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Carcinoma of unknown primary (CUP) is a biopsy-proven (mainly epithelial) 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 approximately 3–5% of all cancers. Most investigators do not include lymphomas, metastatic melanomas, and metastatic sarcomas that present without a known primary tumor as CUP because these cancers have specific stage- and histology-based treatments that guide management.

With the increasing availability of additional sophisticated imaging, invasive diagnostic techniques, and the emergence of effective targeted therapies in several cancers, an individualized management algorithm with an impact on quality of life and survival is critical. 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 in which 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.


No characteristics that are unique to CUP relative to metastases from known primaries have been identified. 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.


Obtaining a thorough medical history from CUP patients is essential, paying particular attention to previous surgeries, removed lesions, and family medical history to assess potential hereditary cancers. Physical examination, including a digital rectal examination in men and breast and pelvic examinations in women, should be performed. Determining the patient's performance status, nutritional status, comorbid illnesses, and cancer-induced complications is essential since these may affect treatment planning.

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 and not helpful in determining the primary tumor site. Men who present with adenocarcinoma and osteoblastic metastasis should undergo a prostate-specific antigen (PSA) test. In patients with undifferentiated or poorly differentiated carcinoma (especially with a midline tumor), elevated β-human chorionic gonadotropin (βhCG) and α fetoprotein (AFP) levels suggest the possibility of an extragonadal germ cell (testicular) tumor. Cytogenetic studies ...

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