Guideline for the diagnosis and management of marginal zone lymphomas: A British Society of Haematology Guideline

The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of patients with marginal zone lymphoma (MZL). These guidelines were compiled according to the BSH process: https://b-s-h.org.uk/media/16732/bsh-guidance-development-process-dec-5-18.pdf. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Recommendations are based on a review of the literature using Medline/Pubmed. Search terms included: marginal zone, MZL, extranodal MZL, MALT, nodal, splenic, treatment, randomised, clinical trial, radioimmunotherapy, hepatitis C, Helicobacter pylori. The search was limited to English language publications and conference abstracts from 1 January 1998 to 20 September 2022. Titles/abstracts obtained were curated and manually reviewed by the writing group, which conducted additional searches using subsection heading terms. The manuscript was reviewed by the BSH Guidelines Haemato-oncology Task Force, the BSH Guidelines Executive Committee and the haemato-oncology sounding board of the BSH. The MZLs are a group of clinically indolent mature B-cell lymphomas derived from memory B cells of the 'marginal' zones of secondary lymphoid tissues. Marginal zone B cells are at the centre of inflammation, autoimmunity and malignant transformation through the coordination of innate and adoptive immunity. MZLs, especially extranodal marginal zone lymphomas (EMZL), frequently arise in the context of chronic infection or autoimmune disease, and, while the various subtypes share many biological, diagnostic and clinical features, they manifest subtype-specific features, resulting in a multisystem presentation. The 5th World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues recognises distinct MZL subtypes according to the microenvironment of involved tissue1—EMZL of mucosa-associated lymphoid (MALT) tissue, splenic marginal zone lymphoma (SMZL) and nodal marginal zone lymphoma (NMZL).2, 3 Paediatric marginal zone lymphoma and primary cutaneous MZL, originally included under NMZL and EMZL/MALT, respectively, are now classified as separate entities. MZL is the third most common lymphoma,4 comprising up to 15% of non-Hodgkin Lymphoma (NHL) in the Western World. Over 60% are EMZL/MALT (which can arise from any site following chronic antigenic stimulation), 20% are SMZL and <10% are NMZL. Incidence increases with age, suggesting cumulative exposure to risk factors. Age-adjusted incidence has increased by 1.1% per year5 with a current UK incidence of 2.62 per 100 000 and a male-to-female ratio of 1.6.4 Diagnosis requires a representative tissue biopsy, bone marrow or peripheral blood sample, depending on the subtype. Diagnostic material should be reviewed by an expert haematopathologist6 in the context of clinical and laboratory features and classified according to the 5th WHO classification of haematolymphoid tumours and/or the International Consensus Classification of Lymphoid Neoplasms.2, 3 Which classification has been used should be stated in the report. There are currently no widely specific diagnostic markers for MZL. Immunohistochemical (IHC) evaluation of tissue relies upon excluding other low-grade B-cell NHL entities. Commonly used IHC markers are listed in Table 1. EMZL/MALT recapitulates Peyer's patch-type lymphoid tissue2 and presents at a variety of extra-nodal sites. Tumours are composed of morphologically heterogeneous small B cells, including marginal zone (centrocyte-like) cells, monocytoid cells, small lymphocytes and centroblast-like cells. There is plasmacytic differentiation in some cases. Neoplastic cells reside in the marginal zones of reactive B-cell follicles, extend into the interfollicular region and colonise the follicles. In epithelial tumours, lymphoepithelial lesions are seen. These are aggregates of ≥3 neoplastic cells with distortion or destruction of the epithelium, often with eosinophilic degeneration of epithelial cells. These are not essential for diagnosis and are not specific for EMZL.7 Helicobacter pylori infection is strongly implicated in the pathogenesis of gastric EMZL/MALT.8 Autoimmunity-associated chronic inflammation (Sjögren syndrome and Hashimoto thyroiditis) may precede EMZL/MALT-affecting salivary glands and thyroid respectively. Primary cutaneous marginal zone lymphoproliferations are now recognised as a distinct entity because of their indolent behaviour and disease-specific survival approaching 100% without the need for aggressive therapies.3 The term 'primary cutaneous marginal zone LPD' is proposed in the International Consensus Classification of mature lymphoid neoplasms. The 5th WHO classification of haematolymphoid tumours categorises the same entity as a 'Primary cutaneous marginal zone lymphoma'.2 Approximately 75% are class-switched (predominantly IgG+), with up to 40% expressing IgG4. Abundant reactive T cells and peripherally located clustered plasma cells are often seen. Cases that are IgM+ (non-class-switched) and show monocytoid B cells warrant exclusion of non-cutaneous primary disease.3 MZLs rarely involve the central nervous system (CNS), either primarily or secondarily. Most CNS MZL is dural EMZL/MALT lymphoma, with lesions often radiologically indistinguishable meningioma9-13; however, MRI may distinguish from meningioma by a more prominent dural tail.14 Histological confirmation has important implications for prognosis and management, as dural EMZL/MALT lymphoma has a better prognosis than high-grade primary central nervous system lymphomas.15, 16 IgG4 expression in light-chain-restricted clonal plasma cells is a feature of MZL involving the CNS. Other EMZL/MALT lymphomas may also develop in the context of IgG4-related disease, and an aetiological association has been suggested.17-21 Site-specific aetiology and reported genetic alterations22 are summarised in Table 2. A diagnosis can usually be established through a combination of morphology and flow cytometry on peripheral blood or aspirated bone marrow, marrow trephine biopsy histology and IHC, but in a minority of cases, a definitive diagnosis may require splenectomy.7 Splenic histology reveals a B-cell neoplasm composed of small lymphocytes that surround and replace the splenic white pulp germinal centres, efface the follicle mantle and merge with a peripheral (marginal) zone of larger cells, including scattered transformed blasts; both small and larger cells infiltrate the red pulp. SMZL shares features with other splenic lymphomas and, without splenectomy, may be indistinguishable from splenic diffuse red pulp lymphoma (Table 3). CD20+ CD103− CD25−/+ CD27+ CD11c+/− CD123− DBA44+ Annexin A1− Cyclin D1− IgD+ CD20 bright+ CD103−/+ CD25− CD27+ CD11c−/+ CD123− DBA44+ Annexin A1− Cyclin D1− IgG+ (rare IgD/IgM+ cases) CD20 bright+ CD103+ CD25+ CD27− CD11c+ CD123+ DBA44+ Annexin A1+ Cyclin D1+ (weak) IgG+ CD20 bright+ CD103+ CD25- CD27+ CD11c+ CD123− DBA44+ Annexin A1- Cyclin D1− IgG+ NMZL is a primary nodal B-cell neoplasm morphologically resembling lymph nodes involvement by EMZL/MALT or SMZL but without evidence of extranodal or splenic disease. Peripheral blood involvement may occur, and bone marrow involvement is seen in one third of cases.2, 41 Table 1 describes IHC that is useful in establishing the diagnosis. Where plasma cell differentiation is prominent, distinction from lymphoplasmacytic lymphoma (LPL) may be difficult. Demonstration of remnants of follicular dendritic cell meshworks favours a diagnosis of NMZL.2 MYD88 gene mutations are usually detected in LPL and rarely in NMZL. A mixture of cell types is seen in NMZL, but the presence of >20% large B cells is concerning for high-grade transformation (HGT).2 However, a diagnosis of diffuse large B-cell lymphoma should only be made if clearly delineated sheets of large B cells are identified. In some cases, an abundant PD1+ follicular helper T-cell infiltrate has been described and may pose a diagnostic challenge in distinction from T-cell lymphoma; this can also be seen in EMZL/MALT.42 Trisomy of chromosomes 3 and 18, gains of 2p and 6p and loss of 1p and 6q are common in NMZL, with frequent somatic variants of KMT2D, PTPRD, NOTCH2 and KLF2.2 Paediatric nodal MZL, now a separate entity in the 5th WHO classification,2 is an indolent disease with a favourable prognosis. It occurs predominantly in boys (M:F, 20:1) presenting with asymptomatic, localised disease involving lymph nodes of the head and neck. Involved nodes display progressive transformation of germinal centres.43 Differential diagnosis includes atypical marginal zone hyperplasia and marginal zone hyperplasia associated with Haemophilus influenzae, wherein the marginal zone cells are IgD-positive.44 Genetic studies are advised in this setting, in view of the differential diagnoses. Population-based long-term data on the transformation of MZL is limited; however, in some studies, a cumulative incidence of transformation to aggressive large B-cell lymphoma of 4.7% at 10 years is described.45 In this study, the highest risk of transformation was observed in patients with SMZL (14%); a range of 4%–15% is described in other studies.46, 47 Risk factors for transformation are discussed in Section "Transformed disease". Histologically, the common form of transformation is to a diffuse large B-cell lymphoma (DLBCL) of non-germinal centre immunophenotype; a diagnosis of DLBCL should only be made if clearly delineated sheets of large B cells are identified.2 A variable proportion of large B cells are present within the neoplastic population in all histological subtypes of MZL. Rarer cases of transformation to classical Hodgkin Lymphoma and plasma cell leukaemia have been described.48, 49 A clonal relationship between the MZL and transformed disease can be demonstrated in many cases, but apparent transformations may in some cases represent clonally unrelated second lymphomas. All patients require a history and full physical examination, blood tests, radiological imaging for staging and baseline measurement of disease (summarised in Table 4). Gastric EMZL/MALT lymphoma accounts for 35% of MZL and ~50% of all EMZL. Rarer subtypes of gastrointestinal MALT lymphoma include small intestinal MALT or its variant immunoproliferative small intestinal disease (IPSID) and colonic MALT lymphoma.50 Patients with gastric EMZL/MALT lymphoma should undergo oesophago-gastro-duodenoscopy (OGD) with biopsies and careful documentation of lesions.51 Mapping biopsies are not essential, but high-quality photography and a detailed description of the site of lesions are advised for comparison. Repeat OGD is recommended in cases of diagnostic uncertainty. Fluorescence in situ hybridisation (FISH) for t(11:18)(q21;q21) and fusion of BIRC3 (formerly API2) and MALT1 is recommended in all cases, as its presence is associated with more advanced disease and a lower rate of response to H. pylori eradication.52 Helicobacter pylori is strongly implicated in the pathogenesis of gastric EMZL/MALT lymphoma. Despite the apparently decreasing incidence of H. pylori-positive gastric EMZL/MALT lymphomas,53 most cases are still thought to be H. pylori positive, particularly in older patients. H. pylori testing should be performed in every patient, with proton pump inhibitor (PPI) and antibiotics discontinued at least 2 weeks before.54 H. pylori infection is primarily evaluated by tissue IHC. In addition, faecal antigen testing (or a carbon-13 urea breath test; CLO) and Helicobacter serology are recommended. Serology is useful with low-level infection and if histology/CLO is negative.55 H. heilmannii in gastric EMZL/MALT and Campylobacter jejuni in IPSID are less frequent causative organisms.56, 57 Bone marrow involvement is rare—just 4.3% in one study58—and bone marrow biopsy is not essential except in patients with cytopenia. The role of positron emission tomography (PET) is not well defined in MZL; PET is, however, increasingly used in MZL for staging of both nodal and extranodal disease59 and subsequent response assessment if fluorodeoxyglucose (FDG) is avid at baseline.7, 60, 61 Since uptake in extranodal sites can vary by extranodal location and lesional size, it is anticipated that baseline scans may be used more often in the future to determine whether PET is the most appropriate modality for response assessment. Gastric EMZL/MALT lymphomas show variable FDG avidity, with reported rates of 50%–60%.59 A retrospective study reported inferior overall survival (OS) and a higher incidence of HGT in gastric EMZL/MALT lymphoma when standardised uptake value was ≥10.62 PET may therefore be considered when HGT is suspected. There is a lack of consensus on the best staging classification for gastrointestinal MALT lymphoma. The 1994 Lugano classification63 is most widely used in the UK but is based primarily on imaging, while the modified Ann-Arbor staging system64, 65 takes into account depth of infiltration and distant lymph node involvement. The more recent Paris staging involves a TNM system using the same principles.66 Table 5 compares the three staging systems. Stage I2E Stage II II1 = Regional LNs II2 = Distant intraabdominal LNs IIE = invasion of adjacent structures Non-gastric EMZL/MALT lymphomas involving the ocular adnexa, skin, lung, salivary gland, thyroid and breast have site-specific genetic profiles that may affect prognosis, in addition to the potential for organ-specific clinical considerations.68 Concomitant autoimmune disease is reported to be more frequent in non-gastric than gastric EMZL/MALT lymphomas, but the prognostic impact is unknown.69 Diagnosis and staging should be tailored to the site involved and include testing for underlying infectious or autoimmune causes (Table 6). Sjögren syndrome (lacrimal gland MZL) C. psittaci 3 months70 Reported range 3–36 months7, 71 Skin (9%) Lymphocytic interstitial pneumonia Achromobacter xylosoxidans SMZL involves the spleen, splenic and hilar nodes, bone marrow and frequently the peripheral blood as villous lymphocytes,23 and can present as isolated lymphocytosis. Cytopenias occur in 25% and are related to hypersplenism and less commonly to auto-antibodies or marrow infiltration.2, 75 Aside from splenic hilar nodal enlargement, lymphadenopathy and other organ involvement are rare at diagnosis.76 Work-up investigations include testing for associated autoimmune phenomena, which occur in ~20%, and testing for hepatitis C. Proposed investigations are summarised in Table 4. The majority of patients with NMZL present with disseminated, albeit often non-bulky nodal disease,77 without splenic or extranodal involvement. Bone marrow involvement is evident in one third of cases.41 Peripheral blood involvement is very rare.78 All patients should undergo computed tomography (CT) or PET/CT staging, which is also helpful to exclude nodal dissemination of EMZL/MALT, which occurs in one third of EMZL/MALT cases.78 HGT occurs at ~1% per year and conveys an inferior OS.79 The strong aetiopathogenic link with H. pylori makes eradication therapy with a PPI and two antibiotics (triple therapy) the mainstay of first-line therapy in gastric EMZL/MALT, irrespective of disease stage and H. pylori status. The NICE recommendation (CG184)80 is a 7-day, twice-daily course of PPI given with amoxycillin and either clarithromycin or metronidazole. In patients allergic to penicillin or with previous exposure to clarithromycin, quadruple therapy for 7 days with twice-daily PPI, bismuth, metronidazole and tetracycline is recommended. European guidelines (Maastricht VI/Florence consensus) recommend 14-day clarithromycin-based triple therapies on the basis of an increased cure rate without significantly increased side effects compared to 7-day regimens.54, 81 The importance of adhering to treatment to improve successful eradication should be explained to patients. Antibiotic therapy should be considered even when evidence of H. pylori is lacking, to cover false negative cases and other Helicobacter species.82 A meta-analysis of published studies reported an overall pooled CR rate of 29.3% in H. pylori-negative cases.53 Response to the first-line H. pylori eradication should be assessed with a stool antigen test or urea breath test ≥6 weeks after starting eradication and ≥2 weeks after stopping PPI.51 Late responses up to a year after treatment are reported, and ~62% achieve a CR 12 months after H. pylori eradication.83 Eradication is less effective in the presence of t(11;18)(q21;q21), when disease extends through the gastric serosa, or where there is perigastric lymph node involvement.84 After successful eradication therapy, a positive serology result may persist for up to 2 years, consistent with the previous infection; follow-up serology is therefore unhelpful to confirm H. pylori eradication. Second-line therapy is recommended for patients with a persistent positive result. Non-responding patients may be resistant to clarithromycin, and samples should be sent for culture and antibiotic sensitivity. In both H. pylori-positive and -negative cases, repeat OGD with multiple biopsies and comparison with previous biopsies is recommended at 3–6 months to assess response. Management thereafter is guided by OGD findings, symptoms and adverse signs such as deep invasion, overt progression, bulk or impending organ damage (Figure 1). Persistent clonality following H. pylori eradication is an acceptable outcome and can be monitored,85 as well as presence of microscopic disease in the absence of symptoms and endoscopic findings.86 The Groupe d'Etude des Lymphomes de l'Adulte (GELA) scoring system87, 88 may be helpful to document histological response when diagnostic biopsies are available for comparison (Table 7). Radiotherapy (RT) is indicated for stage I/IIE gastric EMZL/MALT lymphoma that has failed to respond to or relapses after H. pylori eradication and in the presence of overt progression, deep invasion, lymphadenopathy or presence of t(11;18).89-92 This is highly successful, with reported histological complete responses of 95%–100% on endoscopic follow-up.93-95 Involved-site radiotherapy (ISRT) should include the entire stomach and, if involved, adjacent lymph nodes. Treatment should be given with an empty stomach and planned with an advanced technique such as intensity modulation to minimise radiation dose to the heart, liver and kidneys.95-98 most studies have included patients with a recent that is to be and to appropriate the dose to structures can be well organ the risk of long-term therapy, with H. pylori is indicated for first-line management of patients with advanced stage gastric EMZL/MALT if they are have disease, bulk or impending organ therapy treatment is discussed in Section of The prognosis of gastric EMZL/MALT lymphoma is with survival and The EMZL/MALT prognostic is prognostic in both gastric and non-gastric It three prognostic based on years, stage and with 1 or ≥2 risk factors survival of and In a study of gastric EMZL/MALT patients by the rate was to a small increased risk of gastric in patients with gastric EMZL/MALT long-term follow-up with clinical examination, blood and OGD is recommended for of second including patients complete lymphoma the follow-up is not follow-up every months under is in with and primary gastric EMZL/MALT lymphoma, less is the value of antibiotic therapy in non-gastric EMZL/MALT lymphoma. In patients with localised ocular EMZL/MALT where a causative has been antibiotic therapy can be considered (Table 6). in C. cases can disease in some cases and can be considered in first-line management of ocular with a reported overall response rate of In other non-gastric EMZL/MALT lymphomas where a causative has been for in cutaneous EMZL/MALT lymphoma, evidence is limited to and of antibiotics is not recommended. The after antibiotics is but it may be up to Patients with hepatitis EMZL/MALT lymphoma should treatment with therapy, which may to of disease and Patients with non-gastric EMZL/MALT lymphoma have treatment can be evaluated every 3 months for the 2 years and every months than of patients develop and bone marrow involvement is this bone marrow is not recommended for clinical Where infection is on a biopsy should be treatment of localised disease, in the absence of is either involved for disease or is recommended for treatment of primary cutaneous marginal zone lymphoma based on disease with a small of treatment for may also be Where multiple lesions are a and may be with treatment of lesions with of or or combination treatment for localised disease where is not with antibiotic achieve in EMZL/MALT, with now considered the of based on the of a Response rates are and most patients are A recent published II of involved for localised non-gastric EMZL/MALT lymphoma reported survival and of and in two is also an for EMZL/MALT and ocular EMZL/MALT lymphoma when there is the risk of or data to or are lacking, but retrospective studies have demonstrated that patients with first-line have better including A study the addition of to for not show stage EMZL/MALT lymphoma is and for a and is when it favours other extranodal sites than lymph nodes (Figure can provide and effective for patients with advanced EMZL/MALT and sites. with to no and can be therapy is indicated for patients with advanced disease, after of antibiotics or or where there is evidence of The and is the study in EMZL/MALT lymphoma, involving patients. was more effective than not years for and years for but not improve Treatment with is for and of can also be if combination therapy is not well The II reported for in gastric and non-gastric was and the was with to treatment to in patients complete In clinical the of higher especially in older and/or patients. II from the same group evaluated in EMZL/MALT and NMZL. Reported was for without and for with every weeks for up to 12 A of MZL patients in the no in for compared to and was also more than is therefore not recommended for the treatment of MZL. Table studies in All subtypes 75% 20 57 months 47 months SMZL 61 months = NMZL 61 months = 12 to its therapy for CNS MZL is not or radiotherapy to is most especially for dural and long-term disease even in the presence of of CR rates and with to and However, as this is an indolent lymphoma, lower may also be very effective and significantly less The to or on the site and of Treatment of dural EMZL/MALT with and are but a risk of and is recommended. may be for rare patients presenting with secondary CNS MZL. The literature includes cases with by and The of is Patients with CNS MZL need long-term to an increased risk of disease SMZL patients with hepatitis infection should patients are and can be at 3–6 reported a of and at 10 years, of patients The criteria for treatment include or progressive autoimmune and progressive as in Table There are no published of treatment for therapy for patients include and splenectomy, based on a small II for weeks by 2 for 1 is well and has responses in retrospective data In the retrospective study of were and and rates were and are to the retrospective of 100 SMZL patients years and has in may still have a role in patients with a large and bone marrow disease or A should be performed after appropriate with and has and to In the involving SMZL was and CR with a of and a of highly 25% of patients a adverse A retrospective study of patients no of the evidence that should be for patients. The demonstrated a for when given to SMZL and NMZL patients to or months in the not in the = in at years was patients for therapy or splenectomy, can provide effective to a of splenic and even with very dose of A higher dose may provide more but