Pathological Diagnosis of Thyroid Nodules with Preoperatively Detected TERT Promoter Mutations in the Absence of BRAFV600E: A Bi-Center Series of 52 Cases

Background: Mutations in the promoter region of TERT (TERTp) in thyroid nodules with indeterminate cytology are quoted to confer a high (∼80-95%) probability for thyroid carcinoma when detected on genomic classifier (GC) ThyroSeq. TERTp mutations may also occur in benign and low-risk thyroid neoplasms, and the risk of malignancy (ROM) in nodules harboring TERTp mutations without BRAF^V600E is unknown. We analyzed the ROM and the surgical diagnosis in a retrospective cohort of thyroid nodules with TERTp treated at two academic medical centers. Methods: From 2323 patients with ThyroSeq GC performed on preoperative fine needle aspiration samples, 52 cases (2.3%) were identified harboring TERTp mutations without coexisting BRAF^V600E. Results: The surgical diagnosis was obtained from resection (n = 51) or biopsy (n = 1, anaplastic thyroid carcinoma). The ROM was 65%. The reviewed diagnoses were benign/low-risk neoplasms in 18 (35%), carcinoma-American Thyroid Association (ATA) low/intermediate-risk in 14 (27%), and carcinoma-ATA high-risk in 20 (38.5%). All 18 benign or low-risk neoplasms had their tumor capsule submitted entirely, and 78% underwent total thyroidectomy. The molecular alterations were substratified into four groups: TERTp alone (n = 21, 40%), TERTp + RAS (n = 18, 35%), TERTp + other non-RAS mutation (n = 8, 15%), and TERTp + RAS + other alterations (n = 5, 10%), and the ROM for each group was 57%, 78%, 50%, and 80%, respectively. The frequency of a high-risk malignancy, which would often lead to a recommendation for total thyroidectomy, was 9.5%, 44.5%, 37.5%, and 80%, respectively. The frequency of high-risk carcinomas was significantly higher when a nodule harbored TERTp and other concomitant alterations (48%) compared with TERTp alone (9.5%; p = 0.006). Conclusions: Thirty five percent of TERTp nodules without BRAF^V600E are benign/low-risk thyroid neoplasms, leading to their overtreatment. The incidence of high-risk carcinomas increases in TERTp-mutated nodules with the presence of additional mutations. If the indolent histology found in these lesions is confirmed at the behavior level, lobectomy may be sufficient for the initial management of TERTp thyroid nodules without BRAF^V600E as long as there is no aggressive clinical or imaging feature. This will spare many patients from the side effects of total thyroidectomy.