Case 3 -
Metastatic Epithelioid Angiosarcoma
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Angiosarcoma, Epithelioid, Fine-needle aspiration,
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
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.
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.
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.
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
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. Since these lesions may exhibit a constellation of cytomorphologic features,
it is important to exclude both melanoma and non-small cell carcinoma from the differential diagnosis.
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