When genomics and histopathology diverge: insights from pathologic review of genomic-directed specimens

The evaluation of tumors is increasingly becoming an integrated diagnosis based on combined histologic and genomic evaluations. As more tumors are subjected to genomic analyses, discrepancies between the histologic diagnosis and molecular findings surface. Pathologic review of genomic-directed specimens plays a vital role in understanding and resolving these discrepancies. We aim to assess the frequency of and reasons for discrepant diagnoses in genomic-directed specimens from a precision genomics program. A retrospective review of genomic-directed specimens analyzed through a precision genomics program was performed. We assessed the frequency of discrepancies between the histologic diagnosis and molecular findings. The discrepant cases were further studied to uncover the reasons behind the discrepancy. 381 patients referred to the program had their tumors sequenced. Nine cases (2.4%) had discrepancies between the original histologic diagnosis and molecular findings. These discrepancies were related to a combination of nonspecific morphology, nonconclusive immunophenotypes, and misleading immunophenotypes. While infrequent, diagnostic discrepancies do occur in genomic-directed specimens. These cases are often diagnostically challenging to begin with. Integrated diagnostics (histology, immunohistochemistry, and molecular) and collaborative discussions are critical for resolving and reducing discrepancies.