Other Cancers Cancer of Unknown Primary Site 113

Cancer of unknown primary (CUP) site is a clinical syndrome that includes many types of advanced cancers. Patients are considered to have CUP if no anatomical primary site is identified after clinical evaluation. As diagnostic techniques improve, the spectrum of patients with CUP continues to evolve. Patients with CUP are common. The exact incidence is unknown because many of these patients are assigned other diagnoses and therefore are not accurately represented in tumor registries. Nonetheless, in the United States, CUP accounted for approximately 2% of all cancer diagnoses reported by Surveillance, Epidemiology, and End Results (SEER) registries.1 International registries from seven other countries have reported incidences ranging from 2.3% to 7.8%.2 The authors believe a more realistic estimate of the incidence of these patients is 5% of all invasive cancers, or approximately 80,000 to 90,000 patients per year in the United States. Patients in this heterogeneous group have a wide variety of clinical presentations and histologic tumor types. Most patients have metastatic carcinoma; however, many neoplasms are difficult to categorize using histologic features alone. At autopsy, primary sites (usually <2 cm in size) can be located in the majority of patients; the molecular basis of this unusual biologic behavior is undefined. The preponderance of poorly treated tumor types in autopsy series (lung, pancreas, stomach, colon, liver) has led to negativity surrounding the diagnosis of CUP.3 Until recently, the major advance in the management of CUP was the recognition of several important patient subsets, identified by clinical and/or pathologic features and shown to benefit from specific first-line therapy. For the remainder of CUP patients (about 80%), empiric chemotherapy regimens were developed and resulted in modest benefit. At the time these regimens were developed, most types of solid tumors were poorly treated, and considerable overlap existed in the chemotherapy regimens used to treat sensitive tumor types. In this context, the possibility of developing a broad-spectrum chemotherapy regimen to adequately treat most of the treatable tumor types within the CUP population seemed feasible. However, during the last 20 years, treatments have not only improved for many tumor types, but have also become more site specific. Therefore, the idea of providing optimal treatment to patients with a diverse group of solid tumors using a single chemotherapy regimen is no longer feasible. An accurate prediction of the tissue of origin is now possible for the majority of patients with CUP, using either improved panels of immunohistochemical (IHC) stains or molecular gene expression tumor profiling (MTP). Although the anatomical primary sites cannot be found in most patients even after the tissue of origin is predicted, increasing clinical experience confirms that these predictions can effectively guide site-specific therapy for patients with CUP. This chapter is divided into three major sections. The first section reviews the pathologic evaluation of patients with CUP. New information regarding the emerging and important role of MTP assays is included. In the second section, the clinical evaluation of CUP patients is summarized. Situations in which results from the pathologic evaluation direct the clinical evaluation are addressed. Finally, the treatment of patients with CUP is discussed, with an emphasis on the favorable prognostic subsets and the new paradigm of site-specific therapy directed at the tissue of origin.