cancer of unknown primary: Ancillary testing of cytologic and small biopsy specimens in the era of targeted therapy

Initial evaluation of patients presenting with a suspected malignancy without a clear clinical or radiologic impression of a primary site (so-called cancer of unknown primary, or CUP) frequently includes fine needle aspiration (FNA) to both establish a diagnosis and procure tissue for additional studies. Careful management of limited specimen material is especially important in the modern era, when molecular studies may take precedence over a more definitive tissue diagnosis. This review summarizes our practice habits when encountering a CUP. Broadly, key morphologic patterns in context of patient history and clinical-radiologic impression should guide the selection of a limited panel of IPOX stains to establish first a broad lineage. Subsequently 1–2 site-specific markers may be used to confirm the diagnosis. In difficult cases, it is helpful to convey the situation to the treating physicians, who may prefer to prioritize molecular testing over pursuit of a more definitive diagnosis. Prudent choice of immunoperoxidase (IPOX) studies, based on both key cytomorphologic criteria and continued communications with the clinical team regarding their needs for treatment planning, is critical in CUP cases.