BACKGROUND Unknown or uncertain primary cancer (UPC), also referred to as carcinoma of unknown primary (CUP), accounts for an estimated 3% to 5% of all metastatic cancers. (1) Strictly speaking, the diagnosis of UPC requires a biopsy-proven metastatic malignancy and no identifiable primary tumor after a thorough clinical evaluation that includes physical examination and laboratory and imaging diagnostic tests. (2) However, the frequency at which a pathologist performs a "UPC workup" has been estimated as double the number of cases of UPC. (3) For cases designated as UPC/CUP after routine diagnostic evaluation, the source of these tumors is identified only 20% to 30% of the time ante mortem, even after extensive clinical, imaging, and immunohistochemical (IHC) workups. (4) Unfortunately, prognosis of patients for whom a primary site is not identified is poor, with median survival ranging from 6 to 10 months, in clinical studies of unselected patients with UPC/CUP, to 2 to 3 months in other studies. (2) Comparatively, patients for whom the primary source of cancer is identified have longer survival. (5) Cases of UPC/ CUP remain a source of frustration and psychological burden for both the patient and the medical team.