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

Abstract

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 for and of and is recommended in all cases, as its presence is associated with more disease and a of to pylori Helicobacter pylori is strongly implicated in the pathogenesis of gastric EMZL/MALT the incidence of gastric EMZL/MALT most cases are to be pylori in pylori should be in with and at pylori infection is primarily by tissue In a and Helicobacter are is useful with infection and if is in gastric EMZL/MALT and in are frequent marrow involvement is in one bone marrow biopsy is not essential in patients with The of is not in however, used in MZL for staging of both nodal and extranodal and if is at in extranodal can by extranodal and is that baseline may be used more often in the to is the most for Gastric EMZL/MALT lymphomas show variable with reported of A reported survival and a incidence of in gastric EMZL/MALT lymphoma was may be is There is a of on the staging classification for gastrointestinal MALT The is most widely used in the UK but is based primarily on while the staging into of and lymph The more staging a system using the same Table the staging of EMZL/MALT lymphomas involving the salivary thyroid and have genetic that may in to the for clinical autoimmune disease is reported to be more frequent in than gastric EMZL/MALT but the is Diagnosis and staging should be to the site involved and include for or autoimmune (Table syndrome 3 range SMZL the splenic and bone marrow and frequently the peripheral blood as and can present as in and are to and to or marrow from splenic nodal and other involvement are at include for associated autoimmune which in and for hepatitis are summarised in Table The of patients with NMZL present with often nodal without splenic or extranodal marrow involvement is in one third of Peripheral blood involvement is All patients should undergo or which is also to nodal of EMZL/MALT, which occurs in one third of EMZL/MALT occurs at per and an The with pylori with a and the of in gastric EMZL/MALT, of disease and pylori The is a of with and either or In patients to or with exposure to for with and is guidelines on the of an increased without increased to The of to to should be to should be evidence of pylori is to cases and other Helicobacter A of studies reported an of in to the pylori should be with a or and up to a are and a pylori is in the presence of disease through the gastric or is lymph a may for up to with the is to pylori is recommended for patients with a patients may be to and should be for and In both and cases, OGD with biopsies and with biopsies is recommended at to assess is by OGD and as or following pylori is an and can be as as presence of disease in the of and The may be to histological diagnostic biopsies are for (Table is for gastric EMZL/MALT lymphoma that has to to or pylori and in the presence of or presence of is with reported histological of on should include the and, if lymph should be with an and with an as to to the and most studies have included patients with a that is to be and to the to can be the risk of long-term with pylori is for management of patients with gastric EMZL/MALT if they are have disease, or is discussed in Section of The prognosis of gastric EMZL/MALT lymphoma is with survival and The EMZL/MALT is in both gastric and It based on and with 1 or risk factors survival of and In a of gastric EMZL/MALT patients by the was to a small increased risk of gastric in patients with gastric EMZL/MALT long-term with clinical examination, blood and OGD is recommended for of second including patients lymphoma the is not under is in with and primary gastric EMZL/MALT lymphoma, is the of in EMZL/MALT In patients with localised EMZL/MALT a has been can be (Table in cases can disease in some cases and can be in management of with a reported of In other EMZL/MALT lymphomas a has been for in cutaneous EMZL/MALT lymphoma, evidence is limited to and of is not The is but may be up to Patients with hepatitis EMZL/MALT lymphoma should with which may to of disease and Patients with EMZL/MALT lymphoma have can be 3 for the years and 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 of localised disease, in the of is either involved for disease or is recommended for of primary cutaneous marginal zone lymphoma based on disease with a small of for may also be Where lesions are a and may be with of lesions with of or or combination for localised disease is not with in EMZL/MALT, with now the of based on the of a are and most patients are A of involved for localised EMZL/MALT lymphoma reported survival and of and in is also an for EMZL/MALT and EMZL/MALT lymphoma is the risk of or data to or are but studies have demonstrated that patients with have better including A the of to for not show EMZL/MALT lymphoma is and for a and is favours other extranodal than lymph nodes can provide and for patients with EMZL/MALT and sites. with to no and can be is for patients with disease, of or or is evidence of The and is the in EMZL/MALT lymphoma, involving was more than not years for and years for but not with is for and of can also be if combination is not The reported for in gastric and was and the was with to to in patients In clinical the of especially in and/or from the same group in EMZL/MALT and NMZL. was for without and for with for up to A of MZL patients in the no in for to and was also more than is not recommended for the of MZL. Table studies in All subtypes 75% 20 47 SMZL NMZL to its for CNS MZL is not or to is most especially for dural and long-term disease in the presence of of and with to and However, as this is an indolent lymphoma, may also be and The to or on the site and of of dural EMZL/MALT with and are but a risk of and is may be for 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 reported a of and at 10 of patients The criteria for include or progressive autoimmune and progressive as in Table There are no of for for patients include and splenectomy, based on a small for by for 1 is and has in data In the of were and and were and are to the of 100 SMZL patients years and has in may have a in patients with a large and bone marrow disease or A should be with and has and to In the involving SMZL was and with a of and a of of patients a A of patients no of the evidence that should be for The demonstrated a for to SMZL and NMZL patients to or in the not in the in at years was patients for or splenectomy, can provide to a of splenic and with of A may provide more but a risk of and A full blood should be The of used for in SMZL upon the of staging (Table of of with evidence of clonal B-cell population in peripheral blood by flow cytometry evidence of bone marrow by disease by at of disease of disease of of bone marrow MZL is an and often to is especially with presentation. within of is but associated with for MZL a to follicular including for localised and for asymptomatic, of and in of cases, with no specific for on the trial, of or disease for EMZL/MALT that has with to of There is limited evidence that can be for including have or is in small other low-grade B-cell but with and an increased risk of secondary can be many patients are or have to has in a in MZL and are for MZL. The of in patients with a of demonstrated an of a of and a at were observed all MZL and demonstrated an association between gene mutations and In the trial, demonstrated and and to and in MZL Patients years and to also has a favourable common include and and 3 are These data an important for in MZL. A demonstrated the of in MZL. Other is under include the and was for MZL based on the and In the MZL of to but not to and were more common in is not for MZL in the or an has in and is in combination with small and have also demonstrated in MZL (Table at at T-cell with has demonstrated in MZL, but with of syndrome and to and may also be in MZL, but the data are has a in A of patients and reported and of and respectively. can be for MZL in but should be the of should be that are in MZL, but to their they are no in clinical or for to occurs in with a of years from MZL diagnosis to A large of cases from to including EMZL/MALT cases and to as of was associated with survival for without especially if within of diagnosis for may be to a biopsy site for diagnostic management as for transformed All patients should be advised on of and All patients should be and as by present patients that have and also patients should be specific with and levels should be reviewed by an Lymphoma and other provide to patients and their lymphoma Patients should be involved in to their management the on specific patients to and Patients should provide for using the form or and a of IHC markers should be used for diagnosis of SMZL can usually be by a combination of morphology and flow cytometry on peripheral blood and marrow biopsy should include full with can be in cases is for disease and to high-grade transformation marrow biopsy is recommended for staging of NMZL and and in cases of EMZL/MALT to or localised disease is to a incidence of bone marrow is not recommended for staging of gastric EMZL/MALT, to for patients with gastric EMZL/MALT should include oesophago-gastro-duodenoscopy photography and detailed description of the site of lesions are advised for OGD is recommended in the of diagnostic for of and is also recommended for gastric EMZL/MALT as the presence is a of disease and to pylori Other imaging and may be for additional of EMZL/MALT, according to disease site Helicobacter should be to all patients at of and pylori infection to should be by or at and at Patients with a pylori infection should be by of OGD and for OGD and biopsies should be at to assess lymphoma with management by OGD and disease or long-term OGD is the is by of and The system is recommended to histological should be for patients with localised disease if they are or have in is recommended for with and is for patients with disease if they are and have no OGD at to is recommended for for gastric is recommended in patients with hepatitis infection should be in management of EMZL/MALT are not recommended in other EMZL/MALT lymphomas in the of an is recommended for localised EMZL/MALT lymphoma pylori and should be to patients presenting with disease, disease or with are recommended however, as is no can be especially to patients or if combination is not and is also but more is also and patients can be for if in combination with is not recommended for of MZL in can provide for or to a of is recommended to dural EMZL/MALT lymphoma and can be in cases, but by is with or as a are for patients with secondary CNS MZL clinical for is recommended is recommended in patients with hepatitis infection SMZL patients can be including is recommended for patients criteria for are for patients with depending on age, and should be used if is a clinical of high-grade transformation can be for patients with without bone marrow disease or Splenic can be for patients on and and for patients can be is recommended for disease is usually indolent and should not be a of lymphoma occurs and patients can be for primary for and of and progressive should be for patients with disease should be for patients with disease is an for patients with SMZL and EMZL/MALT have a to is an for patients with SMZL is or is recommended for patients with disease are for or or with clinically or high-grade transformation is an for patients with MZL, and high-grade transformation been for patients within a clinical trial, should be to patients with disease are for including are not in the UK at present but may be on transformation is associated with to and sheets of B-cell the diagnosis be to management proposed this guideline and the All the to the writing and of this The are to for manuscript and useful The all of the UK September for and The for on The for the and useful All have made a full of to the BSH and Task which may be on

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