Disease-Specific and Histological Outcomes of Preoperative TERT Promoter Mutation Detected in Isolation or in Combination with Other Mutations in Thyroid Neoplasms

Background: TERT promoter mutations in thyroid cancer are associated with aggressive disease, including recurrence, distant metastasis, and disease-related mortality. We aim to assess histological and disease-related outcomes when TERT mutation is detected alone or with other alterations during preoperative testing. Methods: A retrospective, single-institution study was performed, including all adult patients undergoing initial diagnostic thyroid nodule evaluation with TERT promoter mutation (C228T/C250T) detected in preoperative thyroid fine needle aspiration samples using TSv3 testing. Results: Of 70 thyroid nodules, 18 (26%) were isolated (iTERT), and 52 (74%) were associated with ≥1 concurrently detected mutation (TERT+). The most common additional abnormalities were BRAF^V600E (23, 44%), RAS (19, 37%), and copy number alterations (CNA; 15, 29%). Patients with iTERT were older than those with TERT+ nodules (p = 0.007). While nodule size was similar between the two groups (mean size 3.2 cm, p = 0.18), Bethesda III/IV cytology was more likely with iTERT (94% vs. Bethesda V/VI 56%, p = 0.007). Histology was available for 9 (50%) iTERT and 51 (98%) TERT+ nodules and malignancy was higher with preoperative detection of TERT+ compared with iTERT (96% vs. 67%, p = 0.02). Poorly differentiated or anaplastic cancers were diagnosed in 33% of the malignancies at an equivalent rate in both cohorts. At median follow-up of 13.1 months (interquartile range 26.2, 7.2-33.4), distant metastasis occurred in 32.7% of patients including 17% (1/6) with iTERT versus 33% of patients with TERT+ (p = 0.65). None of the iTERT patients had locoregional recurrence as compared with 25% of TERT+ patients (p = 0.31). Conclusions: When preoperatively detected, TERT promoter mutations are more often seen in association with additional driver mutations or other genetic alterations such as CNA, but when present, carries a very high risk of malignancy (93%). Up to 1/3 are poorly differentiated or anaplastic thyroid cancer, and this likelihood is equivalent when TERT is present in isolation or in combination with other mutation. Thus, surgery should be strongly considered in iTERT nodules, and total thyroidectomy should be favored when TERT+ is identified.