Current Status of the Spectrum and Therapeutics of Helicobacter pylori-Negative Mucosa-Associated Lymphoid Tissue Lymphoma

SIMPLE SUMMARY: The prevalence of Helicobacter pylori (HP)-negative gastric mucosa-associated lymphoid tissue (MALT) lymphoma has increased over the last two decades, whereas that of HP-positive gastric MALT lymphoma has decreased. Although the role of first-line antibiotics in the treatment of HP-negative gastric MALT lymphomas remains ambiguous, several case series have reported that a first-line HP eradication therapy (HPE)-like regimen could result in complete remission in a proportion of patients with localized HP-negative gastric MALT lymphoma. Previous sporadic reports have indicated that certain patients with extragastric MALT lymphoma can respond to first-line antibiotic treatment as well. These findings suggest that, in contrast to antibiotic-unresponsive tumors, antibiotic-responsive tumors may be recognized within the spectrum of HP-negative MALT lymphoma. In addition to conventional chemotherapy and immunochemotherapy, macrolide antibiotics and immunomodulatory drugs have been previously used and demonstrated to be efficacious. This article provides the spectrum and therapeutics for HP-negative MALT lymphoma. ABSTRACT: Helicobacter pylori (HP)-unrelated mucosa-associated lymphoid tissue (MALT) lymphoma includes the majority of extragastric MALT lymphomas and a small proportion of gastric MALT lymphomas. Although the role of first-line antibiotics in treating HP-negative gastric MALT lymphomas remains controversial, HP eradication therapy (HPE)-like regimens may result in approximately 20–30% complete remission (CR) for patients with localized HP-negative gastric MALT lymphoma. In these patients, H. heilmannii, H. bizzozeronii, and H. suis were detected in sporadic gastric biopsy specimens. Extragastric MALT lymphoma is conventionally treated with radiotherapy for localized disease and systemic chemotherapy for advanced and metastatic diseases. However, a proportion of extragastric MALT lymphomas, such as ocular adnexal lesions and small intestinal lesions, were reported to be controlled by antibiotics for Chlamydophila psittaci and Campylobacter jejuni, respectively. Some extragastric MALT lymphomas may even respond to first-line HPE. These findings suggest that some antibiotic-responsive tumors may exist in the family of HP-negative MALT lymphomas. Two mechanisms underlying the antibiotic responsiveness of HP-negative MALT lymphoma have been proposed. First, an HPE-like regimen may eradicate the antigens of unknown bacteria. Second, clarithromycin (the main component of HPE) may have direct or indirect antineoplastic effects, thus contributing to the CR of these tumors. For antibiotic-unresponsive HP-negative MALT lymphoma, high-dose macrolides and immunomodulatory drugs, such as thalidomide and lenalidomide, have reported sporadic success. Further investigation of new treatment regimens is warranted.