Cancer of unknown primary site and TNM staging: a new paradigm for patient management

Cancer of unknown primary site (CUP) is a syndrome of many different metastatic cancers arising from clinically occult primary tumors. There has been no established staging system applicable since it has not been possible to identify an anatomical primary tumor. In recent years, the globally accepted American Joint Committee on Cancer TNM (tumor-node-metastasis) staging manuals briefly addressed a few rare CUP subsets with highly suspected primary tumors (breast, oropharynx, nasopharynx, melanoma) that could be designated as primary category T0 (no evidence of primary tumor). Similar logic may now be applied to many other patients and TNM staging is an evolving narrative. Diagnostic pathology, particularly immunohistochemical staining and molecular testing, interpreted in the context of clinical features are now capable of diagnosing presumptive occult primaries with reasonable certainty in many other patients creating an avenue for a T0 category as a specific cancer type. This new diagnostic paradigm of lifting the veil of the unknown for some patients and separating them from the historical nondescript CUP diagnosis allows for TNM staging, precision site-specific therapy (SST), prognostication, evaluating treatment results and continuing investigation. Once the tumor type is unmasked and staged, additional molecular characterization and SST are indicated. Many CUP subsets now meet these criteria and considerable clinical trial data have revealed that their outcomes from SST appear superior to empiric chemotherapy and similar to their counterparts with overt primary tumors, although additional prospective comparative studies are warranted. Eventually most of the cancers responsible for the enigmatic CUP syndrome will be identified, making CUP an irrelevant clinical entity.