Answer: A. Adrenocortical carcinoma

Histology: The resection specimen contains sheets of atypical cells with abundant and predominantly eosinophilic cytoplasm, focal cytoplasmic vacuolization, and prominent nucleoli. There is minimal mitotic activity. The adjacent liver does not show evidence of cirrhosis or marked inflammation. There is no necrosis. There is no appreciable bile pigment or melanin pigment. The patient also has a separate morphologically identical mass in the adrenal gland; immunohistochemistry shows the tumors to be positive for inhibin and melan A, and negative for HEPPAR1, S100 and Pax8.

Discussion: The clinical presentation, tumor morphology and immunoprofile support classification as a metastatic adrenocortical carcinoma involving the liver. The differential diagnosis of malignant “pink cell tumors” must always include melanoma, melanoma, melanoma (which can have variable morphology and cytology), followed by adrenocortical carcinoma, hepatocellular carcinoma, and renal cell carcinoma, as well as rarer tumors such as alveolar soft parts sarcoma, clear cell sarcoma, oncocytic neoplasms of the thyroid (Hurthle cell) and parathyroid, and granular cell tumors. Although the tumor in this case shows marked atypical, adrenocortical carcinomas can be deceptively bland. The only definitive criteria for malignancy is the presence of local invasion or metastatic spread. The Wiess and Modified Weiss criteria provide a scoring system for assessing malignancy in primary adrenocortical neoplasms (i.e., predicting which primary lesions have metastatic potential). Briefly, in the Modified Weiss Criteria, the presence of the following features are scored: mitotic rate >5/50 HPF (2 points), abnormal mitoses (1 point), eosinophilic cytoplasm in >75% of tumor (2 points), necrosis (1 point), and capsular invasion (1 point). A total score of 3 or more is suggestive of malignancy. The original Weiss criteria also incorporates nuclear grade, a diffuse architectural pattern, and venous or sinusoidal invasion.

In regards to immunohistochemistry and other characteristic features of neoplasms in the differential diagnosis, adrenocortical neoplasms label for melanA/Mart1, inhibin and calretinin but are negative for most cytokeratin markers (they may label for Cam5.2, but are typically negative for AE1/AE3, CK7 and CK20). Note that adrenocortical neoplasms may contain melanin pigment and are immunoreactive for melanA/Mart1, thus can mimic melanoma. Alveolar soft part sarcomas show nests of loosely cohesive cells with abundant eosinophilic cytoplasm, and they are immunoreactive for cathepsin K; alveolar soft part sarcomas are characterized by a specific translocation of der(17)t(X:17) that results in the fusion of TFE3 with ASPSCR1 (alveolar soft part sarcoma critical region 1). Hepatocellular neoplasms typically label for HePAR1, arginase, glypican 3, CK8/18 (Cam5.2) and polyclonal CEA (pericannalicular pattern). Hepatocellular neoplasms may contain intracytoplasmic bile pigment. Melanomas typically label for HMB45, melanA/Mart1, S100, Sox10 and MITF and are negative for cytokeratin; melanomas may contain melanin pigment. Renal cell carcinomas typically label for Pax8 and RCC, and variably for CK7 or CAIX depending upon the subtype.

References:
1. Aubert S, Wacrenier A, Leroy X, et al. Weiss system revisited: a clinicopathologic and immunohistochemical study of 49 adrenocortical tumors. Am J Surg Pathol. 2002 Dec;26(12):1612-9.
2. Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol. 1984 Mar;8(3):163-9.