Extranodal marginal zone lymphoma: epidemiological, clinical features and treatment outcomes

¹Adult Clinical Haematology Department, Aziza Othmana Hospital, Tunis, Tunisia

^&Corresponding author
Manel Rebah, Adult Clinical Haematology Department, Aziza Othmana Hospital, Tunis, Tunisia

Introduction    

Extranodal marginal zone lymphoma (MZL) is an indolent B-cell lymphoma, accounting for 7% of non-Hodgkin lymphomas (NHL) [1]. It can involve both lymphoid and non-lymphoid organs, with the extranodal form being the most common. Its etiopathogenic mechanism is driven by chronic inflammatory processes linked to persistent antigenic stimulation (e.g., microbial agents), immune-mediated mechanisms (e.g., autoantibodies) or additional molecular pathways. Clinical presentation varies depending on the involved site. Therapeutic management depends on both disease location and stage, though standardised guidelines remain lacking. In Tunisia, few studies have addressed this entity. A better characterisation of these lymphomas could optimise the management of extranodal MZL patients. Our study aimed to describe the epidemiological and clinical features, as well as treatment outcomes, in a series of extranodal MZL patients, and to identify potential prognostic factors.

Case study     

Materials and methods

This was conducted as a retrospective descriptive study in the Clinical Haematology Department of Aziza Othmana Hospital between 2016 and 2021. Patients with an EMZL diagnosis according to World Health Organization (WHO) 2022 criteria were included [2]. The diagnosis was confirmed by a biopsy of the extranodal site on the basis of morphological and immunohistochemical (CD5, CD10, CD23) characteristics. Patients with transformed high-grade lymphoma were not included. We excluded patients with incomplete medical records. We recorded epidemiological characteristics of the patients (age, gender), disease presentation and first initial workup at initial evaluation: Blood count, lactate dehydrogenase, bone marrow biopsy (BMB) and imaging computed tomography (CT) or magnetic resonance imaging (MRI). We noted the treatment modalities and the evolution. The staging of the disease was based on the Ann Arbour classification for non-gastric extranodal MZL and Ann Arbour modified by Mushoff for gastric localisations. Response criteria were based on Cheson and GELA criteria, respectively, for gastric and non-gastric localisations [3,4]. Statistical data was analyzed by Spss 25 version. Survival analyses were performed via the Kaplan-Meier method. Prognostic factors were analysed through univariate analysis (Statistical significance was set at p < 0.05).

Results

We recorded 35 cases of extranodal MZL patients between 2016 and 2021. Epidemiological, clinical and biological features were summarised in Table 1. For gastric localisations, there were five antral locations, four fundic, one in the gastric body, one antrofundic and two pangastric. Non-gastric localisations were detailed in Figure 1. Localised stage (I-II) was noted in 63% of cases, and extended stage (III-IV) was observed in 37% (Figure 2). As for the initial therapy setting, nine patients with gastric MZL had Helicobacter pylori (HP) eradication, one had immunotherapy, and 22 underwent immunochemotherapy (8 R-CHOP, 12 R-CLB, 2 R-CVP). One patient died before initiation of therapy, and two had a watch-and-wait strategy for ocular localisation.

Among the 32 patients treated in the initial setting, 28 were evaluable. Sixty eight percent were showing response (46% complete response (CR)). Six patients had second-line treatment which four obtained CR. Two patients were refractory to treatment which one was salvaged by third-line therapy and an autologous stem cell transplantation and obtained a CR. During follow-up, one patient had a relapse after 8 months of CR and was awaiting salvage therapy, and one patient progressed after three months of partial response. The five-year overall survival (OS) rate was 78% (Figure 3). Four patients died which two of disease progression. The analysis of factors associated with modified OS showed that bone marrow infiltration was an important prognostic factor for survival (p=0,002), as shown in Figure 4.

Discussion     

Marginal zone lymphoma (MZL) is a rare indolent B-cell malignancy accounting for 7% of non-Hodgkin lymphomas in Western countries [5]. A United States study reported that extranodal MZL represented 61% of 7,460 MZL cases, with annual incidence increasing by 1%. A multinational study across 24 countries showed higher extranodal MZL frequency in developed countries (8.8%) versus developing nations (5.2%) [6]. Peak incidence occurs between 50-60 years (median 57 years in our cohort, range 34-83). According to various studies, there is no significant gender predominance, except for certain parotid (p=0.03) and breast localisations [7]. In our study, the male-to-female ratio was 2.5.

Risk factors: extranodal MZL is associated with chronic bacterial infections. The most proven association is with HP with gastric localisation [8]. Other emerging associations exist, such as Borrelia burgdorferi (cutaneous), Chlamydophila psittaci (ocular), Achromobacter xylosoxidans (pulmonary) [9]. Other viral infection associations were identified, such as Human immunodeficiency virus (HIV) and Hepatitis C virus [10]. In our study, we noted 7 cases of HP infection and one case of HIV in cavum localisation. Other chronic immune stimulations may present in autoimmune disorders (Hashimoto thyroiditis, Sjögren syndrome) [11]. Different translocations were identified through different localisations and have the potential to transform into high-grade lymphoma. The most frequent one is the translocation and is associated with HP-negative gastric and pulmonary localisations [12,13].

The most frequent localisation is the stomach, which represents 30 to 35% [14,15] (Table 2). It may present with nausea, vomiting, dyspepsia or rarely B symptoms [16]. Histopathology may show dense lymphoid infiltrate associated with plasmacytoid differentiation or lymphoepithelial lesions. There is no specific marker for extranodal MZL [17]. For initial workup, CT remains the gold standard for imaging in this type of lymphoma. MRI may be essential in salivary glands and ocular localisations [18]. Positron emission tomography is not obligatory, but it can detect bulky masses, lymph node dissemination, bone marrow involvement and suspicion of transformation. Endoscopy can assess mucosal changes for gastric locations (erosions, ulcers, wall thickening) [19], but endoscopic ultrasound can better evaluate wall infiltration and regional nodes [20]. Treatment approaches may differ depending on the stage and localisation. Eradication of HP is recommended in gastric localisations and consists of an association of a proton pump inhibitor with 2 or 3 antibiotics. Assessment of eradication can be done after 6 weeks of treatment, and evaluation of lymphoma after 3 months by a biopsy. Radiotherapy remains the preferred treatment option for localised stage [21]. Surgery is rarely indicated, especially in gastric localisations, because of its association with comorbidities [22]. For systemic disease, immunotherapy and/or chemotherapy may be prescribed.

The standard treatment for this type of lymphoma is the rituximab-chlorambucil (R-Clb) association, which was approved by the IELSG19 study [23]. R-CHOP may be indicated in some aggressive forms [24]. The use of rituximab-bendamustine (R-benda) has also proven its efficacy, with a need for viral prophylaxis [25,26]. Our study allowed a study of a malignant lymphoid hemopathy which had heterogenous clinic characteristics and various treatment approaches. But it had some limitations due to its retrospective character and the insufficient number of patients.

Conclusion     

Extranodal MZL is an indolent lymphoid hemopathy that often remains localised for extended periods. The most common site is gastric, where H. pylori eradication therapy has revolutionised management. Radiotherapy may be considered for localised disease, while immunochemotherapy remains the cornerstone for advanced stages, with R-Clb as the standard regimen and R-CHOP/RCVP reserved for aggressive forms. R-Benda can be offered as second-line therapy. Bruton's tyrosine kinase inhibitors have emerged for refractory or relapsed cases. However, improved understanding of ethiopathogenic mechanisms may allow discovery of more effective and less toxic therapeutic targets.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

Manel Rebah: conception and design of the study and drafting of the manuscript. Manel Rebah, Malek Sayedi, Wafa Miled, Dorra Jaber and Raoudha Mansouri: data collection. Manel Rebah and Malek Sayedi: data analysis and interpretation. Manel Rebah, Malek Sayedi, Wafa Miled, Dorra Jaber, Raoudha Mansouri, Karima Kacem and Raihane Benlakhal: critical revision of the manuscript. Karima Kacem and Raihane Benlakhal: supervision of the study. All authors read and approved the final version of the manuscript.

Tables and figures     

Table 1: epidemiological, clinical and biological characteristics of patients
Table 2: sites distribution according to various studies
Figure 1: non-gastric localisations' distribution
Figure 2: distribution of stages in EMZL
Figure 3: global survival curve
Figure 4: global survival according to osteomedullary infiltration

References