Abstract #1406379: Histopathology of Telomerase Reverse Transcriptase Promoter (TERT) Mutated Indeterminate Thyroid Nodules

Abstract

TERT mutations are enriched in aggressive thyroid cancer. Conversely, most thyroid cancers arising from thyroid nodules with indeterminate cytology (Bethesda III/IV - ITNs) are not aggressive. The objective of this study is to analyze the risk of malignancy and the resultant histopathology of TERT mutated ITNs. A PUBMED search (2009-2022) of molecularly tested ITNs was conducted and data on TERT mutated ITNs with histopathology correlation were extracted. The malignancy rate was calculated for all TERT mutated ITNs, ITNs with isolated TERT mutations, TERT + RAS, and TERT + BRAFV600E co-mutated nodules (+/- additional mutations). Histopathology risk, when described, was assessed within each group. High risk included anaplastic thyroid cancer, widely invasive follicular thyroid cancer, poorly differentiated thyroid cancer, and descriptions of “aggressive behavior”. NIFTP was considered a low-risk malignancy as was minimally invasive follicular thyroid cancer, follicular tumor of uncertain malignant potential, and descriptions of low-risk tumors. Twenty-six manuscripts (published between 2014-2022) reported on 77 TERT mutated ITNs. Thirty ITNs (39%) had an isolated TERT mutation, 34 (44%) had TERT + RAS (+/- a 3rd mutation), 5 (6%) had TERT + BRAFV600E (+/- other mutations) and 8 (10%) had TERT + other mutations. Sixty-five nodules were malignant (84%), with 16 (25%) described with high-risk histopathology, 5 (8%) described as low-risk, and most without any description. Isolated TERT mutations were malignant in 26/30 ITNs (87%) with 9 (35%) described as high risk and none described as low risk. TERT + RAS mutated ITNs were malignant in 29/34 ITNs (85%) with 3 (10%) described as high risk and 4 (14%) described as low risk. Finally, all 5 TERT + BRAFV600E mutated nodules were malignant and 3/5 (60%) were described as high risk. Only 77 TERT mutated ITNs with histopathology correlation have been reported over the last 8 years. TERT mutated ITNs have a high risk of malignancy (84%), and the current data does not show a difference in malignancy rate between isolated TERT mutations and TERT + RAS co-mutated ITNs. Additionally, when described, TERT + RAS co-mutated ITNs did not have a higher rate of high-risk histopathology as compared to isolated TERT mutated lesions. The current data does not describe the histopathology risk in the majority of TERT mutated ITNs. Furthermore, the oncologic outcomes, including rate of recurrence, metastases, and disease specific survival, are unknown. Further data is needed to determine if TERT mutated ITNs should be subjected to aggressive initial treatment.