MALT Lymphoma

Extranodal marginal zone lymphoma (EMZL) of mucosa-associated lymphoid tissue (also called MALToma, MALT lymphoma, and pseudolymphoma) is a group of non-Hodgkin’s lymphomas that have historically been grouped together because they appear to arise from postgerminal center marginal zone B cells and share a similar immunophenotype. MALT lymphoma is thought to arise in the setting of chronic immune stimulation, which is usually due to bacterial, viral, or autoimmune stimuli. MALT lymphomas present with symptoms due to localized involvement of glandular epithelial tissues in the specific site where they develop. Diagnosis of MALT lymphoma is made by morphologic, immunophenotypic, and genetic analysis of biopsy samples. Helicobacter pylori–positive gastric MALT lymphoma is treated with H. pylori eradication therapy, and H. pylori–negative gastric MALT lymphoma is treated with radiation therapy. Nongastric MALT lymphoma is treated based on the involved area and extent of disease. MALT lymphoma patients have a good prognosis, with a median survival of > 10 years.

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Overview

Definition

MALT lymphoma is a clinically indolent non-Hodgkin’s lymphoma postulated to arise from postgerminal center memory B cells with the capacity to differentiate into marginal zone cells and plasma cells.

Epidemiology

  • Relatively uncommon subtype of non-Hodgkin’s lymphoma:
    • 5%–10% of all non-Hodgkin’s lymphomas
    • Approximately half of non-Hodgkin’s lymphomas in stomach, ocular adnexa, and lung
  • Incidence in the United States: 18.3 cases per 1 million person-years
  • Primarily seen in adults (median age at diagnosis: 66 years)
  • Highest incidence in non-Hispanic whites
  • Lowest incidence in African Americans
  • In males, more common involvement in:
    • Stomach
    • Small intestine
    • Skin
    • Kidney
  • In females, more common involvement in:
    • Salivary glands
    • Soft tissue
    • Thyroid

Etiology

  • Generally present in the setting of chronic immune stimulation due to bacterial, viral, or autoimmune stimuli:
    • Implicated autoimmune conditions:
      • Sjögren’s syndrome (parotid extranodal marginal zone lymphoma (EMZL))
      • Systemic lupus erythematosus
      • Relapsing polychondritis
      • Hashimoto’s thyroiditis (thyroid EMZL)
    • Implicated bacteria:
      • Helicobacter pylori gastritis: best-established relationship
      • Chlamydia psittaci (ocular adnexa)
      • Campylobacter jejuni (small intestine)
      • Borrelia afzelii (skin)
      • Achromobacter xylosoxidans (lung)
  • Several translocations resulting in increased activation of nuclear factor kappa-B with and without immune stimulation have been implicated as a potential etiology.

Pathophysiology

  • MALT lymphoma develops because of chronic stimulation of lymphoid tissue: 
    • Leads to local accumulation and proliferation of antigen-dependent B cells and T cells
    • Over time, the B cells, which are still antigen-dependent, develop mutations.
    • Monoclonal B cells then develop additional mutations and become antigen-independent and capable of systemic spread.
  • Proliferation of MALT cells at certain sites depends on activated, antigen-driven T cells.
  • MALT lymphoma reproduces the morphologic features of normal MALT:
    • Reactive follicles are usually present with neoplastic cells occupying the marginal zone and/or the interfollicular region.
    • Neoplastic cells may occasionally colonize follicles.
  • Common chromosome translocations leading to increased expression of nuclear factor kappa-B (which provides a survival advantage to the neoplastic B cells):
    • t(11;18)(q21;q21)
    • t(14;18)(q32;q21)
    • t(1;14)(p22;q32)
    • t(3;14)(p13;q32)
  • Monoclonal gammopathy:
    • Present in 27%–36% of patients
    • Correlates with:
      •  Plasmacytic differentiation
      •  Advanced disease
      •  Involvement of lymph nodes and bone marrow
  • Prototypical example: 
    • H. pylori infection with chronic gastritis
    • May lead to development of gastric MALT
    • Remains localized for significant periods of time (but is a clonal B-cell neoplasm)
    • Frequently recurs
    • Potential for systemic spread
    • Can transform into an aggressive B-cell lymphoma

Clinical Presentation

Clinical presentation varies depending on the location where the MALT lymphoma develops.

  • Stomach:
    • GERD
    • Epigastric pain or discomfort
    • Anorexia
    • Weight loss
    • Occult GI bleeding
  • Ocular adnexa:
    • Slow-growing mass
    • Eye redness
    • Epiphora (excessive eye watering)
  • Salivary gland:
    • Slow-growing mass
    • Minority of patients: bilateral involvement
  • Skin: 
    • Red to violaceous papules, plaques, or nodules
    • Commonly localized to trunk and upper extremities
  • Lung:
    • Asymptomatic
    • Lung nodules and/or airspace consolidation on imaging
  • Small intestine:
    • Intermittent diarrhea
    • Colicky abdominal pain
    • Symptoms related to malabsorption

Dissemination to other sites of MALT tissue:

  • 30% of cases
  • Lymph nodes
  • Marrow

Peripheral blood is usually not involved.

Systemic B symptoms are uncommon:

  • Fevers
  • Night sweats
  • Weight loss

Diagnosis

History

  • Constitutional:
    • Anorexia
    • Weight loss
  • Head, eyes, ears, nose, throat (HEENT):
    • Red, watery eyes
    • Oral mass
  • GI:
    • GERD
    • Epigastric pain and discomfort
    • GI bleeding
    • Diarrhea
    • Colicky abdominal pain
  • Skin: trunk and upper extremity changes
  • Nutritional and performance evaluation using the following performance scales:
    • Eastern Cooperative Oncology Group (ECOG)
    • Karnofsky

Physical exam

  • HEENT:
    • Oral/salivary gland mass
    • Eye redness
    • Epiphora
  • Enlarged lymph nodes
  • Hepatosplenomegaly (if liver or spleen involved)
  • Skin:
    • Reddish papules, plaques, or nodules
    • More common on:
      • Trunk
      • Upper extremities

Laboratory

  • Biopsy of affected site:
    • Morphologic, immunophenotypic, and genetic analysis of the biopsy sample should be analyzed within clinical context:
      • Morphology: polymorphous infiltrate of small cells with reactive-appearing follicles
      • Immunophenotype: B cells positive for CD19, CD20, and CD22 and negative for CD5, CD10, and CD23
      • Genetic analysis: PCR analysis of IgH rearrangement is helpful in differentiating MALT lymphoma from reactive proliferations.
    • Obtain large sample (so cancer is not missed in biopsy sample).
    • Esophagogastroduodenoscopy:
      • For gastric MALT lymphoma
      • Multiple biopsies from each gastric region
    • Biopsies for H. pylori:
      • If negative: perform stool antigen test or urea breath test
      • FISH or PCR testing for t(11;18) to identify tumors unlikely to respond to H. pylori eradication
  • Blood tests (may provide information about organs involved/associated diseases):
    • CBC/DIFF
    • Serum electrolytes
    • Liver function tests
    • Renal function tests
    • ↑ LDH
    • Serum protein electrophoresis (to evaluate for monoclonal gammopathy)
    • Serologic testing:
      • HIV
      • Hepatitis C or B
  • Imaging:
    • CT and MRI:
      • To evaluate for distant disease
      • Extent of primary lesion
      • Do not differentiate malignant MALT lesions from benign
      • Can image chest, abdomen, pelvis, orbits, and salivary glands
    • Whole-body combined fluorodeoxyglucose (FDG) PET/CT to evaluate for:
      • Radiation therapy
      • Suspected large-cell transformation
  • Bone marrow biopsy to confirm suspected early (stage I/II) disease
Gastric malt lymphoma associated with h. Pylori

Gastric MALT lymphoma associated with H. pylori:
a: Lymphoid follicle with a reactive germinal center and a slightly expanded marginal zone (H&E, original magnification, 100X)
b: Immunostaining of H. pylori shows intra-foveolar bacteria with curving configuration, characteristic of H. pylori.

Image: “Gastric mucosa-associated lymphoid tissue lymphoma and Helicobacter pylori infection: a review of current diagnosis and management” by Hu Q, Zhang Y, Zhang X, Fu K. License: CC BY 4.0
Malt lymphoma of the colon

MALT lymphoma of the colon:
Infiltration of malignant-looking lymphoid cells in the lamina propria suggestive of malt lymphoma

Image: “Synchronous adenocarcinoma and mucosa-associated lymphoid tissue lymphoma of the colon” by Devi P, Pattanayak L, Samantaray S. License: CC BY 2.0

Staging

  • Lugano staging system (for gastric involvement):
    • Stage I/II:
      • Single primary lesion
      • Multiple noncontiguous lesions confined to the GI tract that may have nodal involvement
    • No stage III defined
    • Stage IV:
      • Disseminated extranodal involvement or
      • Concomitant supradiaphragmatic nodal involvement
  • Ann Arbor staging system for non-gastric MALT:
    • Stage 1: single lymph node region
    • Stage 2: one side of diaphragm
    • Stage 3: both sides of diaphragm
    • Stage 4: disseminated

Management and Prognosis

Management

  • Gastric MALT lymphoma:
    • H. pylori–positive:
      • H. pylori eradication therapy
      • Follow up with serial endoscopies
      • Treatment failures: treat with radiation therapy (RT)
      • Gastric resection for perforation, uncontrolled bleeding, or obstruction
    • H. pylori–negative:
      • RT
      • Immunotherapy or chemotherapy for RT failure or Lugano stage IV
  • Nongastric MALT lymphoma: treatment is dependent on location and stage of the disease:
    • Involved-site RT (ISRT): primary option
    • Surgery: for diagnostic purposes or for tumors in areas not conducive to RT, such as lung
    • Rituximab if patient cannot receive ISRT or if advanced disease
  • Coexistent large-cell lymphoma (in any site or stage) treated as diffuse large B-cell lymphoma

Prognosis

  • Overall, relatively good prognosis: median survival > 10 years
  • Prognosis is worse with higher-grade MALT lymphoma.
  • MALT International Prognostic Index (MALT-IPI):
    • Prognostic scoring system for MALT lymphoma
    • Identifies patients with high-risk disease that is more likely to progress
    • 3 independent adverse prognostic factors identified:
      • Age ≥ 70 years
      • Stage III or IV
      • Serum LDH level higher than upper limit of normal
    • 3 risk groups:
      • Low risk (no risk factors): overall survival, 99%
      • Intermediate risk (1 risk factor): overall survival, 93%
      • High risk (≥ 2 risk factors): overall survival, 64%

Differential Diagnosis

  • Reactive lesions: painless hyperplastic tissue resulting from a repair response: Reactive lesions develop in response to chronic inflammation. Reactive lesions are usually limited to the follicle. MALT lymphoma can usually be distinguished from reactive lesions by demonstration of immunoglobulin light-chain restriction or clonal IgH rearrangements by molecular techniques. Management is highly variable and depends on the etiology and site.
  • Nodal and splenic marginal zone lymphoma (NMZL): a primary nodal lymphoma with histologic features identical to those of lymph nodes involved by MALT lymphoma or splenic marginal zone lymphoma, but without prominent extranodal involvement: A diagnosis of NMZL is more likely where there is widespread nodal involvement, even if there is splenic enlargement and/or minimal extranodal disease. Management focuses on alleviation of symptoms, reversal of cytopenias, and improvement of quality of life.
  • Other B-cell neoplasms:
    • Diffuse large B-cell lymphoma (DLBCL): the most common subtype of non-Hodgkin’s lymphoma with a primarily extranodal presentation: Diffuse large B-cell lymphoma is very aggressive clinically and has rapid growth. Characterized by large clusters of cells or sheets of large cells, DLBCL is cytogenetically, biologically, and clinically different from MALT lymphoma and has a much worse prognosis. Treatment is with rituximab and/or chemotherapy.
    • Small lymphocytic lymphoma (SLL): a solid-tumor variant of the more common CLL: Small lymphocytic lymphoma is primarily node-based, and extranodal disease develops only late in the disease course. Immunophenotypically, SLL co-expresses CD5 and CD23, while MALT lymphomas do not. Management is primarily observation; there is no commonly agreed-on treatment algorithm.
    • Mantle cell lymphoma (MCL): a mature B-cell non-Hodgkin’s lymphoma composed of small- to medium-sized lymphocytes that can involve GI tract: On immunophenotyping, MCL expresses CD5 and cyclin D1 due to t(11;14) translocation. MALT lymphoma does not express these markers or have this translocation. Management is with combination chemotherapy plus immunotherapy with autologous hematopoietic cell transplantation (HCT).
    • Follicular lymphoma (FL): lymphoma derived from germinal-center B cells with prominent and/or reactive follicles that are sometimes colonized with marginal zone or monocytoid cells: Presentation is usually painless peripheral adenopathy. Management is observation, with treatment directed at alleviating symptoms, including RT and CD20 monoclonal antibody therapy. 

References

  1. Freedman AS, Aster JC. (2020). Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT). UpToDate. Retrieved March 20, 2021, from https://www.uptodate.com/contents/clinical-manifestations-pathologic-features-and-diagnosis-of-extranodal-marginal-zone-lymphoma-of-mucosa-associated-lymphoid-tissue-malt
  2. Freedman AS, Friedberg JW, Ng AK. (2021). Treatment of extranodal marginal node lymphoma of mucosa associated lymphoid tissue (MALT). UpToDate. Retrieved March 20, 2021, from https://www.uptodate.com/contents/treatment-of-extranodal-marginal-zone-lymphoma-of-mucosa-associated-lymphoid-tissue-malt-lymphoma
  3. Kumar V, Abbas AK, Aster JC. (2015). Robbins & Cotran Pathologic Basis of Disease. Philadelphia: Elsevier Saunders.
  4. Novak U, et al. (2011). Genomic analysis of non-splenic marginal zone lymphomas (MZL) indicates similarities between nodal and extranodal MZL and supports their derivation from memory B-cells. Br J Haematol 155(3):362–365. https://pubmed.ncbi.nlm.nih.gov/21883140/
  5. Sagaert X, et al. (2007). The pathogenesis of MALT lymphomas: where do we stand? Leukemia 21(3):89–396. https://pubmed.ncbi.nlm.nih.gov/17230229/
  6. Zucca E, et al. (2020). Marginal zone lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 31(1):17–29. https://pubmed.ncbi.nlm.nih.gov/31912792/

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