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

From the Department of Pathology, VU University Medical Center, Amsterdam; and the Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands

Address reprint requests to Elisabeth Bloemena, MD, PhD, Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, the Netherlands; e-mail: e.bloemena{at}vumc.nl

	ABSTRACT

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PURPOSE: Epstein-Barr virus (EBV) is detected in a substantial subgroup of gastric adenocarcinomas worldwide. We have previously reported that these EBV-positive gastric carcinomas carry distinct genomic aberrations. In the present study, we analyzed a large cohort of EBV-positive and EBV-negative gastric adenocarcinomas for their clinicopathologic features to determine whether they constitute a different clinical entity.

PATIENTS AND METHODS: Using a validated polymerase chain reaction/enzyme immunoassay–based prescreening method in combination with EBER1/2-RNA in situ hybridization, EBV was detected in the tumor cells of 7.2% (n = 41) of the gastric carcinomas from the Dutch D1D2 trial (N = 566; mean follow-up, 9 years). EBV status was correlated with clinicopathologic features collected for the Dutch D1D2 trial.

RESULTS: EBV-positive gastric carcinomas occurred significantly more frequently in males (P < .0001) and in younger patients (P = .012). Most were of the intestinal type according to the Laurén classification (P = .047) or tubular according to the WHO classification (P = .006) and located in the proximal part of the stomach (P < .0001). A significantly lower tumor-node-metastasis system-stage (P = .026) was observed in the patients with EBV-carrying carcinomas, which was solely explained by less lymph node (LN) involvement (P = .034) in these cases. In addition, a better prognosis, as reflected by a longer disease-free period (P = .04) and a significant better cancer-related survival (P = .02), was observed for these patients, which could be explained by less LN involvement, less residual disease, and younger patient age.

CONCLUSION: EBV-carrying gastric adenocarcinomas are a distinct entity of carcinomas, characterized not only by unique genomic aberrations, but also by distinct clinicopathologic features associated with significantly better prognosis.

	INTRODUCTION

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The Epstein-Barr virus (EBV) is known to cause benign and malignant diseases of both lymphoid and epithelial origin [1]. In the last decade, the association of this human -herpes virus with a subgroup of gastric cancer has generally been accepted—that is, in 10% of the gastric adenocarcinomas not otherwise specified (NOS) [2], in more than 80% of the relatively rare lymphoepithelioma-like carcinomas (LELCs) of the stomach [3,4], and in approximately 35% of the stump carcinomas [5,6]. Given that 876,000 new cases of gastric cancer occur per year worldwide [7], the absolute number of EBV-positive gastric cancer cases is considerable and is thus the largest group of EBV-associated malignancies.

An etiologic association between EBV and gastric carcinomas is based on its uniform expression in all tumor cells [8] and its absence in normal epithelium or dysplastic lesions [9]. In addition, the virus is present in a monoclonal and episomal form [10,11] and is transcriptionally active [12,13]. Third, there is serologic evidence of high antiviral titers, especially of EBV viral-capsid antigen IgA and EBV early antigen IgG, many years before the diagnosis of EBV-positive gastric cancer [10,11,14]. However, the exact pathophysiologic mechanism by which EBV contributes to the development of gastric carcinomas remains to be established. Recent studies from our laboratory and others have shown that EBV-carrying gastric carcinomas carry distinct chromosomal aberrations compared with EBV-negative carcinomas [15,16] and that transcripts of the EBV-encoded epithelial oncogene BARF1 are expressed in these gastric carcinomas [13].

Previous studies on clinicopathologic features of EBV-positive gastric cancer showed a male predominance and location in the upper part of the stomach [8,9,17,18]. EBV-carrying gastric adenocarcinomas are also characterized by a prominent CD8+ activated lymphocyte infiltrate [19]. It has been suggested that the EBV-carrying adenocarcinomas NOS do not differ in prognosis compared with their EBV-negative counterpart [20,21]. However, a significantly better prognosis has been established for LELC of the stomach compared with gastric adenocarcinomas not otherwise specified [22-25].

To further evaluate these findings for a European population, we have performed the first large study outside Japan (> 500 cases; Table 1). We studied a Dutch patient population (n = 566) for clinicopathologic features to determine whether EBV-carrying carcinomas form a distinct clinicopathologic entity. Patients with gastric cancer were originally selected for the randomized D1D2 trial performed in the Netherlands between 1989 and 1993, which aimed to determine whether extensive lymph node dissection influenced long-term survival after surgery with curative intent. In that study, a standard limited D1 dissection was compared with an extended D2 lymph-node dissection in terms of mortality, postoperative mortality, and cumulative risk of relapse after surgery [28].

	PATIENTS AND METHODS

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Subjects
We studied the patient population of the Dutch D1D2 trial (N = 711), which has extensively been described by Bonenkamp et al [28]. For the original analysis and all subsequent analyses, permission was obtained from the medical ethical committees of the participating hospitals. This large, randomized surgical study, performed between August 1989 and July 1993, included 80 Dutch hospitals and 52 affiliated pathology departments. In the original study, the extent of lymph node dissection (D1 v D2) in patients with gastric cancer was evaluated. To be eligible for the study, patients had to have a histologically confirmed adenocarcinoma of the stomach without evidence of distant metastasis or coexisting malignancies nor a previous gastrectomy for benign disease. They had to be younger than 85 years and physically suitable for D1 and D2 dissection. Surgery was performed with curative intent. During this study, pathology data and surgical data were collected using standardized forms. Tumor-node-metastasis system classification has been revised according to the 1997 guidelines of the WHO [29]. In this revision, the number of tumor-positive lymph nodes (LNs) determines the N-stage instead of the location of the tumor-positive LN and one LN station (station 12) is now defined as M1. Collection of data is still in progress, with at present a mean follow-up of 9 years. For our study, patients (n = 145) were excluded if tumor sections were no longer available. Statistical analyses of the original patient population and our study population confirmed the absence of bias by availability of patient material. Data described in the Results section is based on 566 patients unless otherwise specified. In addition, no differences in correlations were observed when analyzing the separate D1 and D2 groups for the different parameters.

Histology
Paraffin-embedded tissue sections of the primary tumor were selected based on the original reports from the Dutch pathology database. Presence of tumor in the sections was confirmed by hematoxylin and eosin staining, and histologic typing of the tumors was performed according to both the Laurén classification and WHO guidelines by two pathologists (A.z.H. and E.B.) [30,31]. The pathologists were blinded for the EBV status of the tumors.

LELCs were not distinguished as a separate entity in either classification system. Due to their morphology, they constitute either a diffuse or intestinal type tumor in Laurén, depending on the extent of glandular differentiation and cell size, and a (poorly differentiated) tubular type according to the WHO classification. Early gastric carcinomas were classified as a separate entity defined by not invading the external muscle layer in both classification systems. Because of the inclusion criteria of the D1D2 study, no gastric stump carcinomas were included in the present study [28].

EBV Detection
EBV status of the tumor was determined by a polymerase chain reaction (PCR)/enzyme immunoassay (EIA)–based prescreening method as recently described by us [32]. Briefly, crude DNA extractions were tested by a combination of beta-globin PCR and a sensitive PCR for the BamHI W repeat in the EBV genome. Hybridization of the PCR products in an EIA allowed the semiquantitative detection of the specific PCR products. EBER1/2 RNA in situ hybridization was performed to confirm the presence of EBV in the tumor cells of those cases with a strong hybridization signal after overnight substrate incubation or those cases in which EBV presence could not be ascertained by PCR-EIA because of poor DNA quality, even after DNA purification.

Statistical Analysis
Pearson ² tests were applied, as indicated in the results. Because the tables contained empty cells, a permutation procedure was used to compute the P value. The number of permutations was set at 100,000. Age was analyzed using the Mann Whitney U test. Survival analysis was performed using the Kaplan-Meier method, log-rank testing, and Cox regression. For overall survival analyses, time to event was defined as time of surgery until death, irrespective of cause of death. For cancer-related survival, an event was defined as time of surgery until death due to gastric carcinoma recurrence. If the patient died as a result of a non–cancer-related cause, survival was the same as the disease-free period since surgery. An event was defined as time until relapse to determine the disease-free period. P values less than .05 were considered statistically significant. All statistical analyses were performed with the SPSS 10.0 statistical software program for Windows (SPSS Inc, Chicago, IL).

	RESULTS

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EBV Prevalence
In this large Dutch cohort of gastric carcinoma patients, operated on both in academic hospitals (13% of the study population) and in local hospitals, the overall EBV prevalence was 7.2% (41 of 566 patients).

Patient Population
Although the overall study population consisted of 57% of males and 43% females, 92.7% of the EBV-positive tumors (38 of 41 tumors)occurred in men, and only 7.3% of the EBV-positive tumors arose in women, resulting in a significant male predominance (P < .0001; Table 2).

Tumors
According to the Laurén classification [30], 50.7% of the tumors in the overall population was of the intestinal type, whereas 20.1% had a diffuse-type histology, 2.7% were of mixed histology, and 26.5% were early gastric carcinomas (Table 3). The same distribution was observed in the EBV-negative tumor group (49.7%, 21.3%, 2.9%, and 26.1%, respectively). In contrast, in the population with EBV-positive tumors, only two tumors (4.9%) were of the diffuse histologic type, indicating a significantly smaller number of tumors with this type of histology (P = .047).

Tumors of tubular type were further analyzed according to grade of differentiation. The EBV-positive tumors had a poorer grade of differentiation (described as good, moderate, or poor) compared with the EBV-negative tumor group (P = .002).

In the D1D2 study, standardized forms were used to indicate the localization of the tumor in the stomach. For our analysis, cardia and cardia-middle were defined as proximal (35.7% of the tumors), whereas middle-antrum and antrum were considered to be the distal part of the stomach (56.7% of the tumors; Table 3). In 7.6% of the tumors, the whole stomach was involved. Of the EBV-positive tumors, 82.9% were located in the proximal part of the stomach, and only 32.0% of the EBV-negative tumors were located in the proximal part of the stomach. In addition, only one EBV-positive tumor involved the whole stomach (P < .0001).

WHO tumor-node-metastasis system classification was determined according to the guidelines of 1997 [29]. As shown in Table 3, a significantly lower stage was observed in the EBV-positive tumor group, with 68.3% in stage I versus 41.9% of the EBV-negative tumor population (P = .026). This significant difference in tumor-node-metastasis system stage could solely be attributed to a difference in N stage and not to T stage (P = .094) or M stage (P = .58). A significantly lower N stage was observed in the EBV-positive tumor group. In 63.4% of the patients with EBV-positive tumors, no lymph node metastases were found, compared with 38.7% of the EBV-negative carcinomas (P = .034).

Sixty-one of the EBV-negative cases showed either presence of tumor in the resection margin or positive cytology of ascites or abdominal washing during surgery (R1). This was not observed in any of the EBV-positive cases (P = .021). No correlation was observed between either histology or tumor stage and the R1 cases.

Survival and Disease-Free Period
Consistent with the original data published by Bonenkamp et al [28], we observed no significant difference in overall survival and disease-free period after surgery between the D1 and D2 study arms in the subset of 566 patients analyzed by us during an extended follow-up time with a mean of 9 years.

No difference was observed in the overall survival of the EBV-carrying tumor population (n = 41) compared with patients with an EBV-negative tumor (n = 525; P = .6; Fig 1A). However, a significant difference (P = .02) was observed when the population was analyzed for cancer-related survival (Fig 1B). In addition, a longer disease-free period was observed for the EBV-carrying tumor population (P = .04; Fig 1C).

View larger version (16K): [in this window] [in a new window]   Fig 1. Kaplan-Meier method log-rank testing for overall survival. (A) Cancer-related survival and (B) disease-free period after surgery for (C) EBV-positive (n = 41) versus EBV-negative (n = 525) gastric carcinomas.

When the effects were adjusted for other predictors by multivariate Cox regression analyses, LN involvement, residual disease, and age were the most important factors for both cancer-related survival and disease-free period, whereas EBV, resection type, and sex did not contribute as independent variables.

	DISCUSSION

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In the present study, we demonstrate in a Dutch multicenter trial (N = 566) that EBV-carrying gastric adenocarcinomas are a distinct entity, with different clinicopathologic features in addition to previously described differences in molecular abberations. This is the first large study (> 500 patients) performed outside Japan. In our cohort, the EBV-carrying tumors are observed more often in males and in younger patients. The tumors are localized in the proximal part of the stomach. Histologically, a lower prevalence of diffuse type of tumor (Laurén classification). In this first paper in which the WHO classification for histology is used, a higher prevalence of tubular type tumor is observed. Patients present with less LN involvement and have less residual disease, which results in a better prognosis for patients with EBV-positive carcinomas.

The Netherlands is a country with a low gastric cancer incidence of approximately 2,000 new cases per year [33]. In this population, an EBV prevalence in gastric cancer of 7.2% is observed. This is comparable with the EBV prevalence detected in gastric adenocarcinomas worldwide, including countries with high gastric cancer prevalence, such as Japan [8,9,34], indicating that the overall prevalence of EBV in gastric carcinomas is independent of geographic regions [9,10,26,35].

Our observations of male predominance [8,9], younger patient age, and localization of the tumors in the proximal part of the stomach [9,18] are in agreement with those of several previous studies. However, this is the first large study (> 500 patients) performed outside Japan. Our male to female ratio of 9.8 is the highest described so far, followed by a sex ratio of 7.8 in a Korean study [21], 7.0 in a study from the United States [8], and 6.2 in a Russian cohort [17]. Only in two studies from South America were there relatively more females among patients with EBV-positive gastric cancer [36,37].

The difference in age is significant but small. A trend toward younger age has been observed previously [20,38]; however, absence of a correlation with age has been described as well [9,26].

The localization of the EBV-carrying tumors in the proximal part of the stomach may reflect the physiologic interaction with infectious EBV in saliva and, probably, previously damaged upper gastric epithelium.

Of major importance was the observation of less LN involvement in EBV-positive patients, especially given that no difference was observed in the tumor size of the two groups. This has been described before for LELC [9,39,40]. Less LN involvement was also reflected in a better prognosis of the patients with the EBV-positive tumors in our cohort. Overall survival did not correlate with the EBV status of the tumors, which is most likely a result of the age of the cohort (mean age at intake, 64 years). However, a significantly better cancer-related survival (P = .02) and a longer disease-free period (P = .04) was observed in the EBV-carrying group.

We hypothesize that EBV induces an immune response that prevents the outgrowth of micrometastases in the LNs. This immune response is also reflected by the large CD8+ infiltrate characteristically surrounding the EBV-carrying gastric carcinomas [19]. The target for the immune response could either be an EBV antigen or a cellular EBV-induced antigen.

Molecular analysis of EBV-positive gastric adenocarcinomas versus EBV-negative carcinomas has already shown distinct characteristics for EBV-carrying gastric carcinomas as reflected by different chromosomal aberrations [15], different and lower frequencies of microsatellite instability [41] and allelic loss [16], and more CpG methylation [42]. In addition, specifically in EBV-carrying gastric carcinomas, p53 does not seem to be affected [16], whereas p16 is downregulated by promotor methylation [43]. In the present study, we show that these molecular differences are also reflected in distinct clinicopathologic features indicating that EBV-positive gastric carcinomas are a distinct entity with a unique pathway of carcinogenesis.

EBV-positive gastric cancer can be viewed as an immunotherapeutic experiment of nature in which EBV provides growth advantage of tumor cells but also induces a putative antitumor response that prevents outgrowth of metastases, as reflected by the lower number of lymph node metastases in EBV-positive gastric carcinomas, resulting in a better clinical outcome. As such, it provides a rationale for clinical tumor vaccination trials.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Acknowledgment

 
We thank Bas van Beek, Muriel Verkuijten, and Ralph Warring for excellent technical assistance and Saskia Bulk and Hans Berkhof for statistical advice.

	NOTES

 
Supported by Dutch Cancer Society grant VU99-1990.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted August 8, 2003; accepted December 3, 2003.

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