Endoscopic submucosal dissection in Helicobacter pylori-negative early gastric adenocarcinoma with diffuse large B-cell lymphoma: a two-case report and literature review

Abstract

We describe two rare cases of synchronous early gastric adenocarcinoma (EGA) and diffuse large B-cell lymphoma (DLBCL) involving the stomach and colon in Helicobacter pylori-negative patients. Case 1: A 61-year-old male presenting with abdominal pain was diagnosed with synchronous EGA and colonic DLBCL via endoscopy. Following 8 cycles of R-CDOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). The patient subsequently underwent endoscopic submucosal dissection (ESD) for EGA without gastrectomy. Case 2: A 67-year-old male with a history of gastric DLBCL (treated with 9 cycles of R-CDOP within 6 months) was diagnosed with EGA on surveillance gastroscopy and managed with ESD. Both patients achieved complete resection and remained disease-free at 16-month follow-up. These cases highlight the feasibility of ESD as a curative option for Helicobacter pylori-negative EGA coexisting with DLBCL.

Background

Gastric cancer remains a major global health challenge, ranking as the fifth most common malignancy and the fifth leading cause of cancer-related mortality worldwide [1]. Histologically, gastric adenocarcinoma accounts for over 90% of gastric malignancies [2], while primary gastric lymphoma—predominantly diffuse large B-cell lymphoma (DLBCL)—represents the second most frequent subtype, comprising approximately 5% of cases [3]. The co-occurrence of gastric adenocarcinoma and DLBCL (synchronous malignancies) is strongly associated with Helicobacter pylori infection, reported in > 80% of such cases [3–5]. This correlation stems from Helicobacter pylori’s dual carcinogenic mechanisms: (1) chronic inflammation-driven genomic instability promoting adenocarcinoma, and (2) antigen-triggered B-cell proliferation escalating to lymphomagenesis [5]. Notably, male predominance (male-to-female ratio 2:1) has been consistently observed in these synchronous cases [6]. In contrast, Helicobacter pylori-negative gastric cancer represents an epidemiologically distinct entity, with a reported prevalence of < 1% in Western populations [7– 8]. Consequently, synchronous Helicobacter pylori-negative gastric adenocarcinoma and DLBCL are exceptionally rare, with fewer than 20 cases documented globally [9–11]. This rarity complicates mechanistic understanding, though shared etiologies (e.g., Epstein-Barr virus infection, bile reflux) or immune microenvironment dysregulation have been hypothesized [12].

Traditionally, the standard management of synchronous adenocarcinoma and DLBCL involved gastrectomy (when surgically feasible based on tumor staging), followed by unimodal or multimodal adjuvant therapies including chemotherapy and radiotherapy [13]. However, the advent of advanced endoscopic techniques [14–16], coupled with the predominance of early-stage gastric carcinomas in synchronous presentations, has established endoscopic submucosal dissection (ESD) as a safe and curative organ-preserving alternative to gastrectomy [17, 18]. Concurrently, contemporary therapeutic paradigms for gastric lymphoma now prioritize targeted chemotherapeutic and immunotherapeutic approaches, reserving surgical intervention exclusively for managing acute complications such as hemorrhage or visceral perforation [19].

These cases demonstrate the co-existence of Helicobacter pylori-negative early-stage gastric adenocarcinoma with DLBCL. The effective use of progressive R-CDOP chemotherapy followed by ESD reveals an innovative treatment model that implements organ-preserving strategies alongside comprehensive disease management.

Case presentation

A 61-year-old man went to doctor because of abdominal pain for 1month, he had a history of hypertension, diabetes, and hemorrhoid surgery 20 years earlier, and was taking valsartan, hydrochlorothiazide, dapagliflozin, and metformin. He had no history of tobacco use or alcohol consumption. The PET/CT showed that the lymphoma involved the small intestine, liver, spleen, diaphragm, chest wall, inguinal canal, and multiple groups of lymph nodes above and below the diaphragm. The Deauville score was 5, and according to the PET/CT stage, it was considered Ⅳstage (Fig. 1a). The colonoscopy showed a lesion of ascending colon (Fig. 1c). And the colon biopsies were confirmed as malignant, consistent with diffuse large B-cell lymphoma (DLBCL) (Fig. 1c). Immunohistochemical analysis of the colonic lesion demonstrated the following marker profile: CKpan (negative), CD3 (negative), CD20 (positive), Bcl-2 (positive in 10% of cells), Bcl-6 (positive), CD10 (negative), c-myc (positive in 20% of cells), MUM1 (positive), CD21 (negative), CD19 (positive), CD4 (negative), CD8 (negative), CyclinD1 (negative), CD30 (negative), CD56 (negative), TIA-1 (negative), p53 (weak to moderate positivity in 30% of cells), Ki67 (positive in 80% of cells), and EBER (negative). Combined with the patient’s history and examination results, the patient was diagnosed diffuse large B-cell lymphoma, stage IV, group A, 3 of aaIPI score, high risk. The gastroscopy showed a lesion at the junction of the antrum and body, and the biopsies showed the glands were high-grade intraepithelial neoplasia, and the focal stage was considered as early cancer of differentiated adenocarcinoma (Fig. 1b). No H. pylori was identified on examination of Giemsa-stained specimens (Fig. 1b).A multidisciplinary team evaluated the stage of both gastric adenocarcinoma and colon diffuse large B cell lymphoma. After a multidisciplinary consultation and discussion, he was informed every different therapeutic schedule and its possible result, the patient first chose chemotherapy to treat the lymphoma. Then he received 8 cycles of R-CDOP chemotherapy, included Rituximab 700 mg d0; Cyclophosphamide 1.5 g d1; Vincristine 2 mg d1; Doxorubicin liposome 60 mg d1; Prednisone 100 mg d1-5. The patient underwent follow-up PET/CT re-examination, which demonstrated complete resolution of all lymphoma lesions (Fig. 1d). Then the lesion located in the antrum and body junction was given ESD treatment (Fig. 1e).

Fig. 1.

a PET/CT fused image: Multiple low-density nodules and masses were identified in the liver, with an SUVmax of approximately 13.7. The terminal ileum exhibited wall thickening, luminal narrowing, increased tracer uptake, and an SUVmax of approximately 17.5; b Figure shows respectively the endoscopic white light image, NBI magnified image, endoscopic ultrasound image and pathological image. Under the microscope, various glandular shapes and complex glandular structures can be observed, along with fused glands. The cancer cells show significant atypia, with nuclei of varying sizes and deep staining, and prominent nucleoli, which are typical manifestations of moderately differentiated adenocarcinoma (HE stanning; magniffcation, x40; scale bars, 50 μm). c Figure shows the endoscopic white light image and the pathological image respectively. Under microscopic examination, the tissue demonstrates diffuse proliferation of neoplastic B lymphocytes. These cells are approximately 2 to 3 times larger in volume compared to normal lymphocytes and exhibit morphological features resembling centroblasts. A variable number of reactive cells, including T lymphocytes, plasma cells, and histiocytes, are present in the background (HE stanning; magniffcation, x40; scale bars, 50 μm); d Follow-up CT, PET, and PET/CT fusion imaging demonstrated complete resolution of all lymphoma lesions; e Figure shows the ESD process, including the endoscopic white light image, the incision and dissection image, the post-dissection wound surface, and the specimen after dissection. f Immunohistochemical analysis of the ESD specimens showed negative results for MUC5AC, HER2, and Syn; positive results for Ki-67 and P53; and focal positivity for EBER (magniffcation, x100; scale bars, 50 μm)

As is showed in Fig. 1b, under white light endoscopy, a type Ⅱa + Ⅱc lesion measuring approximately 20 mm×20 mm was observed at the background of atrophic mucosa. The lesion exhibited slight erythema with clearly demarcation line from normal mucosa aera, with no ulceration present. The non-extension sign was negative under sufficient air insufflation (Fig. 1b). On Narrow Band Imaging (NBI) with magnifying observation, an irregular mesh pattern was observed (Fig. 1b). Under endoscopic ultrasound (EUS) examination, the lesion exhibited hypoechoic alterations characterized by thickening of both the mucosal layer and muscularis mucosae, accompanied by focal thinning of the submucosal layer at the lesion’s central portion while maintaining overall submucosal integrity (Fig. 1b). The preliminary diagnosis was moderately differentiated-type mucosal (M) carcinoma, which meets the indications for ESD according to guidelines for gastric cancer from the Japanese Gastric Cancer Association (JGCA) [6]. The ESD procedure was successfully performed by an experienced endoscopist (Fig. 1e), with subsequent histopathological evaluation confirming a moderately differentiated adenocarcinoma exhibiting submucosal invasion to a depth of approximately 300 μm (SM1 category), while maintaining clear resection margins both vertically and horizontally. Immunohistochemical analysis of the ESD specimens revealed negative staining for MUC5AC, HER2, and Syn; positive staining for Ki-67 and P53; and focal positivity for EBER (Fig. 1f). collectively satisfying all established pathological criteria for curative ESD resection according to current JGCA guidelines (2023 edition). Evaluation of curability meets the standard of eCuraB [20]. Follow-up with endoscopic examination at the second postoperative year and abdominal biannual ultrasonography showed no evidence of tumor recurrence.

The other case was a 67-year-old man who was found early gastric cancer of adenocarcinoma, with a history of abdominal discomfort for 2 weeks. He had a previous history of gastric DLBCL for 1 year, and 9 cycles of R-CDOP chemotherapy. The gastric biopsies showed the glands at the minor curvature of gastric body were high-grade intraepithelial neoplasia with focal carcinoma-adenocarcinoma (highly differentiated), and negative for Helicobacter pylori. the lesion of this patient was also given ESD treatment (Fig. 2a). The pathological specimens are as follows: chronic atrophic gastritis, moderate atrophy, moderate intestinal metaplasia, moderate inflammation, mild activity, with some glands showing high-grade intraepithelial neoplasia, and partial canceration-adenocarcinoma (moderately differentiated), confined to the mucosa, without involvement of the surrounding and basal resection margins, Helicobacter pylori (not detected). Immunohistochemical analysis of the gastric body ESD specimens demonstrated the following findings: negative expression of MUC5AC, HER2, and Syn; positive expression of Ki-67 and P53; and focal positivity for EBER in the localized lesion (Fig. 2b).

Fig. 2.

a The ESD procedure for the mucosal solid lesion located in the gastric body was performed smoothly, including the endoscopic white light image, the incision and dissection image, the post-dissection wound surface, and the specimen after dissection; b immunohistochemical examination of the gastric body ESD specimens revealed the following results: MUC5AC, HER2, and Syn were negative; Ki-67 and P53 were positive; and EBER was focally positive in the local lesion (magniffcation, x100; scale bars, 50 μm)

The two patients no longer have any abdominal discomfort after 16 months of ESD operation, so both of them refused reexamination of gastroscopy.

Discussion

Gastric malignancies exhibit distinct histological distributions, with adenocarcinomas constituting 95% of cases, while lymphomas account for approximately 5% [21]. Notably, 30–40% of extranodal non-Hodgkin lymphomas (NHLs) originate in the gastrointestinal tract (GI-NHL), primarily manifesting as diffuse large B-cell lymphoma (DLBCL) or mucosa-associated lymphoid tissue (MALT) lymphoma [22]. Gastric DLBCL typically presents as ulcerative lesions in the gastric body and predominantly affects elderly populations (median age: 61 years) [23], as demonstrated in our two cases. DLBCL is characterized by aggressive biological behavior, necessitating immediate therapeutic intervention upon diagnosis. Assessment by PET/CT is crucial for optimal management of DLBCL, and it is the gold standard for staging and measurement of disease burden at diagnosis, and radiomic features provide valuable additions to existing robust clinicobiological prognostication tools [24]. The patient in Case 1, as previously described in this article, demonstrated extensive lymphoma involvement on initial PET-CT examination: small intestine, liver, spleen, diaphragm, chest wall, inguinal canal, and multiple lymph node groups above and below the diaphragm, with a Deauville score of 5. The clinical staging was determined to be stage IV. Optimal management requires comprehensive staging incorporating both Ann Arbor and Lugano classification systems [25, 26]. R-CHOP has been established as the first-line treatment for DLBCL [27], the current standard therapy for DLBCL with gastric lesions is six to eight cycles of R‐CHOP or three cycles of R‐CHOP followed by involved‐field radiation therapy for early‐stage disease [28]. This standard chemotherapy regimens have reduced surgical indications for primary gastric lymphoma (PGL) to < 5% of cases, now primarily reserved for perforation or hemorrhage [22, 29]. Nevertheless, other existing studies have documented that this standard chemotherapy regimens achieve complete remission in only 65–80% of cases [24], 20–30% of patients develop refractory or recurrent disease [27]. R-CHOP chemotherapy achieved complete remission of the DLBCL and so we have sufficient conditions to treat early gastric cancer.

ESD is an effective therapeutic approach for early gastric cancer. Absolute indication for ESD including a differentiated-type adenocarcinoma without ulcerative findings (UL0), in which the depth of invasion is clinically diagnosed as T1a, and the diameter is > 2 cm. In the first case, the irregular mesh pattern suggests moderately differentiated adenocarcinoma, with the lesion measuring less than 30 mm in diameter and showing no ulcer formation. Initial depth evaluation prior to ESD resection suggested intramucosal carcinoma (T1a), and ESD was subsequently performed. However, post ESD pathology confirmed submucosal invasion reaching 300 μm. Currently, the preoperative prediction of invasion depth in early gastric cancer mainly depends on white light endoscopy and endoscopic ultrasound to determine the presence of submucosal invasion, but the accuracy varies significantly as it largely relies on the endoscopist’s experience [30]. Abe et al. developed a Depth-Predicting Score (DPS) model for differentiated early gastric cancer, assigning 2 points each for marginal elevation and lesion diameter ≥ 30 mm, and 1 point each for remarkable redness and uneven surface [31]. A total score ≥ 3 points suggests deep submucosal invasion (submucosal invasion depth exceeding 500 μm). The DPS model demonstrates high specificity of 93.1–93.7% but relatively low sensitivity of only 29.7–45.9%. Based on the DPS scoring system, the lesion of the first case scored 2 points, suggesting no deep submucosal invasion. Furthermore, EUS has inherent limitations in assessing invasion depth for early gastric cancer, which may be attributed to the restricted accuracy of miniprobe EUS in lesions ≥ 20 mm [32]. As the lesion length increases, the effective scanning range of EUS decreases, potentially leading to missed diagnoses of focal submucosal infiltration. Therefore, accurate assessment of invasion depth in early gastric cancer remains a significant clinical challenge. Based on the post ESD histopathological examination, the evaluation of curability of the first case meets the standard of eCuraB, and follow-up with annual or biannual endoscopy and abdominal ultrasonography or computed tomography (CT) for surveillance of metastases is recommended after eCuraB resection according to guidelines for gastric cancer from the Japanese Gastric Cancer Association (JGCA) [20]. Fortunately, both horizontal and vertical margins were negative on post-ESD pathological examination. During the second postoperative year of follow-up, surveillance endoscopy and biannual abdominal ultrasound examinations revealed no evidence of tumor recurrence.

Long-term follow-up studies demonstrate a 2.3-fold increased risk of metachronous gastric adenocarcinoma (GA) in DLBCL survivors, potentially attributable to either chemotherapy-induced mucosal damage or initial underdetection of microscopic GA foci [33, 34]. In our cases, it is possible that the same underlying mechanism contributes to the development of early gastric cancer. The patients were diagnosed with DLBCL. Following 9 cycles of R-CDOP chemotherapy, early gastric adenocarcinoma was identified via endoscopy and subsequent treatment involved ESD. Advancements in chromoendoscopy and magnifying endoscopy have improved early GA detection rates to 85–92% in specialized centers [35–38]. In these cases, the advancement in diagnostic precision has enabled the implementation of minimally invasive ESD for early gastric carcinoma, circumventing the necessity of surgical procedures. Concerned about the patient’s condition 16 months after the surgery, we contacted the patient again to arrange for a gastroscopy and CT scan. We also informed the patient of the necessity of continuous endoscopic monitoring. However, the patient refused the re-examination, citing no discomfort. This also indicates the lack of compliance and health awareness among Chinese patients, which to some extent explains the higher incidence and mortality rates of tumors in China compared to developed countries. We added them in the discussion section.

While Helicobacter pylori infection remains the primary gastric carcinogen, successful eradication programs have reduced Helicobacter pylori-associated gastric cancer prevalence by 40% over the past decade [39]. This epidemiological shift has highlighted Helicobacter pylori-negative gastric cancer, representing 0.66% of all cases with distinct clinicopathological features [7, 40, 41]: predominance of diffuse-type histology (Lauren classification: 87%), younger age of onset (mean: 52 vs. 68 years in Helicobacter pylori-positive cases), alternative carcinogenic drivers including Epstein-Barr virus (EBV) integration (28–33%), bile acid-induced DNA damage, and CDH1 germline mutations [7, 42, 43]. This case series documents two instances of early gastric carcinoma development in Helicobacter pylori-negative patients. These findings not only emphasize the necessity to investigate non-H. pylori-related carcinogenic pathways, but also suggest a potential increased incidence of early gastric malignancy in patients with concurrent DLBCL, mandating implementation of enhanced endoscopic monitoring protocols in such clinical scenarios.

Conclusions

These cases represent the occurrence of synchronous Helicobacter pylori-negative early gastric adenocarcinoma and DLBCL with concomitant gastric and colonic involvement. The successful application of sequential R-CDOP chemotherapy and ESD demonstrates a paradigm-shifting approach that preserves gastric function while achieving oncological control. Clinically, these findings mandate heightened endoscopic surveillance in DLBCL patients regardless of H. pylori status, particularly given the newly recognized association between B-cell lymphoproliferation and epithelial carcinogenesis in immunocompromised hosts.

Author contributions

Bo Zhang, Xue-Guo Sun, Qing-Juan He, Li Chen and Ti-Dong Shan drafted and edited the manuscript. All the authors confirmed and approved this study.

Funding

No Funding.

Data availability

All data generated or analysed during this study are included in this published article.

Declarations

Ethics approval consent to particiapte

The research was ethically approved by The Affiliated Hospital of Qingdao University. The study was conducted in agreement with the guidelines governing research involving human participants, as outlined by the Ethics Committee of The Affiliated Hospital of Qingdao University (Approval Number:202412081287). All protocols were approved by the Ethics Committee of The Affiliated Hospital of Qingdao University.

Consent for publication

The patient’s legal guardian has provided written informed consent to Publish, authorizing the disclosure of the patient’s personal information and associated imaging data. An informed consents were obtained from all participants.

Informed consent

Informed consent to participate was obtained from participants, and participants were duly informed of her rights and responsibilities and provided explicit written informed consent. An informed consents were obtained from all participants.

Competing interests

The authors declare no competing interests.