EBV-Positive Gastric Adenocarcinomas: A Distinct Clinicopathologic Entity With a Low Frequency of Lymph Node Involvement

Beek, Josine van; Hausen, Axel zur; Kranenbarg, E. Klein; Velde, Cornelis J.H. van de; Middeldorp, Jaap M.; Brule, Adriaan J. C. van den; Meijer, Chris J.L.M.; Bloemena, Elisabeth

doi:10.1200/jco.2004.08.061

Cited by 246 publications

(255 citation statements)

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“…Although previous studies of EBV DNA in gastric tumour tissue and survival have produced inconsistent results (Chang et al, 2001;Lee et al, 2004), some have found improved survival associated with EBV, at least in subgroups (Koriyama et al, 2002;Lee et al, 2004;van Beek et al, 2004). Our association between high EBNA titres and improved survival was also limited to a subgroup, cardia cancers, although this finding may be due to chance.…”

Section: Discussionmentioning

confidence: 61%

Epstein–Barr virus serology and gastric cancer incidence and survival

Koshiol

Qiao

et al. 2007

Br J Cancer

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Among 185 cases of gastric cancer and 200 controls in Linxian, China, Epstein -Barr virus (EBV) seropositivity was not associated with increased risk of gastric cancer. High EBV nuclear antigen titres were associated with longer survival in cardia cancer cases, possibly due to chance. (Young and Rickinson, 2004), leading to speculation that it may also cause gastric cancer.Previous studies relating EBV to gastric cancer have primarily been tumour-based. The only previous study of prediagnostic EBV serology and gastric cancer incidence (Levine et al, 1995) found generally elevated odds ratios (ORs) for EBV seropositivity and gastric cancer, but included only 46 cases. No previous study has evaluated prediagnostic EBV serology and gastric cancer survival.We prospectively evaluated the associations between baseline EBV serology in relation to (1) subsequent gastric cancer and (2) survival among gastric cancer patients in the Linxian General Population Nutrition Intervention Trial (NIT) cohort in China. MATERIALS AND METHODSThe NIT was a cancer chemoprevention trial in Linxian, China, conducted from March 1986 through May 1991, that enrolled 29 584 participants (Blot et al, 1993). Follow-up for additional survival is available through May 2001 (Tran et al, 2005). We analysed the relation of baseline EBV seropositivity to gastric cancer incidence in a nested case -control study of cardia cancer cases (N ¼ 102, a random sample of the 435 cases that arose during the trial period), non-cardia cancer cases (N ¼ 83), and randomly selected controls (N ¼ 200). Case and control selection methods have been described elsewhere (Mark et al, 2000). We also analysed the association between EBV seropositivity and survival among gastric cancer cases.We tested for IgA antibodies against the EBV viral capsid antigen (VCA IgA) and the diffuse early antigen (EA-D IgA), and for IgG antibodies against the EBV viral capsid antigen (VCA IgG), diffuse early antigen (EA-D IgG), restricted early antigen (EA-R IgG), and EBV nuclear antigen complex (EBNA) using immunofluorescence assays, as previously described (Levine et al, 1995). EA-D IgA was not detectable. EBV VCA IgA, EA-D IgG, and EA-R IgG antibodies were detected in o15% of cases and controls and so were categorised as positive or negative. EBV VCA IgG and EBNA antibodies, which were detectable in all subjects, were classified as high if above the median category of antibody titres in controls and low otherwise. VCA IgG antibody titres were also analysed ordinally.Unconditional logistic regression was used to calculate ORs and 95% confidence intervals (CIs) for prediagnostic EBV serostatus and gastric cancer, controlling for age and gender. Other potential confounders (e.g., smoking, alcohol, Helicobacter pylori) were considered but did not affect the estimate for VCA IgG. KaplanMeier curves and age-and gender-adjusted Cox models were used to evaluate gastric cancer survival by baseline VCA IgG and EBNA. RESULTSCases tended to be older than controls and were more likely to be males, sm...

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Section: Discussionmentioning

confidence: 61%

Epstein–Barr virus serology and gastric cancer incidence and survival

Koshiol

Qiao

et al. 2007

Br J Cancer

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“…33 This group also had trend towards better survival, consistent with the reported literature. 23,32,[34][35][36] A significant association with the immunecheckpoint pathway protein programmed death ligand (PD-L1) was seen in the EBV gastric cancer cluster. Similar findings have been noted at genomic levels with amplification of the 9p24.1 locus, which includes the CD274 gene (encoding for PD-L1).…”

Section: Discussionmentioning

confidence: 99%

A protein and mRNA expression-based classification of gastric cancer

et al. 2016

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The overall survival of gastric carcinoma patients remains poor despite improved control over known risk factors and surveillance. This highlights the need for new classifications, driven towards identification of potential therapeutic targets. Using sophisticated molecular technologies and analysis, three groups recently provided genetic and epigenetic molecular classifications of gastric cancer (The Cancer Genome Atlas, 'Singapore-Duke' study, and Asian Cancer Research Group). Suggested by these classifications, here, we examined the expression of 14 biomarkers in a cohort of 146 gastric adenocarcinomas and performed unsupervised hierarchical clustering analysis using less expensive and widely available immunohistochemistry and in situ hybridization. Ultimately, we identified five groups of gastric cancers based on Epstein-Barr virus (EBV) positivity, microsatellite instability, aberrant E-cadherin, and p53 expression; the remaining cases constituted a group characterized by normal p53 expression. In addition, the five categories correspond to the reported molecular subgroups by virtue of clinicopathologic features. Furthermore, evaluation between these clusters and survival using the Cox proportional hazards model showed a trend for superior survival in the EBV and microsatellite-instable related adenocarcinomas. In conclusion, we offer as a proposal a simplified algorithm that is able to reproduce the recently proposed molecular subgroups of gastric adenocarcinoma, using immunohistochemical and in situ hybridization techniques. Gastric carcinoma is the fifth most common malignancy and the third leading cause of cancer-related death worldwide. Despite better control over known risk factors and development of new chemotherapeutic and targeted agents, in the United States, the 5-year overall survival for gastric cancer patients is only 29%. 1 With regard to patient stratification, although several morphologic classifications have been developed, one broadly used system is the Lauren classification, which divides gastric adenocarcinoma into intestinal and diffuse types. 2 The simple two-tiered classification gives a general understanding of the histogenesis and biology of gastric cancer, and has been particularly helpful in evaluating the epidemiologic data. Another widely used system is the WHO classification, which is based on more precise histologic patterns. It is an all-inclusive system, which recognizes all the rare subtypes that were not identified in the Lauren classification. 3 Nevertheless, its clinical utility is doubtful as there is little difference in outcomes between the distinct histological subgroups.Following the successful Trastuzumab for Gastric Cancer (ToGA) trial, the only validated predictive biomarker for personalized therapy of gastric cancer is limited to human epidermal growth factor receptor (Her2) protein expression. 4 Recently, anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody (ramucirumab) has been FDA approved, and anti-epidermal growth factor receptor (EGFR) an...

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“…EBV-associated gastric adenocarcinoma (AC) accounts for up to 10% of gastric cancers and is associated with male gender, development in gastric stumps and favorable outcome. 1 Recently, a particularly high prevalence (27%) of EBV infection has been found in proximally located gastric carcinomas, especially in AC of the gastric cardia. 1,2 Cardiac AC shares a number of characteristic features with AC of the esophagus, i.e., profound male predominance, rising incidence and etiologic association with chronic gastroesophageal reflux.…”

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confidence: 99%

“…1 Recently, a particularly high prevalence (27%) of EBV infection has been found in proximally located gastric carcinomas, especially in AC of the gastric cardia. 1,2 Cardiac AC shares a number of characteristic features with AC of the esophagus, i.e., profound male predominance, rising incidence and etiologic association with chronic gastroesophageal reflux. 3 Both tumor types are therefore regarded as one clinical entity by some authorities.…”

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confidence: 99%