DOI QR코드

DOI QR Code

A Standardized Pathology Report for Gastric Cancer: 2nd Edition

  • Young Soo Park (Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Myeong-Cherl Kook (Center for Gastric Cancer, National Cancer Center) ;
  • Baek-hui Kim (Department of Pathology, Korea University Guro Hospital) ;
  • Hye Seung Lee (Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Dong-Wook Kang (Department of Pathology, Chungnam National University Sejong Hospital, Chungnam National University School of Medicine) ;
  • Mi-Jin Gu (Department of Pathology, Yeungnam University College of Medicine) ;
  • Ok Ran Shin (Department of Hospital Pathology, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Younghee Choi (Department of Pathology, Hallym University Dongtan Sacred Heart Hospital) ;
  • Wonae Lee (Department of Pathology, Dankook University College of Medicine) ;
  • Hyunki Kim (Department of Pathology, Yonsei University College of Medicine) ;
  • In Hye Song (Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine) ;
  • Kyoung-Mee Kim (Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Hee Sung Kim (Department of Pathology, Chung-Ang University Hospital, Chung-Ang University College of Medicine) ;
  • Guhyun Kang (LabGenomics Clinical Laboratories) ;
  • Do Youn Park (St. Maria Pathology Laboratory) ;
  • So-Young Jin (Department of Pathology, Soonchunhyang University Seoul Hospital) ;
  • Joon Mee Kim (Department of Pathology, Inha University School of Medicine) ;
  • Yoon Jung Choi (Department of Pathology, Yongin Severance Hospital, Yonsei University College of Medicine) ;
  • Hee Kyung Chang (Department of Pathology, Kosin University Gospel Hospital, Kosin University College of Medicine) ;
  • Soomin Ahn (Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Mee Soo Chang (Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine) ;
  • Song-Hee Han (Department of Pathology, Dong-A University College of Medicine) ;
  • Yoonjin Kwak (Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • An Na Seo (Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital) ;
  • Sung Hak Lee (Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Mee-Yon Cho (Department of Pathology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine) ;
  • The Gastrointestinal Pathology Study Group of the Korean Society of Pathologists (Korean Society of Pathologists)
  • Received : 2022.12.01
  • Accepted : 2022.12.23
  • Published : 2023.01.31

Abstract

The first edition of 'A Standardized Pathology Report for Gastric Cancer' was initiated by the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists and published 17 years ago. Since then, significant advances have been made in the pathologic diagnosis, molecular genetics, and management of gastric cancer (GC). To reflect those changes, a committee for publishing a second edition of the report was formed within the Gastrointestinal Pathology Study Group of the Korean Society of Pathologists. This second edition consists of two parts: standard data elements and conditional data elements. The standard data elements contain the basic pathologic findings and items necessary to predict the prognosis of GC patients, and they are adequate for routine surgical pathology service. Other diagnostic and prognostic factors relevant to adjuvant therapy, including molecular biomarkers, are classified as conditional data elements to allow each pathologist to selectively choose items appropriate to the environment in their institution. We trust that the standardized pathology report will be helpful for GC diagnosis and facilitate large-scale multidisciplinary collaborative studies.

Keywords

Acknowledgement

This research was supported by a grant of Patient-Centered Clinical Research Coordinating Center (PACEN) funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HC20C0123).

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209-249.  https://doi.org/10.3322/caac.21660
  2. Hong S, Won YJ, Lee JJ, Jung KW, Kong HJ, Im JS, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2018. Cancer Res Treat 2021;53:301-315.  https://doi.org/10.4143/crt.2021.291
  3. Kim WH, Park CK, Kim YB, Kim YW, Kim HG, Bae HI, et al. A standardized pathology report for gastric cancer. Korean J Pathol 2005;39:106-113.
  4. World Health Organization. WHO Classification of Tumours: Digestive System Tumours. Geneva: World Health Organization; 2019.
  5. Guideline Committee of the Korean Gastric Cancer Association (KGCA), Development Working Group & Review Panel. Korean practice guideline for fastric cancer 2018: an evidence-based, multi-disciplinary approach. J Gastric Cancer 2019;19:1-48.  https://doi.org/10.5230/jgc.2019.19.e8
  6. Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol 2016;17:717-726.  https://doi.org/10.1016/S1470-2045(16)00175-3
  7. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376:687-697.  https://doi.org/10.1016/S0140-6736(10)61121-X
  8. Amin MB, Edge SB, Greene FL, Byrd DR, Brookland RK, Washington MK, et al. AJCC Cancer Staging Manual. 8th ed. Cham: Springer; 2017.
  9. Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 2011;14:101-112.  https://doi.org/10.1007/s10120-011-0041-5
  10. Fritz A, Percy C, Jack A, Shanmugaratnam K, Sobin L, Parkin DM, et al. International Classification of Diseases for Oncology (ICD-O). 3rd ed. Lyon: International Agency for Research on Cancer; 2013.
  11. Shi C, Berlin J, Branton PA, Fitzgibbons PL, Frankel WL, Hofstetter WL, et al. Protocol for the examination of specimens from patients with carcinoma of the stomach [Internet]. Northfield (MN): College of American Pathologists; 2020 [cited 2022 Dec 1]. Available from: https://documents.cap.org/ protocols/cp-giupper-esophagus-20-4100.pdf.
  12. Shi C, Badgwell BD, Grabsch HI, Gibson MK, Hong SM, Kumarasinghe P, et al. Data set for reporting carcinoma of the stomach in gastrectomy. Arch Pathol Lab Med 2022;146:1072-1083.  https://doi.org/10.5858/arpa.2021-0225-OA
  13. Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11-20.  https://doi.org/10.1056/NEJMoa055531
  14. Zhang X, Liang H, Li Z, Xue Y, Wang Y, Zhou Z, et al.; RESOLVE study group. Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an openlabel, superiority and non-inferiority, phase 3 randomised controlled trial. Lancet Oncol 2021;22:1081-1092.  https://doi.org/10.1016/S1470-2045(21)00297-7
  15. Kang YK, Yook JH, Park YK, Lee JS, Kim YW, Kim JY, et al. PRODIGY: a phase III study of neoadjuvant docetaxel, oxaliplatin, and S-1 plus surgery and adjuvant S-1 versus surgery and adjuvant S-1 for resectable advanced gastric cancer. J Clin Oncol 2021;39:2903-2913.  https://doi.org/10.1200/JCO.20.02914
  16. Langer R, Becker K. Tumor regression grading of gastrointestinal cancers after neoadjuvant therapy. Virchows Arch 2018;472:175-186.  https://doi.org/10.1007/s00428-017-2232-x
  17. Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry-Amar M, Petiot JF, et al. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer 1994;73:2680-2686. https://doi.org/10.1002/1097-0142(19940601)73:11<2680::AID-CNCR2820731105>3.0.CO;2-C
  18. Dworak O, Keilholz L, Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 1997;12:19-23.  https://doi.org/10.1007/s003840050072
  19. Becker K, Mueller JD, Schulmacher C, Ott K, Fink U, Busch R, et al. Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy. Cancer 2003;98:1521-1530.  https://doi.org/10.1002/cncr.11660
  20. Mirza A, Naveed A, Hayes S, Formela L, Welch I, West CM, et al. Assessment of histopathological response in gastric and gastro-oesophageal junction adenocarcinoma following neoadjuvant chemotherapy: which scoring system to use? ISRN Pathol 2012;2012:519351. 
  21. Karamitopoulou E, Thies S, Zlobec I, Ott K, Feith M, Slotta-Huspenina J, et al. Assessment of tumor regression of esophageal adenocarcinomas after neoadjuvant chemotherapy: comparison of 2 commonly used scoring approaches. Am J Surg Pathol 2014;38:1551-1556.  https://doi.org/10.1097/PAS.0000000000000255
  22. Kim BH, Kim JM, Kang GH, Chang HJ, Kang DW, Kim JH, et al. Standardized Pathology Report for Colorectal Cancer, 2nd edition. J Pathol Transl Med 2020;54:1-19.  https://doi.org/10.4132/jptm.2019.09.28
  23. Tsekrekos A, Vieth M, Ndegwa N, Bateman A, Flejou JF, Grabsch HI, et al. Interobserver agreement of a gastric adenocarcinoma tumor regression grading system that incorporates assessment of lymph nodes. Hum Pathol 2021;116:94-101.  https://doi.org/10.1016/j.humpath.2021.07.003
  24. Davies AR, Myoteri D, Zylstra J, Baker CR, Wulaningsih W, Van Hemelrijck M, et al. Lymph node regression and survival following neoadjuvant chemotherapy in oesophageal adenocarcinoma. Br J Surg 2018;105:1639-1649.  https://doi.org/10.1002/bjs.10900
  25. Reim D, Novotny A, Friess H, Slotta-Huspenina J, Weichert W, Ott K, et al. Significance of tumour regression in lymph node metastases of gastric and gastro-oesophageal junction adenocarcinomas. J Pathol Clin Res 2020;6:263-272.  https://doi.org/10.1002/cjp2.169
  26. Smyth EC, Fassan M, Cunningham D, Allum WH, Okines AF, Lampis A, et al. Effect of pathologic tumor response and nodal status on survival in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy trial. J Clin Oncol 2016;34:2721-2727.  https://doi.org/10.1200/JCO.2015.65.7692
  27. Koh YW, Park YS, Ryu MH, Ryoo BY, Park HJ, Yook JH, et al. Postoperative nodal status and diffuse-type histology are independent prognostic factors in resectable advanced gastric carcinomas after preoperative chemotherapy. Am J Surg Pathol 2013;37:1022-1029.  https://doi.org/10.1097/PAS.0b013e31828778fd
  28. Veronese N, Fassan M, Wood LD, Stubbs B, Solmi M, Capelli P, et al. Extranodal extension of nodal metastases is a poor prognostic indicator in gastric cancer: a systematic review and meta-analysis. J Gastrointest Surg 2016;20:1692-1698.  https://doi.org/10.1007/s11605-016-3199-7
  29. Lee IS, Park YS, Ryu MH, Song MJ, Yook JH, Oh ST, et al. Impact of extranodal extension on prognosis in lymph node-positive gastric cancer. Br J Surg 2014;101:1576-1584.  https://doi.org/10.1002/bjs.9640
  30. Lee IS, Kang HJ, Park YS, Ryu MH, Yook JH, Kang YK, et al. Prognostic impact of extranodal extension in stage 1B gastric carcinomas. Surg Oncol 2018;27:299-305.  https://doi.org/10.1016/j.suronc.2018.05.014
  31. Araki I, Hosoda K, Yamashita K, Katada N, Sakuramoto S, Moriya H, et al. Prognostic impact of venous invasion in stage IB node-negative gastric cancer. Gastric Cancer 2015;18:297-305.  https://doi.org/10.1007/s10120-014-0362-2
  32. Takeuchi A, Ojima T, Katsuda M, Hayata K, Goda T, Kitadani J, et al. Venous invasion is a risk factor for recurrence of pT1 gastric cancer with lymph node metastasis. J Gastrointest Surg 2022;26:757-763.  https://doi.org/10.1007/s11605-021-05238-0
  33. Nishibeppu K, Komatsu S, Ichikawa D, Imamura T, Kosuga T, Okamoto K, et al. Venous invasion as a risk factor for recurrence after gastrectomy followed by chemotherapy for stage III gastric cancer. BMC Cancer 2018;18:108. 
  34. Liebig C, Ayala G, Wilks JA, Berger DH, Albo D. Perineural invasion in cancer: a review of the literature. Cancer 2009;115:3379-3391. https://doi.org/10.1002/cncr.24396
  35. Hanaoka N, Tanabe S, Mikami T, Okayasu I, Saigenji K. Mixed-histologic-type submucosal invasive gastric cancer as a risk factor for lymph node metastasis: feasibility of endoscopic submucosal dissection. Endoscopy 2009;41:427-432.  https://doi.org/10.1055/s-0029-1214495
  36. Takizawa K, Ono H, Kakushima N, Tanaka M, Hasuike N, Matsubayashi H, et al. Risk of lymph node metastases from intramucosal gastric cancer in relation to histological types: how to manage the mixed histological type for endoscopic submucosal dissection. Gastric Cancer 2013;16:531-536.  https://doi.org/10.1007/s10120-012-0220-z
  37. Lee JH, Choi IJ, Han HS, Kim YW, Ryu KW, Yoon HM, et al. Risk of lymph node metastasis in differentiated type mucosal early gastric cancer mixed with minor undifferentiated type histology. Ann Surg Oncol 2015;22:1813-1819.  https://doi.org/10.1245/s10434-014-4167-7
  38. Sekiguchi M, Oda I, Taniguchi H, Suzuki H, Morita S, Fukagawa T, et al. Risk stratification and predictive risk-scoring model for lymph node metastasis in early gastric cancer. J Gastroenterol 2016;51:961-970.  https://doi.org/10.1007/s00535-016-1180-6
  39. Seo HS, Lee GE, Kang MG, Han KH, Jung ES, Song KY. Mixed histology is a risk factor for lymph node metastasis in early gastric cancer. J Surg Res 2019;236:271-277.  https://doi.org/10.1016/j.jss.2018.11.055
  40. Horiuchi Y, Ida S, Yamamoto N, Nunobe S, Ishizuka N, Yoshimizu S, et al. Feasibility of further expansion of the indications for endoscopic submucosal dissection in undifferentiated-type early gastric cancer. Gastric Cancer 2020;23:285-292.  https://doi.org/10.1007/s10120-019-01003-0
  41. Ha TK, An JY, Youn HK, Noh JH, Sohn TS, Kim S. Indication for endoscopic mucosal resection in early signet ring cell gastric cancer. Ann Surg Oncol 2008;15:508-513.  https://doi.org/10.1245/s10434-007-9660-9
  42. Kim BS, Oh ST, Yook JH, Kim BS. Signet ring cell type and other histologic types: differing clinical course and prognosis in T1 gastric cancer. Surgery 2014;155:1030-1035.  https://doi.org/10.1016/j.surg.2013.08.016
  43. Guo CG, Zhao DB, Liu Q, Zhou ZX, Zhao P, Wang GQ, et al. Risk factors for lymph node metastasis in early gastric cancer with signet ring cell carcinoma. J Gastrointest Surg 2015;19:1958-1965.  https://doi.org/10.1007/s11605-015-2915-z
  44. Huh CW, Jung DH, Kim JH, Lee YC, Kim H, Kim H, et al. Signet ring cell mixed histology may show more aggressive behavior than other histologies in early gastric cancer. J Surg Oncol 2013;107:124-129.  https://doi.org/10.1002/jso.23261
  45. Lee IS, Lee S, Park YS, Gong CS, Yook JH, Kim BS. Applicability of endoscopic submucosal dissection for undifferentiated early gastric cancer: mixed histology of poorly differentiated adenocarcinoma and signet ring cell carcinoma is a worse predictive factor of nodal metastasis. Surg Oncol 2017;26:8-12.  https://doi.org/10.1016/j.suronc.2016.12.001
  46. Kim YH, Park JH, Park CK, Kim JH, Lee SK, Lee YC, et al. Histologic purity of signet ring cell carcinoma is a favorable risk factor for lymph node metastasis in poorly cohesive, submucosa-invasive early gastric carcinoma. Gastric Cancer 2017;20:583-590.  https://doi.org/10.1007/s10120-016-0645-x
  47. Chu Y, Mao T, Li X, Jing X, Ren M, Huang Z, et al. Predictors of lymph node metastasis and differences between pure and mixed histologic types of early gastric signet-ring cell carcinomas. Am J Surg Pathol 2020;44:934-942.  https://doi.org/10.1097/PAS.0000000000001460
  48. Japanese Gastric Cancer Society. Regulations for the Treatment of Gastric Cancer. 15th ed. Tokyo: Kanehara Publishing; 2017.
  49. Kim JY, Kim WG, Jeon TY, Kim GH, Jeong EH, Kim DH, et al. Lymph node metastasis in early gastric cancer: evaluation of a novel method for measuring submucosal invasion and development of a nodal predicting index. Hum Pathol 2013;44:2829-2836.  https://doi.org/10.1016/j.humpath.2013.07.037
  50. Ma DW, Lee SJ, Kook MC, Park DY, Ahn S, Ryu KW, et al. The suggestion of revised criteria for endoscopic resection of differentiated-type submucosal gastric cancer. Ann Surg Oncol 2020;27:795-801.  https://doi.org/10.1245/s10434-019-08102-3
  51. Choi JY, Park YS, Jung HY, Son DH, Ahn JY, Han S, et al. Identifying predictors of lymph node metastasis after endoscopic resection in patients with minute submucosal cancer of the stomach. Surg Endosc 2015;29:1476-1483. https://doi.org/10.1007/s00464-014-3828-8
  52. Gotoda T, Yanagisawa A, Sasako M, Ono H, Nakanishi Y, Shimoda T, et al. Incidence of lymph node metastasis from early gastric cancer: estimation with a large number of cases at two large centers. Gastric Cancer 2000;3:219-225.  https://doi.org/10.1007/PL00011720
  53. Park SM, Kim BW, Kim JS, Kim YW, Kim GJ, Ryu SJ. Can endoscopic ulcerations in early gastric cancer be clearly defined before endoscopic resection? A survey among endoscopists. Clin Endosc 2017;50:473-478.  https://doi.org/10.5946/ce.2016.143
  54. Kim JM, Sohn JH, Cho MY, Kim WH, Chang HK, Jung ES, et al. Pre- and post-ESD discrepancies in clinicopathologic criteria in early gastric cancer: the NECA-Korea ESD for Early Gastric Cancer Prospective Study (N-Keep). Gastric Cancer 2016;19:1104-1113.  https://doi.org/10.1007/s10120-015-0570-4
  55. Yabuuchi Y, Takizawa K, Kakushima N, Kawata N, Yoshida M, Yamamoto Y, et al. Discrepancy between endoscopic and pathological ulcerative findings in clinical intramucosal early gastric cancer. Gastric Cancer 2021;24:691-700.  https://doi.org/10.1007/s10120-020-01150-9
  56. Shimoda T, Kushima R, Ono H. Histological features of peptic ulceration and biopsy scar of gastric ESD specimen. Stomach Intest 2013;48:16-24.
  57. Japanese Gastric Cancer Association. Japanese gastric cancer treatment guidelines 2018 (5th edition). Gastric Cancer 2021;24:1-21.  https://doi.org/10.1007/s10120-020-01042-y
  58. Takizawa K, Ono H, Hasuike N, Takashima A, Minashi K, Boku N, et al. A nonrandomized, single-arm confirmatory trial of expanded endoscopic submucosal dissection indication for undifferentiated early gastric cancer: Japan Clinical Oncology Group study (JCOG1009/1010). Gastric Cancer 2021;24:479-491.  https://doi.org/10.1007/s10120-020-01134-9
  59. Hatta W, Gotoda T, Oyama T, Kawata N, Takahashi A, Yoshifuku Y, et al. A scoring system to stratify curability after endoscopic submucosal dissection for early gastric cancer: "eCura system". Am J Gastroenterol 2017;112:874-881.  https://doi.org/10.1038/ajg.2017.95
  60. Uesugi N, Sugai T, Sugimoto R, Eizuka M, Fujita Y, Sato A, et al. Clinicopathological and molecular stability and methylation analyses of gastric papillary adenocarcinoma. Pathology 2017;49:596-603.  https://doi.org/10.1016/j.pathol.2017.07.004
  61. Lee HJ, Kim GH, Park DY, Kim YK, Jeon HK, Lee BE, et al. Endoscopic submucosal dissection for papillary adenocarcinoma of the stomach: is it really safe? Gastric Cancer 2017;20:978-986.  https://doi.org/10.1007/s10120-017-0709-6
  62. Min BH, Byeon SJ, Lee JH, Kim KM, An JY, Choi MG, et al. Lymphovascular invasion and lymph node metastasis rates in papillary adenocarcinoma of the stomach: implications for endoscopic resection. Gastric Cancer 2018;21:680-688.  https://doi.org/10.1007/s10120-017-0785-7
  63. Yasuda K, Adachi Y, Shiraishi N, Maeo S, Kitano S. Papillary adenocarcinoma of the stomach. Gastric Cancer 2000;3:33-38.  https://doi.org/10.1007/PL00011687
  64. Yu H, Fang C, Chen L, Shi J, Fan X, Zou X, et al. Worse prognosis in papillary, compared to tubular, early gastric carcinoma. J Cancer 2017;8:117-123.  https://doi.org/10.7150/jca.17326
  65. Kawamura H, Kondo Y, Osawa S, Nisida Y, Okada K, Isizu H, et al. A clinicopathologic study of mucinous adenocarcinoma of the stomach. Gastric Cancer 2001;4:83-86.  https://doi.org/10.1007/PL00011728
  66. Lee HH, Song KY, Park CH, Jeon HM. Undifferentiated-type gastric adenocarcinoma: prognostic impact of three histological types. World J Surg Oncol 2012;10:254. 
  67. Nakamura K, Eto K, Iwagami S, Ogawa K, Sawayama H, Ishimoto T, et al. Clinicopathological characteristics and prognosis of poorly cohesive cell subtype of gastric cancer. Int J Clin Oncol 2022;27:512-519.  https://doi.org/10.1007/s10147-021-02069-6
  68. Roviello F, Marano L, Ambrosio MR, Resca L, D'Ignazio A, Petrelli F, et al. Signet ring cell percentage in poorly cohesive gastric cancer patients: a potential novel predictor of survival. Eur J Surg Oncol 2022;48:561-569.  https://doi.org/10.1016/j.ejso.2021.09.003
  69. Garcia-Pelaez J, Barbosa-Matos R, Gullo I, Carneiro F, Oliveira C. Histological and mutational profile of diffuse gastric cancer: current knowledge and future challenges. Mol Oncol 2021;15:2841-2867. https://doi.org/10.1002/1878-0261.12948
  70. Kwon CH, Kim YK, Lee S, Kim A, Park HJ, Choi Y, et al. Gastric poorly cohesive carcinoma: a correlative study of mutational signatures and prognostic significance based on histopathological subtypes. Histopathology 2018;72:556-568.  https://doi.org/10.1111/his.13383
  71. Mariette C, Carneiro F, Grabsch HI, van der Post RS, Allum W, de Manzoni G, et al. Consensus on the pathological definition and classification of poorly cohesive gastric carcinoma. Gastric Cancer 2019;22:1-9.  https://doi.org/10.1007/s10120-018-0868-0
  72. Han JP, Hong SJ, Kim HK. Long-term outcomes of early gastric cancer diagnosed as mixed adenocarcinoma after endoscopic submucosal dissection. J Gastroenterol Hepatol 2015;30:316-320.  https://doi.org/10.1111/jgh.12838
  73. Park HK, Lee KY, Yoo MW, Hwang TS, Han HS. Mixed carcinoma as an independent prognostic factor in submucosal invasive gastric carcinoma. J Korean Med Sci 2016;31:866-872.  https://doi.org/10.3346/jkms.2016.31.6.866
  74. Horiuchi Y, Fujisaki J, Yamamoto N, Ishizuka N, Ishiyama A, Yoshio T, et al. Undifferentiated-type predominant mixed-type early gastric cancer is a significant risk factor for requiring additional surgeries after endoscopic submucosal dissection. Sci Rep 2020;10:6748. 
  75. Ozeki Y, Hirasawa K, Sawada A, Ikeda R, Nishio M, Fukuchi T, et al. Mixed histology poses a greater risk for noncurative endoscopic resection in early gastric cancers regardless of the predominant histologic types. Eur J Gastroenterol Hepatol 2021;32:186-193.  https://doi.org/10.1097/MEG.0000000000001894
  76. Shin DH, Kim GH, Lee BE, Lee JW, Ha DW, Jeon HK, et al. Clinicopathologic features of early gastric carcinoma with lymphoid stroma and feasibility of endoscopic submucosal dissection. Surg Endosc 2017;31:4156-4164.  https://doi.org/10.1007/s00464-017-5470-8
  77. Iwasaki K, Suda T, Takano Y, Ohno Y, Yamada E, Okazaki N, et al. Postoperative outcomes of gastric carcinoma with lymphoid stroma. World J Surg Oncol 2020;18:102. 
  78. Huh CW, Jung DH, Kim H, Kim H, Youn YH, Park H, et al. Clinicopathologic features of gastric carcinoma with lymphoid stroma in early gastric cancer. J Surg Oncol 2016;114:769-772.  https://doi.org/10.1002/jso.24385
  79. Inagawa S, Shimazaki J, Hori M, Yoshimi F, Adachi S, Kawamoto T, et al. Hepatoid adenocarcinoma of the stomach. Gastric Cancer 2001;4:43-52.  https://doi.org/10.1007/s101200100016
  80. Roh JH, Srivastava A, Lauwers GY, An J, Jang KT, Park CK, et al. Micropapillary carcinoma of stomach: a clinicopathologic and immunohistochemical study of 11 cases. Am J Surg Pathol 2010;34:1139-1146.  https://doi.org/10.1097/PAS.0b013e3181e7043b
  81. Fujita T, Gotohda N, Kato Y, Kinoshita T, Takahashi S, Konishi M, et al. Clinicopathological features of stomach cancer with invasive micropapillary component. Gastric Cancer 2012;15:179-187.  https://doi.org/10.1007/s10120-011-0094-5
  82. Benedict MA, Lauwers GY, Jain D. Gastric adenocarcinoma of the fundic gland type: update and literature review. Am J Clin Pathol 2018;149:461-473.  https://doi.org/10.1093/ajcp/aqy019
  83. Miyazawa M, Matsuda M, Yano M, Hara Y, Arihara F, Horita Y, et al. Gastric adenocarcinoma of the fundic gland (chief cell-predominant type): a review of endoscopic and clinicopathological features. World J Gastroenterol 2016;22:10523-10531.  https://doi.org/10.3748/wjg.v22.i48.10523
  84. Agaimy A, Rau TT, Hartmann A, Stoehr R. SMARCB1 (INI1)-negative rhabdoid carcinomas of the gastrointestinal tract: clinicopathologic and molecular study of a highly aggressive variant with literature review. Am J Surg Pathol 2014;38:910-920.  https://doi.org/10.1097/PAS.0000000000000173
  85. Willems S, Carneiro F, Geboes K. Gastric carcinoma with osteoclast-like giant cells and lymphoepithelioma-like carcinoma of the stomach: two of a kind? Histopathology 2005;47:331-333.  https://doi.org/10.1111/j.1365-2559.2005.02135.x
  86. Woo HY, Bae YS, Kim JH, Lee SK, Lee YC, Cheong JH, et al. Distinct expression profile of key molecules in crawling-type early gastric carcinoma. Gastric Cancer 2017;20:612-619.  https://doi.org/10.1007/s10120-016-0652-y
  87. Okamoto N, Kawachi H, Yoshida T, Kitagaki K, Sekine M, Kojima K, et al. "Crawling-type" adenocarcinoma of the stomach: a distinct entity preceding poorly differentiated adenocarcinoma. Gastric Cancer 2013;16:220-232. https://doi.org/10.1007/s10120-012-0173-2
  88. Ushiku T, Kunita A, Kuroda R, Shinozaki-Ushiku A, Yamazawa S, Tsuji Y, et al. Oxyntic gland neoplasm of the stomach: expanding the spectrum and proposal of terminology. Mod Pathol 2020;33:206-216.  https://doi.org/10.1038/s41379-019-0338-1
  89. Tsuji Y, Ushiku T, Shinozaki T, Yamashita H, Seto Y, Fukayama M, et al. Risk for lymph node metastasis in Epstein-Barr virus-associated gastric carcinoma with submucosal invasion. Dig Endosc 2021;33:592-597.  https://doi.org/10.1111/den.13823
  90. Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma: an attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 1965;64:31-49.  https://doi.org/10.1111/apm.1965.64.1.31
  91. Park DY, Srivastava A, Kim GH, Mino-Kenudson M, Deshpande V, Zukerberg LR, et al. Adenomatous and foveolar gastric dysplasia: distinct patterns of mucin expression and background intestinal metaplasia. Am J Surg Pathol 2008;32:524-533.  https://doi.org/10.1097/PAS.0b013e31815b890e
  92. Choi WT, Brown I, Ushiku T, Yozu M, Setia N, Srivastava A, et al. Gastric pyloric gland adenoma: a multicentre clinicopathological study of 67 cases. Histopathology 2018;72:1007-1014.  https://doi.org/10.1111/his.13460
  93. Kim JM, Sohn JH, Cho MY, Kim WH, Chang HK, Jung ES, et al. Inter-observer reproducibility in the pathologic diagnosis of gastric intraepithelial neoplasia and early carcinoma in endoscopic submucosal dissection specimens: a multi-center study. Cancer Res Treat 2019;51:1568-1577.  https://doi.org/10.4143/crt.2019.019
  94. Kim JM, Cho MY, Sohn JH, Kang DY, Park CK, Kim WH, et al. Diagnosis of gastric epithelial neoplasia: dilemma for Korean pathologists. World J Gastroenterol 2011;17:2602-2610.  https://doi.org/10.3748/wjg.v17.i21.2602
  95. Watanabe Y, Shimizu M, Itoh T, Nagashima K. Intraglandular necrotic debris in gastric biopsy and surgical specimens. Ann Diagn Pathol 2001;5:141-147.  https://doi.org/10.1053/adpa.2001.25405
  96. Choi IJ, Kook MC, Kim YI, Cho SJ, Lee JY, Kim CG, et al. Helicobacter pylori therapy for the prevention of metachronous gastric cancer. N Engl J Med 2018;378:1085-1095.  https://doi.org/10.1056/NEJMoa1708423
  97. Ono H, Yao K, Fujishiro M, Oda I, Uedo N, Nimura S, et al. Guidelines for endoscopic submucosal dissection and endoscopic mucosal resection for early gastric cancer (second edition). Dig Endosc 2021;33:4-20.  https://doi.org/10.1111/den.13883
  98. Shitara K, Bang YJ, Iwasa S, Sugimoto N, Ryu MH, Sakai D, et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med 2020;382:2419-2430.  https://doi.org/10.1056/NEJMoa2004413
  99. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas [Internet]. Silver Spring (MD): U.S. Food and Drug Administration; 2021 [cited 2022 Dec 1]. Available from: https:// www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecannxki-her2-positive-gastric-adenocarcinomas.
  100. Ajani JA, D'Amico TA, Bentrem DJ, Chao J, Cooke D, Corvera C, et al. Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2022;20:167-192.  https://doi.org/10.6004/jnccn.2022.0008
  101. Hofmann M, Stoss O, Shi D, Buttner R, van de Vijver M, Kim W, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 2008;52:797-805.  https://doi.org/10.1111/j.1365-2559.2008.03028.x
  102. Ahn S, Ahn S, Van Vrancken M, Lee M, Ha SY, Lee H, et al. Ideal number of biopsy tumor fragments for predicting HER2 status in gastric carcinoma resection specimens. Oncotarget 2015;6:38372-38380.  https://doi.org/10.18632/oncotarget.5368
  103. Lee HS, Kim WH, Kwak Y, Koh J, Bae JM, Kim KM, et al. Molecular testing for gastrointestinal cancer. J Pathol Transl Med 2017;51:103-121.  https://doi.org/10.4132/jptm.2017.01.24
  104. Bartley AN, Washington MK, Colasacco C, Ventura CB, Ismaila N, Benson AB 3rd, et al. HER2 testing and clinical decision making in gastroesophageal adenocarcinoma: guideline from the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. J Clin Oncol 2017;35:446-464.  https://doi.org/10.1200/JCO.2016.69.4836
  105. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 2013;31:3997-4013. https://doi.org/10.1200/JCO.2013.50.9984
  106. Van Cutsem E, Bang YJ, Feng-Yi F, Xu JM, Lee KW, Jiao SC, et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer 2015;18:476-484.  https://doi.org/10.1007/s10120-014-0402-y
  107. Tsapralis D, Panayiotides I, Peros G, Liakakos T, Karamitopoulou E. Human epidermal growth factor receptor-2 gene amplification in gastric cancer using tissue microarray technology. World J Gastroenterol 2012;18:150-155.  https://doi.org/10.3748/wjg.v18.i2.150
  108. Liu W, Zhong S, Chen J, Yu Y. HER-2/neu overexpression is an independent prognostic factor for intestinal-type and early-stage gastric cancer patients. J Clin Gastroenterol 2012;46:e31-e37.  https://doi.org/10.1097/MCG.0b013e31823457ea
  109. Lee HE, Park KU, Yoo SB, Nam SK, Park DJ, Kim HH, et al. Clinical significance of intratumoral HER2 heterogeneity in gastric cancer. Eur J Cancer 2013;49:1448-1457.  https://doi.org/10.1016/j.ejca.2012.10.018
  110. Kim MA, Lee HJ, Yang HK, Bang YJ, Kim WH. Heterogeneous amplification of ERBB2 in primary lesions is responsible for the discordant ERBB2 status of primary and metastatic lesions in gastric carcinoma. Histopathology 2011;59:822-831.  https://doi.org/10.1111/j.1365-2559.2011.04012.x
  111. Peng Z, Zou J, Zhang X, Yang Y, Gao J, Li Y, et al. HER2 discordance between paired primary gastric cancer and metastasis: a meta-analysis. Chin J Cancer Res 2015;27:163-171. 
  112. Kim JH, Kim MA, Lee HS, Kim WH. Comparative analysis of protein expressions in primary and metastatic gastric carcinomas. Hum Pathol 2009;40:314-322.  https://doi.org/10.1016/j.humpath.2008.07.013
  113. Fusco N, Rocco EG, Del Conte C, Pellegrini C, Bulfamante G, Di Nuovo F, et al. HER2 in gastric cancer: a digital image analysis in pre-neoplastic, primary and metastatic lesions. Mod Pathol 2013;26:816-824.  https://doi.org/10.1038/modpathol.2012.228
  114. Geng Y, Chen X, Qiu J, Zhou Y, Wang J, Liu L, et al. Human epidermal growth factor receptor-2 expression in primary and metastatic gastric cancer. Int J Clin Oncol 2014;19:303-311.  https://doi.org/10.1007/s10147-013-0542-9
  115. Kochi M, Fujii M, Masuda S, Kanamori N, Mihara Y, Funada T, et al. Differing deregulation of HER2 in primary gastric cancer and synchronous related metastatic lymph nodes. Diagn Pathol 2013;8:191. 
  116. Ieni A, Barresi V, Rigoli L, Caruso RA, Tuccari G. HER2 status in premalignant, early, and advanced neoplastic lesions of the stomach. Dis Markers 2015;2015:234851. 
  117. Zhao W, Sun L, Dong G, Wang X, Jia Y, Tong Z. Receptor conversion impacts outcomes of different molecular subtypes of primary breast cancer. Ther Adv Med Oncol 2021;13:17588359211012982. 
  118. Garrido-Ramos MA. Satellite DNA: an evolving topic. Genes (Basel) 2017;8:230. 
  119. Luchini C, Bibeau F, Ligtenberg MJ, Singh N, Nottegar A, Bosse T, et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann Oncol 2019;30:1232-1243.  https://doi.org/10.1093/annonc/mdz116
  120. Li K, Luo H, Huang L, Luo H, Zhu X. Microsatellite instability: a review of what the oncologist should know. Cancer Cell Int 2020;20:16. 
  121. Jiricny J. Postreplicative mismatch repair. Cold Spring Harb Perspect Biol 2013;5:a012633. 
  122. Ma J, Setton J, Lee NY, Riaz N, Powell SN. The therapeutic significance of mutational signatures from DNA repair deficiency in cancer. Nat Commun 2018;9:3292. 
  123. Peltomaki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol 2003;21:1174-1179.  https://doi.org/10.1200/JCO.2003.04.060
  124. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014;513:202-209. https://doi.org/10.1038/nature13480
  125. Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med 2015;21:449-456.  https://doi.org/10.1038/nm.3850
  126. Setia N, Agoston AT, Han HS, Mullen JT, Duda DG, Clark JW, et al. A protein and mRNA expression-based classification of gastric cancer. Mod Pathol 2016;29:772-784.  https://doi.org/10.1038/modpathol.2016.55
  127. Ahn S, Lee SJ, Kim Y, Kim A, Shin N, Choi KU, et al. High-throughput protein and mRNA expression-based classification of gastric cancers can identify clinically distinct subtypes, concordant with recent molecular classifications. Am J Surg Pathol 2017;41:106-115.  https://doi.org/10.1097/PAS.0000000000000756
  128. Choi YY, Kim H, Shin SJ, Kim HY, Lee J, Yang HK, et al. Microsatellite instability and programmed cell death-ligand 1 expression in stage II/III gastric cancer: post hoc analysis of the CLASSIC randomized controlled study. Ann Surg 2019;270:309-316.  https://doi.org/10.1097/SLA.0000000000002803
  129. Guastadisegni C, Colafranceschi M, Ottini L, Dogliotti E. Microsatellite instability as a marker of prognosis and response to therapy: a meta-analysis of colorectal cancer survival data. Eur J Cancer 2010;46:2788-2798.  https://doi.org/10.1016/j.ejca.2010.05.009
  130. Kim ST, Cristescu R, Bass AJ, Kim KM, Odegaard JI, Kim K, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med 2018;24:1449-1458.  https://doi.org/10.1038/s41591-018-0101-z
  131. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509-2520.  https://doi.org/10.1056/NEJMoa1500596
  132. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409-413.  https://doi.org/10.1126/science.aan6733
  133. Ratti M, Lampis A, Hahne JC, Passalacqua R, Valeri N. Microsatellite instability in gastric cancer: molecular bases, clinical perspectives, and new treatment approaches. Cell Mol Life Sci 2018;75:4151-4162.  https://doi.org/10.1007/s00018-018-2906-9
  134. Jang M, Kwon Y, Kim H, Kim H, Min BS, Park Y, et al. Microsatellite instability test using peptide nucleic acid probe-mediated melting point analysis: a comparison study. BMC Cancer 2018;18:1218. 
  135. Murphy KM, Zhang S, Geiger T, Hafez MJ, Bacher J, Berg KD, et al. Comparison of the microsatellite instability analysis system and the Bethesda panel for the determination of microsatellite instability in colorectal cancers. J Mol Diagn 2006;8:305-311.  https://doi.org/10.2353/jmoldx.2006.050092
  136. Berg KD, Glaser CL, Thompson RE, Hamilton SR, Griffin CA, Eshleman JR. Detection of microsatellite instability by fluorescence multiplex polymerase chain reaction. J Mol Diagn 2000;2:20-28.  https://doi.org/10.1016/S1525-1578(10)60611-3
  137. Deschoolmeester V, Baay M, Wuyts W, Van Marck E, Van Damme N, Vermeulen P, et al. Detection of microsatellite instability in colorectal cancer using an alternative multiplex assay of quasi-monomorphic mononucleotide markers. J Mol Diagn 2008;10:154-159.  https://doi.org/10.2353/jmoldx.2008.070087
  138. Shia J, Ellis NA, Klimstra DS. The utility of immunohistochemical detection of DNA mismatch repair gene proteins. Virchows Arch 2004;445:431-441.  https://doi.org/10.1007/s00428-004-1090-5
  139. McCarthy AJ, Capo-Chichi JM, Spence T, Grenier S, Stockley T, Kamel-Reid S, et al. Heterogenous loss of mismatch repair (MMR) protein expression: a challenge for immunohistochemical interpretation and microsatellite instability (MSI) evaluation. J Pathol Clin Res 2019;5:115-129.  https://doi.org/10.1002/cjp2.120
  140. Renkonen E, Zhang Y, Lohi H, Salovaara R, Abdel-Rahman WM, Nilbert M, et al. Altered expression of MLH1, MSH2, and MSH6 in predisposition to hereditary nonpolyposis colorectal cancer. J Clin Oncol 2003;21:3629-3637.  https://doi.org/10.1200/JCO.2003.03.181
  141. Graham RP, Kerr SE, Butz ML, Thibodeau SN, Halling KC, Smyrk TC, et al. Heterogenous MSH6 loss is a result of microsatellite instability within MSH6 and occurs in sporadic and hereditary colorectal and endometrial carcinomas. Am J Surg Pathol 2015;39:1370-1376. https://doi.org/10.1097/PAS.0000000000000459
  142. . Jansson A, Arbman G, Zhang H, Sun XF. Combined deficiency of hMLH1, hMSH2, hMSH3 and hMSH6 is an independent prognostic factor in colorectal cancer. Int J Oncol 2003;22:41-49.  https://doi.org/10.3892/ijo.22.1.41
  143. Ruszkiewicz A, Bennett G, Moore J, Manavis J, Rudzki B, Shen L, et al. Correlation of mismatch repair genes immunohistochemistry and microsatellite instability status in HNPCC-associated tumours. Pathology 2002;34:541-547.  https://doi.org/10.1080/0031302021000035965-2
  144. Fukayama M, Abe H, Kunita A, Shinozaki-Ushiku A, Matsusaka K, Ushiku T, et al. Thirty years of EpsteinBarr virus-associated gastric carcinoma. Virchows Arch 2020;476:353-365.  https://doi.org/10.1007/s00428-019-02724-4
  145. Chang MS, Kim DH, Roh JK, Middeldorp JM, Kim YS, Kim S, et al. Epstein-Barr virus-encoded BARF1 promotes proliferation of gastric carcinoma cells through regulation of NF-κB. J Virol 2013;87:10515-10523.  https://doi.org/10.1128/JVI.00955-13
  146. Hoebe EK, Le Large TY, Greijer AE, Middeldorp JM. BamHI-A rightward frame 1, an Epstein-Barr virus-encoded oncogene and immune modulator. Rev Med Virol 2013;23:367-383.  https://doi.org/10.1002/rmv.1758
  147. zur Hausen A, Brink AA, Craanen ME, Middeldorp JM, Meijer CJ, van den Brule AJ. Unique transcription pattern of Epstein-Barr virus (EBV) in EBV-carrying gastric adenocarcinomas: expression of the transforming BARF1 gene. Cancer Res 2000;60:2745-2748.  https://doi.org/10.1016/S0016-5085(00)82313-6
  148. Kang GH, Lee S, Kim WH, Lee HW, Kim JC, Rhyu MG, et al. Epstein-barr virus-positive gastric carcinoma demonstrates frequent aberrant methylation of multiple genes and constitutes CpG island methylator phenotype-positive gastric carcinoma. Am J Pathol 2002;160:787-794.  https://doi.org/10.1016/S0002-9440(10)64901-2
  149. Strong MJ, Xu G, Coco J, Baribault C, Vinay DS, Lacey MR, et al. Differences in gastric carcinoma microenvironment stratify according to EBV infection intensity: implications for possible immune adjuvant therapy. PLoS Pathog 2013;9:e1003341. 
  150. Gu L, Chen M, Guo D, Zhu H, Zhang W, Pan J, et al. PD-L1 and gastric cancer prognosis: a systematic review and meta-analysis. PLoS One 2017;12:e0182692. 
  151. Park JH, Kim EK, Kim YH, Kim JH, Bae YS, Lee YC, et al. Epstein-Barr virus positivity, not mismatch repair-deficiency, is a favorable risk factor for lymph node metastasis in submucosa-invasive early gastric cancer. Gastric Cancer 2016;19:1041-1051.  https://doi.org/10.1007/s10120-015-0565-1
  152. Cheng Y, Zhou X, Xu K, Huang J, Huang Q. Very low risk of lymph node metastasis in Epstein-Barr virus-associated early gastric carcinoma with lymphoid stroma. BMC Gastroenterol 2020;20:273. 
  153. Yoon CJ, Chang MS, Kim DH, Kim W, Koo BK, Yun SC, et al. Epstein-Barr virus-encoded miR-BART5-5p upregulates PD-L1 through PIAS3/pSTAT3 modulation, worsening clinical outcomes of PD-L1-positive gastric carcinomas. Gastric Cancer 2020;23:780-795.  https://doi.org/10.1007/s10120-020-01059-3
  154. Lee HS, Chang MS, Yang HK, Lee BL, Kim WH. Epstein-Barr virus-positive gastric carcinoma has a distinct protein expression profile in comparison with Epstein-Barr virus-negative carcinoma. Clin Cancer Res 2004;10:1698-1705.  https://doi.org/10.1158/1078-0432.CCR-1122-3
  155. Longnecker RM, Kieff E, Cohen JI. Esptein-Barr virus. In: Knipe DM, Howley PM, eds. Fields Virology. 6th ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2013:1898-1959.
  156. Boger C, Kruger S, Behrens HM, Bock S, Haag J, Kalthoff H, et al. Epstein-Barr virus-associated gastric cancer reveals intratumoral heterogeneity of PIK3CA mutations. Ann Oncol 2017;28:1005-1014.  https://doi.org/10.1093/annonc/mdx047
  157. Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med 2012;366:2517-2519.  https://doi.org/10.1056/NEJMe1205943
  158. Kwak Y, Seo AN, Lee HE, Lee HS. Tumor immune response and immunotherapy in gastric cancer. J Pathol Transl Med 2020;54:20-33.  https://doi.org/10.4132/jptm.2019.10.08
  159. Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, 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 Oncol 2018;4:e180013.
  160. Shitara K, Ozguroglu M, Bang YJ, Di Bartolomeo M, Mandala M, Ryu MH, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet 2018;392:123-133.  https://doi.org/10.1016/S0140-6736(18)31257-1
  161. Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 2021;398:27-40.  https://doi.org/10.1016/S0140-6736(21)00797-2
  162. DAKO Agilent Technologies. Interpretation Manual: Gastric or Gastroesophageal Junction Adenocarcinoma. PD-L1 IHC 22C3 pharmDx Interpretation Manual: Gastric or Gastroesophageal Juction Adenocarcinoma. Santa Clara (CA): DAKO Agilent Technologies; 2018.
  163. Yang JH, Kim H, Roh SY, Lee MA, Park JM, Lee HH, et al. Discordancy and changes in the pattern of programmed death ligand 1 expression before and after platinum-based chemotherapy in metastatic gastric cancer. Gastric Cancer 2019;22:147-154.  https://doi.org/10.1007/s10120-018-0842-x
  164. Zhou KI, Peterson B, Serritella A, Thomas J, Reizine N, Moya S, et al. Spatial and temporal heterogeneity of PD-L1 expression and tumor mutational burden in gastroesophageal adenocarcinoma at baseline diagnosis and after chemotherapy. Clin Cancer Res 2020;26:6453-6463.  https://doi.org/10.1158/1078-0432.ccr-20-2085
  165. Son SM, Woo CG, Kim DH, Yun HY, Kim H, Kim HK, et al. Distinct tumor immune microenvironments in primary and metastatic lesions in gastric cancer patients. Sci Rep 2020;10:14293. 
  166. Marchio C, Scaltriti M, Ladanyi M, Iafrate AJ, Bibeau F, Dietel M, et al. ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Ann Oncol 2019;30:1417-1427.  https://doi.org/10.1093/annonc/mdz204
  167. Catenacci DV, Rasco D, Lee J, Rha SY, Lee KW, Bang YJ, et al. Phase I escalation and expansion study of bemarituzumab (FPA144) in patients with advanced solid tumors and FGFR2b-selected gastroesophageal adenocarcinoma. J Clin Oncol 2020;38:2418-2426.  https://doi.org/10.1200/JCO.19.01834
  168. Maron SB, Alpert L, Kwak HA, Lomnicki S, Chase L, Xu D, et al. Targeted therapies for targeted populations: anti-EGFR treatment for EGFR-amplified gastroesophageal adenocarcinoma. Cancer Discov 2018;8:696-713.  https://doi.org/10.1158/2159-8290.CD-17-1260
  169. Lee J, Kim ST, Kim K, Lee H, Kozarewa I, Mortimer PG, et al. Tumor genomic profiling guides patients with metastatic gastric cancer to targeted treatment: the VIKTORY Umbrella Trial. Cancer Discov 2019;9:1388-1405.  https://doi.org/10.1158/2159-8290.CD-19-0442
  170. Smyth EC, Cafferkey C, Loehr A, Waddell T, Begum R, Peckitt C, et al. Genomic loss of heterozygosity and survival in the REAL3 trial. Oncotarget 2018;9:36654-36665.  https://doi.org/10.18632/oncotarget.26336
  171. Nakamura Y, Kawazoe A, Lordick F, Janjigian YY, Shitara K. Biomarker-targeted therapies for advanced-stage gastric and gastro-oesophageal junction cancers: an emerging paradigm. Nat Rev Clin Oncol 2021;18:473-487.  https://doi.org/10.1038/s41571-021-00492-2
  172. van Grieken NC, Aoyama T, Chambers PA, Bottomley D, Ward LC, Inam I, et al. KRAS and BRAF mutations are rare and related to DNA mismatch repair deficiency in gastric cancer from the East and the West: results from a large international multicentre study. Br J Cancer 2013;108:1495-1501.  https://doi.org/10.1038/bjc.2013.109
  173. Wen Z, Xiong D, Zhang S, Liu J, Li B, Li R, et al. Case report: RAB10-ALK: a novel ALK fusion in a patient with gastric cancer. Front Oncol 2021;11:645370. 
  174. Lee J, Lee SE, Kang SY, Do IG, Lee S, Ha SY, et al. Identification of ROS1 rearrangement in gastric adenocarcinoma. Cancer 2013;119:1627-1635.  https://doi.org/10.1002/cncr.27967
  175. Fancello L, Gandini S, Pelicci PG, Mazzarella L. Tumor mutational burden quantification from targeted gene panels: major advancements and challenges. J Immunother Cancer 2019;7:183.
  176. Lee KW, Van Cutsem E, Bang YJ, Fuchs CS, Kudaba I, Garrido M, et al. Association of tumor mutational burden with efficacy of pembrolizumab+/-chemotherapy as first-line therapy for gastric cancer in the phase III KEYNOTE-062 study. Clin Cancer Res 2022;28:3489-3498.  https://doi.org/10.1158/1078-0432.CCR-22-0121
  177. Kang SY, Kim DG, Ahn S, Ha SY, Jang KT, Kim KM. Comparative analysis of microsatellite instability by next-generation sequencing, MSI PCR and MMR immunohistochemistry in 1942 solid cancers. Pathol Res Pract 2022;233:153874. 
  178. Ratovomanana T, Cohen R, Svrcek M, Renaud F, Cervera P, Siret A, et al. Performance of next-generation sequencing for the detection of microsatellite instability in colorectal cancer with deficient DNA mismatch repair. Gastroenterology 2021;161:814-826.e7.  https://doi.org/10.1053/j.gastro.2021.05.007
  179. Ascierto PA, Bifulco C, Palmieri G, Peters S, Sidiropoulos N. Preanalytic variables and tissue stewardship for reliable next-generation sequencing (NGS) clinical analysis. J Mol Diagn 2019;21:756-767.  https://doi.org/10.1016/j.jmoldx.2019.05.004
  180. Koh J, Lee KW, Nam SK, Seo AN, Kim JW, Kim JW, et al. Development and validation of an easy-to-implement, practical algorithm for the identification of molecular subtypes of gastric cancer: prognostic and therapeutic implications. Oncologist 2019;24:e1321-e1330.  https://doi.org/10.1634/theoncologist.2019-0058
  181. Ramos MF, Pereira MA, Amorim LC, de Mello ES, Faraj SF, Ribeiro U, et al. Gastric cancer molecular classification and adjuvant therapy: Is there a different benefit according to the subtype? J Surg Oncol 2020;121:804-813.   https://doi.org/10.1002/jso.25792