Case 1 -

Gastric extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) Marsha C. Kinney and Steven H. Swerdlow

Clinical History 62 year old male with mass in stomach Diagnosis: Gastric extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) Case 1 - Figure 1 - Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type in stomach. There is a mucosal and submucosal pale appearing lymphoid infiltrate that surrounds occasional hyperplastic follicular centers. Case 1 - Figure 2 - Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type in stomach. A higher magnification of Figure 1. Case 1 - Figure 3 - Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type in stomach. Note the lymphoepithelial lesion. Case 1 - Figure 4 - Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type in stomach. See the "centrocyte-like" pale cells characteristic of MALT lymphomas. Discussion of Case 1 What is a MALT lymphoma? How do we diagnose gastric MALT lymphomas? Use of paraffin section immunostains in the diagnosis of small B-cell lymphomas What have we learned about the biology of gastric MALT lymphomas? What are the clinical implications of such a diagnosis? What is a MALT lymphoma? Extranodal marginal zone B-cell lymphoma (MZL) of MALT-type is a small B-cell lymphoma defined by its recapitulation of Peyer's patch lymphoid tissue and with the major neoplastic component originating from the marginal zone compartment. [2, 11, 12, 13, 14, 15, 16] The Peyer's patch lymphoid tissue includes follicular/germinal centers with their mantle and more peripheral marginal zones, plasma cells and intraepithelial B-cells. Major histologic components in MALT lymphomas (all components not always present) Marginal zone/monocytoid B-cells Lymphoepithelial lesions Small B-lymphocytes Plasma cells (reactive or neoplastic) Reactive follicular centers ± follicular colonization MALT lymphomas [2, 11, 12, 13, 14, 15, 16] Degree of recapitulation of Peyer's patch varies & can occur at non-mucosal sites. Many arise at sites without normal organized lymphoid tissue and are associated with antigenic stimulation and/or autoimmune disorders. Common sites include stomach (H. pylori), salivary gland (Sjogren's syndrome/other autoimmune), lung, skin, thyroid (Hashimoto's thyroiditis) and other sites in GI tract. Clinical characteristics By definition MALT lymphomas are extranodal; however, patients' initial biopsies may be a lymph node involved by a MZL-MALT. In contrast to most other small B-cell lymphomas, MALT lymphomas are usually localized. Genotypic studies, however, may demonstrate subtle peripheral blood involvement in MALT lymphomas. [17] More conventional studies have shown dissemination in up to one third of cases. [18] MALT lymphomas generally pursue an indolent course sometimes with very late recurrences that are often at MALT site(s). They are potentially curable with non-neoplastic or local therapies. The vast majority, but not all, gastric MALT lymphomas are associated with Helicobacter pylori infection [13, 14, 15] H. pylori leads to accumulation of MALT (gastritis with follicles). H. pylori is found in association with the lymphomas although organisms are more numerous in gastritis. Some do report a somewhat lower incidence of demonstrable H. pylori in gastric MALT lymphomas. The T-cells present respond to the H. pylori and stimulate the B-cells that make autoantibodies. [19, 20] Gastric MALT lymphomas should be identified for clinical purposes [2, 13, 15, 21] Many gastric MALT lymphomas respond to antibiotic induced eradication of H. pylori (median time to remission 5 mo., 3-18 mo.). [13, 14, 21, 22, 23, 24, 25, 26, 27, 28] A complete remission is expected in about >50-80% of patients in most studies. Although studies with a long term follow-up are still needed, only a small proportion of patients appear to relapse(7-13% at median of 2 years). So far, survival with antibiotic therapy has been similar to other therapeutic modalities. [25] Transformation to large cell lymphoma may occur and is one reason for failure to respond to antibiotics (along with invasion beyond the mucosa, lymph node involvement in at least one study, H.pylori negative cases and certain genotypic/karyotypic abnormalities – see below). Gastric MALT lymphomas are indolent with most deaths in one study secondary to solid cancers rather than lymphoma. Results of a large study of 120 patients with early gastric MALT lymphoma followed for a median of 48 months (8-84) after H. pylori eradication. [29] 81% of patients (97) had a complete remission after a median of 125 days (7-829 days). Of these patients, nine relapsed after a median of 421 days (128-1601 days). Of the remaining patients, 9% had a partial remission and 11% showed no response. Histopathology of gastric MALT lymphoma [2, 13, 14, 15] The most typical gastric MALT lymphomas demonstrate mass lesions with a proliferation of pale "monocytoid" "centrocyte-like" cells and other small lymphocytes that grows diffusely, around reactive follicles and sometimes with a more nodular/follicular growth pattern following "follicular colonization." The latter refers to replacement of follicular centers by the lymphoma. Sometimes the colonized follicles are a site where transformation of the neoplastic cells is seen (making distinction from reactive follicles very difficult) and sometimes the neoplastic plasma cell component is found in the colonized follicles. Numerous and usually superficial plasma cells that may or may not be a part of the lymphoma are also not infrequently present. Cases with plasmacytic differentiation may demonstrate Dutcher bodies (PAS positive invaginations of the cytoplasm into the nucleus). Transformed cells/immunoblasts are present but are not numerous. Finally, lymphoepithelial lesions with lymphoid infiltration into the gastric glands and often resulting epithelial changes are present. Cytokeratin stains can be useful in highlighting the lymphoepithelial lesions. It must be recognized that neoplastic "monocytoid" -appearing B-cell proliferations are not all MALT/marginal zone lymphomas and not all MALT lymphomas are monocytoid-appearing. Mantle cell lymphomas can have a very "monocytoid" appearance. [30] They must be distinguished from MALT lymphomas as they are more aggressive, much more likely to be disseminated and have a different molecular pathology (see discussion of case 2). Follicular lymphomas may show extensive marginal zone differentiation. [31] This was suggested to probably be associated with a worse prognosis; however, others have suggested that it has no prognostic implications. Remember: The diagnosis of a marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type should only be used when there are relatively few large transformed cells. The precise criteria for diagnosing diffuse large B-cell lymphomas ("high grade" MALT lymphomas) in this setting are not established. A relatively small increase in transformed cells (1-10% or in another study, clustered large cells making up > 10% of the neoplastic population) may be an adverse prognostic indicator. [32, 33] Although gastrectomies are no longer usually performed for gastric MALT lymphomas, it is worthwhile knowing that they are multifocal. [25, 34] This means that a negative margin documented in the frozen section room does not mean that the remainder of the stomach is necessarily free of the lymphoma. Molecular studies further support this concept and demonstrate that lymphoma can even be present in benign-appearing lymphoid aggregates. [35] Differential diagnosis of gastric MALT lymphoma Chronic gastritis Other small B-cell lymphomas requiring different therapeutic approaches Follicular lymphoma (more likely to be disseminated) Mantle cell lymphoma (more likely to be disseminated and much more aggressive) B-CLL/small lymphocytic lymphoma Peripheral T/NK-cell lymphomas (rare and aggressive) Gastritis versus gastric MALT lymphoma: Scoring system modified from Wotherspoon, et al, 1993 [22] Suspicious, probably reactive Follicles surrounded by small lymphocytes that infiltrate the lamina propria diffusely and occasionally into epithelium Suspicious, probably lymphoma Follicles surrounded by centrocyte-like cells that infiltrate diffusely in the lamina propria and into the epithelium in small groups. MZL-MALT (low grade) Dense diffuse centrocyte-like cell infiltrate in lamina propria with prominent lymphoepithelial lesions. Histologic criteria for low grade gastric lymphoma, Zukerberg, et al, 1990 [36] 72% of low grade gastric lymphomas (at least most of which were undoubtedly MALT lymphomas) had one or more of the following features (versus no inflammatory infiltrates) prominent lymphoepithelial lesions (33%), Dutcher bodies (12%), moderate cytologic atypia (36%). Features more commonly but not exclusively seen in the lymphomas dense lymphoid infiltrates (100% vs. 9%), rare or questionable LEL (47% vs. 9%), muscularis mucosae invasion (100% evaluable cases vs. 43%), ulceration (50% vs. 9%), mild cytologic atypia (32% vs. 10%). Immunophenotypic studies are also critical in the evaluation of gastric lymphoid infiltrates in accomplishing the following: Establishing diagnosis of lymphoma Establishing B-cell origin (exclude an unusual T-cell lymphoma) Exclusion of non-MALT type of B-cell lymphomas that can occur in the GI tract Immunophenotype of small B-cell neoplasms: basic antibody workup [37, 38, 39, 40, 41, 42, 43, 44] CD20+ CD5+ Cyclin D1-, CD23+, FMC7-: B-CLL/SLL Cyclin D1+, CD23-, FMC7+: Mantle cell lymphoma CD5- CD10+, bcl-6+, CD43-: Follicular lymphoma, other follicular center cell lymphomas (DLBCL subset, Burkitt) CD10-, bcl-6-: Marginal zone lymphoma, other All antibodies listed above can be detected using paraffin section immunohistochemistry except FMC7. Not all lymphomas have a typical phenotype (eg, CD5+ MALT lymphomas, CD5- mantle cell lymphomas, CD5+ follicular lymphomas are well described). [45, 46, 47, 48] CD5 in paraffin sections may not be as sensitive as by flow cytometry (80% in our hands, B5 problematic). [37] Be sure internal positive controls are acceptable. For example, T-cells in a B-cell lymphoma should be CD5+. At least some endothelial/histiocyte nuclei should be cyclin D1+. CD43, present on T-cells, a small normal B-cell subset and myeloid/monocytic cells, is usually positive in B-CLL/SLL and MCL but only positive in some marginal zone lymphomas. [37, 39] CD43 is also reported to be positive in some benign salivary gland proliferations associated with lymphoepithelial lesions. [49] Use of additional paraffin-reactive antibodies More B-cells may express CD79a than CD20 in lymphomas with plasmacytic differentiation. CD3 is the best antibody to specifically identify T (NK) cells but beware of non-specific staining especially in plasmacytoid/plasma cells. Kappa and lambda stains are helpful in assessing clonality of plasma cells but in many laboratories are not a reliable way to assess surface immunoglobulin staining. MALT lymphomas can have monoclonal plasma cells or be associated with a reactive plasmacytosis. Use of anti-Bcl-2 (anti-apoptotic protein) immunostain Normal follicular centers have few bcl-2+ cells whereas follicular centers are bcl-2+ in 90-100% follicular grade 1 (small cleaved) lymphomas and 50-90% follicular grade 2/3 (mixed/large cell) cases. [38, 50, 51, 52, 53, 54] Remember that follicles with many T-cells, primary follicles or mantles cut tangentially will be bcl-2 positive since these cells are normally positive. It is also important to know that most other small B-cell lymphomas are also bcl-2 protein positive and can involve follicular structures (follicular colonization). Use of anti-CD10 immunostain [38] CD10 expression is a feature of normal follicular center cells and 60-90% follicular lymphomas Very few interfollicular cells positive. Also present on lymphoblasts, some mature T-cells [55] , neutrophils, some myelomas, some epithelial cells. Sometimes see reticular staining. So finding CD10 on a B-cell neoplasm helps support a FCC origin and finding numerous interfollicular CD10+ B-cells helps support the diagnosis of a neoplasm; however, one must beware because, Benign lymph nodes can have scattered CD10+ cells, reticular staining or sometimes just background staining. CD10, as noted above is on a variety of cells other than FCC In follicular lymphomas, CD10 is often downregulated on the interfollicular neoplastic cells Some normal follicles have only scattered CD10+ cells. Use of anti-Bcl-6 immunostain [38] BCL6 is a transcriptional repressor that is: Expressed by normal follicular center cells and all follicular lymphomas (so more sensitive than CD10 for identifying follicular center cell origin of small B-cells). Not expressed in other small B-cell lymphomas. Also expressed by some cortical thymocytes, ~10% intrafollicular T-cells, <1% interfollicular T-cells (and some T-cell lymphomas). Not all bcl-6+ neoplastic large B-cells are necessarily of FCC origin as bcl-6 rearrangements and mutations may also lead to overexpression. Immunostains in case 1 help support diagnosis of a MALT lymphoma (summary of how immunostains are used to support the diagnosis of a MALT lymphoma) Marked diffuse proliferations of B-cells at extranodal sites suggest B-cell neoplasia. Monoclonal B-cells (flow cytometry) ± monoclonal plasma cells (paraffin) are useful in excluding reactive proliferations MALT lymphomas are usually CD5-, CD10-, generally bcl-6- and always cyclin D1-. Genotype/karyotype in gastric MALT lymphomas [13, 28, 56, 57, 58, 59] Clonal immunoglobulin heavy chain rearrangement is present but sensitive tests demonstrate clones even in the absence of histologically evident lymphoma and especially PCR studies can be falsely negative. Clonal B-cells may be identified in chronic gastritis using PCR studies (may find same clone in subsequent lymphoma). Clonal B-cells remain in a variable proportion of patients with overt marginal zone B-cell lymphomas of MALT type following antibiotic induced complete remission. No cyclin D1 (BCL1/CCND1), BCL2, c-MYC rearrangements. Other important abnormalities in MALT lymphomas that are of both practical & biologic interest – a current area of interest Most common numerical chromosomal abnormality is trisomy 3 (most studies >30- >60%) but not a very specific finding. [60, 61, 62] Many also have other trisomies. t(11;18)(q21;q21) involving the API2 (apoptosis inhibitor-2) and MLT/MALT1 (human paracaspase) genes. [60, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77] Most of these cases lack trisomies. [68, 78, 79] t(1;14)(p22;q32) involving the BCL10 and IgH genes is very rare [15, 60, 73, 80, 81] BCL10 mutations & abnormalities in expression [81, 82, 83] t(14;18)(q32;q21) with MALT1-IGH translocation recently described in subset of MALT lymphomas (reported in 18% of MALTs , but not in gastric cases). [84, 85] – NEWER! t(11;18)(q21;q21) : Detectable using classical cytogenetics, FISH & RT-PCR [66, 67, 68, 69, 70, 86, 87, 88] Gastric MALT lymphomas (135 cases): 33%* Other GI MALT lymphomas (7 cases): 71% Lung MALT lymphomas (112 cases): 43% Conjunctival MALT lymphoma (27 cases): 19% Other MALT lymphomas (160 cases) 4% Nodal/splenic marginal zone lymphomas, diffuse large B-cell lymphomas (155 cases): 0% * Higher in H. pylori negative cases. [89] t(11;18)(q21;q21) [64, 66, 67, 68, 69, 70, 86, 88] When present, usually the sole cytogenetic abnormality. Biologic effect may relate to decreased apoptosis & activation of NF- k B (transcription factor for cell survival molecules) Fusion product but not API2 or human paracaspase alone activate NF- k B In gastric MALT lymphomas, it is associated with a lack of a response to antibiotics (eg, 0/10 responders t(11;18)+ vs. 9/12 nonresponders - [90] ) and disseminated disease. [91, 92] Associated with abnormal nuclear BCL10 expression [81, 82, 83] Although reported by some not to be present in gastritis [86], an abstract from 2000 reported 3/23 cases with H. pylori associated gastritis to demonstrate t(11;18)(q21;q21) by RT-PCR. [93] None of the cases showed clonal VH rearrangement and none had evidence of lymphoma with median follow-up of greater than seven years. BCL10 gene abnormalities in MALT lymphomas [81, 82, 83] Normal BCL10 is a weak promoter of apoptosis and activator of NF- k B. It is a cytoplasmic protein normally strongly expressed in germinal centers, moderately in marginal zone and weakly in mantle zone B-cells. t(1;14) involving the BCL10 gene is an uncommon translocation associated with MALT lymphomas. BCL10 mutations present in 6.3% low grade MALT lymphomas and associated with antibiotic resistant cases (9.5% FL, 4.3% DLBCL). 1/3 cases with t(1;14) had mutation. 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