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Carcinoma of unknown primary (CUP) is a biopsy-proven malignancy for which the anatomic site of origin remains unidentified after a focused search. CUP is one of the 10 most frequently diagnosed cancers worldwide, accounting for 3–5% of all cancers. Most investigators limit CUP to epithelial and undifferentiated cancers and do not include lymphomas, metastatic melanomas, and metastatic sarcomas because these cancers have specific histology- and stage-based treatments that guide management even in the absence of a primary cancer.

The emergence of sophisticated imaging, robust immunohistochemistry (IHC), and genomic and proteomic tools has challenged the “unknown” designation. Additionally, effective targeted therapies in several cancers have moved the paradigm from empiricism to considering a personalized approach to CUP management. The reasons cancers present as CUP remain unclear. One hypothesis is that the primary tumor either regresses after seeding the metastasis or remains so small that it is not detected. It is possible that CUP falls on the continuum of cancer presentation where the primary has been contained or eliminated by the natural body defenses. Alternatively, CUP may represent a specific malignant event that results in an increase in metastatic spread or survival relative to the primary. Whether the CUP metastases truly define a clone that is genetically and phenotypically unique to this diagnosis remains to be determined. Of note, the incidence of intrahepatic cholangiocarcinoma (ICC) is increasing whereas the incidence of CUP is declining during this same time period. Because the liver is a common site of CUP presentation, ICC can be misdiagnosed as CUP. Improvements in diagnostic technologies and awareness among clinicians to differentiate the two are contributing to an increased recognized incidence of ICC.


Studies looking for unique signature abnormalities in CUP tumors have not been positive. Abnormalities in chromosomes 1 and 12 and other complex cytogenetic abnormalities have been reported. Aneuploidy has been described in 70% of CUP patients with metastatic adenocarcinoma or undifferentiated carcinoma. The overexpression of various genes, including Ras, bcl-2 (40%), her-2 (11%), and p53 (26–53%), has been identified in CUP samples, but they have no effect on response to therapy or survival. The extent of angiogenesis in CUP relative to that in metastases from known primaries has also been evaluated, but no consistent findings have emerged. Current focus is on comprehensive genomic profiling that may identify targeted therapeutic approaches to improve outcomes for this disease as discussed below. Additionally, ongoing profiling efforts may also provide insights into CUP biology through recognition of molecular aberrations that especially drive metastatic growth.


Initial CUP evaluation has two goals: search for the primary tumor based on pathologic evaluation of the metastases and determine the extent of disease. Obtaining a thorough medical history from CUP patients is essential, including paying particular attention to previous surgeries, removed lesions, and family medical history to assess potential hereditary cancers. Adequate ...

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