Antigen-dependent progression of mucosa-associated lymphoid tissue (MALT)-type lymphoma in the stomach. Effects of antimicrobial therapy on gastric MALT lymphoma in mice

In humans, low-grade B-cell mucosa-associated lymphoid tissue (MALT) lymphomas of the stomach regress when Helicobacter pylori infection is cured by antimicrobial therapy. Using an animal model of human gastric MALT lymphoma, we observed the effects of Helicobacter felis eradication and the relationship between infection and disease progression. Antimicrobial therapy was given to one-half of the BALB/c mice infected with H. felis for 20 months. Groups of antibiotic-treated and untreated mice were killed 2, 3, and 4 months after antimicrobial therapy (ie, 22, 23, and 24 months after infection). The numbers of mice with MALT decreased after H. felis eradication with no lymphoid follicles seen 4 months after treatment. MALT lymphoma was present in a total of 23% (11/48) of antibiotic-treated infected mice compared with 75% (27/36) in untreated infected mice. These lymphomas were further graded into low-, intermediate-, and high-grade lymphoma. In the untreated mice, lymphoma development was more advanced with 36% low-grade (13/36), 39% intermediate-grade (14/36), and 6% high-grade (large B-cell) lymphoma (2/36) whereas in the treated mice the incidence was 21% (10/48), 6% (3/48), and 0% (0/48), respectively. These observations suggest that antigenic stimulation by H. felis sustained growth and progression of low-grade MALT lymphoma and that primary high-grade gastric lymphomas can evolve from the transformation of these tumors. Eradication of the organism caused low-grade tumors to regress, with inhibition or slowing down of lymphoma development toward high-grade lymphoma. The H. felis mouse model of gastric MALT lymphoma presents an opportunity to address the issues arising from antimicrobial treatment of these tumors in humans.     

Evaluation of CD23 expression in paraffin-embedded gastric lymphomas of mucosa-associated lymphoid tissue

The CD23 antigen is expressed in a normal subset of B lymphocytes and in some non-Hodgkin's lymphomas. Reactivity for anti-CD23 (BU38) is present in paraffin-embedded tissue in the large majority of nodal small lymphocytic lymphomas, as well as in follicular center cell lymphomas. Most studies of gastric lymphomas of mucosa-associated lymphoid tissue (MALT) reported a lack of CD23, but these studies were performed on frozen tissue. We evaluated CD23 staining in paraffin-embedded tissue in a large series of gastric MALT lymphomas, as well as in cases of chronic gastritis. We assayed 49 well-characterized gastric lymphomas (9 high-grade non-MALT and 40 MALT [20 low grade, 13 mixed low and high grade, and 7 high grade]). High-grade MALT lymphomas without a low-grade component were distinguished from high-grade non-MALT lymphomas by the presence of lymphoepithelial lesions composed of large cells. In addition, we studies nine cases of chronic gastritis containing B-cell aggregates. We used anti-CD23 (BU38) in formalin-fixed, paraffin-embedded tissue. All of our low-grade gastric MALT lymphomas lacked CD23 immunoreactivity. One of the 13 mixed low-grade and high-grade lesions showed CD23 expression in the high-grade component. All of the high-grade MALT and high-grade non-MALT lesions lacked CD23. All of the nine cases of chronic gastritis lacked CD23. CD23 highlighted residual follicular dendritic cells and gastric epithelium. We concluded that gastric MALT lymphomas lacked CD23 (BU38) in paraffin-embedded tissue, with rare exceptions. This lack of CD23 expression might represent a useful feature in small or partially crushed biopsy specimens, particularly in the differential diagnosis with follicular small cleaved cell lymphoma presenting in the gastrointestinal tract.     

A clinicopathologic study of primary gastric lymphoma of B-cell type among the Japanese with special reference to low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT)

The most common primary site of low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is the gastrointestinal tract, particularly the stomach. The relationship of MALT lymphomas, however, with the more commonly occurring large B-cell gastric lymphoma has not been directly discussed except in the report of Chan et al. (1990), which lacked clinical information regarding the behavior of these tumors. To elucidate the relationship between high-grade large-cell lymphoma and MALT lymphoma, we studied in detail the histopathological and clinicopathologic features with the survival date of 77 Japanese cases of primary gastric lymphoma (PGL) of B-cell type. Based on degree of morphologically recognizable low- or high-grade components of the tumor, PGL was divided into four types: 18 cases of pure MALT lymphoma (type I); 13 cases of MALT lymphoma with small area of high-grade lymphoma (type II); 22 cases of high-grade lymphoma with small areas of MALT lymphoma (type III); and 24 cases pure high-grade lymphoma (type IV). Corresponding to the differences in the histologic pictures of each type, there were differences in the gross appearance, pathologic stage (including depth of invasion) and prognosis. These data suggests that both MALT and high-grade lymphomas of the stomach belong to the same cell lineage and constitute a pathological spectrum and that the histological grouping of PGL is clinico-pathologically useful.     

Gastrointestinal lymphomas: an overview with emphasis on new findings and diagnostic problems

The first section of this article summarizes the salient clinicopathologic features of the more common types of primary gastrointestinal lymphomas, the recent explosion of information on the low grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), and new findings on multiple lymphomatous polyposis and ulcerative jejunitis. The second section discusses the practical problems that may be encountered in the diagnosis of gastrointestinal lymphomas, including diagnosis of large cell malignancies, distinction between lymphoma and reactive lymphoid hyperplasia, classification of diffuse small B-cell lymphomas (including the potential pitfall of mistaking Burkitt's lymphoma for small B-cell lymphoma), recognition of large cell transformation in low-grade B-cell MALT lymphoma, assessment of gastric biopsies from MALT lymphoma patients after anti-Helicobacter therapy, and assessment of nodal or splenic involvement in low-grade MALT lymphoma.     

Biased VH family usage in primary gastric B cell lymphoma of mucosa-associated lymphoid tissue-type and the selected V beta expression of T cells infiltrating into the lymphoma cells

Seven cases of primary gastric low-grade B cell lymphoma of mucosa-associated lymphoid tissue (MALT) type, two cases of high-grade B cell lymphoma with a low-grade component and three cases of pure high-grade lymphoma were selected for the current study. The Ig VH gene use of lymphoma cells and the V beta repertoires of infiltrating T cells were investigated. The VH gene analysis showed multiple VH family usage in 12 cases, but the MALT-type lymphoma cell usage was found to be biased for the families that have a low number of VH genes (VHIV and V). Another analysis of lymphoma-infiltrating T cells showed restricted expressions of the V beta repertoire in all seven low-grade cases and three high-grade cases. In those 10 cases, a considerable number of CD4-positive T cells infiltrated into lymphoma cells and RAG-1 was also prominently expressed. Based on these findings, it was thus assumed that the normal counterpart of gastric B cell lymphoma of MALT type is different from the conventional B cell lymphoma, and the restricted expression of V beta repertoires is therefore considered to be a characteristic finding in low-grade B cell lymphomas of MALT type as well as in a proportion of high-grade lymphomas (the so called 'high-grade lymphoma of MALT type').     

Lymphomas in patients with Sjogren's syndrome are marginal zone B-cell neoplasms, arise in diverse extranodal and nodal sites, and are not associated with viruses

The occurrence of non-Hodgkin's lymphoma (NHL) is the most serious complication of Sjogren's syndrome (SS). We performed a study of 16 NHLs occurring in patients with an underlying SS. These lymphomas arose not only in salivary glands (7 cases) but also in other mucosal extranodal sites (the stomach [4 cases], the lung [3 cases], the skin [3 cases], the buccal mucosa [1 case], the thymus [1 case]) and in nodal sites (8 cases). Low-grade marginal zone lymphomas (MZL) were diagnosed in 12 of the 16 patients, 9 of mucosa-associated lymphoid tissues (MALT) type in mucosal sites and 3 exclusively nodal. The 4 other patients presented with a high-grade B-cell lymphoma that was probably a histological transformation of an underlying low-grade MZL at least in 3 of the cases involving skin, stomach, and parotid, respectively. A t(14;18) translocation was detected in 1 of 8 lymphomas tested. We detected serum anti-p53 antibodies in 2 of the 14 studied patients. p53 protein was detected in 1 of 11 lymphomas tested. LMP protein and Eber RNAs of Epstein-Barr virus (EBV) were not detected in the 16 NHL biopsies. Using polymerase chain reaction, EBV was never detected except in 1 of 4 parotid lymphomas. No human T-lymphotropic virus 1 or human herpes virus 8 DNAs were detected in NHL biopsies. None of the patients had hepatitis C virus infection found using serological methods. Chemotherapy was usually efficient. In conclusion, lymphomas occurring in patients with an underlying SS are in most cases MZL. These lymphomas are not associated with viruses known to be present in other types of lymphomas. Some of the translocations or mutations of oncogenes or antioncogenes described in other lymphomas are detected in SS-associated lymphomas.     

Gastric malt lymphoma with crystalline immunoglobulin inclusions and secondary immunoblastic lymphoma in a cervical lymph node

A case of gastric B cell lymphoma of the mucosa-associated lymphoid tissue (MALT) with crystalline immunoglobulin inclusions in monotypic plasma cells is reported, which initially presented as a secondary immunoblastic lymphoma in a cervical lymph node. The low-grade MALT lymphoma was diagnosed 14 months after detection of the nodal high-grade lymphoma, but rare crystal-containing plasma cells of identical immunoglobulin isotype found in the immunoblastic lymphoma retrospectively confirmed a common clonal origin. The diagnostic significance of crystalline immunoglobulin inclusions and the unusual initial presentation of MALT lymphoma as a secondary high-grade lymphoma at a distant nodal site are discussed.     

Deletion analysis of the p16 tumor suppressor gene in gastrointestinal mucosa-associated lymphoid tissue lymphomas

BACKGROUND & AIMS: The molecular mechanisms responsible for initiation and progression of gastrointestinal mucosa-associated lymphoid tissue (MALT) lymphomas are largely unknown. The aim of this study was to analyze the p16 tumor suppressor gene in MALT lymphomas of the stomach and colon. METHODS: Tumor samples were obtained from 28 patients with low-grade (n = 12) and high-grade (n = 14) gastric MALT lymphomas and from 2 patients with colonic MALT lymphomas. DNA was extracted from microdissected areas with at least 80% tumor cells. To detect homozygous p16 deletions, a semiquantitative polymerase chain reaction assay was used, whereby either p16 exon 1 or exon 2 was coamplified with an unrelated sequence as internal control. RESULTS: Homozygous p16 deletions were found in 2 of 14 (14%) cases with high-grade gastric MALT lymphomas. Both patients had Helicobacter pylori-associated gastritis; however, DNA extracted from areas of gastritis showed a normal p16 complement. No deletion was found in any of the low-grade gastric or the colonic MALT lymphoma specimens. CONCLUSIONS: In a subset of gastric MALT lymphomas, homozygous p16 deletions are acquired and may contribute to the transformation from a low-grade to a high-grade malignancy.     

DNA methylation in mycobacteria: absence of methylation at GATC (Dam) and CCA/TGG (Dcm) sequences

The histopathology of low-grade primary gastric lymphoma re-capitulates the structure of Peyer's patches (mucosa-associated lymphoid tissue--MALT) rather than lymph nodes, characterised by an increased frequency of trisomy 3. Gastric B-cell lymphoma shows a favourable clinical behaviour, possibly as its growth appears to be influenced by a local antigen in the form of Helicobacter pylori. There is no lymphoid tissue in the normal stomach, but lymphoid tissue accumulates in gastric mucosa almost exclusively as a consequence of H. pylori infection, which has MALT characteristics, and H. pylori is found in over 90% of cases of gastric MALT lymphoma. Laboratory studies have shown that the growth of tumour cells from low-grade gastric lymphomas can be stimulated by H. pylori, and that the effect is strain-specific and mediated by contact-dependent help from H. pylori-specific T-cells. Cases of low-grade gastric lymphoma, when confined to the mucosa, may regress following eradication of H. pylori from the patient's stomach. It remains to be shown whether deeply penetrating or high-grade tumours will respond in the same way. Other outstanding questions relate to the optimum interval between eradication of H. pylori and final evaluation and expected duration of the response. Based on these laboratory and clinical findings it is possible to suggest a scheme for the pathogenesis of gastric MALT lymphoma.     

Seasonal rhythm of red pigment concentrating hormone in the crayfish

To evaluate the significance of microsatellite instability (MI) and loss of heterozygosity (LOH) in the development of gastric lymphoma, we examined 33 tissue-samples of 20 primary gastric B-cell lymphomas (6 low-grade lymphomas of mucosa-associated lymphoid tissue [MALT; 10 samples] and 14 diffuse large B-cell lymphomas [23 samples]). MI and LOH were evaluated at 13 microsatellite loci. In MALT lymphoma, four of six cases showed MI at one to two microsatellite loci (average 1.0 per case, 0.8 per sample), whereas in diffuse B-cell lymphoma, all samples showed MI at one to five microsatellite loci (average 2.4 per case, 2.7 per sample) (p < 0.05 and p = 0.0001). MI at the c-myc gene locus was most frequent in both types of gastric lymphomas (3 of 6 and 11 of 14 cases, respectively). Regional heterogeneity of the MI pattern was observed in two of four cases of MALT lymphoma and in four of five cases of diffuse B-cell lymphoma. On the other hand, LOH was observed only in one MALT lymphoma and in three diffuse B-cell lymphomas. Genetic instability may be an important mechanism for the development and progression of gastric lymphoma. Frequent MI at the c-myc locus might reflect an activated state and the importance of this gene in mucosal lymphocytes of chronic gastritis.     

Oncogene rearrangement in non-Hodgkin's lymphoma with a 14q+ chromosome of unknown origin

Southern blot analysis was performed with a panel of DNA probes to detect rearrangements of c-myc, bcl-1, bcl-2 and bcl-3 in 14 cases of B-cell non-Hodgkin's lymphoma (NHL) with a clonal cytogenetic rearrangement involving the chromosome 14q32 locus and no known donor chromosome [t(14;?)(q32;?)]. In our experience, 21% of all chromosomal abnormalities involving the 14q32 locus in B-cell NHL are of this type. We found oncogene rearrangements in five of the 14 cases: bcl-1 rearrangement on one mantle zone lymphoma, bcl-2 rearrangements in two follicular lymphomas, and c-myc rearrangements in two small noncleaved cell lymphomas. We conclude that a 14q32+ abnormality of unknown origin is a relatively frequent karyotypic finding in B-cell NHL. In one third of the cases, known oncogenes that have been previously described in reciprocal translocations involving the immunoglobulin heavy chain locus were shown to be involved in the 14q32+ abnormality. The translocations in the other cases are likely to have involved one of the above oncogenes with breakpoints not revealed by the probes employed, other known oncogenes, or oncogenes that have not yet been identified.     

Malignant lymphoma of mucosa-associated lymphoid tissue in the larynx

A 36-year-old woman was referred to the department of Otolaryngology/Head and Neck Surgery, University Hospital Vrije Universiteit, because of complaints of hoarseness. A submucosal swelling of the right ventricular fold was found that was subsequently biopsied. Histopathological examination showed a low-grade B-cell non-Hodgkin's lymphoma of mucosa-associated lymphoid tissue (MALT). Treatment consisted of local radiotherapy (to 2800 cGy). During the 2-year follow-up to date there has been no evidence of recurrent disease. To our knowledge, only four cases of MALT lymphomas in the larynx have been reported. The clinical behavior of MALT lymphoma is clearly quite distinct and requires proper recognition to prevent inadvertent misdiagnosis of overtreatment.     

Establishment of a novel human B-cell line (OZ) with t(14;18)(q32;q21) and aberrant p53 expression was associated with the homozygous deletions of p15INK4B and p16INK4A genes

The novel human pre-B cell line OZ was established from a patient with an aggressive form of non-Hodgkin's lymphoma. Karyotypic analysis of both the primary tumour and OZ cells revealed several marker chromosomes, including the t(14;18)(q32;q21) translocation, which involves the Bcl-2 gene, and alterations on chromosome 17p. Southern blot analysis found identical rearrangements in the 5' region of Bcl-2 gene in the primary tumour and OZ cells. Homozygous deletions of the p15INK4B and p16INK4A genes, however, were present only in OZ cells. Western blot analysis detected aberrant small molecular-weight p53 proteins in both cell types. In addition, OZ cells no longer expressed the CD20 antigen. These findings suggest that Bcl-2 gene rearrangement and aberrant p53 expression resulted in the original B-cell tumour. A subsequent transforming event involving the p15INK4B and p16INK4A genes may have generated more immature cells with a growth advantage during in vitro culture. The genetic alterations involving p53, p15INK4B, and p16INK4A may be implicated in the aggressive form of t(14;18)(q32;q21)-bearing tumours and their poor prognosis.     

BCL-6 and other genomic alterations in non-Hodgkin's lymphoma (NHL)

This study reports on the frequency and disease association pattern of a number of gene rearrangements in a large panel of lymphoid tumours (n = 94). We detected the t(11;14) translocation, involving rearrangement of the BCL-1 locus, in 60% of mantle cell lymphomas. The BCL-2 gene, located at band 18q21, was rearranged in 42% of follicle centre lymphomas (FCL) and in 15% of diffuse large B-cell (DLBC) lymphomas. In this study, 80% of the c-MYC rearrangements were detected in aggressive diffuse lymphoma subsets but, interestingly, 9% of FCL showed involvement of t(8q24) translocation. In our study, rearrangements of the BCL-6 gene at band 3q27 were found in 31% of DLBC lymphomas. Interestingly, 50% of the BCL-6 rearrangement positive lymphoma cases had coexisting gene rearrangements involving all of the aforementioned gene loci. The molecular dissection of these genes will improve our understanding of the genesis of the diverse clinicopathological subtypes.     

Ocular adnexal lymphoma. A clinicopathologic study with identification of lymphomas of mucosa-associated lymphoid tissue type

PURPOSE: Extranodal marginal zone B-cell lymphoma (low-grade B-cell lymphoma of mucosa-associated lymphoid tissue [MALT] type) is a distinctive type of lymphoma that usually arises in association with mucosa or other epithelial structures and has an indolent clinical course. The frequency and clinical features of MALT lymphomas in the ocular adnexa have not been well studied. METHODS: The authors examined the clinicopathologic features of ocular adnexal lymphoma, identified a subset of cases with MALT characteristics, and determined patient outcome. RESULTS: The 42 patients, 16 men and 26 women age 35-89 years (mean, 64) were followed an average of 4.8 years. Thirty-two patients had ocular adnexal involvement at presentation (primary ocular adnexal lymphoma) and 10 had a history of lymphoma that relapsed in the orbit (secondary ocular adnexal lymphoma). In the primary group, 23 patients had lymphoma confined to the ocular adnexa, 3 had a single lesion that invaded adjacent structures, and 6 had distant spread at the time of presentation. Twenty-five patients achieved a complete remission. Nine patients, including 6 patients whose disease was localized initially, had progression or relapse of disease in distant sites. At last follow-up, 21 patients were free of disease, 9 were alive with disease and 2 had died of lymphoma. In the secondary group, at last follow-up, 1 patient had died of other causes, free of lymphoma, 3 patients were alive with disease and 5 had died of lymphoma (outcome not known in 1 case). Using the recently described revised European-American lymphoma classification, we found 16 MALT lymphomas, 8 diffuse large B cell, 12 follicular center, 3 mantle cell, 1 B-small lymphocytic lymphoma, and 2 unclassifiable low-grade lymphomas. The most common type of primary lymphoma was MALT type (15 of 30 classifiable cases), and the most common secondary lymphoma was follicular center (6 of 10). No increased frequency of conjunctival or lacrimal gland involvement by MALT lymphomas was found. All 33 lymphomas with immunophenotyping were of B lineage. CONCLUSIONS: Ocular adnexal lymphomas are B-cell tumors that develop in older adults, predominantly among women. Primary orbital lymphomas have a favorable prognosis; a high proportion of them have MALT characteristics.     

Lymphoproliferative disorders of the ocular adnexa

Immunodysregulation appears to play a prominent role in the evolution of some lymphomas, as evidenced by the strong associations between congenital and acquired immunodeficiencies and lymphoid neoplasia, and abnormal ratios of helper T cells in lymphoid proliferations. Lympho-proliferative diseases of the ocular adnexa encompass a spectrum of lesions that may present with similar clinical and radiological features. Most primary lymphoid proliferations of the ocular adnexa consist of small lymphocytes of B-cell origin. Employing morphological, immunohistochemical, and molecular genetic criteria, proliferations may be separated into polyclonal and monoclonal categories. Increased insight into the biology and behavior of these tumors tells us that seemingly benign, as well as frankly malignant proliferations, might disseminate to nodal or extranodal sites. The diagnosis of lymphoproliferative disease of any type necessitates a complete workup for systemic lymphoma. Major prognostic criteria for lymphomas are anatomical site, stage, and histological features. Radiotherapy is employed for localized lymphoid proliferations, with chemotherapy recommended for disseminated disease. Long-term follow-up with semiannual examination is recommended. A significant percentage of primary ocular adnexal lymphoid lesions are MALT-type lymphomas, extranodal low-grade B-cell lymphomas usually associated with mucosal tissues or glandular epithelia. The pathogenesis of this lymphoma in orbital soft tissue, which normally is devoid of lymphoid tissue, lymphatic vessels, and epithelium, is unclear. MALT-type lymphomas of the ocular adnexa follow an indolent course, with long periods between relapses, and are responsive to therapy. Dissemination, when it occurs, preferentially affects other extranodal sites.     

BCL6 gene rearrangements also occur in marginal zone B-cell lymphoma

Marginal zone B-cell lymphoma (MZBCL) represents a distinct subtype of B-cell non-Hodgkin's lymphoma (NHL) which has been recently recognized and defined as a disease entity. Cytogenetically, these lymphomas reveal a high prevalence of trisomy 3, and recent data obtained by comparative genomic hybridization indicate that the chromosomal regions 3q21-23 and 3q25-29 might be of particular pathogenetic significance. We identified structural chromosomal abnormalities involving the region 3q27 and rearrangements of the BCL6 proto-oncogene in three out of 34 (9%) well-defined cases of extranodal, nodal and splenic MZBCL using cytogenetic analysis. Southern blot, and fluorescence in situ hybridization (FISH). All three cases were characterized by a t(3;14)(q27;q32). Two of them showed additional chromosomal abnormalities including trisomy 3, which was found in one case. The patients displayed extranodal disease and did not demonstrate any striking clinical and histological differences when compared with MZBCL lacking BCL6 rearrangement. The present study for the first time demonstrates the occurrence of t(3;14)/BCL6 gene rearrangement in MZBCL, thus suggesting a role of the BCL6 proto-oncogene in the pathogenesis of MZBCL.