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Carcinomas of unknown primary, with their heterogeneous presentations, pose a major problem for oncologists; depending on the extent of evaluation, they comprise 3 to 10% of all tumors diagnosed (1-3). A working definition for carcinoma of unknown primary (CUP) is biopsy-proven metastatic cancer with no identifiable primary source by history, physical examination, chest radiography, complete blood count, chemistry, computed tomography (CT) of the chest, abdomen and pelvis, prostate-specific antigen (PSA) in men, and mammography in women. 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 (2,4,5). It is this considerable heterogeneity that has presented a challenge to the systematic study of CUP. Depending on histologic features, sites of disease, and performance status, a small but significant minority of patients will be long-term survivors (4,6).

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 show that in this population, a search for the primary tumor beyond "routine" evaluation is unrewarding in >90% of cases (2,3,7). 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 which 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, since this cancer diagnosis is the epitome of personalized therapy.

The incidence of CUP is difficult to determine because many patients are given other diagnoses, and CUP is therefore underreported (6). It was estimated that 31,490 new cases of cancer of "other and unspecified primary sites" were diagnosed in 2009, representing more than 2% of all cancers (8). Based on studies explicitly designed to evaluate CUP, the true incidence is thought to be much higher, closer to 6% of all new cancers (9). CUP seems to affect men and women equally and recent large series show a median age at presentation between 59 and 66 years (1,5,10...

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