Zhang Yanhui, Ding Tingting, Cheng Runfen, Wang Ying, Wu Jianghua
Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
National Clinical Research Center of Cancer, Tianjin, China.
Clin Endocrinol (Oxf). 2025 Aug 11. doi: 10.1111/cen.70013.
The diffuse sclerosing variant of papillary thyroid carcinoma (DSV-PTC) is a rare, aggressive subtype with distinct clinicopathological features. This study aimed to characterize its molecular alterations and evaluate their clinical associations.
A retrospective analysis of 51 DSV-PTC cases was conducted. Clinicopathological data were reviewed, and molecular profiling was performed using fluorescent PCR to detect mutations and gene fusions across 12 thyroid cancer-related genes.
This study included eight paediatric cases (15.7%) and 43 adult cases (84.3%) of DSV-PTC. The most common alteration was BRAF mutation (39.2%), followed by RET fusions (25.5%; including CCDC6-RET in 23.5% and NCOA4-RET in 2.0%), ETV6-NTRK3 fusion (5.9%) and TERT promoter mutations (2.0%). Compared with BRAF-mutated tumours, RET fusion-positive cases showed significantly larger primary tumours (p = 0.016), larger metastatic nodes (p = 0.009) and higher T stages (p = 0.046). Paediatric patients exhibited more aggressive features, such as higher rates of lateral neck metastasis and extrathyroidal extension, but had fewer BRAF mutations. The overall recurrence rate was 15.7%, with earlier recurrence in RET fusion cases. One patient with coexisting ETV6-NTRK3 fusion and TERT mutation progressed to anaplastic thyroid carcinoma and died of disease.
DSV-PTC demonstrates substantial molecular heterogeneity. RET fusions are linked to more aggressive behaviour, and paediatric cases often show extensive locoregional spread. Coexisting NTRK and TERT alterations may signal high-risk progression, highlighting the value of molecular stratification in management.
