Diagnostic approaches to cancer of unknown primary—the pathologist’s perspective

Cancer of unknown primary (CUP), a rare metastatic malignancy for which a primary site cannot be established after the diagnostic workup, has an unfavorable prognosis. Histopathological assessment, including comprehensive panels of immunohistochemistry (IHC) of biopsy specimens, remains the mainstay for establishing a diagnosis, identifying a putative tissue of origin (ToO), and guiding therapy decisions. Combining IHC and complex molecular analyses may identify therapy targets to improve patient outcomes. This review focuses on the standard-of-care diagnostic workup of suspected CUP samples, the pathologist’s role in the search for therapy targets, and current as well as future developments in the field.