Endocrinol Metab.  2020 Jun;35(2):443-455. 10.3803/EnM.2020.35.2.443.

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

• Sulaieva O
• Chernenko S
• Selesnov O
• Nechay O
• Maievskyi O
• Falalyeyeva T
• Kobyliak N
• Tsyryuk O
• Penchuk Y
• Shapochka D

• KMID: 2503275
• DOI: http://doi.org/10.3803/EnM.2020.35.2.443

Abstract

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.

Keyword

Thyroid cancer, papillary; Hashimoto disease; Metastasis; T-lymphocytes; Macrophages

Figure

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  Fig. 1 Differences in the number of cytotoxic T lymphocytes in patients of group 1 (A) and group 2 (B, C). (B) Zone of infiltration of intact thyroid tissue in a patient with concomitant Hashimoto thyroiditis. (C) Intratumoral area. Immunohistochemistry using antibodies to CD8 (×200).

• 

  Fig. 2 An increased number of M2 macrophages was independently associated with lymph node metastasis (LNM) development in patients with concomitant Hashimoto thyroiditis. (A) A patient in group 1 without LNM demonstrated a low number of M2 macrophages (×200). (B) A patient in group 2 without LNM (×200). (C) A high number of M2 macrophages in papillary thyroid carcinoma with LNM (×100). (D) Numerous M2 macrophages around metastases of thyroid cancer in the lymph node (×100). Immunohistochemistry using antibodies to CD163 (×200).

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  Fig. 3 The number of immune cells in and around papillary thyroid carcinoma (PTC) in patients with and without concomitant Hashimoto thyroiditis (HT) by lymph node metastasis (LNM) status. (A, B) Number of M2 macrophages (CD163 positive cells) within tumor and in peritumor stroma respectively. (C, D) Count of mast cells (mast cell tryptase [MCT] positive cells) within tumor and in peritumor stroma respectively. (E, F) Number of T-cytotoxic lymphocytes (CD8 positive cells) within tumor and in peritumor stroma respectively. (G, H) Count of plasma cells (CD138 positive cells) within tumor and in peritumor stroma respectively. (I, J) Number of T-regulatory cells (forkhead box P3 [FOXP3] positive cells) within tumor and in peritumor stroma respectively. aStatistically significant difference between patients with and without LNM at P<0.05.

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  Fig. 4 Signal transducer and activator of transcription 6 (STAT6) and vascular endothelial growth factor (VEGF) expression in patients with papillary thyroid carcinoma (PTC) according to Hashimoto thyroiditis (HT) and lymph node metastasis (LNM). (A) STAT6 expression in patients of group 2 in the intact thyroid (×200). (B) STAT6 expression in follicular cells in areas of lymphocyte infiltration associated with histoarchitectural and cytological atypia in group 2 (×200). (C) STAT6 expression in group 2 patients (×100). (D) Low VEGF expression in group 2 patients without LNM. (E) High expression of VEGF in PTC tumor cells associated with LNM. Immunohistochemistry (×200). (F, G) Relationship between STAT6 and VEGF expression in the tumor cells of patients with PTC according to HT (F) and LNM (G) status. IHC, immunohistochemical. aStatistically significant difference in the total score of biomarker expression regarding HT or LNM status at P<0.05.

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