Case 2 -

Epithelioid Hemangioendothelioma Brian Rubin University of Washington Medical Center Seattle, WA

Click on each slide thumbnail image for an enlarged view

Clinical History The patient is a 51 year-old man with a history of ulcerative colitis, treated with Imuran. He noted severe right upper quadrant pain while biking, although he had experienced similar, less intense pain for approximately 1 year. Workup revealed several liver lesions. Core needle biopsy was followed by total liver transplantation. Case 2 - Figure 1 - Gross specimen showing a section of liver with several circular lesions of varying sizes (arrows). Case 2 - Figure 2 - There is a prominent angiocentric growth pattern with tumor cells virtually filling the lumen of a small blood vessel. Case 2 - Figure 3 - Nests and cords of epithelioid cells set in a myxohyaline stroma. Case 2 - Figure 4 - Occasional cells have vacuolated cytoplasm. Case 2 - Figure 5 - The lesional cells are diffusely and strongly positive for CD31. Case 2 - Figure 6 - The infiltrative nature of the lesion can be seen as the lesional cells are negative for cytokeratins AE1/AE3, while the entrapped hepatocytes are strongly positive. Immunohistochemical results: The neoplastic cells were diffusely and strongly positive for CD31 and CD34, and negative for cytokeratins AE1/AE3 and CAM5.2 and for epithelial membrane antigen. Diagnosis: Epithelioid Hemangioendothelioma Discussion/Differential Diagnosis: Epithelioid hemangioendothelioma (EHE) was first described as a distinctive vascular tumor of the soft tissues in 1982. [1] In addition to skin and soft tissue, EHE can arise at virtually any anatomic location. However it is most common in lung, [2] liver, [3] and bone. [4] EHE of soft tissue most commonly arises in the head and neck but also tends to occur in the extremities, anogenital region, mediastinum, or abdomen. [1, 5] EHE of lung, liver, and bone is frequently multicentric while soft tissue lesions are usually solitary. Liver lesions occur with a striking female predominance, while EHE at other sites does not show a sex predilection. EHE occurs over a wide age range with a peak in middle age; it is very rare in children. Presenting symptoms are usually referable to a mass lesion. However, some lesions are painful and this is thought to be related to vascular occlusion. According to the latest edition of the WHO Classification of Tumours of Bone and Soft Tissue, EHE is classified as a malignant soft tissue tumor. [6] EHE is locally aggressive and capable of distant metastasis, most commonly to lungs, liver and regional lymph nodes. Death due to EHE does occur, with reported rates from 13% in soft tissue to 35% in liver and 65% in lung. [7] Gross examination reveals a firm ill-defined soft tissue mass. Occasionally, EHE involves a large vessel with infiltration into the surrounding soft tissues. Liver lesions tend to be circular and more well-defined. Individual tumor nodules can be up to 10 cm in greatest dimension. Histologically, EHE exhibits an infiltrative growth pattern with ill defined margins. Approximately 50% involve/arise from blood vessels. When they involve vessels, they expand the vessel, with tumor cells infiltrating in a whirling pattern through the vessel wall into the surrounding tissue. The vessel wall is preserved but the lumen is usually filled with necrotic debris and/or collagen. Importantly, EHE does not usually show vascular differentiation in the form of well-formed blood vessels. It consists of cords and strands of epithelioid cells that are typically set in a variably myxohyaline stroma. Vascular differentiation at the light microscopic level occurs in the form of vacuolated cytoplasm that may or may not possess red blood cells. In some cases, the vacuoles coalesce, giving the impression that the neoplasm is infiltrating adipose tissue. Usually, there is minimal cellular pleomorphism. However, in about 25% of cases, pleomorphism is present and the cells may have a spindled appearance. Mitotic activity is usually less than 1 mitotic figure/10 hpfs and necrosis is uncommon. Occasionally, the neoplastic cells may form nests or solid sheets. It is not unusual for the stroma to be hyalinized densely and in these cases, the neoplastic cells can be few and difficult to identify. Metaplastic bone can also occur in cases that are densely hyalinized. Immunohistochemically, EHE is positive for a variety of endothelial markers including CD31, CD34, and Factor VIII-AG. Approximately 25% of cases are positive for cytokeratin. [5] Electron microscopy reveals features that are typical of endothelial cells including a well developed basal lamina, pinocytotic vesicles, and Weibel Palade bodies. [4, 8] Although the number of cases that have been karyotyped is very small, EHE appears to have a recurrent chromosomal translocation involving chromosomes 1 and 3 [t(1;3)(p36.3;q25)]. This genetic aberration has been identified in two cases (liver and thigh) by Mendlick et al. [9] and we have seen an additional two cases that involved liver and harbored the identical translocation (unpublished). Histologic features appear to predict clinical behavior to some extent, with the presence of significant atypia, mitotic figures >1/10 hpfs, focal spindle cell cytomorphology, and necrosis, portending a worse prognosis. [1, 5, 7] However, it is not possible to predict behavior with absolute certainty based on the above mentioned criteria since lesions without the aforementioned criteria are still capable of aggressive clinical behavior including the ability to metastasize. Furthermore, it is possible that there is a histologic continuum between EHE and epithelioid angiosarcoma; absolutely reliable criteria do not exist to separate "high grade/malignant" EHE from epithelioid angiosarcoma. At the present time, all EHE should be regarded as malignant for treatment purposes, with wide local excision being the treatment of choice. The differential diagnosis of EHE is broad and includes primarily carcinoma, melanoma, epithelioid sarcoma, and epithelioid angiosarcoma. Carcinoma and melanoma usually show a greater degree of cytologic pleomorphism and are negative for vascular markers. In contrast to poorly differentiated adenocarcinoma, the cytoplasmic vacuoles of EHE do not contain mucin. However, it is important to emphasize that approximately 25% of EHE are positive for cytokeratin, and thus, this is a potential diagnostic pitfall. Unlike melanoma, which is virtually always positive for S-100, EHE is negative for this antigen. Epithelioid sarcoma can be difficult to distinguish from EHE, especially in those cases of EHE with extensive hyalinized stroma. This is further compounded by the immunohistochemical profile of epithelioid sarcoma, which is usually positive for cytokeratins and CD34. However, epithelioid sarcoma is negative for CD31 and usually exhibits a granulomatous growth pattern with central caseating necrosis. As mentioned above, it can be difficult to distinguish higher grade appearing forms of EHE from epithelioid angiosarcoma since they can both have a sheet like growth pattern and are positive for endothelial markers. However, in general, epithelioid angiosarcoma exhibits a greater degree of cellular atypia/pleomorphism, is mitotically active, and frequently has necrosis. References Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer 1982;50:970-81. Dail DH, Liebow AA, Gremlich JT. Intravascular bronchiolar, and alveolar tumor of lung (IVBAT): an analysis of twenty cases of a peculiar sclerosing endothelial tumor. Cancer 1983;51:452-64. Ishak KG, Sesterhenn IA, Goodman ZD, et al. Epithelioid hemangioendothelioma of the liver: a clinicopathologic and follow up study of 32 cases. Human Pathol1984;15:839-52. Tsuneyoshi M, Dorfman HD, Bauer TW. Epithelioid hemangioendothelioma of bone, a clinicopathologic, ultrastructural and immunohistochemical study. Am J Surg Pathol 1986;10:754-64. Mentzel T, Beham A, Calonje E, et al. Epithelioid hemangioendothelioma of skin and soft tissues: clinicopathologic and immunohistochemical study of 30 cases. Am J Surg Pathol 1997;21:363-74. Fletcher CDM, Unni KK, Mertens F. (Eds): World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. IARC Press: Lyon 2002. Weiss SW, Ishak KG, Dail DH, et al. Epithelioid hemangioendothelioma and related lesions. Semin Diagn Pathol 1986;3:259-87. Angervall L, Kindblom L-G, Karlsson K, et al. Atypical hemangioendothelioma of venous origin. A clinicopathologic, angiographic, immunohistochemical, and ultrastructural study of two endothelial tumors within the concept of histiocytoid hemangioma. Am J Surg Pathol 1985;9:504-16. Mendlick MR, Nelson M, Pickering D, et al. Translocation t(1;3)(p36.3;q25) is a nonrandom aberration in epithelioid hemangioendothelioma. Am J SurgPathol 2001;25:684-87.