Cancer of Unknown Primary

Introduction

Cancer of unknown primary (CUP) is a designation given to discordant group of metastatic carcinomas for which the primary site of origin cannot be identified, despite a thorough diagnostic workup that includes a thorough medical history, complete physical examination to include breast, pelvic, and rectal evaluations, complete blood count and biochemical analysis, urinalysis, serum prostate-specific antigen (PSA) in males, and histopathologic review of tissue specimens with immunohistochemistry. Computed tomography (CT) of the chest, abdomen, and pelvis; chest radiography; and mammography in females are performed as indicated. Despite this workup, the treating physician will more than likely still be in a quandary as to the primary site that produced the aggressive metastatic disease. Needless to say, this scenario creates stress not only to the physician but also to the patient in trying to cope with the unknown. Unproven theories regarding the localization of the primary CUP site include: (1) the primary tumor has involuted, and only the metastatic disease is evident, and (2) metastatic disease is favored over the primary growth based on the phenotype and genotype of the tumor.

Epidemiology and Risk Factors

Worldwide, CUP is one of the 10 most frequent cancers, constituting approximately 3% to 5% of all cancer cases. In 2018, according to the American Cancer Society, there were an estimated 31,810 cases of “other & unspecified primary cancer sites” in the United States, accounting for 2% of all cancer cases and an estimated 44,560 deaths. At presentation, the median age of the patient is approximately 60 years, and it is slightly more frequent in males. No risk factors have been identified for this heterogeneous group of neoplasms, and no screening programs have yet been described to detect these neoplasms.

Pathologic Classification and Assessment

Because only carcinomas are included in the diagnosis of CUP, four main histologic types of CUP have been described: well to moderately differentiated adenocarcinomas (50%), undifferentiated or poorly differentiated carcinomas (30%), squamous cell carcinomas (15%), and undifferentiated neoplasms (5%). The latter group includes lymphomas, sarcomas, germ cell tumors, poorly differentiated carcinomas, neuroendocrine tumors, and embryonal malignancies that can be characterized by immunohistochemistry. In children, CUPs represent less than 1% of solid tumors, and the majority of these tumors are embryonal malignancies.

Pathologic assessment is a must to characterize the CUP and is usually accomplished by histologic and cytopathologic evaluation. As an adjunct, electron microscopy is occasionally used to evaluate those CUPs that demonstrate indeterminate features which cannot be resolved or characterized with routine pathologic evaluation. Serum tumor markers, which are mainly overexpressed glycoproteins that are released into the bloodstream by malignant tumors, can help to identify, diagnose, classify, follow-up, and aid in the assessment of response to therapy in some cases. However, these serum tumor markers have low sensitivity and specificity, as they are not expressed specifically by one organ or in one particular tumor. The number of serum tumor markers to be assessed is determined on a case-by-case basis; these markers include but are not limited to carcinoembryonic antigen (CEA), CA125, CA19-9, CDX2, CA15-3, CK-7, CK-20, thyroid transcription factor-1, PSA, alpha-fetoprotein, beta–human chorionic gonadotropin, estrogen receptors, and gross cystic disease fluid protein-15 (GCDFP-15). Some of the tumor markers can even be elevated in benign diseases, such as CEA in inflammatory bowel disease and CA19-9 in pancreatitis.

Role of Molecular Profiling to Determine the Tissue of Origin

Molecular profiling of CUP offers a technique to determine the tissue of origin (ToO), with a possible impact on therapy. Several studies demonstrated the feasibility of using gene expression profiling with DNA microarray to classify uncertain tumors based on their ToO by identifying gene subsets whose expression pertains to a specific cancer class. These studies achieved an accuracy of 78% to 98% in identifying tumor ToO.

Two main strategies have been used to identify the ToO: DNA microarray platforms and quantitative reverse transcription real-time polymerase chain reaction (qRT-PCR). For both of these strategies, messenger RNA is extracted from fresh frozen or formalin-fixed paraffin-embedded tumor tissue. The multigene expression pattern of a CUP cancer is compared with known primary cancers, and a ToO assigned based on the molecular signature it most closely resembles. Some of the molecular assays have been commercialized and are available from several vendors.

In a large study using qRT-PCR to determine the ToO in CUP, 98% of successful assays performed for 252 patients were able to predict the ToO. The most common sites predicted, in descending order, were biliary tract (11%), urothelium, and colorectal. However, the clinical utility of these assays still needs further assessment, as results-based treatment still did not change survival significantly. This testing will become even more important as specific targeted therapies emerge for known cancers, which can then be applied to CUP subsets.