Carcinomas of unknown primary site (CUP) are a group of heterogeneous tumors that share the unique clinical characteristic of metastatic diseases with no identifiable origin at the time of therapy. A CUP is defined as a histologically confirmed metastatic cancer for which the primary site is not identified after a complete physical examination (including pelvic and rectal examination), a histopathologic biopsy examination using immunohistochemistry, and computed tomography (CT) of the thorax, abdomen, and pelvis. It is important to note that patients with upfront metastatic cancer and a clear primary tumor identified after studying a biopsy of the metastasis or after fullbody imaging are not CUP patients. Despite advances in tumor imaging and pathology, patients with CUP still account for about 3% to 5% of all cancer patients in European registries from the Netherlands (The Netherlands Cancer Registry 2003) and Sweden (The National Board of Health and Welfare 2006), and also in the United States, as assessed by Surveillance, Epidemiology, and End Results (SEER) (ACS 2007). Because of a specific and unique phenotype of early and usually aggressive metastatic dissemination with no identifiable primary tumor, CUPs are a challenge for physicians. Patients with CUP have a poor prognosis, attaining a median of 8 to 11 months, and only 25% survive for 1-year.¹,²,³

Patients with metastatic lesions at diagnosis must be classified into those with a primary tumor that is revealed by the metastatic lesion and those with “true” CUP, who are then further classified into established clinicopathologic subsets in order to orient diagnostic approaches and to be able to offer optimal therapeutic management.⁴,⁵

The diagnostic workup of patients with CUP is based on three main components: a careful clinical examination, an extensive histopathologic analysis, and the use of imaging techniques⁴,⁵,⁶,⁷ (Table 25.1).

A. First, a full medical history and physical examination should be obtained to guide the diagnosis of upfront metastatic cancer without an identified primary tumor. Then, patients should undergo a full-body CT scan, and a basic blood and biochemistry analysis with serum tumor marker analyses (prostate-specific antigen [PSA], human chorionic gonadotropin [hCG], alpha-fetoprotein [AFP]) in males if
appropriate. Mammography and breast magnetic resonance imaging (MRI) are recommended for female patients with metastatic adenocarcinoma involving axillary lymph nodes. Other diagnostic methods could also include additional imaging studies, such as positron emission tomography scanning and magnetic resonance scanning of the breast, as well as particular endoscopic procedures.²,^{3 18}F-FDG-PET scans can be useful, particularly if the involved cervical lymph nodes of patients exhibit squamous cell carcinoma.

Finally, the diagnosis of CUP requires pathologic examination of a biopsied tumor with the tissue sample showing an epithelial cancer. A tumor biopsy is essential for tissue examination, immunohistochemical staining, and more specific investigations such as genetic or molecular studies.

CUP is classified into four major histologic subtypes: 50% of cases are well-differentiated or moderately differentiated metastatic adenocarcinoma; 30% are poorly or undifferentiated carcinoma; 15% are squamous cell carcinomas and occur in 15% of all CUP patients; and 5% are undifferentiated neoplasms. Most of them are further characterized by immunohistochemistry and defined as neuroendocrine tumors, lymphomas, germ-cell tumors, melanomas, or sarcomas.

First, a standard pathologic screening is performed to identify different tumor types (such as carcinomas, melanomas, lymphomas, and others) (Table 25.2). In the case of carcinomas, a panel of antibodies can help to pinpoint a possible primary site. In particular, staining for cytokeratins CK7 and CK20 is used to subtype carcinomas: CK7 is widely expressed in breast, pancreas, lung, biliary tract, and transitional epithelium, whereas CK20 is expressed in
gastrointestinal epithelium, especially in the colon, and in transitional epithelium.¹,²,³,⁴ Moreover, if the first screening was inconclusive, a panel of different antibodies could be used for a carcinoma diagnosis. These include CA125, CDX2, cytokeratins 7 and 20, estrogen receptor, gross cystic disease fluid protein 15, lysozyme, mesothelin, PSA, and thyroid transcription factor 1 (Table 25.3).