The diagnostic challenges of patients with carcinoma of unknown primary

Cancer of unknown primary (CUP) is a disease entity encompassing heterogeneous malignancies without a clinically-detectable anatomical primary. It is usually a poor prognosis malignancy with dismal prognosis where molecular and genetic testing were expected to be a major breakthrough.

In this review, we provide an overview of the advances in the understanding of the carcinogenesis, biology, diagnosis and treatment of patients with CUP. This review focuses on the advantages and inconveniences of immunohistochemistry and CUP classifiers in assessing the progress in the management of CUP.

CUP classifiers were expected to gradually replace the classical multistep approach in identifying the culprit tumors to guide site-specific therapy. Immunohistochemistry staining led to the prediction of a single tissue of origin in 10.8-51%. CUP classifiers identified the primary site in 61-89% of these cases and were concordant with immunohistochemistry in 57.1-100%. Immunohistochemistry is cheap, fast and broadly available whereas CUP classifiers are less widely available and have not been validated in randomized control trials. The diagnostic recommendations consist of a standard pathology evaluation based on morphology and algorithmic immunohistochemistry assessment. Physicians should weigh in the input of the CUP classifier to the clinical picture and pathology investigations before performing additional investigations.