Histologic heterogeneity of primary and nodal lesions and intra-nodal comparative analysis after neoadjuvant selpercatinib in RET fusion–positive papillary thyroid carcinoma

• Site-specific response: thyroid nearly fibrotic, nodes ∼60% viable after therapy. • IHC showed p16 upregulation, p-RB loss, and reduced proliferation markers. • GLB1 revealed coarse cytoplasmic granules, supporting senescence-like regression. • Digital morphometry confirmed nuclear shrinkage and shape change (all p < 0.001). RET fusion–positive papillary thyroid carcinoma (PTC) is an aggressive subset increasingly treated with RET inhibitors, but tissue-level correlates of neoadjuvant response remain limited. We report a case of a 65-year-old man with locally advanced, initially unresectable CCDC6::RET -positive PTC who received four months of neoadjuvant selpercatinib followed by complete surgical resection. The resected thyroid tumor bed was largely replaced by dense fibrosis with focal ossification, whereas approximately 60% of the supraclavicular nodal metastasis remained viable, highlighting site-specific heterogeneity. Because the post-treatment thyroid specimen required decalcification and was suboptimal for immunohistochemistry (IHC), IHC was performed on the lymph node specimen, revealing markedly reduced Ki-67, preserved RB protein, and loss of phosphorylated RB (p-RB). Tumor cells showed diffuse nuclear p16 positivity, decreased γH2AX, a wild-type p53 pattern, and minimal p21 expression. Apoptosis was limited, with only scattered cleaved caspase-3 and TUNEL-positive cells. In contrast, GLB1 demonstrated coarse granular cytoplasmic staining, consistent with a senescence-like phenotype. Digital morphometric analysis confirmed cytologic regression, demonstrating smaller, less circular nuclei with reduced nucleus-to-cell area ratios (all p < 0.001). These findings suggest selpercatinib induced senescence-like cytostasis with stromal remodeling rather than extensive apoptosis or ischemic necrosis, and support integrating histology, IHC, and morphometrics as potential endpoints in future neoadjuvant trials for RET-altered thyroid carcinoma.