Molecular and histopathologic characteristics of radioiodine-refractory papillary thyroid cancer

의과대학/박사Radioiodine (RI) ablation after surgery with suppression of thyroid-stimulating hormone is an effective therapy for papillary thyroid cancer (PTC) and leads to an excellent prognosis. However, RI-refractory tumors are aggressive and have poor outcomes. Recently, studies of genetic abnormalities associated with signaling pathways related to PTC have shown that activation and mutation of telomerase reverse transcriptase (TERT) activity is associated with a poor outcome in PTC. We analyzed the proportion of mutations in BRAF V600E and the TERT promoter, and compared the clinicopathological differences between RI-refractory and RI-responsive PTCs. Among 82 patients of RI-refractory PTC, we identified 26 cases for which formalin-fixed, paraffin-embedded tissue from the initial thyroidectomy were available. In the matched RI-responsive group without distant metastasis in the 5 years after surgery, 89 cases of PTC were collected. In the histopathological comparison of the two groups, RI-refractory PTCs showed a significant increase in small tumor clusters without fibrovascular cores (≥ 20% cut-off, especially in tumor centers), hobnail features (≥ 5% cut-off, especially in tumor centers), and in the height/width ratio of tumor cells (maximum ≥ 3). RI-refractory PTC showed significantly increased frequency of tumor necrosis, mitosis, lymph node metastasis, extrarthyroidal tumor extension, and involvement of resection margin. Interestingly, the nuclei of RI-refractory PTCs had an increased tendency to be located between the base and the middle area of tumor cells. TERT promoter mutations were found in 14/26 cases of RI-refractory PTC (53.8%, 13 TERT C228T, 1 TERT C250T) whereas only 1/82 cases of RI-responsive PTC showed TERT promoter mutations (1.2%, TERT C228T). The BRAF V600E mutation was identified in more than 80% of cases in both groups. Coexistence of TERT promoter and BRAF mutations was found in 13/108 (12%) of all PTC cases. TERT promoter mutations were significantly associated with clinicopathologic features mentioned above. Immunohistochemically, expression of NIS and TSHR was decreased in many cases of RI-refractory PTC. The expression of VEGF, VEGFR2, and NF-κB, known to be oncogenic proteins, was somewhat lower in RI-refractory PTC than in RI-responsive PTC. Total loss of expression of PTEN was occasionally present in both groups. β-catenin, which is involved in the WNT-β-catenin pathway, showed cytoplasmic positivity in all cases. Comparison of immunohistochemical results for TERT and BRAF mutations in all PTCs showed no correlation with either mutation, except for TSHR (TERT mutation). Four significant predictors of RI-refractoriness were identified: TERT mutation, height/width of tumor cells > 3, increased small clusters (≥ 20%), and necrosis. Our results suggest that RI-refractory PTCs may be strongly associated with TERT mutations and aggressive histopathologic features (small clusters and hobnail components), especially in tumor centers.ope