Cancer of Unknown Primary

Bailey Decoursey

Background 

  • 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

Presentation 

  • 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 and/or upper EGD 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, gastric, cholangiocarcinoma/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, AFP, CA 125, CA15-3 are often not sensitive or specific and will often be elevated in the setting of many types of adenocarcinoma; however it is still worth obtaining these for diagnostic workup.
    • Consider discussing with Oncology Fellow re: NGS molecular testing after biopsy, as occasionally finding somatic mutations from tumor specimens can help with identification of primary and guide management decisions.
  • 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 – This is important for discussing with patients and families.
  • Empiric chemotherapy may be initiated in consultation with medical oncology
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