title: Cancer of unknown primary (CUP): does cause of death and family history implicate hidden phenotypically changed primaries?
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany; Center for Primary Health Care Research, Lund University, Malmö, Sweden. Electronic address: k.hemminki@dkfz.de.
authors.forename: K
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Bevier
authors.affiliation: Center for Primary Health Care Research, Lund University, Malmö, Sweden; Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, USA.
authors.forename: J
authors.initials: J
authors.lastname: Sundquist
authors.affiliation: Cancer Gene Therapy Group, Molecular Cancer Biology Program & Transplantation Laboratory & Haartman Institute & Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Hemminki
mesh_terms: D002423:Cause of Death; D006801:Humans; D009382:Neoplasms, Unknown Primary / Q000473:pathology*; D010641:Phenotype; D013548:Sweden