Pathology of Vascular Skin Lesions

PATHOLOGY OF VASCULAR SKIN LESIONS CLINICOPATHOLOGIC CORRELATIONS Omar P. Sangüeza, MD Luis Requena, MD HUMANA PRESS ...

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PATHOLOGY OF VASCULAR SKIN LESIONS CLINICOPATHOLOGIC CORRELATIONS

Omar P. Sangüeza, MD Luis Requena, MD

HUMANA PRESS

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CD-ROM Included

PATHOLOGY OF VASCULAR SKIN LESIONS

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CURRENT CLINICAL PATHOLOGY IVAN DAMJANOV, MD SERIES EDITOR Pathology of Vascular Skin Lesions: Clinicopathologic Correlations, by Omar P. Sangüeza, MD, and Luis Requena, MD, 2003 Practical Immunopathology of the Skin, by Bruce R. Smoller, MD, 2002

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PATHOLOGY OF VASCULAR SKIN LESIONS CLINICOPATHOLOGIC CORRELATIONS

OMAR P. SANGÜEZA, MD Departments of Pathology and Dermatology Wake Forest University School of Medicine Winston-Salem, NC

LUIS REQUENA, MD Department of Dermatology Fundación Jiménez Díaz Universidad Autonoma Madrid, Spain

HUMANA PRESS

TOTOWA, medwedi.ru NEW JERSEY

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© 2003 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 www.humanapress.com

All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher.

The content and opinions expressed in this book are the sole work of the authors and editors, who have warranted due diligence in the creation and issuance of their work. The publisher, editors, and authors are not responsible for errors or omissions or for any consequences arising from the information or opinions presented in this book and make no warranty, express or implied, with respect to its contents.

Due diligence has been taken by the publishers, editors, and authors of this book to assure the accuracy of the information published and to describe generally accepted practices. The contributors herein have carefully checked to ensure that the drug selections and dosages set forth in this text are accurate and in accord with the standards accepted at the time of publication. Notwithstanding, as new research, changes in government regulations, and knowledge from clinical experience relating to drug therapy and drug reactions constantly occurs, the reader is advised to check the product information provided by the manufacturer of each drug for any change in dosages or for additional warnings and contraindications. This is of utmost importance when the recommended drug herein is a new or infrequently used drug. It is the responsibility of the treating physician to determine dosages and treatment strategies for individual patients. Further it is the responsibility of the health care provider to ascertain the Food and Drug Administration status of each drug or device used in their clinical practice. The publisher, editors, and authors are not responsible for errors or omissions or for any consequences from the application of the information presented in this book and make no warranty, express or implied, with respect to the contents in this publication. Cover design by Patricia F. Cleary. Cover illustration: Histopathologic features in plaque lesions of Kaposi’s sarcoma: The “promontory” sign evident around preexisting capillaries. (See Fig. 9C in Chapter 9 and companion CD-ROM and discussion on pp. 223–224.) This publication is printed on acid-free paper. ∞ ANSI Z39.48-1984 (American National Standards Institute) Permanence of Paper for Printed Library Materials.

Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Humana Press Inc., provided that the base fee of US $20.00 per copy is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to Humana Press Inc. The fee code for users of the Transactional Reporting Service is: [1-58829-182-0/03 $20.00]. Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1

Library of Congress Cataloging-in-Publication Data Sangüeza, Omar P. Pathology of vascular skin lesions : clinicopathologic correlations / Omar P. Sangüeza, Luis Requena. p. ; cm. -- (Current clinical pathology) Includes bibliographical references and index. ISBN 1-58829-182-0; 1-59259-360-7 (e-book) 1. Skin--Blood vessels--Tumors. 2. Skin--Blood-vessels--Pathophysiology. I. Requena, Luis. II. Title. III. Series. [DNLM: 1. Skin Neoplasms--pathology. 2. Skin Diseases, Vascular--pathology. WR 500 S226p 2003] RC280.S5 S264 2003 616.99'27707--dc21 2002027332

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To Catherine, Edith, and Charles, my beloved family. Without their love, support, and patience neither this book nor any other enterprise would have been possible.

To Koki, in appreciation of her love and limitless patience. Without her, nothing makes sense.

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PREFACE

Why a book on cutaneous vascular proliferations? There are several compelling reasons to justify the existence of a book on this topic. One of the most important is that cutaneous vascular proliferations are exceedingly common and affect a large number of individuals of both sexes and within a wide age range. They make up a broad spectrum of lesions with morphological and biological variations, ranging from hamartomas to highly malignant, aggressive neoplasms. Although the diagnosis of some vascular lesions is straightforward, many entities pose significant problems in diagnosis, classification, and treatment. Within the past two decades there has been an increase in the number of patients affected with Kaposi’s sarcoma, related to the epidemic of the acquired immunodeficiency syndrome (AIDS). As a consequence, a number of variants and vascular lesions that simulate Kaposi’s sarcoma, both clinically and histopathologically, have been described. In addition, other vascular entities not related to Kaposi’s sarcoma have been introduced in the literature. All of these have added confusion to an already complicated field. Since there are no recent textbooks on this subject, we felt an update was overdue. The aim of Pathology of Vascular Skin Lesions: Clinicopathologic Correlations is to provide a comprehensive and in-depth review of all vascular proliferations involving the skin and subcutaneous tissue, including recently described entities. Although our work is primarily directed to pathologists, dermatologists, and dermatopathologists, its wide scope will make it useful to pediatricians and plastic surgeons as well. Pathology of Vascular Skin Lesions: Clinicopathologic Correlations is divided into three parts. The first part covers classification and nomenclature of vascular neoplasms, an area that is still controversial. We propose a new classification with the hope that it will bring more order into a chaotic arena. We recognize that this classification may have some pitfalls and limitations, but we also believe that it is the most logical way to approach the study of vascular proliferations. In order to know what is abnormal, a student of the field should first know what is normal, which is the reason for including a chapter on normal embryology, histology, and anatomy of the skin vasculature. Another chapter is devoted to the use of special techniques for the study of vascular proliferations. In the second part, we include benign proliferations ranging from hamartomas and malformations to benign neoplasms. The final part of the book deals with malignant vascular proliferations, ranging from Kaposi’s sarcoma to angiosarcomas. It includes some new entities, too. The whole of Pathology of Vascular Skin Lesions: Clinicopathologic Correlations was conceived in terms of a clinicopathologic correlation. The clinical and morphologic

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Preface

aspects of each entity are described in detail, including their differential diagnosis, prognosis, and therapy. Each chapter is fully illustrated with both clinical and histopathologic photographs, and we include color versions of all illustrations on the accompanying CD-ROM. Additionally, there is a complete and updated list of references for each particular section. We hope that you find this book interesting and useful. This book was sponsored in part by Pathologists Diagnostic Services, PLLC, in Winston-Salem, NC. Omar P. Sangüeza, MD Luis Requena, MD

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ACKNOWLEDGMENTS Many colleagues contributed clinical pictures, histopathologic slides, or other material for this review. We are very grateful to the following clinicians and pathologists: A. Bernard Ackerman, MD (USA) Antonio Aguilar, MD (Spain) Adolfo Aliaga, MD (Spain) Isabel Febrer, MD (Spain) M. Alba Greco, MD (USA) Gerardo Jaqueti, MD (Spain) Esperanza Jordá, MD (Spain) Helmut Kerl, MD (Austria) Heinz Kutzner, MD (Germany) Pablo Lázaro, MD (Spain) Beatriz López, MD (Spain) José M. Mascaró, MD (Spain) Thomas Mentzel, MD (Germany)

Paula E. North, MD (USA) Celia Requena, MD (Spain) Jorge L. Sánchez, MD (Puerto Rico) Evaristo Sánchez Yus, MD (Spain) Pastor Sangüeza, MD (Bolivia) Andrés Sanz, MD (Spain) Jaime Tschen, MD (USA) Antonio Torrelo, MD (Spain) Sara O. Vargas, MD (USA) Antonio Vélez, MD (Spain) Angel Vera, MD (Spain) Michel Wassef, MD (France).

Special thanks to: Di Lu, MD (USA), who spent countless hours shooting microphotographs; Rita O. Pichardo, MD (Venezuela), who helped to compile and organize all photographic and written material, and to Steven Vogel, MD, who corrected the manuscript, offered support, and provided advice. Figures 10 and 19 in Chapter 6, Figure 13 in Chapter 7, Figure 15 in Chapter 8, Figure 3 in Chapter 11, and Figure 35 in Chapter 8 have been previously published (J Am Acad Dermatol 1977;37:523-49. J Am Acad Dermatol 1997;37:887-20. J Am Acad Dermatol 1998;38:143-75). These figures are reproduced here with permission of Mosby Inc.

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CONTENTS Preface .................................................................................................. vii Acknowledgments .................................................................................. ix Companion CD-ROM ................................................ Inside Back Cover 1

Embryology, Anatomy, and Histology of the Vasculature of the Skin .......................................................... 1 1. Embryologic Aspects 1 2. Anatomic and Histologic Aspects of the Dermis and Blood Vessels 2

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Special Techniques for the Study of Vessels and Vascular Proliferations .............................................................. 7 1. Immunohistochemical Stains 7 2. Molecular Techniques 10 3. Cytogenetic Studies 12

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Classification of Cutaneous Vascular Proliferations ............................. 15

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Cutaneous Vascular Hamartomas ......................................................... 19 1. Phakomatosis Pigmentovascularis 19 2. Eccrine Angiomatous Hamartoma 23

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Cutaneous Vascular Malformations ...................................................... 27 1. 2. 3. 4. 5. 6. 7. 8.

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Cutaneous Lesions Characterized by Dilation of Preexisting Vessels ..................................................................... 73 1. 2. 3. 4. 5.

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Nevus Anemicus 29 Cutis Marmorata Telangiectatica Congenita 32 Nevus Flammeus 37 Hyperkeratotic Vascular Stains 47 Venous Malformations 51 Superficial Cutaneous Lymphatic Malformations 63 Cystic Lymphatic Malformations (Cystic Hygromas) 67 Lymphangiomatosis 70

Spider Angioma (Nevus Araneus) 73 Capillary Aneurysm-Venous Lake 76 Telangiectases 79 Angiokeratomas 86 Lymphangiectases 95

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Cutaneous Vascular Hyperplasias ......................................................... 99 1. 2. 3. 4. 5.

Angiolymphoid Hyperplasia with Eosinophilia 99 Pyogenic Granuloma 105 Bacillary Angiomatosis 112 Verruga Peruana 116 Intravascular Papillary Endothelial Hyperplasia (Masson’s Pseudo-Angiosarcoma) 119 6. Pseudo-Kaposi’s Sarcoma 123 7. Reactive Angioendotheliomatosis 128

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Benign Neoplasms .............................................................................. 133 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

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Angioma Serpiginosum 133 Infantile Hemangiomas 136 Cherry Angiomas (Senile Angiomas) 151 Arteriovenous Hemangioma 154 Hobnail Hemangioma (Targetoid Hemosiderotic Hemangioma) 157 Microvenular Hemangioma 161 Tufted Angioma 164 Glomeruloid Hemangioma 169 Acquired Elastotic Hemangioma 174 Kaposiform Hemangioendothelioma 177 Sinusoidal Hemangioma 182 Giant Cell Angioblastoma 184 Spindle Cell Hemangioma (Formerly Spindle Cell Hemangioendothelioma) 186 Benign Lymphangioendothelioma 191 Benign Vascular Proliferations in Irradiated Skin 195 Glomus Tumors 198 Hemangiopericytoma 208 Cutaneous Myofibroma 212

Malignant Neoplasms ......................................................................... 217 1. Kaposi’s Sarcoma 217 2. Epithelioid Hemangioendothelioma 236 3. Endovascular Papillary Angioendothelioma (Dabska’s Tumor or Papillary Intralymphatic Angioendothelioma) 241 4. Retiform Hemangioendothelioma 245 5. Composite Hemangioendothelioma 250 6. Cutaneous Angiosarcoma of the Face and Scalp of Elderly Patients (Wilson Jones’ Angiosarcoma) 251 7. Cutaneous Angiosarcoma Associated with Lymphedema 258 8. Radiation-Induced Cutaneous Angiosarcoma 262 9. Epithelioid Angiosarcoma 268 10. Malignant Glomus Tumor (Glomangiosarcoma) 271

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Other Cutaneous Neoplasms With a Significant Vascular Component ...................................... 275 1. 2. 3. 4. 5. 6. 7.

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Multinucleate Cell Angiohistiocytoma 275 Angiofibroma 279 Angioleiomyoma 284 Angiolipoma 287 Cutaneous Angiolipoleiomyoma 290 Cutaneous Angiomyxoma 293 Aggressive Angiomyxoma 296

Disorders Erroneously Considered as Vascular Neoplasms ................................................................. 299 1. Kimura’s Disease 299 2. “Malignant” Angioendotheliomatosis (Intravascular Lymphomatosis) 304 3. Acral Pseudolymphomatous Angiokeratoma in Children (APACHE) 309

Index ................................................................................................... 311

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Chapter 1 / Vasculature of the Skin

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Embryology, Anatomy, and Histology of the Vasculature of the Skin CONTENTS EMBRYOLOGIC ASPECTS ANATOMIC AND HISTOLOGIC ASPECTS OF THE DERMIS AND BLOOD VESSELS

The skin is a complex organ responsible for numerous physiologic and immunologic functions. It is conceptually the largest organ of the body (1). It weighs between 3 and 4 kg, constitutes 6% of body weight, and, on the average adult, covers an area of approximately 2 m2. The functions of the skin are numerous and diverse. Notably, it serves as a barrier that excludes harmful chemicals and pathogens while retaining water and endogenous proteins. The skin also modulates body temperature, acts as a sensory organ, protects against physical injury, is a component of the immune system, and has psychosocial and aesthetic importance. It is composed of three principal layers: the epidermis, the dermis, and the subcutaneous tissue. It also houses the adnexa, melanocytes, Langerhans cells and Merkel cells.

1. EMBRYOLOGIC ASPECTS All components of the skin are derived embryologically from either the ectoderm or the mesoderm. The ectoderm gives origin to the epidermis and the epithelial dermal constituents, whereas the mesenchymal components of the dermis are derived from the mesoderm. The earliest evidence of skin is seen at the end of the first month of embryonic life, at which time a single layer of cuboidal epithelium encases the embryo (2). By the fourth to sixth weeks of gestation, this epithelium has evolved into a two-cell layered structure. The outer layer, or periderm, is composed of glycogen-laden cells, superimposed upon cuboidal cells that form the inner or basal layer (2). The periderm is in immediate contact with the amniotic fluid, into which these cells are gradually shed to the point of total disappearance by the 21st week of estimated gestational age (EGA). An intermediate layer develops between the periderm and basal layer by the 11th week. At this point, the inner layer evolves into the stratum germinativum, which continues to proliferate and to serve as the source of epidermal cells throughout life. By the 21st week of EGA, the intermediate layer has differentiated into the stratum spinosum, granulosum, and corneum. The first semblance of cornification is seen after the fifth gestational month.

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Thereafter, there is increased production of keratohyalin granules, and the epidermal cells near the surface lose their nuclei. Complete cornification is normally accomplished by the sixth month of EGA. The dermo-epidermal junction develops during the first trimester, and all the elements of this layer are recognizable thereafter (3). The components of the basal layer are produced by the basal cells of the epidermis. During the first 3 months of intrauterine life, cells migrate from the neural crest to the epidermis, where they become melanoblasts and presumptively also Merkel cells. Merkel discs are recognizable by the 7th month, whereas melanocytes can be identified with special stains by the 10th or 11th week (4). Langerhans cells are derived from the bone marrow to serve as immunomodulators. At entry into the epidermis by the seventh week, they differ from mature Langerhans cells since they express different antigens (5). Human leukocyte antigen-DR, as well as the CD1 antigen, normal constituents of mature Langerhans cells, can be recognized by the 12th week of EGA, whereas Birbeck granules can be identified ultrastructurally 2 weeks earlier (3). Folliculo-sebaceous-apocrine units appear around the ninth week, initially in the head and neck, notably in areas of the future eyebrows, eyelids, upper lip, and chin. They develop in a cephalocaudal direction, and by the fourth month hair follicles are also evident in the abdominal skin and elsewhere. Most of the hair follicles are present by the fifth month, and probably no new hair follicle formation takes place after birth (2). Sebaceous glands remain appended to hair follicles in extrauterine life, but most apocrine glands involute shortly after birth and remain present only in select cutaneous areas, notably the axillae, genital area, and mammary areola. Eccrine glands appear on the palms and soles by the 12th week of EGA. They originate as small proliferations of the basal layer, as protusions into the dermis and epidermis. In the dermis they form unbranched, highly coiled glands whereas in the epidermis they form the acrosyringium. Centrally positioned cells in these proliferations degenerate to create the lumen of the gland; the peripheral cells differentiate into an inner layer of secretory cells and an outer layer of myoepithelial cells. During the first 5–7 weeks of intrauterine life, the dermis is mostly cellular. During this early interval, there is no sharp demarcation between the dermis and the subcutaneous fat, and there are no recognizable adnexal structures within the connective tissue. Between the 8th and 9th weeks, the amount of collagen increases markedly in the extracellular matrix, so consequently by the 10th–12th weeks the cellular dermis has been transformed into a predominantly fibrous dermis. During this interval, the deep boundary of the dermis is defined by a plexus of blood vessels and nerves that lie in a plane between the dermis and subcutaneous fat. Once the dermis has become predominantly fibrous, as it does by approximately the 13th week of EGA, vessels and nerves are recognizable, at all levels of the dermis, unsheathed by connective tissue. Definite papillary and reticular dermis is distinguishable by the 14th week (6) . Nerve endings are recognizable during the fourth gestational week and continue to increase in number thereafter until the seventh month of intrauterine life (7).

2. ANATOMIC AND HISTOLOGIC ASPECTS OF THE DERMIS AND BLOOD VESSELS The dermis, composed of, collagen, elastic fibers, and ground substance, harbors the blood vessels and nerves. The blood supply of the dermis flows from a plexus, located in the deep reticular dermis (Fig. 1). This conduit is connected with three more superficial

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Fig. 1. Drawing of the normal vascularization of the skin. The blood supply of the dermis flows from a plexus, located in the deep reticular dermis. This conduit is connected with three more superficial plexuses, namely, the subpapillary plexus and the paired plexuses around the hair follicles and eccrine glands. From the latter, progressively smaller arterioles ascend into the dermis to branch finally into the numerous capillaries that richly supply the adventitial dermis. The capillary loops that nourish each subepidermal papilla originate from the subpapillary plexus, each loop consisting of an ascendant arterial limb and a descendent venous appendage. The venous limb drains blood into progressively larger venules, which terminally empty into small veins of the subcutaneous plexus.

plexuses, namely, the subpapillary plexus and the paired plexuses around the hair follicles and eccrine glands (8–12). From the latter, progressively smaller arterioles ascend into the dermis to branch into numerous capillaries that richly supply the adventitial dermis. The capillary loops that nourish each subepidermal papilla originate from the subpapillary plexus, each loop consisting of an ascendant arterial limb and a descendant venous appendage. The venous limb drains blood into progressively larger venules, which terminally empty into small veins of the subcutaneous plexus.

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Fig. 2. (A) Artery and vein within the subcutaneous tissue. The artery has a round to oval structure with thick walls; the vein is elongated and the walls are thinner. (B) Higher magnification of an artery showing thick muscular walls. (C) A Verhoeffs elastic stain to demonstrate the prominent lamina elastica of the artery. (D) Vein showing thinner walls and an irregular lumen. (E) Verhoeffs elastic stain showing elastic fibers within the wall; note that the fibers do not form a distinctive structure.

The small arteries of the subcutaneous plexus and the arterioles of the dermis possess three layers: the intima, the media, and the adventitia (Fig. 2). The intima is composed

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of endothelial cells and an internal elastica lamina. The media is formed predominantly of smooth muscle cells, bounded by an external elastica lamina and adventitia that is composed of fibroblasts with type III collagen and elastic fibers. The arterioles of the ascending segment of the capillary loop inwardly possess endothelial cells and outwardly are covered by pericytes, both constituents being surrounded by a basement membrane. The smaller arterioles in the papillary dermis possess a single, continuous layer of endothelial cells, surrounded by a discontinuous layer of elastic fibers and smooth muscle cells. The arteriolar capillaries are lined by a single layer of endothelial cells, surrounded by an incomplete layer of pericytes. Ultrastructurally, there is evidence that the endothelial cells are interconnected. The passage of small molecules and exchange of fluids occur through pinocytosis. Small vesicles formed at the surface of the endothelial cells, transported across the cytoplasm, and released at the contraluminal membrane imbibe molecular elements. Postcapillary venules possess endothelial cells, pericytes, and basal lamina surrounded by thin zones of type III collagen. Venular capillaries are fenestrated, allowing the passage of large molecules. The capillary veins that are part of the descending loop are composed of endothelial cells, plentiful pericytes, and a multilayered basement membrane. The larger venules are endowed with variable amounts of smooth muscle and elastic fibers but no elastic membrane. Veil cells, unlike pericytes, have the appearance of flattened fibroblasts, and lie completely outside the vascular walls of all arterioles, capillaries, and venules in the dermis. The veil cell demarcates the vessels from the surrounding dermis and can be considered an adventitial cell (12). Ultrastructurally, the endothelial cells have a well-developed endoplasmic reticulum; their cytoplasmic compartment contains bundles of filaments with diameters of 5–10 µm and pinocytotic vesicles that measure 50–70 nm across. Distinctively these cells contain Weibel-Palade bodies. These are electron dense, rod-shaped cytoplasmic structures measuring 0.1 × 3 µm. Intrinsically the Weibel-Palade body contains numerous small tubules that measure 15 nm in thickness, as they mark the long axis of the body. In certain regions of the body, notably the central face, the ears, and the pads and nail beds of the fingers and toes, there are special vascular structures known as glomus bodies that modulate blood flow and temperature. These are arteriovenous shunts, in which there are direct connections between arterioles and venules, without interposition of capillaries. The arterial segment, or Suquet-Hoyer canal, has a narrow lumen and a wall of 20–40 µm thick (5). A single layer of lining endothelium is surrounded by a basement membrane. Four to six layers of glomus cells form the media and an adventitia composed of loose connective tissue. Glomus cells have an abundant, clear cytoplasm and round to oval nuclei. Ultrastructurally, these cells have been considered to show smooth muscle differentiation as evidenced by cytoplasm filled with myofilaments. The venous segment of the glomus has a wide lumen with attenuated walls. The lymphatic channels of the skin form a complex network that adheres to the distribution of arterioles and venules. The lymphatics serve in the control of the microcirculation; they line interstitial spaces and provide portals through which macromolecules escape for drainage (13). Even the smallest lymphatic capillaries are relatively large, often flattened tubes lined by an extremely attenuated single layer of endothelium and surrounded by an indistinct and discontinuous basement membrane. They are not endowed with pericytes. In contrast to the endothelial cells of the blood vessels, they contain very few organ-specific characteristics. There are no fenestrae and only a few

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Weibel-Palade bodies. The lymphatics form small plexuses in the upper reticular dermis, just below the subpapillary plexus of venules. There are no lymphatic structures within the papillary dermis, except as a response to inflammation or the presence of raised hydrostatic pressure. Occasional blind loops may extend upward into the base of the papilla, but their numbers are few, even in the papillary foot. The superficial lymphatic network drains into the collecting lymphatics; this retains the features of capillaries with attenuated endothelial cells and absence of smooth muscle. The postcapillary lymph vessels at the border between the dermis and subcutaneous tissue have wider lumina and thicker connective tissue walls, few smooth muscles cells, and occasional valves. These attributes serve to distinguish them from small blood vessels.

References 1. Goldsmith LA. My organ is bigger than your organ. Arch Dermatol 1990;126:301–2. 2. Larsen WJ. Development of integumentary system. In: Human Embryology. New York, Churchill Livingstone, 1993:419–33. 3. Urmacher C. Normal skin. In: Histology for Pathologists. Sternberg SS, ed. New York, Raven Press, 1992:382–97. 4. Holbrook K, Underwood RA, Vogel AM, et al. The appearance, density and distribution of melanocytes in human embryonic and fetal skin revealed by the anti–melanoma monoclonal antibody, HMB-45. Anat Embryol 1989;180:443. 5. Jakubovic HR, Ackerman AB. Structure and function of skin: development, embryology, and physiology. In: Dermatology, 3rd ed. Moschella SL, Hurley HR, eds. Philadelphia, WB Saunders, Co., 1992:3–87. 6. Johnsson CL, Holbrook KA. Development of human embryonic and fetal dermal vasculature. J Invest Dermatol 1989;93:10S–17S. 7. Arthur RP, Shelley WB. The innervation of human epidermis. J Invest Dermatol 1959;32:397–411. 8. Yen A, Braveman IM. Ultrastructure of the human dermal microcirculation. The horizontal plexus of the papillary dermis. J Invest Dermatol 1976;66:131–42. 9. Braveman IM, Yen A. Ultrastructure of the human dermal microcirculation. II. The capillary loops of the dermal papillae. J Invest Dermatol 1977;68:44–52. 10. Braveman IM, Yen KA. Ultrastructure of the human dermal microcirculation. III. The vessels in the mid and lower dermis and subcutaneous fat. J Invest Dermatol 1981;77:197–204. 11. Braveman IM, Yen KA. Ultrastructure of the human dermal microcirculation. IV. Valve containing collecting veins at the dermal-subcutaneous junction. J Invest Dermatol 1983;81:438–42. 12. Braveman IM. Ultrastructure and organization of the cutaneous microcirculation in normal and pathologic states. J Invest Dermatol 1989;93:2S–9S. 13. Braveman IM, Sibley J, Yen KA. A study of the veil cells around normal, diabetic and aged cutaneous microvessels. J Invest Dermatol 1986;86:57–62. 14. Terence RJ. Structure and function of lymphatics. J Invest Dermatol 1989;93:18S–24S.

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Chapter 2 / Special Techniques

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Special Techniques for the Study of Vessels and Vascular Proliferations CONTENTS IMMUNOHISTOCHEMICAL STAINS MOLECULAR TECHNIQUES CYTOGENETIC STUDIES

The recognition of vascular lesions is most often straightforward; however, sometimes the use of additional techniques becomes necessary to secure a more definitive diagnosis, notably when the vascular nature of a neoplasm mimics another category of neoplasm. For example, epithelioid hemangioendotheliomas and epithelioid angiosarcomas may simulate poorly differentiated carcinomas, even to the extent of positivity for the conventional epithelial marker, cytokeratin (1,2). In still other cases the vascular nature of a neoplasm may be obscured by a prominent inflammatory infiltrate (3,4). Special techniques can help clarify the true nature of these problematic neoplasms. Before the era of immunohistochemical techniques, much reliance was placed on histochemical stains. Stains for reticulin and elastic fibers were the gold standard to detect the presence of vascular differentiation. Enzymatic stains were less often employed. Most of these techniques are currently outdated and seldom used. This chapter discusses the evaluation and application of the common markers currently used for the detection of vascular neoplasms. Molecular techniques receive less attention.

1. IMMUNOHISTOCHEMICAL STAINS The most common markers used to assert the vascular nature of a lesion are von Willebrand factor (vWF; formerly factor VIII-related antigen), CD34 (human hematopoietic progenitor cell antigen), CD31 (platelet endothelial cell adhesion molecule-1), and Ulex europaeus lectin. More recently, vascular endothelial growth factor receptor-3 (VEGFR-3) and GLUT1 have been added to the armamentarium of immunohistochemical stains for the characterization of vascular lesions. vWF was one of the first immunohistochemical markers to be developed, and it has been utilized now for more than 15 years (5). The factor is an intrinsic secretory component of endothelial cells. It has limited sensitivity but is present in most types of nonneoplastic endothelium, as well as in serum and body fluids. Although it is a good marker for epithelioid hemangioendotheliomas, it is absent in most angiosarcomas. Being widespread in distribution, it is usually present in areas of hemorrhage, exudation, and necrosis and thus can create heavy background staining that compromises interpretation (6).

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The Ulex europaeus lectin selectively binds a terminal fucosil residue of the H blood group antigen to a unique endothelial glycoprotein. Although this marker generated initial optimism because of its great sensitivity, it was subsequently discovered that the targeted sugar is also present in normal epithelium, as well as in a wide range of epithelial tumors (7). CD34 (human hematopoietic progenitor cell antigen) is a 105–120-kDa transmembrane glycoprotein normally present in human hematopoietic progenitor cells (8). It was initially developed for the characterization of acute leukemias, in which the expression of this antigen is usually correlated with a poor prognosis. It was subsequently found to also be present in endothelial cells, although those of lymphatic vessels express this antibody in a less uniform fashion (9). The most commonly used monoclonal antibodies to CD34 are My10 and QB-END 10, two reagents with comparable reactivities (6,10). It has been validated that CD34 will intensely label mature, well-formed vessels but can be nonreactive or weakly so with immature or poorly formed vessels. Thus, CD34 can be nonreactive in granulation tissue, papillary intravascular endothelial hyperplasia, and bacillary angiomatosis (11). On the other hand, it appears to be a dependable marker for Kaposi’s sarcoma and angiosarcomas (6,12,13). A shortcoming of CD34 is its affinity for other tissues of mesenchymal origin; thus, it stains fibrocytes, fat and perivascular cells. Consequently, many neoplasms including dermatofibrosarcoma protuberans, solitary fibrous tumor, epithelioid sarcomas and gastrointestinal stromal tumors are positive for CD34 (14–17). CD31 is a 130-kDa glycoprotein that mediates platelet cell adhesion to endothelial cells (PECAM1). As one of the cell adhesion molecules, it belongs to the immunoglobulin gene superfamily. Although normally present in endothelial cells, it is also a constituent of platelets, monocytes/macrophages, and subsets of lymphocytes, plasma cells, and hematopoietic stem cells (6). The two monoclonal antibodies most commonly utilized for detection of CD31 are JC/70A and EN4 (18,19). CD31, the most sensitive and specific endothelial marker, is consistently present in angiosarcomas, hemangioendotheliomas, Kaposi’s sarcomas, and hemangiomas (13). Among the nonvascular tumors, an occasional carcinoma or epithelioid sarcoma may show weak staining with this reagent, seemingly because of the partial crossreaction with related homologous adhesion molecules, such as carcinoembryonic antigen (CEA) (6). VEGFR-3 is a tyrosine kinase receptor. Its expression is limited almost exclusively to endothelial cells lining adult lymphatic vessels, as detected by the monoclonal antibody 9D9F9 (20). Although this antibody is highly sensitive for the detection of Kaposi’s sarcoma, in which it marks even the spindle component of this neoplasm, it is also reactive with other vascular neoplasms including angiosarcomas, kaposiform hemangioendotheliomas, Dabska’s tumor, hobnail hemangioma (Fig. 1), and a few cases of infantile hemangiomas (21,22). GLUT1 is an erythrocyte-type facilitative glucose transport protein. It is a member of at least six structurally related proteins, each with a characteristic tissue distribution. Interestingly, it is present in the endothelium of the microvasculature of blood-tissue barriers, such as those of the central nervous system, retina, placenta, ciliary muscle, and endoneurium of peripheral nerves, but it is absent in the vascular endothelium of normal

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Fig. 1. Hobnail hemangioma stained with hematoxylin-eosin and VEGFR-3. (A) At scanning magnification there are dilated vascular structures on the superficial dermis. (B) Many of these vascular structures show thin walls and are lined by a discontinuous layer of endothelial cells, giving a lymphatic appearance to the channels. (C) Higher magnification shows that some endothelial cells protrude within the lumina with a hobnail appearance. (D) Scanning power view of a section of the same case stained with VEGFR-3. (E) Higher magnification demonstrates that endothelial cells lining the lumina express immunoreactivity for VEGFR-3.

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Fig. 2. Infantile hemangioma stained with hematoxylin-eosin and GLUT-1. (A) Scanning power view of the lesion showing a cellular proliferation involving the entire thickness of the dermis. (B) Higher magnification demonstrates numerous vascular channels. (C) Still higher magnification demonstrates that the vascular channels exhibit a capillary appearance and are lined by a single layer of endothelial cells.

vessels of the skin and subcutaneous tissue (23,24). This marker has also been found in infantile hemangiomas at different stages of their evolution (Fig. 2). Its specificity for this category of vascular proliferations is noteworthy, since other lesions including vascular malformations, pyogenic granulomas, kaposiform hemangioendotheliomas, and epithelioid hemangioendotheliomas do not express this marker (23,24).

2. MOLECULAR TECHNIQUES During the past few years seminal discoveries have led to valuable applications of new techniques for the identification and characterization of neoplasms. Techniques such as the polymerase chain reaction, Southern and Northern blot analysis, and in situ hybridization are almost routine in many centers. The enhanced knowledge in cancer genetics is contributing significantly to the prognosis, diagnosis, and treatment of divergent neo-

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Fig. 2. Infantile hemangioma stained with hematoxylin-eosin and GLUT-1. (D) Scanning power view of the same lesion stained with GLUT-1. (E) Numerous cells in the dermis express GLUT-1 immunoreactivity. (F) Higher magnification shows GLUT-1 immunoreactivity in endothelial cells lining the capillary blood vessels.

plasms. Although these specific molecular contributions have predominantly favored hematopoietic malignancies, some soft tissue neoplasms have also benefited. With regard to vascular neoplasms, the most important development has been the association of Kaposi’s sarcoma with human herpes virus 8 (HHV-8). Confirmatory observations during the last few years have found a strong correlation between the presence of this virus and the presence of the neoplasm. HHV-8, also known as Kaposi’s sarcoma-associated herpes virus (KSHV), is a γ-herpes virus. Following the initial report by Chang et al. (25) the recognitions of this association in laboratories around the world were promptly confirmed. HHV-8 is widespread in African and American Indian populations and is of limited prevalence in Northern Europe. An intermediate prevalence is found in Mediterranean countries, Asia, North America, and Central America (26). A pathogenetic role of HHV-8 in KS is unequivocal. The viral genome contains cellular genes that stimulate cell growth and angiogenesis; the virus is present in all clinical variants of KS, and, among all high-risk groups, seroconversion precedes the develop-

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ment of KS. The virus is detectable in both endothelial and spindle cells, even in early lesions (27).

3. CYTOGENETIC STUDIES Only limited cytogenetic studies have been carried out on vascular neoplasms; the most relevant related to angiosarcomas, and Kaposi’s sarcomas. Although no consistent chromosomal abnormalities have been manifested in all cases of angiosarcoma the most common concern the number of chromosomes, with ranges from hypodiploid to hypertriploid. Notable are the abnormalities: trisomy of chromosome 5, translocation (5;15), additions in chromosomes 8 and 20, and losses of chromosomes 7, 22, and Y (27,28). Most commonly, KS manifests: abnormalities in chromosome 7, sometimes with additions, translocation (7;13), multiple additions and deletions. A few cases have also shown abnormalities related to chromosomes 10 and 12 (29,30).

References 1. Gray MH, Rosenberg AE, Dickersin GR, Bhan AK. Cytokeratin expression in epithelioid vascular neoplasms. Hum Pathol 1990;21:212–7. 2. Meis-Kindblom JM, Kindblom LG. Angiosarcoma of soft tissue: a study of 80 cases. Am J Surg Pathol 1998;22:683–97. 3. Mentzel T, Kutzner H, Wollina U. Cutaneous angiosarcoma of the face: clinicopathologic and immunohistochemical study of a case resembling rosacea clinically. J Am Acad Dermatol 1998;38:837–40. 4. Diaz-Cascajo C, de la Vega M, Rey-Lopez A. Superinfected cutaneous angiosarcoma: a highly malignant neoplasm simulating an inflammatory process. J Cutan Pathol 1997;24:56–60. 5. Burgdorf WH, Mukai K, Rosai J. Immunohistochemical identification of factor VIII-related antigen in endothelial cells of cutaneous lesions of alleged vascular nature. Am J Clin Pathol 1981;75:167–71. 6. Miettinen M, Lindenmayer AE, Chaubal A. Endothelial cell markers CD31, CD34, and BNH9 antibody to H- and Y-antigens—evaluation of their specificity and sensitivity in the diagnosis of vascular tumors and comparison with von Willebrand factor. Mod Pathol 1994;7:82–90. 7. DeYoung BR, Swanson PE, Argenyi ZB, et al. CD31 immunoreactivity in mesenchymal neoplasms of the skin and subcutis: report of 145 cases and review of putative immunohistologic markers of endothelial differentiation. J Cutan Pathol 1995;22:215–22. 8. Civin CI, Brovall C, Fackler MJ, Schwartz JF, Shaper JH. Antigenic analysis of hemopoiesis. III. A hematopoietic progenitor cell surface antigen defined by monoclonal antibody raised against KG-1a cells. J Immunol 1984;133:157–65. 9. Suster S, Wong TY. On the discriminatory value of anti-HPCA-1 (CD-34) in the differential diagnosis of benign and malignant cutaneous vascular proliferations. Am J Dermatopathol 1994;16:355–63. 10. Aziza JMC, Selves J, Voigt J-J, et al. Comparison of the reactivities of monoclonal QBEND10 (CD34) and BNH9 in vascular tumors. Appl Immunohistochem 1993;1:51. 11. Schlingemann RO, Rietveld F Jr, de Waal RMW, et al. Leukocyte antigen CD34 is expressed by a subset of cultured endothelial cells and on endothelial cells abluminal microprocesses in the tumor stroma. Lab Invest 1990;62:690–6. 12. Kanitakis J, Narvaez D, Claudy A. Expression of the CD34 antigen distinguishes Kaposi’s sarcoma from pseudo-Kaposi’s sarcoma (acroangiodermatitis). Br J Dermatol 1996;134:44–6. 13. Russell Jones R, Orchard G, Zelger B, Wilson Jones E. Immunostaining for CD31 and CD34 in Kaposi sarcoma. J Clin Pathol 1995;48:1011–6. 14. Kutzner H. Expression of the human progenitor cell antigen CD34 (HPCA-1) distinguishes dermatofibrosarcoma protuberans from fibrous histiocytoma in formalin-fixed, paraffin-embedded tissue. J Am Acad Dermatol 1993; 28:613–7. 15. Van de Rijn M, Rouse R. CD34: a review. Appl Immunohistochem 1994;2:71. 16. Westra WH, Gerald WL, Rosai J. Solitary fibrous tumor. Consistent CD34 immunoreactivity and occurrence in the orbit. Am J Surg Pathol 1994;18:992–8. 17. Weiss SW, Nickoloff BJ. CD-34 is expressed by a distinctive cell population in peripheral nerve, nerve sheath tumors, and related lesions. Am J Surg Pathol 1993;17:1039–45.

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18. Burgio VL, Zupo S, Roncella S, Zocchi M, Ruco LP, Baroni CD. Characterization of EN4 monoclonal antibody: a reagent with CD31 specificity. Clin Exp Immunol 1994;96:170–6. 19. Parums DV, Cordell JL, Micklem K, et al. JC70: a new monoclonal antibody that detects vascular endothelium associated antigen on routinely processed tissue sections. J Clin Pathol 1990;43:752–7. 20. Jussila L, Valtola R, Partanen TA, et al. Lymphatic endothelium and Kaposi’s sarcoma spindle cells detected by antibodies against the vascular endothelial growth factor receptor-3. Cancer Res 1998;58:1599–604. 21. Folpe AL, Veikkola T, Valtola R, Weiss SW. Vascular endothelial growth factor receptor-3 (VEGFR-3): a marker of vascular tumors with presumed lymphatic differentiation, including Kaposi’s sarcoma, kaposiform and Dabska-type hemangioendotheliomas, and a subset of angiosarcomas. Mod Pathol 2000;13:180–5. 22. Lymboussaki A, Partanen TA, Olofsson B, et al. Expression of the vascular endothelial growth factor C receptor VEGFR-3 in lymphatic endothelium of the skin and in vascular tumors. Am J Pathol 1998;153:395–403. 23. North PE, Waner M, Mizeracki A, Mihm MC Jr. GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol 2000;31:11–22. 24. North PE, Waner M, Mizeracki A, et al. A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol 2001;137:559–70. 25. Chang Y, Cesarman E, Pessin MS, et al. Identification of herpesvirus-like DNA sequences in AIDSassociated Kaposi’s sarcoma. Science 1994;266:1865–9. 26. Sturzl M, Zietz C, Monini P, Ensoli B. Human herpesvirus-8 and Kaposi’s sarcoma: relationship with the multistep concept of tumorigenesis. Adv Cancer Res 2001;81:125–59. 27. Kennedy MM, Cooper K, Howells DD, et al. Identification of HHV8 in early Kaposi’s sarcoma: implications for Kaposi’s sarcoma pathogenesis. J Clin Pathol 1998;51:14–20. 28. Schuborg C, Mertens F, Rydholm A, et al. Cytogenetic analysis of four angiosarcomas from deep and superficial soft tissue. Cancer Genet Cytogenet 1998;100:52–6. 29. Mandahl N, Jin YS, Heim S, et al. Trisomy 5 and loss of the Y chromosome as the sole cytogenetic anomalies in a cavernous hemangioma/angiosarcoma. Genes Chromosomes Cancer 1990;1:315–6. 30. Saikevych IA, Mayer M, White RL, Ho RC. Cytogenetic study of Kaposi’s sarcoma associated with acquired immunodeficiency syndrome. Arch Pathol Lab Med 1988;112:825–8.

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Chapter 3 / Cutaneous Vascular Proliferations

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Classification of Cutaneous Vascular Proliferations

The classification of vascular neoplasms has been problematic, with numerous ambiguities that create a conceptual confusion between vascular malformations and authentic vascular neoplasms. The terminology of general pathology, wherein tissue proliferations are designated hamartomas, malformations, hyperplasias, or benign or malignant tumors are imprecise when applied to vascular proliferations. One might first challenge the current nomenclature of vascular proliferations. Importantly, not all vascular proliferations are neoplasms; many are vascular malformations, hyperplasias, or hamartomas, as Mulliken proposed (1). Vascular malformations are defined as anomalies that result from inborn errors of vascular morphogenesis and, by definition, are congenital, i.e., present at birth. Some are seemingly trivial or transitory abnormalities of the vessel walls that only with time, and as a result of progressive ectasia, become noticeable clinically. When such specimens are examined histologically, there may be no evidence of cellular proliferation since their expansion has been a corollary of the growth of the host as well as the progressive ectasia that results from changes in blood or lymphatic flow and pressure. By contrast, hemangiomas are bona fide benign neoplasms that result from proliferation of endothelial cells. The infantile hemangioma is the commonest benign vascular proliferation. Traditionally, these have been considered neoplasms. However, after an initial proliferative phase, they undergo complete regression, through a process of fibrosis, even in the absence of therapy. Thus, they fulfill the definition of “hyperplasia” as utilized in classical pathology and defined herein as an abnormal increase in the absolute number of normal cells in appropriately arranged tissue. Inherent in this terminology is the premise that hyperplasia ceases when its initiating stimulus has been removed; thereafter the tissue may or may not revert completely to its normal state. Thus, the commonest form of hemangioma is best viewed as a manifestation of hyperplasia rather than a neoplasia, as the name hemangioma incorrectly implies. As a further example of imprecision in terms, let us consider the case of infantile hemangiomas, which have been classically termed as “capillary” or “cavernous,” but are not definitively contrasting. Most of the so-called “cavernous” hemangiomas are not authentic hemangiomas (neoplasms) but rather venous malformations with prominently spongy architecture. As still another example, when a typical infantile hemangioma undergoes involution, there is diminished endothelial cell proliferation and increased fibrosis. The latter forms septa that separate dilated vascular spaces lined with flattened endothelium. At this point, the once “capillary” hemangioma may exhibit a more “cavernous” appearance. Such evolutionary changes are responsible for different histologic appearances in the same lesion at different stages, thus the designations “cavernous” hemangioma or “mixed capillary-cavernous” hemangiomas. An individual hemangioma,

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Sangüeza and Requena / Pathology of Vascular Skin Lesions Table 1 Classification of Cutaneous Vascular Anomalies

1. Hamartomas Phakomatosis pigmentovascularis Eccrine angiomatous hamartoma 2. Malformations Functional malformations: Nevus anemicus Anatomic malformations: Capillary: Cutis marmorata telangiectatica congenita Nevus flammeus (port wine stain) Hyperkeratotic vascular stains Venous and arterial Lymphatic Superficial lymphatic malformations Deep (cystic) lymphatic malformations Lymphangiomatosis Combined vascular 3. Dilation of preexisting vessels Blood vessels Spider angioma (nevus araneus) Capillary aneurism-venous lake Telangiectases Unilateral nevoid telangiectasia Generalized essential telangiectasia Hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber Syndrome) Hereditary benign telangiectasia Ataxia-telangiectasia (Louis-Bar syndrome) Cutaneous collagenous vasculopathy Angiokeratomas Solitary angiokeratoma Angiokeratoma of Fordyce Angiokeratoma of Mibelli Angiokeratoma corporis diffusum Lymphatic vessels Lymphangiectases 4. Hyperplasias Angiolymphoid hyperplasia with eosinophilia Pyogenic granuloma Bacillary angiomatosis Verruga peruana Intravascular papillary endothelial hyperplasia (Masson’s pseudoangiosarcoma) Pseudo-Kaposi’s sarcoma Acroangiodermatitis of Mali Stewart-Bluefarb syndrome “Benign” angioendotheliomatosis (reactive angioendotheliomatosis)


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5. Benign Neoplasms With endothelial differentiation Capillaries and venules Angioma serpiginosum Infantile hemangioma Cherry angioma (senile angioma) Acral arteriovenous hemangioma Hobnail hemangioma (Targetoid hemosiderotic hemangioma) Microvenular hemangioma Tufted angioma (angioblastoma) Glomeruloid hemangioma Acquired elastotic hemangioma Kaposiform hemangioendothelioma Veins and arteries Sinusoidal hemangioma Giant cell angioblastoma Spindle cell hemangioma (formerly spindle cell hemangioendothelioma) Lymphatic vessels Benign lymphangioendothelioma Benign vascular proliferations in irradiated skin With glomus cell differentiation Solitary glomus tumor Multiple glomus tumors (glomangiomas) Intravenous glomus tumor With pericytic differentiation Hemangiopericytoma With myoid differentiation Cutaneous myofibroma 6. Malignant Neoplasms Kaposi’s sarcoma Low-grade cutaneous angiosarcomas: Epithelioid hemangioendothelioma Endovascular papillary angioendothelioma (Dabska’s tumor) Retiform hemangioendothelioma Composite hemangioendothelioma High-grade cutaneous angiosarcomas Classic angiosarcoma of the face and scalp of elderly patients Cutaneous angiosarcoma associated with lymphedema Radiation-induced cutaneous angiosarcoma Epithelioid angiosarcoma Malignant glomus tumor (glomangiosarcoma) 7. Other cutaneous neoplasms with a significant vascular component Multinucleate cell angiohistiocytoma Angiofibroma Angioleiomyoma Angiolipoma Cutaneous angiolipoleiomyoma Cutaneous angiomyxoma Aggressive angiomyxoma

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Sangüeza and Requena / Pathology of Vascular Skin Lesions Table 1 (Continued) Classification of Cutaneous Vascular Anomalies

8. Disorders erroneously considered vascular neoplasms Kimura’s disease “Malignant” angioendotheliomatosis (intravascular lymphomatosis) Acral pseudolymphomatous angiokeratoma of children (APACHE)

at any point in time, has its own histopathologic pattern that is quite consistent throughout the depth of the lesion (1). Thus, the so-called cavernous lesions with arrested involution are, in actuality, venous malformations, whereas “cavernous” hemangiomas that proceed with unabated involution are in fact, deep-seated hemangiomas. Therefore, the term “cavernous” is meaningless and should be avoided as descriptive of vascular lesions. Comparably imprecise is the use of terminology that denotes shared histologic similarities for lesions that are otherwise distinctively different in their clinical aspects. For example, the term hemangioendothelioma has been used for lesions that range from low-grade angiosarcomas, namely, epithelioid and retiform hemangioendotheliomas, to lesions that are completely benign, such as spindle cell and eruptive hemangioendotheliomas. The use of this terminology is clearly interpretive, as not all hemangioendotheliomas should be treated the same. With an awareness of the inherent ambiguities, we would like to propose a new classification for cutaneous vascular abnormalities (Table 1). Lesions are grouped according to their most elemental nature, i.e., hamartoma, malformation, or hyperplasia, as modified by their biologic growth potential, namely, benign or malignant. A separate category encompasses lesions created by dilation of native vessels. Because the category of benign vascular neoplasms is by far the most numerous and controversial group, it is classified in accordance with the cardinal, constituent cell in the context of the nature and caliber of the vessel of origin. Thus, the malignant neoplasms of endothelial cells, i.e. angiosarcomas, are classified according to their degree of differentiation into low- and high-grade angiosarcomas. A separate category is established for malignant glomus tumor or glomangiosarcoma. The proposed classification has much in common with those in the most recent review papers of cutaneous vascular proliferations (2–4) and the latest editions of certain dermatology and dermatopathology textbooks (5–7).

References 1. Mulliken JB. Classification of vascular birthmarks. In: Mulliken JB, Young AE, eds. Vascular Birthmarks. Hemangiomas and Malformations. Philadelphia, WB Saunders, 1988;24–37. 2. Requena L, Sangueza OP. Cutaneous vascular anomalies. Part I. Hamartomas, malformations, and dilatation of preexisting vessels. J Am Acad Dermatol 1997;37:523–49. 3. Requena L, Sangueza OP. Cutaneous vascular proliferations. Part II. Hyperplasias and benign neoplasms. J Am Acad Dermatol 1997;37:887–920. 4. Requena L, Sangueza OP. Cutaneous vascular proliferations. Part III. Malignant neoplasms, other cutaneous neoplasms with significant vascular component, and disorders erroneously considered as vascular neoplasms. J Am Acad Dermatol 1998;38:143–75. 5. Grevelink SV, Mulliken JB. Vascular anomalies. In: Freedberg IM, Eisen AZ, Wolff K, et al., eds. Fitzpatrick’s Dermatology in General Medicine. 5th ed. New York, McGraw-Hill, 1999:1175–94. 6. Calonje E, Wilson Jones E. Vascular tumors. Tumors and tumor-like conditions of blood vessels and lymphatics. In: Elder D, Elenitsas R, Jaworsky, Johnson B Jr, eds. Lever’s Histopathology of the Skin, 8th ed. Philadelphia, Lippincott-Raven, 1997:889–932. 7. LeBoit PE, Sangueza OP, Requena L. Vascular neoplasms of the skin. In: Farmer ER, Hood AF, eds. Pathology of the Skin, 2th ed. New York, McGraw-Hill. 2000:1243–304.


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Chapter 4 / Cutaneous Vascular Hamartomas

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Cutaneous Vascular Hamartomas CONTENTS PHAKOMATOSIS PIGMENTOVASCULARIS ECCRINE ANGIOMATOUS HAMARTOMA

Hamartoma is defined as a process that results from an error, which occurs during embryologic development and results in an abnormal arrangement of indigenous tissues in an organ. Hamartomatous cutaneous vascular lesions include phakomatosis pigmentovascularis and the so-called eccrine angiomatous hamartoma. Although both are benign lesions, they may require laser surgery because of the cosmetic disfigurement and discomfort that they produce.

1. PHAKOMATOSIS PIGMENTOVASCULARIS CLINICAL FEATURES The combination of vascular abnormalities and melanocytic nevi is termed phakomatosis pigmentovascularis. It was originally described by Ota et al. (1) in 1947, and since then there have been at least 100 additional reported cases, most of them in the Japanese literature (2–32). There are four variants of this disease (Table 1): type I is characterized by the association of nevus flammeus with nevus pigmentosus and verrucosus (1); type II consists of the association of nevus flammeus and aberrant mongolian spots (1); type III is the combination of a nevus flammeus with nevus spilus (8); and type IV is defined as the association of nevus flammeus, nevus spilus, and aberrant mongolian spots (9). These lesions are further subdivided into subtypes A and B. The A subtype has only cutaneous involvement, whereas the B subtype has both cutaneous and systemic involvement (10). Nevus anemicus can be an additional feature in types II, III, and IV (10). So far, there are no reports of systemic involvement in type I. The most common variant is type II (Fig. 1), which includes all those cases reported as oculocutaneous melanosis (nevus of Ota) associated with Sturge-Weber syndrome and/or Klippel-Trenaunay syndrome (11–17). Initially, it was thought that type II was an oligosymptomatic form of Klippel-Trenaunay syndrome associated with giant nevus spilus (13) . Patients with phakomatosis pigmentovascularis may also have other abnormalities, including glaucoma (15), multiple granular cell tumors (18), congenital triangular alopecia (19,20), circumscribed progressive lentiginosis (21), iris mamillations (22,23), renal angiomas (24), moyamoya disease (25), Becker’s nevus (26), leg-length discrepancy and agenesis of the kidney (27), and neurologic abnormalities (28). The association of generalized nevus spilus and nevus anemicus in a patient with a primary lymphedema has been proposed as a new type of phakomatosis pigmentovascularis (29).

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Sangüeza and Requena / Pathology of Vascular Skin Lesions Table 1 Classification of Phakomatosis Pigmentovascularis Type

Features a

I a,b II a,b III a,b IV a,b a

Nevus flammeus and nevus pigmentosus et verrucosus Nevus flammeus, mongolian spots, ± nevus anemicus Nevus flammeus, nevus spilus, ± nevus anemicus Nevus flammeus, mongolian spots, nevus spilus, ± nevus anemicus

a, cutaneous involvement only; b, cutaneous and systemic involvement.

Fig. 1. Clinical features of phakomatosis pigmentovascularis. (A) The anterior abdomen and the right thigh of this newborn show a combination of erythematous areas of nevus flammeus with bluish areas of dermal melanocytosis. (B)The buttocks and the posterior thighs of the same baby show a combination of similar features.

PATHOGENESIS The most commonly accepted opinion is that phakomatosis pigmentovascularis results from developmental abnormalities of the vasomotor nerves derived from the neural crest and melanocytes (30). It is thought that an alteration in the neural regulation of blood vessels could lead to the development of the vascular abnormalities seen in this condition. This is probably the explanation for the coexistence of nevus flammeus and nevus anemicus characteristic of this disease. The abnormal melanocytic component results from alterations during the migration of the neural crest-derived melanocytes, which produces lesions such as the nevus of Ota, nevus spilus, and mongolian spot. HISTOPATHOLOGIC FEATURES Histopathologically, there are an increased number of dilated thin-walled capillaries and venules in the upper part of the reticular dermis, although occasionally superficial areas of subcutaneous fat are also involved. The melanocytic component consists of spindled-shaped dendritic melanocytes loaded with abundant melanin in their cytoplasm scattered between the collagen bundles of the dermis (Fig. 2). Sometimes, the number of spindled melanocytes is sparse; thus lesions of phakomatosis pigmentovascularis may be misinterpreted as nevus flammeus. Immunohistochemical stains with S-100 protein or HMB-45 are helpful in highlighting the melanocytic component.


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Fig. 2. Histopathologic features of phakomatosis pigmentovascularis. (A) Low-power magnification shows dilated vascular structures at different levels of the dermis. (B) Higher magnification shows the dilated and congestive capillary blood vessels and scattered spindle, dendritic melanocytes with abundant melanin interstitially arranged between collagen bundles of the dermis.

It is important to remember that lesions of nevus flammeus associated with phakomatosis pigmentovascularis are indistinguishable from port wine stain not associated with melanocytic abnormalities. Ultrastructural studies indicate that nevus flammeus associated with phakomatosis pigmentovascularis is surrounded by perivascular nerve fibers, which are not present in isolated nevus flammeus (31). TREATMENT The vascular component of phakomatosis pigmentovascularis may cause psychological trauma to the patient, especially when it involves the face. In that case cosmetic camouflage may be indicated. Laser therapy is also capable of producing good results in treating nevus flammeus of phakomatosis pigmentovascularis (32). There is no description of a melanoma originating in the melanocytic component of phakomatosis pigmentovascularis.

References 1. Ota M, Kawanura T, Ito N. Phacomatosis pigmentovascularis (Ota). Jpn J Dermatol 1947;52:1–3. 2. Hasegawa Y, Yashura M. Phakomatosis pigmentovascularis type IVa. Arch Dermatol 1985;121:651–5. 3. Guillaume JC, Evenou P, Charpentier P, Avril MF. Phacomatose pigmento-vasculaire type IIa. Ann Dermatol Venereol 1988;115:1113–5. 4. Mahroughan M, Mehregan AH, Mehregan DA. Phakomatosis pigmentovascularis. Report of a case. Pediatr Dermatol 1996;13:36–8. 5. Stadhouders-Keet SA, Glastra A, Van Vloten WA. Phakomatosis pigmentovascularis (type IIIa). Ned Tijdschr Geneeskd 1999;143:1337. 6. Cincinnati P, Carucci T, Rutiloni C. La facomatosi pigmento-vascolare. Minerva Pediatr 1996;48:225–8. 7. Murdoch SR, Keefe M. Phakomatosis pigmentovascularis type IIA in a Caucasian child. Pediatr Dermatol 2000;17:157. 8. Toda K. A new type of phacomatosis pigmentovascularis (Ota). Jpn J Dermatol 1966;76:47–51. 9. Hasegawa Y, Yasuhara M. A variant of phakomatosis pigmentovascularis. Sin Res (Osaka) 1979;21:178–86. 10. Hasegawa Y, Yasuhara M. Phakomatosis pigmentovascularis type IVa. Arch Dermatol 1985;121:651–5. 11. Noriega Sanchez A, Markand ON, Herndon JH. Oculocutaneous melanosis associated with the SturgeWeber syndrome. Neurology 1972;22:256–62. 12. Furukawa T, Igata A, Toyokura Y, et al. Sturge-Weber and Klippel-Trenaunay syndrome with nevus of Ota and Ito. Arch Dermatol 1970;102:640–5.

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13. Sigg C, Pelloni F. Oligosymptomatic form of Klippel-Trenaunay-Weber syndrome associated with giant nevus spilus. Arch Dermatol 1989;125:1284–5. 14. Peyron N, Dereure O, Bessis D, Guilhou JJ, Guillot B. La phacomatose pigmento-vasculaire. A propos de 2 cas associés à une angiodysplasie. J Mal Vasc 1993;18:336–9. 15. Teekhasaenee C, Ritch R. Glaucoma in phakomatosis pigmentovascularis. Ophthalmology 1997; 104:150–7. 16. Hagiwara K, Uezato H, Nonaka S. Phacomatosis pigmentovascularis type IIb associated with SturgeWeber syndrome and pyogenic granuloma. J Dermatol 1998;25:721–9. 17. Uysal G, Guven A, Ozhan B, Ozturk MH, Mutluay AH, Tulunay O. Phakomatosis pigmentovascularis with Sturge-Weber syndrome: a case report. J Dermatol 2000;27:467–70. 18. Guiglia MC, Prendiville JS. Multiple granular cell tumors associated with giant speckled lentiginous nevus and nevus flammeus in a child. J Am Acad Dermatol 1991;24:359–63. 19. Kikuchi I, Okazaki M. Congenital temporal alopecia in phakomatosis pigmentovascularis. J Dermatol 1982;9:485–7. 20. Kim HJ, Park KB, Yang JM, Park SH, Lee ES. Congenital triangular alopecia in phakomatosis pigmentovascularis: report of 3 cases. Acta Derm Venereol 2000;80:215–6. 21. Zahorcsek Z, Schmelas A, Schneider I. Progrediente zirkumskripte Lentiginose Phakomatosis pigmentovascularis III/A. Hautarzt 1988;39:519–23. 22. Gilliam AC, Ragge NK, Perez MI, Bolognia JL. Phakomatosis pigmentovascularis type IIb with iris mammillations. Arch Dermatol 1993;129:340–2. 23. Van Gysel D, Oranje AP, Stroink H, Simonsz HJ. Phakomatosis pigmentovascularis. Pediatr Dermatol 1996;13:33–5. 24. Di Landro A, Tadini GL, Marchesi L, Cainelli T. Phakomatosis pigmentovascularis: a new case with renal angiomas and some considerations about the classification. Pediatr Dermatol 1999;16:25–30. 25. Tsuruta D, Fukai K, Seto M, et al. Phakomatosis pigmentovascularis type IIIb associated with moyamoya disease. Pediatr Dermatol 1999;16:35–8. 26. Joshi A, Garg VK, Agrawal S, Agarwalla A, Thakur A. Port-wine stain (nevus flammeus), congenital Becker’s nevus, café-au-lait-macule and lentiginides: phakomatosis pigmentovascularis type Ia—a new combination. J Dermatol 1999;26:834–6. 27. Huang C, Lee P. Phakomatosis pigmentovascularis IIb with renal anomaly. Clin Exp Dermatol 2000;25:51–4. 28. Cho S, Choi JH, Sung KJ, Moon KC, Koh JK. Phakomatosis pigmentovascularis type IIB with neurologic abnormalities. Pediatr Dermatol 2001;18:263. 29. Bielsa I, Paradelo C, Ribera M, Ferrandiz C. Generalized nevus spilus and nevus anemicus in a patient with a primary lymphedema: a new type of phakomatosis pigmentovascularis? Pediatr Dermatol 1998;15:293–5. 30. Libow LF. Phakomatosis pigmentovascularis type IIIb. J Am Acad Dermatol 1993;29:305–7. 31. Smoller BR, Rosen S. Port wine stains: a disease of altered neural modulation of blood vessels? Arch Dermatol 1986;122:177–9. 32. Ono I, Tateshita T. Phacomatosis pigmentovascularis type IIa successfully treated with two types of laser therapy. Br J Dermatol 2000;142:358–61.


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2. ECCRINE ANGIOMATOUS HAMARTOMA Eccrine angiomatous hamartoma (EAH) refers to a cutaneous hamartoma that combines a proliferation of both eccrine glands and thin-walled blood vessels, usually of a capillary nature. So far, 45 examples of EAH have been reported in the literature (1–35), although some of the reported cases may be variations of normal skin (36) or simply vascular malformations located in volar skin, where eccrine glands are normally abundant. EAH was initially reported in 1859 by Lotzbeck (1), who described a lesion of angiomatous appearance on the cheek of a child. Histopathologically, the lesion was composed of numerous clusters of eccrine glands within a stroma containing prominent blood vessels. In 1895 (2), Beier used the term sudoriparous angioma to describe a painful sudoriparous skin lesion of an angiomatous nature. In 1968, Hyman et al. (3) coined the term eccrine angiomatous hamartoma for this lesion and published a literature review on the subject. They noted that similar lesions were previously described under several designations, including secreting sudoriparous angiomatous hamartoma (4), functioning sudoriparous angiomatous hamartoma (5), nevus of sweat glands with angioma (6), and cavernous angiomatosis of the sweat ducts (7). CLINICAL FEATURES Clinically, most lesions of EAH present as solitary, erythematous nodules with an angiomatous appearance, although multiple lesions have also been described (4,7–10,34). They usually appear at birth or during early childhood, and several congenital examples have been described (8,11,12). In an isolated case, the lesion developed after radiotherapy (21). The most commonly affected areas are the acral zones, in particular the palms and soles (Fig. 3), although lesions on the face, neck, and trunk have also been reported. One patient with multiple lesions of EAH on the extensor surface of the wrists also had lesions on the knuckle pads (34). Biologically, the lesions are generally slow growing and asymptomatic, but pain and hyperhidrosis may be an occasional feature of this lesion. The pain is probably owing to nerve involvement (14,15) and the hyperhidrosis presumably results from stimulation of the eccrine component owing to a local increase in temperature caused in turn by the angiomatous component (8,10,14,16).

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Fig. 3. Clinical features of eccrine angiomatous hamartoma. (A) Nodular lesion involving the dorsum of the right toe in a newborn. (B) Nodular lesion involving the tip of the fifth finger.


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Fig. 4. Histopathologic features of eccrine angiomatous hamartoma. (A) Scanning magnification shows numerous dilated vascular structures involving both the upper and deeper dermis. (B) Higher magnification demonstrates an abundant number of eccrine units intermingled with dilated thin-walled vascular structures.

Although the lesions tend to grow slowly, as mentioned before, there are cases that increase rapidly in size. In one reported case the increase in the size of the lesion was noted during pregnancy, indicating a possible hormonal influence. In this particular case, partial amputation of the involved finger was necessary because of severe pain (13). HISTOPATHOLOGIC FEATURES The characteristic histopathologic features of EAH include lobules of mature eccrine glands and ducts closely associated with thin-walled blood vessels, usually of a capillary nature (Fig. 4), although large venous channels have also been reported (12). In addition to these two components that define the lesion, the presence of other structures including fatty tissue (17,27,30), hair follicles (18,19), apocrine glands (10), neurovascular glomic-like bodies (27), and occasional epidermal hyperplasia (32) has been described and lends further support to the hamartomatous nature of the EAH. Immunohistochemical studies have demonstrated that antigens commonly found in eccrine glands, such as carcinoembryonic antigen (CEA) and S-100 protein were qualitatively diminished in the eccrine component of the EAH, whereas endothelial markers such as Ulex europaeus, CD34, CD44, and factor VIII-related antigen were expressed by endothelial cells of the vascular component (10,16). Immunoreactivity for gross cystic disease fluid protein-15 was detected in the eccrine gland component of one case (33). TREATMENT Although it is benign and slow growing, EAH is often painful and may require surgical excision. There have been reports, however, of troublesome lesions in which the pain spontaneously resolved after some time (15).


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References 1. Lotzbeck C. Ein Fall von Schweissdrüsengeschwulst an der Wauge. Virchows Arch Pathol Anat 1859;16:160. 2. Beier E. Über einen Fall von Naevus Subcutaneous (Virchow) mit hochgradiqer Hyperplasie der Knäuelodrüsen. Arch Dermat Syph 1895;31:337. 3. Hyman AB, Harris H, Brownstein MH. Eccrine angiomatous hamartoma. NY State J Med 1968;68: 2803–6. 4. Vilanova X, Piñol Aguade J, Castells A. Hamartoma angiomateux sudoripare sécretant. Dermatologica 1963;127:9–16. 5. Issa O. Hamartoma angiomatoso sudoriparo funcionante. Actas Dermosifiliogr 1964;55:361–5. 6. Söltz-Szötz K. Berich über Fall von Schweissdrüsen naevus Kombiniert mit einem Angiom. Z Hautkr 1958;24:189–92. 7. Archer BWC. Multiple cavernous angiomata of the sweat ducts associated with hemiplegia. Lancet 1927;2:595–6. 8. Domonkos AN, Suarez LS. Sudoriparous angioma. Arch Dermatol 1967;96:552–3. 9. Aloi F, Tomasini C, Pippione M. Eccrine angiomatous hamartoma: a multiple variant. Dermatology 1992;184:219–22. 10. Sulica RL, Kao GF, Sulica VJ, Penneys NS. Eccrine angiomatous hamartoma (nevus): immunohistochemical findings and review of the literature. J Cutan Pathol 1994;21:71–5. 11. Kikuchi J, Kukari Y, Inoves S. Painful eccrine angiomatous nevus on the sole. J Dermatol 1982;9:329–32. 12. Sanmartin O, Botella R, Alegre V, Martinez A, Aliaga A. Congenital eccrine angiomatous hamartoma. Am J Dermatopathol 1992;14:161–4. 13. Gabrielsen O, Elgjo K, Sommerschild H. Eccrine angiomatous hamartoma of the finger leading to amputation. Clin Exp Dermatol 1991;16:44–5. 14. Challa VR, Jona J. Eccrine angiomatous hamartoma: a rare skin lesion with diverse histological features. Dermatologica 1977;155:206–9. 15. Wolf R, Krakowski A, Dorfman B. Eccrine angiomatous hamartoma. A painful step. Arch Dematol 1989;125:1489–90. 16. Smith VC, Montesinos E, Revert A, Ramon D, Molina I, Jorda E. Eccrine angiomatous hamartoma: report of three patients. Pediatr Dermatol 1996;13:139–42. 17. Donati P, Amantea A, Balus I. Eccrine angiomatous hamartoma. A lipomatous variant. J Cutan Pathol 1989:16:227–9. 18. Zeller DJ. Goldman RL. Eccrine-pilar angiomatous hamartoma. Dermatologica 1971;143:100–4. 19. Velasco, JA, Almeida V. Eccrine-pilar angiomatous nevus. Dermatologica 1988;177:317–22. 20. Aloi FG, Molinero A, Ronco A, Pippione M. Nevo eccrino-angiomatoso. G Ital Dermatol Venereol 1989;124:235–6. 21. Dallot A, Chemaly P, Kemeny JL, et al. Hamartome angio-eccrine chez un adulte après radiothérapie. Ann Dermatol Venereol 1992;119:903–4. 22. Diaz-Landaeta L, Kerdel FA. Hyperhidrotic, painful lesion. Eccrine angiomatous hamartoma. Arch Dermatol 1993;129:107. 23. Torres JE, Martin RF, Sanchez JL. Eccrine angiomatous hamartoma. PR Health Sci J 1994;13:159–60. 24. Nair LV, Kurien AM. Eccrine angiomatous hamartoma. Int J Dermatol 1994;33:650–1. 25. Nakayama H, Mihara M, Hattori K, Mishima E, Shimao S. Eccrine angiomatous hamartoma of the sacral region. Acta Derm Venereol 1994;74:477. 26. Calderone DC, Glass LF, Seleznick M, Fenske NA. Eccrine angiomatous hamartoma. J Dermatol Surg Oncol 1994;20:837–8. 27. Damiani S, Riccioni L. Palmar cutaneous hamartoma. Am J Dermatopathol 1998;20:65–8. 28. Michel JL, Secchi T, Balme B, Barrut D, Thomas L, Moulin G. Hamartome angio-eccrine congenital. Ann Dermatol Venereol 1997;124:623–5. 29. Kwon OC, Oh ST, Kim SW, Park GS, Cho BK. Eccrine angiomatous hamartoma. Int J Dermatol 1998;37:787–9. 30. Cebreiro C, Sanchez Aguilar D, Gomez Centeno P, Fernandez Redondo V, Toribio J. Eccrine angiomatous hamartoma: report of seven cases. Clin Exp Dermatol 1998;23:267–70. 31. Nakatsui TC, Schloss E, Krol A, Lin AN. Eccrine angiomatous hamartoma: report of a case and literature review. J Am Acad Dermatol 1999;41:109–11. 32. Tsuji T, Sawada H. Eccrine angiomatous hamartoma with verrucous features. Br J Dermatol 1999;141:167–9.

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33. Tanaka M, Shimizu S, Miyakawa S. Hypertrophic eccrine glands in eccrine angiomatous hamartoma produce gross cystic disease fluid protein 15. Dermatology 2000;200:336–7. 34. Morell DS, Ghali FE, Stahr BJ, McCauliffe DP. Eccrine angiomatous hamartoma: a report of symmetric and painful lesions of the wrists. Pediatr Dermatol 2001;18:117–9. 35. Lee SY, Chang SE, Choi JH, Sung KJ, Moon KC, Koh JK. Congenital eccrine angiomatous hamartoma: report of two patients. J Dermatol 2001;28:338–40. 36. Laeng RH, Heilbrunner J, Itin PH. Late-onset eccrine angiomatous hamartoma: clinical, histological and imaging findings. Dermatology 2001;203:70–4.


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Chapter 5 / Cutaneous Vascular Malformations

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Cutaneous Vascular Malformations CONTENTS NEVUS ANEMICUS CUTIS MARMORATA TELANGIECTATICA CONGENITA NEVUS FLAMMEUS HYPERKERATOTIC VASCULAR STAINS VENOUS MALFORMATIONS SUPERFICIAL CUTANEOUS LYMPHATIC MALFORMATIONS CYSTIC LYMPHATIC MALFORMATIONS (CYSTIC HYGROMAS) LYMPHANGIOMATOSIS

Malformation denotes an abnormal structure that results from an aberration in embryologic development. Although the term malformation is conventionally used as a synonym for hamartoma, the two are different, because hamartoma refers to a potpourri of tissue elements normally present at a particular site. Vascular malformations can be either functional or anatomic. In the case of functional abnormalities, the changes are related mostly to physiologic changes, as is the case for nevus anemicus. In contrast, anatomic vascular malformations exhibit evident morphologic abnormalities of the involved vessels. Anatomic vascular malformations are subdivided into the following groups: capillary, venous, arterial, lymphatic, and combined anomalies (Table 1). Clinically, it is important to separate the vascular malformations into those of low flow and high flow. Low-flow Table 1 Cutaneous Vascular Malformations

Functional Nevus anemicus Anatomical Capillary Cutis marmorata telangiectatica congenita Nevus flammeus (port wine stain) Hyperkeratotic vascular stains Venous and arterial Lymphatic Superficial lymphatic Deep (cystic) lymphatic Lymphangiomatosis Combined vascular malformations

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abnormalities include malformations of capillary, venous, lymphatic, or combination, whereas high-flow abnormalities include arteriovenous malformations (1).

References 1. Mulliken JB. Classification of vascular birthmarks. In: Mulliken JB, Young AE, eds. Vascular Birthmarks. Hemangiomas and Malformations. Philadelphia, WB Saunders, 1988;24–37.


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1. NEVUS ANEMICUS CLINICAL FEATURES Nevus anemicus is an uncommon congenital vascular malformation observed more frequently in women than in men. Clinically, the lesion consists of a localized circumscribed, pale macule with irregular margins occasionally surrounded by satellite macules (1–14). Although the upper chest is the most commonly affected site (Fig. 1), it may occur in any part of the body. Under diascopic pressure, the lesion becomes indistinguishable from the blanched surrounding skin. Wood’s lamp examination does not accentuate the lesion, and the application of friction, cold, or heat does not induce erythema in the involved areas. All these maneuvers are helpful in distinguishing nevus anemicus from vitiligo, hypochromic nevus, and other hypomelanosis. Nevus anemicus can be an additional feature in types II, III, and IV of phakomatosis pigmentovascularis (5,9,12,14). The presence of persistent, localized areas of livid erythema, caused by an increase in the vasoconstrictor tone of the thermoregulatory vessels of the involved skin and leading to relative stasis in the superficial nutritional vasculature, is considered a clinical variant

Fig. 1. Clinical features of a nevus anemicus involving the anterior chest of an adult woman. (A) Hypochromic macule on the right anterior chest. (B) Rubbing of the lesion results in peripheral erythema secondary to vasodilation in adjacent noninvolved skin, whereas the lesion of nevus anemicus remains a whitish color.

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of nevus anemicus (8). The term nevus oligemicus has been proposed for this clinical variant of nevus anemicus. Another variant of nevus anemicus was described by Miura et al. (15). This lesion is characterized by multiple anemic macules on the arms; however, other authors (16) consider this lesion to be an expression of an exaggerated physiologic speckled mottling of the limbs caused by transient changes in the vascular tone of the cutaneous vessels, but not a true variant of nevus anemicus. HISTOPATHOLOGIC FEATURES Since nevus anemicus is a functional anomaly rather than an anatomic one, histopathologic and ultrastructural examination of these lesions demonstrates that vascular structures are essentially normal (1). Intralesional injections of bradykinin, pilocarpine, acetylcholine, 5-hydroxytryptamine, nicotine, or histamine fail to produce vasodilation of the affected areas (1). However, erythema develops after an axillary sympathetic block or the intralesional injection of an α-adrenergic blocking agent (2,3). A disturbance in the regulation of vascular intramural adrenergic receptors may be demonstrated by means of autoradiography, resulting in persistent vascular constriction (6,7). Furthermore, it has been demonstrated that the blood vessels in nevus anemicus do not respond normally to proinflammatory cytokines, at least at the level of E-selectin expression. Additionally, if contact dermatitis affects the area of nevus anemicus, the keratinocytes overlying the area do not express intercellular adhesion molecule-1 and HLA-DR, probably because of the absence of infiltrating lymphocytes (11). All these findings support the conclusion that nevus anemicus results from locally increased vascular reactivity to catecholamines. Autograft transplant shows donor site dominance, lending further support to the idea that the cause of nevus anemicus is either an increased sensitivity to stimulation by vasoconstrictors or inhibition of vasodilator influences (2). The presence of vascular twin nevi, i.e., telangiectatic nevus and nevus anemicus occurring together and adjacent to each other, can be explained as twin spots resulting from allelism of somatic mutations (10). TREATMENT Usually lesions of nevus anemicus do not require treatment. However, if the lesions cause cosmetic disability then camouflage makeup is sufficient.

References 1. Greaves MW, Birkett D, Johson C. Nevus anemicus: a unique catecholamine-dependent nevus. Arch Dermatol 1970;102:172–6. 2. Daniel RH, Hubler WR, Wolf JE, et al. Nevus anemicus: donor-dominant defect. Arch Dermatol 1977;113:53–6. 3. Mountcastle EA, Diestelmeier RM, Lupton GP. Nevus anemicus. J Am Acad Dermatol 1986;14:628–32. 4. Fleischer TL, Zeligman I. Nevus anemicus. Arch Dermatol 1969;100:750–5. 5. Ratz JL, Roenigk HH Jr. Multiple vascular anomalies: report of a case. J Dermatol Surg Oncol 1978;4:684–6. 6. Raff M. Die Bedeutung adrenerger Rezeptoren fur die Entstehung des naevus flammeus und des Naevus anaemicus. Wien Klin Wochenschr 1981;129(suppl):1–14. 7. Dupre A, Bonafe JL, Jouas H. Naevus anemique generalisé acquis. Dermatologica 1981;163:276–81. 8. Davies MG, Greaves MW, Coutss A, Black AK. Nevus oligemicus. A variant of nevus anemicus. Arch Dermatol 1981;117:111–3. 9. Hidano A, Arai Y. Hémihypertrophie congénitale associée à des anomalies cutanées pigmentovasculaires, cérébrales, viscèrales et squelettiques. Ann Dermatol Venereol 1987;114:665–9. 10. Happle R. Allelic somatic mutations may explain vascular twin nevi. Hum Genet 1991;86:321–3.


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11. Mizutani H, Ohyanagi S, Umeda Y, Shimizu M, Kupper TS. Loss of cutaneous delayed hypersensitivity reactions in nevus anemicus. Evidence for close concordance of cutaneous delayed hypersensitivity and endothelial E-selectin expression. Arch Dermatol 1997;133:617–20. 12. Di Landro A, Tadini GL, Marchesi L, Cainelli T. Phakomatosis pigmentovascularis: a new case with renal angiomas and some considerations about the classification. Pediatr Dermatol 1999;16:25–30. 13. Ahkami RN, Schwartz RA. Nevus anemicus. Dermatology 1999;198:327–9. 14. Hasegawa Y, Yasuhara M. Phakomatosis pigmentovascularis type IVa. Arch Dermatol 1985;121:651–5. 15. Miura Y, Tajima S, Ishibashi A, Hata Y. Multiple anemic macules on the arms: a variant form of nevus anemicus? Dermatology 2000;201:180–3. 16. Plantin P, Schoenlaub P. Multiple anemic macules on the arms: not a variant form of nevus anemicus. Dermatology 2001;202:271–2.

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2. CUTIS MARMORATA TELANGIECTATICA CONGENITA Cutis marmorata telangiectatica congenita (CMTC) is usually present at birth and is characterized by the presence of a reticulated cutaneous vascular network of a blue-violet color. These lesions may be either localized or generalized. Van Lohuizen originally (1) described CMTC in 1922 and coined the term. CMTC should be distinguished from cutis marmorata, which is a physiologic response to cold and is prominent in neonates. To emphasize the distinction, some authors have used the term reticulated vascular nevus for CMTC (2). Although some familial cases have been reported (3–6), no recognizable pattern of inheritance has been demonstrated by this disease. In about 50% of patients, CMTC is associated with various other congenital anomalies (5), suggesting that CMTC is the principal cutaneous manifestation of a complex syndrome (3). CLINICAL FEATURES Clinically CMTC can be either localized (7) or generalized (8–10); when the lesions are localized, the distribution is usually segmental, with a sharp midline demarcation. However, the lesions occasionally involve the upper right limb and the lower left limb, in a crossed limb dimelia distribution (11). The areas of involved skin show either a flat or a reticulated erythema, producing a marbled appearance (Fig. 2). Telangiectasias are generally visible within the reticulated lines, and the red-purple hue of the lesions may become more prominent after crying, vigorous movements, or decrease in the ambient temperature. The skin in the affected areas may be atrophic, and ulceration may be a prominent feature (12). The lesions of CMTC show gradual spontaneous improvement

Fig. 2. Clinical features of cutis marmorata telangiectatica congenita. (A) Lesions involving the lower left extremity. (B) Close-up view of the lesions involving the anterior aspect of the left leg.


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with time and in some patients disappear entirely (8–10). In others, however, little or no significant change occurs, and the lesions remain unmodified throughout life. When the face is involved, there is either a diffuse erythema or nevus flammeus that affects the upper lip and philtrum (12–16). Patients with facial lesions are at risk of congenital glaucoma (17–22), which may be bilateral if the involvement is diffuse, especially in those cases affected by nevus flammeus (12,13). However, congenital glaucoma may also be present in patients with facial involvement of CMTC in the absence of nevus flammeus (12,23). Other associated anomalies include hemiatrophy or hemihypertrophy of the body (15,16), atrophy (2,5,6,14,15,24) or hypertrophy (5,14) of the involved limb, macrocephaly (14,16,25–33), mental retardation (13,15,26,28), hydrocephalus (16,26,28,32), neuronal migrations defects (31), hearing loss (16), strabismus (16), persistent ducts arteriosus (13) and other cardiovascular abnormalities (16), cardiac arrhytmia (33), sudden infant death (33), internal arteriovenous malformations (28), hypothyroidism (16), nevus anemicus (16), hemangiomas (13,16,29,32), congenital melanocytic nevus (12), café-au-lait spots (16), asymmetric skull (13,34,35), micrognathia (13), triangular face (13), scaphoid scapulae (13), elevation of the hemidiaphragm (16), lipomas (16), dystrophic teeth (13,31), anomalies of the growth of hair (31), higharched palate (13), cleft palate (14), syndactyly of the fingers or toes (13,15,16,28,32), short fingers (13), polydactyly (32), acral cyanosis (13), simian lines on the palms (14), anal atresia (16,36), rectovaginal and urethrovaginal fistulas (36), absent clitoris (36), hypospadias (37), short stature (13), diffuse demineralization of bones (14), lipoatrophy (34), weakness of the long extensor muscles of both thumbs (14), dislocated hips (31), joint laxity (32), hypoplasia of a lumbar vertebra (35), stridor (31), AdamsOliver syndrome (aplasia cutis congenita with terminal transverse limb defects) (38–43), spina bifida (44), neonatal ascites (45), congenital generalized fibromatosis (46), porencephaly (46), soft tissue herniations on the lower legs (47), and bilateral retinal detachment (48,49), tendinitis stenosans and bowing of the lower legs (50), congenital hypothyroidism (51), double aortic arch (52), hypoplasia of the iliac and femoral veins (53), moyamoya-like vascular abnormalities with factor V Leiden mutation resulting in congenital hypercoagulable disorder (54), and elevated maternal serum human chorionic gonadotrophin level with transitory isolated fetal ascites (55). Despite these numerous anomalies associated with CMTC, most of the cases of this disease present as a solitary abnormality. HISTOPATHOLOGIC FEATURES There is still some debate about the nature of the vascular lesions in CMTC. Although most authors believe that there is true anatomic malformation, others believe that CMTC is a functional malformation. Most of the skin biopsies exhibit dilated capillaries and veins throughout the entire dermis and subcutaneous fat (1,3) whereas in a few cases (13), no vascular abnormalities have been detected. Histopathologic examination of the lesions in a patient with painful lesions of CMTC demonstrated an increased number of nerve fibers (56). Ultrastructural studies have demonstrated an increased number of perithelial cells, as well as atypical endothelium with a discontinuous basal lamina (5). Colored echo-Doppler and phlebography studies have shown dilated deep venous tracts with reflux to the superficial veins (57). Laser Doppler fluxmetry of the involved skin has shown evidence of functional disturbance, which may be the expression of an α-adrenergic innervation deficit of the cutaneous terminal blood vessels (58).

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The differential diagnosis of CMTC is with Bockenheimer’s syndrome or diffuse genuine phlebectasia (12,59,60). Bockenheimer’s syndrome appears in childhood and shows a progressive development of multiple large and painful venous ectasias involving a single limb. Cutaneous lesions similar to those of CMTC may be also seen in newborns with neonatal lupus erythematosus (61,62). TREATMENT The cutaneous lesions of CMTC tend to fade with time, and there is no need to treat these lesions during the first years of life. For persistent cutaneous lesions, treatment with argon or dye laser may be helpful. The discovery of this malformation in the skin of an infant, however, should prompt a diligent search for an associated congenital anomaly by neuropediatric, ophthalmologic, and orthopedic explorations, in addition to dermatologic examination (63).

References 1. van Lohuizen CHJ. Über eine seltene angeborene Hautanomalie (cutis marmorata telangiectatica congenita). Acta Derm Venereol 1922;3:202–11. 2. Brain RT. Naevus vascularis reticularis. Proc Soc Med 1954;47:172–3. 3. Andreev VC, Pramatarov K. Cutis mamorata telangiectatica congenita in two sisters. Br J Dermatol 1979;101:345–50. 4. Kurczinski TW. Hereditary cutis marmorata telangiectatica congenita. Pediatrics 1982;70:52–3. 5. Way BH, Herrmann, J, Gilbert EF, et al. Cutis marmorata telangiectatica congenita. J Cutan Pathol 1974;1:10–25. 6. Rogers M, Poyzer KG. Cutis marmorata telangiectatica congenita. Arch Dermatol 1982;118:895–9. 7. Suarez SM, Grossman ME. Localized cutis marmorata telangiectatica congenita. Pediatr Dermatol 1991;8:329–31. 8. Devillers AC, de Waard-van der Spek FB, Oranje AP. Cutis marmorata telangiectatica congenita: clinical features in 35 cases. Arch Dermatol 1999;135:34–8 9. Amitai DB, Fichman S, Merlob P, Morad Y, Lapidoth M, Metzker A. Cutis marmorata telangiectatica congenita: clinical findings in 85 patients. Pediatr Dermatol 2000;17:100–4. 10. Enjolras O. Cutis marmorata telangiectatica congenita. Ann Dermatol Venereol 2001;128:161–6 11. Sanchez P, Bosch RJ, Herrera E. Cutis marmorata telangiectatica congenita: forme dimelique croisée. Ann Dermatol Venereol 1992;119:647–50. 12. Picascia DD, Esterly NB. Cutis marmorata telangiectatica congenita: report of 22 cases. J Am Acad Dermatol 1989;20:1098–104. 13. Petrozzi WJ, Rahn EK, Mofenson H, et al. Cutis marmorata telangiectatica congenita. Arch Dermatol 1970;101:74–7. 14. Lee S, Lee JB, Kim JH, et al. Cutis marmorata congenita with multiple congenital abnormalities (van Lohuizen’s syndrome). Dermatologica 1981;163:408–12. 15. Lopez-Herce Cid J, Roche Herrero MC, Pascual Castroviejo I. Cutis marmorata telangiectatica congenita. Anomalías asociadas. An Esp Pediatr 1985;22:585–90. 16. Gerritsen MJ, Steijlen PM, Brunner HG, Rieu P. Cutis marmorata telangiectatica congenita: report of 18 cases. Br J Dermatol 2000;142:366–9. 17. Sato SE, Herschler J, Lynch PJ, et al. Congenital glaucoma associated with cutis marmorata congenita telangiectatica: two case reports. J Pediatr Ophthalmol Strabismus 1988;25:13–7. 18. Vazquez F, Lopez B, Requena L, Garcia Perez A. Congenital glaucoma and cutis marmorata telangiectasia: report of the second case. Dermatologica 1989;177:193–4. 19. Lynch PJ. Cutis marmorata telangiectatica congenita associated with congenital glaucoma. J Am Acad Dermatol 1990;22:857. 20. Miranda I, Alonso MJ, Jimenez M, Tomas-Barberan S, Ferro M, Ruiz R. Cutis marmorata telangiectatica congenita and glaucoma. Ophthalmic Paediatr Genet 1990;11:129–32. 21. Kremer I, Metzker A, Yassur Y. Intraoperative suprachoroidal hemorrhage in congenital glaucoma associated with cutis marmorata telangiectatica congenita. Arch Ophthalmol 1991;109:1199–200. 22. Weilepp AE, Eichenfield LF. Association of glaucoma with cutis marmorata telangiectatica congenita: a localized anatomic malformation. J Am Acad Dermatol 1996;35:276–8.


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23. South DA, Jacobs AH. Cutis marmorata telangiectatica congenita (congenital generalized phlebectasia). J Pediatr 1978;93:944–9. 24. Wong V. Cutis marmorata telangiectatica congenita: an unusual presentation with monoatrophy in two Chinese children. J Paediatr Child Health 1997;33:71–3. 25. Stephan MJ, Hall BD, Smith DW, Cohen MM Jr. Macrocephaly in association with unusual cutaneous angiomatosis. J Pediatr 1975;87:353–9. 26. Moore CA, Torriello HV, Abuelo DN, et al. Macrocephaly-cutis marmorata telangiectatica congenita: a distinct disorder with developmental delay and connective tissue abnormalities. Am J Med Genet 1997;2:67–73. 27. Wroblewski I, Joannard A, Francois P, Baudain P, Beani JC, Beaudoing A. Cutis marmorata telangiectatica congenita avec asymétrie corporalle. Pediatrie 1988;43:117–20 28. Clayton-Smith J, Kerr B, Brunner H, et al. Macrocephaly with cutis marmorata, haemangioma and syndactyly—a distinctive overgrowth syndrome. Clin Dysmorphol 1997;6:291–302. 29. Carcao M, Blaser SI, Grant RM, Weksberg R, Siegel-Bartelt J. MRI findings in macrocephaly-cutis marmorata telangiectatica congenita. Am J Med Genet 1998;76:165–7. 30. Vogels A, Devriendt K, Legius E, et al. The macrocephaly-cutis marmorata telangiectatica congenita syndrome. Long-term follow-up data in 4 children adolescents. Genet Couns 1998;9:245–53. 31. Robertson SP, Gattas M, Rogers M, Ades LC. Macrocephaly-cutis marmorata telangiectatica congenita: report of five patients and a review of the literature. Clin Dysmorphol 2000;9:1–9. 32. Franceschini P, Licata D, Di Cara G, Gaula A, Franceschini D, Genitori L. Macrocephaly-cutis marmorata telangiectatica congenita without cutis marmorata? Am J Med Genet 2000;14:265–9. 33. Yano S, Watanabe Y. Association of arrhythmia and sudden death in macrocephaly-cutis marmorata telangiectatica congenita syndrome. Am J Med Genet 2001;102:149–52. 34. Gelmetti C, Console V, Schianchi R, Missaglia R. Cutis marmorata telangiectatica congenita. Descrizione di un nuovo caso. Pediatr Med Chir 1986;8:907–9. 35. Gelmetti C, Schianchi R, Ermacora E. Cutis marmorata telangiectatica congenita. Quatre nouveaux cas et revue de la littérature. Ann Dermatol Venereol 1987;114:1517–28. 36. Del Giudice SM, Nydorf ED. Cutis marmorata telangiectatica congenita with multiple congenital anomalies. Arch Dermatol 1986;122:1060–1. 37. Ben-Amitai D, Merlob P, Metzker A. Cutis marmorata telangiectatica congenita and hypospadias: report of 4 cases. J Am Acad Dermatol 2001;45:131–2. 38. Powell ST, Su WPD. Cutis marmorata telangiectatica congenita: a report of 9 cases and review of the literature. Cutis 1984;34:305–12. 39. Torrielo HV, Graff RG, Florentine MF, Lacina S, Moore WD. Scalp and limb defects with cutis marmorata telangiectatica congenita: Adams-Oliver syndrome? Am J Med Genet 1988;29:269–76. 40. Bork K, Pfeifle J. Multifocal aplasia cutis congenita, distal limb hemimelia, and cutis marmorata telangiectatica in a patient with Adams-Oliver syndrome. Br J Dermatol 1992;127:160–3. 41. Dyall-Smith D, Ramsden A, Laurie S. Adams-Oliver syndrome: aplasia cutis congenita, terminal transverse limb defects and cutis marmorata telangiectatica congenita. Australas J Dermatol 1994;35:19–22. 42. Bjornsdottir US, Laxdal T, Bjornsson J. Cutis marmorata telangiectatica congenita with terminal transverse limb defects. Acta Paediatr Scand 1988;77:780–2. 43. Mempel M, Abeck D, Lange I, et al. The wide spectrum of clinical expression in Adams-Oliver syndrome. A report of two cases. Br J Dermatol 1999;140:1157–60. 44. Schultz RB, Kocoshis S. Cutis marmorata telangiectatica congenita and neonatal ascites. J Pediatr 1979;95:157. 45. Spraker MK, Stack C, Esterly NB. Congenital generalized fibromatosis: a review of the literature and report of a case associated with porencephaly, hemiatrophy, and cutis marmorata telangiectatica congenita. J Am Acad Dermatol 1984;10:365–71. 46. Nicholls DSH, Harper JI. Cutis marmorata tetangiectatica congenita with soft-tissue herniations on the lower legs. Clin Exp Dermatol 1989;14:369–70. 47. Freund E. Diffuse genuine phlebectasia. Arch Surg 1936;33:113–21. 48. Shields JA, Shields CL, Koller HP, Federman JL, Koblenzer P, Barbera LS. Cutis marmorata telangiectatica congenita associated with bilateral congenital retinal detachment. Retina 1990;10:135–9. 49. Pendergast SD, Trese MT, Shastry BS. Ocular findings in cutis marmorata telangiectatica congenita. Bilateral exudative vitreoretinopathy. Retina 1997;17:306–9. 50. Kennedy C, Oranje AP, Keizer K, van den Heuvel MM, Catsman-Berrevoets CE. Cutis marmorata telangiectatica congenita. Int J Dermatol 1992;31:249–52. 51. Pehr K, Moroz B. Cutis marmorata telangiectatica congenita: long-term follow-up, review of the literature and report of a case in conjunction with congenital hypothyroidism. Pediatr Dermatol 1993;10:6–11.

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52 O’Toole EA, Deasy P, Watson R. Cutis marmorata telangiectatica congenita associated with a double aortic arch. Pediatr Dermatol 1995;12:348–50. 53. Morgan JM, Naisby GP, Carmichael AJ. Cutis marmorata telangiectatica congenita with hypoplasia of the right iliac and femoral veins. Br J Dermatol 1997;137:119–22. 54. Gruppo RA, DeGrauw TJ, Palasis S, Kalinyak KA, Bofinger MK. Strokes, cutis marmorata telangiectatica congenita, and factor V Leiden. Pediatr Neurol 1998;18:342–5. 55. Chen CP, Chen HC, Liu FF, et al. Cutis marmorata telangiectatica congenita associated with an elevated maternal serum human chorionic gonadotrophin level and transitory isolated fetal ascites. Br J Dermatol 1997;136:267–71. 56. Lentner A, Bohler U, Wittkopf-Baumann C, Younossi H, Grussendorf-Conen EI. Schmerzhafte Cutis marmorata teleangiectatica congenita. Hautarzt 1992;43:657–60. 57. Lingier P, Munck D, Godart S. Cutis marmorata telangiectatica congenita. A propos de quatre nouveaux cas. Phlebologie 1992;45:489–96. 58. Bormann G, Wohlrab J, Fisher M, Marsch WC. Cutis marmorata telangiectatica congenita: laser Doppler fluxmetry evidence for a functional nervous defect. Pediatr Dermatol 2001;18:110–3. 59. Fitzsimmons JS, Starks M. Cutis marmorata telangiectatica congenita or congenital generalized phlebectasia. Arch Dis Child 1970;45:724–6. 60. Atherton DJ. Naevi and other developmental defects. In: Champion RH, Burton JL, Ebling FJG eds. Textbook of Dermatology, 5th ed., Oxford, Blackwell Scientific, 1992:445–526. 61. Greist MC, Probst E. Cutis marmorata telangiectatica congenita on neonatal lupus. Arch Dermatol 1980;116:1102–3. 62. Carrascosa JM, Ribera M, Bielsa I, Coroleu W, Ferrandiz C. Cutis marmorata telangiectatica congenita or neonatal lupus? Pediatr Dermatol 1996;13:230–2. 63. Rupprecht R, Hundeiker M. Cutis marmorata teleangiectatica congenita. Wichtige Aspekte fur die dermatologisches Praxis. Hautarzt 1997;48:21–5.


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3. NEVUS FLAMMEUS Nevus flammeus is a generic term used to describe congenital vascular malformations that affect newborns. These commonly involve the forehead, face, and neck, although lesions have been described in nearly all anatomic sites including mucous membranes (1). Approximately 25–40% of newborns of all races are born with pink-red macular lesions that involve the midline of the face, occiput, and nuchal regions (2–5). Most of these lesions are small, and are located on the glabellar region of the forehead, where they are commonly known as salmon patch. They tend to disappear during infancy or childhood. In other cases the lesions are present on the nape of the neck; these lesions tend to be much more persistent and in a significant percentage of patients they remain unchanged into adult life. The combination of lesions on the glabellar region and the nape of the neck is known colloquially as stork bite. Inflammatory changes of dermatitis have been described in nuchaloccipital nevus flammeus (6,7). Nuchal nevus flammeus is also considered a valuable skin marker in patients with alopecia areata, indicating a more severe clinical course (8). Involvement of the sacral skin by nevus flammeus is also frequent and, like the occipital lesions, these lesions show a tendency to persist into adult life (9,10). Ocassionally, sacral nevus flammeus is associated with occult spinal dysraphism (11). A less frequent variant of nevus flammeus, is the port wine stain, consisting of large unilateral vascular lesions affecting the face. These lesions also tend to persist during adulthood (2,4,5,12,13). CLINICAL FEATURES Clinically, these small lesions are irregular, dull pinkish red macules that affect the glabella, forehead, upper eyelids, upper lip (Fig. 3) and nuchal region. They usually affect more than one site and have a midline distribution (Fig. 4). Most of the lesions affecting the center of the face fade rapidly with age and disappear during the first year of life (3). By contrast, nuchal and sacral lesions tend to persist into adulthood. Port wine stains present as unilateral deep red or purple macules with a slow but progressive growth throughout life. They also become increasingly darker to eventuate into raised and thickened plaques. Sometimes small angiomatous nodules appear within an otherwise typical port wine stain; in rare instances, a cobblestone pattern of red-purple nodules covers the whole lesion (1,14) (Fig. 5). Although cases of congenital nevus flammeus are relatively common, examples of acquired nevus flammeus are quite rare, and most of the reported cases of the acquired type have been described in association with preceding trauma (15).

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Fig. 3. Small nevus flammeus involving the skin of the upper lip.


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Fig. 4. Extensive nevus flammeus involving the left chest.

Fig. 5. Nevus flammeus involving the face of an older woman. Long-standing lesions become thicker, with red-purple nodules covering the whole lesion.

A variety of abnormalities have been associated with port wine stains. The association of port wine stains and nevus anemicus is a fairly common event (16), and this combination has been termed naevus vascularis mixtus (17). Glaucoma is a frequent complication in facial port wine stains, not only in patients with the Sturge-Weber syndrome. Approximately 10% of all patients with facial port wine stains have glaucoma without


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Fig. 6. Sturge-Weber syndrome. Large nevus flammeus involving the left side of the face.

Fig. 7. Sturge-Weber syndrome. Small nevus flammeus involving the left forehead, eyelid, and nose.

leptomeningeal involvement (18,19). Ipsilateral glaucoma is especially frequent when the lesions of port wine stain involve the areas of inervation of both the ophthalmic and maxillary divisions of the trigeminal nerve. It is less common when the areas of the face affected are those that follow the distribution of the upper divisions of the fifth cranial nerve or when the lesions are located solely below the eye (20). The presence of dilated conjunctival vessels are common when the lids are involved, but this finding does not correlate with either the presence or absence of glaucoma. Choroidal “angioma” is the most characteristic ocular vascular malformation in patients with facial port wine stain and glaucoma (21), and an ophthalmoscopic examination of the fundus of the eye is imperative when a port wine stain is present in close proximity to the eye in a newborn. The Sturge-Weber syndrome consists of a large facial nevus flammeus in the distribution of the ophthalmic division of the trigeminal nerve (Fig. 6) accompanied by ipsilateral leptomeningeal angiomatosis. Ocular involvement is not essential to establish the diagnosis of this syndrome. Clinically, a unilateral port wine stain involving the forehead, eye, and maxillary area characterizes the Sturge-Weber syndrome. Involvement of the upper eyelid and the forehead is generally the rule 18 (Fig. 7). Usually the lesion is unilateral, with a fairly sharp midline delimitation, but sometimes it extends beyond the midline and bilateral facial port wine stains can be seen in approximately 40% of patients (22). Homolateral leptomeningeal angiomatosis is the second component of the syn-

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Fig. 8. Klippel-Trenaunay syndrome. Extensive nevus flammeus involving the posterior aspect of a hypertrophic lower extremity.

drome, although there is no correlation between the extent of the cutaneous lesions and the extent of leptomeningeal involvement. Some authors admit to the possibility of a forme fruste of Sturge-Weber syndrome when unilateral leptomeningeal angiomatosis occurs without facial port wine stain (23–25). Among the neurologic manifestations, epilepsy is the most frequent (22), and there is also some degree of mental retardation, which is more pronounced in patients with bi-hemispheric involvement (26). X-rays of the skull, computed tomography (CT) scanning, and magnetic resonance imaging (MRI) are useful in identifying early cortical calcifications in these patients. Contralateral hemiplegia, hemisensory defects, and homonymous hemianopsia may also occur. Ocular involvement is present in approximately 30–60% of all cases of Sturge-Weber syndrome (18,20). The manifestations are similar to those seen in patients with facial port wine stain without leptomeningeal angiomatosis, although they occur more frequently. Glaucoma, buphthalmos, and blindness are frequent ophthalmologic complications in patients with Sturge-Weber syndrome. Because of the increased cutaneous vascularity, sometimes an overgrowth of the underlying soft tissue and bone, occurs, giving rise to a deformity very similar to that of the Klippel-Trenaunay syndrome (27,28) (Fig. 8). As a matter of fact, Sturge-Weber syndrome is often associated with Klippel-Trenaunay syndrome (29–31). Klippel-Trenaunay syndrome is defined as a nevus flammeus (and sometimes other vascular malformations) associated with soft tissue swelling involving a limb, with or without bony hypertrophy of the affected extremity (31). If these lesions are associated with an underlying arteriovenous anastomosis, then the syndrome is called Parkes-Weber (32). The most common cutaneous lesions in these syndromes consist of one or several port wine stains on the affected limb (33–36).


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Fig. 9. Cobb syndrome. (A) Erythematous patch involving the left anterior chest. (B) The lesion showed a zosteriform arrangement along the left flank. MRI studies demonstrated a vascular malformation involving the same level of the spinal cord.

Port wine stains have also been described in a large series of rare congenital disorders including the following: 1. Phakomatosis pigmentovascularis (37–45). 2. Cobb’s syndrome, which is characterized by a nevus flammeus or other vascular malformations in a dermatomal distribution on the trunk or limb associated with vascular malformations of the spinal canal at the same segmental level as that of the cutaneous lesions (46) (Fig. 9). 3. Wyburn-Mason syndrome, which consists of unilateral retinal arteriovenous malformation associated with ipsilateral aneurysmal arteriovenous malformation and ipsilateral port wine stain in the region of the affected eye (47). This syndrome has also been described in association with Sturge-Weber syndrome (48). 4. Proteus syndrome—the association of hemihypertrophy, macrodactyly, verrucous epidermal nevus, vascular malformations, soft subcutaneous masses, and cerebriform overgrowth of the palmar or plantar surfaces of the hypertrophied limb (49–51).

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Fig. 10. Histopathologic features of nevus flammeus. (A) Low power shows dilated blood vessels in the papillary and reticular dermis. (B) Higher magnification demonstrates that these vessels have thin walls and are lined by a single layer of endothelial cells.

5. Roberts’ syndrome, which consists of a mild facial port wine stain associated with hypomelia, hypotrichosis, growth retardation, and cleft lip (52). 6. TAR syndrome—congenital thrombocytopenia, bilateral absence or hypoplasia of the radius, and port wine stain (53). 7. von Hippel-Lindau syndrome or bilateral retinal angiomatosis in combination with cerebellar or medullar hemangioblastoma and, in some instances, facial port wine stain (54). 8. Beckwith-Wiedemann syndrome, which combines exophthalmos, macroglossia, and gigantism with facial nevus flammeus (55). 9. Rubinstein-Taybi syndrome, defined by mental deficiency, retarded somatic growth, broad thumbs and big toes, antimongoloid palpebral fissures, high palate, and crowded teeth (56). 10. Coats’ disease, which comprises retinal telangiectasia and ipsilateral facial port wine stain (57).

HISTOPATHOLOGIC FEATURES Histopathologically, the findings of isolated nevus flammeus and nevus flammeus associated with other anomalies are identical. The main difference is an increased number of dilated thin-walled capillaries and venules, most of which are situated in the upper part of the reticular dermis (Fig. 10), although occasionally superficial areas of subcutaneous fat are also involved. An increased number of mast cells has been described in the dermis of the lesions of nevus flammeus (58). When angiomatous nodules develop in a patch of


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nevus flammeus, they are made up either of an aggregation of numerous thin-walled vessels whose lumina are of different calibers (59) or, in other instances, they are authentic pyogenic granulomas developed within port wine stains (60–63). Other lesions that may arise in a preexisting nevus flammeus include tufted angioma (63), angiolymphoid hyperplasia with eosinophilia (64), and basal-cell carcinoma (65–68). In some of the patients in whom basal cell carcinoma developed in a preexisting nevus flammeus, there was antecedent of radiotherapy in this area (67). PATHOGENESIS The pathogenesis of port wine stains remains controversial, and the subject has been recently revised (69). Three-dimensional reconstructions, thymidine uptake studies, and ultrastructural observations support the view that port wine stains represent a vascular ectasia rather than a proliferative process (70,71). Furthermore, a detailed study of port wine stains in which vessel size, number, and dermal position were measured indicated that these lesions are not proliferative but result from progressive vascular dilation of preexisting blood vessels. There are two hypotheses that attempt to explain this dilation. One suggests either a defect in the vascular wall or abnormalities of the supporting structure of the dermis surrounding the dilated vessels. Immunofluorescence studies of the different components of the vessel wall, including type IV collagen, fibronectin, and factor VIII, disclosed no abnormalities in lesions of port wine stains (72). Comparative studies of normal blood vessels and vessels of port wine stains utilizing immunohistochemical analysis with four monoclonal antibodies specific for endothelial cells (PAL-E, anti-factor VIII-related antigen, anti-intercellular adhesion molecule-1, and anti-endothelial leukocyte adhesion molecule-1) demonstrated no substantial differences, either in the intensity of staining or the distribution pattern of these antibodies (73). Therefore, a functional alteration seems to be the most reasonable explanation for the etiology of port wine stains. Immunoperoxidase studies with S-100 protein have demonstrated a marked decrease in the nerve fibers associated with ectatic blood vessels of port wine stains (45). Most likely, this is a primary factor in their etiology. A reduction of the sympathetic innervation of the blood vessels leads to a failure to regulate vasoconstriction, which in turn produces progressive vascular ectasia that characterize lesions of port wine stain. In short, port-wine stain results from a neural deficiency of the sympathetic innervation of the blood vessels (45). TREATMENT Small, centrally located salmon patches tend to disappear by the end of the first year of life. Port wine stains, however, persist into childhood and adult life, and newer forms of laser therapy have been highly successful at producing good cosmetic results in facial lesions (74–79). However, there are some anatomic differences. The most successful responses of nevus flammeus treated by laser therapy are seen in young patients (less than 1 year old) with small lesions (under 20 cm2), and in lesions located over bony areas and the central forehead (80). On the other hand, centrofacial lesions and lesions involving maxillary areas in adults and children respond less favorably than lesions located elsewhere on the head and neck (81–83). Since laser treatment has superficial penetration, it cannot reach deeper vessels, so nevus flammeus lesions with a deep component have a poor response to this type of therapy (82,83). Adverse cutaneous reactions after laser therapy for nevus flammeus include hyperpigmentation (84) and atrophic and hypertrophic scars (84,85). Partial recurrences of the nevus flammeus after initially successful laser treatment are common (86,87).

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References 1. Barsky SH, Rosen S, Geer DE, et al. The nature and evolution of port wine stains: a computer assisted study. J Invest Dermatol 1980;74:154–7. 2. Hidano A, Purwoko R, Jitsukawa K. Statistical survey of skin changes in Japanese neonates. Pediatr Dermatol 1986;3:140–4. 3. Leung AKC, Telmesani AMA. Salmon patches in Caucasian children. Pediatr Dermatol 1989;6:185–7. 4. Nanda A, Kaur S, Bhakoo ON, et al. Survey of cutaneous lesions in Indian newborns. Pediatr Dermatol 1989;6:39–42. 5. Rivers JK, Fredericksen PC, Dibdin C. A prevalence survey of dermatoses in the Australian neonate. J Am Acad Dermatol 1990;23:77–81. 6. Tay YK, Morelli J, Weston WL. Inflammatory nuchal-occipital port-wine stains. J Am Acad Dermatol 1996;35:811–3. 7. Bonifazi E, Mazzota F. Inflammatory nuchal-occipital port-wine stains. J Am Acad Dermatol 1998;38:130. 8. Hatzis J, Kostakis P, Tosca A, et al. Nuchal nevus flammeus as a skin marker of prognosis in alopecia areata. Dermatologica 1988;177:149–51. 9. Metzker A, Shamir R. Butterflay-shaped mark: a variant form of nevus flammeus simplex. Pediatrics 1990;85:1069–71. 10. Patrizi A, Neri I, Orlandi C, Marini R. Sacral medial telangiectatic vascular nevus: a study of 43 children. Dermatology 1996;192:301–6. 11. Ben-Amital D, Davidson S, Schwartz M, et al. Sacral nevus flammeus simplex: the role of imaging. Pediatr Dermatol 2000;17:469–71. 12. Alper JG, Holmes, LB. The incidence and significance of birthmarks in a cohort of 4641 newborns. Pediatr Dermatol 1983;1:58–66. 13. Jacobs AH, Walton RG. The incidence of birthmarks in the neonate. Pediatrics 1976;58:218–22. 14. Finley JL, Noe JM, Arndt KA, et al. Port-wine stains: morphological variations and developmental lesions. Arch Dermatol 1984;120:1453–5. 15. Adams BB, Lucky AW. Acquired port-wine stains and antecedent trauma: case report and review of the literature. Arch Dermatol 2000;136:897–9. 16. Mills CM, Lanigan SW, Hughes J, Anstey AV. Demographic study of port wine stain patients attending a laser clinic: family history, prevalence of naevus anemicus and results of prior treatment. Clin Exp Dermatol 1997;22:166–8. 17. Hamm H, Happle R. Naevus vascularis mixtus. Hautarzt 1986;37:388–92. 18. Enjolras O, Riche MC, Merland JJ. Facial port-wine stains and Sturge-Weber syndrome. Pediatrics 1985;76:48–51. 19. Stevenson RF, Morin JD. Ocular findings in nevus flammeus. Can J Ophthalmol 1975;10:136–9. 20. Stevenson RF, Thompson HG, Morin JD. Unrecognized ocular problems associated with port-wine stains of the face in children. Can Med Assoc J 1974;111:953–4. 21. Witschel H, Font RL. Hemangioma of the choroid: a clinicopathological study of 71 cases and a review of the literature. Surv Ophthalmol 1976;20:415–31. 22. Uram M, Zubillaga C. The cutaneous manifestations of Sturge-Weber syndrome. J Clin Neuroophthalmol 1982;2:145–8. 23. Jacobs AH. Sturge-Weber syndrome without port-wine nevus. Pediatrics 1977; 60:785–6. 24. Andriola M, Stolfi J. Sturge-Weber syndrome: report of an atypical case. Am J Dis Child 1972;123:507–10. 25. Crosley CJ, Binet EF. Sturge-Weber syndrome: presentation as a focal seizure without nevus flammeus. Clin Pediatr 1978;17:606–9. 26. Bebin EM, Gomer MR. The intelligence and social achievement of patients with unilateral and bihemispheric Sturge-Weber syndrome. J Child Neurol 1988;3:181–90. 27. Royle HE, Lapp R, Ferrara ED. The Sturge-Weber syndrome. Oral Surg Oral Med Oral Pathol 1966;22:490–7. 28. Cosman B. Clinical experience in the laser therapy of port-wine stains. Lasers Surg Med 1980;1:133–52. 29. Harper PS. Sturge-Weber syndrome with Klippel-Trenaunay syndrome. Birth Defects 1971;7:314. 30. Schofield D, Zaatari GS, Gay BB. Klippel-Trenaunay and Sturge-Weber syndromes with renal hemangioma and double inferior vena cava. J Urol 1986; 136:442–5. 31. Klippel M, Trenaunay P. Du noevus variqueux osteohypertrophique. Arch Gen Med 1900;3:641–72. 32. Parkes Weber F. Angioma formation in connection with hypertrophy of limbs and hemi-hypertrophy. Br J Dermatol 1907;19:231–5.


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33. Adam JS, Cunliffe WJ. The Klippel-Trenaunay-Weber syndrome presenting with cutaneous bleeding. Acta Derm Venereol 1981;62:176–7. 34. Baskerville PA, Ackroyd JS, Thomas ML, et al. The Klippel-Trenaunay syndrome: clinical, radiological and haemodynamic features and management. Br J Surg 1985;72:232–6. 35. Phillips GN, Gordon DH, Mortin EC, et al. The Klippel-Trenaunay syndrome: clinical and radiological aspects. Radiology 1978;128:429–34. 36. Viljoen D, Saxe N, Peran J, et al. The cutaneous manifestations of the Klippel-Trenaunay-Weber syndrome. Clin Exp Dermatol 1987;12:12–17. 37. Toda K. A new type of phacomatosis pigmentovascularis (Ota). Jpn J Dermatol 1966;76:47–51. 38. Hasegawa Y, Yasuhara M. A variant of phakomatosis pigmentovascularis. Sin Res (Osaka) 1979;21:178–86. 39. Hasegawa Y, Yasuhara M. Phakomatosis pigmentovascularis type IVa. Arch Dermatol 1985;121:651–55. 40. Noriega Sanchez A, Markand ON, Herndon JH. Oculocutaneous melanosis associated with the SturgeWeber syndrome. Neurology 1972;22:256–62. 41. Furukawa T, Igata A, Toyokura Y, et al. Sturge-Weber and Klippel-Trenaunay syndrome with nevus de Ota and Ito. Arch Dermatol 1970;102:640–5. 42. Sigg C, Pelloni F. Oligosymptomatic form of Klippel-Trenaunay-Weber syndrome associated with giant nevus spilus. Arch Dermatol 1989;125:1284–5. 43. Guiglia MC, Prendiville JS. Multiple granular cell tumors associated with giant speckled lentiginous nevus and nevus flammeus in a child. J Am Acad Dermatol 1991;24:359–63. 44. Libow LF. Phakomatosis pigmentovascularis type IIIb. J Am Acad Dermatol 1993; 29:305–7. 45. Smoller BR, Rosen S. Port wine stains: a disease of altered neural modulation of blood vessels? Arch Dermatol 1986;122:177–9. 46. Kissel P, Dureux JB. Cobb syndrome. Cutaneo-meningospinal angiomatosis. In: Bruyn GW, Vinken PJ, eds. Handbook of Clinical Neurology. New York, North Holland Publishing, 1972:429–45. 47. Archer DB, Deutman A, Ernest JT, et al. Arteriovenous communications of the retina. Am J Ophthalmol 1973;75:224–91. 48. Ward JB, Kotz NNK. Combined phakomatoses: a case report of Sturge-Weber and Wyburn-Mason syndrome occurring in the same individual. Ann Ophthalmol 1983;15:1112–6. 49. Clark RD, Donnai D, Rogers J, Cooper J, Bardaitser M. Proteus syndrome: an expanded phenotype. Am J Med Genet 1987;27:99–117. 50. Samlaska CP, Levin SW, James WD, Benson PM, Walrer JC, Perlik PC. Proteus syndrome. Arch Dermatol 1989;125:1109–14. 51. Plotz SG, Abeck D, Plotz W, Ring J. Proteus syndrome with widespread portwine stain naevus. Br J Dermatol 1998;139:1060–3. 52. Freeman MVR, Williams DW, Schimke RN, et al. Roberts syndrome. Clin Genet 1974;5:1–16. 53. Ashinoff R, Geronemus RG. Thrombocytopenia-absent radii syndrome and lack of response to the pulsed dye laser. Arch Dermatol 1990;126:1520–1. 54. Horton WA, Wong V, Eldridge R. Von Hippel-Lindau disease. Clinical and pathological manifestations in nine families with 50 affected members. Arch Intern Med 1976;136:769–77. 55. Filippi G, McKusick VA. The Beckwith-Wiedmann syndrome (the exophthalmos-macroglossia-gigantism syndrome): report of two cases and review of the literature. Medicine 1970;49:279–98. 56. Rubinstein JH, Taybi H. Broad thumbs and toes and facial abnormalities. Am J Dis Child 1963;105:588–608. 57. Allen HB, Parlette HL. Coat’s disease: a condition that may mimic Sturge-Weber syndrome. Arch Dermatol 1973;108:413–5. 58. Hagiwara K, Khaskhely NM, Uezato H, Nonaka S. Mast cell “densities” in vascular proliferations: a preliminary study of pyogenic granuloma, portwine stain, cavernous hemangioma, cherry angioma, Kaposi’s sarcoma, and malignant hemangioendothelioma. J Dermatol 1999;26:577–86. 59. Klapman MH, Yao JF. Thickening and nodules in port-wine stains. J Am Acad Dermatol 2001;44:300–2. 60. Swerlick RA, Cooper PH. Pyogenic granuloma (lobular capillary hemangioma) within port-wine stains. J Am Acad Dermatol 1983;8:627–30. 61. Lee JB, Kim M, Lee SC, Won YH. Granuloma pyogenicum arising in an arteriovenous hemangioma associated with a port-wine stain. Br J Dermatol 2000;143:669–71. 62. Katta R, Bickle K, Hwang L. Pyogenic granuloma arising in port-wine stain during pregnancy. Br J Dermatol 2001;144:644–5. 63. Kim TH, Choi EH, Ahn SK, Lee SH. Vascular tumors arising in port-wine stains: two cases of pyogenic granuloma and a case of acquired tufted angioma. J Dermatol 1999;26:813–6.

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64. Burg G. Collision dermatosis: angiolymphoid hyperplasia with eosinophilia developing within a congenital port wine nevus. Dermatology 1993;187:293–5. 65. Sagi E, Aram H, Peled IJ. Basal cell carcinoma developing in a nevus flammeus. Cutis 1984;33:311–2. 66. Lo JS, Sgouros GN, Mohs FE, Snow SN. Basal cell carcinoma within a nevus flammeus. Report of a case. Int J Dermatol 1991;30:725–6. 67. Shah M, Lewis FM, Palmer IR. Three cases of multiple basal cell carcinoma arising in port-wine stains previously treated with thorium X. Br J Dermatol 1996;135:861–2. 68. Wharton SM, Cole RP. Basal cell carcinoma in port wine stains. Br J Plast Surg 2001;54:156–8. 69. Rosen S, Smoller BR. Port-wine stains: a new hypothesis. J Am Acad Dermatol 1987;17:164–6. 70. Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 1982;69:412–22. 71. Braverman IM, Ken-Yen A. Ultrastructure and three-dimensional reconstruction of several macular and papular telangectasias. J Invest Dermatol 1983;81:489–97. 72. Finley JL, Clark RAF, Colvin RB. Immunofluorescent staining with antibodies to factor VIII, fibronectin, and collagenous basement membrane protein in normal human skin and port-wine stains. Arch Dermatol 1982;118:971–5. 73. Neumann R, Leonhartsberger H, Knobler R, Hönigsmann H. Immunohistochemistry of port-wine stains and normal skin with endothelium-specific antibodies PAL-E, anti-ICAM-1, anti-ELAM-1, and antifactor VIIIrAg. Arch Dermatol 1994;130:879–83. 74. Ashinoff R, Geronemus RG. Flashlamp-pumped pulsed dye laser for port-wine stains in infancy: earlier versus later treatment. J Am Acad Dermatol 1991; 24:467–72. 75. Dover JS, Geronemus RG, Stern RS, O’Hare D, Arndt KA. Dye laser treatment of port-wine stains: comparison of the continuous-wave dye laser with a robotized scanning device and the pulsed dye laser. J Am Acad Dermatol 1995;32:237–40. 76. Garden JM, Polla LL, Tan OT. The treatment of port-wine stains by the pulsed dye laser. Arch Dermatol 1988;124:889–96. 77. Cliff S, Misch K. Treatment of mature port wine stains with the PhotoDerm VL. J Cutan Laser Ther 1999;1:101–4. 78. Scherer K, Lorenz S, Wimmershoff M, Landthaler M, Hohenleutner U. Both the flashlamp-pumped dye laser and the long-pulsed tunable dye laser can improve results in port-wine stain therapy. Br J Dermatol 2001;145:79–84. 79. Del Pozo J, Fonseca E. Port-wine stain nodules in the adult: report of 20 cases treated by CO2 laser vaporization. Dermatol Surg 2001;27:699–702. 80. Nguyen CM, Yohn JJ, Huff C, Weston WL, Morelli JG. Facial port wine stains in childhood: prediction of the rate of improvement as a function of the age of the patient, size and location of the port wine stain and the number of treatments with the pulsed dye (585 nm) laser. Br J Dermatol 1998;138:821–5. 81. Renfro L, Geronemus RG. Anatomical differences of port-wine stains in response to treatment with the pulsed dye laser. Arch Dermatol 1993;129:182–8. 82. Troilius A, Svendsen G, Ljunggren B. Ultrasond investigation of port wine stains. Acta Derm Venereol 2000;80:196–9. 83. Eubanks LE, McBurney EI. Videomicroscopy of port-wine stains. Correlation of location and depth of lesion. J Am Acad Dermatol 2001;44:948–51. 84. Seukeran DC, Collins P, Sheehan-Dare RA. Adverse reactions following pulsed tunable dye laser treatment of port wine stains in 701 patients. Br J Dermatol 1997;136:725–9. 85. Gaston DA, Clark DP. Facial hypertrophic scarring from pulsed dye laser. Dermatol Surg 1998;24:523–5. 86. Ozluer SM, Barlow RJ. Partial re-emergence of a port-wine stain following successful treatment with flashlamp-pumped dye laser. Clin Exp Dermatol 2001;26:37–9. 87. Michel S, Landthaler M, Hohenleutner U. Recurrence of port-wine stains after treatment with the flashlamp-pumped pulsed dye laser. Br J Dermatol 2000;143:1230–4.


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4. HYPERKERATOTIC VASCULAR STAINS Hyperkeratotic vascular stains are authentic malformations characterized by the presence of ectatic vessels involving both the dermis and the subcutaneous tissue. The affected vessels do not show endothelial proliferation. Although the term “angiokeratoma” has been generically applied to many of these lesions, it is preferable to restrict this designation to the acquired hyperkeratotic vascular lesions that result from ectasia of preexisting blood vessels of the papillary dermis. Another term frequently used to describe lesions that have superficial and deep involvement of the dermis is “verrucous hemangioma” (1–20). However, this denomination is a misnomer because these lesions are not true hemangiomas (neoplasms) but malformations. Another lesion frequently confused with hyperkeratotic vascular stain is the so-called digital verrucous fibroangioma (21). This lesion is a benign vascular neoplasm composed of capillary blood vessels and fibrous tissue on the fingers with a histopathologic pattern completely different from that of hyperkeratotic vascular stains. CLINICAL FEATURES Most of the lesions of hyperkeratotic vascular stains affect the lower limbs, and usually the involvement is unilateral; bilateral involvement was seen in only one case (9), in which the histopathologic features consisted of a vascular malformation but did not correspond exactly to those of hyperkeratotic vascular stain. Most hyperkeratotic vascular stain lesions are present either at birth or appear shortly after birth. They appear as flat reddish or bluish patches that enlarge slowly; with time, they may acquire a warty appearance (Fig. 11). Sometimes the lesions have a linear arrangement (5), and the presence of small satellite lesions is fairly common. The lesions sometimes bleed as a consequence of superficial trauma (7,13). Occasionally patients with large verrucous vascular malformation may develop Kasabach-Merritt syndrome (11). HISTOPATHOLOGIC FEATURES Histopathologically, hyperkeratotic vascular stains show prominent epidermal hyperplasia with compact hyperkeratosis, papillomatosis, and irregular acanthosis. Within the superficial and deep dermis and sometimes extending into the subcutaneous fat, there are dilated capillaries and venules (8,12) (Fig. 12). Intravascular thrombosis with subsequent organization of the thrombi, resulting in intravascular papillary endothelial hyperplasia, has been described in some lesions (17). In some cases, the degree of epidermal hyperkeratosis of these lesions closely resembles that of verruca vulgaris, but immunoperoxidase and ultrastructural investigations have failed to reveal the presence of human papillomavirus in these lesions (12). The endothelial cells lining the ectatic vessels show immunostaining with CD34 and factor VIII-related antigen, and muscle-specific actin demonstrates a ring of pericytes around each individual blood vessels irrespective of their size (12). TREATMENT Because of the deep vascular component, a wide excision performed at an early age appears to be the best treatment for hyperkeratotic vascular stains (1,12,14–18). Small and superficial lesions can be treated by electrosurgery and with argon laser (22), but because of the depth of extension of most of these lesions (they usually extend into subcutaneous tissue), this superficial therapeutic approach is usually followed by recurrence.

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Fig. 11. Clinical features of a hyperkeratotic vascular malformation involving the posterior aspect of the upper left extremity. (A) The lesions show an angiomatous appearance. (B) Close-up view demonstrates hyperkeratosis covering some areas of the lesion.

References 1. Imperial R, Helwig EB. Verrucous hemangioma. A clinicopathologic study of 21 cases. Arch Dermatol 1967;96:247–53. 2. Loria PR, Derbes VJ, Krafchuk JD. Keratotic hemangiomas. Arch Dermatol 1958; 77:216–9. 3. De Dulanto F, Moreno MA, Martínez FC, Naranjo R. Angioqueratomas negros solitarios y hemangiomas verrugosos. Problemas y transcendencia del diagnóstico diferencial con los melanomas malignos. Actas Dermosifiliogr 1975;66:376–86. 4. De Souza EM, Turini MA, Oliveira TC. Hemangioma verrucoso (acrohemangioma verrucoso neviforme). Med Cut Ibero Lat Am 1981;9:217–20. 5. Klein JA, Barr RJ. Verrucous hemangioma. Pediatr Dermatol 1985;2:191–3. 6. Colonna SM, Rotoli M, Aloi FG. Angioma verrucoso. A proposito di due casi clinici. G Ital Dermatol Venereol 1987;122:309–12. 7. Puig L, Llistosella E, Moreno A, de Moragas JM. Verrucous hemangioma. J Dermatol Surg Oncol 1987;13:1089–92. 8. Rossi A, Bozzi M, Barra E. Verrucous hemangioma and angiokeratoma circumscriptum: clinical and histologic differential characteristics. J Dermatol Surg Oncol 1989;15:88–91. 9. Cruces MJ, de la Torre C. Multiple eruptive verrucous hemangiomas: a variant of multiple hemangiomatosis. Dermatologica 1985;171:106–11. 10. Niechajev IA, Sternby NH. Cutaneous keratotic hemangioma. Scand J Plast Reconstr Surg 1983;17:153–4. 11. Gupta PK, Sharma DC, Kumwat DC, Bomb BS. Kasabach-Merritt syndrome with verrucous hemangiomata. J Assoc Physicians India 1993;41:612.


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Fig. 12. Histopathologic features of a hyperkeratotic vascular malformation (also erroneously named “verrucous hemangioma”). (A) Scanning power shows verrucous epidermis and numerous vascular channels involving both superficial and deep dermis. (B) Higher magnification shows dilated vascular structures with variable thickness of their walls.

12. Chan JKC, Tsang WYW, Calonje E, Fletcher CDM. Verrucous hemangioma. A distinct but neglected variant of cutaneous hemangioma. Int J Surg Pathol 1995; 2:171–6. 13. Wong DS, Hunt SJ, Inserra DW, Abell E. Unilateral keratotic vascular lesion on the leg. Verrucous hemangioma. Arch Dermatol 1996;132:705. 14. Kawaguchi H, Kawaguchi T, Ishii N, Nakajima H, Ichiyama S. Verrucous hemangioma. Acta Derm Venereol 1997;77:405–6. 15. Tan YY, Seah CS, Tan PH. Verrucous hemangioma—a case report. Ann Acad Med Singapore 1998;27:255–7. 16. Jucglá A, Servitge O, Moreno A. Hemangioma verrucoso: estudio clinicopatológico de 10 casos [Abstract]. Actas Dermosifiliogr 1998;89:405–6. 17. Wentscher U, Happle R. Linear verrucous hemangioma. J Am Acad Dermatol 2000;42:516–8.

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18. Calduch L, Ortega C, Navarro V, Martínez E, Molina I, Jorda E. Verrucous hemangioma: report of two cases and review of the literature. Pediatr Dermatol 2000;17:213–7. 19. Mankani MH, Dufresne CR. Verrucous malformations: their presentation and management. Ann Plast Surg 2000;45:31–6. 20. Rupani AB, Madiwale CV, Vaideeswar P. Images in pathology: verrucous haemangioma. J Postgrad Med 2000;46:132–3. 21. Kohda H, Narisawa Y. Digital verrucous fibroangioma: a new variant of verrucous hemangioma. Acta Derm Venereol 1992;72:303–4. 22. Newton JH, McGibbon DH. The treatment of multiple angiokeratomata with argon laser. Clin Exp Dermatol 1987;12:23–5.


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5. VENOUS MALFORMATIONS In the past, venous malformations have been inaccurately known as “cavernous” hemangiomas. They are malformations, not neoplasms, and consist of slow-flowing, hemodynamically inactive vascular malformations that are present at birth and slowly worsen throughout the lifetime of the patient. Some of these lesions are on a continuum of localized venous malformations, which include blue capillary spongy blebs, “cavernous” lesions (in which the venous lacunae are connected to the venous circulation by capillaries), localized saccular anomalies (connected by veins to the venous circulation), and diffuse venous ectasias. Many of the apparently localized and superficial venous lesions tend to coexist with venous ectasias and deep vein anomalies. CLINICAL FEATURES Clinically, venous malformations appear as grouped blue or purple nodules (Figs. 13 and 14). In addition, neighboring veins may be enlarged. The area of involved skin usually shows normal temperature, although hyperhidrosis over the lesion is not uncommon, and there are often recurrent episodes of thrombophlebitis in or around the lesions. Calcified phleboliths are sometimes present in the lesions. The vast majority of solitary venous malformations are asymptomatic. In some cases they may become symptomatic as a result of the gradual enlargement of the lesions, which leads to increased pressure on the surrounding structures, especially nerves. Most venous malformations are sporadic, but there are also familial forms with mendelian inheritance; the gene is found on a locus localized on chromosome 9p (1). The clinical differential diagnosis includes large facial

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Fig. 13. Clinical features of a venous malformation involving the left side of the face of an adult woman. The lesion was present at birth.


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Fig. 14. Venous malformation involving the glans penis.

lesions of multiple plaque-like glomangiomas. These lesions show a blue color and can mimic the appearance of venous malformations, but they consist of multiple plaque-like glomangiomas with glomus cells surrounding the vascular channels (2). In contrast with true venous malformations, these facial plaque-like glomangiomas are poorly compressible, and genetically glomangiomas have recently been mapped on chromosome 1p21-22 (3). Venous malformations may be differentiated from hemangiomas by MRI. This technique is also helpful in determining the extension and infiltration of the malformation into adjacent tissues (4). Venous malformations may be associated with other anomalies. In contrast to hemangiomas, in which bony alterations occur in only 1% of cases, in vascular malformations 34% of patients have skeletal abnormalities (5). Hypoplasia and demineralization are characteristic of venous malformations of the extremities, whereas hypertrophy and distortion of the underlying bones are frequently seen in association with lymphatic malformations. Destructive and intraosseus changes are seen in the arterial or high-flow malformations (5). Extensive venous malformations of the upper or lower limb are characterized by diffuse involvement of the skin, subcutaneous tissue, muscle, and joints, which could lead to a localized intravascular coagulopathy that in the long run may have systemic effects with episodes of thrombosis or bleeding (6). Cutaneous venous malformations may also be a component of several complex syndromes. The blue rubber bleb nevus syndrome is a rare disorder originally described by Bean in 1958 (7). It consists of the association of multiple venous malformations in the skin and gastrointestinal tract. It can be inherited as an autosomal dominant trait, (8–10), although sporadic cases are more common. Soft rubbery nodules that are either blue or purple characterize the cutaneous lesions that are present at birth or appear during early childhood (Fig. 15). They are easily compressed, leaving the skin with a wrinkled surface upon cessation of the pressure. The cutaneous lesions are usually small and few in number; they can involve any area of the skin and mucous membranes of the mouth and genital area. Pain at the site of the lesion during the night has been described as a characteristic clinical symptom of this syndrome, although this feature may be absent in some patients. Hyperhidrosis may be seen on the surface of the skin lesions of patients affected by this syndrome, probably as a consequence of the local increase in temperature. Similar lesions to those of the skin may be present in the gastrointestinal tract, particularly in the


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Fig. 15. Cutaneous lesions of a boy with blue rubber bleb nevus syndrome. (A) There is a large venous malformation involving the left arm and smaller lesions scattered on the back. (B) Close up view of the lesion of the arm.

small bowel. Bleeding of the gastrointestinal lesions may lead to melena and anemia (11–13). It appears that there is no correlation between the number of cutaneous lesions and gastrointestinal lesions. In addition to the venous malformations of the skin, the mucous membranes, and the small bowel, lesions of blue rubber bleb nevus may also involve lung, heart, spleen, liver, urinary tract, brain, meninges, muscle, and joints (14–17). In some cases blue rubber bleb nevus syndrome is associated with Maffucci’s syndrome (18). Maffucci’s syndrome is another entity associated with venous malformations. It was originally described in 1891 and consists of a diffuse asymmetric enchondromatosis associated with multiple vascular malformations and various musculoskeletal deformities (19). It is a nonhereditary disorder and is generally regarded as the result of a mesodermal dysplasia. Patients with this syndrome are usually normal at birth, but multiple cutaneous and mucosal venous malformations appear in early infancy. Clinically, patients affected with this disease present with soft bluish subcutaneous nodules or protruding tumors in the soft tissue that do not involute. Simultaneously with the appearance of the cutaneous and soft tissue lesions, the patient develops hard nodules on multiple sites, including the long bones, hands, fingers, and feet. In severe cases, there are grotesque deformities of the hands and feet as a consequence of the multiple lesions (20) (Fig. 16).

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Fig. 16. (A) Dramatic upper limb deformity with large venous malformations involving the entire right upper extremity in a patient with Maffuci’s syndrome. (B) Close-up view of the lesions of the forearm.

The bone lesions are radiologically translucent and histopathologically consist of enchondromas. Of prime importance is the risk of malignant transformation of the enchondromas into chondrosarcomas, which occur in approximately 15% of the patients (21). Other cutaneous lesions described in patients with Maffucci’s syndrome include caféau-lait macules (22) and cystic lymphatic malformations (23). In addition to chondro-


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Fig. 17. (A) Venous malformation involving the entire lower right extremity in a patient with Klippel-Trenaunay syndrome. (B) Close-up view of the lesions involving the leg.

sarcoma, other malignant neoplasms have been reported in patients with Maffucci’s syndrome including fibrosarcoma (24), angiosarcoma (21), lymphangiosarcoma (25), osteosarcoma (22), malignant ovarian neoplasms (21), gliomas (21), adenocarcinoma of pancreas (24), and other multiple primary malignancies (21,22,24).The differential diagnosis of Maffucci’s syndrome has to be established with Ollier disease’s, in which there is dyschondroplasia without cutaneous vascular lesions (25). Venous malformations are also prominent in and are the main cutaneous manifestation of Klippel-Trenaunay syndrome. The dominant features of this syndrome include cutaneous capillary and venous malformations, congenital varicose veins, and hypertrophy of the involved limb (26) (Fig. 17). When, in addition to the aforementioned features, there is an arteriovenous fistula, the disorder is termed Parkes Weber syndrome (27). Klippel-Trenaunay syndrome affects males and females equally. Most commonly the malformation is unilateral, and the lower limb is the most commonly involved area. However, in rare cases the upper and lower limbs or the upper limb alone are affected; bilateral involvement has also been reported, and occasionally the disease affects the entire trunk. Regardless of the location, the malformation is present at birth, although it may not be clinically apparent at that time. Almost all reported cases are sporadic, although a few cases with a familial tendency have been described (28). Cutaneous lesions of Klippel-Trenaunay syndrome may consist of one or several port wine stains over the affected limb (26,27,29–35), but in addition, it is common to find

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large venous ectatic vessels and vesicular lymphatic lesions (36). These vascular malformations do not blanch significantly under pressure. In many cases varicosities are associated with the venous malformations. The varicosities start from a plexus of veins of the dorsum and lateral side of the foot and extend up a variable distance on the leg. Incompetent perforating veins and deep vein abnormalities, which consist of occlusion by a fibrous band, agenesis, or atresia, are also seen in these patients. The involved limb is usually hypertrophic, and this enlargement is mostly caused by muscle hypertrophy, thickened skin, excessive subcutaneous fat, the bulkiness of the abnormal vascular tissue, and sometimes concomitant lymphedema. Usually there is little increase in bone diameter in the hypertrophic limb. Patients with this syndrome occasionally complain of profuse sweating of the skin involved in the vascular malformation, and the affected areas may also feel warmer than normal. Other systems and organs may show abnormalities in patients with Klippel-Trenaunay syndrome (37); these anomalies usually occur within or adjacent to the area involved by the vascular malformation. They can affect any mesodermal and ectodermal structure, suggesting a more generalized dysplasia of the structures subject to a common teratogenic influence. Venous thrombosis is common in patients with Klippel-Trenaunay syndrome, and therefore these patients have frequent episodes of pulmonary embolism. The simultaneous occurrence of Klippel-Trenaunay syndrome and Fabry’s disease has been described in the same patient (38). Gorham’s syndrome (39) is a rare, nonfamilial disorder, that affects both sexes equally. It is characterized by the development of venous and lymphatic malformations in the skin, mediastinum, and bones (40,41). The osseous lesions cause osteolysis with fibrosis and may lead to the disappearance of entire bones. Roentgenograms demonstrate lytic lesions on the involved bones with little or no sclerosis. Cutaneous lesions usually develop in the areas adjacent to the involved bones and may be accompanied by local muscular atrophy. Usually, Gorham’s syndrome is self-limited (42), although an aggressive variant with a poor prognosis has been described (43). Bannayan-Zonana syndrome is a rare autosomal dominant disorder characterized by benign macrocephaly, lipomas, and cutaneous and visceral vascular malformations (44). The cutaneous lesions are usually deeply situated, bluish nodules (45–47), but lesions resembling superficial lymphatic malformations and angiokeratomas have also been described (48). Visceral involvement may be massive, resulting in life-threatening obstruction of vital organs, including the gastrointestinal tract and the central nervous system (48). The macrocephaly is not associated with hydrocephalus, and most patients remain intellectually normal, although mental retardation has been described in some cases (49). Riley-Smith syndrome is an autosomal dominant condition described in five members of the same family. It consists of macrocephaly without hydrocephalus, pseudopapilledema, and cutaneous capillary, venous, and lymphatic malformations (50). Cutaneous vascular lesions may be present either at birth or appear shortly thereafter. The abdominal wall, hands, feet, and thighs are the most commonly involved sites. The patients remain intellectually and neurologically normal. This syndrome is similar to the Bannayan-Zonana syndrome, except that patients with the Riley-Smith syndrome have pseudopapilledema and do not have systemic lipomatous lesions. In 1980, Ruvalcaba et al. (51) described two male patients thought to be affected with hamartomatous intestinal polyps and spotted pigmentation of the penis. Based on the description of these two patients and other cases from the literature (52,53); Cohen (54)


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suggested that the condition described by Ruvalcaba et al. (51) was a distinctive entity and coined the name Ruvalcaba-Myhre syndrome. Since then, additional cases have been reported under the name of Ruvalcaba-Myhre-Smith syndrome (55–57). In 1988, Dvir et al. (58) described a boy with macrocephaly, pseudopapilledema, lipoangiomatosis, and spotted pigmentation of the penis. Because the patient had clinical features of three syndromes (Bannayan-Zonana, Riley-Smith, and Ruvalcaba-Myhre-Smith), the authors proposed that the three conditions were simply different expressions of a single heredofamilial disorder. Cohen (59) supported this unifying theory and suggested that the “new” syndrome be named after the first authors of the three original reports, i.e., Bannayan-Riley-Ruvalcaba syndrome. Subsequently, additional reports of BannayanRiley-Ruvalcaba syndrome have appeared in the literature, lending further support to the unifying concept (60–62). Recently, patients with Bannayan-Riley-Ruvalcaba syndrome and facial tricholemmomas have been described, raising the possibility that BannayanRiley-Ruvalcaba syndrome and Cowden disease may represent different alleles at the same genetic locus or mutations of two genes in a common pathway (62). Other rare miscellaneous syndromes that may show cutaneous venous malformations include zosteriform venous malformations grouped in a unilateral dermatomal distribution (63,64); hereditary neurocutaneous vascular malformations syndrome (65), which is transmitted as an autosomal dominant trait and it is characterized by the presence of multiple cutaneous vascular malformations associated with intracranial arteriovenous malformations; venous malformations on the face and anterior trunk associated with sternal cleft and atrophic scar on the median abdominal raphe (66); retroauricular hemangiomatous branchial clefts associated with several facial and neurosensorial anomalies (67); sacral vascular malformations associated with renal, genital, osseous, and neurologic malformations (68); cutaneous vascular malformations associated with vascular anomalies of the retina and optic nerve (69); and several members of a family affected by venous malformations involving the mouth, skin, and soft tissues, inherited as an autosomal dominant trait and with no other associated anomalies (70). HISTOPATHOLOGIC FEATURES Histopathologically, venous malformations generally consist of ectatic blood vessels of irregular size and shape involving the deep dermis and subcutaneous fat (Fig. 18). Some of the involved blood vessels show thin walls, whereas others exhibit a thick layer of smooth muscle in their walls. Thrombosis and phleboliths are common, and areas of extravasated erythrocytes, deposits of hemosiderin, and extravascular calcifications are also frequent findings. Some of the cutaneous lesions of the aforementioned complex syndromes associated with venous malformations may show specific histopathologic features. Large blue facial lesions with the clinical appearance of venous malformations showing glomus cells surrounding the vascular structures are better interpreted as glomangiomas (2). In some patients with blue rubber bleb nevus, the cutaneous lesions may also show multiple glomangiomas (18,71–73). The gastrointestinal lesions of patients with blue rubber bleb nevus show similar histopathologic features to those of the cutaneous lesions. The case described as “blue rubber bleb nevus with vascular lesions suggesting a link to the OslerRendu-Weber syndrome” (74) is better interpreted as an example of blue rubber bleb nevus with telangiectatic cutaneous lesions but not related to the Osler-Rendu-Weber syndrome.

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Fig. 18. Histopathologic features of a venous malformation. (A) Scanning power view showing dilated vascular spaces in both superficial and deep dermis. The deeper component shows congestive blood vessels. (B) Higher magnification of the deeper component shows congestive dilated blood vessels. (C) Still higher magnification shows thin-walled blood vessels and hemosiderin deposition on adjacent dermis.

Histopathologically, the cutaneous lesions of Maffucci’s syndrome consist of large, blood-filled vascular channels lined with flat endothelial cells. The walls of the vascular spaces vary from thin, delicate, irregularly outlined walls to thick, fibrous, and smooth


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muscle-containing walls. Several cases of spindle cell hemangiomas in patients with Maffuci’s syndrome have been described (75–83). Spindle cell hemangioma consists of well-circumscribed but not encapsulated nodules that combine features of hemangioma and Kaposi’s sarcoma. Dilated blood vessels appear as thin veins that sometimes contain organized thrombi and phleboliths within their lumina. Interspersed among the dilated blood vessels there are fascicles of spindle cells mimicking Kaposi’s sarcoma, but within the fascicles there are also round cells with prominent vacuolated cytoplasm. Sometimes vacuolization of the cytoplasm of round cells is so marked that they may be mistaken for entrapped fatty tissue. Histopathologically, the cutaneous vascular lesions of patients with Bannayan-RileyRuvalcaba syndrome show different combinations of capillary, venous, and lymphatic malformations (51). TREATMENT Small venous cutaneous malformations may be treated by simple surgical excision, but in those cases in which the vascular malformation is associated with other internal abnormalities, a careful follow-up of the patient is required. It is usually impossible to remove large extensive venous malformations surgically without causing severe scarring and other complications. In those cases involving the limbs, elastic stocking use is mandatory and should be started early in infancy. Management of patients with blue rubber bleb nevus depends on the individual case. Resection of the involved bowel segment may be required in patients with recurrent melena and anemia. Painful cutaneous lesions of glomangiomas may be treated by excision, cryosurgery, or laser therapy (13). Patients with Maffucci’s syndrome require careful follow-up, with radiologic and histopathologic examination of any rapidly enlarging bone lesion for early diagnosis of chondrosarcoma. Surgical excision of the cutaneous vascular malformations may be indicated to improve the appearance of the patient. Spindle cell hemangioma is a benign lesion and excision is curative. Superficial venous varicosities of patients with the Klippel-Trenaunay syndrome may be treated by ligation and stripping to relieve the local pain, but recurrences are common (33). Before excision of the superficial veins, a radiographic exploration should be performed to demonstrate that there is neither absence nor hypoplasia of the deep venous system. Patients with Klippel-Trenaunay syndrome should receive antithrombotic prophylasis prior to any surgery owing to the high risk of thromboembolic complications (33). No effective treatment has been found for patients with Gorham’s syndrome, although radiotherapy may be helpful for bone pain. Patients with Bannayan-Riley-Ruvalcaba syndrome should be explored for detection of neurologic or any other associated internal malformation, and genetic counseling should be given to the family.

References 1. Boon LM, Mulliken JB, Vikkula M, et al. Assignment of a locus for dominantly inherited venous malformations to chromosome 9p. Hum Mol Genet 1994;3:1583–7. 2. Mounayer C, Wassef M, Enjolras O, Boukobza M, Mulliken JB. Facial “glomangiomas”: large venous malformations with glomus cells. J Am Acad Dermatol 2001;45:239–45. 3. Boon LM, Brouillard P, Irrthum A, et al. A gene for inherited cutaneous venous anomalies (“glomangiomas”) localizes to chromosome 1p21-22. Am J Hum Genet 1999;65:125–33. 4. Kern S, Niemeyer C, Darge K, Merz C, Laubenberger J, Uhl M. Differential of vascular birthmarks by MR imaging. An investigation of hemangiomas, venous and lymphatic malformations. Acta Radiol 2000;41:453–7.

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5. Boyd JB, Mulliken JB, Kaban LB, Upton J III, Murray JE. Skeletal changes associated with vascular malformations. Plast Reconstr Surg 1984;74:789–97. 6. Enjolras O, Ciabrini D, Mazoyer E, Laurian C, Herbreteau D. Extensive pure venous malformations in the upper or lower limb: a review of 27 cases. J Am Acad Dermatol 1997;36:219–25. 7. Bean WB. Blue rubber bleb nevi of the skin and gastrointestinal tract. In: Vascular Spiders and Related Lesions of the Skin. Springfield, MO, CC Thomas, 1958:178–85. 8. Berlyne GM, Berlyne N. Anaemia due to “blue rubber bleb” naevus disease. Lancet 1960;2:1275–7. 9. Munkvad M. Blue rubber bleb nevus syndrome. Dermatologica 1983;167;307–9. 10. Walshe MM, Evans CD, Warin RP. Blue rubber bleb naevus. BMJ 1966; 2:931–2. 11. Baker AL, Kahn PC, Binder SC, et al. Gastrointestinal bleeding due to blue rubber bleb nevus syndrome. Gastroenterology 1971;61:530–4. 12. McCauley RGK, Leonidas JC, Bartoshesky LE. Blue rubber bleb nevus syndrome. Radiology 1979;133:375–7. 13. Olsen TG, Milroy SK, Goldman L, et al. Laser surgery for blue rubber bleb nevus. Arch Dermatol 1979;115:81–2. 14. Baiocco FA, Gamoletti R, Negri A, et al. Blue rubber bleb nevus syndrome: a case with predominant ENT localization. J Laryngol Otol 1984;98:317–9. 15. McCarthy JC, Goldberg MJ, Zimbler S. Orthopedic dysfunction in the blue rubber bleb nevus syndrome. J Bone Joint Surg 1982;64A:280–3. 16. Rennie JG, Shortland JR, Mahood JM, et al. Periodic exophthalmos associated with blue rubber bleb nevus syndrome. Br J Ophthalmol 1982;66:594–8. 17. Satya-Murti S, Navada S, Eames F. Central nervous system involvement in blue rubber bleb nevus syndrome. Arch Neurol 1986;43:1184–6. 18. Sakurane HF, Sugai T, Saito T. The association of blue rubber bleb nevus and Maffucci’s syndrome. Arch Dermatol 1967;95:28–36. 19. Maffucci A. Di un caso di encondroma ed angioma multiple: contribuzione alla genesi embrionale dei tumori. Mov Med Chir Nap 1891;13:399–412. 20. Tilsley DA, Burden PW. A case of Maffucci’s syndrome. Br J Dermatol 1981;105:331–6. 21. Lewis RJ, Ketcham AS. Maffucci’s syndrome: functional and neoplastic significance: case report and review of the literature. J Bone Joint Surg 1973; 55A:1465–79. 22. Bean WB. Dyschondroplasia and hemangiomata (Maffucci’s syndrome). II. Arch Intern Med 1958;102:544–50. 23. Suringa DWR, Ackerman AB. Cutaneous lymphangiomas with dyschondroplasia (Maffucci’s syndrome): a unique variant of an unusual syndrome. Arch Dermatol 1970;191:472–4. 24. Johnson JL, Webster Jr, Sippy HI. Maffucci’s syndrome (dyschondroplasia with hemangiomas). Am J Med 1960;28:864–6. 25. Nardell SG. Ollier’s disease: dyschondroplasia. BMJ 1950;2:555–7. 26. Klippel M, Trenaunay P. Du noevus variqueux osteohypertophique. Arch Gen Med 1900;3:641–72. 27. Parkes Weber F. Angioma formation in connection with hypertrophy of limbs and hemi-hypertrophy. Br J Dermatol 1907;19:231–5. 28. Lindenauer SM. Klippel-Trenaunay syndrome. Ann Surg 1965;162:303–10. 29. Cosman B. Clinical experience in the laser therapy of port-wine stains. Lasers Surg Med 1980;1:133–52. 30. Harper PS. Sturge-Weber syndrome with Klippel-Tranaunay syndrome. Birth Defects 1971;7:314. 31. Schofield D, Zaatari GS, Gay BB. Klippel-Trenaunay and Sturge-Weber syndromes with renal hemangioma and double inferior vena cava. J Urol 1986;136:442–5. 32. Adam JS, Cunliffe WJ. The Klippel-Trenaunay-Weber syndrome presenting with cutaneous bleeding. Acta Derm Venereol 1981;62:176–7. 33. Baskerville PA, Ackroyd JS, Thomas ML, et al. The Klippel-Trenaunay syndrome: clinical, radiological and haemodynamic features and management. Br J Surg 1985;72:232–6. 34. Phillips GN, Gordon DH, Mortin EC, et al. The Klippel-Trenaunay syndrome: clinical and radiological aspects. Radiology 1978;128:429–34. 35. Viljoen D, Saxe N, Peran J, et al. The cutaneous manifestations of the Klippel-Trenaunay-Weber syndrome. Clin Exp Dermatol 1987;12:12–7. 36. Servelle M. Klippel-Trenaunay syndrome. Ann Surg 1985;201:365–76. 37. Young AE, Ackroyd J, Baskerville P. Combined vascular malformations. In: Mulliken JB, Young AE, eds. Vascular Birthmarks. Hemangiomas and malformations. Philadelphia, WB Saunders, 1988:247–74. 38. Germain DP. Co-occurrence and contribution of Fabry disease and Klippel-Trenaunay-Weber syndrome to a patient with atypical skin lesions. Clin Genet 2001;60:63–7.


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39. Gorham LW, Wright AW, Shultz HH, et al. Disappearing bones: a rare form of massive osteolysis. Am J Med 1954;17:674–82. 40. Frost JF, Caplan RM. Cutaneous haemangiomas and disappearing bones with a review of cutaneovisceral haemangiomatosis. Arch Dermatol 1965;92:501–8. 41. Gellis SS, Feingold M. Hemangiomas with osteolysis (Gorham’s disease: vanishing bone disease). Am J Dis Child 1978;132:715–6. 42. Mendez AA, Keret D, Robertson W, et al. Massive osteolysis of the femur (Gorham’s disease): a case report and review of the literature. J Pediatr Orthop 1989;9:604–8. 43. Haferkamp O. Uber das Syndrome generalisierte maligne Haemangiomatosis mit Osteolysis. Krebforsch 1962;64:418–26. 44. Bannayan GA. Lipomatosis, angiomatosis, and macrocephalia: a previously undescribed congenital syndrome. Arch Pathol 1971;92:1–5. 45. Higginbottom MC, Schultz P. The Bannayan syndrome: an autosomal dominant disorder consisting of macrocephaly, lipomas, hemangiomas, and risk for intracranial tumors. Pediatrics 1982;69:632–4. 46. Miles HR, Zonana J, MacFarland J. Macrocephaly with hamartomas: Bannayan-Zonana syndrome. Am J Med Genet 1984;19:225–34. 47. Zonana J, Rimoin DL, Davis DC. Macrocephaly with multiple lipomas and hemangiomas. J Pediatr 1976;89:600–3. 48. Klein JA, Barr RJ. Bannayan-Zonana syndrome associated with lymphangiomatous lesions. Pediatr Dermatol 1990;7:48–53. 49. Saul RA, Stevenson RE, Bley R. Mental retardation in the Bannayan syndrome. Pediatrics 1982;69:642–4. 50. Riley HD, Smith WR. Macrocephaly, pseudopapilloedema and multiple hemangiomata: a previously undescribed heredofamilial syndrome. Pediatrics 1960;26:293–300. 51. Ruvalcaba RHA, Myhre S, Smith DW. Sotos syndrome with intestinal polyposis and pigmentary changes of the genitalia. Clin Genet 1980;18:413–6. 52. Halal F. Male to male transmission of cerebral gigantism. Am J Med Genet 1982;12:411–9. 53. Halal F. Cerebral gigantism, intestinal polyposis, and pigmentary spotting of the genitalia. Am J Med Genet 1983;15:161. 54. Cohen MM Jr. The large-for-gestational-age (LGA) infant in dysmorphic perspective. In: Willey AM, Carter TP, Kelly S, Porter IH, eds. Clinical Genetics: Problems in Diagnosis and Counseling. New York, Academic,1982:153–69. 55. DiLiberti JH, Weleber RG, Budden S. Ruvalcaba-Myhre-Smith syndrome: a case with probable autosomal-dominant inheritance and additional manifestations. Am J Med Genet 1983;15:491–5. 56. DiLiberti JH, D’Agostino AN, Ruvalcaba RHA, Schimschock KR. A new lipid storage myopathy observed in individuals with the Ruvalcaba-Myhre-Smith syndrome. Am J Med Genet 1984;18:163–7. 57. Gretzula JC, Hevia O, Schachner LS, et al. Ruvalcaba-Myhre-Smith syndrome. Pediatr Dermatol 1988;5:28–32. 58. Dvir M, Beer S, Aladjem M. Heredofamilial syndrome of mesodermal hamartomas, macrocephaly, and pseudopapilledema. Pediatrics 1988;81:287–90. 59. Cohen MM Jr. Bannayan-Riley-Ruvalcaba syndrome: renaming three formerly recognized syndromes as one etiologic entity. Am J Med Genet 1990;35:291. 60. Gorlin RS, Cohen MM, Leven LS. Bannayan-Riley-Ruvalcaba syndrome (Bannayan-Zonana syndrome, Ruvalcaba-Myhre, Riley-Smith syndrome). In: Gorlin RS, Cohen MM, Leven LS, eds. Syndromes of the Head and Neck. New York, Oxford University Press, 1990:336–8. 61. Gorlin RJ, Cohen MM Jr, Condon LM, Burke BA. Bannayan-Riley-Ruvalcaba syndrome. Am J Med Genet 1992;44:307–14. 62. Fargnoli MC, Orlow SJ, Semel-Concepcion J, Bolognia JL. Clinicopathologic findings in the BannayanRiley-Ruvalcaba syndrome. Arch Dermatol 1996;132:1214–8. 63. Steinway DM, Fretzin DF. Acquired zosteriform cavernous hemangiomas: brief clinical observations. Arch Dermatol 1977;113:848–9. 64. Wilkin JK. Unilateral dermatomal cavernous hemangiomatosis. Dermatologica 1980;161:347–54. 65. Hurst J, Baraitser M. Hereditary neurocutaneous angiomatous malformations: autosomal dominant transmission in two families. Clin Genet 1988;33:44–8. 66. Hersh JH, Waterfill D, Rutledge J, et al. Sternal malformation/vascular dysplasia association. Am J Hum Genet 1985;21:177–84. 67. Hall BD, deLorimier A, Foster LH. Brief clinical report: a new syndrome of hemangiomatous branchial clefts, lip pseudoclefts and unusual facial appearance. Am J Med Genet 1983;14:135–8.

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68. Goldberg NS, Hebert AA, Esterly NB. Sacral hemangiomas and multiple congenital anomalies. Arch Dermatol 1986;122:684–7. 69. Goldberg RE, Pheasant TR, Shields JA. Cavernous hemangioma of the retina: a four generation pedigree with neurocutaneous manifestations and an example of bilateral retinal involvement. Arch Ophthalmol 1979;97:2321–4. 70. Pasyk KA, Argenta LC, Erikson RP. Familial vascular malformations: report of 25 members of one family. Clin Genet 1984;24:221–7. 71. Rice J, Fisher D. Blue rubber-bleb nevus syndrome. Generalized cavernous hemangiomas or venous hamartoma with medulloblastoma of the cerebellum. Case report and review of the literature. Arch Dermatol 1962;86:503–11. 72. Fretzin DF, Potter B. Blue rubber bleb nevus. Arch Intern Med 1965;116:924–9. 73. Hagood MF, Gathright JB Jr. Hemangiomatosis of the skin and gastrointestinal tract: report of a case. Dis Colon Rectum 1975;18:141–6. 74. Rosenblum WI, Nakoneczna I, Konerding HS, Nochlin D, Ghatak NR. Multiple vascular malformation in the “blue rubber bleb naevus” syndrome. A case with aneurysm of vein of Galen and vascular lesions suggesting a link to the Weber-Osler-Rendu syndrome. Histopathology 1978;2:301–11. 75. Weiss SW, Enzinger FM. Spindle cell hemangioendothelioma: a low-grade angiosarcoma resembling a cavernous hemangioma and Kaposi’s sarcoma. Am J Surg Pathol 1986;10:521–30. 76. Scott GA, Rosai J. Spindle cell hemangioendothelioma. Report of seven additional cases of a recently described vascular neoplasm. Am J Dermatopathol 1988;10:281–8. 77. Lawson JP, Scott G. Case report 602. Skeletal Radiol 1990;19:158–62. 78. Murakami J, Sarker AB, Teramoto N, Horie Y, Tagucmi K, Akagi T. Spindle cell hemangioendothelioma: a report of two cases. Acta Pathol Jpn 1993;43:529–34. 79. Pellegrini AE, Drake RD, Qualman SJ. Spindle cell hemangioendothelioma: a neoplasm associated with Maffucci’s syndrome. J Cutan Pathol 1995;22:176–6. 80. Fukunaga M, Ushigome S, Nikaido T, Ishikawa E, Nakamori K. Spindle cell hemangioendothelioma: an immunohistochemical and flow cytometric study of six cases. Pathol Int 1995;45:589–95. 81. Hisaoka M, Koumo H, Aoki T, Hashimoto H. DNA flow cytometric and immunohistochemical analysis of proliferative activity in spindle cell haemangioendothelioma. Histopathology 1995;27:451–6. 82. Fanburg JC, Meis-Kindblom JM, Rosenberg AE. Multiple enchondromas associated with spindle cell hemangioendotheliomas: an overlooked variant of Maffucci’s syndrome. Am J Surg Pathol 1995;19:1029–38. 83. Niechajev IA, Hansson LI. Maffucci’s syndrome. Scand J Plast Reconst Surg 1982;16:215–9.


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6. SUPERFICIAL CUTANEOUS LYMPHATIC MALFORMATIONS CLINICAL FEATURES Superficial cutaneous lymphatic malformations are localized lesions of the cutaneous, subcutaneous, or submucosal lymphatic vessels. These lesions have been referred to in the past as “lymphangiomas,” which is an inaccurate term. The lesions are usually present at birth or appear shortly thereafter; they can be located in any anatomic site but have a predilection for the axillary folds, shoulders, neck, proximal parts of the extremities (Figs. 19 and 20), and tongue (1–3). Superficial lymphatic malformations (inaccurately termed “lymphangioma circunscriptum”) are the commonest variant of cutaneous lymphatic malformation. Clinically, the lesion consists of numerous small vesicle-like lesions, often with a verrucous surface, grouped in a plaque. Sometimes, owing to the presence of blood vessels, purplish areas can be seen within the lesion. The stereotypical superficial lymphatic malformation is accompanied by dilated lymphatic cisterns located in the subcutaneous fat, which results in swelling of the tissue

Fig. 19. Superficial lymphatic malformation involving the posterior aspect of the thigh.

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Fig. 20. Superficial lymphatic malformation involving the anterior aspect of the right forearm. Numerous small vesicle-like lesions grouped in a plaque.


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beneath the superficial vesicles (4,5). It is believed that the superficial vesicles are saccular dilations of the superficial lymphatics secondary to the increased pressure from the pulsating cisterns localized underneath (1). MRI is useful in demonstrating the size and invasiveness of these lesions (6). In rare instances, superficial lymphatic malformations extend deeply and can be associated with visceral lymphatic malformations involving the mediastinum (7) or the bladder wall (8). Superficial lymphatic malformations may be associated with Becker’s nevus (9), and have been described in patients with Maffucci’s (10) and Cobb’s syndrome (11). HISTOPATHOLOGIC FEATURES Histopathologically, superficial lymphatic malformations are situated immediately beneath the epidermis, but they may also involve areas of the reticular dermis (Fig. 21). They consist of dilated lymph vessels, lined by a discontinuous layer of flat endothelial cells (2,12). Sometimes the lymphatic vessels form clusters in the papillary dermis, which gives a papillated or verrucous appearance to the skin surface. Superficial lymphatic malformations are sometimes difficult to distinguish histopathologically from angiokeratomas, especially when the lesions have been traumatized, which results in the presence of erythrocytes within the ectatic lumina. The usual immunohistochemical markers for endothelial cells, such as factor VIII-related antigen, Ulex europaeus, and CD31 do not differentiate between blood and lymphatic vessels (13). In these cases, the use of the new endothelial marker vascular endothelial growth factor receptor-3 can be helpful. This marker is expressed by the lymphatic endothelium but not by the endothelial cells lining blood vessels or neoplasms with blood endothelial differentiation (14,15). Ultrastructural studies of superficial lymphatic malformations demonstrate the presence of a fragmented basal lamina and anchoring filaments (13). TREATMENT Most of the time, superficial cutaneous lymphatic malformations do not require treatment, and it is probably best to leave them untreated. Surgical removal of the superficial vesicles tends to be disappointing, especially if there is a deep component, since removal is followed by local recurrence. Some lesions have been effectively treated with radiotherapy (16), but there is a report of a lymphangiosarcoma arising in a preexisting superficial lymphatic malformation following X-ray therapy (17), and radiotherapy is not currently recommended. The best cosmetic results have been achieved with argon laser (18) or carbon dioxide laser (19–21). Combined therapy, which consists of carbon dioxide laser vaporization for the superficial component of the lesion and transcutaneous sclerotherapy with doxycycline for the deeper cisterns, has also been applied with good results (22).

References 1. Whimster J. The pathology of lymphangioma circumscriptum. Br J Dermatol 1976;94:473–86. 2. Flanagan BP, Helwig EB. Cutaneous lymphangioma. Arch Dermatol 1977;113:24–30. 3. Peachey RDG, Lim CC, Whimster JW. Lymphangioma of the skin: a review of 65 cases. Br J Dermatol 1970;83:519–27. 4. Russell B, Pridie RB. Lymphangioma circumscriptum with involvement of deep lymphatics. Br J Dermatol 1967;79:300. 5. Palmer LC, Strauch WG, Welton WA. Lymphangioma circumscriptum: a case with deep lymphatic involvement. Arch Dermatol 1978;114:394–6. 6. McAlvany JP, Jorizzo JL, Zanolli D, et al. Magnetic resonance imaging in the evaluation of lymphangioma circumscriptum. Arch Dermatol 1993;129:194–7.


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Fig. 21. Histopathologic features of a superficial cutaneous lymphatic malformation. (A) Lowpower view shows dilated vascular structures at all levels of the dermis. (B) Higher magnification shows dilated thin-walled vessels with a lymphatic appearance lined by a single discontinuous layer of endothelial cells. 7. Mordehai J, Kurzbart E, Shinhar D, Sagi A, Finaly R, Nares AJ. Lymphangioma circumscriptum. Pediatr Surg Int 1998;13:208–10. 8. Irvine AD, Sweeney L, Corbett JR. Lymphangioma circumscriptum associated with paravesical cystic retroperitoneal lymphangioma. Br J Dermatol 1996;134:1135–7. 9. Oyler RM, Davis DA, Woosley JT. Lymphangioma associated with Becker’s nevus: a report of coincident hamartomas in a child. Pediatr Dermatol 1997;14:376–9. 10. Suringa DW, Ackerman AB. Cutaneous lymphangiomas with dyschondroplasia (Maffucci’s syndrome). A unique variant of an unusual syndrome. Arch Dermatol 1970;101:472–4. 11. Shim JH, Lee DW, Cho BK. A case of Cobb syndrome associated with lymphangioma circumscriptum. Dermatology 1996;193:45–7. 12. Bauer BS, Kernahan DA, Hugo NE. Lymphangioma circumscriptum: a clinicopathologic review. Ann Plast Surg 1981;7:318–26.

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13. Pearson JM, McWilliam LJ. A light microscopical, immunohistochemical, and ultrastructural comparison of hemangioma and lymphangioma. Ultrastruct Pathol 1990;14:497–504. 14. Lymboussaki A, Partanen TA, Olofsson B, et al. Expression of the vascular endothelial growth factor C receptor VEGFR-3 in lymphatic endothelium of the skin and in vascular tumors. Am J Pathol 1998;153:395–403. 15. Folpe AL, Veikkola T, Valtola R, Weiss SW. Vascular endothelial growth factor receptor-3 (VEGFR-3): a marker of vascular tumors with presumed lymphatic differentiation, including Kaposi’s sarcoma, kaposiform and Dabska-type hemangioendotheliomas, and a subset of angiosarcomas. Mod Pathol 2000;13:180–5. 16. O’Cathail S, Rostom AY, Johnson ML. Successful control of lymphangioma circumscriptum by superficial X-rays. Br J Dermatol 1985;113:611–5. 17. King DT, Duffy DM, Hirose FM, Gurevitch AW. Lymphangiosarcoma arising from lymphangioma circumscriptum. Arch Dermatol 1979;115:969–72. 18. Landthaler M, Haina D, Waidelich W, Braun-Falco O. Behandlung zirkumskripter lymphangiome mit dem Argonlaser. Hautarzt 1982;33:266–70. 19. Bailin PL, Kantor GR, Wheeland RG. Carbon dioxide laser vaporization of lymphangioma circumscriptum. J Am Acad Dermatol 1986;14:257–62. 20. Eliezri YD, Sklar JA. Lymphangioma circumscriptum: review and evaluation of carbon dioxide laser vaporization. J Dermatol Surg Oncol 1988;14:357–64. 21. Haas AF, Narurkar VA. Recalcitrant breast lymphangioma circumscriptum treated by ultrapulse carbon dioxide laser. Dermatol Surg 1998;24:893–5. 22. Wimmershoff MB, Schreyer AG, Glaessl A, et al. Mixed capillary/lymphatic malformation with coexisting port-wine stain: treatment utilizing 3D MRI and CT-guided sclerotherapy. Dermatol Surg 2000;26:584–7.


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7. CYSTIC LYMPHATIC MALFORMATIONS (CYSTIC HYGROMAS) Cystic lymphatic malformations are contrasted with superficial lymphatic malformations, in being deeply located and consisting of subcutaneous painless nodules covered by normal skin (1–3). The lesion may be painful, especially when the tumor is subject to pressure or is bumped. Cases of cystic lymphatic malformations have been described in patients with Maffucci’s syndrome (4). CLINICAL FEATURES Cystic hygroma is a variant of subcutaneous lymphatic malformation whose shape and character are determined by its anatomic location. These lesions most commonly occur in the neck, axilla (Fig. 22), and groin, areas where the presence of loose connective tissue allows for the expansion of the lymphatic channels (5). Cystic hygroma is usually present at birth or appears in early infancy. They present as a large fluid-filled cystic mass that may be diagnosed by transillumination. Cystic hygromas of the posterior triangle of the neck have been associated with hydrops fetalis, Turner’s syndrome (45X0 karyotype), congenital malformations, several varieties of chromosomal aneuploidy, and fetal death (6). Since aneuploidic conditions may recur in subsequent pregnancies, cytogenetic analysis of fetuses born with cystic hygroma is mandatory. HISTOPATHOLOGIC FEATURES Histopathologically, cystic lymphatic malformations are made up of irregular, dilated, and interconnected lymphatic vessels localized in the subcutaneous fat (Fig. 23). Some of these vessels contain bundles of smooth muscle in their walls (7). Nodular collections of lymphocytes, sometimes with germinal centers, may be present within the surrounding connective tissue. Cystic hygroma lesions consist of large uni- or multilocular cystic cavities surrounded by a loose connective tissue stroma. In some areas the stroma may be denser and even sclerotic as a result of compression by the lymphatic cysts.

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Fig. 22. Clinical appearance of a lymphatic malformation on the axilla, with a deep component of subcutaneous nodules and a superficial component of an angiomatous appearance.


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Fig. 23. Histopathologic features of a deep lymphatic malformation. (A) Scanning power view shows dilated vascular structures involving the deeper dermis and subcutaneous tissue. (B) Higher magnification demonstrates that the vascular structures have thin walls and eosinophilic homogeneous material in the lumina, which is lymph.

TREATMENT The small superficial lymphatic malformations may be adequately managed by surgery (8,9), cryotherapy (10), radiotherapy (11), and laser phototherapy (12). Larger and subcutaneous lesions of cystic hygroma show a high rate of recurrence after surgery, and unless the lesion causes severe signs or symptoms, such lesions are best left untreated. Complete regression of cystic hygromas has also been reported with intracystic injections of sclerosing substances with no sequels (13).

References 1. Flanagan BP, Helwig EB. Cutaneous lymphangioma. Arch Dermatol 1977;113:24–30. 2. Peachey RDG, Lim CC, Whimster JW. Lymphangioma of the skin: a review of 65 cases. Br J Dermatol 1970;83:519–27. 3. Harkins GA, Sabiston DC. Lymphangioma in infancy and childhood. Surgery 1960;47:811–22. 4. Suringa DWR, Ackerman AB. Cutaneous lymphangiomas with dyschondroplasia (Maffucci’s syndrome): a unique variant of an unusual syndrome. Arch Dermatol 1970;191:472–4. 5. Bill AH, Sumner DS. A unified concept of lymphangioma and cystic hygroma. Surg Gynecol Obstet 1965;120:79–86. 6. Chervenak FA, Isaacson G, Blakemore KJ, et al. Fetal cystic hygroma cause and natural history. N Engl J Med 1983;309:822–5. 7. Russell B, Pridie RB. Lymphangioma circumscriptum with involvement of deep lymphatics. Br J Dermatol 1967;79:300.


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8. Edwards JM, Peachey RDG, Kinmonth JB. Lymphangiography and surgery in lymphangioma of the skin. Br J Surg 1972;59:36–41. 9. Jordan PR, Sanderson KV, Wilson JSP. Surgical treatment of lymphangioma circumscriptum: a case report. Br J Plast Surg 1977;30:306–7. 10. Nanda Kumar H, Bhaskar Roa C, Kukreja R. Management of lymphangioma by cryoprobe: a case report. J Indian Dent Assoc 1982;54:25–7. 11. O’Cathial S, Rostom AY, Johnson ML. Successful control of lymphangioma circumscriptum by superficial x-rays. Br J Dermatol 1985;113:611–5. 12. Bailin PL, Kantor GR, Wheeland RG. Carbon dioxide laser vaporization of lymphangioma circumscriptum. J Am Acad Dermatol 1986;14:257–62. 13. Ogita S, Tsuto T, Tokiwa K, Takahashi T. Intracystic injection of OK-432. A new sclerosing therapy for cystic hygroma in children. Br J Surg 1987;74:690–1.

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8. LYMPHANGIOMATOSIS This is a rare disorder characterized by the presence of abnormal lymphatic channels in a diffuse or multifocal arrangement. These lesions usually involve both soft tissue and parenchymal organs. Most cases of lymphangiomatosis with both bone and visceral involvement are associated with a poor prognosis and high mortality rate (1). In contrast, patients with involvement solely of soft tissues and bones of the extremities, show slow clinical progression and have a good prognosis (2), although there is a report of a patient with disseminated lymphangiomatosis of the skin and bone who developed disseminated intravascular coagulation (3). The lesions appear either at birth or in early infancy. CLINICAL FEATURES Clinically, the lesions are fluctuant and sponge-like, with progressive swelling of the affected limb (Fig. 24). The overlying skin is usually normal, but it may become secondarily involved and develop a verrucous surface, areas of pigmentation, or vesicle formation. Examples of lymphangiomatosis have been described in patients with kaposiform hemangioendothelioma (4,5). HISTOPATHOLOGIC FEATURES Histopathologically, the lesions of lymphangiomatosis consist of lobules of interconnecting widely dilated lymphatic channels lined by a single, attenuated layer of endothe-

Fig. 24. Lymphangiomatosis resulting in deformity of the right leg of a young woman.


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Fig. 25. Histopathologic features of lymphangiomatosis involving the skin. (A) Scanning magnification shows irregular dilated vascular structures replacing the subcutaneous fat. (B) Higher magnification demonstrates that these vascular structures have walls of variable thickness containing an eosinophilic homgeneous material within the vascular lumina.

lial cells. The lesions can involve dermis, subcutaneous fat (Fig. 25), and sometimes underlying soft tissue and bone. When the lesions are present in the dermis, the lymphatic spaces dissect between collagen bundles and around preexisting dermal and subcutaneous structures, resembling a well-differentiated angiosarcoma (1,2). However, the endothelial cells lack atypia. The lumina of the lymphatic channels either appear empty or

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contain a proteinaceous eosinophilic material. In one case, there was prominent intra- and extravascular extramedullary hematopoiesis with large amounts of hemosiderin in the stroma despite the absence of any apparent intra- or extravascular erythrocytes (2). Immunohistochemical studies have demonstrated that the endothelial cells of the abnormal lymphatic channels stain positive for factor VIII-related antigen and Ulex europaeus I lectin, whereas positivity for CD31 and CD34 is variable from case to case (1,2). These immunohistochemical results confirm the fact that there are no reliable endothelial markers to distinguish between blood vessel and lymphatic endothelium. TREATMENT Treatment of patients with lymphagiomatosis of the limbs consists of surgical reduction with extensive excision of the skin, subcutaneous tissue, and fascia. Although significant clinical improvement is achieved, in some cases the swelling recurrs slowly over succeeding years (2).

References 1. Romani P, Shah A. Lymphangiomatosis and immunohistochemical analysis of four cases. Am J Surg Pathol 1993;17:329–35 2. Singh Gomez C, Calonje E, Ferrar DW, Browse NL, Fletcher CDM. Lymphangiomatosis of the limbs. Clinicopathologic analysis of a series with a good prognosis. Am J Surg Pathol 1995;19:125–33. 3. Lauret P, Monconduit M, Sonlica J. Lymphangiomatose cutanée et osseuse disseminée avec coagulation intra-vasculaire disseminée. Ann Dermatol Venereol 1978;105:759–63. 4. Zukerberg LR, Nickoloff BJ, Weiss SW. Kaposiform hemangioendothelioma of infancy and childhood. An aggressive neoplasm associated with Kasabach-Merritt syndrome and lymphangiomatosis. Am J Surg Pathol 1993;17:321–8. 5. Mentzel T, Mazzoleni G, Dei Tos AP, Fletcher CD. Kaposiform hemangioendothelioma in adults. Clinicopathologic and immunohistochemical analysis of three cases. Am J Clin Pathol 1997;108:450–5.


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Chapter 6 / Cutaneous Lesions with Dilations

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Cutaneous Lesions Characterized by Dilation of Preexisting Vessels CONTENTS SPIDER ANGIOMA (NEVUS ARANEUS) CAPILLARY ANEURYSM-VENOUS LAKE TELANGIECTASES ANGIOKERATOMAS LYMPHANGIECTASES

1. SPIDER ANGIOMA (NEVUS ARANEUS) CLINICAL FEATURES Spider angioma, also known as nevus araneus, is present in approximately 10–15% of adults and young children. The face, neck, upper trunk, and arms are the regions most frequently involved; however, in children, the hands and fingers are the preferred sites (1). A higher incidence of spider angiomas is seen in pregnant women and in patients with chronic liver disease (2–4). In pregnant women, the lesions usually disappear at the end of the pregnancy without therapy. In patients with liver disease, the development of these lesions has been attributed to alcohol, increased plasma levels of estrogen, vascular dilation, and neovascularization. To date only an increased plasma level of substance P has been demonstrated in patients in whom cirrhosis and spider angiomas coexist (5). Clinically, spider angiomas are characterized by a central, slightly elevated, red punctum or “body” of the spider, from which the blood vessels or “legs” of the spider radiate (Fig. 1). Occasionally, pulsation can be observed in the central punctum. HISTOPATHOLOGIC FEATURES Histopathologically, spider angiomas consist of a central ascending arteriole, which ends in a thin-walled ampulla just beneath the epidermis. From this ampulla, thin, delicate arterial branches radiate peripherally into the papillary dermis. Occasionally glomus cells can be identified in the wall of the central arteriole (6,7). In one case a giant solitary spider angioma had an overlying pyogenic granuloma (8). TREATMENT Electrodesiccation of the central punctum is usually followed by extinction of the spider angioma, but recurrences are fairly common. Laser therapy has also been used for treatment of spider angiomas in children (9).

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Fig. 1. (A) Clinical appearance of a spider angioma on the dorsum of the nose. (B) Close-up view of the lesion.

References 1. Wenzl JE, Burgert EO Jr. The spider nevus in infancy and childhood. Pediatrics 1964;33:227–32. 2. Whiting DA, Kallmeyer JC, Simson IW. Widespread arterial spiders in a case of latent hepatitis with resolution after therapy. Br J Dermatol 1970;82:32–6. 3. Witte CL, Hicks T, Renert W, Witte MH, Butler C. Vascular spider: a cutaneous manifestation of hyperdynamic blood flow in hepatic cirrhosis. South Med J 1975;68:246–8.


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4. Li CP, Lee FY, Hwang SJ, et al. Spider angiomas in patients with liver cirrhosis: role of alcoholism and impaired liver function. Scand J Gastroenterol 1999;34:520–3. 5. Li CP, Lee FY, Hwang SJ, et al. Role of substance P in the pathogenesis of spider angiomas in patients with nonalcoholic liver cirrhosis. Am J Gastroenterol 1999;94:502–7. 6. Bean WB. The arterial spider and similar lesions of the skin and mucous membranes. Circulation 1953;8:117–29. 7. Schuhmachers-Brendler R. Beitrag zur morphologishen Pathologie und therapie des Naevus-araneus Rezidivs. Dermatol Wochenschro 1959;139:167–74. 8. Okada N. Solitary giant spider angioma with an overlying pyogenic granuloma. J Am Acad Dermatol 1987;16:1053–4. 9. Tan OT, Gilchrest BA. Laser therapy for selected cutaneous vascular lesions in the pediatric population: a review. Pediatrics 1988;82:652–62.

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2. CAPILLARY ANEURYSM-VENOUS LAKE Capillary aneurysm and venous lake probably represent two different stages in the development of the same lesion. Capillary aneurysm was first described by Epstein et al. (1) in 1956. These authors emphasized the clinical similarity of this lesion with malignant melanomas. In the same year, Bean and Walsh (2) described venous lakes. CLINICAL FEATURES Capillary aneurysm is classically referred to as a suddenly growing dark papule on the face of elderly patients (3) (Fig. 2), although similar lesions may also occur in the oral mucosa (4). Most of the time these are solitary lesions, but multiple lesions have been reported (5). The majority of capillary aneurysms are asymptomatic, but occasionally the affected patients may complain of tenderness or pruritus. Venous lakes are small, dark blue, dome-shaped, soft papules occurring in elderly patients on skin exposed to sun. The lesions are easily compressed. The face, ears, and lips (Fig. 3) are the most common sites (2). HISTOPATHOLOGIC FEATURES Capillary aneurysm presents with a widely dilated thin-walled venule just beneath the epidermis, lined by a single layer of endothelial cells. No smooth muscle or elastic tissue is discernible in the vessel wall. The presence of a thrombus within the lumen is charac-

Fig. 2. Multiple capillary aneurysms on the face of an adult man.


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Fig. 3. Venous lake on the lower lip of an elderly woman.

Fig. 4. Histopathologic features of a capillary aneurysm. (A) A dilated and congestive blood vessel involving the entire dermis. (B) Higher magnification shows the thin vessel wall. Probably venous lake and capillary aneurysm are just two different stages of evolution of the same lesion.

teristic of this lesion (3,6) (Fig. 4). In many cases the thrombus undergoes recanalization and shows areas of papillary endothelial hyperplasia. Most of the vessels involved in capillary aneurysms are venules, so the term capillary is a misnomer. Venous lakes are histopathologically identical to “capillary” aneurysms, except for the absence of a luminal thrombus (2) (Fig. 5). In most cases there is severe sun damage in the adjacent dermis. Venous lakes result from faulty elastic tissue in elderly patients (7). As mentioned earlier, capillary aneurysms and venous lakes are the same lesion. Capillary aneurysms represent

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Fig. 5. Histopathologic features of a venous lake. (A) Low-power shows a dilated vascular channel in the upper dermis. (B) Higher magnification shows a thin-walled vascular structure.

the early lesion in which there is superficial vein thrombosis with subsequent dilation. When the thrombus lyses, usually before excision, the lesion acquires the appearance of a venous lake. In short, “capillary” aneurysm and venous lake are two different stages in the development of superficial venous varicosities. TREATMENT Sclerosing injections and compression therapy have been ineffective (5). Simple excision is curative of lesions of capillary aneurysm-venous lake. Careful cryotherapy, electrocautery, or therapy with argon laser also give good results (8).

References 1. Epstein E, Novy FG, Skahen RA, Krause ME. Melanoma-simulating nodules due to capillary aneurysms. Cali Med 1956;85:22–5. 2. Bean WB, Walsh JR. Venous lakes. Arch Dermatol 1956;74:459–63. 3. Epstein E, Novy FJ Jr, Allington HV. Capillary aneurysms of the skin. Arch Dermatol 1965;91:335–41. 4. Weathers DR, Fine RH. Thrombosed varyx of oral cavity. Arch Dermatol 1971; 104:427–30. 5. Pokorny M, Vanek J, Pavcova S. Multiple kapillare aneurysmen. Hautartz 1987;38:541–3. 6. Weiner HA. Capillary aneurysms of the skin. Arch Dermatol 1966;96:670–3. 7. Alcalay J, Sandbank M. The ultrastructure of cutaneous venous lakes. Int J Dermatol 1987;26:645–6. 8. Neumann RA, Knobler RM. Venous lakes (Bean-Walsh) of the lips—treatment experience with the argon laser and 18 months follow-up. Clin Exp Dermatol 1990;15:115–8.


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3. TELANGIECTASES Telangiectasia denotes a condition characterized by the permanent dilation of vessels. It involves mainly venules, although capillaries and arterioles of the subpapillary plexus are occasionally affected. Telangiectases can be seen in numerous and disparate conditions such as collagen vascular diseases, cutaneous mastocytosis and chronic graft-versus-host disease, but they also appear as a consequence of trauma, sun damage, or radiodermatitis. These types of telangiectasis are secondary and are not covered in this chapter. Entities in which telangiectasias are the primary pathologic process are reviewed in this section. These include the following diseases: unilateral nevoid telangiectasia, generalized essential telangiectasia, hereditary hemorrhagic telangiectasia, hereditary benign telangiectasia, ataxia-telangiectasia, and cutaneous collagenous vasculopathy.

Unilateral Nevoid Telangiectasia This term was proposed by Selmanowitz (1) in 1970 to describe a condition characterized by a proliferation of telangiectases in a dermatomal distribution. Other designations for this disease include “linear telangiectasia” (2), “unilateral spider nevi” (3,4), and unilateral telangiectasia (5) (Fig. 6). The lesions are distributed unilaterally and consist of numerous, thread-like telangiectases. The dermatomes most frequently involved are those that follow the inervation of the trigeminal, the third, and the fourth cervical nerves (2). The lesions may be either congenital or acquired. The congenital form is more

Fig. 6. Clinical features of unilateral nevoid telangiectasia. (A) Lesions with linear arrangement along the upper left extremity of a young woman. (B) Close-up view showing telangiectases on the dorsum of the hand.

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Fig. 7. Generalized essential telangiectasia involving the anterior right thigh of an adult woman.

common in males (2,6–8), whereas the acquired form predominantly affects females. Acquired lesions in females usually occur during the times in which there is a physiologic rise in the levels of estrogen, such as puberty (9,10) and pregnancy (11,12 ). In males it is usually associated with pathologic elevations of estrogen, such as in chronic liver disease (13,14). Unilateral nevoid telangiectasia has been described in patients with hepatitis C (15) and carcinoid syndrome with liver metastasis (16). The telangiectases usually resolve when the levels of estrogen decrease; lesions that developed during pregnancy show complete regression during the postpartum period (12). In addition to the skin, telangiectases may also involve the oral and gastric mucosa (17). There is a report of a patient who developed lesions of polymorphic light eruption occurring solely on the area of the skin involved by unilateral nevoid telangiectasia (18).

Generalized Essential Telangiectasia Originally described by Becker in 1926 (19), this disease is more common in women than in men. The lesions first appear on the lower extremities (Fig. 7), and progress, gradually and symmetrically, to involve the trunk and arms (20). In some instances, the conjunctiva and oral mucosa are also involved (21), but bleeding diathesis is uncommon (22), and there is no association with internal disease. The report of Graves’ disease in a patient with generalized essential telangiectasia is probably a coincidence (23). Most of the cases occur sporadically, but there are a few examples of generalized essential telangiectasia with familial incidence (24).


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Fig. 8. Osler-Rendu-Weber disease. (A) Telangiectases on the palms. (B) Telangiectases on the lateral margin of the tongue.

Hereditary Hemorrhagic Telangiectasia This disease, also known as Osler-Rendu-Weber disease, is an autosomal dominant condition characterized by telangiectases involving the skin, mucous membranes, and internal organs. The disease usually begins in childhood and manifests with frequent nosebleeds, but the characteristic telangiectases on the skin, and oral and nasal mucosa do not appear until adolescence. In a few families affected by hereditary hemorrhagic telangiectasia, mutations have been shown in the gene encoding for the transforming growth factor receptor endoglin. However, there is genetic heterogeneity, suggesting involvement of the coding genes for other transforming growth factor receptors (25). Telangiectases in internal organs are especially frequent in the gastrointestinal tract (26– 30), and melena is a common complication (26). Other sites that may bleed include the liver (27), lungs (28), and brain (29). When the brain is involved, it may show arteriovenous fistulas or other vascular malformations, and neurologic symptoms secondary to embolic abscesses may develop as complications in patients with hereditary hemorrhagic telangiectasia (31). Cutaneous lesions consist of telangiectases involving the palms and the soles, especially the area under the nails. In addition, the mucosa of the lips, tongue, palate, and nasal mucous membrane may also show prominent lesions (Fig. 8).

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Hereditary benign telangiectasia is the term applied to designate the benign counterpart of hereditary telangiectasia. It is transmitted as an autosomal dominant trait and is characterized by widespread cutaneous telangiectases. The mucous membranes are unaffected, and neither bleeding, nor diathesis nor systemic vascular lesions are seen (32–34). Louis-Bar syndrome or ataxia-telangiectasia is another hereditary disorder characterized by the presence of telangiectases. It is an autosomal recessive inherited disorder. Telangiectases of this syndrome affect children and involve the face, neck, limbs, and conjunctiva (35). Some of these patients develop progressive cerebellar ataxia, and there is also a profound dysfunction of the immune system with an increased risk for the development of lymphomas and leukemias. Cutaneous collagenous vasculopathy is a recently described entity characterized by asymptomatic generalized cutaneous telangiectases without either mucosal or nail involvement. There is no family history and no clinical evidence of systemic disease or bleeding diathesis. Although the etiology is unknown, it is presumably caused by a genetic defect that alters the production of collagen, which in turn leads to an alteration in the cutaneous microvasculature (36). HISTOPATHOLOGIC FEATURES Histopathologically, telangiectases are characterized by the presence of dilated blood vessels, mostly capillaries in the superficial dermis (Fig. 9). Uhlin and McCarty (37) described an increase in the number of estrogen and progesterone receptors in the walls of the dilated capillaries in lesions of unilateral nevoid telangiectasia compared with normal skin. Other authors have not been able to corroborate these findings (15,16,38,39). Ultrastructurally, the dilated vessels of unilateral nevoid telangiectasia show characteristics of venules (40). In lesions of generalized essential telangiectasia, McGrae and Winkelmann demonstrated the absence of alkaline phosphatase activity in the vessel walls, which indicates that the ectasia occurs in the venous portion of the capillary loops (20). The absence of estrogen and progesterone receptors in the involved vessels of generalized essential telangiectasia suggests that hormones do not play a role in the development of this disorder (41). It has been suggested that focal intravascular coagulation induced by bacteria could have a role in the pathogenesis of progressive ascending telangiectasia (42). Ultrastructurally, the telangiectatic vessels of generalized essential telangiectasia show features of the postcapillary venules of the upper horizontal plexus. These have thickened walls, produced by the peripheral deposition of basement membrane material admixed with reticulin fibers (43). Dilated thin-walled vessels, adjacent to overlying epidermis or the epithelium of the affected mucous membrane, characterize the telangiectases in patients with Osler-RenduWeber disease. One layer of flattened endothelial cells lines these vessels. In many cases there is the presence of a lymphocytic infiltrate around the dilated vessels, even in early lesions (44) . Ultrastructurally, these vessels show absence of pericytes, and they resemble postcapillary venules (30,44). In addition, there are gaps between endothelial cells, a result of the loss of normal connections between the endothelial cell processes. The perivascular connective tissue is also defective. There are increased amounts of amorphous and fine filamentous material in addition to abnormally large collagen fibrils with an irregular banding pattern (30). The defective perivascular tissue is held respon-


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Fig. 9. Histopathologic features of telangiectases. (A) Scanning magnification shows skin with almost normal appearance. (B) Higher magnification, however, demonstrates dilated and congestive blood capillaries at the dermal papillae.

sible for the breakdown of the function of the adjacent endothelial cells, resulting in hemorrhage. Under a conventional microscope, the lesions of cutaneous collagenous vasculopathy show dilation of the small vessels of the superficial plexus with thickened walls produced by deposits of a hyaline perivascular material, that has the same tinctorial properties of the collagen. Thus, the deposits are positive for periodic acid-Schiff (PAS)- and colloidal iron stains; immunohistochemically, they stain with collagen type IV, fibronectin, and laminin, but they are actin-negative. Ultrastructurally, the vessels demonstrate features of postcapillary venules with increased amounts of collagen deposition around the basal lamina. In addition to the regular bands of collagen, there are abnormal fibers showing widely spaced bands of 100–150-nm periodicity (Luse bodies). There are a few pericytes without intracytoplasmic filaments, and a few veil or fibroblastic cells are seen embedded within the collagen (36). TREATMENT In most cases, treatment of the telangectasias is directed to control the anemia with iron replacement. Cutaneous telangiectases of unilateral nevoid telangiectasia, generalized essential telangiectasia, hereditary hemorrhagic telangiectasia, hereditary benign telangiectasia,

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ataxia-telangiectasia, and cutaneous collagenous vasculopathy may be sealed by laser therapy (45–52). Injections of sclerosing substances are helpful, but they may leave unsatisfactory cosmetic results. In severe cases of Osler-Rendu-Weber disease, in which nasal bleeding may cause severe anemia, replacing the nasal mucosa with split graft may be required; however, this procedure has serious hazards.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.

24.

25.


Selmanowitz VJ. Unilateral nevoid telangiectasia. Ann Intern Med 1970;73:87–90. Aram H, Salomon LM. Linear telangiectasia. Acta Derm Venereol 1970;50:302–4. Cunliffe WJ, Dodman B, Butterworth MJ. Unilateral spider naevi. Br J Dermatol 1972;87:51–2. Trueb RM, Burg G. Unilaterale “naevoide” Spidernaevi. Vasa 1993;22:82–5. Koopmanns-van Dorp B. Unilaterale telangiectasieen in de zwangerschap. Ned Tijdschr Geneeskd 1972;116:691–2. Wilkin JK. Unilateral dermatomal superficial telangiectasia. Dermatologica 1978;157:33–41. Person JR, Ossi MJ, Mundra R, et al. Unilateral nevoid telangiectasia. Arch Dermatol 1979;115:1034. Jucas JJ, Rietschel RL, Lewis CW. Unilateral nevoid telangiectasia. Arch Dermatol 1979;115:359–60. Wagner RF Jr, Grande DJ, Bhawan J, et al. Unilateral dermatomal superficial telangectasia overlapping Becker’s melanosis. Int J Dermatol 1989;28:595–6. Colver GB, Shrank AB, Ryan TJ. Unilateral dermatomal superficial telangiectasia. Clin Exp Dermatol 1985;10:455–8. Woollons A, Darley CR. Unilateral naevoid telangiectasia syndrome in pregnancy. Clin Exp Dermatol 1996;21:459–60. Grupper C, Bermejo D, Bouyx P, Belperron P, Verret JL, Schnitzler L. Telangiectasies stellaries naevoides unilaterales acquises ou congenitales. A propos de 5 cas. Ann Dermatol Venereol 1978;105:691–7. Wilkin JK, Smith JG Jr, Cullison DA. Unilateral dermatomal superficial telangiectasia: nine new cases and a review of unilateral dermatomal superficial telangiectasia. J Am Acad Dermatol 1983;8:468–77. Capron JP, Kantor G, Dupas JL, Degott C, Locquet MC. Unilateral nevoid telangiectasia and chronic liver disease. Report of a case and review of the literature. Am J Gastroenterol 1981;76:47–51. Hynes LR, Shenefelt PD. Unilateral nevoid telangiectasia: occurrence in two patients with hepatitis C. J Am Acad Dermatol 1997;36:819–22. Beacham BE, Kurgansky D. Unilateral naevoid telangiectasia syndrome associated with metastatic carcinoid tumor. Br J Dermatol 1991;124:86–8. Anderton RL, Smith JG Jr. Unilateral nevoid telangiectasia with gastric involvement. Arch Dermatol 1975;111:617–21. Creamer D, Clement M, McGregor JM, Hawk JL. Polymorphic light eruption occurring solely on an area of naevoid telangiectasia. Clin Exp Dermatol 1999;24:202–3. Becker SW. Generalized telangiectasia: clinical study with special consideration of the etiology and pathology. Arch Dermatol 1926;14:387–426. McGrae JD Jr, Winkelmann RK. Generalized essential telangiectasia: report of a clinical and histochemical study of 13 patients with acquired cutaneous lesions. JAMA 1963;185:909–13. Gentele H, Lodin A. Telangiectasia essentialis generalisata of unknown origin. Acta Derm Venereol 1957;37:465–70. Checketts SR, Burton PS, Bjorkman DJ, Kadunce DP. Generalized essential telangiectasia in the presence of gastrointestinal bleeding. J Am Acad Dermatol 1997;37:321–5. Buckley R, Smith KJ, Skelton HG. Generalized essential telangiectasia in a patient with Graves’ disease: should the spectrum of autoimmune diseases associated with generalized telangiectasia be expanded? Cutis 2000;65:175-7. Bourlond A, Minet A, Marcoux C, Frankart M, de Selys R. Angiomatose familiale micronodulaire generalisée (telangiectases essentielles generalisées). Observations cliniques, etude ultrastructurale. Ann Dermatol Venereol 1988;115:909–17. Haitjema T, Westermann CJ, Overtoom TT, et al. Hereditary hemorrhagic telangiectasia (Osler-WeberRendu disease): new insights in pathogenesis, complications, and treatment. Arch Intern Med 1996;156:714–9.

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26. Smith CR Jr, Bartholomew LG, Cain JG. Hereditary hemorrhagic telangiectasia and gastrointestinal hemorrhage. Gastroenterology 1963;44:1–6. 27. Wanless IR, Gryfe A. Nodular transformation of the liver in hereditary hemorrhagic telangiectasia. Arch Pathol 1986;110:331–5. 28. Chandler D. Pulmonary and cerebral arteriovenous fistula with Osler’s disease. Arch Intern Med 1965;116:277–82. 29. Waller JD, Greenberg JH, Lewis CW. Hereditary hemorrhagic telangiectasia with cerebrovascular malformations. Arch Dermatol 1976;112:49–52. 30. Hashimoto K, Pritzker MS. Hereditary hemorrhagic telangiectasia. An electron microscopic study. Oral Surg Oral Med Oral Pathol 1972;34:751–68. 31. Swanson DL, Dahl MV. Embolic abscesses in hereditary hemorrhagic telangiectasia. J Am Acad Dermatol 1991;24:580–3. 32. Wells, RS, Dowling GB. Hereditary benign telangiectasia. Br J Dermatol 1971; 84:93–4. 33. Ryan TJ, Wells RS. Hereditary benign telangiectasis. Trans St John’s Hosp Dermatol Soc 1971; 57:148–56. 34. Gold MH, Eramo L, Prendiville JS. Hereditary benign telangiectasia. Pediatr Dermatol 1989;6:194–7. 35. Smith LL, Cornely SL. Ataxia-telangiectasia or Louis-Bar syndrome. J Am Acad Dermatol 1985;12:681–96. 36. Salama S, Rosenthal D. Cutaneous collagenous vasculopathy with generalized telangiectasia: an immunohistochemical and ultrastructural study. J Cutan Pathol 2000;27:40–8 37. Uhlin SR, McCarty KS Jr. Unilateral nevoid telangiectatic syndrome. The role of estrogen and progesterone receptors. Arch Dermatol 1983;119:226–8. 38. Tok J, Berberian BJ, Sulica VI. Unilateral nevoid telangiectasia syndrome. Cutis 1994;53:53–4. 39. Taskapan O, Harmanyeri Y, Sener O, Aksu A. Acquired unilateral nevoid telangiectasia syndrome. Acta Derm Venereol 1997;77:62–3. 40. Reymond JL, Stoebner P, Amblard P. Telangiectases naevoides acquises. Dermatologica 1979; 159:489–94. 41. Person JR, Longcope C. Estrogen and progesterone receptors are not increased in generalized essential telangiectasia. Arch Dermatol 1985;121:836–37. 42. Shelley WB, Fierer JA. Focal intravascular coagulation in progressive ascending telangiectasia: ultrastructural studies of Ketoconazole-induced involution of vessels. J Am Acad Dermatol 1984;10:876–87. 43. Braverman IM, Ken-Yen A. Ultrastructure and three-dimensional reconstruction of several macular and papular telangiectases. J Invest Dermatol 1983;81:489–97. 44. Braverman IM, Keh A, Jacobson BSA. Ultrastructure and three-dimensional organization of the telangiectases of hereditary hemorrhagic telangiectasia. J Invest Dermatol 1990;95:422–7. 45. Apfelberg DB, Maser MR, Lash H, Flores J. Expanded role of the argon laser in plastic surgery. J Dermatol Surg Oncol 1983;9:145–51. 46 Goldman MP, Bennet RG. Treatment of telangiectases: a review. J Am Acad Dermatol 1987;17:167–82. 47. McCoy S, Hanna M, Anderson P, McLennan G, Repacholi M. An evaluation of the copper-bromide laser for treating telangiectasia. Dermatol Surg 1996;22:551–7. 48. Goldberg DJ, Meine JG. Treatment of facial telangiectases with the diode-pumped frequency-doubled Q-switched Nd:YAG laser. Dermatol Surg 1998;24:828–32. 49. Goldberg DJ, Meine JG. A comparison of four frequency-doubled Nd:YAG (532 nm) laser systems for treatment of facial telangiectases. Dermatol Surg 1999;25:463–7. 50. Dave RU, Mahaffey PJ, Monk BE. Cutaneous lesions in hereditary haemorrhagic telangiectasia: successful treatment with the tunable dye laser. J Cutan Laser Ther 2000;2:191–3. 51. Buscaglia DA, Conte ET. Successful treatment of generalized essential telangiectasia with the 585-nm flashlamp-pumped pulsed dye laser. Cutis 2001;67:107–8. 52. Gambichler T, Avermaete A, Wilmert M, Altmeyer P, Hoffmann K. Generalized essential telangiectasia successfully treated with high-energy, long-pulse, frequency-double Nd:YAG laser. Dermatol Surg 2001;27:355–7.

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4. ANGIOKERATOMAS The term angiokeratoma is used to refer to several unrelated conditions, whose common denominator is the presence of dilated blood vessels in association with epidermal hyperplasia. The designation of angiokeratoma should be restricted to those acquired vascular lesions that result from the ectatic dilation of preexisting vessels in the papillary dermis, accompanied by hyperkeratotic epidermis. Excluded from this category are the lesions described as “angiokeratoma circumscriptum,” which are better interpreted as hyperkeratotic capillary-lymphatic malformations and are described in the corresponding chapter. CLINICAL FEATURES Four clinical variants of angiokeratomas have been recognized, although their biologic significance varies greatly. They range from lesions that have very little clinical repercussion to widespread eruptions that are a manifestation of potentially fatal, systemic, metabolic diseases. Solitary angiokeratomas consist of small, warty, black, well-circumscribed papules (Fig. 10) that may affect any anatomic site, including the oral cavity, although the lower limbs are the most frequent location (1,2). The lesion is thought to be the result of injury, trauma, or chronic irritation to the wall of a venule in the papillary dermis (3). Sometimes solitary angiokeratomas develop thrombosis and recanalization with the development of secondary intravascular papillary endothelial hyperplasia. Because of their color, these lesions may be clinically confused with malignant melanoma (4) (Fig. 11). Fordyce’s angiokeratoma is characterized by the presence of multiple purple to dark papules, measuring 2–4 mm in diameter. They are most common in the scrotum (Fig. 12) and vulva (Fig. 13) of elderly people (5,6), however, there are examples of congenital Fordyce’s angiokeratoma (7). Scrotal angiokeratomas may be associated with varicocele, inguinal hernia, and thrombophlebitis (5). The lesions may develop after surgical injuries to the genital veins (8), and there have been cases of angiokeratomas involving the glans penis mucosa of young patients that developed after circumcisional surgery (9). Similar lesions have been described in the vulva of young females (10–12). These lesions are thought to be the result of increased venous pressure that occurs during pregnancy (13) or secondary to the use of contraceptive pills (14).

Fig. 10. Solitary angiokeratoma involving the internal aspect of the thigh.


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Fig. 11. Solitary angiokeratoma on the anterior aspect of the thigh. Lesions such as the one showed in this figure may occasionally be misdiagnosed as malignant melanoma owing to their blue or black color.

Fig. 12. Angiokeratomas of Fordyce involving the skin of the scrotum in an elderly man.

Mibelli’s angiokeratoma is inherited in an autosomal dominant fashion (15). The lesions consist of several dark papules with a slightly hyperkeratotic surface, usually on the dorsum of the fingers, toes, and interdigital spaces (Fig. 14). They usually appear in childhood or adolescence, they are more common in females, and they may be associated with acrocyanosis and chilblains (16). In rare instances, ulceration of the fingertips may appear as a complication of Mibelli’s angiokeratoma (17). Angiokeratoma corporis diffusum is the most unusual variant of all the angiokeratomas. It represents a cutaneous manifestation of a group of hereditary enzymatic

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Fig. 13. Angiokeratomas of Fordyce involving the vulva of an elderly woman.

Fig. 14. Angiokeratomas of Mibelli in the inner border of the left hand.

disorders, but there is also an idiopathic form that presents with no other associated anomalies. Among the different diseases associated with angiokeratoma corporis diffusum, Fabry’s disease is the most common. Fabry’s disease is a rare error of the metabolism that results in a deficiency of the lysosomal enzyme hydrolase α-galactosidase A. It is transmitted as an X-linked recessive trait. The gene responsible for the coding of α-galactosidase A has been localized to the middle of the long arm of the X chromosome. As an X-linked disease, Fabry’s disease exclusively affects males; females may be asymptomatic carriers and may have corneal dystrophic changes that can be detected by slit-lamp examination (18,19). As a consequence of the enzymatic defect, glycosphingolipids, predominantly trihexosylceramide, accumulate within the lysosomes of endothelial cells, fibroblasts, pericytes, and smooth muscle fibers of the dermis. There is also an accumulation of this material in other organs including ganglion cells, nerves, cornea, heart, and kidney, resulting in cardiac, renal, ocular, and neurologic abnormalities (20). Angiokeratomas of Fabry’s disease usually appear shortly before puberty. They are small, punctate, dark red papules, some of them less than 1 mm, mainly located in the lower part of abdomen, genitalia, buttocks, and thighs in a bathing-trunk distribution (Figs. 15, 16, and 17). A frequent and asymptomatic finding is the so-called cornea verticillata, which is a superficial corneal dystrophy. This finding is of diagnostic importance for the detection of mild cases and female carriers. Other cutaneous manifestations include dry skin, anhidrosis, hyperthermic crises (21), and acroparaesthesiae secondary to capillary changes in the nail matrix (22). In rare instances patients with Fabry’s disease may also present with concur-


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Fig. 15. Angiokeratoma corporis diffusum in a patient with Fabry’s disease. Multiple small red papules involving the left flank.

rent Klippel-Trenaunay-Weber syndrome (23). Patients with Fabry’s disease who are devoid of cutaneous lesions have been reported (24). Angiokeratoma corporis diffusum is not exclusive to Fabry’s disease and has also been described in association with other rare inherited lysosomal storage diseases such as fucosidosis type II (25,26), galactosidosis type II (27), Kanzaki’s disease or deficiency of α-N-acetylgalactosaminidase (28–30), aspartylglycosaminuria (31), sialidosis type II (32), adult-onset GM1 gangliosidosis (33), and β-mannosidase deficiency (34–36). By the same token, rare cases of angiokeratoma corporis diffusum have been described in patients without metabolic anomalies (37–40). In some of these patients the angiokeratomas were multiple and presented in a zosteriform distribution (41). These angiokeratomas have been described in patients with cutaneous and cerebral hemangiomas (42), tuberous sclerosis (43), blue rubber bleb nevus syndrome (44), and juvenile dermatomyositis (45). In a recent report, angiokeratoma corporis diffusum not associated with metabolic disease was described in a three-generation family with autosomal dominant transmission. Some of the affected patients showed arteriovenous shunts with hypertrophy of the affected limb (46). HISTOPATHOLOGIC FEATURES Histopathologically, all variants of angiokeratomas are identical under a conventional microscope. Common features of all angiokeratomas include the presence of dilated thin-

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Fig. 16. Angiokeratoma corporis diffusum in a patient with Fabry’s disease. (A) Lesions of angiokeratoma involved the dorsum of the foot. (B) Close-up view shows that small red papules are also present in the spaces among the toes.

Fig. 17. Angiokeratoma corporis diffusum in a patient with Fabry’s disease with small red papules on the buttocks.

walled blood vessels lined by a layer of endothelial cells in the papillary dermis and a variable degree of hyperkeratosis (1). Occasionally, angiokeratomas may be seen overlying deep vascular malformations (47). Hyperkeratosis is usually absent in Fordyce’s angiokeratomas and in angiokeratoma corporis diffusum (Fabry’s disease). Ultrastruc-


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tural studies have demonstrated quantitative alterations of cytoplasmic organelles within the endothelial cells (48). In patients with Fabry’s disease, there is vacuolization of the cytoplasm of the endothelial cells of the arterioles and smooth muscle cells of the arrector pili. The presence of these vacuoles may be a clue to the specific diagnosis in sections stained with hematoxylin and eosin. However, in most cases the amount of glycolipid in the skin is small, making it extremely difficult, if not impossible, to identify them in routinely prepared sections. Special stains such as Sudan black B (49) and PAS (50) highlight the presence of glycolipid deposits within the vacuoles in patients with Fabry’s disease and related disorders (Fig. 18). The lipid material is double refractile, which can be demonstrated by means of polariscopic examination of unfixed, or formalin-fixed frozen sections. Deposits of glycolipids in patients with Fabry’s disease are not restricted to the lesions of angiokeratoma but may also be seen in skin that appears to be normal (51). Electron microscopy examination of the skin in Fabry’s disease shows large, electrodense lipid deposits in endothelial cells, pericytes, fibroblasts, arrector pili muscles, and secretory, ductal, and myoepithelial cells of the eccrine glands (52). These deposits show a characteristic lamellar structure(53–58), not seen in other types of angiokeratomas or in lesions of angiokeratoma corporis diffusum with no enzymatic anomalies (38–45). Other ultrastructural findings in patients with Fabry’s disease consist of intersecting short, crescentshaped, tightly packed membranes in the endothelial cells of the small cutaneous blood vessels (59) and cytoplasmic vacuoles in the epithelial cells of the eccrine glands (60). TREATMENT Small angiokeratomas may be managed by diathermy, electrodessication and curettage, or cryotherapy with liquid nitrogen. Good cosmetic results have been reported with laser therapy (61–67). For larger lesions the preferred treatment is surgical excision if treatment is required. Recombinant human α-galactosidase A replacement therapy has been demonstrated to be safe and efficient in reversing the chief clinical manifestations in patients with Fabry’s disease (68).

References 1. Imperial R, Helwig EB. Angiokeratoma: a clinicopathological study. Arch Dermatol 1967;95:166–75. 2. Kumar MV, Thappa DM, Shanmugam S, Ratnakar C. Angiokeratoma circumscriptum of the oral cavity. Acta Derm Venereol 1988;78:472. 3. Foucar E, Mason WV. Angiokeratoma circumscriptum following damage to underlying vasculature. Arch Dermatol 1986;122:245–6. 4. Goldman L, Gibson SH, Richfield DF. Thrombotic angiokeratoma circumscriptum simulating melanoma. Arch Dermatol 1981;117:138–9. 5. Imperial R, Helwig EB. Angiokeratoma of the scrotum (Fordyce type). J Urol 1967;98:379–87. 6. Agger P, Osmundsen PE. Angiokeratoma of the scrotum (Fordyce). Acta Derm Venereol 1970;50:221–4. 7. Patrizi A, Neri I, Trevisi P, Landi C, Bardazzi F. Congenital angiokeratoma of Fordyce. J Eur Acad Dermatol Venereol 1998;10:195–6. 8. Bisceglia M, Carosi I, Castelvetere M, Nurgo R. Angiocheratomi multipli dello scroto, “tipo Fordyce.” Su un cado ad insorgenza iatrogena. Pathologica 1998;90:46–50. 9. Carrasco L, Izquierdo MJ, Fariña MC, Martín L, Moreno C, Requena L. Strawberry glans penis: a rare manifestation of angiokeratomas involving the glands penis. Br J Dermatol 2000;142:1256–7. 10. Novick NL. Angiokeratoma vulvae. J Am Acad Dermatol 1985;12:561–3. 11. Clark JR, Wheelock JB. Angiokeratoma of the vulva. A case report. J Reprod Med 1988;33:473–4. 12. Cohen PR, Young AW Jr, Tovell HM. Angiokeratoma of the vulva: diagnosis and review of the literature. Obstet Gynecol Surv 1989;44:339–46.

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Chapter 6 / Cutaneous Lesions with Dilations 13. 14. 15. 16. 17. 18.

19.

20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.

32. 33.

34. 35. 36. 37. 38. 39.

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Imperial R, Helwig EB. Angiokeratomas of the vulva. Obstet Gynecol 1967;29:307–12. Novick NL. Angiokeratoma vulvae. J Am Acad Dermatol 1985;12:561–3. Pringle JJ. Four cases of angiokeratoma from one family. Br J Dermatol 1913; 25:40–53. Haye KR, Rebello DJA. Angiokeratoma of Mibelli. Acta Derm Venereol 1961;41:56–60. Dave VK, Main RA. Angiokeratoma of Mibelli with necrosis of the fingertips. Arch Dermatol 1972;106:726–8. Fox MF, Dutoit DL, Warnich L, et al. Regional localization of alpha-galactosidase (GLA) to Xpter→q22, hexosaminidase B (HEXB) to 5 q13→qter and arylsulphatase B (ARSB) to 5 pter→q13. Cytogenet Cell Genet 1984;38:45–9. Bishop DF, Calhoun DH, Bernstein MS, et al. Structure of the human alpha-galactosidase A gene: 5' control elements, intron/exon splice junction sequence and alternative 3' termination. Am J Hum Genet 1987;41(suppl):A208. Wallace HJ. Anderson-Fabry disease. Br J Dermatol 1973;88:1–21. Kang WH, Chun SI, Lee S. Generalized anhidrosis associated with Fabry’s disease. J Am Acad Dermatol 1987;17:883–7. Jansen W, Lentner A, Genzel I. Capillary changes in angiokeratoma corporis diffusum Fabry. J Dermatol Sci 1994;7:68–70. Germain DP. Co-occurrence and contribution of Fabry disease and Klippel-Trenaunay-Weber syndrome to a patient with atypical skin lesions. Clin Genet 2001;60:63–7. Clarke JTR, Knack J, Crawhall JC, et al. Ceramide trihexosidase (Fabry’s disease) without skin lesions. N Engl J Med 1971;284:233–5. Epinette WW, Norins AL, Zeman W, Patel V. Angiokeratoma corporis diffusum with alpha-L fucosidase deficiency. Arch Dermatol 1973;107:754–7. Patel V, Watanabe I, Zeman W. Deficiency of alpha-L-fucosidase. Science 1972;176:420–7. Ishibashi A, Tsuboi R, Shinmei M. β-Galactosidase and neuraminidase deficiency associated with angiokeratoma corporis diffusum. Arch Dermatol 1984;120:1344–6. Kanzaki T, Yokota M, Mizuno N, Matsumoto Y, Hirabayashi Y. Novel lysosomal glycoaminoacid storage disease with angiokeratoma corporis diffusum. Lancet 1989;1:875–7. Kanzaki T, Wang AM, Desnick RJ. Lysosomal alpha-N-acetylgalactosaminidase deficiency: the enzymatic defect in angiokeratoma corporis diffusum with glycopeptiduria. J Clin Invest 1991;88:707–11. Chabás A, Coll MJ, Aparicio M, Rodríguez E. Mild phenotypic expression of alpha-N-acetylgalactosaminidase deficiency in two adult siblings. J Inherit Metab Dis 1994;17:724–31. Gehler J, Sewell AC, Becker C, Hartmann J, Spranger J. Clinical and biochemical delineation of aspartylglycosaminuria as observed in two members of an Italian family. Helv Paediatr Acta 1981;36:179–89. Miyatake T, Atsumi T, Obayashi T, et al. Adult type neuronal storage disease with neuraminidase deficiency. Ann Neurol 1978;6:232–44. Wenger DA, Sattler M, Mueller T, Myers GG, Schneimann RS, Nixon GW. Adult GM 1 gangliosidosis: clinical and biochemical studies on two patients and comparison to other patients called variant or adult GM 1 gangliosidosis. Clin Genet 1980;17:323–34. Cooper A, Sarharwalla IB, Roberts MM. Human β-mannosidase deficiency. N Engl J Med 1986;315:1231. Cooper A, Hatton C, Thornley M, Sardwalla IB. Human β-mannosidase deficiency: biochemical findings in plasma, fibroblasts, white cells and urine. J Inherit Metab Dis 1988;11:17–29. Rodríguez Serna M, Botella Estrada R, Chabás A, et al. Angiokeratoma corporis diffusum associated with β-mannosidase deficiency. Arch Dermatol 1996;132:1219–22. Holmes RC, Fenson AW, McKee P, Cairns RJ, Black MM. Angiokeratoma corporis diffusum in a patient with normal enzyme activities. J Am Acad Dermatol 1984;10:384–7. Crovato F, Rebora A. Angiokeratoma corporis diffusum and normal enzyme activities. J Am Acad Dermatol 1985;12:885–6. Marsden J, Allen R. Widespread angiokeratomas without evidence of metabolic disease. Arch Dermatol 1987;123:1125–7.

Fig. 18. (Opposite page) Histopathologic features of angiokeratoma in a patient with Fabry’s disease. (A) Low-power view shows dilated vascular spaces in the papillary dermis. (B) Higher magnification demonstrates the thin walls of the vascular channels. (C) PAS stain demonstrates PAS-positive deposits within the endothelial cells.

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40. Frappaz A, Ferrier MC, Hermier C, et al. Angiokeratoma corporis diffusum avec activité enzimatique normale. Ann Dermatol Venereol 1987;114:1383–7. 41. Eizaguirre X, Landa N, Raton JA, Díaz Pérez JL. Multiple angiokeratomas with zosteriform distribution in two sisters. Int J Dermatol 1994;33:641–2. 42. Ostlere L, Hart Y, Misch KJ. Cutaneous and cerebral hemangiomas associated with eruptive angiokeratomas. Br J Dermatol 1996;135:98–101. 43. Gil Mateo MP, Miquel FJ, Velasco AM, Pitarch A, Fortea JM, Aliaga A. Widespread angiokeratomas and tuberous sclerosis. Br J Dermatol 1996;135:280–2. 44. Trattner A, Krichely D, David M. Blue rubber bleb nevus syndrome associated with diffuse angiokeratoma. Cutis 1997;59:264–6. 45. Shannon PL, Ford MJ. Angiokeratomas in juvenile dermatomyositis. Pediatr Dermatol 1999;16:488–51. 46. Calzavara-Pinton P, Colombi M, Carlino A, et al. Angiokeratoma corporis diffusum and arteriovenous fistulas with dominant transmission in the absence of metabolic disease. Arch Dermatol 1995;131:57–62. 47. Kraus MD, Lind AC, Alder SL, Dehner LP. Angiomatosis with angiokeratoma-like features in children: a light microscopic and immunophenotypic examination of four cases. Am J Dermatopathol 1999;21:350–5. 48. Gioglio L, Porta C, Moroni M, Nastasi G, Gangarossa I. Scrotal angiokeratoma (Fordyce): histopathological and ultrastructural findings. Histol Histopathol 1992;7:47–55. 49. Frost P, Spaeth GL, Tanaka Y. Fabry’s disease. Glycolipid lipidosis. Arch Intern Med 1966;117:440–6. 50. Hashimoto K, Gross BG, Lever WF. Angiokeratoma corporis diffusum (Fabry). Histochemical and electron microscopic studies of the skin. J Invest Dermatol 1965;44:119–28. 51. de Groot WP. Angiokeratoma corporis diffusum Fabry. Dermatologica 1964;128:321–49. 52. Nakamura T, Kaneko H, Nishino I. Angiokeratoma corporis diffusum (Fabry disease): ultrastructural studies of the skin. Acta Derm Venereol 1981;61:37–41. 53. Hashimoto K, Lieberman P, Lamkin N Jr. Angiokeratoma corporis diffusum (Fabry’s disease): a lysosomal disease. Arch Dermatol 1976;112:1416–23. 54. Luderschmidt C, Wolff HH. Intracytoplasmic granules with lamellae as signs of heterozygous Fabry’s disease. Am J Dermatopathol 1980;2:57–61. 55. Strayer DS, Santa Cruz D. Intracytoplasmic granules with lamellae in Fabry’s disease. Am J Dermatopathol 1980;2:63–4. 56. Breathnach SM, Black MM, Wallace HJ. Anderson-Fabry disease. Characteristic ultrastructural features in cutaneous blood vessels in a 1-year-old boy. Br J Dermatol 1980;103:81–4. 57. Voglino A, Paradisi M, Dompe G, Onetti Muda A, Faraggiana T. Angiokeratoma corporis diffusum (Fabry’s disease) with unusual features in a female patient. Light and electron microscopic investigation. Am J Dermatopathol 1988;10:343–8. 58. Lao LM, Kumakiri M, Mima H, et al. The ultrastructural characteristics of eccrine sweat glands in a Fabry disease patient with hypohidrosis. J Dermatol Sci 1998;18:109–17. 59. Elleder M, Ledvinova J, Vosmik F, Zeman J, Stejskal D, Lageron A. An atypical ultrastructural pattern in Fabry’s disease: a study on its nature and incidence in 7 cases. Ultrastruct Pathol 1990;14:467–74. 60. Idoate MA, Pardo-Mindan FJ, Gonzalez Alamillo C. Fabry’s disease without angiokeratomas showing unusual eccrine gland vacuolation. J Pathol 1992;167:65–8. 61. Flores JT, Apfelberg DB, Maser MR et al. Angiokeratoma of Fordyce: successful treatment with the argon laser. Plast Reconstr Surg 1984;74:835–8. 62. Newton JH, McGibbon DH. The treatment of multiple angiokeratomata with the argon laser. Clin Exp Dermatol 1987;12:23–5. 63. Hobbs ER, Ratz JL. Argon laser treatment of angiokeratomas. J Dermatol Surg Oncol 1987;13:1319–20. 64. Pasyk KA, Argenta LC, Schelbert EB. Angiokeratoma circumscriptum: successful treatment with the argon laser. Ann Plast Surg 1988;20:183–90. 65. Lapins J, Emtestam L, Marcusson JA. Angiokeratomas in Fabry’s disease and Fordyce’s disease: successful treatment with Cooper vapour laser. Acta Derm Venereol 1993;73:133–5. 66. Occella C, Bleidl D, Rampini P, Schiazza L, Rampini E. Argon laser treatment of cutaneous multiple angiokeratomas. Dermatol Surg 1995;21:170–2. 67. Meyer WR, Dotters DJ. Laser treatment of recurrent vulvar angiokeratomas associated with Noonan syndrome. Obstet Gynecol 1996;87:863–5. 68. Eng CM, Guffon N, Wilcox WR, et al. Safety and efficacy of recombinant human alpha-galactosidase A-replacement therapy in Fabry’s disease. N Engl J Med 2001;345:9–16.


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5. LYMPHANGIECTASES CLINICAL FEATURES Lymphangiectases are the lymphatic counterparts of angiokeratomas resulting from the acquired permanent dilation of lymphatic capillaries. They develop in areas of the skin affected by obstruction or destruction of lymphatic drainage. Clinically, lymphangiectases localized on genital or plantar skin may mimic warts (1–4). Lymphangiectases have been described as a result of interference of lymphatic vessels secondary to surgery (5,6), scarring from scrofuloderma (7), photoaging and topical corticosteroid application (8), porphyria cutanea tarda (9), hepatic cirrhosis with ascites (10), mastectomy (11,12), and radiotherapy for breast carcinoma (13–17). In the penis and scrotum, lymphangiectases develop as a complication of a surgical procedure for a sacrococcygeal tumor (18); on the vulva and thigh they are usually secondary to Crohn’s disease (19,20), or they develop after surgery and radiotherapy for cervical carcinoma (1,21–25). Lymphangiectases of Fordyce may also appear in the genital region of elderly people without evidence of damage of the lymphatic drainage (26). Lymphangiectases have also been described as consequence of alterations in the collagen or elastic tissue, including penicillamine dermopathy (27). Clinically, lymphangiectases appear as multiple, persistent, translucent, thick-walled white vesicles, of 2–5 mm in diameter. Some lesions may have a polypoid shape, and punction provokes the flow of a milky liquid (Fig. 19). The involved area appears to be sprinkled with lymphangiectatic vesicles with areas of normal-appearing skin among them. HISTOPATHOLOGIC FEATURES Histopathologically, lymphangiectasias are characterized by the presence of dilated lymphatic vessels positioned within papillary dermis (Fig. 20). Sometimes lymphangiectases rise above the level of the adjacent skin. The vessels lack contents or show a homogeneous material within their lumina, and they are lined by a thin wall with a single discontinuous layer of endothelial cells. The degree of epidermal hyperplasia in lymphangiectases is usually less marked than in angiokeratomas. The differential diagnosis between lymphangiectases and superficial lymphatic malformations is established by the absence of a deep lymphatic component; the dilated vessels are confined to the papillary dermis, and they result from dilation of preexisting lymphatic capillaries.

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Fig. 19. Lymphangiectases involving the inner aspect of the thigh. Punction provoked the flow of a milky fluid.


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Fig. 20. Histopathologic features of lymphangiectases. (A) Low-power view shows an exophytic lesion that contains dilated vascular structures. (B) Higher magnification demonstrates that the vascular channels are lined by a thin wall of a discontinous layer of endothelial cells.

Authentic, superficial lymphatic malformations may show lymphangiectases as part of their superficial component; however, they have a deep component with characteristic valves in their walls (23). TREATMENT Surgical excision of the superficial vesicles tends to be disappointing, and recurrences are common. Palliative results have been achieved with sclerotherapy and (28) laser therapy (29–32).

References 1. Harwood CA, Mortimer PS. Acquired vulval lymphangiomata mimicking genital warts. Br J Dermatol 1993;129:334–6. 2. El Sayed F, Bazex J, Bouissou X, et al. Acquired cutaneous lymphangiectasia mimicking plantar warts. Br J Dermatol 1995;132:1014–6. 3. Darmstadt GL. Perianal lymphangioma circumscriptum mistaken for genital warts. Pediatrics 1996;98:461–3. 4. Mu XC, Tran TA, Dupree M, Carlson JA. Acquired vulvar lymphangioma mimicking genital warts. A case report and review of the literature. J Cutan Pathol 1999;26:150–4. 5. Ziv R, Schewach-Millet M, Trau H. Lymphangiectasia: a complication of thoracotomy for bronchial carcinoid. Int J Dermatol 1988;27:123.


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6. Moon SE, Youn JI, Lee YS. Acquired cutaneous lymphangiectasia. Br J Dermatol 1993;129:193–5. 7. Di Leonardo M, Jacoby RA. Acquired cutaneous lymphangiectasias secondary to scarring from scrofuloderma. J Am Acad Dermatol 1986;14:688–90. 8. Pena JM, Ford MJ. Cutaneous lymphangiectases associated with severe photoaging and topical corticosteroid application. J Cutan Pathol 1996;23:175–81. 9. Stone MS. Central-facial papular lymphangiectases: an uncommon manifestation of porphyria. J Am Acad Dermatol 1997;36:493–5. 10. Garcia-Doval I, de la Torre C, Losada A, Ocampo C, Rodríguez T, Cruces MJ. Acquired cutaneous lymphangiectasia in a patient with cirrhotic ascites. J Eur Acad Dermatol Venereol 1999;13:109–12. 11. Plotnick H, Richfield D. Tuberous lymphangiectatic varices secondary to radical mastectomy. Arch Dermatol Syphilol 1956;74:466–8. 12. Kurwa A, Waddinton E. Post mastectomy lymphangiomatosis. Br J Dermatol 1968;80:840. 13. Prioleau PG, Santa Cruz DJ. Lymphangioma circumscriptum following radical mastectomy and radiation therapy. Cancer 1978;42:1989–91. 14. Leshin B, Whitaker D, Foucar E. Lymphangioma circumscriptum following mastectomy and radiation therapy. J Am Acad Dermatol 1986;15:1117–9. 15. Gianelli V, Rockley PF. Acquired lymphangiectasis following mastectomy and radiation therapy— report of a case and review of the literature. Cutis 1996;58:276–8. 16. Bouzit N, Grezard P, Communal PH, Mironneau I, Balme B, Perrot H. Lymphangiectasies cutanées acquises après traitement chirurgical et radiothérapie du cancer du sein. A propos de 2 cas. J Gynecol Obstet Biol Reprod 1999;28:384–7. 17. Diaz Cascajo C, Borghi S, Weyers W, Retzlaff H, Requena L, Metze D. Benign lymphangiomatous papules of the skin following radiotherapy: a report of five new cases and review of the literature. Histopathology 1999;35:319–27. 18. Weakley DR, Juhlin EA. Lymphagiectases and lymphangiomata. Arch Dermatol 1961;84:574–8. 19. Dap RF, van der Meijden WI. Vulvaire lymphangiectasieen bij de ziekte Crohn. Ned Tijdschr Geneeskd 2000;26:1692–5. 20. Handfield-Jones SE, Prendiville WJ, Norman S. Vulval lymphangiectasia. Genitourin Med 1989; 65:335–7. 21. Young AW Jr, Wind RM, Tovell HM. Lymphangioma of vulva: acquired following treatment for cervical cancer. NY State J Med 1980;80:987–9. 22. Kennedy CTC. Lymphangiectasia of the vulva following hysterectomy and radiotherapy. Br J Dermatol 1990;123 (suppl 37):92–3. 23. Fisher I, Orkin M. Acquired lymphangioma (lymphangiectasis): report of a case. Arch Dermatol 1970;101:230–4. 24. LaPolla J, Foucar E, Leshin B, et al. Vulvar lymphangioma circumscriptum: a rare complication of therapy for squamous cell carcinoma of the cervix. Gynecol Oncol 1985;22:363–6. 25. Ambrojo P, Fernandez Cogolludo E, Aguilar A, Sanchez Yus E, Sanchez de Paz F. Cutaneous lymphangiectases after therapy for carcinoma of the cervix: a case with unusual clinical and histological features. Clin Exp Dermatol 1990;15:57–9. 26. Cecchi R, Bartoli L, Brunetti L, Pavesi M, Giomi A. Lymphangioma circumscriptum of the vulva of late onset. Acta Derm Venereol 1995;75:79–93. 27. Goldstein JB, McNutt NS, Hambrick GW, Hsu MA. Penicillamine dermopathy with lymphangiectases. A clinical, immunohistologic, and ultrastructural study. Arch Dermatol 1989;125:92–7. 28. Ahmed DD, Waldorf JC, Randle HW. Cutaneous lymphangiectasis: treatment with sclerotherapy. Plast Reconstr Surg 1998;101:434–6. 29. Landthaler M, Hohenleutner U, Braun Falco O. Acquired lymphangioma of the vulva: palliative treatment by means of laser vaporization carbon dioxide. Arch Dermatol 1990;126:967–8. 30. Egan CA, Rallis TM, Zone JJ. Multiple scrotal lymphangiomas (lymphangiectases) treated by carbon dioxide laser ablation. Br J Dermatol 1998;139:561–2. 31. Novak C, Spelman L. Low energy fluence CO2 laser treatment of lymphangiectasia. Australas J Dermatol 1998;39:277–8. 32. Loche F, Schwarze HP, Bazex J. Treatment of acquired cutaneous lymphangiectasis of the thigh and vulva with a carbon dioxide laser. Acta Derm Venereol 1999;79:335.

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Cutaneous Vascular Hyperplasias CONTENTS ANGIOLYMPHOID HYPERPLASIA WITH EOSINOPHILIA PYOGENIC GRANULOMA BACILLARY ANGIOMATOSIS VERRUGA PERUANA INTRAVASCULAR PAPILLARY ENDOTHELIAL HYPERPLASIA (MASSON’S PSEUDO-ANGIOSARCOMA) PSEUDO-KAPOSI’S SARCOMA REACTIVE ANGIOENDOTHELIOMATOSIS

1. ANGIOLYMPHOID HYPERPLASIA WITH EOSINOPHILIA Angiolymphoid hyperplasia with eosinophilia (AHE) was first described by Wells and Whimster in 1969 (1). These authors considered the process to be a late stage of Kimura’s disease, a disorder described in the Japanese literature 20 years earlier (2). Following this description, the concept that AHE and Kimura’s disease were the same entity was widely accepted. It later became clear that the entities are different, and currently most authors believe that AHE and Kimura’s disease are two separate entities (3–8). To complicate the issue further, different names have been used to describe AHE, to wit: atypical pyogenic granuloma (9), pseudopyogenic granuloma (10), inflammatory angiomatous nodule (10), papular angioplasia (11), inflammatory arteriovenous hemangioma (12), intravenous atypical vascular proliferation (13), cutaneous histiocytoid hemangioma (7,14), and epithelioid hemangioma (15). Many of these terms are confusing and in our opinion it is best not to apply them to this particular entity. Take for example the term histiocytoid hemangioma (14). This term has been used to describe a wide spectrum of vascular proliferations, both benign and malignant, all of which are histopathologically characterized by the presence of endothelial cells with a histiocytoid appearance. Because this term is not specific and does not designate a single entity it is better not to use it. Another confusing term is epithelioid hemangioma (15), since it can be confused with epithelioid hemangioendothelioma, an entirely different clinicopathologic entity. We believe that the term AHE is the most appropriate denomination for this entity because it is well established in the literature (1,16–19), it adequately describes the lesion from a histopathologic point of view, and it does not lead to confusion with other terms. CLINICAL FEATURES Clinically, AHE is characterized by nodules or papules of angiomatoid appearance predominantly located on the head, especially around the ears (Fig. 1), forehead, and scalp. Less commonly lesions of AHE have been described in the mouth (20,21), trunk,

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Fig. 1. Angiolymphoid hyperplasia with eosinophilia. Multiple nodules with angiomatous appearance involving the posterior aspect of the ear.

extremities (16,17,19,22,23), vulva (24,25), penis (26), and inner canthus of the eye (27). Most of the time AHE is not associated with other diseases; however, there is a report of a patient with AHE associated with pachydermoperiostosis (28). AHE has also been described in HIV-infected patients (29). When the lesions are multiple, they tend to be grouped or confluent. Symptomatic lesions may be painful, pruritic, or pulsatile (19). Lesions do not involute spontaneously and often recur after excision (30). Some patients have peripheral eosinophilia, but this feature is less frequent and less marked than in Kimura’s disease. HISTOPATHOLOGIC FEATURES Histopathologically, AHE consists of well-circumscribed nodules involving the dermis and/or the subcutaneous fat (Fig. 2). Under scanning magnification two distinct components are seen, irregular blood vessels and a dense inflammatory infiltrate. The vascular component comprises irregular, thick-walled blood vessels lined by plump endothelial cells, which protrude into the lumen. The walls of the vessels often have thickened bundles of smooth muscle and abundant mucin. The endothelial cells lining the vessels are plump, with large round to oval nuclei and abundant eosinophilic cytoplasm, which often contains prominent vacuoles as an expression of primitive vascular differentiation. The endothelial cells can form solid sheets, and the angiomatous nature of the lesion becomes less evident. Occasionally the proliferation of endothelial cells is so prominent, especially within the lumina of large vessels, that it can be confused with malignant neoplasms (13). In some cases, the endothelial cells cluster together, giving the appearance of multinucleated cells with immature vascular lumina (31). The presence of plump endothelial cells is quite characteristic of AHE, and different names have been employed to describe them, including histiocytoid (14), epithelioid (15), or hobnail endothelial cells. The stroma consists of fibrovascular tissue that invariably contains lymphocytes, eosinophils, mast cells, and sometimes mucin deposits. In some cases,


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Fig. 2. Histopathologic features of angiolymphoid hyperplasia with eosinophilia. (A) Scanning power shows an exo-endophytic lesion involving the entire thickness of the dermis. (B) The vascular channels are lined by plump endothelial cells, some of them with vacuoles in their cytoplasm. (C) The inflammatory infiltrate is mostly composed of lymphocytes and eosinophils.

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lymphoid follicles with germinal centers are present, but usually they are not as prominent as in Kimura’s disease. Immunohistochemical studies have demonstrated that the endothelial cells are positive for factor VIII-related antigen (19,20,32–35), Ulex europaeus I lectin (26,32), actin, and vimentin (32). The lymphocytes present within the infiltrate consist primarily of polytypic B-lymphocytes (33). Ultrastructurally, the characteristic endothelial cells contain Weibel-Palade bodies (20,32–34,36,37). The true nature of AHE is uncertain. Human herpesvirus 8 (HHV8) has been detected in some lesions of AHE (38,39), but these findings could be not confirmed by other authors (23,40,41). In some cases there is an antecedent of trauma (15,19,42). When the biopsy is large and deep enough, an arteriovenous shunt is found in a significant percentage of cases (15,19,43). These features suggest that AHE is not a true neoplasm, but a reactive hyperplastic process that occurs probably secondary to damage and repair of an artery or vein (15,42). DIFFERENTIAL DIAGNOSIS The differential diagnosis with Kimura’s disease can be established on the basis of both the clinical and histopathologic features (3–8). Clinically, Kimura’s disease consists of skin-colored subcutaneous masses that in extreme cases distort the outline of the face dramatically, as a consequence of the presence of large infiltrates of inflammatory cells within the dermis and subcutaneous tissues. Usually patients also show intense peripheral eosinophilia and lymphadenopathy. Histopathologically Kimura’s disease is devoid of the vascular abnormalities seen in AHE, and when plump endothelial cells are present in the blood vessels they are a focal finding. The main findings are represented by the presence of numerous, closely packed lymphoid follicles that extend throughout the dermis and subcutaneous fat, and sometimes into the lymph nodes and internal organs. Within these infiltrates there are numerous eosinophils. In brief, Kimura’s disease is not a disorder of blood vessels, but an inflammatory systemic process of unknown etiology. TREATMENT Surgery, cryotherapy, or laser therapy (44–49) can adequately manage lesions of AHE, but larger lesions show a tendency to persist (30), unless the arteriovenous shunt is excised. Partial improvement of the lesions of AHE has been reported after intralesional injection of interferon-α-2a (50) or interferon-α-2b (51), as well as after oral administration of pentoxifylline (52), indomethacin (53), or isotretinoin (54).

References 1. Wells GC, Whimster IW. Subcutaneous angiolymphoid hyperplasia with eosinophilia. Br J Dermatol 1969;81:1–15. 2. Kimura T, Yoshimura S, Ishikawa E. Abnormal granuloma with proliferation of lymphoid tissue. Trans Soc Pathol Jpn 1948;37:179–80. 3. Chan JKC, Hui PK, Ng CS, Yuen NWF, Kung ITM, Gwi E. Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) and Kimura’s disease in Chinese. Histopathology 1989;15:557–74. 4. Googe PB, Harris NL, Mihm MC Jr. Kimura’s disease and angiolymphoid hyperplasia with eosinophilia: two distinct histopathological entities. J Cutan Pathol 1987;14:263–71. 5. Kung ITM, Gibson JB, Bannatyne PM. Kimura’s disease: a clinico-pathological study of 21 cases and its distinction from angiolymphoid hyperplasia with eosinophilia. Pathology 1984;16:39–44. 6. Kuo TT, Shih LY, Chan HL. Kimura’s disease. Involvement of regional lymph nodes and distinction from angiolymphoid hyperplasia with eosinophilia. Am J Surg Pathol 1988;12:843–54. 7. Rosai J. Angiolymphoid hyperplasia with eosinophilia of the skin. Its nosological position in the spectrum of the histiocytoid hemangioma. Am J Dermatopathol 1982;4:175–84.


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8. Urabe A, Tsuneyoshi M, Enjoji M. Epithelioid hemangioma versus Kimura’s disease. A comparative clinicopathologic study. Am J Surg Pathol 1987;11:758–66. 9. Peterson WC Jr, Fusaro RM, Goltz RW. Atypical pyogenic granuloma: a case of benign hemangioendotheliomatosis. Arch Dermatol 1964;90:197–201. 10. Wilson Jones E, Bleehen SS. Inflammatory angiomatous nodules with abnormal blood vessels occuring about the ears and scalp (pseudo- or atypical pyogenic granuloma). Br J Dermatol 1969;81:804–16. 11. Wilson Jones E, Marks R. Papular angioplasia: vascular papules of the face and scalp simulating malignant vascular tumors. Arch Dermatol 1970;102:422–7. 12. Girard C, Graham JH, Johnson WC. Arteriovenous hemangioma (arteriovenous shunt): a clinicopathological and histochemical study. J Cutan Pathol 1974;1:73–87. 13. Rosai J, Akerman LR. Intravenous atypical vascular proliferation: a cutaneous lesion simulating a malignant blood vessel tumor. Arch Dermatol 1974;109:714–7. 14. Rosai J, Gold J, Landy R. The histiocytoid hemangiomas: a unifying concept embracing several previously described entities of the skin, soft tissue, large vessels, bone, and heart. Hum Pathol 1979;10:707–30. 15. Fetsch JF, Weiss SW. Observations concerning the pathogenesis of epithelioid hemangioma (angiolymphoid hyperplasia). Mod Pathol 1991;4:449–55. 16. Mehregan AH, Shapiro L. Angiolymphoid hyperplasia with eosinophilia. Arch Dermatol 1971;103:50–7. 17. Reed RJ, Terazakis N. Subcutaneous angioblastic lymphoid hyperplasia with eosinophilia (Kimura’s disease). Cancer 1972;29:489–97. 18. Castro C, Winkelmann RK. Angiolymphoid hyperplasia with eosinophilia in the skin. Cancer 1974;34:1696–705. 19. Olsen TG, Helwig EB. Angiolymphoid hyperplasia with eosinophilia: a clinopathologic study of 116 patients. J Am Acad Dermatol 1985;12:781–96. 20. Masa FC, Fretzin DF, Chowdhury L, et al. Angiolymphoid hyperplasia demonstrating extensive skin and mucosal lesions controlled with vinblastine therapy. J Am Acad Dermatol 1984;11:333–9. 21. Tsuboi H, Fujimura T, Katsuoka K. Angiolymphoid hyperplasia with eosinophilia in the oral mucosa. Br J Dermatol 2001;145:365–6. 22. Imbling FD Jr, Viegas SF, Sanchez RL. Multiple angiolymphoid hyperplasia with eosinophilia of the hand: report of a case and review of the literature. Cutis 1996;58:345–8. 23. Arnold M, Geilen CC, Coupland SE, et al. Unilateral angiolymphoid hyperplasia with eosinophilia involving the left arm and hand. J Cutan Pathol 1999;26:436–40. 24. Aguilar A, Ambrojo P, Requena L, Olmos L, Sanchez Yus E. Angiolymphoid hyperplasia with eosinophilia limited to the vulva. Clin Exp Dermatol 1990;15:65–7. 25. Scurry J, Dennerstein G, Brenan J. Angiolymphoid hyperplasia with eosinophilia of the vulva. Aust N Z Obstet Gynaecol 1995;35:347–8. 26. Srigley JR, Ayala AG, Ordoñez NG, et al. Epithelioid hemangioma of the penis: a rare and distinctive vascular lesion. Arch Pathol Lab Med 1985;109:51–4. 27. Mariatos G, Gorgoulis VG, Laskaris G, Kittas C. Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) in the inner canthus. J Eur Acad Dermatol Venereol 2001;15:90–1. 28. Kanekura T, Mizumoto JI, Kanzaki T. Pachydermoperiostosis with angiolymphoid hyperplasia with eosinophilia. J Dermatol 1994;21:133–4. 29. D’Offizi G, Ferrara R, Donati P, Bellomo P, Paganelli R. Angiolymphoid hyperplasia with eosinophilia in HIV infection. AIDS 1995;9:813–4. 30. Bendl BJ, Asano K, Lewis RJ. Nodular angioblastic hyperplasia with eosinophilia and lymphofolliculosis. Cutis 1977;19:327–9. 31. Sakamoto F, Hashimoto T, Takenouchi T, Ito M, Nitto H. Angiolymphoid hyperplasia with eosinophilia presenting multinucleated cells in histology: an ultrastructural study. J Cutan Pathol 1998;25:322–6. 32. Angervall L, Kindblom LG, Karlsson K, et al. Atypical hemangioendothelioma of venous origin: a clinicopathologic angiographic immunohistochemical, and ultrastructural study of two endothelial tumors within the concept of histiocytoid hemangioma. Am J Surg Pathol 1985;9:504–16. 33. Wrigth DH, Padley NR, Judd MA. Angiolymphoid hyperplasia with eosinophilia simulating lymphadenopathy. Histopathology 1981;5:127–40. 34. Ose D, Vollmer R, Shelburne J, et al. Histiocytoid hemangioma of the skin and scapula: a case report with electron microscopy and immunohistochemistry. Cancer 1983;51:1656–62. 35. Burgdorf WHC, Mukai K, Rosai J. Immunohistochemical identification of factor VIII related antigen in endothelial cells of cutaneous lesions of alleged vascular nature. Am J Clin Pathol 1981;75:167–71.

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36. Daniels DG, Schrodt GR, Fliegelman MT, et al. Ultrastructural study of a case of angiolymphoid hyperplasia with eosinophilia. Arch Dermatol 1974;109:870–2. 37. Eady RAJ, Wilson Jones E. Pseudopyogenic granuloma: enzyme histochemical and ultrastructural study. Hum Pathol 1977;8:653–68. 38. Gyulai R, Kemeny L, Adam E, Nagy F, Dobozy A. HHV8 DNA in angiolymphoid hyperplasia of the skin. Lancet 1996;347:1837. 39. Oksenhendler E, Cazals-Hatem D, Schulz TF, et al. Transient angiolymphoid hyperplasia and Kaposi’s sarcoma after primary infection with human herpesvirus 8 in a patient with human immunodeficiency virus infection. N Engl J Med 1998;338:1585–90. 40. Lebbe C, Pellet C, Flageul B, et al. Sequences of human herpesvirus 8 are not detected in various nonKaposi sarcoma vascular lesions. Arch Dermatol 1997;133:919–20. 41. Jang KA, Ahn SJ, Choi JH, et al. Polymerase chain reaction (PCR) for human herpesvirus 8 and heteroduplex PCR for clonality assessment in angiolymphoid hyperplasia with eosinophilia and Kimura’s disease. J Cutan Pathol 2001;28:363–7. 42. Vadlamudi G, Schinella R. Traumatic pseudoaneurism: a possible early lesion in the spectrum of epithelioid hemangioma/angiolymphoid hyperplasia with eosinophilia. Am J Dermatopathol 1998;20:113–7. 43. Onishi Y, Ohara K. Angiolymphoid hyperplasia with eosinophilia associated with arteriovenous malformation: a clinicopathological correlation with angiography and serial estimation of serum levels or renin, eosinophil cationic protein and interleukin 5. Br J Dermatol 1999;140:1153–6. 44. Hobbs ER, Bailin PL, Ratz JL, Yarbrough CL. Treatment of angiolymphoid hyperplasia of the external ear with carbon dioxide laser. J Am Acad Dermatol 1988;19:345–9. 45. Letzman BH, McMeekin T, Gaspari AA. Pulsed dye laser treatment of angiolymphoid hyperplasia with eosinophilia lesions. Arch Dermatol 1997;133:920–1. 46. Rohrer TE, Allan AE. Angiolymphoid hyperplasia with eosinophilia successfully treated with a longpulsed tunable dye laser. Dermatol Surg 2000;26:211–4. 47. Papadavid E, Krausz T, Chu AC, Walker NP. Angiolymphoid hyperplasia with eosinophilia successfully treated with the flash-lamp pulsed-dye laser. Br J Dermatol 2000;142:192–4. 48. Gupta G, Munro CS. Angiolymphoid hyperplasia with eosinophilia: successful treatment with pulsed dye laser using the double pulse technique. Br J Dermatol 2000;143:214–5. 49. Fosko SW, Glaser DA, Rogers CJ. Eradication of angiolymphoid hyperplasia with eosinophilia by copper vapor laser. Arch Dermatol 2001;137:863–5. 50. Shenefelt PD, Rinker M, Caradonna S. A case of angiolymphoid hyperplasia with eosinophilia treated with intralesional interferon alfa-2a. Arch Dermatol 2000;136:837–9. 51. Rampini P, Semino M, Drago F, Rampini E. Angiolymphoid hyperplasia with eosinophilia: successful treatment with interferon alpha 2b. Dermatology 2001;202:343. 52. Person JR. Angiolymphoid hyperplasia with eosinophilia may respond to pentoxifylline. J Am Acad Dermatol 1994;31:117–8. 53. Nomura K, Sasaki C, Murai T, Mitsuhashi Y, Sato S. Angiolymphoid hyperplasia with eosinophilia: successful treatment with indomethacin farnesil. Br J Dermatol 1996;134:189–90. 54. Oh CW, Kim KH. Is angiolymphoid hyperplasia with eosinophilia a benign vascular tumor? A case improved with oral isotretinoin. Dermatology 1998;197:189–91.


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2. PYOGENIC GRANULOMA Pyogenic granuloma (PG) is a fairly common lesion that is still the subject of controversy. Most authors regard PG as a hyperplastic process; the lesion grows rapidly at sites of superficial trauma, and in some cases lesions of PG are associated with endocrine alterations or medication and usually involute upon cessation of the stimuli. Other authors, however, prefer to include PG with the group of vascular neoplasms. Among the arguments used to support the neoplastic nature of PG is the presence of a lobular architecture, similar to that seen in other neoplastic processes including tufted hemangioma. Mills et al. (1) noted that a lobular pattern is a repeatable finding in some stages of the development of all variants, including both the subcutaneous and intravenous forms. These authors coined the term lobular capillary hemangioma for such lesions and considered them to be benign neoplasms, based on their microscopic morphology. However, capillaries arranged in a lobular pattern can be seen in different vascular proliferations, both hyperplasias and neoplasias (2); therefore, this is not a compelling argument in favor of either the hyperplastic or neoplastic nature of PG. An additional issue is the name pyogenic granuloma. Semantically, it is obviously an unfortunate term, because the lesion does not contain pus and it is not composed of granulomas. We consider PGs to be hyperplasias rather than neoplasias for the following reasons: the lesion often appears as a response to trauma, hormonal factors (3), or retinoid therapy; (4–7); in the early stages it is indistinguishable from granulation tissue, and it resolves into a nubbin of scar tissue; widespread lesions appear in an eruptive fashion, but they usually resolve spontaneously within a few months (8); and lesions in pregnant women as well as lesions secondary to oral contraceptive pills or retinoid therapy usually regress following parturition (9) or withdrawal of the responsible drug (4–7,10–13). In our opinion, these are all compelling reasons that militate against the neoplastic nature of PG and in favor of a hyperplastic one. Thus PG is discussed along with other hyperplastic processes in this part of the book. We agree that there is a problem with the name, but unfortunately it is firmly entrenched in the dermatologic literature and for that reason we continue to use it in this monograph. Furthermore, the term lobular capillary hemangioma is also problematic, because some of the lesions are composed almost exclusively of veins. In sum, PG is neither a hemangioma nor a neoplasm; the lesion is an inflammatory and hyperplastic condition, better interpreted as a florid expression of granulation tissue proliferation. CLINICAL FEATURES PG affects both the skin and the mucous membranes. Clinically, these lesions typically present as a papule or polyp with a glistening surface, which bleeds easily. It preferentially affects the gingiva, lips (Fig. 3), mucosa of the nose, fingers, and face (1,9,14), but examples of PG have been described in all parts of the skin and mucous membranes including the vulva (15), scrotum (16), penis (17), and glans penis (18). In a epidemiologic study of 325 cases (9), cutaneous lesions accounted for 86% of the lesions, with mucosal lesions representing only 12% of the cases. Overall, male patients outnumbered female patients. The peak incidence for PG is around the second decade of life. PG usually develop at the site of a preexisting injury, where they evolve rapidly over a period of weeks to a maximum size and then shrink and become replaced by fibrous tissue, which eventually disappears within a few months. PG is especially common in children and

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Fig. 3. Pyogenic granuloma, a dome-shaped papule with angiomatous appearance, involving the lower lip of a boy.

young adults. The gingival lesions that develop during pregnancy, known as epulis gravidarum, are identical to PG (2). In rare instances, PG may develop within a preexisting lesion such as a nevus flammeus (19–22) or in a spider angioma (23). When the lesions are multiple, these tend to be grouped in a localized area (23–34) (Fig. 4), but they can also extend in a eruptive and disseminated fashion (8,35–39). With a few exceptions, multiple recurrent lesions are more common in adolescents and young adults, and they occur after attempts at electrodesiccation or surgical removal of the primary single lesion. Multiple lesions can also occur after removal of melanocytic lesions (40) or in burns (41). The most common site for multiple lesions is the trunk, especially the interscapular region. Eruptive widespread lesions of PG have been described as a paraneoplastic manifestation in a patient affected with Hodgkin’s disease (38), but in most cases no underlying disease is identified (8,35–37). Rare variants of PG include the subcutaneous (42,43) and intravenous (44–48) forms. Lesions quite similar to PG have been reported in patients receiving oral retinoid therapy for acne or psoriasis (4–7), oral indinavir (10,11), as well as topical applications of tretinoin (12) or tazarotene creams (13). HISTOPATHOLOGIC FEATURES Early lesions of PG are identical to granulation tissue, to wit, numerous capillaries and venules disposed radially to the skin surface, which is often eroded and covered with scabs (Fig. 5). The stroma is edematous and contains a mixed inflammatory infiltrate with lymphocytes, histiocytes, plasma cells, neutrophils, and an increased number of mast cells (49). Fully developed lesions of PG are polypoid and show a lobular pattern with fibrous septa intersecting the lesion, hence the name lobular capillary hemangioma (1) used by some authors for this stage of the lesion. Each lobule is composed of aggregations of capillaries and venules lined by plump endothelial cells. At this stage the lesion has reepithelialized entirely, and it is covered by epidermis with collarettes of hyperplastic adnexal epithelium partially embracing the lesion at the periphery. The inflammatory infiltrates are sparse, and edema of the stroma has disappeared. In the late stages of PG there is a steady increase in the amount of fibrous tissue, so as the fibrotic struts widen, the lobules of capillaries become smaller and, with time, PG evolves into a fibroma. When the specimen is deep enough, a small feeding artery and one or more veins may be seen ascending from the subcutaneous fat throughout the reticular dermis to enter the base of a PG directly. The histopathologic findings are the same in all variants.


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Fig. 4. Multiple recurrent lesions after electrodesiccation of a PG on the scalp of an elderly patient.

Uncommon histopathologic features in lesions of PG include intravascular papillary endothelial hyperplasia (50) and extramedullary hematopoiesis (51). When the lesions of PG recur, they may show some atypical features and in some cases even resemble an angiosarcoma. In recurrent lesions there are anastomosing vascular channels lined by endothelial cells that infiltrate and dissect between the dermal collagen bundles, vaguely mimicking an angiosarcoma, specially in the deeper areas of the lesion (24). When lesions of PG develop within a vein (Fig. 6), they are usually attached to the wall of the vein by a stalk, and the lobular pattern is less prominent than in their extravascular counterparts (44). Immunoperoxidase investigations have documented factor VIII-related antigen positivity in the endothelial cells lining large vessels but negativity in the cellular areas (52), whereas Ulex europaeus I lectin binds to the endothelial cells in both large vessels and cellular aggregates (53). Ultrastructural studies have demonstrated the capillary nature of most of the blood vessels that make up PG (45,54,55). Polymerase chain reaction (PCR) investigations for human papillomavirus (56) and HHV8 (57) have yielded negative results. Immunohistochemical studies have demonstrated the expression of inducible nitric oxide synthase (58), increased expression of vascular endothelial growth factor (59), low apoptotic rate expression of Bax/Bcl-2 proteins (60), and strong expression of phosphorylated mitogen-activated protein kinase (61) in PG lesions.

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Fig. 5. Histopathologic features of PG. (A) Low power shows a polypoid lesion with eroded surface. (B) Higher magnification demonstrates capillary blood vessels surrounded by inflammatory infiltrate of neutrophils and lymphocytes. (C) Blood vessels lined by uniform cuboidal endothelial cells without atypia.


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TREATMENT The pedunculated lesions of PG are easily removed by electrodesiccation and curettage. Other therapies that are successful include sclerotherapy with monoethanolamine oleate (62) and laser therapy (63–65). When the proliferating vessels extend deep within the reticular dermis, recurrences are frequent. In these cases, an excision including a narrow ellipse of normal adjacent tissue should be performed.

References 1. Mills SE, Cooper PH, Fechner RE. Lobular capillary hemangioma: the underlying lesion of pyogenic granuloma: a study of 73 cases from the oral and nasal mucous membranes. Am J Surg Pathol 1980;4:471–9. 2. LeBoit PE. Lobular capillary proliferation: The underlying process in diverse benign cutaneous vascular neoplasms and reactive conditions. Semin Dermatol 1989;8:298–310. 3. Musalli NG, Hopps RM, Johnson NW. Oral pyogenic granuloma as a complication of pregnancy and the use of hormonal contraceptives. Int J Gynecol Obstet 1976;14:187–91. 4. Campbell JP, Grekin RC, Ellis CN, Matsuda-John SS, Swanson NA, Voorhes JJ. Retinoid therapy is associated with excess granulation tissue responses. J Am Acad Dermatol 1983;9:708–13. 5. Blumental G. Paronychia and pyogenic granuloma like lesions with isotretinoin. J Am Acad Dermatol 1984;10:677–8. 6. Hodak E, David M, Feverman EJ. Excess granulation tissue during etretinate therapy. J Am Acad Dermatol 1984;11:1166–7. 7. Miller RAW, Ross JB, Martin J. Multiple granulation tissue lesions occurring in isotretinoin treatment of acne vulgaris—successful response to topical corticosteroid therapy. J Am Acad Dermatol 1985;12:888–9. 8. Wilson BB, Greer KE, Cooper PH. Eruptive disseminated lobular capillary hemangioma (pyogenic granuloma). J Am Acad Dermatol 1989;21:391–4. 9. Harris MN, Desai R, Chuang TY, Hood AF, Mirowski GW. Lobular capillary hemangiomas: an epidemiologic report, with emphasis on cutaneous lesions. J Am Acad Dermatol 2000;42:1012–6. 10. Bouscarat F, Bouchard C, Bouhour D. Paronychia and pyogenic granuloma of the great toes in patients treated with indinavir. N Engl J Med 1998;338:1776–7. 11. Sass JO, Jakob-Solder B, Heitger A, Tzimas G, Sarcletti M. Paronychia with pyogenic granuloma in a child treated with indinavir: the retinoid-mediated side effect theory revisited. Dermatology 2000;200:40–2. 12. Mackenzie-Wood AR, Wood G. Pyogenic granuloma-like lesions in a patient using topical tretinoin. Australas J Dermatol 1998;39:248–50. 13. Dawkins MA, Clark AP, Feldman SR. Pyogenic granuloma-like lesion associated with topical tazarotene therapy. J Am Acad Dermatol 2000;43:154–5. 14 Kerr DA. Granuloma pyogenicum. Oral Surg Oral Med Oral Pathol 1950;4:158–76. 15. Gupta S, Radotra BD, Kumar B. Multiple genital lobular capillary haemangioma (pyogenic granuloma) in a young woman: a diagnostic puzzle. Sex Transm Infect 2000;76:51–2. 16. Abdul Gaffoor PM. Pyogenic granuloma of the scrotum. Cutis 1998;62:282. 17. Tomasini C, Puiatti P, Bernego MG. Multiple pyogenic granuloma of the penis. Sex Transm Infect 1998;74:221–2. 18. Maeda Y, Izutani T, Yonese J, Ishikawa Y, Fukui I. Pyogenic granuloma of the glans penis. Br J Urol 1998;82:771–2. 19. Swerlick RA, Cooper PH. Pyogenic granuloma (lobular capillary hemangioma) within port-wine stains. J Am Acad Dermatol 1983;8:627–30. 20. Lee JB, Kim M, Lee SC, Won YH. Granuloma pyogenicum arising in an arteriovenous hemangioma associated with a port-wine stain. Br J Dermatol 2000;143:669–71.

Fig. 6. (Opposite page) Histopathologic features of intravascular PG. (A) Low power shows a blood vessel with obliterated lumen. (B) Higher magnification demonstrates that the lumen is obliterated by a capillary blood vessel proliferation.

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21. Katta R, Bickle K, Hwang L. Pyogenic granuloma arising in port-wine stain during pregnancy. Br J Dermatol 2001;144:644–5. 22. Kim TH, Choi EH, Ahn SK, Lee SH. Vascular tumors arising in port-wine stains: two cases of pyogenic granuloma and a case of acquired tufted angioma. J Dermatol 1999;26:813–6. 23. Okada N. Solitary giant spider angioma with an overlying pyogenic granuloma. J Am Acad Dermatol 1987;16:1053–4. 24. Warner J, Wilson Jones E. Pyogenic granuloma recurring with multiple satellites. A report of 11 cases. Br J Dermatol 1968;80:218–27. 25. Blickenstalff RD, Roenigk RK, Peters MS, Goellner JR. Recurrent pyogenic granuloma with satellitosis. J Am Acad Dermatol 1989;21:1241–4. 26. Coskey RJ, Mehregan AH. Granuloma pyogenicum with multiple satellite recurrences. Arch Dermatol 1967;96:71–3. 27. Dillman AM, Miller RC, Hansen RC. Multiple pyogenic granulomata in childhood. Pediatr Dermatol 1991;8:28–31. 28. De Graciansky P, Leclercq R, Timsit ED, Nguyen NL, Beer F. Granulome pyogenique recidivant avec multiple satellites. Ann Dermatol Syphilol 1971;98:408–9. 29. Zaynoum ST, Juljulian HH, Kurban AK. Pyogenic granuloma with multiple satellites. Arch Dermatol 1974;109:689–91. 30. Allen RG, Rooman OG. Pyogenic granuloma recurrent with satellite lesions. J Dermatol Surg Oncol 1979;5:490–3. 31. Amerigo J, Gonzalez-Campora R, Galera H, Sanchez-Conejo J, Moreno J, Sotillo J. Recurrent pyogenic granuloma with multiple satellites. Clinicopathological and ultrastructural study. Dermatologica 1983;166:117–21. 32. Patrice SJ, Wiss K, Mulliken JB. Pyogenic granuloma (lobular capillary hemangioma): a clinicopathologic study of 178 cases. Pediatr Dermatol 1991;8:267–76. 33. Strohal R, Gillitzer R, Zonzits E, Stingl G. Localized vs generalised pyogenic granuloma: a clinicopathologic study. Arch Dermatol 1991;127:856–61. 34. Taira JW, Hill TL, Everett MA. Lobular capillary hemangioma (pyogenic granuloma) with satellitosis. J Am Acad Dermatol 1992;27:297–300. 35. Nappi O, Wick MR. Disseminated lobular capillary hemangioma (pyogenic granuloma): a clinicopathologic study of two cases. Am J Dermatopathol 1986; 8:379–85. 36. Juhlin L, Hjertquist SO, Ponten J, Wallin J. Disseminated granuloma: pyogenicum. Acta Derm Venereol 1970;50:134–6. 37. Kaminsky AR, Otero AC, Kaminsky CA, et al. Multiple disseminated pyogenic granuloma. Br J Dermatol 1978;98:461–4. 38. Pembroke AC, Grice K, Levanntine AV, et al. Eruptive angiomata in malignant disease. Clin Exp Dermatol 1978;3:147–56. 39. Shah M, Kingston TP, Cotterill JA. Eruptive pyogenic granulomas: a successfully treated patient and review of the literature. Br J Dermatol 1995;133:795–6. 40. Deroo M, Eeckhout I, Naeyaert JM. Eruptive satellite vascular malformations after removal of a melanocytic naevus. Br J Dermatol 1997;137:292–5. 41. Ceyhan M, Erdem G, Kotiloglu E, et al. Pyogenic granuloma with multiple dissemination in a burn lesion. Pediatr Dermatol 1997;14:213–5. 42. Cooper PH, Mills SE. Subcutaneous granuloma pyogenicum: lobular capillary hemangioma. Arch Dermatol 1982;118:30–3. 43. Park YH, Houh D, Houh W. Subcutaneous and superficial granuloma pyogenicum. Int J Dermatol 1996;35:205–6. 44. Cooper PH, McAllister HA, Helwig EB. Intravenous pyogenic granuloma: a study of 18 cases. Am J Surg Pathol 1979;3:221–8. 45. Ulbright TM, Santa Cruz DJ. Intravenous pyogenic granuloma: case report with ultrastructural findings. Cancer 1980;45:1646–52. 46. Pesce C, Valente S, Gandolfo AM, Lenti E. Intravascular lobular capillary haemangioma of the lip. Histopathology 1996;29:382–4. 47. Song MG, Kim HJ, Lee ES. Intravenous pyogenic granuloma. Int J Dermatol 2001;40:57–9. 48. Qian LH, Hui YZ. Intravenous pyogenic granuloma: immunohistochemical considerations—a case report. Vasc Surg 2001;35:315–9.


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49. Hagiwara K, Khaskhely NM, Uezato H, Nonaka S. Mast cell “densities” in vascular proliferations: a preliminary study of pyogenic granuloma, portwine stain, cavernous hemangioma, cherry angioma, Kaposi’s sarcoma, and malignant hemangioendothelioma. J Dermatol 1999;26:577–86. 50. Inaloz HS, Patel G, Knight AG. Recurrent intravascular papillary endothelial hyperplasia developing from a pyogenic granuloma. J Eur Acad Dermatol Venereol 2000;15:156–8. 51. Rowlands CG, Rapson D, Morell T. Extramedullary hematopoiesis in a pyogenic granuloma. Am J Dermatopathol 2000;22:434–8. 52. Burgdorf WHC, Mukai K, Rosai J. Immunohistochemical identification of factor VIII related antigen in endothelial cells of cutaneous lesions of alleged vascular nature. Am J Clin Pathol 1981;75:167–71. 53. Miettinen M, Holthofer H, Lehto V-P et al. Ulex europaeus lectin as marker for tumors derived from endothelial cells. Am J Clin Pathol 1983;79:32–6. 54. Davies MG, Barton SP, Atai F, et al. The abnormal dermis in pyogenic granuloma: histochemical and ultrastructural observations. J Am Acad Dermatol 1980;2:132–42. 55. Marsch WC. Zur ultrastruktur des eruptiven kapillären Hämangioms (“Granuloma pyogenicum”). Hautarzt 1984;35:92–6. 56. Miller AM, Sahl WJ, Brown SA, et al. The role of human papillomavirus in the development of pyogenic granulomas. Int J Dermatol 1997;36:673–6. 57. De Aloe G, Rubegni P, Pacenti L, Miracco C, Fimiani M. Human herpesvirus type 8 is not associated with pyogenic granulomas with satellite recurrence. Br J Dermatol 2001;144:202–3. 58. Shimizu K, Naito S, Urata Y, Sekine I, Kondo T, Katayama I. Inductible oxide synthase is expressed in granuloma pyogenicum. Br J Dermatol 1998;138:769–73. 59. Bragado R, Bello E, Requena L, et al. Increased expression of vascular endothelial growth factor in pyogenic granulomas. Acta Derm Venereol 1999;79:422–5. 60. Nakamura T. Apoptosis and expression of Bax/Bcl-2 proteins in pyogenic granuloma: a comparative study with granulation tissue and capillary hemangioma. J Cutan Pathol 2000;27:400–5. 61. Arbiser JL, Weiss SW, Arbiser ZK, et al. Differential expression of active mitogen-activated protein kinase in cutaneous endothelial neoplasms: implications for biologic behavior and response to therapy. J Am Acad Dermatol 2001;44:193–7. 62. Matsumoto K, Nakanishi H, Seike T, Koizumi Y, Mihara K, Kubo Y. Treatment of pyogenic granuloma with a sclerosing agent. Dermatol Surg 2001;27:521–3. 63. Gonzalez S, Vibhagool C, Falo LD Jr, Momtaz KT, Grevelink J, Gonzalez E. Treatment of pyogenic granulomas with the 585 nm pulsed dye laser. J Am Acad Dermatol 1996;35:428–31. 64. Tay YK, Weston WL, Morelli JG. Treatment of pyogenic granuloma in children with the flashlamppumped pulsed dye laser. Pediatrics 1997;99:368–70. 65. Kirschner RE, Low DW. Treatment of pyogenic granuloma by shave excision and laser photocoagulation. Plast Reconstr Surg 1999;104:1346–9.

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3. BACILLARY ANGIOMATOSIS In 1983, Stoler et al. (1) called attention to an unusual infection occurring in patients affected with AIDS. These authors described their cases as “An atypical subcutaneous infection associated with acquired immune deficiency syndrome.” Four years later Cockerell et al. (2) reported on similar cases, using the term “epithelioid angiomatosis,” to emphasize the vascular nature of these proliferations. A year later, LeBoit et al. in San Francisco, suggested the possibility of an infectious agent as the cause of the disease. These authors also suggested the possibility of a relationship between the agent of bacillary angiomatosis and the causative agent of cat scratch disease (3). A few months later, the same group confirmed the infectious nature of the disease utilizing the Warthin-Starry technique to demonstrate the organism (4). CLINICAL FEATURES Bacillary angiomatosis preferentially affects patients with AIDS (2–4), but it has also been described in patients with other immunodeficiency disorders including leukemic patients (5), patients receiving systemic steroid therapy (6), and renal transplant recipients receiving cyclosporine and prednisone (7). Several recent reports have also documented bacillary angiomatosis in immunocompetent patients, both children (8,9) and adults (10–12) without HIV infection and without risk factors for the disease. The causative microorganisms of bacillary angiomatosis are of the genus Bartonella (formerly Rochalimaea) (13). Two species of Bartonella cause bacillary angiomatosis: B. quintana and B. henselae. Because of the difficulty in culturing these organisms, the diagnosis of bacillary angiomatosis was initially established based on the clinical features of the disease combined with serologic studies, molecular biology studies, or tissue demonstration of the organisms using the Warthin-Starry staining technique. Currently, the diagnosis of Bartonella infection can be established based on the results of blood, cutaneous, or visceral cultures (14) or PCR methods for the detection of Bartonella sp (15). Despite numerous attempts HHV-8 has not been demonstrated in lesions of bacillary angiomatosis (16,17). The vast majority of patients with bacillary angiomatosis are advanced AIDS patients with CD4+ lymphocytic counts of less than 200 cells/mm3. There is a strong association between a cat scratch or bite and bacillary angiomatosis; furthermore, B. henselae has been isolated from the blood and fleas of infected cats, supporting the notion that cats may serve as a reservoir of the disease in some patients. It is also possible that humans may act as reservoirs of the disease; chronic B. quintana bacteremia has been demonstrated in homeless patients in different geographic areas (18). Bacillary angiomatosis can involve the skin and/or internal organs. It is usually accompanied by systemic symptoms (19). Cutaneous lesions are either single or multiple; some patients have a widespread eruption with a myriad of lesions. Lesions on the skin usually begin as small, red to purple, pinpoint-size papules that increase in size to form nodules and tumors. Individual lesions often resemble PG (Fig. 7). When deep lesions are present, they appear as erythematous subcutaneous nodules that may attain several centimeters in diameter (20). In other occasions the subcutaneous nodules present as violaceous plaques and tumors resembling Kaposi’s sarcoma. Atypical clinical presentations include large fungating masses (21) and ulcers (22). Involvement of the oral and genital mucous membranes is fairly common (23).


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Fig. 7. Bacillary angiomatosis in a patient with AIDS.

HISTOPATHOLOGIC FEATURES Histopathologically (24–26), bacillary angiomatosis exhibits a lobular pattern with a prominent proliferation of capillaries separated by connective tissue septa (Fig. 8). The connective tissue is less evident than in PG. Polypoid lesions often show collarettes of adnexal epithelium at the periphery, which imparts even more similarity to PG. The endothelial cells lining vessels are plump, with an epithelioid appearance, and protrude into the vascular lumens. Neutrophils and leukocytoclastic debris are characteristically found throughout the lesions, and they are a helpful clue to the specific diagnosis. The most characteristic and specific finding in sections stained with hematoxylin and eosin stain is the presence of aggregates of a granular purplish material of variable size. With either Warthin-Starry stain or electron microscopy these aggregates are revealed to be masses of bacteria, which are found more frequently in the deeper cellular areas. In general, the number of neutrophils generally parallels the number of the amphophilic granular aggregates. TREATMENT Bacillary angiomatosis responds well to treatment with oral erythromycin or tetracycline, although repeated courses may be necessary because the disease has a tendency to relapse.

References 1. Stoler MH, Bonfiglio TA, Steigbigel RT, et al. An atypical subcutaneous infection associated with acquired immune deficiency syndrome. Am J Clin Pathol 1983;80:714–8. 2. Cockerell CJ, Webster GF, Whitlow MA, et al. Epithelioid angiomatosis: a distinct vascular disorder in patients with the acquired immunodeficiency syndrome or AIDS-related complex. Lancet 1987;2:654–6. 3. LeBoit PE, Berger TG, Egbert BM, et al. Epithelioid hemangioma —like vascular proliferation in AIDS. Manifestation of cat-scratch disease bacillus or infection? Lancet 1988;1:960–3. 4. Koehler JE, LeBoit PE, Egbert BM, et al. Cutaneous vascular lesions and disseminated cat-scratch disease in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. Ann Intern Med 1988;109:449–55. 5. Milde P, Brunner M, Borchard F, et al. Cutaneous bacillary angiomatosis in a patient with chronic lymphocytic leukemia. Arch Dermatol 1995;131:933–6.

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Fig. 8. Histopathologic features of bacillary angiomatosis. (A) Scanning magnification shows the involvement of the entire thickness of the dermis with abundant vascular channels. (B) Higher magnification demonstrates that the endothelial cells lining vessels are plump and have an epithelioid appearance. Some of the cells contain granular purple material within their cytoplasm, which are masses of bacteria. (C) Warthin-Starry stain demonstrates numerous bacteria within the cytoplasm of the endothelial cells.


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6. Schwartz RA, Gallardo MA, Kapila R, et al. Bacillary angiomatosis in an HIV seronegative patient on systemic steroid therapy. Br J Dermatol 1996;135:982–7. 7. Cline MS, Cummings OW, Goldman M, Filo RS, Pescovitz MD. Bacillary angiomatosis in a renal transplant recipient. Transplantation 1999;27:296–8. 8. Paul MA, Fleischer AB, Wieselthier JS, White WL. Bacillary angiomatosis in an immunocompetent child. The first reported case. Pediatr Dermatol 1994;11:338–41. 9. Smith KJ, Skelton HG, Tuur S, Larson PL, Angritt P. Bacillary angiomatosis in an immunocompetent child. Am J Dermatopathol 1996;18:597–600. 10. Cockerell CJ, Bergstresser PR, Myrie-Williams C, et al. Bacillary epithelioid angiomatosis occurring in an immunocompetent individual. Arch Dermatol 1990;126:787–90. 11. Tappero JW, Koehler JE, Berger TG, et al. Bacillary angiomatosis and bacillary splenitis in immunocompetent adults. Ann Intern Med 1993;118:363–5. 12. Karakas M, Baba M, Aksungur VL, Homan S, Memisoglu HR, Uguz A. Bacillary angiomatosis on a region of burned skin in a immunocompetent patient. Br J Dermatol 2000;143:609–11. 13. Welch DF, Slater LN. Bartonella. In: Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH, eds. Manual of Clinical Microbiology, 6th ed. Washington DC, AMS Press, 1995:690–5. 14. Cockerell CJ. Bacillary angiomatosis and related diseases caused by Rochalimaea. J Am Acad Dermatol 1995;32:783–90. 15. Gasquet S, Maurin M, Brouqui P, Lepidi H, Raoult D. Bacillary angiomatosis in immunocompromised patients. AIDS 1998;12:793–803. 16. Relman DA, Fredricks DN, Yoder KE, Mirowski G, Berger T, Koehler JE. Absence of Kaposi’s sarcomaassociated herpesvirus DNA in bacillary angiomatosis-peliosis lesions. J Infect Dis 1999;180:1386–9. 17. Nayler SJ, Allard U, Taylor L, Cooper K. HHV-8 (KSHV) is not associated with bacillary angiomatosis. Mod Pathol 1999;52:345–6. 18. Brouqui P, Lascola B, Roux V, Raoult D. Chronic Bartonella quintana bacteremia in homeless patients. N Engl J Med 1999;340:184–9. 19. Cockerell CJ, LeBoit PE. Bacillary angiomatosis: a newly characterized pseudoneoplastic, infectious, cutaneous vascular disorder. J Am Acad Dermatol 1990;22:501–12. 20. Schwartz RA, Nychay SG, Janniger CK, Lambert WC. Bacillary angiomatosis presentation of six patients, some with unusual features. Br J Dermatol 1997;136:60–5. 21. Fagan WA, DeCamp NC, Kraus EW, Pulitzer DR. Widespread cutaneous bacillary angiomatosis and a large fungating mass in an HIV-positive man. J Am Acad Dermatol 1996;35:285–7. 22. Carrascosa JM, Ribera M, Bielsa I, Raventos A, Vaquero M, Ferrandiz C. Bacillary angiomatosis presenting as a malleolar ulcer. Arch Dermatol 1995;131:963–4. 23. Levell NJ, Bewley AP, Chopra S, et al. Bacillary angiomatosis with cutaneous and oral lesions in an HIV-infected patient from the U.K. Br J Dermatol 1995;132:113–5. 24. LeBoit PE, Berger TG, Egbert BM, et al. Bacillary angiomatosis: the histopathology and differential diagnosis of pseudoneoplastic infection in patients with human immunodeficiency virus infection. Am J Surg Pathol 1989;13:909–20. 25. Szaniawski WK, Don PH, Bitterman SR, Schachner JR. Epithelioid angiomatosis in patients with AIDS. Report of seven cases and review of the literature. J Am Acad Dermatol 1990;23:41–8. 26. Cockerell CJ. The clinical-pathologic spectrum of bacillary (epithelioid) angiomatosis. Prog AIDS Pathol 1990;2:111–26.

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4. VERRUGA PERUANA Verruga peruana is the cutaneous manifestation of bartonellosis, a disease that occurs in two forms, an acute life-threatening anemia and a chronic form that manifests with warty lesions and/or subcutaneous nodules on the skin. Bartonellosis, also known as Oroya’s fever and Carrion’s disease has been known since the early 1600s. The disease is endemic to specific areas of Peru and several neighboring countries. The first documented epidemic of the disease was in the 1870s, during the construction of a railroad from Lima to Oroya, hence the name Oroya’s fever. An estimated 7000 railway workers died from the acute form of the disease during this time. A medical student by the name of Daniel Carrion is credited with the demonstration that the verruga lesions of the skin were merely another manifestation of bartonellosis. He inoculated himself with material obtained from a skin lesion and died 21 days later after developing the acute form of the disease. CLINICAL FEATURES This rare tropical disease is caused by Bartonella bacilliformis and closely resembles bacillary angiomatosis both clinically and histopathologically (1). The infection usually produces an acute, life-threatening disease termed Oroya fever. The survivors of this fever usually develop cutaneous lesions with an angiomatous appearance that clinically and histopathologically is indistinguishable from bacillary angiomatosis. However, in an epidemiologic context the diseases are different, B. bacilliformis being restricted almost entirely to the endemic areas. Patients with verruga peruana exhibit papules, nodules, and tumors. These lesions often have a similar clinical appearance to lesions of PG and bacillary angiomatosis (Fig. 9). There is a certain predilection for the cutaneous mucosal joints. As in the case of bacillary angiomatosis, the number of lesions varies from a few to thousands. HISTOPATHOLOGIC FEATURES Histopathologically, the lesions of verruga peruana consist of an exophytic, pedunculated papule composed of a proliferation of capillaries and venules, with prominent endothelial cells and bounded by epithelial collarettes at the lateral margins of the lesion (1,2) (Fig. 10). In contrast to bacillary angiomatosis, in which neutrophils are the predominant inflammatory cells, the lesions of verruga peruana exhibit an inflammatory infiltrate mostly composed of lymphocytes and plasma cells. The microorganisms of verruga peruana form intracellular inclusions termed Roca-Lima bodies, a difference from the organisms of bacillary angiomatosis, which form extracellular clumps of purplish granular material. Organisms of B. bacilliformis can be demonstrated with the Warthin-Starry stain. Immunohistochemical studies have demonstrated that the cells lining the vascular spaces are endothelial cells expressing immunoreactivity for both factor VIII-related antigen and Ulex europaeus-1 lectin (1). Ultrastructural studies have demonstrated that Roca-Lima bodies consist of phagosomes containing organisms and interstitial matrixlike material as well as a cisternal channels with similar contents (1). TREATMENT Most of the cutaneous lesions resolve spontaneously over weeks to months. There is also a variable response to antibiotic therapy with chloramphenicol, penicillin and combined tetracycline and streptomycin.


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Fig. 9. Clinical aspects of verruga peruana. (A) Multiple lesions with angiomatous appearance on the face of a Peruvian girl. (B) The same patient had similar lesions on the anterior chest and abdomen.

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Fig. 10. Histopathologic features of verruga peruana. (A) Low power shows a dome-shaped eroded papule (B) Higher magnification demonstrates that the lesion is composed of epithelioid endothelial cells with large pale cytoplasm, some of them with vacuolization. A mitotic figure is also seen.

References 1. Arias-Stella J, Liberman PH, Erlandson RA, Arias-Stella J Jr. Histology, immunohistochemistry, and ultrastructure of the verruga in Carrion’s disease. Am J Surg Pathol 1986;10:595–610. 2. Arias-Stella J, Lieberman PH, Garcia Cáceres U, et al. Verruga peruana mimicking neoplasms. Am J Dermatopathol 1987;9:279–91.


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5. INTRAVASCULAR PAPILLARY ENDOTHELIAL HYPERPLASIA (MASSON’S PSEUDO-ANGIOSARCOMA) Intravascular papillary endothelial hyperplasia (IPEH) is not a specific entity but a histopathologic pattern that can be found in multiple vascular proliferations. In 1923, Masson (1) described IPEH as a process in hemorrhoid veins using the term “hémangioendothéliome végétant intravasculaire.” He believed that these lesions were true neoplasms (1). In 1932, Henschen (2) reassessed this process and proposed a reactive etiology. The term intravascular papillary endothelial hyperplasia was coined by Clearkin and Enzinger in 1976 (3). Currently, IPEH is considered to be a reactive endothelial hyperplasia that develops in response to intravascular thrombosis, with subsequent organization and recanalization of the thrombus (3–17). In some cases, IPEH develops as a posttraumatic phenomenon (18). Lesions of IPEH may develop in vascular proliferations such as hemangiomas (5, 8), angiokeratomas (10), PGs, (5, 8,19), lymphangiomas (9,10), venous lakes (4), capillary aneurysms (11), and angiolymphoid hyperplasia with eosinophilia (15), as well as in phlebectasias (6,12) and hematomas (16,17). Occasionally no thrombus is found, which has led some authors to propose that the lesion is a primary endothelial proliferation with secondary thrombus formation (9,11,14). It seems most likely, however, that in lesions without a thrombus the endothelial hyperplasia has persisted after the thrombus has disappeared (3). CLINICAL FEATURES The diagnosis of IPEH is based on microscopic examination, since this condition lacks specific clinical findings; suffice to say that most of these lesions are located on the extremities, with a predilection for the fingers. When the lesion occurs in a preexisting vascular neoplasm, the clinical findings are usually those of the latter. Some authors have classified IPEH into three types, namely, a pure or intravascular form, a mixed form that develops in a preexisting hemangioma or other vascular neoplasm, and a third form that did not fit into either cathegory (20). Using this classification, a study of 91 cases demonstrated that lesions of the pure form were most frequently situated in the subcutaneous tissue of the fingers (14 cases), in the head and neck (7 cases), and in the region between the elbows and hands (6 cases). For the mixed form, there was no preferential site (20). Another peculiar aspect is that lesions of IPEH seem to be particularly frequent in the oral mucosa (Fig. 11), involving particularly the lower lip and the tongue (21–25), although examples of this entity have been described in different locations including the hand (26), forearm (27), penis (28), and foot (29,30). In some cases there can be numerous lesions, simulating Kaposi’s sarcoma (12,31). Occasionally, IPEH can occur in female patients who developed ipsilateral lymphedema secondary to surgery and radiation therapy for breast carcinoma, and in these cases they can mimic Stewart-Treves syndrome (32). HISTOPATHOLOGIC FEATURES Histopathologically, the proliferation of endothelial cells is present within one or more vascular lumina that have been occluded by a thrombus. In fully developed lesions, numerous papillary fronds lined by a single layer of plump endothelial cells extend from the wall of the vessel into the lumina (Fig. 12). In some areas, the tips of the papillae appear to float freely within the lumen. Endothelial cells line the papillae, and they have a central core made up of fibrin or hyalinized connective tissue. Often, the papillary

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Fig. 11. Intravascular papillary endothelial hyperplasia involving the oral mucosa. The lesion consisted of a papule with angiomatous appearance.

vascular structures are surrounded by sclerotic connective tissue; in these areas, IPEH may resemble a well-differentiated angiosarcoma. However, their sharp circumscription, the intravascular location, the lack of pleomorphism and mitotic figures in the endothelial cells, and the absence of a pattern of dissecting vascular spaces into the adjacent tissue are features that allow the microscopist to rule out an angiosarcoma. Lesions included under the descriptive name “benign atypical vascular lesions of the lip” represent examples of IPEH (33). Immunohistochemical studies have documented the endothelial nature of the cells lining the papillations (13,31), and ultrastructurally the lesion resembles granulation tissue (7). Flow cytometric analysis of cases of IPEH has demonstrated diploid DNA contents (34). TREATMENT Simple excision of the lesions of IPEH is usually curative, although recurrent cases have been also described (35,36).

References 1. Masson P. Hémangioendothéliome végétant intravasculaire. Bull Soc Anat Paris 1923;93:517–32. 2. Henschen F. L’endovasculite proliferante thrombopoietique dans la lesion vasculaire locale. Ann Anat Pathol 1932; 9:113–121. 3. Clearkin KP, Enzinger FM. Intravascular papillary endothelial hyperplasia. Arch Pathol Lab Med 1976;100:441–4.


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Fig. 12. Histopathologic features of intravascular papillary endothelial hyperplasia. (A) Low power shows a dilated blood vessel with intraluminal thrombosis. (B) Higher magnification shows irregular vascular channels with papillary formations lined by plump endothelial cells. 4. Salyer WR, Salyer DC. Intravascular angiomatosis: development and distinction from angiosarcoma. Cancer 1975;36:995–1001. 5. Kuo TT, Sayers CP, Rosai J. Masson’s “vegetant intravascular hemangioendothelioma”: a lesion often mistaken for angiosarcoma. Study of seventeen cases located in the skin and soft tissues. Cancer 1976;38:1227–36. 6. Barr RJ, Graham JH, Sherwin LA. Intravascular papillary endothelial hyperplasia. A benign lesion mimicking angiosarcoma. Arch Dermatol 1978;114:723–6. 7. Kreutner A, Smith RM, Trefny FA. Intravascular papillary endothelial hyperplasia. Light and electron microscopic observations of a case. Cancer 1978;42:2304–10. 8. Amerigo J, Matilla A, Gonzalez Campora R, Galera Davison H. Vegetant intravascular hemangioendothelioma of the skin. Report of 3 cases with critical pathogenic study. Dermatologica 1979;159:476–81. 9. Kuo TT, Gonzalo Gomez L. Papillary endothelial proliferation in cystic lymphangiomas. A lymphatic vessel counterpart of Masson’s vegetant intravascular hemangioendothelioma. Arch Pathol Lab Med 1979;103:306–8. 10. Amerigo J, Berry CL. Intravascular papillary endothelial hyperplasia in the skin and subcutaneous tissue. Virchows A Pathol Anat Histol 1980;387:81–90. 11. Paslin DA. Localized primary cutaneous intravascular papillary endothelial hyperplasia. J Am Acad Dermatol 1981;4:316–8. 12. Reed CN, Cooper PH, Swerlick RA. Intravascular papillary endothelial hyperplasia. Multiple lesions simulating Kaposi’s sarcoma. J Am Acad Dermatol 1984;10:110–3.

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13. Albrecht S, Kahn HJ. Immunohistochemistry of intravascular papillary endothelial hyperplasia. J Cutan Pathol 1990;17:16–21. 14. Rosai J, Akerman LR. Intravascular atypical vascular proliferation. Arch Dermatol 1974;109:704–17. 15. Cooper PH. Vascular tumors. In: Farmer R, Hood AF, eds. Pathology of the Skin. Norwalk, CT, Appleton & Lange, 1990:804–46. 16. Pins MR, Rosenthal DI, Springfield DS, Rosemberg AE. Florid extravascular papillary endothelial hyperplasia (Masson’s pseudoangiosarcoma) presenting as a soft-tissue sarcoma. Arch Pathol Lab Med 1993;117:259–63. 17. Chen KT. Extravascular papillary endothelial hyperplasia. J Surg Oncol 1987;36:52–4. 18. Borrelli L, Ciniglio M, Faffulli N, Del Torto M. Intravascular papillary endothelial hyperplasia in the hand of a fencer. Pathologica 1992;84:551–6. 19. Inaloz HS, Patel G, Knight AG. Recurrent intravascular papillary endothelial hyperplasia developing from a pyogenic granuloma. J Eur Acad Dermatol Venereol 2000;15:156–8. 20. Hashimoto H, Daimaru Y, Enjoji M. Intravascular papillary endothelial hyperplasia. A clinicopathologic study of 91 cases. Am J Dermatopathol 1983;5:539–46. 21. Heyden G, Dahl I, Angervall L. Intravascular papillary endothelial hyperplasia in the oral mucosa. Oral Surg Oral Med Oral Pathol 1978;45:83–7. 22. Buchner A, Merrell PW, Carpenter WM, Leider AS. Oral intravascular papillary endothelial hyperplasia. J Oral Pathol Med 1990;19:419–22. 23. Stern Y, Braslavsky D, Shpitzer T, Feinmesser R. Papillary endothelial hyperplasia in the tongue: a benign lesion that may be mistaken for angiosarcoma. J Otolaryngol 1994;23:81–3. 24. Tosios K, Koutlas IG, Papanicolaou SI. Intravascular papillary endothelial hyperplasia of the oral soft tissues: report of 18 cases and review of the literature. J Oral Maxillofac Surg 1994;52:1263–8. 25. De Courten A, Fuffer R, Samson J, Lombardi T. Intravascular papillary endothelial hyperplasia of the mouth: report of six cases and literature review. Oral Dis 1999;5:175–8. 26. Wehbe MA, Otto NR. Intravascular papillary endothelial hyperplasia in the hand. J Hand Surg [Am] 1986;11:275–9. 27. Schwartz IS, Parris A. Cutaneous intravascular papillary endothelial hyperplasia: a benign lesion that may simulate angiosarcoma. Cutis 1982;29:66–9. 28. Dekio S, Tsujino Y, Jidoi J. Intravascular papillary endothelial hyperplasia on the penis: report of a case. J Dermatol 1993;20:10:657–9. 29. Cisco RW, McCormac RM. Intravascular papillary endothelial hyperplasia of the foot. J Foot Ankle Surg 1994;33:610–6. 30. Kato H. Two cases of intravascular papillary endothelial hyperplasia developing on the sole. J Dermatol 1996;23:655–7. 31. Stewart M, Smoller BR. Multiple lesions of intravascular papillary endothelial hyperplasia (Masson’s lesions). Arch Pathol Lab Med 1994;118:315–6. 32. Romani J, Puig L, Costa I, de Moragas JM. Masson’s intravascular papillary endothelial hyperplasia mimicking Stewart-Treves syndrome: report of a case. Cutis 1997;59:148–50. 33. Renshaw AA, Rosai J. Benign atypical vascular lesions of the lip. A study of 12 cases. Am J Surg Pathol 1993;17:557–65. 34. Levere SM, Barsky SH, Meals RA. Intravascular papillary endothelial hyperplasia: a neoplastic “actor” representing an exaggerated attempt at recanalization mediated by basic fibroblast growth factor. J Hand Surg [Am] 1994;19:559–64. 35. Katzman B, Caliguri DA, Klein DM, Nicastri AD, Chen P. Recurrent intravascular papillary endothelial hyperplasia. J Hand Surg [Br] 1997;22:113–5. 36. Yamamoto T, Marui T, Mizuno K. Recurrent intravascular papillary endothelial hyperplasia of the toes. Dermatology 2000;200:72–4.


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6. PSEUDO-KAPOSI’S SARCOMA Pseudo-Kaposi’s sarcoma is an unfortunate term applied to two completely different processes, acroangiodermatitis of Mali and the Stewart-Bluefarb syndrome. Acroangiodermatitis of Mali (1) refers to skin lesions on the lower extremities of patients with chronic venous insufficiency, and Stewart-Bluefarb syndrome (2) is an arteriovenous malformation that clinically resembles Kaposi’s sarcoma.

Clinical Features Clinically, the Stewart-Bluefarb syndrome usually presents early in life and involves the lower extremities of young adults unilaterally (Fig. 13). Purple papules and macules appear, which in some instances are painful and become ulcerated. The affected limb may have an increased temperature, with varicose veins, and a palpable thrill can be felt as an expression of the underlying arteriovenous shunt. Similar changes have been described at the site of cutaneous shunts for hemodyalisis (3–5) (Figs. 14 and 15) in paralyzed extremities (6,7) and in patients with Klippel-Trenaunay syndrome (8,9). Acroangiodermatitis of Mali is simply exaggerated stasis dermatitis. The lesions are usually bilateral and develop in elderly patients with chronic venous insufficiency (Fig. 16). They have a predilection for the dorsal aspect of the feet and ankles. The lesions begin as violaceous macules and patches that develop slowly into soft, nontender, red to purple papules and nodules. Patients also present with scaly and indurated purple plaques, and

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Fig. 13. Stewart-Bluefarb syndrome in the lower extremity of young male patient. An underlying arteriovenous shunt was present.


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Fig. 14. Acroangiodermatitis involving the forearm and the hand, distally to the site of a cutaneous arteriovenous shunt for hemodialysis.

Fig. 15. Acroangiodermatitis involving the inner aspect of the forearm distally to the site of a cutaneous arteriovenous shunt for hemodialysis. The lesion showed the appearance of a purpuric plaque.

changes of stasis dermatitis are evident on the adjacent skin. Lesions identical to those of acroangiodermatitis of Mali may be seen in the distal part of an amputation stump (10,11) (Fig. 17) induced by a suction-socket prosthesis (12). HISTOPATHOLOGIC FEATURES Both types of pseudo-Kaposi’s sarcoma resemble Kaposi’s sarcoma clinically, but histopathologically they are completely different. In the Mali’s variant, the histopathologic findings are those of stasis dermatitis, namely, there is an increased number of thickwalled vessels lined by plump endothelial cells, extravasation of erythrocytes, and deposits of hemosiderin (Fig. 18). These changes are confined to the upper half of the dermis. In Stewart-Bluefarb syndrome, the entire dermis may be affected and, in large specimens, an arteriovenous shunt may be identified. Histopathologically, the differential diagnosis with early stages of Kaposi’s sarcoma is usually straightforward, keeping in mind that the patch and plaque stages of Kaposi’s sarcoma are characterized by a proliferation of irregular jagged blood vessels, which are present around preexisting venules and adnexa and are lined by thin endothelial cells. As a rule, the papillary dermis is spared in the early stages of Kaposi’s sarcoma. Recently, the expression of CD34 antigen has been proposed as a feature to histopathologically distinguish lesions of pseudo-Kaposi’s sarcoma from authentic Kaposi’s sarcoma. CD34 positivity is detected in both endothelial cells and perivascular spindle cells of Kaposi’s sarcoma, whereas no such expression is seen in pseudo-Kaposi’s sarcoma (13). Furthermore; HHV-8 is not demonstrated in lesions of pseudo-Kaposi’s sarcoma (14).


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Fig. 16. Acroangiodermatitis of Mali involving the inner aspect of the ankle of an elderly male.

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Fig. 17. Acroangiodermatitis of Mali involving the distal part of an amputation stump.


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Fig. 18. Histopathologic features of acroangiodermatitis. (A) Scanning magnification show lobular proliferations of capillaries at the superficial dermis. (B) Higher magnification demonstrates that the lobules are composed of plump endothelial cells with extravasation of erythrocytes and deposits of hemosiderin.

TREATMENT Treatment of acroangiodermatitis of Mali is unsatisfactory and often unnecessary. If it is required, treatment of venous insufficiency of the lower extremities may be followed by slow improvement of the cutaneous lesions. Patients with Stewart-Bluefarb syndrome should consult with a vascular surgeon in order to embolize or excise the arteriovenous shunt under angiographic control (15).

References 1. Mali JWH, Kuiper JT, Hamers AA. Acro-angiodermatitis of the foot. Arch Dermatol 1965;92:515–8. 2. Bluefarb SM, Adams LA. Arteriovenous malformation with angiodermatitis. Stasis dermatitis simulating Kaposi’s disease. Arch Dermatol 1967;96:176–81. 3. Goldblum OM, Kraus E, Bronner AK. Pseudo-Kaposi’s sarcoma of the hand associated with an acquired, iatrogenic arteriovenous fistula. Arch Dermatol 1985;121:1038–40. 4. Landthaler M, Stolz W, Eckert F, Schmoeckel C, Braun-Falco O. Pseudo-Kaposi’s sarcoma occurring after placement of arteriovenous shunt. A case report with DNA content analysis. J Am Acad Dermatol 1989;21:499–505.


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5. Kim TH, Kim KH, Kang JS, Kim JH, Hwang IY. Pseudo-Kaposi’s sarcoma associated with acquired arteriovenous fistula. J Dermatol 1997;24:28–33. 6. Meynadier J, Malbos S, Guilhon JJ, et al. Pseudo-angiosarcomatose de Kaposi sur membre paralytique. Dermatologica 1980;16:190–7. 7. Landthaler M, Langehenke H, Holzmann H, Braun Falco O. Akroangiodermatitis Mali (“PseudoKaposi”) and gelähmten Beinen. Hautarzt 1988;39:304–7. 8. Lund Kofoed M, Klemp P, Thestrup-Pedersen K. The Klippel-Trenaunay syndrome with acroangiodermatitis (pseudo-Kaposi’s sarcoma). Acta Derm Venereol 1985;65:75–7. 9. Lyle WG, Given KS. Acroangiodermatitis (pseudo-Kaposi’s sarcoma) associated with KlippelTrenaunay syndrome. Ann Plast Surg 1996;37:654–6. 10. Kolde G, Wörheide J, Baumgartner R, Bröcker EB. Kaposi-like acroangiodermatitis in an above-knee amputation stump. Br J Dermatol 1989;120:575–80. 11. Gucluer H, Gurbuz O, Kotiloglu E. Kaposi-like acroangiodermatitis in an amputee. Br J Dermatol 1999;141:380–1. 12. Badell A, Marcoval J, Graells J, Moreno A, Peyri J. Kaposi-like acroangiodermatitis induced by a suction-socket prosthesis. Br J Dermatol 1994;131:915–7. 13. Kanitakis J, Narvaez D, Claudy A. Expression of the CD34 antigen distinguishes Kaposi’s sarcoma from pseudo-Kaposi’s sarcoma (acroangiodermatitis). Br J Dermatol 1996;134:44–6. 14. Krengel S, Goerdt S, Kruger K, Schnitzler P, Geiss M, Tebbe B, Blume-Peytavi U, Orfanos CE. Kaposiforme, HHV-8-negative Akroangiodermatitis bei chronisch-venoser insuffizienz. Hautarzt 1999;50:208–13. 15. Utermann S, Kahle B, Petzoldt D. Erfolgreiche Langzeittherapie bei Stewart-Bluefarb-Syndrom. Hautarzt 2000;51:336–9.

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7. REACTIVE ANGIOENDOTHELIOMATOSIS Angioendotheliomatosis is a broad term that encompasses two different processes, one malignant and the other benign. Malignant angioendotheliomatosis is an intravascular form of malignant lymphoma, whereas the reactive or benign form of angioendotheliomatosis is a self-limited intravascular proliferation of endothelial cells that occurs in the skin as a response to a different stimuli (1). CLINICAL FEATURES Reactive angioendotheliomatosis is usually limited to the skin, and, in contrast to what was initially thought, is not necessarily associated with an underlying infection. Cases of reactive angioendotheliomatosis have been described in patients with subacute bacterial endocarditis, Chagas’ disease, allergic response to cow’s milk protein, pulmonary tuberculosis, cryoproteinemia, chronic lymphatic leukemia, hepatopathy and hypertensive portal gastropathy, antiphospholipid syndrome, rheumatoid arthritis, dermal amyloid angiopathy, and severe peripheral vascular atherosclerotic disease, but also in patients with no underlying disease (2–16). Clinically, the lesions appear as red-brown or violaceous nodules or plaques over the face (Fig. 19), arms, and legs (2). In addition, petecchiae, ecchymoses, and small areas

Fig. 19. Reactive angioendotheliomatosis in a patient with cryoglobulinemia. Purpuric plaques on the cheeks of an elderly woman.


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of necrosis are frequently observed (3,5). The pathogenesis remains unclear, but a circulating angiogenic factor has been proposed by some investigators (4,6). Wick and Rocamora (1) suggested that reactive angioendotheliomatosis is an unusual residual of leukocytoclastic vasculitis. In cases associated with cryoglobulinemia or cold agglutinins, the luminal deposits of cryoproteins may be the stimulus to induce the proliferation of endothelial cells (7,17). A similar pathogenesis has been proposed for glomeruloid hemangioma in POEMS syndrome (18). Reactive intravascular angiomatosis of the skin with local deposits of intravascular immunoglobulin resulting in a vascular proliferation with a glomeruloid pattern has also been described in patients with monoclonal gammopathy and chronic lymphocytic B-leukemia (19). In the cases of peripheral atherosclerotic disease, vascular insufficiency from the occluded arteries appears to be the inciting factor for the endothelial proliferation, because when the blood flow is restored by a graft bypass, the lesions resolve (8,20). We have seen examples of both intravascular and diffuse dermal reactive angioendotheliomatosis that appeared in acral areas of the forearm and hand secondary to iatrogenic arteriovenous fistulas for hemodialysis that resolved when the arteriovenous fistula was removed. We postulated that a local increase of vascular endothelial growth factor, as is the case in hypoxia, was the cause of the endothelial proliferation (21). Kunstfeld et al. (22) have recently described an example of diffuse dermal reactive angioendotheliomatosis with lesions involving the trunk in a patient undergoing chronic hemodialysis. HISTOPATHOLOGIC FEATURES Histopathologically, the intravascular form of reactive angioendotheliomatosis exhibits dilated blood vessels that contain a proliferation of endothelial cells often occluding the lumina of the vessels; occasionally there are associated fibrin thrombi (Fig. 20). Focally, recanalized “glomeruloid” blood vessels are seen, especially in the cases associated with cryoglobulinemia (7,17). Endothelial cells do not show atypia, and mitotic figures are not identified. Involved vessels are surrounded by a scanty inflammatory infiltrate of lymphocytes, neutrophils, and extravasated erythrocytes. In the cases of reactive angioendotheliomatosis associated with severe peripheral vascular atherosclerotic disease, the histopathologic picture is different. In these cases the proliferation is not localized to preexisting vessels, or if it is, proliferation is minimal; what is more prominent is the presence of diffuse, interstitial proliferations of endothelial cells that percolate between the collagen bundles of the reticular dermis (8,20–23). Immunohistochemical studies have demonstrated that the proliferating cells in reactive angioendotheliomatosis are endothelial cells, because they expressed factor VIII-related antigen, Ulex europaeus I lectin, CD34, CD31, and vimentin, but they failed to express leukocyte antigens such as leukocyte common antigen, LN2, MT1, UCHL1, and L26, as well as epithelial membrane antigen and cytokeratins (1,7,8,18,22). In some cases, proliferation of pericytic myoepithelial cells, identified by their staining with antibodies to muscle-associated proteins, are present within and around affected blood vessels (1,9,22). In rare instances of intravascular reactive angioendotheliomatosis, the proliferating intravascular cells did not mark with endothelial cell markers but with markers of histiocytic differentiation; for this type of lesion the term of intravascular histiocytosis has been proposed (24,25). PCRs carried out in paraffin-embedded sections of reactive angioendotheliomatosis for HHV-8 DNA have been negative (22).

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Fig. 20. Histopathologic features of reactive angioendotheliomatosis. (A) Low power shows numerous vascular structures scattered at different levels of the dermis. (B) Higher magnification demonstrates plump endothelial cells and fibrin thrombi occluding the lumina of the vessels. (C) Immunohistochemical studies reveal that most of the endothelial cells express immunoreactivity for CD31.

TREATMENT Cutaneous lesions of reactive angioendotheliomatosis require no treatment; most of them regress spontaneously when the cause is eliminated. In two recently described cases of diffuse dermal reactive angioendotheliomatosis, the lesions responded respectively to treatment with oral methylprednisolone (22) and isotretinoin (23).


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References 1. Wick MR, Rocamora A. Reactive and malignant “angioendotheliomatosis”: a discriminant clinicopathologic study. J Cutan Pathol 1988;15:260–71. 2. Pleger L, Tappeiner I. Zuz kenntnis der systemisierteu Endotheliomatose der cutanen Blutgefasse (Reticuloendotheliose?). Hautarzt 1959;10:359–63. 3. Ruiter M, Mandema E. New cutaneous syndrome in subacute bacterial endocarditis. Arch Inten Med 1964;113:283–90. 4. Pasyk K, Depowski M. Proliferating systemized angioendotheliomatosis of a 5-month- old infant. Arch Dermatol 1978;114:1512–5. 5. Gottron HA, Nickolowski W. Extrarenale Löhlein Herdnephritis der Haut bei Endocarditis. Arch Klin Exp Dermatol 1958;207:156–76. 6. Person JR. Systemic angioendotheliomatosis. A possible disorder of a circulating angiogenic factor. Br J Dermatol 1977;96:329–31. 7. LeBoit PE, Solomon AR, Santa Cruz DJ, Wick MR. Angiomatosis with luminal cryoprotein deposition. J Am Acad Dermatol 1992;27:969–73. 8. Krell JM, Sanchez RL, Solomon AR. Diffuse dermal angiomatosis: a variant of reactive cutaneous angioendotheliomatosis. J Cutan Pathol 1994;21:363–70. 9. Lazova R, Slater C, Scott G. Reactive angioendotheliomatosis. Case report and review of the literature. Am J Dermatopathol 1996;18:63–9. 10. Martin S, Pitcher D, Tschen J, Wolf JE Jr. Reactive angioendotheliomatosis. J Am Acad Dermatol 1980;2:117–23. 11. Schmidt K, Hartig C, Stadler R. Reaktive Angioendotheliomatose bei chronisch lymphatischer Leukamie. Hautartz 1996;47:550–5. 12. Quinn TR, Alora MB, Momtaz KT, Taylor CR. Reactive angioendotheliomatosis with underlying hepatopathy and hypertensive portal gastropathy. Int J Dermatol 1998;37:382–5. 13. Creamer D, Black MM, Calonje E. Reactive angioendotheliomatosis with the antiphospholipid syndrome. J Am Acad Dermatol 2000;42:903–6. 14. Tomasini C, Soro E, Pippione M. Angioendotheliomatosis in a woman with rheumatoid arthritis. Am J Dermatopathol 2000;22:334–8. 15. Ortonne N, Vignon-Pennamen MD, Majdalani G, Pinquier L, Janin A. Reactive angioendotheliomatosis secondary to dermal amyloid angiopathy. Am J Dermatopathol 2001;23:315–9. 16. Brazzelli V, Baldini F, Vasallo C, et al. Reactive angioendotheliomatosis in an infant. Am J Dermatopathol 1999;21:42–5. 17. Porras-Luque JI, Fernandez-Herrera J, Dauden E, Fraga J, Fernández-Villalta MJ, García-Díez A. Cutaneous necrosis by cold agglutinins associated with glomeruloid reactive angioendotheliomatosis. Br J Dermatol 1998;139:1068–72. 18. Chan JKC, Fletcher CDM, Hicklin GA, et al. Glomeruloid hemangioma: a distinctive cutaneous lesion of multicentric Castleman’s disease associated with POEMS syndrome. Am J Surg Pathol 1990;14:1036–46. 19. Salama SS, Jenkin P. Angiomatosis of skin with local intravascular immunoglobulin deposits, associated with monoclonal gammopathy. A potential cutaneous marker for B-chronic lymphocytic leukemia. A report of unusual case with immunohistochemical and immunofluorescence correlation and review of the literature. J Cutan Pathol 1999;26:206–12. 20. Kimyai-Asadi A, Nousari HC, Ketabchi N, Henneberry JM, Costarangos C. Diffuse dermal angiomatosis: a variant of reactive angioendotheliomatosis associated with atherosclerosis. J Am Acad Dermatol 1999;40:257–9. 21. Requena L, Fariña MC, Renedo G, Alvarez A, Sanchez Yus E, Sangueza OP. Intravascular and diffuse dermal reactive angioendotheliomatosis secondary to iatrogenic arteriovenous fistulas. J Cutan Pathol 1999;26:159–64. 22. Kunstfeld R, Petzelbauer P. A unique case of benign disseminated angioproliferation combining features of Kaposi’s sarcoma and diffuse dermal angioendotheliomatosis. J Am Acad Dermatol 2001;45:601–5. 23. McLaughlin ER, Morris R, Weiss SW, Arbiser JL. Diffuse dermal angiomatosis of the breast: response to isotretinoin. J Am Acad Dermatol 2001;45:462–5. 24. O’Grady JT, Shahidullah H, Doherty VR, Al-Nafussi A. Intravascular histiocytosis. Histopathology 1994;24:265-8. 25. Rieger E, Soyer HP, LeBoit PE, Metze D, Slovak R, Kerl H. Reactive angioendotheliomatosis or intravascular histiocytosis? An immunohistochemical and ultrastructural study in two cases of intravascular histiocytic cell proliferation. Br J Dermatol 1999;140:497–504.

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Chapter 8 / Benign Neoplasms

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Benign Neoplasms CONTENTS ANGIOMA SERPIGINOSUM INFANTILE HEMANGIOMAS CHERRY ANGIOMAS (SENILE ANGIOMAS) ARTERIOVENOUS HEMANGIOMA HOBNAIL HEMANGIOMA (TARGETOID HEMOSIDEROTIC HEMANGIOMA) MICROVENULAR HEMANGIOMA TUFTED ANGIOMA GLOMERULOID HEMANGIOMA ACQUIRED ELASTOTIC HEMANGIOMA KAPOSIFORM HEMANGIOENDOTHELIOMA SINUSOIDAL HEMANGIOMA GIANT CELL ANGIOBLASTOMA SPINDLE CELL HEMANGIOMA (FORMERLY SPINDLE CELL HEMANGIOENDOTHELIOMA) BENIGN LYMPHANGIOENDOTHELIOMA BENIGN VASCULAR PROLIFERATIONS IN IRRADIATED SKIN GLOMUS TUMORS HEMANGIOPERICYTOMA CUTANEOUS MYOFIBROMA

1. ANGIOMA SERPIGINOSUM Hutchinson (1) first described angioma serpiginosum in 1889, under the term “a peculiar form of a serpiginous and infective nevoid disease.” He used the term “infective” to describe the pattern of progression of the disease, rather than to suggest an infectious etiology. Angioma serpiginosum is a neoplasm characterized by a proliferation of endothelial cells and formation of new capillaries and not simply a dilation of preexisting capillaries, as in telangiectases (2). Therefore, this lesion is included among the benign vascular neoplasms. CLINICAL FEATURES Clinically, the lesions of angioma serpiginosum are characterized by multiple, minute, red to purple grouped macules that extend over a period of months to years in a serpiginous and gyrate patterns (3).There is no evidence of inflammation, hemorrhage, or pigmentation, although the purple points do not blanch completely after the application of pressure, which could cause the misinterpretation of the lesions as purpura (4). In doubtful cases, epiluminescence microscopy has been proposed as a helpful technique in

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Fig. 1. Clinical appearance of angioma serpiginosum. Multiple minute red-purple grouped macules.

distinguishing angioma serpiginosum from purpuric dermatoses (5). Frequently, there is a background of diffuse erythema. The condition is asymptomatic and occurs predominantly in young females, starting in childhood. Most cases are sporadic, but two families affected by angioma serpiginosum with an autosomal dominant inheritance have been reported (6). The lesion has a predilection for the extremities, most frequently the lower limbs (7,8) (Fig. 1), although cases involving extensive areas of the trunk and extremities have been also described (9). It is usually unilateral, at least initially, but when bilateral involvement is present, it shows an asymmetric distribution. In rare cases, the lesions may follow the Blaschko lines (10). Occasionally, angioma serpiginosum may involve the ocular and nervous system (11). After an initial period of growth, the lesions usually remain stable in adult life, and sometimes there is partial or complete regression (12). A group of lesions that has been described as atypical angioma serpiginosum are better interpreted as superficial hyperkeratotic vascular malformations (13). HISTOPATHOLOGIC FEATURES Histopathologically, angioma serpiginosum consists of clusters of dilated capillaries housed in the dermal papillae and lined by thick walls (Fig. 2). An inflammatory infiltrate is characteristically absent (14–17). Ultrastructural studies have demonstrated in the thick-walled vessels ectasias of the arteriolar type (18) that are composed of two layers: an inner layer consisting of a delicate fibrillary material and the outer layer composed of collagen bundles (19,20). The presence of numerous concentrically arranged pericytes has also been described (20). TREATMENT In some cases spontaneous and complete regression of the lesion occurs. When this is not the case good cosmetic results have been reported after treatment of lesions of angioma serpiginosum with laser therapy (21,22).

References 1. Hutchinson J. A peculiar form of serpiginosum and infective naevoid disease. Arch Surg 1889;1:275. 2. Neumann E. Some new observations on the genesis of angioma serpiginosum. Acta Derm Venereol 1971;51:194–8.


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Fig. 2. Histopathologic features of angioma serpiginosum. (A) Low power shows capillary blood vessels involving the dermal papillae. (B) Higher magnification shows that these grouped capillary blood vessels have thick walls.

3. Stevenson MJ, Lincoln CS. Angioma serpiginosum. Arch Dermatol 1967;95:16–22. 4. Cox NH, Paterson WD. Angioma serpiginosum: a simulator of purpura. Postgrad Med J 1991;67: 1065–6. 5. Ohnishi T, Nagayama T, Morita T, et al. Angioma serpiginosum: a report of 2 cases identified using epiluminescence microscopy. Arch Dermatol 1999;135:1366–8. 6. Marriott PJ, Munro DD, Ryan T. Angioma serpiginosum—familial incidence. Br J Dermatol 1975; 93:701–6. 7. Yaffee HS. Angioma serpiginosum. Arch Dermatol 1967;95:667. 8. Thiers H, Moulin G. Angiome serpigineux de Hutchinson. Bull Soc Fr Dermatol Syphiligr 1969;76:138. 9. Katta R, Wagner A. Angioma serpiginosum with extensive cutaneous involvement. J Am Acad Dermatol 2000;42:384–5. 10. Gerbig AW, Zala L, Hunziker T. Angioma serpiginosum, eine Hautveranderung entlang den BlaschkoLinien? Hautarzt 1995;46:847–9. 11. Gautier-Smith PC, Sanders MD, Sanderson KV. Ocular and nervous system involvement in angioma serpiginosum. Br J Ophthalmol 1971;55:433–43. 12. Litoux P. Angiome serpigineux (deux observations). Bull Soc Fr Dermatol Syphiligr 1969;76:54. 13. Michalowski R, Urban J. Atypical angioma serpiginosum: a case report. Dermatologica 1982; 164:331–7. 14. Baker LP, Sachs PM. Angioma serpiginosum. Arch Dermatol 1965;92:613–20. 15. Burda A, Piechocki M. Uber das sogenannte Angioma serpiginosum. Hautarzt 1968;19:499–504. 16. Barabasch R, Baur M. Angioma serpiginosum. Ein Name für verschiedene dermatologische Krankheitsbilder. Hautarzt 1971;22:436–42. 17. Laugier P. L’angiome serpigineux de Hutchinson. Dermatologica 1967;135:369–74. 18. Reymond JL, Stoebner P, Amblard P. Telangiectasies naevoides acquises. Dermatologica 1979;159:489–94. 19. Kumakiri M, Katoh N, Miura Y. Angioma serpiginosum. J Cutan Pathol 1980;7:410–21. 20. Chavaz P, Laugier P. Angiome serpigineux de Hutchinson: etude ultrastructurale. Ann Dermatol Venereol 1981;108:429–36. 21. Polla LL, Tan OT, Garden JM, Parrish JA. Tunable pulsed dye laser for the treatment of benign cutaneous vascular ectasia. Dermatologica 1987;174:11–7. 22. Long CC, Lanigan SW. Treatment of angioma serpiginosum using a pulsed tunable dye laser. Br J Dermatol 1997;136:631–2.

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2. INFANTILE HEMANGIOMAS Infantile hemangiomas are the most common vascular proliferation in infancy. Traditionally this lesion has been classified among the benign neoplasms or hemangiomas since it is created by a rapid proliferation of endothelial cells. However, their pattern of behavior calls to mind a hyperplasia rather than a neoplasm, as the lesion characteristically has an initial rapid proliferative phase followed by a quiescent, nonproliferative (or stable) phase, followed by involution. Although hemangiomas may be present at birth, they usually delay appearance until the second week of life. Erroneously, for many years infantile hemangiomas were designated as capillary, cavernous, or mixed. In accordance with this classification, superficial hemangiomas exhibited a “capillary” proliferation, deep hemangiomas exhibited “cavernous” configurations, and a hemangioma that resided in the superficial and deep dermis exhibited “mixed capillary and cavernous” components. Mulliken and Glowacki (1) affirmed that all hemangiomas, at a given point in time, show a remarkably consistent architectural pattern throughout the entire depth of the lesion. Thus the terms “capillary” and “cavernous” are inappropriate both clinically and histopathologically. It is more appropriate to designate bright red hemangiomas as superficial and those with normal overlying skin as deep. Hemangiomas with both superficial and deep components appear bright red in their exophytic portions which overlie the subcutaneous nodule. CLINICAL FEATURES Superficial hemangiomas are found within the papillary dermis, whereas deep hemangiomas are located in the reticular dermis and subcutaneous fat. Coloration is reflective of the location of the lesion, with variance from a vivid crimson color in those of the superficial dermis, to a bluish hue, overlain by normal skin, in those situated in the lower dermis. Dilated veins or telangiectases may be seen on the surface of a deep hemangioma. During infancy, it may be difficult to distinguish a hemangioma from a vascular malformation (2). As distinctive features, hemangiomas are rarely visible at birth, but they appear 2–3 wk thereafter and they grow rapidly during the first weeks of life. Contrastingly, vascular malformations are usually evident at birth and enlarge commensurate with the child’s growth. As exceptions to this rule: (1) the noninvoluting congenital hemangioma (3) is present at birth, grows proportionately with the child, and does not regress; and (2) the congenital nonprogressive hemangioma (4) is present at birth, does not show the typical postnatal proliferative phase, and remains stable. Coloration is helpful in distinguishing a hemangioma from a vascular malformation. The bright red color of a superficial hemangioma deepens during the first year of life, whereas the hue of a vascular malformation persists unaltered. Palpation is also helpful. Hemangiomas have a firm or rubbery consistency, whereas vascular malformations are soft, easily compressible, masses. Unequivocal distinction is not always possible. Reexamination after a few weeks usually resolves the problem, since rapid growth during the early weeks of life favors the diagnosis of hemangioma. As a practical matter, there is rarely need for an immediate diagnosis and therapy. Imaging studies are also useful. Noninvasive techniques, such as ultrasonography with Doppler studies, may disclose the high-flow pattern of a hemangioma which is distinct from a solid tumor or vascular malformation (5). With computed tomography, a proliferative hemangioma appears as a well-circumscribed homogeneous lesion, whereas a vascular malformation shows heterogeneous densities, sometimes with calcifications and multilocular cysts (6). Mag-


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Fig. 3. Infantile hemangioma involving the tip of the nose.

netic resonance imaging (MRI) demonstrates well-circumscribed, densely lobulated masses with an intermediate signal intensity on T1-weighted images and a moderately hyperintense signal on T2-weighted images (7). Infantile hemangiomas have a high prevalence. They affect 1–3% of all neonates (8,9) and approx 10% of infants by the end of the first year of life (10,11). Evidence clearly defines a higher incidence in premature infants, inversely related to the gestational age at birth (12,13). The incidence of hemangioma is 10 times greater in children born of women who had chorionic-villus sampling compared with children of women without this maternal history (14). The incidence among twins denies hereditary factors (15). In rare instances, however, hemangiomas are familial, and several kindreds reflect an autosomal dominant pattern of inheritance (16). At its inception, the lesion appears as a pink macule that enlarges to become a domeshaped, red to purple plaque with a smooth or lobulated surface. Although they may occur anywhere on the skin, the head (Fig. 3) and neck (Fig. 4) are favorite locations, with the trunk and limbs constituting sites of next frequency. Not uncommonly, hemangiomas involve mucous membranes of the oral and genital regions. A solitary lesion is the rule; however, 15–20% of involved infants manifest multiplicity. There may be visceral lesions too (see below). Infantile hemangiomas characteristically proceed through different stages: a growth phase during the early years of life, a stable period, and then characteristically, spontaneous regression. Virtually, 100% of infantile hemangiomas undergo some degree of

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Fig. 4. Ulcerated infantile hemangioma on the dorsum of the neck.

spontaneous regression (Fig. 5). It has been estimated that approx 30% of infantile hemangiomas will have resolved by the third birthday, about 50% by the fifth, and about 70% by the seventh (17,18). If the hemangioma does not show signs of regression by the time a child is 5 or 6 years of age, complete regression is unlikely. Lesions that exhibit early changes of regression typically do so more rapidly with better cosmetic results (18). The likelihood of spontaneous regression in infantile hemangiomas is not related to their size, conventional anatomic location, number of aggregated lesions, or age of first appearance. Nevertheless, unconventional hemangiomas of the tip of the nose, lip, and parotid area are notably slow to involute (18). The appearance of white streaks of fibrosis on the surface of a lesion is an early sign of regression. When the resolution is complete, the affected area may resemble normal skin, but more commonly retains degrees of atrophy, telangiectases, or redundant anetodermic skin. Occasionally, infantile hemangiomas ulcerate during their proliferative phase with resultant (1) permanent loss of tissue; (2) mutilation of the involved area; (3) recurrent bleeding; or (4) secondary infection with septicemia (19). The location of the lesion may introduce singular complications: (1) hemangiomas on the eyelids can impair vision and result in amblyopia; (2) lesions of the nose, mouth, or upper airway may interfere with feeding and/or respiration; and (3) hemangiomas on the ear may block the external auditory canal sufficiently to impair hearing (20,21). In all these cases, directed treatment may be required (22). A consumptive coagulopathy (Kasabach-Merritt syndrome) is a serious complication of large hemangiomas. This rare syndrome, first described in 1940 (23), consists of thrombocytopenic purpura and chronic consumptive coagulopathy. Hemorrhage is a consequence of platelet sequestration and the consumption of clotting factors within the vascular spaces of the hemangioma (24–38). In general, this syndrome is associated with


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Fig. 5. Regression of infantile hemangioma (A) Infantile hemangioma involving the lateral aspect of the elbow in a 6-mo-old boy. (B) The same lesion 2 yr later.

large hemangiomas localized on a limb or a portion of the trunk and proximal adjacent limb. It has also been described in association with visceral angiomatosis, multiple glomangiomas, and the blue rubber bleb nevus syndrome. Recent studies, however, have confirmed that most cases of Kasabach-Merritt syndrome are not associated with common infantile hemangiomas, but with kaposiform hemagioendothelioma and tufted angioma (39–41). Kasabach-Merritt syndrome occurs with greatest frequency during the early weeks of life. Clinically, this coagulopathy should be suspected in children with large hemangiomas who show pallor, petechiae or ecchymoses, bruisability, prolonged bleeding from superficial abrasions or rapid changes in the size or appearance of a hemangioma. In these cases, the hematologic evaluation should be prompt and should include hematocrit, platelet count, prothrombin time, partial thromboplastin time, fibrinogen level, and determination of fibrin split products (24). Although, in most cases Kasabach-Merritt syndrome is self-limited and remits when the hemangioma begins to involute, it could be fatal, with mortality figures cited from 20 to 30% (25,26). Consumption coagulopathy and/or bleeding diathesis necessitate prompt therapy. Extensive hemangiomas of the neck and face (PHACES syndrome) may be associated with multiple anomalies, notably (1) posterior fossa malformations; (2) hemangiomas of the cervicofacial region; (3) arterial anomalies; (4) cardiac anomalies; (5) ocular anomalies; and (6) sternal or abdominal clefting or ectopia cordis (42–48) (Figs. 6 and 7). Hemangiomas of the lumbosacral region are markers for occult spinal malformations and anomalies of the anorectal and urogenital regions (49,50). Imaging of the spine is indicated for all patients with midline hemangiomas in this region. Multiple cutaneous hemangiomas can coexist with visceral hemangiomas, an association that has been variously termed diffuse neonatal hemangiomatosis, (51) disseminated hemangiomatosis (52). disseminated eruptive hemangiomas (53), or miliary hemangiomas (54). (Figs. 8 and 9).Visceral lesions can involve the liver, gastrointestinal tract, spleen, pancreas, adrenals, lungs, heart, skeletal muscle, salivary glands, kidney, bladder, testes, thymus, thyroid, bone, meninges, brain, and eyes (51–60). Extensive visceral involvement is associated with higher mortality during the early months of life, with death resultant from congestive heart failure. Other complications include intestinal bleeding, obstructive jaundice, convulsions, and central nervous system hemorrhage.

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Fig. 6. PHACES syndrome. Extensive hemangioma involving the neck, face, and anterior chest.

Fig. 7. PHACES syndrome. Extensive hemangioma involving the neck, face, and parotid gland.

Accordingly, infants with multiple cutaneous hemangiomas should be investigated by ultrasound, X-ray, or MRI to rule out the possibility of visceral involvement. Multiple


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Fig. 8. Diffuse neonatal hemangiomatosis. Multiple infantile hemangiomas scattered all over the skin. The baby also had hemangiomas in the liver.

Fig. 9. Diffuse neonatal hemangiomatosis. Multiple infantile hemangiomas on the face, forearm, and hand. The patient had extensive involvement of the lungs and liver by hemangiomas that caused his demise.

cutaneous hemangiomas, without signs or symptoms of visceral involvement, have been termed benign neonatal hemangiomatosis (61,62) to reflect of the benign nature of the disease. Spontaneous regression should be anticipated in mild cases of diffuse neonatal hemangiomatosis (63) as well as in benign neonatal hemangiomatosis (61). HISTOPATHOLOGIC FEATURES The histopathologic composition of infantile hemangiomas varies with the age of the lesion. Early hemangiomas are highly cellular and are characterized by plump endothelial cells aligned to vascular spaces with small inconspicuous lumina (Fig. 10). At this early stage, the vascular nature of the lesion may not be readily apparent. A moderate number of normal mitotic figures may be present, and numerous mast cells may be seen in the intervening stroma. It has been suggested that mast cells play a role in the production of angiogenic factors that regulate the growth of the lesion (64,65). However, longstanding hemangiomas have been found to have significantly more mast cells than hemangiomas of recent origin; these findings obviate a role for mast cells in the early proliferation of hemangiomas, indicating a contribution to the maturation of blood vessels in the benign neoplasm (66). In some cases, capillary proliferation may involve perineural spaces, but this should not be regarded as evidence of malignancy (67). As the lesions mature, blood flow increases, the endothelium flattens, and the lumina of the vessels enlarge and become more obvious (Fig. 11). During this interval the vessels

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Fig. 10. Histopathologic features of an early infantile hemangioma. (A) The entire thickness of the dermis is involved by a cellular proliferation. (B) Higher magnification shows lobules of plump endothelial cells with small inconspicuous lumina. (C) Still higher magnification shows vacuoles and small channels as signs of primitive vascular differentiation.

present a “cavernous” appearance that can be misinterpreted as a venous malformation. Regression is portrayed as progressive interstitial fibrosis and adipose metaplasia, a process without known stimulus. Congenital hemangiomas have a varied histopathologic appearance. Noninvoluting congenital hemangiomas (3) feature lobular collections of small, thin-walled vessels with large, often stellate, central lumina, separated by variable amounts of fibrous tissue richly supplied with normal and abnormal veins and arteries. The lobules are predominantly composed of rounded or curved small, thin-walled channels lined by endothelial cells and surrounded by one or more layers of pericytes. Several stellate vessels occupy the center of the lobule. Most endothelial cells lining the intralobular vessels have abundant cytoplasm and contain small, dark, hyperchromatic nuclei that protrude into the lumen, thus creating a hobnail appearance. Many of the cells contain round, intracytoplasmic eosinophilic globules. The vascular elements between lobules are predominantly elongated tortuous veins, many of which possess variable amounts of smooth muscle and elastic tissue. Scattered vessels resemble lymphatic vessels, and accordingly, some possess valves. Congenital nonprogressive hemangiomas (4) are highly cellular, with multiple welldefined lobules of proliferating capillaries that anastomose with each other to form ribbons within the dermis or subcutaneous tissue. In contrast to conventional infantile


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Fig. 11. Histopathologic features of a mature hemangioma. (A) Dilated vascular structures with congestive lumina are easily seen at different levels of the dermis. (B) The vascular structures show thin walls and their lumina replete with erythrocytes.

hemangioma, in which the tumor lobules are separated by normal tissue, bands of abnormal, dense fibrous tissue or progressive sclerosis of capillary lobules separate the tumor nodules of congenital nonprogressive hemangiomas (Fig. 12). Hemosiderin deposits and small foci of dystrophic calcification are also present within both the capillary lobules and the fibrous septi, as reminders that past hemorrhage or thrombosis play a role in the evolution of these hemangiomas. Immunohistochemical studies of hemangiomas demonstrate that the cells, which line the lumina, express endothelial markers such as factor VIII-related antigen and CD34. A few of the interstitial cells are positive for CD34 and α-smooth muscle actin, attesting to their identity as pericytes. The remainder of the interstitial cells are negative for these markers but strongly positive for factor XIIIa. Predominantly mitotic activity, as determined by the PC-10 antibody, is concentrated in the interstitial cells of areas with less apparent vascularity and more prominent cellularity (65,68). These findings suggest that hemangiomas are neoplasms derived from primitive cells with the capacity for differentiation toward endothelial cells and pericytes (68). Hemangiomas in the proliferative phase express high levels of angiogenic molecules such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor/vascular permeability factor (VEGF/ VPF) (69), as well as high levels of the intercellular adhesion molecule (ICAM)-3 (70), type IV collagenase (71), urokinase (71), and E-selectin (71). Interferon-β (IFN-β) is

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Fig. 12. Histopathologic features of congenital nonprogressive hemangioma. (A) Cellular hemangioma composed of multiple well-defined lobules of proliferating capillaries. (B) Bands of abnormal, dense fibrous tissue separate the capillary lobules of congenital nonprogressive hemangiomas. (C) The lobules are composed of aggregations of plump endothelial cells containing vascular lumina inside.


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notably absent (69). During the regression phase, apoptosis is more in evidence (72). Urinary levels of basic fibroblast growth factor (bFGF) are elevated considerably in infants with hemangiomas, and this offers a potential means of monitoring the efficacy of treatment (73). Recent immunohistochemical studies have demonstrated that the endothelial cells of infantile hemangiomas express immunoreactivity for the erythrocyte-type glucose transporter protein GLUT-1 (74,75) (Fig. 13) and the placenta-associated antigens Fc RII, Lewis Y antigen (LeY), and merosin (74). Their presence supplies evidence that infantile hemangiomas and human placenta share a unique microvascular phenotype. On the other hand, immunohistochemical studies have failed to demonstrate placental alkaline phosphatase and human placental lactogen in infantile hemangiomas. These findings do not support the notion that placental trophoblasts play a role in the development of infantile hemangiomas (76). Immunohistochemical studies for GLUT-1 in noninvoluting congenital hemangioma (3) and congenital nonprogressive hemangioma (4) have yielded negative results. The summarized evidence suggests that congenital hemangiomas are histopathologically and immunophenotypically distinct from classical infantile hemangiomas. By ultrastructural studies, hemangiomas exhibit small vascular spaces lined by a single continuous layer of endothelial cells surrounded by a basement membrane and pericytes (77,78). Intracytoplasmic vacuoles are present and are interpreted as an expression of the early stages in lumen formation (79). Weibel-Palade bodies are either poorly formed or unrecognizable in the earlier lesions. Crystaloid inclusions of uncertain nature have been observed in the immature endothelial cells (80,81). The vascular spaces within hemangiomas may have ultrastructural features of capillaries, venules, and arterioles (82). TREATMENT The treatment of infantile hemangiomas has to be individualized for each patient. Most lesions regress spontaneously during the first years of life, and the best cosmetic results are often achieved with expectant management. When hemangiomas interfere with important structures or functions, active treatment is required. Options include intralesional or systemic corticosteroids, sclerosing injections, cryotherapy, laser therapy, compression and embolization, surgical excision, and radiotherapy (83–91). The proper alternative is governed by the location, size, and phase of development of the hemangioma as well as personal experience in the management of each therapy, and knowledge of the advantages and disadvantages of the available therapeutic options. In most children with Kasabach-Merritt syndrome, surgery is not generally an option because of the precarious hematologic status of the patient and the large size of the lesions, although it has been performed successfully in some cases (25,27,28). In some patients, a course of prednisone therapy at a dosage of 2–4 mg/kg/d has elevated the platelet count and caused shrinkage of the hemangioma (24,29–31). Corticosteroids increase the survival time of platelets, reduce the vascular mass, and restore the integrity of the clotting system. Radiotherapy has been administered to patients with KasabachMerritt syndrome, but its potential long-term negative sequelae have lessened the acceptability or this therapy (32,33). Additional therapeutic options include INF-α-2a (34) and pentoxifylline (35). Administration of heparin may be required if thrombosis and bleeding occur. It is recommended at a dosage of 100 U/kg every 4 h until bleeding ceases, the platelet count is stable, and the coagulation defect is under control (26). Heparinization should be followed by replacement of platelet concentrates, fresh frozen plasma, and

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Fig. 13. An early infantile hemangioma stained with hematoxylin-eosin and GLUT-1. (A) Low power shows a cellular proliferation involving the entire thickness of the dermis. (B) Higher magnification demonstrates that some small vascular lumina are also seen in the cellular proliferation. (C) Still higher magnification demonstrates that the lumina are lined by plump endothelial cells. (D) A section of the same infantile hemangioma immunohistochemically stained for GLUT-1. (E) Higher magnification demonstrates GLUT-1 immunoreactivity of most endothelial cells lining vascular lumina.


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cryoprecipitate (36,37). Aspirin and dipyridamole, both inhibitors of platelet functions, have been used with benefit (38).

References 1. Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg 1982;69:412–22. 2. Mulliken JB. Diagnosis and natural history of hemangiomas. In: Mulliken JB, Young AE, eds. Vascular Birthmarks. Hemangiomas and Malformations. Philadelphia, WB Saunders, 1988;41–61. 3. Enjolras O, Mulliken JB, Boon LM, Wassef M, Kozakewich HPW, Burrows PE. Noninvoluting congenital hemangioma: a rare cutaneous vascular anomaly. Plast Reconstr Surg 2001;107:1647–54. 4. North PE, Waner M, James CA, Mizeracki A, Frieden IJ, Mihm MC Jr. Congenital nonprogressive hemangioma. A distinct clinicopathologic entity unlike infantile hemangioma. Arch Dermatol 2001;137:1607–20. 5. Enjolras O, Mulliken JB. The current management of vascular birthmarks. Pediatr Dermatol 1993;10:311–33. 6. Burrows PE, Laor T, Paltil H, Robertson RL. Diagnostic imaging in the evaluation of vascular birthmarks. Dermatol Clin 1998;16:455–8. 7. Dubois J, Garel L, Grignon A, et al. Imaging of hemangiomas and vascular malformations in children. Acad Radiol 1998;5:390–400. 8. Jacobs AH, Walton RG. The incidence of birthmarks in the neonate. Pediatrics 1976;58:218–22. 9. Hidano A, Purwoko R, Jitsukawa K. Statistical survey of skin changes in Japanese neonates. Pediatr Dermatol 1986;3:140–4. 10. Holmdahl K. Cutaneous hemangiomas in premature and mature infants. Acta Paediatr 1955;44:370–9. 11. Jacobs AH. Strawberry hemangiomas: the natural history of the untreated lesion. Calif Med 1957; 86:8–10. 12. Amir J, Metzker A, Krikler R, et al. Strawberry hemangioma in preterm infants. Pediatr Dermatol 1987;3:331–2. 13. Powell TG, West CR, Pharaoh POD, et al. Epidemiology of strawberry haemangioma in low birth weight infants. Br J Dermatol 1987;116:635–41. 14. Burton BK, Schulz CJ, Angle B, Burd LI. An increased incidence of haemangiomas in infants born following chorionic villus sampling (CVS). Prenat Diagn 1995;15:209–14. 15. Cheung DS, Warman ML, Mulliken JB. Hemangioma in twins. Ann Plast Surg 1997;38:269–74. 16. Blei F, Walter J, Orlow SJ, Marchuk DA. Familial segregation of hemangiomas and vascular malformations as an autosomal dominant trait. Arch Dermatol 1998;134:718–22. 17. Bowers RE, Graham EA, Tomlinson KM. The natural history of the strawberry nevus. Arch Dermatol 1960;82:667–80. 18. Nakayama H. Clinical and histological studies of the classification and the natural course of the strawberry mark. J Dermatol 1981;2:277–91. 19. Yagupski P, Giladi Y. Group A β-hemolytic streptococcal septicemia complicating infected hemangioma in children. Pediatr Dermatol 1987;4:24–6. 20. Ferguson CF, Flake CG. Subglotic hemangioma as a cause of respiratory obstruction in infants. Ann Otol Rhinol Laryngol 1961;75:1095–122. 21. Stigmar G, Crawford JS, Ward CM, Thomson MG. Ophthalmic sequelae of infantile hemangiomas of the eyelids and orbit. Am J Ophthalmol 1978;85:806–12. 22. Healey GB, Fearon B, French R, et al. Treatment of subglotic hemangioma with the carbon dioxide laser. Laryngoscope 1980;90:809–13. 23. Kasabach HH, Merritt KK. Capillary hemangioma with extensive purpura: report of a case. Am J Dis Child 1940;59:1063–70. 24. Esterly NB. Kasabach-Merritt syndrome in infants. J Am Acad Dermatol 1983;8:504–13. 25. Shim WKT. Hemangiomas of infancy complicated by thrombocytopenia. Am J Surg 1968;116:896–906. 26. Lang PG, Dubin HV. Hemangioma-thrombocytopenia syndrome: a disseminated intravascular coagulopathy. Arch Dermatol 1975;111:105–7. 27. Orenstein DM, Yonas H, Bilenker R, et al. Hemangioma thrombocytopenia syndrome. Am J Dis Child 1977;131:680–1. 28. Alves JCR, Fernal WH, Christo MC, et al. Giant hemangioma of the thigh (Kasabach-Merritt syndrome): resection with temporary clamping of the common iliac artery. Br J Plast Surg 1985;38:426–32.

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29. Evans J, Batchelor ADR, Stark G, et al. Hemangioma with coagulopathy sustained response to prednisone. Arch Dis Child 1975;50:809–12. 30. Edgerton MT. The treatment of hemangiomas: with special reference to the role of steroid therapy. Ann Surg 1976;183:517–32. 31. Brown SH Jr, Neerhout RC, Fonkalsrud EW. Prednisone therapy in the management of large hemangiomas in infants and children. Surgery 1972;71:168–73. 32. Carnelli V, Bellini F, Ferrari M, et al. Giant hemangioma with consumption coagulopathy: sustained response to heparin and radiotherapy. J Pediatr 1977;91:504–5. 33. David TJ, Evans DIK, Stevens RF. Haemangioma with thrombocytopenia (Kasabach-Merritt syndrome). Arch Dis Child 1983;58:1022–3. 34. Ezekowitz RA, Mulliken JB, Folkman J. Interferon alpha-2a therapy for life-threatening hemangiomas of the infancy. N Engl J Med 1992;326:1456–63. 35. de Prost Y, Teilla CD, Bordemer C, et al. Successful treatment of Kasabach-Merritt syndrome with pentoxifylline. J Am Acad Dermatol 1991;25:854–5. 36. Corrigan JJ Jr. Disseminated intravascular coagulopathy. Pediatrics 1979;64:37–46. 37. Bell R. Disseminated intravascular coagulation. Johns Hopkins Med J 1980;146:289–99. 38. Koerper MA, Addiego JE Jr, de Lorimier AA, et al. Use of aspirin and dipyridamole in children with platelet trapping syndromes. J Pediatr 1983;102:311–4. 39. Enjolras O, Wassef M, Mazoyer E, et al. Infants with Kasabach-Merritt syndrome do not have “true” hemangiomas. J Pediatr 1997;130:631–40. 40. Sarkar M, Mulliken JB, Kozakewich HP, Robertson RL, Burrows PE. Thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon) is associated with kaposiform hemangioendothelioma and not with common infantile hemangioma. Plast Reconstr Surg 1997;100:1377–86. 41. Alvarez-Mendoza A, Lourdes TS, Ridaura-Sanz C, Ruiz-Maldonado R. Histopathology of vascular lesions found in Kasabach-Merritt syndrome: review based on 13 cases. Pediatr Dev Pathol 2000;3:556–60. 42. Kishnani P, Iafolla AK, McConkie-Rosell A, Van Hove JLK, Kanter RJ, Kahler SG. Hemangioma, supraumbilical midline raphe, and coarctation of the aorta with a right aorta arch: single causal entity? Am J Med Genet 1995;59:44–8. 43. Opitz JM, Gilbert EF. CNS anomalies at the midline as a “developmental field.” Am J Med Genet 1982;12:443–55. 44. Pascual-Castroviejo I, Viano J, Moreno F, et al. Hemangiomas of the head, neck and chest with associated vascular brain anomalies: a complex neurocutaneous syndrome. AJNR Am J Neuroradiol 1996;17:461–71. 45. Esterly NB. Hemangiomas in infants and children: clinical observations. Pediatr Dermatol 1992;9:353–5. 46. Frieden IJ, Reese V, Cohen D. PHACE syndrome: the association of posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Arch Dermatol 1996;132:307–11. 47. Reese V, Frieden IJ, Paller AS, et al. Association of facial hemangiomas with Dandy-Walker and other posterior fossa malformations. J Pediatr 1993;122:379–84. 48. Hersh JH, Waterfill D, Rytledge J, et al. Sternal malformation/vascular dysplasia association. Am J Med Genet 1985;21:177–86. 49. Albright AL, Gartner JC, Wiener ES. Lumbar cutaneous hemangiomas as indicators of tethered spinal cords. Pediatrics 1988;83:977–80. 50. Goldberg NS, Hebert AA, Esterly NB. Sacral hemangiomas and multiple congenital anomalies. Arch Dermatol 1986;122:684–7. 51. Golitz LE, Rudikoff J, O’Meara OP. Diffuse neonatal hemangiomatosis. Pediatr Dermatol 1986;3:145–52. 52. Burke EC, Winkelmann RK, Strickland MK. Disseminated hemangiomatosis of the newborn with central nervous system involvement. Am J Dis Child 1964;108:408–24. 53. Esterly NB, Margileth AM, Kahn G, et al. Management of disseminated eruptive hemangiomata in infants. Pediatr Dermatol 1984;1:312–7. 54. Burman D, Mansell PWA, Warin RP. Miliary hemangiomata in the newborn. Arch Dis Child 1967;42:193–7. 55. Dachman AH, Lichtenstein JE, Friedman AC, et al. Infantile hemangioendothelioma of the liver: a radiologic-pathologic-clinical correlation. AJR 1983;140:1091–6. 56. Jackson C, Greene HL, O’Neill J, et al. Hepatic hemangioendothelioma: angiographic appearance and apparent prednisone responsiveness. Am J Dis Child 1977;131:74–7. 57. Schiliro G, Guarnieri B, Russo A. A case of multiple neonatal haemangiomatosis with favorable outcome following steroid therapy. Acta Paediatr Scand 1976;65:267–70.


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58. Stillman AE, Hansen RC, Hallinan V, et al. Diffuse neonatal hemangiomatosis with severe gastrointestinal involvement: favorable response to steroid therapy. Clin Pediatr 1983;22:589–91. 59. Weiss MJ, Ernest JT. Diffuse congenital hemangiomatosis with infantile glaucoma. Am J Ophthalmol 1976;81:216–8. 60. Balaci E, Sumner TE, Auringer ST, Cox TD. Diffuse neonatal hemangiomatosis with extensive involvement of the brain and cervical spinal cord. Pediatr Radiol 1999;29:441–3. 61. Stern JK, Wolf JE Jr, Jarratt M. Benign neonatal hemangiomatosis. J Am Acad Dermatol 1981;4:442–5. 62. Held JL, Harber RS, Silvers DN, et al. Benign neonatal hemangiomatosis: review and description of a patient with unusually persistent lesions. Pediatr Dermatol 1990;7:63–6. 63. Keller L, Bluhm JF III. Diffuse neonatal hemangiomatosis. A case with heart failure and thrombocytopenia. Cutis 1979;23:295–7. 64. Glowacki J, Mulliken JB. Mast cells in hemangiomas and vascular malformations. Pediatrics 1982;70:48–51. 65. Gonzalez-Crussi F, Reyes Mugica M. Cellular hemangiomas (hemangioendotheliomas) in infants: light microscopic, immunohistochemical and ultrastructural observations. Am J Surg Pathol 1991;15:769–78. 66. Shea CR, Prieto VG. Mast cells in angiolipomas and hemangiomas of human skin: are they important for angiogenesis? J Cutan Pathol 1994;21:247–51. 67. Calonje E, Mentzel T, Fletcher CDM. Pseudomalignant perineural invasion in cellular (“infantile”) capillary haemangiomas. Histopathology 1995;26:157–64. 68. Smoller BR, Apfelberg DB. Infantile (juvenile) capillary hemangioma: a tumor of heterogeneous cellular elements. J Cutan Pathol 1993;20:330–6. 69. Bielenberg DR, Bucana CD, Sanchez R, Mulliken JB, Folkman J, Fidler IJ. Progressive growth of infantile cutaneous hemangiomas is directly correlated with hyperplasia and angiogenesis of adjacent epidermis and inversely correlated with expression of the endogenous angiogenesis inhibitor, IFN-beta. Int J Oncol 1999;14:401–8. 70. Verkarre V, Patey-Mariaud de Serre N, Vazeux R, et al. ICAM-3 and E-selectin endothelial cell expression differentiate two phases of angiogenesis in infantile hemangiomas. J Cutan Pathol 1999;26:17–24. 71. Takahashi K, Mulliken JB, Kozakewich HPW, Rogers RA, Folkman J, Ezekowitz AB. Cellular markers that distinguish the phases of hemangioma during infancy and childhood. J Clin Invest 1994;93: 2357–64. 72. Razon MJ, Kraling BM, Mulliken JB, Bischoff J. Increased apoptosis coincides with onset of involution in infantile hemangioma. Microcirculation 1998;5:189–95. 73. Chang E, Boyd A, Nelson CC, et al. Successful treatment of infantile hemangiomas with interferon alpha-2b. J Pediatr Hematol Oncol 1997;19:237–44. 74. North PE, Waner M, Mizeracki A, Mihm MC Jr. GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol 2000;31:11–22. 75. North PE, Waner M, Mizeracki A, et al. A unique microvascular phenotype shared by juvenile hemangiomas and human placenta. Arch Dermatol 2001;137:559–70. 76. Bree AF, Siegfried E, Sotelo-Avila C, Nahass G. Infantile hemangiomas. Speculation on placental trophoblastic origin. Arch Dermatol 2001;137:573–7. 77. Taxy JB, Gray Sr. Cellular angiomas of infancy: an ultrastructural study of two cases. Cancer 1979;43:2322–31. 78. Tani M, Kaibuchi S, Morata Y, et al. Ultrastructure of hypertrophic hemangioma. J Cutan Pathol 1983;10:133–7. 79. Furusato M, Fukunaga M, Kikuchi Y, et al. Two-and-three dimensional ultrastructural observations of angiogenesis in juvenile hemangioma. Virchows Arch (B) 1984;46:229–37. 80. Kumakiri M, Muramoto F, Tsukinaga I, Yoshida T, Ohura T, Miura Y. Crystalline lamellae in the endothelial cells of a type of hemangioma characterized by the proliferation of immature endothelial cells and pericytes-angioblastoma (Nakagawa). J Am Acad Dermatol 1983;8:68–75. 81. Pasyk KA, Grabb WC, Cherry GW. Crystalloid inclusions in endothelial cells of cellular and capillary hemangiomas: a possible sign of cellular immaturity. Arch Dermatol 1983;119:134–7. 82. Waldo ED, Vuletin JC, Kaye GT. The ultrastructure of vascular tumors: additional observations and a review of the literature. Pathol Annu 1977;12:279–308. 83. Sato Y, Frey EE, Wicklund B, Kisker CT, Smith WL. Embolization therapy in the management of infantile hemangioma with Kasabach Merritt syndrome. Pediatr Radiol 1987;17:503–4. 84. Enjolras O, Borsik M, Herbreteau D, Merland JJ, Hadjean E, Huy PT. Indications chirurgicales dans les angiomes de face. Ann Otolaryngol Chir Cervicofac 1993;110:192–7.

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85. Chowdri NA, Darzi MA, Fazili Z, Igbal S. Intralesional corticosteroid therapy for childhood cutaneous hemangiomas. Ann Plast Surg 1994;33:46–51. 86. Lacour M, Syed S, Linward J, Harper JI. Role of the pulsed dye laser in the management of ulcerated capillary haemangiomas. Arch Dis Child 1996;74:161–3. 87. Sarihan H, Mocan H, Yildiz K, Abes M, Akyazici R. A new treatment with bleomycin for complicated cutaneous hemangioma in children. Eur J Pediatr Surg 1997;7:158–62. 88. Burstein FD, Simms C, Cohen SR, Williams JK, Paschal M. Intralesional laser therapy of extensive hemangiomas in 100 consecutive pediatric patients. Ann Plast Surg 2000;44:188–94. 89. Reischle S, Schuller-Petrovic S. Treatment of capillary hemangiomas of early childhood with a new method of cryosurgery. J Am Acad Dermatol 2000;42:809–13. 90. Bassukas ID, Abuzahra F, Hundeiker M. Regressionsphase als therapeutisches Ziel der kryochirurgischen Behandlung wachsender kapillarer Sauglingshamangiome. Behandlungsentscheidung, Behandlungsstrategie und Ergebnisse einer offenen klinischen Studi. Hautarzt 2000;51:231–8. 91. Haywood RM, Monk BE, Mahaffey PJ. The treatment of early cutaneous capillary hemangiomata (strawberry naevi) with the tunable dye laser. Br J Plast Surg 2000;53:302–7.


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3. CHERRY ANGIOMAS (SENILE ANGIOMAS) CLINICAL FEATURES Senile or cherry angiomas, also known as Campbell de Morgan spots, are among the most frequently acquired cutaneous vascular lesions. They appear early in adulthood, most commonly on the trunk (Fig. 14) and, with time, may increase in number and size. On presentation, they are small red papules that resist compression. In 1970, Seville et al. (1) described an outbreak of cherry angiomas in over a 1000 patients in the Northwest of England. These observers were unable to demonstrate a causative organism and suggested that the outbreak could have been related to a recent rise in the atmospheric temperature, since the number of lesions per patient increased and decreased proportionate to the temperature. In 1988, (2) Honish et al. described an outbreak of cherry hemangiomas in a nursing home. Eruptive cherry hemangiomas have also been concurrent with echo viral infections (3), as well as with exposures to chemical compounds, notably glycol ether solvent 2-butoxyethanol (4), sulfur mustard gas (5), and bromides (6). Hormonal factors have also been suspected. It has been observed that pregnant women are prone to develop lesions that involute post partum (7). We have observed two female patients with the sudden eruption of hundreds of widely disseminated cutaneous, cherry angiomas (unpublished observations). One patient had a prolactinoma (Fig. 15); the other had elevated serum levels of prolactin without evidence of a functional tumor. In still another case, a patient with systemic amyloidosis developed purpuric halos around multiple cherry hemangiomas (8). HISTOPATHOLOGIC FEATURES Microscopically, the cherry angioma consists of dilated capillary blood vessels localized in the superficial dermis (Fig. 16). The vessels have variably thickened walls. Fully developed lesions are associated with a loss of the rete ridges of the epidermis, which leads to the formation of a peripheral collarette of adnexal epithelium, thus creating a polypoid lesion (9,10). Mast cells may be numerous (11), whereas the endothelial cells that line the vessels express strong carbonic anhydrase activity, which correlates with the fenestration of the venous capillaries (12). Proliferation activity is very low, as demonstrated by an absence of immunohistochemical reactivity for Ki67 (13). Ultrastructurally, cherry angiomas are composed of capillaries and postcapillary venules with walls thickened by multiple layers of basal lamina (14) wherein immunohistochemical markers have identified collagen type IV, laminin, and collagen type VI (15).

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Fig. 14. Cherry hemangiomas scattered on the anterior chest of an adult man.


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Fig. 15. Numerous small cherry hemangiomas scattered all over the skin. This woman also had a prolactinoma.

Fig. 16. Histopathologic features of cherry hemangioma. (A) Low-power view shows a wellcircumscribed vascular proliferation. (B) Higher magnification demonstrates the capillary nature of the proliferating vessels.

TREATMENT Although individual lesions can be destroyed by electrocautery (16), cryotherapy (17), or laser therapy (18–21), treatment is sanctioned only for cosmetic reasons (5).


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References 1. Seville RH, Rao PS, Hutchinson DN, Birchall G. Outbreak of Campbell de Morgan spots. Br Med J 1970;1:408–9. 2. Honish A, Grimsrud K, Miedzinski L, Gold E, Cherry RR. Outbreak of Campbell de Morgan spots in a nursing home—Alberta. Can Dis Wkly Rep 1988;14:211–2. 3. Cherry JD, Bobinski JE, Horvath FL, Comerci GD. Acute hemangioma-like lesions associated with ECHO viral infections. Pediatrics 1969;44:498–502. 4. Raymond LW, Williford LS, Burke WA. Eruptive cherry angiomas and irritant symptoms after one acute exposure to the glycol ether solvent 2-butoxyethanol. J Occup Environ Med 1998;40:1059–64. 5. Firooz A, Komeili A, Dowlati Y. Eruptive melanocytic nevi and cherry angiomas secondary to exposure to sulfur mustard gas. J Am Acad Dermatol 1999;40:646–7 6. Cohen AD, Cagnano E, Vardy DA. Cherry angiomas associated with exposure to bromides. Dermatology 2001;202:52–3. 7. Barter RH, Letterman GS, Schurter M. Hemangiomas in pregnancy. Am J Obstet Gynecol 1963;87:625–34. 8. Schmidt CP. Purpuric halos around hemangiomas in systemic amyloidosis. Cutis 1991;48:141–3. 9. Salamon T, Lazovic O, Milicevic M. Histologic findings in angioma senile. The phenomenon of epidermal-dermal survillance. Dermatologica 1973;147:284–8. 10. Salamon T, Lazovic O, Milicevic M. Über einige histologische Befunde bei dem sogenannten Angioma senile. Dermatol Monatsschr 1973;159;1021–8. 11. Hagiwara K, Khaskhely NM, Uezato H, Nonaka S. Mast cell “densities” in vascular proliferations: a preliminary study of pyogenic granuloma, portwine stain, cavernous hemangioma, cherry angioma, Kaposi’s sarcoma, and malignant hemangioendothelioma. J Dermatol 1999;26:577–86. 12. Eichhorn M, Jungkunz W, Worl J, Marsch WC. Carbonic anhydrase is abundant in fenestrated capillaries of cherry hemangioma. Acta Derm Venereol 1994;74:51–3. 13. Tuder RM, Young R, Karasek M, Bensch K. Adult cutaneous hemangiomas are composed of nonreplicating endothelial cells. J Invest Dermatol 1987;89:594–7. 14. Sala F, Crosti C, Menni S, Piccinno R. Cherry hemangioma: an SEM study. J Cutan Pathol 1984;11:531–3. 15. Tamm E, Jungkunz W, Marsch WC, Lutjen-Drecoll E. Increase in types IV and VI collagen in cherry haemangiomas. Arch Dermatol Res 1992;284:275–82. 16. Robinson JK. Electrodesiccation of nevi aranei (“spiders”) and senile angiomas. J Dermatol Surg Oncol 1980;6:794–5. 17. Aversa AJ, Miller OF. Cryo-curettage of cherry angiomas. J Dermatol Surg Oncol 1983;9:930–1. 18. Landthaler M, Haina D, Waidelich W, Braun-Falco O. A three-year experience with the argon laser in dermatotherapy. J Dermatol Surg Oncol 1984;10:456–61. 19. Grekin RC, Flynn TC, Cooper D, Geisse J. Efficacy of a 2-mm spot size lens for the treatment of superficial vascular lesions with a flashlamp-pumped dye laser. Int J Dermatol 1997;36:865–9. 20. Aghassi D, Anderson RR, Gonzalez S. Time-sequence histologic imaging of laser-treated cherry angiomas with in vivo confocal microscopy. J Am Acad Dermatol 2000;43:37–41. 21. Gupta G, Bilsland D. A prospective study of the impact of laser treatment on vascular lesions. Br J Dermatol 2000;143:356–9.

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4. ARTERIOVENOUS HEMANGIOMA This lesion was first described in 1956 by Biberstein and Jessner (1), who termed it cirsoid aneurysm, because they noted a spiraled blood vessel (feeder vessel) extending from the subcutaneous fat into the lesion. Little attention was paid to this entity until recently when it was renamed arteriovenous hemangioma (2,3) or acral arteriovenous tumor (4–7). The latter name is not totally appropiate, because the lesion affects different areas of the body and not only acral skin. CLINICAL FEATURES Arteriovenous hemangioma is a neoplasm that occurs in mid-adult life and presents as a blue to red papule measuring 0–1.0 cm (Fig. 17), mainly affecting facial skin. Larger lesions (8) as well as intraoral (9) and vulvar (10) examples have been also described. Usually the lesions are solitary, although multiple examples have been cited. When the lesions are multiple, they tend to cluster together. Occasionally, they are associated with other abnormalities including epidermal nevus syndrome, vascular hamartomas, and malformations (11), and several examples of multiple arteriovenous hemangiomas have been described in patients with chronic liver disease(12–14). HISTOPATHOLOGIC FEATURES Histopathologically, acral arteriovenous hemangioma consists of a well-circumscribed proliferation of thick-walled muscle-containing blood vessels, lined by a single layer of endothelial cells involving the upper and midreticular dermis (Fig. 18). Intermingled with the thick-walled blood vessels, there are also thin-walled dilated blood vessels. The thick-walled blood vessels resemble arteries, but a well-formed elastic internal membrane is absent. Therefore, they are probably ectatic veins (9). Serial sections are helpful in identifying both the arteriovenous shunts (in about one-fourth of the cases studied) (2) and the spiraled ascending small muscular artery (“feeder” vessel). Some lesions recently described as symplastic hemangioma probably represent ancient arteriovenous hemangiomas with atypical cells caused by degenerative changes that occur in long-standing lesions (15). There is one reported case of an arteriovenous hemangioma that also exhibited the histopathologic changes of a verruciform xanthoma (16). The precise nature of acral arteriovenous hemangioma is uncertain. Girard et al. (2) consider it to be a multicentric hamartoma of the subpapillary vascular plexus with one or more arteriovenous anastomoses. Carapeto et al. (4) have proposed that a hamartoma of the Sucquet-Hoyer canal of the glomus body is the cause of the arteriovenous hemangioma. The latter interpretation, however, is unlikely because glomus cells are usually absent in arteriovenous hemangioma (9), and, to date, they have been identified in only one example of all the reported cases (14). TREATMENT A local excision suffices as the treatment for lesions of arteriovenous hemangioma.

Fig. 18. (Opposite page) Histopathologic features of acral arteriovenous hemangioma. (A) Low power shows a well-circumscribed proliferation of blood vessels in the dermis. (B) Higher magnification demonstrates that these blood vessels have thick walls and a single layer of endothelial cells.


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Fig. 17. Arteriovenous hemangioma. Solitary angiomatous papule on the posterior neck.

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References 1. Biberstein HH, Jessner M. A cirsoid aneurysm of the skin. Dermatologica 1956;113:129–41. 2. Girard C, Graham JH, Johnson WC. Arteriovenous hemangioma (arteriovenous shunt). J Cutan Pathol 1974;1:73–87. 3. Rosen T. Arteriovenous hemangioma. Cutis 1979;24:57–9. 4. Carapeto FJ, Garcia-Pérez A, Winkelmann RK. Acral arteriovenous tumor. Acta Derm Venereol 1977;57:155–8. 5. Carapeto FJ, Armijo M. Tumeur acrale arterio-veineuse. Ann Dermatol Venereol 1978;105:977–9. 6. Persson JR. Acral arteriovenous tumor. Acta Derm Venereol 1978;58:95. 7. Connelly MG, Winkelmann RK. Acral arteriovenous tumor: a clinicopathologic review. Am J Surg Pathol 1985;9:15–21. 8. Neumann RA, Knobler M, Schuller Petrovic S, et al. Giant arteriovenous hemangioma (cirsoid aneurysm) of the nose. J Dermatol Surg Oncol 1989;15:739–42. 9. Koutlas IG, Jessurum J. Arteriovenous hemangioma: a clinicopathological and immunohistochemical study. J Cutan Pathol 1994;21:343–9. 10. Lazarou G, Goldberg MI. Vulvar arteriovenous hemangioma. A case report. J Reprod Med 2000;45:439–41. 11. Calzavara Pinton P, Carlino A, Manganoni AM, Donzelli C, Faccheti F. Sindrome del nevo epidermico con malformazioni e amartomi vascolari multipli. G Ital Dermatol Venereol 1990;125:251–4. 12. Akiyama M, Inamoto N. Arteriovenous hemangiomas on the foreheads of patients with chronic liver disease. Arch Intern Med 1998;158:1469. 13. Satomi H, Imakado S, Ichikawa E, Fujisawa H, Otsuka F. A case of arteriovenous hemangioma associated with liver cirrhosis. Dermatology 1999;199:278. 14. Akiyama M, Inamoto N. Arteriovenous haemangioma in chronic liver disease: clinical and histopathologic features of four cases. Br J Dermatol 2001;144:604–9. 15. Kutzner H, Winzer M, Mentzel T. Symplastisches Hamangiom. Hautarzt 2000;51:327–31. 16. Kishimoto S, Takenaka H, Shibagaki R, Nagata M, Katoh N, Yasuno H. Verruciform xanthoma arising in an arteriovenous haemangioma. Br J Dermatol 1998;139:546–8.


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5. HOBNAIL HEMANGIOMA (TARGETOID HEMOSIDEROTIC HEMANGIOMA) Santa Cruz and Aronberg (1) first described this lesion under the term targetoid hemosiderotic hemangioma. After the original description, a few cases of mostly single lesions were reported in the literature (2–14). Recently, Guillou et al. (15) revisited the lesion and coined the term hobnail hemangioma, which is currently the preferred term. CLINICAL FEATURES Most lesions are characterized by a brown to violaceous central papule, surrounded by a thin, pale area and a peripheral ecchymotic ring (Fig. 19). The ecchymotic halo ultimately disappears, in contrast to the central papule which persists. However, there are hemangiomas with histopathologic features identical to those of targetoid hemosiderotic hemangioma that do not have the targetoid appearance. Thus the term hobnail hemangioma appears to be a more appropriate name (1,16–17). HISTOPATHOLOGIC FEATURES Histopathologically, hobnail hemangioma has a distinctive biphasic appearance. The center of the lesion is composed of dilated, irregular, thin-walled ectatic vascular spaces positioned in the superficial dermis (Fig. 20). These vascular spaces sometimes exhibit intraluminal papillary projections and fibrin thrombi at different stages of organization. Prominent, plump, endothelial cells with a hobnail appearance line the papillary projections. The deep areas are distinct from the peripheral areas of the lesion because they show irregular, angulated, thin-walled, slit-shaped vascular channels that dissect collagen bundles of the dermis. In these areas, dermal fibrosis, hemosiderin deposits, extravasated red blood cells, and a sparse mononuclear inflammatory infiltrate are frequent findings. Hobnail hemangioma focally exhibits features reminiscent of retiform hemangioendothelioma, Kaposi’s sarcoma, benign lymphangioendothelioma, and Dabska’s tumor (1,17,18).

Fig. 19. Clinical features of hobnail hemangioma. Some lesions, such as the one shown in this figure, have a targetoid appearance, with a central angiomatous papule surrounded by an ecchymotic halo.

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Fig. 20. Histopathologic features of hobnail hemangioma. (A) Scanning power shows a vascular proliferation involving the upper half of the dermis. (B) Higher magnification shows irregular vascular spaces between collagen bundles of the dermis. (C) Still higher magnification demonstrates that the irregular slit-like spaces are lined by endothelial cells that seem to dissect between collagen bundles of the dermis. Note also the abundant extravasation of erythrocytes.


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Immunohistochemical studies have demonstrated that the endothelial cells lining the vascular spaces of hobnail hemangioma stain weakly for factor VIII-related antigen and strongly with Ulex europaeus I lectin, CD 34, and CD31 (1–3,16). Smooth muscle actinpositive pericytes are observed focally around some of the abnormal vascular spaces (1). Four out of eight cases studied stained positive for vascular endothelial growth factor receptor-3 (VEGFR-3), which suggests a lymphatic line of differentiation for this distinctive vascular neoplasm(17). The histopathologic differential diagnosis with the patch stage of Kaposi’s sarcoma can be difficult. Hobnail hemangioma shows dilated vessels with intraluminal papillary projections lined by prominent endothelial cells, a feature that is absent in Kaposi’s sarcoma. The vascular channels at the periphery of the lesion do not surround preexisting vascular and adnexal structures in the dermis, as is the case in the patch stage of Kaposi’s sarcoma. Furthermore, in contrast to patch lesions of Kaposi’s sarcoma, there is abundant hemosiderin and absence of plasma cells in the inflammatory infiltrate. Evidence seems to support the fact that hobnail hemangioma with a targetoid appearance results from trauma to a preexisting hemangioma or angiokeratoma, with subsequent development of thrombi and recanalization. The central and superficial areas of the lesion show intraluminal projections and thrombi, closely resembling the intravascular papillary endothelial hyperplasia of Masson, lending further support to the view that hobnail hemangiomas are traumatized hemangiomas or angiokeratomas. Once thrombosis and canalization occur, the preexisting vessels at the center of the lesion persist, whereas the peripheral ecchymotic halo disappears. Support for this sequence is shared by other authors (14,19). Carlson et al. (14) compared the clinicopathologic features of 33 cases of hobnail hemangioma with those of 20 cases of solitary angiokeratoma and found an overlap of the clinical and histopathologic features in both groups. The authors concluded that the histopathologic findings of extravasated red blood cells, hemosiderin, telangiectases, lymphangiectases, and fibrosis implicate trauma as the cause of these acquired vascular proliferations. Christenson and Seabury Stone (19) described a patient with lesions showing histopathologic features of hobnail hemangioma, which developed after trauma of an inflammatory cutaneous lesion. TREATMENT Surgical excision is curative, and recurrences have been not reported.

References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.


Santa Cruz DJ, Aronberg J. Targetoid hemosiderotic hemangioma. J Am Acad Dermatol 1988;19:550–8. Rapini RP, Golitz LE. Targetoid hemosiderotic hemangioma. J Cutan Pathol 1990;17:233–5. Vion B, Frenk E. Targetoid hemosiderotic hemangioma. Dermatology 1992;184:300–2. Benes P, Douglass M, Lowe L. Targetoid hemosiderotic hemangioma; a series of four cases [Abstract]. J Cutan Pathol 1993;20:533. Krahl D, Petzoldt D. Targetoides hamosiderotisches Hamangiom. Eine weitere Differentialdiagnose des Kaposi-Sarkoms. Hautarzt 1994;45:34–7. Lowe L. Self assessment—1993. Targetoid hemosiderotic hemangioma. J Cutan Pathol 1994;21:568–9. Perrin C, Rodot S, Ortonne JP, Michiels JF. L’hémangiome en cible hémosidériniqué. Ann Dermatol Venereol 1995;122:111–4. Margaroth GS, Tigelaar RE, Longley J, Luck LE, Leffell DJ. Targetoid hemangioma associated with pregnancy and the menstrual cycle. J Am Acad Dermatol 1995;32:282–4. Held JL, Malhotra R. Targetoid hemosiderotic hemangioma. Fitzpatrick’s J Clin Dermatol 1995;3:70. Fariña MC, Montalvo N, Piqué E, et al. Hemangioma hemosiderótico en diana: un nuevo caso y revisión de la literatura. Actas Dermosifiliogr 1995;86:383–7.

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11. Ho C, McCalmont TH. Targetoid hemosiderotic hemangioma: report of 24 cases, with emphasis on unusual features and comparison to early Kaposi’s sarcoma [Abstract]. J Cutan Pathol 1995;22:67. 12. Ly S, Versapuech J, Vergier B, Beylot-Barry M, Beylot C. Guess what? Targetoid hemosiderotic hemangioma. Eur J Dermatol 1998;8:583–5. 13. Avci O, Soyal MC, Sagol O, Gunes AT. Targetoid hemosiderotic hemangioma [Letter]. J Eur Acad Derm Venereol 1998;11:186–7. 14. Carlson JA, Daulat S, Goodheart HP. Targetoid hemosiderotic hemangioma—a dynamic vascular tumor: report of 3 cases with episodic and cyclic changes and comparison with solitary angiokeratomas. J Am Acad Dermatol 1999;41:215–24. 15. Guillou L, Calonje E, Speight P, Rosai J, Fletcher CD. Hobnail hemangioma: a pseudomalignant vascular lesion with a reappraisal of targetoid hemosiderotic hemangioma. Am J Surg Pathol 1999;23:97–105. 16. Santoja C, Torrelo A. Hobnail hemangioma. Dermatology 1995;191:154–6. 17. Mentzel T, Partanen TA, Kutzner H. Hobnail hemangioma (“targetoid hemosiderotic hemangioma”): clinicopathologic and immunohistochemical analysis of 62 cases. J Cutan Pathol 1999;26:279–86. 18. Requena L, Sangueza OP. Cutaneous vascular proliferations. Part II. Hyperplasias and benign neoplasms. J Am Acad Dermatol 1997;37:887–919. 19. Christenson LJ, Seabury Stone M. Trauma-induced simulator of targetoid hemosiderotic hemangioma. Am J Dermatopathol 2001;23:221–3.


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6. MICROVENULAR HEMANGIOMA Microvenular hemangioma is a recently described benign vascular neoplasm. Hunt et al. (1) coined this name in 1991, but the lesions described in 1989 by Bantel et al (2) as microcapillary hemangiomas probably represent the same entity. So far, 25 cases have been reported in the literature (1–9). CLINICAL FEATURES Microvenular hemangioma is an acquired, slowly growing asymptomatic lesion with angiomatous appearance. It is usually solitary, varying in size from 0.5 to 2 cm. It most commonly affects the upper limbs, particularly the forearms. However, lesions on the trunk (Fig. 21), face, and lower limbs have also been recorded (3,4,9). In some patients, a histogenetic relationship between microvenular hemangioma and hormonal factors such as pregnancy and hormonal contraceptives has been postulated (2,4), but this feature has not been corroborated by other authors. An example of microvenular hemangioma developed in a patient with Wiskott-Aldrich syndrome (9). Hemangiomas identical to microvenular hemangiomas can be seen in patients with POEMS syndrome (10). HISTOPATHOLOGIC FEATURES Histopathologically, microvenular hemangioma appears as a poorly circumscribed proliferation of irregularly branched, round to oval, thin-walled blood vessels lined by a single layer of endothelial cells. They involve the entire reticular dermis, and a variable degree of dermal sclerosis is present in the stroma (Fig. 22). The lumina of the neoplastic blood vessels are inconspicuous and often collapse with only a few erythrocytes in them. Immunohistochemically, the cells lining the lumina show positivity for factor VIIIrelated antigen and Ulex europaeus I lectin (1–3), which qualifies them as endothelial cells. Some smooth muscle actin, positive perithelial cells have also been described surrounding these vascular spaces (3,5). The main differential diagnosis of microvenular hemangioma is with Kaposi’s sarcoma in the patch stage. Kaposi’s sarcoma shows irregular anastomosing vascular spaces, newly formed ectatic vascular channels surrounding preexisting normal blood vessels and adnexa (promontory sign), plasma cells, hyaline (eosinophilic) globules, and small

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Fig. 21. Microvenular hemangioma. Angiomatous plaque on the anterior chest of a girl.


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Fig. 22. Histopathologic features of microvenular hemangioma. (A) Scanning power shows a proliferation of irregular blood vessels with inconspicuous lumina involving the dermis. (B) Higher magnification demonstrates irregular vascular spaces lined by endothelial cells. (C) Still higher magnification shows plump endothelial cells lining the inconspicuous lumina.

interstitial fascicles of spindle cells. All these features are absent in microvenular hemangioma. Characteristic of microvenular hemangioma is the presence of monomorphous small, elongated blood vessels with inconspicuous lumina involving the full thickness of the reticular dermis. TREATMENT Lesions of microvenular hemangioma are cured by simple excision.

References 1. Hunt SJ, Santa Cruz DJ, Barr RJ. Microvenular hemangioma. J Cutan Pathol 1991;18:235–40. 2. Bantel E, Grosshans E, Ortonne JP. Zuz Kenntnis mickrokapillärer angiome, beobachtungen bei schwangeren bzw. unter hormoneller antikonzeption stehenden Frauen. Z Hautkr 1989;64:1071–4. 3. Aloi F, Tomasini C, Pippione M. Microvenular hemangioma. Am J Dermatopathol 1993;15:534–8. 4. Satge D, Grande-Goburdhun J, Grosshans E. Hémangiome microcapillaire. Ann Dermatol Venereol 1993;120:297–8.


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5. Horn MS, Stern JB. Small red nodule on the leg of a young woman. Microvenular hemangioma. Arch Dermatol 1995;131:483. 6. Black RJ, McCusker GM, Eedy DJ. Microvenular haemangioma. Clin Exp Dermatol 1995;20:260–2. 7. Sanz Trelles A, Ojeda Martos A, Jiménez Fernández A, Vera Castaño A. Microvenular hemangioma: a new case in a child. Histopathology 1998;32:89–90. 8. Fukunaga M, Ushigome S. Microvenular hemangioma. Pathol Int 1998;48:237–9. 9. Rikihisa W, Yamamoto O, Kohda F, et al. Microvenular hemangioma in a patient with Wiskott-Aldrich syndrome. Br J Dermatol 1999;141:752–4. 10. Ackerman AB, Guo Y, Vitale P. Clues to Diagnosis in Dermatopathology II. Chicago, ASCP Press, 1992:285–8.

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7. TUFTED ANGIOMA Tufted angioma is an unusual, acquired vascular neoplasm first described by Wilson Jones in 1976 (1). A similar lesion was previously described by MacMillan and Champion (2) in 1971 under the name progressive capillary hemangioma. The neoplasm described by Nakagawa as angioblastoma also appears to be identical to acquired tufted angioma (3–5), although not all authors agree on this point (6). CLINICAL FEATURES Clinically, lesions of tufted angioma most commonly affect children and young adults, but both congenital and very late onset cases have been described (7–11). Most cases are sporadic, although a family with several members affected by tufted angioma has been reported (12). In this particular family, the mode of transmission was in an autosomal dominant fashion. The lesions have a predilection for the neck, upper chest, back, and shoulders (4,13,14), although examples of tufted angioma have also been reported on the head, extremities (Fig. 23), and oral mucosa (15–18). Tufted angioma grows slowly and insidiously and may eventually come to cover a large area of the trunk or neck. In most cases the growth is halted after some years, but there is a slight tendency toward spontaneous regression (19). The clinical appearance of the lesions is variable. Some of them are characterized by enlarging erythematous or brown macules or plaques with an angiomatous appearance; other lesions may resemble granulomas or a connective tissue abnormality. In some cases the lesions are tender (20,21) whereas in other cases, there is hyperhidrosis on the surface (21,22). Raised papules resembling pyogenic granulomas are sometimes seen within the area of the lesion (23), and occasionally the lesions may show a linear arrangement (24).Tufted angiomas have been associated with nevus flammeus (25,26) and other vascular malformations (27), pregnancy (28), and nonregressing lipodystrophy centrifugalis abdominalis (29). There is also a single example of tufted angioma described in a liver transplant recipient (30). In some cases the lesions spread by infiltration, leading to sclerosing plaques (31). Many cases of Kasabach-Merritt syndrome are associated with tufted angioma (32–38). It has been demonstrated that in most cases of Kasabach-

Fig. 23. Clinical features of tufted hemangioma. An angiomatous plaque involving the inner aspect of the arm.


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Fig. 24. Histopathologic features of tufted hemangioma. (A) Low power shows multiple cellular lobules at different levels of the dermis separated by connective tissue. (B) Higher magnification demonstrates that each lobule is composed of aggregates of endothelial cells with some small vascular lumina. (C) Still higher magnification showing aggregations of endothelial cells with small capillary lumina containing erythrocytes.

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Merritt syndrome the underlying lesion is not an infantile hemangioma, as was originally thought, but is either a tufted angioma or a kaposiform hemangioendothelioma. HISTOPATHOLOGIC FEATURES Histopathologically, tufted angioma is quite characteristic. There are multiple individual vascular lobules within the dermis and subcutaneous fat (Fig. 24). These aggregations are more prominent in the middle and lower part of the dermis. Each lobule is composed of aggregates of endothelial cells that whorl concentrically around a preexisting vascular plexus. Some lobules bulge into the walls of dilated thin-walled vascular structures, giving these vessels a slit-like or semilunar appearance(23,28,39). This peculiar shape in addition to the angiocentricity of the vascular structures prompted the name tufted angioma. Small capillary lumina are identified within the aggregations of endothelial cells. Unusual histopathologic findings in tufted angioma include a mucinous stroma (22), abundant eccrine sweat glands (40), and an intravenous location of the lesion (41). Immunohistochemically, the cells in the capillary tufts are weakly positive or negative for factor VIII related antigen. They exhibit strong positivity for Ulex europaeus I lectin, EN4, CD31, CD34, and α-smooth muscle actin, which is related to the immature nature of the endothelial cells (4,42). The cells that show reactivity for smooth muscle actin most likely represent pericytes (23). Ultrastructural studies have shown characteristic crystalloid inclusions within endothelial cells in addition to Weibel-Palade bodies (13). The differential diagnosis of tufted angioma includes Kaposi’s sarcoma and occasionally infantile hemangiomas. The “cannonball” pattern is characteristic of tufted angioma. Nodular lesions of Kaposi’s sarcoma are composed of interlacing fascicles of spindle cells lining slit-like vessels, and an inflammatory infiltrate of plasma cells is usually present (43). Infantile hemangiomas occasionally present with a lobular pattern, but these collections are present only focally. In addition, tufted angiomas are rare in infants. TREATMENT Tufted angioma showing spontaneous regression is a rare event (24,40,44–46). For the treatment of these lesions, soft radiation has been recommended (13). Satisfactory results have been also reported with surgery (47), pulse dye laser (11,48), high-dose systemic steroids (49), and interferon-α, (50–54) although there is a report of one case that failed to respond to intralesional injections of interferon-α (55).

References 1. 2. 3. 4. 5.

6. 7. 8.


Wilson Jones E. Malignant vascular tumors. Clin Exp Dermatol 1976;1:287–312. MacMillan A, Champion RH. Progressive capillary haemangioma. Br J Dermatol 1971;85:492–3. Nakagawa K. Case report of angioblastoma of the skin. Nippon Hifuka Gakkai Zasshi 1949;59:92–4. Wilson Jones E, Orkin M. Tufted angioma (angioblastoma). A benign progressive angioma not to be confused with Kaposi’s sarcoma or low-grade angiosarcoma. J Am Acad Dermatol 1989;20:214–25. Igarashi M, Oh-i T, Koga M. The relationship between angioblastoma (Nakagawa) and tufted angioma: report of four cases with angioblastoma and a literature-based comparison of the two conditions. J Dermatol 2000;27:537–42. Cho KH. Tufted angioma: is it the same as angioblastoma (Nakagawa)? Arch Dermatol 1997;133:789. Satomi I, Tanaka Y, Murata J, Fujisawa R. A case of angioblastoma (Nakagawa) Rinsho Dermatol (Tokyo) 1981;23:703–9. Kim KJ, Lee MW, Choi JH, Sung KJ, Moon KC, Koh JK. A case of congenital tufted angioma mimicking cavernous hemangioma. J Dermatol 2001;28:514–5.

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9. Hebeda CL, Scheffer E, Starink TM. Tufted angioma of late onset. Histopathology 1993;23:191–3. 10. Descours H, Grezard P, Chouvet B, Labeille B. Angiome en touffes acquis de l’adulte. Ann Dermatol Venereol 1998;125:44–6. 11. Dewerdt S, Callens A, Machet L, Grangeponte MC, Vaillant L, Lorette G. Angiome en touffes acquis de l’adulte: échec du traitement par laser à colorant pulse. Ann Dermatol Venereol 1998;125:47–9. 12. Heagerty AHM, Rubin A, Robinson TWE. Familial tufted angioma. Clin Exp Dermatol 1992;17:344–5. 13. Kumakiri M, Muramoto F, Tsukinaga I, Yoshida T, Ohura T, Miura Y. Crystalline lamellae in the endothelial cells of a type of hemangioma characterized by the proliferation of immature endothelial cells and pericytes-angioblastoma (Nakagawa). J Am Acad Dermatol 1983;8:68–75. 14. Okada E, Tamura A, Ishikawa O, Miyachi Y. Tufted angioma (angioblastoma): case report and review of 41 cases in the Japanese literature. Clin Exp Dermatol 2000;25:627–30. 15. Ward KA, Kennedy CT, Ashworth MT. Acquired tufted angioma frequently develops at sites other than the neck and upper trunk. Clin Exp Dermatol 1996;21:80. 16. Kleinegger CL, Hammond HL, Vincent SD, Finkelstein MW. Acquired tufted angioma: a unique vascular lesion not previously reported in the oral mucosa. Br J Dermatol 2000;142:794–9. 17. Daley T. Acquired tufted angioma of the lower lip mucosa. J Can Dent Assoc 2000;66:137. 18. Michel S, Hohenleutner U, Stolz W, Knuchel-Clarke R, Helmig M, Landthaler M. Buschelartiges angiom (“tufted angioma”). Klin Padiatr 2001;213:39–42. 19. Allen PW. Three new vascular tumors—tufted angioma, kaposiform infantile hemangioendothelioma, and proliferative cutaneous angiomatosis. Int J Surg Pathol 1994;2:63–72. 20. Sumitra S, Yesudian P. Painful tufted angioma precipitated by trauma. Int J Dermatol 1994;33:675–6. 21. Bernstein EF, Kantor G, Howe N, Savit RM, Koblenzer P, Uitto J. Tufted angioma of the thigh. J Am Acad Dermatol 1994;31:307–11. 22. Cho KH, Kim SH, Park KC, et al. Angioblastoma (Nakagawa)— is it the same as tufted angioma? Clin Exp Dermatol 1991;16:110–3. 23. Padilla RS, Orkin M, Rosai J. Acquired “tufted” angioma (progressive capillary hemangioma). A distinctive clinicopathologic entity related to lobular capillary hemangioma. Am J Dermatopathol 1987;9:292–300. 24. Jang KA, Choi JH, Sung KJ, Moon KC, Koh JK. Congenital linear tufed angioma with spontaneous regression. Br J Dermatol 1998;138:912–3. 25. Alessi E, Bertani E, Sala F. Acquired tufted angioma. Am J Dermatopathol 1986;8:426–9. 26. Kim TH, Choi EH, Ahn SK, Lee SH. Vascular tumors arising in port-wine stains: two cases of pyogenic granuloma and a case of acquired tufted angioma. J Dermatol 1999;26:813–6. 27. Michel S, Hohenleutner U, Stolz W, Landthaler M. Acquired tufted angioma in association with a complex cutaneous vascular malformation. Br J Dermatol 1999;141:1142–4. 28. Kim YK, Kim HJ, Lee KG. Acquired tufted angioma associated with pregnancy. Clin Exp Dermatol 1992;7:458–9. 29. Hiraiwa A, Takai K, Fukui Y, Adachi A, Fujii H. Non-regressing lipodystrophia centrifugalis abdominalis with angioblastoma (Nakagawa). Arch Dermatol 1990;126:206–9. 30. Chu P, LeBoit PE. An eruptive vascular proliferation resembling acquired tufted angioma in the recipient of a liver transplant. J Am Acad Dermatol 1992;26:322–5. 31. Catteau B, Enjolras O, Delaporte E, Friedel J, Breviere G, Wassef M. Angiome en touffes sclérosant. A propos de 4 observations aux membres inférieurs. Ann Dermatol Venereol 1998;125:682–7. 32. Enjolras O, Wassef M, Mazoyer E, et al. Infants with Kasabach-Merritt syndrome do not have “true” hemangiomas. J Pediatr 1997;130:631–40. 33. Leaute-Labreze C, Bioulac-Sage P, Labbe L, Meraud JP, Taieb A. Tufted angioma asssociated with platelet trapping syndrome: response to aspirin. Arch Dermatol 1997;133:1077–9. 34. Enjolras O, Wassef M, Dosquet C, et al. Syndrome de Kasabach-Merritt sur angiome en touffes congénital. Ann Dermatol Venereol 1998;125:257–60. 35. Nakamura E, Ohnishi T, Watanabe S, Takahashi H. Kasabach-Merritt syndrome associated with angioblastoma. Br J Dermatol 1998;139:164–6. 36. Seo SK, Suh JC, Na GY, Kim IS, Sohn KR. Kasabach-Merritt syndrome: identification of platelet trapping in a tufted angioma by immunohistochemistry technique using monoclonal antibody to CD61. Pediatr Dermatol 1999;16:392–4. 37. Enjolras O, Mulliken JB, Wassef M, et al. Residual lesions after Kasabach-Merritt phenomenon in 41 patients. J Am Acad Dermatol 2000;42:225–35.

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38. Alvarez-Mendoza A, Lourdes TS, Ridaura-Sanz C, Ruiz-Maldonado R. Histopathology of vascular lesions found in Kasabach-Merritt syndrome: review based on 13 cases. Pediatr Dev Pathol 2000;3: 556–60. 39. Croue A, Habersetzer M, Leclech C, Forest JL, Saint-Andre JP, Verret JL. Le “tufted angioma” (angiome en touffes). Une tumeur vasculaire benigne à différencier du sarcoma de Kaposi. Arch Anat Cytol Pathol 1993;41:159–63. 40. Ban M, Kamiya H, Kitajima Y. Tufted angioma of adult onset, revealing abundant eccrine glands and central regression. Dermatology 2000;201:68–70. 41. Fukunaga M. Intravenous tufted angioma. APMIS 2000;108:287–92. 42. Mentzel T, Wollina U, Castelli E, Kutzner H. Buschelartiges Hamangiom (“tufted angioma”). Klinischpathologische und immunohistologische Analyse von funf Fallen einer distinkten Entitat im Spektrum der kapillaren Hamangiome. Hautarzt 1996;47:369–75. 43. Nielsen H, Nielsen PL. Cutaneous tufted angioma as differential diagnosis to Kaposi’s sarcoma in HIV infection. AIDS 1994;8:707–8. 44. Miyamoto T, Mihara M, Mishima, E, et al. Acquired tufted angioma showing spontaneous regression. Br J Dermatol 1992;127:645–8. 45. Lam WY, Mac-Moune Lai F, Look CN, Choi PC, Allen PW. Tufted angioma with complete regression. J Cutan Pathol 1994;21:461–6. 46. McKenna KE, McCusker G. Spontaneous regression of a tufted angioma. Clin Exp Dermatol 2000;25:656–8. 47. Verret JL, Leclech C, Croue A, Forest JL, Peria PH, Matard B. Tufted angioma (angioblastome). Ann Dermatol Venereol 1994;121:140. 48. Frenk E, Vion B, Merot Y, Ruffieux C. Tufted angioma. Dermatologica 1990;181:242–3. 49. Munn SE, Jackson JE, Russell Jones R. Tufted haemangioma responding to high-dose systemic steroids: a case report and review of the literature. Clin Exp Dermatol 1994;19:511–4. 50. Suarez SM, Pensler JM, Paller AS. Response of deep tufted angioma to interferon alpha. J Am Acad Dermatol 1995;33:124–6. 51. Park KC, Ahn PS, Lee YS, Kim KH, Cho KH. Treatment of angioblastoma with recombinant interferonalpha 2. Pediatr Dermatol 1995;12:184–6. 52. Robenzadeh A, Don PC, Weinberg JM. Treatment of tufted angioma with interferon alfa: role of bFDG. Pediatr Dermatol 1998;15:482. 53. Wilmer A, Kaatz M, Bocker T, Wollina U. Tufted angioma. Eur J Dermatol 1999;9:51–3. 54. Wollina U. Interferon for tufted angioma. Pediatr Dermatol 1999;16:338. 55. Fariña MC, Torrelo A, Mediero IG, Zambrano A. Angioma en penacho. Actas Dermosifiliogr 1996;87:563–7.


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8. GLOMERULOID HEMANGIOMA The term glomeruloid hemangiomas was coined by Chan et al. (1) in 1990 to describe a distinctive vascular proliferation that occurs in patients affected with the POEMS syndrome. POEMS is an acronym for this syndrome, which includes: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy (M protein), and skin lesions. Other terms for the POEMS syndrome include Takatsuki’s syndrome, Crow-Fukase syndrome, plasma cell dyscrasia with polyneuropathy and endocrine disorders. POEMS syndrome and multicentric Castleman’s disease are closely related, and some authors consider them to be overlapping entities (2). CLINICAL FEATURES There are several cutaneous manifestations in POEMS syndrome, including hyperpigmentation, hypertrichosis, scleroderma-like skin thickening, digital clubbing, edema, nail changes, acquired ichthyosis, multiple seborrheic keratosis, livedo reticularis, purpura, ulcers, flushing, Raynaud’s phenomenon, and angiomas (3–7). The exact frequency of angiomas in patients with POEMS syndrome is difficult to judge, but the incidence ranges from 26 to 44% (5,6). When present, the angiomas are small, firm, red to violaceous, dome-shaped papules that measure a few millimeters in diameter (Fig. 25) and are usually located on the trunk and proximal parts of the extremities (1,7–12). In some cases the angiomatous lesions resemble eruptive histiocytomas (13). HISTOPATHOLOGIC FEATURES Histopathologically, the vascular lesion in patients with POEMS syndrome fall into four categories, namely, microvenular hemangiomas (14), cherry hemangiomas (9,10), multinucleate cell angiohistiocytomas (13), and glomeruloid hemangiomas (1,11,12,15–17). Glomeruloid hemangiomas seem to be fairly specific for POEMS syndrome, because they have not been reported in other settings. Furthermore, POEMS syndrome patients affected with cherry hemangiomas occasionally show miniature foci with glomeruloid features(1). Microscopically, glomeruloid hemangioma consists of multiple ectatic vascular structures containing aggregates of capillary loops resembling renal glomeruli (Fig. 26). The capillaries are lined with either flat or plump endothelial cells with vacuoles and surrounded by pericytes. The vacuoles in the cytoplasm of the endothelial cells contain eosinophilic PAS positive globules that represent deposits of immunoglobulins absorbed through circulation (1,12). The endothelial nature of the cells is further confirmed by immunohistochemistry. The neoplastic cells are positive for factor VIII-related antigen, Ulex europaeus I lectin, and vimentin, whereas muscle-specific actin is negative (15). Two different types of endothelial cells have been described in glomeruloid hemangioma (18). The first type consists of endothelial cells that have large vesicular nuclei with open chromatin and large amounts of cytoplasm. These cells are positive for CD31, CD34, and Ulex europaeus I lectin, but not for CD68. The second type of endothelial cells consists of cells with small nuclei containing a dense chromatin and scant cytoplasm. This second type of cells is positive for CD31 and CD68, whereas CD34 and Ulex europaeus I lectin are negative. Speculation remains as to the histogenesis of glomeruloid hemangioma. Chan et al. (1) postulated that the deposition of immunoglobulins within the endothelial cells stimulates the proliferation of these cells in a glomeruloid fashion. The description of cases of reactive angioendotheliomatosis with a glomeruloid pattern in patients with cryoglobu-

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Fig. 25. Patient with POEMS syndrome and multiple angiomatous papules all over the skin. (A) Small angiomatous papules scattered on the buttocks and trunk. (B) Similar lesions on the dorsum of the foot.

linemia (19), cold agglutinins syndrome (20), and local intravascular immunoglobulin deposits associated with monoclonal gammopathy (21); lends further support to this hypothesis. Additional possible explanations for the development of vascular proliferations in patients with POEMS syndrome include the production of angiogenic factors by proliferating plasma cells or an increased level of serum estrogens (9).


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Fig. 26. Histopathologic features of glomeruloid hemangioma. (A) Scanning power showing an exophytic and pedunculated lesion. (B) Higher magnification demonstrates dilated vascular structures with their lumina filled by a lobular capillary proliferation. (C) Still higher magnification shows aggregates of capillary loops within dilated lumina closely resembling a renal glomerulus.

The differential diagnosis of glomeruloid hemangioma includes other lesions showing a predominant intravascular growth. Intravascular pyogenic granuloma is characterized by lobules of capillaries embedded in a fibromyxoid stroma, forming a polypoid mass that protrudes into a vein, but these lesions lack a glomeruloid arrangement. In intravascular papillary endothelial hyperplasia or Masson’s tumor, fibrinoid or fibrous cores

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form the intravascular papillary projections, but well-formed capillaries are absent. Acquired tufted angioma is composed of solid aggregates of endothelial cells forming lobules. They lack a glomeruloid arrangement, and there is no evidence of eosinophilic PAS-positive deposits within the endothelial cells. Malignant endovascular papillary angioendothelioma (Dabska’s tumor) is also characterized by intravascular papillary endothelial tufts, but the endothelial cells are atypical and the vascular channels are less well formed when compared to glomeruloid hemangioma. TREATMENT Most patients with POEMS syndrome have a progressive, disabling clinical course with a poor prognosis, in spite of any therapy. Combination chemotherapy can be useful for treatment of the plasma cell dyscrasia, but there is only partial response to alkylating agents and prednisone. Plasmapheresis has been found to be ineffective (5). The 5-year survival rate in patients with POEMS syndrome is higher than that in patients with multiple myeloma. In a series of 38 patients with POEMS syndrome, 60% of patients had a 5-year survival rate (5).

References 1. Chan JKC, Fletcher CDM, Hicklin GA, Rosai J. Glomeruloid hemangioma. A distinctive cutaneous lesion of multicentric Castleman’s disease associated with POEMS syndrome. Am J Surg Pathol 1990;14:1036–46. 2. Frizzera G. Castleman’s disease and related disorders. Semin Diagn Pathol 1988;5:346–64. 3. Derevre O, Guillot B, Dandurand M, Bataille R. Les signes cutanés du syndrome POEMS. Ann Dermatol Venereol 1990;117:283–90. 4. Shelley WB, Shelley ED. The skin changes in the Crow-Fukase (POEMS) syndrome. Arch Dermatol 1987;123:85–7. 5. Miralles GD, O’Fallon JR, Talley NJ. Plasma-cell dyscrasia with polineuropathy: the spectrum of POEMS syndrome. N Engl J Med 1992;327:1919–23. 6. Perniciaro C. POEMS syndrome. Semin Dermatol 1995;14:162–5. 7. Zea Mendoza A, Alonso Ruiz A, Garcia Vadillo A, et al. POEMS syndrome with neuroarthropathy and nodular regenerative hyperplasia of the liver. Arthritis Rheum 1984;27:1053–7. 8. Ishikawa O, Nihei Y, Ishikawa H. The skin changes of POEMS syndrome. Br J Dermatol 1987;117:523–6. 9. Kanitakis J, Roger H, Soubrier M, Dubost JJ, Chouvet B, Souteyrand P. Cutaneous angiomas in POEMS syndrome. An ultrastructural and immunohistochemical study. Arch Dermatol 1988;124:695–8. 10. Puig L, Moreno A, Domingo P, Llistosella E, de Moragas JM. Cutaneous angiomas in POEMS syndrome. J Am Acad Dermatol 1985;12:961–4. 11. Judge MR, McGibbon DH, Thompson RPH. Angioendotheliomatosis associated with Castleman’s lymphoma and POEMS syndrome. Clin Exp Dermatol 1993;18:360–2. 12. Rongioletti F, Gambina C, Lerza R. Glomeruloid hemangioma. A cutaneous marker of POEMS syndrome. Am J Dermatopathol 1994;16:175–8. 13. del Rio R, Alsina M, Monteagudo J, et al. POEMS syndrome and multiple angioproliferative lesions mimicking histiocytomas. Acta Derm Venereol 1994;74:388–90. 14. Ackerman AB, Guo Y, Vitale P. Clues to Diagnosis in Dermatopathology II. Chicago, ASCP Press, 1992:285–8. 15. Tsang WYW, Chan JKC, Fletcher CDM. Recently characterized vascular tumours of skin and soft tissues. Histopathology 1991;19:489–501. 16. Yang SG, Cho KH, Bang YJ, Kim CW. A case of glomeruloid hemangioma associated with multicentric Castleman’s disease. Am J Dermatopathol 1998;20:266–70. 17. Tsai CY, Lai CH, Chan HL, Kuo TT. Glomeruloid hemangioma—a specific marker of POEMS syndrome. Int J Dermatol 2001;40:403–6. 18. Kishimoto S, Takenaka H, Shibagaki R, Noda Y, Yamamoto M, Yasuno H. Glomeruloid hemangioma in POEMS syndrome shows two different immunophenotypic endothelial cells. J Cutan Pathol 2000;27:87–92.


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19. LeBoit PE, Salomon AR, Santa Cruz DJ, Wick MR. Angiomatosis with luminal cryoprotein deposition. J Am Acad Dermatol 1992;27:969–73. 20. Porras-Luque JI, Fernandez-Herrera J, Dauden E, Fraga J, Fernández-Villalta MJ, García-Díez A. Cutaneous necrosis by cold agglutinins associated with glomeruloid reactive angioendotheliomatosis. Br J Dermatol 1998;139:1068–72. 21. Salama SS, Jenkin P. Angiomatosis of skin with local intravascular immunoglobulin deposits, associated with monoclonal gammopathy. A potential cutaneous marker for B-chronic lymphocytic leukemia. A report of unusual case with immunohistochemical and immunofluorescence correlation and review of the literature. J Cutan Pathol 1999;26:206–12.

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9. ACQUIRED ELASTOTIC HEMANGIOMA Acquired elastotic hemangioma is a recently described variant of cutaneous hemangioma (1). These lesions develop during adulthood on chronically sun-damaged skin, on the extensor surface of the forearms or the lateral aspects of the neck. It mainly affects middle-aged and elderly women. CLINICAL FEATURES Acquired elastotic hemangioma presents as a slightly elevated, irregularly shaped, solitary lesion with violaceous coloration (Fig. 27). The lesions are usually well-demarcated plaques that range from 2 to 5 cm in diameter. The lesions blanch under diascope pressure. In the described cases, the suggested clinical diagnoses were basal cell carcinoma, hemangioma, or Bowen’s disease. In most cases there is no evidence of previous trauma at the site of the lesion. HISTOPATHOLOGIC FEATURES Histopathologically, acquired elastotic hemangioma consists of a proliferation of capillary blood vessels involving the superficial dermis in a band-like arrangement parallel to the epidermis (1) (Fig. 28). A narrow band of noninvolved papillary dermis separates the newly formed capillaries from the normal or flattened epidermis. The capillary proliferation involves the papillary and upper reticular dermis, but the deep reticular dermis is characteristically spared. The neoformed capillaries show small cleftlike or round lumina and contain few erythrocytes. Cellular atypia of endothelial cells is absent, and very few mitotic figures are identified. No hemosiderin deposits or extravasated erythrocytes are seen. The connective tissue surrounding or intermingled with the newly formed capillaries shows intense solar elastosis, which is seen as basophilic degeneration of the individual collagen bundles or amorphous basophilic granular material replacing the normal collagen bundles of the superficial dermis. Immunohistochemically, the neoplastic endothelial cells of acquired elastotic hemangioma express strong positive immunoreactivity for CD31 and CD34. A continuous rim of α-smooth muscle actin-positive pericytes surrounds the majority of the neoplastic

Fig. 27. Clinical features of acquired elastotic hemangioma. An angiomatous plaque with linear configuration is seen on the external aspect of the arm of an elderly woman.


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Fig. 28. Histopathologic features of acquired elastotic hemangioma. (A) Low power shows a cellular proliferation with a band-like arrangement along the superficial dermis. (B) Higher magnification shows that the cellular proliferation is composed of capillary blood vessels embedded in a dermis with severe solar elastosis. (C) Still higher magnification shows aggregates of endothelial cells with small capillary lumina.

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vascular channels. Proliferating markers Ki-67 and MPM-2 stain only a few of the nuclei of the endothelial cells of the newly formed blood vessels. TREATMENT In the described series, treatment consisted of local surgical excision in all cases. No recurrence developed during follow-up of the patients (1).

References 1. Requena L, Kutzner H, Mentzel T. Acquired elastotic hemangioma. A clinico-pathologic variant of hemangioma. J Am Acad Dermatol 2002;47:371–376.


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10. KAPOSIFORM HEMANGIOENDOTHELIOMA CLINICAL FEATURES Kaposiform hemangioendothelioma is a rare but distinctive vascular neoplasm that most commonly affects children. Although the retroperitoneum is the most frequent location (1–5), it may also be found in the skin (2,4,6,7). When the neoplasm is positioned in deep soft tissue, mediastinum, or retroperitoneum, it may be associated with the consumption coagulopathy that characterizes Kasabach-Meritt syndrome (1,2,6,8–11) (Fig. 29). Furthermore, it has recently been demonstrated that in most cases of KasabachMerritt syndrome, the underlying cutaneous vascular lesion is usually either a tufted angioma or a kaposiform hemangioendothelioma (Fig. 30) and not a large infantile hemangioma, as was originally thought (12–20). In some cases, kaposiform hemangioendothelioma may be associated with lymphangiomatosis (2). HISTOPATHOLOGIC FEATURES Kaposiform hemangioendothelioma combines features of cellular infantile hemangioma and Kaposi’s sarcoma (Fig. 31). Characteristically, the neoplasm is composed of several ill-circumscribed nodules separated by connective tissue. Each nodule is formed by an admixture of small round capillaries and solid glomeruloid nests containing round to oval endothelial cells with epithelioid features. The endothelial cells may contain hemosiderin, hyaline globules, and vacuoles as an expression of primitive vascular differentiation (1,2,21). The multinodular pattern of the neoplasm closely resembles that of tufted angioma, but the nodules of kaposiform hemangioendothelioma are larger and less circumscribed and often involve deep soft tissue and bone (22). Within these nodules, there are also short fascicles of spindle cells that are intertwined with slit-like and crescent-shaped vascular spaces in which red blood cells and fibrin thrombi may be identified. The fascicular areas bear striking resemblance to the nodular lesions of Kaposi’s sarcoma; however, a multinodular pattern is usually absent in authentic Kaposi’s sarcoma. Furthermore, infiltrates of plasma cells present around the nodules of Kaposi’s sarcoma are not seen in kaposiform hemangioendothelioma. Atypia and mitotic figures are usually absent in kaposiform hemangioendothelioma; areas of amianthoid-like fibers have been reported in one case (23). In those cases in which kaposiform hemangioendothe-

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Fig. 29. Kasabach-Merritt syndrome in a baby with retroperitoneal and cutaneous kaposiform hemangioendothelioma.


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Fig. 30. Large kaposiform hemangioendothelioma involving the leg of a baby.

lioma is associated with lymphangiomatosis, there is a sharp separation between the two lesions (2). Immunohistochemical studies have provided dissimilar results. In some cases the neoplastic cells were positive for factor VIII-related antigen and Ulex europaeus I lectin (1,7), whereas in others these endothelial markers were negative (2,21). In most cases the neoplastic cells are positive for vimentin, CD31, and CD34 (2,7,21), and negative for muscle-specific actin. In the better formed vascular channels of the neoplasm, the latter marker highlights pericytes that form a ring around the negatively stained endothelial cells (1,2,7,21). GLUT1 antibody is negative (24), but VEGFR-3 has been reported to be positive in six cases studied (25), which suggests at least partial lymphatic endothelial differentiation of the neoplastic cells in kaposiform hemangioendothelioma. So far, no evidence of human herpesvirus 8 infection has been detected in lesions of kaposiform hemangioendothelioma (15). Electron microscopy studies in two cases have documented small groups of tightly cohesive attenuated endothelial cells with poor canalization and Fig. 31. (Opposite page) Histopathologic features of kaposiform hemangioendothelioma. (A) Scanning power showing a well-circumscribed nodular proliferation. (B) Higher magnification demonstrates that the lesion is composed of solid aggregations of spindle cells with inconspicuous vascular lumina. (C) Still higher magnification demonstrates short fascicles of spindle cells with small lumina between them and extravasated erythrocytes. (D) Large dilated and congestive vascular spaces are seen in other areas of the lesion.


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only slit-like lumina. Basal lamina was occasionally present but was discontinuous and poorly formed. Only rare pericytes were seen around these endothelial groups. WeibelPalade bodies were not identified within the neoplastic cells (2). TREATMENT In contrast to infantile hemangioma, lesions of kaposiform hemangioendothelioma show no tendency to regress over time; however, to our knowledge, no patient with this neoplasm has developed a distant metastasis and therefore it should be considered a benign neoplasm (26). However, depending on the location and size of the lesion, there may be some complications. Large neoplasms situated within the mediastinum or retroperitoneum are unresectable and may cause death owing to complications of the consumption coagulopathy. Those cases may be successfully treated with systemic steroids (27), interferon-α-2a (13,14) or combined therapies including systemic corticosteroids, INF-α, vincristine, and radiation (15). Other therapies include embolization, systemic interferon, cyclophosphamide, ε-aminocaproic acid, compression therapy (16), and chemotherapy with vincristine, cyclophosphamide, and actinomycin D (18). More localized neoplasms occurring in superficial soft tissues are curable with wide local excision.

References 1. Tsang WYW, Chan JKC. Kaposi-like infantile haemangioendothelioma: a distinctive vascular neoplasm of the retroperitoneum. Am J Surg Pathol 1991;15:982–9. 2. Zukerberg LR, Nickoloff BJ, Weiss SW. Kaposiform hemangioendothelioma of infancy and childhood. An aggressive neoplasm associated with Kasabach-Merritt syndrome and lymphangiomatosis. Am J Surg Pathol 1993;17:321–8. 3. Ekfors TO, Kujari M, Herva R. Kaposi-like infantile hemangioendothelioma. Am J Surg Pathol 1993;17:314–6. 4. Neidt GW, Greco MA, Wierczorek R, Blanc WA, Knowles DM. Hemangioma with Kaposi’s sarcomalike features. Pediatr Pathol 1989;9:567–75. 5. Suster S. Epithelioid and spindle cell hemangio-endothelioma of the spleen: report of a distinctive splenic vascular neoplasm of childhood. Am J Surg Pathol 1992;16:785–92. 6. Allen PW. Three new vascular tumors—tufted angioma, kaposiform infantile hemangioendothelioma, and proliferative cutaneous angiomatosis. Int J Surg Pathol 1994;2:63–72. 7. Fukunaga M, Ushigome S, Ishikawa E. Kaposiform haemangioendothelioma associated with KasabachMerritt syndrome. Histopathology 1996;28:281–4. 8. McPartlin DW, Ghufoor K, Patel SK, Jayaraj S. A rare case of cutaneous kaposiform haemangioendothelioma. Int J Clin Pract 1999;53:562–3. 9. Gianotti R, Gelmetti C, Alessi E. Congenital cutaneous multifocal kaposiform hemangioendothelioma. Am J Dermatopathol 1999;21:557–61. 10. Zamecnik M, Koys F, Mikleova Z, Michal M. Additional case of kaposiform hemangioendothelioma in an adult. Cesk Patol 2001;37:128–9. 11. Lalaji TA, Haller JO, Burgess RJ. A case of head and neck kaposiform hemangioendothelioma simulating a malignancy on imaging. Pediatr Radiol 2001;31:876–8. 12. Enjolras O, Wassef M, Mazoyer E, et al. Infant with Kasabach-Merritt syndrome do not have “true” hemangiomas. J Pediatr 1997;130:631–40. 13. Deb G, Jenker A, Del Sio L, et al. Spindle cell (kaposiform) hemangioendothelioma with KasabachMerritt syndrome in an infant: successful treatment with alpha-2-a interferon. Med Pediatr Oncol 1997;28:358–61. 14. Sarkar M, Mulliken JB, Kozakewich HP, Robertson RL, Burrows PE. Thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon) is associated with kaposiform hemangioendothelioma and not with common infantile hemangioma. Plast Reconstr Surg 1997;100:1377–86. 15. Vin-Christian K, McCalmont TH, Frieden IJ. Kaposiform hemangioendothelioma. An aggressive, locally invasive vascular tumor that can mimic hemangioma of infancy. Arch Dermatol 1997;133:1573–8.


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16. Blei F, Karp N, Rofsky N, Rosen R, Greco MA. Successful multimodal therapy for kaposiform hemangioendothelioma complicated by Kasabach-Merritt phenomenon: case report and review of the literature. Pediatr Hematol Oncol 1998;15:295–305. 17. Arnaout MK, Pappo AS. Kaposiform hemangioendothelioma with associated Kasabach-Merritt phenomenon. The Hemophilia Growth and Development Study. J Pediatr 1998;133:788. 18. Hu B, Lachman R, Phillips J, Peng SK, Sieger L. Kasabach-Merritt syndrome-associated kaposiform hemangioendothelioma successfully treated with cyclophosphamide, vincristine, and actinomycin D. J Pediatr Hematol Oncol 1998;20:567–9. 19. Enjolras O, Mulliken JB, Wassef M, et al. Residual lesions after Kasabach-Merritt phenomenon in 41 patients. J Am Acad Dermatol 2000;42:225–35. 20. Alvarez-Mendoza A, Lourdes TS, Ridaura-Sanz C, Ruiz-Maldonado R. Histopathology of vascular lesions found in Kasabach-Merritt syndrome: review based on 13 cases. Pediatr Dev Pathol 2000;3:556–60. 21. Mentzel T, Mazzoleni G, Dei Tos AP, Fletcher CD. Kaposiform hemangioendothelioma in adults. Clinicopathologic and immunohistochemical analysis of three cases. Am J Clin Pathol 1997;108:450–5. 22. Chu P, LeBoit PE. An eruptive vascular proliferation resembling acquired tufted angioma in the recipient of a liver transplant. J Am Acad Dermatol 1992;26:322–5. 23. Zamecnik M, Mikleova Z, Michal M. Kaposiform hemangioendothelioma in adult. Report of a case with amianthoid-like fibrosis and angiectases. Cesk Patol 2000;36:163–7. 24. North PE, Waner M, Mizeracki A, Mihm MC Jr. GLUT1: a newly discovered immunohistochemical marker for juvenile hemangiomas. Hum Pathol 2000;31:11–22. 25. Folpe AL, Veikkola T, Valtola R, Weiss SW. Vascular endothelial growth factor receptor-3 (VEGFR-3): a marker of vascular tumors with presumed lymphatic differentiation, including Kaposi’s sarcoma, kaposiform and Dabska-type hemangioendothelioma, and a subset of angiosarcomas. Mod Pathol 2000;13:180–5. 26. Mac-Moune Lai F, To KF, Choi PC, Leung PC, et al. Kaposiform hemangioendothelioma: five patients with cutaneous lesion and long follow-up. Mod Pathol 2001;14:1087–92. 27. Beaubien ER, Ball NJ, Storwick GS. Kaposiform hemangioendothelioma: a locally aggressive vascular tumor. J Am Acad Dermatol 1998;38:799–802.

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11. SINUSOIDAL HEMANGIOMA CLINICAL FEATURES It has recently been proposed by Calonje and Fletcher (1) that sinusoidal hemangioma be considered a distinctive variant of hemangioma. These lesions most frequently affect adult women and present as a solitary, acquired subcutaneous nodule; however, examples of sinusoidal hemangioma have also been described in children (2). The most usual location of the lesions is on the upper extremities (Fig. 32), shoulders, breast, and anterior abdominal wall. Clinically, sinusoidal hemangioma can be confused with angiosarcomas, melanoma, ganglion, or epidermoid cysts. HISTOPATHOLOGIC FEATURES Widely dilated, thin-walled vascular channels that interconnect with each other characterize sinusoidal hemangioma (Fig. 33). In some areas the neoplasm shows a pseudopapillary pattern. These thin-walled vessels ramify and anastomose with each other to a much greater extent than conventional hemangiomas do. The lining endothelium is single-layered, with focal pleomorphism and hyperchromasia, which, combined with the pseudopapillae, sometimes raises the possibility of an angiosarcoma. Areas of calcification have been described in one example of sinusoidal hemangioma (3). TREATMENT The lesions of sinusoidal hemangioma are cured by simple local excision. Follow-up of the patients has revealed no tendency toward either local recurrences or metastasis.

References 1. Calonje E, Fletcher CDM. Sinusoidal hemangioma. A distinctive benign vascular neoplasm within the group of cavernous hemangiomas. Am J Surg Pathol 1991;15:1130–5. 2. Enjolras O, Wassef M, Brocheriou-Spelle I, Josset P, Tran Ba Huy P, Merland JJ. Hémangiome sinusoidal. Ann Dermatol Venereol 1998;125:575–80. 3. Nakamura M, Miyachi Y. Calcifying sinusoidal haemangioma on the back. Br J Dermatol 1999; 141:377–8.

Fig. 32. Clinical features of sinusoidal hemangioma: an angiomatous plaque on the dorsum of the hand of an elderly man.


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Fig. 33. Histopathologic features of sinusoidal hemangioma. (A) Low power shows a well-circumscribed nodule. (B) Higher magnification shows interconnecting, thin-walled vascular channels at the periphery of the lesion. (C) These thin-walled vessels ramify and frequently show a pseudopapillary pattern.

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12. GIANT-CELL ANGIOBLASTOMA CLINICAL FEATURES Congenital infiltrating giant cell angioblastoma is the descriptive term used by Gonzalez-Crussi et al. (1) to report a single case of a unique vascular neoplasm that involved the right hand and forearm of a 3-month-old girl. More recently, Vargas et al. (2), described three additional cases also in children (2), on the hypothenar area of the hand, the palate and the scalp. The lesion on the hand was painful. Clinically, congenital infiltrating giant cell angioblastoma presents as an ulcerated soft tissue mass. HISTOPATHOLOGIC FEATURES Histopathologically, giant cell angioblastomas feature nodular and plexiform aggregates of plump cells with histiocytoid characteristics, often in combination with multinucleate giant cells that possess several nuclei, and prominent nucleoli. The overall appearance resembles a nonnecrotizing granuloma (Fig. 34). The cellular aggregates may form concentric patterns of oval or spindle cells disposed around vascular structures of small caliber. The aggregates have been interpreted as abortive attempts at formation of blood vessels. Other areas of the lesion may exhibit an overtly angiomatous appearance with irregular branching vascular channels lined by plump endothelial cells. A resemblance to a hemangiopericytoma is created. In still other foci, the neoplastic cells have a uniform spindle shape in an arrangement that features a storiform pattern. Small vessels may extend into perineural and intraneural areas. The stroma between the neoplastic aggregates is characteristically loose and often infiltrated by lymphocytes, plasma cells, and mast cells. The cells that line the vascular spaces display immunohistochemical positivity for factor VIII-related antigen and CD31, whereas the peripheral cells of the nodular aggregates express muscle actin (1,2). GLUT1 antibody is negative in the neoplastic endothelial cells (2). CD68 antibody shows a strong affinity for the multinucleate giant cells and also the large mononucleate cells. The endothelial cells, the large mononuclear cells, and the multinucleate giant cells lack immunoreactivity for desmin, S-100 protein, leukocyte common antigen, epithelial membrane antigen, and CAM 5.2 cytokeratin (2).Ultrastructural examination has demonstrated that cells around the lumina were immature endothelial cells, whereas the plump periendothelial cells appear as modified pericytes. The multinucleate giant cells and the large mononucleate forms have a histiocytic lineage, as judged by their immunohistochemical and electron microscopy characteristics (2). TREATMENT The natural history and the growth potential of the giant cell angioblastoma remain poorly defined. The initial reported case extensively involved nerves, soft tissues, and bone of the forearm and necessitated amputation (1). Two subsequent cases were successfully treated with subtotal excision and interferon-α (2). As judged from limited experience, the clinical features, histopathologic findings, and follow-up data suggest that the giant cell angioblastoma is a benign vascular neoplasm, unlikely to metastasize, but prone to create significant local problems by its infiltrative properties (2).

References 1. Gonzalez-Crussi F, Chou P, Crawford SE. Congenital, infiltrating giant cell angioblastoma. A new entity? Am J Surg Pathol 1991;15:175–83. 2. Vargas SO, Perez-Atayde AR, González-Crussi F, Kozakewich HP. Giant cell angioblastoma. Three additional occurrences of a distint pathologic entity. Am J Surg Pathol 2001;25:185–96.


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Fig. 34. Histopathologic features of giant cell angioblastoma. (A) Scanning power shows multiple cellular aggregates involving the full thickness of the dermis. (B) Each aggregate is composed of concentrically oriented plump cells with a histiocytoid appearance around inconspicuous vascular lumina. (C) Still higher magnification shows histiocytoid cells and some multinucleated giant cells, resembling granulomas.

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13. SPINDLE CELL HEMANGIOMA (FORMERLY SPINDLE CELL HEMANGIOENDOTHELIOMA) To designate a unique neoplasm, (1) Weiss and Enzinger descriptively coined the term spindle cell hemangioendothelioma. In 1986, they reported on 26 cases with the initial interpretation that the entity was a low-grade angiosarcoma, based on the observation that one case had metastasized to a regional lymph node (1). This individual case had recurred locally 19 times; it was irradiated and finally showed the histopathologic features of a conventional high-grade angiosarcoma. Thus, the malignant transformation was possibly a complication of the radiation therapy and not an expression of the natural history of the neoplasm. Since then, approximately 200 additional cases of spindle cell hemangioendothelioma have been reported in the literature (2–39). Extensive follow-up, available for most of these cases, indicates that the natural lesion has no metastatic potential and that local recurrence represents contiguous growth along blood vessels. Accordingly, the lesion has been renamed spindle cell hemangioma and is currently viewed as a benign vascular proliferation (28,39–41). Moreover, the indolent course of spindle cell hemangioma and its aversion to metastasize has prompted some authors to suggest that the lesion is not neoplastic, but rather a reactive process, perhaps a response to repeated episodes of intravascular thrombosis and recanalization (11,15,17,22,42). Admittedly, this interpretation remains controversial, with some advocates considering it a benign vascular neoplasm and others a malformation in which vascular thrombosis supervenes (28,39). CLINICAL FEATURES Although spindle cell hemangiomas occur most often in the distal regions of the extremities of children and young adults (3) (Fig. 35), examples of this lesion have been reported in the buttock (16), oral cavity (23), spinal cord (26), and penis (32). It affects both sexes equally, without gender predilection. Several cases of spindle cell hemangioma have been described in patients with Maffucci’s syndrome (1,3, 7,18,21,22,24,25, 28,29,31,34), thus lending credence to the possibility that many of the lesions originally described as cavernous hemangiomas in Maffucci’s syndrome may have been spindle cell hemangiomas. Other associated conditions include Klippel-Trenaunay syndrome (11), early-onset varicosities (11), congenital lymphedema (1,11), epithelioid hemangioendothelioma (5,20), and superficial cutaneous lymphatic malformation (31). Interestingly, three of the patients with coexistence of spindle cell hemangioma and Maffucci’s

Fig. 35. Clinical features of spindle cell hemangioma. An angiomatous nodule involving the heel of a young man.


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Fig. 36. Histopathologic features of spindle cell hemangioma. (A) Low power shows a wellcircumscribed dermal nodule and dilated vascular spaces. (B) Fascicles of spindle cells and dilated congestive blood vessels of thin walls. (C) Still higher magnification shows prominent vacuolization of the cells.

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syndrome developed angiosarcomas in other regions of the body separated from those affected by spindle cell hemangioma (11,24,28). Although many lesions present initially as a single nodule, most become multifocal within an anatomic region, acquiring the characteristic features of firm, bluish nodules. HISTOPATHOLOGIC FEATURES Histopathologically, spindle cell hemangiomas are well-circumscribed but not encapsulated nodules (Fig. 36) that combine the features of hemangioma and Kaposi’s sarcoma. They are rich in dilated, thin-walled, blood vessels sometimes occupied by organized thrombi and phleboliths. Interspersed between the blood vessels is a stroma of spindle cells in fascicles closely resembling Kaposi’s sarcoma. The fascicles often contain round cells with vacuolated cytoplasm, sometimes so marked as to be misinterpreted as entrapped adipose tissue (28,39). Most lesions are partially or exclusively intravascular (28). Immunohistochemical studies have demonstrated that the endothelial cells lining the blood vessels, as well as the plump rounded cells with vacuolated cytoplasm, express positivity for factor VIII-related antigen, Ulex europaeus I lectin, and CD34 (1,3,10,11, 14,18,22). Contrastingly, the spindle cells are negative for these markers but express immunoreactivity for smooth muscle markers, including HHF35, α-smooth muscle actin, desmin, and collagen type IV, thus providing evidence that they are immature pericytes (22). Immunohistochemical studies with proliferating markers, such as proliferating cell nuclear antigen (PCNA) and Ki67, regularly disclose low proliferative activity (25). DNA flow cytometric studies in 14 cases showed, with only one exception, diploid configurations, with low proliferative indexes (12,22,25), in accordance with the indolent growth of this entity. Ultrastructural studies provided similar conclusions; the round cells possessed ultrastructural characteristics of endothelial cells, whereas the spindle cells were less differentiated mesenchymal cells with features of fibroblasts (3,10,11,14,15). Nodular forms of Kaposi’s sarcoma constitute a singular differential diagnosis with spindle cell hemangioma. However, distinguishingly, the nodules of Kaposi’s sarcoma have a paucity of dilated blood vessels and generally lack the epithelioid round cells with vacuolated cytoplasm. The presence of the HHV-8 in Kaposi’s sarcoma individualizes this lesion (30). TREATMENT Spindle cell hemangiomas may be approached surgically, but the lesions persist in approx 60% of the cases (28). Persistence has been attributed to contiguous growth within the neighboring vessels not necessarily in continuity with the original site (39). One patient with spindle cell hemangioma was successfully treated with recombinant interleukin-2 (38). Although the clinical courses of 200 cases of spindle cell hemangiomas were not marred by regional or distant metastasis (28), close follow-up is needed in patients with spindle cell hemangioma and Maffucci’s syndrome, as significant inherent risks are potentially created by the association with the latter disease.

References 1. Weiss SW, Enzinger FM. Spindle cell hemangioendothelioma: a low grade angiosarcoma resembling cavernous hemangioma and Kaposi’s sarcoma. Am J Surg Pathol 1986;10:521–30. 2. Lessard M, Barnhill, RL. Spindle cell hemangioendothelioma. J Am Acad Dermatol 1988;18:393–5. 3. Scott GA, Rosai J. Spindle cell hemangioendothelioma. Report of seven additional cases of a recently described neoplasm. Am J Dermatopathol 1988;10:281–8.


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4. Wu KK. Spindle cell hemangioendothelioma of the foot. J Foot Surg 1989;28:475–8. 5. Zoltie N, Roberts PF. Spindle cell haemangioendothelioma in association with epithelioid haemangioendothelioma. Histopathology 1989;15:544–6. 6. Rios Martín JJ, Gonzalez Campora R, Armas Padron JR, Moreno Jimenez JC, Camacho Martínez F. Hemangioendotelioma de células fusiformes. Actas Dermosifiliogr 1989;80:481–4. 7. Lawson JP, Scott G. Case report 602: spindle cell hemangioendothelioma (SCH) and enchondromatosis (a form of Maffuci syndrome) in a patient with acute myelocytic leukemia (AML). Skeletal Radiol 1990;19:158–62. 8. Habeck JO. Das spindelzellhamangioendotheliom-ein niedrig malignes Angiosarkom. Pathologe 1990;11:94–6. 9. Steinbach LS, Ominsky SH, Shpall S, Perkocha LA. MR imaging of spindle cell hemangioendothelioma. J Comput Assist Tomogr 1991;15:155–7. 10. Terashi H, Itami S, Kurata S, Sonoda T, Takayasu S, Yokoyama S. Spindle cell hemangioendothelioma. Report of three cases. J Dermatol 1991;18:104–11. 11. Fletcher CDM, Beham A, Schmid C. Spindle cell haemangioendothelioma: a clinicopathological and immunohistochemical study indicative of a non-neoplastic lesion. Histopathology 1991;18:291–301. 12. Nikorowitsch R, Kindermann D. Zum Spindelzellhamangioendotheliom. Histomorphologische, immunohistochemische und DNA zytometrische Befunde. Pathologe 1991;12:327–30. 13. Marcoval Caus J, Pagerols Bonilla X, Iñiguez Navarro D, Sais Puigdemont G, Moreno Carazo A, Peyri Rey J. Hemangioendotelioma de células fusiformes. Estudio de dos casos y revisión de la literatura. Actas Dermosifiliogr 1991;32:449–51. 14. Ding J, Hashimoto H, Imayama S, Tsuneyoshi M, Enjoji M. Spindle cell haemangioendothelioma: probably a benign vascular lesion not a low-grade angiosarcoma. A clinicopathological, ultrastructural and immunohistochemical study. Virchows Arch A Pathol Anat 1992;420:77–85. 15. Imayama S, Murakamai Y, Hashimoto H, Hori Y. Spindle cell hemangioendothelioma exhibits the ultrastructural features of reactive vascular proliferation rather than of angiosarcoma. Am J Clin Pathol 1992;97:279–87. 16. Ono CM, Mitsunaga MM, Lockett LJ. Intragluteal spindle cell hemangioendothelioma. An unusual presentation of a recently described vascular neoplasm. Clin Orthop 1992;281:224–8. 17. Battocchio S, Facchetti F, Brisigotti M. Spindle cell hemangioendothelioma: further evidence against its proposed neoplastic nature. Histopathology 1993;22:296–8. 18. Murakami J, Sarker AB, Teramoto N, Horie Y, Taguchi K, Akagi T. Spindle cell hemangioendothelioma: a report of two cases. Acta Pathol Jpn 1993;43:529–34. 19. Eltorky M, McChesney T, Sebes J, Hall JC. Spindle cell hemangioendothelioma. Report of three cases and review of the literature. J Dermatol Surg Oncol 1994;20:196–202. 20. Azadeh B, Attallach MF, Ejeckam GC. Spindle cell hemangioendothelioma in association with epithelioid hemangioendothelioma. Cutis 1994;53:134–6. 21. Pellegrini AE, Drake RD, Qualman SJ. Spindle cell hemangioendothelioma: a neoplasm associated with Maffuci’s syndrome. J Cutan Pathol 1995;22:173–6. 22. Fukunaga M, Ushigome S, Nikaido T, Ishikawa E, Nakamori K. Spindle cell hemangioendothelioma: an immunohistochemical and flow cytometric study of six cases. Pathol Int 1995;45:589–95. 23. Tosios K, Koutlas IG, Kapranos N, Papanicolau SI. Spindle-cell hemangioendothelioma of the oral cavity. A case report. J Oral Pathol Med 1995;24:379–82. 24. Fanburg JC, Meis-Kindblom JM, Rosemberg AE. Multiple enchondromas associated with spindle-cell hemagioendotheliomas. An overlooked variant of Maffucci’s syndrome. Am J Surg Pathol 1995; 19:1029–38. 25. Hisaoka M, Kouho H, Aoki T, Hashimoto H. DNA cytometric and immunohistochemical analysis of proliferative activity in spindle cell haemangioendothelioma. Histopathology 1995;27:451–6. 26. Mahdavi Z, Grafe MR, Ostrup R, Kormanik P, Chamberlain MC. Spindle cell hemangioendothelioma of the spinal cord. J Neurooncol 1996;27:231–4. 27. Patel SV, Bass FD, Niemi WJ, Pressman MM. Spindle cell hemangioendothelioma: a case presentation and literature review of a rare lower extremity tumor. J Foot Ankle Surg 1996;35:309–11. 28. Perkins P, Weiss SW. Spindle cell hemangioendothelioma. An analysis of 78 cases with reassessment of its pathogenesis and biologic behavior. Am J Surg Pathol 1996;20:1196–204. 29. Hisaoka M, Aoki T, Kouho H, Chosa H, Hashimoto H. Maffucci’s syndrome associated with spindle cell hemagioendothelioma. Skeletal Radiol 1997;26:191–4.

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30. Hisaoka M, Hashimoto H, Iwamasa T. Diagnostic implication of Kaposi’s sarcoma-associated herpesvirus with special reference to the distinction between spindle cell hemangioendothelioma and Kaposi’s sarcoma. Arch Pathol Lab Med 1998;122:72–6. 31. Yañez S, Val-Bernal JF, Mira C, Echevarria MA, González-Vela MC, Arce F. Spindle cell hemangioendothelioma associated with multiple skeletal enchondromas: a variant of Maffucci’s syndrome. Gen Diagn Pathol 1998;143:331–5. 32. Gradner TL, Elston DM. Multiple lower extremity and penile spindle cell hemangioendotheliomas. Cutis 1998;62:23–6. 33. Bodemer C, Fraitag S, Amoric JC, Benaceur S, Brunelle F, De Prost Y. Hémangioendotheliome à cellules fusiformes dans une varieté monomelique et multinodulaire chez l’enfant. Ann Dermatol Venereol 1997;124:857–60. 34. Enjolras O, Wassef M, Merland JJ. Syndrome de Maffucci: une fausse malformation veineusse? Un cas avec hémangioendothelioma à cellules fusiformes. Ann Dermatol Venereol 1998;125:512–5. 35. Keel SB, Rosemberg AE. Hemorrhagic epithelioid and spindle cell hemangioma: a newly recognized, unique vascular tumor of bone. Cancer 1999;85:1966–72. 36. Isayama T, Iwasaki H, Ogata K, Naito M. Intramuscular spindle cell hemangioendothelioma. Skeletal Radiol 1999;28:477–80. 37. Tomasini C, Aloi F, Soro E, Elia V. Spindle cell hemangioma. Dermatology 1999;199:274–6. 38. Setoyama M, Shimada H, Miyazono N, Baba Y, Kanzaki T. Spindle cell hemangioendothelioma: succesful treatment with recombinant interleukin-2. Br J Dermatol 2000;142:1238–9. 39. Weiss SW, Goldblum JR. Enzinger and Weiss’s Soft Tissue Tumors, 4th ed., St. Louis, Mosby, 2001;853–6. 40. Mentzel T, Kutzner H. Hemangioendotheliomas: heterogeneous vascular neoplasms. Dermatopathol Pract Concep 1999:5:102–9. 41. Requena L, Ackerman AB. Hemangioendothelioma? Dermatopathol Pract Concep 1999;5:110–2. 42. Fletcher CDM. The non-neoplastic nature of spindle cell hemangioendothelioma. Am J Clin Pathol 1992;98:545–6.


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14. BENIGN LYMPHANGIOENDOTHELIOMA Benign lymphangioendothelioma is a rare lymphatic neoplasm characterized in a series of eight patients by Wilson Jones et al. in 1990 (1). Shortly thereafter these authors coined the name acquired progressive lymphangioma for the same lesion (2). So far, only 37 cases of this uncommon neoplasm have been reported (1–19), under the names acquired progressive lymphangioma (2–5,9–11,13,14) or benign lymphangioendothelioma (1,6–,8,12,15,17–19). The lesion described as acquired progressive lymphangioma of the skin following radiotherapy for breast carcinoma (11) is best interpreted as a benign, radiation-induced vascular proliferation of the breast (see the next chapter). The lesion designated as self-healing pseudoangiosarcoma (16) seemingly represents a transient benign lymphangioendothelioma. CLINICAL FEATURES The lesions of benign lymphangioendothelioma are reddish or bruise-like, slowly enlarging plaques that lack site predilection (Fig. 37). They can be found on the wrist (1), face (3,18), scalp (3,18), neck (18), shoulder (1,18), arm (5,6), forearm (1,18), breast (9,18), back (1,18), abdominal wall (4,16), buttock (14), knee (10), thigh (1,6–8,13,17), toes (18), sole (18), and oral mucosa (18). Typically, the lesion appears during adolescence or in young adults as an asymptomatic plaque that increases in size through the years. With the exception of one patient who had involvement of both forearms (1), and another

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Fig. 37. Clinical features of benign lymphangioendothelioma. A plaque with angiomatous appearance involving the anterior thigh of an adult man.


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who presented with two separate lesions involving the face and the arm (3), most patients have solitary lesions. Lesions have developed in sites previously involved by trauma (3,17), notably following femoral arteriography (13), and after a tick bite (15). In one patient, benign lymphangioendothelioma manifested clinically as an actinic keratosis (19). HISTOPATHOLOGIC FEATURES Benign lymphangioendotheliomas appear histologically as delicate, thin-walled, endothelium-lined spaces entrapped between collagen bundles (Fig. 38). The appearance may be confined to the papillary dermis, but it can extend into the reticular dermis and subcutaneous fat. In superficial areas, the vascular channels are arranged horizontally, often becoming smaller and more convoluted at deeper levels. The newly formed vessels may dissect preexisting vessels as well as adnexal structures of the dermis. The vascular spaces are variably empty or occupied by proteinaceous material. Some vessels show stromal papillary projections that call to mind papillary endothelial hyperplasia. Erythrocytes and hemosiderin deposits are characteristically absent. Endothelial cells are present in greater numbers in lesional vessels than in normal lymphatic channels. They may crowd together but regularly lack nuclear atypia. Immunohistochemically, the endothelial cells express affinity for Ulex europaeus I lectin (1,8,14,17), but are unpredictable for factor VIII-related antigen, some cases positive (8,14,17,18) and others negative (1,7,13). In addition, the endothelial cells may show immunoreactivity for CD31(17,18), CD34 (8,17,18), HLA-DR (8), smooth muscle actin (8,18), and ICAM-1 (8). Some studies have demonstrated the presence of type IV collagen (5,14,17) and desmin (5,14) in the matrix that surrounds the vascular channels, thus creating conjecture that benign lymphangioendothelioma is a complex hamartoma, which combines blood vessel, lymphatic, and smooth muscle components. Electron microscopic studies have revealed the presence of both tight junctions and well-formed, continuous basement membranes in the absence of Weibel-Palade bodies (8,13). Benign lymphangioendothelioma may mimic the patch stage of Kaposi’s sarcoma, and some authorities (20) have considered the two entities to be indistinguishable. Wilson Jones et al. (1), in their original series, emphasized that it is sometimes impossible to make this differentiation in the absence of clinical information. However, the differential diagnosis can be substantiated by the absence of erythrocytes, hemosiderin deposits, and plasma cells in lesions of benign lymphangioendothelioma; their presence frequently characterizes early lesions of Kaposi’s sarcoma. Benign lymphangioendothelioma may also mimic low-grade angiosarcoma. However, contrastingly, angiosarcoma occurs predominantly on the face and scalp of elderly patients, and it bears atypical endothelial cells that form multilayers in less differentiated areas. Extravasated erythrocytes, hemosiderin deposits, and a mixed or plasma-cell rich inflammatory infiltrate are common features in angiosarcoma. TREATMENT Some lesions of benign lymphangioendothelioma have resolved spontaneously (7,16). Surgical excision is generally curative (1,4), but some lesions have persisted after incomplete removal. Marked improvement of extensive lesions has been reported following therapy with oral prednisolone (3), or oral antibiotics (5), namely, ciprofloxacin and clindamycin, which were given for other reasons (14).


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Fig. 38. Histopathologic features of benign lymphangioendothelioma. (A) Irregular slit-like vascular spaces are present involving different levels of the dermis. (B) The vascular spaces appear empty and are lined by a discontinuous single layer of endothelial cells. A discrete inflammatory infiltrate of lymphocytes is present in the stroma. (C) Higher magnification demonstrates that endothelial cells lining the cleft-like vessels show no nuclear atypia.

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References 1. Wilson Jones E, Winkelmann RK, Zachary CB, Reda AM. Benign lymphangioendothelioma. J Am Acad Dermatol 1990;23:229–35. 2. Wilson Jones E. Malignant vascular tumours. Clin Exp Dermatol 1976;1:287–312. 3. Watanabe M, Kishiyama K, Ohkawara A. Acquired progressive lymphangioma. J Am Acad Dermatol 1983;8:663–7. 4. Tadaki T, Aiba S, Masu S, Tagami H. Acquired progressive lymphangioma as a flat erythematous patch on the abdominal wall of a child. Arch Dermatol 1988;124:699–701. 5. Zhu WY, Penneys NS, Reyes B, Khatib Z, Schachner L. Acquired progressive lymphangioma. J Am Acad Dermatol 1991;24:813–5. 6. Chemaly PH, Cricks B, Besseige H, Grossin M, Belaich S. Lymphangio-endotheliome benin. Ann Dermatol Venereol 1992;119:912–3. 7. Mehregan DR, Mehregan AH, Mehregan DA. Benign lymphangioendothelioma: report of 2 cases. J Cutan Pathol 1992;19:502–5. 8. Herron GS, Rouse RV, Kosek JC, Smoller BR, Egbert BM. Benign lymphangioendothelioma. J Am Acad Dermatol 1994;31:362–8. 9. Meunier L, Barneon G, Meynadier J. Acquired progressive lymphangioma. Br J Dermatol 1994; 131:706–8. 10. Soohoo L, Mercurio MG, Brody R, Zaim MT. An acquired vascular lesion in a child. Acquired progressive lymphangioma. Arch Dermatol 1995;131:341–2. 11. Rosso R, Gianelli U, Carnevali L. Acquired progressive lymphangioma of the skin following radiotherapy for breast carcinoma. J Cutan Pathol 1995;22:164–7. 12. Querol I, Cordoba A, Cisneros MT, Viguri A, Urbiola E. Linfangioendotelioma benigno. Med Cut Iber Lat Am 1995;23:243–7. 13. Kato H, Kadoya A. Acquired progressive lymphangioma occurring following femoral arteriography. Clin Exp Dermatol 1996;21:159–62. 14. Grunwald MH, Amichi B, Avinoach I. Acquired progressive lymphangioma. J Am Acad Dermatol 1997;37:656–7. 15. Wilmer A, Kaatz M, Mentzel T, Wollina U. Lymphangioendothelioma after a tick bite. J Am Acad Dermatol 1998;39:126–8. 16. Bencini PL, Sala F, Valeriani D, et al. Self-healing pseudoangiosarcoma. Unusual vascular proliferation resembling a vascular malignancy of the skin. Arch Dermatol 1988;124:692–4. 17. Sevila A, Botella Estrada R, Sanmartín O, et al. Benign lymphangioendothelioma of the thigh simulating a low-grade angiosarcoma. Am J Dermatopathol 2000;22:151–4. 18. Guillou L, Fletcher CD. Benign lymphangioendothelioma (acquired progressive lymphangioma), a lesion not to be confused with well-differentiated angiosarcoma and patch stage Kaposi’s sarcoma. Clinicopathologic analysis of a series. Am J Surg Pathol 2000;24:1047–57. 19. Yiannias JA, Winkelmann RK. Benign lymphangioendothelioma manifested clinically as actinic keratosis. Cutis 2001;67:29–30. 20. Sanchez JL, Ackerman AB. Vascular proliferations of the skin and subcutaneous fat. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, eds. Dermatology in General Medicine, 4th ed., New York, McGraw-Hill, 1993;1209–43.


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15. BENIGN VASCULAR PROLIFERATIONS IN IRRADIATED SKIN Benign vascular proliferations are well recognized lesions in previously irradiated areas of the skin. The nomenclature in the literature is complex, compounded by such terms as lymphangiectases (1), benign lymphangiomatous papules (2), lymphangiomas (3–13), atypical vascular lesions (14), and benign lymphangioendothelioma (15). These vascular lesions appear within the field of radiation, and the interval between the application of radiotherapy and the appearance of the cutaneous lesions spans several years (16). CLINICAL FEATURES The cutaneous lesions include papules, small vesicles, and erythematous plaques (Fig. 39). Benign appearing lymphangiomatous papules and plaques are the most common. Confusingly, the term lymphangioma circumscriptum (9,10,12,13) has been applied by some authors to the localized malformations of lymphatic vessels of the superficial dermis and as such bears no relation to the lesion under consideration in this chapter (17). Benign lymphangiomatous papules and plaques are the lymphatic counterpart of telangiectases. They result from acquired permanent dilation of lymphatic capillaries that have appeared in areas of the skin affected by obstruction or destruction of the lymphatics. It is conjectured that they result from interference in the drainage of lymphatic vessels secondary to radiotherapy (1–13) or surgery (18). Benign lymphangiomatous papules and plaques, however, may also appear in the skin of the elderly without any evidence of primary lymphatic injury (19). HISTOPATHOLOGIC FEATURES Under low magnification, the lesions appear as relatively well-circumscribed capillary proliferations centered in the dermis, without extension into the subcutaneous fat. The epidermis is usually spared (Fig. 40). Most lesions show irregularly dilated lymphatic spaces that branch and anastomose within the superficial dermis. The vascular spaces, devoid of content, are lined by a discontinuous single layer of endothelial cells with flattened nuclei. Commonly, adjacent vascular channels lie “back-to-back,” separated only by a thin layer of endothelial cells. Multiple papillary projections, covered by a single layer of endothelium, project into the lumina of the dilated lymphatic. The stroma

Fig. 39. Clinical features of a benign vascular proliferation in irradiated skin. This patient with breast carcinoma was treated with mastectomy and subsequent radiotherapy. In addition to the abundant telangiectases secondary to radiodermatitis, there are scattered small papules with an angiomatous appearance.

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Fig. 40. Histopathologic features of benign vascular proliferation in irradiated skin. (A) Low power shows dilated vascular spaces at different levels of the dermis. (B) These vessels show a lymphatic appearance, with thin walls and a single and discontinuous layer of endothelial cells lining their lumina. In some vessels there are small intraluminal papillary projections of endothelial cells.

consists of fibrillary collagen rich with spindle, or stellate, fibroblasts. Nodular infiltrates of lymphocytes with germinal centers are occasionally present in the vicinity of the dilated vascular channels. Rarely, vascular proliferations are poorly circumscribed and focally intermingled with irregular jagged vascular spaces that may permeate the entire dermis. Endothelial cells line the latter inconspicuously. Irregular slit-like vascular spaces may be seen between collagen bundles of the dermis, together with tufts of endothelial cells that protrude into the lumina of the newly formed vessels (16). The endothelial cells that line the vascular spaces express immunoreactivity for CD31, but they do so only focally or not at all for CD34. Although a minority of newly formed vessels show an attenuated muscle layer, external to the endothelial cells, which has on occasion immunoreactivity for α-smooth muscle actin antibody, this marker is usually nonreactive. Reactivity for Ki-67 is negative among the endothelial cell nuclei (16). The immunohistochemical profile substantiates the lymphatic nature of these newly formed vessels. Some dermal vascular responses to irradiation, such as the benign lymphangioendothelioma (15) or an atypical angiomatous proliferation (14), may mimic the histopathologic appearance of the patch stage of Kaposi’s sarcoma or even a well-differentiated angiosarcoma. In contrast to the patch stage of Kaposi’s sarcoma, atypical benign vas-


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cular proliferations, as induced by radiation, do not contain erythrocytes or hemosiderin deposits, or stromal plasma cells. The striking tufts of endothelial cells and the intravascular papillary projections, evidenced in the vascular proliferations of irradiated skin, are absent in the lesions of Kaposi’s sarcoma. In contrast to well-differentiated angiosarcoma, atypical dermal vascular proliferations in irradiated skin do not involve the subcutaneous tissues. Distinctively, they have no cytologic atypia. The nuclei of the endothelial cells are monomorphous, have inconspicuous nucleoli, and lack mitotic figures. In contrast, the endothelial cells of an angiosarcoma may form stratified layers that irregularly line anastomostic channels, to a degree not seen in the atypical vascular proliferations of irradiated skin. TREATMENT The vascular proliferations in irradiated skin do not call for therapy, and the accounts in the literature have not provided examples of metastasis.

References 1. Ambrojo P, Fernández-Cogolludo E, Aguilar A, et al. Cutaneous lymphangiectases after therapy for carcinoma of the cervix: a case with unusual clinical and histological features. Clin Exp Dermatol 1990;15:57–9. 2. Díaz-Cascajo C, Borghi S, Weyers W, Retzlaff H, Requena L, Metze D. Benign lymphangiomatous papules of the skin following radiotherapy. A report of five new cases and review of the literature. Histopathology 1999;35:319–27. 3. Fisher I, Orkin M. Acquired lymphangioma (lymphangiectasis). Arch Dermatol 1970;101:230–4. 4. Gianelli V, Rockley PF. Acquired lymphangiectases following mastectomy and radiation therapy. Report of a case and review of the literature. Cutis 1996;58:276–8. 5. Handfield-Jones SE, Prendville WJ, Norman S. Vulval lymphangiectasia. Genitourin Med 1989; 65:335–7. 6. Harwood CA, Mortimer PS. Acquired vulvar lymphangiomata mimicking genital warts. Br J Dermatol 1993;129:334–6. 7. Kennedy CTC. Lymphangiectasia of the vulva following hysterectomy and radiotherapy. Br J Dermatol 1990;123 (suppl. 37):92–3. 8. Kurwa A, Waddinton E. Post mastectomy lymphangiomatosis. Br J Dermatol 1968;80:840. 9. LaPolla J, Foucar E, Leshin B et al. Vulvar lymphangioma circumscriptum: a rare complication of therapy for squamous cell carcinoma of the cervix. Gynecol Oncol 1985;22:363–6. 10. Leshin B, Whitaker D, Foucar E. Lymphangioma circumscriptum following mastectomy and radiation therapy. J Am Acad Dermatol 1986;15:1117–9. 11. Plotnick H, Richfield D. Tuberous lymphangiectatic varices secondary to radical mastectomy. Arch Dermatol Syphilol 1956;74:466–8. 12. Prioleau PG, Santa Cruz DJ. Lymphangioma circumscriptum following radical mastectomy and radiation therapy. Cancer 1978;42:1989–91. 13. Young AW Jr, Wind RM, Tovell HM. Lymphangioma of vulva: acquired following treatment for cervical cancer. NY State J Med 1980;80:987–9. 14. Finenberg S, Rosen PP. Cutaneous angiosarcoma and atypical vascular lesions of the skin and breast after radiation therapy for breast carcinoma. Am J Clin Pathol 1994;102:757–63. 15. Rosso R, Gianelli U, Carnevali L. Acquired progressive lymphangioma of the skin following radiotherapy for breast carcinoma. J Cutan Pathol 1995;22:164–7. 16. Requena L, Kutzner H, Mentzel T, Durán R, Rodríguez-Peralto JL. Benign vascular proliferations in irradiated skin. Am J Surg Pathol 2002;26:328–37. 17. Requena L, Sangueza OP. Cutaneous vascular anomalies. Part I. Hamartomas, malformations, and dilatation of preexisting vessels. J Am Acad Dermatol 1997;37:523–9. 18. Ziv R, Schewach-Millet M, Trau H. Lymphangiectasia: a complication of thoracotomy for bronchial carcinoid. Int J Dermatol 1988;27:123. 19. Cecchi R, Bartoli L, Brunetti L, Pavesi M, Giomi A. Lymphangioma circumscriptum of the vulva of late onset. Acta Derm Venereol 1995;75:79–93.

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16. GLOMUS TUMORS Glomus tumors are uncommon neoplasms that arise from modified smooth muscle cells normally present in specialized arteriovenous shunts in acral sites, mainly the fingertips. These anatomic structures, known as the Sucquet-Hoyer canals, contribute to temperature regulation. Sucquet-Hoyer canals are lined by endothelial cells and possess several intramural layers of glomus cells. The vascular channel connects an afferent arteriole to an efferent venule (1). Glomus tumors are considered to originate from the glomus cells; thus they occur preferentially in acral areas (2).However, “renegade” or “ectopic” glomus tumors have been described in extracutaneous sites notably in the bone (3), stomach (4), colon (5), trachea (6), and mediastinum (7). Since glomus bodies are sparse, or presumptively absent in these areas, conceptually glomus tumors may arise from either ectopic glomus cells or from undifferentiated perivascular cells (8). CLINICAL FEATURES Two types of glomus tumors have been described, solitary and multiple. They do not fully share distribution, clinical characteristics, or histopathologic features (9). The solitary glomus tumor is more common. It creates a small, purple nodule preferentially in acral areas of the extremities, especially nail beds of the fingers (Fig. 41) and toes (2). Subungual lesions may create a blue-red flush and with time may erode the distal phalanx (10,11). There is a striking predominance among female patients (10). The lesion frequently creates severe paroxysmal pain, usually precipitated by exposure to cold or minor pressure. The cause of the pain is a subject of conjecture. However, the recently demonstrated substance P in nerve fibers of glomus tumors incriminates this substance, since it is known to be a primary sensory afferent neurotransmitter for mediating painful stimuli (12). Solitary glomus tumors may on occasion occur in aberrant locations. They typically appear in the early adult years, although not always. In general, they affect both sexes, although there is a female predominance (10,11). Multiple glomus tumors are much less common than their solitary counterpart. They are termed glomangiomas descriptively in accordance with their angiomatous appearance. In contrast to the solitary glomus lesion, glomangiomas present during childhood as small bluish nodules situated deep in the dermis and widely scattered in the skin (Fig. 42). Multiple lesions have been noted to aggregate in an anatomic region (13–18). Glomangiomas are rarely subungual. They are less commonly painful. Noteably, multiple glomangiomas are often inherited in an autosomal dominant manner (9,19–25). The gene is located in chromosome 1p21-22 (26). Presumably, sporadic cases occur from somatic mutation of the same gene. Glomangiomas are often sufficiently large to be raised, soft, and compressible. As such they can be mistaken for lesions of the blue rubber bleb nevus syndrome, even in the absence of intestinal bleeding (27). Patients may develop KasabachMerritt syndrome (28). Occasionally, glomangiomas present as a solitary telangiectatic plaque-like lesion (29) (Fig. 43). Mounayer et al. (30) recently reported seven patients with multiple large facial plaque-like glomangiomas that mimicked common facial venous malformations (Fig. 44). These extensive facial glomangiomas were not painful. Unlike facial venous malformations, the large facial glomangiomas described by Mounayer et al. (30) were distinctly nodular, deep blue or purple, and poorly compressible. Histopathologic study disclosed one or several rows of glomus cells present in the walls of the large tortuous venous channels.


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Fig. 41. Clinical features of subungual glomus tumor. A purple nodule is seen under the nail plate.

Fig. 42. Clinical features of multiple glomus tumors. Multiple small blue nodules scattered on the back of an adult woman.

Glomangiomyomas consist of tumors composed of neoplastic cells that show a gradual transition from glomus cells to elongated, mature smooth muscle cells (Fig. 45). HISTOPATHOLOGIC FEATURES Histopathologically, solitary glomus tumors are customarily solid, well-circumscribed nodules surrounded by compressed fibrous tissue. The neoplasm is cytologically formed of clusters of round or polygonal monomorphous glomus cells with large, round, plump

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Fig. 43. Rare variant of solitary glomangioma with the appearance of a telangiectatic plaque. Histopathologic study demonstrated conventional features of glomangioma.

Fig. 44. Large facial glomangioma mimicking a common facial venous malformation.

nuclei and scant eosinophilic cytoplasm (Fig. 46). Endothelium-lined vascular spaces create a core in the center of some of these clusters. The uniformity of the neoplastic cells and their lack of pleomorphism are characteristic attributes of glomus tumors. Some lesions acquire a mucinous stroma (2). Abundant nerve fibers (10) and mast cells (31) are seen in some solitary glomus tumors. Rare histopathologic variants include (1) lesions with large, hyperchromatic nuclei that probably represent a degenerative phenomenon (32); (2) glomus tumors composed of glomus cells with abundant granular cytoplasm,


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Fig. 45. Clinical features of glomangiomyoma. An exophytic and pedunculated lesion with an angiomatous appearance on the back of an adult woman.

which have been termed “oncocytic” glomus tumors (9,33,34); (3) intravascular glomus tumors (35,36); (4) intraneural glomus tumors (8,37); (5) epithelioid glomus tumor (38); and (6) infiltrating glomus tumors (39,40). The lesions termed glomangiomyomas consist of glomus tumors in which there is an admixture of glomus cells and elongated, mature smooth muscle cells (32) (Fig. 47) . Histopathologically, glomangiomas are less well-circumscribed lesions than solitary glomus tumors. Some are made up of several nodules within the dermis. Some have an appearance that calls to mind a hemangioma (Fig. 48). These are composed of irregular dilated endothelium-lined vascular channels that contain red blood cells and, distinctively, have small intramural aggregations of glomus cells. Glomus cells may form cords or small clusters in adjacent stroma, but numerically they are sparse relative to their numbers in a solitary glomus tumor. As stated, some lesions can be difficult to distinguish from a conventional hemangioma; this is particularly true when thrombosis and phlebolith formation occurs within the vascular channels of a glomangioma (Fig. 49). Glomus cells were once considered pericytes (31). However, ultrastructural studies have demonstrated that the cells of the normal glomus, as well as the neoplastic cells of both the solitary and the multiple glomus tumors, contain pinocytotic vesicles and are surrounded by a basal lamina. Abundant numbers of myofilaments condense focally to form dense bodies within the cytoplasm, in testimony to the cell’s nature as a modified smooth muscle cell (2,9,20,22,31,40–48). Immunohistochemically, glomus cells express vimentin, muscle-specific actin, and α-smooth muscle actin (36,49–55). Desmin positivity has been described by some authors

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Fig. 46. Histopathologic features of subungual glomus tumor. (A) Scanning power shows a mostly solid cellular proliferation. (B) Higher magnification shows that the lesion is composed of clusters of round monomorphous cells. (C) Still higher magnification demonstrates that neoplastic cells have large round or plump nuclei and scant eosinophilic cytoplasm, all characteristics of glomus cells.

(51,52,56), but this finding has been not corroborated by others (36,48,53). Laminin and type IV collagen outline the glomus cells (51). Highly cellular glomus tumors can be mistaken for solid apocrine hidradenomas (50). However, immunohistochemistry resolves this histopathologic dilemma since apocrine hidradenomas express immunoreactivity for cytokeratins and carcinoembryonic antigen, whereas glomus tumors do not (50). TREATMENT The cure for solitary glomus tumors is simple excision. In patients with multiple lesions, excision should be restricted to painful lesions. Successful treatment of multiple glomangiomas has been reported with electron beam irradiation (57) and laser therapy (58–61). Although glomus tumors are benign neoplasms, very rare examples of glomangiosarcomas have arisen in the setting of a benign glomus tumor in patients with multiple glomangiomas (62).

References 1. Masson P. Le glomus neuromyo-arteriel des régions tactil et ses tumeurs. Lyon Chir 1924:21:257–80. 2. Tsuneyoshi M, Enjoji M. Glomus tumor: a clinicopathologic and electron microscopic study. Cancer 1982;50:1601–7.


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Fig. 47. Histopathologic features of glomangiomyoma. (A) Low power shows dense cellular proliferations involving the entire thickness of the dermis. (B) Neoplastic cells show intermediate characteristics between glomus cells and mature smooth muscle cells. (C) Cellular aggregates are mostly solid, with inconspicuous vascular lumina. 3. Kobayashi Y, Kawaguchi T, Imoto K, et al. Intraosseous glomus tumor in the sacrum: a case report. Acta Pathol Jpn 1990;40:856–9. 4. Kanwar YS, Manaligod JR. Glomus tumor of the stomach: an ultrastructural study. Arch Pathol 1975;99:392–7. 5. Barua R. Glomus tumor of the colon: first reported case. Dis Colon Rectum 1988;31:138–40. 6. Kim YI, Kim JH, Suh JS, et al. Glomus tumor of the trachea: report of a case with ultrastructural observations. Cancer 1989;64:881–6. 7. Brindley GV. Glomus tumor of the mediastinum. J Thorac Surg 1949;18:417–20. 8. Calonje E, Fletcher CDM. Cutaneous intraneural glomus tumor. Am J Dermatopathol 1995;17:395–8. 9. Pepper MC, Laubenheiner R, Cripps DJ. Multiple glomus tumors. J Cutan Pathol 1977;4:244–57. 10. Stout AP. Tumors of the neuromyoarterial glomus. Am J Cancer 1935;24:255–72. 11. Shugart RR, Soule EH, Johnson EW Jr. Glomus tumor. Surg Gynecol Obstet 1963;117:334–40. 12. Kishimoto S, Nagatani H, Miyashita A, Kobayashi K. Immunohistochemical demonstration of substance P-containing nerve fibers in glomus tumors. Br J Dermatol 1985;113:213–8. 13. Laymon CW, Paterson WC. Glomangioma (glomus tumor): a clinico-pathologic study with special reference to multiple lesions appearing during pregnancy. Arch Dermatol 1965;92:509–13. 14. Landthaler M, Braun-Falco O, Ecklert F, Stolz W, Dorn M. Wolf HH. Congenital multiple plaque-like glomus tumor. Arch Dermatol 1990;126:1203–7. 15. Gorlin RJ, Fusaro RM, Benton JW. Multiple glomus tumor of pseudocavernous hemangioma type. Report of a case manifesting a dominant inheritance pattern. Arch Dermatol 1960;82:776–8. 16. Yoon T-Y, Lee H-T, Chang S-H. Giant congenital multiple patch-like glomus tumors. J Am Acad Dermatol 1999;40:826–8.

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Fig. 49. Histopathologic features of large facial glomangioma mimicking a common facial venous malformation. (A) Low power shows dilated vascular channels involving different levels of the dermis. (B) Higher magnification demonstrates that these dilated vascular channels are surrounded by clusters of glomus cells. Fig. 48. (Opposite page) Histopathologic features of glomangioma. (A) Low power shows cellular aggregates and dilated vascular structures at different levels of the dermis. (B) Higher magnification demonstrates that the vascular channels are surrounded by round monomorphous cells. (C) Still higher magnification demonstrates that the cells surrounding the vascular channels show characteristics of glomus cells.

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17. Yang J-S, Ko J-W, Suh K-S, Kim S-T. Congenital multiple plaque-like glomangiomyoma. Am J Dermatopathol 1999;21:454–7. 18. Carvalho VO, Taniguchi K, Giraldi S, et al. Congenital plaquelike glomus tumor in a child. Pediatr Dermatol 2001;18:223–6. 19. Hatchome N, Kado T, Tagami H. Numerous papular glomus tumors localized on the abdomen. Acta Derm Venerol (Stockh) 1986;66:161–4. 20. Rycroft RJG, Menter MA, Sharvill DE, et al. Hereditary multiple glomus tumors. Trans St John’s Hosp Derm Soc 1975;61:70–81. 21. Conant M, Wiesenfeld S. Multiple glomus tumors of the skin. Arch Dermatol 1971;103:481–7. 22. Goodman TF, Abele DC. Multiple glomus tumors. Arch Dermatol 1971;103:11–23. 23. Taafe A, Barker D, Wyat EH, Bury HPR. Glomus tumors: a clinicopathological survey. Clin Exp Dermatol 1980;5:219–25. 24. Requena L, Requena C, Sánchez M, et al. Glomangiomas multiples hereditarios. Actas Dermosifiliogr 1987;78:245–7. 25. Blume-Peytavi U, Adler YL, Geilen CC, et al. Multiple familial cutaneous glomangioma: a pedigree of 4 generations and critical analysis of histologic and genomic differences of glomus tumors. J Am Acad Dermatol 2000;42:633–9. 26. Boon LM, Brouillard P, Irrthum A, et al. A gene for inherited cutaneous venous anomalies (“glomangiomas”) localized to chromosome 1p21-22. Am J Hum Genet 1999;65:125–33. 27. Mukhtar JAK, Pfeger L. Angiomatosis cutis disseminata (Beziehungenzum Blue Rubber Bleb Nevus). Hautarzt 1964;15:230–5. 28. McEvoy BF, Waldman PM, Tye MJ. Multiple hamartomatous glomus tumors of the skin. Arch Dermatol 1971;104:188–91. 29. Requena L, Galvan C, Sánchez Yus E, Sangueza O, Kutzner H, Furio V. Solitary plaque-like telangiectatic glomangioma. Br J Dermatol 1998;139:902–5. 30. Mounayer C, Wassef M, Enjolras O, Boukobza M, Mulliken J. Facial “glomangiomas”: large facial venous malformations with glomus cells. J Am Acad Dermatol 2001;45:239–45. 31. Murad TM, von Haam E, Murthy MSN. Ultrastructure of a hemangiopericytoma and a glomus tumor. Cancer 1968;22:1239–49. 32. Enzinger FM, Weiss SW. Soft Tissue Tumors. 3rd ed., St. Louis, Mosby, 1995:701–83. 33. Slater DN, Cotton DWK, Azzopardi JG. Oncocytic glomus tumour: a new variant. Histopathology 1987;11:523–31. 34. Shin DLH, Park SS, Lee JH, et al. Oncocytic glomus tumor of the trachea. Chest 1990;98:1021–3. 35. Beham A, Fletcher CDM. Intravenous glomus tumor: a previously undescribed phenomenon. Virchows Arch Pathol Anat 1991;418:175–7. 36. Googe PB, Griffin WC. Intravenous glomus tumor of the forearm. J Cutan Pathol 1993;20:359–63. 37. Kline SC, Russell Moore J, de Mente SH. Glomus tumor originating within a digital nerve. J Hand Surg 1990;15A:98–101. 38. Pulitzer DR, Martin PC, Reed RJ. Epithelioid glomus tumor. Hum Pathol 1995; 26:1022–7. 39. Gould EW, Manivel JC, Albores-Saavedra J, Monforte H. Locally infiltrative glomus tumors and glomangiosarcomas: a clinical ultrastructural and immunohistochemical study. Cancer 1990;65:310–8. 40. Skelton HG, Smith KJ. Infiltrative glomus tumor arising from a benign glomus tumor: a distinctive immunohistochemical pattern in the infiltrative component. Am J Dermatopathol 1999;21:562–6. 41. Tarnowski WM, Hashimato K. Multiple glomus tumors: an ultrastructural study. J Invest Dermatol 1969;52:474–8. 42. Venkatachalam MA, Greally JG. Fine structure of glomus tumor: similarity of glomus cells to smooth muscle. Cancer 1969;23:1176–84. 43. Goodman TF. Fine structure of the cells of the Sucquet-Hoyer canal. J Invest Dermatol 1972;59:363–9. 44. Luders G, Schlote W, Reinhard M. Zur Ultrastruktur von Glomustumorem und Glomusorganen. Arch Klin Exp Dermatol 1970;238:398–416. 45. Toker C. Glomangioma: an ultrastructural study. Cancer 1969;23:487–92. 46. Murata Y, Tsuji M, Tani M. Ultrastructure of multiple glomus tumor. J Cutan Pathol 1984;11:53–8. 47. Harris M. Ultrastructure of a glomus tumor. J Clin Pathol 1971;24:520–3. 48. Miettinem M, Lehto V-P, Virtanen I. Glomus tumor cells evaluation of smooth muscle and endothelial cell properties. Virchows Arch (B) 1983;43:139–49. 49. Hague S, Modlin IM, West AB. Multiple glomus tumors of the stomach with intravascular spread. Am J Surg Pathol 1992;16:291–9.


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50. Haupt HM, Stern JB, Berlin SJ. Immunohistochemistry in the differential diagnosis of nodular hidradenoma and glomus tumor. Am J Dermatopathol 1992;14:310–4. 51. Nuovo MA, Grimes MM, Knowless DM. Glomus tumors: clinicopathologic and immunohistochemical analysis of forty cases. Surg Pathol 1990;3:31–40. 52. Porter PG, Bigler SA, McNutt NS, et al. The immunophenotype of hemangiopericytoma and glomus tumors with special reference to muscle protein expression: an immunohistochemical study and review of the literature. Mod Pathol 1991;4:46–52. 53. Schurch W, Skalli O, Lagace R, et al. Intermediate filament proteins and actin isoforms as markers for soft tissue tumor differentiation and origin. III. Hemangiopericytomas and glomus tumors. Am J Pathol 1990;136:771–86. 54. Kaye VM, Dehner LP. Cutaneous glomus tumor: a comparative immunohistochemical study with pseudoangiomatous intradermal melanocytic nevi. Am J Dermatopathol 1991;13:2–6. 55. Dervan PA, Tobbia IN, Casey M, et al. Glomus tumours: an immunohistochemical profile of 11 cases. Histopathology 1989:14:483–91. 56. Brooks IJ, Miettinen M, Virtanen J. Desmin immunoreactivity in glomus tumors. Am J Clin Pathol 1987;87:292. 57. Nishimoto K, Nishimoto M, Yamamoto S, Nakagawa T, Takaiwa T, Tanabe M. Multiple glomus tumours: successful treatment with electron beam irradiation. Br J Dermatol 1990;123:657–61. 58. Goldman L. Laser treatment of multiple progressive glomangiomas. Arch Dermatol 1978;114:1853–4. 59. Goldman L. Laser treatment of multiple glomangiomas: progress report of 13 yr after treatment. Arch Dermatol 1981;117:451–2. 60. Barnes L, Estes SA. Laser treatment of hereditary multiple glomus tumors. J Dermatol Surg Oncol 1986;12:912–5. 61. Sharma JK, Miller R. Treatment of multiple glomangioma with tuneable dye laser. J Cutan Med Surg 1999;3:167–8. 62. Brathwaite CD, Poppiti RJ. Malignant glomus tumor: a case report of widespread metastases in a patient with multiple glomus body hamartomas. Am J Surg Pathol 1996;20:233–8.

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17. HEMANGIOPERICYTOMA Since Stout and Murray’s initial description of hemangiopericytoma in 1942 (1), this entity has been a controversial subject. The controversy is fueled by the uncertainty of the cell of origin, wherein pericytes are indistinguishable by light microscopy from endothelial cells and fibroblasts. In addition, there are no established histopathologic criteria to differentiate the benign and malignant forms of hemangiopericytoma. Since several soft tissue neoplasms share histopathologic features with hemangiopericytoma, many authors consider this neoplasm to be merely a histopathologic pattern rather than a distinctive entity. However, currently it is generally accepted that hemangiopericytomas create a histopathologic pattern of a specific entity. A critical review on this subject has been published recently (2). Hemangiopericytomas are most commonly found within the soft tissues of the extremities, especially those of the thigh, pelvic fossa, and retroperitoneum. Although they rarely affect the skin, cutaneous and subcutaneous forms of hemangiopericytoma have been reported (3–7). CLINICAL FEATURES Although the lesion usually presents as a solitary firm nodule on an extremity (Fig. 50), multiplicity of lesions have been encountered (8,9). HISTOPATHOLOGIC FEATURES Enzinger and Smith (10) distinguish two types of hemangiopericytomas: adult and congenital, or infantile types. These variants differ both clinically and histopathologically (10). The adult variant of hemangiopericytoma is more common and usually appears as a single nodule in the soft tissue of a limb (10–12). Histopathologically, it is characterized by compact cellular areas that embody endothelium-lined, branching vessels. Individual cells show round to oval nuclei and cytoplasm with ill-defined borders. The

Fig. 50. Clinical features of hemangiopericytoma. An erythematous nodule on the knee of an adult man.


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Fig. 51. Histopathologic features of hemangiopericytoma. (A) Scanning power shows a wellcircumscribed lesion containing numerous irregular dilated vascular structures. (B) Irregular branching endothelium-lined vascular channels are surrounded by tightly packed cellular areas.

vascular channels form a continuous network distinguished by the presence of a “stag horn” or “antler-like” configuration (5) (Fig. 51). The stroma may be myxoid or fibrotic, with rare foci of cartilaginous and osseus metaplasia (10). Although the benign and malignant forms of hemangiopericytoma may be very difficult to distinguish one from the other, prominent mitotic activity, necrosis, hemorrhage, increased cellularity, and large gross size are the most frequent indices of metastatic potential (10). The congenital form of hemangiopericytoma originates almost exclusively in the subcutis, as a multilobulated (10) and sometimes multicentric lesion (13,14). Although the congenital and infantile forms of hemangiopericytoma possess the characteristic cellular morphology and anastomotic vascular configurations of the adult form, they are multilobulated neoplasms. Distinctively, even though mitotic figures and necrosis may be present, the lesions invariably follow a benign course (10,13,15). Mentzel et al. (16) have recently proposed that infantile hemangiopericytoma and infantile myofibromatosis are a spectra of a single entity. Immunohistochemically, the neoplastic cells of a hemangiopericytoma express reactivity for vimentin, factor XIIIa, HLA-DR, CD34, and CD57 (17–20), but they do not

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stain for factor VIII-related antigens, Ulex europaeus I lectin, α-smooth muscle actin, desmin, myoglobin, cytokeratin, and epithelial membrane antigen (19–23). Ultrastructural studies have demonstrated that the neoplastic cells simulate normal pericytes, since they have large round nuclei, pale cytoplasm with few organelles, numerous elongated extensions, abundant numbers of pinocytotic/vesicles, and a basal lamina that surrounds each individual cell (9,24–29). In addition to the appearance of classic pericytes, other cells have intermediate morphologies between pericytes and smooth muscle cells. They contain dense bodies, bundles of microfilaments, and attachment plates (9,24,26–28). TREATMENT In view of the marginal histologic criteria for assessment of biologic behavior among hemangiopericytomas, complete surgical excision is desirable. Radiotherapy has been ineffectual (30).

References 1. Stout AP, Murray MR. Hemangiopericytoma: a vascular tumor featuring Zimmerman’s pericytes. Ann Surg 1942;116:26–33. 2. Nappi O, Ritter JH, Pettinato G, Wick MR. Hemangiopericytoma: histopathological pattern or clinicopathological entity. Semin Diagn Pathol 1995; 12:221–32. 3. Cole HN Jr, Reagan JW, Lund HZ. Hemangiopericytoma. Arch Dermatol 1955;72:328–34. 4. Sims CF, Kirsch N, MacDonald RG. Hemangiopericytoma. Arch Dermatol Syph 1948;58:194–205. 5. Bianchi O, Abulafia J, Mirande L. Hémangiopericytoma cutané. Ann Dermatol Syph 1968;95:269–84. 6. Reich H. Das Hamangiopericytom. Hautarzt 1973;24:275–85. 7. Schneider W, Undeutsch W. Seltene Blutgefassgeschwulste der Haut. Hautarzt 1967;18:437–45. 8. Saunders TS, Fitzpatrick TB. Multiple hemangiopericytomas: their distinction from glomangiomas (glomus tumor). Arch Dermatol 1957;76:731–4. 9. Kuhn C III, Rosai J. Tumors arising from pericytes: ultrastructure and organ culture of a case. Arch Pathol 1969;88:653–63. 10. Enzinger FM, Smith BH. Hemangiopericytoma: an analysis of 106 cases. Hum Pathol 1976;7:61–82. 11. McMaster MJ, Soule EH, Ivins JC. Hemangiopericytoma: a clinicopathologic study and long-term follow-up of 60 patients. Cancer 1976;36:2232–44. 12. Argenvall L, Kindblom L-G, Nielsen JM, et al. Hemangiopericytoma: a clinicopathologic, angiographic and microangiographic study. Cancer 1978;42:2412–27. 13. Kauffman SL, Stout AP. Hemangiopericytoma in children. Cancer 1960;13:695–710. 14. Hayes MM, Dietrich BE, Uys CJ. Congenital hemangiopericytomas of skin. Am J Dermatopathol 1986;8:148–53. 15. Altmeyer P, Nodl F. Das Hamangioperizytom des Sanglings. Hautarzt 1976;27:272–6. 16. Mentzel T, Calonje E, Nascimiento AG, Fletcher CDM. Infantile hemangiopericytoma versus infantile myofibromatosis: study of a series suggesting a continuous spectrum of infantile myofibroblastic lesions. Am J Surg Pathol 1994;18:922–30. 17. Nemes Z. Differentiation markers in hemangiopericytoma. Cancer 1992;69:133–40. 18. Aziza J, Mazerolles C, Selves J, et al. Comparison of the reactivities of monoclonal antibodies QBEND10 (CD34) and BNH9 in vascular tumors. Appl Immunohistochem 1993;1:51–60. 19. Traweek ST, Kandalaft PL, Mehta P, et al. The human hematopoietic progenitor cell antigen (CD34) in vascular neoplasia. Am J Clin Pathol 1991;96:25–31. 20. D’Amore E, Manivel JC, Sung JH. Soft tissue and meningeal hemangiopericytomas: an immunohistochemical and ultrastructural study. Hum Pathol 1990;21:414–23. 21. Porter PG, Bigler SA, McNutt NS, et al. The immunophenotype of hemangiopericytoma and glomus tumors with special reference to muscle protein expression: an immunohistochemical study and review of the literature. Mod Pathol 1991;4:46–52. 22. Schurch W, Skalli O, Lagace R, et al. Intermediate filament proteins and actin isoforms as markers for soft tissue tumor differentiation and origin. III. Hemangiopericytomas and glomus tumors. Am J Pathol 1990;136:771–86.


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23. Miettinen M, Holthofer H, Lehto VP, et al. Ulex europaeus I lectin as a marker for tumors derived from endothelial cells. Am J Clin Pathol 1983;79:32–6. 24. Murad TM, von Haam E, Murthy MSN. Ultrastructure of a hemangiopericytoma and a glomus tumor. Cancer 1968;22:1239–49. 25. Battifora H. Hemangiopericytoma: ultrastructural study of five cases. Cancer 1973;31:1418–32. 26. Nunnery EW, Kahn LB, Reddick RL, et al. Hemangiopericytoma: a light microscopic and ultrastructural study. Cancer 1981;47:906–13. 27. Hahn MJ, Dawson R, Esterly JA, et al. Hemangiopericytoma: an ultrastructural study. Cancer 1973;31:255–61. 28. Dardick I, Hammar SP, Scheithauer BW. Ultrastructural spectrum of hemangiopericytoma: a comparative study of fetal, adult and neoplastic pericytes. Ultrastruct Pathol 1989;13:111–34. 29. Ramsey HJ. Fine structures of hemangiopericytoma and hemangioendothelioma. Cancer 1966; 19:2005–18. 30. O’Brien P, Basfiled RD. Hemangiopericytoma. Cancer 1965;18:249–52.

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18. CUTANEOUS MYOFIBROMA In 1981, Chung and Enzinger (1) proposed the term infantile myofibromatosis for a clinicopathologic entity with myofibroblastic differentiation. They recognized solitary and multicentric forms, the former being the more common. Although most of their lesions occurred in children, these authors also acknowledged occasional cases of myofibromatosis in adults and (1), subsequent reports have reaffirmed this observation. Paradoxically, the solitary type of myofibroma occurs more commonly in adults with lesions located preferentially in the dermis (2–15). Terms such as cutaneous myofibroma (3) and solitary myofibroma (4,5) have been most appropriately used to describe this distinctive lesion. Infantile myofibromatosis usually presents before the age of 2 years. In addition to the skin, these lesions may involve deeper structures such as muscle and bone. Although most lesions are disposed to spontaneous regression, visceral involvement is predisposed to fatality. Contrastingly, the lesions of adult myofibroma are solitary, appear during adult life, show no tendency to regress, affect only the dermis and subcutaneous tissue, and manifest an entirely benign biologic behavior. CLINICAL FEATURES Clinically, adult cutaneous myofibroma appears as a solitary cutaneous or subcutaneous nodule, firm in consistency, and lacking specific clinical features that allow a definite diagnosis prior to biopsy. Both genders are affected with equal frequency, the distal portions of the upper and lower extremities (Fig. 52) being the most commonly targeted (12). The lesions may be painful (12). HISTOPATHOLOGIC FEATURES Among cutaneous adult myofibromas, the histologic appearance varies with the duration of the lesion (12). Earlier lesions feature the vascular component. In this vascular type of cutaneous adult myofibroma, variable numbers of endothelium-lined vascular

Fig. 52. Cutaneous myofibroma involving the inner aspect of the foot.


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spaces branch irregularly and closely resemble hemangiopericytoma. In addition, there are sheets of monomorphic, round to polygonal cells with a glomus-like appearance. Most cases intermingle the hemangiopericytoma-like areas with the glomus-like cells; however sometimes the primitive pericyte-like cells surround only the anastomosing endothelium-lined hemangiopericytoma-like areas. The stroma consists of sclerotic collagenous bundles intermingled with whorls of smooth muscle-like cells and focal calcification. Some tumors show a polypoid growth into the vascular spaces, and these vascular plugs may create the false appearance of vascular invasion. Mature lesions show either a nodular or a multinodular pattern. The nodular or cellular type of adult cutaneous myofibroma is characteristically a sharply circumscribed but nonencapsulated, single intradermal nodule, composed of solid aggregations of plump spindle cells with myofibroblastic appearances. In some areas, the neoplastic cells assume perivascular arrangements and show transitions with the smooth muscle cells of the intratumoral vessels. The neoplastic cells possess an elongated tapered or cigar-shaped nucleus, abundant pale eosinophilic cytoplasm, and distinct borders. In some lesions of the nodular type of cutaneous adult myofibroma, there is a central sclerotic acellular area surrounded by a more highly cellular area richly endowed with a slit-like vascular space. The multinodular or biphasic type of adult cutaneous myofibroma displays multiple, well-circumscribed nodules wherein spindle and plump cells are featured in whorls (Fig. 53). Endothelium-lined vascular slits may be present at the periphery of some of the nodules, or, alternately, areas of irregularly branching vascular channels may create the appearance of a hemangiopericytoma. In contrast to infantile myofibromatosis, which generally exhibits a characteristic zonation (the peripheral areas are composed of plump spindle-shaped cells arranged in whorls, and the central areas show prominent vascular hemangiopericytoma-like components and more primitive cells with vesicular nuclei, eosinophilic cytoplasm, and indistinct cellular margins), the multinodular or biphasic variant of cutaneous adult myofibroma shows a more haphazard arrangement or even reversed zonation pattern. Neoplastic cells within the nodules are plump and elongated, with a myofibroblastic appearance. They exhibit morphologic features of fibroblasts and smooth muscle cells. In some nodules, the neoplastic cells blend with the smooth muscle cells of the vessel walls, reminiscent of a vascular origin. A second population of more immature mesenchymal cells impart, a pericytic appearance, as they surround the nodules. Hyalinization of the stroma is more prominent in the center of the nodules and is a characteristic feature of this multinodular variant of adult cutaneous myofibroma. Aged lesions of cutaneous adult myofibroma have a leiomyomatous or fascicular appearance. This leiomyoma-like or fascicular type of cutaneous adult myofibroma creates poorly circumscribed fascicles of spindle cells, with large pale eosinophilic cytoplasm and elongated tapering nucleus. The arrangement is haphazard, and it may intermingle with thick collagen bundles and mucin. Vascularity is not prominent. Preexisting smooth muscle fascicles may appear entrapped within the lesion. Immunohistochemically, the neoplastic cells of the cutaneous adult myofibroma show strong expression of vimentin and both muscle-specific actin and α-smooth muscle actin, whereas desmin is negative. The vascular markers CD31, CD34, and factor VIII-related antigen stain the endothelium-lined vascular spaces but are not expressed by the neoplastic cells (12). Ultrastructurally, neoplastic cells of cutaneous adult myofibroma appear as undifferentiated mesenchymal forms with features of fibroblasts, myofibroblasts, and

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pericytes (12). Neoplastic cells with a myofibroblastic appearance have folded nuclei and a few intracytoplasmic filaments with focal densities. They may attach to the cell membrane or to groups of pinocytotic vesicles. Pericytoid cells are smaller, with a round nucleus and clear cytoplasm that contain sparse organelles. Hints of luminal vascular formations appear as clefts between adjacent cells. The cells that surround these clefts show round nuclei and clear cytoplasm, and they are cojoined by tight junctions. Occasionally, rudimentary Weibel-Palade bodies are present in the cells that surround irregular vascular lumina. The histogenesis of the cutaneous adult myofibroma is still uncertain. Immunohistochemical and ultrastructural characteristics of the neoplastic cells support myofibroblastic differentiation. However, other histopathologic features argue in favor of a vascular origin (2). With respect to the putative cell of origin, the pericyte is the most likely candidate. It is currently viewed as a resting stem cell (16,17). Pericytes are acknowledged to be capable of transformation into other mesenchymal cells (18). Their differentiation into myofibroblasts and smooth muscle cells has been documented in ultrastructural studies of hemangiopericytomas (19) and glomus tumor of the lung (20). Furthermore, the myopericyte, an intermediate cell between the pericyte and a smooth muscle cell, has been recently proposed as the progenitor of the myofibromatosis-like hemangiopericytoma (21). Accordingly, cutaneous adult myofibroma might be a benign vascular neoplasm probably derived from myopericytes of the vascular walls (12).This histogenetic interpretation has been recently set forth by other authors (22,23). TREATMENT Cutaneous adult myofibroma is a benign neoplasm cured by simple excision.

References 1. Chung EB, Enzinger FM. Infantile myofibromatosis. Cancer 1981;48:1807–18. 2. Daimaru Y, Hashimoto H, Enjoji M. Myofibromatosis in adults (adult counterpart of infantile myofibromatosis). Am J Surg Pathol 1989;13:859–65. 3. Smith KJ, Skelton HG, Barrett TL, Lupton GP, Graham JH. Cutaneous myofibroma. Mod Pathol 1989;2:603–9. 4. Beham A, Badve S, Suster S, Fletcher CDM. Solitary myofibroma in adults. Clinicopathologic analysis of a series. Histopathology 1993;22:335–41. 5. Kutzner H, Hügel H, Rütten A, Braun M. Erworbenes gutartiges Myofibrom der Haut (Adultes Myofibrom). Hautarzt 1993;44:561–8. 6. Wolfe JT, Cooper PH. Solitary cutaneous “infantile” myofibroma in a 49-year-old woman. Hum Pathol 1990;21:562–4. 7. Sahin AA, Ro JY, Ordoñez NG, et al. Myofibroblastoma of the tongue. An immunohistochemical, ultrastructural, and flow cytometric study. Am J Clin Pathol 1990;94:773–7. 8. Hogan SF, Salassa JR. Recurrent adult myofibromatosis. A case report. Am J Clin Pathol 1992; 97:810–4. 9. Lundgren L, Kindblom LG, Meis-Kindblom JM. Adult myofibromatosis: reactive or neoplastic? [Abstract]. Mod Pathol 1995;8:8A.

Fig. 53. (Opposite page) Histopathologic features of the multinodular or biphasic variant of cutaneous myofibroma. (A) Low power shows multiple well-circumscribed grouped nodules of spindle and plump cells arranged in whorls. (B) Neoplastic cells within the nodules are plump, elongated spindle cells with a myofibroblastic appearance surrounded by a second population of more immature cells. (C) Higher magnification demonstrates that the peripheral cells of the nodules show a pericytic appearance.

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10. Kutzner H, Braun M, Embacher G, Schröder J. Infantile Myofibromatose in der Adoleszenz. Z Hautkr 1991;66:327–35. 11. Kutzner H, Requena L, Hügel H, Rütten A. Adult myofibroma: an acquired neoplasm of vascular character. Dermatopathol Pract Concep 1996;2:191–6. 12. Requena L, Kutzner H, Hugel H, Rutten A, Furio V. Cutaneous adult myofibroma: a vascular neoplasm. J Cutan Pathol 1996;23:445–57. 13. Guitart J, Ritter JH, Wick MR. Solitary cutaneous myofibromas in adults: report of six cases and discussion of differential diagnosis. J Cutan Pathol 1996;23:437–44. 14. Rahimi S, Santoni M, Muda AO. Adult solitary cutaneous myofibroma: a case report. Gen Diagn Pathol 1996;142:109–11. 15. Val-Bernal JF, Garijo MF. Solitary cutaneous myofibroma of the glans penis. Am J Dermatopathol 1996;18:317–21. 16. Dardick I, Hammar SP, Scheithauer BW. Ultrastructural spectrum of hemangiopericytoma. A comparative study of fetal, adult, and neoplastic pericytes. Ultrastruct Pathol 1989;13:111–54. 17. Nemes Z. Differentiation markers in hemangiopericytoma. Cancer 1992;69:133–40. 18. Movat HZ, Fernando VP. The fine structure of the terminal vascular bed. IV. Venules and their perivascular cell (pericytes, adventitial cells). Exp Mol Pathol 1964;3:98–114. 19. Nunnery EW, Kahn LB, Reddick RL, Lipper S. Hemangiopericytoma: a light microscopic and ultrastructural study. Cancer 1981;47:906–14. 20. Brooke ALT, Huffer WE, Belchis DA. A vascular lesion with smooth muscle differentiation presenting as a coin lesion in the lung: glomus tumor versus hemangiopericytoma. Am J Clin Pathol 1983; 80:765–71. 21. Dictor M, Elner A, Anderson T, Ferno M. Myofibromatosis-like hemangiopericytoma metastasizing as differentiated vascular smooth muscle myosarcoma. Myopericytes as a subset of “myofibroblasts”. Am J Surg Pathol 1992;16:1239–47. 22. Granter SR, Badizadegan K, Fletcher CDM. Myofibromatosis in adults, glomangiopericytoma, and myopericytoma. A spectrum of tumors showing perivascular myoid differentiation. Am J Surg Pathol 1998;22:513–25. 23. Kutzner H. Perivaskülare Myome: ein neues Konzept “myofibroblastärer” Tumoren mit perivaskulärer myoider Differenzierung. Verh Dtsch Ges Path 1998;82:301–8.


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Chapter 9 / Malignant Neoplasms

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Malignant Neoplasms CONTENTS KAPOSI’S SARCOMA EPITHELIOID HEMANGIOENDOTHELIOMA ENDOVASCULAR PAPILLARY ANGIOENDOTHELIOMA (DABSKA’S TUMOR OR PAPILLARY INTRALYMPHATIC ANGIOENDOTHELIOMA) RETIFORM HEMANGIOENDOTHELIOMA COMPOSITE HEMANGIOENDOTHELIOMA CUTANEOUS ANGIOSARCOMA OF THE FACE AND SCALP OF ELDERLY PATIENTS (WILSON JONES’ ANGIOSARCOMA) CUTANEOUS ANGIOSARCOMA ASSOCIATED WITH LYMPHEDEMA RADIATION-INDUCED CUTANEOUS ANGIOSARCOMA EPITHELIOID ANGIOSARCOMA MALIGNANT GLOMUS TUMOR (GLOMANGIOSARCOMA)

Table 1 summarizes the classification of cutaneous malignant vascular neoplasms.

1. KAPOSI’S SARCOMA Moritz Kaposi (1) first described this unusual lesion in 1872 using the term “idiopathic multiple pigmented sarcoma of the skin.” Until recently, Kaposi’s sarcoma was a rare disease mainly affecting elderly men of Mediterranean, East European, or Jewish heriTable 1 Malignant Cutaneous Vascular Neoplasms Kaposi’s sarcoma Low-grade cutaneous angiosarcomas Epithelioid hemangioendothelioma Endovascular papillary angioendothelioma (Dabska’s tumor) Retiform hemangioendothelioma Composite hemangioendothelioma High-grade cutaneous angiosarcomas Cutaneous angiosarcoma of the face and scalp of elderly patients Cutaneous angiosarcoma associated with lymphedema Radiation-induced cutaneous angiosarcoma Epithelioid angiosarcoma Malignant glomus tumor (glomangiosarcoma) Malignant hemangiopericytoma

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tage; central Africans, in whose countries the disease is endemic; and immunosuppressed patients such as renal transplant recipients (2–4). The situation changed dramatically in 1981, when cases of Kaposi’s sarcoma started to be reported in young homosexual men (5–7). Since then it has reached epidemic proportions. The large number of cases associated with AIDS has had a profound impact on our understanding of Kaposi’s sarcoma. Excellent reviews on the epidemiology and clinical and histopathologic aspects of Kaposi’s sarcoma have been published recently (8–11). From an epidemiologic point of view, four distinct variants of Kaposi’s sarcoma are recognized (10): 1. Classic Kaposi’s sarcoma affects elderly patients, most frequently males. A racial predisposition is recorded, with an increased incidence in Ashkenazi Jews and individuals of Mediterranean descent (2,3). It follows a chronic course, and the lesions predominantly involve the lower parts of the legs. 2. The African-endemic variant of Kaposi’s sarcoma occurs mainly in equatorial Africa, where it represented approximately half of all the tumors reported to the Kampala Cancer Registry from 1989 through 1991 (12). This variant of Kaposi’s sarcoma has been subdivided into two groups: a benign nodular disease, affecting mainly young adults, and a fulminant lymphadenopathic form. This latter form is fatal, it predominantly affects children, and it kills most of the patients within 2–3 years (13). 3. The iatrogenic, immunosuppressive, drug-associated form of Kaposi’s sarcoma is especially frequent in renal transplant recipients (14,15), although it has also been reported in other organ transplant recipients (16), as well as in a wide spectrum of patients receiving immunosuppressive drug therapy for different reasons (17–19). The clinical course of this form is chronic, although it is more aggressive than the classic form. The lesions usually regress after discontinuation of the immunosuppressive therapy (20–22). 4. AIDS-associated Kaposi’s sarcoma is especially frequent in homosexual men, and is found in 21% of all homosexual men with AIDS (23). Thanks to the use of highly effective antiretroviral therapy, in recent years the incidence of Kaposi’s sarcoma in AIDS patients has decreased. It has been proposed that Kaposi’s sarcoma in AIDS patients is a sexually transmitted disease ( 23–28), presumably induced by a viral cofactor. Studies evaluating various types of sexual practices have found an increased risk for AIDSassociated Kaposi’s sarcoma in homosexual men who practice oro-anal and anal intercourse (29,30).

Previous epidemiologic studies suggested the possibility of an infectious agent in the etiology of Kaposi’s sarcoma. Cytomegalovirus (CMV) was initially proposed as one of the potential agents, although no consistent association between CMV infection and any of the forms of Kaposi’s sarcoma has been definitively established (30–47). The viral genome of CMV is not integrated into Kaposi’s sarcoma cells (39). The presence of either CMV DNA or RNA in Kaposi’s sarcoma tissues or antibodies to CMV in the serum of patients with Kaposi’s sarcoma (48–50), does not imply that CMV plays an important role in the pathogenesis of this disease. Other viruses have also been implicated. Huang et al. (51) utilized the polymerase chain reaction technique to demonstrate the presence of human papillomavirus (HPV)-16-related DNA fragments in tissue specimens of patients affected with this disease, both with and without AIDS. Immunohistochemistry has also shown specimens of classic Kaposi’s sarcoma and AIDS-associated Kaposi’s sarcoma to be positive for HPV antigens (52).


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Chang and co-workers (53) established the most recent and relevant findings regarding the pathogenesis of Kaposi’s sarcoma. Using representational difference analysis, these authors have identified DNA sequences homologous to δ-herpesviridae in more than 90% of the tissue specimens of Kaposi’s sarcoma from patients with AIDS. The sequences were homologous to, but distinct from, capsid and tegument protein genes of the δ-herpesviridae, herpesvirus saimiri, and Epstein-Barr virus. This Kaposi’s sarcomaassociated herpesvirus, also known as human herpesvirus-8 (HHV-8), is the first human member of a group of viruses known as Rhadinoviruses (54). The findings of Chang et al. (53) have been corroborated and expanded by other authors. Thus, HHV-8 has been found not only in AIDS-associated Kaposi’s sarcoma (55–62), but also in HIV-seronegative homosexual men with Kaposi’s sarcoma (61), classic Kaposi’s sarcoma (60– 63), African-endemic Kaposi’s sarcoma (60,62,64), and posttransplantation and iatrogenic immunosuppression-associated Kaposi’s sarcoma (65), supporting the notion that this newly described herpesvirus is involved in the pathogenesis of all variants of Kaposi’s sarcoma. Furthermore, the dissemination of Kaposi’s sarcoma correlates with the detectability of viral DNA in mononuclear cells of the peripheral blood cells of patients without AIDS (66). However, caution and skepticism are necessary before drawing definitive conclusions about the relationship between Kaposi’s sarcoma and HHV8. Previous experiences investigating the relationship between Kaposi’s sarcoma and other viruses have proved to be unfounded; as a matter of fact, HHV-8 has also been detected in other proliferative processes such as AIDS-related body cavity lymphomas (67,68), multicentric Castleman’s disease (69), and non-Kaposi’s sarcoma skin lesions of transplant patients (70). CLINICAL FEATURES The clinical features and the biologic behavior of Kaposi’s sarcoma are different and depend on the epidemiologic type. The classic type of Kaposi’s sarcoma that affects mainly elderly patients usually starts as a bluish red macule on the distal areas of the lower extremities (Fig. 1). The lesions progress slowly and eventually coalesce to form large plaques. The lesions spread in a centripetal fashion and can be associated with edema of the involved leg. Initially, the process is unilateral, but in advanced stages it involves both lower extremities. Later on, the lesions become nodular, and some of them may show a hyperkeratotic or verrucous surface (Figs. 2 and 3). Long-standing lesions erode and ulcerate, and in some cases there is colonization by anaerobic bacteria. In addition to the cutaneous lesions, patients with long-standing classic Kaposi’s sarcoma may also show mucous membranes and visceral involvement. Most of the time the extracutaneous lesions are asymptomatic. The nodular variant of African-endemic Kaposi’s sarcoma exhibits a clinical appearance and biologic behavior similar to the classic form of Kaposi’s sarcoma. In contrast, the lymphadenopathic type of African-endemic Kaposi’s sarcoma predominantly affects children, and the lesions are usually confined to the lymph nodes, although in rare cases the skin and mucous membranes are also affected. This variant runs an aggressive course, and in most cases patients succumb to the disease within a few years. Kaposi’s sarcoma associated with immunosuppressive drugs usually runs a clinical course similar to that seen in classic Kaposi’s sarcoma, but the lesions resolve entirely upon withdrawal of the offending agent. However, with use of prolonged, high-dose

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Fig. 1. Clinical features of classic Kaposi’s sarcoma. An angiomatous plaque involving the lateral ankle and foot of an elderly man.

Fig. 2. Nodular stage of classic Kaposi’s sarcoma with multiple nodules on the leg.

immunosuppressive drugs, the process sometimes shows a more aggressive course, similar to that seen in AIDS patients with Kaposi’s sarcoma, and a significant percentage of these patients die from the disseminated disease. Although AIDS-associated Kaposi’s sarcoma can appear at any stage of the HIV disease, the process is more common in patients with advanced immunosuppression; most patients have CD4+ T-cell counts lower than 500 cells/mm3 (10). This variant


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Fig. 3. Multiple nodular lesions on the foot in long-standing classic Kaposi’s sarcoma.

Fig. 4. Clinical features of AIDS-associated Kaposi’s sarcoma. Violaceous papules and nodules on the back.

displays a number of clinical features that differ considerably from those seen in the other forms of the disease. AIDS patients usually present with early lesions of Kaposi’s sarcoma because of the awareness and anxiety produced by the disease in these patients. The lesions present as small, pink-to-violaceous macules (Figs. 4 and 5), preferentially along the lines of skin cleavage (71). The macules evolve into oblong papules and nodules. In contrast to the lesions of classic Kaposi’s sarcoma, which mainly affect the distal parts

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Fig. 5. Clinical features of AIDS-associated Kaposi’s sarcoma. Lesions of Kaposi’s sarcoma are intermingled with plaques of psoriasis on the anterior chest.

of the lower extremities, the lesions of AIDS-associated Kaposi’s sarcoma are often distributed over the chest and face (Fig. 6). In some cases the oral mucosa is the first affected site, with the mucosa of the hard palate (Fig. 7) being the most frequently involved area (72). The ocular conjunctiva is another frequently affected site. In general, lesions of this variant progress quickly and disseminate over the entire face, head, and trunk. In some areas, they coalesce to form large plaques; erosions and ulcerations are less frequent than in classic Kaposi’s sarcoma. Extracutaneous involvement is frequently encountered in the lymph nodes, the gastrointestinal tract, and the lungs. Lesions at these sites account for approximately 10–20% of the fatalities of patients with AIDS-associated Kaposi’s sarcoma (73). HISTOPATHOLOGIC FEATURES There are no fundamental differences in the histologic appearance of the lesions among the different types of Kaposi’s sarcoma. Although some authors have pointed out differences between classic and AIDS-associated Kaposi’s sarcoma (74–77), these differences are probably related to the subtle changes seen in the early lesions of AIDS-related Kaposi’s sarcoma. The earliest lesions of Kaposi’s sarcoma, known as the patch stage (71), are characterized by inconspicuous changes and may produce the erroneous impression of an inflammatory condition (78). At scanning magnification these lesions show sparse,


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Fig. 6. Clinical features of advanced stage of AIDS-associated Kaposi’s sarcoma. (A) Numerous violaceous papules and nodules along the lines of skin cleavage on the back. (B) In some areas, the lesions coalesce to form large plaques.

superficial and deep perivascular mononuclear cell infiltrates in conjunction with an increased number of irregular, jagged, vascular spaces lined by thin endothelial cells (Fig. 8). The vessels are mainly found in the upper part of the dermis. The neoplastic vessels of Kaposi’s sarcoma show a tendency to be present around preexisting normal

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Fig. 7. AIDS-associated Kaposi’s sarcoma involving the oral mucosa.

adnexae and blood vessels, producing the so-called promontory sign (71) (Fig. 9). In other areas, the blood vessels infiltrate between collagen bundles of the dermis, giving the appearance that they are “dissecting” the stroma. In rare instances, the newly formed blood vessels form clusters that resemble small hemangiomas (71,74). The inflammatory cells present are predominantly lymphocytes and plasma cells. The presence of plasma cells around newly formed irregular blood vessels is a helpful clue in the histopathologic diagnosis of the patch stage of Kaposi’s sarcoma (71). Another characteristic feature of patch stage lesions of Kaposi’s sarcoma is the presence of scattered necrotic endothelial cells, a feature that has been emphasized at both the conventional microscopy (77) and ultrastructural level (41). Hemosiderin-laden macrophages are another feature frequently found in early lesions of Kaposi’s sarcoma. The histopathologic features just described for the patch lesions can also be seen in clinically normal areas of skin in patients who have Kaposi’s sarcoma elsewhere, which supports the notion of the diffuseness of the process from its inception (79,80). Plaque lesions of Kaposi’s sarcoma tend to involve the entire dermis and even the upper part of the subcutaneous fat. At this stage, there is an increased number of spindle cells arranged in short fascicles between collagen bundles centered around proliferating vascular channels. The spindle cells line irregularly shaped, slit-like vascular spaces that contain isolated erythrocytes. They display minimal or no atypia, with only a few to no mitotic figures.


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Fig. 8. Histopathologic features of patch stage Kaposi’s sarcoma. (A) At scanning magnification, the lesions consists of increased numbers of jagged spaces at different levels of the dermis. (B) Higher magnification shows that the jagged spaces are lined by thin endothelial cells. (C) At this point it is possible to see inflammatory infiltrate with some plasma cells and extravasated erythrocytes.

When the number of spindle cells increases, lesions of Kaposi’s sarcoma become nodular. Then the spindle cells are arranged in interwoven fascicles with erythrocytes scattered in the interstices (Fig. 10). Nuclear atypia, pleomorphism, and mitotic figures may be seen but are usually not very prominent. In rare instances, however, especially

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Fig. 9. Histopathologic features in plaque lesions of Kaposi’s sarcoma. (A) Scanning power shows involvement of the upper part of the dermis by the neoplastic process. (B) Higher magnification shows irregular vascular spaces and inflammatory infiltrate. (C) The “promontory” sign is evident around preexisting capillaries. (D) Numerous plasma cells are present in the stroma surrounding the areas of “promontory” sign.


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Fig. 10. Histopathologic features in nodular lesions of Kaposi’s sarcoma. (A) Scanning magnification shows a well-circumscribed cellular nodule in the dermis. (B) Higher magnification demonstrates that the nodule is composed of fascicles of spindle cells. Some congestive vascular lumina are also seen. (C) Spindle cells are monomorphous, and nuclear atypia, pleomorphism, and mitotic figures are not usually prominent.

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in the African variant (81), a significant number of mitotic figures and atypical cells may be seen in lesions of Kaposi’s sarcoma. A rather characteristic, but probably not specific, finding is the presence of the so-called hyaline globules. Although these are most common in the plaque and nodular lesions of Kaposi’s sarcoma, they can be present at any stage of the disease. These globules are periodic acid-Schiff (PAS)-positive and diastase-resistant, consist of eosinophilic spherules measuring between 1 and 10 µm, and are located both intra- and extracellularly. Most likely these hyaline globules represent degenerated erythrocytes that are phagocytized and confined to the phagolysosomes of the neoplastic cells (82–85). These globules have been also described in other vascular proliferations such as angiosarcomas, pyogenic granulomas, and granulation tissue (84). In rare instances, lesions of Kaposi’s sarcoma may present clinically as bullous lesions with histopathologic features of a lymphangioma. These lesions show irregular vascular channels lined by a single layer of flattened endothelial cells devoid of erythrocytes within the dermis (86–94). The absence of hemosiderin deposits and the scarcity of spindle cells also contribute to a lymphangiomatous appearance of the lesions. Occasionally, the lymphangiomatous pattern can be seen focally within an otherwise stereotypical lesion of Kaposi’s sarcoma. There have been patients with classic Kaposi’s sarcoma in which some lesions showed a lymphangioma-like pattern, whereas other lesions of the same patient exhibited the typical findings associated with Kaposi’s sarcoma, with abundant extravasated erythrocytes and hemosiderin deposits. Chronic lymphedema (86) and/ or the use of electron beam therapy (94) on the involved extremity may be responsible for the formation of the lymphangioma-like lesions in Kaposi’s sarcoma. From a histogenetic point of view, current evidence suggests that Kaposi’s sarcoma is a proliferative process. Ultrastructural and immunohistochemical studies have shown that the spindle cell component shows endothelial differentiation (95,96). Whether this represents endothelium of blood vessels or lymphatics remains to be determined (97–107). Wellformed vessels in lesions of Kaposi’s sarcoma are lined by cells that are positive for factor VIII-related antigen, but studies for this marker in neoplastic spindle cells have provided conflicting results (96,99,102–109). In contrast, Ulex europaeus I lectin has consistently been detected in the spindle cells (99,108). Rutgers et al. (97) concluded that spindle cells in Kaposi’s sarcoma are blood vascular endothelial cells, because they stain with monoclonal antibodies OKM5, anti-E92, and HCl, which react with blood capillary endothelium, but not with lymphatic endothelium. Identical conclusions were reported by Scully et al. (109) on the basis of the immunoreactivity of spindle cells with the antibody B721. Russell Jones et al. (99,108) noted that immunoreactivity of the spindle cells varies with the stage and type of the lesions. Early patch stage lesions have the profile of a lymphatic lesion because the cells are positive for the antibody EN-4, which stain all types of endothelial cells, but are negative with the antibody PAL-E, which is specific for blood vessel endothelium. Nodular lesions of Kaposi’s sarcoma stain with EN-4 and express variable immunoreactivity with PAL-E (99,108). Beckstead et al. (101) also favored lymphatic endothelial differentiation because of the lack of HLA-DR/Ia and alkaline phosphatase and the intense staining with 5' nucleotidase. In contrast, the presence of abundant laminin and type IV collagen surrounding many of the individual spindle cells has been interpreted as evidence favoring a blood vascular endothelium rather than lymphatic endothelium differentiation (110–112). More recently, Weich et al.


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(113) have suggested a close relationship between the Kaposi’s sarcoma cell and the vascular smooth muscle cell, since the tumors express mRNA for α-smooth muscle actin. Different investigators have found that the Kaposi’s sarcoma cells express the CD34 antigen, also known as the human progenitor cell antigen. This is a 105–120-kDa singlechain transmembrane glycoprotein expressed constitutively by endothelial cells of small blood, but not lymphatic, vessels in several tissues (114–118). A nonvascular origin for the spindle cells of the Kaposi’s sarcoma has also been suggested, based on the presence of many factor XIIIa-positive spindle cells in the lesions, suggesting that the factor XIIIa-expressing dermal dendrocyte (a member of the mononuclear phagocytic system) may be the cell of origin for the spindle-shaped cells of Kaposi’s sarcoma (119,120). Other authors, however, believe that these factor XIIIapositive dendritic cells represent reactive hyperplasia of dermal dendrocytes, rather than neoplastic cells (107). More recently, vascular endothelial growth factor receptor-3 (VEGFR-3) (121–124) and podoplanin (123,125), two relatively sensitive and specific markers for lymphatic endothelium, have been identified in most Kaposi’s sarcomas, supporting a lymphatic differentiation for this neoplasm. Ultrastructural studies have documented that under electron microscopy most of the spindle cells exhibit characteristics of endothelial cells, although a few of them also show features of pericytes and fibroblasts (126). The cells surrounding vascular spaces show few intercellular junctions, with gaps between them. A fragmented basal lamina encircles the luminal cells in absence of pericytes. These ultrastructural features seem to be more compatible with lymphatic than blood vascular differentiation, but it is possible that their absence may be the result of the dilation of blood vessels (41). The differential diagnosis of Kaposi’s sarcoma from pseudo-Kaposi’s sarcoma lesions is usually straightforward. In both the acroangiodermatitis and arteriovenous malformation variants of pseudo-Kaposi’s sarcoma lesions, the blood vessels of the papillary dermis are involved, demonstrating a lobular proliferation of round, dilated, thick-walled capillaries, with plump endothelial cells (127). This vascular proliferation is superimposed on a background of dermal fibrosis, erythrocyte extravasation, and abundant hemosiderin. The irregular jagged vascular channels with slit-like lumina surrounding preexisting capillaries, found in early lesions of Kaposi’s sarcoma, are not seen. Benign lymphangioendothelioma can be also mistaken for early lymphangioma-like lesions of Kaposi’s sarcoma. Similarities include thin-walled, endothelium-lined vascular spaces between collagen bundles that appear to “dissect” the dermis. However, these vascular spaces of benign lymphangioendothelioma are usually arranged horizontally in the dermis and show no tendency to surround preexisting blood vessels as in Kaposi’s sarcoma. Furthermore, the absence of extravasated erythrocytes, hemosiderin, and plasma cells is also helpful. The clinical appearance of the lesion is helpful, too, because benign lymphangioendothelioma presents as a solitary lesion. Hobnail hemangioma also shares common histopathologic features with Kaposi’s sarcoma, especially at the periphery of the lesion. In these areas, there are irregular angulated vascular lumina that appear to be dissecting collagen bundles and abundant hemosiderin, raising the possibility of early lesions of Kaposi’s sarcoma. However, in the central areas of hobnail hemangioma, there are widely dilated vascular lumina with intraluminal papillary projections, prominent endothelial cells, and frequent fibrin thrombi. These features are not seen in Kaposi’s sarcoma.

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Spindle cell hemangioma is frequently confused with nodules of Kaposi’s sarcoma because in both entities there are fascicles of spindle cells with slit-like vascular spaces containing erythrocytes. However, spindle cell hemangioma shows dilated blood vessels and areas of epithelioid cells, with prominent cytoplasmic vacuoles, which are not seen in nodules of Kaposi’s sarcoma. Kaposiform hemangioendothelioma bears a striking resemblance to the nodular lesions of Kaposi’s sarcoma; however, the clinical settings are different. Kaposi’s sarcoma is uncommon in infancy, and kaposiform hemangioendothelioma is a solitary neoplasm. Furthermore, histopathologically, kaposiform hemangioendothelioma shows a lobulated growth pattern and hemangioma-like areas, especially at the periphery of the lobules. The biologic behavior of Kaposi’s sarcoma depends on the epidemiologic type of the disease and the immune status of the host. There have been diverse opinions as to whether Kaposi’s sarcoma represents a reactive vascular proliferation or a true neoplastic proliferation. Currently, there is a consensus that Kaposi’s sarcoma does not produce metastasis in the manner of conventional sarcomas, but rather it develops in a multifocal fashion (128). This notion is based on the finding of changes in internal organs such as the lymph nodes, gastrointestinal tract, lung, and kidney similar to those seen in the lesions of the patch stage of Kaposi’s sarcoma in the skin. Despite the lack of metastatic potential, patients can succumb to the effects of Kaposi’s sarcoma. Immunocompetent individuals affected with the classic variant of Kaposi’s sarcoma have a mortality rate between 10 and 20% after 10 years, whereas Kaposi’s sarcoma in AIDS patients has a far more aggressive course; the overall mortality rate is 41% and death occurs within a relatively short period of time (129). TREATMENT The treatment of Kaposi’s sarcoma includes local and/or systemic therapy. The appropriate selection of therapy in each case depends on the epidemiologic variant of the disease, the number of lesions, and the immune status of the patient. In patients with AIDS, new antiretroviral therapies, in particular the protease inhibitors, appear to be changing the clinical course of Kaposi’s sarcoma. Local therapies include liquid nitrogen cryotherapy, radiation therapy, laser therapy, and intradermal therapy with cytotoxic chemotherapy drugs or interferon. Systemic therapies include limited intervention with interferon, with or without zidovudine, and more aggressive intervention with single or multiagent chemotherapy modalities. Therapeutic options for the different clinical settings of Kaposi’s sarcoma have been recently reviewed by Tappero et al. (10). The most recent alternatives consist of topical treatment with alitretinoin gel (130), and the administration of liposomal doxorubicin (131) or vinorelbine (132).

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2. EPITHELIOID HEMANGIOENDOTHELIOMA The term hemangioendothelioma is used for vascular neoplasms that histopathologically appear to be intermediate between hemangiomas and angiosarcomas (1). The problem with this term is that it has been used for various lesions with completely different biologic behaviors. Thus, it has been applied to benign lesions such as spindle cell hemangioendothelioma and kaposiform hemangioendothelioma, but it was also used for low-grade angiosarcomas, including epithelioid hemangioendothelioma and retiform hemangioendothelioma (2,3). To avoid confusion, more logical denominations should be used for some of the vascular proliferations, currently covered by this term (3) (Table 2). CLINICAL FEATURES Epithelioid hemangioendothelioma is a low-grade angiosarcoma first described by Weiss and Enzinger in 1982 (4). It usually appears as a solitary, slightly painful soft tissue tumor (5), although similar lesions have also been reported in the skin (6–13) and oral cavity (14–16). In some cases the lesions consist of ulcerated nodules (17). Epithelioid hemangioendotheliomas may occur at any age, but they are rare during childhood (18). They affect both sexes in approximately equal proportion. At least one-half of the cases are closely associated with or arise within a vessel, usually a vein (5). In some of these cases, the occlusion of the vessel accounts for most of the symptoms, such as edema and/ or thrombophlebitis. Occasional associations with other neoplasms have been reported including epithelioid dermatofibroma and a Spitz nevus, suggesting an underlying “epithelioid” predisposition that could be responsible for the epithelioid appearance in all three tumors (19). Multiple eruptive lesions involving the right arm and humerus have also been described (20) (Fig. 11). A case of an epithelioid hemangioendothelioma in association with a spindle cell hemangioendothelioma has also been published (21). Before a diagnosis of primary cutaneous epithelioid hemangioendothelioma is established, the possibility of cutaneous metastasis from a visceral epithelioid hemangioendothelioma should be excluded (22,23). Table 2 Proposed Terminology for Neoplasms Currently Named Hemangioendothelioma Conventional terminology Benign vascular proliferations Infantile hemangioendothelioma Spindle cell hemangioendothelioma Kaposiform hemangioendothelioma Malignant vascular proliferations Epithelioid hemangioendothelioma Endovascular papillary hemangioendothelioma

Retiform hemangioendothelioma Composite hemangioendothelioma


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Proposed terminology

Infantile hemangioma Spindle cell hemangioma Kaposiform hemangioma Well-differentiated epithelioid angiosarcoma Well-differentiated endovascular papillary angiosarcoma of children (Dabska’s tumor) Well-differentiated retiform angiosarcoma Well-differentiated composite angiosarcoma

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Fig. 11. Eruptive multiple epithelioid hemangioendothelioma involving the anterior chest of an adult man.

HISTOPATHOLOGIC FEATURES Cutaneous epithelioid hemangioendothelioma presents as a circumscribed dermal nodule with an overlying acanthotic epidermis (Fig. 12). In some cases there is a striking acrosyringeal proliferation, which resembles an eccrine syringofibroadenoma (13). The neoplasm is composed of cords, strands, and nests of plump, epithelioid cells embedded in a fibromyxoid or sclerotic stroma. Many of the neoplastic cells contain vacuoles in their cytoplasm as a sign of primitive vascular differentiation. Slight cellular pleomorphism and occasional mitotic figures may be seen. Rarely, large, distinct vascular channels are present mainly in the central areas of the neoplasm. Occasionally, the stroma may show foci of osseous metaplasia (24). Lesions that develop within a vessel extend centrifugally from the lumen of the vascular structure to the adjacent soft tissue, preserving the architecture of the involved vessel. The lumen is filled with necrotic debris and dense collagen. In many cases epithelioid hemangioendotheliomas are difficult to differentiate from metastatic adenocarcinomas. The latter usually contain vacuoles within the neoplastic cells, while in the former there may be erythrocytes within the vacuoles (4,5,13,25). Immunohistochemistry is also useful in this differential diagnosis. The neoplastic cells of epithelioid hemangioendothelioma express immunoreactivity for factor VIII-related antigen, Ulex europaeus I lectin, CD31, and CD34 (1,5–10,13,25), but they may also stain with cytokeratins (25,26) and α-smooth muscle actin (13,25). The epithelioid forms of angiosarcoma involving the skin and superficial soft tissues can also mimic epithelioid hemangioendothelioma. However, epithelioid angiosarcoma is composed of solid sheets of neoplastic cells, many of them atypical, with abundant mitotic figures and with necrosis occurring in both individual cells and large areas of the neoplasm (necrosis en masse). Electron microscopic studies in epithelioid hemangioendothelioma have demonstrated that the neoplastic cells show characteristics of endothelial cells, with well-developed basal lamina,

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Fig. 12. Histopathologic features of epithelioid hemangioendothelioma (A) Low power shows a relative well-circumscribed nodule in the dermis. (B) The cellular nodule is mostly solid, but vascular channels are also present. (C) Cytoplasmic vacuolization is prominent in many neoplastic cells. (D) Higher magnification demonstrates that neoplastic cells show an epithelioid appearance, and many of them contain vacuoles in their cytoplasm. Numerous erythrocytes are seen both in the vacuoles and extravasated.

pinocytotic vesicles, and occasional Weibel-Palade bodies. They differ from normal endothelial cells by the presence of abundant intermediate filaments that fill the cytoplasm (27). TREATMENT Treatment of superficial forms of epithelioid hemangioendothelioma includes wide excision and clinical evaluation of the regional lymph nodes, since this is the most common metastatic site. Metastases occur more frequently in the histopathologically malignant forms. Fewer than half the patients who developed metastases died of their disease, because most of the metastases occur in regional lymph nodes and excision of these structures is curative, or provides at least long-term disease-free survival (1). However, the follow-up of a recent series of 30 patients with epithelioid hemangioendothelioma of skin and soft tissues demonstrated systemic metastases in 21% of the cases, and 17% of the patients died because of the tumor (25). Therefore, epithelioid hemangioendothelioma of the soft tissues should be regarded as a fully malignant, rather than borderline, vascular neoplasm, although the prognosis is better than in conventional angiosarcoma.

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References 1. Enzinger FM, Weiss SW. Hemangioendothelioma: Vascular tumors of intermediate malignancy. In: Soft Tissue Tumors, 3rd ed. St Louis, MO, Mosby, 1995:627–40. 2. Mentzel T, Kutzner H. Hemangioendotheliomas: heterogeneous vascular neoplasms. Dermatopathol Pract Concept 1999:5:102–9. 3. Requena L, Ackerman AB. Hemangioendothelioma? Dermatopathol Pract Concept 1999;5:110–2. 4. Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma. A vascular tumor often mistaken for a carcinoma. Cancer 1982;50:970–81. 5. Weiss SW, Ishak KG, Dial DH, Sweet DE, Enzinger FM. Epithelioid hemangioendothelioma and related lesions. Semin Diagn Pathol 1986;3:259–87. 6. Ellis GL, Kratochvill FJ. Epithelioid hemangioendothelioma of the head and neck: a clinicopathologic report of twelve cases. Oral Surg Oral Med Oral Pathol 1986;61:61–8. 7. Tyring S, Guest P, Lee P, Little W, Jaffe K, Pritchett R. Epithelioid hemangioendothelioma of the skin and femur. J Am Acad Dermatol 1989;20:362–6. 8. Resnik KS, Kantor GR, Spielvogel RL, Ryan E. Cutaneous epithelioid hemangioendothelioma without systemic involvement. Am J Dermatopathol 1993;15:272–6. 9. Diaz Cascajo C, Rey López A. Hemangioendotelioma de células fusiformes. Estudio de un caso. Actas Dermosifiliogr 1994;85:221–4. 10. Malane SL, Sau P, Benson PM. Epithelioid hemangioendothelioma associated with reflex sympathetic dystrophy. J Am Acad Dermatol 1992;26:325–8. 11. McKenzie ML. Epithelioid hemangioendothelioma of the wrist. Plast Reconstr Surg 1985;76:781–3. 12. Polk P, Webb JM. Isolated cutaneous epithelioid hemangioendothelioma. J Am Acad Dermatol 1997;36:1026–8. 13. Quante M, Patel NK, Hill S, et al. Epithelioid hemangioendothelioma presenting in the skin. A clinicopathologic study of eight cases. Am J Dermatopathol 1998;20:541–6. 14. De Araujo VC, Marcucci G, Sesso A, de Araujo NS. Epithelioid hemangioendothelioma of the gingiva: case report and ultrastructural study. Oral Surg Oral Med Oral Pathol 1987;63:472–7. 15. Marrogi AJ, Boyd D, el-Mofty S, Waldron C. Epithelioid hemangioendothelioma of the oral cavity: report of two cases and review of literature. J Oral Maxillofac Surg 1991;49:633–8. 16. Orsini G, Fioroni M, Rubini C, Piatelli A. Epithelioid hemangioendothelioma of the oral cavity: report of case. J Oral Maxillofac Surg 2001;59:334–7. 17. Grezard P, Balme B, Ceruse P, Bailly C, Dujardin T, Perrot H. Ulcerated cutaneous epithelioid hemangioendothelioma. Eur J Dermatol 1999;9:487–90. 18. Roh HS, Kim YS, Suhr KB, Yoon TY, Lee JH, Park JK. A case of childhood epithelioid hemangioendothelioma. J Am Acad Dermatol 2000;42:897–9. 19. Zelger BG, Wambacher B, Steiner H, Zelger B. Cutaneous epithelioid hemangioendothelioma, epithelioid cell histiocytoma and Spitz nevus. Three separate epithelioid tumors in one patient. J Cutan Pathol 1997;24:641–7. 20. Kanik H, Hall JD, Bhawan J. Eruptive epithelioid hemangioendothelioma with spindle cells. Am J Dermatopathol 1995;17:612–7. 21. Zoltie N, Roberts PF. Spindle cell hemangioendothelioma in association with epithelioid hemangioendothelioma. Histopathology 1989;15:544–6. 22. Vignon-Pennamen MD, Varroud-Vial C, Jannsen F, Degott C, Verola O, Cottenot F. Metastases cutanées d’un hémangioendothéliome épithelioide hépatique. Ann Dermatol Venereol 1989;116:864–6. 23. Vignon-Pennamen MD, Rybojad M, Verola A, Morel P. Hémangioendothéliome épithelioide: evolution dans 3 cas. Ann Dermatol Venereol 1997;124:165–6. 24. Kiryu H, Hashimoto H, Hori Y. Ossifiying epithelioid hemangioendothelioma. J Cutan Pathol 1996;23:558–61. 25. Mentzel T, Beham A, Calonje E, Katenkamp D, Fletcher CD. Epithelioid hemangioendothelioma of skin and soft tissues: clinicopathologic and immunohistochemical study of 30 cases. Am J Surg Pathol 1997;21:363–74. 26. Gray MH, Rosenberg AE, Dicersin GR, Bhan AK. Cytokeratin expression in epithelioid vascular neoplasms. Hum Pathol 1990;21:212–7. 27. Vasquez M, Ordoñez NG, English GW, Mackay B. Epithelioid hemangioendothelioma of soft tissue: report of a case with ultrastructural observations. Ultrastruct Pathol 1998;22:73–8.


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3. ENDOVASCULAR PAPILLARY ANGIOENDOTHELIOMA (DABSKA’S TUMOR OR PAPILLARY INTRALYMPHATIC ANGIOENDOTHELIOMA) CLINICAL FEATURES Maria Dabska first described this rare but distinctive variant of low-grade angiosarcoma in 1969 (1). In her original report, she described six children ranging in age from 4 months to 15 years affected with the disease. Clinically, the lesions presented as enlarging cutaneous lesions that occurred either as a diffuse swelling or intradermal tumors. Affected sites included the head, neck, and extremities (Fig. 13). After the original report, only a few reports of endovascular papillary angioendothelioma have appeared (2–10). In most cases the neoplasms were located in the skin and subcutaneous fat and preferentially affected infants and young children. However, adult cases have also been reported (2,10,11), and identical lesions have been described in both the spleen (12) and bone (13). A case of Dabska’s tumor developed within a preexisting vascular malformation in a patient with angiomatosis (7), another patient with Dabska’s tumor showed an associated lymphedema of the involved extremity (8), and still another patient developed a Dabska’s tumor within a preexisting deep intramuscular vascular malformation (9). HISTOPATHOLOGIC FEATURES Histopathologically, the neoplasm is composed of interconnecting vascular channels lined by atypical endothelial cells. The vascular spaces vary in size and shape ranging from narrow channels to large vascular structures. The most characteristic histopathologic feature consists of papillary plugs of atypical endothelium, with a central sclerotic core of connective tissue, projecting into the lumina and producing a glomeruloid appearance (Fig. 14). The endothelial cells are round to polyhedral with an atypical, hyperchromatic and eccentrically placed nuclei, located in the luminal border of the cell, producing a surface bulge, accounting for the term “hobnail” or “matchstick.” Because of to the striking presence of these endothelial cells, some authors have proposed the name hobnail

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Fig. 13. Dabska’s tumor involving the posterior aspect of the leg of a boy with multiple vascular malformations.


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hemangioendothelioma to group two closely related neoplasms, Dabska’s tumor and retiform hemangioendothelioma (see the next section) (14). The cytoplasm of some hobnail endothelial cells contains vacuoles as an expression of primitive lumen formation (3). Mitotic figures may be seen, but only a few. In some vessels, intraluminal lymphocytes are intermingled with the endothelial cells, indicating an intimate association between the endothelial cells and the stromal lymphocytic component (4,8). Some of the lesions described as Dabska’s tumor such as the one described by de Dulanto and Armijo (2) in an adult, are somewhat different. This particular lesion consisted of multiple dilated vascular channels involving the dermis with their lumina mostly filled with solid proliferations of endothelial cells and without prominent papillary projections (2). Immunohistochemical studies in Dabska’s tumor have demonstrated that the neoplastic cells express immunoreactivity for factor VIII-related antigen, Ulex europaeus I lectin, C 3.1 antibody (an endothelial marker), CD31, CD34, and muscle-specific actin, but they do not stain with S-100 protein, cytokeratins, epithelial membrane antigen, LeuM1, HLA-DR, α1-antichymotrypsin, or leukocyte common antigen (4,6–8,10,11). VEGFR-3, a recently introduced marker for lymphatic endothelium, was positive in the cases studied (11,15), supporting a lymphatic differentiation for this neoplasm. On the basis of these findings, some authors have proposed the term papillary intralymphatic angioendothelioma as the best name for this neoplasm (11). Flow cytometry studies have shown diploid cells (8). Other authors believe that endovascular papillary angioendothelioma is not a distinctive entity but a histopathologic pattern that may be seen in different vascular lesions such as angiosarcoma, retiform hemangioendothelioma, and glomeruloid hemangioma (16). Retiform hemangioendothelioma is another variant of low-grade angiosarcoma, also characterized by the presence of hobnail endothelial cells, that occurs mostly in adults and is histopathologically characterized by long retiform vessels lined by a single layer of hobnail endothelial cells (see the next section) (17). Some lesions of retiform hemangioendothelioma show overlapping histopathologic features, with some areas of intravascular papillary structures having hyaline collagenous cores and lined by hobnail endothelial cells, and other areas composed of long arborizing blood vessels arranged in a retiform pattern. These cases support the notion that Dabska’s tumor and retiform hemangioendothelioma are two closely related neoplasms. Ultrastructurally, neoplastic cells of Dabska’s tumor show irregular nuclei, abundant cytoplasmic filaments condensed in the perinuclear area, and abundant pinocytotic vesicles. Weibel-Palade bodies have been also identified in some cells. The hyaline globules are composed of abundant electron-dense basement membrane material (3,4,6). TREATMENT Treatment of malignant endovascular papillary angioendothelioma consists of wide excision accompanied by regional lymphadenectomy when these structures appear to be clinically involved. Only two cases of Dabska’s original description had regional Fig. 14. (Opposite page) Histopathologic features of Dabska’s tumor. (A) Scanning power shows an exophytic lesion. (B) Higher magnification shows irregular vascular spaces at different levels of the dermis. (C) Some of these vascular channels show intraluminal papillary projections lined by endothelial cells. (D) Many of these endothelial cells are polyhedral, with atypical hyperchromatic nuclei. The cytoplasm of some of the cells contains vacuoles, as an expression of primitive lumen formation.

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lymph node metastases, and one of these patients later died of widespread pulmonary metastases (18).

References 1. Dabska M. Malignant endovascular papillary angioendothelioma of the skin in childhood. Clinicopathologic study of 6 cases. Cancer 1969;24:503–10. 2. de Dulanto F, Armijo Moreno M. Malignant endovascular papillary hemangioendothelioma of the skin. Acta Derm Venereol 1973;53:403–8. 3. Patterson K, Chandra RS. Malignant endovascular papillary angioendothelioma. A cutaneous borderline tumor. Arch Pathol Lab Med 1985;109:671–3. 4. Manivel JC, Wick MR, Swanson PE, Patterson K, Dehner LP. Endovascular papillary angioendothelioma of childhood: a vascular lesion possibly characterized by “high” endothelial cell differentiation. Hum Pathol 1986;17:1240–4. 5. Magnin PH, Schroh RG, Barquin MA. Endovascular papillary angioendothelioma in children. Pediatr Dermatol 1987;4:332–5. 6. Morgan J, Robinson MJ, Rosen LB, Unger H, Niven J. Malignant endovascular papillary angioendothelioma (Dabska tumor). A case report and review of the literature. Am J Dermatopathol 1989;11:64–8. 7. Quecedo E, Martínez Escribano J, Febrer I, Oliver V, Velasco M, Aliaga A. Dabska tumor developing within a preexisting vascular malformation. Am J Dermatopathol 1996;18:302–7. 8. Fukunaga M, Ushigome S, Shishikura Y, Yokoi K, Ishikawa E. Endovascular papillary angioendothelioma-like tumor associated with lymphoedema. Histopathology 1995;27:243–9. 9. Argani P, Athanasian E. Malignant endovascular papillary angioendothelioma (Dabska tumor) arising within a deep intramuscular hemangioma. Arch Pathol Lab Med 1997;121:992–5. 10. Yamada A, Uematsu K, Yasoshima H, et al. Endovascular papillary angioendothelioma (Dabska tumor) in an elderly woman. Pathol Int 1998;48:164–7. 11. Fanburg-Smith JC, Michal M, Partanen TA, Alitalo K, Mietinen M. Papillary intralymphatic angioendothelioma (PILA): a report of twelve cases of a distinctive vascular tumor with phenotypic features of lymphatic vessels. Am J Surg Pathol 1999;23:1004–10. 12. Katz JA, Mahoney DH, Shukla LW, Smith CW, Gresik MV, Hawkins HK. Endovascular papillary angioendothelioma in the spleen. Pediatr Pathol 1988;8:185–93. 13. McCarthy EF, Lietman S, Argani P, Frassica FJ. Endovascular papillary angioendothelioma (Dabska tumor) of bone. Skeletal Radiol 1999;28:100–3. 14. Weiss SW, Goldblum JR. Hobnail (Dabska-retiform) hemangioendothelioma. In: Enzinger and Weiss’s Soft Tissue Tumors, 4th ed., St. Louis, MO, Mosby, 2001:906–13. 15. Folpe AL, Veikkola T, Valtola R, Weiss SW. Vascular endothelial growth factor receptor-3 (VEGFR-3): a marker of vascular tumors with presumed lymphatic differentiation, including Kaposi’s sarcoma, kaposiform and Dabska-type hemangioendotheliomas, and a subset of angiosarcomas. Mod Pathol 2000;13:180–5. 16. Fukunaga M. Endovascular papillary angioendothelioma (Dabska tumor). Pathol Int 1998;48:840–1. 17. Calonje E, Fletcher CDM, Wilson-Jones E, Rosai J. Retiform hemangioendothelioma. A distinctive form of low-grade angiosarcoma delineated in a series of 15 cases. Am J Surg Pathol 1994;18:115–25. 18. Schwartz RA, Dabski C, Dabska M. The Dabska tumor: a thirty-year retrospect. Dermatology 2000;201:1–5.


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4. RETIFORM HEMANGIOENDOTHELIOMA Calonje et al. (1) have recently reported 15 cases of a distinctive variant of low-grade angiosarcoma of the skin for which they coined the term retiform hemangioendothelioma (1). The lesions described were located preferentially on the lower and upper limbs, although isolated lesions were also present on the scalp, trunk, and penis. The age range of the reported patients was from 9 to 78 years. Retiform hemangioendothelioma arose in the setting of chronic lymphedema in one patient and in another following radiotherapy for carcinoma of the uterine cervix. Additional cases have recently been added to the literature (2–8). Most of the patients were adults, but cases in children have also been reported (1,5). CLINICAL FEATURES Clinically, lesions of retiform hemangioendothelioma present as slowly growing exophytic masses or plaque-like dermal and subcutaneous nodules preferentially located on the extremities (Fig. 15). In two cases, multiple lesions developed in different anatomic sites (3,6). HISTOPATHOLOGIC FEATURES Retiform hemangioendothelioma consists of elongated, arborizing blood vessels involving the dermis, arranged in an architectural pattern reminiscent of that of the normal rete testis (Fig. 16). Monomorphic hobnail endothelial cells line the vessels composing the neoplasm. Cytologic atypia is minimal in the hobnail cells of retiform hemangioendothelioma, and few or no mitotic figures are seen. In some areas, the retiform pattern is obscured by the presence of a dense inflammatory infiltrate of mature lymphocytes. In addition to the retiform pattern, there are also more solid areas composed of epithelioid or spindle cells and some dilated vascular channels with intraluminal papillary projections similar to those seen in Dabska’s tumor. As previously stated, it is probable that Dabska’s tumor and retiform hemangioendothelioma are closely related neoplasms. Examples combining features of these two hemangioendotheliomas in the same lesion have been described (1,5). The term composite hemangioendothelioma has recently been proposed to designate vascular neoplasms that show a combination of benign, low-grade malignant and malignant components of hemangioendothelioma (9). In these composite hemangioendotheliomas, the predominant histologic components are those of epithelioid and retiform hemangioendothelioma, but areas with spindle cells and angiosarcoma-like elements were also identified (see the next section). Immunohistochemically, the neoplastic endothelial cells lining vascular spaces show immunoreactivity for factor VIII-related antigen, Ulex europaeus I lectin, CD31, and CD34 (1,2,6,8). The spindle cells of the solid areas also express Ulex europaeus I lectin and CD31 but are negative for factor VIII-related antigen and CD34. Cytokeratins and smooth muscle actin are negative. The lymphocytic infiltrate usually shows a mixture of B (CD20+) and T (CD3+) cells (1,6), although the intraluminal lymphocytes are predominantly T-cells (1). As in Dabska’s tumor, VEGFR-3, the recently introduced marker for lymphatic endothelium, has been detected in the hobnail cells of retiform hemangioendothelioma (10,11), supporting the possibility of a lymphatic differentiation for this neoplasm. One case of retiform hemangioendothelioma studied by flow cytometry was shown to be diploid (2), and DNA sequences of HHV-8 were detected in an example of retiform

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Fig. 15. Clinical features of retiform hemangioendothelioma. (A) Multiple violaceous nodules grouped in a plaque. (B) Close-up view shows the angiomatous appearance of some of the nodules.

hemangioendothelioma in a 73-year-old woman with no evidence of immunodeficiency or HIV infection (8). TREATMENT All patients affected with retiform hemangioendothelioma were initially treated with surgical excision. With a median follow-up of 7.25 years in 14 cases, retiform hemangioendothelioma has proved to be a low-grade angiosarcoma that recurs frequently but has a very low metastatic rate, since a single regional lymph node developed in only one patient and there have been no tumor-related deaths.


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Fig. 16. Histopathologic features of retiform hemangioendothelioma. (A) Scanning power shows a lesion involving diffusely the entire dermis. (B) Many elongated vascular channels are present throughout the lesion. (Continued)

References 1. Calonje E, Fletcher CDM, Wilson Jones E, Rosai J. Retiform hemangioendothelioma. A distinctive form of low-grade angiosarcoma delineated in a series of 15 cases. Am J Surg Pathol 1994;18:115–25. 2. Fukunaga M, Endo Y, Masui F, Yoshikawa T, Ishikawa E, Ushigome S. Retiform haemangioendothelioma. Virchows Arch 1996;428:301–4.

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Fig. 16. (C) These elongated vascular channels are lined by plump endothelial cells. (D) Many of the endothelial cells lining the elongated vascular channels show epithelioid appearance. (E) In some areas of the stroma there are dense aggregations of mature lymphocytes.

3. Duke D, Dvorak AM, Harris TJ, Cohen LM. Multiple retiform hemangioendotheliomas. A low-grade angiosarcoma. Am J Dermatopathol 1996;18:606–-10. 4. Dufau JP, de Saint Maur PP, Bellavoir A, Gros P. Hemangioendotheliome retiforme. Ann Pathol 1997;17:47–51. 5. Sanz-Trelles A, Rodrigo-Fernández I, Ayala-Carbonero A, Contreras-Rubio F. Retiform hemangioendothelioma. A new case in a child with diffuse endovascular papillary endothelial proliferation. J Cutan Pathol 1997;24:440–4.


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6. Mentzel T, Stengel B, Katenkamp D. Retiformes hemangioendotheliom. Klinisch-pathologischer Fallbericht und Diskussion der Gruppe der niedrig-malignen vaskularen Tumoren. Pathologe 1997;18:390–4. 7. Schommer M, Herbst RA, Brodersen JP, et al. Retiform hemangioendothelioma: another tumor associated with human herpesvirus type 8? J Am Acad Dermatol 2000;42:290–2. 8. El Darouti M, Marzouk SA, Sobhi RM, Bassiouni DA. Retiform hemangioendothelioma. Int J Dermatol 2000;39:365–8. 9. Nayler SJ, Rubin BP, Calonje E, Chan JK, Fletcher CD. Composite hemangioendothelioma: a complex, low-grade vascular lesion mimicking angiosarcoma. Am J Surg Pathol 2000;24:352–61. 10. Fanburg-Smith JC, Michal M, Partanen TA, Alitalo K, Mietinen M. Papillary intralymphatic angioendothelioma (PILA): a report of twelve cases of a distinctive vascular tumor with phenotypic features of lymphatic vessels. Am J Surg Pathol 1999;23:1004–10. 11. Folpe AL, Veikkola T, Valtola R, Weiss SW. Vascular endothelial growth factor receptor-3 (VEGFR-3): a marker of vascular tumors with presumed lymphatic differentiation, including Kaposi’s sarcoma, kaposiform and Dabska-type hemangioendotheliomas, and a subset of angiosarcomas. Mod Pathol 2000;13:180–5.

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5. COMPOSITE HEMANGIOENDOTHELIOMA CLINICAL FEATURES The descriptive term composite hemangioendothelioma was chosen by Nayler et al. (1) to describe eight cases of a previously uncharacterized neoplasm. These neoplasms showed an unusual combination of various types of hemangioendothelioma including benign, low-grade malignant and malignant vascular components. So far, all the cases reported have involved adult patients, with a median age of 39.5 years. The lesions arose predominantly on the hands and feet and were usually present for several years before diagnosis. HISTOPATHOLOGIC FEATURES Composite hemangioendothelioma consists of an admixture of different components that vary from lesion to lesion. There is also variation in the proportion of each of the components, as well as the manner in which each component is distributed throughout the lesion. In most cases, the predominant histopathologic components are those of epithelioid and retiform hemangioendothelioma, but areas with spindle cells are also identified in some neoplasms. Angiosarcoma-like areas are at least focally present in most cases. One of the reported neoplasms was associated with an arteriovenous malformation, and another was associated with a superficial lymphatic malformation. Immunohistochemically, lesions of composite hemangioendothelioma stain focally with at least two endothelial markers. Most neoplastic endothelial cells lining the vascular structures are positive for factor VIII-related antigen, CD31, and CD34 (1). Smooth muscle actin stain is usually confined to the stroma and walls of the nonneoplastic vessels. Composite hemangioendothelioma should not be confused with polymorphous hemangioendothelioma, which is an extremely rare vascular neoplasm mainly occurring in lymph nodes, although it has also been reported in soft tissue (2). Histopathologically, polymorphous hemangioendothelioma is characterized by a combination of solid, primitive vascular and angiomatous patterns, with relatively uniform cytologic features. In other words, polymorphous hemangioendothelioma refers to lesions showing a combination of solid and angiomatous components, whereas the term composite hemangioendothelioma describes lesions combining different types of hemangioendotheliomas in the same lesion. TREATMENT All described examples of composite hemangioendothelioma were surgically excised. Three tumors persisted locally after incomplete excision, and one patient developed soft tissue and lymph node metastases several years after the original excision (1). No tumorrelated deaths owing to composite hemangioendothelioma have been reported so far.

References 1. Nayler S, Rubin BP, Calonje E, Chan JKC, Fletcher CDM. Composite hemangioendothelioma. A complex, low-grade vascular lesion mimicking angiosarcoma. Am J Surg Pathol 2000;24:352–61. 2. Nascimento AG, Keeney GL, Sciot R, Fletcher CDM. Polymorphous hemangioendothelioma. A report of two cases, one affecting extranodal soft tissues, and review of the literature. Am J Surg Pathol 1997;21:1083–9.


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6. CUTANEOUS ANGIOSARCOMA OF THE FACE AND SCALP OF ELDERLY PATIENTS (WILSON JONES’ ANGIOSARCOMA) Angiosarcoma of the scalp and face in the elderly was first described by Caro and Stubenrauch in 1945 (1), but it was Wilson Jones in 1964 (2) who provided detailed information about the clinical and histopathologic aspects of this variant of cutaneous angiosarcoma. Cutaneous angiosarcoma of the face and scalp predominantly affects elderly patients and is usually located on the scalp and upper forehead. Men are affected more frequently than women (2–8). No predisposing factors are recorded, and the influence of chronic sun damage is questionable since many patients develop angiosarcoma of the scalp despite having a full head of hair (6,7). CLINICAL FEATURES Clinically, angiosarcomas of the face appear as ill-defined bruise-like areas that simulate a hematoma (Figs. 17 and 18). In some cases, they begin with facial edema; especially of the eyelids, with only minimal erythema (1,6,9). More advanced lesions present as indurated plaques with raised, nodular, and occasionally ulcerated components accompanied by smaller satellite lesions in the vicinity (Fig. 19). Some cases are multifocal, which makes it difficult to clinically determine the extension of these lesions (10). The neoplasm spreads gradually and centrifugally in a relatively short period; and in advanced cases, large parts of the scalp, face, and neck become affected. Atypical presentations of angiosarcoma of the face and scalp include superinfected angiosarcoma simulating an inflammatory process (11) and angiosarcoma resembling rosacea (12). Most cases of cutaneous angiosarcoma of the face and scalp present solely as cutaneous lesions; however, this neoplasm has been described in association with thrombocytopenia (13), in immunosuppressed patients with renal transplantation (14), and in patients with xeroderma pigmentosum (15). In contrast to Kaposi’s sarcoma, in which there is

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Fig. 17. Early stage of cutaneous angiosarcoma involving the nose. The lesion consists of an illdefined bruise-like area that simulates a hematoma.


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Fig. 18. Early stage of angiosarcoma involving the scalp. The lesion appears as an ill-circumscribed area of erythema.

strong evidence of a link to HHV-8, there seems to be is no association with angiosarcoma (16–19), and the reports alleging findings to the contrary are questionable (20). HISTOPATHOLOGIC FEATURES Histopathologically, angiosarcomas of the face and scalp usually extend far beyond the clinically visible boundaries of the lesion (3). There is a considerable amount of morphologic variation from lesion to lesion and within different areas of the same tumor. Well-differentiated angiosarcomas appear as irregular, dilated, vascular channels lined with flattened endothelial cells that have an innocuous appearance, which may lead them to be confused with a hemangioma or lymphangioma. However, careful observation of these lesions reveals the presence of irregular vascular channels dissecting through the dermis (Fig. 20). These channels tend to communicate with each other, forming an anastomosing network. Furthermore, some of the endothelial cells appear to be large, hyperchromatic, and pleomorphic, protruding within the vascular lumina, and forming small papillations. In less differentiated angiosarcomas, there are solid proliferations of polygonal or spindle-shaped pleomorphic endothelial cells, with prominent mitotic activity and poorly formed vascular spaces. This sometimes makes it difficult to distinguish them from carcinoma, melanoma, or high-grade fibrosarcoma (7,21). Of considerable value for the diagnosis of these cases is the presence of cytoplasmic vacuoles within the neoplastic cells (3). Patchy lymphoid infiltrates are also a common


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Fig. 19. Large angiosarcoma of the scalp in an elderly man. The lesion consists of a bruise-like plaque, with an ulcerated surface, involving the entire posterior scalp and extending to the neck and upper back.

finding in angiosarcomas of the face and scalp. In rare instances, dense nodular infiltrates of lymphocytes with a germinal center formation may be seen scattered throughout the lesion, and at first glance the neoplasm may be misinterpreted as a cutaneous lymphoma or pseudolymphoma. The number of erythrocytes present within the vascular spaces varies from a few to none in the poorly differentiated areas. Preexisting adnexal, neural, and vascular structures of the dermis are frequently involved and are destroyed by the tumor. Uncommon cytologic variants of cutaneous angiosarcoma of the face and scalp include granular cell angiosarcoma (22,23) and angiosarcoma with foamy cells (24). In some angiosarcomas, numerous single necrotic neoplastic cells are scattered throughout the neoplastic aggregations of endothelial cells, giving the lesions a starry-sky appearance (25). Most cutaneous angiosarcomas of the face and scalp are positive for factor VIII-related antigen (26–30), and Ulex europaeus I lectin (31–33). A significant percentage of these lesions, however, are negative for both markers. Ulex europaeus I lectin is more sensitive, but less specific than factor VIII-related antigen in identifying angiosarcomas (21). Other antibodies that have been employed in immunohistochemical studies of cutaneous angiosarcoma include thrombomodulin, an antagonist of factor VIII-related antigen, which is positive in most angiosarcomas, but also in other nonvascular neoplasms (34), CD34 (33), and CD31 (33,35), although not all angiosarcomas express this latter marker (36). More recent immunohistochemical studies have shown that angiosarcomas express VEGFR-3 (37–39) and podoplanin (40), suggesting a lymphatic differentiation. Over-

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expression of basic fibroblastic growth factor (41), angiopoietin-2, Tie-1 and Tie-2 mRNA receptors of the endothelium (42), and Ets-1 protooncogene and metalloproteinase genes such as collagenase-1 (MMP-1) (43) have been correlated with the growth and progression of angiosarcoma. Cytogenetic studies of angiosarcomas have demonstrated hypodiploid or hypertriploid numbers of chromosomes, with the most frequent alterations being gains in chromosomes 5, 8, and 20 and losses in chromosomes 7 and 22 and the Y chromosome (44–46). Examination of well-differentiated angiosarcomas under the electron microscope demonstrates that neoplastic cells contain ultrastructural characteristics of endothelial cells, namely, basal lamina along the anteluminal border, numerous tight junctional complexes between adjacent cells, abundant pinocytotic vesicles usually oriented along the plasma membrane, and moderate amount of cytofilaments (3). Weibel-Palade bodies are rarely found in cutaneous angiosarcomas (3,47). In poorly differentiated angiosarcomas, features of endothelial differentiation are less conspicuous; there are only scant pinocytotic vesicles, clefts between adjacent cells, and vacuoles within the cytoplasm as an expression of primitive or abortive vascular differentiation (3,47). TREATMENT The prognosis of cutaneous angiosarcoma of the face and scalp is rather poor. In the largest series reported to date, Holden et al. (6) found that only 12% of patients survived for 5 or more years, with approximately half of the patients dying within 15 months of the debut of the tumor. Maddox and Evans (5) documented similar findings in a series of 17 patients. These authors also noted an increased survival in patients with lesions less than 5 cm in diameter and in tumors with a prominent lymphocytic infiltrate. There was no prognostic correlation with the sex, location of the lesion, histologic differentiation, or mitotic activity. When the lesions metastasize, the cervical lymph nodes are the earliest involved sites, but widespread dissemination to the lung, liver, spleen, and skeleton appear shortly thereafter. The ideal therapy is wide surgical excision of the lesion, followed by radiotherapy (6,48,49), but this cannot be readily accomplished with angiosarcomas of the face and scalp, because they frequently extend beyond the clinically apparent margins of the lesion. Preoperative assessment of the tumor margins by biopsies of the periphery of the lesion or Mohs’ surgery are the best techniques to delineate the extension of the tumor and to plan adequate treatment (50). Despite the overall poor prognosis, seven patients with cutaneous angiosarcoma of the face and scalp treated with wide-field electron beam therapy have shown apparent eradication of cutaneous lesions and prolonged survival, although pulmonary metastases developed 10 years later in two of these patients (5). Adjuvant systemic chemotherapy with liposome-encapsulated doxorubicin (51,52), interferon-α2a and 13-cis-retinoic acid (53), paclitaxel (54), or intralesional interferon-α2b and interleukin-2 (55) has been used in patients with angiosarcoma of the scalp and face with variable results.

Fig. 20. (Opposite page) Histopathologic features of cutaneous angiosarcoma of the scalp. (A) Scanning power shows a poorly circumscribed lesion involving the entire dermis and extending to the subcutaneous tissue. (B) Higher magnification shows multiple irregular vascular channels dissecting through the dermis. (C) Still higher magnification shows that the irregular vascular spaces are lined by endothelial cells. (D) Many of these endothelial cells show hyperchromatic nuclei protruding within the vascular lumina.

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References 1 Caro MR, Stubenrauch CH Jr. Hemangioendothelioma of the skin. Arch Dermatol Syph 1945;51: 295–304. 2. Wilson Jones E. Malignant angioendothelioma of the skin. Br J Dermatol 1964;76:21–39. 3. Rosai J, Sumner HW, Major MC, Kostianovsky M, Perez Mesa C. Angiosarcoma of the skin. A clinicopathologic and fine structural study. Hum Pathol 1976;7:83-109. 4. Cooper PH. Angiosarcomas of the skin. Semin Diagn Pathol 1987;4:2–17. 5. Maddox JC, Evans HL. Angiosarcoma of skin and soft tissue. A study of forty-four cases. Cancer 1981;48:1907–21. 6. Holden CA, Spittle MF, Wilson Jones E. Angiosarcoma of the face and scalp, prognosis and treatment. Cancer 1987;59:1046–57. 7. Wilson Jones E. Malignant vascular tumors. Clin Exp Dermatol 1976;1:287–312. 8. Hodgkinson DJ, Soule EH, Woods JE. Cutaneous angiosarcoma of the head and neck. Cancer 1979;44:1106–13. 9. Tay YK, Ong BH. Cutaneous angiosarcoma presenting as recurrent angio-oedema of the face. Br J Dermatol 2000;143:1346–8. 10. Kacker A, Antonescu CR, Shaha AR. Multifocal angiosarcoma of the scalp: a case report and review of the literature. Ear Nose Throat J 1999;78:302–5. 11. Diaz-Cascajo C, de la Vega M, Rey-López A. Superinfected cutaneous angiosarcoma: a highly malignant neoplasm simulating an inflammatory process. J Cutan Pathol 1997;24:56–60. 12. Mentzel T, Kutzner H, Wollina U. Cutaneous angiosarcoma of the face: clinicopathologic and immunohistochemical study of a case resembling rosacea clinically. J Am Acad Dermatol 1998;38:837–40. 13. Satoh T, Takahashi Y, Yokozeki H, Katayama I, Nishioka K. Cutaneous angiosarcoma with thrombocytopenia. J Am Acad Dermatol 1999;40:872–6. 14. Kibe Y, Kishimoto S, Katoh N, Yasuno H, Yasumura T, Oka T. Angiosarcoma of the scalp associated with renal transplantation. Br J Dermatol 1997;136:752–6. 15. De Silva BD, Nawroz I, Doherty VR. Angiosarcoma of the head and neck associated with xeroderma pigmentosum variant. Br J Dermatol 1999;141:166–7. 16. Lin BT, Chen YY, Battifora H, Weiss LM. Absence of Kaposi’s sarcoma-associated herpesvirus-like DNA sequences in malignant vascular tumors of the serous membranes. Mod Pathol 1996;9:1143–6. 17. Li N, Anderson WK, Bhawan J. Further confirmation of the association of human herpesvirus 8 with Kaposi’s sarcoma. J Cutan Pathol 1988;25:413–9. 18. Lasota J, Miettinen M. Absence of Kaposi’s sarcoma-associated virus (human herpesvirus-8) sequences in angiosarcoma. Virchows Arch 1999;434:51–6. 19. Martínez-Escribano JA, del Pino Gil Mateo M, Miquel J, Ledesma E, Aliaga A. Human herpesvirus 8 is not detectable by polymerase chain reaction in angiosarcoma. Br J Dermatol 1998;138:546–7. 20. McDonagh DP, Liu J, Gaffey MJ, et al. Detection of Kaposi’s sarcoma-associated herpesvirus-like DNA sequence in angiosarcoma. Am J Pathol 1996;149:1363–8. 21. Enzinger FM, Weiss SW. Malignant vascular tumors. In: Soft Tissue Tumors, 3rd ed. St. Louis, MO, Mosby, 1995:641–77. 22. McWilliam LJ, Harris M. Granular cell angiosarcoma of the skin: histology, electron microscopy and immunohistochemistry of a newly recognized tumor. Histopathology 1985;9:1205–16. 23. Hitchcock MG, Hurt MA, Santa Cruz DJ. Cutaneous granular cell angiosarcoma. J Cutan Pathol 1994;21:256–62. 24. Ackerman AB, Guo Y, Vitale P, Vossaert K. Clues to Diagnosis in Dermatopathology III. Chicago, ASCP Press, 1993:357–60. 25. Smith KJ, Lupton GP, Skelton HG. Cutaneous angiosarcomas with a starry-sky pattern. Arch Pathol Lab Med 1997;121:980–4. 26. Burgdorf WHC, Mukai K, Rosai J. Immunohistochemical identification of factor VIII related antigen in endothelial cells of cutaneous lesions of alleged vascular nature. Am J Clin Pathol 1981;75:167–71. 27. Sehested M, Hou-Jensen K. Factor VIII-related antigen as an endothelial cell marker in benign and malignant diseases. Virchows Arch Pathol Anat 1981;391:217–25. 28. Guarda LA, Ordoñez NG, Smith JL Jr, et al. Immunoperoxidase localization of factor VIII in angiosarcomas. Arch Pathol Lab Med 1982;106:515–6. 29. Mukai K, Rosai J. Factor VIII related antigen: an endothelial marker. In: DeLellis RA, ed. Diagnostic Immunohistochemistry. New York, Masson, 1984:253–61. 30. Swanson PE, Wick MR. Immunohistochemical evaluation of vascular neoplasms. Clin Dermatol 1991;9:243–53.


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31. Miettinen M, Holthofer H, Veli-Pekka L, et al. Ulex europaeus I lectin as a marker for tumors derived from endothelial cells. Am J Clin Pathol 1983;79:32–6. 32. Ordoñez NG, Batsakis JG. Comparison of Ulex aeropaeus I lectin and factor VIII related antigen in vascular lesions. Arch Pathol Lab Med 1984;108:129–32. 33. Orchard GE, Zelger B, Jones EW, Jones RR. An immunohistochemical assessment of 19 cases of cutaneous angiosarcoma. Histopathology 1996;28:235–40. 34. Yonezawa S, Marayuma I, Tanaka S, et al. Thrombomodulin as a marker for vascular tumors: comparative study with factor VIII and Ulex europaeus I lectin. Am J Clin Pathol 1987;88:405–11. 35. DeYoung BR, Wick MR, Fitzgibbon JF, et al. CD31: an immunospecific marker for endothelial differentiation in human neoplasms. Appl Immunohistochem 1993;1:97–103. 36. Poblet E, Gonzalez Palacios F, Jimenez FJ. Different immunoreactivity of endothelial markers in well and poorly differentiated areas of angiosarcomas. Virchows Arch 1996;428:217–21. 37. Hashimoto M, Ohsawa A, Onhnishi A, et al. Expression of vascular endothelial growth factor and its receptor mRNA in angiosarcoma. Lab Invest 1995;73:859–63. 38. Brown LF, Tognazzi K, Dvorak HF, Harrist TJ. Strong expression of kinase insert domain-containing receptor, a vascular permeability factor/vascular endothelial growth factor receptor in AIDS-associated Kaposi’s sarcoma and cutaneous angiosarcoma. Am J Pathol 1996;148:1065–74. 39. Folpe AL, Veikkola T, Valtola R, Weiss SW. Vascular endothelial growth factor receptor-3 (VEGFR-3): a marker of vascular tumors with presumed lymphatic differentiation, including Kaposi’s sarcoma, kaposiform and Dabska-type hemangioendotheliomas, and a subset of angiosarcomas. Mod Pathol 2000;13:180–5. 40. Breiteneder-Geleff S, Soleiman A, Kowalski H, et al. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries. Podoplanin as a specific marker for lymphatic endothelium. Am J Pathol 1999;154:385–94. 41. Yamamoto T, Umeda T, Yokozeki H, Nishioka K. Expression of basic fibroblast growth factor and its receptor in angiosarcoma. J Am Acad Dermatol 1999;41:127–9. 42. Brown LF, Dezube BJ, Tognazzi K, Dvorak HF, Yancopoulos GD. Expression of Tie1, Tie2, and angiopoietins 1, 2, and 4 in Kaposi’s and cutaneous angiosarcoma. Am J Pathol 2000;156:2179–83. 43. Naito S, Shimizu K, Nakashima M, et al. Overexpression of ETS-1 transcription factor in angiosarcoma of the skin. Pathol Res Pract 2000;196:103–9. 44. Molina A, Bangs CD, Donlon T. Angiosarcoma of the scalp with a complex hypotetraploid karyotype. Cancer Genet Cytogenet 1989;41:268–72. 45. Mandahl M, Jin Y, Heim S, et al. Trisomy 5 and loss of the Y chromosome as the sole cytogenetic anomalies in a cavernous hemangioma/angiosarcoma. Genes Chromosomes Cancer 1990;1:315–8. 46. Schuborg C, Mertens F, Rydholm A, et al. Cytogenetic analysis of four angiosarcomas from deep and superficial soft tissue. Cancer Genet Cytogenet 1998;100:52–6. 47. Mackay B, Ordoñez NG, Huang WL. Ultrastructural and immunocytochemical observations on angiosarcoma. Ultrastruct Pathol 1989;13:97–106. 48. Mark RJ, Poen JC, Tran LM, et al. Angiosarcoma: a report of 67 patients and a review of the literature. Cancer 1996;77:2400–6. 49. Brand CU, Yawalkar N, von Briel C, Hunziker T. Combined surgical and X-ray treatment for angiosarcoma of the scalp: report of a case with a favourable outcome. Br J Dermatol 1996;134:763–5. 50. Bullen R, Larson PO, Landeck AE, et al. Angiosarcoma of the head and neck managed by a combination of multiple biopsies to determine tumor margin and radiation therapy. Report of three cases and review of the literature. Dermatol Surg 1998;24:1105–10. 51. Jackel A, Deichmann M, Waldmann V, Bock M, Naher H. Regression of metastatic angiosarcoma of the skin after systemic treatment with liposome-encapsulated doxorubicin and interferon alpha. Br J Dermatol 1999;140:1187–8. 52. Wollina U, Fuller J, Graefe T, Kaatz M, Lopatta E. Angiosarcoma of the scalp: treatment with liposomal doxorubicin and radiotherapy. J Cancer Res Clin Oncol 2001;127:396–9. 53. Spieth K, Gille J, Kaufmann R. Therapeutic efficacy of interferon alfa-2a and 13-cis-retinoic acid in recurrent angiosarcoma of the head. Arch Dermatol 1999;135:1035–7. 54. Fata F, O’Reilly E, Ilson D, et al. Paclitaxel in the treatment of patients with angiosarcoma of the scalp of face. Cancer 1999;15:2034–7. 55. Ulrich L, Krause M, Brachmann A, Franke I, Gollnick H. Successful treatment of angiosarcoma of the scalp by intralesional cytokine therapy and surface irradiation. J Eur Acad Dermatol Venereol 2000;14:412–5.

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7. CUTANEOUS ANGIOSARCOMA ASSOCIATED WITH LYMPHEDEMA Stewart and Treves (1) first described the development of cutaneous angiosarcoma in lymphedematous areas in 1948. Since then, this disorder has been known as StewartTreves syndrome. In their original report, these authors reported six patients with postmastectomy lymphedema on the ipsilateral arm in whom angiosarcomas developed several years after this procedure. A large number of additional cases rapidly appeared in the literature (2–10). In addition to lymphedema secondary to mastectomy, this type of angiosarcoma has also been described in areas of lymphedema secondary to a variety of other mechanisms, including axillary node dissection for metastatic melanoma in males (11), lymphedema of the abdominal wall following lymph node dissection for carcinoma of the penis (12), congenital lymphedema (3,4,13–16), lymphedema secondary to a filarial infection (17–22), chronic idiopathic lymphedema (3,15,18,22–27), morbid obesity with lymphedema(28), and angiosarcoma complicating elephantiasis (29). Angiosarcomas arising in areas of lymphedema have been designated lymphangiosarcomas on the presumption that the neoplasms originated from dilated lymphatic vessels. However, this assertion has not been definitively proved, and immunohistochemical and ultrastructural studies support a hemangiomatous differentiation. Therefore at this time the term angiosarcoma is justified for neoplasms that develop in lymphedematous areas (30). More than 90% of all angiosarcomas associated with chronic lymphedema occur following mastectomy for breast carcinoma (3). The mastectomy invariably includes removal of the axillary lymph nodes, and in some patients, but not all, there is also the antecedent of adjuvant radiotherapy to the affected area. The risk of developing angiosarcoma in postmastectomy patients who have a survival of 5 years or more is approximately 0.5% (19). The interval between the mastectomy and the development of angiosarcoma ranges from 1 to 30 years. The arm, most often the upper inner aspect, is the most frequent site for early involvement. Less commonly, the tumor appears more distally, on the elbow or on the forearm. In rare instances, postmastectomy angiosarcoma has been reported in patients who have experienced little or no lymphedema. CLINICAL FEATURES Clinically, these lesions appear as bruise-like areas or violaceous nodules superimposed on the brownish nonpitting edema of the affected limb (31) (Fig. 21). After the appearance of the lesions, there is a rapid increase in their number and size, and they may undergo ulceration. In advanced cases, they spread distally to the hands and proximally to the chest wall. The clinical appearance and the histologic behavior of angiosarcomas in lymphedematous extremities unassociated with mastectomy are essentially identical to those of postmastectomy angiosarcoma. HISTOPATHOLOGIC FEATURES Angiosarcomas that originate in areas of chronic lymphedema exhibit similar histopathologic features to those of angiosarcoma of the scalp and face (30,32). They appear as irregular vascular spaces that form an intricate network of freely anastomosing vessels containing erythrocytes with extensive dissection of collagen. Endothelial cell nuclei are plump and hyperchromatic. Patchy lymphoid infiltrates are sometimes present around


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Fig. 21. Cutaneous angiosarcoma associated with chronic postmastectomy lymphedema (StewartTreves syndrome). (A) The entire upper extremity appears edematous, with multiple angiomatous nodules. (B) In addition to the nodules, there are ill-delimited angiomatous plaques.

the newly formed vessels. In some cases, there is a verrucous epidermal hyperplasia, presumably caused by lymphedema and the involvement of the papillary dermis (33). From a histogenetic point of view, the relationship between chronic lymphedema and angiosarcoma is enigmatic. Stewart and Treves, in their original report (1), postulated that unknown carcinogens within lymphatic fluid, acting in a locus minoris resistentia , induced the neoplastic change, a view that was also held by other authors (2). More recently, it has been suggested that the lymphedema modifies the biochemical or immunologic status of the affected limb fostering, the development of angiosarcoma (5,14). The notion that areas with chronic lymphedema are “immunologically privileged sites” is supported by the observation that skin grafts survive for long periods when they are transferred to lymphedematous extremities (20,21). Immunohistochemical studies in cutaneous angiosarcomas developing in lymphedematous extremities have documented positivity for factor VIII-related antigen (8,34), and ultrastructural examination has demonstrated the presence of pericytes and WeibelPalade bodies in some cases (7,8,35,36). These special studies are useful in establishing a differential diagnosis between Stewart-Treves angiosarcoma and metastatic breast carcinoma in a lymphedematous arm, since both entities may show similar clinical and histopathologic features. In metastatic breast carcinoma, the neoplastic cells express

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immunoreactivity for cytokeratin owing to their epithelial nature, whereas factor VIIIrelated antigen is negative (37). TREATMENT Survival in angiosarcoma associated with lymphedema may be worse than in other forms of cutaneous angiosarcoma. Woodward et al. (3) reported a mean survival time of patients with angiosarcoma following mastectomy of 19 months, compared with 34 months for cutaneous angiosarcomas not related to lymphedema. Sordillo et al. (6) reported a mean survival time of 31 months. A longer survival time has been reported in patients initially treated with radical surgery, including limb disarticulation, or hindquarter or forequarter amputation (30). Other studies have found no significant difference in survival when cases initially treated with wide excision were compared with those treated with amputation (38).

References 1. Stewart FW, Treves N. Lymphangiosarcoma in postmastectomy lymphedema. Cancer 1948;1:64–81. 2. Herrmann JB. Lymphangiosarcoma of the clinically edematous extremity. Surg Gynecol Obstet 1965;121:1107–15. 3. Woodward AH, Ivins JC, Soule EH. Lymphangiosarcoma arising in chronic lymphedematous extremities. Cancer 1972;30:562–72. 4. Taswell HF, Soule HE, Coventry MB. Lymphangiosarcoma arising in chronic lymphedematous extremities. J Bone Joint Surg 1962;44A:277–94. 5. Schreiber H, Barry FM, Russell WC, Macon WL IV, Ponsky JL, Pories WJ. Stewart-Treves syndrome. A lethal complication of postmastectomy lymphedema and regional immune deficiency. Arch Surg 1979;114:82–5. 6. Sordillo PP, Chapman R, Hajdu DI, Magill GB, Golbey RB. Lymphangiosarcoma. Cancer 1981; 48:1674–9. 7. Silverberg SG, Kay S, Koss LG. Postmastectomy lymphangiosarcoma: utrastructural observations. Cancer 1971;27:100–8. 8. Kanitakis J, Bendalac A, Marchand C, et al. Stewart-Treves syndrome: a histogenetic (ultrastructural and immunohistochemical) study. J Cutan Pathol 1986;13:30–9. 9. Hultberg BM. Angiosarcoma in chronically lymphedematous extremities: two cases of Stewart-Treves syndrome. Am J Dermatopathol 1987;9:406–12. 10. Hildebrandt G, Mittag M, Gutz U, Kunze ML, Haustein UF. Cutaneous breast angiosarcoma after conserving treatment of breast cancer. Eur J Dermatol 2001;11:580–3. 11. Chen KTK, Bauer V, Flam MS. Angiosarcoma in postsurgical lymphedema. An unusual occurrence in a man. Am J Dermatopathol 1991;13:488–92. 12. Calnan J, Cowdell RH. Lymphangioendothelioma of the anterior abdominal wall: report of a case. Br J Surg 1959;46:375–9. 13. Dubin HU, Creehan EP, Headington JT. Lymphangiosarcoma and congenital lymphedema of the extremity. Arch Dermatol 1974;110:608–14. 14. Laskas JJ Jr, Shelley WB, Wood MG. Lymphangiosarcoma arising in congenital lymphedema. Arch Dermatol 1975;111:86–9. 15. Mackezie DM. Lymphangiosarcoma arising in chronic congenital and idiopathic lymphedema. J Clin Pathol 1971;24:524–9. 16. Merrick T, Erlandson RA, Hajdu SI. Lymphangiosarcoma of a congenitally lymphedematous extremity. Arch Pathol 1971;91:365–71. 17. Muller R, Hajdu SI, Brenan MF. Lymphangiosarcoma associated with chronic filarial lymphedema. Cancer 1987;59:179–83. 18. Alessi E, Sala F, Berti E. Angiosarcomas in lymphedematous limbs. Am J Dermatopathol 1986;8:371–8. 19. Shirger A. Postoperative lymphedema: etiologic and diagnostic factors. Med Clin North Am 1962;46:1045–50. 20. Stark RB, Dwyer EM, DeForest M. Effect of surgical ablation of regional lymph nodes on survival of skin homographs. Ann NY Acad Sci 1960;87:140–5.


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21. Lambert PB, Frank HA, Bellman S, et al. The role of the lymph trunks in the response to allogenic skin transplants. Transplantation 1965;3:62–73. 22. Sordillo EM, Sordillo PP, Hadju SI, et al. Lymphangiosarcoma after filarial infection. J Dermatol Surg Oncol 1981;7:235–9. 23. Baes H. Angiosarcoma in a chronic lymphedematous leg. Dermatologica 1967;134:331–6. 24. Sinclair SA, Sviland L, Natarajan S. Angiosarcoma arising in a chronically lymphoedematous leg. Br J Dermatol 1998;138:692–4. 25. Simonetti V, Folgaresi M, Motolese A. Angiosarcoma of the lower leg in chronic lymphoedema. Acta Derm Venereol 1999;79:251–2. 26. Azurdia RM, Guerin DM, Verbov JL. Chronic lymphoedema and angiosarcoma. Clin Exp Dermatol 1999;24:270–2. 27. Nakazono T, Kudo S, Matsuo Y, et al. Angiosarcoma associated with chronic lymphedema (StewartTreves syndrome) of the leg: MR imaging. Skeletal Radiol 2000;29:413–6. 28. Azam M, Saboorian H, Bieligk S, Smith T, Molberg K. Cutaneous angiosarcoma complicating morbid obesity. Arch Pathol Lab Med 2001;125:531–3. 29. Hallel-Haevy D, Yerushalmi J, Grunwald MH, Avinoach I, Halevy S. Stewart-Treves syndrome in a patient with elephantiasis. J Am Acad Dermatol 1999;41:349–50. 30. Enzinger FM, Weiss SW. Malignant vascular tumors. In: Soft Tissue Tumors, 3rd ed. St. Louis, MO, Mosby, 1995:641–77. 31. Bisceglia M, Attino V, D’Addeta C, Murgo R, Fletcher CD. Le sindrome di Stewart e Treves in fase precoce: presentazione di due casi e revisione della letteratura. Pathologica 1996;88:483–90. 32. Cooper PH. Angiosarcomas of the skin. Semin Diagn Pathol 1987;4:2–17. 33. Diaz-Cascajo C, Weyers W, Borghi S, Reichel M. Verrucous angiosarcoma of the skin: a distinct variant of cutaneous angiosarcoma. Histopathology 1998;32:556–61. 34. Capo V, Ozello L, Fenoglio CM, et al. Angiosarcomas arising in edematous extremities. Hum Pathol 1985;16:144–50. 35. McWilliam LJ, Harris M. Histogenesis of postmastectomy angiosarcoma: an ultrastructural study. Histopathology 1985;9:331–43. 36. Kindblom L-G, Stenman G, Angervall L. Morphological and cytogenetic studies of angiosarcoma in Stewart-Treves syndrome. Virchows Arch A Pathol Anat Histopathol 1991;419:439–45. 37. Hashimoto K, Hatsumoto M, Eto H, et al. Differentiation of metastatic breast carcinoma from StewartTreves angiosarcoma. Arch Dermatol 1985;121:742–6. 38. Grobmyer SR, Daly JM, Glotzbach RE, Grobmyer AJ. Role of surgery in the management of postmastectomy extremity angiosarcoma (Stewart-Treves syndrome). J Surg Oncol 2000;73:1182–8.

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8. RADIATION-INDUCED CUTANEOUS ANGIOSARCOMA Postirradiation cutaneous angiosarcoma is a rare condition that has been described following the use of radiotherapy for the treatment of diverse conditions. These include cutaneous hemangiomas (1,2), acne (3), hand eczema (4), X-ray depilation for scalp ringworm during childhood (5), and malignant neoplasms such as carcinoma of the cervix (6–9), endometrium (10), ovary (11), and breast (12–26), Hodgkin’s disease (27), penile squamous cell carcinoma (28), or peripheral primitive neuroectodermal tumor (29). The ensuing angiosarcoma usually manifests after a long interval, ranging from 4 to 40 years (mean 23.3 years) when radiation therapy was administered for benign conditions, and from 4 to 25 years (mean 12.3 years), for patients in whom radiation therapy was used for malignant tumors. These differences are probably related to the higher dosage and harder radiation in the group of patients with previous malignancy. Preexisting radiodermatitis of the involved area has been described in some cases (3,8,15,30,31). CLINICAL FEATURES The clinical appearance of postirradiation cutaneous angiosarcoma varies from case to case. Diffuse infiltrative plaques (Fig. 22), papulo-nodules, and ulcerated lesions have been described. All lesions occurred in the area of irradiation or its immediate vicinity, and because most of the cases appeared following radiation for breast and genitourinary malignant tumors, the chest wall and the lower abdominal wall are the sites most frequently involved by postirradiation angiosarcomas. Most of these patients had no evidence of lymphedema, suggesting that radiation is the most important etiologic factor. HISTOPATHOLOGIC FEATURES Postirradiation angiosarcoma shows a histopathologic picture similar to that of other variants of cutaneous angiosarcoma (Fig. 23). In early lesions, neoplastic vessels infiltrate collagen bundles of the entire thickness of the dermis and often extend to the subcutaneous tissue. The endothelial cells lining these vessels show variable atypia, but at least some have large hyperchromatic nuclei and protrude into the lumina of the irregular vascular channels. Sometimes papillations lined by protuberant endothelial cells are present. As the lesions become increasingly cellular, aggregations of epithelioid neoplastic cells develop. In these aggregations, vacuoles within the cytoplasm of neoplastic cells are seen as an expression of primitive luminal differentiation. Mitotic figures are frequently seen in the solid-appearing zones. A frequent finding is the presence of lymphoid nodules in both the superficial and deep areas of the dermis. In the advancing edges of these solid areas there are jagged vessels similar to those seen in earlier lesions infiltrating between collagen bundles of the dermis. Cutaneous angiosarcoma originating in irradiated areas of the skin should be distinguished histopathologically from the benign vascular proliferations arising in irradiated skin (see Chapter 8, Subheading 15.), which have received different names in the literature, including lymphangiectases (32), benign lymphangiomatous papules (33), lymphangioma (34–44), atypical vascular lesions (45), benign lymphangioendothelioma (46), or benign vascular proliferations in irradiated skin (47). Histopathologically, they consist of relatively well-circumscribed vascular proliferations involving the dermis, without extension to the subcutaneous fat, and they do not involve the epidermis. Most lesions show irregular dilated vascular spaces, with a branching and anastomosing pattern, and a lymphatic appearance in the superficial dermis. A discontinuous single layer


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Fig. 22. (A) Angiosarcoma of the breast appeared after radiation for breast carcinoma. (B) Close-up view showing the angiomatous appearance of the plaques of angiosarcoma.

of endothelial cells with spindled or flattened nuclei lines the vascular channels, and their lumina appear empty. In many areas, adjacent vascular channels show a “back-to-back” arrangement, with the two vascular lumina only separated by a thin layer of endothelial cells. Numerous small papillary projections, also lined by a single layer of endothelial cells, are seen projecting into the lumina of the dilated lymphatic vessels. The stroma of the lesions consists of fibrillary collagen and numerous spindled or stellate fibroblasts.

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In some cases, dense nodular infiltrates of lymphocytes with germinal centers are present in the vicinity of the dilated vascular channels. Furthermore, in contrast to well-differentiated angiosarcomas, benign vascular proliferations in irradiated skin do not involve the subcutaneous tissue, and there is no substantial cytologic atypia because the nuclei of endothelial cells lining the vascular channels are monomorphous, with inconspicuous nucleoli and no mitotic figures. In contrast, angiosarcomas may present with multiple layers of atypical endothelial cells lining irregular vascular and anastomosing channels, the so-called piling-up phenomenon; this is not seen in atypical vascular proliferations in irradiated skin. TREATMENT In general, the prognosis for angiosarcoma originating in irradiated areas is poor (6), although there are cases of radiation-induced low-grade cutaneous angiosarcomas with multiple recurrences. However, they did not produce metastasis (11). Treatment consists of radical surgery with wide margins of noninvolved tissue. The neoplasm usually extends far beyond the clinically visible boundaries of the lesion, and metastases have already developed by the time surgery is performed.

References 1. Caldwell JB, Ryan MT, Benson PM, James WD. Cutaneous angiosarcoma arising in the radiation site of a congenital hemangioma. J Am Acad Dermatol 1995;33:865–70. 2. Cabo H, Cohen ES, Casas GJ, Allevato M, Woscoff A. Cutaneous angiosarcoma arising on the radiation site of a congenital facial hemangioma. Int J Dermatol 1998;37:638–9. 3. Seo IS, Warner TFCS, Warren JS, Bennett JF. Cutaneous postirradiation sarcoma. Ultrastructural evidence of pluripotential mesenchymal cell derivation. Cancer 1985;56:761–7. 4. Girard C, Johnson WC, Graham JH. Cutaneous angiosarcoma. Cancer 1970;26:868–83. 5. Stone NM, Holden CA. Postirradiation angiosarcoma. Clin Exp Dermatol 1997;22:46–7. 6. Goette EK, Detlefs RL. Postirradiation angiosarcoma. J Am Acad Dermatol 1985;12:922–6. 7. Maddox JC, Evans HL. Angiosarcoma of skin and soft tissue. A study of forty-four cases. Cancer 1981;48:1907–21. 8. Krasagakis K, Hettmannsperger U, Tebbe B, Garbe C. Cutaneous metastatic angiosarcoma with a lethal outcome, following radiotherapy for a cervical carcinoma. Br J Dermatol 1995;133:610–4. 9. Kim MK, Huh SJ, Kim DY, et al. Secondary angiosarcoma following irradiation—case report and review of the literature. Radiat Med 1998;16:55–60. 10. Paik HH, Komorowski R. Hemangiosarcoma of the abdominal wall following irradiation therapy of endometrial carcinoma. Am J Clin Pathol 1976;66:810–4. 11. Chen TK, Goffman KD, Hendricks EJ. Angiosarcoma following therapeutic irradiation. Cancer 1979;44:2044–8. 12. Edeiken S, Russo DP, Knecht J, et al. Angiosarcoma after tylectomy and radiation therapy for carcinoma of the breast. Cancer 1992;70:644–7. 13. Rubin E, Maddox WA, Mazur MT. Cutaneous angiosarcoma of the breast 7 years after lumpectomy and radiation therapy. Radiology 1990;174:258–60. 14. Sessions SC, Smenk RD. Cutaneous angiosarcoma of the breast after segmental mastectomy and radiation therapy. Arch Surg 1992;127:1362–3. 15. Stokkel MPM, Peterse HL. Angiosarcoma of the breast after lumpectomy and radiation therapy for adenocarcinoma. Cancer 1992;69:2965–8.

Fig. 23. (Opposite page) Histopathologic features of postirradiation angiosarcoma of the breast. (A) Scanning power shows dense cellular aggregates at the superficial dermis. (B) Higher magnification demonstrates that these cellular aggregates are surrounding elongated, slit-like vascular spaces. (C) Still higher magnification shows that neoplastic cells are pleomorphic, with hyperchromatic nuclei and numerous mitotic figures.

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16. Moskaluk CA, Merino MJ, Danforth DN, Medeiros LJ. Low-grade angiosarcoma of the skin of the breast: a complication of lumpectomy and radiation therapy for breast carcinoma. Hum Pathol 1992;23:710–4. 17. Bolin DJ, Lukas GM. Low-grade dermal angiosarcoma of the breast following radiotherapy. Am Surg 1996;62:668–72. 18. Autio P, Kariniemi AL. Angiosarcoma. A rare secondary malignancy after breast cancer treatment. Eur J Dermatol 1999;9:118–21. 19. Majeski J, Austin RM, Fitzgerald RH. Cutaneous angiosarcoma in an irradiated breast after breast conservation therapy for cancer: association with chronic breast lymphedema. J Surg Oncol 2000;74:208–12. 20. Cafiero EF, Gipponi M, Peressini A, et al. Radiation-associated angiosarcoma: diagnostic and therapeutic implications: two cases reports and review of the literature. Cancer 1996;77:2496–502. 21. Cancellieri A, Eusebi V, Mambellin V, et al. Well-differentiated angiosarcoma of the skin following radiotherapy. Pathol Res Pract 1991;187:301–6. 22. Givens SS, Ellerbroek NA, Butler JJ, et al. Angiosarcoma arising in an irradiated breast: a case report and review of the literature. Cancer 1989;64:2214–6. 23. Marchal C, Weber B, de Lafontan B. Nine breast angiosarcomas after conservative treatment for breast carcinoma: a survey from French comprehensive cancer centers. Int J Radiat Oncol Biol Phys 1999;44:113–9. 24. Otis CN, Peschel R, McKhann C et al. The rapid onset of cutaneous angiosarcoma after radiotherapy for breast cancer. Cancer 1986;57:2130–4. 25. Parham DM, Fisher C. Angiosarcomas of the breast developing post radiotherapy. Histopathology 1997;31:189–95. 26. Shaikh NA, Beaconsfield T, Walker M, et al. Postirradiation angiosarcoma of the breast: a case report. Eur J Surg Oncol 1988;14:449–51. 27. Richards PG, Bessell EM, Goolden AWG. Spinal extradural angiosarcoma occurring after treatment for Hodgkin’s disease. Clin Oncol 1983;9:165–8. 28. Prescott RJ, Mainwaring AR. Irradiation-induced penile angiosarcoma. Postgrad Med J 1990;66:576–9. 29. Coffin CM, Vietti TJ, Land VJ, et al. Cutaneous angiosarcoma as a second malignant neoplasm after peripheral primitive neuroectodermal tumor. Med Pediatr Oncol 1992;20:352–6. 30. Hodgkinson DJ, Soule EH, Woods JE. Cutaneous angiosarcoma of the head and neck. Cancer 1979;44:1106–13. 31. Calnan J, Cowdell RH. Lymphangioendothelioma of the anterior abdominal wall: report of a case. Br J Surg 1959;46:375–9. 32. Ambrojo P, Fernández-Cogolludo E, Aguilar A, et al. Cutaneous lymphangiectases after therapy for carcinoma of the cervix: a case with unusual clinical and histological features. Clin Exp Dermatol 1990;15:57–9. 33. Díaz-Cascajo C, Borghi S, Weyers W, Retzlaff H, Requena L, Metze D. Benign lymphangiomatous papules of the skin following radiotherapy. A report of five new cases and review of the literature. Histopathology 1999;35:319–27. 34. Fisher I, Orkin M. Acquired lymphangioma (lymphangiectasis). Arch Dermatol 1970;101:230–4. 35. Gianelli V, Rockley PF. Acquired lymphangiectases following mastectomy and radiation therapy. Report of a case and review of the literature. Cutis 1996;58:276–8. 36. Handfield-Jones SE, Prendville WJ, Norman S. Vulval lymphangiectasia. Genitourin Med 1989;65:335–7. 37. Harwood CA, Mortimer PS. Acquired vulvar lymphangiomata mimicking genital warts. Br J Dermatol 1993;129:334–6. 38. Kennedy CTC. Lymphangiectasia of the vulva following hysterectomy and radiotherapy. Br J Dermatol 1990;123(suppl. 37):92–3. 39. Kurwa A, Waddinton E. Post mastectomy lymphangiomatosis. Br J Dermatol 1968;80:840. 40. LaPolla J, Foucar E, Leshin B, et al. Vulvar lymphangioma circumscriptum: a rare complication of therapy for squamous cell carcinoma of the cervix. Gynecol Oncol 1985;22:363–6. 41. Leshin B, Whitaker D, Foucar E. Lymphangioma circumscriptum following mastectomy and radiation therapy. J Am Acad Dermatol 1986;15:1117–9. 42. Plotnick H, Richfield D. Tuberous lymphangiectatic varices secondary to radical mastectomy. Arch Dermatol Syphilol 1956;74:466–8. 43. Prioleau PG, Santa Cruz DJ. Lymphangioma circumscriptum following radical mastectomy and radiation therapy. Cancer 1978;42:1989–91.


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44. Young AW Jr, Wind RM, Tovell HM. Lymphangioma of vulva: acquired following treatment for cervical cancer. NY State J Med 1980;80:987–9. 45. Finenberg S, Rosen PP. Cutaneous angiosarcoma and atypical vascular lesions of the skin and breast after radiation therapy for breast carcinoma. Am J Clin Pathol 1994;102:757–63. 46. Rosso R, Gianelli U, Carnevali L. Acquired progressive lymphangioma of the skin following radiotherapy for breast carcinoma. J Cutan Pathol 1995;22:164–7. 47. Requena L, Kutzner H, Mentzel T, Durán R, Rodríguez-Peralto JL. Benign vascular proliferations in irradiated skin. Am J Surg Pathol 2002;26:328–37.

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9. EPITHELIOID ANGIOSARCOMA CLINICAL FEATURES This is a rare variant of the cutaneous angiosarcoma recently described (1–7). Clinically, lesions of cutaneous epithelioid angiosarcoma are indistinguishable from conventional angiosarcoma (Fig. 24). Perhaps the preferential location of these lesions on the lower extremities is the only distinctive clinical feature, although lesions on the scalp and face have also been described (1,5). Radiation exposure (3), a reaction to a foreign body (7), and chronic immunosuppression in the setting of renal transplantation (8) have been implicated as possible causes. HISTOPATHOLOGIC FEATURES Histopathologically, cutaneous epithelioid angiosarcoma mimics an epithelial neoplasm. The tumor is composed of sheets of rounded epithelioid cells with a large cytoplasm, vesicular nuclei, and prominent nucleoli (Fig. 25). Areas of irregular vascular channels lined by atypical endothelial cells that dissect the collagen bundles are not prominent, but the finding of such areas has high diagnostic value. In some areas, epithelioid cells exhibit cytoplasmic vacuoles as an expression of primitive luminal differentiation. Immunohistochemistry corroborates the vascular nature of this epithelioid neoplasm because expression of factor VIII-related antigen, Ulex europaeus I lectin, CD31, and CD34 have been documented in examples of cutaneous epithelioid angiosarcoma (1–5). However, these tumors also consistently express cytokeratins (3–6,9), attributable to the abundance of intracytoplasmic intermediate filaments in neoplastic cells, and this phenomenon may result in the misinterpretation of this type of angiosarcoma as carcinoma. Ultrastructural studies have documented a prominent cytoskeleton of intermediate filaments, numerous pinocytotic vesicles, and scarce (1,3) or no (2,5,7) Weibel-Palade bodies in neoplastic cells of cutaneous epithelioid angiosarcoma.

Fig. 24. Clinical features of epithelioid angiosarcoma. Erythematous nodules with angiomatous appearance. Fig. 25. (Opposite page) Histopathologic features of epithelioid angiosarcoma. (A) Low power shows a cellular proliferation involving the entire dermis. (B) Higher magnification demonstrates solid aggregations of neoplastic cells with some inconspicuous vascular lumina. (C) Still higher magnification demonstrates that neoplastic cells have an epithelioid appearance, and many of them exhibit prominent vacuolization of their cytoplasm as an expression of primitive luminal differentiation.


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TREATMENT Wide surgical excision of the neoplasm is necessary. Despite claims of a better prognosis for this variant of cutaneous angiosarcoma (2), these have a highly aggressive course, and most of the patients develop widespread metastatic disease within a year of presentation (3).

References 1. Perez Atayde AR, Achenbach H, Lack EE. High-grade epithelioid angiosarcoma of the scalp. An immunohistochemical and ultrastructural study. Am J Dermatopathol 1986;8:411–8. 2. Marrogi AJ, Hunt SJ, Santa Cruz DJ. Cutaneous epithelioid angiosarcoma. Am J Dermatopathol 1990;12:350–6. 3. Fletcher CDM, Beham A, Bekir S, Clarke AMT, Marley NJE. Epithelioid angiosarcoma of deep soft tissue: a distinctive tumor readily mistaken for an epithelial neoplasm. Am J Surg Pathol 1991;15:915–24. 4. Maiorana A, Fante R, Fano RA, Collina G. Epithelioid angiosarcoma of the buttock. Case report with immunohistochemical study on the expression of keratin polypeptides. Surg Pathol 1991;4:325–32. 5. Prescott RJ, Banerjee SS, Eyden BP, Haboubi NY. Cutaneous epithelioid angiosarcoma: a clinicopathological study of four cases. Histopathology 1994;25:421–9. 6. McCluggage WG, Clarke R, Toner PG. Cutaneous epithelioid angiosarcoma exhibiting cytokeratin positivity. Histopathology 1995;27:291–4. 7. Jennings TA, Peterson L, Axiotis CA, Friedlaender GE, Cooke RA, Rosai J. Angiosarcoma associated with foreign body material. Cancer 1988; 62:2436–44. 8. Wehrli BM, Janzen DL, Shokeir O, Masri BA, Byrne SK, O’Connell JX. Epithelioid angiosarcoma arising in a surgically constructed arteriovenous fistula: a rare complication of chronic immunossuppression in the setting of renal transplantation. Am J Surg Pathol 1998;22:1154–9. 9. Ng WK, Collins RJ, Law D, Gwi E. Cutaneous epithelioid angiosarcoma: a potential diagnostic trap for cytopathologists. Diagn Cytopathol 1997;16:160–6.


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10. MALIGNANT GLOMUS TUMOR (GLOMANGIOSARCOMA) Glomangiosarcomas are exceptionally rare, to the point that some authors doubt their existence. The most controversial issue is the recognition and acceptance of malignant glomus tumors in which no benign component is present. In the literature there are only a few reports of this neoplasm (1–14). The first report of a malignant variety of glomus tumor (MGT) was by Lumley and Stansfeld in 1972 (1). A year later, Anagnostou et al. (15) identified 1 MGT in a series of 20 subcutaneous glomus tumors studied. In most instances, there was no recurrence of the tumor, and the few recurrences were usually classified as locally infiltrating glomus tumors with indistinct capsular borders (4,5,7). CLINICAL FEATURES The lesions of glomangiosarcomas are larger and deeper than conventional glomus tumors, and they are predominantly located on the extremities, where they appear as subcutaneous masses. The tumors affect men and women equally (12). Metastatic disease has been documented in only 10 cases of histopathologically defined MGT, and in 8 of these patients, death was a consequence of the widespread metastases from the glomangiosarcoma (6,10,12). Locally aggressive behavior appears to be more common in these neoplasms. HISTOPATHOLOGIC FEATURES There are three proposed categories for malignant glomus tumors: (1) locally infiltrative glomus tumor—these are neoplasms that lack atypical features but show locally aggressive behavior (LIGT); (2) glomangiosarcomas that result from the transformation of a glomus tumor (GABG)—these are the most common type of MGT, and remaining areas of typical GT can be identified (Fig. 26); and (3) de novo glomangiosarcoma (GADN), the most unusual form of MGT (4). In the second group, there are sarcomatous areas intermingled with areas of benign glomus tumor. In these cases it is important to identify the benign component, as it is the most important clue to the diagnosis of glomangiosarcoma. The malignant areas appear as poorly circumscribed and infiltrative neoplasms composed of fascicles of spindle cells or aggregations of round glomoid cells with nuclear pleomorphism, frequent mitotic figures, and foci of necrosis en masse. In some neoplasms, there is a peculiar arrangement of neoplastic cells, with small round glomus cells at the periphery and central areas of spindle cells (12). A diagnosis of glomangiosarcoma should be not misconstructed in cases of long-standing glomus tumors, in which it is possible to see glomus cells with large hyperchromatic nuclei, probably as result of degenerative changes similar to those seen in ancient schwannoma. Some authors have proposed the name symplastic glomus tumor for these benign glomus tumors with nuclear atypia (12). In the absence of the benign glomus tumor component, the diagnosis of glomangiosarcoma nearly always presupposes the use of immunohistochemistry. Immunohistochemical studies in cases of glomangiosarcoma have demonstrated immunoreactivity of neoplastic cells for vimentin, collagen type IV, muscle-specific actin, and smooth muscle actin, whereas neuron-specific enolase, desmin, Leu-7, CD34, and S-100 protein positivities are detected focally in only some cases (2,12). Some neoplastic cells express caldesmon and calponin (12). Factor VIII-related antigen was negative in neoplastic cells (3). In one example of a glomangiosarcoma derived from a benign glomus tumor, immunohistochemical studies demonstrated that bcl-2, an inhibitor of apoptosis, was strongly

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Fig. 26. Malignant glomus tumor (glomangiosarcoma). (A) Low-power magnification shows a large, asymmetric neoplasm involving the entire dermis. (B) The superficial part of the neoplasm reveals vascular structures of a glomus tumor. (C) Other areas of the neoplasm demonstrate a cellular neoplasm, composed of cuboidal cells with some degree of nuclear pleomorphism. (D) At this power there are necrotic cells and an increased number of mitotic figures.

expressed in the glomangiosarcoma areas, with only weak staining in the benign areas. The proliferation index of glomangiosarcoma was almost 10-fold higher than that of the benign glomus tumor. Numerous nuclei of glomangiosarcoma were intensely stained for the tumor suppressor protein p53 (11). Ultrastructural studies (2,3) have demonstrated that neoplastic cells of glomangiosarcoma show prominent nucleoli, poorly developed organelles, and some bundles of tonofilaments. Micropinocytotic vesicles have also been identified in some cases (3). Histopathologically the differential diagnosis of glomangiosarcoma includes nodular hidradenoma, leiomyosarcoma, and hemangiopericytoma. Nodular hidradenomas are neoplasms with sweat gland differentiation that are usually well circumscribed. Leiomyosarcomas are usually poorly circumscribed, large, asymmetrical neoplasms with muscle differentiation. Hemangiopericytomas are composed of branching vessels of variable size and shape, which give the neoplasm a characteristic “staghorn” configuration. TREATMENT Complete removal by surgical excision is essential if local recurrence and eventual metastasis are to be avoided. Wide excision of the lesion has been found to be adequate therapy.

References 1. Lumley JSP, Stansfeld AG. Infiltrating glomus tumour of lower limb. BMJ 1972;1:484–5. 2. Aiba M, Hirayama A, Kuramochi S. Glomangiosarcoma in a glomus tumor. An immunohistochemical and ultrastructural study. Cancer 1988;61:1467–71. 3. Gould EW, Manivel JC, Albores-Saavedra J, Monforte H. Locally infiltrative glomus tumors and glomangiosarcomas. A clinical, ultrastructural, and immunohistochemical study. Cancer 1990;65:310–8. 4. Noer H, Krogdahl A. Glomangiosarcoma of the lower extremity. Histopathology 1991;18:365–6. 5. Watanabe K, Hoshi N, Tsu-Ura Y, et al. A case of glomangiosarcoma. Fukushima J Med Sci 1995;41: 71–7. 6. Brathwaite CD, Poppiti RJ Jr. Malignant glomus tumor. A case report of widespread metastases in a patient with multiple glomus body hamartomas. Am J Surg Pathol 1996;20:233–8.

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7. Hiruta N, Kameda N, Tokudome T, et al. Malignant glomus tumor: a case report and review of the literature. Am J Surg Pathol 1997;21:1096–103. 8. Wetherington RW, Lyle WG, Sangueza OP. Malignant glomus tumor of the thumb: a case report. J Hand Surg [Am] 1997:22:1098–102. 9. López Rios F, Rodriguez Peralto JL, Castaño E, Ballestin C. Glomangiosarcoma of the lower limb: a case report with a literature review. J Cutan Pathol 1997;24:571–4. 10. Watanabe K, Sugino T, Kusakabe T, Suzuki T. Glomangiosarcoma of the hip: report of a highly aggressive tumour with widespread distant metastases. Br J Dermatol 1998;139:1097–1101. 11. Hegyi L, Cormack GC, Grant JW. Histochemical investigation into the molecular mechanisms of malignant transformation in a benign glomus tumour. J Clin Pathol 1998;51:872–4. 12. Folpe AL, Fanburg-Smith JC, Mietinen M, Weiss SW. Atypical and malignant glomus tumors. Analysis of 52 cases, with a proposal for the reclassification of glomus tumors. Am J Surg Pathol 2001;25:1–12. 13. Rodríguez-Justo M, Aramburu-González JA, Santoja C. Glomangiosarcoma of abdominal wall. Virchows Arch 2001;438:418–20. 14. Kayal JD, Hampton RW, Sheehan DJ, Washington CV. Malignant glomus tumor: a case report and review of the literature. Dermatol Surg 2001;27:837–40. 15. Anagnostou GD, Papademetriou DG, Toumazani MN. Subcutaneous glomus tumor. Surg Gyn Obstet 1973;136:45–50.


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Chapter 10 / Other Neoplasms

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Other Cutaneous Neoplasms With a Significant Vascular Component CONTENTS MULTINUCLEATE CELL ANGIOHISTIOCYTOMA ANGIOFIBROMA ANGIOLEIOMYOMA ANGIOLIPOMA CUTANEOUS ANGIOLIPOLEIOMYOMA CUTANEOUS ANGIOMYXOMA AGGRESSIVE ANGIOMYXOMA

Table 1 summarizes the cutaneous neoplasms with a significant vascular component that are included in this section.

1. MULTINUCLEATE CELL ANGIOHISTIOCYTOMA CLINICAL FEATURES Multinucleate cell angiohistiocytoma was first described by Smith and Wilson Jones in 1985 (1). To our knowledge, 44 examples of this lesion have been reported in the literature (1–18). The lesions develop more frequently in women than in men (ratio, 36:8). The age range of these patients was 24 to 75, with a mean of 56 years. The lesions were most often located on the limbs, especially on the dorsal parts of the hands or wrists (13 cases) and the thighs (4 cases), although lesions on the face (2–4,6,8) and chest (3) have also been described. Bilateral lesions occurred in some patients (3), and a 24-yearold man presented with generalized multinucleate cell angiohistiocytoma, with multiple papules on the trunk and extremities (11).

Table 1 Cutaneous Neoplasms with a Significant Vascular Component Multinucleate cell angiohistiocytoma Angiofibroma Angioleiomyoma Angiolipoma Cutaneous angiolipoleiomyoma Cutaneous angiomyxoma Aggressive angiomyxoma

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Fig. 1. Clinical appearance of multinucleate cell angiohistiocytoma. Multiple small papules with an angiomatous appearance on the anterior thigh of an adult woman.

Clinically, multinucleate cell angiohistiocytoma is characterized by multiple domeshaped papules, from 2 to 15 mm in diameter and of an erythematous or violaceous color (Fig. 1). The lesions appear grouped on an anatomic area, are usually asymptomatic, and show slow progression over years without associated disease. One patient had a multinucleate cell angiohistiocytoma that appeared clinically as a large cutaneous plaque (15), and another patient with multinucleate cell angiohistiocytoma also had mycosis fungoides (16). HISTOPATHOLOGIC FEATURES Histopathologically, multinucleate cell angiohistiocytoma consists of a proliferation of capillaries and venules involving the full thickness of the dermis. These vessels exhibit round lumina surrounded by a sparse inflammatory infiltrate composed mainly of lymphocytes and plasma cells (5). Characteristically, there are multinucleated cells with geometric shapes and scalloped or angulated cytoplasm sparsely scattered throughout the lesion (Fig. 2). The collagen bundles tend to be slightly coarse and are arranged haphazardly or vaguely parallel to the skin surface. The overlying epidermis is often hyperplastic(2,3). Immunohistochemical studies have demonstrated that cells lining the vascular component of the lesion are clearly labeled with endothelial markers including factor VIII-related antigen (2–4,9), PAL-E (2,4), EN4 (2), BMA120 (2–4), and Ulex europaeus I lectin (3,4), whereas the mononuclear interstitial cells were positive for factor XIIIa (3,4,9,12), lisozyme (3), and α1-antitrypsin (3) but were negative for MAC387 (3) and S-100 protein (3). The multinucleated giant cells only labeled positively with vimentin (3) . The lymphocytes present interstitially were predominantly T-lymphocytes (2–4,9). Investigations for human herpesvirus-8 (HHV-8) in lesions of mutinucleate cell angiohistiocytoma yielded negative results (18). Ultrastructural studies have shown that the multinucleated cells of multinucleate cell angiohistiocytoma exhibit characteristics of cells in transitional stages between activated fibroblasts and fully developed multinucleated giant cells (2). The main differential diagnosis of multinucleate cell angiohistiocytoma is with dermatofibroma. Even though some authors believe that these are different entities (5), on the basis of the clinical, histopathologic, immunohistochemical and ultrastructural char-


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Fig. 2. (A) Low power shows a combination of dilated vascular spaces, mild fibrosis, and slight hyperplasia of the epidermis. (B) At higher magnification, there are dilated vascular spaces and multinucleated fibrocytes.

acteristics of multinucleate cell angiohistiocytoma, it is considered a histopathologic variant of dermatofibroma with a prominent vascular component and peculiar multinucleated cells. Furthermore, we have seen examples of stereotypical dermatofibroma that showed focally histopathologic features of multinucleate cell angiohistiocytoma. TREATMENT Multinucleate cell angiohistiocytoma is an entirely benign condition, and cases of spontaneous regression of the lesions have been described (3,5). In some patients, multiple lesions were successfully treated with argon laser (7).

References 1. Smith NP, Wilson Jones E. Multinucleate cell angiohistiocytoma—a new entity [Abstract]. Br J Dermatol 1985;113(suppl 29):15. 2. Smolle J, Auboeck L, Gogg-Retzer I, Soyer HP, Kerl H. Multinucleate cell angiohistiocytoma: a clinicopathological, immunohistochemical and ultrastructural study. Br J Dermatol 1989;121:113–21.

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3. Wilson Jones E, Cerio R, Smith NP. Multinucleate cell angiohistiocytoma: an acquired vascular anomaly to be distinguished from Kaposi’s sarcoma. Br J Dermatol 1990;122:651–3. 4. Annesi G, Girolomo G, Gianetti A. Multinucleate cell angiohistiocytoma. Am J Dermatopathol 1992;14:340–4. 5. Shapiro PE, Nova MP, Rosmarin LA, Halperin AJ. Multinucleate cell angiohistiocytoma: a distinct entity diagnosable by clinical and histologic features. J Am Acad Dermatol 1994;30:417–22. 6. Jones AC, Mullins D, Jimenez F. Multinucleate cell angiohistiocytoma of the upper lip. Oral Surg Oral Med Oral Pathol 1994;78:743–7. 7. Kopera D, Smolle J, Kerl H. Multinucleate cell angiohistiocytoma: treatment with argon laser. Br J Dermatol 1995;133:308–10. 8. Shields JA, Eagle RC Jr, Shields CL, Sohmer KK. Multinucleate cell angiohistiocytoma of the orbit. Am J Ophthalmol 1995;120:402–3. 9. Cribier B, Gambini C, Rainero M, Grosshans E. Multinucleate cell angiohistiocytoma. A review and report of four cases. Acta Derm Venereol 1995;75:337–9. 10. Duncan LM, Baden HP. Vascular papules on the dorsum of the hands. Multinucleate cell angiohistiocytoma (MCAH). Arch Dermatol 1996;132:703. 11. Chang SN, Kim HS, Kim SC, Yang WI. Generalized multinucleate cell angiohistiocytoma. J Am Acad Dermatol 1996;35:320–2. 12. Le Cam-Savin C, Dallot A, Chemaly P, Martin A, Choudat L, Amoroux J. Angiohistiocytome à cellules multinuclées. A propos de six cas. Ann Pathol 1996;16:435–8. 13. Romiti R, Perniciaro C, White JW Jr. Multinucleate cell angiohistiocytoma. Cutis 1997;59:190–2. 14. Aloi F, Solaroli C, Tomasini C, Pippione M. Multinucleate cell angiohistiocytoma: a report of two cases. J Eur Acad Dermatol Venereol 1998;11:51–4. 15. Issa AA, Lui H, Shapiro J, Trotter MJ. Plaque-type multinucleate cell angiohistiocytoma. J Cutan Med Surg 1998;3:112–4. 16. Bader RS, Telang GH, Vonderheid EC. Multinucleate-cell angiohistiocytoma occurring in a patient with mycosis fungoides. Cutis 1999;63:145–8. 17. Belgodere X, Wechsler J, Pasqualini G, Paoli M. Angiohistiocytome à cellules multinuclées. Ann Dermatol Venereol 1999;126:431–2. 18. Sass U, Noel JC, Andre J, Simonart T. Multinucleate cell angiohistiocytoma: report of two cases with no evidence of human herpesvirus-8 infection. J Cutan Pathol 2000;27:258–61.


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2. ANGIOFIBROMA CLINICAL FEATURES Angiofibroma is considered by some authors to be a generic term encompassing lesions described as fibrous papules of the nose, facial lesions of tuberous sclerosis, pearly penile papules, oral fibromas, and perifollicular fibromas (1) . However, other authors believe that at least some of these entities have enough distinguishing histopathologic features to be considered distinct lesions (2–5). Still others believe there is an angiofibromatous reactive pattern that is common to the lesions described under the names of facial lesions of tuberous sclerosis, subungual and periungual fibromas, acquired acral fibrokeratomas, fibrous papules of the nose, and pearly penile papules (6). The angiofibromas of the face seen in patients with tuberous sclerosis consist of several papules and nodules with a predilection for the butterfly area of the face and nasolabial grooves (7) (Fig. 3). They develop in childhood and in many cases are the presenting sign of the disease (8). Cases with unilateral agminated facial angiofibromas have been considered as forme fruste or segmental expression of tuberous sclerosis (9,10). Patients with tuberous sclerosis may also have angiofibromas in the genital region (11). However, multiple angiofibromas are not exclusive to tuberous sclerosis and have also been described in patients with neurofibromatosis type 2 (12) and in patients with

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Fig. 3. Multiple facial angiofibromas in a patient with tuberous sclerosis.


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Fig. 4. Clinical appearance of a solitary angiofibroma. Small, dome-shaped papule close to the nose.

multiple endocrine neoplasia type 1 (MEN-1). This consists of a heritable tendency to develop tumors of parathyroid, pituitary, and entero-pancreatic endocrine tissues and results from a germline mutation in the MEN-1 gene (13–17). Solitary giant facial angiofibroma can be seen in patients without any associated disease (18). Fibrous papule of the nose is a fairly common lesion that occurs in adults nearly always as a solitary lesion on the lower portion of the nose or on the adjacent skin of the face (1–5). It is usually dome-shaped, firm, and small, not exceeding 5 mm in diameter (Fig. 4). In most cases, it is skin-colored and clinically can be confused with a melanocytic nevus or a basal cell carcinoma. Acral fibrokeratomas include lesions reported as acquired digital fibrokeratomas (19–22), acquired periungual fibrokeratomas (23), and periungual fibromas (Köenen tumors) of tuberous sclerosis (24). Pearly penile papules are persistent asymptomatic, white papules, 1–3 mm in diameter, occurring circumferentially on the coronal margin and sulcus of the penis (25,26). They are found in about 10% of young adult males and are more common in the uncircumcised (25). HISTOPATHOLOGIC FEATURES Histopathologically, all these lesions share several features and have been thought by some authors to represent hyperplasias of the papillary and adventitial dermis (27). The common characteristic pattern of all these lesions consists of an increased number of small blood vessels associated with perivascular and periadnexal fibrosis arranged con-


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Fig. 5. Histopathologic features of angiofibroma. (A) Scanning power shows a well-circumscribed and exophytic lesion. (B) Dilated vascular structures are one of the main components of the lesion. Distorted hair follicles, such as those seen in this particular case, are also frequent findings. (C) Large bizarre fibroblasts, some of them multinucleated, are present in the stroma of the lesion.

centrically in an onion skin-like fashion (6) (Fig. 5). The fibrous tissue usually contains stellate fibroblasts, some of them multinucleated. Some of the features have been proposed to be characteristic for the different lesions. Thus, bizarre cells in the dermis and melanocytic hyperplasia at the dermoepidermal junction are seen more commonly in fibrous papule of the nose; compact hyperkeratosis and vertical arrangement of thick

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collagen bundles in acral fibrokeratomas and an absence of folliculosebaceous units in pearly penile papules. Uncommon histopathologic variants of fibrous papule of the face include fibrous papule with granular cells (28) and clear cell fibrous papule (29). Immunohistochemical studies have shown that the large stellate fibroblastic cells that characterize these lesions express factor XIIIa but not S-100 protein (30–34). α1-antitrypsin and lysozyme were detected in one study (35). Factor XIIIa appears to be important in the promulgation of the fibroplasias (30). Ultrastructural studies have suggested that the stellate cells are fibroblastic or fibrohistiocytic (5,36,37). TREATMENT Cutaneous angiofibromas are entirely benign lesions and may be removed by shave excision and dermabrasion (38,39). Excellent cosmetic results have been reported in facial angiofibromas of tuberous sclerosis managed with laser therapy (40–43).

References 1. Maigel WN, Ackerman AB. Fibrous papule of the face. Am J Dermatopathol 1979;1:329–40. 2. Pinkus H. Perifollicular fibromas. Pure periadnexal adventitial tumors. Am J Dermatopathol 1979;1:341–2. 3. Reed R. Fibrous papule of the face. Melanocytic angiofibroma. Am J Dermatopathol 1979;1:343–4. 4. McGibbon DH, Wilson Jones E. Fibrous papule of the face (nose). Fibrosing nevocytic nevus. Am J Dermatopathol 1979;1:345–8. 5. Santa Cruz DJ, Prioleau PG. Fibrous papule of the face. An electron microscopic study of two cases. Am J Dermatopathol 1979;1:349–52. 6. Weedon D. In: Symmers WSC, ed. The Skin. Edinburgh, Churchill Livingstone, 1992:25. 7. Sanchez NP, Wick MR, Perry HO. Adenoma sebaceum of Pringle: a clinicopathologic review, with a discussion of related pathologic entities. J Cutan Pathol 1981;8:395–403. 8. Nickel WR, Reed WB. Tuberous sclerosis: special reference to the microscopic alterations in the cutaneous hamartomas. Arch Dermatol 1962;85:209–24. 9. Anliker MD, Dummer R, Burg G. Unilateral agminated angiofibromas: a segmental expression of tuberous sclerosis. Dermatology 1997;195:176–8. 10. Garcia Muret MP, Pujol RM, de Moragas JM. Angiofibromes multiples et unilateraux de la face: forme fruste de la sclerose tubereuse de Bourneville. Ann Dermatol Venereol 1998;125:325–7. 11. Nico MM, Ito LM, Valente NY. Genital angiofibromas in tuberous sclerosis: two cases. J Dermatol 1999;26:111–4. 12. Jaffe AT, Heyman WR, Schnur RE. Clustered angiofibromas on the ear of a patient with neurofibromatosis type 2. Arch Dermatol 1998;134:760–1. 13. Darling TN, Skarulis MC, Steinberg SM, Marx SJ, Spiegel AM, Turner M. Multiple facial angiofibromas and collagenomas in patients with multiple endocrine neoplasia type 1. Arch Dermatol 1997;133:853–7. 14. Pack S, Turner ML, Zhuang Z, et al. Cutaneous tumors in patients with multiple endocrine neoplasia type 1 show allelic deletion of the MEN1 gene. J Invest Dermatol 1998;110:438–40. 15. Boni R, Vortmeyer AO, Pack S, et al. Somatic mutations of the MEN1 tumor suppressor gene detected in sporadic angiofibromas. J Invest Dermatol 1998;110:539–40. 16. Hoang-Xuan T, Steger JW. Adult-onset angiofibroma and multiple endocrine neoplasia type I. J Am Acad Dermatol 1999;41:890–2. 17. Sakurai A, Matsumoto K, Ikeo Y, et al. Frequency of facial angiofibromas in Japanese patients with multiple endocrine neoplasia type 1. Endocr J 2000;47:569–73. 18. Stough DB, Metheny R. Giant angiofibroma without accompanying tuberous sclerosis. Cutis 1988;42:429–32. 19. Kint A, Baran R, De Keyser H. Acquired (digital) fibrokeratoma. J Am Acad Dermatol 1985;12:816–21. 20. Herman PS, Datnow B. Acquired (digital) fibrokeratomas. Acta Derm Venereol 1974;54:73–6. 21. Bart RS, Andrade R, Kopf AW, Leider M. Acquired digital fibrokeratomas. Arch Dermatol 1968;97:120–9. 22. Hare PJ, Smith PAJ. Acquired (digital) fibrokeratoma. Br J Dermatol 1969;81:667–70. 23. Cahn RL. Acquired periungual fibrokeratoma. Arch Dermatol 1977;113:1564–8.


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24. Kint A, Baran R. Histopathologic study of Koenen tumors. Are they different from acquired digital fibrokeratoma? J Am Acad Dermatol 1988;18:369–72. 25. Glicksman JM, Freeman RG. Pearly penile papules. A statistical study of incidence. Arch Dermatol 1966;93:56–59. 26. Ackerman AB, Kornberg R. Pearly penile papules. Acral angiofibromas. Arch Dermatol 1973;108:673–5. 27. Reed RJ, Ackerman AB. Pathology of the adventitial dermis. Anatomic observations and biologic speculations. Hum Pathol 1973;4:207–17. 28. Guitart J, Bergfeld WF, Tuthill RJ. Fibrous papule of the nose with granular cells: two cases. J Cutan Pathol 1991;18:284–7. 29. Soyer HP, Kutzner H, Metze D, Cerroni L, Kerl H, Ackerman AB. Fibrous papule with clear fibrocytes. Dermatopathol Pract Concept 1997;3:110–3. 30. Penneys NS. Factor XIII expression in the skin. Observations and a hypothesis. J Am Acad Dermatol 1990;22:484–8. 31. Cerio R, Rao BK, Spaull J, Wilson Jones E. An immunohistochemical study of fibrous papule of the nose: 25 cases. J Cutan Pathol 1989;16:194–8. 32. Cerio R, Wilson Jones E. Factor XIIIa postivity in fibrous papule. J Am Acad Dermatol 1990;22:138–9. 33. Spiegel J, Nadji M, Penneys NS. Fibrous papule: an immunohistochemical study with antibody to S-100 protein. J Am Acad Dermatol 1983;9:360–2. 34. Rosen LB, Suster S. Fibrous papule. A light microscopic and immunohistochemical study. Am J Dermatopathol 1988;10:109–15. 35. Kwan TH, Smoller BR, Schneider DR. Alfa 1-antitrypsin and lisozyme in fibrous papule and angiofibromas. J Am Acad Dermatol 1985;12:99–101. 36. Ragaz A, Berezowsky V. Fibrous papules of the face. A study of five cases by electron microscopy. Am J Dermatopathol 1979;1:353–5. 37. Bhawam J, Edelstein L. Angiofibromas in tuberous sclerosis: a light and electron microscopic study. J Cutan Pathol 1977;4:300–7. 38. Drake DB, Morgan RF, Cooper PH. Shave excision and dermabrasion for facial angiofibroma in tuberous sclerosis. Ann Plast Surg 1992;28:377–80. 39. Verhayden CN. Treatment of the facial angiofibromas of tuberous sclerosis. Plast Reconstr Surg 1996;98:777–83. 40. Hoffman SJ, Walsh P, Morelli JG. Treatment of angiofibroma with the pulsed tunable dye laser. J Am Acad Dermatol 1993;29:790–1. 41. Boixeda P, Sanchez-Miralles E, Azaña JM, Arrazola JM, Moreno R, Ledo A. CO2, argon, and pulsed dye laser treatment of angiofibromas. J Dermatol Surg Oncol 1994;20:808–12. 42. Kaufman AJ, Grekin RC, Geisse JK, Frieden IJ. Treatment of adenoma sebaceum with the Cooper vapor laser. J Am Acad Dermatol 1995;33:77–4. 43. Tope WD, Kageyama N. “Hot” KTP-laser treatment of facial angiofibromas. Lasers Surg Med 2001;29:78–81.

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3. ANGIOLEIOMYOMA CLINICAL FEATURES Angioleiomyoma is a benign neoplasm that arises from the smooth muscle of a vein wall. It does not have a distinctive clinical appearance, but pain and tenderness may be clinical symptoms suggestive of the angioleiomyomatous nature of a subcutaneous nodule. However, not all angioleiomyomas are painful (1), and pain can also be a presenting symptom of other cutaneous neoplasms, such as glomus tumors, spiradenomas, angiolipomas, or neuromas. The mechanism of pain in angioleiomyoma is uncertain. Some immunohistochemical studies have postulated a relationship of the pain to nerve fibers, especially those located within the tumor parenchyma (2). A lower mast cell density has been described in painful angioleiomyomas compared with painless lesions, and this finding may reflect increased mast cell degranulation (3). Clinically, angioleiomyoma appears as a subcutaneous nodule of firm consistency. The neoplasms most frequently appear on the extremities, especially the legs (4,5), although lesions on the face, trunk, oral cavity, hand, and nail bed (Fig. 6) have also been reported (6–10). HISTOPATHOLOGIC FEATURES Histopathologically, angioleiomyomas are well-circumscribed dermal nodules surrounded by connective tissue and separated from it by clefts (Fig. 7) Within the nodule, variable-sized veins with muscular walls can be identified, and smooth muscle bundles extend tangentially from the periphery of the vessels. The lumina of the veins is rounded or slit-like. As a rule, angioleiomyomas contain only a small amount of collagen. Areas of mucinous degeneration have been described, especially in large angioleiomyomas (11). The cases described as pleomorphic angioleiomyoma showed pleomorphic cells with atypical nuclei but without mitotic figures and probably correspond to long-standing angioleiomyomas with degenerative changes similar to those seen in ancient schwannoma (12,13). Similar lesions have been described as symplastic hemangiomas (14).There are

Fig. 6. Clinical features of angioleiomyoma. A dome-shaped nodule on the toe tip. Fig. 7. (Opposite page) Histopathologic features of angioleiomyoma. (A) Scanning power shows a well-circumscribed nodule in the deep dermis. (B) Higher magnification demonstrates that the lesion is composed of fascicles of smooth muscle bundles. (C) Still higher magnification shows cells with spindle nuclei, which have blunt ends and are cigar shape.


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reported cases of angioleiomyomas having arisen within a dermatofibroma (15) and lymphocytic nodules, with germinal center formation, scattered in a large angioleiomyoma. Uncommon histopathologic variants of cutaneous angioleiomyoma include epithelioid angioleiomyoma, in which an angioleiomyoma is composed of neoplastic cells with abundant cytoplasm (16); palisaded angioleiomyoma with prominent Verocay body formation (17); and intravascular angioleiomyoma, which consists of an angioleiomyoma that has developed within the lumen of a blood vessel (18). Immunohistochemically, angioleiomyoma expresses positivity for muscle-specific actin, α-smooth muscle actin, desmin, and collagen type IV (2,15,19). Low-weight cytokeratin reactivity may be seen in scattered cells of angioleimyoma (12). Ultrastructural studies in angioleiomyomas have demonstrated that they are composed of normal-appearing smooth muscle cells (20,21). TREATMENT Angioleiomyoma is a benign neoplasm. The report describing a cutaneous leiomyosarcoma with coexistent superficial angioleiomyoma is the rare exception to the rule (22). Simple surgical excision of angioleiomyoma cures the pain caused by this neoplasm.

References 1. Montgomery H, Winkelmann RK. Smooth-muscle tumors of the skin. Arch Dermatol 1959;79:32–41. 2. Hasegawa T, Seki K, Yang P, Hirose T, Hizawa K. Mechanism of pain and cytoskeletal properties in angioleiomyomas: an immunohistochemical study. Pathol Int 1994;44:66–72. 3. Geddy PM, Gray S, Reid WA. Mast cell density and PGP 9.5-immunostained nerves in angioleiomyoma: their relationship to painful symptoms. Histopathology 1993;22:387–90. 4. Duhig JT, Ayer JP. Vascular leiomyoma. Arch Pathol 1959;68:424–30. 5. Bardach H, Ebner H. Das Angioleiomyom der Haut. Hautarzt 1975;26:638–42 6. Hachisuga T, Hashimoto T, Enjoji M. Angioleiomyoma: a clinical reapprasial of 562 cases. Cancer 1984;54:126–30. 7. Reichart P, Reznik-Schuller H. The ultrastructure of an oral angiomyoma. J Oral Pathol 1977;6:25–34. 8. Requena L, Baran R. Digital angioleiomyoma: An uncommon neoplasm. J Am Acad Dermatol 1993;29:1043–4. 9. Lawson GM, Salter DM, Hooper G. Angioleiomyomas of the hand. Report of 14 cases. J Hand Surg [Br] 1995;20:479–83. 10. Baran R, Requena L, Drape JL. Subungueal angioleiomyoma masquerading as a glomus tumor. Br J Dermatol 2000;142:1239–41. 11. MacDonald DM, Sanderson KV. Angioleiomyoma of the skin. Br J Dermatol 1974;91:161–8. 12. Martínez JA, Quecedo E, Fortea JM, Oliver V, Aliaga A. Pleomorphic angioleiomyoma. Am J Dermatopathol 1996;19:409–12. 13. Kawagishi N, Kashiwagi T, Ibe M, Manabe A, Ishida-Yamamoto A, Hashimoto Y, Iizuka H. Pleomorphic angioleiomyoma. Am J Dermatopathol 2000;22:268–71. 14. Kutzner H, Winzer M, Mentzel T. Symplastisches Hemangiom. Hautarzt 2000;51:327–31. 15. Requena L, Ortiz S, Sanchez M, Sanchez Yus E. Angioleiomyoma within a histiocytoma. J Cutan Pathol 1990;17:278–80. 16. Heffernan MP, Smoller BR, Kohler S. Cutaneous epithelioid angioleiomyoma. Am J Dermatopathol 1998;20:213–7. 17. Baugh W, Quigley MM, Barret TL. Palisaded angioleiomyoma. J Cutan Pathol 2000;27:526–8. 18. Sajben FP, Barnette DJ, Barret TL. Intravascular angioleiomyoma. J Cutan Pathol 1999;26:165–7. 19. Requena L, Kutzner H, Hugel H, Rutten A, Furio V. Cutaneous adult myofibroma. A vascular neoplasm. J Cutan Pathol 1996;23:445–57. 20. Seymour AE, Henderson DW. Electron microscopy in surgical pathology. A selective review. Pathology 1981;13:111–35. 21. Seifert HW. Ultrastructural investigation on cutaneous angioleiomyoma. Arch Dermatol 1981;117:91–9. 22. White IR, MacDonald DM. Cutaneous leiomyosarcoma with coexistent superficial angioleiomyoma. Clin Exp Dermatol 1981;6:333–7.


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4. ANGIOLIPOMA CLINICAL FEATURES Angiolipomas occur as subcutaneous lesions (Fig. 8), most often multiple, that arise in young adults. They may be located in any part of the body, but the forearm is the most common location. Characteristically, angiolipomas are tender or painful on touch or palpation (1). Clinically they resemble lipomas, although they have a greater tendency to be multiple, and a hereditary occurrence has been described (2). Multiple angiolipomas have been described associated with ordinary lipomas and parathyroid adenomas in a patient with Birt-Hogg-Dube syndrome (3), and another patient had an angiolipoma within a giant congenital melanocytic nevus (4). HISTOPATHOLOGIC FEATURES Histopathologically, angiolipomas consist of subcutaneous nodules, usually well circumscribed and composed of mature adipose tissue and varying numbers of blood vessels (Fig. 9). The proportion of fatty tissue and vascular channels varies from lesion to lesion, but the vascularity tends to be more prominent in the subcapsular areas. Dilated capillaries engorged with erythrocytes make up the angiomatous component. Characteristically, many of these capillaries contain fibrin thrombi. Dixon et al. (5) demonstrated fluorescein-labeled antihuman fibrinogen in the thrombi and, to a lesser degree, in the surrounding endothelial cells. In one report, hemorrhagic infarction of the fat and myocardial infarction were present in association with numerous fibrin thrombi and disseminated intravascular coagulation (6). Large myelinated nerves have been found in the surrounding connective tissue of angiolipomas and may be responsible for the pain of the lesions (2). Increased numbers of mast cells have been demonstrated in angiolipomas compared with ordinary lipomas, which is probably related to the maturation of blood vessels in these neoplasms (7). Ultrastructural studies in angiolipoma have shown mature fat cells interspersed with blood vessels lined by endothelial cells. Interestingly, Weibel-Palade bodies were sparse in these endothelial cells (5).

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Fig. 8. Clinical features of angiolipoma. A subcutaneous and tender nodule.


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Fig. 9. Histopathologic features of angiolipoma. (A) Scanning power showing a well-circumscribed nodule with a fatty appearance. (B) Higher magnification shows that there is also an angiomatous component. (C) The angiomatous component is made up of dilated capillaries containing erythrocytes.

In rare instances, lesions similar to angiolipoma but containing intense cellularity have been described as cellular angiolipomas (8,9). The lesions described as infiltrating angiolipomas or subcutaneous angiolipomas extending to the underlying skeletal muscle are probably better interpreted as intramuscular hemangiomas (10–12). Cytogenetic studies of angiolipomas have demonstrated a normal karyotype, a finding in striking contrast to ordinary lipomas, spindle cell and pleomorphic lipomas,


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lipoblastomas, and hibernomas, most of which have characteristic clonal chromosomal aberrations (13). TREATMENT If required, a simple excision cures the lesion. Multiple angiolipomas have been successfully treated by liposuction surgery (14).

References 1. Howard WR, Helwig EB. Angiolipoma. Arch Dermatol 1960;82:924–31. 2. Belcher RW, Czarnetzki BM, Carney JF, et al. Multiple (subcutaneous) angiolipomas: clinical, pathological and pharmacologic studies. Arch Dermatol 1974;110:583–5. 3. Chung JY, Ramos-Caro FA, Baers B, Ford MJ, Flowers F. Multiple lipomas, angiolipomas, and parathyroid adenomas in a patient with Birt-Hogg-Dube syndrome. Int J Dermatol 1996;35:365–7. 4. Won JH, Ahn SK, Lee SH, Kim SC, Choi SI. Congenital giant pigmented nevus associated with angiolipoma. J Dermatol 1993;20:381–3. 5. Dixon AY, McGregor DH, Lee SH. Angiolipomas: an ultrastructural and clinicopathological study. Hum Pathol 1981;12:737–47. 6. Rustin GJS. Diffuse intravascular coagulation in association with myocardical infarction and multiple angiolipomas. Postgrd Med 1977;53:228–9. 7. Shea CR, Prieto VG. Mast cells in angiolipomas and hemangiomas of human skin: are they important for angiogenesis? J Cutan Pathol 1994;21:247–51. 8. Hunt SJ, Santa Cruz DJ, Barr RJ. Cellular angiolipoma. Am J Surg Pathol 1990;14:75–81. 9. Kanik AB, Oh CH, Bhawan J. Cellular angiolipoma. Am J Dermatopathol 1995;17:312–5. 10. Dionne GP, Seemayer TA. Infiltrating lipomas and angiolipomas revisited. Cancer 1974;33:732–8. 11. Lin JJ, Lin F. Two entities in angiolipoma. Cancer 1974;34:720–7. 12. Puig L, Moreno A, de Moragas JM. Infiltrating angiolipoma: report of two cases and review of the literature. J Dermatol Surg Oncol 1986;12:617–9. 13. Sciot R, Akerman M, Dal Clin P, et al. Cytogenetic analysis of subcutaneous angiolipoma: further evidence supporting its difference from ordinary pure lipomas: a report of the CHAMP Study Group. Am J Surg Pathol 1997;21:441–4. 14. Kaneko T, Tokushige H, Kimura N, Moriya S, Toda K. The treatment of multiple angiolipomas by liposuction surgery. J Dermatol Surg Oncol 1994;20:690–2.

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5. CUTANEOUS ANGIOLIPOLEIOMYOMA CLINICAL FEATURES Angiomyolipoma (1–6) and angiolipoleiomyoma (7) are the terms given to an uncommon benign neoplasm consisting of a proliferation of blood vessels, smooth muscle bundles, and fat tissue. To our knowledge, only 15 cases of cutaneous angiolipoleiomyoma have been described in the literature (1–8). Clinically, the lesions appear late in life, the age range of the patients being from 33 to 77 years (mean, 54 years). The lesion seems to be more frequent in men than in women (ratio, 13:2). The acral skin of the ears, fingers (Fig. 10), and toes is the most common location. Angiomyolipoma may also appear in the nasal cavity (9). The clinical impression is either cyst or lipoma, and in none of the reported cases was there a history of tuberous sclerosis. HISTOPATHOLOGIC FEATURES Histopathologically, cutaneous angiolipoleiomyoma appears as a well-circumscribed pseudoencapsulated nodule located in deeper reticular dermis or subcutaneous fat (Fig. 11). Most of the lesions are easily “shelled-out,” and the specimen usually includes no epidermis. The tumors consist of three main components: vascular spaces, smooth muscle bundles, and adipose tissue. The proportion of the three components varies from lesion to lesion. The vascular spaces appear as thin-walled blood vessels, but there are also vessels with a thick muscular coat. The smooth muscle is arranged in interlacing fascicles in the stroma and around many vascular spaces, as is seen in angioleiomyomas. The lipomatous component consists of lobulated masses of mature fat tissue separated by thin strands of collagen bundles. As a rule, no cytologic atypia or mitotic figures are noted, although a single case showing nuclear pleomorphism and hyperchromatism in the smooth muscle component has been reported (4). Immunohistochemically, the endothelial cells lining the vascular spaces express factor VIII-related antigen and Ulex europaeus I lectin (2,3,5) but are negative for myoglobin (2). S-100 protein failed to identify neural elements within the lesion (2,3). In contrast to renal angiomyolipoma, cutaneous angiomyolipoma does not express immunoreactivity for HMB-45 (5,8). Electron microscopic studies have been performed in a single case (2). The vessel walls of that case were lined by cells with the ultrastructural characteristics of endothelial cells, including WeibelPalade bodies. Beneath the endothelial cells, there was a proliferation of smooth muscle

Fig. 10. Clinically cutaneous angiolipoleiomyoma presents as a well-circumscribed nodule like this example of a nodule of the on the tip of the thumb.


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Fig. 11. Histopathologic features of angiolipoleiomyoma. (A) Scanning power showing a wellcircumscribed lesion. (B) Mature adipose tissue, blood vessels, and smooth muscle bundles are the three components of the lesion. (C) Higher magnification shows fascicles of spindled smooth muscle cells.

cells containing myofilaments, dense bodies, and pinocytotic vesicles. The adipocytes showed no abnormal ultrastructural features. TREATMENT Local excision is enough treatment for cutaneous angiolipoleiomyoma.

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References 1. Argenyi ZB, Piette WW, Goeken J. Cutaneous angiomyolipoma: a light microscopic, immunohistochemical, and electron microscopic study [Abstract]. J Cutan Pathol 1986;13:434. 2. Argenyi ZB, Piette WW, Goeken JA. Cutaneous angiomyolipoma: a light microscopic, immunohistochemical, and electron-microscopic study. Am J Dermatopathol 1991;13:497–502. 3. Mehregan DA, Mehregan DR, Mehregan AH. Angiomyolipoma. J Am Acad Dermatol 1992;27:331–3. 4. Rodriguez Fernandez A, Caro Mancilla A. Cutaneous angiomyolipoma with pleomorphic changes. J Am Acad Dermatol 1993;29:115–6. 5. Val-Bernal FJ, Mira C. Cutaneous angiomyolipoma. J Cutan Pathol 1996;23:364–8. 6. Ortiz Rey JA, Valbuena Ruvira L, Bouso Montero M, Sacristan Lista F. Angiomiolipoma cutáneo. Patología 1996;29:115–8. 7. Fitzpatrick JE, Mellette JR, Hwang RJ, Golitz LE, Zaim T, Clemous D. Cutaneous angiolipoleiomyoma. J Am Acad Dermatol 1990;23:1093–8. 8. Buyukbabani N, Tetikkurt S, Ozturk AS. Cutaneous angiomyolipoma: report of two cases with emphasis on HMB-45 utility. J Eur Acad Dermatol Venereol 1998;11:151–4. 9. Watanabe K, Suzuki T. Mucocutaneous angiomyolipoma. A report of 2 cases arising in the nasal cavity. Arch Pathol Lab Med 1999;123:789–92.


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6. CUTANEOUS ANGIOMYXOMA CLINICAL FEATURES Cutaneous myxomas have been firmly established in recent years, especially when they are present as part of Carney’s complex. This is an autosomal dominant complex consisting of endocrine hyperactivity (Cushing’s syndrome, testicular tumors, and acromegaly), spotty pigmentation, psammomatous melanotic schwannoma, and multiple myxomas (cutaneous, cardiac, and mammary) (1–5). A patient with multiple cutaneous myxomas and other anomalies of Carney’s complex progressed to scleromyxedema (6). Multiple cutaneous myxomas, however, have also been described without other elements of Carney’s complex (7,8). Solitary myxomas are not related to Carney’s complex and may appear as cutaneous or subcutaneous nodules, especially in acral sites (9–11). When there is a prominent vascular component, the lesion is designated angiomyxoma (9–11). Clinically, cutaneous angiomyxomas appear as slow-growing nodules that have been present for several years before excision (Fig. 12). Some solitary angiomyxomas appear as congenital lesions (12), and, in rare instances, solitary cutaneous angiomyxoma may be large (13). HISTOPATHOLOGIC FEATURES Histopathologically, the lesions are fairly well-circumscribed, multilobulated nodules, with abundant blood vessels, especially at the periphery and delicate septa of collagen bundles extending into the lesion (14). Individual nodules appear as sparsely cellular with abundant mucinous material (Fig. 13). Stellate and spindle-shaped stromal cells are scattered throughout the myxoid material. Cytologic atypia is mild at most, and mitotic figures are rare. Sometimes dilated thin-walled blood vessels filled by erythrocytes are scattered within the mucoid material, imparting an angiomatous appearance to the lesion. Often, hyperplastic epithelia from entrapped adnexa, in the form of small epidermoid cysts, thin strands of squamous epithelium, and small buds of basaloid cells, are seen embedded in the lesion (14). A mixed inflammatory infiltrate is common, particularly

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Fig. 12. Clinical features of cutaneous angiomyxoma. A subcutaneous nodule on the dorsum of the toe.


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Fig. 13. Histopathologic features of cutaneous angiomyxoma. (A) Low power shows an exophytic lesion. The dermis exhibits a myxoid appearance. (B) Thin, spindle-shaped cells and capillaries embedded in a myxoid stroma. (C) These spindle-shaped cells show no nuclear atypia.


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stromal neutrophils, a feature unique to this neoplasm compared with other cutaneous myxoid lesions (14). Immunohistochemical studies have shown that the cellular component of the lesion is positive with vimentin and α-smooth muscle actin but negative for CD34, S-100 protein, factor XIIIa, Leu-7, Kp1, MAC387, and desmin (10,14), supporting a myofibroblastic differentiation. Electron microscopic examination of these cells demonstrated ultrastructural characteristics of fibroblasts (9). Some cutaneous myxomas arise in the genital region (15), and they should be differentiated from aggressive angiomyxoma. The latter lesion tends to be larger, extends to deeper structures, and has a vascular component different from that of cutaneous angiomyxoma, because the vascular component of aggressive angiomyxoma consists of variable-sized vessels that range from small thin-walled capillaries to large vessels with secondary changes including perivascular hyalinization and thick vessel walls. TREATMENT Cutaneous angiomyxomas are benign neoplasms, but local recurrences have been reported in 38% of cases (1,14), probably because they are subcutaneous and poorly demarcated lesions.

References 1. Carney JA, Headington JT, Su WPD. Cutaneous myxomas: a major component of myxomas, spotty pigmentation, and endocrine overactivity. Arch Dermatol 1986;122:790–8. 2. Carney JA. Psammomatous melanotic schwannoma: a distinctive heritable tumor with special associations, including cardiac myxoma and the Cushing syndrome. Am J Surg Pathol 1990;14:206–22. 3. Handley J, Carson D, Sloan J, et al. Multiple lentigines, myxoid tumour and endocrine overactivity; four cases of Carney complex. Br J Dermatol 1992;126:367–71. 4. Carney JA. Carney complex: the complex of myxomas, spotty pigmentation, endocrine overactivity, and schwannomas. Semin Dermatol 1995;14:90–8. 5. Egan CA, Stratakis CA, Turner ML. Multiple lentigines associated with cutaneous myxomas. J Am Acad Dermatol 2001;44:282–4. 6. Craig NM, Putterman AM, Roenigk RK, Wang TD, Roenigk HH. Multiple periorbital cutaneous myxomas progressing to scleromyxedema. J Am Acad Dermatol 1996;34:928–30. 7. Murphy CM, Grau-Massanes M, Sanchez RL. Multiple cutaneous myxomas. Report of a case without other elements of Carney’s complex. J Cutan Pathol 1995;22:556–62. 8. Bernardeu K, Serpier H, Salmon Ehr V, Metz D, Pluot M, Kalis B. Myxomes cutanés multiples isolés. Ann Dermatol Venereol 1998;125:30–3. 9. Allen PW, Dymock RB, MacCormac LB. Superficial angiomyxomas with and without epithelial components. Am J Surg Pathol 1988;12:519–30. 10. Wilk M, Schmoeckel C, Kaiser HW, Hepple R, Kreysel HW. Cutaneous angiomyxoma: a benign neoplasm distinct from cutaneous focal mucinosis. J Am Acad Dermatol 1995;33:352–5. 11. Alaiti S, Nelson FP, Ryoo JW. Solitary cutaneous myxoma. J Am Acad Dermatol 2000;43:377–9. 12. Bedlow AJ, Sampson SA, Holden CA. Congenital superficial angiomyxoma. Clin Exp Dermatol 1997;22:237–9. 13. Lockshin NA, Boswell JT. Giant cutaneous angiomyxoma. Cutis 1978;21:673–4. 14. Calonje E, Guerin D, McCormick D, Fletcher CD. Superficial angiomyxoma: clinicopathologic analysis of a series of distinctive but poorly recognized cutaneous tumors with tendency for recurrence. Am J Surg Pathol 1999;23:910–7. 15. Fetsch JF, Laskin WB, Tavassoli FA. Superficial angiomyxoma (cutanous myxoma): a clinicopathologic study of 17 cases arising in the genital region. Int J Gynecol Pathol 1997;16:325–34.

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7. AGGRESSIVE ANGIOMYXOMA CLINICAL FEATURES An entirely different lesion from cutaneous angiomyxoma has been described by Stepper and Rosai (1) under the term aggressive angiomyxoma. The lesion occurs in the genital (Fig. 14), perineal, and pelvic regions, and women are chiefly affected (1–5), but there have also been some reported examples in men involving the scrotum, perineal, and perianal areas (6–8). Aggressive angiomyxomas are soft polypoid masses that show an infiltrative growth but lack metastases. HISTOPATHOLOGIC FEATURES Histopathologically, the tumor is composed of stellate or spindle-shaped cells and either thin or thick hyalinized vascular channels immersed within a myxoid matrix that is rich in collagen bundles (Fig. 15). There is no cellular atypia or mitotic figures. Immunohistochemically, the stromal cells of aggressive angiomyxoma express vimentin, muscle specific actin, and α-smooth muscle actin (2,3,5–9). In addition, some studies have demonstrated that the stromal cells were immunoreactive for desmin (3,5,7,9), whereas myosin, CD34, factor VIII-related antigen, α1-antitrypsin, α1-antichymotrypsin, S-100 protein, neuron-specific enolase, estrogen and progesterone receptors, and chromogranin were negative. Electron microscopic examination showed fibroblast-like (2) or myofibroblast-like cells (1). Recently, Fletcher et al. (10) have described angiomyofibroblastoma of the vulva, a benign neoplasm distinct from aggressive angiomyxoma. According to these authors, angiomyofibroblastoma is smaller, better circumscribed, more cellular, and has a more abundant vascular component than aggressive angiomyxoma. Immunohistochemically, the stromal cells of angiomyofibroblastoma are desmin-positive and actin-negative (10). TREATMENT Wide local excision is recommended for aggressive angiomyxoma, but local recurrence is frequent because of the difficulty of excising of this poorly circumscribed neoplasm completely.

Fig. 14. Clinical features of aggressive angiomyxoma. A poorly circumscribed nodular lesion on the pubis of an elderly woman.


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Fig. 15. Histopathologic features of aggressive angiomyxoma. (A) Low power shows a poorly circumscribed nodular lesion with a myxoid appearance involving the entire thickness of the dermis. (B) Spindle cells embedded in a myxoid stroma. (C) Abundant dilated blood vessels are another component of the lesion.

References 1. Steeper TA, Rosai J. Aggressive angiomyxoma of the female pelvis and perineum: report of nine cases of a distinctive type of gynecologic soft-tissue neoplasm. Am J Surg Pathol 1983;7:463–75. 2. Begin LR, Clement PB, Kirk ME, et al. Aggressive angiomyxoma of pelvic soft part: a clinicopathologic study of nine cases. Hum Pathol 1985;16:621–8. 3. Manivel C, Steeper T, Swanson P, Wick M. Aggressive angiomyxoma of the pelvis: an immunoperoxidase study [Abstract]. Lab Invest 1987;56:46A.

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4. Skalova A, Michal M, Husek K, Zamecnik M, Leivo I. Aggressive angiomyxoma of the pelvioperineal region. Immunohistochemical and ultrastructural study of seven cases. Am J Dermatopathol 1993;15:446–51. 5. Fetsch JF, Laskin WB, Lefkowitz M, Kindblom LG, Meis-Kindblom JM. Aggressive angiomyxoma. A clinicopathologic study of 29 female patients. Cancer 1996;78:79–90. 6. Tsang WYW, Chan JKC, Lee KC, et al. Aggressive angiomyxoma: a report of four cases occurring in men. Am J Surg Pathol 1992;16:1059–65. 7. Clatch RJ, Drake WK, Gonzalez JG. Aggressive angiomyxoma in men: a report of two cases associated with inguinal hernias. Arch Pathol Lab Med 1993;117:911–3. 8. Iezzoni JL, Fechner RE, Wong LS, Rosai J. Aggressive angiomyxoma in males. A report of four cases. Am J Clin Pathol 1995;104:391–6. 9. Fetsch JF, Laskin WB, Lefkowitz M, et al. Aggressive angiomyxoma: a clinicopathologic study of 26 cases [Abstract]. Mod Pathol 1995;8:89A. 10 Fletcher CDM, Tsang WYW, Fisher C, Lee KC, Chan JKC. Angiomyofibroblastoma of the vulva. A benign neoplasm distinct from aggressive angiomyxoma. Am J Surg Pathol 1992;16:373–82.


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Chapter 11 / Mistaken Vascular Neoplasms

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Disorders Erroneously Considered as Vascular Neoplasms CONTENTS KIMURA’S DISEASE “MALIGNANT” ANGIOENDOTHELIOMATOSIS (INTRAVASCULAR LYMPHOMATOSIS) ACRAL PSEUDOLYMPHOMATOUS ANGIOKERATOMA IN CHILDREN (APACHE)

Table 1 summarizes a series of disparate disorders that have been erroneously considered as vascular neoplasms and are described in this chapter.

1. KIMURA’S DISEASE CLINICAL FEATURES Kimura’s disease is an inflammatory disorder of the soft tissue that consists of proliferations of lymphoid and angiomatous tissues accompanied by lymphadenopathy, peripheral blood eosinophilia, and elevated IgE levels. Kimura et al. (1) originally described the disorder in 1948 as “an unusual granulation combined with hyperplastic changes of lymphatic tissue.” Subsequently, several reports of the disorder appeared in the literature, mostly in Oriental patients (2–8). It usually presents as a massive subcutaneous swelling (Fig. 1) preferentially located in periauricular and submandibular regions of young men. The rare occurrence of Kimura’s disease in Caucasians caused confusion between Kimura’s disease and angiolymphoid hyperplasia with eosinophilia. In fact, Wells and Whimster (9), in their original description of angiolymphoid hyperplasia with eosinophilia in 1969, linked this disorder to Kimura’s disease, considering angiolymphoid hyperplasia to be late stage Kimura’s disease. After that, these terms were used synonymously by several authors (10–15). Rosai et al. (16,17) were the first to note that Kimura’s disease and angiolymphoid hyperplasia with eosinophilia are two differ-

Table 1 Disorders Erroneously Considered as Vascular Neoplasms Kimura’s disease “Malignant” angioendotheliomatosis (angiotropic or intravascular lymphoma) APACHE (acral pseudolymphomatous angiokeratoma of children)

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Fig. 1. Clinical appearance of Kimura’s disease showing swelling of the left forehead of an adult man.

ent clinicopathologic entities. Recent reports have also supported this opinion (2–6,8,18). According to these authors, the differential diagnosis between Kimura’s disease and angiolymphoid hyperplasia with eosinophilia can be established on the basis of both clinical and histopathologic features. Clinically, Kimura’s disease occurs mainly in young men who present with large swellings of the subcutaneous soft tissue. The disorder is frequently accompanied by enlarged regional lymph nodes, nephrotic syndrome, peripheral blood eosinophilia, and elevated serum IgE. This disease has a striking predilection for males. Patients with Kimura’s disease also have elevated levels of interleukin (IL)-4, IL-5, and IL-13 mRNA in peripheral blood mononuclear cells (19,20), and the Th2 cytokines probably play a role in the development of this process. In contrast, angiolymphoid hyperplasia with eosinophilia consists of papules or nodules with an angiomatous appearance which are located superficially and which bleed easily. It is not accompanied by either lymphadenopathy or peripheral blood eosinophilia, and the serum level of IgE is normal. In the cases reported, one patient had Kimura’s disease associated with ulcerative colitis (20), and another patient presented with lymphadenopathy, cutaneous nodules, and oral ulcerations (21). HISTOPATHOLOGIC FEATURES Histopathologically, there are also several differences between angiolymphoid hyperplasia and Kimura’s disease. Viewed at low power, angiolymphoid hyperplasia with eosinophilia appears as an angiomatous lesion, with thin- or thick-walled blood vessels lined by prominent endothelial cells with a “histiocytoid” (16) or “epithelioid” (22,23) appearance that characteristically show vacuolated cytoplasm. In contrast, low-power views of lesions of Kimura’s disease show as a subcutaneous inflammatory disorder, with lymphoid aggregates with prominent germinal center formation and infiltration of countless numbers of eosinophils (Fig. 2). The blood vessels in lesions of Kimura’s disease are

Fig. 2. (Opposite page) Histopathologic features of Kimura’s disease. (A) Low power shows prominent germinal center formation involving the entire thickness of the dermis. (B) Germinal centers show a central pale area and a peripheral ring of mature lymphocytes. (C) Numerous eosinophils are present in the infiltrate.


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abundant but never reach the degree of proliferation seen in angiolymphoid hyperplasia with eosinophilia. Endothelial cells in blood vessels of Kimura’s disease may appear to be prominent, and epithelioid and even to have cytoplasmic vacuoles, but these are focal findings compared to the more universal alteration of the blood vessels in lesions of angiolymphoid hyperplasia with eosinophilia. In short, Kimura’s disease seems to be an inflammatory systemic process of unknown etiology rather than a disorder of blood vessels. An increased number of mast cells have been described in lesions of Kimura’s disease, and it seems that the number of mast cells and the vascularity of the lesion run parallel, with sparse numbers of mast cells and blood vessels in early lesions and a gradual increase in fully developed lesions (24). Late stage lesions of Kimura’s disease exhibit a dense hyaline fibrosis. Some authors have postulated that the slow release of mediators of cytokines from mast cells by piecemeal degranulation may contribute to the pathomechanism of Kimura’s disease (25). Polymerase chain reaction investigations for human herpesvirus 8 (HHV-8) yielded negative results in lesions of Kimura’s disease (26), and DNA of Epstein-Barr virus has been detected in a single case (27). TREATMENT Patients with Kimura’s disease are in good general health and have no evidence of systemic lymphoreticular proliferation. Surgical excision of the lesions is often followed by recurrences. Some patients with Kimura’s disease have been successfully treated with cyclosporine (19,28) or pentoxifylline (21).

References 1. Kimura T, Yoshimura S, Ishikama E. On the unusual granulation combined with hyperplastic changes of lymphatic tissues. Trans Soc Pathol Jpn 1948;37:178–80. 2. Kung ITM, Gibson JB, Bannatyne PM. Kimura’s disease: a clinicopathological study of 21 cases and its distinction from angiolymphoid hyperplasia with eosinophilia. Pathology 1984;16:39–44. 3. Googe PB, Harris NL, Mihn, MC Jr. Kimura’s disease and angiolymphoid hyperplasia with eosinophilia: two distinct histopathological entities. J Cutan Pathol 1987;14:263–71. 4. Urabe A, Tsuneyoshi M, Enjoji M. Epithelioid hemangioma versus Kimura’s disease: a comparative clinicopathologic study. Am J Surg Pathol 1987;11:758–66. 5. Kuo T-T, Shih L-Y, Chan H-L. Kimura’s disease. Involvement of regional lymph nodes and distinction from angiolymphoid hyperplasia with eosinophilia. Am J Surg Pathol 1988;12:843–54. 6. Chan JKC, Ng CS, Yuen NWF, Kung ITM, Gwi G. Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) and Kimura’s disease in Chinese. Histopathology 1989;15:557–74. 7. Hui PK, Chan JK, Ng CS, et al. Lymphadenopathy of Kimura’s disease. Am J Surg Pathol 1989; 13:177–86. 8. Chun SI, Ji HG. Kimura’s disease and angiolymphoid hyperplasia with eosinophilia: clinical and histopathologic differences. J Am Acad Dermatol 1992;27:954–8. 9. Wells GC, Whimster IW. Subcutaneous angiolymphoid hyperplasia with eosinophilia. Br J Dermatol 1969;81:1–15. 10. Reed RJ, Terazakis N. Subcutaneous angioblastic lymphoid hyperplasia with eosinophilia (Kimura’s disease). Cancer 1972;29:489–97. 11. Kim BM, Sithian N, Cucolo GF. Subcutaneous angiolymphoid hyperplasia (Kimura’s disease). Report of a case. Arch Surg 1975;110:1246–8. 12. Buchner A, Silverman Jr S, Wara WM, Hansnen LS. Angiolymphoid hyperplasia with eosinophilia (Kimura’s disease). Oral Surg 1980;49:309–13. 13. Thompson JW, Colman M, Williamson C, Ward PH. Angiolymphoid hyperplasia with eosinophilia of the external ear canal. Treatment with laser excision. Arch Otolaryngol 1981;107:316–9. 14. Olsen TG, Helwig EB. Angiolymphoid hyperplasia with eosinophilia: a clinicopathologic study of 116 patients. J Am Acad Dermatol 1985;12:781–96.


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15. Eisenberg, E, Lowlicht R. Angiolymphoid hyperplasia with eosinophils: a clinicopathologic conference. J Oral Pathol 1985;14:216–23. 16. Rosai J, Gold J, Landy R. The histiocytoid hemangiomas. A unifying entity embracing several previously described entities of the skin, soft tissue, large vessels, bone, and heart. Hum Pathol 1979; 10:707–30. 17. Rosai J. Angiolymphoid hyperplasia with eosinophilia of the skin. Its nosological position in the spectrum of the histiocytoid hemangioma. Am J Dermatopathol 1982;4:175–84. 18. Helander SD, Peters MS, Kuo T-T, Su WPD. Kimura’s disease and angiolymphoid hyperplasia with eosinophilia: new observations from immunohistochemical studies of lymphocyte markers, endothelial antigens, and granulocyte proteins. J Cutan Pathol 1995;22:319–26. 19. Katagiri K, Itami S, Hatano Y, Yamaguchi T, Takayasu S. In vivo expression of IL-4, IL-5, IL-13 and IFN-gamma mRNAs in peripheral blood mononuclear cells and effect of cyclosporin A in a patient with Kimura’s disease. Br J Dermatol 1997;137:972–7. 20. Sugaya M, Suzuki T, Asahina A, Nakamura K, Ohtsuki M, Tamaki K. Kimura’s disease associated with ulcerative colitis: detection of IL-5 mRNA expression of peripheral blood mononuclear cells and colon lesion. Acta Derm Venereol 1998;78:375–7. 21. Hongcharu W, Baldassano M, Taylor CR. Kimura’s disease with oral ulcers: response to pentoxifylline. J Am Acad Dermatol 2000;43:905–7. 22. Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma. A vascular tumor often mistaken for a carcinoma. Cancer 1982;50:970–81. 23. Weiss SW, Ishak KG, Dial DH, Sweet DE, Enzinger FM. Epithelioid hemangioendothelioma and related lesions. Semin Diagn Pathol 1986;3:259–87. 24. Wong KT, Shamsol S. Quantitative study of mast cells in Kimura’s disease. J Cutan Pathol 1999;26:13–6. 25. Aoki M, Kawana S. The ultrastructural patterns of mast cell degranulation in Kimura’s disease. Dermatology 1999;199:35–9. 26. Jang KA, Ahn SJ, Choi JH, et al. Polymerase chain reaction (PCR) for human herpesvirus 8 and heteroduplex PCR for clonality assessment in angiolymphoid hyperplasia with eosinophilia and Kimura’s disease. J Cutan Pathol 2001;28:363–7. 27. Nagore E, Llorca J, Sanchez-Motilla JM, Ledesma E, Fortea JM, Aliaga A. Detection of Epstein-Barr virus DNA in a patient with Kimura’s disease. Int J Dermatol 2000;39:618–20. 28. Kaneko K, Aoki M, Hattori S, Sato M, Kawana S. Successful treatment of Kimura’s disease with cyclosporine. J Am Acad Dermatol 1999;41:893–4.

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2. “MALIGNANT” ANGIOENDOTHELIOMATOSIS (INTRAVASCULAR LYMPHOMATOSIS) CLINICAL FEATURES “Malignant” angioendotheliomatosis, in contrast to reactive angioendotheliomatosis, is an aggressive disease generally associated with progressive clinical manifestations leading to the demise of the patient, usually less than a year after presentation. Until recently, it was assumed that the cells within the blood vessels of malignant angioendotheliomatosis represented a proliferation of endothelial cells. However, immunohistochemical and ultrastructural studies have established that these cells are neoplastic lymphocytes, and the disorder is now named intravascular lymphomatosis. Approximately 100 cases have been reported in the literature (1–29), and in the past, a dozen synonyms have been used to name this disorder (18). Cutaneous lesions of intravascular lymphomatosis consist of tender erythematous or purple nodules and plaques on the trunk and extremities (Fig. 3). In a patient with cutaneous hemangiomas and intravascular lymphoma, the lymphoma initially was clinically confined to the hemangiomas of the skin; despite chemotherapy, the disease progressed, and was fatal 23 months after initial diagnosis (29). Telangiectasia may be prominent over the lesions. The disease most commonly affects older adults. More often, initial signs of intravascular lymphomatosis are central nervous system disturbances, including vision impairment, transient episodes of aphasia, weakness, hemiparesis, sensory loss, seizures, and progressive dementia (3,6,24). Intravascular lymphomatosis is a rapidly fatal disease with secondary involvement of the liver, lungs, spleen, adrenal, thyroid, and kidneys (4,12). HISTOPATHOLOGIC FEATURES Histopathologically, cutaneous lesions of intravascular lymphomatosis consist of dilated blood vessels in the dermis and subcutaneous fat that appear to be filled with highly atypical cells, with hyperchromatic nuclei and numerous mitotic figures (Fig. 4). These cells may be enmeshed in fibrin platelet thrombi. The lumen of the larger involved vessels may be thrown into folds, resulting in a glomeruloid appearance. Extension of the infiltrate into vessel walls or perivascular connective tissue is a frequent feature. Originally, intravascular cells in malignant angioendotheliomatosis were considered to be endothelial cells, and some initial immunohistochemical studies reported factor VIII-related antigen positivity in intraluminal cells (13,23). Ultrastructural studies identified Weibel-Palade bodies (23,24), also supporting an endothelial nature for intravascular neoplastic cells. However, most immunohistochemical studies failed to demonstrate factor VIII related antigen reactivity in intravascular cells (1,5,7,11,12,18,20,21,26,27), and Ulex europaeus I lectin has consistently failed to bind to either intravascular or extravascular infiltrates (1,11,12,14,21,26,27). Previous studies describing factor VIIIrelated antigen staining have been attributed to nonspecific staining, owing to adsorption of platelet-derived factor VIII-related antigen by tumor cells embedded in fibrin platelet thrombi (1,8,11,12,15), or staining of endothelial cells that appeared intraluminally because of the complex intraluminal folding of the affected blood vessel (19). Furthermore, additional immunohistochemical studies have demonstrated beyond any doubt that intraluminal neoplastic cells in malignant angioendotheliomatosis express immunoreactivity for leukocyte markers (1,2,7,9,12,14,22,26,27).


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Fig. 3. Clinical features of intravascular lymphomatosis. (A) Multiple nodules on the left flank of a young man. (B) Subcutaneous nodules on the posterior left knee.


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Fig. 4. Histopathologic features of intravascular lymphomatosis. (A) Low power shows cellular aggregations at different levels of the dermis. (B) Higher magnification demonstrates that these cellular aggregations are within vascular lumina. (C) Still higher magnification demonstrates that many of the cells in the vascular lumina show pleomorphic and hyperchromatic nuclei and frequent mitotic figures. (D) Immunohistochemical studies demonstrate that intraluminal cells express immunoreactivity for the lymphocytic marker leukocyte commom antigen.

Most of the cases of intravascular lymphomatosis subjected to immunophenotyping studies showed a B-cell phenotype (1,7,9,10,16,17,19,22), but cases with a T-cell phenotype have also been described (9,21,22,26,27). In rare instances, neoplastic cells were negative for all pertinent markers, and their nature remains uncertain (12). Genotypic


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analysis has been reported for four cases, three demonstrating clonal rearrangement of the immunoglobulin gene (17,19,28), and the fourth clonal T-cell receptor rearrangement (21). Similar conclusions have been reached from ultrastructural studies, and initial reports supporting an endothelial nature for intravascular proliferating cells (3,6,23,24), have been critically reviewed. It seems likely that these investigators mistook reactive endothelial cells for the malignant cells in question (7,11,12). TREATMENT Although isolated patients with intravascular lymphomatosis have responded to treatment with chemotherapy (9,25), the prognosis of the disease is poor, and most patients die within a year of presentation. REFERENCES 1. Wick MR, Rocamora A. Reactive and malignant “angioendotheliomatosis”: a discriminant clinicopathologic study. J Cutan Pathol 1988;15:260–71. 2. Ansell J, Bhawan J, Cohen S, et al. Histiocytic lymphoma and malignant angioendotheliomatosis. One disease or two? Cancer 1982;50:1506–12. 3. Scott PWB, Silvers DN, Helwig EB. Proliferating angioendotheliomatosis. Arch Pathol 1975;99:323–6. 4. Braverman I, Lerner AB. Diffuse malignant proliferation of vascular endothelium. A possible new clinical and pathologic entity. Arch Dermatol 1961;84:72–80. 5. Yamamura Y, Akamizu H, Hirata T, Kito S, Hamada T. Malignant lymphoma presenting with neoplastic angioendotheliosis of the central nervous system. Clin Neuropathol 1983;2:62–8. 6. Wick MR, Scheithaver BW, Okazaki H, et al. Cerebral angioendotheliomatosis. Arch Pathol Lab Med 1982;106:342–6. 7. Bhawan J, Wolff SM, Ucci AA, et al. Malignant lymphoma and malignant angioendotheliomatosis: one disease. Cancer 1985;55:570–6. 8. Dominguez FE, Rosen LB, Kramer HC. Malignant angioendotheliomatosis proliferans. Am J Dermatopathol 1986;8:419–25. 9. Sheibani K, Battifora H, Winberg CD, et al. Further evidence that “malignant angioendotheliomatosis” is an angiotropic large-call lymphoma. N Engl J Med 1986;314:943–8. 10. Willemze R, Kroyswijk MRJ, Debruin CD, et al. Angiotropic (intravascular) large cell lymphoma of the skin previously classified as malignant angioendotheliomatosis. Br J Dermatol 1987;116:393–9. 11. Wrotnowski U, Mills SE, Cooper PH. Malignant angioendotheliomatosis. An angiotropic lymphoma. Am J Clin Pathol 1985;83:244–8. 12. Wick MR, Mills SE, Scheithauer BW, et al. Reassessment of malignant “angioendotheliomatosis:” evidence in favor of its reclassification as “intravascular lymphomatosis.” Am J Surg Pathol 1986;10:112–3. 13. Fulling KH, Gersell DJ. Neoplastic angioendotheliomatosis: histologic, immunohistochemical, and ultrastructural findings in two cases. Cancer 1982;51:1107–18. 14. Carroll TJ, Schelper RL, Goeken JA, et al. Neoplastic angioendotheliomatosis: immunopathologic and morphologic evidence for intravascular malignant lymphomatosis. Am J Clin Pathol 1986;85:169–75. 15. Mori S, Itoyama S, Mohri N, et al. Cellular characteristics of neoplastic angioendotheliomatosis. An immunohistochemical marker study of 6 cases. Virchows Arch Pathol Anat 1985;407:167–75. 16. Ferry JA, Harris NL, Picker LJ, et al. Intravascular lymphomatosis (malignant angioendotheliomatosis). A B-cell neoplasm expressing surface homing receptor. Mod Pathol 1988;1:444–52. 17. Otrakji CL, Voight W, Amador A, et al. Malignant angioendotheliomatosis: a true lymphoma. A case of intravascular malignant lymphomatosis studied by Southern blot hybridization analysis. Hum Pathol 1988;19:475–8. 18. Bhawan J. Angioendotheliomatosis proliferans systemisata: an angiotropic neoplasm of lymphoid origin. Semin Diagn Pathol 1987;4:18–27. 19. Petroff N, Koger OW, Fleming MG, et al. Malignant angioendotheliomatosis: an angiotropic lymphoma. J Am Acad Dermatol 1989;21:727–33. 20. Molina A, Lombard C, Donlon T, Bangs CD, Dorfman RF. Immunohistochemical and cytogenetic studies indicate that malignant angioendotheliomatosis is a primary intravascular (angiotropic) lymphoma. Cancer 1990;66:474–9.

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21. Sepp N, Schuler G, Romani N, et al. “Intravascular lymphomatosis” (angioendotheliomatosis): evidence for a T-cell origin in two cases. Hum Pathol 1990;21:1051–8. 22. Hisashi T, Tadaaki E, Toyohiro T, Masuzou K, Yokio F, Syouji K. Congenital angiotropic lymphoma (intravascular lymphomatosis) of the T-cell type. Cancer 1991;67:2131–6. 23. Kitagawa M, Matsubara O, Song SY, et al. Neoplastic angioendotheliomatosis. Immunohistochemical and electron microscopic findings in three cases. Cancer 1985;56:1134–43. 24. Petito CK, Gottlieb GJ, Dougherty JH, et al. Neoplastic angioendotheliomatosis: Ultrastructural study and review of the literature. Ann Neurol 1978;3:393–9. 25. Keahey TM, Guerry D IV, Tuthill RJ, Bondi EE. Malignant angioendotheliomatosis proliferans treated with doxorubicin. Arch Dermatol 1982;118:512–4. 26. Setoyama M, Mizoguchi S, Orikawa T, Tashiro M. A case of intravascular malignant lymphomatosis (angiotropic large-cell lymphoma) presenting memory T-cell phenotype and its expression of adhesion molecules. J Dermatol 1992;19:263–9. 27. Sangueza O, Hyder DM, Sangueza P. Intravascular lymphomatosis: report of an unusual case with T-cell phenotype occurring in an adolescent male. J Cutan Pathol 1992;19:226–31. 28. Kamesaki H, Matsui Y, Ohno Y, et al. Single case report: angiocentric lymphoma with histologic features of neoplastic angioendotheliomatosis presenting with predominant respiratory and hematologic manifestations. Am J Clin Pathol 1990;94:768–72. 29. Rubin MA, Cossman J, Freter CE, Azumi N. Intravascular large cell lymphoma coexisting within hemangiomas of the skin. Am J Surg Pathol 1997;21:860–4.


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3. ACRAL PSEUDOLYMPHOMATOUS ANGIOKERATOMA IN CHILDREN (APACHE) CLINICAL FEATURES Ramsay et al. (1,2) have described a group of children presenting with unilateral, multiple, persistent angiomatous papules on acral regions of the hands and feet, termed acral pseudolymphomatous angiokeratoma in children (APACHE). The histopathology of the lesions revealed a well-circumscribed, dermal lymphohistiocytic infiltrate with prominent thickened capillaries. An additional case has been reported by Hara et al. (3). HISTOPATHOLOGIC FEATURES Histopathologically, lesions consisted of the presence of a subepidermal, well-circumscribed, dense, nodular lymphohistiocytic infiltrate with occasional plasma cells, eosinophils, and a few multinucleated giant cells. Prominent capillaries are noted within and around the infiltrate (Fig. 5) Immunohistochemistry revealed the main cellular components to be an admixture of B- and T-lymphocytes (2,4), and, according to Kaddu et al. (4), lesions of APACHE are better interpreted as a variant of cutaneous pseudolymphoma rather than an angiokeratoma. TREATMENT Simple excision of the lesions is curative.

References 1. Ramsay B, Dahl MGC, Malcolm AJ, Soyer HP, Wilson Jones E. Acral pseudolymphomatous angiokeratoma of children (APACHE). Br J Dermatol 1988;119(suppl 33):13. 2. Ramsay B, Dahl MGC, Malcolm AJ, Wilson Jones E. Acral pseudolymphomatous angiokeratoma of children. Arch Dermatol 1990;126:1524–5. 3. Hara M, Matsunaga J, Tagami H. Acral pseudolymphomatous angiokeratoma of children (APACHE): a case report and immunohistologic study. Br J Dermatol 1991;124:387–8. 4. Kaddu S, Cerroni L, Pilatti A, Soyer HP, Kerl H. Acral pseudolymphomatous angiokeratoma. A variant of cutaneous pseudolymphomas. Am J Dermatopathol 1994;16:130–3.

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Fig. 5. Histopathologic features of APACHE. (A) Low power magnification showing dense infiltrates within the dermis admixed with vessels. (Continued)


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Fig. 5. Histopathologic features of APACHE. (B) The infiltrates are composed of uniform lymphocytes, whereas the vessels show thick walls and prominent endothelial cells. (C) Other areas show a predominant vascular component.


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INDEX Acquired acral fibrokeratoma, 279 Acquired elastotic hemangioma, 174 clinical features, 174 histopathologic features, 174–175 immunohistochemistry, 174 treatment, 175 Acral pseudolymphomatous angiokeratoma in children (APACHE) histopathologic features, 309, 310 treatment, 309 Acroangiodermatitis of Mali, 123–124, 125–126 Acrosyringium, 2 Aggressive angiomyxoma cutaneous angiomyxoma and, 295, 296 histopathologic features, 296, 297, 298 immunohistochemistry, 296 Alopecia areata, 37 Amniotic fluid, 1 Angioblastoma, 164 Angioendothelioma endovascular papillary, see Dabska’s tumor papillary intralymphatic, see Dabska’s tumor Angioendotheliomatosis, 128 malignant, 128, see also Intravascular lymphomatosis reactive, see Reactive angioendotheliomatosis Angiofibroblastoma of the vulva, 296 Angiofibroma clinical features, 279–280 histopathologic features, 280–282 immunohistochemistry, 282 treatment, 282 Angiokeratoma, 47, 64, 86 acral pseudolymphomatous in children (APACHE), 309, 310 circumscriptum, 86 clinical features, 86–89 corporis diffusum, 87–88, 89, 90, 91, see also Fabry’s disease Fordyce’s, 86, 90 histopathologic features, 89–91, 92 Mibelli’s, 87 treatment, 91

Angioleiomyoma clinical features, 284 epithelioid, 286 histopathologic features, 284–286 immunohistochemistry, 284, 286 intravascular, 286 palisaded, 286 treatment, 286 Angiolipoma cellular, 288 clinical features, 287 histopathologic features, 287–289 infiltrating, 288 lipoma vs., 287 multiple, 287 subcutaneous, 288 treatment, 289 Angiolymphoid hyperplasia with eosinophilia (AHE) clinical features, 99–100 differential diagnosis, 102 HHV8 and, 99 histopathologic features, 100–102 immunohistochemistry, 102 Kimura’s disease and, 99, 102, 299–300 nevus flammeus and, 43 treatment, 102 Angioma cherry, see Cherry angioma choroidal, 39 spider, see Spider angioma sudoriparous, 23 tufted, see Tufted angioma Angioma serpiginosum, 133 atypical, 134 clinical features, 133–134 histopathologic features, 134 treatment, 134 Angiomatosis bacillary, see Bacillary angiomatosis bilateral retinal, 42 epithelioid, 112 homolateral leptomeningeal, 39–40 ipsilateral leptomeningeal, 39

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Angiomyxoma, 293, see also Aggressive angiomyxoma; Cutaneous angiomyxoma Angiosarcoma CD31 and, 8 CD34 and, 8 cutaneous, associated with lymphedema, see Cutaneous angiosarcoma associated with lymphedema cutaneous, of the face and scalp, see Cutaneous angiosarcoma of the face and scalp cutaneous, radiation-induced, see Radiationinduced cutaneous angiosarcoma epithelioid, see Epithelioid angiosarcoma VEGFR-3 and, 8 vWF and, 7 Wilson Jones’, see Cutaneous angiosarcoma of the face and scalp Antigens CD1, 2 factor VIII-related, 7 human leukocyte,-DR, 2 Apocrine glands, 2 Arteries adventitia, 5 intima, 4–5 media, 5 Arteriovenous hemangioma, 154 clinical features, 154, 155 histopathologic features, 154, 155 inflammatory, 99 treatment, 154 Ataxia-telangiectasia, 82, 84 Atypical pyogenic granuloma, 99 Atypical vascular lesions, 195 radiation-induced cutaneous angiosarcoma and, 262

Bacillary angiomatosis, 112 clinical features, 112 histopathologic features, 113, 114 Kaposi’s sarcoma and, 112 treatment, 113 verruga peruana and, 116 Bannayan-Riley-Ruvalcaba syndrome, 57, 59 Bannayan-Zonana syndrome, 56 Bartonella bacilliformis, 116 henselae, 112 quintana, 112 Bartonellosis, 116 Beckwith-Wiedemann syndrome, 42 Benign atypical vascular lesions of the lip, 120


312

Benign lymphangioendothelioma, 191, 195 clinical features, 191–192 differential diagnosis, 192 histopathologic features, 192, 193 hobnail hemangioma and, 157 immunohistochemistry, 192 Kaposi’s sarcoma and, 192, 196, 229 radiation-induced cutaneous angiosarcoma and, 262 treatment, 192 Benign lymphangiomatous papules, 195 radiation-induced cutaneous angiosarcoma and, 262 Benign neonatal hemangiomatosis, 141 Benign vascular proliferations radiation-induced cutaneous angiosarcoma and, 262 Benign vascular proliferations, in irradiated skin, 195 clinical features, 195 histopathologic features, 195–197 treatment, 197 Birbeck granules, 2 Birt-Hogg-Dube syndrome, 287 Blue capillary sponge blebs, 51 Blue rubber bleb nevus syndrome, 52–53, 57, 59, 198 Bockenheimer’s syndrome, 34 Café-au-lait macules, 54 Campbell de Morgan spots, 151 Capillary aneurysm, 76 clinical features, 76 histopathologic features, 76–78 treatment, 78 Carcinoembryonic antigen (CEA), 8 Carcinomas, 7 Carney’s complex, 293 Carrion’s disease, 116 Castleman’s disease, 169, 219 Cat scratch disease, 112 CD1, 2 CD31, 7, 8 CD34, 7, 8 Cherry angioma clinical features, 151 histopathologic features, 151–152 immunohistochemistry, 151 treatment, 152 Chondrosarcoma, 54–55 Choroidal angioma, 39 Cirsoid aneurysm, 154 Coats’ disease, 42 Cobb’s syndrome, 41

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313

Collagen, embryological, 2 Composite hemangioendothelioma clinical features, 250 histopathologic features, 250 immunohistochemistry, 250 treatment, 250 Cornification, 1–2 Cowden disease, 57 Crow-Fukase syndrome, 169 Cutaneous angiolipoleiomyoma clinical features, 290 histopathologic features, 290–291 immunohistochemistry, 290 treatment, 292 Cutaneous angiomyxoma aggressive angiomyxoma and, 295, 296 Carney’s complex and, 293 clinical features, 293 immunohistochemistry, 295 treatment, 295 Cutaneous angiosarcoma, radiation-induced, see Radiation-induced cutaneous angiosarcoma Cutaneous angiosarcoma associated with lymphedema, 258 clinical features, 258 differential diagnosis, 259–60 histopathologic features, 258–260 immunohistochemistry, 259–60 treatment, 260 Cutaneous angiosarcoma of the face and scalp, 251 clinical features, 251–252, 253 fig immunohistochemistry, 253, 255 Kaposi’s sarcoma and, 251–252 treatment, 255 Cutaneous collagenous vasculopathy, 82, 83, 84 Cutaneous histiocytoid hemangioma, 99 Cutaneous myofibroma, 212 clinical features, 212 histopathologic features, 212–215 immunohistochemistry, 213 pericytes and, 215 treatment, 215 Cutaneous pseudolymphoma, 309 Cutis marmorata telangiectatica congenita (CMTC), 32 anomalies associated with, 33 clinical features, 32–33 differential diagnosis, 34 histopathologic features, 33–34 treatment, 34 Cystic hygromas, see Cystic lymphatic malformations Cystic lymphatic malformations, 54, 67 clinical features, 67

histopathologic features, 67, 68 fig. superficial lymphatic malformations vs., 67 treatment, 68 Cytogenetic studies, 12 Cytokeratin, 7 Cytomegalovirus (CMV), 218 Dabska’s tumor angiosarcoma and, 243 clinical features, 241 glomeruloid hemangioma and, 172, 243 histopathologic features, 241–243 hobnail hemangioendothelioma and, 241, 243 hobnail hemangioma and, 157 immunohistochemistry, 243 retiform hemangioendothelioma and, 243 treatment, 243–244 VEGFR-3 and, 8, 243 Dermatofibroma epithelioid, 236 multinucleate cell angiohistiocytoma and, 276– 277 Dermatofibrosarcoma protuberans, 8 Dermis blood supply, 2–3 composition, 2 embryological development of, 1, 2 Digital verrucous fibroangioma, 47 Disseminated eruptive hemangiomas, 139 Disseminated hemangiomatosis, 139 Eccrine angiomatous hamartoma (EAH), 19, 23 clinical features, 23–24 histopathologic features, 24 immunohistochemistry, 24 treatment, 24 Eccrine glands, 2 Ectoderm, 1 Embryo, skin of, 1–2 Endothelial cells, 5 Endovascular papillary angioendothelioma, see Dabska’s tumor Epidermis, 1, 2 Epithelioid angioleiomyoma, 286 Epithelioid angiomatosis, 112 Epithelioid angiosarcoma, 7 clinical features, 268 histopathologic features, 268–269 immunohistochemistry, 268 treatment, 270 Epithelioid dermatofibroma, 236 Epithelioid hemangioendothelioma, 236 carcinoma and, 7 clinical features, 236–237

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314

Index

differential diagnosis, 237, 239 eccrine syringofibroadenoma and, 237 GLUT-1 and, 10 histopathologic features, 237–239 immunohistochemistry, 237, 239 kaposiform hemangioendothelioma and, 236 retiform hemangioendothelioma and, 236 spindle-cell hemangioma and, 186, 236 treatment, 239 vWF and, 7 Epithelioid hemangioma, 99 Epithelium, embryologic, 1 Epulis gravidarum, 106 Fabry’s disease, 56, 88–89, 90, 91, 92, see also Angiokeratoma: corporis diffusum Factor VIII-related antigen, 7 Fibroangioma digital verrucous, 47 Fibrokeratoma acquired acral, 279 Fibrous papule of the nose, 279, 280 Fordyce’s angiokeratoma, 86, 90 Generalized essential telangiectasia, 80, 83 histopathologic features, 82–83 Giant-cell angioblastoma clinical features, 184 hemangiopericytoma and, 184 histopathologic features, 184, 185 treatment, 184 Glaucoma, 38–39 Glomangiomas, 57, 198, 201 Glomangiomyoma, 201 Glomangiosarcoma, 271–273 clinical features, 271 differential diagnosis, 273 hemangiopericytoma and, 273 histopathologic features, 271–273 immunohistochemistry, 271, 273 leiomyosarcoma and, 273 nodular hidradenoma and, 273 treatment, 273 Glomeruloid hemangioma, 169 clinical features, 169 differential diagnosis, 171–172 endovascular papillary angioendothelioma and, 172, 243 histogenesis, 169–170 histopathologic features, 169–172 immunochemistry, 169 intravascular papillary endothelial hyperplasia and, 171–172


314

intravascular pyogenic granuloma and, 171 treatment, 172 Glomus bodies, 5 Glomus cells, 5 Glomus tumors, 198 apocrine hidradenomas and, 202 blue rubber bleb nevus syndrome and, 198 clinical features, 198–199, 201 fig. glomangiomas and, 198, 201 glomangiomyomas and, 201 histopathologic features, 199–202, 203–205 immunohistochemistry, 201–202 Kasabach-Merritt syndrome and, 198 malignant, see Glomangiosarcoma as pericytes, 201 treatment, 202 GLUT-1, 7, 8, 10 Gorham’s syndrome, 56, 59 Graves’ disease, 80

Hair follicles, 2 Hamartoma defined, 19 eccrine angiomatous, see Eccrine angiomatous hamartoma (EAH) Hemangioendothelioma, 18 CD31 and, 8 composite, see Composite hemangioendothelioma epithelioid, see Epithelioid hemangioendothelioma hobnail, see Hobnail hemangioendothelioma kaposiform, see Kaposiform hemangioendothelioma polymorphous, 250 retiform, see Retiform hemangioendothelioma spindle cell, see Spindle cell hemangioma Hemangioma, 15 acquired elastotic, see Acquired elastotic hemangioma arteriovenous, see Arteriovenous hemangioma cavernous, 51 CD31 and, 8 congenital, 142 congenital nonprogressive, 142–143 cutaneous histiocytoid, 99 disseminated eruptive, 139 epithelioid, 99 glomeruloid, see Glomeruloid hemangioma histiocytoid, 99 hobnail, see Hobnail hemangioma infantile, see Infantile hemangioma

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Index

315

intramuscular, 288 lobular capillary, 105 microvenular, see Microvenular hemangioma miliary, 139 multiple cutaneous, 140–141 noninvoluting congenital, 142 progressive capillary, 164 sinusoidal, see Sinusoidal hemangioma spindle cell, see Spindle cell hemangioma targetoid hemosiderotic, see Hobnail hemangioma verrucous, 47 visceral, 139–141 Hemangiomatosis benign neonatal, 141 disseminated, 139 neonatal, 139 Hemangiopericytoma, 208 clinical features, 208 giant-cell angioblastoma and, 184 glomangiosarcoma and, 273 histopathologic features, 208–210 immunohistochemistry, 209–210 infantile myofibromatosis and, 209 treatment, 210 Hereditary benign telangiectasia, 82, 83 Hereditary hemorrhagic telangiectasia, 81–82 histopathologic features, 82–83 treatment, 83–84 Hibernoma, 289 Hidradenoma apocrine, 202 nodular, 273 Histiocytoid hemangioma, 99 Histochemical stains, 7 Hobnail hemangioendothelioma, 241, 243 Hobnail hemangioma, 157 benign lymphangioendothelioma and, 157 clinical features, 157 Dabska’s tumor and, 157 differential diagnosis, 159 histopathologic features, 157–159 immunohistochemistry, 159 Kaposi’s sarcoma and, 157, 159, 229 retiform hemangioendothelioma and, 157 treatment, 159 VEGFR-3 and, 8, 159 Hodgkin’s disease, 106 Human hematopoietic progenitor cell antigen, see CD34 Human herpesvirus-8 (HHV-8), 219 AHE and, 99 Kaposi’s sarcoma and, 11 Human leukocyte antigen-DR, 2

Human papillomavirus (HPV), 218 Hyperkeratotic capillary-lymphatic malformations, 86 Hyperkeratotic vascular malformations, 134 Hyperkeratotic vascular stains, 47 clinical features, 47, 48 histopathologic features, 47, 49 treatment, 47 Hyperplasia, 15 Hypochromic nevus, 29 Hypomelanosis, 29

Immunohistochemical stains, 7–10, see also subheading immunohistochemistry under names of lesions Infantile hemangioma, 15, 136 capillary, 15, 18, 136 cavernous, 15, 18, 136 clinical features, 136–141 deep, 136 GLUT-1 and, 10, 145 histopathologic features, 141–145 immunohistochemistry, 143, 145 kaposiform hemangioendothelioma and, 177 Kasabach-Merritt syndrome and, 138–139, 145–46 mixed, 136 prevalence, 137 stages, 137–138 superficial, 136 treatment, 145–146 tufted angioma and, 166 VEGFR-3 and, 8, 143 Infantile myofibromatosis, 209, 212 Inflammatory angiomatous nodule, 99 Intramuscular hemangioma, 288 Intravascular angioleiomyoma, 286 Intravascular lymphomatosis clinical features, 304, 305 histopathologic features, 304, 306–307 immunohistochemistry, 304 treatment, 307 Intravascular papillary endothelial hyperplasia (IPEH), 119 clinical features, 119 glomeruloid hemangioma and, 171–172 histopathologic features, 119–120, 121 Kaposi’s sarcoma and, 119 Stewart-Treves syndrome and, 119 treatment, 120 Intravascular pyogenic granuloma glomeruloid hemangioma and, 171 Intravenous atypical vascular proliferation, 99

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Index

Kaposiform hemangioendothelioma clinical features, 177 epithelioid hemangioendothelioma and, 236 GLUT-1 and, 10 histopathologic features, 177–180 immunohistochemistry, 178 infantile hemangioma and, 177 Kaposi’s sarcoma and, 177, 230 Kasabach-Merritt syndrome and, 177 treatment, 180 tufted angioma and, 166, 177 VEGFR-3 and, 8, 178 Kaposi’s sarcoma, 59, 217–219 African-endemic variant, 218, 219 AIDS-associated, 218, 220–222 bacillary angiomatosis and, 112 benign lymphangioendothelioma and, 192, 196, 229 CD31 and, 8 CD34 and, 8, 229 classic, 218, 219, 222 clinical features, 219–222, 223, 224 cutaneous angiosarcoma of the face and scalp and, 251–252 cytomegalovirus (CMV) and, 218 differential diagnosis, 229–230 HHV-8 and, 11 histogenesis, 228 histopathologic features, 222–230 hobnail hemangioma and, 157, 159, 229 HPV antigens and, 218 hyaline globules in, 228 immunohistochemistry, 218, 228–229 immunosuppressive form of, 218, 219–220 IPEH and, 119 kaposiform hemangioendothelioma and, 177, 230 microvenular hemangioma and, 161–162 nodular, 225, 227–228 patch stage, 222–24, 228 pathogenesis, 219 spindle cell hemangioma and, 188, 230 spindle cells, 224–225, 229 treatment, 230 VEGFR-3 and, 8, 229 Kaposi’s sarcoma-associated herpes virus (KSHV), 11 Kasabach-Merritt syndrome, 47, 138–139, 145–146 glomus tumors and, 198 kaposiform hemangioendothelioma and, 177 tufted angioma and, 164, 166 Keratohyalin granules, 2 Kimura’s disease AHE and, 99, 102, 299–300


316

clinical features, 299–300 histopathologic features, 300–302 treatment, 302 Klippel-Trenaunay syndrome, 19, 40, 55–56, 59, 89, 186

Langerhans cells, 2 Leiomyosarcoma glomangiosarcoma and, 273 Linear telangiectasia, 79 Lipoblastoma, 289 Louis-Bar syndrome, 82 Lymphangiectases, 195 clinical features, 95 histopathologic features, 95–96 radiation-induced cutaneous angiosarcoma and, 262 treatment, 96 Lymphangioma, 63, 195 acquired progressive, 191 circumscriptum, 63, 195 radiation-induced cutaneous angiosarcoma and, 262 Lymphangiomatosis, 70 clinical features, 70 histopathologic features, 70–72 immunohistochemistry, 72 treatment, 72 Lymphangiosarcomas, 258 Lymphedema angiosarcoma associated with, see Cutaneous angiosarcoma associated with lymphedema cutaneous angiosarcoma associated with, see Cutaneous angiosarcoma associated with lymphedema

Maffucci’s syndrome, 53–55, 58–59, 67, 186, 188 Malformation, defined, 27 Malignant angioendotheliomatosis, 128, see also Intravascular lymphomatosis Malignant glomus tumor (MGT), see Glomangiosarcoma Melanoblasts, 2 Melanocytes, 2, 20 Merkel cells, 2 Mesoderm, 1 Mibelli’s angiokeratoma, 87 Microvenular hemangioma, 161 clinical features, 161 differential diagnosis, 161–62 histopathologic features, 161–162 Kaposi’s sarcoma and, 161–162

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Index

317

POEMS syndrome and, 161 treatment, 162 Wiskott-Aldrich syndrome and, 161 Miliary hemangioma, 139 Molecular techniques, 10–11 Multinucleate cell angiohistiocytoma clinical features, 275–276 dermatofibroma and, 276–277 differential diagnosis, 276–277 histopathologic features, 276–277 immunohistochemistry, 276 treatment, 277 Multiple endocrine neoplasia type 1 (MEN-1), 280 My10, 8 Myofibroma, adult, 212–213 Myofibromatosis, 212 infantile, 212, 213 Myopericytes, 215 Naevus vascularis mixtus, 38 Neonatal hemangiomatosis, 139 Neurofibromatosis type 2, 279 Nevus blue rubber bleb, see Blue rubber bleb nevus hypochromic, 29 Spitz, 236 telangiectatic, 30 Nevus anemicus clinical features, 29–30 histopathologic features, 30 phakomatosis pigmentovascularis and, 19, 20, 29 port wine stains and, 38 treatment, 30 Nevus araneus, see Spider angioma Nevus flammeus, see also Port wine stain clinical features, 37–42 histopathologic features, 42–43 immunohistochemistry, 43 nuchal-occipital, 37 pathogenesis, 43 phakomatosis pigmentovascularis and, 19, 20, 21 pyogenic granuloma (PG) and, 106 treatment, 43 tufted angioma and, 164 Nevus of Ota, 19 Nevus oligemicus, 30 Nevus pigmentosus, 19 Nevus spilus, 19 Nevus verrucosus, 19 9D9F9, 8 Nodular hidradenoma glomangiosarcoma and, 273

Oculocutaneous melanosis, 19 Oroya’s fever, 116 Osler-Rendu-Weber syndrome, 57, 81, 82, 84 Pachydermoperiostosis, 100 Palisaded angioleiomyoma, 286 Papillary intralymphatic angioendothelioma, see Dabska’s tumor Papular angioplasia, 99 Parkes-Weber syndrome, 40, 55 Pearly penile papules, 279, 280 Pericytes cutaneous myofibroma and, 215 glomus tumors as, 201 Periderm, 1 Periungual fibroma, 279 PHACES syndrome, 139 Phakomatosis pigmentovascularis clinical features, 19–20 histopathologic features, 20–21 nevus anemicus and, 19, 20, 29 nevus flammeus and, 19, 20, 21 pathogenesis, 20 port wine stains and, 41 treatment, 21 Phlebectasia, diffuse genuine, 34 Pinocytosis, 5 Plasma cell dyscrasia, 169 Platelet endothelial cell adhesion molecule-1 (PECAM1), see CD31 Pleomorphic lipoma, 288 Plexuses, 2–4 POEMS syndrome, 161, 169 Polymerase chain reaction, 10 Polymorphous hemangioendothelioma, 250 Port wine stain, 21, 37–39, see also Nevus flammeus Progressive capillary hemangioma, 164 Proteus syndrome, 41 Pseudo-Kaposi’s sarcoma, 123 clinical features, 123–124 histopathologic features, 124–125 treatment, 125–126 Pseudopyogenic granuloma, 99 Purpuric dematoses, 134 Pyogenic granuloma GLUT-1 and, 10 Pyogenic granuloma (PG) atypical, 99 clinical features, 105–106 histopathologic features, 106–108 immunohistochemistry, 107 intravascular, see Intravascular pyogenic granuloma

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Index

nevus flammeus and, 106 spider angioma and, 73, 106 treatment, 109 QB-END 10, 8 Radiation-induced cutaneous angiosarcoma, 262 atypical vascular lesions and, 262 benign lymphangioendothelioma and, 262 benign lymphangiomatous papules and, 262 benign vascular proliferations and, 262 clinical features, 262, 263 fig histopathologic features, 262–265 lymphangiectases and, 262 lymphangioma and, 262 treatment, 265 Reactive angioendotheliomatosis, 128 clinical features, 128–129 histopathologic features, 129–130 immunohistochemistry, 129 treatment, 130 Retiform hemangioendothelioma, 245 angiosarcoma and, 245 clinical features, 245, 246 endovascular papillary angioendothelioma and, 243 epithelioid hemangioendothelioma and, 236, 245 histopathologic features, 245–246, 247–248 hobnail hemangioendothelioma and, 243 hobnail hemangioma and, 157 immunohistochemistry, 245–246 treatment, 246 Rhadinoviruses, 219 Riley-Smith syndrome, 56 Roberts’ syndrome, 42 Rochalimaea, see Bartonella Rubinstein-Taybi syndrome, 42 Ruvalcaba-Myhre-Smith syndrome, 57 Ruvalcaba-Myhre syndrome, 57

Salmon patch, 37, 43 Scleromyxedema, 293 Self-healing pseudoangiosarcoma, 191 Senile angioma, see Cherry angioma Sinusoidal hemangioma clinical features, 182 histopathologic features, 182, 183 treatment, 182 Skin embryology, 1–2 functions, 1 lymphatic channels, 5–6


318

Spider angioma clinical features, 73 histopathologic features, 73 pyogenic granuloma (PG) and, 73, 106 treatment, 73 Spindle cell hemangioendothelioma, see Spindle cell hemangioma Spindle cell hemangioma, 59, 186 clinical features, 186, 188 differential diagnosis, 188 epithelioid hemangioendothelioma and, 186, 236 histopathologic features, 187, 188 immunohistochemistry, 188 Kaposi’s sarcoma and, 188, 230 Klippel-Trenaunay syndrome and, 186 Maffucci’s syndrome and, 186, 188 treatment, 188 Spindle cell lipoma, 288 Spitz nevus, 236 Stewart-Bluefarb syndrome, 123, 124, 126 Stewart-Treves syndrome, 119, 258 Stork bite, 37 Stratum germinativum, 1 Stratum granulosum, 1 corneum, 1 Stratum spinosum, 1 Sturge-Weber syndrome, 19, 38, 39–40 Subungual fibroma, 279 Sucquet-Hoyer canal, 5 Sucquet-Hoyer canals, 198 Sudoriparous angioma, 23 Superficial cutaneous lymphatic malformations clinical features, 63–64 histopathologic features, 64 immunohistochemistry, 64 treatment, 64 Takatsuki’s syndrome, 169 Targetoid hemosiderotic hemangioma, see Hobnail hemangioma TAR syndrome, 42 Telangiectases, 79–84 Tuberous sclerosis, 279 Tufted angioma, 164 clinical features, 164, 166 differential diagnosis, 166 histopathologic features, 165, 166 immunohistochemistry, 166 infantile hemangioma and, 166 kaposiform hemangioendothelioma and, 166, 177 Kasabach-Merritt syndrome and, 164, 166 nevus flammeus and, 164 treatment, 166

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319

Ulex europaeus lectin, 7 Unilateral nevoid telangiectasia, 79–80, 82, 83 Unilateral spider nevi, 79 Unilateral telangiectasia, 79 Vascular endothelial growth factor receptor-3, see VEGFR-3 Vascular malformations, 27–28 defined, 15 Vascular proliferations classification, 15–18 VEGFR-3, 7, 8 Venous lake, see Capillary aneurysm Venous malformations, 51 clinical features, 51–57 histopathologic features, 57–59 treatment, 59

Verruga peruana, 116 bacillary angiomatosis and, 116 clinical features, 116, 117 histopathologic features, 116, 118 immunohistochemistry, 116 treatment, 116 Visceral hemangiomas, 139–141 Vitiligo, 29 von Hippel-Lindau syndrome, 42 von Willebrand factor (vWF), 7–8, see also Factor VIII-related antigen Weibel-Palade bodies, 5 Wilson Jones’ angiosarcoma, see Cutaneous angiosarcoma of the face and scalp Wiskott-Aldrich syndrome, 161 Wyburn-Mason syndrome, 41

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COMPANION CD-ROM TO PATHOLOGY OF VASCULAR SKIN LESIONS: CLINICOPATHOLOGIC CORRELATIONS BY

OMAR P. SANGÜEZA, MD LUIS REQUENA, MD The CD-ROM attached to the back cover contains color versions in jpeg format of all illustrations in the companion title. It is compatible with Apple and PC computers equipped with at least 6X CD-ROM readers. Illustrations are viewable in Web browsers; consult operating system Help as needed. Sponsored in part by Pathologists Diagnostic Services, PLLC, Winston-Salem, NC.

Limited Warranty and Disclaimer Humana Press Inc. warrants the CD-ROM contained herein to be free of defects in materials and workmanship for a period of 30 days from the date of the book’s purchase. If within this 30-day period Humana Press receives written notification of defects in materials or workmanship, and such notification is determined by Humana Press to be valid, the defective disk will be replaced. In no event shall Humana Press or the author and producers of this CD-ROM be liable for any damages whatsoever arising from the use or inability to use the files contained therein. The authors of this book have used their best efforts in preparing this material. Neither the authors nor the publisher make warranties of any kind, express or implied, with regard to the information contained within this CD-ROM, including, without limitation, warranties of merchantability or fitness for a particular purpose. No liability is accepted in any event or for any damages, including incidental or consequential damages, lost profits, costs of lost data or program material, or otherwise in connection with or arising out of the furnishing, performance, or use of the files on this CD-ROM.

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CURRENT CLINICAL PATHOLOGY™ SERIES EDITOR: IVAN DAMJANOV, MD

PATHOLOGY OF VASCULAR SKIN LESIONS CLINICOPATHOLOGIC CORRELATIONS Omar P. Sangüeza, MD Departments of Pathology and Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC

Luis Requena, MD Department of Dermatology, Fundación Jiménez Diaz, Universidad Autonoma, Madrid, Spain

Cutaneous vascular proliferations are exceedingly common, and with the recent identification of new diseases, their diagnosis, classification, and treatment can be complicated. In Pathology of Vascular Skin Lesions: Clinicopathologic Correlations, Omar P. Sangüeza, MD, and Luis Requena, MD, review in detail all the vascular proliferations involving the skin and subcutaneous tissue, including recently described disease entities. Superbly illustrated with both clinical and histopathologic photographs, the book moves from a proposed new system of classification and nomenclature for vascular neoplasms, to a full discussion of benign and malignant proliferations, including hamartomas, benign neoplasms, and several newly reported related diseases. The authors provide an in-depth description of the clinical and morphologic aspects of each entity and detail their clinicopathologic correlation, differential diagnosis, prognosis, and therapy. Additional chapters outline the normal embryology, histology, and anatomy of skin vasculature, as well as the use of special techniques for the study of vascular proliferations. An accompanying CDROM provides precise color versions of all illustrations appearing in the book. Comprehensive and practical, Pathology of Vascular Skin Lesions: Clinicopathologic Correlations provides dermatologists, pathologists, and skin researchers with a complete, authoritative guide to the diagnosis and treatment of vascular proliferations of the skin, all generously illustrated with a wide-ranging array of clinical cases and histopathologic specimens. FEATURES • Accompanying CD-ROM with color versions of all illustrations appearing in the book • A new system of classification and nomenclature for vascular neoplasms

• Comprehensive and up-to-date guide to benign and malignant proliferations of the skin • Clinical and histopathologic pictures of all described vascular proliferations of the skin

CONTENTS Embryology, Anatomy, and Histology of the Vasculature of the Skin. Special Techniques for the Study of Vessels and Vascular Proliferations. Classification of Cutaneous Vascular Proliferations. Cutaneous Vascular Hamartomas. Cutaneous Vascular Malformations. Cutaneous Lesions Characterized by Dilation of Preexisting Vessels. Cutaneous Vascular Hyperplasias. Benign Neoplasms. Malignant Neoplasms. Other Cutaneous Neoplasms With Significant Vascular Component. Disorders Erroneously Considered as Vascular Neoplasms. Index.

90000

CD-ROM Included Current Clinical Pathology™ Pathology of Vascular Skin Lesions: Clinicopathologic Correlations ISBN: 1-58829-182-0 E-ISBN: 1-59259-360-7 humanapress.com

9 781588 291820

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