Background: Our study aimed to determine the frequency of microsatellite instability (MSI) and characterize the associations between MSI status, PD-L1 expression, and clinicopathological features in Vietnamese patients with gastric cancer. Methods: We performed a retrospective cohort study that analyzed 87 patients with gastric cancer who underwent gastrectomy from January 2020 to March 2023. MSI status was assessed by immunohistochemistry for mismatch repair proteins. PD-L1 expression was evaluated by tumor proportion score (TPS) and combined positive score (CPS). Associations between MSI, PD-L1, and clinicopathologic factors were analyzed. Results: MSI-high (MSI-H) was identified in 13.8% of tumors and significantly associated with intestinal subtype, moderate differentiation, necrosis, tumor-infiltrating lymphocytes, and PD-L1 positivity. Lymphatic invasion correlated with increased TPS. Intestinal classification correlated with higher CPS. Conclusion: MSI-H identifies a subset of gastric cancers with distinct features. PD-L1 expression is associated with aggressive disease parameters. Biomarker-based stratification may guide personalized therapy.

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians 2018; 68(6): 394–424. doi: 10.3322/caac.21492

2. Song Z, Wu Y, Yang J, et al. Progress in the treatment of advanced gastric cancer. Tumour Biology 2017; 39(7): 1010428317714626. doi: 10.1177/1010428317714626

3. Zepeda-Najar C, Xavier Palacios-Astudillo R, Chávez-Hernández JD, et al. Prognostic impact of microsatellite instability in gastric cancer. Contemporary Oncology 2021; 25(1): 68–71. doi: 10.5114/wo.2021.104939

4. Svenson N. Overcoming resistance in gastrointestinal cancers. Available online: https://www.targetedonc.com/view/overcoming-resistance-in-gastrointestinal-cancers (accessed on 25 August 2023).

5. Jin Y, Chen DL, Wang F, et al. The predicting role of circulating tumor DNA landscape in gastric cancer patients treated with immune checkpoint inhibitors. Molecular Cancer 2020; 19(1): 154. doi: 10.1186/s12943-020-01274-7

6. Eto S, Yoshikawa K, Nishi M, et al. Programmed cell death protein 1 expression is an independent prognostic factor in gastric cancer after curative resection. Gastric Cancer 2015; 19(2): 466–471. doi: 10.1007/s10120-015-0519-7

7. Sughayer MA, Dabbagh TZ, Battah AH. PD-L1 expression is a favorable prognostic marker in gastric carcinoma. Applied Immunohistochemistry & Molecular Morphology 2020; 28(10): 748–754. doi: 10.1097/pai.0000000000000834

8. Wu Y, Cao D, Qu L, et al. PD-1 and PD-L1 co-expression predicts favorable prognosis in gastric cancer. Oncotarget 2017; 8(38): 64066–64082. doi: 10.18632/oncotarget.19318

9. Yamashita K, Iwatsuki M, Harada K, et al. Prognostic impacts of the combined positive score and the tumor proportion score for programmed death ligand-1 expression by double immunohistochemical staining in patients with advanced gastric cancer. Gastric Cancer 2019; 23(1): 95–104. doi: 10.1007/s10120-019-00999-9

10. Pereira MA, Ramos MFKP, Dias AR, et al. Scoring systems for PD-L1 expression and their prognostic impact in patients with resectable gastric cancer. Virchows Archiv 2020; 478(6): 1039–1048. doi: 10.1007/s00428-020-02956-9

11. Brierley JD, Gospodarowicz MK, Wittekind C. Skin tumours. TNM Online 2017; 131–132. doi: 10.1002/9780471420194.tnmc26.pub3

12. Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 2011; 14(2): 101–112. doi: 10.1007/s10120-011-0041-5

13. Laurén P. The two histological main types of gastric carcinoma: Diffuse and so-called intestinal-type carcinoma. Acta Pathologica Microbiologica Scandinavica 1965; 64(1): 31–49. doi: 10.1111/apm.1965.64.1.31

14. Nagtegaal ID, Odze RD, Klimstra D, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology 2019; 76(2): 182–188. doi: 10.1111/his.13975

15. Tumor grade. Available online: https://www.cancer.gov/about-cancer/diagnosis-staging/diagnosis/tumor-grade (accessed on 30 October 2023).

16. Fuchs TL, Sioson L, Sheen A, et al. Assessment of Tumor-infiltrating Lymphocytes Using International TILs Working Group (ITWG) System Is a Strong Predictor of Overall Survival in Colorectal Carcinoma: A Study of 1034 Patients. The American Journal of Surgical Pathology. 2020; 44(4):536–544.

17. Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017; 390(10111): 2461–2471. doi: 10.1016/S0140-6736(17)31827-5

18. Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: Phase 2 clinical KEYNOTE-059 trial. JAMA Oncology 2018; 4(5): e180013. doi: 10.1001/jamaoncol.2018.0013

19. Umar A. RESPONSE: Re: Revised bethesda guidelines for hereditary nonpolyposis colorectal cancer (lynch syndrome) and microsatellite instability. JNCI Journal of the National Cancer Institute 2004; 96(18): 1403–1404. doi: 10.1093/jnci/djh281

20. Bateman AC. DNA mismatch repair proteins: Scientific update and practical guide. Journal of Clinical Pathology 2021; 74(4): 264–268. doi: 10.1136/jclinpath-2020-207281

21. Lou L, Wang L, Zhang Y, et al. Sex difference in incidence of gastric cancer: An international comparative study based on the Global Burden of Disease Study 2017. BMJ Open 2020; 10(1): e033323. doi: 10.1136/bmjopen-2019-033323

22. Wong MCS, Huang J, Chan PSF, et al. Global incidence and mortality of gastric cancer, 1980–2018. JAMA Netw Open 2021; 4(7): e2118457. doi: 10.1001/jamanetworkopen.2021.18457

23. Wanebo HJ, Kennedy BJ, Chmiel J, et al. Cancer of the stomach. A patient care study by the American College of Surgeons. Annals of Surgery 1993; 218(5): 583–592. doi: 10.1097/00000658-199321850-00002

24. Zhong N, Yu Y, Chen J, et al. Clinicopathological characteristics, survival outcome and prognostic factors of very young gastric cancer. Clinical and Experimental Medicine 2022; 23(2): 437–445. doi: 10.1007/s10238-022-00822-3

25. Kim K, Cho Y, Sohn JH, et al. Clinicopathologic characteristics of early gastric cancer according to specific intragastric location. BMC Gastroenterology 2019; 19(1): 24. doi: 10.1186/s12876-019-0949-5

26. Tsurumaru D, Miyasaka M, Nishimuta Y, et al. Differentiation of early gastric cancer with ulceration and resectable advanced gastric cancer using multiphasic dynamic multidetector CT. European Radiology 2015; 26(5): 1330–1337. doi: 10.1007/s00330-015-3938-2

27. Crew KD, Neugut AI. Epidemiology of gastric cancer. World Journal of Gastroenterology 2006; 12(3): 354–362. doi: 10.3748/wjg.v12.i3.354

28. Lee YJ, Kim JH, Park JJ, et al. The implications of endoscopic ulcer in early gastric cancer: Can we predict clinical behaviors from endoscopy? PLoS One 2016; 11(10): e0164339. doi: 10.1371/journal.pone.0164339

29. Guo P, Li Y, Zhu Z, et al. Prognostic value of tumor size in gastric cancer: An analysis of 2,379 patients. Tumour Biology 2013; 34(2): 1027–1035. doi: 10.1007/s13277-012-0642-6

30. Chen Y, Jia Y, Peng Z, Wang G. The prognostic role of tumor size in stage T1 gastric cancer. World Journal of Surgical Oncology 2022; 20(1): 135. doi: 10.1186/s12957-022-02596-0

31. Ren MH, Qi XS, Chu YN, et al. Risk of lymph node metastasis and feasibility of endoscopic treatment in ulcerative early gastric cancer. Annals of Surgical Oncology 2020; 28(4): 2407–2417. doi: 10.1245/s10434-020-09153-7

32. Bilici A, Dane F, Seker M, et al. Is subdivision of pT2 tumors superior to lymph node metastasis for predicting survival of patients with gastric cancer? Review of 224 patients from four centers. Digestive Diseases and Sciences 2011; 56(11): 3226–3234. doi: 10.1007/s10620-011-1721-z

33. Kim DG, An JY, Kim H, et al. Clinical implications of microsatellite instability in early gastric cancer. Journal of Gastric Cancer 2019; 19(4): 427–437. doi: 10.5230/jgc.2019.19.e38

34. An JY, Kim H, Cheong J, et al. Microsatellite instability in sporadic gastric cancer: Its prognostic role and guidance for 5-FU based chemotherapy after R0 resection. International Journal of Cancer 2011; 131(2): 505–511. doi: 10.1002/ijc.26399

35. Hu B, Hajj NE, Sittler S, et al. Gastric cancer: Classification, histology and application of molecular pathology. Journal of Gastrointestinal Oncology 2012; 3(3): 251–261. doi: 10.3978/j.issn.2078-6891.2012.021

36. Berlth F. Pathohistological classification systems in gastric cancer: Diagnostic relevance and prognostic value. World Journal of Gastroenterology 2014; 20(19): 5679–5684. doi: 10.3748/wjg.v20.i19.5679

37. Assumpção PP, Barra WF, Ishak G, et al. The diffuse-type gastric cancer epidemiology enigma. BMC Gastroenterology 2020; 20(1): 223. doi: 10.1186/s12876-020-01354-4

38. Feng F, Liu J, Wang F, et al. Prognostic value of differentiation status in gastric cancer. BMC Cancer 2018; 18(1): 865. doi: 10.1186/s12885-018-4780-0

39. Guan WL, Ma Y, Cui YH, et al. The impact of mismatch repair status on prognosis of patients with gastric cancer: A multicenter analysis. Frontiers in Oncology 2021; 11: 712760. doi: 10.3389/fonc.2021.712760

40. Ott PA, Le DT, Kim JW, et al. Nivolumab (NIVO) in patients (pts) with advanced (adv) chemotherapy-refractory (CT-Rx) esophagogastric (EG) cancer according to microsatellite instability (MSI) status: checkmate 032. Annals of Oncology 2017; 28: v229–v230. doi: 10.1093/annonc/mdx369.058

41. Nakashima H, Honda M, Inoue H, et al. Microsatellite instability in multiple gastric cancers. International Journal of Cancer 1995; 64(4): 239–242. doi: 10.1002/ijc.2910640405

42. Falchetti M, Saieva C, Lupi R, et al. Gastric cancer with high-level microsatellite instability: Target gene mutations, clinicopathologic features, and long-term survival. Human Pathology 2008; 39(6): 925–932. doi: 10.1016/j.humpath.2007.10.024

43. Jahng J. Endoscopic and clinicopathologic characteristics of early gastric cancer with high microsatellite instability. World Journal of Gastroenterology 2012; 18(27): 3571. doi: 10.3748/wjg.v18.i27.3571

44. Kim JY, Shin NR, Kim A, et al. Microsatellite instability status in gastric cancer: A reappraisal of its clinical significance and relationship with mucin phenotypes. Korean Journal of Pathology 2013; 47(1): 28–35. doi: 10.4132/koreanjpathol.2013.47.1.28

45. Grogg KL, Lohse CM, Pankratz VS, et al. Lymphocyte-rich gastric cancer: Associations with epstein-barr virus, microsatellite instability, histology, and survival. Modern Pathology 2003; 16(7): 641–651. doi: 10.1097/01.mp.0000076980.73826.c0

46. Mansuri N, Birkman EM, Heuser VD, et al. Association of tumor-infiltrating T lymphocytes with intestinal-type gastric cancer molecular subtypes and outcome. Virchows Arch 2020; 478(4): 707–717. doi: 10.1007/s00428-020-02932-3

47. Choi E, Chang MS, Byeon SJ, et al. Prognostic perspectives of PD-L1 combined with tumor-infiltrating lymphocytes, Epstein-Barr virus, and microsatellite instability in gastric carcinomas. Diagnostic Pathology 2020; 15(1): 69. doi: 10.1186/s13000-020-00979-z

48. Polom K, Marrelli D, Roviello G, et al. PIK3CA mutation in gastric cancer and the role of microsatellite instability status in mutations of exons 9 and 20 of the PIK3CA gene. Advances in Clinical and Experimental Medicine 2018; 27(7): 963–969. doi: 10.17219/acem/70795

49. Quaas A, Biesma HD, Wagner AD, et al. Microsatellite instability and sex differences in resectable gastric cancer—A pooled analysis of three European cohorts. European Journal of Cancer 2022; 173: 95–104. doi: 10.1016/j.ejca.2022.06.025

50. Zhu L, Li Z, Wang Y, et al. Microsatellite instability and survival in gastric cancer: A systematic review and meta-analysis. Molecular and Clinical Oncology 2015; 3(3): 699–705. doi: 10.3892/mco.2015.506

51. Kim ST, Cristescu R, Bass AJ, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nature Medicine 2018; 24(9): 1449–1458. doi: 10.1038/s41591-018-0101-z

52. Wang L, Zhang Q, Ni S, et al. Programmed death-ligand 1 expression in gastric cancer: Correlation with mismatch repair deficiency and HER2-negative status. Cancer Medicine 2018; 7(6): 2612–2620. doi: 10.1002/cam4.1502

53. Wang YL, Gong Y, Lv Z, et al. Expression of PD1/PDL1 in gastric cancer at different microsatellite status and its correlation with infiltrating immune cells in the tumor microenvironment. Journal of Cancer 2021; 12(6): 1698–1707. doi: 10.7150/jca.40500

54. Yoshida T, Ogura G, Tanabe M, et al. Clinicopathological features of PD-L1 protein expression, EBV positivity, and MSI status in patients with advanced gastric and esophagogastric junction adenocarcinoma in Japan. Cancer Biology & Therapy 2022; 23(1): 191–200. doi: 10.1080/15384047.2022.2038002

55. Haraguchi N, Arigami T, Uenosono Y, et al. Clinical significance of primary tumor score determined by tumor depth and size in patients with resectable gastric cancer. Oncotarget. 2018; 9(9): 8512–8520. doi: 10.18632/oncotarget.23953

56. Saito H, Kono Y, Murakami Y, et al. Highly activated PD-1/PD-L1 pathway in gastric cancer with PD-L1 expression. Anticancer Research 2018; 38(1): 107–112. doi: 10.21873/anticanres.12197

57. Kim DH, Bae GE, Suh KS, et al. Clinical significance of tumor and immune cell PD-L1 expression in gastric adenocarcinoma. In Vivo 2020; 34(6): 3171–3180. doi: 10.21873/invivo.12152

58. Tan IB, Ivanova T, Lim KH, et al. Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. Gastroenterology 2011; 141(2): 476–485.e11. doi: 10.1053/j.gastro.2011.04.042

59. Pereira MA, Ramos MFKP, Dias AR, Ribeiro R, Cardili L, Zilberstein B, et al. Scoring systems for PD-L1 expression and their prognostic impact in patients with resectable gastric cancer. Virchows Archiv. 2021;478(6):1039–1048.

60. Polom K, Marano L, Marrelli D, et al. Meta-analysis of microsatellite instability in relation to clinicopathological characteristics and overall survival in gastric cancer. British Journal of Surgery 2017; 105(3): 159–167. doi: 10.1002/bjs.10663

61. Chen X, Zhang H, Wang M, et al. Relationship between programmed death ligand 1 expression and other clinicopathological features in a large cohort of gastric cancer patients. Frontiers in Immunology 2022; 13: 783695. doi: 10.3389/fimmu.2022.783695