Programmed cell death ligand (PD-L1)/PD-1 expression has been studied in a variety of cancers and blockage of PD-L1/PD-1 pathway is a cornerstone of immunotherapy. We studied PD-L1/PD-1 immunohistochemical expression in 47 thyroid gland specimens in groups of (1) Hashimoto thyroiditis (HT) only; (2) HT and follicular epithelial dysplasia (FED); and (3) HT, FED, and papillary thyroid carcinoma (PTC). PD-1 positivity was found in immune cells, namely in lymphocytes, macrophages, and plasma cells with mean values for lymphocytes and macrophages 9% in HT group, 4% in FED group, and 4% in PTC group. PD-L1 positivity was identified in both immune cells and in the normal epithelial cells. In the HT group, mean PD-L1 staining on immune cells was 6%, in FED group 5%, and in PTC group 7%. The mean PD-L1 staining on the epithelial cells in the inflammatory parenchyma was 11.7% in HT, 13.4% in FED, and 8.3% in PTC group. The mean PD-L1 staining of FED foci was 47.2% in FED group and 33.6% in PTC group. The mean tumor proportion score (TPS) was 10.4%, and the mean combined positive score (CPS) was 15.5. At the moment, PTC is not a target of immunotherapy. However, understanding the complex issue of concurrent inflammation and autoimmunity can importantly influence the cancer treatment in future.

Department of Biological and Environmental Science University of Jyväskylä Jyväskylä Finland

Department of Biology Faculty of Medicine in Pilsen Charles University Plzen Czech Republic

Department of Education and Research Hospital Nova of Central Finland Jyväskylä Finland

Department of Otorhinolaryngology and Head and Neck Surgery 1st Faculty of Medicine University Hospital Motol Charles University Prague 5 Czech Republic

Department of Pathology Central Finland Health Care District Jyväskylä Finland

Faculty of Medicine and Health Technology Tampere University Tampere Finland

Pathology Fimlab Laboratories Tampere Finland

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Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74. PubMed

Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology. 2007;121:1–14. PubMed PMC

Pusztaszeri MP, Faquin WC, Sadow PM. Tumor‐associated inflammatory cells in thyroid carcinomas. Surg Pathol Clin. 2014;7:501–14. PubMed

Pusztaszeri MP, Bongiovanni M, Brimo F. Do we need PD‐L1 as a biomarker for thyroid cytologic and histologic specimens? Cancer Cytopathology. 2020;128:177–89. PubMed

Galdiero MR, Varricchi G, Marone G. The immune network in thyroid cancer. Oncoimmunology. 2016;5:e1168556. PubMed PMC

Ehrlich P. Ueber den jetzigen stand der karzinomforschung. Ned Tijdschr Geneeskd. 1919;52:73–209.

Guarino V, Castellone MD, Avilla E, Melillo RM. Thyroid cancer and inflammation. Mol Cell Endocrinol. 2010;321:94–102. PubMed

Ehlers M, Schott M. Hashimoto’s thyroiditis and papillary thyroid cancer: are they immunologically linked? Trends Endocrinol Metab. 2014;25:656–64. PubMed

Arif S, Blanes A, Diaz‐Cano SJ. Hashimoto’s thyroiditis shares features with early papillary thyroid carcinoma. Histopathology. 2002;41:357–62. PubMed

Kholová I, Kalfert D, Lintusaari J, Rajakorpi E, Ludvíková M. Follicular epithelial dysplasia as Hashimoto thyroiditis‐related atypia: a series of 91 specimens. Endocr Pathol. 2021;32:368–74. PubMed PMC

Chui MH, Cassol CA, Asa SL, Mete O. Follicular epithelial dysplasia of the thyroid: morphological and immunohistochemical characterization of a putative preneoplastic lesion to papillary thyroid carcinoma in chronic lymphocytic thyroiditis. Virchows Arch. 2013;462:557–63. PubMed

Nasr MR, Mukhopadhyay S, Zhang S, Katzenstein AL. Absence of the BRAF mutation in HBME1+ and CK19+ atypical cell clusters in Hashimoto thyroiditis: supportive evidence against preneoplastic change. Am J Clin Pathol. 2009;132:906–12. PubMed

Gasbarri A, Sciacchitano S, Marasco A, Papotti M, Di Napoli A, Marzullo A, et al. Detection and molecular characterisation of thyroid cancer precursor lesions in a specific subset of Hashimoto’s thyroiditis. Br J Cancer. 2004;91:1096–104. PubMed PMC

Kalfert D, Ludvikova M, Kholova I, Ludvik J, Topolocan O, Plzak J. Combined use of galectin‐3 and thyroid peroxidase improves the differential diagnosis of thyroid tumors. Neoplasma. 2020;67:164–70. PubMed

Ma H, Yan J, Zhang C, Qin S, Qin L, Liu L, et al. Expression of papillary thyroid carcinoma‐associated molecular markers and their significance in follicular epithelial dysplasia with papillary thyroid carcinoma‐like nuclear alterations in Hashimoto’s thyroiditis. Int J Clin Exp Pathol. 2014;7:7999–8007. PubMed PMC

Prasad ML, Huang Y, Pellegata NS, de la Chapelle A, Kloos RT. Hashimoto’s thyroiditis with papillary thyroid carcinoma (PTC)‐like nuclear alterations express molecular markers of PTC. Histopathology. 2004;45:39–46. PubMed

Sukari A, Nagasaka M, Al‐Hadidi A, Lum LG. Cancer immunology and immunotherapy. Anticancer Res. 2016;36:5593–606. PubMed

Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases–elimination, equilibrium and escape. Curr Opin Immunol. 2014;27:16–25. PubMed PMC

Aghajani M, Graham S, McCafferty C, Shaheed CA, Roberts T, DeSouza P, et al. Clinicopathologic and prognostic significance of programmed cell death ligand 1 expression in patients with non‐medullary thyroid cancer: a systematic review and meta‐analysis. Thyroid. 2018;28:349–61. PubMed

Wan B, Deng P, Dai W, Wang P, Dong Z, Yang C, et al. Association between programmed cell death ligand 1 expression and thyroid cancer: a meta‐analysis. Medicine (Baltimore). 2021;100:e25315. PubMed PMC

Girolami I, Pantanowitz L, Mete O, Brunelli M, Marletta S, Colato C, et al. Programmed death‐ligand 1 (PD‐L1) is a potential biomarker of disease‐free survival in papillary thyroid carcinoma: a systematic review and meta‐analysis of PD‐L1 immunoexpression in follicular epithelial derived thyroid carcinoma. Endocr Pathol. 2020;31:291–300. PubMed

Bai Y, Niu D, Huang X, Jia L, Kang Q, Dou F, et al. PD‐L1 and PD‐1 expression are correlated with distinctive clinicopathological features in papillary thyroid carcinoma. Diagn Pathol. 2017;12:72. PubMed PMC

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;29:317–23. PubMed

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;7:32318–28. PubMed PMC

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;52:318–22. PubMed

Aghajani MJ, Yang T, McCafferty CE, Graham S, Wu X, Niles N. Predictive relevance of programmed cell death protein 1 and tumor‐infiltrating lymphocyte expression in papillary thyroid cancer. Surgery. 2018;163:130–6. PubMed

Ahtiainen M, Elomaa H, Väyrynen JP, Wirta E‐V, Kuopio T, Helminen O, et al. Immune contexture of MMR‐proficient primary colorectal cancer and matched liver and lung metastases. Cancers. 2021;13:1530. PubMed PMC

Ahtiainen M, Wirta E‐V, Kuopio T, Seppälä T, Rantala J, Mecklin J‐P, et al. Combined prognostic value of CD274 (PD‐L1)/PDCDI (PD‐1) expression and immune cell infiltration in colorectal cancer as per mismatch repair status. Mod Pathol. 2019;32:866–83. PubMed

Kinter AL, Godbout EJ, McNally JP, Sereti I, Roby GA, O'Shea MA, et al. 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;181:6738–46. PubMed

Shi R‐L, Qu N, Luo T‐X, Xiang J, Liao T, Sun G‐H, et al. Programmed death‐ligand 1 expression in papillary thyroid cancer and its correlation with clinicopathologic factors and recurrence. Thyroid. 2017;27:537–45. PubMed

Álvarez‐Sierra D, Marín‐Sánchez A, Ruiz‐Blázquez P, de Jesús Gil C, Iglesias‐Felip C, González Ó, et al. Analysis of the PD‐1/PD‐L1 axis in human autoimmune thyroid disease: Insights into pathogenesis and clues to immunotherapy associated thyroid autoimmunity. J Autoimmun. 2019;103. PubMed

Wang DY, Johnson DB, Davis EJ. Toxicities associated with PD‐1/PD‐L1 blockade. Cancer J. 2018;24:36–40. PubMed PMC

Imblum BA, Baloch ZW, Fraker D, LiVolsi VA. Pembrolizumab‐induced thyroiditis. Endocr Pathol. 2019;30:163–7. PubMed

D'Andréa G, Lassalle S, Guevara N, Mograbi B, Hofman P. From biomarkers to therapeutic targets: the promise of PD‐L1 in thyroid autoimmunity and cancer. Theranostics. 2021;11:1310–25. PubMed PMC

Ritzmann F, Borchardt K, Vella G, Chitirala P, Angenendt A, Herr C, et al. Blockade of PD‐1 decreases neutrophilic inflammation and lung damage in experimental COPD. Am J Physiol Lung Cell Mol Physiol. 2021;320:L958–68. PubMed PMC

Ries J, Agaimy A, Wehrhan F, Baran C, Bolze S, Danzer E, et al. Importance of the PD‐1/PD‐L1 axis for malignant transformation and risk assessment of oral leukoplakia. Biomedicines. 2021;9:194. PubMed PMC

Yagyuu T, Funayama N, Imada M, Kirita T. Effect of smoking status and programmed death‐ligand 1 expression on the microenvironment and malignant transformation of oral leukoplakia: A retrospective cohort study. PLoS One. 2021;16:e0250359. PubMed PMC

Laville D, Casteillo F, Yvorel V, Tiffet O, Vergnon J‐M, Péoc’h M, et al. Immune Escape Is an Early Event in Pre‐Invasive Lesions of Lung Squamous Cell Carcinoma. Diagnostics (Basel). 2020;10:503. 10.3390/diagnostics10070503. PubMed DOI PMC

Lagisetty KH, McEwen DP, Nancarrow DJ, Schiebel JG, Ferrer‐Torres D, Ray D, et al. Immune determinants of Barrett's progression to esophageal adenocarcinoma. JCI Insight. 2021;6:e143888. PubMed PMC

Bucau M, Gault N, Sritharan N, Valette E, Charpentier C, Walker F, et al. PD‐1/PD‐L1 expression in anal squamous intraepithelial lesions. Oncotarget. 2020;11:3582–9. PubMed PMC

Tien TZ, Lee JNLW, Lim JCT, Chen X‐Y, Thike AA, Tan PH, et al. Delineating the breast cancer immune microenvironment in the era of multiplex immunohistochemistry/immunofluorescence. Histopathology. 2021;79:139–59. PubMed

Tan WCC, Nerurkar SN, Cai HY, Ng HHM, Wu D, Wee YTF, et al. Overview of multiplex immunohistochemistry/immunofluorescence techniques in the era of cancer immunotherapy. Cancer Commun. 2020;40:135–53. PubMed PMC