Burkitt Lymphoma

Question 1

What is the definition of Burkitt lymphoma ?

Answer 1

• highly aggressive but curable lymphoma that can present at extranodal sites or as a leukemia
• medium sized B cells with basophilic cytoplasm and numerous mitotic figures
• usually have a demonstrable MYC gene rearrangement
• frequency of EBV infection varies

Question 2

What is the epidemiology of Burkitt lymphoma ?

Answer 2

• there are 3 epidemiological variants: Endemic, Sporadic, and Immunodeficiency associated
• differ based on geography, clinical presentation and molecular findings

Question 3

What are the key epidemiological features of Endemic Burkitt lymphoma ?

Answer 3

• usually in equatorial Africa and Papua New Guinea
• often seen in areas with endemic malaria infections
• in these areas BL is the most common childhood malignancy
• it peaks around 4-7 years of age with a M:F of 2:1

Question 4

What is the epidemiology of Sporadic BL ?

Answer 4

• seen throughout the world, mainly in kids and young adults
• incidence is low in US and Europe, frequently accounts for 30-50% of childhood lymphomas
• median age of adults is 30 years, but also a peak in elderly patients can be seen
• still slightly increased M:F of 2-3:1

Question 5

What is the epidemiology of Immunodeficiency associated BL ?

Answer 5

• more common in the setting of HIV infection

* usually in this setting, BL appears early in HIV infection when CD4 counts are still high

Question 6

What is the etiology of Burkitt lymphoma?

Answer 6

• EBV is present in >95% of Endemic BL (also a link with malaria, P. Falciparum)
  
  • supports the idea of polymicrobial disease pathogenesis
• In sporadic BL, EBV present in 20-30% of cases
  
  • appears to be higher in adults than in children
• In immunodeficiency cases, EBV is present in 25-40%

Question 7

What is the localization of BL?

Answer 7

• extranodal sites are frequently involved with variation on the 3 variants
  
  • but in all 3, CNS involvement is a risk
• Endemic BL
  
  • face, jaw bones and orbit (50-70%)
  • distal ileum, cecum, omentum, gonads, kidneys, breasts, long bones, and bone marrow
• Sporadic BL
  
  • usually have abdominal masses, most common ileocecal region
  • lymph node presentation is unusual but more common in adults vs. kids

Question 8

What are the clinical features of Burkitt lymphoma ?

Answer 8

• patients often have bulky disease, short doubling time of the tumor
• specific clinical symptoms are related to the site of involvement
• patients are at risk of a rapid tumor lysis syndrome

Question 9

What is the Burkitt leukemia variant?

Answer 9

• a leukemia phase can be observed in patients with bulky disease
• rarely, males can present purely as leukemia with peripheral blood and bone marrow involvement
• Burkitt lymphoma tends to involve the CNS early in the disease
• Note:
  involvement of the bone marrow or presentation as acute leukemia is uncommon in the the
  Endemic BL

Question 10

What the characteristic macroscopic features of Burkitt lymphoma?

Answer 10

• organs have fleshy masses often with associated necrosis and hemorrhage
• nodal involvement is rare in sporadic and endemic BL
  
  • more frequently seen in immunodeficiency related

Question 11

What are key microscopic features of BL?

Answer 11

• tumor cells are medium in size and show diffuse, monotonous growth pattern
• cells look cohesive but have these characteristic squared off borders
• nuclei are round with finely clumped chromatin and contain multiple basophilic medium sized, paracentric nuceloli
• cytoplasm is deeply basophilic with lipid vacuoles
• multiple apoptotic and mitotic figures with tingible body macrophages
  
  • some cases have a florid granulomatous infiltrate making diagnosis difficult
  • these cases present with limited stage and have a good prognosis
• more pleomorphism or even plasmacytoid morphology is seen in adults with immunodeficiency

Question 12

What is the immunophenotype of BL?

Answer 12

• moderate to strong membrane IgM with light chain restriction
• Positive:
  
  • B cell markers: CD19, CD20, CD22, CD79a, and Pax5
  • Germinal center markers: CD10 and BCL6
  • CD38, CD77, and CD43 usually positive as well
  • MYC strong expression and high proliferation index 100%
  • Note: TCL1 is strongly expressed in pediatric BL
• Negative:
  
  • CD5, CD23, CD138, BCL2, and TdT

Question 13

What aberrant immunophenotypes have been described in BL?

Answer 13

• CD5 expression and lack of CD10 with weak patchy BCL2 have been described
• IMP
  
  • high BCL2 expression should not be seen and suggest an alternate diagnosis
• IMP
  Burkitt leukemia blasts have similar immunophenotype to BL rather than B-ALL

Question 14

What can be seen in approximately 2% of BL leukemia form?

Answer 14

• in otherwise classic BL with t(8;14) or variant translocation involving MYC
  
  • have a precursors B phenotype with TdT and CD34 expression
    
    • absence of CD20 and surface Ig
• reason for this is unknown

Question 15

What is the postulated normal counterpart to BL?

Answer 15

• germinal center B cell

Question 16

What are the antigen receptor genes in BL?

Answer 16

• tumor cells have clinal IG rearrangements with somatic hypermutation and intraclonal diversity

Question 17

What are the key cytogenetic abnormalities in BL?

Answer 17

• Hallmark is MYC translocation at band 8q24.2 usually to the IGH region on 14q32
  
  • t(8;14(
• OR can also be translocated to IgK or IgL
  
  • t(2;8) or t(8;22) respectively
• most breakpoints arise from somatic hypermutations rather than aberrant VDJ recombinations
  
  • in endemic BL the breakpoints are dispersed all over the gene
    IMP
  • MYC translocations are NOT specific to BL

Question 18

What other chromosomal abnormalities can be seen in BL ?

Answer 18

• Gains of 1q, 7, and 12
• Losses of 6q, 13q32-34 and 17 p
• these chromosomal aberrations may play a role in disease progression but in general BL does NOT have a complex karyotype

Question 19

What percentage of BL lack the MYC gene translocation ?

Answer 19

• ~10%
• but at this point all MYC translocations cannot be entirely identified so it may be one that has just not been picked up yet
  
  • MYC mRNA and protein expression suggests the presence of MYC and alternative mechanisms deregulating MYC
  • some of these may constitute BL with 11q aberration

Question 20

What is normally seen by gene expression profiling for BL?

Answer 20

• slight differences between the endemic and sporadic BL exist

Question 21

What are some abnormalities that have been identified by NGS in BL ?

Answer 21

• Sporadic BL
  
  • mutations in TCF3 (transcription factor, aka E2A) or in ID3 (TCF3 negative regulator) are seen
    In 70% of cases
  • these mutations activate B-cell receptor signaling which maintains BL survival by PIK3 pathway
  • overall mutations higher in sporadic vs. endemic BL
• Other mutations
  
  • CCND3, P53, RHOA, SMARCA4, and ARID1A
• Inverse relationship between mutation burden and EBV infection
  
  • mutations seem to drive the process in the absence of EBV

Question 22

Has there been a genetic susceptibility to BL identified?

Answer 22

• individuals with Duncan Disease (X-linked lymphoproliferative syndrome)
  
  • SH2D1A mutation
  • greatly increased risk of developing BL

Question 23

What are the prognostic and predictive factors for BL ?

Answer 23

• aggressive but curable lymphoma
• intensive chemotherapy leads to long-term survival of 70-90% with children doing better than adults
• Adverse prognostic factors
  
  • advanced stage disease
  • bone marrow and CNS involvement
  • unresected tumor >10 cm
  • high serum LDH
• if relapse occurs it is usually within the first year after diagnosis

Question 24

What is the definition of Burkitt-like lymphoma with 11q aberration?

Answer 24

• resembles BL morphologically and to a large extent phenotypically
• lack the MYC gene rearrangement
• contain chromosome 11q alterations
  
  • proximal gains and telomeres losses
  • usually interstitial gains, particularly a minimal region gain in 11q23.2-23.3
  • losses of 11q24.1

Question 25

What other cytogenetic abnormalities are seen in Burkitt-like lymphoma ?

Answer 25

• usually lack the gains of 1q

- have more complex karyotypes as compared to BL

Question 26

What morphological differences can be identified in Burkitt-like lymphoma with 11q ?

Answer 26

• usually more pleomorphic as compared to BL
• can grow occasionally in a follicular pattern
• frequently have a nodal presentation

Question 27

How does the clinical course compare of Burkitt-like lymphoma with 11q vs. BL ?

Answer 27

• clinical course appears to be similar but only a few cases have been reported
• also can present in the post-transplant setting