NORTHFIELD, Ill. (January 21, 2026) — For patients with cancers of unknown primary (CUP) and other diagnostically ambiguous tumors, molecular testing may help pathologists identify tumor origin and guide targeted treatment decisions, according to a new article from the College of American Pathologists (CAP).
In “Utility of Molecular Testing in the Diagnostic Workup of Difficult-to-Classify Tumors,” authors Jie-Fu Chen, MD, FCAP, Personalized Healthcare Committee member and JinJuan Yao, MD, PhD, FCAP, outline how advances in genomic, transcriptomic, and epigenetic profiling are helping pathologists navigate some of the most challenging diagnostic scenarios in oncology.
While histologic examination and immunohistochemistry remain the foundation of cancer diagnosis, the authors explain that molecular profiling can provide critical additional insight when conventional approaches fall short. This is especially true for CUP, tumors with unclear site-of-origin or prior oncologic history, and cases requiring determination of whether multiple tumors represent separate primaries or metastatic disease.
“When faced with a difficult-to-classify tumor, molecular testing may be able to suggest the potential tumor type or primary site, which will inform the clinical management plan by allowing established tumor-type-specific treatment protocols,” shares Dr. Chen. “In the case where tumor type remains elusive, molecular testing may identify biomarkers or actionable alterations for targeted therapies, especially the cancer type agnostic options.”
The article highlights how molecular features, especially recurrent genomic alterations and mutational signatures, can suggest tumor type or site of origin in various clinical scenarios and, in some cases, change the variant categorization of actionable targets for therapy. The authors also discuss the growing role of machine learning and artificial intelligence–based algorithms in tumor classification, while emphasizing the importance of understanding their capacities and potential limitations, and interpreting results within the full clinical and pathologic context.
“As molecular technologies continue to advance, they are enhancing traditional pathology,” notes Dr. Yao, underscoring the continued need for expert interpretation to ensure accurate diagnosis and optimal patient care.
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About the College of American Pathologists
As the world’s largest organization of board-certified pathologists and leading provider of laboratory accreditation and proficiency testing programs, the College of American Pathologists (CAP) serves patients, pathologists, and the public by fostering and advocating excellence in the practice of pathology and laboratory medicine worldwide. For more information, visit the CAP Newsroom, CAP.org and yourpathologist.org to watch pathologists at work and see the stories of the patients who trust them with their care.