TERT Promoter Mutation as a Prognostic Indicator in Papillary Thyroid Carcinoma

Papillary thyroid carcinoma (PTC) is generally considered a curable disease. However, not all PTC behaves the same. Knowledge of tumor genetics offers an important tool for guiding clinical decision making and risk stratification in PTC. We present an interesting case of a patient initially thought to have intermediate risk PTC, who later presented with distant metastatic disease, associated with a high-risk tumor mutation.

Case Description:

A 69-year-old female with a history of PTC presented for endocrine medical management. Her initial surgery was a left hemithyroidectomy in her native country. A completion thyroidectomy in 2012 showed only a microcarcinoma. She received 105 mCi I-131 and a post therapy scan showed a large focus of uptake in the lower neck without distant metastasis. Whole body scan (WBS) one year later showed only mild uptake in the lower neck. Tumor markers remained mildly elevated. She was lost to follow-up for several years and presented again in 2020 for evaluation of a new mandibular mass. A positron emission tomography (PET) scan showed evidence of bone metastasis in the left mandible as well as pulmonary metastases. Excisional biopsy confirmed metastatic PTC and genetic testing showed the presence of a telomerase reverse transcriptase (TERT) gene promotor mutation. Mutations for BRAF, RET and NTRK fusion were not detected. The patient had repeat I-131 therapy, which showed uptake only in the mandibular mass. Her stimulated thyroglobulin (Tg) level was over 200 ng/mL. Her mandibular mass increased further in size and she was referred to medical oncology. Tyrosine kinase inhibitor (TKI) chemotherapy was initiated. After two months, the mass regressed and Tg level improved to 39 ng/mL.

Discussion:

TERT promotor mutations in PTC were first identified in 2013. The mutations cause de novo formation of E-twenty-six (ETS) transcriptional factor binding sites, resulting in increased telomerase activity and creating a pathway for malignant transformation at the cellular level. TERT mutation is associated with high-risk and aggressive tumor behavior. Identification of these mutations can guide risk stratification and medical decision-making at the time of diagnosis. In our case, the complicated clinical course might have been anticipated if the presence of a TERT mutation was known at the time of diagnosis. This case highlights the importance of timely identification of genetic alterations in PTC for the purpose of prognosticating the clinical trajectory and providing better individualized care to patients.