Section 2 -

Hemangioendothelioma: Borderline Vascular Tumors Sharon W. Weiss Department of Pathology and Laboratory Medicine Emory University

Introduction "Hemangioendothelioma," a term proposed in the 1980's for vascular tumors with borderline histologic features, is currently used to refer to vascular tumors with borderline biologic behavior. [1, 2] Such lesions can be locally aggressive and/or display metastasis but at a significantly reduced rate compared to angiosarcoma. They can be divided into 3 categories: The first, most indolent group, consistently have a benign appearance, nearly always occur in children and young adults and display, in part, lymphatic vascular differentiation. The second more aggressive group display a wider range in histologic appearance, usually occur in adults, and display blood vascular differentiation. The last group are incompletely characterized and, hence, provisionally considered hemangioendotheliomas. I. Consistently Histologically Benign and Rarely Metastasize Kaposiform Hemangioendothelioma The kaposiform hemangioendothelioma is a rare tumor, often associated with lymphatic abnormalities and Kasabach Merritt phenomenon (KMP), which occurs nearly exclusively during the childhood. One half occurring during the first year of life alone. [3] It has features common to both capillary hemangioma and Kaposi sarcoma, and for that reasons many terms have been used for these tumors including "kaposi-like infantile hemangioendothelioma" and "hemangioma with Kaposi sarcoma-like features." On the skin they present as an ill-defined violaceous plaque. In deep soft tissue the tumor infiltrates as multiple coarse nodules which often evoke a striking desmoplasia. Alternating between areas resembling a capillary hemangiomas and Kaposi's sarcoma, the nodules are punctuated by glomeruloid structures, a signature feature of the lesion. Consisting of small CD31-positive vessels surrounded by actin-positive pericytes the glomeruloid structures seem to be specialized zones of platelet and red cell destruction. When carefully studied, most kaposiform hemangioendotheliomas have an impressive lymphatic component consisting of thin-walled vessels surrounding the vascular tumor nodules or in the extreme case by a discrete lymphangioma. Immunohistochemically, these tumors have a profile which suggests the participation of both blood vascular and lymphatic components. Most cells within the tumors express the vascular markers CD31, CD34, and fli1 protein whereas the peripheral lymphatic component noted above express lymphatic markers (e.g. D240). These lesions show no tendency to regress and the eventual outcome is strongly influenced by site, clinical extent, and the development of consumption coagulopathy. A majority of patients can be cured following surgical excision of the tumor. Death occurs in about 10% of patients either from the local effects of disease or from complications of KMP. [3] Regional lymph nodes metastases are rare; to date distant metastases have not been reported. However, given the fact that fewer than 100 cases have been reported it is not inconceivable that the potential for distant metastasis exists but at a very low and as yet undetectable, rate. Hobnail Hemangioendothelioma (Retiform and Dabska-type Hemangioendothelioma) Hobnail hemangioendothelioma encompass two entities which have overlapping clinical and histologic features: the retiform hemangioendothelioma [4] and Dabska-type hemangioendothelioma [5, 6] both of which are characterized by a hobnail or cuboidal endothelial cell. This cell is identified by its apically placed, occasionally grooved, nucleus which produces a surface "hobnail" or "matchstick" bulge. They vary in size and shape from small lymphocytoid cells with a high nucleo-cytoplasmic ratio to larger cuboidal or tall columnar cells. Hobnail hemangioendothelioma may be seen in children and young adults, although lesions with classic features of the Dabska tumor typically occur in children, whereas retiform ones more commonly occur in adults (mean 4th decade). Both, however, develop as an ill-defined or plaque like lesion of the skin and subcutaneous tissue sometimes associated with overlying violaceous discoloration. About one half of cases occur in the distal portion of the extremity but other sites may be affected. The Dabska type hemangioendothelioma, also termed papillary intralymphatic angioendothelioma (PILA), [6] is characterized by well formed vessel set against a backdrop of a lymphangioma or hemangioma. The vessels are lined by cuboidal endothelium which form intraluminal papillations containing hyaline cores. The retiform hemangioendothelioma, consists of numerous elongated vessels, resembling the shape of the rete testis, which replace the dermis and extend into subcutis. They are lined by a single layer of hobnail endothelial cells. [4] The vessels, often surrounded by a hyaline sclerosis and lymphocytes, intercommunicate with one another, but dissection of the collagen planes by small groups of endothelial cells, as is seen in conventional angiosarcoma, does not occur. Intraluminal papillary are rare to absent. The immunohistochemistry of the Dabska and retiform is remarkably similar. The neoplastic endothelial cells express CD31, CD34, and VEGFR-3. This staining profile, in association with weak staining for von Willebrand factor, is quite consistent with a tumor of lymphatic differentiation and has led to the term "papillary intralymphatic angioendothelioma (PILA)." [6] Hobnail hemangioendotheliomas, whether of the Dabska or retiform type, appear to be low grade lesions with a limited capacity for regional lymph node metastasis. Sixty percent of patients with retiform hemangioendotheliomas developed local recurrence and 1 of 14 patients developed a lymph node metastasis. [4] In the series of Dabska-type hemangioendotheliomas, reported by Fanburg-Smith et al, none of the 8 cases developed recurrence or metastasis within a median follow up of 9 years. [6] II. Wider Histologic Range and Metastasize More Frequently Epithelioid Hemangioendothelioma This epithelioid hemangioendotheliomas, unlike lesions in the first category, occurs in patients of all ages. It develops as a solitary, superficial or deep soft tissue mass which, unlike virtually all other vascular tumors, commonly arises from a vessel and extends centrifugally from the lumen to the soft tissue. [8, 9, 10] The tumors are composed of short cords or solid nests of rounded to slightly spindled endothelial cells which are embedded in a distinctive matrix which varies from chondroid to hyaline-appearing. The epithelioid endothelial cells typically display a vacuole, or miniature lumen, which "blisters" the cell. The cells are strongly CD31 positive and often weakly or focally cytokeratin positive. Although this tumor is capable of producing regional and distant metastasis, it does so far less frequently than conventional angiosarcoma. Approximately 10-20% of patients develop recurrences and 30% metastasis to regional lymph nodes, lung, liver, and bone. Fewer than half of the patients who develop metastases die of their disease, however, probably because many develop lymph node metastases only. Metastasis usually occurs with tumors having "atypical features" such as cellular atypia, mitotic activity (>1/10 HPF), necrosis, or extensive spindling. This suggests the need to stratify these lesions into two groups: typical and atypical. Because the metastatic rate of epithelioid hemangioendotheliomas is higher than other members of the family of "hemangioendothelioma," the WHO has suggested these be grouped as angiosarcomas. [2] Recently a non random chromosomal translocation t(1:3)(p36.3;q25) has been identified in two cases of epithelioid hemangioendotheliom [7] indicating that this tumor comprises part of the growing list of translocation-associated soft tissue tumors. Category III Lesions with Limited Experience Epithelioid sarcoma like hemangioendothelioma [11] and composite hemangioendothelioma [12] have been reported in two small series and are provisionally considered hemangioendothelioma. The former consists of sheets or clusters of eosinophilic "epithelioid" cells having a keratin-positive, CD31-positive phenotype and grows as multiple nodules in either superficial or deep soft tissue similar to an epithelioid sarcoma. There is usually little or no evidence of vasoformation by light microscopy and diagnosis, therefore, depends on confirmatory immunohistochemistry. To date this tumor has been characterized by either by local recurrences and/regional metastasis. Composite hemangioendothelioma, as the name implies contains mixtures of patterns: epithelioid and retiform hemangioendothelioma, spindle cell hemangioma, and low and high grade angiosarcoma References Weiss, SW, Goldblum JR Enzinger and Weiss's Soft Tissue Tumors, CV Mosby, Philadelphia, 2001, pp 891-915. Fletcher, CDM, Unni, KK, Mertens, F: Tumors of Soft Tissue and Bone. World Health Organization Classification of Tumours, IARC Press, Lyon, France, 2002, pp. 163-177. Lyons LL, North PE, Mac-Moune Lai F, et al. Kaposiform hemangioendothelioma: a study of 33 cases emphasizing its pathologic, immunophenotypic, and biologic uniqueness from juvenile hemangiomas. Amer J Surg Pathol 28:559, 2004. 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 18:115, 1994. Dabska M: Malignant endovascular papillary angioendothelioma of the skin in childhood. Cancer 24:503, 1969. Fanburg-Smith, JC, Michal, M, Partanen et al: Papillary intralymphatic angioendothelioma (PILA): a report of twelve cases of a distinctive vascular tumor with phenotypic feature of lymphatic vessels. Am J Surg Pathol 23:1004, 1999. Mendlick, MR, Nelson, M, Pickering, D, et al: Translocation t(w:3)(p36;q25) is a non random aberration in epithelioid hemangioendothelioma. Amer J Surg Pathol 25:684-7, 2001. Mentzel, T, Beham, A, Calonje, E, Katenkamp, D, Fletcher, CD: Epithelioid hemangioendothelioma of skin and soft tissues: clinicopathologic and immunohistochemical study of 30 cases. Amer J Surg Pathol 21:363, 1997. Weiss SW, Enzinger FM: Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer 50:970, 1982. Weiss SW, Ishak KG, Dail DH, et al: Epithelioid hemangioendothelioma and related lesions. Semin Diagn Pathol 3:259, 1986.. Billings , SD, Folpe , AL, Weiss, SW: Epithelioid sarcoma-like hemangioendothelioma. Amer J Surg Pathol 27:48, 2003. Nayler, SJ, Rubin, BP, Calonje, Chan, JK, Fletcher, CD: Composite hemangioendothelioma: a complex, low-grade vascular lesion mimicking angiosarcoma. Am J Surg Pathol 24:352, 2000.