HAEM5:Primary cutaneous marginal zone lymphoma

Haematolymphoid Tumours (WHO Classification, 5th ed.)

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Primary Author(s)*

Molly Walkenhorst, 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)	Primary cutaneous marginal zone lymphoma

Definition / Description of Disease

Primary cutaneous marginal zone lymphoma (PCMZL) is an indolent non-Hodgkin lymphoma arising in skin without evidence of extracutaneous disease at the time of diagnosis. The tumor is comprised of monotypic, CD5-negative, CD10-positive neoplastic small B-cells with monotypic plasma cells, and a variable number of reactive T-cells infiltrating the dermis, often forming follicles with reactive germinal centers. Clonal immunoglobulin rearrangement may be present, thus determining the subtype as class-switched versus non-class-switched heavy-chain immunophenotype. There must be no evidence of extracutaneous disease at the time of diagnosis and other cutaneous lymphomas must be excluded.

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Synonyms / Terminology

• Primary cutaneous marginal zone lymphoproliferative disorder (acceptable)
• Primary cutaneous immunocytoma (historical; no longer in use)
• Primary cutaneous plasmacytoma (historical; no longer in use)

Epidemiology / Prevalence

• 30-40% of all primary cutaneous B-cell lymphomas
• Predominantly affects adults in the fifth and sixth decades of life
• Male preponderance
• Unknown etiology in most cases
• Possible causes include chronic antigenic stimulation by intradermally applied antigens (e.g. tattoo pigments, vaccines, tick-borne bacteria, etc.)
• Association with Borrelia burgdorferi infection in endemic Europe but not associated in USA or Asia
• Patients tend to have increased gastrointestinal disorders and various autoimmune diseases as well

Clinical Features

• Present with multifocal or, less frequently, solitary red or violaceous plaques or nodules

Sites of Involvement

• Skin
  • Most commonly on the trunk and arms

Morphologic Features

• Dense dermal infiltrate composed of:
  • Small lymphocytes
  • Plasma cells
    • Located at periphery of lymphoid infiltrates or in subepidermal compartment
    • Heavy chain immunophenotype show different morphologies:
      • Non-class-switched forms
        • Sheets of B-lymphocytes and few T-lymphocytes
        • Scattered plasma cells
      • Class-switched forms
        • Large number of reactive T-lymphocytes but can occasionally be obscured by the neoplastic B cells
        • Peripherally clustered monotypic plasma cells
  • Follicles with reactive germinal centers (most cases)
  • clusters of plasmacytoid dendritic cells at periphery of infiltrates

Immunophenotype

• Neoplastic B cells have the following immunophenotype:

Finding	Marker
Positive	CD20
Positive	CD22
Positive	CD79a
Positive	BCL2
Negative	CD5
Negative	CD10
Negative	BCL6
Negative	Cyclin D1

• Associated reactive germinal centers B cells
  • BCL6 positive
  • BCL2 negative
• Plasmacytoid dendritic cells
  • CD123 positive
• Plasma cells
  • CD138 and CD79a positive
  • Plasma cells often have monotypic expression of immunoglobulin light chains
  • The immunoglobulin heavy chain can be either non-class-switched or class-switched
    • Non-class-switched heavy chain
      • Produce IgM
      • Positive for CXCR3 expression
      • Approximately 10% of cases have IgM positivity
    • Class-switched heavy chain
      • Produce IgG, IgA, or IgE
      • No expression of CXCR3
      • Approximately 90% of cases have IgG, IgA, or IgE positivity
  • IgG4 expressed by plasma cells in 13-35% of cases, though not related to IgG4-related disease.

Chromosomal Rearrangements (Gene Fusions)

Heavy and light chain immunoglobulin gene clonal rearrangements

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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).

Individual Region Genomic Gain / Loss / LOH

None

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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).

Characteristic Chromosomal Patterns

None

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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).

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
FAS (CD95) gene mutation	Apoptosis regulator	>60% of cases						Suggests that apoptosis defect underlies the pathogenesis of PCMZL
SLAMF1 somatic mutation
SPEN somatic mutation
NCOR2 somatic mutation

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.

Epigenomic Alterations

None

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

Genetic Diagnostic Testing Methods

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Familial Forms

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Additional Information

• Favorable prognosis
  • 5-year disease-specific survival rate >98%
• Recurrence is common
• 4% of patients will have extracutaneous spread, particularly in patients with longstanding multifocal disease

Links

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References

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EXAMPLE Book

1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.

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. *Citation of this Page: “Primary cutaneous marginal zone lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Primary_cutaneous_marginal_zone_lymphoma.