Skip to main content
Top
Published in: Gastric Cancer 3/2016

01-07-2016 | Original Article

Epstein-Barr virus infection serves as an independent predictor of survival in patients with lymphoepithelioma-like gastric carcinoma

Authors: Byung-Hoon Min, Chung Hyun Tae, Soo Min Ahn, So Young Kang, Sook-Young Woo, Seonwoo Kim, Kyoung-Mee Kim

Published in: Gastric Cancer | Issue 3/2016

Login to get access

Abstract

Background

The pathogenesis and clinicopathologic characteristics of Epstein–Barr virus (EBV)-negative lymphoepithelioma-like gastric carcinoma (LELC) are still unclear. In addition, it remains controversial whether EBV infection itself affects the prognosis of LELC.

Methods

Between 1995 and 2011, 145 LELC patients (124 patients with EBV infection and 21 patients without EBV infection) underwent radical gastrectomy with D2 lymph node dissection. The clinicopathologic features and prognosis of EBV-negative LELC cases were compared with those of EBV-positive LELC cases. The median duration of follow-up after surgery was 55 months. Microsatellite instability (MSI) analysis was performed on 20 EBV-negative LELC cases.

Results

EBV-negative LELC accounted for 14.5 % of the total LELC cases. EBV-negative LELC was significantly associated with older age, female sex, advanced T stage, and advanced American Joint Committee on Cancer (AJCC) tumor stage compared with EBV-positive LELC. In univariate analysis, patients with EBV-negative LELC had significantly shorter overall, disease-specific, and recurrence-free survival than those with EBV-positive LELC. The 5-year overall survival rates were 81.0 % for patients with EBV-negative LELC and 96.2 % for patients with EBV-positive LELC. In a Cox proportional hazards model, EBV infection, age, and AJCC tumor stage were identified as independent predictors of overall survival. MSI-high, MSI-low, and microsatellite-stable tumors accounted for 25, 10, and 65 % of EBV-negative LELC cases, respectively. MSI status did not affect the prognosis of EBV-negative LELC cases.

Conclusions

EBV infection serves as an independent predictor of survival in patients with LELC. EBV-negative LELC exhibited clinicopathologic features and prognosis distinct from those of EBV-positive LELC.
Literature
1.
go back to reference Song HJ, Srivastava A, Lee J, Kim YS, Kim KM, Ki Kang W, et al. Host inflammatory response predicts survival of patients with Epstein-Barr virus-associated gastric carcinoma. Gastroenterology. 2010;139(84–92):e2.PubMed Song HJ, Srivastava A, Lee J, Kim YS, Kim KM, Ki Kang W, et al. Host inflammatory response predicts survival of patients with Epstein-Barr virus-associated gastric carcinoma. Gastroenterology. 2010;139(84–92):e2.PubMed
2.
go back to reference Corvalan A, Ding S, Koriyama C, Carrascal E, Carrasquilla G, Backhouse C, et al. Association of a distinctive strain of Epstein-Barr virus with gastric cancer. Int J Cancer. 2006;118:1736–42.CrossRefPubMed Corvalan A, Ding S, Koriyama C, Carrascal E, Carrasquilla G, Backhouse C, et al. Association of a distinctive strain of Epstein-Barr virus with gastric cancer. Int J Cancer. 2006;118:1736–42.CrossRefPubMed
3.
go back to reference Burke AP, Yen TS, Shekitka KM, Sobin LH. Lymphoepithelial carcinoma of the stomach with Epstein-Barr virus demonstrated by polymerase chain reaction. Mod Pathol. 1990;3:377–80.PubMed Burke AP, Yen TS, Shekitka KM, Sobin LH. Lymphoepithelial carcinoma of the stomach with Epstein-Barr virus demonstrated by polymerase chain reaction. Mod Pathol. 1990;3:377–80.PubMed
4.
go back to reference Horiuchi K, Mishima K, Ohsawa M, Aozasa K. Carcinoma of stomach and breast with lymphoid stroma: localisation of Epstein-Barr virus. J Clin Pathol. 1994;47:538–40.CrossRefPubMedPubMedCentral Horiuchi K, Mishima K, Ohsawa M, Aozasa K. Carcinoma of stomach and breast with lymphoid stroma: localisation of Epstein-Barr virus. J Clin Pathol. 1994;47:538–40.CrossRefPubMedPubMedCentral
5.
go back to reference Grogg KL, Lohse CM, Pankratz VS, Halling KC, Smyrk TC. Lymphocyte-rich gastric cancer: associations with Epstein-Barr virus, microsatellite instability, histology, and survival. Mod Pathol. 2003;16:641–51.CrossRefPubMed Grogg KL, Lohse CM, Pankratz VS, Halling KC, Smyrk TC. Lymphocyte-rich gastric cancer: associations with Epstein-Barr virus, microsatellite instability, histology, and survival. Mod Pathol. 2003;16:641–51.CrossRefPubMed
6.
go back to reference Kijima Y, Ishigami S, Hokita S, Koriyama C, Akiba S, Eizuru Y, et al. The comparison of the prognosis between Epstein-Barr virus (EBV)-positive gastric carcinomas and EBV-negative ones. Cancer Lett. 2003;200:33–40.CrossRefPubMed Kijima Y, Ishigami S, Hokita S, Koriyama C, Akiba S, Eizuru Y, et al. The comparison of the prognosis between Epstein-Barr virus (EBV)-positive gastric carcinomas and EBV-negative ones. Cancer Lett. 2003;200:33–40.CrossRefPubMed
7.
go back to reference Nakamura S, Ueki T, Yao T, Ueyama T, Tsuneyoshi M. Epstein-Barr virus in gastric carcinoma with lymphoid stroma. Special reference to its detection by the polymerase chain reaction and in situ hybridization in 99 tumors, including a morphologic analysis. Cancer. 1994;73:2239–49.CrossRefPubMed Nakamura S, Ueki T, Yao T, Ueyama T, Tsuneyoshi M. Epstein-Barr virus in gastric carcinoma with lymphoid stroma. Special reference to its detection by the polymerase chain reaction and in situ hybridization in 99 tumors, including a morphologic analysis. Cancer. 1994;73:2239–49.CrossRefPubMed
8.
go back to reference van Beek J, Zur Hausen A, Klein Kranenbarg E, van de Velde CJ, Middeldorp JM, van den Brule AJ, et al. EBV-positive gastric adenocarcinomas: a distinct clinicopathologic entity with a low frequency of lymph node involvement. J Clin Oncol. 2004;22:664–70.CrossRefPubMed van Beek J, Zur Hausen A, Klein Kranenbarg E, van de Velde CJ, Middeldorp JM, van den Brule AJ, et al. EBV-positive gastric adenocarcinomas: a distinct clinicopathologic entity with a low frequency of lymph node involvement. J Clin Oncol. 2004;22:664–70.CrossRefPubMed
9.
go back to reference Herath CH, Chetty R. Epstein-Barr virus-associated lymphoepithelioma-like gastric carcinoma. Arch Pathol Lab Med. 2008;132:706–9.PubMed Herath CH, Chetty R. Epstein-Barr virus-associated lymphoepithelioma-like gastric carcinoma. Arch Pathol Lab Med. 2008;132:706–9.PubMed
10.
go back to reference Lee JH, Kim SH, Han SH, An JS, Lee ES, Kim YS. Clinicopathological and molecular characteristics of Epstein-Barr virus-associated gastric carcinoma: a meta-analysis. J Gastroenterol Hepatol. 2009;24:354–65.CrossRefPubMed Lee JH, Kim SH, Han SH, An JS, Lee ES, Kim YS. Clinicopathological and molecular characteristics of Epstein-Barr virus-associated gastric carcinoma: a meta-analysis. J Gastroenterol Hepatol. 2009;24:354–65.CrossRefPubMed
11.
go back to reference Murphy G, Pfeiffer R, Camargo MC, Rabkin CS. Meta-analysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location. Gastroenterology. 2009;137:824–33.CrossRefPubMedPubMedCentral Murphy G, Pfeiffer R, Camargo MC, Rabkin CS. Meta-analysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location. Gastroenterology. 2009;137:824–33.CrossRefPubMedPubMedCentral
12.
go back to reference Camargo MC, Kim WH, Chiaravalli AM, Kim KM, Corvalan AH, Matsuo K, et al. Improved survival of gastric cancer with tumour Epstein-Barr virus positivity: an international pooled analysis. Gut. 2014;63:236–43.CrossRefPubMed Camargo MC, Kim WH, Chiaravalli AM, Kim KM, Corvalan AH, Matsuo K, et al. Improved survival of gastric cancer with tumour Epstein-Barr virus positivity: an international pooled analysis. Gut. 2014;63:236–43.CrossRefPubMed
13.
go back to reference Park S, Choi MG, Kim KM, Kim HS, Jung SH, Lee JH, et al. Lymphoepithelioma-like carcinoma: a distinct type of gastric cancer. J Surg Res. 2015;194:458–63.CrossRefPubMed Park S, Choi MG, Kim KM, Kim HS, Jung SH, Lee JH, et al. Lymphoepithelioma-like carcinoma: a distinct type of gastric cancer. J Surg Res. 2015;194:458–63.CrossRefPubMed
14.
15.
go back to reference Chang MS, Lee HS, Kim CW, Kim YI, Kim WH. Clinicopathologic characteristics of Epstein-Barr virus-incorporated gastric cancers in Korea. Pathol Res Pract. 2001;197:395–400.CrossRefPubMed Chang MS, Lee HS, Kim CW, Kim YI, Kim WH. Clinicopathologic characteristics of Epstein-Barr virus-incorporated gastric cancers in Korea. Pathol Res Pract. 2001;197:395–400.CrossRefPubMed
16.
go back to reference Gulley ML, Pulitzer DR, Eagan PA, Schneider BG. Epstein-Barr virus infection is an early event in gastric carcinogenesis and is independent of bcl-2 expression and p53 accumulation. Hum Pathol. 1996;27:20–7.CrossRefPubMed Gulley ML, Pulitzer DR, Eagan PA, Schneider BG. Epstein-Barr virus infection is an early event in gastric carcinogenesis and is independent of bcl-2 expression and p53 accumulation. Hum Pathol. 1996;27:20–7.CrossRefPubMed
17.
go back to reference Park ES, Do IG, Park CK, Kang WK, Noh JH, Sohn TS, et al. Cyclooxygenase-2 is an independent prognostic factor in gastric carcinoma patients receiving adjuvant chemotherapy and is not associated with EBV infection. Clin Cancer Res. 2009;15:291–8.CrossRefPubMed Park ES, Do IG, Park CK, Kang WK, Noh JH, Sohn TS, et al. Cyclooxygenase-2 is an independent prognostic factor in gastric carcinoma patients receiving adjuvant chemotherapy and is not associated with EBV infection. Clin Cancer Res. 2009;15:291–8.CrossRefPubMed
18.
go back to reference Lertprasertsuke N, Tsutsumi Y. Gastric carcinoma with lymphoid stroma. Analysis using mucin histochemistry and immunohistochemistry. Virchows Arch A Pathol Anat Histopathol. 1989;414:231–41.CrossRefPubMed Lertprasertsuke N, Tsutsumi Y. Gastric carcinoma with lymphoid stroma. Analysis using mucin histochemistry and immunohistochemistry. Virchows Arch A Pathol Anat Histopathol. 1989;414:231–41.CrossRefPubMed
19.
go back to reference Minamoto T, Mai M, Watanabe K, Ooi A, Kitamura T, Takahashi Y, et al. Medullary carcinoma with lymphocytic infiltration of the stomach. Clinicopathologic study of 27 cases and immunohistochemical analysis of the subpopulations of infiltrating lymphocytes in the tumor. Cancer. 1990;66:945–52.CrossRefPubMed Minamoto T, Mai M, Watanabe K, Ooi A, Kitamura T, Takahashi Y, et al. Medullary carcinoma with lymphocytic infiltration of the stomach. Clinicopathologic study of 27 cases and immunohistochemical analysis of the subpopulations of infiltrating lymphocytes in the tumor. Cancer. 1990;66:945–52.CrossRefPubMed
20.
go back to reference Watanabe H, Enjoji M, Imai T. Gastric carcinoma with lymphoid stroma. Its morphologic characteristics and prognostic correlations. Cancer. 1976;38:232–43.CrossRefPubMed Watanabe H, Enjoji M, Imai T. Gastric carcinoma with lymphoid stroma. Its morphologic characteristics and prognostic correlations. Cancer. 1976;38:232–43.CrossRefPubMed
21.
go back to reference 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;10:1698–705.CrossRefPubMed 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;10:1698–705.CrossRefPubMed
22.
go back to reference Saiki Y, Ohtani H, Naito Y, Miyazawa M, Nagura H. Immunophenotypic characterization of Epstein-Barr virus-associated gastric carcinoma: massive infiltration by proliferating CD8+ T-lymphocytes. Lab Invest. 1996;75:67–76.PubMed Saiki Y, Ohtani H, Naito Y, Miyazawa M, Nagura H. Immunophenotypic characterization of Epstein-Barr virus-associated gastric carcinoma: massive infiltration by proliferating CD8+ T-lymphocytes. Lab Invest. 1996;75:67–76.PubMed
23.
go back to reference Tokunaga M, Land CE, Uemura Y, Tokudome T, Tanaka S, Sato E. Epstein-Barr virus in gastric carcinoma. Am J Pathol. 1993;143:1250–4.PubMedPubMedCentral Tokunaga M, Land CE, Uemura Y, Tokudome T, Tanaka S, Sato E. Epstein-Barr virus in gastric carcinoma. Am J Pathol. 1993;143:1250–4.PubMedPubMedCentral
24.
go back to reference van Beek J, Zur Hausen A, Snel SN, Berkhof J, Kranenbarg EK, van de Velde CJ, et al. Morphological evidence of an activated cytotoxic T-cell infiltrate in EBV-positive gastric carcinoma preventing lymph node metastases. Am J Surg Pathol. 2006;30:59–65.CrossRefPubMed van Beek J, Zur Hausen A, Snel SN, Berkhof J, Kranenbarg EK, van de Velde CJ, et al. Morphological evidence of an activated cytotoxic T-cell infiltrate in EBV-positive gastric carcinoma preventing lymph node metastases. Am J Surg Pathol. 2006;30:59–65.CrossRefPubMed
25.
go back to reference Chang MS, Kim WH, Kim CW, Kim YI. Epstein-Barr virus in gastric carcinomas with lymphoid stroma. Histopathology. 2000;37:309–15.CrossRefPubMed Chang MS, Kim WH, Kim CW, Kim YI. Epstein-Barr virus in gastric carcinomas with lymphoid stroma. Histopathology. 2000;37:309–15.CrossRefPubMed
26.
go back to reference American Joint Committee on Cancer. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.CrossRef American Joint Committee on Cancer. AJCC cancer staging manual. 7th ed. New York: Springer; 2010.CrossRef
28.
go back to reference Kuzushima K, Nakamura S, Nakamura T, Yamamura Y, Yokoyama N, Fujita M, et al. Increased frequency of antigen-specific CD8+ cytotoxic T lymphocytes infiltrating an Epstein-Barr virus-associated gastric carcinoma. J Clin Invest. 1999;104:163–71.CrossRefPubMedPubMedCentral Kuzushima K, Nakamura S, Nakamura T, Yamamura Y, Yokoyama N, Fujita M, et al. Increased frequency of antigen-specific CD8+ cytotoxic T lymphocytes infiltrating an Epstein-Barr virus-associated gastric carcinoma. J Clin Invest. 1999;104:163–71.CrossRefPubMedPubMedCentral
29.
go back to reference Chiaravalli AM, Feltri M, Bertolini V, Bagnoli E, Furlan D, Cerutti R, et al. Intratumour T cells, their activation status and survival in gastric carcinomas characterised for microsatellite instability and Epstein-Barr virus infection. Virchows Arch. 2006;448:344–53.CrossRefPubMed Chiaravalli AM, Feltri M, Bertolini V, Bagnoli E, Furlan D, Cerutti R, et al. Intratumour T cells, their activation status and survival in gastric carcinomas characterised for microsatellite instability and Epstein-Barr virus infection. Virchows Arch. 2006;448:344–53.CrossRefPubMed
30.
go back to reference Leung SY, Yuen ST, Chung LP, Chu KM, Wong MP, Branicki FJ, et al. Microsatellite instability, Epstein-Barr virus, mutation of type II transforming growth factor beta receptor and BAX in gastric carcinomas in Hong Kong Chinese. Br J Cancer. 1999;79:582–8.CrossRefPubMedPubMedCentral Leung SY, Yuen ST, Chung LP, Chu KM, Wong MP, Branicki FJ, et al. Microsatellite instability, Epstein-Barr virus, mutation of type II transforming growth factor beta receptor and BAX in gastric carcinomas in Hong Kong Chinese. Br J Cancer. 1999;79:582–8.CrossRefPubMedPubMedCentral
31.
go back to reference Chetty R. Gastrointestinal cancers accompanied by a dense lymphoid component: an overview with special reference to gastric and colonic medullary and lymphoepithelioma-like carcinomas. J Clin Pathol. 2012;65:1062–5.CrossRefPubMed Chetty R. Gastrointestinal cancers accompanied by a dense lymphoid component: an overview with special reference to gastric and colonic medullary and lymphoepithelioma-like carcinomas. J Clin Pathol. 2012;65:1062–5.CrossRefPubMed
32.
go back to reference Park HY, Kang SY, Kang GH, Bae GE, Lee SE, Kim KM, et al. EBV infection and mismatch repair deficiency mediated by loss of hMLH1 expression contribute independently to the development of multiple synchronous gastric carcinomas. J Surg Oncol. 2012;106:777–82.CrossRefPubMed Park HY, Kang SY, Kang GH, Bae GE, Lee SE, Kim KM, et al. EBV infection and mismatch repair deficiency mediated by loss of hMLH1 expression contribute independently to the development of multiple synchronous gastric carcinomas. J Surg Oncol. 2012;106:777–82.CrossRefPubMed
Metadata
Title
Epstein-Barr virus infection serves as an independent predictor of survival in patients with lymphoepithelioma-like gastric carcinoma
Authors
Byung-Hoon Min
Chung Hyun Tae
Soo Min Ahn
So Young Kang
Sook-Young Woo
Seonwoo Kim
Kyoung-Mee Kim
Publication date
01-07-2016
Publisher
Springer Japan
Published in
Gastric Cancer / Issue 3/2016
Print ISSN: 1436-3291
Electronic ISSN: 1436-3305
DOI
https://doi.org/10.1007/s10120-015-0524-x

Other articles of this Issue 3/2016

Gastric Cancer 3/2016 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.