Cancer of unknown primary (CUP) is a primary metastatic malignant epithelial or undifferentiated neoplasm for which a standardized diagnostic workup fails to identify a site of origin.  CUP constitutes approximately 2% of all human cancers, but has a high mortality rate, with median survival less than 1 year.

The most common histology is adenocarcinoma: approximately 50% of CUP cases are well- or moderately differentiated adenocarcinomas. 30% are poorly differentiated adenocarcinomas or undifferentiated carcinoma, 15% are squamous cell carcinomas and the remainder are undifferentiated neoplasms.  Sarcomas, melanomas, germ cell tumours, neuroendocrine tumours and haematological malignancies are not generally included as “CUP” cases, even if the exact site of origin of the tumour is not clear.

Diagnostic challenges include tumours with non-specific morphologic or immunophenotypic features (such as a “biliary-type” adenocarcinoma with CK7+/CK20- immunophenotype), tumours showing aberrant differentiation (such as a SMARCA4-deficient non-small cell lung carcinoma), undifferentiated malignancies (such as undifferentiated melanoma) and rare tumours.

The diagnosis of CUP requires a multidisciplinary approach, with interpretation of histopathological findings in the context of comprehensive clinical history (including history of prior malignancy), clinical examination, evaluation of serum tumour markers, and review of radiology +/- nuclear medicine +/- endoscopic findings.  As diagnostic biopsy often comprises only a small quantity of tumour tissue (e.g. core biopsy), a stepwise approach to immunohistochemistry and, sometimes, molecular testing may be warranted, aiming to provide all necessary diagnostic and prognostic information on limited tissue available.

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Krämer A, Bochtler T, Pauli C, et al.  Cancer of unknown primary:  ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.  Annals of Oncology 2023 34(3):228-246.  https://doi.org/10.1016/j.annonc.2022.11.013.

Beauchamp K, Moran B, O’Brien T, et al. Carcinoma of unknown primary (CUP):  an update for histopathologists.  Cancer and Metastasis Reviews 2023;42:1189-1200. https://doi.org/10.1007/s10555-023-10101-6

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Pauli C, Bochtler T, Mileshkin L, et al. A Challenging Task: Identifying Patients with Cancer of Unknown Primary (CUP) According to ESMO Guidelines: The CUPISCO Trial Experience. The Oncologist 2021;26:e769–e779.