Epithelioid Haemangioendothelioma

Epithelioid haemangioendothelioma of somatic soft tissue should be staged according to the American Joint Committee on Cancer (AJCC) eighth-edition TNM staging system for soft tissue sarcoma of the trunk and extremities. For tumors occurring within the abdominal and thoracic cavities, AJCC eighth-edition staging is not applicable. Instead, it is recommended that the size of the largest lesion is recorded if possible.

Epithelioid haemangioendothelioma is characterized by a t(1;3)(p36;q23-q25) resulting in a WWTR1-CAMTA1 fusion in > 90% of cases. The translocation is present in tumors across all anatomical sites and clinical behaviors. The WWTR1 (TAZ) protein is one of two end effectors of the Hippo pathway, a highly conserved tumor suppressive signal transduction pathway. Fusion of WWTR1 (TAZ) to CAMTA1 results in dysregulation of the Hippo pathway, such that WWTR1-CAMTA1 resides constitutively in the nucleus, driving oncogenic transformation.
A separate translocation event, YAP1-TFE3, has been identified in a subset of epithelioid haemangioendotheliomas with distinct morphological features. YAP1, similar to WWTR1 (TAZ), is a downstream transcriptional regulator of the Hippo pathway, and there is substantial sequence homology between the two proteins. TFE3, a well-known oncogenic transcription factor involved in other soft tissue tumor translocations, is upregulated in these lesions as a result of this fusion.

Tumors in visceral or deep soft tissue locations are usually larger than superficial ones, and they may measure > 10 cm. The cut surface is typically white and firm. For soft tissue tumors that arise from a small to medium-sized vein (as many as 50%), origin from a vessel can be grossly identifiable, usually as a firm, tan-tinged mass circumscribed by the vessel wall.

Angiocentric tumors expand the vessel wall, obliterate the lumen, and spread centrifugally into surrounding tissue, where they induce a sclerotic response. Infiltrative growth into adjacent skeletal muscle or fat may be seen. Epithelioid haemangioendothelioma is characterized by cords and nests of epithelioid cells in a myxohyaline stroma. Tumor cells have moderate amounts of eosinophilic cytoplasm and round nuclei with inconspicuous nucleoli. Intracytoplasmic vacuoles are sometimes present and may contain erythrocytes. In most cases, there is only minimal atypia and mitotic count is very low. The stroma is variably myxoid and hyaline; in some cases, hyaline stroma may obscure the tumor cells. Cystic degeneration, hemorrhage, sclerosis, and metaplastic ossification may be present.
Epithelioid haemangioendothelioma with YAP1-TFE3 fusion shows distinctive histological features. The tumor cells usually have brightly eosinophilic cytoplasm and are more likely to show solid growth and often form vascular spaces; the latter feature is generally not seen in the classic form of epithelioid haemangioendothelioma.

A small subset (< 10%) of epithelioid haemangioendotheliomas have atypical histological features, including nuclear pleomorphism, increased mitotic activity, solid sheet-like growth, and necrosis. In some cases, these tumors may resemble epithelioid angiosarcoma. In such cases, the presence of areas of conventional epithelioid haemangioendothelioma or nuclear CAMTA1 expression supports the diagnosis. This latter group of lesions is often associated with more aggressive behavior. The tumor cells of epithelioid haemangioendothelioma express the endothelial markers CD34, CD31, podoplanin (D2-40), FLI1, and ERG; however, there may be substantial variability in the degree of staining for a given marker. Epithelial antigens are expressed in as many as 40% of cases (CK7, CK8, CK18, pan-keratin), but expression of EMA is unusual. SMA expression is present in approximately 50% of cases. Epithelioid haemangioendothelioma with WWTR1-CAMTA1 typically shows diffuse strong nuclear expression of CAMTA1, which is a surrogate for the WWTR1-CAMTA1 fusion protein. Tumors with YAP1-TFE3 fusion show diffuse nuclear TFE3 expression; however, TFE3 is less specific in this regard, because expression can be seen in tumors with WWTR1-CAMTA1 fusion.

Not clinically relevant

The prognosis differs depending on the anatomical site. Epithelioid haemangioendotheliomas of soft tissues can be indolent; however, approximately 21% will metastasize and pursue an aggressive clinical course, with death in approximately 17% of patients. Risk stratification into high-risk and low-risk groups based on a combination of mitotic activity (> 3 mitoses per 10 mm²; > 3 mitoses per 50 high-power fields, assuming a field diameter of 0.5 mm and an area of 0.2 mm²) and tumor size (> 3 cm) has shown a worse prognosis for patients with both features (5-year disease-specific survival rate: 59%) compared with patients with neither feature (5-year disease-specific survival rate: 100%). Severe cytological atypia, spindled morphology, and the presence of necrosis have not been shown to be indicative of aggressive behavior in epithelioid haemangioendothelioma of soft tissue, and even tumors with bland morphological features can metastasize. However, in the recently identified YAP1-TFE3 subset of cases, metastatic rate may be higher, with metastases reported in 3 of 6 cases in the original study. Epithelioid haemangioendothelioma arising in lung or bone has a worse prognosis than soft tissue tumors, and patients often present with metastatic disease. By contrast, cutaneous epithelioid haemangioendothelioma has an excellent prognosis.

Identification of the WWTR1-CAMTA1 or YAP1-TFE3 fusion transcripts helps distinguish epithelioid haemangioendothelioma from other tumors.

Essential: classic epithelioid haemangioendothelioma is composed of cords or nests of epithelioid cells with cytoplasmic vacuolization within a myxochondroid or hyaline stroma; epithelioid haemangioendothelioma with YAP1-TFE3 fusion shows either solid growth or well-formed vascular channels lined by epithelioid endothelial cells with moderate nuclear atypia and abundant pale cytoplasm.

Desirable (in selected cases): CAMTA1 expression by immunohistochemistry and/or WWTR1-CAMTA1 fusion; TFE3 overexpression by immunohistochemistry and/or TFE3 gene rearrangement (YAP1-TFE3 gene fusion).