Cancer of Unknown Primary Site: Not All is Lost!

A Cancer of Unknown Primary Site (CUPS) is defined as a metastatic tumor for which the site of origin remains unknown after establishing tissue diagnosis despite a standard diagnostic approach. It is still not known whether CUP is an entity with dormancy of primary as its hallmark or a distinct entity with specific genetic aberrations which define it as a primary metastatic disease. It poses a diagnostic challenge to the pathologists and often poses a therapeutic dilemma for the oncologists. The diagnostic algorithm includes; age, gender, histology, site of metastasis, distribution and natural history of disease, and expression of tissue specific markers by the malignant clones as revealed on immunostains, e.g. TTF1 for thyroid gland and adenocarcinoma lung, PSA for prostate gland, estrogen/ progesterone receptors and gross cystic disease fluid protein-15 for breast cancer, etc. Despite extensive and expensive diagnostic work up, in almost 20-45% cases the site of their origin remains unknown, however the yield rises to 70-80% after postmortem examination. While the pathology teams are working to resolve the primary site, the oncology teams are adamant on identifying subset of patients that may be treatable and potentially curable. However, CUPS remains aggressive, and generally associated with a poorer prognosis with a median survival of less than a year. The review focuses on current practices in diagnoses and treatment of an occasionally rare, and a challenging entity.