Version May 2024
INTRODUCTION — The non-Hodgkin lymphoma subtype of marginal zone lymphoma represents a group of lymphomas that have been historically classified together because they appear to arise from post-germinal center marginal zone B cells.
Several marginal zone lymphoma subtypes are recognized in the World Health Organization classification of lymphoid neoplasms:
●Extranodal marginal zone lymphoma (EMZL) of mucosa associated lymphoid tissue (MALT lymphoma)
●Nodal marginal zone lymphoma
●Splenic marginal zone lymphoma
EMZL arises in a number of epithelial tissues, including the stomach, salivary gland, lung, small bowel, thyroid, ocular adnexa, skin, and elsewhere. While it has a tendency to remain localized to the tissue of origin for long periods of time, it is a clonal B cell neoplasm that frequently recurs locally and has potential for systematic spread and transformation to an aggressive B cell lymphoma.
This topic review will discuss the treatment of EMZL. The pathogenesis, clinical manifestations, pathologic features, and diagnosis of this disorder is presented separately, as is the diagnosis and management of nodal marginal zone lymphoma, splenic marginal zone lymphoma, and primary cutaneous marginal zone lymphoma.
●(See "Splenic marginal zone lymphoma".)
●(See "Nodal marginal zone lymphoma".)
●(See "Primary cutaneous marginal zone lymphoma".)
GASTRIC MZL — Gastric marginal zone lymphoma (MZL) is the most common subtype of extranodal marginal zone lymphoma (EMZL). Our approach is generally consistent with that of the European Society of Medical Oncologists and National Comprehensive Cancer Network (algorithm 1) [1,2]. Areas of significant divergence are noted below.
Pretreatment evaluation — Patients with newly diagnosed gastric MZL undergo a pretreatment evaluation to determine the extent of disease, Helicobacter pylori infection status, and comorbidities that might impact treatment. In addition to a history and physical examination, it is our practice to perform the following pretreatment studies:
●Physical examination should include an assessment of the eyes, ears, nose, and throat as well as the lymph node regions, liver, spleen, and skin.
●Evaluation of nutritional and performance status using the Eastern Cooperative Oncology Group (ECOG) or Karnofsky performance scales (table 1 and table 2). (See "The role of parenteral and enteral/oral nutritional support in patients with cancer".)
●An esophagogastroduodenoscopy with multiple biopsies taken from each region of the stomach, duodenum, and gastroesophageal junction, and from any site with an abnormal appearance. Endoscopic ultrasound may be used to determine the depth of invasion and involvement of perigastric lymph nodes.
●Tumor biopsy should be tested for H. pylori. If H. pylori is negative by histopathology, evaluate with noninvasive testing (stool antigen test or urea breath test). In addition, fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) testing for t(11;18) should be performed to identify MALT1 translocation, which identifies tumors unlikely to respond to H. pylori eradication therapy. (See "Indications and diagnostic tests for Helicobacter pylori infection in adults".)
●Additional laboratory studies include a complete blood count with differential, chemistries with liver and renal function, electrolytes, lactate dehydrogenase (LDH), and serum protein electrophoresis. Patients should undergo serologic testing for HIV, hepatitis B virus, and hepatitis C virus. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
●Imaging to evaluate for distant disease with computed tomography (CT) of the chest, abdomen, pelvis, orbits, and salivary gland, or with whole body combined fluorodeoxyglucose positron emission tomography with computed tomography (FDG PET/CT). Whole body FDG PET/CT is gaining in acceptance, especially for patients with localized disease being evaluated for radiation therapy and in cases of suspected large cell transformation [1-5]. Unlike in some lymphoma subtypes, FDG PET/CT has a low sensitivity for identifying bone marrow involvement in extranodal MZL. In a series of 208 patients with extranodal MZL of whom 16 percent had pathologically confirmed bone marrow involvement, FDG PET/CT had the following test characteristics for identifying bone marrow involvement: sensitivity 39 percent, specificity 99 percent, positive predictive value 87 percent, negative predictive value 90 percent [6]. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Imaging'.)
●Unilateral bone marrow biopsy and aspirate should be performed to confirm suspected early (stage I/II) disease.
●Individuals with childbearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)
Staging — The Ann Arbor staging system used for most lymphomas is inadequate for the staging of gastrointestinal lymphoma since it does not incorporate information on the depth of tumor invasion known to affect prognosis. Several other staging systems have been proposed, but with limited consensus. The lack of a uniform staging system has hindered the direct comparison of clinical trials. The most widely accepted staging system is the Lugano staging system.
The Lugano staging system was developed to incorporate measures of distant nodal involvement (table 3) [7]. Stage I or II disease includes a single primary lesion or multiple, noncontiguous lesions confined to the gastrointestinal tract that may have nodal involvement. There is no stage III in the Lugano system. Stage IV disease displays disseminated extranodal involvement or concomitant supra-diaphragmatic nodal involvement.
For the purposes of this review, we will use the Lugano staging system to describe the treatment.
Stage I or II H. pylori positive — The majority of patients with gastric EMZL present with Lugano stage I or II disease with active H. pylori infection. There have been no randomized clinical trials comparing different treatment options in this population. Prospective single-arm trials and retrospective series have evaluated the use of H. pylori eradication, radiation therapy (RT), and surgery. Of these, H. pylori eradication has emerged as the preferred treatment because of its low side effect profile and demonstrated efficacy (algorithm 1).
After initial therapy, patients must be monitored with serial endoscopies to evaluate for disease response, EMZL recurrence, and the development of gastric adenocarcinoma. Treatment failures should be treated with local RT administered with curative intent. Gastric resection is reserved for patients with complications such as perforation, bleeding, or obstruction [8-11].
H. pylori eradication — For patients who have stage I or II H. pylori-positive gastric EMZL, we recommend initial H. pylori eradication therapy followed by surveillance rather than immediate RT (algorithm 1). There have been no comparisons of various H. pylori eradication regimens in this setting, and a choice among these depends on local resistance patterns and patient-related factors such as penicillin allergy. (See "Treatment regimens for Helicobacter pylori in adults" and "Association between Helicobacter pylori infection and gastrointestinal malignancy".)
Several small single-arm trials and larger retrospective series have evaluated H. pylori eradication therapy for the treatment of gastric EMZL. A comparison of these trials is limited by a lack of consensus regarding response evaluation and the definition of complete response (CR). The following is a summary of the results of these trials [12-20]:
●Almost all patients were able to successfully eradicate the H. pylori infection, but approximately 20 percent required a second course of H. pylori-directed therapy to do so.
●Histologic CR was achieved in 50 to 83 percent of patients.
●The median time from H. pylori eradication to CR was 15 months but ranged from five months to over three years.
●After a median follow-up of 6.8 years, one study reported disease relapse in 16 of 74 patients (22 percent) [19].
In comparison, patients treated with RT almost always attain a CR and have lower relapse rates (less than 5 percent), but have a potential for more complications [21-25]. Gastrectomy is associated with high morbidity and higher recurrence rates than seen with RT [8-11].
Up to one-third of gastric EMZL will demonstrate the t(11;18) translocation [18,26-29]; such patients have a lower chance of responding to H. pylori eradication therapy. As an example, one study with a median follow-up of over five years, reported lower rates of continuous CR following antibiotic treatment in tumors with t(11;18) when compared with those without this translocation (30 versus 77 percent, respectively) [12]. Despite this lower response rate, we use H. pylori eradication for the initial management of these patients because of its low toxicity profile and chance of long-term control in a minority of patients.
Few studies have evaluated the use of adjuvant chemotherapy in patients achieving a CR. A randomized trial of adjuvant chlorambucil versus observation in patients achieving histologic CR with H. pylori eradication failed to show a progression-free or overall survival benefit [30].
Response evaluation — Patients initially treated with H. pylori eradication therapy are evaluated after the completion of treatment to determine whether the H. pylori was successfully eradicated and whether there has been a tumor response (algorithm 1):
●Confirm eradication – At least four weeks after the completion of H. pylori eradication therapy, testing should be performed to confirm eradication of infection. Up to 20 percent of patients will require a second H. pylori eradication regimen to fully eliminate the infection. We offer up to three eradication regimens before pursuing alternative therapies. (See "Indications and diagnostic tests for Helicobacter pylori infection in adults", section on 'Confirm eradication in all patients'.)
●Assess tumor response – After successful eradication of H. pylori, patients should undergo periodic upper endoscopy with multiple biopsies to evaluate for tumor response and monitor for relapse [31,32]. While this has not been formally studied, we typically perform endoscopy with biopsies every three months until a histologic CR is attained, and then perform endoscopy every six months for at least the first two years and then suggest endoscopy every 18 months and as clinically indicated. Surveillance can stop in asymptomatic patients once two sequential endoscopies show no abnormalities on biopsy. Surveillance endoscopy in patients with persistent chronic gastritis, gastric atrophy, and gastric/intestinal metaplasia is discussed in more detail separately. (See "Gastric intestinal metaplasia", section on 'Endoscopic surveillance in selected patients'.)
Unfortunately, there has been little consensus regarding what constitutes a CR of gastric EMZL. The Wotherspoon histological index (table 4) originally devised to differentiate between gastritis and EMZL at the time of diagnosis has been reported to have a high rate of inter-observer variation when applied to post-treatment biopsy specimens [12,33,34]. Using these criteria, patients who demonstrate grade 0 to 2 lesions are considered to have a histologic CR, while grade 3 lesions are classified as a partial response (PR). In contrast, the GELA score defines a histological CR as a normal or empty lamina propria and/or fibrosis with absent or sparse plasmacytes and lymphoid cells in the lamina propria without lymphoepithelial lesions [33,35]. While there appears to be a low degree of inter-observer variation when the GELA score is used, prospective studies are needed to validate its prognostic value [33].
While successful treatment with radiation usually results in the disappearance of B cell clonality [36], treatment with H. pylori eradication therapy often demonstrates persistent B cell clonality on molecular studies [37]. The ultimate clinical significance of persistent clonality in these treatment settings is unclear [17,37-39]. As an example, in a study of patients achieving histologic CR following eradication of H. pylori, there was no significant difference in the rate of histologic relapse between those who did or did not achieve molecular remission [17]. We reserve molecular testing for patients on clinical trials and define CR in clinical practice based upon histologic criteria.
Treatment failures — Approximately 20 to 30 percent of patients do not respond to H. pylori eradication therapy or demonstrate relapse during follow-up. Histology should be reviewed carefully at this time to confirm the presence of EMZL and absence of a more aggressive lymphoma, such as diffuse large B cell lymphoma [40].
The appropriate timing of second-line therapy is complicated by the sometimes slow response to H. pylori eradication therapy with attainment of CR taking up to three years. In general, we consider RT such as that given for H. pylori-negative gastric EMZL if disease is still present after 12 to 18 months (algorithm 1). (See 'Stage I or II H. pylori negative' below.)
Patients with relapsed EMZL have five-year survival rates as high as 80 to 90 percent. Treatment options include localized radiation for disease limited to the stomach or perigastric nodes and single-agent rituximab or chemoimmunotherapy for those with Lugano stage IV disease. (See 'Advanced stage' below.)
Stage I or II H. pylori negative
Initial therapy — A minority of patients with Lugano stage I or II gastric EMZL will not demonstrate active infection with H. pylori at the time of diagnosis. For such patients, we suggest local RT administered with curative intent rather than H. pylori eradication therapy or other therapies (algorithm 1). This is principally due to the high CR rates, low toxicity profile, and long-term remissions associated with this approach. Support for this approach is even stronger in tumors that demonstrate the t(11;18) translocation, as these tumors have a lower chance of responding to H. pylori eradication therapy [12]. If t(11;18) is negative and H. pylori is negative on biopsy, we sometimes offer H. pylori eradication therapy in addition to RT depending on the quality of the biopsy specimen. Immunotherapy and chemotherapy are reserved for patients failing or recurring after RT and those with Lugano stage IV disease.
Our approach for this population is consistent with that of the National Comprehensive Cancer Network, but differs slightly from that of the European Society of Medical Oncologists (ESMO) [1,2]. ESMO considers a trial of H. pylori eradication therapy reasonable since testing for H. pylori is not 100 percent sensitive and responses to eradication therapy have been reported.
The data regarding these and other treatment options come from retrospective studies and small, single agent prospective trials. There have been no clinical trials directly comparing these treatment strategies.
●Radiation therapy – Local RT (total dose of 25 to 30 gray [Gy] administered over three to four weeks) results in high rates of overall and complete responses (100 and 98 percent, respectively) for stage I or II gastric EMZL with few local relapses and five-year disease-free and overall survival rates ranging from 94 to 98 and 77 to 94 percent, respectively [21-25,41-45]. In one study, estimated median progression-free and overall survival were over 17 years [44]. A small series suggests that 24 Gy may be adequate [41]. Toxicities are limited in duration and include anorexia, malaise, nausea, and/or dyspepsia.
●Single-agent rituximab – Single-agent rituximab results in overall and complete response rates of approximately 77 and 46 percent, respectively [46-49]. Rituximab therapy is relatively well tolerated but carries risks of infusion reactions and of hepatitis B reactivation among patients positive for HBsAg or anti-HBc. The risk of hepatitis B reactivation is discussed in more detail separately. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab' and "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
●Incorporation of chemotherapy – When rituximab is combined with chemotherapy, the response rates increase, as do the associated toxicities. Unlike RT, chemoimmunotherapy is not curative. Data regarding the efficacy of chemoimmunotherapy and choice of regimen in marginal zone lymphoma are described separately. (See "Nodal marginal zone lymphoma", section on 'Incorporation of chemotherapy'.)
●There have been case reports of tumor responses to H. pylori eradication in H. pylori-negative patients, presumably due to false negative results of H. pylori testing [15,19,50,51]. We do not offer H. pylori eradication to patients without evidence of active H. pylori infection.
Restaging — We perform serial endoscopies at one and two years after completion of RT. If the patient is disease-free after two years, we do not perform further endoscopies unless new symptoms develop. As described above, there is no general consensus regarding the preferred response criteria. (See 'Response evaluation' above.)
Persistent disease — Most patients with Lugano stage I or II H. pylori-negative gastric EMZL can achieve a CR with initial RT. Those patients who fail to achieve a CR may be candidates for treatment with single agent rituximab or a combination of rituximab and chemotherapy as described in the section above. (See 'Initial therapy' above.)
Patients who choose rituximab or combination therapy for their initial management may be candidates for RT if there is persistent disease or if they develop localized relapse. Those who progress despite single-agent rituximab, combination therapy, and RT are treated with serial chemotherapy regimens. (See "Nodal marginal zone lymphoma", section on 'Choice of therapy'.)
Advanced stage — Patients with Lugano stage IV gastric EMZL are treated with H. pylori eradication therapy if they have active H. pylori infection, and then generally observed until the development of symptoms at which time they undergo treatment with rituximab and/or chemotherapy. For those without active H. pylori infection, treatment is postponed until symptoms develop. The preferred therapy at progression is not clearly defined and most data in this population come from retrospective series or extrapolation of data from other indolent non-Hodgkin lymphomas.
Our approach to such patients is similar to that used for nodal marginal zone lymphoma. This is described in more detail separately. (See "Nodal marginal zone lymphoma", section on 'Choice of therapy'.)
NON-GASTRIC MZL
General principles — Extranodal marginal zone lymphoma (EMZL) can involve the ocular adnexa, lung, lacrimal and salivary glands, thyroid, small intestine, breast, synovium, dura, skin, and soft tissues. The treatment of non-gastric EMZL depends principally on the stage of disease and area involved (table 5).
●Patients with involvement of a single extralymphatic site (IE) or a lymph node extending into a contiguous extralymphatic organ or tissue (IIE) are generally treated with local therapy or managed expectantly.
●In comparison, more advanced disease is treated with rituximab and/or chemotherapy in a similar fashion to nodal marginal zone lymphoma. (See "Nodal marginal zone lymphoma", section on 'Treatment'.)
The pretreatment evaluation usually involves extensive staging studies, which differ depending on the site of disease.
Of importance, patients with EMZL of any stage who demonstrate coexistent large cell lymphoma are treated as diffuse large B cell lymphoma. (See 'Histologic transformation' below.)
Stage I or II disease — Involved-site radiation therapy (ISRT) is the preferred treatment for most patients with involvement of a single extralymphatic site (IE) or a lymph node extending into a contiguous extralymphatic organ or tissue (IIE). Alternatives for patients who are not ideal candidates for RT due to tumor location (eg, lung) or comorbidities include initial observation, single-agent rituximab, or resection.
Select patients may be candidates for antimicrobial therapy directed at an underlying infection. Adjuvant chemotherapy has not improved disease-free survival (DFS) or overall survival (OS) in non-gastric EMZL. Specific considerations based on the site of involvement are discussed separately. (See 'Site-specific considerations' below.)
●Radiotherapy – ISRT to 24 gray (Gy) in 12 fractions is the principal therapy for most cases of stage I EMZL [42,52]. This lymphoma is very sensitive to radiation and doses should not exceed 30 Gy. With standard RT doses, rates of complete response (CR) and local control are in excess of 90 percent [23,44,53-66]. In contrast, low-dose radiation (eg, 4 Gy in two fractions) is generally not appropriate for treatment with curative intent since it is associated with a higher local relapse rate [67,68]. However, a low-dose response-adapted approach can be considered in selected patients with small volume disease, especially in those with significant comorbidities or toxicity concerns due to location of involvement [69].
●Single-agent rituximab – In one study of single-agent rituximab in 35 patients with EMZL, approximately half with stage I or II disease, the overall and complete response rates were 73 and 43 percent, respectively [48]. The median duration of response was 10.5 months overall but was longer among those who were chemotherapy-naïve. Rituximab therapy is relatively well tolerated but carries risks of infusion reactions and of hepatitis B reactivation among patients positive for HBsAg or anti-HBc. The risk of hepatitis B reactivation is discussed in more detail separately. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab' and "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
●Surgery – Surgery may be used as initial therapy for stage I or II EMZL in locations not amenable to RT, although this is uncommon given the low doses of radiation required [21,23,55,63,70-74]. In addition, the pathologic diagnosis of EMZL may become apparent only after a resection has taken place. If EMZL is diagnosed with an excisional biopsy and there is no evidence of residual disease, patients may be followed with close observation. However, if an initial surgical specimen demonstrates positive margins, adjuvant involved-field RT is administered to avoid local recurrence.
●Adjuvant chemotherapy – While EMZL has a high response rate to chemotherapy, the benefit of adjuvant chemotherapy after RT has yet to be proven [75,76].The addition of anthracycline-based chemotherapy to RT in one randomized study of 98 previously untreated patients with stage IE primary orbital EMZL did not improve the results obtained following RT alone [77].
●Antimicrobials – Patients with hepatitis C virus (HCV) infection not requiring immediate lymphoma-directed therapy should be evaluated for antiviral treatment. A number of reports, primarily from Europe, have described remissions following HCV treatment in patients with indolent lymphoma, including marginal zone lymphoma. In a multicenter, phase 2 trial of genotype-appropriate direct-acting antiviral therapy in patients with HCV infection and indolent lymphoma not requiring immediate lymphoma-directed therapy, all patients achieved a sustained virologic response, 45 percent achieved a tumor response, and the three-year progression-free survival was 76 percent [78]. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Patients with hepatitis C'.)
For patients with MZL of the ocular adnexa, there is mixed evidence regarding the use of antibiotics directed against the presumed causative agent, Chlamydia psittaci. (See 'Ocular adnexa MZL' below.)
Unlike in gastric EMZL, the benefit of H pylori-directed antibiotic therapy for non-gastric EMZL is unproven. In a prospective study of 77 patients with non-gastric EMZL, evidence for infection with H. pylori was present in 45 percent [79]. However, in the 16 H. pylori-positive patients receiving antibiotic treatment before anti-lymphoma therapy, partial regression of the lymphoma was seen in only one patient (ie, regression of a colonic lesion in a patient with both parotid and colonic disease).
Stage III or IV disease — The treatment of patients with non-gastric extranodal disease plus multiple sites of nodal involvement (stage III or IV) is not clearly defined, and most data in this population come from retrospective series or extrapolation of data from other indolent non-Hodgkin lymphomas. Our approach to such patients is similar to that used for nodal marginal zone lymphoma. This is described in more detail separately. (See "Nodal marginal zone lymphoma", section on 'Choice of therapy'.)
Follow up — Long-term treatment success with any therapy for EMZL is limited. As an example, a study of patients with EMZL who had achieved CR after initial therapy described relapses in 32 of 86 at a median time of 47 months (range: 14 to 307 months), suggesting the need for long-term observation of these patients [80]. When planning the post-treatment surveillance strategy, care should be taken to limit the number of CT scans, particularly in younger individuals, given concerns about radiation exposure and the risk for second malignancies. (See "Radiation-related risks of imaging".)
Following the completion of therapy, patients are seen at periodic intervals to monitor for treatment complications and assess for possible relapse or progression. The frequency and extent of these visits depend on the comfort of both the patient and physician. There have been no prospective, randomized trials comparing various schedules of follow-up. We generally follow patients every three to six months for the first two years and then every 6 to 12 months out to five years.
Site-specific considerations
Ocular adnexa MZL — Most patients with EMZL of the ocular adnexa present with stage I or II disease; we perform extensive staging studies to identify the up to one-quarter of patients with multifocal involvement, including bilateral disease [81,82], although other experts suggest a less aggressive staging approach given the relatively low yield of some studies (eg, bone marrow biopsy, incorporation of PET) [83]. A tumor, node, metastasis (TNM) staging system has been proposed for ocular adnexa lymphomas but is not commonly used in clinical practice [84]. We perform the following studies:
●Physical examination includes a detailed assessment of the eyes, ears, nose, and throat as well as the lymph node regions, liver, spleen, and skin.
●Laboratory studies include complete blood count with differential, chemistries with liver and renal function, electrolytes, and lactate dehydrogenase (LDH). Patients should undergo serologic testing for HIV, hepatitis B virus, and hepatitis C virus. We do not routinely test for chlamydial infection on diagnostic tissue because studies in the United States patient population suggest infection is very rare, unlike the epidemiology in Italy.
●Imaging examination includes gadolinium-enhanced magnetic resonance imaging (MRI) of the orbits and near structures plus either CT of chest, abdomen, and pelvis, or whole-body positron emission tomography/computed tomography (PET/CT).
●Unilateral bone marrow biopsy and aspirate is performed by some contributors to confirm suspected stage I or II disease in all patients, while others limit this to select patients (eg, those with multifocal disease).
The data regarding treatment of these patients come from retrospective series and small prospective studies. We offer localized RT to most patients but recognize that selected patients may reasonably choose observation after initial resection. Other experts may offer antibiotics or intralesional rituximab, although the data regarding these approaches are less clear.
●Localized RT – For most patients with stage I or II EMZL of the ocular adnexa that can be encompassed in a single radiation field, we suggest localized RT rather than other therapies. Radiation is typically administered at a dose of 24 to 25 Gy in conventional daily fractions [42,52]. The clinical target volume (CTV) generally includes the whole orbit, but for conjunctival cases, the CTV can include the conjunctival reflection to the fornices without including the entire orbit. With this approach, in-field relapses are uncommon and approximately 35 to 40 percent will relapse within five years, often at a contralateral or distant site [23,85-88]. At these doses, early radiation toxicity includes cutaneous and/or conjunctival reactions, while long-term effects include cataract formation (30 to 50 percent), xerophthalmia (20 to 40 percent), and retinopathy (2 percent). While lens shielding may reduce the risk of cataract development, it may also increase the risk of local relapse. Higher doses (eg, 36 Gy) should not be used and can result in ischemic retinopathy, optic atrophy, corneal ulceration, and vision loss due to neovascular glaucoma.
●Observation – Select patients may be observed following initial resection. The pathologic diagnosis of EMZL may become apparent only after a resection has taken place. Complete resection may be possible for patients with conjunctival and lacrimal gland lesions. Patients with negative surgical margins may be observed initially. Adjuvant involved-site RT is offered to those with positive surgical margins for local control. Older adults and asymptomatic patients may also select initial observation following surgery. In a retrospective study with a median follow-up of seven years, 25 of 36 patients (69 percent) with marginal zone lymphoma of the ocular adnexa did not require therapy beyond biopsy or resection [89]. The median time to the initiation of therapy was 4.8 years and only two patients died due to progressive lymphoma.
●Antibiotics – There is controversy regarding the use of antibiotics directed against the presumed causative agent, Chlamydia psittaci. Antibiotics have shown variable efficacy against EMZL [90-95]. As examples:
•In an international phase 2 trial of 44 patients with stage I ocular adnexal EMZL, 34 (77 percent) had detectable C. psittaci and were treated with doxycycline [94]. An at least partial response was seen in 22 patients (six complete). At a median follow-up of 37 months, the estimated rate of PFS at five years was 55 percent.
•In a Korean trial, 90 patients with EMZL of the ocular adnexa were treated with one or two three-week cycles of doxycycline [96]. An at least partial response was seen in 24 patients (27 percent), four of which were complete. After a median follow-up of 40 months, the estimated five-year PFS was 61 percent. Approximately one-third had local recurrence responsive to chemotherapy and/or RT.
The long-term prognosis following antibiotic therapy is not known, however, and patients considered for antibiotic therapy alone are best treated on specific protocols and require long and careful follow-up care by an experienced hematologist/oncologist.
●Intralesional rituximab – In a phase 2 study, 20 patients with EMZL of the ocular adnexa refractory to prior therapy were treated with serial intralesional injections of rituximab [97]. For those with no response after four injections, rituximab injections were supplemented with autologous serum. The overall response rate was 65 percent (12 complete, 1 partial). After a median follow-up of 42 months, 12 patients remained free of relapse. The treatment was well tolerated; there were three mild local reactions.
Response assessment and long-term follow-up includes care from an ophthalmologist and imaging with MRI. The frequency of imaging depends on the comfort of the patient and clinician. (See 'Follow up' above.)
Salivary gland MZL — Staging of patients with EMZL of the salivary glands includes both an assessment of disease extent as well as studies for associated conditions. We perform the following studies:
●Physical examination includes a detailed assessment of the eyes, ears, nose, and throat as well as the lymph node regions, liver, spleen, and skin.
●Laboratory studies include complete blood count with differential, chemistries with liver and renal function, electrolytes, LDH, and serologic testing for HIV, hepatitis B virus, and hepatitis C virus. Patients should be evaluated for Sjögren's disease. (See "Diagnosis and classification of Sjögren’s disease", section on 'Diagnosis'.)
●Imaging examination includes gadolinium-enhanced MRI of the orbits and near structures plus either CT of chest, abdomen, and pelvis, or whole-body PET/CT.
●Unilateral bone marrow biopsy and aspirate should be performed to confirm suspected stage I or II disease.
As with other sites of involvement, stage I or II EMZL of the salivary glands that can be encompassed within a single radiation field is often treated with RT, which may result in xerostomia. More advanced disease can be treated with single-agent rituximab or the combination of rituximab and chemotherapy. While a tissue biopsy is necessary to establish the diagnosis, more extensive surgery is discouraged since it can result in facial nerve injury, fistulas, and sialoceles.
In a retrospective study of 247 patients with salivary gland EMZL, initial therapy consisted of surgery and/or RT (57 percent); systemic chemotherapy and/or rituximab (37 percent); and observation (6 percent) [63]. Median PFS was nine years and did not differ between those receiving localized versus systemic therapy. Other studies have reported median OS of up to 18 years in this population [59,98].
The use of systemic therapy in salivary gland EMZL is similar to that used for nodal marginal zone lymphoma. This is described in more detail separately. (See "Nodal marginal zone lymphoma", section on 'Choice of therapy'.)
Thyroid MZL — Staging of patients with thyroid EMZL includes both an assessment of disease extent as well as studies for associated conditions. We perform the following studies:
●Physical examination includes a detailed assessment of the eyes, ears, nose, and throat as well as the lymph node regions, liver, spleen, and skin.
●Laboratory studies include complete blood count with differential, chemistries with liver and renal function, electrolytes, LDH, and serologic testing for HIV, hepatitis B virus, and hepatitis C virus. Given an association with Hashimoto's thyroiditis, we evaluate for hypothyroidism. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults".)
●Imaging examination with CT of neck, chest, abdomen, and pelvis, or whole-body PET/CT.
●Unilateral bone marrow biopsy and aspirate should be performed to confirm suspected early (stage I/II) disease.
The data regarding treatment of these patients come from retrospective series and small prospective studies. For most patients with stage I or II thyroid EMZL that can be encompassed in a single radiation field, we suggest localized RT rather than other therapies. With this approach, responses are seen in over 90 percent with the majority attaining a CR [99,100]. Approximately 90 percent will be alive and free of recurrence at five years.
In addition to hypothyroidism from underlying Hashimoto thyroiditis or infiltration of the thyroid by the lymphoma, patients who receive radiation to the thyroid are at risk for developing primary hypothyroidism. The risk increases with higher doses of radiation and longer time interval from the initial radiation.
We recommend checking thyroid function within six months after high dose radiation and at least annually thereafter indefinitely (thyroid-stimulating hormone [TSH] for most patients). Additionally, children and young adults with radiation exposure to the thyroid should be monitored for radiation-associated thyroid neoplasia. This topic is reviewed in more detail separately. (See "Overview of cancer survivorship care for primary care and oncology providers" and "Disorders that cause hypothyroidism", section on 'External neck irradiation' and "Radiation-induced thyroid disease".)
Lung MZL — Primary lung EMZL is sometimes referred to as bronchial associated lymphoid tissue lymphoma. We perform the following staging studies:
●Physical examination includes a detailed assessment of the eyes, ears, nose, and throat as well as the lymph node regions, liver, spleen, and skin.
●Laboratory studies include complete blood count with differential, chemistries with liver and renal function, electrolytes, LDH, and serologic testing for HIV, hepatitis B virus, and hepatitis C virus.
●Imaging examination includes either a CT of chest, abdomen, and pelvis, or a whole-body PET/CT with a dedicated chest CT.
●Unilateral bone marrow biopsy and aspirate should be performed to confirm suspected stage I or II disease.
A pathologic diagnosis is usually made based on a biopsy obtained using minimally invasive procedures such as transbronchial biopsy or image-guided percutaneous biopsy. Definitive resection, while associated with high CR rates, is usually unnecessary and has major short- and long-term risks [101].
We usually offer treatment with single-agent rituximab. Observation with serial imaging is an acceptable alternative for asymptomatic patients [102]. We avoid curative RT doses in this population because of the long-term morbidity associated with damage to normal lung tissue from RT. Low-dose RT of 4 Gy in two fractions can be offered to palliate patients with symptoms [42,103].
Small intestine MZL — EMZL of the small intestine is also known as immunoproliferative small intestinal disease (IPSID), alpha heavy chain disease, Mediterranean lymphoma, and Seligman disease. (See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas", section on 'Lymphoma of the small intestine'.)
●Physical examination should include an assessment of the lymph node regions, liver, spleen, and skin.
●Evaluation of nutritional and performance status using the Eastern Cooperative Oncology Group (ECOG) or Karnofsky performance scales (table 1 and table 2). (See "The role of parenteral and enteral/oral nutritional support in patients with cancer".)
●Upper and lower endoscopy to evaluate the extent of gastrointestinal involvement.
●Tumor biopsy should be tested for H. pylori and Campylobacter jejuni. If H. pylori is negative by histopathology, evaluate with noninvasive testing (stool antigen test or urea breath test). (See "Indications and diagnostic tests for Helicobacter pylori infection in adults".)
●Additional laboratory studies include a complete blood count with differential, chemistries with liver and renal function, electrolytes, LDH, serum protein electrophoresis and immunofixation. Patients should undergo serologic testing for HIV, hepatitis B virus, and hepatitis C virus. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
●A contrast-enhanced CT scan of the chest, abdomen, and pelvis should be performed to evaluate for distant disease.
●Unilateral bone marrow biopsy and aspirate should be performed to confirm suspected stage I or II disease.
IPSID is rare and few data are available for guiding treatment. Surgery is rarely indicated because intestinal involvement is generally diffuse. For patients who are diagnosed at an early stage, treatment with antibiotics directed against C. jejuni or H. pylori may lead to regression [104-107]. The choice of antibiotic is discussed separately. (See "Treatment regimens for Helicobacter pylori in adults" and "Campylobacter infection: Clinical manifestations, diagnosis, and treatment".)
Most patients ultimately relapse with an aggressive B cell lymphoma. For such patients, treatment is similar to the management of histologic transformation of follicular lymphoma to diffuse large B cell lymphoma. Five-year survival rates as high as 70 percent are seen in patients treated with combination chemotherapy plus tetracycline to control diarrhea and malabsorption [108,109]. (See "Histologic transformation of follicular lymphoma".)
Cutaneous MZL — Primary cutaneous marginal zone lymphoma refers to those cases of EMZL that present in the skin when there is no evidence of extracutaneous disease after the completion of an initial staging evaluation. This is discussed in more detail separately. (See "Primary cutaneous marginal zone lymphoma".)
HISTOLOGIC TRANSFORMATION — An integral part of the natural history of all indolent non-Hodgkin lymphomas, including extranodal marginal zone lymphoma (EMZL), is progression to a higher grade histologic subtype, such as diffuse large B cell lymphoma [110].
Large cell transformation should be suspected in patients with systemic B symptoms (eg, fatigue, night sweats, weight loss), elevations in lactate dehydrogenase (LDH), and/or rapidly enlarging lymph nodes. If large cell transformation is suspected clinically, a positron emission tomography (PET) scan can help guide biopsy site selection.
There are few data to guide the selection of therapy in the setting of large cell transformation. We manage large cell transformation in a similar fashion to histologic transformation of follicular lymphoma. This is discussed in more detail separately. (See "Histologic transformation of follicular lymphoma" and "Autologous hematopoietic cell transplantation in follicular lymphoma", section on 'Following histologic transformation'.)
PROGNOSIS — As a whole, patients with EMZL have a relatively good prognosis with a median survival beyond 10 years [111]. However, EMZL is a heterogeneous disease and a prognostic score, called the "MALT-IPI" may be able to identify patients with high-risk disease that is more likely to progress.
The MALT-IPI was developed using prospective data from 401 patients receiving treatment for newly diagnosed EMZL and validated in a separate cohort of 633 patients [112]. Three independent adverse prognostic factors were identified:
●Age ≥70 years
●Stage III or IV (table 5)
●Serum lactate dehydrogenase (LDH) level greater than the upper limit of normal
The following three risk groups and their corresponding five-year event-free survival (EFS), progression-free survival (PFS), overall survival (OS), and cause-specific survival (CSS) were:
●Low risk (zero risk factors): EFS 70 percent, PFS 76 percent, OS 99 percent, CSS 100 percent
●Intermediate risk (one risk factor): EFS 56 percent, PFS 63 percent, OS 93 percent, CSS 98 percent
●High risk (two or more risk factors): EFS 29 percent, PFS 33 percent, OS 64 percent, CSS 84 percent
A large, single-center analysis evaluated risk factors for histologic transformation to a higher grade lymphoma and its impact on survival [110]. In this cohort of 453 patients with biopsy-proven MZL, histologic transformation was documented at the time of diagnosis in seven patients and subsequently in 27 patients. Histologic transformation was more likely in those with an elevated LDH, >4 nodal sites involved, and failure to achieve a complete remission after initial treatment. Patients with histologic transformation had lower five-year survival rates (65 versus 86 percent).
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Marginal zone lymphoma".)
SUMMARY AND RECOMMENDATIONS
●Classification – Extranodal marginal zone lymphoma (EMZL) of mucosa associated lymphoid tissue (also called MALT lymphoma) is a clinically indolent B cell non-Hodgkin lymphoma that arises in epithelial tissues. While it has a tendency to remain localized to the tissue of origin for long periods of time, it frequently recurs locally and has potential for systematic spread and transformation to an aggressive B cell lymphoma.
For treatment purposes, EMZL is separated into those developing in the stomach (gastric EMZL) and those developing in non-gastric extranodal locations. Of importance, patients with EMZL of any site and stage who demonstrate coexistent large cell lymphoma are treated as diffuse large B cell lymphoma. (See "Initial treatment of advanced stage diffuse large B cell lymphoma".)
●Gastric EMZL – The treatment of gastric EMZL is dictated primarily by the disease stage (table 3) and the presence or absence of a concomitant H. pylori infection (algorithm 1):
•All patients with H. pylori infection should receive H. pylori eradication therapy. For patients who have stage I or II H. pylori-positive gastric EMZL, we recommend initial H. pylori eradication therapy followed by surveillance rather than immediate radiation therapy (RT) (Grade 1C). A choice among H. pylori eradication regimens depends on availability and patient-related factors. (See 'H. pylori eradication' above.)
•For patients who have stage I or II H. pylori-negative gastric EMZL that can be encompassed in a single radiation field, we suggest initial treatment with local RT rather than H. pylori eradication therapy, rituximab, and/or chemotherapy (Grade 2C). (See 'Initial therapy' above.)
•For patients with stage IV gastric EMZL we suggest treatment with H. pylori eradication therapy if H. pylori-positive followed by observation until the development of symptoms at which time chemotherapy is initiated rather than immediate treatment with rituximab and/or chemotherapy (Grade 2C). (See 'Advanced stage' above.)
•Patients are evaluated after the completion of treatment to determine whether the H. pylori was successfully eradicated (if appropriate) and whether there has been a tumor response. (See 'Response evaluation' above.)
●Non-gastric EMZL – The treatment of non-gastric EMZL depends principally on the stage of disease and area involved:
•For most patients with stage I or II non-gastric EMZL that can be encompassed in a single radiation field, we suggest treatment with involved-site RT rather than other treatment modalities (Grade 2C). Alternatively, a subset of patients with stage I disease may be observed initially with plans to initiate RT at the time of disease progression. (See 'Stage I or II disease' above.)
•For most patients with more advanced stage non-gastric EMZL, we suggest treatment with rituximab with or without chemotherapy in a similar fashion to that used for nodal marginal zone lymphoma (Grade 2C). (See "Nodal marginal zone lymphoma", section on 'Choice of therapy' and 'Stage III or IV disease' above.)
Some sites of involvement require adjustments to the pretreatment evaluation and management strategy given the risks of radiation toxicity and underlying comorbidity. Importantly, we avoid curative RT doses to sites of lung involvement because of the long-term morbidity associated with damage to normal lung tissue from RT. (See 'Site-specific considerations' above.)
●Histologic transformation – Large cell transformation should be suspected in patients with systemic B symptoms (eg, fatigue, night sweats, weight loss), elevations in lactate dehydrogenase, and/or rapidly enlarging lymph nodes. If large cell transformation is suspected clinically, a positron emission tomography (PET) scan can help guide biopsy site selection. (See 'Histologic transformation' above.)
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