Immunotherapy response in microsatellite-stable poorly differentiated thyroid carcinoma with mismatch repair deficiency and high tumor mutational burden.

Poorly differentiated thyroid carcinoma (PDTC) is a rare and aggressive malignancy with a poor prognosis. Immunotherapy is typically guided by agnostic biomarkers such as microsatellite instability-high or high tumor mutational burden (TMB); however, these biomarkers are uncommon in PDTC. Therefore, identifying alternative predictive biomarkers remains an urgent necessity. We report the case of a 71-year-old woman who presented with life-threatening locoregional disease and was ineligible for radioiodine or tyrosine kinase inhibitors due to a prior subarachnoid hemorrhage. Molecular profiling of the resected tumor revealed a high TMB (10 mut/Mb), somatic mutations in MSH2 and ATM, and microsatellite stability (MSS). Immunohistochemistry demonstrated complete loss of MSH2/MSH6 expression, while PD-L1 expression was 20% (tumor proportion score). Based on these findings, pembrolizumab was initiated as first-line therapy. The patient experienced clinical improvement and maintained a sustained partial response for seven months, with excellent tolerability. This case represents one of the few documented reports of PDTC with MSS exhibiting marked responsiveness to immunotherapy. Our findings underscore that alternative biomarkers, such as somatic mutations in DNA repair genes including MSH2 and ATM, may predict unexpected responses to immune checkpoint blockade and inform therapeutic decisions, even in the context of MSS and borderline TMB. Broader implementation of molecular profiling is warranted to identify such patients.