Sections show liver cores infiltrated by a poorly differentiated epithelioid neoplasm composed of cells arranged in nests, trabeculae and cords in a desmoplastic stroma. The cells exhibit a marked degree of pleomorphism. They have moderate to abundant amphophilic-eosinophilic cytoplasm, with hyperchromatic nuclei, irregular nuclear borders and conspicuous nucleoli. Numerous mitoses (typical and atypical) and apoptotic bodies are seen. There is no definitive evidence of mucin production or keratinization.

The morphological features are not specific for any site of origin. Given the clinical history, metastases from the bladder, prostate or lower GI need to be excluded both clinically (review current imaging), histologically (compare morphology to previous biopsy/resection specimens if available), and immunohistochemically (Prostate: PSA/PSAP/AR; Urothelial: CK7/CK20/p63/GATA3; Anal SCC: p40/p63). Of note, a primary intrahepatic cholangiocarcinoma can assume any of the histological patterns of a metastatic carcinoma and in the absence of high-grade intraepithelial neoplasia within the intrahepatic bile ducts, the distinction can be difficult to impossible. A mucin panel (MUC 1+/2+/3+) and a keratin panel (CK7+/19+/20-) even though not specific, can aid in the diagnosis.