Mechanisms of the Impact of Hashimoto Thyroiditis on Papillary Thyroid Carcinoma Progression: Relationship with the Tumor Immune Microenvironment.

BACKGROUND: The relationship between Hashimoto thyroiditis (HT) and papillary thyroid carcinoma (PTC) remains uncertain. We assessed the impact of HT on the tumor immune microenvironment (TIME) in PTC. METHODS: Thirty patients with PTC (group 1) and 30 patients with PTC and HT (group 2) were enrolled in this pilot study. The distribution and number of CD8+ lymphocytes, plasma cells (CD138+), regulatory T cells (forkhead box P3 [FOXP3+)], mast cell tryptase (MCT+), and M2 macrophages (CD163+) were evaluated. To test the hypothesis that HT impacts PTC development via signal transducer and activator of transcription 6 (STAT6) activation and M2 macrophage polarization, we investigated STAT6 expression in tumor and stromal cells. We also evaluated vascular endothelial growth factor (VEGF) expression by lymph node metastasis (LNM) status. RESULTS: TIME showed significant between-group differences. Group 1 patients demonstrated immune desert or immune-excluded immunophenotypes, while an inflamed phenotype with more CD8+ cells (P<0.001) predominated in group 2. Immune-excluded TIME was associated with the highest LNM rate. In PTC, LNM was associated with more numerous CD163+ cells. Moreover, LNM in group 1 was associated with increased numbers of mast cells peritumorally and FOXP3+ cells intratumorally and peritumorally. Group 2 demonstrated higher STAT6 but not higher VEGF expression in tumor cells. High VEGF expression was associated with LNM regardless of HT status. CONCLUSION: Concomitant HT impacted PTC signaling via STAT6 and TIME by increasing the number of CD8+ cells. LNM is associated with increases in CD163+ cells and VEGF expression in PTC, whereas HT affected LNM through different mechanisms.

Thyroid stimulating hormone levels and BRAFV600E mutation contribute to pathophysiology of papillary thyroid carcinoma: Relation to outcomes?

AIMS: The aim of this study was to evaluate the relation between the level of thyroid stimulating hormone (TSH) and progression of papillary thyroid carcinoma (PTC) with or without BRAFV600E mutation. METHODS: The medical records and laboratory data of 547 patients with PTC and 94 patients with follicular adenoma (FA) were collected. The relationship between hormones levels and such end-points as extrathyroid extension (ETE), lymphovascular invasion (LVI) and lymph node metastasis (LNM) was assessed. In addition, age, gender, BRAFV600E mutation status, histological type and Hashimoto's thyroiditis (HT) were considered. KEY FINDINGS: Most of the patients with PTC had hormones levels within the normal range, however, serum TSH concentration was significantly higher in PTC comparing with FA (P = 0.022). High levels of TSH in PTC were more frequent among women rather than men (P = 0.03) due to the gender differences in coexisting HT rate (P = 0.003). In contrast, LNM rate was higher in men (P = 0.0014). Coexisting HT significantly decreased the risk of ETE (OR = 0.67; 95%CI 0.44-1.00; P = 0.05) and LNM (OR = 0.59; 95%CI 0.37-0.94; P = 0.028) among males with PTC. However, there was no significant relationship between HT and PTC-related ETE and LNM in females. BRAFV600E mutation was associated with presence of lymphocytic infiltration (P < 0.001) but not with HT (P = 0.08) and violation of thyroid function. CONCLUSION: The present study showed the lack of significant relationship between TSH levels and PTC aggressiveness (LNM, TNM stage, BRAFV600E mutation). Higher TSH levels were found in patients with coexisting HT that was associated with female sex and multifocality of PTC.