Key points:

●      Marginal zone lymphomas (MZLs) represent a distinct subset of indolent B-cell lymphomas, including extranodal, nodal, and splenic variants.

●      MZLs account for 7-8% of non-Hodgkin lymphomas, representing the third most common type of B-cell non-Hodgkin lymphoma.

●      The incidence of MZL has increased by approximately 1% per year, likely due to improved diagnostic tools.

○      MZLs encompass three pathology subtypes: extranodal MZL (EMZL) of mucosa-associated lymphoid tissue (MALT lymphoma), splenic MZL (SMZL), and nodal MZL (NMZL).

○      Despite shared histopathological and immunophenotypic features, their clinical presentation varies significantly based on the site of origin and genetic abnormalities.

●      Chronic antigenic stimulation leads to the expansion of reactive B-cell clones, eventually resulting in malignant transformation. Key genetic alterations identified in MZL, comprising mutations in NOTCH2, KLF2, and TNFAIP3 genes, affect critical pathways regulating cell survival, proliferation, and immune response.

●      Several prognostic tools have been developed to refine risk assessment in MZL subtypes, including the MALT-International Prognostic Index (MALT-IPI), the Haemoglobin Platelets Lactate Dehydrogenase Lymphadenopathy  score and its simplified version. Recently, the MZL-International Prognostic Index (MZL-IPI) has emerged as a comprehensive model integrating data from all MZL subtypes and incorporating rigorously validated clinical parameters (See Table 1 and Figure 1 in original paper).

●      MZL typically has an indolent course, with early-stage disease having an excellent prognosis. Both gastric and extragastric MALT lymphomas exhibit favourable survival outcomes, with 5-year overall survival (OS) rates exceeding 90% and 10-year survival rates of 75-80%. SMZL also generally has a good prognosis, with about two-thirds of patients surviving five years post diagnosis and around 20% remaining therapy-free for several years.

●      With the introduction of the CD20 antibody rituximab in the treatment, the prognosis of NMZL has improved over the last few years. In different case series, the OS at 5 years was between 57% and 97%; the heterogeneity of the diagnosis might partially explain this difference because of the changes in the pathological delineation and the staging procedures, as well as in the treatment.

●      Although the median survival exceeds 10 years, MZL still negatively impacts life expectancy compared with the general population, with the exception of gastric MALT, which has a survival similar to that of the general population, especially when diagnosed in early stages.

○      In EMZL recurrence is common, affecting 50-60% of patients, with a median time to relapse of approximately 5 years.

○      One-third of patients with SMZL may develop an aggressive disease course, with a median survival of approximately 4 years.

●      Furthermore, early disease progression (i.e. progression of disease at 24 months) and histological aggressive transformation (HT) have emerged as key adverse prognostic factors in relapsed/refractory (R/R) MZL, similar to other indolent non-Hodgkin lymphomas.

●      Treatment strategies vary according to subtype and disease stage. Overall, therapeutic approaches follow general principles:

○      If an infectious pathogenetic association exists, it is treated regardless of disease stage and symptoms.

○      Radiotherapy is used with curative intent for localized disease.

○      Systemic treatments are generally deferred until symptoms arise.

○      In R/R setting, when HT is excluded, the use of non-cross-resistant chemotherapies is being increasingly replaced by targeted immunotherapies.

○      Emerging monoclonal antibodies such as tafasitamab and loncastuximab, and bispecific antibodies and chimeric antigen receptor T-cell therapy  are currently being evaluated in R/R MZL.