Radiation Oncology/NHL/Burkitt lymphoma

Burkitt's Lymphoma

Overview

• Burkitt's lymphoma and Burkitt cell leukemia (BL) are classified as different manifestations of the same disease by WHO
• It is a highly aggressive B-cell neoplasm, typically with extranodal presentation
• Epidemiology
  • In children: 30-50% of lymphomas
  • In adults: ~1 of lymphomas
  • Male predominance 3-4:1
• Burkitt's lymphoma has several subtypes:
  • Endemic (young children, Africa, associated with EBV and translocation of the MYC gene)
  • Sporadic (older kids, not associated with EBV but has MYC translocation)
  • Immunocompromised hosts
  • Burkitt's-like lymphoma (older age, not associated with MYC gene)

Clinical Presentation

• Endemic
  • Prevalence 100/1,000,000 children
  • Typically presents with jaw or facial bone tumor
  • Common extranodal spread to bone marrow, meninges, mesentery, ovary/testis, kidney, breast
• Sporadic
  • Prevalence 1/1,000,000 children
  • Typically with abdominal presentation, often with massive bulk and ascites
  • Extranodal spread as above, including CNS spread
• Immunocompromised
  • Typically involves lymph nodes, and may present as acute leukemia
  • Frequently in patients with high CD4 count and no opportunistic infections
• Burkitt-like lymphoma
  • Typically involves lymph nodes, nasopharynx, or GI tract
  • High propensity for bone marrow and CNS as above
  • B-symptoms in ~30% patients
• All types tend to have very high serum LDH, and serum electrolyte imbalances

Pathology

• On microscopy has "starry sky" pattern (generated by phagocytic histiocytes engulfing apoptotic nuclear debris)
• Medium-sized cells, very high mitotic fraction, frequent apoptosis
• Translocation is chromosome 8 myc locus with 3 possible partners (accounting for 90% of translocations):
  • The Ig heavy chain region on chromosome 14 : t(8;14)
  • The kappa light chain locus on chromosome 2: t(2;8)
  • The lambda light chain locus on chromosome 22: t(8;22).
  • However, 5-10% of DLBCL also have t(8;14) translocation. Because DLBCL is 20x more prevalent in adults, having t(8;14) creates a diagnostic challenge between Burkitt's and DLBCLC
• Originates from germinal center B-cells (like Germinal B-cell DLBCL, but has different molecular signature)
• Distinction between Burkitt's lymphoma and DLBCL is imprecise. Gene profiles appear to differentiate the diseases better
  • Only 53% concordance among expert hematopathologists
  • Molecular signatures: 17% and 34% of Burkitt's cases (see below) were classified by pathologists as DLBCL
  • WHO committees suggest the following
    • If morphologic features are intermediate, diagnosis of Burkitt's should only be made if the Ki-67 fraction of viable cells is at least 99 percent.
    • If morphologic features suggest DLBCL, but have with a high proliferation fraction or t(8;14), they should be classified as DLBCL.

• Charite, 2006 (Germany) PMID 16760442 -- "A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling." (Hummel M, N Engl J Med. 2006 Jun 8;354(23):2419-30.)
  • Gene analysis. 220 mature aggressive B-cell lymphomas. Molecular Burkitt's lymphoma (mBL) signature developed: 58 gene set. Some patients with this signature had morphologic appearance of DLBCL
  • 5-year OS: mBL 75%, GCB-DLBCL 51%, ABC-DLBC 12%
  • Myc locus survival: breakpoint 15% vs. no breakpoint 44%
  • Conclusion: molecular definition of Burkitt's lymphoma

• Molecular Profiling Project, 2006 PMID 16760443 -- "Molecular diagnosis of Burkitt's lymphoma." (Dave SS, N Engl J Med. 2006 Jun 8;354(23):2431-42.)
  • Gene analysis. 303 patients with aggressive lymphomas, 25 pathological Burkitt's. Gene profile developed. Some samples submitted as DLBCL had molecular profile of Burkitt's
  • Survival (28 patients): better with intensive chemo vs CHOP (SS)
  • Conclusion: Gene-expression profiling is accurate to differentiate BL and DLBCL

Treatment

• Intense chemotherapy such as CODOX/IVAC-M necessary; CHOP insufficient
• Prophylactic intrathecal chemotherapy or chemotherapy that crosses BBB essential
• Adults benefit from intense pediatric protocols, but often do not tolerate side effects
• Risk of developing tumor lysis syndrome is high
• Complete remission rates very high, but ultimate cure rate less than DLBCL
  • Long-term survival may be as high as 50-70% in selected patients
  • Bone marrow or CNS involvement results in poor prognosis, with long-term survival 0-30%
• RT was initially used for patients with initial CNS involvement, but use now is minimal