Cancer of unknown primary site: improved patient management with molecular and immunohistochemical diagnosis.

Cancer of unknown primary site (CUP) is a common heterogeneous clinicopathologic syndrome, but investigations and publications regarding these patients are rare. For the last 20 years, empiric "broad-spectrum" chemotherapy has been the standard therapy for the majority of these patients. More recently, improved immunocytochemistry and advent of gene-expression profiling have provided the diagnostic tools necessary to accurately define the tissue of origin in most patients. Molecular profiling assays complement standard pathologic diagnosis, and a recently reported large prospective study demonstrated an improvement in outcome for patients treated with site-specific therapy directed by the molecular assay diagnoses compared with empiric chemotherapy. Survival in molecularly diagnosed patients was as expected for those particular tumor types. The evaluation of patients has become more standardized. The empiric-chemotherapy era is ending and customized therapies based on accurate tissue of origin diagnoses have arrived. Eventually the recognition of the molecular aberrations responsible for the growth and metastasis of solid tumors, regardless of the tissue of origin, will lead to more precise and effective therapy for patients with advanced cancers.