Skip to content

Cancer of Unknown Primary

Bailey DeCoursey


  • Cancer of unknown primary (CUP) accounts for 2% of all cancer diagnoses
  • Often, CUP is discovered incidentally on imaging tests or due to symptomatic metastasis


  • Asymptomatic and found on imaging
  • Often generalized fatigue and weight loss
  • May have irregular, persistent lymphadenopathy at a particular site

Initial Evaluation

  • Physical exam: including pelvic / breast exam for females and prostate/testicular exam for males
  • CMP, CBC w/ diff, UA, PSA in males, fecal occult blood screening
  • CT C/A/P with contrast (reveals the origin in up to 35% of pts)
  • Once lesions are identified pt’s should undergo biopsy of the most accessible lesion
  • If imaging is suggestive of GI origin, or pt has liver metastasis without other obvious dominant lesion, colonoscopy should be performed
    • If physical exam with breast abnormalities, or pt has axillary lymphadenopathy, bilateral mammography should be performed
    • Breast MRI may be considered even in the setting of negative mammography if clinical suspicion is high

Evaluation following biopsy

  • Adenocarcinoma (70% of CUP)
    • Most common primary: pancreas, lung, liver, HPB tree, and kidney
    • Interestingly, prostate and breast cancer account for a small percentage of CUP despite being the most common malignancies
    • Most common metastasis: liver, lungs, lymph nodes and bones
    • Evaluation:
      • Primary is most likely to be identified by biopsy
      • If clinical suspicion is high for certain primary site, this should be relayed to pathology so they may perform appropriate staining
      • Tissue PSA can be positive even in the setting of normal serum PSA
      • Serum studies such as CEA, CA19-9, CA 125, CA15-3 are often not sensitive or specific and will often be elevated in the setting of many types of adenocarcinoma
  • Neuroendocrine tumors (1% of CUP)
    • High grade
    • Most common primary: lung (bronchogenic)
    • Most common metastasis: mediastinal and retroperitoneal LN
    • Evaluation: CT of chest ± bronchoscopy will likely identify site
    • If unrevealing, IHC staining and molecular cancer classifying assays will likely be helpful
  • Squamous cell carcinoma (5% of CUP)
    • Work up depends on the location of adenopathy as follows:
      • Upper and mid-cervical lymphadenopathy
        • Most common primary: head and neck cancer
        • Evaluation: CT head and neck, direct laryngoscopy, nasopharyngoscopy
      • Lower cervical/supraclavicular lymphadenopathy
        • Most common primary: lung or head and neck
        • Evaluation: CT chest, CT head and neck, direct laryngoscopy as indicated
      • Inguinal lymphadenopathy
        • Most common primary: genital or anorectal origin
        • Evaluation
        • Females: careful external and internal genital examination
        • Males: close external genital examination
        • Anoscopy and DRE in all pt
  • In up to 60% of cases, a primary site may never be identified
  • Empiric chemotherapy may be initiated in consultation with medical oncology