Integrating Molecular Sequencing Into the Pathological Diagnosis of Clinically Suspected Non-Small Cell Lung Carcinomas.

Cancer panel sequencing has been rapidly adopted into clinical practice for the detection of actionable genetic variants in advanced non-small cell lung carcinomas. Unexpected molecular results may lead to reexamination of the clinical diagnosis; however, this scenario has not been systematically evaluated. We reviewed cancer panel next-generation sequencing results from 1007 consecutive patients performed for the clinical indication of non-small cell lung carcinoma along with the corresponding clinical history and anatomical pathology findings. The final integrative diagnosis was a cancer of extrapulmonary origin in 12 of 1007 patients (1.2%). Molecular evidence supporting the final diagnoses included the detection of an UV radiation-associated mutational signature (n = 6), gene fusions (n = 2), and mutations (n = 4). The integrative diagnoses included undifferentiated melanoma, cutaneous squamous cell, and basal cell carcinomas, thyroid carcinoma, urothelial carcinoma, hepatocellular carcinoma, pancreatic adenocarcinoma, intrahepatic cholangiocarcinoma, and synovial sarcoma. A small but nonnegligible proportion of clinically suspected non-small cell lung carcinomas had a final diagnosis of cancer of extrapulmonary origin after clinical next-generation sequencing. The integration of clinical, microscopic, and molecular evidence can aid diagnosis and guide personalized oncology care.