Overview of various techniques/platforms with critical evaluation of each.

OPINION STATEMENT: Patients with cancer of unknown primary are common and can present in a variety of ways with different histological features. Despite best clinical effort in pretreatment diagnostic workup, many patients classified as having cancer of unknown primary (CUP) often are still left with no definitive diagnosis of the primary organ or tissue of origin to account for the metastatic disease. Whereas advances in immunohistochemical techniques have improved the diagnostic yield to some extent, the challenges remain substantial for most patients with CUP in whom initial therapy is typically chosen empirically. In recent years, development of molecular gene profiling of tumor offers new possibilities to better characterize, diagnose, and classify the tissue of origin of various metastatic CUP to better inform optimal therapy. The premise behind the development of improved diagnostic tools to better diagnose the organ or tissue of origin for metastatic disease of unknown primary is that an organ/tissue-specific tailored therapy of choice would favorably impact the treatment outcome. There are now three commercially available molecular profiling platforms for the purpose of diagnosing the tissue of origin in the otherwise CUP patients: 1) bioTheranostics: Cancer TYPE ID® (qRT-PCR for mRNA); 2) Pathworks®: Tissue of origin test (microarray for mRNA expression); and 3) Rosetta Genomics-Prometheus: miRview™ mets (ProOnc Tumor SourceDxT) (qRT-PCR for microRNA). Whereas these are new technologic platforms that offer new promise for better diagnostics and perhaps better therapeutic strategies in cancer therapy, each of the platforms has its own strengths and limitations due to their test of choice and assay source materials and technical platform itself. However, a fundamental question that needs be further addressed regarding the utility of these novel molecular profiling assays is whether they represent more superior approaches than genomic profiling assays using rapidly emerging cancer genomics next-generation sequencing (NSG) platforms. Because cancer is nowadays understood as genomic disease, the genomic alterations (e.g., mutations, copy number variations, chromosomal translocations, splicing variants) may offer more important insights into the cancer pathogenesis. More importantly, these genomic information may be more relevant in guiding personalized/precision cancer therapy than merely empiric chemotherapy based on tissue/organ-of-origin information. Ideally, further comparative studies and demonstration of utilities would be needed and eagerly anticipated to determine which diagnostic approach ultimately could impact the clinical outcome of patients with CUP.