Introduction

Patients with cancer of an unknown primary site present the healthcare professional with many challenges. Managing the problems related to the advanced stage of their condition is difficult and the unresolved diagnosis confronts patients, their families, and their caregivers with an added level of uncertainty. In this chapter, we review the natural history, the diagnostic evaluation, patterns of disease spread, treatment, and palliative care issues related to the management of patients with cancer of an unknown primary site.

Definition and natural history

Cancer of an unknown primary site (CUP) is defined as a pathologically proven malignancy in the absence of a known site of origin after an adequate diagnostic work-up. Cancers with a specific histology that portend a specific treatment, such as lymphomas, melanoma, and sarcomas, are not considered cancers of an unknown primary site, even if the area in the body where they originated cannot be determined.

The incidence of CUP has been estimated at between 0.5% and 7% of all patients with invasive cancer in the US.

Unlike that of most patients who present with an obvious primary tumor, the natural history of patients with CUP does not display an ordinate sequence of events: Progression from the original site to neighboring anatomical structures, regional lymph nodes, and distant metastatic sites is usually not apparent. The diagnosis of CUP is based on the absence of a known site of origin of the cancer and therefore requires a painstaking exclusion of all possible primary sites.