Papiller Karsinomda PD-L1’in Aşırı Ekspresyonu ve Klinikopatolojik Değişkenlerle İlişkisi

Amaç: Metastatik papiller tiroid kanserli (papillary thyroid cancer, PTC) hastalarda standart tedavi yeterli olmayabilir ve tedaviye anti-PD-1 ajanların da eklenmesi faydalı olabilir. Bu nedenle bu çalışma, PTC karsinomu kapsamında, nodüler guatr (NG) ve Hashimoto tiroiditi (HT) hastalarında PD-L1 ekspresyonunun karşılaştırılması ve değerlendirilmesi amacıyla yapılmıştır. Gereç ve Yöntemler: Ocak 2011 ile Aralık 2017 tarihleri arasında, NG, HT ve PTC nedeniyle tiroidektomi yapılmış olan, her hasta grubundan otuz beş hasta belirlendi. 105 hastanın doku örneklerinden yeni kesitler alınarak immünohistokimyasal olarak anti-PD-L1 boyası uygulandı. Histolojik tip, tümör çapı, kapsül invazyon (capsule invasion, CI) ve lenfovasküler invazyon (lymphovascular invasion, LVI) değerlendirildi. Bulgular: PTC tanısı alan hastaların 9’u (%25,7) klasik, 10’u (%28,6) foliküler, 6’sı (%17,1) onkositik, 5’i (%14,3) enkapsüle, 2’si (%5,7) solid, 1’i (%2,9) uzun hücreli ve 2’si (%5,7) Warthin benzeri tip olarak tanımlandı. PTC’li hastalarda PD-L1 ekspresyonu, NG ve HT olan hastalardan anlamlı olarak daha yüksekti (p<0,001). PTC’li hastalarda artmış PD-L1 ekspresyonu ve boyama yoğunluğu ile tiroid LVI varlığı arasında anlamlı bir ilişki vardı (p=0.047). Ayrıca foliküler, uzun hücreli ve onkositik alt tip PTC’li hastalarda PD-L1 ekspresyonu ve LVI’nın daha şiddetli olduğu gözlendi (sırasıyla p=0,011, p=0,026). Sonuç: PTC’li hastalarda PD-L1 ekspresyonunun arttığı gözlendi. Foliküler, uzun hücreli ve onkositik alt tip PTC’li hastalarda PD-L1 ekspresyonu ve LVI’nın daha şiddetli olduğu gözlendi.

Anahtar Kelimeler:

Papiller tiroid karsinomu, Hashimoto tiroiditi, Nodüler Guatr, PD-L1

Overexpression of PD-L1 in Papillary Carcinoma and Its Association with Clinicopathological Variables

Aim: Standard treatment may not be sufficient in patients with metastatic papillary thyroid cancer (PTC), and it may be beneficial to add PD-1 agents to the treatment. Therefore, this study was conducted to compare and evaluate the expression of PD-L1 in patients with nodular goiter (NG) and Hashimoto's thyroiditis (HT) within the scope of PTC carcinoma. Material and Methods: Thirty-five patients from each group who underwent thyroidectomy for NG, HT, and PTC, between January 2011 and December 2017 were identified. Immunohistochemically, an anti-PD-L1 stain was applied by taking new sections from the tissue samples of 105 patients. The histological type, tumour diameter, capsule invasion (CI), and lymphovascular invasion (LVI) were evaluated. Results: Nine (25.7%) of the patients with PTC were defined as classic, 10 (28.6%) as follicular, 6 (17.1%) as oncocytic, 5 (14.3%) as encapsulated, 2 (5.7%) as solid, 1 (2.9%) tall cell, and 2 (5.7%) as Warthin-like. The expression of PD-L1 in the patients with PTC was significantly higher than in the patients with NG and HT (p<0.001). There was a significant relationship between the increased PD-L1 expression and staining intensity and presence of thyroid LVI in the patients with PTC (p=0.047). In addition, the PD-L1 expression and LVI were observed to be more severe in patients with follicular, tall cell, and oncocytic subtype PTC (p=0.011, p=0.026, respectively). Conclusion: It was observed that the PD-L1 expression increased in patients with PTC. PD-L1 expression and LVI were more severe in patients with follicular, tall cell, and oncocytic subtype of PTC.

Keywords:

Papillary thyroid carcinoma, Hashimoto thyroiditis, Nodular Goiter, PD-L1,

PDF

___

Lim H, Devesa SS, Sosa JA, Check D, Kitahara CM. Trends in thyroid cancer incidence and mortality in the United States, 1974-2013. JAMA. 2017;317(13):1338-48.
Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, et al. Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 2016;66(4):271-89.
Rahman GA. Extend of surgery for differentiated thyroid cancer: recommended guideline. Oman Med J. 2011;26(1):56-8.
Guerrero MA, Clark OH. Controversies in the management of papillary thyroid cancer revisited. ISRN Oncol. 2011;2011:303128.
Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26(1):1-133.
Shin DS, Ribas A. The evolution of checkpoint blockade as a cancer therapy: what's here, what's next? Curr Opin Immunol. 2015;33:23-35.
Mahoney KM, Rennert PD, Freeman GJ. Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov. 2015;14(8):561-84.
Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy--inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18(24):6580-7.
Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 2018;560(7718):382-6.
Bastman JJ, Serracino HS, Zhu Y, Koenig MR, Mateescu V, Sams SB, et al. Tumor-infiltrating T cells and the PD-1 checkpoint pathway in advanced differentiated and snaplastic thyroid cancer. J Clin Endocrinol Metab. 2016;101(7):2863-73.
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-64.
Callahan MK, Postow MA, Wolchok JD. Targeting T cell co-receptors for cancer therapy. Immunity. 2016;44(5):1069-78.
Ahn S, Kim TH, Kim SW, Ki CS, Jang HW, Kim JS, et al. Comprehensive screening for PD-L1 expression in thyroid cancer. Endocr Relat Cancer. 2017;24(2):97-106.
Fadia M, Fookeerah P, Ali S, Shadbolt B, Greenaway T, Perampalam S. PD-L1 expression in papillary thyroid cancer with and without lymphocytic thyroiditis: a cross sectional study. Pathology. 2020;52(3):318-22.
James BC, Timsina L, Graham R, Angelos P, Haggstrom DA. Changes in total thyroidectomy versus thyroid lobectomy for papillary thyroid cancer during the past 15 years. Surgery. 2019;166(1):41-7.
Nie X, Tan Z, Ge M. Skip metastasis in papillary thyroid carcinoma is difficult to predict in clinical practice. BMC Cancer. 2017;17(1):702.
Baloch ZW, LiVolsi VA. Special types of thyroid carcinoma. Histopathology. 2018;72(1):40-52.
DiMarco AN, Wong MS, Jayasekara J, Cole-Clark D, Aniss A, Glover AR, et al. Risk of needing completion thyroidectomy for low-risk papillary thyroid cancers treated by lobectomy. BJS Open. 2019;3(3):299-304.
Luster M, Aktolun C, Amendoeira I, Barczyński M, Bible KC, Duntas LH, et al. European Perspective on 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: Proceedings of an Interactive International Symposium. Thyroid. 2019;29(1):7-26.
Chistiakov DA. Immunogenetics of Hashimoto's thyroiditis. J Autoimmune Dis. 2005;2(1):1.
Kwon JH, Nam ES, Shin HS, Cho SJ, Park HR, Kwon MJ. P2X7 receptor xxpression in coexistence of papillary thyroid carcinoma with Hashimoto's thyroiditis. Korean J Pathol. 2014;48(1):30-5.
Liang J, Zeng W, Fang F, Yu T, Zhao Y, Fan X. Clinical analysis of Hashimoto thyroiditis coexistent with papillary thyroid cancer in 1392 patients. Acta Otorhinolaryngol Ital. 2017;37(5):393-400.
Kurukahvecioglu O, Taneri F, Yüksel O, Aydin A, Tezel E, Onuk E. Total thyroidectomy for the treatment of Hashimoto's thyroiditis coexisting with papillary thyroid carcinoma. Adv Ther. 2007;24(3):510-6.
Del Rio P, Cataldo S, Sommaruga L, Concione L, Arcuri MF, Sianesi M. The association between papillary carcinoma and chronic lymphocytic thyroiditis: does it modify the prognosis of cancer? Minerva Endocrinol. 2008;33(1):1-5.
Lee JH, Kim Y, Choi JW, Kim YS. The association between papillary thyroid carcinoma and histologically proven Hashimoto's thyroiditis: a meta-analysis. Eur J Endocrinol. 2013;168(3):343-9.
Lubin D, Baraban E, Lisby A, Jalali-Farahani S, Zhang P, Livolsi V. Papillary thyroid carcinoma emerging from Hashimoto thyroiditis demonstrates increased PD-L1 expression, which persists with metastasis. Endocr Pathol. 2018;29(4):317-23.
Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, O'Shea MA. The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol. 2008;181(10):6738-46.
Chowdhury S, Veyhl J, Jessa F, Polyakova O, Alenzi A, MacMillan C, et al. Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants. Oncotarget. 2016;7(22):32318-28.
Cunha LL, Marcello MA, Morari EC, Nonogaki S, Conte FF, Gerhard R, et al. Differentiated thyroid carcinomas may elude the immune system by B7H1 upregulation. Endocr Relat Cancer. 2013;20(1):103-10.
Zhou B, Wei L, Qin J. Analyze and compare the predictors of ipsilateral central lymph node metastasis in papillary thyroid carcinoma with cT1a and cT1b stage. Asian J Surg. 2021:44(11):1357-62.
Shi RL, Qu N, Luo TX, Xiang J, Liao T, Sun GH, et al. Programmed death-ligand 1 expression in papillary thyroid cancer and its correlation with clinicopathologic factors and recurrence. Thyroid. 2017;27(4):537-45.
Moon S, Chung HS, Yu JM, Yoo HJ, Park JH, Kim DS, et al. Associations between Hashimoto thyroiditis and clinical outcomes of papillary thyroid cancer: A meta-analysis of observational studies. Endocrinol Metab (Seoul). 2018;33(4):473-84.
Corsello SM, Barnabei A, Marchetti P, De Vecchis L, Salvatori R, Torino F. Endocrine side effects induced by immune checkpoint inhibitors. J Clin Endocrinol Metab. 2013;98(4):1361-75.
Vita R, Guarneri F, Agah R, Benvenga S. Autoimmune thyroid disease elicited by NY-ESO-1 vaccination. Thyroid. 2014;24(2):390-4.