Splenic B-cell lymphoma/leukaemia with prominent nucleoli

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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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Note: consider content on the overview page: Splenic B-cell Lymphoma/Leukemia, Unclassifiable

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Primary Author(s)*

  • Snehal Patel, MD, PhD

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category B-cell lymphoid proliferations and lymphomas
Family Mature B-cell neoplasms
Type Splenic B-cell lymphomas and leukaemias
Subtype(s) Splenic B-cell lymphoma/leukaemia with prominent nucleoli

Definition / Description of Disease

  • HCLv is a rare chronic neoplasm of B-cell origin seen mostly in adults
  • Name derives from clinicopathologic similarity to hairy cell leukemia (HCL) but with important differences
  • Marked splenomegaly and marrow infiltration result in left flank discomfort, fatigue, and susceptibility to infections
  • Most respond poorly to monotherapy with a purine analog or interferon alpha (used for HCL)
  • Lack BRAF p.Val600Glu (V600E) mutations but some have mutations in MAP2K1

Synonyms / Terminology

  • Prolymphocytic variant of hairy cell leukemia

Epidemiology / Prevalence

  • ~0.2% of lymphoid leukemias
  • Median age: 70 years
  • Males:Females: 2:1

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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Signs & Symptoms

  • Often asymptomatic
  • Splenic enlargement and/or discomfort
  • B-symptoms (weight loss, fever, night sweats)
  • Fatigue
  • Bruising
  • Lymphadenopathy (uncommon)

Laboratory findings

  • Cytopenias
  • Lymphocytosis
  • No monocytopenia


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[1][2]

Sites of Involvement

  • Spleen (red pulp)
  • Bone marrow
  • Blood
  • Liver
  • Lymph node (uncommon)


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[1][2]

Morphologic Features

  • Intermediate-sized lymphoid cells
  • Abundant pale blue-grey lacey cytoplasm
  • prolymphocytoid or blastoid nuclear features
  • Cytoplasmic projections either villous or hair-like
  • "Fried egg" appearance of cells (tissue sections)
  • Interstitial pattern of marrow involvement
  • No/minimal reticulin fibrosis


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[1][2]

Immunophenotype

Finding Marker
Positive (B-cell lineage markers) CD19, CD20 (bright), CD22, CD79b, PAX5, FMC7, sIg (bright, monotypic)
Positive CD11c, CD72, CD103
Negative (HCL markers) CD25, CD123, annexin A1, TRAP, BRAF V600E
Negative CD5, CD10, CD23, CD38, CD43, BCL1


editUnassigned References
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[1][2]

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).


editv4:Chromosomal Rearrangements (Gene Fusions)
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  • No consistent gene fusions


editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).
Please incorporate this section into the relevant tables found in:
  • Chromosomal Rearrangements (Gene Fusions)
  • Individual Region Genomic Gain/Loss/LOH
  • Characteristic Chromosomal Patterns
  • Gene Mutations (SNV/INDEL)
Alteration Clinical Significance Note
BRAF activating mutations Diagnostic Excludes HCL
MAP2K1 activating mutations Prediction May be targetable with MEK inhibitors[3]
IGHV4-34 Prediction Reduced response to purine analogs[4]
IGHV4-34 Prognostic Less favorable prognosis[4]
  • The 2017 WHO notes that whether cases that are classified as classical HCL but lack BRAF mutations and harbor MAP2K1 mutations are more like HCLv remains to be established

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).

editv4:Genomic Gain/Loss/LOH
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Chromosome Number Gain/Loss/Amp/LOH Consequence Prevalence
17p13 Loss TP53 deletion 42%[1]
11q22 Loss ATM deletion 22%[1]

Characteristic Chromosomal Patterns

Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis. Do not delete table.)

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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  • Preferential utilization of IGHV4-34 (Immunoglobulin heavy chain variable segment) in 40%[5] and has clinical implications[4]

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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Gene* Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other) Prevalence
MAP2K1 Oncogene GOF 7-50%[1][6][7][8][9]
TP53 Tumor Suppressor LOF 29%[8] - 38%[7]
KMT2C Tumor Suppressor LOF 25%[7]
KDM6A Tumor Suppressor LOF 13%[7] - 50%[9]
ARID1A Tumor Suppressor LOF 13%[7] - 25%[9]
CREBBP Tumor Suppressor LOF 13%[7] - 25%[9]
CCND3 Oncogene change of function 13%[7]
U2AF Oncogene change of function 13%[7]

‡Specific mutations in these genes can be found in cBioPortal and COSMIC.

  • There is wide variation in the reported prevalence of MAP2K1 mutations across studies for unclear reasons

Epigenomic Alterations

  • Epigenetic dysregulation is expected in a subset of HCLv due to mutations in epigenetic regulators:
    • KMT2C is a histone methyltransferase
    • KDM6A is a histone demethylase
    • CREBBP is a histone acetyltransferase
    • ARID1A is a SWI/SNF family member

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
editv4:Genes and Main Pathways Involved
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Molecular feature Pathway Physiologic outcome
MAP2K1 activating mutations MAPK signaling Unregulated cell growth and proliferation
KMT2C, KDM6A, CREBBP, and ARID1A LOF mutations Histone modification, chromatin remodeling Abnormal gene expression program
TP53 LOF mutations DNA damage, apoptosis Cell survival and genomic instability

Genetic Diagnostic Testing Methods

  • HCLv is a provisional entity and definitive diagnostic criteria have not been determined
  • BRAF p.Val600Glu testing may be useful diagnostically in limited situations to exclude HCL
  • BRAF p.Val600Glu may be detected by IHC using a mutant-specific antibody[10][11] or various molecular methods (NGS, real-time PCR, massARRAY, etc.)
  • The mutant-specific antibody does not detect other BRAF mutations
  • BRAF p.Val600Glu and Non-p.Val600Glu mutations and MAP2K1 mutations can be interrogated with NGS in a single assay[2]
  • IGHV4-34 utilization can be detected by NGS and Sanger sequencing of IgH mRNA

Familial Forms

  • Not described

Additional Information

  • N/A

Links

References

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  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Angelova, Evgeniya A.; et al. (2018). "Clinicopathologic and molecular features in hairy cell leukemia-variant: single institutional experience". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 31 (11): 1717–1732. doi:10.1038/s41379-018-0093-8. ISSN 1530-0285. PMID 29955146.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Maitre, Elsa; et al. (2019). "Hairy cell leukemia: 2020 update on diagnosis, risk stratification, and treatment". American Journal of Hematology. 94 (12): 1413–1422. doi:10.1002/ajh.25653. ISSN 0361-8609.
  3. ↑ Andritsos, Leslie A.; et al. (2018). "Trametinib for the treatment of IGHV4-34, MAP2K1-mutant variant hairy cell leukemia". Leukemia & Lymphoma. 59 (4): 1008–1011. doi:10.1080/10428194.2017.1365853. ISSN 1042-8194.
  4. ↑ 4.0 4.1 4.2 Arons, Evgeny; et al. (2009). "VH4-34+ hairy cell leukemia, a new variant with poor prognosis despite standard therapy". Blood. 114 (21): 4687–4695. doi:10.1182/blood-2009-01-201731. ISSN 0006-4971. PMC 2780305. PMID 19745070.CS1 maint: PMC format (link)
  5. ↑ Xi, Liqiang; et al. (2012). "Both variant and IGHV4-34–expressing hairy cell leukemia lack the BRAF V600E mutation". Blood. 119 (14): 3330–3332. doi:10.1182/blood-2011-09-379339. ISSN 0006-4971. PMC 3321859. PMID 22210875.CS1 maint: PMC format (link)
  6. ↑ Mason, Emily F.; et al. (2017). "Detection of activating MAP2K1 mutations in atypical hairy cell leukemia and hairy cell leukemia variant". Leukemia & Lymphoma. 58 (1): 233–236. doi:10.1080/10428194.2016.1185786. ISSN 1029-2403. PMID 27241017.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 Durham, Benjamin H.; et al. (2017). "Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations". Blood. 130 (14): 1644–1648. doi:10.1182/blood-2017-01-765107. ISSN 1528-0020. PMC 5630011. PMID 28801450.
  8. ↑ 8.0 8.1 Waterfall, Joshua J.; et al. (2014). "High prevalence of MAP2K1 mutations in variant and IGHV4-34-expressing hairy-cell leukemias". Nature Genetics. 46 (1): 8–10. doi:10.1038/ng.2828. ISSN 1546-1718. PMC 3905739. PMID 24241536.
  9. ↑ 9.0 9.1 9.2 9.3 Maitre, Elsa; et al. (2018). "New generation sequencing of targeted genes in the classical and the variant form of hairy cell leukemia highlights mutations in epigenetic regulation genes". Oncotarget. 9 (48): 28866–28876. doi:10.18632/oncotarget.25601. ISSN 1949-2553. PMC 6034755. PMID 29989027.
  10. ↑ Ritterhouse, Lauren L.; et al. (2015). "BRAF V600E mutation-specific antibody: A review". Seminars in Diagnostic Pathology. 32 (5): 400–408. doi:10.1053/j.semdp.2015.02.010.
  11. ↑ Loo, Eric; et al. (2017). "BRAF V600E Mutation Across Multiple Tumor Types: Correlation Between DNA-based Sequencing and Mutation-specific Immunohistochemistry". Applied Immunohistochemistry & Molecular Morphology: 1. doi:10.1097/PAI.0000000000000516. ISSN 1541-2016.

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: “Splenic B-cell lymphoma/leukaemia with prominent nucleoli”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Splenic_B-cell_lymphoma/leukaemia_with_prominent_nucleoli.

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