(6.10) First Report of Pre-operative Detection of Two TERT Promoter Mutations Within a Papillary Thyroid Carcinoma

Telomerase reverse transcriptase promoter (TERT) mutations are associated with aggressive thyroid cancer and are most frequently found in anaplastic and poorly differentiated thyroid cancer. Pre-operative thyroid nodule molecular testing can detect TERT, denoting a high risk of malignancy and possible aggressive clinical features such as extrathyroidal extension and regional (if not distant) lymph node metastases. There are two described hot spot point mutations: the more common C228T and a C250T variant.  Canonically, these mutations are mutually exclusive and drive monoallelic TERT expression. In this report, we describe a case of both the C228T and C250T variants being detected in the same thyroid cancer.

Case(s) Description :

A 62-year-old female presented with neck discomfort and left anterior swelling. She had a TSH of 2.43 (ref 0.45-4.5 uIU/mL), TPO abs of 326 (ref 0-34 IU/mL) and Tg abs of 1.8 (ref 0-0.9 IU/mL). Neck ultrasound reported a 2.3 cm mixed iso and hypoechoic nodule with possible microcalcifications (TR4 by ACR-TIRADs). Fine needle aspiration biopsy resulted in Bethesda VI cytology, consistent with papillary thyroid cancer (PTC). The sample was sent for Afirma molecular testing and was found to have a BRAFV600E mutation along with TERT mutations at the C228T and C250T locations on different alleles. Kinship (relatedness between individuals) analysis was performed on the sample and confirmed the result was from the same patient and not due to sample cross contamination.

Histopathology of a total thyroidectomy with central lymph node dissection showed a 4.0 cm classic PTC with clinical invasion into the strap muscle, lymphatic invasion, and a focally positive anterior surgical margin. Five of 24 lymph nodes were positive with no extranodal extension noted. The final pathological stage was pT3bN1aMx (currently stage II disease by AJCC 8^th edition). Approximately 6 weeks postoperatively the patient had a TSH of 0.29 uIU, thyroglobulin level of < 0.1 ng/mL and anti-thyroglobulin antibodies of 3 (ref 0.9-3.9 IU/mL) and was being prepared for radioiodine ablation therapy.

Discussion :

To our knowledge, this is the first report of dual TERT mutations in a thyroid carcinoma and the first reported in pre-operative testing. This phenomenon has been reported in glioma, melanoma, and bladder cancer. Given the potential of transcriptional compensation, it is unknown if monoallelic dual TERT promoter mutations would be less activating of overall telomerase activity than would biallelic mutations as found here. Clinical correlation with future cases will be of interest.