Andrew M. Intlekofer and Ariela Noy
Definition and Pathogenesis
• Highly aggressive B-cell NHL characterized by Myc translocation [t(8;14)(q24;q32) in 85% or variants]
• Cell of origin = germinal center or postgerminal center B cell
• DNA breaks are introduced in germinal center B cells undergoing Ig class-switching or somatic hypermutation
• Mistakes in DNA repair result in translocations that deregulate Myc expression by placing it under control of Ig gene enhancers
• Whole genome sequencing studies identified recurrent somatic mutations in TCF3 (E2A), ID3, & CCND3 (cyclinD3) (Nature 2012;490:116)
Epidemiology
• 3 distinct clinical forms: Endemic, sporadic, immunodeficiency-associated
• Endemic: Primarily in equatorial Africa (30–50% of childhood CA), male:female, 2:1, strongly a/w EBV infxn
• Sporadic (nonendemic): US, Western Europe, 30% of pediatric lymphoma (peak age 11), <1% of adult NHL (peak age 30), male:female, 4:1
• Immunodeficiency-associated: HIV+ pts, usu CD4 count >200, incidence not impacted by HAART
Clinical Presentation
• Rapidly growing mass, doubling time <24 h, B sx (fever, sweats, wt loss)
• Typical site: Endemic Æ jaw, sporadic Æ abdomen, HIV Æ LN + extranodal
• Common involvement of extranodal sites including GI tract, mesentery, testes, ovary, kidney, breast, nasopharynx, CNS, BM, ascites, pleural effusion
Diagnostic Evaluation
• Excisional/incisional bx → histology shows sheets of medium-sized atypical lymphoid cells, extensive necrosis, frequent mitosis (Ki67 > 95%), classic “starry sky” appearance, prominent cytoplasmic vacuoles
• Immunophenotype: CD19+, CD20+, CD10+, Bcl6+, κ/λ restricted (κ > λ), surface IgM+, CD43+, CD5–, Bcl2–, TdT–, CD23–
• Karyotype, cytogenetics, FISH: Most common t(8:14) = (Myc:Ig heavy chain), less common t(2:8) = (κ light chain:Myc); t(8:22) = (Myc:λ light chain)
• Lab evaluation: CBC w/diff, CMP, phos, UA, LDH, B2M, HIV, HBV sAg/cAb
• BM bx: BM involvement in ∼70% of cases
• LP: To r/o CNS involvement, CSF cytology, & flow cytometry
• CT C/A/P w/contrast to determine extent of disease
• Echo & ECG prior to anthracycline Rx
• Fertility preservation: Sperm banking for men, women often have few options given rapid disease progression
Staging and Risk Stratification
• Ann Arbor Staging:
Stage I = single LN region or single extranodal site (IE)
Stage II = multiple LN on one side of diaphragm
Stage III = multiple LN on both sides of diaphragm
Stage IV = LN plus extranodal sites or multiple extranodal sites
A = no B sx
B = B sx (fevers, drenching sweats, wt loss >10% BW)
X = mass >10 cm
• Risk stratification:
Low risk = nl LDH & single mass <10-cm diameter
High risk = all others
Principles of Treatment
• Burkitt lymphoma is highly curable w/intensive chemotherapy, 2-y OS >70% w/modern tx regimens (see below), older adults (age >60) much lower OS
• Tx should be initiated ASAP, often w/in 48 hrs
• Tx consists of intensive regimens, usu requiring in pt monitoring
• Almost all Burkitt lymphoma regimens include CNS Ppx in the absence of overt CNS disease
→ CNS penetrating systemic drugs = high dose MTX & cytarabine
→ IT MTX & cytarabine alone = CNS Ppx
→ Known leptomeningeal disease requires intensification of IT Rx, typically delivered via Ommaya reservoir
• Virtually all pts should receive tumor lysis Ppx: IVF + allopurinol + phosphate binder ± rasburicase
• Addition of rituximab to regimens likely improves outcomes
• No role for RT (unless palliative)
Refractory Disease
• Clinical trial is preferable
• Off-protocol tx includes regimen above (not previously received) or DLBCL type salvage regimen followed by HDT w/ASCR
Supportive Care
• RBC & plt transfusions as needed
• Growth factor support w/G-CSF to prevent neutropenic fever
• Infectious Ppx for VZV & PCP/PJP
• HIV + pts: If on HAART pay attention to chemotherapy interactions