Pocket Oncology (Pocket Notebook Series), 1st Ed.

PRIMARY CNS LYMPHOMA

Anita Kumar and Thomas J. Kaley

Definition

• NHL involving the CNS, including the brain, leptomeninges, spinal cord, & eye

Epidemiology

• Rare subtype of NHL (1% of cases)

• Rare subtype of 1° CNS tumors (3% of cases)

• Age-adjusted incidence 0.47/100000 person-y

• In immunocompetent pts, median age at dx 60 y

Risk Factors

• Congenital immunosuppression: Ataxia-telangiectasia, Wiskott–Aldrich syndrome, & sev. common & combined variable immunodeficiencies

• HIV infxn: CD4 count <500 cells/μL

• Iatrogenic immune suppression: Solid organ transplant or HSCT

• Autoimmune disorder: RA, SLE, Sjögren syndrome, MG, sarcoidosis, & vasculitis

Pathogenesis

• Pathogenesis is incompletely understood

• EBV may represent a causal link, but not present in all cases

Histopathology

• 95% of PCNSLs are DLBCL

• Angiocentric neoplasm, typically w/perivascular distribution

• Immunophenotype: Positive B-cell markers (CD19, CD20). Majority positive for BCL-6, MUM1, & BCL-2 while negative for CD10

• T-cell PCNSL approximately 2% of cases

• Molecular testing: Positive for Ig heavy chain gene rearrangement

Clinical Subtypes

• Overlap between subtypes w/multifocal disease in >50% of cases:

Intracranial parenchymal lesion: Solitary or multiple (>90% of cases)

Leptomeningeal or periventricular lesions: Either a/w adjacent parenchymal disease or diffuse (30%)

Ocular: Infiltration of vitreous humor, retina, choroid, & optic nerve (10–20%)

Intradural spinal cord lesion: Lower cervical & upper thoracic most common sites (rare)

Neurolymphomatosis: Invasion of peripheral nerves, cranial nerves, spinal nerves, or ganglia (rare)

Clinical Presentation

• Presenting s/s may vary depending on site of disease: Focal neurologic deficits (70%), mental status changes (43%), signs of elevated ICP (33%), seizures (14%), & visual sx (4%) (J Neurosurg 2000;92:261)

Diagnosis and Initial Evaluation

• Contrast-enhanced brain MRI: Lesions are isointense to hypointense on T1- or T2-weighted images & enhances frequently. PCNSL presents as solitary intracranial lesion in 60–70% of cases, often located in hemispheres, basal ganglia, corpus callosum, & periventricular regions

• Contrast-enhanced head CT if MRI contraindicated

• Definitive pathologic dx required: Stereotactic needle bx of the brain indicated in most cases. In select cases, vitreal bx or CSF analysis may secure dx. W/ isolated neurolymphomatosis, nerve bx required

• Withhold steroids if possible until pathologic dx confirmed: PCNSL responds rapidly to steroid Rx & lesions can regress on radiographs, making bx more difficult. Unless evidence of mass effect/impending herniation, hold initial steroids or for at least 7–10 d pre-bx

• Initial evaluation: Bilateral slit lamp eye examination, MRI spine, LP & CSF fluid analysis (if safe w/o evidence of elevated ICP), HIV, & CT CAP. In select cases, BM bx, testicular U/S, or FDG-PET scan

Poor Prognostic Factors

• International Extranodal Lymphoma Study Group Prognostic Score: Age >60 y, PS ≥2, Elevated LDH, Elevated CSF protein, Deep region involvement (JCO 2003;21:266)

Staging

• Not applicable, typically disease is limited to CNS (Ann Arbor stage IE)

• Evaluate to exclude systemic lymphoma & define extent of disease

Adequate Performance Status (>40%)

• Combined modality Rx: Standard of care for fit pts. A phase 3 noninferiority trial of HD-MTX w/ or w/o WBRT was negative, but there was no OS difference between arms (Lancet Oncol 2010;11:1036)

• Pre-irradiation chemotherapy:

HD-MTX containing regimen: Phase 2 randomized trial compared HD-MTX w/ or w/o HD-Ara-C. CRR & 3-y OS were 46 vs. 18%, P = 0.006 & 46 vs. 32%, P = 0.07 respectively (Lancet 2009;374:1512)

Single-agent HD-MTX: Optimal dose 3.5 mg/m2

• RT: WBRT. For intraocular lymphoma, ocular irradiation. WBRT is a/w significant neurotoxicity, 25–35% (J Clin Oncol 1998;16:859)

Poor Performance Status (<40% Despite Steroid Therapy)

• WBRT: Rarely curative alone, median survival 10–18 mos (J Neuro Oncol 1999;43:241)

• Non-MTX containing chemotherapy

Investigational

• Rituximab: Unclear benefit

• Intrathecal/intraventricular chemotherapy: Unclear benefit

• HDC w/ASCT: Low level of evidence

HIV-positive PCNSL

• HAART in conjunction HD-MTX versus WBRT