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INFECTION-DEPENDENT LOW-GRADE LYMPHOID NEOPLASIA: HOW GENERAL IS THE MALT LYMPHOMA PARADIGM?   HM SHAPIRO  
    In attempting to understand a newly discovered lymphoproliferative condition, it may be useful to consider recent findings relating gastrointestinal lymphomas to bacterial infection.
 
    Gastric lymphomas of the type now known as lymphomas of Mucosa Associated Lymphoid Tissue, or MALT lymphomas (1), have long been recognized to be slow-growing, with excellent prospects for long-term survival following treatment by surgery with or without radiation therapy (2). In many cases, lesions which would now be recognized as gastric lymphomas were classified as “pseudolymphoma”, reflecting the fact that they looked like lymphomas, but apparently did not spread to lymph nodes or elsewhere, and the observation that patients might survive for ten years or more without any treatment other than antacids and ulcer drugs, which relieved the symptoms
of pain and bleeding.
 
    Modern thinking on gastric lymphomas is largely based on the work of Peter Isaacson and his colleagues, who were largely responsible for the definition of the concept of MALT lymphomas (1, 3). Although gastric MALT lymphomas are among the most common tumors of this type, mucosal associated lymphoid tissue is not present in the normal stomach. MALT lymphomas of other sites in which lymphoid tissue is not normally found, such as the salivary glands and thyroid, arise following the acquisition of lymphoid tissue in these organs as a result of autoimmune disease (Sjogren's syndrome and Hashimoto's thyroiditis, respectively); in the stomach, lymphoid follicles develop in association with chronic gastritis.
 
    The predominant cell in MALT lymphomas is a B-cell resembling the centrocytes seen in the lymphoid follicles normally present in the intestinal submucosa.  It is phenotypically CD21+CD35+CD5-CD10-. Isaacson et al., defined the lesions as neoplastic for several reasons. Monoclonality is demonstrable by light chain staining and heavy chain gene rearrangement, although there is typically no rearrangement of either bcl-1, bcl-2, or c-myc (4), which are often rearranged in other types of lymphoma. Other evidence for the neolastic nature of the cell comes from cytogenetic abnormalities which include rearrangements of chromosome 1p, trisomy 3, and trisomy 7 (5).
 
    Intensive microscopic examination of gastrectomy specimens from a small number of patients revealed small foci of lymphoma distinct from the original lesion scattered throughout the specimen in all cases (6); the apparent multifocal nature of the tumor may explain the development of local relapse after a long disease-free interval, which is typical of such relatively infrequent recurrences as do occur.
 
    Despite its multifocality, gastric MALT lymphoma generally appeared to remain localized to the stomach and adjacent areas, rather than spreading to lymph nodes, marrow, etc. This property was formerly attributed to the centrocyte-like nature of the neoplastic cells, since normal centrocytes do not circulate through the nodes, etc. as do other types of lymphocytes. However, by using anti-idiotype antibodies, Isaacson’s group demonstrated scattered MALT lymphoma cells in anatomically and otherwise histopathologically normal lymph nodes and spleen removed during surgery for gastric lesions.
 
    It is now recognized that MALT lymphoma of the stomach only develops in the presence of gastritis, which nearly always is a consequence of infection by Helicobacter pylori; this organism, which is also associated with peptic ulcer disease and gastric carcinoma, was identified in biopsy or surgical specimens from 101 of 110 patients (92%) with gastric MALT lymphomas (7).  Isaacson’s group tested the hypothesis that gastric MALT lymphomas result from neoplastic transformation of cells involved in a normal immune response by placing cells from several gastric MALT lymphomas in culture with several strains of H. pylori, using other bacteria and phorbol ester as control stimuli. Phorbol ester induced proliferation of cells from all specimens; the neoplastic B-cells proliferated otherwise only in the presence of both the specific strain of H. pylori found in the patient and T-cells also taken from the tumor (8). This pattern of antigen- and T-cell-dependent proliferation in vitro is consistent with the observation of microscopic foci of tumor, but not of larger lesions, in lymph nodes and the spleen, where antigen, in this case, H. pylori, is absent. Interestingly enough, the immunoglobulins produced by the neoplastic B-cells appear to react with autoantigens, rather than with H. pylori (9, 10); such reactivity is observed in other types of lymphoma as well.
 
    There is a high incidence of both gastric MALT lymphoma and H. pylori infection in the region of Feltre in northeastern Italy (11); this was the site of a clinical trial in which six patients with gastric MALT lymphoma demonstrated by endoscopic biopsy were treated with a combination of bismuth salts, metronidazole, and amoxicillin for two weeks to eradicate H. pylori. Follow-up biopsies were done 4 to 10 months later; in five of six patients, the lymphoma had disappeared to the extent that molecular techniques failed to demonstrate residual disease in the stomach (12). Other authors have also found high rates of complete or partial regression of gastric MALT lymphomas following antibacterial therapy directed against H. pylori (13-17), although some relapses have been noted after initially successful treatment (18).
 
    Progressive genetic changes in successive stages of the evolution from premalignant lesions to malignant tumors, such as have been demonstrated in other types of cancer, have been noted in gastric MALT lymphoma, as well (19), and additional genetic changes have been seen in connection with progression of a low-grade MALT lymphoma to a high grade lesion with leukemic involvement (20).
 
    Immunoproliferative Small Intestinal Disease (IPSID), earlier known as “Mediterranean lymphoma” (1, 21), and now classified as an intestinal MALT lymphoma, is another condition which, at least in its earlier, lower grade forms, apparently exhibits growth dependence on factors related to infection.  While gastric MALT lymphomas are more common in the fifth and successive decades, IPSID predominantly affects young adults, generally presenting with symptoms of malabsorption. About 50 per cent of cases are accompanied by a paraproteinemia in which there is overproduction of the heavy chain of IgA.  Early stage IPSID frequently disappears after therapy with tetracycline or other broad-spectrum antibiotics; however, the disease can progress to a high-grade lymphoma with a relatively poor prognosis, placing a premium on early diagnosis and therapy.
 
    It seems unlikely that gastric MALT lymphoma and IPSID represent the only neoplasms in which a host environment altered by infection provides some stimulus for tumor growth, although it remains to be seen how widely the paradigm which has emerged from studies of these diseases may usefully be extended to other, more common cancers. It would certainly be appropriate to investigate the interactions between infectious and toxic agents, autoimmunity, and other host factors in newly discovered lymphoproliferative syndromes.
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19. Calvert R, Randerson J, Evans P, et al. Genetic abnormalities during transition from
      Helicobacter-pylori-associated gastritis to low-grade MALToma. Lancet 1995; 345:26-7.
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