Case 3 -

Metastatic Epithelioid Angiosarcoma Christine Booth Cleveland Clinic Cleveland, OH

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Key Words: Angiosarcoma, Epithelioid, Fine-needle aspiration, Cytology Clinical History: A 77-year old man with a history of glomerulonephritis status post renal transplant (1992) and chronic immunosuppression complains of a red nodule on his scalp. He also has a history significant for squamous cell and basal cell carcinomas of the skin, actinic keratoses and a superficial melanoma. On exam, there is an area of erythema and thickening on the right side of the face measuring 5 cm in greatest dimension. There is also a right posterior cervical mass measuring 6 x 6 cm, most likely representing matted lymph nodes. The fine needle aspiration was performed on the right posterior cervical mass. Case 3 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 3 - Figure 1 DiffQuik Case 3 - Figure 2 DiffQuik Case 3 - Figure 3 Pap Stain Case 3 - Figure 4 Pap Stain Case 3 - Figure 5 Cell Block Cytologic Diagnosis: Malignant epithelioid neoplasm, consistent with angiosarcoma. Comment: The malignant cells are positive for CD31 and are negative for cytokeratin AE1/AE3, supporting the above diagnosis. Histology Diagnosis: Prior scalp shave biopsy at an outside institution showed a malignant epithelioid neoplasm, most consistent with angiosarcoma. Immunostains demonstrated that the tumor cells were positive for CD31, D240, and Fli-1 and were negative for cytokeratin AE1/AE3, S-100 protein, CD34 and Pankeratin. Cytologic Findings: The Diff-Quik stained smears of the fine-needle aspirate specimenare hypercellular with both clusters and single malignant cells present within a bloody background. Many of the cell groups form a pseudoglandular or microacinar pattern in which the cell cytoplasm is oriented toward the center and the nuclei are situated around the edge of the cell cluster. Occasional binucleate and multinucleate forms are present. The malignant cells are large and pleomorphic with eccentrically located nuclei, imparting a plasmacytoid appearance to the cells. The nuclei are at least 3 – 4 times the size of a normal lymphocyte nucleus, which can also be seen in the background. The cytoplasm contains numerous fine vacuoles. Mitotic figures are common, many of which are atypical. Rare histiocytes are also present in the background. The Papanicolaou-stained liquid-based preparation virtual slide confirms the above findings and also highlights the prominent nucleoli and thick, irregular nuclear membranes. The cell block contains cells predominantly in pseudoglandular formations, with eccentrically located nuclei and dark chromatin. Immunostains performed on the cell block material stained the cytoplasm of the tumor cells positive for CD 31. The malignant cells were negative for cytokeratin AE1/AE3. Discussion: Angiosarcomas are rare endothelial-derived malignancies, representing less than 2% of sarcomatous lesions overall. They are most often located on the skin of elderly individuals, but have also been reported in the deep soft tissues, breast, thyroid, liver, spleen, heart, lung, kidney, adrenal, testis, prostate, uterus, ovaries, bone and serous membranes. Though most often patients present with cutaneous manifestations, angiosarcomas rarely arise de novo in the deep soft tissues. When diagnosed in the deep soft tissues, angiosarcomas have an aggressive clinical behavior. On the skin, they may appear as an ecchymotic nodule, a hematoma or a plaque with a violaceous appearance. Most angiosarcomas are primary malignancies, but cases may develop secondarily in patients who have received prior radiation therapy, patients with a history of chronic lymphedema or fistulas, or in association with long-standing foreign body exposure. It can be difficult to make a cytologic diagnosis of angiosarcoma due to overlapping cytologic features with much more common malignancies including poorly differentiated non-small cell carcinoma and malignant melanoma. In addition, the cytologic features of angiosarcomas, in particular, epithelioid angiosarcomas, vary. However, several features are characteristic and should help one to at least entertain this lesion in the list of differential diagnostic possibilities when present. Fine needle aspirate smears may vary from scantly to highly cellular. Most often, the malignant cells are present in a bloody background. Both loose cell clusters and single epithelioid cells may be seen. The clusters may show a pseudoglandular or microacinar appearance with an attempt at central lumen formation. The cells are large (3 – 4 times the size of a lymphocyte) with an eccentrically located nucleus. The cells most often contain a single large nucleus, but occasional binucleate and multinucleate forms have also been described. Other features described in epithelioid angiosarcomas include tumor cells with cytoplasmic hemosiderin and erythrophagocytosis (red cells present within the cytoplasm of tumor cells). Rarely, the individual cells may have a cytoplasmic vacuole with intraluminal red blood cells. Several cases have demonstrated a "rhabdoid" appearance to the cells, in particular with a Romanovsky-type stain, in which the nucleus is pushed to the side by an adjacent density within the cytoplasm. Mitoses, including atypical mitotic figures, are often frequent. In addition, nuclear grooves, signet-ring like cells and necrosis may be seen. The differential diagnostic possibilities of epithelioid angiosarcoma include malignant melanoma and poorly differentiated non-small cell carcinoma. Malignant melanomas share similar cytologic features to some of those described in epithelioid angiosarcomas, including a dispersed, single cell pattern of plasmacytoid cells with an eccentric nucleus. Fine-needle aspirate smears of malignant melanoma contain cells with predominantly single nuclei and some binucleate forms. The nuclei often have a single, prominent nucleolus. A cytologic feature often seen in melanoma, but not described in epithelioid angiosarcomas, is intranuclear cytoplasmic invaginations. Even with the help of immunostain results, the fine-needle aspiration biopsy diagnosis of epithelioid angiosarcoma remains difficult. This is because epithelioid angiosarcomas are often positive for cytokeratin stains (which may mislead one to further consider a diagnosis of a poorly-differentiated non-small cell carcinoma) and may also stain non-specifically for S-100 protein (which may lead to an incorrect diagnosis of malignant melanoma). However, epithelioid angiosarcomas should be consistently negative for other markers of melanocytic differentiation including HMB-45 and Melan-A. In addition, the malignant cells may stain with antibodies to Factor VIII, CD31 and CD34, all markers of vascular differentiation. Ultrastructurally, Weibel-Palade bodies (a marker of endothelial derivation) may not be identified. In conclusion, it is important to consider the combination of the patient's clinical history, the fine needle aspirate cytologic features and the judicious use of immunostains to confirm a diagnosis of epithelioid angiosarcoma. 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