Burkitt Lymphoma Flashcards
What is the definition of Burkitt lymphoma ?
- 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
What is the epidemiology of Burkitt lymphoma ?
- there are 3 epidemiological variants: Endemic, Sporadic, and Immunodeficiency associated
- differ based on geography, clinical presentation and molecular findings
What are the key epidemiological features of Endemic Burkitt lymphoma ?
- 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
What is the epidemiology of Sporadic BL ?
- 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
What is the epidemiology of Immunodeficiency associated BL ?
- more common in the setting of HIV infection
* usually in this setting, BL appears early in HIV infection when CD4 counts are still high
What is the etiology of Burkitt lymphoma?
- 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%
What is the localization of BL?
- 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
What are the clinical features of Burkitt lymphoma ?
- 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
What is the Burkitt leukemia variant?
- 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
What the characteristic macroscopic features of Burkitt lymphoma?
- 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
What are key microscopic features of BL?
- 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
What is the immunophenotype of BL?
- 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
What aberrant immunophenotypes have been described in BL?
- 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
What can be seen in approximately 2% of BL leukemia form?
- 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
- have a precursors B phenotype with TdT and CD34 expression
- reason for this is unknown
What is the postulated normal counterpart to BL?
- germinal center B cell
What are the antigen receptor genes in BL?
- tumor cells have clinal IG rearrangements with somatic hypermutation and intraclonal diversity
What are the key cytogenetic abnormalities in BL?
- 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
- in endemic BL the breakpoints are dispersed all over the gene
What other chromosomal abnormalities can be seen in BL ?
- 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
What percentage of BL lack the MYC gene translocation ?
- ~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
What is normally seen by gene expression profiling for BL?
- slight differences between the endemic and sporadic BL exist
What are some abnormalities that have been identified by NGS in BL ?
- 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
- mutations in TCF3 (transcription factor, aka E2A) or in ID3 (TCF3 negative regulator) are seen
- 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
Has there been a genetic susceptibility to BL identified?
- individuals with Duncan Disease (X-linked lymphoproliferative syndrome)
- SH2D1A mutation
- greatly increased risk of developing BL
What are the prognostic and predictive factors for BL ?
- 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
What is the definition of Burkitt-like lymphoma with 11q aberration?
- 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
What other cytogenetic abnormalities are seen in Burkitt-like lymphoma ?
- usually lack the gains of 1q
- have more complex karyotypes as compared to BL
What morphological differences can be identified in Burkitt-like lymphoma with 11q ?
- usually more pleomorphic as compared to BL
- can grow occasionally in a follicular pattern
- frequently have a nodal presentation
How does the clinical course compare of Burkitt-like lymphoma with 11q vs. BL ?
- clinical course appears to be similar but only a few cases have been reported
- also can present in the post-transplant setting
