Helicobacter pylori Eradication Therapy, the Reasonable First Line Therapy for Gastric Mucosa-Associated Lymphoid Tissue Lymphoma Irrespective of Infection Status and Disease Stages

It seems very interesting and also strange that a malignant disease can be treated with antibiotics and acid suppressant combination therapy, rather than chemotherapy or radiotherapy. Infectious agents such as hepatitis B virus and hepatitis C virus, Epstein-Barr virus, Helicobacter pylori, and herpes simplex virus are well known causative agents for chronic inflammation associated cancers including hepatocellular carcinoma, stomach cancer, and cervical cancer. Even though the very early event of carcinogenesis starts from the chronic persistent infection status, once established cancers must be treated with chemo- and radiotherapy. Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is the only exception from the rules.

Gastric MALT lymphoma is a shortened name of extranodal marginal zone B cell lymphoma of mucosa associated lymphoid tissue of stomach and typically a low-grade malignancy. In addition to B cell monoclonality, this is characterized by a dense lymphoid infiltrate mainly composed of small-size lymphocytes that invade and destroy the gastric epithelium, configuring the lymphoepithelial lesion which is pathognomonic of MALT lymphoma diagnosis.¹

The discovery of the strong relationship between H. pylori infection and gastric MALT lymphoma naturally suggested H. pylori eradication to treat lymphoma. The effectiveness of eradication has been well accepted and both hematology and gas-troenterology international guidelines currently advise H. pylori eradication as first-line therapy for gastric MALT lymphoma.^2–4 It is more interesting that H. pylori eradication therapy is also indicated as a first line to H. pylori negative gastric MALT lymphoma and lymphoma in advanced stage.

The article by Gong et al.,⁵ titled as “Helicobacter pylori eradication therapy is effective as the initial treatment for patients with H. pylori-negative and disseminated gastric mucosa-associated lymphoid tissue lymphoma” provides an additional evidence for this interesting clinical phenomenon. A total of 345 cases of gastric MALT lymphoma who had received eradication therapy as their first line treatment were enrolled by using medical record retrospectively. H. pylori positivity was 91.9% and H. pylori eradication therapy achieved complete remission in 82.3% for H. pylori-positive patients and 57.1% for H. pylori-negative patients (p=0.001). In this study, investigators claimed that the complete remission rates were comparable, 74.4% for stage IE2 or above and 83.3% for stage IE1 disease after administration of H. pylori eradication treatment (p=0.167). Because H. pylori negative patients were relatively small in number (28/345) and patients in stage IE2 or above also occupied a limited proportion (39/345), degree of effectiveness of H. pylori eradication on the gastric MALT lymphoma in stage IE2 or above should be interpreted carefully. Nonetheless, it is definitely true that, considering the low cost and risk of H. pylori eradication regimen, eradication therapy as a first line is worthwhile as a first step to gastric MALT lymphoma treatment regardless of the H. pylori status and disease stage.

How dose H. pylori eradication treatment work on patients with H. pylori negative gastric MALT lymphoma? The first explanation is the possibility of false negativity of H. pylori infection. All diagnostic tests have limitations in the detection power and hostile intragastric environments including severe inflammation and mucosal atrophy can reduce or even remove H. pylori colonization. As an intrinsic limitation of a retrospective study, investigators cannot control the quality of diagnostic tests and false negative cases cannot be corrected with additional steps including serology, polymerase chain reaction, and so on. The second is a hypothesis of non-H. pylori intragastric bacterial contribution to gastric MALT lymphoma.⁶ Beyond traditional culture based research, recent investigations on gastric microbiota employ immunologic, molecular and genetic tools. The presence of Helicobacter heilmannii-associated gastritis was reported in Korea and Japan and the possible association to MALT lymphoma was claimed also in animal model.⁷ However, we have no evidence of any microbe other than H. pylori in human. H. pylori associated gastric MALT lymphoma need specific H. pylori strain which can interact with specific interleukin-2 producing T cell and result in proliferation of B cell expression IL-2 receptor.^8,9 If there is other microbe which can induce MALT lymphoma, it may need research in strains level, not species.

It is more difficult to answer the mechanism of H. pylori eradication on advanced stage gastric MALT lymphoma in which lymphoma expands beyond mucosa to deep gastric wall structure, regional lymph nodes, distant organ and even to bone marrow.¹⁰ At now, we have no clear explanation. During the disease progression, gastric MALT lymphoma is considered to go through the H. pylori dependent period and then H. pylori independent period. If advanced disease responds to the H. pylori eradication therapy, the transit between these two periods must be not a break but be connected with a smooth overlapping. Even more, data regarding the etiological role of H. pylori for diffuse large B cell lymphoma (DLBCL) is accumulating, there are several reports about remission achievement in DLBCL after H. pylori eradication therapy.

Negative predictive factors for lymphoma remission after H. pylori eradication includes advanced stage disease, deeper invasion of lymphoma into gastric wall, presence of the t(11;18) API2-MALT1 translocation, proximal location of lymphoma in stomach and the Western ethnicity. What if we fail in remission achievement with H. pylori eradication? Although no specific guidelines on the management of these patients are available, the European Society of Medical Oncology (ESMO) recommends the use of conventional antineoplastic therapeutic approaches.³ In ESMO clinical practice guideline for gastric MALT lymphoma, radiotherapy or chemotherapy are reserved for symptomatic lymphoma or lymphoma with other treatment indications including overt progression, deep invasion or nodal involvement, presence of t(11:18) translocation, bulky disease, impending organ damage, and patient preference.³ At present, failure to remission induction with H. pylori eradication therapy does neither mean delayed administration of definite anticancer therapy nor increase the risk of disease progression. Possibly, we need finer stratification of gastric MALT lymphoma according to the remission induction failure risk of H. pylori eradication and the disease progression risk if not treated earlier with antineoplastic therapy. The clinical evidences definitely support the H. pylori eradication as a first line therapy for gastric MALT lymphoma, irrespective of H. pylori infection status and disease stage.