Cellular leiomyomas, 271 Central core disease, 386, 386f Central nervous system degenerative diseases of, 418-420 denervating diseases of, 395t diseases of, 398 metabolic diseases of, 413, 413t neoplasms of, 421-426 classification of, 416t location and age, 421d

Central nervous system—cont 'd spongy degeneration of, in infancy, 415, 415f toxic diseases of, 413, 413t Central pontine myelinolysis, 413, 413f 414f Centronuclear myopathy, 386, 387f Cerebellar infarcts, acute, 408, 408f Cerebellum, cystic astrocytoma of, in child, 422, 422f Cerebral abscesses, 410, 410f Cerebral arteries, granulomatous giant cell vasculitis of, 36, 36f Cerebral aspergillosis, 410-411, 411f Cerebral cortex, granular atrophy of, 409, 409f Cerebral infarcts in middle cerebral artery distribution, 408, 408f old, 408, 408f Cerebral ischemia, 408-409 chronic, 408-409 Ceruminous adenoma, 454f 455 Cervical intraepithelial neoplasia, 266, 267f CIN I, 266, 267, 267f CIN Il, 266, 267, 267f CIN III, 266, 267, 267f Cervix, tumors of, 266-268 Chagas disease, 16, 16f Chalazion, 436, 436f Charcot-Leyden crystals, 59f Charcot-Marie-Tooth disease, 428-429 type I, 428-429, 429f Chemical gastritis, 126, 127f " Chicken wire " calcifications, 375 "Chicken wire " fibrosis, 154, 154f Children; see also Infancy cystic astrocytoma of cerebellum in, 422, 422f teratomas of, 246 Chlantydia infection, 260 Chloroma, 96 "Chocolate" cysts, 263, 263f Cholangiocellular carcinoma, 163, 163f Cholangitic abscesses, 150, 150f 156, 157f Cholangitis bacterial, 150, 150f chronic nonsuppurative destructive, 155, 155f primary sclerosing, 156, 156f Cholecystitis, 164, 164f acute, 164, 164f chronic, 164, 164f chronic active, 164, 165f follicular, 164 Cholestasis, 152, 153f Cholesteatomas, 452-453, 452f Chondroblastoma, 375, 375f Chondrodermatitis nodularis chronica helicis, 450, 450f Chondroid, 375 Chondroma, periosteal, 373, 374f Chondromatosis, synovial, 382f 383 Chondromyxoid fibroma, 373-375, 374f Chondrosarcoma, 350, 375, 376f classic, 375-376, 376f clear cell, 377, 377f dedifferentiated, 376 extraskeletal myxoid, 350, 350f mesenchymal, 376-377, 377f of soft tissue, 350, 350f variants, 376 Chordoma, 380, 381f Chorioamnionitis, acute, 289-290, 289f


460

Choriocarcinoma, 245, 246f 282, 290, 292f features of, 291t Choroid plexus papillomas, 424, 424f Choroid sympathetic uveitis, 436f 437 Choroidal malignant melanoma, 443, 443f epithelioid cell type, 444, 444f mixed spindle and epithelioid cell type, 444, 444f Chronic myeloid leukemia, 80, 80f Chronic obstructive pulmonary disease, 60 Churg-Strauss syndrome, 390, 391f 430 Ciliary body, medulloepithelioma of, 446, 446f CIN; see Cervical intraepithelial neoplasia Circulatory disturbances of brain, 405-409 gastrointestinal, 124 hepatobiliary, 146-147 pulmonary, 57-58 Cirrhosis, 158, 158f 159f alcoholic, 154, 154f biliary, 156, 156f primary, 155-156, 155f causes of, 158t classification of, 158 macronodular, 158, 158f micronodular, 158, 158f Cirsoid aneurysms, 35, 35f CIS; see Carcinoma in situ Clear cell adenocarcinoma of ovary, 277f 278 of vagina, 265, 265f 266f Clear cell carcinoma of breast, 308, 308f of endometrium, 268, 269f of ovary, 278 Clear cell chondrosarcoma, 377, 377f Clear cell sarcoma, 348 Cleft lip, 102 Cleft palate, 102, 102f Clostridium difficile infection, 130 Clue cells, 260, 261f CML; see Chronic myeloid leukemia CMV; see Cytomegalovirus Coal workers' pneumoconiosis, 62, 63f Coarctation of the aorta, 6, 7d, 9, 11f Colitis amebic, 130 collagenous, 132, 132f eosinophilic, 132 infectious, 130 ischemic, 124, 124f lymphocytic, 132 noninfectious, 132 pseudomembranous, 130, 131f 132f ulcerative, 132-133, 133f Collagenous colitis, 132, 132f Collapsing glomerulopathy, 218, 219f " Collar button" configuration, 443 Colloid carcinoma, 306 Colloid cysts, 426, 426f Colon; see also Large intestine adenocarcinoma of, 139, I39f metastasis from, 285, 285f neuroendocrine tumors of, 140, 140f right, adenocarcinoma of, 139, 139f sigmoid, adenocarcinoma of, 139, 139f Comedo-like necrotic material, 302 Complete transposition of great arteries, 6, 6f

Compound melanocytic nevus, 324-325, 325f with architectural disorder, 325-326, 325f 326f congenital, 324-325, 325f Condyloma acuminatum, 260, 260f anal, 140, 140f Congenital aortic stenosis, 6, 8f Congenital cavernous hemangioma, giant, 102, 103f Congenital compound melanocytic nevus, 324-325, 325f Congenital cystic adenomatoid malformation, 50, 51f Congenital glaucoma, 439-440, 440f Congenital heart disease, 2-9 Congenital hypertrophic cardiomyopathy, 18, 18f 19f Congenital hypoplasia, 6, 8f Congenital lymphangiectasia, 122, 123f Congenital myopathies, 386, 387t Congestion, passive acute, 146, 146f chronic, 146, 146f Conjunctivitis, 436 chronic follicular, 436, 436f Conn syndrome, 199, 201d Connective tissue disease, mixed, 319 Conotruncal anomalies, 4, 4d Constrictive pericarditis, 25, 26f Contraction band necrosis, 22, 23f Contrecoup lesions, 403, 403f Contusions, 403, 403f coup, 403, 403f postcontusion angle recession, 439, 439f COPD; see Chronic obstructive pulmonary disease Cornea diseases of, 440-441, 440f-441f enlarged, 439-440, 440f Corneal dystrophy Fuchs, 440-441, 440f granular, 440, 440f lattice, 440f 441 macular, 441, 441f Corneal guttae, 441 Coronary artery diseases of, 20-24 recanalization, 20, 21f Coronary atherosclerosis, 20, 20f 21f outcomes of, 20, 21d Coronary thrombus, 20, 21f Corrosive esophagitis, 110, 111f Cortical (soft) cataracts, 442, 442f Cortical defects, fibrous, 377 Corticomedullary differentiation, strlmal, 98, 98f Corticotroph adenoma, 184, 185f " Cotton candy lung," 60, 61f " Cotton wool spots," 437, 437f Coup contusions, 403, 403f Craniopharyngioma, 182f 183 Crescentic glomerulonephritis, 224-225 diseases that present as, 224t, 225 Creutzfeldt-Jakob disease, 412, 412f Cribriform carcinoma, 307, 307f Cribriform hyperplasia, 249, 249f Crohn disease, 133, 133f 133t, 134f Crooke hyaline, 183, 183f Crotalaria alkaloids, 146

Cryoglobulinemia, 232, 232f Cryptococcal infection, 453, 453f Cryptorchidism, 240, 240f Crystal-induced arthritis, 360-361 Curling ulcers, 124, 124f Curshman spiral, 59f Cushing disease, 199, 200f 201d Cushing syndrome, 199, 201d macronodular hyperplasia of adrenal in, 199-201, 200f Cylindroma, 454f 455 Cystadenocarcinoma, mucinous, 276f 277 Cystadenoma of borderline malignancy mucinous endocervical (miillerian), 275-277, 276f mucinous intestinal, 275-277, 276f mucinous, 172 of appendix, 136, I37f intestinal, 275, 275f 276f of pancreas, 172, 172f serous, 172, 172f I73f 273-275, 274f Cystadenoma lymphomatosum, papillary, 114 Cystic adenomatoid malformation, congenital, 50, 51f Cystic astrocytoma, 422, 422f Cystic carcinoma, adenoid, 116f 117 Cystic developmental kidney diseases, 212, 212d Cystic fibrosis, 60, 61f 168, 169f Cystic hyperplasia, endometrial, 261-263, 262f Cystic-like tumors, adenoid, 249 Cystic teratoma, benign, 282, 283f Cystic tumors, solid, 172-174, I73f Cysticercosis, 411, 411f Cystitis, 233 acute, 232f 233 chronic, 233, 233f caused by prostatic hyperplasia, 232f 233 interstitial, 233, 233f massive hemorrhagic, 233, 233f pseudomembranous, 233, 233f Cysts aneurysmal bone, 380-383, 381f bronchogenic, 50, 50f "chocolate," 263, 263f colloid, 426, 426f dental, 105-107 dentigerous, 105, 105f dermoid, 282, 283f Edrinococccusgranulosus, 151, 151f fissural (nonodontogenic), 106d of jaws, 106t of liver, 159 mucous retention, 108, 109f multicystic encephalopathy, 402f 403 multicystic renal dysplasia, 213, 213f odontogenic, 106d orthokeratotic, 107, 107f of pancreas, 168, 168f parakeratotic, 106f polycystic kidney disease, 212-213 polycystic ovarian disease, 262f 263 radicular, 107, 107f unicystic ameloblastomas, 105, 105f Cytologic atypia lentiginous junctional melanocytic nevus with minimal architectural disorder and, 324, 324f


461

Cytologic atypia-cont'd lentiginous junctional melanocytic nevus with moderate architectural disorder and, 324, 324f lentiginous junctional melanocytic nevus with severe architectural disorder and, 324, 325f Cytomegalovirus infection, 149 adrenal, 198f 199 viral pneumonia caused by, 56, 56f D Dalen-Fuchs nodules, 436f 437 Dandy-Walker malformation, 400-401, 401f Darier disease, 312, 312f 313f de Quervain thyroiditis, 186, 187f Debranching enzyme deficiency, 392, 392f Degeneration balloon cell, 444 hepatolenticular, 414 multisystem, 418 spongy, of CNS, in infancy, 415, 415f subacute combined, of spinal cord, 413-414, 414f Degenerative diseases of bones, 357-359 calcific aortic stenosis, 13, 14f of central nervous system, 417-420 of joints, 361, 362d, 362f retinal, 441 Dejerine-Sottas disease, 429, 429f Dementia, senile, 418 Demyelinating diseases, 416-417 Demyelinating polyneuropathy, chronic inflammatory, 431, 431f Demyelinating polyradiculoneuropathy, chronic inflammatory, 431, 431f Demyelination, 426-427 segmental, 427, 427f 428f Dendritic cell sarcomas, 96, 96f Denervation chronic, 396, 396f with reinnervation, 396, 397f related muscle diseases, 395-396, 39St stages of, 395, 395d Denervation atrophy, 396, 396f Dense deposit disease, 220, 220f Dental cysts, 105-107 Dental tumors, 112 Dentigerous cysts, 105, 105f Dermatitis psoriasiform, 314-316, 316f seborrheic, 321, 322f Dermatitis herpetiformis, 316, 317f Dermatofibrosarcoma protuberans, 338, 338f Dermatomyositis, 319, 319f 390, 391f Dermatoses immune-mediated, 316-319 inflammatory, 316-323 Dermoids, 282, 283f DES; see Diethylstilbestrol Descemet membrane, 439-440, 440f Desmoid tumor, 337, 337f Desmoplastic melanoma, 327, 327f Desmoplastic small round cell tumors, intraabdominal, 350, 351f Desquamative interstitial pneumonia, 66, 67f 67t

Developmental anomalies of lungs, 50 of upper digestive tract, 102-103 Developmental disorders of bones and joints, 356-357 cystic, of kidney, 212, 212d of female reproductive system, 258 of gastrointestinal tract, 122 of kidney, 210-214 of male' reproductive system, 240-241 of nervous system, 400-401 of pancreas, 168 of urinary tract, 210-214 DFSP; see Dermatofibrosarcoma protuberans Diabetes mellitus, 177-179 of chronic pancreatitis, 179, 179f classification of, 177 renal lesions of, 229 secondary, 178t, 179, 179f type 1 (insulin-dependent), 177-179, 178f 178t type 2 (non-insulin-dependent), 1784 179, 179f Diabetic glomerulosclerosis, 229, 229f 230f diffuse, 229, 230f Diabetic microaneurysms, of retina, 437, 438f Diabetic retinopathy, proliferative, 437, 438f Diaphragmatic hernia, 110, 110d Diastolic and systolic disorder; see Restrictive cardiomyopathy Diastolic disorder; see Hypertrophic cardiomyopathy Diethylstilbestrol, exposure in utero to, 265, 266f Dieulafoy ulcer, 124, 125f Digestive tract; see also Gastrointestinal tract upper, 101-119 diseases of, 100 Dilated cardiomyopathy, 17, 17f causes of, 18d Diphtherial myocarditis, 16, 16f Discoid lupus erythematosus, 318, 318f Dissecting aneurysms of aorta, 35, 35f Diverticula, 126, 126f esophageal, 110, 110d Meckel diverticulum, 122, 122f Diverticulosis, 126, 126f Drug-induced hepatitis, 152, 152f Drug-induced liver diseases, 152, I52f-153f 152t Drug-induced myositis, 390, 391f Drug-induced vasculitis, 39, 39f Drug reactions, allergic, 58, 59f Dubin-Johnson syndrome, 144, 144f Duchenne muscular dystrophy, 388, 388f Ductal breast carcinoma, infiltrating not otherwise specified, 303-305, 304f nuclear atypia in, 305, 305f Ductal carcinoma in situ comedo type, 302, 302f lobular, 302-303, 303f noncomedo type, 302, 303f Ductal hyperplasia, 296 atypical, 296, 301-302, 301f florid, 296, 297f Ductal papilloma, 300, 300f subareolar type, 300, 300f Duhring disease, 316 Dyscrasias, plasma cell, 82-83, 82t Dysgenesis gonadal, 258t, 259f mixed gonadal, 259f

Dysgerminoma, 282, 282f Dysplasia Barrett esophagus with, 118, 118f bronchopulmonary, 52, 53f fibrous, 378, 378f keratinizing intraepithelial, 47, 47f osteofibrous, 378 renal, 213, 213f thymic simple, 98, 98f with stromal corticomedullary differentiation, 98, 98f Dysplastic junctional melanocytic nevus, 324 Dysraphism, 400 Dystrophin-sarcoglycan complex, 386, 387d Dystrophy Becker, 388 corneal Fuchs, 440-441, 440f granular, 440, 440f lattice, 440f, 441 Duchenne, 388, 388f facioscapulohumeral, 388, 389f limb girdle, 388, 389f macular, 441, 441f muscular, 386-388 myotonic, 388, 389f

E Ear, 449-455 diseases of, 448 external (outer) inflammatory lesions of, 450-453 tumors of, 455 inner pathologic changes of, 453-454 tumors of, 455 middle chronic otitis media of, 451, 452f inflammatory lesions of, 450-453 tumors of, 455 neoplasms of, 455 Ear canal external, cylindroma of, 454f, 455 keratin implantation granuloma of, 450, 45lf The early amnion rupture sequence, 288f 289 Echinococcus granulosus cyst, 151, 151f Ectopia crossed, 210 of kidney, 210, 210d, 210f Ectopic pregnancy, 288f 289 Edema, of brain, 404f, 405 Elastofibroma, 336, 337f Elliptocytosis, 74, 75f Emboli pulmonary, 57 saddle, 57, 57f Embryoid bodies, 242-244, 244f Embryonal carcinoma of ovary, 282 of testis, 244, 245f Embryonal rhabdomyosarcoma, 346, 346f of vagina, 266, 266f Emphysema, 60 centriacinar (centrilobular), 60, 61f panacinar (panlobular), 60, 61f paraseptal or irregular, 60


462

Empty sella syndrome, 183 primary, 182d, 183 Encephalitis herpesvirus, 412, 412f toxoplasmic, 411, 41 If viral, acute, 412, 412f Encephalomalacia, 408 Encephalomyelopathy, subacute necrotizing, 414, 415f Encephalopathy, multicystic, 402f 403 Enchondroma, 372-373, 373f End-stage testis disease, 242, 243f Endocarditis acute bacterial, 11, 11f on chronic healing endocarditis, 12, 12f on chronic rheumatic endocarditis, 12, 12f acute rheumatic, 10, 10f chronic healing, 12, 12f chronic rheumatic acute bacterial endocarditis on, 12, 12f of aortic valve, 10, 11f of mitral valve, 10, 11f fungal, 12, 12f infective, 11-12, 12f complications of, 12t nonbacterial thrombotic, 13, 13f verrucous, 10, 10f Endocervical (miillerian) cystadenoma, mucinous, 275-277, 276f Endocrine glands, 181-207; see also specific glands diseases of, 180 Endocrine pancreas, tumors of, 176-177 Endolymphatic sac, low-grade adenocarcinoma of, 455, 455f Endolymphatic stromal myosis, 270 Endometrial adenocarcinoma, 268, 269f staging, 268, 269t Endometrial carcinoma, 268, 268t classification of, 268, 268t Endometrial hyperplasia, 261-263, 262f complex (adenomatous), 261-263, 262f with atypia, 261-263, 262f simple (cystic), 261-263, 262f Endometrial stromal nodules, 270, 270f benign, 270 Endometrial stromal sarcoma, 277 high-grade, 270-271 low-grade, 270, 270f Endometrial stromal tumors, 270-271 Endometrioid adenocarcinoma, 276f 277 well-differentiated, 277, 277f Endometrioid adenofibroma, 277, 277f Endometrioid carcinoma, 268, 276f, 277, 277f Endometriosis, 126f 263 ovarian, 263, 263f Endophthalmitis, 437 fungal, 436f 437 Endothelial tumors, 341, 341t Entamoeba histolytica, 130, 132f Enteritis, fungal, 129, 129f Enterobius vermicularis, 130, 131f Eosinophilia, 58, 59f Eosinophilic granuloma, 382f, 383 Eosinophilic myocarditis, 16, 17f Eosinophilic pneumonia, 58, 59f Ependymoma, 422-424, 423f Ephelis, 323 Epicardium, metastatic melanoma of, 27, 28f

Epidermal necrolysis, toxic, 317 Epidermal tumors, 328-331 Epididymis diseases of, 238 tumors of, 248, 248f classification of, 243t Epididymoorchitis, suppurative, 241, 241f Epidural hematoma, 405 Epidural hemorrhage, 405, 406d Epispadia, 211 Epithelial downgrowth, 439-440 Epithelial-myoepithelial carcinoma, 117, 117f Epithelial proliferative lesions, 296 Epithelial tumors, 161-163 calcifying odontogenic, 112, 113f of salivary gland, 112, 113t of urinary bladder, 235, 235t Epithelioid hemangioendothelioma, 163, 163f 342f 343 Epithelioid hemangioma, 450 of pinna, 450, 451f Epithelioid leiomyomas, 271 Epithelioid leiomyosarcomas, 345, 345f Epithelioid sarcoma, 352f 353 Epithelium, squamous, tumors of, 112, 112f Epulis, 103-104, 104f Erosive or corrosive esophagitis, 110, 111 f Erythema induratum, 320, 320f Erythema multiforme, 316-317, 317f Erythema multiforme minor, 317 Erythema nodosum, 320, 320f Erythroderma desquamativum, 321 Erythroid hyperplasia, 74, 74f Erythroid hypoplasia, 74, 75f Erythroplakia, 112, 112f Erythroplasia of Queyrat, 263-264, 328 Escherichia coli infection, 241 Esophageal diverticula, 110, 110d Esophageal lesions, 110-111 Esophageal tumors, 118 Esophageal varices, 110, 11Of Esophagitis, 104, 105f erosive or corrosive, 110, 1 1 1f reflux, 110, l l if ulcerative, 110, 1 l 1 f Esophagus anomalies of, 103 Barrett, 110, 111f with dysplasia, 118, 118f with early carcinoma, 118, 118f carcinoma of, 118, 118f diseases of, 100 " nutcracker, " 110 ESS; see Endometrial stromal sarcoma Etat lacunaire, 408, 408f Ewing sarcoma, 379, 380f Exocrine pancreas, tumors of, 172-174 benign, 172-174 of borderline malignancy, 172-174 classification of, 172t Exocytosis, misplaced, 184f Exstrophy, of urinary bladder, 211, 211f External canal, cylindroma of, 454f 455 External ear inflammatory lesions of, 450-453 tumors of, 455 Extralobar bronchopulmonary sequestration, 50, 51f

Extramammary Paget disease, 264, 264f Extramedullary hematopoiesis, 77, 77f Extraocular tumors, 443, 443f Extraskeletal myxoid chondrosarcoma, 350, 350f Exudates, hard retinal, 437, 437f 438f Eye(s), 435-446 changes in systemic diseases, 437-438, 437f438f diseases of, 434 inflammation of, 436-437 systemic diseases that affect, 437, 437t tumors of, 443-446

F Fabry disease, 214, 215f Facial malformations, complex, 102, 102f Facioscapulohumeral dystrophy, 388, 389f Falciparum malaria, 151, 152f Fallopian tubes, 256 Familial adenomatous polyposis coli, 139, 139f Familial amyloid neuropathy, 430, 430f Fasciitis nodular, 336, 336f proliferative, 336, 336f Fatty liver, 153, 153f Fatty streaks, 34f 35 Female pseudohermaphrodite, 258t Female reproductive system, 257-293 developmental disorders of, 258 diseases of, 256 hormonally induced changes, 261-263 intersex syndromes affecting, 258t Females, intersex syndromes affecting, 258t Feminization, testicular, 259f Femur, head of, osteonecrosis of, 361, 361f Fetoplacental infections, 289 Fibrinohemorrhagic pericarditis, 25, 26f Fibrinoid necrosis, 32, 33f Fibrinous pericarditis, 25, 25f Fibroadenoma, 298, 298f Fibroblastic lesions, 336-337 Fibroblastic tumors, benign, 336-337 Fibrocystic changes, 296, 297f Fibrohistiocytic tumors, 338, 338t Fibrolamellar hepatocellular carcinoma, 162, 162f Fibromas, 279, 279f ameloblastic, 112, 113f chondromyxoid, 373-375, 374f nonossifying, 377, 378f Fibromatoses, 337 Fibrosarcomas, 279 Fibrosis " chicken wire, " 154, 154f "onionskin," 156, 156f pericardial, 25, 25t perineurial, 433 periportal hepatic "pipe stem" type, 151, 152f pulmonary forms of, 67t idiopathic, 66, 67f replacement, in myocardium, 17, 17f Fibrous cortical defect, 377 Fibrous dysplasia, 378, 378f Fibrous hamartoma of infancy, 336-337, 337f Fibrous histiocytoma, malignant, 338, 339f Fibrous lesions of bone, 377-378 classification of, 377 Fibrous tissue tumors, 336, 336t


463

FIGO; see International Federation of Gynecology and Obstetrics Fissural cysts, 106d Fistula, tracheoesophageal, 50, 50d Fleurettes, 424 Flexner-Wintersteiner rosettes, 424 Floppy mitral valves, 13, 13f Florid hyperplasia, 296, 297f "Flower-shaped " nuclei, 80, 81f Follicular adenoma, 188, 189f atypical, 188 with bizarre nuclei, 190, 190f hyalinizing trabecular pattern, 188-190, 190f microfollicular pattern, 188, 189f with papillary hyperplasia, 188, 189f variants of, 188 Follicular carcinoma, 191-193, 192f features of, 190t minimally invasive type, 192f 193 widely invasive type, 192f 193 Follicular cholecystitis, 164 Follicular conjunctivitis, chronic, 436, 436f Follicular dendritic cell sarcomas, 96, 96f Follicular hyperplasia, 84, 84f lymph node, 84, 84f lymphoid, 98 Follicular lymphoma, 90, 91f 92f mixed small cleaved and large cell, 90, 92f predominantly large cell, 90, 92f predominantly small cleaved cell, 90, 91f Follicular salpingitis, chronic, 260, 261f Follicular thymitis, 98, 99f Forbes disease, 392 Foreign bodies, gastrointestinal, 125 Freckles, 323 "Fried egg " cells, 422, 423f Friedreich ataxia, 420, 420f Fuchs corneal dystrophy, 440-441, 440f Fucosidosis, 414 Fungal endocarditis, 12, 12f Fungal endophthalmitis, 436f 437 Fungal enteritis, 129, 129f Fungal gastritis, 126, 127f Fungal infections of brain, 410-411 of skin, 314 Fungal vasculitis, 36, 36f Fusobacterium infection, 289-290, 289f

G Gallbladder carcinoma of, 164, 165f diseases of, 164 hydrops of, 164, 165f porcelain, 164, 165f Gallstones, 156, 157f 164, 164f Ganglioneuroblastoma, 206, 206f Ganglioneuroma, 206, 206f Gardnerella vaginalis, 260, 261f Gastric carcinoma, 134, 135d Gastric tumors, 134 Gastritis, 126-128 acute, 126 chemical, 126, 127f chronic, 126 corrosive, 110, I l 1 f fungal, 126, 127f hypertrophic, 128, 128f

Gastritis-cont ' d infectious, 126 type A, 126, 127f 128t type B, 126-128, 127f 1281 Gastrointestinal tract, 121-141 circulatory disturbances of, 124 developmental disorders of, 122 diseases of, 120 organ-specific diseases of, 126-133 positiorral anomalies of, 122 tumors of, 134-140 upper, 100, 101-119 Gastropathy, 128, 128f Generalized lymphadenopathy, persistent, 84, 85f Genetic disorders of bones and joints, 356-357 of kidney, 210-214 of male reproductive system, 240-241 of nervous system, 400-401 of pancreas, 168 of urinary tract, 210-214 Genetic hemochromatosis, 144, 145f Genetic metabolic myopathies, 392-394 Genitalia female, intersex syndromes affecting, 2581 male, infections of, 241-242 Genodermatoses, 313 Geographic pattern, 84, 84f Germ cell aplasia, 240f 241 Germ cell teratomas, 416t Germ cell tumors classification of, 416t mixed stromal, 247, 247f of ovary, 282-283 pathogenesis of, 242-244, 243d of testis, 242-246 Gerstmann-Straussler-Scheinker syndrome, 412 Gestational trophoblastic disease, 290, 290f-292f definition of, 290 features of, 290, 291t Giant axonal neuropathy, 429, 429f Giant cell tumor of bone, 378-379, 379f Giant cell vasculitis, granulomatous, 36, 36f Giant congenital cavernous hemangioma, 102, 103f Gingiva, pyogenic granuloma of, 103-104, 104f "Gitter cells, " 408 Glandular malignant schwannoma, 348 Glaucoma, 438-440, 439f-440f closed-angle, 438 congenital, 439-440, 440f open-angle, 438 primary, 438 secondary, 438 Glaucomatous cupping, end-stage, of optic nerve head, 439, 439f Glaucomatous retinal atrophy, 439, 439f Gleason grading system of prostatic adenocarcinoma, 255f 255t of prostatic carcinoma, 252f, 253 Glial neoplasms, 416t Glioblastoma multiforme, 422, 423f Globoid cell leukodystrophy, 415, 415f Glomerular basement membrane anti-glomerular basement membrane disease, 224-225 thin basement membrane nephropathy, 214, 214f

Glomerular diseases hereditary, 213-214 immune-mediated, 217-226 Glomerulonephritis chronic, 224, 224f crescentic, 224-225 diseases that present as, 224t, 225 Henoch-Schonlein purpura, 222-223 membranoproliferative, 219-220 membranous, 220-222, 221f 222f 226, 227f postinfectious, 223f 224, 224f proliferative diffuse, 225-226, 226f focal and segmental, 225-226, 226f systemic lupus erythematosus, 225 Glomerulopathy collapsing, 218, 219f "primary, " 217, 217t Glomerulosclerosis diabetic, 229, 229f 230f diffuse, 229, 230f focal and segmental, 217-218, 218f 218t Glomus tumors, 343, 343f Glycogen storage diseases, 144, 144f Glycogenosis type I, 214, 215f type II, 392 type III, 392 type IV, 392 Goblet cell carcinoid, 136, 137f Goiter, 185 nodular, 185, I85f Gonadal agenesis, 258t Gonadal dysgenesis, 259f with abnormal karyotype, 258t with male karyotype, 258t mixed, 259f with normal karyotype, 258t Gonadoblastomas, 247, 247f Goodpasture disease, 224-225 Gout, 230, 231f 360, 36lf Granular atrophy, 409, 409f Granular corneal dystrophy, 440, 440f Granulated lymphocytic leukemia, 80, 81f Granuloma eosinophilic, 382f 383 hepatic, 152, 153f keratin implantation, 450, 451f Majocchi, 314, 314f, 315f pyogenic, 103-104, 104f 341, 342f Granuloma annulare, 319, 319f 320f Granulomatosis lymphomatoid, 94 Wegener, 60, 60f Granulomatous diseases, 319-320 noninfectious, 319 Granulomatous giant cell vasculitis, 36, 36f Granulomatous interstitial nephritis, 227, 228f Granulomatous orchitis, 241-242 Granulomatous thyroiditis, subacute, 186, 187f Granulosa cell tumors, 278, 279f juvenile, 278-279, 279f Graves disease, 186, 186f 187f 437, 438f pathophysiologic mechanism of, 186, 186d Gray hepatization, 54, 54f "Ground glass " hepatocytes, 148f 149 " Ground glass " lesions of fibrous dysplasia, 378, 378f


464

"

Ground glass " lesions-cont ' d of osteofibrous dysplasia, 378 " Ground glass " nuclei of herpes simplex-infected cells, 104, 105f of papillary carcinoma, 191, 191f Guillain-Barre syndrome, 430, 431f Gynandroblastoma, 281 H Hailey-Hailey disease, 312, 313f Hairy cell leukemia, 80, 81f of spleen, 96, 97f Hamartoma fibrous, of infancy, 336-337, 337f pulmonary, 70, 70f Hamman-Rich syndrome, 67t Hard metal disease, 62, 63f Hashimoto thyroiditis, 186-187, I88f fibrous variant, 187-188, 189f Hashitoxicosis, 187 Hay fever, 42 Healing endocarditis, chronic, 12, 12f Heart, 1-29 amyloidosis of, 18, 19f malformations, 2 Heart disease, xx carcinoid, 13, 13f congenital, 2-9 rheumatic, 9-10 Heinz bodies, 76f 77 Helicobacter pylori infection, 126-128, 127f 128f Hemangioblastomas, 425-426, 426f Hemangioendothelioma, 343 epithelioid, 163, 163f 342f 343 forms, 343 Kaposiform, 343 spindle cell, 343 Hemangioma, 163, 343 epithelioid, 450 of pinna, 450, 451f giant congenital cavernous, of tongue, 102, 103f intestinal, 124, 125f retinal capillary, 438, 438f sclerosing, 70, 71f variants, 343 Hemangiopericytoma, 343-344, 344f 425-426 Hemangiosarcoma, 27, 28f Hematoma epidural, 405 subdural acute, 405, 405f chronic, 405, 405f 406d Hematopericardium, 22, 23f 25 Hematopoiesis, extramedullary, 77, 77f Hematopoietic neoplasms, 416t Hematopoietic proliferations, 95-96 Hematopoietic system, 73-99 diseases of, 72 Hemochromatosis, 144, 145f Hemolytic anemia, 76f 77 Hemorrhage epidural, 405, 406d hypertensive, acute, 407, 407f intracerebral, 407, 407f intracranial, 405-407 spinal, 407, 407f subarachnoid, 407

Hemorrhage-cont'd subependymal, 401, 401f 402f Hemorrhagic cystitis, massive, 233, 233f Hemorrhagic pancreatitis, acute, 169-170, 169d, 169f 170f Henoch-Schonlein purpura, 39, 39f 222-223, 223f Henoch-Schonlein purpura glomerulonephritis, 222-223 Hepatic abscesses, biliary, 150, 150f Hepatic amebiasis, 151, 151f Hepatic fibrosis, periportal, 151, 152f Hepatic granulomas, 152, 153f Hepatic necrosis acetaminophen-induced, 152, 152f HBV-induced massive, 148f 149 Hepatitis, 147 alcoholic, 153, 154f autoimmune, 155, 155f caused by pathogens other than hepatitis viruses, 149-150 chronic, 148f 149 autoimmune, 155 drug-induced, 152, 153f drug-induced, 152,152f herpesvirus, 149, 149f infectious, 147-151 Q fever, 149, 149f viral, 147-149, 147f histopathology of, 144, 145f Hepatitis A, 148t Hepatitis B, 1481 Hepatitis B virus infection chronic, 148f 149 massive hepatic necrosis caused by, 148f 149 Hepatitis C, 148t Hepatitis C virus infection carrier state, 148f 149 chronic, 148f 149 Hepatitis D, 148t Hepatitis E, 1481 Hepatization gray, 54, 54f red, 54 Hepatobiliary tract, 143-165 circulatory disorders of, 146-147 hereditary metabolic diseases that affect, 144 tumor-like conditions of, 159-161 tumors of, 159-163 Hepatoblastoma, 162-163, 162f Hepatocellular adenoma, 161, 161f Hepatocellular carcinoma, 161-162, 161f, 162f Hepatocytes, "ground glass," 148f 149 Hepatolenticular degeneration, 414 Hereditary amyloid neuropathy, 430. 430f Hereditary glomerular diseases, 213-214 Hereditary hyperbilirubinemias, 144, 145t Hereditary metabolic diseases, 144 Hereditary peripheral neuropathies, 428-430, 4281 Hereditary skin diseases, 312 Hereditary spherocytosis, 77, 77f Hereditary tubular diseases, 213-214 Hereditary tyrosinemia, 144, 144f Hermaphrodites pseudohermaphrodites female, 2581 male, 2581 true, 258t

Hernia uteri inguinalis, 259f Hernias, 125 diaphragmatic, 110, 110d of parahippocarnpal gyrus, 404f, 405 Herpes simplex virus, 260 Herpes simplex virus infection " ground glass" nuclei of, 104, 105f of skin, 314, 315f Herpes zoster, 314, 315f Herpesvirus encephalitis, 412, 412f Herpesvirus hepatitis, 149, 149f Herpesvirus infection, 260, 260f Hibernoma, 340, 340f Hilar squamous cell carcinoma, 68, 68f Hirschsprung disease, 122, 123f Histiocytes, von Hansemann, 233 Histiocytic necrotizing lymphadenitis, 84, 85f Histiocytoma, malignant fibrous, 338, 339f Histiocytosis, Langerhans cell, 95-96, 95f Histiocytosis X, 182f 183 Histoplasma capsulatum, 54 Histoplasma capsulatum infection, 410-411 Histoplasmosis, 198f 199 HIV; see Human immunodeficiency virus Hodgkin disease, 87-88, 87f classification of, 87t histopathologic subtypes, 87-88 lymphocyte depletion type, 88, 88f lymphocyte predominance type, 87, 87f mixed cellularity type, 88, 88f nodular sclerosis type, 87-88, 88f nodular type, 86f, 87 reticular type, 88, 88f Holoprosencephaly, 400, 400f Homer Wright rosettes, 424 Horseshoe kidney, 210, 211f HPV; see Human papillomavirus HSV; see Herpes simplex virus Human immunodeficiency virus -associated nephropathy, 218, 219f infection, 314-316, 316f -related lymphadenopathy, 84, 85f Human papillomavirus infection, 314, 315f Hunner ulcer, 233, 233f Huntington disease, 419, 419f Hurthle cell adenoma, 190, 190f Hurthle cell carcinoma, 190t, 193, 193f Hyaline arteriosclerosis, 32, 32f " Hyaline fibers," 388 Hyaline membrane disease, 52, 52f Hyaline necrosis, sclerosing, 154 Hyalinized trabecular adenoma, 188-190, 190f Hyalinosis, 217 Hydatidiform mole complete, 290, 290f ' features of, 29l t invasive, 290, 292f partial, 290, 2914 292f Hydrochloric acid ingestion, 110, Ilif Hydropericardium, 25 Hydropic abortus, 290, 291 t, 293f Hydrops, 164, 165f Hyperaldosteronism, 199, 201d Hyperbilirubinemias, hereditary, 144, 1451 Hypercortisolism, 199, 201d Hyperparathyroidism, 195, 359, 359f Hyperplasia adenomatous, 250, 251f


Hyperplasia-cont'd adrenal medullary, 203, 203f adrenocortical, 199-201, 200f atypical, 301-302 atypical adenomatous, 250 atypical basal cell, 249 atypical ductal, 301-302, 301f atypical intraductal, 301-302, 301f atypical intralobular, 301, 301f, 302 atypical lobular, 301, 301f 302 basal cell, 248 cribriform, 249, 249f ductal, 296 endometrial, 261-263, 262f erythroid, 74, 74f florid, 296, 297f focal nodular, 160, 160f follicular, 84, 84f lymphoid, 98 lobular, 296 macronodular, 199-201, 200f papillary follicular adenoma with, 188, 189f inflammatory, 103, I03f parathyroid, 195, 196f postatrophic, 248 prostatic benign, 248-250, 248f 249f chronic cystitis caused by, 232f 233 reactive, of thyrotroph cells, 183, 183f stromal, with atypia, 249f 250 thyroid, 185-186 Hyperplastic arteriosclerosis, 32, 32f 33f Hyperplastic polyps, 138f 139 Hypersensitivity pneumonia, 58, 59f Hypertension chronic (benign), 32, 33f malignant, 32, 33f pulmonary, 58 Hypertensive arteriosclerosis, 32 Hypertensive hemorrhage, acute, 407, 407f Hypertrophic cardiomyopathy, 18, 18f 19f causes of, 18d congenital, 18, 18f 19f Hypertrophic gastritis, 128, 128f Hypertrophic neuropathy, localized, 433 Hypogonadism, hypogonadotropic, 241, 241f Hypogonadotropic hypogonadism, 241, 241f Hypoparathyroidism, 195 Hypoperfusion, intestinal, 124, 124f Hypophysitis, lymphocytic, 182f 183 Hypopituitarism, 182-183 Hypoplasia congenital, 6, 8f erythroid, 74, 75f pulmonary, 50, 51f thymic, 98, 98f Hypospadia, 211, 211f Hypospermatogenesis, 241, 241f Hypothyroidism, 183, 183f

I IBD; see Inflammatory bowel disease Ichthyosis, 312 Ichthyosis vulgaris, 312, 312f IgA; see I mmunoglobulin A Ileitis, backwash, 133 Ileus, meconium, 125, 125f

Immune-mediated adrenalitis, 199, 199f Immune-mediated dermatoses, 316-319 I mmune-mediated glomerular diseases, 217-226 I mmune-mediated lung diseases, 58-60 I mmune-mediated vasculitis, 38-39 I mmunoblastic lymphoma, large cell, 92, 92f I mmunodeficiency, primary, 98, 98f I mmunoglobulin A nephropathy, 222-223, 222f-223f I mpact injuries, 403, 404d I mpetigo, 313-314, 313f Inborn errors of metabolism, 414-415 Inclusion body myositis, 390, 391f " Indian file " cell arrangement, 305 Infancy fibrous hamartoma of, 336-337, 337f spinal muscular atrophy of, 396, 397f spongy degeneration of CNS in, 415, 415f teratomas of, 246 Infarction bile, 156, 157f of brain, 402 cerebellar, acute, 408, 408f cerebral, 408, 408f myocardial, 22, 22f 23f complications of, 22-24, 23f, 24f pulmonary, 57, 57f Infection; see also specific infections aspiration of infected amniotic fluid, 52, 53f bacterial acute, 149-150 of nervous system, 410 of skin, 313-314 biliary, 150-151 of bones and joints, 363-364 chronic, 60 of female reproductive system, 260 fetoplacental, 289 fungal of brain, 410-411 of skin, 314 of inner ear, 453, 453f lower urinary tract, 232-233 of male genital organs, 241-242 metazoal, 411 of nervous system, 409-410 placental, 289-290 postinfectious glomerulonephritis, 223f 224, 224f protozoal, 411 pulmonary, 54-56 skin, 312-316 vaginal, 260, 261f vasculitis induced by, 36 viral, 56, 56f of central nervous system, 412 of skin, 314-316 Infectious adrenalitis, 198f 199 Infectious colitis, 130 Infectious hepatitis, 147-151 Infectious mononucleosis, 149, 149f Infective endocarditis, 11-12, 12, 12f complications of, 12t Infiltrating ductal breast carcinoma not otherwise specified, 303-305, 304f nuclear atypia in, 305, 305f Infiltrating lobular carcinoma, 305, 306f Infiltration, pulmonary, 58, 59f

Inflammation of appendix, 130-132 of eye, 436-437 of large intestine, 130-132 of ocular adnexa, 436-437 Inflammatory bowel disease, 132-133 Inflammatory demyelinating polyneuropathy, chronic, 431, 431f Inflammatory demyelinating polyradiculoneuropathy, chronic, 431, 431f Inflammatory dermatoses, 316-323 Inflammatory diseases of bones and joints, 363-367 pelvic, 260 Inflammatory lesions of external and middle ear, 450-453 of upper digestive tract, 103-104 of upper respiratory tract, 42 Inflammatory myopathies, 389-390, 389t Inflammatory neuropathies, 430-431 Inflammatory papillary hyperplasia, 103, 103f Inflammatory pseudotumors, 70, 71f Injuries, impact vs nonimpact, 403, 404d Inner ear infections of, 453, 453f pathologic changes of, 453-454 tumors of, 455 Inspissated meconium, 125, 125f Insulin-dependent diabetes mellitus, 177-179, 178f, 178t International Federation of Gynecology and Obstetrics (FIGO), 268, 269t International Lymphoma Study Group, 89, 89t International Society of Gynecological Pathologists, 290 Intersex syndromes, 258t Interstitial cystitis, 233, 233f Interstitial lung diseases, idiopathic, 66 Interstitial nephritis acute, 227, 227f 228f etiologies of, 227, 228t granulomatous, 227, 228f Interstitial pancreatitis, 169, 169f Interstitial pneumonia acute, 67t desquamative, 66, 67f 67t nonspecific, 67t usual, 66, 67t Interventricular septum, rupture of, 22-24, 24f Intestinal angiodysplasia, 124, 12Sf Intestinal cystadenocarcinoma, mucinous, 276f 277 Intestinal cystadenoma, mucinous, 275-277, 276f Intestinal duplications, 122, 122f Intestinal hemangioma, 124, 125f Intestinal lumen, obstructions and dilatations of, 125-126 Intestinal lymphangiectasia, 122, 123f Intestinal polyps, 136-139, 137t Intestinal tract; see Gastrointestinal tract Intestines; see also Colon; Large intestine; Small intestine mantle cell lymphoma of, 136, 136f Intraabdominal desmoplastic small round cell tumors, 350, 351f Intracerebral hemorrhage, 407, 407f Intracranial hemorrhages, 405-407


466

Intraductal hyperplasia, atypical, 301-302, 301f Intraductal papillary mucinous adenoma, 172, 173f Intraductal papillary mucinous carcinoma, 172, 173f Intraductal papillary mucinous neoplasms, 172, 173f Intraductal papilloma, 172, 173f 300, 300f Intraepidermal neoplasms, melanocytic, 324, 324f-325f Intraepithelial dysplasia, keratinizing, 47, 47f Intraepithelial lesions, squamous high-grade, 267, 267f low-grade, 267, 267f Intraepithelial neoplasia anal, 140, 140f vulvar intraepithelial neoplasia with, 263f 264 cervical, 266, 267f prostatic, 250 squamous grade I, 328, 329f grade II, 328, 329f grade III, 328, 329f vulvar, 263-264, 263f Intralobar sequestration, 50, 51f Intralobular hyperplasia, atypical, 301, 301f 302 Intraocular tumors, 443, 443f Intraosseous well-differentiated osteosarcoma, 370-372, 371f Intraventricular hemorrhage, 401 Intussusception, 125, 126f Invasive acral lentiginous melanoma, 327, 328f Invasive carcinoma of breast, 303-305 variants, 306-308 of cervix, 267, 268f cribriform, 307, 307f papillary, 308, 308f squamous cell of cervix, 267, 268f of vulva, 264, 264f Iris lesions, 317 Ischemia acute, of large bowel, 124, I24f cerebral, 408-409 Ischemic colitis, 124, 124f Ischemic neuropathies, 430, 430f Islet cell tumors, 176-177, 176f 177f J Jaws, cysts of, 106t Joints, 355-383 degenerative diseases of, 357-359, 361, 362d, 362f developmental disorders involving, 356-357 diseases involving, 354 genetic disorders involving, 356-357 infections of, 363-364 inflammatory diseases of, 363-367 neoplasms of, 367-383 tumors and tumor-like lesions, 383 Juvenile granulosa cell tumors, 278-279, 279f Juvenile nasopharyngeal angiofibroma, 44, 45f Juvenile polyps, 138f 139 Juvenile thyroiditis, 188 Juvenile xanthogranuloma, 332f 333, 333f

K Kaposi sarcoma, 333, 333f Kaposiform hemangioendothelioma, 343 Karyotype, male, gonadal dysgenesis with, 258t Kawasaki disease, 38f 39 Kearns-Sayre syndrome, 394, 394f Keratin implantation granuloma, 450, 451f Keratin plugs, 450, 451f Keratinizing intraepithelial dysplasia, 47, 47f Keratitis, 437, 437f Keratoacanthoma, 330, 330f Keratoconus, 441, 441f Keratocyst odontogenic, 105 parakeratotic, 105-107 Keratopathy, pseudophakic bullous, 440, 440f Keratosis actinic, 328, 329f seborrheic, 328, 328f Keratosis obturans, 450 Kerion, 314 Kidney disease cystic developmental, 212, 212d multiple myeloma, 232, 232f polycystic, 212-213 Kidneys, 209-237; see also under Renal developmental disorders of, 210-214 diseases of, 208 ectopia of, 210, 210d, 210f genetic disorders of, 210-214 horseshoe, 210, 211f malrotation of, 210, 210f metabolic and/or toxic disorders, 228-229 " thyroidization of, " 216, 216f tumors of, 234-235 vascular disorders of, 216-217 Kiel classification, 89, 89t Kikuchi disease, 84, 85f Klebsiella rhinoscleromatis infection, 42, 42f Klinefelter syndrome, 240, 240f " Knife edge gyri, " 418, 419f Kogoj, spongiform pustules of, 321 Krabbe disease, 415 Krukenberg tumor, 284f 285, 285f Kuru, 412 L Laceration, 403-405, 403f Lactating adenoma, 298, 298f Lacunae, multiple, 408-409, 408f Langerhans cell histiocytosis, 95-96, 95f Large cell lymphoma, 92, 93f diffuse, 92, 92f immunoblastic, 92, 92f Large intestine; see also Colon acute ischemia of, 124, 124f carcinoma of, 139-140 inflammation of, 130-132 Laryngeal papillomas, 44 Laryngeal polyps, 44, 45f Laryngitis, chronic, 42, 43f Larynx carcinoma of, 47, 47f diseases of, 40 keratinizing intraepithelial dysplasia of, 47, 47f squamous cell carcinoma of, 47, 47f Lattice corneal dystrophy, 440f 441

Leigh disease, 414, 415f Leiomyoblastoma, 271, 345, 345f Leiomyomas, 271, 272f 344, 344f bizarre (symplastic), 271 categories, 344 cellular, 271 epithelioid, 271 metastasizing, 273 mitotically active, 273 multiple, 271, 271f spindle cell, 134, 135f of stomach, 134, 135f Leiomyomatosis intravenous, 272f 273 peritoneal, 272f 273 Leiomyomatosis peritonealis disseminata, 272f, 273 Leiomyosarcoma, 272f 273, 344-345, 345f epithelioid, 345, 345f of uterus, 272f 273 Lennert lymphoma, 94, 94f Lentiginous junctional melanocytic nevus, 324 with minimal architectural disorder and cytologic atypia, 324, 324f with moderate architectural disorder and cytologic atypia, 324, 324f with severe architectural disorder and cytologic atypia, 324, 325f Lentiginous melanoma, acral, 327 invasive, 327, 328f Lentigo, 323, 323f 324f solar, 323 Lentigo maligna melanoma, 326-327, 327f Lesions; see also Tumors brain, 401-402 breast, 294 "cannonball," 70, 71f Caplan, 62, 63f contrecoup, 403, 403f epithelial proliferative, 296 esophageal, 110-111 fibroblastic, 336-337 fibrous, 377-378 inflammatory of external and middle ear, 450-453 of upper digestive tract, 103-104 of upper respiratory tract, 42 iris, 317 lymphoepithelial, 90, 91f malformative and nonneoplastic mass, 416t. 426 melanocytic, 323, 323t " napkin ring-like, " 139, 139f oral, 108-109 organ-specific, 105-111 pigmentary, 323-328 "punched-out," 82, 82f salivary gland, 108-109 target, 317 tumor-like benign fibroblastic, 336-337 of joints, 383 of prostate, 248-253 valvular, 9-13 Leukemias, 78-81 acute, 78 acute lymphoblastic, 78, 79f acute monoblastic, 78, 79f


467

Leukemias-cont' d acute myeloblastic, with maturation, 78, 79f acute myeloid, 78, 78f of spleen, 96, 97f chronic, 80 chronic myeloid, 80, 80f of spleen, 96, 97f hairy cell, 80, 81f of spleen, 96, 97f lymphocytic chronic, 80, 81f chronic B-cell, 80, 81f granulated cell, 80, 81f promyelocytic, 78, 79f T-cell, adult, 80, 81f Leukodystrophies, 414-415 globoid cell, 415, 415f . Leukoencephalopathy progressive multifocal, 417, 418f subcortical arteriosclerotic, 409, 409f Leukomalacia, periventricular, 402, 402f Leukoplakia, 112 Leydig cell tumors, 246, 247f Lichen planus et acuminatus atrophicans, 263 Limb girdle dystrophy, 388, 389f Lindau disease, 426 Lip(s), cleft, 102 Lipid storage diseases, 144 Lipid storage myopathy, 393, 393f Lipoblastoma, 340, 340f Lipoid proteinosis, 129-130, 130f Lipoleiomyomas, 271 Lipoma, 339, 340f of small intestine, 136, 136f spindle cell, 339, 340f subtypes, 339 Lipomatous tumors, 339-340, 339t Liposarcoma, 340, 341f dedifferentiated, 340 myxoid, 340, 341f pleomorphic, 340, 341f round cell, 340, 341f subtypes, 340 well-differentiated, 340 Listeria monocytogenes, 289-290, 290f Liver; see also under Hepatic circulatory disorders of, 146-147 fatty, 153, 153f drug-induced change, 152, 153f hereditary metabolic diseases that affect, 144 metastases to, 163, 164f umbilication in, 163, 164f Liver diseases, 142 alcoholic, 153-154, 154f autoimmune, 155-156 drug-induced, 152, 152f-153f 152t polycystic, 159, 159f Lobar pneumonia, 54, 54f Lobular carcinoma, infiltrating, 305, 306f Lobular ductal carcinoma in situ, 302-303, 303f Lobular hyperplasia, 296 atypical, 301, 301f 302 Localized hypertrophic neuropathy, 433 Long bones, adamantinoma of, 380, 381f Lower nephron nephrosis, 229 Lower urinary tract infections, 232-233 Ludwig angina, 104, 104f Lung abscess, 54, 55f

Lung diseases idiopathic interstitial, 66 i mmune-mediated, 58-60 perinatal, 52 Lung tumors, 68-70, 69t benign, 70 metastatic, 70, 71f Lungs, 49-71 " cotton candy, " 60, 61f developmental anomalies of, 50 diseases of, 48 sarcomas of, 70, 70f Lupus erythematosus, 317-319 discoid, 318, 318f subacute, 317 systemic, 225-226, 317, 319, 319f acute, 318, 318f "butterfly rash " of, 318, 318f Lupus erythematosus profundus, 318 Lupus nephritis, 226, 227f diffuse proliferative, 225-226, 226f focal proliferative, 225-226, 226f mesangial proliferative, 225, 226f scoring system, 225t WHO classification of, 225t Lupus panniculitis, 318-319 Luteoma, stromal, 281, 281f Lymph node hyperplasia, 84, 84f Lymph nodes acute myeloid leukemia involving, 96, 96f hematopoietic proliferations in, 95-96 Lymph vessels, endothelial tumors of, 341, 341t Lymphadenitis, histiocytic necrotizing, 84, 85f Lymphadenopathy, 84 HIV-related, 84, 85f persistent generalized, 84, 85f reactive, 84-85, 84t Lymphangiectasia congenital, 122, I23f intestinal, 122, 123f Lymphangiomas, 342f 343 variants, 343 Lymphoblastic leukemia, acute, 78, 79f Lymphoblastic lymphoma, 94, 95f of spleen, 96, 97f Lymphocytes Hodgkin disease with depletion of, 88, 88f Hodgkin disease with predominance of, 87, 87f

Lymphocytic colitis, 132 Lymphocytic hypophysitis, 182f 183 Lymphocytic leukemia chronic, 80, 81f granulated cell, 80, 81f Lymphocytic myoepithelial sialadenitis, 108 Lymphocytic thyroiditis, nonspecific, 186, 187f Lymphoepithelial lesions, 90, 91f Lymphoepitheliomas, 47 Lymphofollicular thymitis, 98, 99f Lymphoid follicular hyperplasia, 98 Lymphoid system, 73-99 diseases of, 72 Lymphoma angiocentric, 94, 94f Burkitt, 94-95, 95f ovarian, 285, 285f diffuse large cell, 92, 92f

Lymphoma-cont 'd diffuse mixed large cell, 92 diffuse mixed small and large cell, 92, 93f follicular, 90, 91f 92f follicular mixed small cleaved and large cell, 90, 92f follicular predominantly large cell, 90, 92f follicular predominantly small cleaved cell, 90, 91f large cell, 92, 93f large cell immunoblastic, 92, 92f lymphoblastic, 94, 95f of spleen, 96, 97f lymphoepithelioid T-cell (Lennert), 94, 94f mantle cell, 90, 90f, 91f of intestine, 136, 136f of spleen, 96, 97f marginal zone, 89, 90f monocytoid, 89 non-Hodgkin, 89-95 small lymphocytic, 89, 90f small noncleaved cell, 94-95 T-cell AILD-like, 93-94, 94f lymphoepithelioid, 94, 94f peripheral, 92-93, 93, 93f 94f post-thymic, 92 of spleen, 96, 97f T-cell rich B-cell, 92, 93f Lymphomatoid granulomatosis, 94 Lymphoproliferative disorders, chronic, 80, 81t Lysosomal disorders, 414

M Macroadenomas, 184 Macroaneurysm, retinal arterial, 437, 438f Macroglobulinemia, Waldenstrom, 82, 83f 129-130 Macroglossia, 102, 103f Macular degeneration, 441, 441f Macular dystrophies, 441, 441f Macules, 62, 63f Maffucci syndrome, 372 Majocchi granuloma, 314, 314f 315f Malabsorption small intestinal diseases that cause, 129-130, 129t syndromes, 129t Malacoplakia, 241-242, 242f Malaria, 151, 152f Male karyotype gonadal dysgenesis with, 258t male pseudohermaphrodite with, 258t Male pseudohermaphrodite, 2581 Male reproductive system, 239-255 developmental disorders of, 240-241 diseases of, 238 genetic disorders of, 240-241 infections of, 241-242 Male XX, 258t Malformations Arnold-Chiari, 400-401, 400f cardiac, 2 complex facial, 102, 102f congenital cystic adenomatoid, 50, 51f Dandy-Walker, 400-401, 401f Malformative and nonneoplastic mass lesions, 416t, 426


468

Malignancy, borderline endometrioid adenofibroma of, 277, 277f intraductal papillary mucinous tumors of, 172, 173f mucinous endocervical (mullerian) cysta denoma of, 275-277, 276f mucinous intestinal cystadenoma of, 275-277, 276f of ovary, 273-275 serous, of ovary, 273-275, 274f 275f Malignant fibrous histiocytoma, 338, 339f Malignant hypertension, 32, 33f Malignant melanoma, 326-328, 326f 327f choroidal, 443, 443f epithelioid cell type, 444, 444f mixed spindle and epithelioid cell type, 444, 444f spindle A cell type, 444, 444f spindle B cell type, 444, 444f Malignant mesothelioma, 64, 65f Malignant schwannoma, glandular, 348 Malignant tumors anal, 140 bone-forming, 369-370 Brenner tumors, 278, 278f cartilage-forming tumors, 375-377 mixed mullerian, 270f 271, 271f neural, 348, 3481 of peripheral nerve sheath, 348, 348f of salivary gland, 117 serous, 275, 275f thyroid, 190-194 triton, 348 of upper respiratory tract, 45-47 Mallory bodies, 153-154, 154f Mallory-Weiss syndrome, 110, 1 1 1 f Malrotation of kidney, 210, 210f Maltoma, 89, 90f Mammary ducts and lobules, 296, 296d Mantle cell lymphoma, 90, 90f 91f of intestine, 136, 136f of spleen, 96, 97f Marble bone disease, 356 Marchiafava-Bignami disease, 413 Marginal zone lymphoma, 89, 90f Mass lesions, nonneoplastic, 4161, 426 Masson bodies, 58, 59f Mastoid bone, xanthoma of, 450, 451f Meckel diverticulum, 122, 122f Meconium, inspissated, 125, 125f Meconium ileus, 125, 125f Medullary carcinoma, 193-194, 194f 306, 307f variants of, 194, 195f Medullary thymoma, 98, 99f Medulloblastoma, 424, 424f Medulloepithelioma, 446, 446f Megacolon, toxic, 133 Megaureters, 211, 211f Melanocytes, atypism of, 324 Melanocytic lesions, 323, 3231 Melanocytic neoplasms classification of, 4161 intraepidermal, 324, 324f-325f grade I, 324, 324f grade 11, 324, 324f grade III, 324, 325f Melanocytic nevus compound, 324-325, 325f

Melanocytic nevus-cont'd with architectural disorder, 325-326, 325f 326f junctional with architectural disorder and atypism of melanocytes, 324 dysplastic, 324 lentiginous, 324, 324f 325f Melanoma, 443-444 acral lentiginous, 327 invasive, 327, 328f desmoplastic, 327, 327f of esophagus, 118, 119f histologic features of, 3231 malignant, 326-328, 326f 327f 444, 444f choroidal, 443, 443f metastatic, of epicardium, 27, 28f neurotropic, 327 nodular, 327 superficial spreading, 327, 327f Melanosis, primary acquired, 443 Membranes, rupture of abnormal, 289 the early amnion rupture sequence, 288f 289 Membranoproliferative glomerulonephritis, 219-220 type I, 219-220, 219f type II, 220, 220f type III, 220 Membranous glomerulonephritis, 220-222, 221f 222f secondary, 220, 2201 Menetrier disease, 128, 128f Meningeal neoplasms, 416t Meningioma, 425, 425f Meningitis bacterial, 410, 410f tuberculous, 410, 410f Merkel cell carcinoma, 332f 333 Mesenchymal chondrosarcoma, 376-377, 377f .of soft tissue, 350, 350f Mesenchymal tumors, 163, 163f 333 Mesenteric arteries or veins, occlusion of, 124, 124f Mesenteric artery thrombosis, 124, 124f Mesothelioma, malignant, 64, 65f Metabolic diseases of bone, 357-359 hereditary, of liver, 144 of kidneys, 228-229 of nervous system, 413-415 that affect eyes, 437, 4371 Metabolic myopathies, genetic, 392-394 Metabolism, inborn errors of, 414-4 .15 Metaplastic carcinoma, 308, 308f Metastatic melanoma, of epicardium, 27, 28f Metastatic tumors from colon adenocarcinoma, 285, 285f from leiomyoma, 273 of liver, 163, 164f of lungs, 70, 71f Metazoal infections, 411 MFH; see Malignant fibrous histiocytoma "Mice," 363 Michaelis-Gutmann bodies, 233 Microabscesses, Munro, 321 Microadenomas, 176, 177f 184

Microaneurysms, diabetic, of retina, 437, 438f Microangiopathy, 430, 430f thrombotic, 216-217, 217f Microemboli, intramyocardial, 20, 21f Microglandular adenosis, 296 Micrognathia, 102, 102f Middle cerebral artery, cerebral infarcts in distribution of, 408, 408f Middle ear chronic otitis media of, 451, 452f inflammatory lesions of, 450-453 tumors of, 455 Mikulicz cells, 42f Miliary tuberculosis, 54 Miller-Dieker syndrome, 401, 401f Milroy disease, 122, 123f Minimal change disease, 217, 217f 218f Misplaced exocytosis, 184f Mitochondria) myopathy, 394, 394f Mitotically active leiomyomas, 273 Mitral valve chronic rheumatic endocarditis of, 10, l if floppy, 13, 13f Mixed connective tissue disease, 319 Mixed germ cell stromal tumors, 247, 247f Mixed gonadal agenesis, 2581 Mixed gonadal dysgenesis, 259f Mixed mullerian tumors, 271 malignant, 270f 271, 271f Mixed neuronal-glial neoplasms, 4161, 424 Mixed small cleaved and large cell lymphoma, 90, 92f Mixed tubulovillous polyps, 139 Mixed tumors, benign, of vagina, 265-266, 266f Molluscuw contagiosuw, 314, 315f Monckeberg medial calcific sclerosis, 32, 33f Monoblastic leukemia, acute, 78, 79f "Morocco leather" brain, 401, 401f Morton neuroma, 433, 433f Motor neuron disease, 420 Mouth, diseases of, 100 MPGN; see Membranoproliferative glomerulonephritis Mucha-Habermann disease, 322-323 Mucinous adenocarcinoma, 172, 173f Mucinous (noncystic) carcinoma of breast, 306, 307f or large intestine, 139-140 of pancreas, 174, 175f Mucinous cystadenocarcinoma, 276f 277 Mucinous cystadenoma of appendix, 136, 137f of borderline malignancy endocervical (mullerian), 275-277, 276f intestinal, 275-277, 276f of intestinal type, 275, 275f, 276f Mucinous tumors of borderline malignancy, 172, 173f intraductal papillary, 172, 173f of ovary, 275-277 Mucoceles, 108, 108f 109f Mucoepidermoid carcinoma, 117 Mucormycosis, rhinocerebral, 41 1, 411 f Mucous retention cysts, 108, 109f Mullerian adenosarcoma, 271, 271f Mullerian cystadenoma, mucinous, 275-277, 276f Mullerian ducts, persistent, 259f


469

Mullerian inhibitory substance deficiency, 258t persistent mullerian duct syndrome secondary to, 259f Mullerian tumors, mixed, 271 malignant, 270f 271, 271f Multicystic encephalopathy, 402f 403 Multifocal leukoencephalopathy, progressive, 417, 418f Multiinfarct state, 409, 409f Multiple endocrine neoplasia syndromes, 193, 193t type 1, 176, 177f type 2B, 205, 205f Multiple leiomyoma, 271, 271f Multiple myeloma, 82, 82f 83f diagnostic criteria for, 83t kidney disease, 232, 232f Multiple sclerosis, 416-417, 417f Multisystem atrophy, 419, 419f Mumps orchitis, 241, 242f Munro microabscesses, 321 Mural thrombus, over myocardial infarction, 24, 24f Muscle(s) skeletal, 385-397 striated dystrophin-sarcoglycan complex of, 386, 387d tumors of, 345-346 Muscle diseases, 384 denervation-related, 395-396, 395t Muscular dystrophy, 386-388 Becker, 388 Duchenne, 388, 388f myotonic, 388, 389f Myasthenia gravis, 98, 99f Mycobacterium avium-intracellulare infection, 150, 150f intestinal, 129, 129f Mycobacterium tuberculosis infection, 363 Myelinolysis, central pontine, 413, 413f 414f Myelinolytic diseases, 415 Myeloblastic leukemia, acute, 78, 79f Myeloblasts, 78, 78f Myelodysplastic syndromes, primary, 80t Myelofibrosis, 77, 77f Myeloid leukemia acute, 78, 78f of lymph node, 96, 96f of spleen, 96, 97f chronic, 80, 80f of spleen, 96, 97f Myeloma, multiple, 82, 82f, 83f diagnostic criteria for, 83t kidney disease, 232, 232f Myelomonocytic leukemia, chronic, 80t Myocardial abscess, 16, 16f Myocardial diseases, 14-18 Myocardial infarction, 22, 22f, 23f complications of, 22-24, 23f, 24f subendocardial, 22, 22f transmural, 22, 22f rupture of, 22, 23f Myocarditis, 14-18 causes of, 14, 14t classification of, 14, 14t diphtherial, 16, 16f eosinophilic, 16, 17f

Myocarditis-cont'd idiopathic, 16, 17f microscopic appearance of, 14, 15f types of pathogens, 14t Myocardium inflammations of, 14 replacement fibrosis in, 17, 17f Myoepithelial sialadenitis, lymphocytic, 108 Myoepithelioma, 114, 115f Myometrium, tumors of, 271-272 Myopathy centronuclear, 386, 387f congenital, 386, 3871 genetic metabolic, 392-394 inflammatory, 389-390, 389t lipid storage, 393, 393f mitochondrial, 394, 394f nemaline (rod), 386, 386f sarcotubular, 386, 387f Myophosphorylase deficiency, 393, 393f Myosis, endolymphatic stromal, 270 Myositis drug-induced, 390, 391f inclusion body, 390, 391f proliferative, 336, 336f Myositis ossificans, 349, 349f Myospherulosis, 42, 43f Myotonic muscular dystrophy, 388, 389f Myxoid chondrosarcoma, extraskeletal, 350, 350f Myxoid liposarcoma, 340, 341f Myxoma cardiac, 27, 27f nerve sheath, 347, 347f

N Nail-patella syndrome, 214, 215f "Napkin ring-like" lesions, 139, 139f Nasal diseases, 40 Nasal papillomas, 44, 44f Nasal polyps, 42, 43f Nasal sinuses, diseases of, 40 Nasal tumors, 45, 46f Nasal vestibule, squamous cell carcinoma of, 45, 46f Nasopharyngeal angiofibroma, juvenile, 44, 45f Nasopharyngeal carcinoma, 45-47, 46f classification of, 46t subtypes, 45-47 Nasopharynx, diseases of, 40 National Cancer Institute, 89, 89t Necrolysis, toxic epidermal, 317 Necrosis acetaminophen-induced hepatic, 152, 152f acute tubular, 228-229, 229f contraction band, 22, 23f fibrinoid, 32, 33f massive HBV-induced hepatic, 148f, 149 of pancreas, 170f 171 osteonecrosis, 361 papillary, 230, 230f "piecemeal," 149 pituitary, 182, 182f sclerosing hyaline, 154 Necrotic material, comedo-like, 302 Necrotizing encephalomyelopathy, subacute, 414, 415f Necrotizing lymphadenitis, histiocytic, 84, 85f

Necrotizing sialometaplasia, 108, 109f Neisseria gonorrhoeae infection, 363 Nemaline myopathy, 386, 386f Neomembrane, 405, 405f Neonatal atelectasis, 52, 52f Neonatal pneumonia, 52 Neonatal pulmonary hypoplasia, 50, 51f Neonatal respiratory distress syndrome, 52, 52f Neoplasia anal intraepithelial, 140, 140f vulvar intraepithelial neoplasia with, 263f 264 cervical intraepithelial, 266, 267f prostatic intraepithelial, 250 squamous intraepithelial grade I, 328, 329f grade II, 328, 329f grade III, 328, 329f vulvar intraepithelial, 263-264, 263f Neoplasms; see Tumors Nephritis anti-glomerular basement membrane, 224-225, 225f interstitial acute, 227, 227f 228f 228t granulomatous, 227, 228f lupus, 226, 227f mesangial proliferative, 225, 226f scoring system, 225t WHO classification of, 225t Nephroangiosclerosis, 216, 216f Nephroblastoma, 234 Nephrocalcinosis, 230 Nephropathy analgesic abuse, 239 HIV-associated, 218, 219f IgA, 222-223, 222f-223f thin basement membrane, 214, 214f Nephrosclerosis, 216 Nephrosis lower nephron, 229 primary glomerulopathies responsible for, 217, 217t Nerve sheath myxoma, 347, 347f Nerve sheath neoplasms, 416t Nervous system, 399-433 central degenerative diseases of, 418-420 denervating diseases of, 395t diseases of, 398 metabolic diseases of, 413, 413t neoplasms of, 416t, 421-426, 421d spongy degeneration of, in infancy, 415, 415f toxic diseases of, 413, 413t circulatory disturbances, 405-409 developmental disorders of, 400-401 genetic disorders of, 400-401 infections of, 409-410 metabolic diseases of, 413-415 peripheral diseases of, 398, 426-433 neoplasms of, 432-433 toxic diseases of, 413-415 Nesidioblastosis, 168 diagnostic criteria for, 168 diffuse, 168, 168f Neural tumors, 347-348


470

Neural tumors-cont ' d benign, 347, 347t malignant, 348, 348t Neurilemmoma, 432, 432f Neuroblastoma, 205-206, 205f 206f olfactory, 45, 46f Neurodegenerative diseases, 418-420, 418t Neuroendocrine tumors, 416t, 424 anal, 140, 140f of CNS, 283, 284f of pancreas, 176 Neuroepithelioma, peripheral, 350, 351f Neurofibroma, 347, 347f 432, 432f Neurogenic atrophy, chronic, 396, 396f Neuroma, Morton, 433, 433f Neuronal neoplasms, 424 Neuropathy amyloid familial, 430, 430f hereditary, 430, 430f giant axonal, 429, 429f inflammatory, 430-431 ischemic, 430, 430f localized hypertrophic, 433 peripheral, 395t, 426-428 hereditary, 428-430, 428t tomaculous, 429-430, 430f Neuroschisis, 400 Neurotropic melanoma, 327 Neutrophilic satellitosis, 154, 154f Nevus Becker, 323 blue, 332f 333 histologic features of, 323t junctional melanocytic with architectural disorder, 324, 324f dysplastic, 324 lentiginous, 324, 325f pigmented spindle cell, of Reed, 326 Spitz, 326, 326f Niemann-Pick disease, 414 Nipple, Paget disease of, 307, 307f Nodular adrenocortical disease, primary pig mented, 200f 201 Nodular fasciitis, 336, 336f Nodular goiter, 185, 185f Nodular hyperplasia, focal, 160, 160f Nodular sclerosis, 87-88, 88f Nodular thickening, 6, 8f Nodular transformation, 160-161, 160f Nodular vasculitis, 320, 321f Nodules in coal workers ' pneumoconiosis, 62, 63f rheumatoid, 364-366, 366f silicotic, 62, 62f stromal benign endometrial, 270 endometrial, 270, 270f vocal cord, 44, 45f Non-Hodgkin lymphoma, 89-95 classification of, 89, 89t Kiel, 89, 89t Working Formulation vs Revised European-American Lymphoma, 89, 89t Nose, diseases of, 40 Nuclear sclerotic cataracts, 442, 442f "Nutcracker esophagus," 110

0 Obstruction biliary, 156, 157f of intestinal lumen, 125-126 Obstructive pulmonary disease, chronic, 60 Occlusion of mesenteric arteries or veins, 124, 124f Ochronosis, 360-361, 361f Ocular adnexa, 435-446 inflammation of, 436-437 tumors of, 443-446 Ocular disorders, 438-443 Ocular toxocariasis, 437, 437f Odontogenic adenomatoid tumor, 112, 112f Odontogenic cysts, I06d Odontogenic keratocyst, 105 Odontogenic tumors, 112, 113t calcifying epithelial, 112, 113f Olfactory neuroblastoma, 45, 46f Oligodendroglioma, 422, 423f Olivopontocerebellar atrophy, 419, 419f Omphalocele, 122, 122f Oncocytic (Hurthle cell) adenoma, 190, 190f Oncocytic (Hurthle cell) carcinoma, I90t, 193, 193f Oncocytoma, 114, 115f " Onionskin " fibrosis, 156, 156f Opisthorchis sinensis infection, 151, 152f Optic nerve head, end-stage glaucomatous cupping of, 439, 439f Oral lesions, 108-109 Oral tumors, 112 Orchitis granulomatous, 241-242 mumps, 241, 242f Organizing pneumonia, 54, 55f bronchiolitis obliterans with, 66 idiopathic, 66, 67t " Orphan Annie " nuclei, 191, 191f Orthokeratotic cysts, 107, 107f Osler-Weber-Rendu disease, 124, 125f Osteitis deformans, 359 Osteitis fibrosa cystica, 359 Osteoarthritis, 361 Osteoblastoma, 368-369, 368f Osteochondroma, 372, 373f Osteodystrophy, renal, 358-359, 359f Osteofibrous dysplasia, 378 Osteogenesis imperfecta, 356 type II, 356, 356f 357f Osteoid osteoma, 367-368, 368f Osteoma, 367, 367f osteoid, 367-368, 368f Osteomalacia, 358-359, 358f Osteomyelitis, 363-364, 363f 364f Osteonecrosis, 361 of head of femur, 361, 361f Osteopetrosis, 356-357, 357f Osteoporosis, 357-358, 357f active, 358, 358f inactive, 358, 358f Osteosarcoma classic, 369 conventional, 369-370, 369f 370f intraosseous well-differentiated, 370-372, 371f parosteal, 370, 371f periosteal, 370, 371f

Osteosarcoma-cont ' d of soft tissue, 349, 350f telangiectatic, 372, 372f variants, 370-372 Otitis media, 451-452 chronic, 451, 451f of middle ear, 451, 452f low-grade, 451, 452f Otosclerosis, 454, 454f Outer ear; see also External ear tumors of, 455 Ovarian diseases, 256 polycystic, 262f 263 Ovarian endometriosis, 263, 263f Ovarian tumors, 273-285 classification of, 273t metastatic, 284-285 mucinous, 275-277 serous, 273-275 transitional cell, 278 unclassified, 284-285 Ovulation, anovulatory cycle, 261-263, 261f Oxalate crystals, 230 Oxalosis, 230, 231f

P Paget disease, 453f 454 of anus, 140, 141f of bone, 359-360, 359f 360f extramammary, 264, 264f of nipple, 307, 307f phases of, 360 vulvar, 264, 264f Palate, cleft, 102, 102f Panacinar (panlobular) emphysema, 60, 61f Pancarditis, 9 Pancreas, 167-179 annular, 168, 168f carcinoma of, 174, 174f 175f not otherwise specified, 174 carcinoma of body of, 174, 174f carcinoma of tail of, 174, 174f cysts of, 168, 168f developmental disorders of, 168 diseases of, 166 endocrine, tumors of, 176-177 exocrine, tumors of, 172-174 genetic disorders of, 168 neuroendocrine tumors of, 176 Pancreatic ducts, villous adenoma of, 172, 173f Pancreatic pseudocysts, 171, 171f Pancreatitis, 169-171 acute, 170f complications of, 170f, 171 . acute hemorrhagic, 169-170, 169d, 169f 170f acute interstitial, 169 chronic, 171, 171f diabetes mellitus of, 178t, 179, 179f interstitial, 169, 169f viral, 169, 169f Pancreatoblastoma, 174, 176f Panencephalitis, subacute sclerosing, 412, 417, 417f Panophthalmitis, 437 Papillary adenocarcinoma serous, 268, 269f villoglandular, 268, 268f Papillary adenoma, 172, 173f


471

Papillary carcinoma, 190-191, 191f diffuse sclerosing variant, 191, 192f features of, 190t follicular variant, 191, 191f invasive, 308, 308f solid growth pattern, 191, 192f of thyroid gland, 190-191 variants of, 191, 192f Papillary cystadenoma lymphomatosum, 114 Papillary hyperplasia follicular adenoma with, 188, 189f inflammatory, 103, 103f Papillary mutinous neoplasms, intraductal, 172, 173f Papillary muscle rupture, 22-24, 24f Papillary necrosis, 230, 230f Papillary pneumocytoma, 70 Papilloma choroid plexus, 424, 424f ductal, 300, 300f intraductal, 172, 173f 300, 300f laryngeal, 44 nasal, 44, 44f schneiderian, 44, 44f transitional cell, everted type, 236f of urinary bladder, 236f, 237 Paraganglioma, 455, 455f Parahippocampal gyrus, herniation of, 404f 405 Parakeratotic cysts, 106f Parakeratotic keratocyst, 105-107 Paraneoplastic syndromes, 416t Parapsoriasis, 322, 322f Parathyroid adenoma, 195-196, 197f Parathyroid carcinoma, 196, 197f Parathyroid glands, diseases of, 195-196 Parathyroid hyperplasia, 195, 196f Parkinson disease, 420, 420f Parkinsonism, idiopathic, 420 Parosteal osteosarcoma, 370, 371f Parotid gland, pleomorphic adenoma of, 114, 114f Parvovirus B19-induced erythroid hypoplasia, 74, 75f Patent ductal artery, 2, 3f PCOD; see Polycystic ovarian disease Peliosis hepatic, 147, 147f Pelvic inflammatory disease, 260 Pemphigus, 316 Pemphigus vulgaris, 316, 316f Penis, diseases of, 238 Peptic ulcers, 126-128, 128f Pericardial diseases, 25, 25f-26f Pericardial fibrosis, 25, 25t Pericarditis, 25 causes of, 25, 25t constrictive, 25, 26f fibrinohemorrhagic, 25, 26f fibrinous, 25, 25f tuberculous, 25, 26f Pericardium, hemangiosarcoma of, 27, 28f Perinatal brain lesions, 401-402 Perinatal lung diseases, 52 Perineurial fibrosis, 433 Perineurioma, 432-433, 433f Perineuritis, 431, 431f Periosteal chondroma, 373, 374f Periosteal osteosarcoma, 370, 371f Peripheral adenocarcinoma, 68, 68f Peripheral anterior synechiae, 439, 439f

Peripheral blood smears, 74-77, 75f-76f Peripheral nerve sheath tumors, 348, 348f Peripheral nerves diseases of, 398, 426-433 neoplasms of, 432-433 Peripheral neuroepithelioma, 350, 351f Peripheral neuropathies, 3951, 426-428 classification of, 426 hereditary, 428t inflammatory, 430-431 ischemic, 430, 430f Peripheral T-cell lymphomas, 92-93, 93, 93f 94f Periportal hepatic fibrosis, 151, 152f Peritoneal adhesions, 125 Peritonitis, I70f, 171 Perivascular pseudorosettes, 422, 423f Perivascular tumors, 343-344, 343t Periventricular leukomalacia, 402, 402f Persistent generalized lymphadenopathy, 84, 85f Persistent mUllerian duct syndrome, 259f Persistent truncal artery, 6, 6f Peutz-Jeghers polyps, 138f 139 Peutz-Jeghers syndrome, 324 Pharyngitis, 104 Pharynx, diseases of, 100 Pheochromocytoma, 203-205, 203f 204f Phyllodes tumors, 250, 299, 299f 300f Pick bodies, 418, 419f Pick cells, 418, 419f Pick disease, 418, 419f PII3; see Pelvic inflammatory disease PIE; see Pulmonary infiltration and eosinophilia Pigmentary lesions, 323-328 Pigmented nodular adrenocortical disease, 200f 201 Pigmented spindle cell nevus of Reed, 326 Pigmented villonodular synovitis, 383 PIN; see Prostatic intraepithelial neoplasia Pineal tumors, 416t, 424-425 Pineoblastomas, 424-425, 425f Pineocytomas, 424-425, 425f Pinna, epithelioid hemangioma of, 450, 451f "Pipe stem " type of periportal hepatic fibrosis, 151, 152f Pituitary adenoma, 183f 184, 184f frequency of, 183t Pituitary carcinoma, 184 Pituitary gland diseases of, 182-184 hypofunction of, 182 reactive changes in, 183, 183f tumors of, 183-184 Pituitary necrosis, 182, 182f Pityriasis lichenoides et varioliformis acute, 322-323, 322f Pityriasis rosea, 321-322, 322f Pityrosporum, 321 Placenta abnormal implantation of, 289 abnormal separation of, 289 abnormalities of, 287 composition of, 287, 287d development of, 286d, 287 dichorionic diamniotic, 287, 287f disorders of, 287-290 extrauterine implantation of, 288f 289 infections of, 289-290 monochorionic diamniotic, 287, 287f

Placenta accreta, 288f 289 Placental site trophoblastic tumor, 290, 292f features of, 291t lesions easily confused with, 290, 293f Plaque coronary, rupture of, 20, 21d coronary atherosclerotic, 20, 20f Plaque jaune, 404f 405 Plasma cell dyscrasias, 82-83, 82t Pleomorphic adenoma, 114, 114f Pleomorphic liposarcoma, 340, 341f Pleomorphic rhabdomyosarcoma, 346 PLEVA; see Pityriasis lichenoides et varioliformis acute Plexiform tumorlets, 270 Plexogenic pulmonary arteriopathy, 58, 58f PNET; see Peripheral neuroepithelioma Pneumoconioses, 62-64 coal workers', 62, 63f Pneumocystis carinii pneumonia, 56, 56f Pneumocytoma, papillary, 70 Pneumonia bronchopneumonia, 54, 54f classification of, 54 early, amniotic fluid aspiration with, 52, 53f eosinophilic, 58, 59f hypersensitivity, 58, 59f interstitial acute, 671 desquamative, 66, 67f 67t nonspecific, 67t usual, 66, 67t lobar, 54, 54f necrotizing, 54, 55f neonatal, 52 organizing, 54, 55f bronchiolitis obliterans with, 66 idiopathic, 66, 67t Pneumocystis carinii, 56, 56f phases of, 54 resolution phase, 54 Staphylococcus aureus, 54, 55f tuberculous, 54 viral, 56, 56f Polyarteritis nodosa, 39, 39f 430, 431f Polychondritis, relapsing, 450, 451f Polycystic kidney disease, 212-213 autosomal dominant, 212, 212f autosomal recessive, 212-213, 213f subtypes of, 212 Polycystic liver disease, 159, 159f Polycystic ovarian disease, 262f 263 Polymicrogyria, 401, 401f Polymorphic reticulosis, 94 Polymorphous low-grade adenocarcinoma, 117, 117f Polymyositis, 390, 390f Polyneuropathy, chronic inflammatory demyelinating, 431, 431f Polypoid nodules of vocal cords, bilateral, 44, 45f Polyps hyperplastic, 138f 139 intestinal, 136-139, 137t juvenile, 138f 139 mixed tubulovillous, 139 nasal, 42, 43f


472

Polyps-cont 'd Peutz-Jeghers, 138f 139 solitary laryngeal, 44, 45f Polyradiculoneuropathy, chronic inflammatory demyelinating, 431, 431f Pompe disease, 392 Pons, astrocytoma of, 422, 422f Porcelain gallbladder, 164, 165f Porencephaly, 402f 403 Pork tapeworm infection, 411, 411f Porokeratosis, 312, 312f Portal vein thrombosis, 147, I47f Positional anomalies of gastrointestinal tract, 122 renal, 210, 210d Pott disease, 364, 364f Potter syndrome, 102, 102f PPNAD; see Pigmented nodular adrenocortical disease Pregnancy, ectopic, 288f 289 Presbycusis, 453, 453f Prognathia, 102, 102f Progressive multifocal leukoencephalopathy, 417, 418f Prolactin cell adenoma, 184, 184f Proliferative fasciitis, 336, 336f Proliferative myositis, 336, 336f Promyelocytic leukemia, 78, 79f Prostate atrophy of, 248 carcinoma of, 250-253, 251f 252f Gleason grading system of, 252f 253 variants of, 253, 253f diseases of, 238 tumor-like lesions of, 248-253 tumors of, 248-253 Prostatic adenocarcinoma Gleason grading system of, 253, 255f 255t variants of, 254t Prostatic hyperplasia benign, 248-250, 248f 249f chronic cystitis caused by, 232f 233 Prostatic intraepithelial neoplasia, 250, 251f architectural patterns of, 250d morphologic continuum of, 250d Proteinosis, pulmonary alveolar, 66, 67f Protozoal infections, 411 Pseudocysts, pancreatic, 171, 171f Pseudoexfoliation syndrome, 439, 439f Pseudogout, 360 Pseudohermaphrodites female, 258t male, with normal male karyotype, 258t Pseudomembranous colitis, 130, 13lf 132f Pseudomembranous cystitis, 233, 233f Pseudomonas aeruginosa infection acute keratitis and scleritis caused by, 437, 437f of male genital organs, 241 Pseudomyxoma peritonei, 277 Pseudopapillary tumors, solid, 172-174, 173f Pseudophakic bullous keratopathy, 440, 440f Pseudorosettes, perivascular, 422, 423f Pseudotumors, inflammatory, 70, 71f Psoriasiform dermatitis, 314-316, 316f Psoriasis, 321, 321f parapsoriasis, 322, 322f PSTT; see Placental site trophoblastic tumor

PTCL; see Peripheral T-cell lymphomas Pulmonary alveolar proteinosis, 66, 67f Pulmonary anomalies, 50, 51f Pulmonary arteriopathy, plexogenic, 58, 58f Pulmonary atresia, 4, 4d, 5f Pulmonary blastoma, 70, 70f Pulmonary circulatory disorders, 57-58 Pulmonary disease, chronic obstructive, 60 Pulmonary emboli, 57 Pulmonary fibrosis forms of, 67t idiopathic, 66, 67f Pulmonary hamartoma, 70, 70f Pulmonary hypertension, 58 primary or idiopathic, 58 secondary, 58 Pulmonary hypoplasia, 50, 51f Pulmonary infarction, 57, 57f Pulmonary infections, 54-56 Pulmonary infiltration and eosinophilia, 58, 59f Pulmonary interstitial air, 52, 53f Pulmonary neoplasms, 68-70 Pulmonary stenosis, 6, 7d, 8f 9 Pulmonary thromboembolism, 57, 57f Pulmonary tuberculosis, 54, 55f " Punched-out" lesions, 82, 82f Purpura anaphylactoid or rheumatoid, 222 Henoch-Schonlein, 39, 39f 222-223, 223f Pustules, spongiform, of Kogoj, 321 Pyelonephritis, 228, 228f acute, 228, 228f chronic, 228, 228f Pyloric stenosis, 122, 123f Pyogenic abscesses, 409, 409d Pyogenic granuloma, 103-104, 104f 341, 342f Pyropoildlocytosis, 74, 75f

Q Q fever hepatitis, 149, 149f Queyrat, erythroplasia of, 263-264, 328

R Radial scar formation, 296 Radicular cysts, 107, I07f Rash, butterfly, 318, 318f Reactive lymphadenopathy, 84-85, 84t REAL; see Revised European-American Lymphoma classification Recanalization, coronary artery, 20, 21f Red hepatization, 54 Reed, pigmented spindle cell nevus of, 326 Reed-Sternberg cells, 86f 87 Reflux esophagitis, 110, 111f Reid index, 60 Reinnervation, denervation with, 396, 397f Relapsing polychondritis, 450, 451f Renal abnormalities, positional, 210, 210d Renal agenesis, 210, 210f Renal amyloidosis, 82, 83f Renal cell carcinoma, 234, 234f classification of, 234t grading of, 234t Renal dysplasia, 213, 213f Renal osteodystrophy, 358-359, 359f Renal pelvis transitional cell carcinoma of, 235, 235f tumors of, 234-235

Renal tubules acute tubular necrosis, 228-229, 229f toxic, 228-229, 229t hereditary diseases, 213-214 tubulointerstitial diseases, 227-232 Replacement fibrosis, 17, 17f Reproductive system female, 256, 257-293 male, 238, 239-255 Respiratory distress syndrome, neonatal, 52, 52f Respiratory tract, upper, 41-47 diseases of, 40 Restrictive cardiomyopathy, 18, 19f causes of, 18d Rete testis, tumors of, 248, 248f Reticulosis, polymorphic, 94 Retina diabetic microaneurysms of, 437, 438f hard exudates of, 437, 437f Retinal arterial macroaneurysm, 437, 438f Retinal atrophy, glaucomatous, 439, 439f Retinal capillary hemangioma, 438, 438f Retinal degenerative changes, 441 Retinal degenerative diseases, 441 Retinal detachment, 441, 441f Retinitis pigmentosa, 441, 441f Retinoblastoma, 445-446, 445f 446f Retinocytoma, 446 Retinoma, 446 Retinopathy, proliferative diabetic, 437, 438f Revised European-American Lymphoma classification of non-Hodgkin lymphoma, 89, 89t Rhabdomyoma, 27, 28f 345 adult, 345, 345f Rhabdomyosarcoma, 237, 237f 346, 346f alveolar, 346 botryoid, 346 embryonal, 346, 346f of vagina, 266, 266f pleomorphic, 346 spindle cell, 346 types, 346 Rheumatic carditis, 9, 9f Rheumatic endocarditis acute, 10, 10f chronic acute bacterial endocarditis on, 12, 12f of aortic valve, 10, 11f of mitral valve, 10, 11f Rheumatic heart disease, 9-10 Rheumatoid arthritis, 364-366, 364f 365f 366f pathogenesis of, 364, 365d Rheumatoid nodules, 364-366, 366f Rheumatoid purpura, 222 Rhinocerebral mucormycosis, 411, 411f Rhinorrhea, 42 Rhinoscleroma, 42, 42f Rhinosporidiosis, 42, 43f Rhinosporidium seeberi infection, 42, 43f Rhizopus pneumonia, 36 " Rice bodies, " 363, 363f 364, 366f Rickets, 358, 358f Rickettsia infection, 36, 37f Riedel thyroiditis, 188, 189f Rochalunaea henselae infection, 147 Rocky Mountain spotted fever, 36, 37f Rod myopathy, 386, 386f


473

Rosettes Flexner-Wintersteiner, 424 Homer Wright, 424 Round cell liposarcoma, 340, 341f " Rubber head, " 356, 356f Rubella infection, 453, 453f Rubella virus, 453 Runny nose; see Rhinorrhea Rupture of membranes abnormal, 289 the early amnion rupture sequence, 288f 289

S Saddle emboli, 57, 57f Salivary duct carcinoma, 117, 117f Salivary gland(s) diseases of, 100 lesions of, 108-109 marginal zone lymphoma of, 89, 90f tumors of, 112-117 epithelial, 112, 113t malignant, 117 Salivary gland-like carcinoma, 308, 308f Salpingitis, chronic, 260, 261f Sarcoglycan, 386, 387d Sarcoidosis, 64, 64f 74, 75f 431, 431f Sarcoma alveolar soft-part, 352f 353 botryoid, 266, 266f clear cell, 348 dendritic cell, 96, 96f endometrial stromal, 277 high-grade, 270-271 low-grade, 270, 270f epithelioid, 352f 353 of esophagus, 118 Ewing, 379, 380f Kaposi, 333, 333f of lung, 70, 70f synovial, 351f 353 undifferentiated, 163 Sarcomatoid tumors, 278 Sarcotubular myopathy, 386, 387f Satellitosis, neutrophilic, 154, 154f Schistosomiasis, 151, 152f Schneiderian papilloma, 44, 44f Schwann cells, 206, 206f Schwannoma, 347, 347f 432, 432f glandular malignant, 348 Scleritis, acute, 437, 437f Sclerosing adenosis, 296 Sclerosing cholangitis, 156, 156f Sclerosing hemangioma, 70, 71f Sclerosing hyaline necrosis, 154 Sclerosing panencephalitis, subacute, 412, 417, 417f Sclerosing stromal tumors, 280f 281 Sclerosis amyotrophic lateral, 420, 420f 421f denervation atrophy caused by, 396, 396f Monckeberg medial calcific, 32, 33f multiple, 416-417, 417f otosclerosis, 454, 454f systemic, 32, 33f tympanosclerosis, 452, 452f Sclerotic cataracts, nuclear, 442, 442f Sebaceous carcinoma, 117, 117f 332f 333 Seborrheic dermatitis, 321, 322f

Seborrheic keratosis, 328, 328f Secretory carcinoma, 308, 308f Seminoma, 244, 244f spermatocytic, 246, 246f Senecio alkaloids, 146 Senile dementia, 418 Septal defects, 2 Sequestrum, 363 Serous carcinoma, 275, 275f Serous cystadenoma, 173f 273-275, 274f Serous papillary adenocarcinoma, 268, 269f Serous tumors borderline malignant, 273-275, 274f 275f malignant, 275, 275f of ovary, 273-275 Sertoli cell tumors, 247, 247f large cell calcifying type, 247, 247f variants of, 247 Sertoli cells, 240f Sertoli-Leydig cell tumors, 280f 281 histologic patterns, 281 sarcomatoid variant, 281, 281f Sex cord stromal tumors with annular tubules, 281, 281f in female, 278-281 in male, 246-247 Shunts, cardiovascular, 2, 2d Sialadenitis, 104, 104f chronic, 104, 104f lymphocytic myoepithelial, 108 Sialadenoma papilliferum, 114, 115f Sialolithiasis, 108, 108f Sialometaplasia, necrotizing, 108, 109f Sickle cell anemia, 76f 77, 78f Siderosis, 62, 63f Sigmoid colon, adenocarcinoma of, 139, 139f Signet-ring carcinoma, 308, 308f Silicatosis, 62, 62f Silicosis, 62, 62f SIN; see Squamous intraepithelial neoplasia "Singer's node, " 44, 45f Sjogren syndrome, 108, 109f Skeletal muscles, 385-397 diseases of, 384 Skin, 311-333 Skin diseases, 310 granulomatous, 319-320 hereditary, 312 idiopathic, 321-323 Skin infections, 312-316 bacterial, 313-314 fungal, 314 viral, 314-316 Skin neoplasms, 323-333 SLE; see Systemic lupus erythematosus Small cell carcinoma of esophagus, 118 with hypercalcemia, 284, 284f of lung, 68, 68f of urinary bladder, 237, 237f Small intestine diseases that cause malabsorption, 129-130, 129t lipoma of, 136, 136f tumors of, 136, 136f Small lymphocytic lymphoma, 89, 90f Small noncleaved cell lymphoma, 94-95 Burkitt type, 94-95, 95f

Small noncleaved cell lymphoma-cont ' d non-Burkitt type, 94-95, 95f subtypes, 94 Small plaque parapsoriasis, 322 Small round cell tumors intraabdominal desmoplastic, 350, 351f of soft tissues, 350 Small vessel vasculitis, 39, 39f Smooth muscle cell tumors, 344-345 Smooth muscle tumors, 344, 344t "Soap bubble" pattern, 380, 381f Soft-part sarcoma, alveolar, 352f 353 Soft tissue, 335-353 definition of, 334 diseases of, 334 mesenchymal chondrosarcoma of, 350, 350f Soft-tissue tumors, 334, 350-353, 351t WHO classification of, 343, 343t Solar lentigo, 323 Solid cystic tumors, 172-174, I73f Solid pseudopapillary tumors, 172-174, 173f Somatostatinoma, 176-177, 177f Spermatocytic seminoma, 246, 246f Spermatogenesis disturbances of, 240f 241 maturation arrest of, 240f 241 Spherocytosis, 74, 75f hereditary, 77, 77f Spinal cord infections of, 409-410 subacute combined degeneration of, 413-414, 414f trauma of, 403-405 Spinal cord hemorrhage, 407, 407f Spinal cord neoplasms, 416t Spinal muscular atrophy fascicular, 396, 397f infantile, 396, 397f Spindle cell hemangioendothelioma, 343 Spindle cell leiomyoma, 134, 135f Spindle cell lipoma, 339, 340f Spindle cell nevus, pigmented, of Reed, 326 Spindle cell rhabdomyosarcoma, 346 Spine, tuberculosis of, 364, 364f Spitz nevus, 326, 326f Spleen, neoplasms involving, 96 Splenic artery, cirsoid aneurysm of, 35, 35f Splenomegaly, 96, 96t Spongiform pustules of Kogoj, 321 Spongy degeneration, of CNS, in infancy, 415, 415f Squamous cell carcinoma of bronchus, 68, 68f esophageal, 118, 118f hilar, 68, 68f invasive of cervix, 267, 268f of vulva, 264, 264f of larynx, 47, 47f of nasal vestibule, 45, 46f of skin, 328, 329f of vagina, 265 variants of, 112 verrucous, 112, 112f of vocal cord, 47, 47f vulvar, 263 Squamous epithelium, tumors of, 112, 112f


474

Squamous intraepithelial lesion high-grade, 267, 267f low-grade, 267, 267f Squamous intraepithelial neoplasia grade I, 328, 329f grade II, 328, 329f grade III, 328, 329f SSPE; see Subacute sclerosing panencephalitis " Staghorn " pattern, 344f Staphylococcus aureus pneumonia, 54, 55f Staphylococcus infection, 11, 313, 363 Steatosis, 153, 153f Stenosis aortic, 6, 7d congenital, 6, 8f degenerative calcific, 13, 14f arterial, 6, 7d pulmonary, 6, 7d, 8f 9 pyloric, 122, 123f valvular, 6, 7d Steroid lipid (cell) tumors, 281, 281f Stevens-Johnson syndrome, 317 Stomach adenocarcinoma of, 134, 135f carcinoma of, 134, 134f 135f diseases of, 120 leiomyoma of, 134, 135f marginal zone lymphoma of, 89, 90f Stomatitis, 103 acute, 103, 103f Stones gallstones, 156, 157f 164, 164f urinary, 230, 230f Strep throat, 104 Streptococcus infection

acute poststreptococcal glomerulonephritis, 223f 224 in bones and joints, 363 Streptococcus pneumoniae, 11 Stress erosions, acute, 124 Striated muscle, tumors of, 345-346 Stromal corticomedullary differentiation, 98, 98f Stromal hyperplasia, 249f 250 Stromal luteoma, 281, 281f Stromal myosis, endolymphatic, 270 Stromal nodules, endometrial, 270, 270f Stromal sarcomas, endometrial, 277 high-grade, 270-271 low-grade, 270, 270f Stromal tumors endometrial, 270-271 gastrointestinal, 134, 135f mixed germ cell, 247, 247f sclerosing, 280f 281 sex cord, 246-247, 278-281 with annular tubules, 281, 281f Strums ovarii, 283, 284f Strumal carcinoid, 283, 284f Subacute combined degeneration of spinal cord, 413-414, 414f Subacute granulomatous thyroiditis, 186, 187f Subacute lupus erythematosus, 317 Subacute necrotizing encephalomyelopathy, 414, 415f Subacute sclerosing panencephalitis, 412, 417, 417f Subarachnoid hemorrhage, 407 acute, 407, 407f

Subarachnoid hemorrhage-cont ' d caused by rupture of berry aneurysm, 407, 407f Subcapsular cataracts anterior, 442-443, 442f posterior, 442f 443 Subdural hematoma acute, 405, 405f chronic, 405, 405f 406d Subependymal hemorrhage, 401, 401f 402f Superficial spreading melanoma, 327, 327f Suppurative epididymoorchitis, 241, 241f Swyer syndrome, 258t Sympathetic uveitis, choroid, 436f 437 Symplastic leiomyomas, 271 Syndactyly, 357 Synechiae, peripheral anterior, 439, 439f Synovial chondromatosis, 382f 383 Synovial sarcoma, 351f 353 Synovitis tuberculous, 363, 363f villonodular, 382f 383 Syphilitic aneurysms, 35, 36f Syphilitic aortitis, 36, 37f Syringocystadenoma papilliferum, 331, 331f 332f Systemic diseases eye changes in, 437-438, 437f-438f that affect eyes, 437, 437t Systemic lupus erythematosus, 225-226, 317, 319, 319f acute, 318, 318f "butterfly rash " of, 318, 318f Systemic lupus erythematosus glomerulo nephritis, 225 Systolic disorder; see Dilated cardiomyopathy

T T-cell leukemia, adult, 80, 81f T-cell lymphoma adult, 80, 81f AILD-like, 93-94, 94f angiocentric, 94, 94f lymphoepithelioid, 94, 94f peripheral, 92-93, 93, 93f 94f post-thymic, 92 of spleen, 96, 97f T-cell rich B-cell lymphomas, 92, 93f Taenia solium infection, 411, 411f Takayasu arteritis, 38, 38f Tapeworm infection, 411, 411f Target lesions, 317 Tay-Sachs disease, 414, 414f 415f "Teardrop" shapes, 307, 307f TEARS; see The early amnion rupture sequence Teeth anomalies of, 103 diseases of, 100 Telangiectatic osteosarcoma, 372, 372f Teratocarcinomas, 244, 245, 245f Teratomas, 245, 245f of adult testis, 245, 245f benign, 282, 283f benign cystic, 282, 283f germ cell, 416t immature, 283, 283f grade I, 283, 283f grade II, 283, 283f grade III, 283, 284f of infancy and childhood, 246

Testicular feminization, 259f syndrome, 258t Testis abnormal development of, 240 adult, teratoma of, 245, 245f in AIDS, 242, 243f diseases of, 238 end-stage disease of, 242, 243f rete, tumors of, 248, 248f tumors of, 242-248, 243t tunica vaginalis, tumors of, 248, 248f Testosterone synthesis defect, 258t Tetralogy of Fallot, 4, 4d, 5f Thalassemia, 76f 77 Thecomas, 279-281, 279f 280f Thickening, nodular, 6, 8f Thin basement membrane nephropathy, 214, 214f Thoracic aorta, dissecting aneurysms of, 35, 35f Throat, "strep, " 104 Thromboembolism, pulmonary, 57, 57f Thrombosis mesenteric artery, 124, 124f portal vein, 147, 147f Thrombotic endocarditis, nonbacterial, 13, 13f Thrombotic microangiopathy, 216-217, 217f Thrombus coronary, 20, 21f mural, 24, 24f Thymic carcinoma, 98, 99f Thymic dysplasia simple, 98, 98f with stromal corticomedullary differentiation, 98, 98f Thymic hypoplasia, 98, 98f Thymitis follicular, 98, 99f lymphofollicular, 98, 99f Thymoma, 98, 99f Thymus diseases of, 98-99 in primary immunodeficiency states, 98, 98f Thyroid gland carcinoma of features of, 190t poorly differentiated, 194, 195f undifferentiated (anaplastic), 194, 195f diseases of, 185-194 hyperplasia of, 185-186 tumors of benign, 189-190 malignant, 190-194 Thyroiditis, 186-188 atrophic, 188 de Quervain, 186, 187f forms of, 186, 187t Hashimoto, 186-187, 188f fibrous variant, 187-188, 189f juvenile, 188 nonspecific lymphocytic, 186, 187f Riedel, 188, 189f subacute, 186, 187f subacute granulomatous, 186, 187f "Thyroidization" of kidney, 216, 216f Thyrotroph cells, reactive hyperplasia of, 183, 183f Tinea, 314, 314f Tinea versicolor, 314, 314f


475

Tissue; see also Soft tissue changes in anemia, 77, 77f, 78f Tomaculous neuropathy, 429-430, 430f Tongue anomalies of, 102, 102f giant congenital cavernous hemangioma of, 102, 103f Tophi, 360 Toxic acute tubular necrosis, 228-229, 229t Toxic disorders of kidneys, 228-229 of nervous system, 413-415 Toxic epidermal necrolysis, 317 Toxic megacolon, 133 Toxocariasis, ocular, 437, 437f Toxoplasmic encephalitis, 411, 411f Trabecular adenoma, hyalinized, 188-190, 190f Tracheoesophageal fistula, 50, 50d Transitional cell carcinoma of ovary, 278 of renal pelvis, 235, 235f of urinary bladder, 236f 237 Transitional cell papilloma, everted type, 236f Transplant rejection cardiac, 16, 16f 17f classification of, 16 Transposition of great arteries, complete, 6, 6f Trauma, of brain and spinal cord, 403-405 Treponema pallidum infection, 36, 37f in bones and joints, 363 syphilitic aneurysms of, 35, 36f Trichinella spiralis, 390, 390f Trichinosis, 390, 390f Trichobezoar, 125, 125f Trichoepithelioma, 331, 331f Trichomonas vaginalis infection, 260, 261f Triton tumor, 348 Tropheryma whippelii infection, 129 Trophoblastic disease, gestational, 290, 290f-292f Trophoblastic tumors, placental site, 290, 291 t, 292f Trypanosoma cruzi, 16, 16f Tuberculosis, 199, 199f 260, 261f cavitary, 54 miliary, 54 pulmonary, 54, 55f of spine, 364, 364f Tuberculous arthritis, 363, 363f Tuberculous meningitis, 410, 410f Tuberculous pericarditis, 25, 26f Tuberculous pneumonia, 54 Tuberculous synovitis, 363, 363f Tubular adenoma, 138f 139 adenocarcinoma in, 139, 139f Tubular carcinoma, 306-307, 307f Tubular diseases, hereditary, 213-214 Tubular necrosis, acute, 228-229, 229f toxic, 228-229, 229t Tubulointerstitial diseases, 227-232 Tubulovillous polyps, mixed, 139 Tumor-like conditions of bones, 380-383 hepatobiliary, 159-161 of lungs, 70 Tumor-like lesions benign fibroblastic, 336-337 of joints, 383 of prostate, 248-253

Tumors adenoid basal cell, 249 adenoid cystic–like, 249 adenomatoid, 248, 248f odontogenic, 112, 112f adnexal, 331-333 adrenocortical, 201-203 anal, 140 of appendix, 136, 137f astrocytic, 422 benign anal, 140 bone-forming, 367-369 fibroblastic, 336-337 of lung, 70 neural, 347, 347t of pancreas, 172-174 thyroid, 189-190 of upper respiratory tract, 44 bone, 380-383 bone-forming, 349-350, 349t benign, 367-369 malignant, 369-370 of bones and joints, 367-383 borderline malignant of ovary, 273-275 of pancreas, 172-174 of breast, 298-308 Brenner, 278, 278f brown, of hyperparathyroidism, 359, 359f carcinoid, 68, 69f 136, 136f bronchial, 68, 69f goblet cell, 136, 137f pulmonary, 68, 69f strumal, 283, 284f cardiac, 27 cartilage-forming, 349-350, 349t benign, 372-375 malignant, 375-377 of central nervous system, 421-426 classification of, 416t location and age, 421d secondary, 416t therapeutic complications of, 416t of cervix, 266-268 dental, 112 desmoid, 337, 337f diffuse or sarcomatoid, 278 of ear, 455 of endocrine pancreas, 176-177 endothelial, 341, 341t epidermal, 328-331 of epididymis, 243t, 248, 248f epithelial, 161-163 esophageal, 118 of exocrine pancreas, 172-174 extraocular, 443, 443f of eye, 443-446 fibrohistiocytic, 338, 338t fibrous tissue, 336, 336t gastric, 134 gastrointestinal, 134-140 germ cell classification of, 416t of ovary, 282-283 of testis, 242-246 giant cell, of bone, 378-379, 379f glial, 416t

Tumors—coned glomus, 343, 343f granulosa cell, 278, 279f juvenile, 278-279, 279f hematopoietic, 416t of hepatobiliary tract, 159-163 of inner ear, 455 intraductal papillary mucinous, 172, 173f intraocular, 443, 443f islet cell, 176-177, 176f 177f of joints, 383 of kidney, 234-235 Krukenberg, 284f, 285, 285f Leydig cell, 246, 247f lipomatous, 339-340, 339t lung, 68-70, 69t malignant anal, 140 bone-forming, 369-370 mixed mullerian, 270f, 271, 271f neural, 348, 3481 peripheral nerve sheath, 348, 348f of salivary gland, 117 serous, 275, 275f thyroid, 190-194 triton, 348 of upper respiratory tract, 45-47 marrow, 379 melanocytic, 416t melanocytic intraepidermal, 324, 324f-325f meningeal, 416t mesenchymal, 163, I63f 333 metastatic to liver, 163 of lungs, 70, 71f of ovary, 284-285 of middle ear, 455 mixed benign, of vagina, 265-266, 266f mixed germ cell stromal, 247, 247f mixed mullerian, 271 mixed neuronal-glial, 416t, 424 mucinous, 275-277 of myometrium, 271-272 nasal, 45, 46f nerve sheath, 416t neural, 347-348 neuroendocrine, 416t, 424 of CNS, 283, 284f of colon, 140, 140f of pancreas, 176 neuronal, 424 of ocular adnexa, 443-446 odontogenic, 112, 113t calcifying epithelial, 112, 113f oral, 112 of outer ear, 455 of ovary, 273-285, 273t of peripheral nerves, 432-433 perivascular,343-344,343t phyllodes, 250, 299, 299f 300f pineal, 416t, 424-425 of pituitary gland, 183-184 of prostate, 248-253 pulmonary, 68-70 of rete testis, 248, 248f salivary gland, 112-117 secondary, 416t serous, of ovary, 273-275


476

Tumors-cont'd Sertoli cell, 247, 247f Sertoli-Leydig cell, 280f 281 sarcomatoid variant, 281, 281f sex cord, 281, 281f skin, 323-333 of small intestine, 136, 136f small round cell, 350 smooth muscle, 344-345, 344t soft-tissue, 334, 350-353, 351t WHO classification of, 343, 343t solid cystic, 172-174, 173f solid pseudopapillary, 172-174, 173f spinal cord, 416t of spleen, 96 of squamous epithelium, 112, 112f steroid lipid (cell), 281, 281f of striated muscle, 345-346 stromal endometrial, 270-271 gastrointestinal, 134, 135f sclerosing, of ovary, 280f 281 sex cord, 246-247, 278-281, 281f testicular, 242-248, 243t transitional cell, 278 trophoblastic, placental site, 290, 291t, 292f of tunica vaginalis testis, 248, 248f unclassified, of ovary, 284-285 of upper digestive tract, 112-119 urinary bladder, 235-237 urinary tract, 234 of uterus, 268-273 of vagina, 265-266 vascular in bones, 380 in nervous system, 416t, 425-426 in soft tissue, 341-343, 341t of vulva, 263-264 Wilms, 234, 235f yolk sac, 246, 246f Tunica vaginalis testis, tumors of, 248, 248f Turner's syndrome, 258t, 259f Tympanosclerosis, 452, 452f Typhoid fever, 149-150, 150f Tyrosinemia, hereditary, 144, 144f

U UIP; see Usual interstitial pneumonia Ulcerative colitis, 132-133, 133f 133t Ulcerative esophagitis, 110, 111f Ulcers aphthous, 103, 103f Curling, 124, 124f Dieulafoy, 124, 125f gastrointestinal, 124 Hunner, 233, 233f peptic, 126-128, 128f Ulegyria, 402-403, 402f Umbilication, in liver, 163, 164f Upper digestive tract, 101-119 developmental anomalies of, 102-103 diseases of, 100 inflammatory lesions of, 103-104 organ-specific lesions of, 105-111 tumors of, 112-119 Upper respiratory tract, 41-47 benign tumors of, 44 diseases of, 40

Upper respiratory tract-cont 'd inflammatory lesions of, 42 malignant tumors of, 45-47 Ureaplasma infection, 260 Ureter, megaureters, 211, 211f Urinary bladder exstrophy, 211, 211f Urinary bladder tumors, 235-237, 235t, 236f 237f Urinary stones, 230, 230f Urinary tract, 209-237 developmental disorders of, 210-214 diseases of, 208 genetic disorders of, 210-214 lower, infections of, 232-233 tumors of, 234 Urolithiasis, 230, 230f Usual interstitial pneumonia, 66, 67t Uterus diseases of, 256 tumors of, 268-273 Uveitis, sympathetic, 436f 437 V Vagina diseases of, 256 embryonal rhabdomyosarcoma of, 266, 266f tumors of, 265-266 benign mixed, 265-266, 266f Vaginal adenosis, 265, 265f Vaginal infections, 260, 261f Valvular lesions, 9-13 Varices, esophageal, 110, 110f Vascular disorders, renal, 216-217 Vascular tumors in bones, 380 in nervous system, 416t, 425-426 in soft tissue, 341-343, 341t Vasculitis, 36-39 causes of, 36, 37t classification of, 38 clinical syndromes of, 38, 38d drug-induced, 39, 39f fungal, 36, 36f granulomatous giant cell, 36, 36f i mmune-mediated, 38-39 infection-induced, 36 nodular, 320, 321f small vessel, 39, 39f Venoocclusive disease, 146, 146f Ventricular aneurysm, 24, 24f Ventricular septal defects, 2, 3f inlet, 2 membranous, 2, 3f muscular outlet, 2, 3f outlet, 2, 3f pulmonary atresia with, 4, 4d, 5f Verruca plana, 314, 315f Verrucous carcinoma anal, 140, 141f oral, 112, 112f Verrucous endocarditis, 10, 1Of Villitis caused by L. monocytogenes, 289-290, 290f chronic, 290, 290f Villoglandular adenocarcinoma, 268, 268f Villoglandular papillary adenocarcinoma, 268, 268f Villonodular synovitis, 382f 383

Villous adenoma, 138f 139 of pancreatic ducts, 172, 173f VIN; see Vulvar intraepithelial neoplasia Viral arthritis, 363 Viral encephalitis, acute, 412, 412f Viral hepatitis, 147-149, 147f histopathology of, 144, 145f, 148t Viral infections, 56, 56f of central nervous system, 412 of skin, 314-316 Viral pancreatitis, 169, 169f Viral pneumonia, 56, 56f Visceral larva migrans syndrome, 58 Vocal cord nodules, 44, 45f Vocal cords, true, carcinoma of, 47, 47f Volvulus, 125, 126f von Hansemann histiocytes, 233 von Hippel-Lindau disease, 426 low-grade adenocarcinoma of endolymphatic sac with, 455, 455f retinal capillary hemangioma in, 438, 438f Von Meyenburg complexes, 159, 160f Vulva diseases of, 256 herpesvirus infection of, 260, 260f tumors of, 263-264 Vulvar intraepithelial neoplasia, 263-264, 263f W Waldenstrom macroglobulinemia, 82, 83f 129-130 Wedl cells, 442f, 443 Wegener granulomatosis, 60, 60f Weibel-Palade bodies, 343 Wernicke disease, 413 chronic, 413, 413f Wernicke encephalopathy, 413, 413f Whipple disease, 129, 130f Wilms tumor, 234, 235f Wilson disease, 144, 145f 414, 414f Working Formulation classification of nonHodgkin lymphoma, 89, 89t World Health Organization (WHO) classification of cysts of jaws, 106t classification of lupus nephritis, 225t classification of nasopharyngeal carcinoma, 46t classification of ovarian tumors, 273t classification of soft-tissue tumors, 343, 343t classification of tumors of exocrine pancreas, 172t definition of gestational trophoblastic disease, 290

x Xanthofibroma, 383 Xanthogranuloma, juvenile, 332f 333, 333f Xanthoma, 450, 451f 47,XXX syndromes, 258t Y Yolk sac carcinoma, 282, 282f Yolk sac tumors, 246, 246f

Z " Zellballen " appearance, 455, 455f Zenker, Friedrich, 62



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