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PD-L1, MMR, and EGFR expression in gastrointestinal neuroendocrine tumors Skip to content Yıl 2024, Cilt: 49 Sayı: 2, 400 – 406, 30.06.2024
Sevil Karabağ , Meltem Öznur
https://doi.org/10.17826/cumj.1445549
Öz Amaç: Literatürde gastrointestinal nöroendokrin tümörlerle (NET) ilgili kısıtlı çalışma bulunmaktadır. Bu çalışmada gastrointestinal sistem yerleşimli G1, G2 ve G3 nöroendokrin tümörlerde PD-L1 ve EGFR ekspresyonunu saptamak, gradeler arasındaki ilişkiyi incelemek, MMR protein kaybını ve bunun PD-L1 ile ilişkisini araştırmayı amaçladık. Gereç ve Yöntem: Bu çalışmaya Ocak 2017 ile Ocak 2021 tarihleri arasında primer gastrointestinal NET tanısı konulan tüm hastalar dahil edildi. PD-L1, EGFR, MLH1, MSH2, MSH6 ve PMS2’yi immünohistokimya ile değerlendirdik. Çalışmaya toplam 30 hasta dahil edildi. Bulgular: Olgular mide, pankreas, kolon, apendiks ve karaciğer yerleşimli idi. Olguların 14 (47%) G1, 7(23%) si G2, 9 (30%) u G3 nöroendokrin tümördü. Tümör ve/veya tümör mikroçevresi immün hücrelerde(TMIC) G1 dört, G2 iki, G3 iki olguda olmak üzere toplam 8 olguda (28%) PD-L1 ekspresyonu saptandı. Histolojik grade ile PD-L1 ekspresyonu arasında anlamlı ilişki saptanmadı. Olguların 16’sında (53%) en az bir MMR ekspresyonunda kayıp izlendi. PD-L1 ekspresyonu olan 8 olgunun beşinde MMR kaybı saptandı, üçünde izlenmedi. Hiçbir olguda EGFR ekspresyonu saptanmadı. Sonuç: Gastrointestinal NET’lerin %53’ünde MMR protein kaybı ve %27’sinde PD-L1 ekspresyonu gözlemledik. Çalışmamızın, Mikrosatellit instable NET’lerde bir tedavi alternatifi olabilecek immün kontrol noktası inhibitörleri ile ilgili gelecekteki çalışmalara öncü olabileceğini düşünmekteyiz.
Anahtar Kelimeler Nöroendokrin tümör, PD-L1, MMR, EGFR, immunohistokimya
Etik Beyan The study (protocol-2021.94.04.12) was approved by the Non-Interventional Clinical Trials Ethics Committee.
Destekleyen Kurum The authors received no financial support for the research.
Teşekkür The authors thank Dr Ayşegül İsal Arslan for sharing her neuroendocrine carcinoma cases for this research.
Kaynakça La Rosa S, Vanoli A. Gastric neuroendocrine neoplasms. In: M Fukayama, M Rugge, M Washington, eds. Digestive System Tumours. WHO Classification of Tumours: 104-109. IARC Press. 2019. Xing J, Ying H, Li J, Gao Y, Sun Z, Li J et al. Immune checkpoint markers in neuroendocrine carcinoma of the digestive system. Front Oncol. 2020;28:132. Yang MW, Fu XL, Jiang YS, Chen XJ, Tao LY, Yang JY et al. Clinical significance of programmed death 1/programmed death ligand 1 pathway in gastric neuroendocrine carcinomas. World J Gastroenterol. 2019;14;25:1684-96. Pedoeem A, Azoulay-Alfaguter I, Strazza M, Silverman GJ, Mor A. Programmed death-1 pathway in cancer and autoimmunity. Clin Immunol. 2014;153:145-52. Patel SP, Kurzrock R. PD-L1 Expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14:847–56. Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373:1270–1. Cunha LL, Marcello MA, Rocha-Santos V, Ward LS. Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way. Endocr Relat Cancer. 2017;24:T261–T281. Simon S, Labarriere N. PD-1 expression on tumor-specific T cells: friend or foe for immunotherapy? Oncoimmunology. 2017;7:e1364828. Ferrata M, Schad A, Zimmer S, Thomas J, Musholt TJ, Bahr K, Kuenzel J. PD-L1 expression and ımmune cell ınfiltration in gastroenteropancreatic(gep) and non-gep neuroendocrine neoplasms with high proliferative activity. Front Oncol. 2019;7;9:343. Fraune C, Simon R, Hube-Magg C, Makrypidi-Fraune G, Kluth M, Büscheck F et al. Homogeneous MMR deficiency throughout the entire tumor mass occurs in a subset of colorectal neuroendocrine carcinomas. Endocr Pathol. 2020;31:182–9. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. New Engl J Med. 2003;349:247–57. Cortes-Ciriano I, Lee S, Park WY, Kim TM, Park PJ. A molecular portrait of microsatellite instability across multiple cancers. Nat Commun. 2017;6;8:15180. Lee JK, Lee J, Kim S, Kim S, Youk J, Park S et al. Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas. J Clin Oncol. 2017;35:3065-74. Morgan S, Slodkowska E, Parra-Herran C, Mirkovic J. PD-L1, RB1 and mismatch repair protein immunohistochemical expression in neuroendocrine carcinoma, small cell type, of the uterine cervix. Histopathology. 2019;74:997-1004. Kontić M, Čolović Z, Paladin I, Gabelica M, Barić A, Pešutić-Pisac V. Association between EGFR expression and clinical outcome of laryngeal HPV squamous cell carcinoma. Acta Otolaryngol. 2019;139:913–7. Wang X, Teng F, Kong L, Yu J. PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther. 2016;9:5023–39. Calderaro J, Rousseau B, Amaddeo G, Mercey M, Charpy C, Costentin C et al. Programmed death ligand 1 expression in hepatocellular carcinoma: relationship with clinical and pathological features. Hepatology. 2016;64:2038–46. Cavalcanti E, Armentano R, Valentini AM, Chieppa M, Caruso ML. Role of PD-L1 expression as a biomarker for GEP neuroendocrine neoplasm grading. Cell Death Dis. 2017;8:e3004. Kim ST, Ha SY, Lee S, Ahn S, Lee J, Park SH et al. The impact of PD-L1 expression in patients with metastatic GEP-NETs. J Cancer. 2016;7:484-89. Mandal R, Samstein RM, Lee KW, Havel JJ, Wang H, Krishna C et al. Genetic diversity of tumors with mismatch repair deficiency influences anti–PD-1 immunotherapy response. Science. 2019;03:485–91. Sahnane N, Furlan D, Monti M, Romualdi C, Vanoli A, Vicari E et al. Microsatellite unstable gastrointestinal neuroendocrine carcinomas: a new clinicopathologic entity. Endocr Relat Cancer. 2015;22:35–45. Olevian DC, Nikiforova MN, Chiosea S, Sun W, Bahary N, Kuanet SF al. Colorectal poorly differentiated neuroendocrine carcinomas frequently exhibit BRAF mutations and are associated with poor overall survival. Hum Pathol. 2016;49:124–34. Salem ME, Puccini A, Grothey A, Raghavan D, Goldberg RM, Xiu J et al. Landscape of tumor mutation load, mismatch repair deficiency, and pd-l1 expression in a large patient cohort of gastrointestinal cancers. Mol Cancer Res. 2018;16:805-12. Park HY, Kwon MJ, Suk Kang H, Kim YJ, Kim NY, Kim MJ et al. Targeted next-generation sequencing of well-differentiated rectal, gastric, and appendiceal neuroendocrine tumors to identify potential targets. Hum Pathol. 2019;87:83–94 Chen HJ, Poran A, Unni AM, Huang SX, Elemento O, Snoeck HW et al. Generation of pulmonary neuroendocrine cells and SCLC-like tumors from human embryonic stem cells. J Exp Med. 2019;216:674–87
PD-L1, MMR, and EGFR expression in gastrointestinal neuroendocrine tumors Yıl 2024, Cilt: 49 Sayı: 2, 400 – 406, 30.06.2024
Sevil Karabağ , Meltem Öznur
https://doi.org/10.17826/cumj.1445549
Öz Purpose: There are limited studies on gastrointestinal neuroendocrine tumors (NETs) in the literature. This study aimed to determine PD-L1 and EGFR expression in primary G1 and G2 NETs and neuroendocrine carcinoma located in the gastrointestinal system, explore the relationship between grades, and investigate the loss of DNA mismatch repair (MMR) protein expression and its association with PD-L1 expression. Materials and Methods: All patients diagnosed with primary gastrointestinal NETs between January 2017 and January 2021 were included in this study. The study evaluated the protein expression of PD-L1, EGFR, MLH1, MSH2, MSH6, and PMS2 by immunohistochemistry. A total of 30 patients were included in the study. Results: PD-L1 expression was detected in tumor cells and/or tumor microenvironment immune cells in 8 cases (28%), consisting of four G1, two G2, and two NEC cases. There was no significant relationship between histological grade and PD-L1 expression. A loss of expression of at least one MMR protein was noted in 16 cases (53%). A loss of MMR protein expression was detected in five of the eight cases with PD-L1 expression. EGFR expression was not detected in any of the cases. Conclusion: The study revealed a loss of MMR protein expression in 53% and PD-L1 expression in 27% of gastrointestinal NETs. This study might be a pioneer for future studies on immune checkpoint inhibitors in microsatellite-unstable NETs, thereby contributing to providing a treatment alternative for this group of patients.
Anahtar Kelimeler Neuroendocrin tumors, PD-L1, MMR, EGFR, immunohistochemistry
Etik Beyan The study (protocol-2021.94.04.12) was approved by the Non-Interventional Clinical Trials Ethics Committee.
Destekleyen Kurum The authors received no financial support for the research.
Teşekkür The authors thank Dr Ayşegül İsal Arslan for sharing her neuroendocrine carcinoma cases for this research.
Kaynakça La Rosa S, Vanoli A. Gastric neuroendocrine neoplasms. In: M Fukayama, M Rugge, M Washington, eds. Digestive System Tumours. WHO Classification of Tumours: 104-109. IARC Press. 2019. Xing J, Ying H, Li J, Gao Y, Sun Z, Li J et al. Immune checkpoint markers in neuroendocrine carcinoma of the digestive system. Front Oncol. 2020;28:132. Yang MW, Fu XL, Jiang YS, Chen XJ, Tao LY, Yang JY et al. Clinical significance of programmed death 1/programmed death ligand 1 pathway in gastric neuroendocrine carcinomas. World J Gastroenterol. 2019;14;25:1684-96. Pedoeem A, Azoulay-Alfaguter I, Strazza M, Silverman GJ, Mor A. Programmed death-1 pathway in cancer and autoimmunity. Clin Immunol. 2014;153:145-52. Patel SP, Kurzrock R. PD-L1 Expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 2015;14:847–56. Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med. 2015;373:1270–1. Cunha LL, Marcello MA, Rocha-Santos V, Ward LS. Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way. Endocr Relat Cancer. 2017;24:T261–T281. Simon S, Labarriere N. PD-1 expression on tumor-specific T cells: friend or foe for immunotherapy? Oncoimmunology. 2017;7:e1364828. Ferrata M, Schad A, Zimmer S, Thomas J, Musholt TJ, Bahr K, Kuenzel J. PD-L1 expression and ımmune cell ınfiltration in gastroenteropancreatic(gep) and non-gep neuroendocrine neoplasms with high proliferative activity. Front Oncol. 2019;7;9:343. Fraune C, Simon R, Hube-Magg C, Makrypidi-Fraune G, Kluth M, Büscheck F et al. Homogeneous MMR deficiency throughout the entire tumor mass occurs in a subset of colorectal neuroendocrine carcinomas. Endocr Pathol. 2020;31:182–9. Ribic CM, Sargent DJ, Moore MJ, Thibodeau SN, French AJ, Goldberg RM et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. New Engl J Med. 2003;349:247–57. Cortes-Ciriano I, Lee S, Park WY, Kim TM, Park PJ. A molecular portrait of microsatellite instability across multiple cancers. Nat Commun. 2017;6;8:15180. Lee JK, Lee J, Kim S, Kim S, Youk J, Park S et al. Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas. J Clin Oncol. 2017;35:3065-74. Morgan S, Slodkowska E, Parra-Herran C, Mirkovic J. PD-L1, RB1 and mismatch repair protein immunohistochemical expression in neuroendocrine carcinoma, small cell type, of the uterine cervix. Histopathology. 2019;74:997-1004. Kontić M, Čolović Z, Paladin I, Gabelica M, Barić A, Pešutić-Pisac V. Association between EGFR expression and clinical outcome of laryngeal HPV squamous cell carcinoma. Acta Otolaryngol. 2019;139:913–7. Wang X, Teng F, Kong L, Yu J. PD-L1 expression in human cancers and its association with clinical outcomes. Onco Targets Ther. 2016;9:5023–39. Calderaro J, Rousseau B, Amaddeo G, Mercey M, Charpy C, Costentin C et al. Programmed death ligand 1 expression in hepatocellular carcinoma: relationship with clinical and pathological features. Hepatology. 2016;64:2038–46. Cavalcanti E, Armentano R, Valentini AM, Chieppa M, Caruso ML. Role of PD-L1 expression as a biomarker for GEP neuroendocrine neoplasm grading. Cell Death Dis. 2017;8:e3004. Kim ST, Ha SY, Lee S, Ahn S, Lee J, Park SH et al. The impact of PD-L1 expression in patients with metastatic GEP-NETs. J Cancer. 2016;7:484-89. Mandal R, Samstein RM, Lee KW, Havel JJ, Wang H, Krishna C et al. Genetic diversity of tumors with mismatch repair deficiency influences anti–PD-1 immunotherapy response. Science. 2019;03:485–91. Sahnane N, Furlan D, Monti M, Romualdi C, Vanoli A, Vicari E et al. Microsatellite unstable gastrointestinal neuroendocrine carcinomas: a new clinicopathologic entity. Endocr Relat Cancer. 2015;22:35–45. Olevian DC, Nikiforova MN, Chiosea S, Sun W, Bahary N, Kuanet SF al. Colorectal poorly differentiated neuroendocrine carcinomas frequently exhibit BRAF mutations and are associated with poor overall survival. Hum Pathol. 2016;49:124–34. Salem ME, Puccini A, Grothey A, Raghavan D, Goldberg RM, Xiu J et al. Landscape of tumor mutation load, mismatch repair deficiency, and pd-l1 expression in a large patient cohort of gastrointestinal cancers. Mol Cancer Res. 2018;16:805-12. Park HY, Kwon MJ, Suk Kang H, Kim YJ, Kim NY, Kim MJ et al. Targeted next-generation sequencing of well-differentiated rectal, gastric, and appendiceal neuroendocrine tumors to identify potential targets. Hum Pathol. 2019;87:83–94 Chen HJ, Poran A, Unni AM, Huang SX, Elemento O, Snoeck HW et al. Generation of pulmonary neuroendocrine cells and SCLC-like tumors from human embryonic stem cells. J Exp Med. 2019;216:674–87 Toplam 25 adet kaynakça vardır.
Ayrıntılar Birincil Dil İngilizce Konular Patoloji Bölüm Araştırma Yazarlar Sevil Karabağ Tekirdağ Namık Kemal Üniversitesi, Tıp Fakültesi 0000-0002-8855-3798 Türkiye
Meltem Öznur TEKİRDAĞ NAMIK KEMAL ÜNİVERSİTESİ 0000-0002-6396-3168 Türkiye
Yayımlanma Tarihi 30 Haziran 2024 Gönderilme Tarihi 1 Mart 2024 Kabul Tarihi 19 Nisan 2024 Yayımlandığı Sayı Yıl 2024 Cilt: 49 Sayı: 2
Kaynak Göster MLA Karabağ, Sevil ve Meltem Öznur. “PD-L1, MMR, and EGFR Expression in Gastrointestinal Neuroendocrine Tumors”. Cukurova Medical Journal, c. 49, sy. 2, 2024, ss. 400-6, doi:10.17826/cumj.1445549.
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