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Marginal zone lymphoma (MZL) is the most common indolent lymphoma primarily arising in the central nervous system (CNS). To date, 207 cases of primary CNS MZL (PCNSMZL) were published, mostly as single case reports or small case series. It most commonly presents as extra-axial dural-based masses, more frequently in middle-aged women, displaying an insidious onset, with a long history of symptoms preceding the diagnosis. PCNSMZL can be radiographically mistaken for meningioma. PCNSMZL consists of CD20 + , CD3 - small B lymphocytes with varying degrees of plasmacytic differentiation and low proliferation index. Trisomy 3, but not MALT1 or IgH translocation, is a common genetic abnormality. Other recurrent genetic abnormalities involve TNFAIP3 and NOTCH2. Ethiopathogenesis was poorly investigated. Due to its rarity, standard of care remains to be defined; it exhibits an excellent prognosis after varied treatments, such as surgery, radiotherapy, chemotherapy or their combinations. Nevertheless, each treatment should be considered after an accurate analysis of overtreatment risk. Short follow-up is a major limitation in reported PCNSMZL cases, which restrains our knowledge on long-term results and iatrogenic sequels. This review was focussed on presentation, differential diagnoses, pathological findings, treatment options and clinical outcomes of PCNSMZL; recommendations for best clinical practice are provided., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Splenic marginal zone B-cell lymphoma (SMZL) is a heterogeneous clinico-biological entity. The clinical course is variable, multiple genes are mutated with no unifying mechanism, and essential regulatory pathways and surrounding microenvironments are diverse. We sought to clarify the heterogeneity of SMZL by resolving different subgroups and their underlying genomic abnormalities, pathway signatures, and microenvironment compositions to uncover biomarkers and therapeutic vulnerabilities. We studied 303 SMZL spleen samples collected through the IELSG46 multicenter international study (NCT02945319) by using a multiplatform approach. We carried out genetic and phenotypic analyses, defined self-organized signatures, validated the findings in independent primary tumor metadata and in genetically modified mouse models, and determined correlations with outcome data. We identified 2 prominent genetic clusters in SMZL, termed NNK (58% of cases, harboring NF-κB, NOTCH, and KLF2 modules) and DMT (32% of cases, with DNA-damage response, MAPK, and TLR modules). Genetic aberrations in multiple genes as well as cytogenetic and immunogenetic features distinguished NNK- from DMT-SMZLs. These genetic clusters not only have distinct underpinning biology, as judged by differences in gene-expression signatures, but also different outcomes, with inferior survival in NNK-SMZLs. Digital cytometry and in situ profiling segregated 2 basic types of SMZL immune microenvironments termed immune-suppressive SMZL (50% of cases, associated with inflammatory cells and immune checkpoint activation) and immune-silent SMZL (50% of cases, associated with an immune-excluded phenotype) with distinct mutational and clinical connotations. In summary, we propose a nosology of SMZL that can implement its classification and also aid in the development of rationally targeted treatments., (© 2022 by The American Society of Hematology.)

This paper summarizes two sessions of the workshop during the XIX meeting of the European Association for Haematopathology (EAHP) held in Edinburgh in September 2018 dedicated to lymphomas of the gastrointestinal tract. The first session focused on the clinical and pathological features of primary gastrointestinal T cell and NK-cell lymphoproliferative disorders. The distinction between precursor lesions (RCD type 2) and enteropathy-associated T cell lymphoma were stressed, including the discussion of new diagnostic markers for the identification of aberrant phenotypes. Indolent T cell lymphoproliferative disorders of the gastrointestinal tract cases showed phenotypic heterogeneity with novel molecular alterations in few cases, such as STAT3-JAK2 fusion. In addition, novel clonal markers of disease, such as AXL and JAK3 somatic variants support the neoplastic nature of NK-cell enteropathy. The session on gastrointestinal tract B cell lymphoproliferations was dedicated to B cell lymphoproliferative disorders that arise primarily in the gastrointestinal tract (i.e., duodenal-type follicular lymphoma) or preferentially involve the digestive tract, such as large B cell lymphoma with IRF4 translocation and mantle cell lymphoma (MCL), including diverse molecular subtypes (i.e., CCND3-positive MCL mimicking MALT lymphoma). Challenging cases of high-grade B cell lymphomas with complex genetic profiles demonstrated the usefulness of novel molecular diagnostic methods such as targeted NGS to identify high-risk genetic features with potential clinical impact.

Patients with indolent conjunctival lymphomas exhibit good prognosis, with exceptional cases of dissemination, and are suitable candidates for intralesional therapies. We report the first prospective phase 2 trial using intralesional rituximab supplemented with autologous serum in adults with relapsed/refractory indolent CD20+ lymphoma of the conjunctiva (NCT01514344). Patients received 4 weekly intralesional injections of rituximab, followed by 6 monthly injections; 500 μL of autologous serum was added to rituximab in patients with lymphoma unresponsive to weekly doses. Safety, activity, and antitumor effect of autologous serum were investigated. Twenty patients with mucosa-associated lymphoid tissue (MALT)-type lymphoma were enrolled. Tolerability was excellent, with only 3 mild local reactions. After weekly injections, 11 patients achieved tumor regression, 8 had stable disease, and 1 experienced progressive disease; 9 patients received autologous serum, with response improvement in 4 cases (3 complete responses, 1 partial response). At the end of treatment, 12 patients achieved a complete remission, and 1 achieved a partial response, with an overall response rate of 65% (95% confidence interval, 45-85). At a median follow-up of 42 months (range, 10-78), 12 patients remain relapse free, with 5-year progression-free survival and time-to-next-treatment rates of 59% ± 11% and 69% ± 11%, respectively. Three patients with local relapse were retreated with intralesional rituximab and serum; 2 achieved a complete response that lasted 25+ and 38+ months. Thus, intralesional rituximab is a safe and active therapy in patients with relapsed conjunctival MALT lymphoma. The addition of autologous serum improves response in some cases. Retreatment of local relapses can result in a second durable remission., (© 2020 by The American Society of Hematology.)

Marginal zone B-cell lymphomas (MZLs) are a group of clinically indolent B-cell lymphomas postulated to derive from memory B lymphocytes in the 'marginal zone' of secondary lymphoid tissue. Today, MZL is recognised as a nosological umbrella term encompassing distinct entities with some shared phenotypic and genotypic features, including extranodal marginal zone B-cell lymphoma (EMZL) or mucosa-associated lymphoid tissue (MALT) lymphoma, splenic MZL, and nodal MZL, accounting for approximately 70%, 20%, and 10% of MZLs, respectively. These lymphomas share some phenotypic and genotypic features and have some variants and related provisional diseases, but are different in regards to their clinical and molecular characteristics. In addition, they are frequently associated with chronic antigenic stimulation represented either by infectious agents, particularly bacteria and viruses, or autoimmune diseases as exemplified by Sjögren syndrome, Hashimoto thyroiditis, and newly recognised IgG4-related disease. Furthermore, several chromosomal translocations have been identified in EMZL. In this review, we will focus on the updated histopathological criteria and the main problems with differential diagnoses in order to aid the diagnostic approach in our routine practice., (Copyright © 2019. Published by Elsevier B.V.)

The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n = 488), i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL), as well as provisional entities (n = 76), according to the WHO classification. The most striking Ig gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different Ig gene distributions depending on the primary site of involvement. Cross-entity comparisons of the MZ Ig sequence dataset with a large dataset of Ig sequences (MZ-related or not; n = 65 837) revealed four major clusters of cases sharing homologous ('public') heavy variable complementarity-determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia, but also rheumatoid factors and non-malignant splenic MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Purpose There is no consensus on the optimal systemic treatment of patients with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The IELSG-19 phase III study, to our knowledge, was the first such study to address the question of first-line treatment in a randomized trial. Patients and Methods Eligible patients were initially randomly assigned (1:1 ratio) to receive either chlorambucil monotherapy (6 mg/m 2 /d orally on weeks 1 to 6, 9 to 10, 13 to 14, 17 to 18, and 21 to 22) or a combination of chlorambucil (same schedule as above) and rituximab (375 mg/m 2 intravenously on day 1 of weeks 1, 2, 3, 4, 9, 13, 17, and 21). After the planned enrollment of 252 patients, the protocol was amended to continue with a three-arm design (1:1:6 ratio), with a new arm that included rituximab alone (same schedule as the combination arm) and with a final sample size of 454 patients. The main end point was event-free survival (EFS). Analysis of chlorambucil versus the combination arm was performed and reported separately before any analysis of the third arm. Results At a median follow-up of 7.4 years, addition of rituximab to chlorambucil led to significantly better EFS (hazard ratio, 0.54; 95% CI, 0.38 to 0.77). EFS at 5 years was 51% (95% CI, 42 to 60) with chlorambucil alone, 50% (95% CI, 42 to 59) with rituximab alone, and 68% (95% CI, 60 to 76) with the combination ( P = .0009). Progression-free survival was also significantly better with the combination ( P = .0119). Five-year overall survival was approximately 90% in each arm. All treatments were well tolerated. No unexpected toxicities were recorded. Conclusion Rituximab in combination with chlorambucil demonstrated superior efficacy in mucosa-associated lymphoid tissue lymphoma; however, improvements in EFS and progression-free survival did not translate into longer overall survival.

Nodal marginal zone B cell lymphomas (NMZLs) are a rare group of lymphoid disorders part of the spectrum of marginal zone B-cell lymphomas, which encompass splenic marginal one B-cell lymphoma (SMZL) and extra nodal marginal zone of B-cell lymphoma (EMZL), often of MALT-type. Two clinicopathological forms of NMZL are recognized: adult-type and pediatric-type, respectively. NMZLs show overlapping features with other types of MZ, but distinctive features as well. In this review, we will focus on the salient distinguishing features of NMZL mostly under morphological/immunophenotypical/molecular perspectives in views of the recent acquisitions and forthcoming updated 2016 WHO classification of lymphoid malignancies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Ocular adnexal marginal zone lymphoma (OAML) represents 1-2% of all non Hodgkin lymphomas. In the last few years many advances in understanding the pathogenesis and the molecular basis involved in its development have been done. Many potential risk factors have been proposed; a dysregulation of immune response in association with a chronic antigenic stimulation, have been hypothesized as possible pathogenic mechanism. In particular, Chlamydia psittaci infection has been related to OAML arising, and eradicating antibiotic therapy has been addressed as a safe and cost-effective approach. Management of OAML is still heterogeneous and matter of debate. There is no consensus about the best upfront treatment and therapeutic decision should take into account several patient-, lymphoma- and treatment-related factors. Novel agents and chemotherapy-free strategies are being investigated to reduce side effects and improve tumor control. This review is focused in recent knowledge improvements in this lymphoma., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In the last decades some bacteria have been associated with a various extent with marginal zone (extra nodal, nodal and splenic types) lymphomas are frequently associated with chronic infections, with important clinical, molecular, biological, and therapeutic implications. The well-known correlation between Helicobacter pylori and gastric MALT-lymphoma, the recently reported links between Chlamydia psittaci and ocular adnexal MALT-lymphoma and Borrelia burgdorferi and cutaneous MALT lymphoma constitute the most studied examples; in addition, Campylobacter jejuni and some more recent associations encompassing Achromobacter xylosoxidans and Haemophilus influenzae will be further reported. Biological and clinical features, therapeutic implications and future perspectives of these lymphoma-microbial associations are discussed in this review., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Nodal marginal zone lymphoma (NMZL) is a rare, indolent B-cell tumor that is distinguished from splenic marginal zone lymphoma (SMZL) by the different pattern of dissemination. NMZL still lacks distinct markers and remains orphan of specific cancer gene lesions. By combining whole-exome sequencing, targeted sequencing of tumor-related genes, whole-transcriptome sequencing, and high-resolution single nucleotide polymorphism array analysis, we aimed at disclosing the pathways that are molecularly deregulated in NMZL and we compare the molecular profile of NMZL with that of SMZL. These analyses identified a distinctive pattern of nonsilent somatic lesions in NMZL. In 35 NMZL patients, 41 genes were found recurrently affected in ≥3 (9%) cases, including highly prevalent molecular lesions of MLL2 (also known as KMT2D; 34%), PTPRD (20%), NOTCH2 (20%), and KLF2 (17%). Mutations of PTPRD, a receptor-type protein tyrosine phosphatase regulating cell growth, were enriched in NMZL across mature B-cell tumors, functionally caused the loss of the phosphatase activity of PTPRD, and were associated with cell-cycle transcriptional program deregulation and increased proliferation index in NMZL. Although NMZL shared with SMZL a common mutation profile, NMZL harbored PTPRD lesions that were otherwise absent in SMZL. Collectively, these findings provide new insights into the genetics of NMZL, identify PTPRD lesions as a novel marker for this lymphoma across mature B-cell tumors, and support the distinction of NMZL as an independent clinicopathologic entity within the current lymphoma classification., (© 2016 by The American Society of Hematology.)

Purpose: Prompted by the extensive biases in the immunoglobulin (IG) gene repertoire of splenic marginal-zone lymphoma (SMZL), supporting antigen selection in SMZL ontogeny, we sought to investigate whether antigen involvement is also relevant post-transformation., Experimental Design: We conducted a large-scale subcloning study of the IG rearrangements of 40 SMZL cases aimed at assessing intraclonal diversification (ID) due to ongoing somatic hypermutation (SHM)., Results: ID was identified in 17 of 21 (81%) rearrangements using the immunoglobulin heavy variable (IGHV)1-2*04 gene versus 8 of 19 (40%) rearrangements utilizing other IGHV genes (P= 0.001). ID was also evident in most analyzed IG light chain gene rearrangements, albeit was more limited compared with IG heavy chains. Identical sequence changes were shared by subclones from different patients utilizing the IGHV1-2*04 gene, confirming restricted ongoing SHM profiles. Non-IGHV1-2*04 cases displayed both a lower number of ongoing SHMs and a lack of shared mutations (per group of cases utilizing the same IGHV gene)., Conclusions: These findings support ongoing antigen involvement in a sizable portion of SMZL and further argue that IGHV1-2*04 SMZL may represent a distinct molecular subtype of the disease., (©2015 American Association for Cancer Research.)

Recent studies on splenic marginal zone lymphoma identified distinct mutations in genes belonging to the B-cell receptor and Toll-like receptor signaling pathways, thus pointing to their potential implication in the biology of the disease. However, limited data is available regarding the exact role of TLRs. We aimed at characterizing the expression pattern of TLRs in splenic marginal zone lymphoma cells and their functional impact on the activation, proliferation and viability of malignant cells in vitro. Cells expressed significant levels of TLR1, TLR6, TLR7, TLR8, TLR9 and TLR10 mRNA; TLR2 and TLR4 showed a low, variable pattern of expression among patients whereas TLR3 and TLR5 mRNAs were undetectable; mRNA specific for TLR signaling molecules and adapters was also expressed. At the protein level, TLR1, TLR6, TLR7, TLR9 and TLR10 were detected. Stimulation of TLR1/2, TLR2/6 and TLR9 with their respective ligands triggered the activation of IRAK kinases, MAPK and NF-κB signaling pathways, and the induction of CD86 and CD25 activation molecules, although in a heterogeneous manner among different patient samples. TLR-induced activation and cell viability were also inhibited by a specific IRAK1/4 inhibitor, thus strongly supporting the specific role of TLR signaling in these processes. Furthermore, TLR2/6 and TLR9 stimulation also significantly increased cell proliferation. In conclusion, we demonstrate that splenic marginal zone lymphoma cells are equipped with functional TLR and signaling molecules and that the stimulation of TLR1/2, TLR2/6 and TLR9 may play a role in regulating disease pathobiology, likely promoting the expansion of the neoplastic clone., (Copyright© Ferrata Storti Foundation.)

Splenic marginal zone lymphoma is a rare lymphoma. Loss of 7q31 and somatic mutations affecting the NOTCH2 and KLF2 genes are the commonest genomic aberrations. Epigenetic changes can be pharmacologically reverted; therefore, identification of groups of patients with specific epigenomic alterations might have therapeutic relevance. Here we integrated genome-wide DNA-promoter methylation profiling with gene expression profiling, and clinical and biological variables. An unsupervised clustering analysis of a test series of 98 samples identified 2 clusters with different degrees of promoter methylation. The cluster comprising samples with higher-promoter methylation (High-M) had a poorer overall survival compared with the lower (Low-M) cluster. The prognostic relevance of the High-M phenotype was confirmed in an independent validation set of 36 patients. In the whole series, the High-M phenotype was associated with IGHV1-02 usage, mutations of NOTCH2 gene, 7q31-32 loss, and histologic transformation. In the High-M set, a number of tumor-suppressor genes were methylated and repressed. PRC2 subunit genes and several prosurvival lymphoma genes were unmethylated and overexpressed. A model based on the methylation of 3 genes (CACNB2, HTRA1, KLF4) identified a poorer-outcome patient subset. Exposure of splenic marginal zone lymphoma cell lines to a demethylating agent caused partial reversion of the High-M phenotype and inhibition of proliferation., (© 2015 by The American Society of Hematology.)

Extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT) is an indolent B-cell non-Hodgkin lymphoma (NHL) arising in lymphoid populations that are induced by chronic inflammation in extra nodal sites. The stomach is the most commonly affected organ, and MALT lymphoma is clearly associated with a gastroduodenitis induced by a microbial pathogen, Helicobacter pylori, thus gastric MALT lymphoma represents a paradigm for evaluating inflammatory-associated lymphomagenesis. Variable levels of evidence have indicated a possible association between other microorganisms and non-gastric MALT lymphomas. In addition to infectious etiology, chronic inflammation arising as a result of autoimmune diseases such as Sjogren's syndrome or Hashimoto thyroiditis, poses a significant risk factor for developing NHL. Recently, genetic alterations affecting the NF-κB pathway, a major signaling pathway involved in many cancers, have been identified in MALT lymphoma. This review will present MALT lymphoma as an example of the close pathogenetic link between chronic microenvironmental inflammation and tumor development, showing how these observations can be integrated into daily clinical practice, also in terms of therapeutic implications, with particular focus on the NF-κB pathway., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives: To assess Chlamydophila psittaci (Cp) subclinical infection in patients with Sjögren's syndrome (SS)., Methods: Seventy-four SS patients (55.4 ±13.4 yrs; 94.6% females) were studied. Among them, 18 had salivary gland mucosa-associated lymphoid tissue (MALT) B-cell lymphoma, 20 myoepithelial sialoadenitis (MESA), and 36 no lymphoproliferative disorders (LPD). The presence of Cp DNA was assessed in peripheral blood of all patients by specific PCR protocols. Paired salivary gland samples were also investigated whenever available (34 cases), including lymphomatous and non-lymphomatous samples, as well as major and minor salivary gland tissues. As controls, 225 blood donors were analysed in the peripheral blood., Results: Overall, Cp DNA was detected in 11/74 (14.9%) SS patients vs. 1/225 (0.4%) controls (p<0.0001). Cp was detected at higher frequency in MALT lymphoma patients (6/18, 33.3%), as compared with MESA (3/20, 15%) or patients without LPD (2/36, 5.6%), (MALT lymphomas vs. others: p=0.02). A similar Cp prevalence was observed in blood vs. salivary gland tissues, however with a higher frequency in the major than in the minor salivary glands (5/18, 27.8%, vs. 1/17, 5.9%, p=0.18). Cp-positive patients were all rheumatoid factor positive (11/11, 100% vs. 40/63, 63.5% Cp-negative; p=0.014), while no difference was noticed for anti-SSA/SSB positivity., Conclusions: In the light of accepted models of MALT B-cell lymphomagenesis and considering previous data implicating Cp infection in ocular adnexa MALT lymphoma, our results suggest that Cp infection could be involved also in a fraction of patients with SS developing lymphoma. The potential therapeutic implications of these findings appear worthwhile.

A link with infectious agents, bacteria and viruses in particular, has been reported for many lymphoma entities. Marginal zone lymphomas (extranodal, nodal and splenic forms) are frequently associated with chronic infections, with important clinical, molecular, biological, and therapeutic implications. The well-known correlation between Helicobacter pylori and gastric MALT-lymphoma, the recently reported links between Chlamydophila psittaci and ocular adnexal MALT-lymphoma and Borrelia burgdorferi and cutaneous MALT lymphoma constitute the best studied examples of lymphomagenic activity of bacteria, while the hepatitis C virus represents the most extensively investigated virus associated with marginal zone lymphomas. Biological and clinical features, therapeutic implications and future perspectives of these lymphoma-microbial associations are discussed in this review., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Purpose of Review: This review is focused on the effect of Helicobacter pylori eradication with antibiotics in patients with primary gastric lymphomas of indolent and aggressive nature., Recent Findings: Gastrointestinal lymphoma is the most common form of extranodal lymphoma, involving primarily the stomach in 60-75% of cases. The most common histological subtypes are diffuse large B-cell lymphoma (DLBCL) and marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT)-type. H. pylori infection has been implicated in the pathogenesis of gastric MALT lymphoma; its role in gastric DLBCL remains controversial. Recently, international guidelines established that patients with gastric MALT lymphoma should be treated with upfront H. pylori-eradicating antibiotic therapy and that residual microscopic or molecular disease does not need for additional antiblastic treatment. The excellent prognosis of patients with gastric DLBCL managed with conservative chemo-radiotherapy led some investigators to test H. pylori eradication as exclusive treatment in prospective trials, keeping chemo-radiotherapy for unresponsive patients. This conservative strategy was well tolerated and active in patients with limited-stage DLBCL (±MALT areas) of the stomach., Summary: H. pylori eradication is a suitable strategy as exclusive upfront treatment for both patients with MALT-type lymphomas or with DLBCL of the stomach. Additional trials are needed to elucidate related controversial issues.

The International Extranodal Lymphoma Study Group (IELSG) promoted this study to determine the inter-observer agreement in the application of the Groupe d' Etude des Lymphomes de l' Adulte (GELA) histological scoring system for evaluating residual disease in post-treatment gastric biopsies of patients with gastric Mucosa-Associated Lymphoid Tissue (MALT) lymphoma (GML). Twenty-one patients with Helicobacter pylori -associated GML and treated with anti-H. pylori therapies were considered. A total of 154 biopsy sets from follow-up endoscopic procedures after H. pylori eradication were examined independently by seven pathologists from four European countries, following histological criteria suggested by the GELA scoring system. The overall concordance rate was 83% with a kappa value of 0·64, indicating a significant agreement among the seven observers. Most non-concordant responses clustered across the border of complete remission (CR) and probable minimal residual disease (pMRD), a distinction that does not imply critical clinical impact. Accordingly, when the analysis considered CR/pMRD as a single entity, the responses showed an overall concordance rate of 89% with kappa value of 0·83, thus indicating a high degree of inter-observer agreement. This study provides additional validation of the GELA histological grading system. This scheme can therefore be recommended in routine practice and deserves to be used in prospective clinical trials., (© 2012 Blackwell Publishing Ltd.)

Aims: The aim of this study was to search for a molecule selectively expressed by marginal zone (MZ) lymphomas (MZLs), whose diagnosis is currently based on morphological criteria and negativity for markers detectable in other B-cell lymphomas., Methods and Results: Two thousand one hundred and four peripheral lymphomas of various types were immunostained with a monoclonal antibody against immunoglobulin superfamily receptor translocation-associated 1 (IRTA1), which recognizes the equivalents of MZ in human lymphoid tissues other than spleen. IRTA1 expression was restricted to extranodal (93%) and nodal MZLs (73%) and to lymphomas with MZ differentiation. Extranodal MZL cells with the strongest IRTA1 expression were usually located adjacent to epithelia, mimicking the IRTA1 expression pattern of normal and acquired mucosa-associated lymphoid tissue (MALT). The cytological features, growth pattern and IRTA1 positivity in nodal MZLs suggest they may derive from IRTA1(+) perifollicular B cells or monocytoid B cells detectable in reactive lymph nodes. Double immunostaining for IRTA1/bcl-6 tracked the colonization of B-cell follicles by MZL cells, and showed modulation of their phenotype (e.g. acquisition of bcl-6) during recirculation through germinal centres. MZL cells differentiating into plasma cells usually lost IRTA1., Conclusions: These results further expand our knowledge of the biology of MZLs, and highlight IRTA1 as the first positive marker for MZLs, enabling more accurate diagnosis of these neoplasms., (© 2012 Blackwell Publishing Ltd.)

Primary splenic small B-cell lymphomas mostly comprise the distinct entity of splenic marginal-zone lymphoma (SMZL) and the provisional category of splenic lymphoma/leukemia unclassifiable, mainly represented by the hairy cell leukemia variant and splenic diffuse red pulp small B-cell lymphoma (SDRL). Until recently, histopathologic examination of splenectomy specimens was considered mandatory for the diagnosis of SMZL. However, nowadays, mainly because of advances in chemoimmunotherapy, splenectomy is performed much less frequently. We evaluated the diagnostic efficacy of bone marrow biopsy (BMB) histopathology in the diagnostic approach toward SMZL and SDRL and tested whether it may serve as a substitute for spleen histopathology in the differential diagnosis between these 2 entities. To this end, we conducted a paired assessment of BMB and spleen diagnostic samples from 46 cases with a diagnosis of SMZL (n=32) or SDRL (n=14) based on spleen histopathology. We demonstrate that detailed immunohistopathologic BMB evaluation offers adequate evidence for the confirmation of these entities and their differential diagnosis from other small B-cell lymphoma histotypes. Notably, the immunophenotypical profile of SMZL and SDRL was identical in both BMB and spleen specimens for 21 evaluated markers. Paired assessment of BMB and spleen specimens did not identify discriminating patterns of BMB infiltration, cytology, and/or immunohistology between SMZL and SDRL. Accordingly, bone marrow histopathology contributes significantly in confirming the diagnosis of SMZL and SDRL. However, presently it is not possible to distinguish SMZL from SDRL on the basis of BMB evaluation alone; hence, histopathologic examination of the spleen remains the "gold standard" approach.

Purpose: The pathogenic association between Chlamydophila psittaci (Cp) and ocular adnexal marginal zone lymphoma (OAMZL) and the efficacy of doxycycline monotherapy have been investigated in retrospective series with variations in stage, management, and follow-up duration. To our knowledge, this is the first international phase II trial aimed at clarifying Cp prevalence and activity of first-line doxycycline in a homogeneous series of consecutive patients with newly diagnosed stage I OAMZL., Patients and Methods: Forty-seven patients were registered. Tumor tissue, conjunctival swabs, and peripheral blood from 44 patients were assessed for seven Chlamydiaceae infections by three polymerase chain reaction protocols. Thirty-four patients with measurable or parametrable disease were treated with doxycycline and assessed for chlamydial eradication and lymphoma response (primary end point)., Results: Cp DNA was detected in biopsies of 39 patients (89%); no other Chlamydiaceae were detected. Twenty-nine patients had Cp DNA in baseline swabs and/or blood samples and were evaluable for chlamydial eradication, which was achieved in 14 patients (48%). Lymphoma regression was complete in six patients and partial in 16 (overall response rate, 65%; 95% CI, 49% to 81%); 11 had stable disease, and one had progressive disease. At a median follow-up of 37 months (range, 15 to 62 months), 20 patients remained relapse free (5-year progression-free survival [PFS] ± standard deviation, 55% ± 9%). Cp eradication was associated with improved response rate (86% v 47%; P = .02) and 5-year PFS (68% v 47%; P = .11)., Conclusion: Upfront doxycycline is a rational and active treatment for patients with stage I Cp-positive OAMZL. Lymphoma regression is consequent to Cp eradication, which can easily be monitored on conjunctival and blood samples. Prospective trials aimed at identifying more effective administration schedules for doxycycline are warranted.

We performed an immunogenetic analysis of 345 IGHV-IGHD-IGHJ rearrangements from 337 cases with primary splenic small B-cell lymphomas of marginal-zone origin. Three immunoglobulin (IG) heavy variable (IGHV) genes accounted for 45.8% of the cases (IGHV1-2, 24.9%; IGHV4-34, 12.8%; IGHV3-23, 8.1%). Particularly for the IGHV1-2 gene, strong biases were evident regarding utilization of different alleles, with 79/86 rearrangements (92%) using allele (*)04. Among cases more stringently classified as splenic marginal-zone lymphoma (SMZL) thanks to the availability of splenic histopathological specimens, the frequency of IGHV1-2(*)04 peaked at 31%. The IGHV1-2(*)04 rearrangements carried significantly longer complementarity-determining region-3 (CDR3) than all other cases and showed biased IGHD gene usage, leading to CDR3s with common motifs. The great majority of analyzed rearrangements (299/345, 86.7%) carried IGHV genes with some impact of somatic hypermutation, from minimal to pronounced. Noticeably, 75/79 (95%) IGHV1-2(*)04 rearrangements were mutated; however, they mostly (56/75 cases; 74.6%) carried few mutations (97-99.9% germline identity) of conservative nature and restricted distribution. These distinctive features of the IG receptors indicate selection by (super)antigenic element(s) in the pathogenesis of SMZL. Furthermore, they raise the possibility that certain SMZL subtypes could derive from progenitor populations adapted to particular antigenic challenges through selection of VH domain specificities, in particular the IGHV1-2(*)04 allele.

Evidence from certain geographical areas links lymphomas of the ocular adnexa marginal zone B-cell lymphomas (OAMZL) with Chlamydophila psittaci (Cp) infection, suggesting that lymphoma development is dependent upon chronic stimulation by persistent infections. Notwithstanding that, the actual immunopathogenetical mechanisms have not yet been elucidated. As in other B-cell lymphomas, insight into this issue, especially with regard to potential selecting ligands, could be provided by analysis of the immunoglobulin (IG) receptors of the malignant clones. To this end, we studied the molecular features of IGs in 44 patients with OAMZL (40% Cp-positive), identifying features suggestive of a pathogenic mechanism of autoreactivity. Herein, we show that lymphoma cells express a distinctive IG repertoire, with electropositive antigen (Ag)-binding sites, reminiscent of autoantibodies (auto-Abs) recognizing DNA. Additionally, five (11%) cases of OAMZL expressed IGs homologous with autoreactive Abs or IGs of patients with chronic lymphocytic leukemia, a disease known for the expression of autoreactive IGs by neoplastic cells. In contrast, no similarity with known anti-Chlamydophila Abs was found. Taken together, these results strongly indicate that OAMZL may originate from B cells selected for their capability to bind Ags and, in particular, auto-Ags. In OAMZL associated with Cp infection, the pathogen likely acts indirectly on the malignant B cells, promoting the development of an inflammatory milieu, where auto-Ags could be exposed and presented, driving proliferation and expansion of self-reactive B cells.

Background: Ocular adnexal marginal zone B-cell lymphoma (OAMZL) has been associated with Chlamydophila psittaci, an infection that may be transmitted by carrier animals. However, it is still unclear whether exposure to animals affects the risk of OAMZL in comparison with other lymphoma histotypes. We therefore investigated the role of professional and/or domestic exposures to animals in the occurrence of OAMZL, as compared with other types of lymphoma., Methods: A hospital-based case-control study was carried out on 43 consecutive OAMZL patients (cases) and 87 consecutive patients with nodal non-Hodgkin's lymphomas (NHLs; controls). Multiple logistic regression (MLR) odds ratios (ORs), and 95% confidence intervals (CIs) were used to estimate the association between exposures to animals and OAMZL risk., Results: A higher proportion of cases reported a lifetime exposure to household animals (79.1% vs 64.4% among controls), with a non-statistical significant MLR-OR of 2.18 (95% CI: 0.85-5.62). The OAMZL cases more frequently reported a history of occupation in breeding and/or slaughtering than controls (34.9% vs 6.9%), with an overall increased risk of 7.69 (95%CI: 2.65-22.34)., Conclusion: These results indicate that, compared with nodal NHLs, the risk of OAMZL is markedly increased by contact with animals, particularly by occupational exposures.

MALT lymphomas present common features, but important differences are associated with involvement of specific anatomical sites, many likely contributing to the biology. To test the existence of genetic alterations specific for primary anatomical sites of involvement, genomic profiles obtained with high-density arrays were analyzed in 130 MALT lymphomas across a spectrum of anatomic sites. Trisomies 3 and 18 and del(6q23) occurred at a similar frequency. Instead, gains at 6p appeared significantly more common among MALT lymphomas involving the orbital adnexa. Gastric involvement showed a trend for a higher frequency of 8q gains. In conclusion, MALT lymphomas appear to bear a common set of recurrent unbalanced genomic alterations independent of the anatomical site. This differs from what has been observed for common chromosome translocations. Only a few alterations such as gains at 6p and, possibly, gains at 8q show preferential involvement at specific anatomical sites.

Extranodal marginal zone B-cell lymphomas are linked to bacterial infections that vary according to the anatomical site. The occurrence of these lymphomas in the central nervous system is a very rare event, and the identification of specific bacteria in this setting has not been previously addressed. Herein, we report for the first time a case of primary central nervous system marginal zone B-cell lymphoma involving the choroid plexus associated with Chlamydophila psittaci infection. No concomitant ocular involvement was detected. C psittaci was identified with 3 independent methods, and through immunohistochemistry, it was visualized in the cytoplasm of monocytes/macrophages present within lymphomatous tissues. This observation points toward the opportunity to investigate the prevalence of C psittaci infection in central nervous system lymphomas, particularly in those with low-grade histologic features., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The diagnosis of gastric MALT lymphoma is frequently difficult for the general histopathologist. During recent years there have been relevant changes in the therapeutic approach to gastric MALT lymphoma and our knowledge about its pathogenesis has greatly improved. The management of this disease actually requires a close cooperation between the histopathologist and the clinicians. The histology report of biopsies of a newly diagnosed or of an already treated case implies information of clinical and therapeutical relevance. This paper aims at giving the histopathologist a general knowledge about the state of art of this disease and its management. The diagnostic process leading to a complete and competent report is then described step by step., (Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd.. All rights reserved.)

Marginal zone B-cell lymphomas (MZLs) have been divided into 3 distinct subtypes (extranodal MZLs of mucosa-associated lymphoid tissue [MALT] type, nodal MZLs, and splenic MZLs). Nevertheless, the relationship between the subtypes is still unclear. We performed a comprehensive analysis of genomic DNA copy number changes in a very large series of MZL cases with the aim of addressing this question. Samples from 218 MZL patients (25 nodal, 57 MALT, 134 splenic, and 2 not better specified MZLs) were analyzed with the Affymetrix Human Mapping 250K SNP arrays, and the data combined with matched gene expression in 33 of 218 cases. MALT lymphoma presented significantly more frequently gains at 3p, 6p, 18p, and del(6q23) (TNFAIP3/A20), whereas splenic MZLs was associated with del(7q31), del(8p). Nodal MZLs did not show statistically significant differences compared with MALT lymphoma while lacking the splenic MZLs-related 7q losses. Gains of 3q and 18q were common to all 3 subtypes. del(8p) was often present together with del(17p) (TP53). Although del(17p) did not determine a worse outcome and del(8p) was only of borderline significance, the presence of both deletions had a highly significant negative impact on the outcome of splenic MZLs.

Chlamydiae are obligate intracellular bacteria that grow in eukaryotic cells and cause a wide spectrum of diseases. They can establish persistent infections, are mitogenic in vitro, promote polyclonal cell proliferation in vivo and induce resistance to apoptosis in infected cells-properties that might contribute to tumorigenesis. In fact, Chlamydophila psittaci (Cp) has been linked to the development and maintenance of ocular adnexal marginal zone B-cell lymphoma (OAMZL). In this indolent malignancy, Cp is transported by monocytes and macrophages and causes both local and systemic infection. Cp elementary bodies are viable and infectious in the conjunctiva and peripheral blood of patients with OAMZL. Bacterial eradication with antibiotic therapy is often followed by lymphoma regression. Despite recent advances in the understanding of this bacterium-lymphoma association, several questions remain unanswered. For instance, prevalence variations among different geographical areas and related diagnostic and therapeutic implications remain a major investigational issue. We will focus on clinical and therapeutic implications of chlamydial infections in patients with lymphomas and summarize the current knowledge on the association between Cp infection and OAMZL. Available data on the epidemiology, biology and pathogenesis of this association are analyzed and new investigative and clinical approaches are discussed.

Ocular adnexal MALT lymphoma (OAML) is linked to Chlamydophila psittaci (Cp) infection. Viability and infectivity of Cp, demonstrated by growth in culture, has not been yet investigated in these patients. We conducted a single-center prospective case-control study to assess the prevalence, viability and infectivity of Cp in 20 OAML patients and 42 blood donors registered in a 6-month period. The presence of Cp in conjunctival swabs and peripheral blood mononuclear cells (PBMC) of patients and donors was assessed by TETR-PCR and in vitro cultures. From an epidemiological point of view, OAML patients often resided in rural areas, and reported a history of chronic conjunctivitis and prolonged contact with household animals (85% vs. 38% of donors; p = 0.00001). Cp was detected in lymphoma tissue in 15 (75%) patients. Cp DNA was detected in conjunctival swabs and/or PBMC from 10 (50%) patients and in PBMC from 1 (2%) donor (p = 0.01). Viability and infectivity of Cp, demonstrated by growth in culture, were confirmed in conjunctival swabs and/or PBMC from 5 (25%) patients, but not in donors (p = 0.002). This prospective study demonstrates, for the first time, that Cp present in the conjunctiva and PBMC of OAML patients is capable to grow and be isolated in cell cultures. Cp infection is common in OAML patients and exceptional in blood donors. Epidemiological data of OAML patients (prolonged contact with household animals and chronic conjunctivitis) are consistent with Cp exposure risk.

Since the first publication in 2004, a large number of reports have raised the question of an association between ocular adnexal lymphoma and Chlamydia psittaci. The results of this scientific debate, however, remain controversial. The primary objective of this paper was therefore to raise important questions concerning the interpretation of the different and heterogeneous data on the association between Chlamydophila psittaci and ocular adnexal lymphoma, namely the impact of the methodology used and the epidemiological variability of seroprevalence of C. psittaci antibodies. This paper also provides some methodological suggestions for future studies in the field of chlamydia-lymphoma associations.

Non-Hodgkin's lymphomas constitute one half of malignancies arising in the orbit and the ocular adnexae. Mucosa-associated lymphoid tissue (MALT)-type lymphoma is the most common histological category in this anatomic region. The incidence of ocular adnexal lymphoma of mucosa-associated lymphoid tissue-type (OAML) is increasing and recent studies offered new relevant insights in molecular, pathogenetic and therapeutic issues on these neoplasms. A pathogenetic model of antigen-driven lymphoproliferation similar to that reported for Helicobacter pylori-related gastric MALT lymphomas has been hypothesized for OAML. This notion is supported by the association between OAML and Chlamydophila psittaci infection, an association that is of likely pathogenetic relevance and may influence both the biological behavior and the therapeutic management of these neoplasms. However, this association displays evident geographical variability indicating that other etiopathogenic agents could be involved. These recent acquisitions coupled with the occurrence of chromosomal translocations and other genetic alterations, as well as additional risk factors like autoimmune disorders have contributed to render OAML an exciting challenge for a broad group of physicians and scientists. OAML is an indolent and rarely lethal malignancy that, in selected patients, can be managed with observation alone. Lymphomatous lesions are frequently responsible for symptoms affecting patient's quality of life, requiring, therefore, immediate treatment. Several therapeutic strategies are available, often associated with relevant side-effects. However, the therapeutic choice in OAML is not supported by consolidated evidence due to the lack of prospective trials. In this review, we analyze the most relevant biological, molecular, pathological and clinical features of OAML and propose some therapeutic guidelines for patients affected by this malignancy.

Non-Hodgkin lymphomas constitute 50% of all orbital malignancies. Mucosa-associated lymphoid tissue (MALT)-type lymphoma is the most common histology category in this anatomic region. Ocular adnexal lymphoma of MALT-type is an indolent and rarely lethal malignancy that can often be managed with observation alone. Occasionally, lymphomatous lesions determine the symptoms that condition a patient's quality of life, and so require an immediate antineoplastic treatment. Several strategies are available, but reliable indications supported by prospective trials do not exist. Some therapeutic strategies are associated with substantial side effects and require a well-balanced therapeutic decision, which should take into account several variables related to the patient, the lymphoma, and the treatment itself. In this review, the authors analyze related literature and propose therapeutic guidelines for the management of ocular adnexal lymphoma of MALT-type.