Cancer of unknown primary site (CUP) is a deadly disease diagnosed through metastases at various organs without primary tumor identification. Despite the major molecular and technological advances, the carcinogenesis of CUP remains enigmatic which hampers adequate study design of treatments leading to survival improvement. To date, the pathogenesis of CUP is still debatable with one hypothesis considering CUP simply a group of metastatic tumors with unidentified primaries and another considering it a distinct entity with specific genetic and phenotypic aberrations. Familial CUP seems to favor the first hypothesis due to common genetic predisposition factors between known primaries and CUP. Two clinical implications may be withdrawn from the pathogenesis of familial clustering of CUP. The detailed family history and environmental risk factors may orient towards the primary tumor identification. Smoking avoidance and adherence to general population guidelines for cancer screening would be strongly encouraged.
Keywords: CUP; Cancer of unknown primary; Familial; Genetics.