Extranodal Marginal Zone Lymphoma

9 Interesting Facts of Extranodal Marginal Zone Lymphoma of MALT Type

1. Extranodal marginal zone B-cell lymphoma/MALT (mucosa-associated lymphoid tissue) lymphoma arises in the B cells of the mucosa-associated lymphoid tissue and is 1 of 3 distinct clinical subtypes of marginal zone lymphomas
2. Gastric MALT lymphoma is the most common form; nongastric forms may arise in any extranodal location but most commonly involve the thyroid or salivary gland, lungs, or eyes
3. Cause is linked to chronic immune stimulation resulting from infection, associated inflammation, and autoimmune disease; gastric MALT lymphoma is strongly linked to Helicobacter pylori infection
4. Diagnosis is based on history, physical examination, diagnostic imaging, histopathology, and immunohistochemical evaluation of biopsy specimens from organ involved; specimens in suspected gastric MALT lymphoma cases are also tested for Helicobacter pylori
5. Laboratory tests and additional imaging studies may help determine extent of disease for staging and associated complications or comorbidities
6. Treatment is based on anatomic location, histologic subtype, stage, and severity of symptoms at presentation; radiation therapy, chemotherapy, and immunotherapy are treatment options
7. Helicobacter pylori eradication therapy is the mainstay of treatment in patients with Helicobacter pylori–positive gastric MALT lymphoma
8. Surgery is rarely indicated for gastric MALT lymphoma, but it may have a role in localized nongastric forms
9. Prognosis is generally favorable; however, long-term monitoring is required for potential relapse

Terminology

• Extranodal marginal zone B-cell lymphoma/MALT (mucosa-associated lymphoid tissue) lymphoma arises in the B cells of mucosa-associated lymphoid tissue 
  • 1 of 3 distinct clinical subtypes of marginal zone lymphomas; other types include nodal marginal zone lymphoma and splenic marginal zone lymphoma
• Comprises approximately 4% of non-Hodgkin lymphoma cases in the United States 
• Can arise at any extranodal site; stomach is the most frequently involved organ, followed by ocular adnexa, salivary glands, and lung 
• Typically remains localized in the tissue of origin for a prolonged period of time; however, dissemination is possible, occurring in up to 25% of nongastric MALT lymphoma cases 

Classification

• Extranodal (extralymphatic) sites include the gastrointestinal tract, blood, bone, bone marrow, gonads, kidneys, liver, lungs, skin, uterus, ocular adnexa (eg, orbital soft tissue, lacrimal glands), and central nervous system 
  • Lymphatic or nodal sites of involvement include lymph nodes, thymus, Waldeyer ring, and spleen
• Extranodal marginal zone B-cell lymphoma/MALT lymphomas are classified as gastric, nongastric/noncutaneous, or cutaneous
  • Approximately half of all MALT lymphoma cases involve the gastrointestinal tract, with the stomach most often affected 
  • Common nongastric sites of involvement include the skin, parotid and salivary glands, head and neck structures, ocular adnexa and orbit, lung, thyroid, and breast 
• Staging is not currently standardized for extranodal marginal zone/MALT lymphomas
  • Ann Arbor staging system developed for nodal lymphomas is of limited value in staging primary extranodal lymphoma 
    • Lugano modification of the Ann Arbor staging system 
      • Stage Ie: confined to gastrointestinal tract (single or multiple primary tumors)
      • Stage IIe: extends into abdomen
        • Includes involvement of perigastric lymph nodes, distant regional lymph nodes, or adjacent structures
      • Stage IV: distant metastasis
  • Lugano staging system for gastrointestinal lymphomas is widely used and the TNM staging system has also been adapted for gastric lymphoma (Paris staging system) 
    • Stage I: confined to gastrointestinal tract (single or multiple primary tumors)
      • I1 (T1N0M0): confined to mucosa or submucosa
      • I2: extends to muscularis propria or serosa
        • T2N0M0: involves muscularis propria
        • T3N0M0: involves serosa
    • Stage II: extends into abdomen
      • II1 (T1-3, N1, M0): local nodal involvement (perigastric lymph nodes)
      • II2 (T1-3, N2, M0): distant nodal involvement (more distant regional lymph nodes)
    • Stage IIE (T4N0M0): penetrates serosa to involve adjacent organs and tissues (invasion of adjacent structures), with or without lymph node involvement (N0-2)
    • Stage IV: disseminated extranodal involvement or concomitant supradiaphragmatic nodal involvement
      • T1 to T4, N3, M0: involves extra-abdominal lymph nodes on both sides of the diaphragm
      • T1 to T4, N0 to N3, M1: distant metastasis with or without nodal involvement; in Paris staging system, this category applies to noncontiguous gastrointestinal sites and T1 to T4, N0 to N3, M2 is used when non-gastrointestinal sites are involved

Diagnosis

Clinical Presentation

History

• Clinical presentation of MALT lymphoma is variable and depends on location of disease; frequently asymptomatic 
• Gastric MALT lymphoma, the most common subtype, typically presents with symptoms of dyspepsia, reflux, nausea, epigastric discomfort, or weight loss 
  • Acute hematemesis or symptoms associated with anemia are rare 
  • B symptoms (eg, fever, night sweats) are extremely rare 
• Salivary gland MALT lymphoma may present with nontender facial swelling
• Ocular adnexal MALT lymphoma presents with varying symptoms depending on involved ocular structures 
  • Approximately 25% of patients present with conjunctival involvement, including ocular discharge, pain, discomfort, pruritus, and dryness 
  • Intraorbital involvement may manifest with diplopia or ptosis 
• Pulmonary MALT lymphoma typically presents with nonspecific symptoms such as cough, exertional dyspnea, hemoptysis, and chest pain; many cases are asymptomatic 
• Thyroid gland MALT lymphoma commonly presents as an enlarging neck mass; large masses may be associated with dysphagia, choking, and hoarseness 
  • Patients often have a history of Hashimoto disease

Physical examination

• Clinical findings are typically nonspecific; possible findings relate to location of disease
  • Gastric MALT lymphoma
    • Epigastric tenderness or mass on palpation
    • Rarely, pallor as a result of anemia
  • Salivary gland MALT lymphoma 
    • Movable, palpable mass in the salivary gland
      • Most frequently involving parotid gland, followed by the submandibular gland and, lastly, minor salivary and sublingual glands 
  • Ocular adnexal MALT lymphoma
    • Intraorbital involvement 
      • Most common findings include exophthalmos, palpable mass, and ptosis 
      • Additional signs include orbital edema, epiphora, and impaired eye movements 
    • Conjunctival involvement is indicated by classic salmon-red patch conjunctival masses in the fornices
    • Funduscopic evaluation may show extraocular muscle imbalance and limited excursion of the eye due to the lesion 
      • Choroidal folds may be observed in tumors with rapid growth 
  • Pulmonary MALT lymphoma 
    • No specific signs on physical examination; patients are frequently asymptomatic
    • Advanced cases may present with signs of pleural effusion or pulmonary fibrosis, such as decreased chest expansion on side of effusion due to decreased ventilation; resonance may be dull and flat to percussion 
  • Thyroid MALT lymphoma 
    • Palpable neck mass
    • Tracheal deviation (if large mass)

Causes

• Cause is linked to chronic immune stimulation resulting from chronic infectious condition or autoimmune disease 
  • Strong evidence supports a pathogenic role of Helicobacter pylori infection in cases of gastric MALT lymphoma, as infection is present in approximately 90% of cases 
  • Other pathogens implicated in MALT lymphomas arising from other sites include Borrelia burgdorferi (cutaneous), Chlamydia psittaci (ocular adnexa), and Campylobacter jejuni (small intestine) 
  • Hepatitis C virus may have a causative role as positive hepatitis C serology is seen in approximately 35% of cases of nongastric MALT lymphoma 
  • Autoimmune processes are also linked to the pathogenesis of nongastric MALT lymphoma 
    • Hashimoto disease often precedes the development of thyroid MALT lymphoma 
    • Myoepithelial sialadenitis, a manifestation of Sjögren syndrome, often precedes the development of salivary gland (specifically parotid) MALT lymphoma 

Risk factors and/or associations

Age

• Median age of presentation is in the sixth decade of life 

Sex

• Nongastric MALT lymphoma is slightly more common in females than in males; gastric MALT lymphoma has similar incidence in both sexes 

Genetics

• Most common aberration found in MALT lymphomas is the t(11;18)(q21;q21) translocation (found in 13%-35% of cases) 
• An additional common mutation is the t(14;18)(q32;q21) translocation, which occurs in 15% to 20% of MALT lymphomas 
  • Most commonly found in nongastric cases (eg, liver, lung, ocular adnexa) 
• Other mutations aberrations include t(3;14)(p14.1;q32) translocation (detected in 50% of thyroid involvement cases and in 20% of ocular adnexal cases), t(1;14)(p22;q32) translocation (occurs in 1%-2% of cases involving stomach, lung, and skin), and 6q23.3 deletion 

Ethnicity/race

• Overall incidence rates for MALT lymphoma were highest among non-Hispanic Whites and lowest among Blacks, with a few exceptions 
  • Salivary gland MALT lymphoma incidence ratios were higher in Hispanics compared with non-Hispanic Whites 
  • Asians and Pacific Islanders had significantly higher incidence ratios for colon/rectal MALT lymphoma and ocular adnexal MALT lymphoma compared to non-Hispanic Whites 

Diagnostic Procedures

Primary diagnostic tools

• Gastric MALT lymphoma
  • Diagnosis of gastric MALT lymphoma is based on endoscopy and biopsy findings in patients with suggestive gastrointestinal symptoms
    • Endoscopy (esophagogastroduodenoscopy/upper gastrointestinal tract endoscopy) allows for definitive histopathologic diagnosis via direct visualization and biopsy
    • Histopathologic staining for Helicobacter pylori is performed
  • Evaluate all cases with comprehensive history, physical examination, diagnostic imaging, and the following laboratory tests: 
    • CBC
    • Comprehensive metabolic panel
    • Serum lactate dehydrogenase level
      • Elevated levels of lactate dehydrogenase are associated with a poorer prognosis 
    • β₂-microglobulin
      • Elevated levels are associated with a poorer prognosis 
    • Hepatitis C serology
    • Noninvasive Helicobacter pylori testing (eg, blood antibody test, urea breath test, stool antigen test) if Helicobacter pylori test results are negative on histopathology
      • Order of testing will usually depend on availability or ease of testing
    • Hepatitis B serology (if considering rituximab therapy)
    • CT of chest, abdomen, and pelvis
    • Pregnancy test in patients of childbearing age (if chemotherapy or radiation therapy planned)
    • In selected cases:
      • Bone marrow biopsy with or without aspirate when there is an absence of gastric lymphoma regression after Helicobacter pylori eradication therapy
        • Precedes locoregional radiation therapy 
      • Echocardiography or multiple gated acquisition scanning (if anthracycline- or anthracenedione-based regimen indicated)
      • Endoscopy with or without ultrasonography and biopsies to evaluate the involvement of regional lymph nodes and extent of gastric wall infiltration 
      • Serum protein electrophoresis
      • PET-CT, particularly if involved site radiation therapy is planned
      • Molecular genetic testing
• Nongastric MALT lymphoma
  • Diagnosis is established on basis of clinical and radiologic features and histopathology, as well as immunophenotyping material obtained at lesion biopsy 
    • Orbital MALT lymphoma diagnosis relies heavily on MRI and orbit ultrasonographic findings 
    • Conjunctival MALT lymphoma diagnosis is based on macroscopic aspects of the lesion (eg, salmon-red patch, swelling) and subsequent tissue sampling by biopsy or resection 
    • Pulmonary MALT lymphoma diagnosis uses contrast-enhanced CT of the thorax as standard tool to define extent of disease 
      • Routine chest radiography often can detect pulmonary lymphomas (in cases with an alveolar aspect) 
      • Tissue samples for histologic analysis can be collected by bronchoscopy, surgical resection, or fine-needle aspirate 
    • Thyroid and salivary gland MALT lymphoma diagnosis relies on ultrasonography to identify nodules or masses in the thyroid and/or salivary glands; MRI may also be used to better identify tumor border and extension for staging 
      • Needle biopsy may be implemented in cases of thyroid MALT lymphoma 
      • Open biopsy is preferred in cases of parotid MALT lymphoma to preserve the facial nerve 
    • Breast MALT lymphoma is investigated by mammography and MRI
    • Histopathologic diagnosis is determined from tissue samples obtained by bronchoscopy (pulmonary cases), open biopsy, or needle biopsy (thyroid and pulmonary cases)
  • Evaluate all patients with comprehensive history, physical examination, diagnostic imaging, and the following laboratory tests: 
    • CBC
    • Comprehensive metabolic panel
    • Serum lactate dehydrogenase level
      • Elevated levels are associated with a poorer prognosis
    • Hepatitis B serology (if considering rituximab therapy)
    • Hepatitis C serology
    • CT of chest, abdomen, and pelvis
    • Whole body PET-CT (required if radiotherapy planned)
    • Pregnancy test in patients of childbearing age (if chemotherapy or radiation therapy planned)
    • In select cases:
      • Echocardiography or multiple gated acquisition scanning (if anthracycline- or anthracenedione-based regimen indicated)
      • Bone marrow biopsy with or without aspirate in patients with multifocal disease
      • Upper gastrointestinal endoscopy with biopsies of multiple anatomic sites when head/neck or lung is involved
      • MRI with contrast enhancement for neurologic evaluation
      • Serum protein electrophoresis
      • Screening for autoimmune disease
      • Molecular genetic testing

Imaging

• MRI
  • Useful in diagnosis of MALT lymphomas involving head and neck structures (eg, orbit, thyroid, salivary glands)
  • Orbital MALT lymphoma will typically show a characteristic mass with distinct margins and an isointense signal on T1-weighted images and isohyperintense on T2-weighted images with variable enhancement after contrast material injection 
    • Diffusion-weighted MRI is useful for distinguishing orbital lymphoma from other orbital masses; low values in the apparent diffusion coefficient are useful in differentiating lymphomas from other masses 
  • Salivary and thyroid MALT lymphomas typically appear on MRI as low signal intensity on T1-weighted images and low to high signal intensity on T2-weighted images 
• Ultrasonography
  • Useful in diagnosis of MALT lymphomas involving head and neck structures (eg, orbit, thyroid, salivary glands)
  • Common ultrasonographic patterns of the salivary and thyroid glands include 1 of the following: 
    • Markedly hypoechoic area with interspersed linear echogenic strands 
    • Markedly hypoechoic with lobulated and segmental appearance 
  • Ophthalmic ultrasonogram can show presence of intraocular mass or retinal detachment
• CT
  • Useful in diagnosis of pulmonary MALT lymphoma
    • Most common radiologic presentation is a mass (2-8 cm) located on the lower lobes 
      • Multiple nodules are present in less than 10% of patients 
    • Interstitial infiltrate is detected in 10% of patients 
• Plain radiographs
  • Chest radiograph can show air bronchogram and poor margins in cases of pulmonary MALT lymphoma 
    • About one-half of patients with pulmonary MALT lymphoma have an air bronchogram 

Procedures

• Direct visualization of the upper gastrointestinal tract using a video gastroscope with tissue biopsy obtained from suspicious areas
• Biopsy of a tissue specimen obtained during procedure confirms or excludes malignancy and determines if Helicobacter pylori infection is present
• Provides definitive histopathologic diagnosis of gastric MALT lymphoma
• To evaluate for suspected gastric malignancy or other gastroesophageal disease in patients with unexplained gastrointestinal symptoms
• To obtain tissue for diagnosis, histologic classification, and molecular biomarkers
• Clinical evidence of acute perforation
• Medical instability
• Do not perform immunophenotyping in patients on immunosuppressive medications
• Perforation
• Bleeding
• Endoscopy may demonstrate mucosal ulceration, hyperplasia, polyp, or infiltrative lesion 
• Diagnosis is confirmed by hematopathologic review of an endoscopic biopsy with a minimum of 1 representative paraffin block of the tumor
  • Immunophenotyping establishes the diagnosis; consists of immunohistochemistry panel, cell surface marker analysis, and in some cases, molecular analysis, cytogenetics, or fluorescence in situ hybridization for various mutations
• Evaluate tumor specimen for Helicobacter pylori 
  • If result is positive, test for t(11;18)(q21;q21) translocation by fluorescence in situ hybridization or polymerase chain reaction; locally advanced disease, which is less likely to respond to antibiotics, is more likely in presence of t(11;18)(q21;q21) translocation 
• Collection of tissue specimen for histopathologic examination; performed either via open surgical resection or percutaneously under CT or ultrasonographic guidance
  • Excisional biopsy: entire lump or suspicious area is removed
  • Incisional biopsy (also called core biopsy): sample of tissue is removed with preservation of histologic architecture of sample tissue
  • Needle biopsy (ie, aspiration biopsy): sample of tissue or fluid is removed with a needle without preservation of histologic architecture of sample tissue cells
• Mass lesion suggestive of malignancy
• Uncontrolled bleeding diathesis
• Bleeding at site of biopsy
• Hematoma formation
• Infection
• Diagnosis is confirmed by hematopathologic review of an endoscopic biopsy with a minimum of 1 representative paraffin block of the tumor 
  • Immunophenotyping establishes the diagnosis; consists of immunohistochemistry panel and cell surface marker analysis by flow cytometry 
  • In some cases, molecular analysis is useful, using karyotype or fluorescence in situ hybridization to detect antigen receptor gene rearrangements 

Differential Diagnosis

Most common

• Gastric adenocarcinoma (Related: Gastric Cancer) 
  • Aggressive malignant epithelial tumor of the gastrointestinal tract, usually manifesting in an advanced stage
  • Helicobacter pylori infection is the most important risk factor for development
  • Similarly to gastric MALT lymphoma, presents with nonspecific gastrointestinal symptoms such as dyspepsia, epigastric discomfort, or hematochezia, and constitutional symptoms such as weight loss
  • Differentiate on basis of history and endoscopic and histopathologic findings
• Peptic ulcer disease (Related: Peptic Ulcer Disease)
  • Ulcerations in the stomach or duodenum resulting from an imbalance between mucosal protective factors and various mucosal-damaging mechanisms
  • Like gastric MALT lymphoma, may also be associated with Helicobacter pylori infection
  • Presentation with epigastric pain and burning, which may be associated with weight loss and loss of appetite, may be indistinguishable from gastric MALT lymphoma
    • However, classic ulcer-related pain is relieved by intake of certain foods or liquids (eg, ice cream, milk) or antacids
  • Differentiate on basis of history and endoscopic findings
• Gastroesophageal reflux disease (Related: Gastroesophageal Reflux Disease in Adults)
  • Characterized by backflow of gastric contents through an incompetent gastroesophageal sphincter
  • Features include postprandial heartburn and retrosternal discomfort that is exacerbated by bending over or lying flat
  • Most cases can be diagnosed on the basis of clinical history; diagnosis can generally be made with reasonable certainty if the patient complains of heartburn and regurgitation of gastric contents
  • Differentiate from gastric MALT lymphoma on basis of history and endoscopic findings
    • Endoscopy can establish the presence or absence of associated esophagitis, Barrett esophagus, or esophageal stricture
• Functional dyspepsia
  • Upper gastrointestinal tract discomfort in the absence of any structural disease that can explain the symptoms; diagnosis of exclusion
  • Causes are poorly characterized and condition may be multifactorial
  • Presentation with postprandial fullness, early satiety, and epigastric pain and burning may be indistinguishable from gastric MALT lymphoma
  • Unlike gastric MALT lymphoma, not associated with significant weight loss, anorexia, vomiting, or hematochezia
  • Differentiate from gastric MALT lymphoma on basis of history and endoscopic findings

Treatment

• Treatment algorithm for localized (stage IE or II) Helicobacter pylori–positive gastric MALT lymphoma. – Treatment algorithm for the management of gastric MALT lymphoma confined to the stomach, with or without regional lymph node involvement.From Thieblemont C et al: Clinical aspects and therapy of gastrointestinal MALT lymphoma.

Treatment Goals

• Helicobacter pylori eradication for Helicobacter pylori–positive gastric MALT lymphoma 
• Eradication or regression of lymphoma for both gastric and nongastric MALT lymphomas

Admission criteria

• Admit patients with severe gastrointestinal hemorrhage

Recommendations for specialist referral

• Referral to gastroenterologist and oncologist is recommended for diagnosis and treatment planning for gastric MALT lymphoma
• Referral to medical and radiation oncologists is recommended to determine treatment strategies for both gastric and nongastric cases of MALT lymphoma
• Additional referrals to specialists for nongastric cases may be necessary, depending on organ or tissue involvement
  • May include an ophthalmologist for ocular or conjunctival involvement and an endocrinologist for thyroid involvement

Treatment Options

Overview

• Gastric MALT lymphoma
  • Initial therapy depends on stage of disease and Helicobacter pylori status
    • Stage I1, I2, or II1 and positive Helicobacter pylori status 
      • Prescribe currently accepted antibiotic therapy to eradicate Helicobacter pylori, followed by endoscopy and biopsy at 3 months to confirm Helicobacter pylori eradication and restage lymphoma 
        • Common regimens include clarithromycin plus amoxicillin (or metronidazole) for 10 to 14 days 
        • Use of proton pump inhibitor (eg, rabeprazole, omeprazole, lansoprazole) accompanies antibiotic therapy 
      • Subsequent management consists of observation if Helicobacter pylori and lymphoma have been eradicated, or second line antibiotic therapy and/or involved-site radiation therapy if Helicobacter pylori and/or lymphoma persist
      • If patients have Helicobacter pylori infection and t(11;18)(q21;q21) translocation and if disease persists at reevaluation, antibiotic therapy is followed by involved-site radiation therapy or rituximab (if involved-site radiation therapy is contraindicated) 
      • For regions of submucosa or regional lymph nodes involvement, earlier involved-site radiation therapy may be considered if disease persists at reevaluation 
    • Stage I1, I2, or II1 and negative Helicobacter pylori status 
      • Initial treatment consists of involved-site radiation therapy (preferred) or rituximab (if involved-site radiation therapy is contraindicated)
      • Treatment is followed by endoscopy and biopsy for restaging at 3 months
      • Treatment with Helicobacter pylori–directed antibiotic therapy has been successful in small case series and may warrant further study 
    • Stage IIE, II2, or IV 
      • Treat if any of the following are present:
        • Patient is a candidate for a clinical trial
        • Gastrointestinal bleeding or other symptoms
        • Threatened end-organ function
        • Bulky and/or progressive disease
        • Patient requests treatment
      • Observe if patient is asymptomatic and no indications for treatment are present
      • Treatment consists of induction chemoimmunotherapy or locoregional radiation therapy 
        • Immunotherapy includes anti-CD20 monoclonal antibody (rituximab) 
        • Rituximab may be administered alone or in combination with the CHOP (RCHOP) regimen, CVP (RCVP) regimen, or bendamustine
        • In older or frail patients, rituximab may be used alone or in combination with chlorambucil or cyclophosphamide 
        • Other first line regimens include ibritumomab tiuxetan and lenalidomide 
      • Surgical resection is only indicated for specific situations such as life-threatening gastrointestinal hemorrhage 
• Nongastric MALT lymphoma
  • Initial therapy depends on location and stage of disease and extent of margins 
    • Consider empiric therapy with doxycycline before starting treatment of ocular MALT lymphoma 
    • Stage I or II
      • Involved-site radiation therapy is preferred first line therapy 
      • Surgery may be considered for certain sites including the lungs, thyroid, breast, and colon/small bowel 
      • Rituximab is an option when surgery or radiation therapy is not feasible 
      • Observation is not usually recommended, but may be considered for patients in whom radiation therapy could result in significant morbidity or in whom diagnostic biopsy was excisional with negative margins 
    • Stage IV
      • Involved-site radiation therapy 
      • Chemoimmunotherapy or chemotherapy alone may also be considered for advanced recurrent or refractory disease after radiation therapy 
      • Observation may be considered for patients in whom radiation therapy could result in significant morbidity or in whom diagnostic biopsy was excisional with negative margins

Rationale

• Gastric MALT lymphoma
  • Antibiotic therapy is indicated as first line therapy in all Helicobacter pylori–positive cases regardless of stage as eradication frequently induces cure 
  • Presence of submucosa, regional lymph node involvement, or t(11;18)(q21;q21) translocation predicts tumor nonresponse to antibiotics and is an indication for earlier initiation of involved-site radiation therapy 
  • Incurability of advanced-stage disease using conventional therapy warrants investigational therapy (clinical trial) when possible 
• Nongastric MALT lymphoma
  • Radiation therapy alone is an effective treatment option for nongastric MALT lymphomas, warranting its use as a first line therapeutic option 
  • Surgical excision for diagnostic purposes may be sufficient to remove primary tumor in select cases 
  • Chemotherapy with or without addition of immunotherapy has demonstrated an improved response rate in advanced and disseminated cases 

Outcomes

• Gastric MALT lymphoma
  • Helicobacter pylori eradication and radiation therapy are the most effective treatment strategies
    • Eradication of Helicobacter pylori with antibiotic therapy alone results in lymphoma regression in approximately 78% of patients with gastric lymphoma 
      • 5-year overall survival rate after Helicobacter pylori eradication therapy is approximately 95% 
      • 5-year disease-free survival rate after Helicobacter pylori eradication therapy is approximately 86% 
    • Complete remission rates in patients with primary localized gastric MALT lymphoma initially treated with radiation therapy (30 Gy) alone range from 96% to 98% 
      • Intensity-modulated radiation therapy using lower doses (24 Gy) was also associated with high rates of complete response and overall survival at 2-year follow-up 
    • In patients who received second line radiation therapy after eradication therapy for Helicobacter pylori failed, complete remission rate was 89% and 5-year cause-specific overall survival rate was 93% 
  • Surgical resection has not been shown to offer benefit over other treatment modalities
  • There are limited data demonstrating benefits of chemotherapy in localized disease; however, chemotherapy may be effective in patients with advanced systemic disease or relapse
    • In patients with advanced cases of gastric MALT lymphoma, single-agent chemotherapy with either chlorambucil or cyclophosphamide achieved a complete remission rate of 75%; use of cladribine resulted in complete remission rate of 84% 
      • Combination chemotherapy with mitoxantrone, chlorambucil, and prednisone was also effective in a small sample of patients with MALT lymphoma 
  • Immunotherapy with rituximab has been evaluated as initial therapy and as second line therapy
    • Complete remission rate and 2-year progression-free survival rate of 100% when used in combination with fludarabine in previously untreated patients
    • Rituximab plus chlorambucil resulted in an improved remission rate and overall survival compared to rituximab alone in previously untreated patients with gastric MALT lymphoma with t(11;18)(q21;q21) translocation 
    • In patients with stage IE1 and IE2 disease who received second line immunotherapy with rituximab after eradication therapy for Helicobacter pylori failed, overall response rate was 77% and complete remission rate was 46% 
    • Rituximab combined with CHOP resulted in a complete remission rate of 77% in patients with relapsed disease 
• Nongastric MALT lymphoma
  • Radiation therapy is the most effective treatment modality
    • In patients with localized nongastric MALT lymphoma, radiation therapy alone resulted in a 10-year relapse-free rate of 95%, 68%, and 67% for patients with primary lymphomas of the thyroid, salivary glands, and orbital adnexa, respectively 
  • Chemotherapy has been evaluated alone and in combination with other therapies
    • Among patients with advanced nongastric MALT who received chemotherapy with or without radiation therapy or surgery, overall response rate was 92% and complete remission rate was 72% 
      • After median follow-up of 3.4 years, estimated overall 5-year survival rate was 90% and estimated progression-free survival rate was 60% 
      • Both 5-year progression-free and overall survival rates were 100% in primary conjunctival disease, 23% and 80% respectively for primary disease involving the orbit, and 67% and 97% respectively for primary disease in the salivary gland
    • In patients with advanced nongastric MALT lymphoma treated with chemotherapy alone, overall response rate was 65% 
      • For patients in this group, overall response rate was 90% for those treated with surgery alone and 76% for those treated with radiation therapy alone 
  • Immunotherapy with rituximab has been studied alone or in combination with chemotherapy 
    • Overall response rate of 80% when used as a single agent and 100% when used in combination with fludarabine 

Drug therapy

• Helicobacter pylori eradication therapy
  • Combination of clarithromycin plus amoxicillin (or metronidazole if patient is allergic to penicillin) plus a proton pump inhibitor 
    • Regimens listed by proton pump inhibitor
      • Omeprazole 
        • Omeprazole Oral capsule, gastro-resistant sprinkles; Adults: 20 or 40 mg PO twice daily with clarithromycin and either amoxicillin or metronidazole for 14 days. FDA-labeling suggests additional 14 to 18 days of omeprazole 20 mg PO once daily in patients with ulcers.
        • Omeprazole Gastro-resistant tablet; Adults: 20 mg PO twice daily as part of a combination therapy. Quadruple therapy includes a proton pump inhibitor (PPI) with clarithromycin, amoxicillin, and metronidazole for 10 to 14 days. Hybrid therapy includes amoxicillin plus PPI for 7 days followed by PPI with clarithromycin, amoxicillin, and metronidazole for 7 days. Sequential therapy includes PPI and amoxicillin for 5 to 7 days followed by PPI with clarithromycin and metronidazole for 5 to 7 days.
      • Rabeprazole 
        • Rabeprazole Sodium Oral capsule, gastro-resistant sprinkles; Adults: 20 or 40 mg PO twice daily with clarithromycin and either amoxicillin or metronidazole for 14 days.
        • Rabeprazole Sodium Oral capsule, gastro-resistant sprinkles; Adults: 20 mg PO twice daily as part of a combination therapy. Quadruple therapy includes a proton pump inhibitor (PPI) with clarithromycin, amoxicillin, and metronidazole for 10 to 14 days. Hybrid therapy includes amoxicillin plus PPI for 7 days followed by PPI with clarithromycin, amoxicillin, and metronidazole for 7 days. Sequential therapy includes PPI and amoxicillin for 5 to 7 days followed by PPI with clarithromycin and metronidazole for 5 to 7 days.
      • Lansoprazole 
        • Amoxicillin Trihydrate Oral capsule, Clarithromycin Oral tablet, Lansoprazole Oral capsule, gastro-resistant sprinkles; Adults: 30 mg lansoprazole PO, 1,000 mg amoxicillin PO, and 500 mg clarithromycin PO twice daily for 10 to 14 days
        • Lansoprazole Oral capsule, gastro-resistant sprinkles; Adults: 30 or 60 mg PO twice daily with clarithromycin and either amoxicillin or metronidazole for 14 days.
• Chemotherapy 
  • Alkylating agents
    • Chlorambucil
    • Cyclophosphamide
  • Purine nucleoside analogues
    • Bendamustine
    • Fludarabine
    • Cladribine
  • Anthracyclines
    • Doxorubicin
  • Plant alkaloids
    • Vincristine
• Cytolytic monoclonal antibody
  • Rituximab
• Corticosteroids
  • Prednisone

Nondrug and supportive care

Radiation therapy 

• For most sites, whole organ irradiation is the standard approach; partial organ irradiation may be considered if this is not feasible or poses risk of toxicity 
• Dose is site dependent
  • For localized gastric MALT lymphoma cases, a dose of 30 Gy is preferred 
  • For stage I or II nongastric MALT lymphoma cases, a dose of 24 to 30 Gy is preferred 
  • Lower doses (24 Gy) are used in orbital disease 

Comorbidities

• Hepatitis C
  • Consider hepatitis C antiviral therapy in patients with hepatitis C-associated lymphoma 

Monitoring

• Gastric MALT lymphoma 
  • Restage with endoscopy and multiple biopsies 3 months after initial treatment with antibiotics, or 3 to 6 months after initial treatment with radiation therapy or rituximab 
    • Purpose of biopsies is to rule out large cell lymphoma
  • Patients who have achieved complete remission have clinical follow-up every 3 to 6 months for 5 years, then yearly as clinically indicated 
    • Optimal interval for subsequent follow-up endoscopy and imaging has not been established
    • European guidelines recommend endoscopy and biopsy every 6 months for 2 years, then every 12 to 18 months 
  • Patients with residual lymphoma are followed up with endoscopy and biopsy every 3 to 6 months 
• Nongastric MALT lymphoma 
  • Clinical follow-up is conducted every 3 to 6 months for 5 years, and then yearly as clinically indicated 
    • Follow-up includes diagnostic tests and imaging based on site of disease 

Complications

• Disseminated disease
  • Up to 25% of patients with nongastric MALT lymphoma have disseminated disease (including bone marrow involvement) at presentation; gastric MALT lymphoma typically remains localized 
• Local organ complications
  • Vary by location of primary disease (eg, intestinal obstruction, gastrointestinal hemorrhage, urinary outflow obstruction, lung fibrosis, pleural effusion)
• Chemo- or radiation therapy–related complications
  • Radiation therapy for ocular adnexal MALT lymphoma can result in cataract formation (30%-50% of patients) and xerophthalmia (20%-40% of patients) 
  • Perforation of gastric lymphoma rarely occurs in patients receiving chemotherapy (about 0.9%-1.1% of cases) 

Prognosis

• Both gastric and nongastric forms of MALT lymphoma tend to present as localized, indolent disease with favorable prognosis 
• Overall 5-year survival rate for extranodal marginal zone/MALT lymphoma is approximately 94% 
• Stage also influences mortality rates as demonstrated by the following 5-year incidence rates of lymphoma-related deaths: 
  • Stage I: 6.1% 
  • Stage II: 13.6% 
  • Stage IV: 17.6% 
• Prognosis is influenced by age of patient, stage at diagnosis, and lactate dehydrogenase level 
  • MALT international prognostic index classifies patients into the following 3 groups based on these 3 factors (eg, patient aged 70 years or older, Ann Arbor stage III or IV, and elevated lactate dehydrogenase): 
    • Low risk (0 factors): 5-year progression-free survival rate of 70%
    • Intermediate risk (1 factor): 5-year progression-free survival rate of 56%
    • High risk (2 or more factors): 5-year progression-free survival rate of 29%

Sources

1: Joshi M et al: Marginal zone lymphoma: old, new, targeted, and epigenetic therapies. Ther Adv Hematol. 3(5):275-90, 2012