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Carcinoma of unknown primary (CUP) is a biopsy-proven malignancy for which the anatomic site of origin remains unidentified after an intensive 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 cancers and do not include lymphomas, metastatic melanomas, and metastatic sarcomas because these cancers have specific histology- and stage-based treatments that guide management.

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.


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 studied 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. Using the Sequenom (SQM) Massarray platform, a study in consecutive CUP patients showed that the overall mutational rate was surprisingly low (18%). No “new” low-frequency mutations were found using a panel of mutations involving the P13K/AKT pathway, MEK pathway, receptors, and downstream effectors. Nevertheless, it is possible that newer “deep sequencing” techniques in select patients may yield consistent abnormalities.


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 physical examination, including a digital rectal examination in men and breast and pelvic examinations in women, should be performed based on clinical presentation.

Role of serum tumor markers and cytogenetics

Most tumor markers, including CEA, CA-125, CA 19-9, and CA 15-3, when elevated, are nonspecific ...

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