Carcinoma of Unknown Primary

Carcinoma of unknown primary (CUP) is a diverse group of heterogeneous cancers presenting without a primary site and accounts for about 2% to 4% of all cancers. The past two decades have seen significant change in our approach to CUP patients. Therapy strategies have moved away from the empiric combination cytotoxic therapies and the “one treatment fits all” approach. The primary focus has been on improved methods to identify the putative primary tumor and to direct therapy at that tumor type. Albeit not uniform, there is consensus that the evaluation needs to be focused, with imaging and invasive tests based on symptomatology and pathologic evaluation. Although it has limitations including variable tissue antigenicity and interpretation, immunohistochemistry remains a powerful tool in the judicious pathologic assessment of metastatic tumor tissue. Over the last several years, cancer classifying tissue of origin profiling libraries has generated enormous data, analyses of which have led to additional insights. Using next generation sequencing, there is a push toward personalizing cancer care through the use of genomic tools to identify driver and actionable mutations in individual tumors. For this approach to be successful in CUP, it will require continued understanding of unique molecular insights for select CUP subsets, as well as leveraging novel drugs that are effective against specific mutations in known cancers.