Primary Diffuse Large B-cell Lymphoma of the CNS

Primary Diffuse Large B-cell Lymphoma of the CNS

Tariq Muzzafar, MBBS

Gross photograph of brain involved by primary diffuse large B-cell lymphoma (DLBCL) demonstrates a well-circumscribed mass image involving basal ganglia. The cut surface is heterogeneous and granular.

Diffuse large B-cell lymphoma involving the brain. The neoplasm has a “starry sky” pattern, indicating high proliferation and cell turnover.



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


  • Primary central nervous system lymphoma


  • Diffuse large B-cell lymphoma confined to central nervous system &/or intraocular location

  • Immunocompromised patients are excluded from this category of disease

  • Distinct entity in World Health Organization (WHO) 2008 classification


Infectious Agents

  • In immunocompetent patients, there is no etiologic relationship with known viruses

Origin of Lymphoma-initiating Cells

  • Unknown; possibilities include

    • Benign systemic B cells entering CNS under physiologic conditions

    • Dissemination of systemic lymphoma

      • Extra-CNS disease eliminated by immune response, but lymphoma cells survive in immuneprivileged CNS

Molecular Heterogeneity

  • Features encompass spectrum of systemic DLBCL subtypes: Germinal center (GC) and activated B cell (ABC)

  • Germinal center origin supported by following features

    • Immunophenotype: CD10 &/or Bcl-6(+)

    • Very high load of somatic mutations of Ig genes

      • Mutations ongoing

      • May be caused by reactive T cells and antigen-presenting cells in presence of unknown antigen

  • ABC origin supported by following features

    • IgM expression

    • Lack of class switch recombination

    • Activation of NF-κB pathway

  • Suggested pathogenesis

    • Lymphoma originates from germinal center B cells destined to become IgM-expressing memory B cells

    • Subsequent maturation steps blocked

Possible Transforming Events

  • Chromosomal translocations

    • BCL-6 gene at chromosome locus 3q27

      • Correlated with shorter overall survival

    • Recurrent Ig gene translocations

      • Present in ˜ 15% of cases

  • Ongoing aberrant somatic hypermutation (SHM)

    • Increased 2-5x compared with DLBCL

  • 6q deletions

    • Correlated with shorter overall survival

    • PRDM1 gene on 6q22-23 locus may function as tumor suppressor gene in subset of cases

      • Belongs to protein tyrosine phosphatase superfamily

      • Involved in cell contact and adhesion

      • Loss of protein expression in 76% of cases

  • Gene inactivation by DNA methylation

    • DAPK or MGMT

    • CDKN2A (P14ARF and P16INK4a)

  • Mutations of tumor suppressor genes

    • MYC, PAX-5, PIM1, Rho/TTF

    • Due to aberrant and ongoing somatic hypermutation

Other Factors

  • Role of CNS microenvironment

    • Not known whether B cells enter CNS as benign reactive cells or as malignant lymphoma cells

    • Extracerebral relapse rare

    • Lymphoma cell angiotropism may be due to

      • Interactions between homing receptors and ligands expressed by CNS endothelial cells

  • IGHV4-34 gene segment shows preferential usage in DLBCL-CNS

    • Open reading frame maintained

    • CNS microenvironment may favor development of lymphomas with specific Ig genes; or

    • Neurotropic viruses or superantigens may elicit antibodies encoded by IgHV4-34 gene segment

      • B cells may expand and persist in CNS



  • Incidence

    • Less than 1% of all non-Hodgkin lymphomas

    • Approximately 2-3% of brain tumors

    • Incidence is reported to be increasing

  • Age

    • Median: 60 years

  • Gender

    • Slight male preponderance

  • Ethnicity

    • No ethnic predisposition


  • In descending order: Cerebrum, cerebellum, and brainstem

    • Supratentorial in 60% of patients

  • Spinal cord in 1%

  • Intraocular

    • ˜ 20% of patients with DLBCL-CNS have intraocular involvement at diagnosis

    • ˜ 80% of patients with intraocular lymphoma develop contralateral and parenchymal CNS lesions

    • Ocular disease may precede clinically detectable brain lesions

  • Multifocal in 20-40%

  • Extraneural sites rarely involved


  • Focal neurologic symptoms and signs in 50-80%

  • Psychiatric symptoms and signs in 20-30%

  • Seizures less frequent than in other brain tumors due to deep location

  • Symptoms and signs of raised intracranial pressure in ˜ 30%

  • Asymmetric cranial neuropathies in leptomeningeal involvement

  • Presents with intraocular involvement in ˜ 5%

    • Blurred vision and floaters

    • Ocular slit-lamp examination

      • Lymphoma cells in vitreous or retina

  • B symptoms (fever, night sweats, weight loss) rare

Laboratory Tests

  • Human immunodeficiency virus (HIV) serology is negative in DLBCL-CNS

    • DLBCL-CNS in HIV(+) patients is considered as separate category

  • Cerebrospinal fluid (CSF) analysis

    • Lymphoma cells identified by cytology in ˜ 25% of cases

    • Assessment for B-cell clonality

      • Flow cytometry

      • PCR

  • Serum lactate dehydrogenase (LDH) levels may be elevated

  • Ocular interleukin (IL)-10 levels elevated in patients with ocular involvement

Natural History

  • Disappearance of lesions (“ghost tumors”) can occur

    • Rarely spontaneous

    • More often corticosteroid-induced


  • Options, risks, complications

    • Patients ≥ 60 years

      • Tumors demonstrate low radiosensitivity

      • High incidence of delayed neurotoxicity

      • Radiotherapy (RT) may be deferred

    • Refractory disease

      • Intensive chemotherapy (ICT) with autologous stem cell transplantation (ASCT)

    • Salvage treatment

      • ICT-ASCT may be useful

      • 2nd-line chemotherapeutic agents

    • Primary intraocular lymphoma

      • Initial treatment similar to that for other DLBCL-CNS cases

      • Goal is to eradicate reservoir of disease in eye and decrease risk of recurrence

      • Dedicated ocular radiotherapy, intraocular chemotherapy

  • Surgical approaches

    • CNS

      • Biopsy for pathologic diagnosis

      • Resection performed only for herniation due to mass effect

      • Median survival following surgery alone: 1-4 months

    • Ocular

      • Biopsy of vitreous, choroid, or retina for diagnosis

  • Drugs

    • High-dose methotrexate (MTX)-based chemotherapy only as initial treatment

      • Highly chemosensitive tumor

      • Used infrequently

      • Combined with blood-brain barrier disruption

      • Delayed neurotoxicity less common

  • Radiation

    • Whole-brain radiotherapy (WBRT) alone

      • DLBCL-CNS is usually radiosensitive

      • Microscopic diffuse lesions present even in radiologically localized disease

      • Delayed neurotoxicity frequent

      • Limited survival benefit

  • High-dose MTX-based chemotherapy + WBRT

    • Median survival time: 2-4 years

    • 5-year survival rate: 20-40%

  • Anti-CD20 antibodies (rituximab)

    • Direct intraventricular/intrathecal administration

    • May be useful for leptomeningeal and ocular disease

    • Intravenous rituximab used in combination with high-dose MTX-based chemotherapy


  • Poor prognosis of DLBCL-CNS compared with patients with systemic DLBCL may be due to

    • Immune-privileged location

    • Intrinsic aggressive biologic behavior

  • Several prognostic scoring systems proposed

    • International Extranodal Lymphoma Study Group prognostic index (0-5 scale)

      • Age, performance status, lactate dehydrogenase level, CSF protein, and involvement of deep structures

    • Nottingham/Barcelona score (0-3 scale)

      • Age, performance status, and extent of brain disease

    • Memorial Sloan Kettering Cancer Center prognostic score

      • Age and Karnofsky performance status score

  • Ocular involvement is not independent risk factor

  • Response to corticosteroids is favorable prognostic marker

  • Bcl-6 expression reported to be associated with better prognosis

Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Primary Diffuse Large B-cell Lymphoma of the CNS
Premium Wordpress Themes by UFO Themes
%d bloggers like this: