Vascular Tumors Ed Clinically, Ranging from Dermal Melanocytic Nevus and Heman- Gioma to Fibrous Histiocytoma (6)

Home , Angiofibroma, Angioma, Angiosarcoma, Hemangioendothelioma, Lymphangiomatosis, Microvenular hemangioma

1999; Vol. 32, Nº 3 New entities in pathology ofsoft tissue tumors

7. Gerald WL, Ladanyi M, de Álava E at al. Clinical, Pathologic and molecular diagnoses include rare tufted hemangioma and “targetoid hemo- spectrum of tumors associated with t(11;22)(p13;q12): Desmoplastic small siderotic hemangioma” (see below). round cell tumorand its variants.J Olin Oncol 1998; 16: 3028-3036. 8. Antoneacu CR, Gerald WL, Magid MS at al. Molecular variants of the EWS- Hobnail hemangioma WT1 gene fusion in desmoplastic small round cell tumor. Diagn Mol Pathol 1998; 7: 24-28. (“targetoid hemosiderotic hemangioma” 9. de Álava E, Ladanyi M, Rosai J, Gerald WL, Detection ofchimeric transcripts Hobnail hemangioma is a further recently recognized benign vas- in desmoplastic small round cell tumor and related developmental tumors by cular lesion. The original term “targetoid hemosiderotic heman- reverse transcriptase polymerase chain reaction. A specific diagnostic assay gioma” resulted from the characteristic targetoid clinical appear- Am J Pathol 1995; 147: 1584-1591. 10. Katz RL, Quezado M, Senderowicz AM et al. Anintra-abdominalsmall round cell ance (4). Further expanded clinicopathological studies have shown neoplasm with features of primitive neuroectodermal and desmoplastic round clearly that most vascular lesions showing histological features of cell tumorand a EWS/FLI-1 fusion transcript Hum Pathol 1997; 28: 502-509. this distinctive neoplasm lack this clinical appearance, which is also 11. Ordi J, de Álava E, Tome A at al. lntraabdominal desmoplastic small round cell evident in other conditions (5, 6). In order to emphasize the inde- tumorwith EWS/ERG fusion transcript. Am J Surg Pathol 1998; 22:1026-1032. pendent diagnostic hobnail cytomorphology it the targetoid appearance is evident, the alternative term of hobnail hemangioma was proposed (5, 7). Hobnail hemangioma represents a superficially located lesion in which a broad spectrum of diagnoses is suggest- Vascular tumors ed clinically, ranging from dermal melanocytic nevus and hemangioma to fibrous histiocytoma (6). It affects mainly adults with a T. Mentzel slight male predominance; most common anatomic locations are the extremities and the trunk (6), and rare cases were reported in the Dept. of Pathology University of Jena, Germany head and neck region (5, 8). Diagnostic criteria of hobnail hemangioma are a biphasic growth pattern (dilated vascular spaces on the surface and more narrow vascular spaces infiltrating deeper Introduction parts of the dermis) and a hobnail cytomorphology of neoplastic endothelial cells (plump and prominent cells with scanty, ill-defined Vascular tumors are a large and heterogeneous group of mes- cytoplasm and large, mostly hyperchromatic nuclei). Further fea- enchymal lesions and Span a broad spectrum of morphology and tures include an associated lymphocytic infiltrate, fibrosis of the clinical behavior. Despite recent developments, the exact classifi- dermal collagen and hemosiderin deposits. These morphological cation of vascular tumors is still problematic because conceptual features vary according to the age of the neoplasm. More mature confusion persists in the distinction between vascular malforma- examples are composed predominantly of narrow vascular struc- tions, reactive and truly neoplastic endothelial lesions. In addition, tures, and in few cases overlapping features to retiform heman- there exists an expanding group of vascular neoplasms in which morphological features do not predict reliably the clinical behavior, gloendothelioma (see below) were noted (5). In contrast, “early” examples of hobnail hemangioma are mainly composed of dilated as well as benign vascular neoplasms that closely mimic more vascular structures in the upper dermis resembling features of aggressive lesions (i.e., angiosarcoma, Kaposi’s sarcoma) (1). In this review, recently characterized vascular tumors of skin and soft early Kaposi’s sarcoma and lymphangioma (4, 6). Immunohisto- tissues are briefly discussed, including benign and low-grade chemically, endothelial cells stain positively for CD31, whereas malignant lesions which simulate early forms of Kaposi’s sarcoma CD34 stains only a minority of cases (6). In contrast to other benign and aggressive angiosarcoma. neoplasms of blood vessels, neoplastic vascular structures are not surrounded by a complete layer of actin-positive pericytes (5, 6). Microvenular hemangioma Furthermore, a limited number of cases stained positively for vascular endothelial growth factor receptor (VEGFR-3) (6), a recently Microvenular hemangioma is a distinctive vascular proliferation in described marker of lymphatic endothelial cells. These results and the spectrum ofcapillary hemangiomas which is easily mistaken for early Kaposi’s sarcoma or cutaneous angiosarcoma. Clinically, the evidence ot associated lymphocytes and the described mor- most cases present as a small, enlarging papule on the limbs of phological features suggest a lymphatic line of differentiation of young to middle-aged adults (2). Histologically, a proliferation of neoplastic cells in hobnail hemangioma (6). Despite the bland clin- irregularly branching, thin-walled venules is seen, which infiltrate ical picture, hobnail hemangioma may show worrisome histological the sclerotic dermal collagen. These narrow neoplastic vascular features and the diagnosis ofpatch- or lymphangioma-like Kaposi’s structures are lined by inconspicuous, sometimes plump endothe- sarcoma, well-differentiated angiosarcoma, and retiform heman- lial cells surrounded by actin-positive pericytes. No prominent gloendothelioma is suspected. In addition to different clinical fea- inflammatory infiltrate or hemosiderin deposits are noted. The evi- tures of evolving Kaposi’s sarcoma, hobnail hemangioma is char- dence of lobular aggregates of small capillaries in deeper parts of acterized by a biphasic growth pattern and hemosiderin deposits. some lesions suggests a close relationship to ordinary capillary Early examples of Kaposi’s sarcoma are seen in the reticular but hemangioma (3). The main differential diagnosis of microvenular not in the papillary dermis, show an adnexocentric growth and fre- hemangioma is patch-stage Kaposi’s sarcoma. However, the lack quently contain plasma cells. Cutaneous angiosarcoma occurs irregular anastomosing vascular spaces, plasma cells and hyaline mainly in the head and neck region of elderly patients, and is char- globules is of help in the distinction of microvenular hemangioma. acterized morphologically by anastomosing vascular structures Anastomosing neoplastic vascular structures in aggressive cuta- lined by atypical and proliferative active endothelial cells. Low- neous angiosarcoma are lined by atypical endothelial cells. In addi- grade malignant retiform hemangioendothelioma presents clinically tion, no biphasic proliferation of CD31+ endothelial cells and actin- usually as an exophytic or plaque-like vascular tumor and is charac- positive pericytes is evident in angiosarcoma. Further differential terized by a high rate of often repeated local recurrences (7). The

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small size ofcircumscribed hobnail hemangioma is ofhelp in the dis- Within the lobules, short cellular fascicles of spindle-shaped cells tinction of both entities, however, there are rare neoplasms showing are intertwined with slit-like vascular spaces reminiscent of those overlapping morphological features between both entities (5). seen in Kaposi’s sarcoma. Ectatic capillaries lined by flat endothelial cells containing frequently hyaline thrombi are found in the Retiform hemangioendothelioma periphery of some tumor lobules. Occasionally, small nests of Retiform hemangioendothelioma (RHE) is a distinctive vascular polygonal epithelioid cells are scattered throughout the neoplasms neoplasm that arises mainly in the distal extremities of young (15). Immunohistochemical markers confirm the endothelial nature adults. Occasionally, it is seen on the trunk, penis, orscalp (7), and of the elongated cells that line the narrow vascular spaces, and rare cases of multicentric lesions were reported (9). Clinically, RHE intralesional pericytes that stain positively for smooth muscle actin is characterized by an infiltrative growth pattern and a high rate of are also seen; spindle cells may be positive for 0D34 focally. In local recurrences, but metastasis to a lymph node has only been adults, KHE has to be distinguished from nodular Kaposi’s sarco- seen in one patient so far (7). The morphologic hallmark of RHE is ma. The lack of a lobulargrowth pattern and dilated capillaries with long, arborizing, thin-walled vascular spaces that infiltrate in a reti- hyaline thrombi in Kaposi’s sarcoma, which is often associated with form pattern reminiscent of the normal rete testis. The neoplastic chronic inflammatory infiltrate, is of help. In addition, tumor cells in vascular spaces are lined by a single layer of monomorphic hobnail Kaposi’s sarcoma stain constantly positive for 0D34 and are actin endothelial cells without prominent atypia and increased mitotic negative. Spindle cell hemangioma (“spindle cell hemangioen- activity. Solid areas composed of plump oval or polygonal neoplas- dothelioma”) is seen mainly in the distal extremities, and shows his- tic cells are often present in deeper parts of lesions, whereas tologically a biphasic pattern of cavernous vascular structures and superficially, dilated vascular structures with intraluminal papillary ramifying vascular spaces associated with bland spindle cells and projections are infrequently evident. Neoplastic cells are positive scattered epithelioid endothelial cells. In a superficial location KHE for endothelial markers, but surrounding actin-positive pericytes must be distinguished also from tufted hemangioma. Tufted are not evident. A prominent lymphocytic infiltrate composed of hemangioma is characterized by an irregular, cannon-ball distribu- mature B and T lymphocytes is present in at least 50% of cases. tion of vascular tufts and lacks lymphangiomatous changes (16). The most important differential diagnosis of RHEis aggressive cuta-

neous angiosarcoma, which may show focally, retiform features as Polymorphou s hemangioendothelioma well. However, cutaneous angiosarcoma occurs primarily in the head Polymorphous hemangioendothelioma (PHE) is an exceedingly and neck region of elderly patients and is characterized by anasto- rare neoplasm that was first described in lymph nodes (17) and mosing and dissecting vascular spaces lined by atypical endothelial subsequently in extranodal soft tissue (18). In one of the four cells that are often arranged in layers and tufts. Malignant endovas- patients with follow-up information, local recurrence and pulmonary cular papillary angioendothelioma (Dabska tumor) is a further rare metastasis developed, and the patient died. At the moment, PHE vascular neoplasm composed of hobnail endothelial cells. Although should be best regarded as a vascular tumor of low-grade malig- described almost 30 years ago (10), it still represents a vascular lesion which is poorly understood and in which it is difficult to repro- nancy. Histologically, PHE is characterized by solid zones of poly- duce diagnostic criteria. In contrast to the original description, it has gonal tumorcells admixed with an angiomatous component showing clefts and groups of ectatic vascular spaces lined by plump hobnail also been reported in adult patients, and a rather benign clinical behavior has recently been proposed (11). At the moment it seems endothelial cells without striking afypia and proliferative activity. that Dabska tumor comprises a morphological spectrum of lesions The polygonal cells contain scant cytoplasm and uniform oval or showing overlap with retiform hemangioendothelioma (12) and other round nuclei. Neoplastic cells are positive variably for different vascular entities. endothelial markers. In contrast to spindle cell hemangioma, PHE does not contain spindle cell fascicles but solid tumor areas. The Kaposiform hemangioendothelioma absence of epithelioid endothelial cells with characteristic cytoplas- micvacuoles as well as the lack of myxohyaline stroma are of help Kaposiform hemangioendothelioma (KHE) is a recently recog- in distinguishing PHE from epithelioid hemangioendothelioma. nized, uncommon vascular neoplasm that occurs most frequently Most importantly, PHE must be separated from angiosarcoma and in neonates and young children and appears as a solitary lesion in metastatic carcinoma. Angiosarcoma shows dissecting and anas- deep soft tissues of the retroperitoneum, chest wall, upper extrem- tomosing vascular channels lined by atypical endothelial cells. ities, and head and neck region (13, 14). More recently, KHE has Special stains and immunohistochemical markers enable the also been found in dermal and subcutaneous tissue of adult exclusion of metastatic carcinoma. patients (15). KHE is sometimes associated with intestinal obstruc- tion, jaundice or Kasabach-Merritt syndrome, and in rare cases References features of lymphangiomatosis are seen. KHE was regarded as a 1. Fletcher 0DM. Vascular tumors: An update with emphasis on the diagnosis of low-grade malignant vascular neoplasm because it sometimes pur- angiosarcoma and borderline vascular neoplasms. In: Weiss SW, Brooks JSJ. sues an aggressive clinical course. Although KHE is associated (Eds.). Soft Tissue Tumors. Willliams & Wilkins, Baltimore, 1996; 181-206. with a relatively high mortality rate, deaths are almost always relat- 2. Hunt SJ, Santa Cruz DJ, Barr RJ. Microvenular hemangioma. J Cutan Pathol ed to locally invasive effects or as a result of bleeding and con- 1991; 18: 235-240. sumption coagulopathy. To date, no metastasis of KHE has been 3. Aloi F, Tomasini C, Pippione M. Microvenular hemangioma. Am J recorded, and small and superficially located lesions amenable to Dermatopathol 1993; 15: 534-538. 4. Santa Cruz DJ, Aronberg J. Targetoid hemosiderotic hemangioma. J Am Acad complete surgical excision are characterized by a favorable clinical Dermatol 1988; 19: 550-558. course. It seems best to classify KHE as a locally aggressive but 5. Guillou L, Calonie E, Speight P et al. Hobnail hemangioma: A benign vascular nonmetastasizing vascular neoplasm. KHE is characterized by cel- lesion mimicking patch stage Kaposi’s sarcoma and retiform hemangioen- lular lobules of neoplastic cells that are separated by fibrous septa. dothelioma. Am J Surg Pathol 1999.

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6. Mentzel T, Kutzner, K. Hobnail hemangioma (“targetoid hemosiderotic hae- Collagenous fibroma (desmoplastic fibroblastoma mangioma”): Clinicopathologic and immunohistochemical analysis of 62 cases. J Cutan Pathol (submitted). Desmoplastic fibroblastoma was first described by Evans (1) and 7. Calonje E, Fletcher CDM, Wilson-Jones E et al. Retiform hemangioendothe- has subsequently been renamed “collagenous fibroma” for fairly lioma. A distinctive form oflow-grade angiosarcoma delineated in a series of sound linguistic reasons (2, 3). Collagenous fibroma affects mainly 15 cases. Am J Surg Pathol 1994; 18:115-125. adults (most often over the age of 40) with a male predominance 8. Santonja C, Torrelo A. Hobnail hemangioma. Dermatology 1995; 191: 154- and presents usually as a painless, slowly growing subcutaneous 156. mass, most often less than 4 cmin diameter (although larger lesions g. Duke D, Dvorak AM, Harris TJ et al. Multiple retiform hemangioendotheliomas. A low-grade angiosarcoma. Am J Dermatopathol 1996; 18: 606-610. do occur). The anatomical distribution is wide, with some predilection 10. Dabska M. Malignant endovascularpapillary angioendothelioma of the skin in for the upper limb and shoulder regions and occasional cases are childhood. Clinicopathologic study of 6 cases. Cancer 1969; 24: 503-510. intramuscular. These lesions seem not to recur locally, 11. Fanburg-Smith JC, Michal M, Miettinen M. Dabska tumor(malignant endovas- Grossly collagenous fibromas appear fusiform or ovoid, firm and cular papillary angioendothelioma), Study of 10 cases. Archives D’Anatomie et rubbery and well circumscribed but, histologically, most cases have de Cytologie Pathologiques. Clin Exp Pathol 1998; 46: 1 7A. infiltrative margins with entrapment of fat or skeletal muscle. They 12. Sanz-Trelles A, Rodrigo Fernández I, Ayala-Carbonero A et pal. Retiform hemangioendothelioma. A new case in a child with diffuse endovascular pap- are often centered on fascial or aponeurotic tissue and are com- illary endothelial proliferation. J Cutan Pathol 1997; 24: 440-444. posed of spindle-shaped or stellate fibroblasts, sparsely and hap- 13. Tsang WYW, Chan JKC. Kaposi-like infantile hemangioendothelioma. A dis- hazardly distributed in a copious collagenous or focally myxoid tinctive vascular tumor of the retroperitoneum. Am J Surg Pathol 1991; 15: matrix containing very few blood vessels, Tumor cell nuclei are main- 982-989. ly ovoid with small nucleoli and mitoses are generally absent or very 14. Zukerberg LR, Nicoloff BJ, Weiss SW. Kaposiform hemangioendothelioma of hard to find. Necrosis and cytologic atypia are not seen. infancy and childhood. An aggressive neoplasm associated with Kasabach- Immunohistochemistry shows focal actin (smooth muscle actin or Merrill syndrome and lymphangiomatosis. Am J Surg Pathol 1993; 17: 321- 328. HHF35) positivity in many cases and, as with other lesions having a 15. Mentzel T, Mazzoleni G, Del Tos AP et al. Kaposiform hemangioendothelioma myofibroblastic component, rare keratin-positive cells may be seen. in adults. Clinicopathologic and immunohistochemcialanalysis of three cases. Differential diagnosis includes principally nodular fasciitis, Am J Clin Pathol 1997; 108: 450-455. which generally affects younger patients, is both more cellular and 16. Wilson-Jones E, Orkin M. Tuftedangioma (angioblastoma): A benign progres- more vascular and often shows microcystic and inflammatory com- sive angioma not to be confused with Kaposi’s sarcoma orlow-grade angiosar- ponents; fibroma of tendon sheath, which generally arises in the coma. JAm Acad Dermatol 1989; 20: 214-225. hands or feet, is better circumscribed, often more cellular and con- 17. Chan JKC, Frizzera G, Fletcher CDM et pal. Primary vascular tumors of lymph nodes other than Kaposi’s sarcoma, Analysis of 3g cases and delineation of tains slit-like vascular channels; and desmoid fibromatosis, which two new entities. Am J Surg Pathol 1992; 16: 335-350. is usually deep-seated, more cellular and has a consistently fasci- 18. Nascimento AG, Keeney GL, Sciot R et al. Polymorphous hemangioendothe- cular growth pattern. lioma. A report of two cases, one affecting extranodal soft tissues, and review of the literature, Am J Surg Pathol 1997; 21: 1083-1089. Giant cell angiofibroma Giant cell angiofibroma is an uncommon fibroblastic neoplasm which was first described in the orbital region (4). It has subsequently become clear that giant cell angiofibroma may also occur outside the orbital region (5) and cases may even occur on the Fibrous and myofibroblastic tumors trunk and the extremities (personal unpublished observations). Nevertheless, based on our experience of more than 30 cases, most C.D.M. Fletcher examples of giant cell angiofibroma occur in the head and neck region of adults with a slight predilection for males. Occasional cases Dept. of Pathology Harvard Medical SChool and Brigham and recur locally in a nondestructive fashion but I have not to date Women’s Hospital, Boston, Massachusetts, USA. encountered a case which metastasized, Giant cell angiofibromas are relatively circumscribed neoplasms characterized by a rather patternless growth of round or Introduction plump spindled tumor cells admixed with multinucleate giant cells, set in a collagenized or myxoid matrix with a prominent network of In the past, a very wide variety of tumorS were labelled as “fibroma” small blood vessels. Hyalinization of vessel walls may be promi- or “fibrosarcoma” without further qualification. With time, these nent. Tumor cells of giant cell angiofibroma have ill-defined palely generic terms have been shown to subsume a spectrum of numer- eosinophilic cytoplasm and plump nuclei which often show irregu- ous reactive and neoplastic lesions with striking clinicopathological lar folding and pseudoinclusions. In most cases irregularly shaped differences and often different therapeutic implications, With the pseudovascular spaces are noted, and these are lined by mononu- advent of electron microscopy and immunohistochemistry it has clear and multinucleate tumor cells. Mitotic figures are very rare. become clear that many so-called fibrous lesions show, in varying Immunohistochemically, tumor cells are strongly positive for CD34, degree, both fjbroblastic and myofibroblastic differentiation (the whereas myogenic and epithelial markers as well as S-100 protein fibromatoses and fasciitis family being prime examples). It remains and CD31 are negative. a matter of controversy whether these are functional variants of a In contrast to giant cell angiofibroma, giant cell fibroblastoma single cell type or whether there exist primarily myofibroblastic occurs mainly in early childhood and is characterized by a diffusely lesions. By necessity, this brief overview focuses only on some of infiltrative growth and a high rate of local recurrence. Morpholo- the lesions which have been characterized (or more clearly under- gically, giant cell fibroblastoma lacks the prominent vascular pattern stood) in the past 5 years. characteristic of giant cell angiofibroma. More complicated seems

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