Carcinoma of unknown primary: check the liver... thanks to TTF-1

Carcinoma of unknown primary (CUP) is not uncommon and poses both diagnostic and therapeutic challenges. Recent developments in immunohistochemical (IHS) stains in diagnostic pathology help resolve many of these clinical dilemmas. Antibodies against Thyroid Transcription Factor (TTF-1), a relatively new and organ specific marker that stains lung and thyroid malignancies, are commonly included in the first battery of stains when dealing with a CUP. The usual pattern of staining for TTF-1 is purely nuclear. However, it was recently noticed that TTF-1 stains the mitochondria of benign hepatocytes and tumor cells in hepatocellular carcinoma. We would like to report two cases where the clue to the hepatic origin of CUP was the presence of cytoplasmic staining for TTF-1. Description of both cases with pertinent literature review will be offered. Two patients were seen at the James H. Quillen Veterans Administration Medical Center (VAMC), where one had a right chest wall mass with previous history of prostatic carcinoma and the other was found to have a lytic rib lesion with a previous history of lung squamous cell carcinoma. FNA and core biopsies were performed on both lesions where the initial pathological interpretations were nonsmall cell carcinoma. IHS revealed positivity for cytokeratin-7 and granular cytoplasmic staining for TTF-1. Further workup using stains for Alpha Fetoprotein, Hepatocyte Paraffin (Hep Par 1) and CEA confirmed the diagnosis of metastatic hepatocellular carcinoma (HCC). Paying attention to cytoplasmic staining for TTF-1 in any CUP should prompt further pathological and clinical evaluation to rule out hepatocellular carcinoma.