Primary Diffuse Large B-cell Lymphoma of the CNS

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Primary Author(s)*

Laveniya Satgunaseelan, FRCPA, Department of Neuropathology, Royal Prince Alfred Hospital

Cancer Category/Type

Mature B-cell neoplasms

Cancer Sub-Classification / Subtype

Primary diffuse large B-cell lymphoma of the CNS (CNS-DLBCL)

Definition / Description of Disease

CNS-DLBCL is defined as a DLBCL arising in the brain, spinal cord, leptomeninges or eye, and excludes the dura, intravascular lymphomas, secondary involvement of the CNS by lymphoma and those lymphomas associated with immunodeficiency[1].

Synonyms / Terminology

Primary CNS lymphoma; primary intraocular lymphoma; lymphomatosis cerebri[1].

Epidemiology / Prevalence

CNS-DLBCL comprises 1% of all non-Hodgkin lymphomas[2] and 3.2% of all primary brain tumours[3], with an overall incidence rate of 0.47 per 100,000 person-years[4]. Incidence peaks in the 5th to 7th decades, with a significantly higher incidence in males[4].

Clinical Features

Signs and Symptoms Clinical presentation is heterogeneous, depending on site of involvement (e.g. brain, leptomeninges, eyes, cranial nerves and spinal cord), and can include[5]:

Cognitive dysfunction

Psychomotor slowing

Headache

Focal neurological symptoms (e.g. cranial nerve palsies or hemiparesis if spinal cord involvement)

Visual impairment if eye involvement[6]

Laboratory Findings No established serological studies for CNS-DLBCL[7]

CSF studies – low glucose levels, cytological examination (identification of atypical lymphoid proliferation)[7], flow cytometry

Sites of Involvement

Brain, spinal cord, leptomeninges and eye.

Morphologic Features

Cytomorphology: Atypical cells with intermediate to large-sized nuclei, with irregular round to ovoid nuclei with centroblastic or immunoblastic morphology[1].

Growth pattern: Highly cellular tumours with diffusely infiltrative growth pattern. Infiltration and aggregation of tumour cells in a perivascular distribution is characteristic. Large areas of necrosis can also be seen.

Tissue reaction: Reactive inflammatory infiltrate comprised of mature T-cells and microglial activation, with accompanying reactive gliosis.

Immunophenotype

Finding Marker[1]
Positive (universal) PAX5, CD19, CD20, CD22, CD79a, IgM, IgD, light chain restriction (kappa/lambda) 
Positive (subset) BCL6 (60-80%), IRF4/MUM1 (90%), CD10 (<10%), HLA-A/HLA-B/HLA-C/HLA-DR, BCL2, MYC
Negative (universal) CD38, CD138, IgG, EBV

Chromosomal Rearrangements (Gene Fusions)

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
t(3;14)(q27;q32) 5’BCL6 / 3’IGH - 17%-20%[8][9] Yes Yes (PMID: 18645192) Unknown Overexpression of Bcl6 and impairment of IGH immunoglobulin due to translocation is thought to be a contributor to CNS-DLNCL pathogenesis[9].
t(14;18)(q31;q21) 5’IGH / 3’BCL2 - 6.7%[9] Yes Unknown Unknown Uncommon translocation in CNS-DLBCL; can be found in CNS-DLBCL involving meninges, or secondary involvement by extra-CNS DLBCL[9].
t(8;14)(q24;q32) 5’MYC / 3’IGH - 3%[10] Yes Unknown Unknown Rare translocation in CNS-DLBCL[11]
t(12;14)(p13;q32) 5’ ETV6 / 3’IGH - 18%[12] Yes Yes [12] Unknown Novel surrogate fusion in CNS-DLBCL indicating favorable prognosis[12].
t(9;22)(p24;q11) 5’PD-L2 / 3’IGL - 13%[8] Yes Unknown Unknown Translocations involving PD-L1 and PD-L2 are potentially the basis of immune evasion in CNS-DLBCL[8].
t(9;19)(p24;p13) 5’PD-L1 / 3’BCNP1 - 13%[8] Yes Unknown Unknown

Individual Region Genomic Gain/Loss/LOH

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
18 Gain chr18: 45,900,000-61,300,000 [hg38] chr18 No No No Common recurrent gain (43%) involving BCL2 gene[13].
19 Gain chr19:55,800,001-58,617,616 [hg38] chr19 No No No Common recurrent gain (47%) involving ZNF cluster[13].
19 Gain chr19:42,900,001-44,700,000 [hg38] chr19 No No No Recurrent gain (37%) involving ZNF cluster[13].
12 Gain chr12: 1-133,275,309 [hg38] chr12 No No No Recurrent gain (26%) involving STAT6 and CD27[13].
6 Loss chr6:105,000,001-114,200,000 [hg38] chr6 No No No Common recurrent loss (52%) involving PRDM1[13].
6 Loss chr6:32,100,001-33,500,000 [hg38] chr6 No No No Loss affecting 74% of CNS-DLBCL cases overall, with region harboring MHC genes including HLA-DRB, HLA-DQA and HLA-DQB (37% homozygous deletion and 37% uniparental disomy)[13].
8 Loss chr8:54,600,001-60,600,001 [hg38] chr8 No No No Common recurrent loss (32%) involving TOX, CA8 and RAB2A[13].
9 Loss chr9:19,900,001-25,600,000 [hg38] chr9 No No No Common recurrent loss (48%) involving CDKN2A/B (32% homozygous deletion; 16% partial uniparental disomy)[13].

Characteristic Chromosomal Patterns

Not applicable

Gene Mutations (SNV/INDEL)

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
MYD88;

GOF mutation

Oncogene 50% to 76%[14][15] CARD11 Nil Yes No No Common missense mutation is MYD88 L265P. Affects NF-kB pathway synergistically with CARD11 (occurring in 29%[8]).
CD79B; GOF mutation Oncogene 83%[15] Nil MYD88 Yes No No Both CD79B and MYD88 lead to constitutive action of NF-kB pathway[15].
SHIP;

Loss of function

Tumor suppressor gene 25%[16] Nil No No No Component of B-cell receptor signaling cascade altered by point mutation in SHIP[16].

Epigenomic Alterations

Promoter hypermethylation of genes has been established as a potential pathogenetic mechanism in CNS-DLBCL[17]. Genes affected include DAPK (84% of CNS-DLBCL cases), CDKN2A/B (75%), TSP1 (68%), MGMT (52%) and RFC (30%)[17][18]). RFC promoter hypermethylation may have a theranostic role in those treated with high-dose methotrexate regimens.

Genes and Main Pathways Involved

Genetic alterations observed in CNS-DLBCL converge on the NF-kB pathway, leading to its constitutive activation. The gene pathways upstream of the NF-kB complex are affected in CNS-DLBCL. These include the B-cell receptor pathway (SHIP, CD79B), its target pathway, the BCM complex (CARD11, MALT1) and toll-like receptor pathway (MYD88)[16][19].

Genetic Diagnostic Testing Methods

Diagnostic testing methods include karyotyping, fluorescent in situ hybridization, RT-PCR and next generation sequencing techniques (whole genome/whole exome sequencing).

Familial Forms

Not applicable

Additional Information

Not applicable

Links

Diffuse large B-cell lymphoma, Not Otherwise Specified

Lymphomas Associated with HIV Infection

References

  1. 1.0 1.1 1.2 1.3 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.
  2. Fox, Christopher P.; et al. (2019-02). "Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma". British Journal of Haematology. 184 (3): 348–363. doi:10.1111/bjh.15661. ISSN 1365-2141. PMID 30467845. Check date values in: |date= (help)
  3. Rigau, Valérie; et al. (2011-11). "French brain tumor database: 5-year histological results on 25 756 cases". Brain Pathology (Zurich, Switzerland). 21 (6): 633–644. doi:10.1111/j.1750-3639.2011.00491.x. ISSN 1750-3639. PMC 8094058 Check |pmc= value (help). PMID 21554472. Check date values in: |date= (help)
  4. 4.0 4.1 Villano, J. L.; et al. (2011-10-25). "Age, gender, and racial differences in incidence and survival in primary CNS lymphoma". British Journal of Cancer. 105 (9): 1414–1418. doi:10.1038/bjc.2011.357. ISSN 1532-1827. PMC 3241537. PMID 21915121.
  5. Calimeri, T.; et al. (2021-08). "How we treat primary central nervous system lymphoma". ESMO open. 6 (4): 100213. doi:10.1016/j.esmoop.2021.100213. ISSN 2059-7029. PMC 8287145 Check |pmc= value (help). PMID 34271311 Check |pmid= value (help). Check date values in: |date= (help)
  6. Pels, Hendrik; et al. (2006-07). "Primary central nervous system lymphoma". Current Treatment Options in Neurology. 8 (4): 346–357. doi:10.1007/s11940-006-0024-8. ISSN 1092-8480. PMID 16942677. Check date values in: |date= (help)
  7. 7.0 7.1 Scott, Brian J.; et al. (2013-03-01). "A systematic approach to the diagnosis of suspected central nervous system lymphoma". JAMA neurology. 70 (3): 311–319. doi:10.1001/jamaneurol.2013.606. ISSN 2168-6157. PMC 4135394. PMID 23319132.
  8. 8.0 8.1 8.2 8.3 8.4 Chapuy, Bjoern; et al. (2016-02-18). "Targetable genetic features of primary testicular and primary central nervous system lymphomas". Blood. 127 (7): 869–881. doi:10.1182/blood-2015-10-673236. ISSN 1528-0020. PMC 4760091. PMID 26702065.
  9. 9.0 9.1 9.2 9.3 Zorofchian, Soheil; et al. (2018-12). "Characterization of genomic alterations in primary central nervous system lymphomas". Journal of Neuro-Oncology. 140 (3): 509–517. doi:10.1007/s11060-018-2990-6. ISSN 1573-7373. PMID 30171453. Check date values in: |date= (help)
  10. Cady, Francois M.; et al. (2008-10-10). "Del(6)(q22) and BCL6 rearrangements in primary CNS lymphoma are indicators of an aggressive clinical course". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 26 (29): 4814–4819. doi:10.1200/JCO.2008.16.1455. ISSN 1527-7755. PMC 2653136. PMID 18645192.
  11. Montesinos-Rongen, Manuel; et al. (2002-10). "Interphase cytogenetic analysis of lymphoma-associated chromosomal breakpoints in primary diffuse large B-cell lymphomas of the central nervous system". Journal of Neuropathology and Experimental Neurology. 61 (10): 926–933. doi:10.1093/jnen/61.10.926. ISSN 0022-3069. PMID 12387458. Check date values in: |date= (help)
  12. 12.0 12.1 12.2 Bruno, Aurélie; et al. (2018-07-05). "Identification of novel recurrent ETV6-IgH fusions in primary central nervous system lymphoma". Neuro-Oncology. 20 (8): 1092–1100. doi:10.1093/neuonc/noy019. ISSN 1523-5866. PMC 6280140. PMID 29432597.
  13. 13.0 13.1 13.2 13.3 13.4 13.5 13.6 13.7 Schwindt, H.; et al. (2009-10). "Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma". Leukemia. 23 (10): 1875–1884. doi:10.1038/leu.2009.120. ISSN 1476-5551. PMID 19494841. Check date values in: |date= (help)
  14. Montesinos-Rongen, Manuel; et al. (2011-12). "Activating L265P mutations of the MYD88 gene are common in primary central nervous system lymphoma". Acta Neuropathologica. 122 (6): 791–792. doi:10.1007/s00401-011-0891-2. ISSN 1432-0533. PMID 22020631. Check date values in: |date= (help)
  15. 15.0 15.1 15.2 Nakamura, T.; et al. (2016-04). "Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas". Neuropathology and Applied Neurobiology. 42 (3): 279–290. doi:10.1111/nan.12259. ISSN 1365-2990. PMID 26111727. Check date values in: |date= (help)
  16. 16.0 16.1 16.2 Deckert, Martina; et al. (2014-02). "Systems biology of primary CNS lymphoma: from genetic aberrations to modeling in mice". Acta Neuropathologica. 127 (2): 175–188. doi:10.1007/s00401-013-1202-x. ISSN 1432-0533. PMID 24240734. Check date values in: |date= (help)
  17. 17.0 17.1 Chu, Linda C.; et al. (2006-11-15). "Epigenetic silencing of multiple genes in primary CNS lymphoma". International Journal of Cancer. 119 (10): 2487–2491. doi:10.1002/ijc.22124. ISSN 0020-7136. PMID 16858686.
  18. Ferreri, Andrés J. M.; et al. (2004-09). "Aberrant methylation in the promoter region of the reduced folate carrier gene is a potential mechanism of resistance to methotrexate in primary central nervous system lymphomas". British Journal of Haematology. 126 (5): 657–664. doi:10.1111/j.1365-2141.2004.05109.x. ISSN 0007-1048. PMID 15327516. Check date values in: |date= (help)
  19. Vater, I.; et al. (2015-03). "The mutational pattern of primary lymphoma of the central nervous system determined by whole-exome sequencing". Leukemia. 29 (3): 677–685. doi:10.1038/leu.2014.264. ISSN 1476-5551. PMID 25189415. Check date values in: |date= (help)


Notes

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