Epithelioid angiosarcoma is a highly aggressive vascular malignancy associated with a very poor prognosis and early metastasis. It is a rare histologic variant of angiosarcoma characterized by epithelioid morphology. The epithelioid appearance is especially problematic because it is commonly mistaken by pathologists as a nonsarcomatous neoplasm such as a carcinoma or melanoma. The tumor has a predilection for males in middle to late life. It most commonly arises in the deep soft tissues, but can also be found in the bone, skin, thyroid and adrenals. Although most angiosarcomas are de novo malignancies, some tumors are known to develop in the post-radiation setting, as in this case.
The cell block highlights many similar features including pleomorphic cells arranged singly and in clusters with ovoid-to-spindle shapes and abundant granular cytoplasm. Some of the dissociated cells also show “rhabdoid” morphology, including small peripheral nuclei and abundant, dense eosinophilic cytoplasm. This “rhabdoid” appearance has been described and may often be confused with other epithelioid sarcomatous tumors, carcinomas and melanomas.
Epithelioid angiosarcomas display a wide range of morphologies. Typically, the tumor has a diffuse growth pattern composed of sheets, nests or cords of epithelioid endothelial cells with abundant cytoplasm, large vesicular nuclei and prominent nucleoli. Angioformative areas are often present consisting of anastomosing vessels lined by cytologically atypical endothelial cells with numerous mitoses and often intraluminal papillary formations. Areas of necrosis and hemorrhage are common (Figures 4 and 5). A chondromyxoid matrix is commonly observed in epithelioid hemangioendothelioma, a low-grade malignant vascular tumor, which is also in the differential diagnosis.
Immunohistochemically, the epithelioid endothelial cells usually show strong reactivity for CD31 (Figure 6), and variable/focal positivity for CD34, Factor VIII, epithelial membrane antigen, vimentin and CD68.
Fli-1, a nuclear transcription factor, demonstrates strong and diffuse expression in 85% of epithelioid angiosarcomas. Although Fli-1 is highly sensitive and specific for both benign and malignant vascular neoplasms, positive expression can help to distinguish epithelioid angiosarcomas from important mimics such as epithelioid sarcomas and carcinomas. The lymphovascular marker, D2-40, has far less diagnostic value. D2-40 is weakly expressed in a majority of epithelioid angiosarcomas, but it lacks specificity and is commonly expressed in epithelioid sarcomas and in various carcinomas.
Cytokeratin is often diffusely and strongly positive in epithelioid angiosarcomas, with positivity ranging from 78 to 100 percent in various studies. This marker is not helpful in distinguishing epithelioid angiosarcomas from mimics which express cytokeratin, including epithelioid sarcomas and carcinomas.
A poorly differentiated deep soft tissue malignancy with an “epithelioid” appearance and similar aspiration cytomorphology has a fairly short differential diagnosis. It includes malignant melanoma, epithelioid sarcoma and epithelioid hemangioendothelioma.
Malignant melanomas should be a high consideration on the differential diagnosis based on location and cytomorphology. Melanomas invade the deep soft tissues and often show a single cell pattern with large, spindle to ovoid-shaped cells. These cells often have eccentrically placed nuclei and prominent nucleoli (called “macronucleoli”). Furthermore, malignant melanomas may also demonstrate “rhabdoid”morphology and often have melanin pigment which may be easily confused with hemosiderin pigment. In this case, the patient had no prior history of melanoma and the cytomorphology and concurrent histopathology were in keeping with an epithelioid angiosarcoma.
Epithelioid sarcoma is another rare soft tissue malignancy which has a very similar cytomorphology and may be difficult to distinguish from an epithelioid angiosarcoma. The cells are round to polygonal-shaped cells (“epithelioid”) and often have a single cell pattern or may be admixed with loosely cohesive clusters of cells. Spindle-shaped cells may also be present. These cells also often have peripherally-placed, smooth-bordered nuclei with abundant eosinophilic cytoplasm and mild to moderate nuclear pleomorphism. “Rhabdoid” morphology may also be seen in the proximal type, as in an epithelioid angiosarcoma. There are a few slight differences, however, including that the cells are often binucleate or multinucleate with smaller nucleoli and a variable number of cytoplasmic vacuoles. Despite similar cytomorphologic features, our patient’s clinical history was far more consistent with an epithelioid angiosarcoma. Epithelioid sarcomas have a predil ection for adolescent to young adults and often involve the distal extremities (especially the hands and feet). Our patient was an older male with a lesion involving the hip.
Lastly, another entity which may be considered in the differential diagnosis is an epithelioid hemangioendothelioma, another rare low-grade vascular neoplasm. This neoplasm has similar cellular features to an epithelioid angiosarcoma, including round to polygonal cells arranged singly and in loose clusters with peripheral nuclei and abundant cytoplasm. One notable difference is frequent intranuclear inclusions (“pseudoinclusions”) and rarely, intracytoplasmic vacuoles. Other differences include frequent binucleation and very minimal nuclear pleomorphism with few mitoses, which is in stark contrast to the marked nuclear pleomorphism seen in our patient’s smear. Moreover, the stroma tends to show hyalinization or chondromyxoid differentiation. These tumors tend to occur in visceral organs and many other foci in the head and neck region and the torso.