Cancer of unknown primary

Last updated: June 13, 2023

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Summarytoggle arrow icon

Cancer of unknown primary (CUP) is a metastatic cancer that has no identified site of origin following the completion of a standard oncologic evaluation. CUPs are a heterogeneous group of cancers with different histopathologies and varied manifestations. Collectively, CUPs account for approximately 3–5% of all malignancies. The initial diagnostic workup of CUP is focused on trying to locate the site of the primary tumor based on the imaging and histopathology findings. If a primary site cannot be identified, the cancer is classified into a favorable or unfavorable subgroup. CUPs in the favorable subgroup have clinical manifestations, histopathology findings, or biomarkers similar to known primary cancers and are treated with standard anticancer treatment regimens for the equivalent primary cancer. Patients with a tumor in the unfavorable subgroup (80–85%) receive empiric low-dose chemotherapy, but the median survival is poor (typically less than one year).

Epidemiologytoggle arrow icon

  • Incidence: 4.1 per 100,000 (account for 3–5% of all malignancies worldwide) [2][3]
  • Median age at diagnosis: 65 years [4]
  • Sex: slight preponderance in men [4]

Epidemiological data refers to the US, unless otherwise specified.

Clinical featurestoggle arrow icon

Diagnosticstoggle arrow icon


Routine studies for CUP [3][6][7]

Laboratory studies


Analysis of the tumor [3][8]

Patients who have had a mastectomy should have an MRI to assess residual breast tissue.

Additional studies [3][6][7]

Peripheral blood tumor markers should not be performed routinely because they are frequently not specific for tumor sites. They may, however, be helpful in certain clinical presentations. [5]

PET-CT scan may be useful in patients with CUP who have cervical adenopathy or a single metastatic tumor site; it has limited utility in other patients. [3]

Treatmenttoggle arrow icon

Approach [3][6][9]

Favorable subgroup of CUP [3][4][10]

  • CUPs with clinical manifestations, histopathology findings, or biomarkers consistent with a specific tissue of origin and likely to respond to site-specific anticancer therapy [4]
  • Account for 15–20% of CUPs [3]
  • Managed with anticancer treatment similar to that given for an equivalent primary neoplasm
  • Long-term disease control is possible in 30–60% of patients. [3][10]
Management of favorable subgroup of CUP [3][4][10]
Examples Management
Squamous cell carcinoma affecting nonsupraclavicular cervical lymph nodes

Treat as head and neck squamous cell carcinoma.

Colorectal immune or molecular markers are present Treat as colorectal cancer.
Cancers with isolated axillary lymph node involvement in women and transmen Treat as breast cancer.
Papillary or serous peritoneal carcinoma in women and transmen Treat as ovarian cancer.
Bone metastases and elevated PSA in men and transwomen Treat as prostate cancer.
Midline lymph node involvement in men and transwomen Treat as germ cell tumor.
Neuroendocrine cancers (well-differentiated and poorly differentiated) Amenable to empiric chemotherapy
Cancers with a single metastatic deposit Amenable to resection and/or radiotherapy with/without empiric chemotherapy

Unfavorable subgroup of CUP

Targeted therapy based on the results of gene expression assays and molecular testing in CUP is unproven but rapidly evolving. [6]

Prognosistoggle arrow icon

Referencestoggle arrow icon

  1. $Contributor Disclosures - Cancer of unknown primary. None of the individuals in control of the content for this article reported relevant financial relationships with ineligible companies. For details, please review our full conflict of interest (COI) policy:.
  2. Mnatsakanyan E, Tung WC, Caine B, Smith-Gagen J. Cancer of unknown primary: time trends in incidence, United States. Cancer Causes Control. 2014; 25 (6): p.747-57.doi: 10.1007/s10552-014-0378-2 . | Open in Read by QxMD
  3. Fizazi K, Greco FA, Pavlidis N, Daugaard G, Oien K, Pentheroudakis G. Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015; 26: p.v133-v138.doi: 10.1093/annonc/mdv305 . | Open in Read by QxMD
  4. Kato S, Alsafar A, Walavalkar V, Hainsworth J, Kurzrock R. Cancer of Unknown Primary in the Molecular Era. Trends in Cancer. 2021; 7 (5): p.465-477.doi: 10.1016/j.trecan.2020.11.002 . | Open in Read by QxMD
  5. Hanna L, Crosby T, Macbeth F. Practical Clinical Oncology. Cambridge University Press ; 2015
  6. 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; 38: p.20-25.doi: 10.1200/EDBK_100014 . | Open in Read by QxMD
  7. Losa F, Fernández I, Etxaniz O, et al. SEOM-GECOD clinical guideline for unknown primary cancer. Clin Transl Oncol. 2022; 24 (4): p.681-692.doi: 10.1007/s12094-022-02806-x . | Open in Read by QxMD
  8. Losa F, Soler G, Casado A, et al. SEOM clinical guideline on unknown primary cancer (2017). Clin Transl Oncol. 2017; 20 (1): p.89-96.doi: 10.1007/s12094-017-1807-y . | Open in Read by QxMD
  9. Qaseem A, Usman N, Jayaraj JS, Janapala RN, Kashif T. Cancer of Unknown Primary: A Review on Clinical Guidelines in the Development and Targeted Management of Patients with the Unknown Primary Site. Cureus. 2019.doi: 10.7759/cureus.5552 . | Open in Read by QxMD
  10. Olivier T, Fernandez E, Labidi-Galy I, et al. Redefining cancer of unknown primary: Is precision medicine really shifting the paradigm?. Cancer Treat Rev. 2021; 97: p.102204.doi: 10.1016/j.ctrv.2021.102204 . | Open in Read by QxMD

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