Cancer of unknown primary (CUP): does cause of death and family history implicate hidden phenotypically changed primaries?

Cancer of unknown primary (CUP) is diagnosed at the metastatic stage. We aimed to identify hidden primary cancers in CUP patients by comparison with cancers in family members. We take use of the fact that the cause of death in CUP patients is often coded as the cancer in the organ of fatal metastasis. Forty-one thousand five hundred and twenty-three CUP patients were identified in the Swedish Family-Cancer Database, and relative risks (RRs) were calculated for cancer in offspring when family members were diagnosed with CUP and died of the cancer diagnosed in offspring. The RR for lung cancer in offspring was 1.85 when a family member was diagnosed with CUP and died of lung cancer. Significant familial associations were found for seven other cancers. Many familial associations were also significant when offspring CUP patients died of the cancer diagnosed in family members. The cause of death after CUP diagnosis frequently matched the cancer found in a family member, suggesting that the CUP had originated in that tissue. The metastasis had probably undergone a phenotypic change, complicating pathological tissue assignment. These novel data suggest that some CUP cases are phenotypically modified primary cancers rather than cancers of unknown primaries.