Lymphoma & related disorders

Mature B cell neoplasms

Small B cell lymphomas with lymphoplasmacytic differentiation / marginal zone lymphomas

MALT-marginal zone



Last staff update: 19 April 2022

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PubMed Search: Marginal zone lymphoma MALT type

Mario L. Marques-Piubelli, M.D.
Roberto N. Miranda, M.D.
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Cite this page: Marques-Piubelli ML, Miranda RN. MALT-marginal zone. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomaMALT.html. Accessed August 17th, 2022.
Definition / general
Essential features
Terminology
  • Low grade B cell lymphoma of MALT
  • MALToma
ICD coding
  • ICD-O: 9699/3 - marginal zone B cell lymphoma, NOS
  • ICD-10: C88.4 - extranodal marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)
Epidemiology
Sites
Pathophysiology
  • Somatic hypermutation and rearrangements in immunoglobulin heavy chain variable (IGHV) genes associated to cell surface and chemokine receptors of chronic inflammatory / infectious processes play an important role in the lymphomagenesis (Leuk Lymphoma 2012;53:1032, Blood 2016;127:2082, F1000Res 2018;7:406, Best Pract Res Clin Haematol 2018;31:57, World J Gastrointest Oncol 2022;14:153, Best Pract Res Clin Haematol 2017;30:13, Appl Immunohistochem Mol Morphol 2021;29:56)
    • Most common mutated IGH VH families by site:
      • Stomach: IGH VH3-30 and IGH VH3-23
      • Ocular adnexa: IGH VH4-34
      • Skin: IGH VH1-69 and IGH VH4-59
      • Lung: IGH VH3 and IGH VH4
      • Salivary gland: IGH VH1-69
    • In all types of MZL, both canonical and noncanonical NFκB activation can mediate the activation, neoplastic transformation and maintenance of the neoplastic lymphocytes
      • Antigen stimulation of BCR and TCR, followed by phosphorylation of CARD11, BCL10 and MALT1
        • Interaction with TRAF6 and NFκB essential modulator
        • TNFAIP3 (A20) performs a negative regulation of the whole pathway and due to mutations and deletions in this gene, the pathway may hyperactivate
    • Cases of gastric MALT lymphoma related to Helicobacter pylori infection may have upregulation of cyclin A2 and loss of PTEN
      • Same mechanism is described in diffuse large B cell lymphoma (DLBCL)
  • Recurrent CCR6 mutations impair its internalization and consequently the neoplastic cells are more resistant to apoptosis and more likely to have malignant transformation (Haematologica 2022 Feb 10 [Epub ahead of print])
    • HBD2, CCL20 and HD5 are ligands that could be expressed in epithelial cells
Etiology
Clinical features
Diagnosis
  • Gastric MALT lymphoma (Best Pract Res Clin Gastroenterol 2014;28:1069)
    • Endoscopic mapping of the stomach is recommended due to the nonspecific presentation
      • Minimum of 10 biopsies of visible lesions and no specified number of normal mucosae
      • No standard protocol for follow up
        • Usually, biopsies are performed every 3 - 6 months for the first 2 years of follow up
Laboratory
  • Laboratory abnormalities are not common (Best Pract Res Clin Haematol 2018;31:57, Br J Haematol 2022;196:1353)
    • Elevated serum β2 microglobulin (~30%)
    • Monoclonal gammopathy (~30%)
      • Association with advanced stage and bone marrow involvement
    • Elevated serum immunoglobulin paraprotein (~20 - 30%)
      • Most common types are IgM κ, IgM L and IgG L
      • Associated with advanced age, bone marrow involvement, B symptoms, advanced stage of disease, elevated serum β2 microglobulin, multiple sites of involvement, nodal involvement, high MALT International Prognostic Index (IPI)
    • Iron deficiency anemia (~10%)
    • Elevated serum lactate dehydrogenase (LDH) (~10%)
Radiology description
  • For the detection of lesions, the value of 18F fluorodeoxyglucose positron emission tomography is controversial; it seems to show more concordant results for lesions located in tissues with low and homogeneous physiologic uptake (Blood 2016;127:2082, Cancers (Basel) 2022;14:750)
Prognostic factors
  • Factors associated with worse outcomes: MALT IPI (Leuk Lymphoma 2013;54:1891, Best Pract Res Clin Haematol 2018;31:57, Blood 2017;130:1409, Front Oncol 2021;11:681689)
    • Low (0), intermediate (1) and high (≥ 2) risk according to the presence of the following factors:
      • Advanced age (≥ 70 years)
      • Elevated LDH
      • Ann Arbor Stage III / IV
    • Other factors that may be associated with worse outcome: relapse at the original or distant sites, elevated serum immunoglobulin paraproteinemia and bone marrow involvement
  • Localized forms of MALT lymphoma are usually early stage (IE / IIE) of disease and have similar outcomes compared with localized nodal MZL (Leuk Lymphoma 2013;54:1891)
  • Transformation to DLBCL may occur in up to ~20% of cases and is associated with a worse prognosis (Leuk Lymphoma 2012;53:1032, Blood 2016;127:2082, Br J Haematol 2021;193:369)
    • In cases of gastric MALT lymphoma, it is associated with hepatic involvement, advanced stage disease and hepatitis C infection
    • Genetic factors associated with transformation: mutation and allelic loss of p53, hypermethylation of p15 and p16, and p16 deletion
    • Cases of typical MALT lymphoma with different methylation profiles, MALT lymphoma with increased large cells and transformation to DLBCL
  • Gastrointestinal MALT lymphoma may have inferior outcome when compared with nongastrointestinal localization (Leuk Lymphoma 2013;54:1891, Best Pract Res Clin Gastroenterol 2014;28:1069)
    • t(11;18) is associated to response to H. pylori treatment and better outcomes
  • Advanced stage (III / E / IVE) may occur in ~30% of patients and recurrence may happen in extranodal and nodal sites (Leuk Lymphoma 2012;53:1032)
  • 5 year overall survival (OS) by affected site (Leuk Lymphoma 2013;54:1891):
    • Central nervous system: 100%
    • Thyroid gland: 95%
    • Skin: 91%
    • Oral cavity: 88%
    • Bone and soft tissue: 86%
    • Ocular adnexa: 84%
    • Breast: 79%
    • Lung and respiratory tract: 77%
    • Colon: 72%
    • Stomach: 71%
    • Urinary tract: 65%
  • Median 10 year recurrence free survival: 57% (Blood 2016;127:2082)
Case reports
  • 12 year old girl with gastric MALT lymphoma presenting with iron deficiency anemia and gastric perforation (BMC Pediatr 2019;19:63)
  • 37 year old woman with primary cutaneous marginal zone lymphoma (PCMZL) presented as a rosacea-like lesion (JAAD Case Rep 2020;6:902)
  • 56 year old woman with primary colonic MALT lymphoma presenting as a single mass on hepatic flexure of the colon (Am J Case Rep 2017;18:491)
  • 73 year old woman with monoclonal gammopathy and primary oral cavity MALT lymphoma (BMC Oral Health 2021;21:597)
  • 74 year old woman with a previous history of tuberculosis presenting with a pulmonary opacity diagnosed as a primary pulmonary MALT lymphoma (Biomed Hub 2019;4:1)
Treatment
Microscopic (histologic) description
  • Atypical lymphoid infiltrate is located in the marginal zone of reactive follicles and extends to interfollicular or intrafollicular (follicular colonization) regions (Leuk Lymphoma 2012;53:1032, J Clin Pathol 2007;60:361)
  • Reactive follicles may be present and are helpful in the diagnosis (J Clin Pathol 2007;60:361)
  • Lymphoepithelial lesion (Leuk Lymphoma 2012;53:1032, Best Pract Res Clin Gastroenterol 2014;28:1069, J Clin Pathol 2007;60:361)
    • Aggregates of 3 or more marginal zone cells with distortion or destruction of the epithelium
      • Presence of individual cells in the epithelium is not sufficient to define a lymphoepithelial lesion
    • Eosinophilic degeneration is observed
    • Presence is not pathognomonic for MALT lymphoma and can be found in reactive conditions
  • Diagnostic clues for the diagnosis by site:
    • Orbit (PLoS One 2014;9:e104004):
      • Nodular or diffuse infiltrate composed by monocytoid, centrocyte-like and lymphoplasmacytic cells
    • Stomach and intestine (Best Pract Res Clin Gastroenterol 2014;28:1069, Am J Clin Pathol 2022;157:23):
      • Dense lymphoid infiltrate that replaces the lamina propria, associated or not with lymphoepithelial lesions
        • Lymphoepithelial lesions are not common in colorectal cases
    • Lung (J Clin Pathol 2007;60:361, Eur Respir J 2009;34:1408):
      • Lymphangitic pattern of infiltration with spread through bronchovascular structures, interlobular septa and visceral pleura
      • Lymphoepithelial lesion is seen on the bronchial or bronchiolar epithelium
      • Angiotropism, fibrosis and necrosis may be found
    • Salivary gland (Leuk Lymphoma 2012;53:1032):
      • Background of chronic sialadenitis
      • Atrophic acinar parenchyma
      • Monocytoid cells around epithelial / myoepithelial islands
    • Skin (Am J Clin Pathol 2020;154:428):
      • Dense lymphoid infiltrate with nodular or diffuse pattern
        • Admixture of small lymphocytes, lymphoplasmacytic and plasma cells
      • Grenz zone
    • Breast (Clin Lymphoma Myeloma Leuk 2019;19:244):
      • Diffuse or nodular neoplastic infiltrate of monocytoid cells admixed with reactive follicles
      • Lymphoepithelial lesions may be present
    • Thyroid (Eur Thyroid J 2020;9:11):
      • Lymphoepithelial lesions and epithelial ball
        • Neoplastic cells inside a thyroid follicular epithelium
      • Scattered hyperplastic germinal centers in the background
  • Transformation to DLBCL:
    • Large cells with centroblastic appearance disposed in clusters of more than 20 cells, or sheet proliferation
Microscopic (histologic) images

Contributed by Roberto N. Miranda, M.D.
Salivary gland lymphoepithelial lesion

Salivary gland lymphoepithelial lesion

Cytokeratin and lymphoepithelial lesion

Cytokeratin and lymphoepithelial lesion

CD20 positivity in salivary gland lymphoepithelial lesion

CD20 positivity in salivary gland lymphoepithelial lesion

Gastric gland lymphoepithelial lesion

Gastric gland lymphoepithelial lesion

Thyroid gland MALT lymphoma

Thyroid gland MALT lymphoma

Primary cutaneous marginal zone lymphoma (PCMZL)

PCMZL


PCMZL subepidermal lesion

PCMZL subepidermal lesion

PCMZL - CD20 positive

PCMZL - CD20 positive

PCMZL - CD3 negative

PCMZL - CD3 negative

Lung BALT lymphoma Lung BALT lymphoma Lung BALT lymphoma

Lung BALT lymphoma


Lymphoepithelial lesion of the stomach

Lymphoepithelial lesion of the stomach

Stomach MALT lymphoma

Stomach MALT lymphoma

Lambda light chain restriction

Lambda light chain restriction

Kappa negativity

Kappa negativity

Breast MALT lymphoma

Breast MALT lymphoma

CD10 negativity in MALT lymphoma

CD10 negativity in MALT lymphoma


BCL6 negativity in MALT lymphoma

BCL6 negativity in MALT lymphoma

Cytology description
  • Monomorphic pattern (Leuk Lymphoma 2012;53:1032, J Clin Pathol 2007;60:361):
    • Monocytoid or centrocyte-like appearance: intermediate size, distinct cell borders, nuclei with regular contours and rim of clear cytoplasm
  • Polymorphic pattern (Leuk Lymphoma 2012;53:1032, J Clin Pathol 2007;60:361):
    • Lymphocytes with monocytoid, centrocyte-like (small to intermediate size, small irregular) nuclei are the most predominant component
    • Scattered cells with centroblastic-like appearance: large cells with dispersed chromatin
    • Plasma cells are frequent and close to the epithelium
Positive stains
Flow cytometry description
Molecular / cytogenetics description
  • Hypermutation of immunoglobulin heavy chain variable genes in up to 75% of patients (Leuk Lymphoma 2012;53:1032, J Clin Pathol 2007;60:361)
  • B cell clonality may remain in cases with histological remission in up to 50% of patients (J Clin Pathol 2007;60:361)
    • May be associated with delay in achieve complete remission and probability to relapse
  • Recurrent chromosomal aberrations (Leuk Lymphoma 2012;53:1032, Blood 2016;127:2082, Am J Surg Pathol 2006;30:1546, Leuk Res 2020;95:106399):
    • Stomach: t(11;18)(q21;q21), t(1;14)(p22;q32) and trisomies 3, 7, 12 and 18
    • Ocular adnexa: t(11;18)(q21;q21), t(14;18)(q32;q21), t(3;14)(p14.1;q32), deletion 6p23 (TNFAIP3) and trisomies 3 and 18
    • Intestine: t(11;18)(q21;q21), t(1;14)(p22;q32) and trisomies 3, 12 and 18
    • Skin: t(14;18)(q32;q21), t(3;14)(p14.1;q32) and trisomies 3 and 18
    • Lung: t(11;18)(q21;q21), t(14;18)(q32;q21), t(1;14)(p22;q32) and trisomies 3, 12 and 18
    • Salivary gland: t(11;18)(q21;q21), t(14;18)(q32;q21) and trisomies 3, 7 and 18
    • Thyroid gland: t(3;14)(p14.1;q32) and trisomies 3 and 12
    • Breast: trisomies 3 and 18
  • Aneuploidy is associated with t(14;18)(q32;q21) / IGH-MALT1 and t(1;14)(p22;q32) / IGH-BCL10 (Am J Surg Pathol 2006;30:1546)
    • Both MALT1 and BCL10 are associated with NFκB activation
  • Somatic mutations in PIM1 and cMYC (World J Gastrointest Oncol 2022;14:153)
    • Usually missense, 46% of gastric MALT lymphomas and 30% of nongastric
  • Somatic mutations or deletions of PIK3CD, CREBBP, KMTDC, SPEN, TET2 and TNFRSF14 (F1000Res 2018;7:406, Haematologica 2019;104:e558)
  • Somatic mutations or deletions of TNFAIP3 (6p23) (F1000Res 2018;7:406, Haematologica 2019;104:e558)
    • Directly involved in NFκB activation
  • Tumor suppressor genes can be silenced in cases of MALT progression (F1000Res 2018;7:406)
    • CDKN2A, DAPK1 and CDH1
Sample pathology report
  • Esophagus, endoscopic biopsy:
    • Squamous epithelium with no significant pathologic changes
  • Stomach (greater curvature), endoscopic biopsy of a mass:
    • Extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT) involving gastric mucosa (see comment)
  • Stomach (lesser curvature), endoscopic biopsy:
    • Antral mucosae with moderate chronic inactive gastritis
    • No intestinal metaplasia identified
    • Helicobacter pylori present
  • Duodenum, endoscopic biopsy:
    • Duodenal mucosa with no pathologic changes
  • Comment: According to clinical notes, patient is a 60 year old woman who presented with abdominal pain and anemia for the past 10 months. She underwent endoscopic examination that showed large ulcerated noncircumferential lesion on the greater curvature of the stomach, which was biopsied.
  • Histologic sections from the mass in the greater curvature show gastric mucosa with dense infiltration of the lamina propria composed predominantly of small to intermediate monocytoid lymphocytes, small lymphocytes (centrocyte-like), plasma cells and eosinophils. The monocytoid lymphocytes show clear cytoplasm, irregular nuclear contour and hyperchromatic chromatin. Lymphoepithelial lesion is extensively present.
  • Immunohistochemical studies were performed on the greater curvature lesion and the lymphoma cells were positive for CD20, PAX5, CD43, BCL2 and negative for CD3, CD5, CD10, BCL6 and SOX11. The lymphoma cells showed kappa light chain restriction. CD21 highlighted the follicular dendritic meshwork and Ki67 was ~20% on the neoplastic cells.
  • No morphologic findings to support infiltration by lymphoma in esophageal, gastric lesser curvature and duodenum biopsies.
Differential diagnosis
Board review style question #1
Which of the following is true about extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)?

  1. Association with infectious agents and autoimmune disorders is rarely described
  2. Bone marrow involvement is common and detected in up to 90% of patients
  3. NFκB pathway activation is a shared feature of several subtypes of MALT lymphoma
  4. Trisomies 3 and 18 are extremely rare in MALT lymphoma
Board review style answer #1
C. NFκB pathway activation is a shared feature of several subtypes of MALT lymphoma. There is an important overlap in the molecular signatures of different subtypes of MALT lymphoma, which involve activation of canonical and noncanonical NFκB pathway.

Comment Here

Reference: MALT - marginal zone
Board review style question #2

What is the characteristic immunophenotype of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)?

  1. CD20+ / BCL2- / CD10- / BCL6+ / CD43- / EBER-
  2. CD20+ / BCL2+ / CD10- / BCL6- / CD43+ / EBER-
  3. CD20+ / BCL2+ / CD10- / BCL6- / CD43- / EBER+
  4. CD20- / BCL2+ / CD10+ / BCL6- / CD43- / EBER+
Board review style answer #2
B. CD20+ / BCL2+ / CD10- / BCL6- / CD43+ / EBER-. MALT lymphoma cells have a B cell phenotype (CD19+, CD20+, PAX5+) and are usually positive for BCL2 and CD43 and negative for CD10 and BCL6. EBV is not associated with MALT lymphoma.

Comment Here

Reference: MALT - marginal zone
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