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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. Acroangio- dermatitis 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). Acroangio- dermatitis 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

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 thick- walled 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 differen- tial 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.

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 simulat- ing 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 (“Pseudo- Kaposi”) 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 Klippel- Trenaunay 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 tuber- culosis, 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 exhib- its 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 clinico-

pathologic 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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8 Benign Neoplasms

CONTENTS

NGIOMA ERPIGINOSUM A S 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 pig- mentation, 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 doubt- ful 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 Blaschko- Linien? 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. Tradi- tionally 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” configu- rations, 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 commen- surate 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. Reex- amination 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 dome- shaped, 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 glo- mangiomas, 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). Consump- tion 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 produc- tion of angiogenic factors that regulate the growth of the lesion (64,65). However, long- standing 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 well- defined 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 deter- mined 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 trans- porter 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 phos- phatase 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 Kasabach- Merritt 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). Hepariniza- tion 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).

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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 out- come 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 kryo- chirurgischen 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)

C LINICAL 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 organ- ism 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).

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 well- circumscribed 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. Dermatol- ogy 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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