Marginal zone lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

•This updated ESMO Clinical Practice Guideline provides key recommendations on the management of marginal zone lymphomas.•Authorship includes a multidisciplinary group of experts from different institutions and countries in Europe and abroad.•A summary of recommendations is provided, including levels of evidence and grades of recommendation where applicable.•The distinct disease entities (i.e. extranodal, nodal and splenic marginal zone lymphomas) are discussed separately.•Organ-specific peculiarities are addressed in the recommendations for extranodal marginal zone lymphomas (MALT lymphomas). In the last update of the World Health Organization (WHO) classification, the marginal zone B-cell lymphomas (MZLs) comprise extranodal MZL (EMZL) of mucosa-associated lymphoid tissue (MALT), also known as MALT lymphoma, splenic MZL (SMZL) with or without villous lymphocytes and nodal MZL (NMZL) with or without monocytoid B cells. These are three distinct clinical entities with specific diagnostic criteria and different genetic features, clinical behaviour and therapeutic implications.1Campo E. Pileri S.A. Jaffe E.S. et al.Nodal marginal zone B-cell lymphoma.in: Swerdlow S.H. Campo E. Harris N.L. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. IARC, Lyon2017: 263-265Google Scholar, 2Piris M.A. Isaacson P.I. Swerdlow S.H. et al.Splenic marginal zone lymphoma.in: Swerdlow S.H. Campo E. Harris N.L. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. IARC Press, Lyon2017: 223-225Crossref Scopus (21) Google Scholar, 3Cook J.R. Isaacson P.G. Chott A. et al.Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma).in: Swerdlow S.H. Campo E. Harris N.L. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. IARC Press, Lyon2017: 259-262Google Scholar The onset of an overt MZL, particularly of SMZL, may be preceded by the appearance of clonal B cells in the blood, a condition recently described as clonal B-cell lymphocytosis of marginal zone origin (CBL-MZ).4Xochelli A. Kalpadakis C. Gardiner A. et al.Clonal B-cell lymphocytosis exhibiting immunophenotypic features consistent with a marginal-zone origin: is this a distinct entity?.Blood. 2014; 123: 1199-1206Crossref PubMed Scopus (66) Google Scholar MZLs represent approximately 5%–15% of all non-Hodgkin lymphomas in the Western world. EMZLs comprise approximately two-thirds and can arise at any extranodal site, usually in the context of chronic antigenic stimulation due either to infections or autoimmune disorders. The stomach is the most common site, followed by ocular adnexa, lung and salivary glands. SMZL accounts for ∼20% and NMZL for <10% of cases. Aetiological heterogeneity is apparent across the anatomical sites, probably influenced by either intrinsic genetic/molecular characteristics or geographical factors and environmental exposures. Overall, the incidence appears to have increased in the last two decades (possibly because of improved pathological diagnosis), despite a decline in the incidence of Helicobacter pylori-associated gastric MZLs.5Zucca E. Bertoni F. The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance.Blood. 2016; 127: 2082-2092Crossref PubMed Scopus (164) Google Scholar The diagnosis should follow the current 2017 WHO classification and requires an adequate tumour biopsy [IV, A]. The typical (centrocyte-like) marginal zone B cells have small- to medium-sized, slightly irregular nuclei with inconspicuous nucleoli, moderately dispersed chromatin and pale cytoplasm. The accumulation of abundant pale-staining cytoplasm may lead to a monocytoid appearance.3Cook J.R. Isaacson P.G. Chott A. et al.Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma).in: Swerdlow S.H. Campo E. Harris N.L. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. IARC Press, Lyon2017: 259-262Google Scholar Differential diagnosis from mimics of MZL mainly depends upon immunohistochemistry (IHC), including at least CD20, CD10, CD5, CD23, cyclin D1, immunoglobulin (Ig) D and SOX-11 [IV, B] (Table 1). It is recommended that diagnostic and follow-up biopsies of MZL should be reviewed and confirmed by an expert haematopathologist.6Dreyling M. Thieblemont C. Gallamini A. et al.ESMO Consensus conferences: guidelines on malignant lymphoma. Part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma.Ann Oncol. 2013; 24: 857-877Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar Although there are no entirely definitive criteria, a diagnosis of evolution to large B-cell lymphoma should be made when there are clearly separated sheets of large cells comprising >20% of the neoplastic population [V, B].Table 1Immunohistochemical and molecular markers in MZLMoleculeType of testExpected resultLevel of recommendationCD20IHCPositiveMandatoryCD5IHCNegativeaFew exceptions may occur.MandatoryCD23IHCNegative/positiveSuggestedbIn cases with small cell morphology, irrespectively of CD5-concurrent positivity.CD10IHCNegativeMandatoryIgDIHCNegativecIn cases with splenomegaly, as it is usually positive in SMZL.SuggestedCyclin D1IHCNegativeMandatorydIn cases positive for CD5.MYD88 mutationPCRNegativeSuggestedeWhen present, a differential diagnostic problem with LPL arises (cases of MZL with MYD88 mutation may represent rare exceptions).IgD, immunoglobulin D; IHC, immunohistochemistry; LPL, lymphoplasmacytic lymphoma; MZL, marginal zone lymphoma; PCR, polymerase chain reaction; SMZL, splenic marginal zone lymphoma.a Few exceptions may occur.b In cases with small cell morphology, irrespectively of CD5-concurrent positivity.c In cases with splenomegaly, as it is usually positive in SMZL.d In cases positive for CD5.e When present, a differential diagnostic problem with LPL arises (cases of MZL with MYD88 mutation may represent rare exceptions). Open table in a new tab IgD, immunoglobulin D; IHC, immunohistochemistry; LPL, lymphoplasmacytic lymphoma; MZL, marginal zone lymphoma; PCR, polymerase chain reaction; SMZL, splenic marginal zone lymphoma. This condition is defined by the presence of circulating clonal B cells with phenotypic features consistent with a marginal zone origin in the absence of splenomegaly, hepatomegaly, lymphadenopathy or other symptoms and signs suggestive of an established lymphoma. Unlike chronic lymphocytic leukaemia (CLL)-like monoclonal B-cell lymphocytosis (MBL) which may precede the development of CLL, there is no defined cut-off in the clonal B-cell lymphocyte count for discriminating CBL-MZ from MZL. Only a minority (15%–20%) of patients will eventually progress to an overt lymphoma, most often an SMZL.4Xochelli A. Kalpadakis C. Gardiner A. et al.Clonal B-cell lymphocytosis exhibiting immunophenotypic features consistent with a marginal-zone origin: is this a distinct entity?.Blood. 2014; 123: 1199-1206Crossref PubMed Scopus (66) Google Scholar Lymphoepithelial lesions are neither essential for the diagnosis of EMZL nor absolutely specific for this entity, as they can be seen in some reactive conditions as well as in other lymphoma subtypes. In gastric MZL, if the presence of active H. pylori infection is not demonstrated by (immuno)histochemistry, it must be ruled out by serology, urea breath test and/or stool antigen test.7Ruskone-Fourmestraux A. Fischbach W. Aleman B.M. et al.EGILS consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.Gut. 2011; 60: 747-758Crossref PubMed Scopus (249) Google Scholar In addition to routine histology and IHC, fluorescent in situ hybridisation (FISH) studies for detection of t(11;18)(p21;p21) may be useful for identifying gastric MZL patients who are unlikely to respond to antibiotic therapy [III, B].5Zucca E. Bertoni F. The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance.Blood. 2016; 127: 2082-2092Crossref PubMed Scopus (164) Google Scholar In most instances, the diagnosis of splenic small B-cell lymphomas of marginal origin, usually SMZL, can be established without a splenectomy specimen, through a combination of peripheral blood/bone marrow aspirate morphology and flow cytometry, as well as bone marrow biopsy histology and IHC, reviewed by expert haematopathologists/haematologists [IV, B].2Piris M.A. Isaacson P.I. Swerdlow S.H. et al.Splenic marginal zone lymphoma.in: Swerdlow S.H. Campo E. Harris N.L. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. IARC Press, Lyon2017: 223-225Crossref Scopus (21) Google Scholar,8Franco V. Florena A.M. Iannitto E. Splenic marginal zone lymphoma.Blood. 2003; 101: 2464-2472Crossref PubMed Scopus (133) Google Scholar,9Matutes E. Oscier D. Montalban C. et al.Splenic marginal zone lymphoma proposals for a revision of diagnostic, staging and therapeutic criteria.Leukemia. 2008; 22: 487-495Crossref PubMed Scopus (204) Google Scholar However, the accuracy and reproducibility of this approach have not yet been fully investigated. In a minority of cases, the definitive diagnosis may not be possible without splenectomy. The same holds for the definitive differential diagnosis between SMZL and splenic diffuse red pulp lymphoma, as they share similar features in the peripheral blood and bone marrow.10Ponzoni M. Kanellis G. Pouliou E. et al.Bone marrow histopathology in the diagnostic evaluation of splenic marginal-zone and splenic diffuse red pulp small B-cell lymphoma: a reliable substitute for spleen histopathology?.Am J Surg Pathol. 2012; 36: 1609-1618Crossref PubMed Google Scholar,11Swerdlow S.H. Campo E. Pileri S.A. et al.The 2016 revision of the World Health Organization classification of lymphoid neoplasms.Blood. 2016; 127: 2375-2390Crossref PubMed Scopus (4468) Google Scholar Neoplastic lymphocytes in SMZL often display villi; however, these are not seen in all cases (sometimes for technical reasons) and not every lymphoma displaying villi corresponds to SMZL.2Piris M.A. Isaacson P.I. Swerdlow S.H. et al.Splenic marginal zone lymphoma.in: Swerdlow S.H. Campo E. Harris N.L. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. IARC Press, Lyon2017: 223-225Crossref Scopus (21) Google Scholar NMZL shares morphological and immunophenotypic similarities with other MZLs, and its differential diagnosis from other indolent lymphomas can be particularly difficult, unless so-called ‘monocytoid B-cell morphology’ is prominent. A small monoclonal component, usually IgM, may be detected and, in such cases, differential diagnosis from lymphoplasmacytic lymphoma (LPL) may be necessary. Since MYD88 gene mutations are detected in the large majority of LPLs, this molecular aberration may be used for diagnostic purposes, with the knowledge that MZLs rarely harbour MYD88 mutations.12Swerdlow S.H. Kuzu I. Dogan A. et al.The many faces of small B cell lymphomas with plasmacytic differentiation and the contribution of MYD88 testing.Virchows Arch. 2016; 468: 259-275Crossref PubMed Scopus (78) Google Scholar In all cases, but particularly for NMZL, the histopathological diagnosis must be established with full knowledge of the clinical and radiological presentation [IV, A]. NMZL is also seen in children. Notably, paediatric NMZL has distinct morphological and clinical characteristics. It is much more common in boys, usually presents as asymptomatic and localised disease and has a much better prognosis than adult-onset cases.1Campo E. Pileri S.A. Jaffe E.S. et al.Nodal marginal zone B-cell lymphoma.in: Swerdlow S.H. Campo E. Harris N.L. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. IARC, Lyon2017: 263-265Google Scholar Mandatory initial staging for all MZL subtypes should include:•history and physical examination, noting lymph node regions, eyes and ears, nose and throat, liver and spleen;•full blood and differential counts, with flow cytometry of peripheral blood mandatory in NMZL and SMZL and optional in EMZL;•biochemistry, including renal and liver function tests;•protein electrophoresis;•lactate dehydrogenase (LDH) and β2 microglobulin (B2M);•optional direct antiglobulin (Coombs) test in SMZL;•serum and urine immunofixation;•serology for hepatitis C virus (HCV) [if positive, including HCV-RNA polymerase chain reaction (PCR) test and virus genotyping];•cryoglobulins and cryocrit if HCV-positive;•hepatitis B virus (HBV) markers and human immunodeficiency virus (HIV) serology. Bone marrow aspirate (with morphology and flow cytometry) and biopsy are mandatory in NMZL and SMZL and highly recommended in EMZL, particularly in non-gastric lymphoma and when only local treatment is planned. Imaging should include complete chest and abdominal computed tomography (CT) scan [or magnetic resonance imaging (MRI)] and imaging of the orbits and salivary glands [IV, B]. Positron emission tomography (PET) scanning has generally been considered of little clinical utility; however, this is now being reconsidered as a result of the increased sensitivity of modern PET-CT equipment. It may be useful in cases when only localised treatment is planned. PET scanning should also be considered when clinical and/or laboratory data suggest transformation to high-grade histology and to guide decisions on which lymph node to target for biopsy [IV, B]. Endoscopic ultrasound (US) for gastric MZL can be used to define gastric wall infiltration and perigastric lymph node involvement. EMZL usually remains localised for a prolonged period within the tissue of origin, but involvement of regional lymph nodes and multiple mucosal sites may be present at diagnosis. Within the stomach, the disease is usually multifocal. Concomitant involvement of multiple mucosal sites is not rare, particularly in non-gastric EMZLs, with disseminated disease reported in 25%–50% of cases. Bone marrow infiltration has been described in 2%–20% of cases, with lower rates in recent series, and is more common in non-gastric lymphomas.13Raderer M. Kiesewetter B. Ferreri A.J. Clinicopathologic characteristics and treatment of marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma).CA Cancer J Clin. 2016; 66: 153-171Crossref PubMed Scopus (135) Google Scholar EMZLs with lymph node or bone marrow involvement at presentation carry a worse prognosis, but this is not the case for those with involvement of multiple mucosal sites.14Zucca E. Conconi A. Pedrinis E. et al.Nongastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue.Blood. 2003; 101: 2489-2495Crossref PubMed Scopus (418) Google Scholar The best system for staging of gastric MZL is controversial.6Dreyling M. Thieblemont C. Gallamini A. et al.ESMO Consensus conferences: guidelines on malignant lymphoma. Part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma.Ann Oncol. 2013; 24: 857-877Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar,7Ruskone-Fourmestraux A. Fischbach W. Aleman B.M. et al.EGILS consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.Gut. 2011; 60: 747-758Crossref PubMed Scopus (249) Google Scholar The Lugano staging system has been widely used previously, but more modern systems have been proposed, such as the Paris staging system which describes the depth of gastric wall involvement more accurately, a parameter that may predict the response to H. pylori eradication (Table 2).7Ruskone-Fourmestraux A. Fischbach W. Aleman B.M. et al.EGILS consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.Gut. 2011; 60: 747-758Crossref PubMed Scopus (249) Google Scholar,15Ruskone-Fourmestraux A. Dragosics B. Morgner A. et al.Paris staging system for primary gastrointestinal lymphomas.Gut. 2003; 52: 912-913Crossref PubMed Scopus (96) Google ScholarTable 2Comparison of the Lugano and Paris staging systems for gastrointestinal tract lymphoma7Ruskone-Fourmestraux A. Fischbach W. Aleman B.M. et al.EGILS consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.Gut. 2011; 60: 747-758Crossref PubMed Scopus (249) Google Scholar,16Mazloom A. Rodriguez A. Ha C.S. et al.Incidence of gastric involvement in patients with nongastrointestinal extranodal marginal zone lymphoma.Cancer. 2011; 117: 2461-2466Crossref PubMed Scopus (7) Google ScholarAdapted from Ruskone-Fourmestraux et al.7Ruskone-Fourmestraux A. Fischbach W. Aleman B.M. et al.EGILS consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.Gut. 2011; 60: 747-758Crossref PubMed Scopus (249) Google Scholar and Mazloom et al.16Mazloom A. Rodriguez A. Ha C.S. et al.Incidence of gastric involvement in patients with nongastrointestinal extranodal marginal zone lymphoma.Cancer. 2011; 117: 2461-2466Crossref PubMed Scopus (7) Google ScholarLugano staging systemParis staging systemTumour extensionStage IConfined to the GI tract(single primary or multiple, non-contiguous)T1m N0 M0T1sm N0 M0T2 N0 M0T3 N0 M0MucosaSubmucosaMuscularis propriaSerosaStage IIII1II2Extending into abdomenLocal nodal involvementDistant nodal involvementT1–3 N1 M0T1–3 N2 M0Perigastric lymph nodesMore distant regional nodesStage IIEPenetration of serosa to involve adjacent organs or tissuesT4 N0–2 M0Invasion of adjacent structures with or without abdominal lymph nodesStage IVDisseminated extranodal involvement or concomitant supra-diaphragmatic nodal involvementT1–4 N3 M0T1–4 N0–3 M1T1–4 N0–3 M2Extra-abdominal lymph nodesDistant (non-contiguous) GI sites involvementNon-GI sites involvementGI, gastrointestinal.T describes the gastric wall infiltration; N describes the regional lymph node involvement; M describes distant dissemination. Open table in a new tab GI, gastrointestinal. T describes the gastric wall infiltration; N describes the regional lymph node involvement; M describes distant dissemination. The initial staging procedures must take into account the specific site of presentation (Table 3) and for gastric MZL must include an oesophagogastroduodenoscopy (EGD) with multiple biopsies taken from each region of the stomach, duodenum and gastroesophageal junction and from any site with an abnormal appearance. Routine EGD may also be advisable for patients with non-gastrointestinal MZL, particularly females, those with primary involvement of lung, upper airways and salivary glands and those with a high International Prognostic Index (IPI) score, elevated serum B2M level or H. pylori infection, regardless of the primary site.16Mazloom A. Rodriguez A. Ha C.S. et al.Incidence of gastric involvement in patients with nongastrointestinal extranodal marginal zone lymphoma.Cancer. 2011; 117: 2461-2466Crossref PubMed Scopus (7) Google Scholar,17Ogusa E. Tomita N. Ishii Y. et al.Clinical manifestations of primary pulmonary extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue in Japanese population.Hematol Oncol. 2013; 31: 18-21Crossref PubMed Scopus (6) Google ScholarTable 3Specific staging and work-up procedures for EMZL at different primary anatomic sitesSiteExamNotesStomachEGDEndoscopic USIHCFISH or PCR assayMandatoryOptional, to evaluate the regional lymph nodes and gastric wall infiltrationMandatory, to evaluate Helicobacter pylori status. Faecal antigen or breath test and serology studies are recommended when the results of histology are negativeOptional, to detect t(11;18) translocationSmall intestine (IPSID)PCR, IHC or ISHCampylobacter jejuni search in the tumour biopsyColonColonoscopy and EGDOcular adnexaOrbital and salivary glands imaging (MRI or CT)Head and neck imaging (MRI or CT)PCRIf clinically indicatedIf clinically indicatedChlamydophila psittaci search in the tumour biopsy and PBMCs (optional, according to the geographical distribution of the infection)Salivary glandsENT examination and echographyEGDAnti-SSA/Ro and anti-SSB/La antibodiesTo rule out association with Sjogren syndromeLungBronchoscopy and bronchoalveolar lavageEGDBreastMammography and breast sonographyMRI (or CT scan)ThyroidThyroid echographyCT scan of the neckThyroid function testsSkinPCRBorrelia burgdorferi search in the tumour biopsyCT, computed tomography; EGD, oesophagogastroduodenoscopy; EMZL, extranodal marginal zone B-cell lymphoma; ENT, ear, nose and throat; FISH, fluorescent in situ hybridisation; IHC, immunohistochemistry; IPSID, immunoproliferative small intestinal disease; ISH, in situ hybridisation; MRI, magnetic resonance imaging; PBMC, peripheral blood mononuclear cell; PCR, polymerase chain reaction; US, ultrasound. Open table in a new tab CT, computed tomography; EGD, oesophagogastroduodenoscopy; EMZL, extranodal marginal zone B-cell lymphoma; ENT, ear, nose and throat; FISH, fluorescent in situ hybridisation; IHC, immunohistochemistry; IPSID, immunoproliferative small intestinal disease; ISH, in situ hybridisation; MRI, magnetic resonance imaging; PBMC, peripheral blood mononuclear cell; PCR, polymerase chain reaction; US, ultrasound. SMZL typically involves the spleen, hilar lymph nodes, bone marrow and, frequently, the blood. Some patients are diagnosed following the incidental finding of a peripheral lymphocytosis. In advanced-stage SMZL, symptomatic splenomegaly and cytopaenia may be the presenting features.18Thieblemont C. Felman P. Callet-Bauchu E. et al.Splenic marginal-zone lymphoma: a distinct clinical and pathological entity.Lancet Oncol. 2003; 4: 95-103Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 19Thieblemont C. Felman P. Berger F. et al.Treatment of splenic marginal zone B-cell lymphoma: an analysis of 81 patients.Clin Lymphoma. 2002; 3: 41-47Abstract Full Text PDF PubMed Scopus (128) Google Scholar, 20Thieblemont C. Davi F. Noguera M.E. et al.Splenic marginal zone lymphoma: current knowledge and future directions.Oncology (Williston Park). 2012; 26: 194-202PubMed Google Scholar Some cases of disseminated MZL may present with splenomegaly and lymph node enlargement at distant sites. Approximately 20% of patients have autoimmune manifestations including autoimmune haemolytic anaemia (AIHA), immune thrombocytopaenia, cold agglutinin disease, circulating anticoagulants, acquired von Willebrand disease or angioedema as a result of acquired C1-esterase inhibitor deficiency. The role of PET is uncertain and SMZL is usually staged by CT. Abdominal sonography may give additional information to CT scanning for the detection of splenic focal lesions.21Traverse-Glehen A. Bertoni F. Thieblemont C. et al.Nodal marginal zone B-cell lymphoma: a diagnostic and therapeutic dilemma.Oncology (Williston Park). 2012; 26 (103–104): 92-99PubMed Google Scholar,22Arcaini L. Rossi D. Paulli M. Splenic marginal zone lymphoma: from genetics to management.Blood. 2016; 127: 2072-2081Crossref PubMed Scopus (96) Google Scholar PET-CT should be considered if high-grade transformation is suspected. NMZL usually presents with disseminated lymphadenopathy (mostly cervical and abdominal), with or without bone marrow and blood involvement at diagnosis. The disease is often advanced at presentation and 10%–20% of patients present with B symptoms (unexplained weight loss >10% in 6 months, unexplained fever >38°C, drenching night sweats). Anaemia occurs in ∼25% of patients and thrombocytopaenia in 10%. Initial staging follows the rules for other nodal lymphomas, with the main goal to discriminate localised from advanced-stage disease and to have measurable disease for evaluation of treatment response.21Traverse-Glehen A. Bertoni F. Thieblemont C. et al.Nodal marginal zone B-cell lymphoma: a diagnostic and therapeutic dilemma.Oncology (Williston Park). 2012; 26 (103–104): 92-99PubMed Google Scholar, 22Arcaini L. Rossi D. Paulli M. Splenic marginal zone lymphoma: from genetics to management.Blood. 2016; 127: 2072-2081Crossref PubMed Scopus (96) Google Scholar, 23Berger F. Felman P. Thieblemont C. et al.Non-MALT marginal zone B-cell lymphomas: a description of clinical presentation and outcome in 124 patients.Blood. 2000; 95: 1950-1956Crossref PubMed Google Scholar Staging should rule out primary EMZL, since around one-third of cases represent nodal dissemination of an EMZL.21Traverse-Glehen A. Bertoni F. Thieblemont C. et al.Nodal marginal zone B-cell lymphoma: a diagnostic and therapeutic dilemma.Oncology (Williston Park). 2012; 26 (103–104): 92-99PubMed Google Scholar,24Arcaini L. Paulli M. Burcheri S. et al.Primary nodal marginal zone B-cell lymphoma: clinical features and prognostic assessment of a rare disease.Br J Haematol. 2007; 136: 301-304Crossref PubMed Scopus (64) Google Scholar The International Extranodal Lymphoma Study Group (IELSG) has developed an EMZL-specific prognostic index using data from more than 400 patients enrolled in a large prospective randomised trial. This index, named MALT-IPI, uses three simple clinical parameters (age ≥70 years, Ann Arbor stage III or IV and elevated LDH) and allows the discrimination of three groups of patients with low, intermediate and high risk (corresponding to the presence of 0, 1 or ≥2 of these factors, respectively). The 5-year event-free survival rates in these groups were 70%, 56% and 29%, respectively. The MALT-IPI distinguished patients with different progression-free, overall and cause-specific survival. Its prognostic utility was retained in gastric and non-gastric lymphomas, as well as in patients treated with different modalities, and was confirmed in a large external validation set of more than 600 patients.25Thieblemont C. Cascione L. Conconi A. et al.A MALT lymphoma prognostic index.Blood. 2017; 130: 1409-1417Crossref PubMed Scopus (110) Google Scholar However, there are no data yet to indicate that the choice of therapy should be based on this index. An Italian lymphoma cooperative group (Intergruppo Italiano Linfomi; IIL) developed a prognostic model in more than 300 patients based on three risk factors (haemoglobin <12 g/dl, albumin <35 g/l and elevated LDH level).26Arcaini L. Lazzarino M. Colombo N. et al.Splenic marginal zone lymphoma: a prognostic model for clinical use.Blood. 2006; 107: 4643-4649Crossref PubMed Scopus (187) Google Scholar A newer prognostic model (named HPLL on the basis of the determinant factors: haemoglobin concentration, platelet count, LDH level and extrahilar lymphadenopathy) has been developed by the SMZL Study Group from an international retrospective survey of nearly 600 patients27Montalban C. Abraira V. Arcaini L. et al.Risk stratification for splenic marginal zone lymphoma based on haemoglobin concentration, platelet count, high lactate dehydrogenase level and extrahilar lymphadenopathy: development and validation on 593 cases.Br J Haematol. 2012; 159: 164-171Crossref PubMed Scopus (65) Google Scholar and identified three risk groups with significantly different outcomes [IV, C]. A simplified version of the HPLL was later proposed and validated.28Montalban C. Abraira V. Arcaini L. et al.Simplification of risk stratification for splenic marginal zone lymphoma: a point-based score for practical use.Leuk Lymphoma. 2014; 55: 929-931Crossref PubMed Scopus (32) Google Scholar,29Kalpadakis C. Pangalis G.A. Angelopoulou M.K. et al.Validation of the simplified prognostic score for splenic marginal zone lymphoma of the Splenic Marginal Zone Lymphoma Working Group.Leuk Lymphoma. 2014; 55: 2640-2642Crossref PubMed Scopus (14) Google Scholar Analogous to the MALT-IPI, there is no evidence supporting the use of these indices to decide whether and which therapy should be given. There is no specific prognostic score established for NMZL. The Follicular Lymphoma International Prognostic Index (FLIPI), although not validated for NMZL, may help discriminate between low- and high-risk patients in smaller patient cohorts.24Arcaini L. Paulli M. Burcheri S. et al.Primary nodal marginal zone B-cell lymphoma: clinical features and prognostic assessment of a rare disease.Br J Haematol. 2007; 136: 301-304Crossref PubMed Scopus (64) Google Scholar Helicobacter pylori eradication therapy should be given to all patients with gastric MZL, irrespective of stage [II, A].5Zucca E. Bertoni F. The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance.Blood. 2016; 127: 2082-2092Crossref PubMed Scopus (164) Google Scholar, 6Dreyling M. Thieblemont C. Gallamini A. et al.ESMO Consensus conferences: guidelines on malignant lymphoma. Part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma.Ann Oncol. 2013; 24: 857-877Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar, 7Ruskone-Fourmestraux A. Fischbach W. Aleman B.M. et al.EGILS consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT.Gut. 2011; 60: 747-758Crossref PubMed Scopus (249) Google Scholar,30Thieblemont C. Zucca E. Clinical aspects and therapy of gastrointestinal MALT lymphoma.Best Pract Res Clin Haematol. 2017; 30: 109-117Crossref PubMed Scopus (26) Google Scholar,31Bertoni F. Coiffier B. Salles G. et al.MALT lymphomas: pathogenesis can drive treatment.Oncology (Williston Park). 2011; 25 (1147): 1134-1142PubMed Google Scholar Anti-H. pylori regimen should be chosen based on the regional microbial ecology; usually triple-therapy regimens combining a proton-pump inhibitor (PPI) for 4 weeks plus clarithromycin with either amoxicillin or metronidazole for 10–14 days are highly effective.32Fuccio L. Laterza L. Zagari R.M. et al.Treatment of Helicobacter pylori infection.BMJ. 2008; 337: a1454Crossref PubMed Scopus (41) Google Scholar,33Zullo A. Hassan C. Cristofari F. et al.Effects of Helicobacter pylori eradication on early stage gastri