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Carcinomas of unknown primary (CUPs), with their heterogeneous presentations, pose a challenge on the diagnostic and therapeutic fronts. Depending on the extent of evaluation, CUP comprises 3% to 5% of all tumors diagnosed (1,2,3). A working definition for CUP is biopsy-proven metastatic cancer with no identifiable primary source by history; physical examination; chest radiography; complete blood cell count; chemistry; computed tomography (CT) of the chest, abdomen and pelvis; prostate-specific antigen (PSA) in men; and mammography in women (2). The natural history of disease for CUP is diverse and is dependent on multiple variables, such as, age, number of metastatic sites, dominant area of disease, and histology. This considerable heterogeneity presents a challenge to the systematic study of CUPs. In addition, the emergence of sophisticated imaging, robust immunohistochemistry (IHC), and genomic and proteomic tools have challenged the “unknown” designation. Depending on histologic features, sites of disease, and performance status, a small but significant minority of patients will be long-term survivors, and it is important to identify these groups of patients (4,5).

This chapter discusses the evaluation of patients with CUP and optimal therapeutic strategies in the era of sophisticated diagnostics. The differing natural histories in CUP, depending on both the sites of disease and histology, are also discussed. Studies showed that, in this population, a search for the primary tumor beyond “routine” evaluation is unrewarding in the majority of patients (5). This fact has caused much consternation for both patients and physicians. The foundation for cancer treatment traditionally relies on identification of the tumor origin, thereby allowing treatment to be chosen based on the known natural history as well as specific therapies that have been proven effective for the cancer; this is becoming even more important with the rapid emergence of targeted therapies. Without knowledge of the primary site, the oncologist is often hesitant to recommend therapy, especially given the disease heterogeneity. Although most patients with metastatic CUP have tumors that respond poorly to current treatments and will consequently have a poor prognosis, it has become evident over the last two decades that subsets of patients with CUP have a favorable prognosis and respond to chemotherapy or can be successfully treated with regional therapy alone. The current era of sophisticated diagnostics and introduction of targeted therapies has been particularly important in the CUP setting; this cancer entity is the epitome of personalized therapy.


The incidence of CUP cancers as estimated from the cancer registries and databases of “unknown and unspecified cancers” is reported to be approximately 3%-4% of all cancers (6). This is probably an overestimation because this group includes a mix of patients: those with true CUP, those with primaries not yet diagnosed at the time of death, and those with difficult-to-diagnose tumors. Further, improved imaging allowing identification of small primary tumors suggests ...

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