Catching the Silent Culprits: TERT Promoter Mutation Screening of Minimally Invasive Follicular and Oncocytic Thyroid Carcinoma in Clinical Practice

De-escalation of thyroid cancer treatment is crucial to prevent overtreatment of indolent disease, but it remains important to identify clinically aggressive cases. TERT promoter mutations are molecular events frequently associated with high-risk thyroid tumors with poor outcomes and may identify cases at risk of dissemination. In various international guidelines, small minimally invasive follicular thyroid carcinoma and oncocytic thyroid carcinoma (miFTC/miOTC) are classified as low-risk lesions and are not recommended adjuvant treatment. Our study aimed to explore the association between size-based risk assessment and TERT promoter mutations. Between 2019 and May 2024, 84 miFTCs/miOTCs diagnosed at our department underwent digital droplet PCR analysis targeting TERT promoter mutational hotspots C228T and C250T in clinical routine. TERT promoter mutations were found in 10 out of 84 cases (11.9%). Mutated cases were pT1 (n = 1), pT2 (n = 3), or pT3 (n = 6). Patients with mutated tumors were older compared to patients with wild-type tumors (median age of 71 years vs. 57 years, p = 0.041). There were no significant differences regarding patient sex, tumor size, Ki-67 labeling index, or the presence of distant metastases. Notably, 30% of mutations displayed variant allele frequencies < 10%, possibly suggesting subclonal events. To conclude, TERT promoter mutations in miFTCs and miOTCs were associated with higher patient age and were often suspected to be subclonal. However, they did not affect clinical outcomes, possibly due to short follow-up. Reflex testing for this genetic alteration in miFTCs and miOTCs could be justified regardless of tumor size, though the clinical benefit remains uncertain.