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  • Carcinoma of unknown primary (CUP) is defined as biopsy-proven metastatic cancer where a primary site is unidentifiable after adequate workup.

  • CUP is a rare tumor with an incidence of less than 10 per 100,000 individuals and constitutes nearly 2% of all cancers diagnosed in the United States.

  • Favorable and specific clinicopathologic subsets in CUP should be identified and treated with selective and aggressive treatments.

  • Limited data support the use and therapeutic impact of molecular profiling assays for tissue of origin (ToO) determination in CUP.

  • Chemotherapy for patients with CUP can be either empiric or site-specific (guided by putative primary site determined by clinicopathologic factors), and novel effective therapies for known primaries may impact the treatment decision.

  • Overall prognosis in CUP is poor, but a great degree of heterogeneity based on patient and disease characteristics exists.


Carcinomas of unknown primary (CUPs), with their heterogeneous presentations, pose a challenge diagnostically and therapeutically. Depending on the extent of evaluation, CUP comprises about 2% of all malignancies.1–3 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 proven to be 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 ...

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