EBV-GCLS is indeed a very rare (1.3%, 8/595) variant of early gastric carcinoma but demonstrated in this cohort several important clinicopathologic features as follows: 1. High susceptibility (50%, 4/8) in the gastric cardia and fundus of male patients; 2. Low propensity for lymphovasuclar invasion (12.5%, 1/8) and the absence of LNM (0%, 0/8); 3. Overwhelming predominance in deep submucosal (SM2) invasion (100%, 8/8); 4. Universally poor differentiation (100%, 8/8); 5. Excessive prevalence (50%, 4/8) for synchronous non-gastric malignant tumors in the stomach (gastrointestinal stroma tumor) and extra-gastric organs (clear cell renal cell carcinoma); and 6. A higher 5-year survival rate, although a significant statistical level was not reached because of the small sample size of study patients. These features, if confirmed with larger samples in the future, may have a significant impact on clinical management of patients with this rare variant of early gastric carcinomas.
Gastric carcinoma with lymphoid stroma was first report by Watanabe et al in 1976, and its prevalence ranges from 1–4% for all gastric carcinomas.[5, 18] The variation in prevalence of gastric carcinoma with lymphoid stroma is much greater in early gastric carcinomas, ranging from 0.6–8%.[7, 16] The wide range in prevalence may be due to different study methods used for case selection.[7, 16] Several studies in Asia, Europe, and America reveal the prevalence close to 9% for EBV-associated early and advanced gastric carcinomas.[16, 19–21] In our present study, the frequency of EBV infection in gastric carcinoma with lymphoid stroma (72.7%, 8/11) is in agreement with that of previous studies.[5–7, 10, 22] The prevalence of EBV infection in conventional early gastric carcinoma in our study (1.8%, 2/109) was lower than that previously reported. The discrepancy may be related to the exclusion of gastric stump carcinoma and synchronous gastric carcinoma in our cohort, because up to 35% gastric stump carcinomas showed EBV infection and EBV-associated gastric carcinoma often have multiple synchronous gastric carcinomas.[19, 23, 24]
As illustrated in the present study, EBV-GCLS demonstrated histopathologic patterns characterized by a pushing tumor invasion front, dense intra-tumoral lymphocytic infiltration, poor tumor cell differentiation, high nuclear grade, and sheet, cluster, or nest growth patterns, as described previously.[5, 15, 25] Tubular-glandular components in various proportions were also observed.[5, 22] Some rare morphologic manifestations, such as epithelioid granulomas, mucinous or signet-ring cell component, and squamous differentiation were not observed in our cohort, but have been reported previously.[26–28] Overall, it is not difficult to make a correct diagnosis for this rare cancer in resection specimens. However, it would be challenging to accurately diagnose this rare early gastric carcinoma in small biopsies, especially in cases with conventional tubular adenocarcinoma showing focal dense lymphocytic infiltrate. Sometimes, the diffuse lymphoid infiltration may lead to a suspicion of mucosa-associated lymphoid tissue lymphoma.[4, 17] However, the intramucosal irregularly anastomosing tubules and cords in a lace-like growth pattern seen in 5 of 8 our cases of EBV-GCLS may be the most important histologic clue for this rare carcinoma in a small biopsy.[16, 29, 30] The cytokeratin immunostaining and EBER in situ hybridization tests would be helpful to rule out the diagnosis of lymphoma by highlighting the existence of neoplastic epithelial cells with characteristic architecture in EBV-GCLS.[27, 30]
We showed that EBV-GCLS occurred mainly in male patients and was located primarily in the proximal stomach, poorly differentiated, and invaded deep submucosa (SM2), which parallel to those reported before.[6, 7, 31] Poor tumor differentiation and SM2 invasion in early gastric carcinoma are expected to have a high risk of LNM and should be excluded from endoscopic therapy. Surprisingly, LNM was absent in all 8 cases of EBV-GCLS in our series. Our findings confirmed the result of previous study by Lim et al, that the frequency of LNM in early gastric carcinoma with lymphoid stroma is significantly lower than that in conventional early gastric carcinoma in T1b stage-matched comparison cases. The very low risk of LNM in EBV-associated gastric carcinoma has been repeatedly reported in both early and advanced gastric carcinomas.[9, 16, 18, 27, 33] The frequency of LNM reported in previous studies of EBV-associated early gastric carcinomas varies from 4.2–9.1%.[6, 16] Because all EBV-GCLS cases underwent D2 lymphadenectomy and the average number of retrieved lymph node was 22.3 per case, the differences in frequency of LNM between the previous reports and our current study may be due to the small sample size in the present study, but not related to the surgery quality or methods. Therefore, the results of our study along with those of previous reports suggest the potential benefits of endoscopic therapy for EBV-GCLS cases that don’t meet the current curability indications.
The prognosis of patients with gastric carcinoma with lymphoid stroma has been reported to be better than that of conventional gastric carcinoma.[6, 9, 10, 34] In fact, EBV infection has been found to be an independent risk factor for better overall survival among patients with gastric carcinoma with lymphoid stroma. In our cohort, the overall 5-year survival rate of patients with EBV-GCLS is better than that with conventional gastric carcinoma, irrespective of invasion depth; yet the difference was not statistically significant, which appear to be related to the small sample size.
One novel, but intriguing finding in our study was the significantly more frequent presence of synchronous non-gastric malignant tumors in patients with EBV-GCLS than those with conventional early gastric carcinomas. To the best of our knowledge, only one previous study described the similar finding in gastric carcinoma with lymphoid stroma, in which 2 of 7 cases were associated with gastrointestinal stromal tumor or leiomyoma. Although the underlying mechanism for the association remains to be investigated, the implication of this finding is considerable as to appropriate clinical management of patients with EBV-GCLS. Thus, resection strategies for two different tumors in the same patient may need to be carefully evaluated in the decision-making process to balance the pros and cons between endoscopic and surgical resection approaches. For patients with EBV-GCLS and synchronous non-gastric malignant tumors, as shown in case 5 of our series, it is particularly important to discuss the curability of endoscopic treatment for EBV-GCLS, especially in the patient who may be unable to tolerate two surgical resections because of poor overall functionality.
There are several limitations to our current investigation. First, any retrospective study inherits selection bias, which was, however, minimized in this study by collecting consecutive cases for this project. Second, although this is the first case series in small case number focused on EBV-GCLS in the Chinese population, the results in our study may not be generalized to other patient populations. Our data require validations by future studies with large samples, especially in other ethnic patient populations.