Cancer of unknown primary site: evolving understanding and management of patients.

Cancer of unknown primary site is a common clinicopathologic syndrome representing a very heterogeneous group of patients with metastatic cancers and clinically undetectable primary tumor sites. The standard treatment for these patients for the last 15 years has been empiric "broad-spectrum" chemotherapy. In recent years, improved immunocytochemistry and the emergence of gene expression profiling have provided the diagnostic tools necessary to accurately define the tissue of origin in the majority of patients. Recent data have confirmed the ability of molecular profiling assays to complement standard pathologic diagnosis, and a large prospective study has documented a survival improvement for patients treated with site-specific therapy directed by the molecular assay diagnoses of their tissues of origin compared to empiric chemotherapy. The clinicopathologic evaluation of patients is now more standardized. The era of empiric chemotherapy administered to all patients is coming to an end, and customized therapies are favored. The management of patients has evolved with the ability to confidently define the tissue of origin. Further delineation of the molecular aberrations in advanced solid tumors, regardless of the primary tumor site, signals a more precise and perhaps more effective therapy for each patient.