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Gene expression array analysis to determine tissue of origin of carcinoma of unknown primary

Approximately 2% to 5% of advanced cancers that present as metastatic cases are considered tumors of unknown origin when the primary tumor site is not determined, also known as carcinoma of unknown primary (CUP). The rationale for identifying the primary tumor for such metastatic cases traditionally has been for the purpose of providing patients with cancer-specific treatment recommendations. This was especially relevant in the era before targeted therapy, when histotype and site of origin were the key parameters to define the treatment regimen. However, as targeted therapies increase in number and breadth, the concept of treatment on the basis of site of origin is likely to be replaced progressively by treatment on the basis of molecular signature. In this editorial, we suggest that, although the CUP test is just gaining popularity and use, it is also about to become obsolete. We also argue that next-generation sequencing (NGS) and therapeutic choice based on molecular signature will eliminate the need for site-of-origin type tests. Traditionally, site-of-origin information has been an important part of clinical management. Although some CUPs fall into a ‘‘favorable subset’’ characterized by similarity to good-prognosis tumor types, such as germ cell tumors or lymphoma, the remaining 80% of patients with CUP fall into a poor prognosis group characterized by a median survival of approximately 7 to 12 months from diagnosis. CUPs are predominantly adenocarcinomas (90%), and the remaining tumors are divided evenly between squamous carcinomas and neuroendocrine carcinomas. Among adenocarcinomas, pancreatic and lung cancers are the most common primary sites (approximately 25% each), followed by colon, stomach, breast, ovarian, prostate, and solid organ tumors (kidney, thyroid, and liver); the similar appearance among adenocarcinoma metastatic biopsies is confounding to the diagnosis of these tumors. Nonetheless, CUP tests (whether based on expression levels or immunohistochemistry [IHC]) had clinical utility because they helped guide therapy. In a recent edition of Cancer (Cancer Cytopathology), Stancel et al evaluated the feasibility of applying the Pathwork tissue-of-origin gene expression test (Pathwork Diagnostics, Redwood City, Calif) on cellblocks prepared from cytologic body fluid specimens. In this follow-up commentary, we describe the current methodologies for identifying the primary tumor site for CUPs along with the advantages and disadvantages of each method. We illustrate that the lack of a criterion (gold) standard to compare the accuracy of each methodology represents a major challenge, because, even upon autopsy, a primary tumor may not be identified in 70% to 80% of patients with CUPs. To complicate matters further, the molecular assays described sometimes use IHC results, the previous criterion standard, for assessing the accuracy of their tumor site classifications. This is