Pathologic evaluation of unknown primary cancer.

The pathologic approach to metastases of unknown primary cancer (UPC) is stepwise and uses the clinical context, morphology, and, where necessary, immunohistochemistry (IHC). This review covers the initial approach to a UPC biopsy; the diagnosis of malignancy and broad tumor typing into carcinoma, melanoma, lymphoma, or sarcoma; and further subtyping of carcinoma into germ cell (broadly included), squamous, neuroendocrine, and solid organ including liver and renal, and adenocarcinomas. Finally, for adenocarcinoma, the prediction of primary tumor site, including lung, pancreas, stomach, colon, ovary, prostate, and breast, is discussed. For each tumor type, the morphologic features are presented alongside established useful IHC markers, with a description of their staining patterns and common diagnostic dilemmas. Optimal tissue handling and IHC interpretation, quality assurance, and limitations also are discussed. The target readership is oncologists, but other clinicians and trainee pathologists also may find the content of use.