Answer: E. Epithelioid Sarcoma

Histology:
The wedge resection of lung reveals a subpleural area of fibrosis with central necrosis surrounding by a peripheral rim atypical epithelioid cells. Cytologically, the individual cells are epithelioid with pale pink cytoplasm, high nuclear-to-cytplasmic ratios, prominent nucleoli and frequent mitotic figures. Architecturally, the atypical cells appear to be either making or lining slit-like and alveolar-like spaces, giving the impression of either vascular formation or an alveolar growth pattern. The patient has a history of a forearm epithelioid sarcoma. Immunostains on the lung lesion reveal it to be positive for AE1/AE3 and CD34, and negative for CD31, with loss of INI-1 labeling.

Discussion:
The wedge resection of lung reveals an atypical epithelioid proliferation that has a slit-like (pseudo-vascular) or alveolar-like growth pattern, mimicking a vascular neoplasm, lung adenocarcinoma in situ (bronchioalveolar carcinoma), or adenocarcinoma with lepidic growth. Indeed, without the clinical history of a known epithelioid sarcoma of soft tissue diagnosed six years prior, the diagnosis of metastatic epithelioid sarcoma a priori would be very difficult. As always, clinical history is key. Primary epithelioid sarcomas most commonly involve the distal extremities, characteristically display nodular growth with associated granulomatous inflammation, and are unique among sarcomas in that they can metastasize to lymph nodes and may develop late metastatic spread. The immunopanel performed in this case includes a cytokeratin (AE1/AE3), “vascular markers” CD31 and CD34, and INI-1, which are stains that cover the entities of carcinoma, angiosarcoma, and epithelioid sarcoma.

Carcinomas are immunoreactive for cytokeratin such as AE1/AE3, retain nuclear INI-1 labeling, and are usually negative for CD34 and CD31. Cytokeratin labeling is typically used to support a diagnosis of carcinoma; however cytokeratin labeling can be seen in some sarcomas—most notably epithelioid angiosarcoma and epithelioid sarcoma, but also leiomyosarcoma—and this is a potential diagnostic pitfall. Epithelioid angiosarcomas are typically immunoreactive for both CD34 and CD31 and retain nuclear INI-1 labeling, but may also display cytokeratin positivity. Epithelioid sarcomas are positive for cytokeratin and CD34, but are negative for CD31 and characteristically display loss of nuclear INI-1 labeling. INI-1 is a tumor suppressor gene, and loss of INI-1 labeling by immunohistochemistry is characteristically seen in epithelioid sarcoma, malignant rhabdoid tumor, renal medullary carcinoma, myoepithelial carcinomas, and extraskeletal myxoid chrondrosarcomas

References:
1. Hollmann TJ, Hornick JL. INI1-deficient tumors: diagnostic features and molecular genetics. Am J Surg Pathol. 2011 Oct;35(10):e47-63.