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


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.


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

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].

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


Diffuse large B-cell lymphoma, Not Otherwise Specified

Lymphomas Associated with HIV Infection


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