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.


TERMINOLOGY


Abbreviations



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


Synonyms



  • Primary central nervous system lymphoma


Definitions



  • 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


ETIOLOGY/PATHOGENESIS


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


CLINICAL ISSUES


Epidemiology



  • 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


Site



  • 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


Presentation



  • 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


Treatment



  • 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


Prognosis



  • 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
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