TERT Promoter Mutations Were Not Found in Papillary Thyroid Microcarcinomas That Showed Disease Progression on Active Surveillance

Dear Editor:

Papillary thyroid microcarcinomas (PTMCs) generally have an extremely indolent course. We started an active surveillance clinical trial for low-risk PTMCs in 1993, and at 10 years' surveillance, only 8% of the patients showed enlargement by ≥3 mm of their PTMCs, and only 3.8% of the patients showed novel nodal metastasis (1). Importantly, all of the patients who had such an increase or metastasis were treated successfully with a rescue surgery. Given the safety of this approach, the 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer now acknowledge that active surveillance can be considered an alternative to immediate surgery in patients with low-risk PTMC (2). However, a small minority of our active-surveillance patients did show disease progression. If such tumors could be identified at their presentation, possibly using fine-needle aspiration specimens, the management of PTMC patients will be improved.

The combination of BRAF and TERT promoter mutations was recently reported to be associated with poor outcomes of clinical papillary thyroid carcinomas (PTCs) (3). We therefore sought to determine whether these mutations are associated with the progression of PTMCs, toward the goal of predicting progression or non-progression at presentation.

From May 1995 to December 2012, 1252 patients with low-risk PTMCs chose active surveillance at Kuma Hospital, and 188 of them later underwent a conversion surgery for various reasons, including the patient's change of mind, enlargement of associated nodules, and the appearance of primary hyperparathyroidism, as well as an increase in tumor size and appearance of lymph node metastasis. We selected the three groups of patients for the present study: the non-progressing group, which comprised 11 patients whose tumors did not progress for >5 years on active surveillance; the size-increase group, which comprised 10 patients whose tumors increased by ≥4 mm in size (here we set the criteria of tumor increase at 4 mm rather than 3 mm as used in our previous studies in order to select tumors with an obvious growing nature); and the LN metastasis group, which comprised five patients who showed the appearance of novel lymph node metastasis (Table 1). The median ages of the patients in these three groups were 62, 46, and 38 years, respectively. The non-progressing patients were older than the size-increase patients and the LN metastasis patients. These age differences were consistent with our study of patient ages and the progression of PTMCs under active surveillance (1). The median tumor sizes at presentation were similar at 6–7 mm for all three groups. The median tumor size at surgery was 5.5 mm larger than the initial tumor size in the size-increase group, whereas the sizes at surgery were not significantly different from the initial tumor sizes in the non-progressing and LN metastasis groups.

The histological subtypes did not show a clear relation to disease progression. The proportions of patients with pathological nodal metastasis were 55%, 60%, and 100%, respectively, for the non-progressing, size-increase, and LN metastasis groups. Ki-67 labeling index (Ki-67 LI) values of >5% were detected in 27%, 60%, and 0% of the three groups, respectively.

We extracted tumor DNA from micro-dissected formalin-fixed, paraffin-embedded tissues of the primary lesions of these patients' surgical specimens. The DNA was analyzed for presence of BRAF and TERT promoter mutations, as described previously (4). The BRAF^V600E mutation was detected in 64%, 70%, and 80% of the non-progressing, size-increase, and LN metastasis groups, respectively (Table 1), indicating that the analysis of the BRAF mutation status at presentation was not predictive in terms of tumor characteristics. The TERT promoter mutations (C228T and C250T) were not detected in any of the samples in the three groups (Table 1). Thus, TERT promoter mutations were not detected, regardless of the progression of PTMCs. Although the patient numbers of each group was small, the patients were carefully selected from 1252 patients undergoing active surveillance, representing both non-progressing and progressing tumors and lymph node metastasis. Nevertheless, we did not detect TERT promoter mutations in any of the above cases.

In our previous study, the Ki-67 LI was significantly higher in the patients who underwent surgery after nonoperative management because of tumor enlargement (5). In that study, Ki-67 LI values >5% were detected in 8%, 50%, and 9.1% of patients with stable disease, those with tumor enlargement, and those who developed nodal metastasis, respectively. These data indicate that the tumors in these patient groups differ from each other in their biological nature, and suggest that the discrimination of their characteristics should be possible at their presentation, hopefully with fine-needle aspirates.

Although the presence of BRAF and TERT promoter mutations were reported to be associated with the prognosis of PTCs, TERT promoter mutations were not found in 15 PTMCs that showed disease progression on active surveillance or in 10 PTMCs without progression.