H pylori -Negative MALT-Associated Extranodal Marginal Zone Lymphoma: A Comprehensive Case Report and Literature Review

Abstract

Extranodal marginal zone B-cell lymphoma (ENMZL) of mucosa-associated lymphoid tissue (MALT), a rare subtype of B-cell lymphoma, is typically associated with Helicobacter pylori (H pylori) infection, especially in gastric cases. However, this article presents 2 unique cases of H pylori-negative colonic ENMZL, challenging the conventional understanding of the disease. The first case involves an 80-year-old male diagnosed with Stage 1E ENMZL in the descending colon, and the second describes a 74-year-old male with sigmoid colon ENMZL. Both cases lacked H pylori infection, adding complexity to their management. Accompanying these case studies is a comprehensive literature review, delving into the epidemiology, pathology, clinical features, diagnosis, and treatment of H pylori-negative ENMZL, with a focus on gastrointestinal involvement. This review highlights the importance of considering H pylori-negative cases in ENMZL diagnosis and management, illustrating the need for further research and individualized treatment approaches in this uncommon lymphoma subtype.

Introduction

Extranodal marginal zone B-cell lymphoma (ENMZL), also known as mucosa-associated lymphoid tissue (MALT) lymphoma, was first identified by Peter Isaacson and Dennis Wright in 1983. ¹ This malignancy originates from B-cell lymphocytes in the marginal zone of secondary lymphoid follicles. ² Extranodal marginal zone B-cell lymphoma accounts for approximately 5% to 8% of all B-cell lymphomas.^3,4 In the United States, the estimated incidence is 18.3 cases per million person-years. ⁵ The most commonly affected site is the gastrointestinal tract, particularly the stomach. However, ENMZL can also occur in other locations, including the ocular adnexa, lung, lacrimal and salivary tracts, skin, breast, and thyroid.^6-19 Numerous studies have demonstrated a strong link between Helicobacter pylori (H pylori) infection and ENMZL,^20-26 with approximately 90% of patients with gastric MALT lymphoma testing positive for H pylori serology and culture.^20,27 However, other factors such as Chlamydia psittaci, Borrelia afzelii, and autoimmune disorders have also been implicated in the pathogenesis of ENMZL.^28-30 In this article, we present 2 cases of ENMZL in the colonic mucosa that tested negative for H pylori. In addition, we review the published literature and studies on gastrointestinal ENMZL not associated with H pylori infection.

Case Descriptions

Case 1

An 80-year-old male presented initially to the emergency room for abdominal fullness and bloating. A computed tomography (CT) of the abdomen and pelvis showed a 3 cm massive intraluminal filling defect in the duodenal bulb. An outpatient gastroenterology follow-up was recommended. An esophagogastroduodenoscopy (EGD) 1 month later showed grade C esophagitis, 2 gastric ulcers, excavated lesions in the duodenal bulb, and a few ulcers in the second portion of the duodenum. Biopsies did not reveal any neoplasms, and H pylori was negative. He was subsequently placed on a proton pump inhibitor for 6 weeks and underwent a follow-up EGD after 3 months with a screening colonoscopy. The EGD showed that the esophagitis, gastric, and duodenal ulcers had healed. Colonoscopy revealed multiple polyps in the ascending, transverse colon that showed villous adenoma on biopsy; however, a solitary sessile polyp in the descending polyp was found, for which the biopsy was positive for Stage 1E ENMZL. Helicobacter pylori was negative on biopsy. Fluorescence In Situ Hybridization (FISH) was positive for the MALT1 gene. CD21 and IgD were positive. Helicobacter pylori breath test was negative, and no H pylori was detected on stool studies. Patient was started on triple therapy (lansoprazole/amoxicillin/clarithromycin) and referred to oncology. Positron emission tomography (PET) scan revealed diffuse hypermetabolic activity throughout the colon. The patient was referred to oncology, and a wait and watch approach with close observation was undertaken. A follow colonoscopy 6 months later showed a completely resolved lesion in the descending colon.

Case 2

A 74-year-old male was initially referred to the gastroenterology clinic for a 6 month history of constipation with a change in caliber of his stools. There was no history of weight loss, loss of appetite, or indications of gastrointestinal bleeding. His last colonoscopy was 12 years prior to his presentation which he reported to be normal. His colonoscopy reveals a solitary 6 mm polyp in the sigmoid colon. This was removed with a cold snare. Histopathology showed it to be ENMZL. CD20, CD43, CD21, and bcl2 were positive. B-cell rearrangement was positive. MALT1 gene was not detected, and there was no translocation. No H pylori was seen. Stool samples were also negative for H pylori. Patient was referred to oncology. His PET scan was unremarkable, and flow cytometry was negative. His treatment was focused on managing symptoms of constipation, and it was decided that as this was resected, he will be closely followed up. On his 6 month follow-up, patient remains well and asymptomatic.

Discussion and Literature Review

Epidemiology

Approximately two thirds of all gastrointestinal ENMZL involve the stomach,^31,32 with about 90% of these gastric cases associated with H pylori infection. ²⁰ However, studies on gastric ENMZL have identified a subset of patients without documented H pylori infection. Systematic reviews suggest that 5% to 10% of gastric lymphomas are H pylori-negative.^33,34 Rectal ENMZL, regardless of H pylori status, is rare, constituting less than 1% of colorectal malignancies. Extragastric H pylori-negative ENMZL is even rarer.^35-41 A literature review covering colorectal ENMZL cases published between 1993 and 2017 found that 74% were located in the rectum. ⁴² Of these, only 19% of 44 tested cases were H pylori-positive. Our literature review from 1999 to 2017 identified 8 cases of H pylori-negative rectal ENMZL,^43-48 and 3 cases of H pylori-negative colonic ENMZL. ⁴⁹ Single case reports of H pylori-negative ENMZL in the ileum and esophagus have also been documented.^50,51 Extranodal marginal zone B-cell lymphoma in the small intestine, known as immunoproliferative small intestinal disease (IPSID), is predominantly found in the Mediterranean and African regions, accounting for one third of the small intestinal lymphomas in these areas. ⁵² Two studies reported no association between IPSID and H pylori.^52,53 No significant differences in age and sex have been observed between H pylori-negative and H pylori-positive ENMZL cases. ⁵⁴

Pathology

Given the significant association of gastric ENMZL with H pylori and the fact that approximately 75% of H pylori-positive gastric ENMZL cases achieve complete remission (CR) with H pylori eradication (H pyloriE) therapy,^55,56 it is postulated that chronic H pylori infection stimulates lymphoid cells, leading to lymphoma development. Typically, ENMZL arises in sites originally devoid of lymphoid tissue, which accumulate lymphoid tissue in response to chronic infection or autoimmune disease. ⁵⁷ Apart from H pylori, other bacteria, viruses, or autoimmune stimuli can also induce this chronic stimulation.

Helicobacter heilmannii (HH) has been implicated in the pathogenesis of ENMZL. ⁵⁸ A study comparing 202 patients with H pylori gastritis to 202 with HH gastritis found that 3.4% of patients with HH gastritis had MALT lymphoma. This study also noted focal colonization in the antrum of patients with HH gastritis, in contrast to the diffuse form in H pylori gastritis. ²⁵ Another study involving 5 patients with primary gastric low-grade MALT lymphoma, which responded to H pylori eradication therapy, associated these cases with HH gastritis diagnosed via the Warthin-Starry staining, serology, and culture. ⁵⁸ The mechanisms of chronic inflammation triggering lymphoid cells in patients with HH remain largely unknown. Other organisms implicated in gastric ENMZL include hepatitis C virus, Borrelia burgdorferi, and C psittaci. ⁵⁹ The incidental presence of these organisms in mild lymphoma tissue has not been thoroughly studied. ⁶⁰ Campylobacter jejuni has been identified in cases of MALT lymphoma of the small intestine.^30,61

Autoimmune conditions are predominantly associated with extragastric ENMZL, especially in the salivary glands.^62-66 Systemic lupus erythematosus (SLE) and Sjogren’s syndrome have been linked with ENMZL. A pooled analysis of 12 case-control studies found that Sjogren’s syndrome was associated with a 6.5-fold risk of non-Hodgkin’s lymphoma and a 34% increased risk of marginal zone lymphoma, predominantly in the parotid gland. ⁶⁷ A case series of 80 patients diagnosed with MALT lymphoma identified 13 cases of chronic autoimmune thyroiditis. Of these, 4 had mild lymphoma in the stomach and 1 in the small intestine. Interestingly, 7 of the 13 patients had an H pylori infection, although the association with chronic autoimmune thyroiditis remains unclear. ⁶⁸

Four chromosomal translocations are typically observed in ENMZL: t(11;18)(q21;q21), t(14;18)(q32;q21), t(1;14)(p22;q32), and t(3;14)(p14.1;q32). These translocations activate the nuclear factor kappa B (NF-κB) through the BCL10/MALT1 signal complex, enhancing the survival of ENMZL cells. ⁵⁷ They have been extensively studied as prognostic factors and indicators of lymphomas unresponsive to H pylori eradication therapy.^69,70 About 30% of all MALT lymphoma cases feature the t(11;18)(q21;21) translocation, which is usually unresponsive to H pyloriE and significantly associated with H pylori-negative lymphomas.^34,60 These lymphomas are often advanced but rarely undergo high-grade transformation.^69,71 Notably, this translocation is the most common chromosomal abnormality in ENMZL cases with a strong association with the CagA-positive strain of H pylori. ⁷²

Clinical Features

The stomach is the most common site of involvement for ENMZL, although it can also affect other parts of the gastrointestinal tract. Patients with gastric ENMZL may be asymptomatic or present with symptoms such as epigastric pain, anorexia, weight loss, occult blood loss, or symptoms indicative of reflux disease. ⁷³ Small intestinal lesions often manifest as diarrhea, abdominal pain, or malabsorption.^30,74,75 In advanced stages, obstruction or ascites may develop. However, classic B symptoms like fever, night sweats, and weight loss are rare in gastric ENMZL. ⁷⁶ Extranodal marginal zone B-cell lymphoma associated with H pylori may be clinically indistinguishable from those not associated with this bacterium. Although H pylori causes gastritis, ENMZL does not typically present with gastritis symptoms. In cases with a concerning history, clinical features of autoimmune diseases such as Sjogren’s syndrome or SLE should be evaluated.

A systematic review encompassing 38 studies with a total of 2000 patients, comparing high-grade and low-grade lymphomas, found that alarm symptoms (anemia, hemorrhage, vomiting, and weight loss) were significantly more prevalent in those with high-grade lymphomas. ⁷⁷ The correlation with H pylori status in these cases was not established. Rectal MALT lymphomas can be asymptomatic, but they may also present with rectal bleeding, hematochezia, and constipation.^42,78 A literature review of multiple case reports indicated that the most common clinical findings in these cases are hematochezia followed by positive fecal occult blood tests. ⁴²

Diagnosis

To diagnose ENMZL, histopathology, immunophenotyping, and genetic analysis of biopsy samples are crucial. Endoscopic examination of gastric MALT lymphomas reveals no significant differences between H pylori-positive and H pylori-negative cases.^42,79 The non-specific nature of these endoscopic findings is evident across various types of lymphomas. For instance, in a study of over 1000 patients, 52% of lesions were ulcerative, 23.5% hypertrophic, 12.7% appeared normal, and 9.7% were exophytic. ⁷⁷ When no obvious mass is detected but suspicion for a submucosal lesion remains high, endoscopic ultrasound-guided fine needle aspiration or submucosal resection may offer a more sensitive method for sample collection.^80-82

Colorectal ENMZL often appears as a solitary polypoid nodule, but in 30% of cases, multiple lesions are observed. ⁴² These are predominantly located in the rectum, and when present in the colon, they are more likely to be proximal to the hepatic flexure. ⁴² In some cases, lesions are elevated, necessitating endoscopic ultrasonography. ⁴⁴ Endoscopic ultrasonography and magnifying endoscopy are also valuable in staging ENMZL and assessing clinical remission.

Testing for H pylori infection is a critical component of ENMZL management, as H pylori eradication therapy has been shown to significantly contribute to the remission of MALT lymphoma.^83-89 Helicobacter pylori testing can be performed through biopsy or culture of biopsies. Non-invasive tests include urea breath testing or stool antigen testing, which detect active infection. Serology can indicate both active and past infections. For C jejuni, associated with IPSID, serological testing is used. Additional autoimmune conditions like Sjogren’s syndrome or SLE can also be investigated through serology.

Testing for MALT1 translocation, such as t(11;18), is typically conducted using the polymerase chain reaction (PCR) techniques. Comprehensive imaging of the chest, abdomen, and pelvis is necessary to evaluate for potential distant spread.

Treatment

Gastric ENMZL and Helicobacter pylori eradication therapy

The European Gastrointestinal Lymphoma Study recommends H pyloriE therapy for all patients with H pylori-negative gastric ENMZL, based on the possibility of false-negative tests failing to detect H pylori or HH.^58,90 A retrospective analysis of 11 patients with H pylori-negative gastric ENMZL from 1998 to 2009 showed that 3 out of 11 responded completely to H pyloriE, whereas another 3 showed successful outcomes with H pyloriE combined with radiotherapy. ⁹¹ This analysis included 4 other studies with 31 patients, where 10 (32%) showed complete response to H pyloriE. Reports of complete eradication vary from 13.6% to 83% across various studies.^55,92,93 In a study of 17 H pylori-negative patients treated initially with H pyloriE, 5 achieved CR, and another 5 non-responders achieved CR with added radiotherapy. ⁹⁴ This study noted that non-responders often had multiple lesions, and all lesions were confined to the gastric body, suggesting lesion location can predict response to H pyloriE.^55,79,95-97 The presence of t(11;18) translocation has been linked to significant resistance to H pyloriE.^{46,55,60,69,96,98} No significant differences were observed in relapse rates between H pylori-positive and H pylori-negative ENMZL post-H pyloriE treatment. ⁹⁹

Gastric extranodal marginal zone B-cell lymphoma and radiation therapy

Radiation therapy (RT) has been effective in achieving CR for early-stage lymphoma. A prospective study showed that 14 out of 22 patients with stage I/II H pylori-negative ENMZL treated with RT achieved complete response, with a 5-year overall survival rate of 91%. ¹⁰⁰ The study reported better responses to RT compared with H pyloriE. ⁵³ Another study found a 92.9% regression rate in patients with H pylori-negative and H pyloriE-resistant ENMZL treated with RT. ⁵³ Other studies have noted a 40% overall relapse rate, usually at distant mucosal sites.^101-105 Long-term follow-up revealed only 1 patient developing distant recurrence out of 13 who received RT. ¹⁰⁶

Gastric extranodal marginal zone B-cell lymphoma and chemotherapy

Surveillance, Epidemiology, and End Results (SEER) studies between 1997 and 2007 indicated better responses to rituximab than to combination chemotherapy for gastric ENMZL. ¹⁰⁷ Older studies showed a 64% response rate to rituximab. ¹⁰⁸ An observational study found that patients treated with combination chemotherapy (alkylating agents + rituximab) responded better than those treated with only alkylating agents or rituximab alone. ¹⁰⁹ A case series of 26 patients, 56% of whom were H pylori-negative and had been previously treated with H pyloriE, surgery, or alkylating agents, found that 12 patients achieved complete response to rituximab. ¹¹⁰

Extragastric extranodal marginal zone B-cell lymphoma treatment modalities

Limited data are available on H pylori-negative colorectal MALT lymphomas. Various treatments include irrigation therapy, chemotherapy, surgery, radiotherapy, and endomucosal resection (EMR). ¹¹¹ Management of early-stage IPSID can involve local regional radiotherapy, surgery, rituximab, or observation. A trial of H pyloriE is sometimes suggested even if H pylori is negative. ¹¹¹ Antibiotics have shown mixed effectiveness in treating extragastric MALT lymphomas. Regression of rectal MALT lymphomas with H pyloriE has been observed in several case reports.^43,45,47-49 RT has been effective in H pylori-negative ENMZL, and chemotherapy with rituximab has shown promise, although studies have not always defined H pylori status.^112-118

Conclusions

This case reports and review sheds light on the complexities of H pylori-negative MALT-Associated Extranodal Marginal Zone Lymphoma, challenging traditional understandings of its association with H pylori infection. The unique case studies presented emphasize the importance of considering ENMZL in differential diagnoses regardless of H pylori status and underscore the need for individualized treatment approaches. This work highlights the necessity for further research into this rare lymphoma subtype to improve diagnostic accuracy and treatment effectiveness.