TERT promoter-mutated thyroid carcinomas: prognostic and histologic insights according to the WHO 2022 classification

TERT promoter mutations are late molecular events associated with tumour dedifferentiation and aggressive behaviour in thyroid carcinomas (TCs). Although certain adverse histologic features, particularly tall cell morphology, are enriched in TERT promoter-mutated papillary thyroid carcinoma (PTC), their independent prognostic significance within the American Thyroid Association (ATA) high-risk group remains uncertain. This study aimed to assess its prognostic relevance and characterize the histologic spectrum of TERT promoter-mutated TCs, including differentiated high-grade thyroid carcinoma (DHGTC), to refine risk stratification.

We retrospectively analysed 151 TCs harbouring TERT promoter mutations, reclassified according to the WHO 2022 classification, which includes newly defined DHGTC. The low frequency of TERT promoter mutations in PTC (2.4%) likely reflects the reclassification of cases previously diagnosed as PTC to DHGTC. Tall cell morphology remained strongly associated with TERT promoter mutations but did not confer additional prognostic significance within this ATA high-risk group. Furthermore, applying the stricter WHO criteria for TC-PTC (≥3× height criteria) did not enhance risk stratification. Importantly, histologic features indicative of tumour progression, including loss of polarity/cohesiveness and early necrotic change, were frequently observed and significantly associated with aggressive clinicopathologic features. Accordingly, tumours exhibiting these features may not only reflect progression toward high-grade disease but also serve as surrogate histologic indicators of underlying TERT promoter mutations.

Our study provides valuable insights into TERT promoter-mutated TCs, broadening their recognized morphologic spectrum and highlighting the importance of incorporating such features into routine evaluation to improve risk stratification and better identify aggressive tumours.