BRAF V600E and TERT promoter mutations and their impact on recurrent papillary thyroid carcinoma progression

Abstract

Papillary thyroid carcinoma (PTC) is the most prevalent histological subtype of thyroid cancer. However, it remains unclear whether BRAF V600E, TERT promoter (TERT-p), and certain pathological markers, such as loss of polarity/loss of cell cohesiveness (LOP/LCC), tall cells, mitotic count, and Ki-67 labeling index (LI) in recurrent tumors, are associated with clinical outcomes in patients with PTC after reoperation for recurrent PTC. This study investigates the impact of BRAF V600E and TERT-p mutations on progression-free survival (PFS) after reoperation for recurrent PTC. Cox regression analysis was employed to identify parameters associated with PFS. During a mean follow-up period of 27 months after reoperation, 39 patients (21.3%) experienced disease progression. Coexistence of BRAF V600E and TERT-p mutations (double mutation: Dmut) was observed in 21.3% of patients. TERT-p, Dmut, LOP/LCC (≥10%), mitotic count (≥3 per 2 mm2), and Ki-67 LI were found to be significantly associated with disease progression in unadjusted analyses. In a multivariable analysis, these associations remained significant, with hazard ratios and 95% confidence intervals for TERT-p, Dmut, LOP/LCC, mitotic count, and Ki-67 LI being 5.98 (2.31-15.5), 5.44 (2.21-13.3), 6.81 (2.00-23.2), 5.05 (2.07-12.3), and 5.85 (2.48-13.7), respectively. Extranodal extension was associated with disease progression in both unadjusted and multivariable analyses. TERT-p, Dmut, Ki-67 LI, LOP/LCC, mitotic count, and extranodal extension were identified as independent risk factors for poor PFS after reoperation. Close surveillance following reoperation is recommended for patients exhibiting these factors.

Keywords: TERT; disease progression; loss of polarity/loss of cell cohesiveness; mitosis; recurrent papillary thyroid carcinoma.

Figure 1

Flow diagram showing the number of participants and description of the study design. PTC: papillary thyroid cancer, unstim-Tg: unstimulated thyroglobulin.

Figure 2

Loss of polarity/loss of cell cohesiveness (LOP/LCC) in the invasive front area (hematoxylin–eosin). (A) Solitary cells (arrowheads) and small nests (arrows), accompanied by desmoplastic changes. Scale bar indicates 240 μm. (B) Enlarged hyperchromatic nuclei in solitary cells arranged in irregular rows, accompanied by desmoplastic changes. Scale bar indicates 120 μm. (C) Large nests with micropapillary structures. Scale bar indicates 240 μm.

Figure 3

PFS using the Kaplan–Meier method, stratified by TERT promoter (A), double mutation (B), loss of polarity/loss of cell cohesiveness (LOP/LCC) (C), extranodal extension (D), mitotic count (E), and Ki-67 LI (F). There were significant differences in PFS between the two groups for each factor. All results are unadjusted PFS.