Updates in Surgery

, Volume 70, Issue 2, pp 225–232 | Cite as

Clinical impact of molecular classifications in gastric cancer

  • Daniele MarrelliEmail author
  • Karol Polom
  • Alessandro Neri
  • Franco Roviello
Review Article
Part of the following topical collections:
  1. Gastric Cancer Surgery


Treatment options to gastric cancer (GC) have been changing in recent years from a standard to a tailored approach. Different individualized procedures can range from endoscopic resection, D2 with open or minimally invasive approach, to neo-adjuvant therapy followed by extended surgery. In more advanced stages, a combined approach with the inclusion of intraperitoneal chemo-hyperthermia (HIPEC) may represent a new advanced option. The inclusion of histological type according to Laurén classification in the flowchart of treatment could increase both accuracy and effectiveness of such tailored approach. New molecular classifications of GC have been introduced recently and translational clinical studies are ongoing. These classifications are expected to be included in multidisciplinary treatment of GC. In particular, in the group with microsatellite instability a less extended lymphadenectomy may be proposed. Also tailored neo-adjuvant treatment may be proposed according to molecular classifications. The group of patients with epithelial-to-mesenchymal transition shows very high propensity to peritoneal dissemination, as well as N-metastases, and may benefit from prophylactic HIPEC and extended lymphadenectomy when confirmed in prospective trials.


Stomach cancer Multimodality approach Tailored treatment Lauren histotype Translational research Mismatch repair deficiency 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

All procedures followed were in accordance with the Ethical Standards of the Responsible Committee on Human Experimentation (independent Scientific Committe of Siena University) and with the Helsinki declaration of 1975 and revised in 2008.

Informed consent

Informed consent was obtained from all patients for being included in the study. Additional written informed consent for the treatment of personal and sensible data was obtained from all patients prior to the data collection and evaluation.


  1. 1.
    Marrelli D, Polom K, de Manzoni G, Morgagni P, Baiocchi GL, Roviello F (2015) Multimodal treatment of gastric cancer in the west: where are we going? World J Gastroenterol 21(26):7954CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127(12):2893–2917. CrossRefPubMedGoogle Scholar
  3. 3.
    Japanese Gastric Cancer Association (2017) Japanese gastric cancer treatment guidelines 2014 (ver. 4). Gastric Cancer 20:1–19CrossRefGoogle Scholar
  4. 4.
    Smyth EC, Verheij M, Allum W, Cunningham D, Cervantes A, Arnold D, ESMO Guidelines Committee (2016) Gastric cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 27(suppl 5):v38–v49CrossRefPubMedGoogle Scholar
  5. 5.
    Lee JH, Kim JG, Jung HK et al (2014) Clinical practice guidelines for gastric cancer in Korea: an evidence-based approach. J Gastric Cancer 14:87–104CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    De Manzoni G, Marrelli D, Baiocchi GL et al (2017) The italian research group for gastric cancer (GIRCG) guidelines for gastric cancer staging and treatment: 2015. Gastric Cancer 20:20–30CrossRefPubMedGoogle Scholar
  7. 7.
    Tokunaga M, Ohyama S, Hiki N, Fukunaga T, Aikou S, Yamaguchi T (2010) Can superextended lymph node dissection be justified for gastric cancer with pathologically positive para-aortic lymph nodes? Ann Surg Oncol 17:2031–2036CrossRefPubMedGoogle Scholar
  8. 8.
    Roviello F, Pedrazzani C, Marrelli D, Di Leo A, Caruso S, Giacopuzzi S, Corso G, de Manzoni G (2010) Super-extended (D3) lymphadenectomy in advanced gastric cancer. Eur J Surg Oncol 36:439–446CrossRefPubMedGoogle Scholar
  9. 9.
    Eom BW, Joo J, Kim YW, Park B, Park JY, Yoon HM, Lee JH, Ryu KW (2013) Is there any role of additional retropancreatic lymph node dissection on D2 gastrectomy for advanced gastric cancer? Ann Surg Oncol 20:2669–2675CrossRefPubMedGoogle Scholar
  10. 10.
    Kodera Y, Kobayashi D, Tanaka C, Fujiwara M (2015) Gastric adenocarcinoma with para-aortic lymph node metastasis: a borderline resectable cancer? Surg Today 45(9):1082–1090CrossRefPubMedGoogle Scholar
  11. 11.
    Morita S, Fukagawa T, Fujiwara H, Katai H (2016) The clinical significance of para-aortic nodal dissection for advanced gastric cancer. Eur J Surg Oncol 42:1448–1454CrossRefPubMedGoogle Scholar
  12. 12.
    Marrelli D, Ferrara F, Giacopuzzi S, Morgagni P, Di Leo A, De Franco L, Pedrazzani C, Saragoni L, De Manzoni G, Roviello F (2017) Incidence and prognostic value of metastases to “posterior” and para-aortic lymph nodes in resectable gastric cancer. Ann Surg Oncol 24(8):2273–2280. CrossRefPubMedGoogle Scholar
  13. 13.
    Han DS, Suh YS, Kong SH, Lee HJ, Choi Y, Aikou S, Sano T, Park BJ, Kim WH, Yang HK (2012) Nomogram predicting long-term survival after d2 gastrectomy for gastric cancer. J Clin Oncol 30:3834–3840CrossRefPubMedGoogle Scholar
  14. 14.
    Marrelli D, Morgagni P, de Manzoni G, Marchet A, Baiocchi GL, Giacopuzzi S, Coniglio A, Mocellin S, Saragoni L, Roviello F, Italian Research Group for Gastric Cancer (2015) External validation of a score predictive of recurrence after radical surgery for non-cardia gastric cancer: results of a follow-up study. J Am Coll Surg 221:280–290CrossRefGoogle Scholar
  15. 15.
    Marrelli D, Morgagni P, de Manzoni G, Coniglio A, Marchet A, Saragoni L, Tiberio G, Roviello F; Italian Research Group for Gastric Cancer (IRGGC) (2012) Prognostic value of the 7th AJCC/UICC TNM classification of noncardia gastric cancer: analysis of a large series from specialized Western centers. Ann Surg 255(3):486–491. CrossRefGoogle Scholar
  16. 16.
    Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR; Upper Gastrointestinal Clinical Studies Group of the National Cancer Research Institute of the United Kingdom (2008) Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 358:36–46. CrossRefGoogle Scholar
  17. 17.
    Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P (2011) Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol 29:1715–1721. CrossRefPubMedGoogle Scholar
  18. 18.
    Al-Batran SE, Hofheinz RD, Pauligk C et al (2016) Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol 17(12):1697–1708. CrossRefPubMedGoogle Scholar
  19. 19.
    Polom K, Marano L, Roviello G, Petrioli R, Piagnerelli R, de Franco L, Marrelli D, Roviello F (2016) Evolution and emerging future of cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion in gastric cancer: from treating the incurable to preventing recurrence. Int J Hyperth 32(2):173–179. CrossRefGoogle Scholar
  20. 20.
    Glehen O, Passot G, Villeneuve L, Vaudoyer D, Bin-Dorel S, Boschetti G, Piaton E, Garofalo A (2014) GASTRICHIP: d2 resection and hyperthermic intraperitoneal chemotherapy in locally advanced gastric carcinoma: a randomized and multicenter phase III study. BMC Cancer 14:183. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Cancer Genome Atlas Research Network (2014) Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513(7517):202–209. CrossRefGoogle Scholar
  22. 22.
    Cristescu R, Lee J, Nebozhyn M et al (2015) Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Nat Med 21(5):449–456. CrossRefPubMedGoogle Scholar
  23. 23.
    Marrelli D, Roviello F, de Manzoni G, Morgagni P, Di Leo A, Saragoni L, De Stefano A, Folli S, Cordiano C, Pinto E, Italian Research Group for Gastric Cancer (2002) Different patterns of recurrence in gastric cancer depending on Lauren’s histological type: longitudinal study. World J Surg 26(9):1160–1165. CrossRefGoogle Scholar
  24. 24.
    Wu H, Rusiecki JA, Zhu K, Potter J, Devesa SS (2009) Stomach carcinoma incidence patterns in the United States by histologic type and anatomic site. Cancer Epidemiol Biomarkers Prev 18(7):1945–1952. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Laurén PA, Nevalainen TJ (1993) Epidemiology of intestinal and diffuse types of gastric carcinoma. A time-trend study in Finland with comparison between studies from high- and low-risk areas. Cancer 71(10):2926–2933CrossRefPubMedGoogle Scholar
  26. 26.
    Henson DE, Dittus C, Younes M, Nguyen H, Albores-Saavedra J (2004) Differential trends in the intestinal and diffuse types of gastric carcinoma in the United States, 1973-2000: increase in the signet ring cell type. Arch Pathol Lab Med 128(7):765–770PubMedGoogle Scholar
  27. 27.
    Anderson WF, Camargo MC, Fraumeni JF Jr, Correa P, Rosenberg PS, Rabkin CS (2010) Age-specific trends in incidence of noncardia gastric cancer in US adults. JAMA 303(17):1723–1728. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Marrelli D, Pedrazzani C, Morgagni P, de Manzoni G, Pacelli F, Coniglio A, Marchet A, Saragoni L, Giacopuzzi S, Roviello F and Italian Research Group for Gastric Cancer (2011) Changing clinical and pathological features of gastric cancer over time. Br J Surg 98(9):1273–1283. CrossRefGoogle Scholar
  29. 29.
    Marrelli D, De Stefano A, de Manzoni G, Morgagni P, Di Leo A, Roviello F (2005) Prediction of recurrence after radical surgery for gastric cancer: a scoring system obtained from a prospective multicenter study. Ann Surg 241(2):247–255. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Kattan MW, Karpeh MS, Mazumdar M, Brennan MF (2003) Postoperative nomogram for disease-specific survival after an R0 resection for gastric carcinoma. J Clin Oncol 21(19):3647–3650. CrossRefPubMedGoogle Scholar
  31. 31.
    Han DS, Suh YS, Kong SH, Lee HJ, Choi Y, Aikou S, Sano T, Park BJ, Kim WH, Yang HK (2012) Nomogram predicting long-term survival after d2 gastrectomy for gastric cancer. J Clin Oncol 30(31):3834–3840. CrossRefPubMedGoogle Scholar
  32. 32.
    Roviello F, Rossi S, Marrelli D, Pedrazzani C, Corso G, Vindigni C, Morgagni P, Saragoni L, de Manzoni G, Tomezzoli A. (2006) Number of lymph node metastases and
its prognostic significance in early gastric cancer: a multicenter Italian study. J Surg Oncol 94:275–280; discussion 4Google Scholar
  33. 33.
    Marrelli D, Mazzei MA, Pedrazzani C, Di Martino M, Vindigni C, Corso G, Morelli E, Volterrani L, Roviello F (2011) High accuracy of multislices computed tomography (MSCT) for para-aortic lymph node metastases from gastric cancer: a prospective single-center study. Ann Surg Oncol 18(8):2265–2272. CrossRefPubMedGoogle Scholar
  34. 34.
    de Manzoni G, Di Leo A, Roviello F, Marrelli D, Giacopuzzi S, Minicozzi AM, Verlato G (2011) Tumor site and perigastric nodal status are the most important predictors of para-aortic nodal involvement in advanced gastric cancer. Ann Surg Oncol 18(8):2273–2280. CrossRefPubMedGoogle Scholar
  35. 35.
    de Manzoni G, Verlato G, Bencivenga M, Marrelli D, Di Leo A, Giacopuzzi S, Cipollari C, Roviello F (2015) Impact of super-extended lymphadenectomy on relapse in advanced gastric cancer. Eur J Surg Oncol 41(4):534–540. CrossRefPubMedGoogle Scholar
  36. 36.
    Roviello F, Marrelli D, de Manzoni G, Morgagni P, Di Leo A, Saragoni L, De Stefano A; Italian Research Group for Gastric Cancer (2003) Italian research group for gastric cancer. prospective study of peritoneal recurrence after curative surgery for gastric cancer. Br J Surg 90(9):1113–1119. CrossRefGoogle Scholar
  37. 37.
    Sasako M, Sano T, Yamamoto S, Kurokawa Y, Nashimoto A, Kurita A, Hiratsuka M, Tsujinaka T, Kinoshita T, Arai K, Yamamura Y, Okajima K; Japan Clinical Oncology Group (2008) D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer. N Engl J Med 359(5):453–462. CrossRefGoogle Scholar
  38. 38.
    Roviello F, Pedrazzani C, Marrelli D, Di Leo A, Caruso S, Giacopuzzi S, Corso G, de Manzoni G (2010) Super-extended (D3) lymphadenectomy in advanced gastric cancer. Eur J Surg Oncol 36(5):439–446. CrossRefPubMedGoogle Scholar
  39. 39.
    Pedrazzani C, Marrelli D, Pacelli F, Di Cosmo M, Mura G, Bettarini F, Rosa F, de Manzoni G, Roviello F (2012) Gastric linitis plastica: which role for surgical resection? Gastric Cancer 15(1):56–60. CrossRefPubMedGoogle Scholar
  40. 40.
    Roviello F, Caruso S, Neri A, Marrelli D (2013) Treatment and prevention of peritoneal carcinomatosis from gastric cancer by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: overview and rationale. Eur J Surg Oncol 39(12):1309–1316.] CrossRefPubMedGoogle Scholar
  41. 41.
    Wang G, Hu N, Yang HH, Wang L, Su H, Wang C, Clifford R, Dawsey EM, Li JM, Ding T, Han XY, Giffen C, Goldstein AM, Taylor PR, Lee MP (2013) Comparison of global gene expression of gastric cardia and noncardia cancers from a high-risk population in China. PLoS ONE 8(5):e63826CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Shah MA, Khanin R, Tang L, Janjigian YY, Klimstra DS, Gerdes H, Kelsen DP (2011) Molecular classification of gastric cancer: a new paradigm. Clin Cancer Res 17(9):2693–2701CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Tan IB, Ivanova T, Lim KH, Ong CW, Deng N, Lee J, Tan SH, Wu J, Lee MH, Ooi CH, Rha SY, Wong WK, Boussioutas A, Yeoh KG, So J, Yong WP. Tsuburaya A. Grabsch H, Toh HC, Rozen S, Cheong JH, Noh SH, Wan WK, Ajani JA, Lee JS, Tellez MS, Tan P. (2011) Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. Gastroenterology 141(2):476–485; 485.e1–11Google Scholar
  44. 44.
    Deng N, Goh LK, Wang H, Das K, Tao J, Tan IB, Zhang S, Lee M, Wu J, Lim KH, Lei Z, Goh G, Lim QY, Tan AL, Sin Poh DY, Riahi S, Bell S, Shi MM, Linnartz R, Zhu F, Yeoh KG, Toh HC, Yong WP, Cheong HC, Rha SY, Boussioutas A, Grabsch H, Rozen S, Tan P (2012) A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut 61(5):673–684CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Zouridis H, Deng N, Ivanova T, Zhu Y, Wong B, Huang D, Wu YH, Wu Y, Tan IB, Liem N, Gopalakrishnan V, Luo Q, Wu J, Lee M, Yong WP, Goh LK, Teh BT, Rozen S, Tan P (2012) Methylation subtypes and large-scale epigenetic alterations in gastric cancer. Sci Transl Med 4(156):156ra140. CrossRefPubMedGoogle Scholar
  46. 46.
    Wang K, Yuen ST, Xu J, Lee SP, Yan HH, Shi ST, Siu HC, Deng S, Chu KM, Law S, Chan KH, Chan AS, Tsui WY, Ho SL, Chan AK, Man JL, Foglizzo V, Ng MK, Chan AS, Ching YP, Cheng GH, Xie T, Fernandez J, Li VS, Clevers H, Rejto PA, Mao M, Leung SY (2014) Whole-genome sequencing and comprehensive molecular pro ling identify new driver mutations in gastric cancer. Nat Genet 46(6):573–582CrossRefPubMedGoogle Scholar
  47. 47.
    Liu J, McCleland M, Stawiski EW, Gnad F, Mayba O, Haverty PM, Durinck S, Chen YJ, Klijn C, Jhunjhunwala S, Lawrence M, Liu H, Wan Y, Chopra V, Yaylaoglu MB, Yuan W, Ha C, Gilbert HN, Reeder J, Pau G, Stinson J, Stern HM, Manning G, Wu TD, Neve RM, de Sauvage FJ, Modrusan Z, Seshagiri S, Firestein R, Zhang Z. (2104) Integrated exome and transcriptome sequencing reveals ZAK isoform usage in gastric cancer. Nat Commun 5: 3830Google Scholar
  48. 48.
    Polom K, Marano L, Marrelli D, De Luca R, Roviello G, Savelli V, Tan P, Roviello F (2018) Meta-analysis of microsatellite instability in relation to clinicopathological characteristics and overall survival in gastric cancer. Br J Surg 105(3):159–167. CrossRefPubMedGoogle Scholar
  49. 49.
    Marrelli D, Polom K, Pascale V, Vindigni C, Piagnerelli R, De Franco L, Ferrara F, Roviello G, Garosi L, Petrioli R, Roviello F (2016) Strong prognostic value of microsatellite instability in intestinal type non-cardia gastric cancer. Ann Surg Oncol 23(3):943–950. CrossRefPubMedGoogle Scholar
  50. 50.
    Polom K, Marrelli D, Roviello G, Pascale V, Voglino C, Rho H, Marini M, Macchiarelli R, Roviello F (2017) Molecular key to understand the gastric cancer biology in elderly patients—the role of microsatellite instability. J Surg Oncol 115(3):344–350. CrossRefPubMedGoogle Scholar
  51. 51.
    Polom K, Marrelli D, Pascale V, Ferrara F, Voglino C, Marini M, Roviello F (2017) The pattern of lymph node metastases in microsatellite unstable gastric cancer. Eur J Surg Oncol 43(12):2341–2348. CrossRefPubMedGoogle Scholar
  52. 52.
    Smyth EC, Wotherspoon A, Peckitt C, Gonzalez D, Hulkki-Wilson S, Eltahir Z, Fassan M, Rugge M, Valeri N, Okines A, Hewish M, Allum W, Stenning S, Nankivell M, Langley R, Cunningham D (2017) Mismatch repair deficiency, microsatellite instability, and survival: an exploratory analysis of the medical research council adjuvant gastric infusional chemotherapy (MAGIC) trial. JAMA Oncol 3(9):1197–1203. CrossRefPubMedGoogle Scholar
  53. 53.
    Huang L, Wu RL, Xu AM (2015) Epithelial-mesenchymal transition in gastric cancer. Am J Transl Res 7(11):2141–2158PubMedPubMedCentralGoogle Scholar
  54. 54.
    Zheng HX, Cai YD, Wang YD, Cui XB, Xie TT, Li WJ, Peng L, Zhang Y, Wang ZQ, Wang J, Jiang B (2013) Fas signaling promotes motility and metastasis through epithelial-mesenchymal transition in gastrointestinal cancer. Oncogene 32(9):1183–1192. CrossRefPubMedGoogle Scholar
  55. 55.
    Okubo K, Uenosono Y, Arigami T, Yanagita S, Matsushita D, Kijima T, Amatatsu M, Uchikado Y, Kijima Y, Maemura K, Natsugoe S (2017) Clinical significance of altering epithelial-mesenchymal transition in metastatic lymph nodes of gastric cancer. Gastric Cancer 20(5):802–810. CrossRefPubMedGoogle Scholar
  56. 56.
    Garattini SK, Basile D, Cattaneo M, Fanotto V, Ongaro E, Bonotto M, Negri FV, Berenato R, Ermacora P, Cardellino GG, Giovannoni M, Pella N, Scartozzi M, Antonuzzo L, Silvestris N, Fasola G, Aprile G (2017) Molecular classifications of gastric cancers: novel insights and possible future applications. World J Gastrointest Oncol 9(5):194–208. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Corso G, Carvalho J, Marrelli D, Vindigni C, Carvalho B, Seruca R, Roviello F, Oliveira C (2013) Somatic mutations and deletions of the E-cadherin gene predict poor survival of patients with gastric cancer. J Clin Oncol 31(7):868–875. Epub 2013 Jan 22 CrossRefPubMedGoogle Scholar
  58. 58.
    Camargo MC, Kim WH, Chiaravalli AM, Kim KM, Corvalan AH, Matsuo K, Yu J, Sung JJ, Herrera-Goepfert R, Meneses-Gonzalez F, Kijima Y, Natsugoe S, Liao LM, Lissowska J, Kim S, Hu N, Gonzalez CA, Yatabe Y, Koriyama C, Hewitt SM, Akiba S, Gulley ML, Taylor PR, Rabkin CS (2014) Improved survival of gastric cancer with tumour Epstein-Barr virus positivity: an international pooled analysis. Gut 63(2):236–243. CrossRefPubMedGoogle Scholar
  59. 59.
    Almhanna, K, and Scott A. (2017). PD-L1 antibodies for EBV-positive gastric cancer, Going beyond PD-L1 expression and microsatellite instability. JNCI (accepted to print)Google Scholar

Copyright information

© Italian Society of Surgery (SIC) 2018

Authors and Affiliations

  • Daniele Marrelli
    • 1
    Email author
  • Karol Polom
    • 1
  • Alessandro Neri
    • 1
  • Franco Roviello
    • 1
  1. 1.Department of Medicine, Surgery and NeurosciencesUniversity of SienaSienaItaly

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