Definition

• Cancers of unknown primary site (CUP) account for 2% of cancers (has decreased over time as definition has changed and testing has improved).
• Patients present with symptoms that originate from the involved site of metastasis. 
• By definition, initial evaluation—including history, physical exam, radiographic imaging, and initial round of immunohistochemical stains on a tissue biopsy—have failed to identify the primary site.
• <10% subsequent detection of anatomic primary, though most have small primary at autopsy.

Evaluation

• Step 1: localize and retrieve tissue.
  • CT chest/abdomen/pelvis with contrast (PET/CT not needed in most cases).
  • Biopsy the most accessible site: core biopsy preferred over FNA.
  • Endoscopic and other evaluation based on symptoms (e.g. MRI brain if CNS symptoms).
• Step 2: what is the histology of the CUP?
  • Many histologies possible: adenocarcinoma (most frequent), poorly differentiated carcinoma, squamous cell carcinoma, neuroendocrine tumor, lymphoma, melanoma, sarcoma, thyroid carcinoma, germ cell tumor.
• Step 3: based on the histology, follow steps to identify and treat the primary site.
  • In all cases, discuss with path. They may be able to do multiple rounds of stains to arrive at a diagnosis. More commonly now we are also sending molecular testing to try to identify the site of origin, but this does not have definitive evidence to support routine use in CUP workup currently.
  • Recommendations below are from NCCN guidelines for occult primary cancers. In other guidelines, mammogram and PSA are controversial.
  • Adenocarcinoma or poorly differentiated carcinoma:
    • Isolated/predominant cervical nodes: workup/treat as head/neck primary (rare for adeno).
    • Supraclavicular/axillary nodes: neck CT, mammo, PSA (>40 yo).
    • Mediastinum: germ cell markers (AFP, B-HCG), mammo, PSA (>40 yo).
    • Lung nodules/pleural effusion: CA-125, mammo, PSA (>40 yo).
    • Peritoneal disease/ascites: urine cytology, CA-125, mammo, PSA (>40 yo).
    • RP mass: urine cytology, CA-125, mammo, PSA (>40 yo), AFP, B-HCG, testicular u/s (<65 yo).
    • Inguinal nodes: CA-125, PSA (>40 yo).
    • Liver lesions: endoscopic evaluation (EGD/colo), AFP, mammo.
    • Bone lesions: bone scan or PET, directed imaging of painful/concerning lesions, mammo, PSA.
    • Brain lesions: mammogram.
    • Multiple sites: mammogram, PSA. 
  • Squamous cell:
    • Head/neck/supraclavicular nodes: workup and treat as head/neck cancer (MRI/CT, ENT consult for endoscopic evaluation).
    • Inguinal nodes: though perineal/genital/lower extremity exam, anoscopy. 
  • Bone lesions: bone scan or PET, directed imaging of painful/concerning lesions.
    • If a primary is found, treat as that cancer type.
    • If no primary is found, treat what it resembles the most.
  • Cervical nodes: head/neck cancer.
  • Axillary nodes in women: breast cancer.
  • Bone lesions in men with elevated PSA: prostate cancer.
  • Mediastinal lesion <40 yo: germ cell tumor.
  • Mediastinal lesion >50 yo: non-small cell lung cancer.
  • Mediastinal squamous cell cancer: non-small cell lung cancer.
• If no obvious pattern, can give empiric chemotherapy (e.g. carboplatin/paclitaxel), but low response rate (<40%) and poor prognosis (median overall survival <12 months).
• Outcomes improved with site-specific therapy, so important to identify primary site if possible.
• Molecular testing helpful to guide treatment: pembrolizumab approved for MSI-H solid tumors regardless of site of origin, and some targeted therapies too (e.g. NTRK inhibitors if NTRK mutation present).

Key Points

• CUP workup includes CT CAP with contrast and tissue biopsy (core biopsy preferred) with immunohistochemical stains.
• If biopsy and stains do not reveal a diagnosis, next steps in workup/treatment depend on metastatic distribution and histology.
• Can treat with chemotherapy even if cancer type not determined, but outcomes are worse with “non-specific” chemotherapy regimens.
• The role of molecular testing in CUP is still evolving.

Fizazi K, Greco FA, Pavlidis N, et al. Cancers of unknown primary site: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015 Sep;26 Suppl 5:v133-8.

Hainsworth JD, Greco FA. Cancer of unknown primary site: New treatment paradigms in the era of precision medicine. Am Soc Clin Oncol Educ Book. 2018 May 23;38:20-5.

NCCN guidelines. Occult primary (Cancer of unknown primary [CUP]). Version 3.2020. Updated May 12, 2020. Accessed June 9, 2020. https://www.nccn.org/professionals/physician_gls/pdf/occult.pdf

Varadhachary GR, Raber MN. Cancer of unknown primary site. N Engl J Med 2014; 371:757-65.