HAEM5:Nodal marginal zone lymphoma

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

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Primary Author(s)*

Andrew Ly, DO and Shivani Golem, PhD, FACMG

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	B-cell lymphoid proliferations and lymphomas
Family	Mature B-cell neoplasms
Type	Marginal zone lymphoma
Subtype(s)	Nodal marginal zone lymphoma

Definition / Description of Disease

Nodal marginal zone lymphoma (NMZL) is an uncommon subtype of non-Hodgkin lymphoma. It is a primary nodal B-cell lymphoma with histological features similar to Splenic marginal zone lymphoma and Extranodal marginal zone lymphoma involving lymph nodes, but without evidence of splenic or extranodal disease.

Synonyms / Terminology

• Monocytoid B-cell lymphoma
• Parafollicular B-cell lymphoma (no longer in use)

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Epidemiology / Prevalence

• 1.5-1.8% of all lymphoid neoplasms
• Median age ~60 years old
• Both sexes are affected equally
• Cases also occur in children and are separately diagnosed as HAEM5:Paediatric nodal marginal zone lymphoma
• Association with autoimmune diseases
• Association with Hepatitis C virus infection reported in some studies but not all studies

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Clinical Features

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Signs and Symptoms	EXAMPLE: Asymptomatic (incidental finding on complete blood counts) EXAMPLE: B-symptoms (weight loss, fever, night sweats) EXAMPLE: Fatigue EXAMPLE: Lymphadenopathy (uncommon)
Laboratory Findings	EXAMPLE: Cytopenias EXAMPLE: Lymphocytosis (low level)

editv4:Clinical Features

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• Asymptomatic, localized or generalized lymphadenopathy
• B symptoms (fever, night sweats, and weight loss)
• Bone marrow involvement

The presence of a primary extranodal marginal zone lymphoma should be ruled out due to the possibility of a nodal dissemination of a MALT lymphoma occurring in patients with a history of Sjogren syndrome and Hashimoto thyroiditis.

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Sites of Involvement

• Lymph nodes
• Bone marrow
• Peripheral blood

Morphologic Features

• Variable populations of lymphoma cells
  1. Centrocyte-like and monocytoid B-cells
  2. Plasma cells
  3. Scattered transformed B cells
• Lymph nodes show small lymphoma cells surrounding reactive follicles (marginal zone distribution)
  1. Extension to interfollicular areas and follicular colonization may be present
  2. Diffuse or partial nodal effacement may be present
• Bone marrow shows lymphoma cells in interstitial, nodular, intertrabecular or paratrabecular distribution

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Immunophenotype

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Finding	Marker
Positive (universal)	EXAMPLE: CD1
Positive (subset)	EXAMPLE: CD2
Negative (universal)	EXAMPLE: CD3
Negative (subset)	EXAMPLE: CD4

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Finding	Marker
Positive (B-cell lineage markers)	CD19, CD20, CD22, PAX5, FMC7, CD79a, sIg
Positive (most cases)	BCL2, MNDA, IRTA1
Variable positivity	CD5, CD43, CD23
Negative	CD10, Cyclin D1, BCL6, LMO2

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Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: 3'ABL1 / 5'BCR	EXAMPLE: der(22)	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add reference)	Yes	No	Yes	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

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• Recurrent chromosomal translocations that are frequent in other lymphoid malignancies and associated with extranodal MZL are not detected.

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editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

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• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

• None.

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Individual Region Genomic Gain / Loss / LOH

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Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7:1- 159,335,973 [hg38]	EXAMPLE: chr7	Yes	Yes	No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8:1-145,138,636 [hg38]	EXAMPLE: chr8	No	No	No	EXAMPLE: Common recurrent secondary finding for t(8;21) (add reference).

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Chromosome Number	Gain/Loss/Amp/LOH	Region
3	Gain	N/A
12	Gain	N/A
18	Gain	N/A
6	Loss	6q23-24

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Characteristic Chromosomal Patterns

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Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: Co-deletion of 1p and 18q	Yes	No	No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns

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• Deletions in 7q31

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Gene Mutations (SNV / INDEL)

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Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification				EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

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Whole-exome sequencing (WES) study have identified mutations involved in NOTCH, nuclear factor κB (NF-κB), B-cell receptors and toll like receptor pathways . In one study, 16% (4/25) of cases identified a BRAF (V600E) mutation with associated strong IgD expression. In one of the four BRAF positive mutation, two non-hotspot mutations were detected (L597Q and N581I) which was previously found in BRAF V600 wild-type melanoma. In the same study, mutations of KMT2D (7/25, 28%), TET2 (5/25, 20%), and EZH2 (5/25, 20%) were among the more frequent mutated genes. CREBBP, TNFRSF14, FAS, TNFAIP3, KLF2, and CXCR4 mutations were also detected. In another study, which investigated genetic lesions in 35 patients with NMZL, PTPRD mutations were found in 14.3% (5/35) of patients and PTPRD locus deletions were found in 5.7% (2/35) of patients. Mutations were also identified in another study for NFKBIE and ITPR2 mutations involved in the NF-κB pathway and B-cell receptor mediated calcium signal pathway. However, in this study they did not find any PTPRD mutations or BRAF mutations, demonstrating the diverseness of the disease. No BRAF mutations have yet to be identified in other studies on NMZL.

Other Mutations

Immunoglobulin genes are clonally rearranged consisting of mutated IGHV3 and IGHV4 family members, particularly IGHV4-34 and cases associated with hepatitis C use IGHV1-69.

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Epigenomic Alterations

• Not known in this specific subtype.

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations	EXAMPLE:  Histone modification, chromatin remodeling	EXAMPLE:  Abnormal gene expression program

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• NF-κB pathway and B-cell receptor mediated calcium signal pathway.

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Genetic Diagnostic Testing Methods

• No diagnostic test is specifically established.

Familial Forms

• Not known in this specific subtype.

Additional Information

None

Links

• HAEM5:Paediatric nodal marginal zone lymphoma
• HAEM5:Splenic marginal zone lymphoma
• Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue

References

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Notes

*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

*The hierarchical tumour classification structure displayed on this page is reproduced from the WHO Classification of Tumours with permission from the copyright holder, ©International Agency for Research on Cancer.

*Citation of this Page: “Nodal marginal zone lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/10/2025, https://ccga.io/index.php/HAEM5:Nodal_marginal_zone_lymphoma.