Burkitt Lymphoma: Disease Primers

nature reviews disease primers https://doi.org/10.
1038/s41572-022-00404-3
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Burkitt lymphoma
Cristina López1,2, Birgit Burkhardt 3, John K. C. Chan 4, Lorenzo Leoncini5, Sam M. Mbulaiteye 6
, Martin D. Ogwang7,
Jackson Orem8, Rosemary Rochford9, Mark Roschewski 10 & Reiner Siebert2
Abstract Sections
Burkitt lymphoma (BL) is an aggressive form of B cell lymphoma that Introduction
can affect children and adults. The study of BL led to the identification Epidemiology
of the first recurrent chromosomal aberration in lymphoma, t(8;14) Mechanisms/pathophysiology
(q24;q32), and subsequent discovery of the central role of MYC and
Diagnosis, screening and
Epstein–Barr virus (EBV) in tumorigenesis. Most patients with BL are prevention
cured with chemotherapy but those with relapsed or refractory disease
Management
usually die of lymphoma. Historically, endemic BL, non-endemic
Quality of life
sporadic BL and the immunodeficiency-associated BL have been
recognized, but differentiation of these epidemiological variants is Outlook
confounded by the frequency of EBV positivity. Subtyping into EBV+

and EBV− BL might better describe the biological heterogeneity of the
disease. Phenotypically resembling germinal centre B cells, all types
of BL are characterized by dysregulation of MYC due to enhancer
activation via juxtaposition with one of the three immunoglobulin
loci. Additional molecular changes commonly affect B cell receptor
and sphingosine-1-phosphate signalling, proliferation, survival and
SWI–SNF chromatin remodelling. BL is diagnosed on the basis of
morphology and high expression of MYC. BL can be effectively treated
in children and adolescents with short durations of high dose-intensity
multiagent chemotherapy regimens. Adults are more susceptible to
toxic effects but are effectively treated with chemotherapy, including
modified versions of paediatric regimens. The outcomes in patients
with BL are good in high-income countries with low mortality and few
late effects, but in low-income and middle-income countries, BL is
diagnosed late and is usually treated with less-effective regimens
affecting the overall good outcomes in patients with this lymphoma.
A full list of affiliations appears at the end of the paper. e-mail: reiner.siebert@uni-ulm.de
Nature Reviews Disease Primers | (2022) 8:78 1

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Introduction the three immunoglobulin gene loci in the form of IGH::MYC, IGK::MYC
In 1958, Denis Parson Burkitt’s report on jaw sarcomas in children in or IGL::MYC is now considered the genetic hallmark of all subtypes of
equatorial Africa established Burkitt lymphoma (BL) as a new medical BL and a very early event in BL pathogenesis. This Primer focuses on
entity1. However, earlier references to BL exist, such as African wood art prototypical BL that has typical morphology and presentation linked
resembling facial BL and clinical notes written as early as 1897 (refs.2–6). to IG::MYC. Other lymphoma subtypes are not reviewed and are consid-
The earliest case of BL in the USA was reported in 1928 (ref.7). ered for the differential diagnosis of BL only, including those with some
BL has been central in advancing haematopathology and cancer morphological features of BL (such as MYC-negative high-grade B cell
research, ranging from epidemiology to molecular cancer biology. lymphomas with 11q aberrations or other high-grade B cell lymphomas)
The establishment of BL cell lines soon after the description of the and lymphatic neoplasms that might carry IG::MYC or another form of
disease8–10 established BL as a model neoplasm pioneering the fields structural variant affecting MYC (such as subsets of precursor B cell
of viral oncogenesis, tumour cytogenetics, driver gene identification neoplasms called B lymphoblastic leukaemia/lymphoma with MYC
and molecular pathogenesis. The first known human tumour virus, rearrangement, or high-grade B cell and diffuse large B cell lymphomas,
Epstein–Barr virus (EBV), was discovered in BL tumour cells in 1964 lymphomas not otherwise specified, diffuse large B cell lymphomas
(ref.10), and was later confirmed in other lymphoid and epithelial can- and high-grade B cell lymphomas with MYC and BCL2 rearrangements,
cers, leading to the identification of EBV as an essential factor in B cell mantle cell lymphomas or plasma cell (multiple myelomas).
immortalization. In addition, BL was the first lymphoma for which a IG::MYC is the hallmark of all three historically recognized epidemi-
recurrent chromosomal abnormality was described: balanced trans- ological manifestations of BL, namely endemic BL (eBL), non-endemic
location between 8q and 14q11,12. Extensive molecular studies then sporadic BL (sBL) and immunodeficiency-associated BL (iBL) (Table 1).
revealed that this chromosomal translocation involves the MYC onco- However, the designation of eBL or sBL subtypes is descriptive without
gene located on 8q24 and the immunoglobulin heavy chain gene locus quantitative epidemiological or biological definitions based on cellular
on 14q32 (IGH; resulting in IGH::MYC), the immunoglobulin light chain biology or pathogenetic mechanisms. It has long been recognized that
gene locus on 2p12 (IGK; resulting in IGK::MYC) or the immunoglobulin the designation of cases as sporadic is contextual, that is, cases that are
light chain gene locus on 22q11 (IGL; resulting in IGL::MYC)13–15. In this labelled endemic in one geographical region may occur sporadically
Primer, the term IG::MYC describes any of these three translocations in areas where BL is considered sporadic, and vice versa4,17, but a lack
and resulting juxtapositions. of a biological definition differentiating eBL from sBL has hampered
BL is a mature B cell lymphoma with phenotypic features of a the study of these cases. In turn, given the current global population
subset of physiological B cells of the germinal centre16. Translocation mobility, individuals with BL from endemic areas can present elsewhere
of the MYC oncogene next to one of the regulatory elements of one of in the world. Moreover, the conditions that include inborn errors of
immunity and acquired immunodeficiencies (referred to as iBL) are
arbitrarily defined and occur in geographical regions associated with
Table 1 | Characteristics of the three traditional sBL as well as eBL. Next-generation sequencing (NGS) data of primary
epidemiological variants of Burkitt lymphoma BL tissues confirmed the old hypothesis that EBV+ BL is to some extent
Characteristic Endemic BL Sporadic BL Immunodeficiency-
biologically distinct from EBV− BL regardless of the epidemiological
associated BL subtype18–22. Thus, subtyping BL based on the EBV status might be more
appropriate, and was recommended by WHO in 2022 (ref.23).
Age group Mainly All ages All ages, but mostly
affected children; peak older patients In this Primer, we review key aspects of BL including its epidemiol-
incidence (40–70 years) ogy, pathophysiology and pathomechanisms, including germline and
between 4 and somatic genetics, oncogenic viruses and altered molecular pathways.
7 years of age
We discuss the diagnosis and management of patients with BL, as well as
Male to female 2:1 2–3:1 in adults; Men more their quality of life, and highlight open research questions to improve
ratio higher in children commonly affected disease outcomes. Explanation of terms relevant to B cell-related
Preferential Jaw, kidneys, Abdomen (Peyer’s Lymph nodes and immunology are provided in Box 1.
clinical facial bones, patches) bone marrow
presentation abdomen
Epidemiology
Prevalent Malaria belt in Worldwide Worldwide Incidence
geographical Africa and New
Geographical patterns. Globally, the age-standardized incidence
regions Guinea
rates (ASR) of BL vary threefold to fivefold within and across continents
Epstein–Barr >90% of 15–30% of 25–40% of patients (Fig. 1a). The highest rates are observed in equatorial Africa, where
virus infection patients patients
association the BL ASR is high (>4 cases per million person-years) and considered
endemic in a geographical belt spanning 10°N to 10°S of the equator24.
Most prevalent Class III Class I (exon Class I
MYC breakpoint (far upstream and intron of
BL is the first or second most common childhood cancer within this belt
region in t(8;14) of MYC) MYC) and class in Africa, and the third most common specified childhood lymphoid
(q24;q32) II (immediately malignancy in many regions outside Africa. Although BL in sub-Saharan
upstream of MYC) Africa (SSA) is historically considered endemic, BL rates in SSA vary
Mechanisms of SHM and CSR SHM and CSR SHM and CSR nearly 50-fold comparing the highest rates in Malawi (19.3 cases per
t(8;14)(q24;q32) mechanisms mechanisms mechanisms million person-years) with those in Ethiopia (0.4 cases per million
Prognosis Undergoing aggressive chemotherapy, 90% of children person-years)25. Of note, the BL rates are highest in regions with high
and 50–60% of adults survive disease-free temperature suitability for transmission of Plasmodium falciparum,
CSR, class switch recombination; SHM, somatic hypermutation. a unicellular protozoan parasite that can cause malaria in humans

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(Fig. 1b), such as Malawi, Uganda and Cameroon, and low in areas with
low temperature suitability for transmission of P. falciparum, such
as Ethiopia and around Nairobi in Kenya, and Mali (Fig. 1c). Factors
Box 1
that foster P. falciparum transmission include high rainfall (50 cm per
year), temperatures >20 °C and elevation <1,400 m above sea level26, Glossary of relevant B cell
facilitating mosquito breeding and parasite growth in mosquitoes,
and are associated with BL risk27,28. Although data are sparse for tropi- immunology terms
cal regions of Central and South America, BL ASR in these areas are
intermediate (2–3.9 cases per million person-years) or low (<2 cases Germinal centres
per million person-years) compared with equivalent areas in Africa, Microanatomical structures in secondary lymphoid tissue that
and vary threefold across countries, and BL ASR in North America and are essential for B cell proliferation and differentiation, memory
Europe are in the intermediate range but geographically variable. generation, antibody isotype switching and affinity maturation upon
BL ASR in Canada and in some countries in Europe (Czech Republic, stimulation by an antigen, resulting in the generation of memory
Belarus, Ukraine and Poland) and the Russian Federation are in the low cells and plasma precursor cells.
range. The lowest BL ASR have been recorded in Asia, particularly in
China and India, where rates are one-sixth of that in the USA and one- Switch regions
twentieth of that in Uganda. BL rates in Israel, Saudi Arabia and Turkey, DNA sequences located at a 2–10 kb region upstream of antibody
geographically grouped as Asia, are similar to the rates in Europe. heavy chain constant region gene segments involved in the DNA
Despite issues related to case ascertainment and incomplete registra- recombination and the heavy chain switch synthesis from IgM
tion, the geographical patterns have provided useful insights and have to IgG, IgA or IgE.
triggered research into the underlying biological factors and mecha-
nisms. For example, the finding that BL rates in India and China are Peyer’s patches
lower than those in the USA and Uganda is surprising, as the epidemiol- Also referred to as aggregated lymphoid nodules, these organized
ogy of P. falciparum and EBV, the best known risk factors for BL, is more lymphoid follicles form oblong elevations on the mucous membrane
similar between Africa and India and China than between the USA and of the small intestine. The role of Peyer’s patches is in the induction of
Europe. These differences could be due to differing EBV pathogenicity immune tolerance or defence against pathogens. The IgA antigens
for BL between Asia and Africa, and EBV in Africa that is more closely are initiated by cognate B cells in Peyer’s patches.
related to that circulating in the USA and Europe29. BL subtypes were
historically defined as eBL, sBL and iBL, but this system was superseded Class switch recombination
in 2022 by the new WHO recommendation to classify BL subtypes A molecular process that remodels immunoglobulin genes
based on EBV status23. The prevalence of EBV+ BL is ~95% in SSA17, 75% resulting from the originally expressed heavy chain constant region
in North Africa30, ~50% in Brazil31,32 and ~20% in the USA33 and Europe34. gene to another immunoglobulin gene constant region. Genomic
The prevalence of EBV+ BL in Asia is unknown. translocations resulting from this mechanism can occur in B cells
when the breakpoints are located in the switch immungloblulin
Temporal, age and sex patterns. BL rates are twofold to fourfold heavy chain regions.
higher in males than in females in every country and vary geographi-
cally in both high-income countries (HICs) and low-income countries V(D)J
(LICs). The male predominance is a consistent feature of BL in all age A molecular process in which three gene segments, VH, DH and JH,
groups and across geographical regions, potentially due to a role of are joined to encode the heavy chain variable region, resulting
BL-associated recessive genetic factors on sex chromosomes35,36, in the expression of a pre-B cell receptor if the rearrangement is
or other host or environmental factors such as hormonal or microbial productive. Genomic translocations resulting from this process
sex differences37. can be generated in precursor B cells and are characterized by
Analysis of the number of BL diagnoses between 1963 and 2002 breakpoints that are directly adjacent to the immunoglobulin heavy
on four continents excluding Africa revealed that BL rates increased chain JH or adjacent to regions where the immunoglobulin heavy chain
during that period38, confirming data from the USA39. These changes DH joins the JH region (DHJH).
can be attributed to increasing global awareness of BL and the effects
of the HIV epidemic during the 1970s and 1980s on BL rates, particularly BCR signalling
in the USA, Europe and Australia. That the temporal increase in BL due B cell receptor (BCR) signalling can be activated via two different
to HIV infection was caused by immunodeficiency became apparent mechanisms: antigen-induced and antigen-independent
starting in 1982 when an excess of high-grade lymphomas, including autonomous (tonic) activation. Tonic BCR signalling is required
BL, was reported in young homosexual men (20–50 years of age) in the for B cell survival and development and it is antigen-independent.
USA40,41 and Europe42. Potential temporal trends in SSA, North Africa, On the other hand, chronic active BCR promotes the continuous
the Middle East and the Caribbean are unknown. proliferation of B cell lymphoma cells.
BL can occur at any age, but the proportion of BL diagnosed in the
age group 0–14 years compared with all age groups is ~13% in the USA
and Europe, ~50% in Israel and Turkey and 62–100% in some African 40 years of age and a third peak in the older age group (70 years) (Fig. 2).
regions, possibly because BL in adults is missed in those countries43. BL rates in the age group 15–54 years are lower than those in the pae-
In the USA, BL rates have a trimodal pattern, with an early peak in the diatric and older age groups, representing the trough of a U-shaped
paediatric age group (0–14 years), a second peak in the group around age-specific incidence curve38,39,44. Although data are sparse for

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a
Age standardized
incidence
(per 100,000 population)
<1
1–<2
2–<4
4–<7
7–10
>10
No data
P. falciparum temperature
suitability index
0
1
Unsuitable data

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Fig. 1 | Burkitt lymphoma incidence and P. falciparum temperature suitability index in 2010 (data from Malaria Atlas Project; https://malariaatlas.
suitability index. a, World map showing age-standardized Burkitt lymphoma org/explorer/#/). c, Enlarged map of the East Africa region with an overlay of the
incidence rates per million person-years (world standard) for males and females age-standardized Burkitt lymphoma incidence rates per million person-years and
in 38 countries with >30 cases for the period 2008–2012, using data from the P. falciparum temperature suitability index. Adapted from ref.43, CC BY 4.0
ref.306. b, World map showing the distribution of the P. falciparum temperature (https://creativecommons.org/licenses/by/4.0/).
ages >35 years in Africa, a bimodal pattern emerges when data are to malaria is of interest. Germline factors may contribute to rare famil-
grouped by region, except for Southern Africa where the pattern is ial cases, such as germline variants in TCF4 and CHD8 reported in two
more like that in the USA, Australia and the UK. related children in Uganda68. The germline genetic risk factors for
Multimodality is an epidemiological manifestation of biological BL reported in the sBL setting include inborn errors of immunity, such
heterogeneity. The heterogeneity in BL may reflect associations with as Purtilo–Duncan syndrome/X-linked lymphoproliferative (XLP)
EBV infection rates at different ages. EBV status is major determinant disease (OMIM 308240) or XMEN disease (OMIM 300853), and
of the somatic genomic heterogeneity of BL, and one study in Germany DNA repair disorders, such as ataxia telangiectasia (OMIM 615919),
has shown that the proportion of EBV+ patients with BL increases with and developmental disorders, such as Williams–Beuren syndrome
age at BL diagnosis36. (OMIM 194050)69.
Of note, caution is warranted in the interpretation of historical EBV is detected in 10–20% of tumours in the sBL setting33,70 but in
epidemiological data, particularly in older age groups, owing to 90% of tumours in the endemic setting18, indicating that EBV status is
changes in lymphoma classification over time. a major determinant of BL genetic subtype and incidence in different
settings. In addition, nutritional deficiencies, such as dietary selenium71
Mortality and magnesium72, have also been noted as risk factors for BL. Discovery
Although BL is considered a highly curable tumour, mortality in of XMEN (OMIM 300853)73, a genetic disorder of the magnesium ion
patients with BL varies considerably between HICs and low-income transporter that is associated with intracellular magnesium deficiency
and middle-income countries (LMICs). In HICs, patients are usually in natural killer cells and selective deficits in EBV immunity, leading to
diagnosed early and treated with high dose-intensity combination high EBV load and a high rate of EBV+ lymphoma, identified intracellular
therapy45–48, resulting in low mortality. In LMICs49, patients are often magnesium deficiency as a potential cofactor in EBV control. In a study
diagnosed late and are usually treated with less-effective low-dose of blood samples collected from African children with and without BL as
regimens50. US Surveillance Epidemiology End Results (SEER) program well as from healthy women who did not have XMEN, magnesium defi-
data analysis for patients diagnosed between 1973 and 2005 revealed ciency was found to be significantly more likely in women with a high
that BL-related mortality 5 years after diagnosis was ~25% in those EBV load than in women with a low EBV load and plasma magnesium
aged 0–19 years, ~50% in those aged 20–59 years and ~75% in those aged levels were found to be significantly lower in children with BL than in
≥60 years39. Older age and Black ethnicity are associated with higher healthy children72. This suggests that dietary magnesium deficiency
mortality51 in the USA, possibly due to diagnosis at advanced disease might impair EBV control. If those findings are confirmed, they would
stages, lower likelihood of using effective high dose-intensity therapy, raise the question as to whether dietary supplementation might restore
or other ill-defined disparities. However, temporal trends suggest EBV control and also prevent EBV+ BL.
that BL-related mortality is decreasing in more developed regions of The risk of BL is considerably increased in individuals with
the world51, presumably because of improvements in combination immunosuppression resulting from HIV infection, in individuals receiv-
therapies and supportive care45,52. BL mortality data from LMICs are ing immunosuppressive therapy to prevent solid-organ transplant
sparse. A population-based study of BL mortality in Zimbabwe, Uganda, rejection and in individuals with inborn errors of immunity such as
Kenya and Ivory Coast found a 3-year survival of ~41% of children diag- XLP syndrome23,33,74. Populations with HIV infection in the USA, Europe
nosed with BL53, a rate similar to 44% found in a hospital-based study and Australia have a 50–60-fold higher risk of developing BL than the
in Uganda54. general population75–77. The risk of BL peaks at CD4 lymphocyte counts
Few studies have evaluated long-term adverse events in survivors well above the laboratory cut-off for AIDS onset (200 cells/μl)75 with
of childhood BL, perhaps because the disease is rare in HICs, where cumulative HIV RNA as an important confounding factor78. These find-
treatments are curative, whereas access to treatment is limited in ings suggest that both chronic immune activation and expression of
Africa, where many cases occur. Overall, a range of survival has been functional CD4 lymphocytes may influence the development of BL.
reported55–57, suggesting that sufficient numbers of patients exist to However, the increase in the risk of BL in people living with HIV infection
investigate long-term survival after BL treatment. in Africa is modest at twofold to sixfold79–81. The risk of developing BL in
people living with HIV infection in India82 and China83 also seems to be
Risk factors substantially lower than that reported in higher-income regions. The
BL is a multifactorial disease in which the influence of infectious agents, underlying reasons for the lower HIV-related BL risk in LMICs compared
germline predisposition and mucosal immune response is implicated. with the risk in HICs are unclear, but may include under-detection,
Recurrent infection with P. falciparum and no infection with EBV dur- diagnostic misclassification and competing mortality.
ing childhood are the best-characterized infectious risk factors for BL Comorbidities seem to occur rarely in BL. In Africa, the most fre-
in endemic settings58. The occurrence of BL is correlated with inten- quent comorbidity is tropical splenomegaly84, which should be dis-
sity27,28,59 of malaria transmission (Fig. 1), having low anti-malaria anti- tinguished from splenic involvement by BL and treated accordingly.
body titres in plasma to antigens that elicit protective immunity60–62, Isolated cases of the co-occurrence of BL with tuberculosis, diabetes
and infection with multiple parasite clones, also called complexity of mellitus85,86, rheumatoid arthritis87 and other lymphomas, particu-
infection63–65. BL risk is decreased in children carrying genetic variants larly Hodgkin lymphoma88, have been reported in different regions of
that protect against malaria, such as the sickle cell trait66,67, suggesting the world. Patients with BL may also have rare syndromes, including
that children who lack protection against P. falciparum infection are Erdheim–Chester disease89 and acquired generalized lipodystrophy87,
particularly vulnerable to the development of BL (Fig. 3). In BL occur- suggesting that BL is a suitable co-disease in vivo model for disease
ring in the endemic setting, an association with germline susceptibility discovery and exploration.

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0.02 Fig. 2 | Multimodal age-specific incidence rates of Burkitt

Paediatric Adult Elderly lymphoma. Kennel density plots for the age distribution of Burkitt
Relative frequency of BL in USA
lymphoma (BL) cases in the USA for the period 1973–2005. Adapted
from ref.43, CC BY 4.0 (https://creativecommons.org/licenses/
by/4.0/).
0.01
0
0 10 20 30 40 50 60 70 80 90 100
Average age (years)
Mechanisms/pathophysiology subtype of B lymphoblastic leukaemia/lymphoma characterized by

Since the landmark cytogenetic studies in the 1970s11, it is now well MYC rearrangement23,92.
established that BL in all settings (or subtypes) is characterized by a The breakpoints of IGH::MYC at the MYC locus fall into three
comparatively simple karyotype containing the distinctive transloca- classes: those located within the MYC locus, affecting the first exon
tion t(8;14)(q24;q32) or one of its variants t(2;8)(p12;q24) and t(8;22) or the first intron of MYC, are class I breakpoints, those immediately
(q24;q11) in a background of few, if any, other chromosomal altera- upstream (5′, centromeric) of MYC are class II breakpoints, and those
tions14,90–93. Typical, but not specific, secondary changes are gains in 1q, located far upstream (5′, centromeric) of MYC are class III breakpoints.
trisomy 7 and trisomy 12, alterations in 13q as well as deletions in 6q and In sBL and iBL, class I and class II breakpoints seem to be predominant,
17p94–96. This low genomic complexity is an intrinsic feature of BL and is whereas class III breakpoints are enriched in eBL. The variant MYC
present in all epidemiological subtypes97. Chromosomal complexity can translocations occurring with IGL and IGK typically have breakpoints
occur during clonal evolution or relapse, but is rare overall. Cytogenetic located downstream (3′, telomeric) of MYC.
evolution is mostly linear, according to karyotype analysis91. However, The molecular consequence of all three translocations is deregu-
a study from 2021, in which high-resolution techniques, copy number lated expression of the MYC oncogene via enhancer hijacking. This takes
arrays and whole-exome sequencing were used, suggested that relapsed place on the derivative chromosome 14 for IGH::MYC and on the deriva-
BL shows parallel dependent evolution interpreted as non-linear clonal tive chromosome 8 for IGL::MYC and IGK::MYC. In some patients, cryptic
evolution characterized by new aggressive subclones evolving in paral- insertions of MYC into an immunoglobulin gene locus or of immuno-
lel from the common ancestral progenitor cell98. Further investigation globulin gene enhancer elements into the MYC locus occur instead of
in a larger populations is required but studies seem to agree that core typical chromosomal translocation, which might be hard to detect
driver mutations remain stable in clonally related relapses, probably using conventional diagnostic tests such as fluorescence in situ hybridi-
favouring a linear, late-branching clonal evolution model99,100. zation (FISH)109–111. Non-coding enhancer RNAs (eRNAs) are a subgroup
of long non-coding RNAs transcribed from the enhancer regions that
IG::MYC can regulate gene expression by several mechanisms112. Interest-
The defining molecular feature of BL is activation of MYC through ingly, the eRNA AL928768.3 has been identified in IGH::MYC BL cells
juxtaposition of the transcriptional enhancer element of one of the suggesting a possible role in MYC overexpression and BL development113.
immunoglobulin gene loci (Fig. 4). In roughly 80% of patients with MYC transcript overexpression mainly originates from the trans-
BL, the translocation occurs between MYC and the IGH locus. Less located MYC allele, irrespective of the partner gene101. An alternative
frequently, MYC is rearranged with one of the immunoglobulin light MYC transcript has been identified in patients with class I breakpoints,
chain genes IGK or IGL12,14,15. Aberrant class switch recombination (CSR) using an alternative transcription start site within the canonical first
and aberrant somatic hypermutation (SHM) are the two main mecha- intron of MYC101. Somatic mutation of the translocated allele is frequent,
nisms resulting in IGH::MYC in BL, which are both considered to occur further contributing to its pathogenicity; for example, by altering
in the germinal centre101,102. Aberrant CSR results in the location of phosphorylation and acetylation sites in the MYC protein associated
IGH:MYC breakpoints in the switch regions of the C-gene segments with protein stability101 (Fig. 4c).
encoding the immunoglobulin isotypes IgM, IgD, IgG, IgA and IgE, Although BCL2 rearrangements are absent and BCL6 transloca-
respectively103. By contrast, breakpoints derived from aberrant SHM tions are unusual in BL, very rare cases of direct BCL6::MYC (so-called
are located within or adjacent to rearranged V(D)J genes104. CSR and pseudo double-hit) have been reported114,115. Further investigation of
SHM are mediated by activation-induced cytidine deaminase (AID), whether hijacking of BCL6 regulatory elements by MYC can substitute
which is active in the germinal centre B cell (GCB) compartment104,105. for IG::MYC in BL development is warranted.
In the variant translocations t(2;8) and t(8;22), the breaks on chro- New sequencing technologies have identified additional onco-
mosomes 2 and 22 are frequently located 5′ of IGK and IGL constant genes subjected to immunoglobulin gene enhancer hijacking, which
region segments, respectively, and are usually generated by SHM101. can cooperate with MYC in the pathogenesis of BL101. Remarkably, some
In contrast to earlier reports, IGH::MYC due to aberrant V(D)J recom- of these events seem to occur earlier in the evolution of the tumour than
bination, which usually takes place in B cell progenitors, seems to be the pathognomonic IG::MYC translocation, suggesting that IG::MYC
rare or absent in BL92,106–108. Such translocations are the hallmark of a may not always be the initial genetic event in BL101.

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A distinctive feature of BL is its primary extranodal presentation BL in the breasts of pregnant and lactating women can similarly be
with predilection for the ileocaecal region and the jaw (Fig. 5a). These explained by this proposed cell-of-origin, as it is well documented that
locations are somewhat paradoxical, as BL is thought to derive from a in pregnant and lactating women B cells poised to express IgA leave the
GCB, on the basis of immunophenotype (for example, CD10+, BCL-6+, gastrointestinal tract and migrate to the breast as part of the maternal
CD38bright)116, the gene expression programme117,118 and somatic muta- immunological protection of the newborn via IgA-containing breast
tions in V regions119. However, others have argued that EBV+ BL is derived milk122,125–127.
from post-germinal memory B cells, owing to the pattern of EBV gene Mouse models have confirmed that MYC deregulation alone is
expression120. Of note, in sBL, the IGH breakpoints of IGH::MYC are insufficient in driving lymphomagenesis128–130. Indeed, MYC overex-
enriched in the IGHA switch region compared with other germinal pression in non-malignant B cells induces apoptosis131. Thus, additional
centre-derived B cell lymphomas carrying IGH translocations101,121. IgA pathogenetic changes are required, either before or within a short
confers mucosal immunity, and its production increases after birth window after MYC activation to lead to full lymphomagenesis.
to reach a plateau in adolescence, paralleled by an increase in Peyer’s
patches in the intestines122,123 (Fig. 5b). The slope of this development Genetic and molecular alterations
matches the age-associated incidence of BL in childhood. Thus, it Whole-exome and whole-genome sequencing, DNA methylation
is tempting to speculate that BL may develop from a B cell popula- profiling and RNAseq analysis have identified broad mechanisms
tion poised to express IgA during a primary immune response. In this underlying gene deregulation in BL. The affected pathways and pro-
regard, IgA-poised B cells in immunological reactions during denti- tein complexes targeted by these mechanisms are conserved and
tion or tooth exchange (in conjunction with EBV or other microbiota) converge on specific pathways, including tonic B cell receptor (BCR)
could predispose to the jaw manifestations101,124. The presentation of signalling, proliferation and survival, SWI–SNF chromatin remodelling,
P. falciparum Epigenomic or genomic alterations sBL/EBV –

antigen in core complexes and/or pathways
eBL/EBV+
Immune by somatic variants
response • EBV-associated gene signalling
• ID3/TCF3/BCR signalling
• SWI–SNF complex
EBV • Proliferation
Inhibition • Cell cycle deregulation Exponential Late
of apoptosis • Sphingosine-1-phosphate signalling growth (short changes
doubling time) i.e. FBXO11
± 6–8 weeks
to clinical
presentation
IG::MYC
Germline variants
• Primary mucosal ↑ AID
immune response
• Germline predisposition
• DNA repair
• Immune response GC-passage
• Malaria predisposition
Fig. 3 | Model of Burkitt lymphoma pathogenesis. Several factors modulate overexpression probably mostly leads to apoptosis of the IG::MYC-positive cells
Burkitt lymphoma (BL) pathogenesis. These include germline predisposition, (indicated by the sinusoidal line). Additional genetic events (in part like the ID3
exposure to different pathogens (for example, Plasmodium falciparum and mutation linked to aberrant somatic hypermutation during germinal centre
Epstein–Barr virus (EBV)), and acquisition of core alterations driving this (GC) passage) and/or pathogenic exposures (that is, P. falciparum promoting
lymphoma. The effect of these multiple factors could have different impacts expression of activation-induced cytidine deaminase (AID) or EBV inducing GC
in different populations leading to variable epidemiological subtypes, but reaction) deregulating core pathways and complexes are needed to overcome
the IG::MYC translocations (IGH::MYC, IGK::MYC or IGL::MYC) are a common the apoptotic negative feedback triggered in abnormal cells for the evolution to
genetic feature present in both subtypes endemic BL (eBL) and sporadic BL BL disease. These events ultimately lead to full transformation of the aberrant
(sBL). IG::MYC translocations occur randomly and probably as very early events IG::MYC-positive clone and subsequent (close to) exponential growth of the
linked to antigenic triggers particularly in B cells of the mucosal immune system tumour cells, during which the cells might further acquire (few) late genetic
undergoing a primary immune response. Nevertheless, pure consequent MYC changes until clinical presentation.

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a 14q32
Chromosome 14
106.011 mb 107.297 mb
IGH A2 E G4 G2 A1 G1 G3 D M J D V
IGH regions and B cell Enhancer Constant CSR or SHM

remodelling involved elements region
Distribution
breakpoints Breakpoint region Breakpoint region
in BL subtypes of sBL and iBL of eBL
8q24
b Chromosome 8
128.748 mb 128.750 mb 128.752 mb
128.749 mb 128.750 mb 128.753 mb

Distribution
SNVs/indels
Alternative Canonical
Transcription Start start start
start site
MYC
Distribution 300kb
breakpoints downstream
Class III Class II Class I
Distribution
breakpoints Breakpoint region Breakpoint region
in BL subtypes of eBL of sBL and iBL
Breakpoints
of IG::MYC
translocation t(8;14) t(2;8) and t(8;22)
c MYC protein
MBI MBII Myc-amino terminal region HLH Myc-LZ
Phosphorylation Mutation Acetylation
Fig. 4 | Breakpoints of IGH::MYC translocation in Burkitt lymphoma. transcription start sites: the canonical site and an alternative site that is located
Schematic representation displaying the IGH and MYC breakpoints of the in intron 1. Translocation breakpoints exist in different regions. Translocation
IGH::MYC translocation in Burkitt lymphoma (BL). a, Aberrant class switch resulting in IGH::MYC have breakpoint sites predominantly upstream of exon 2.
recombination (CSR) results in the location of IGH::MYC breakpoints. Breakpoints in that region can be grouped depending on their location (classes I,
Chromosome 14 contains the IGH locus constant (C) regions (beige) and the II and III) which is associated with the different BL subtypes. The breakpoints
J, D and V regions (blue), and the enhancer elements (red stars). Breakpoint regions leading to the variant translocations with immunoglobulin light chains (t(2;8)
differ depending on BL subtype, represented by the brackets. The squares and t(8;22)) occur downstream of MYC. c, The lower panel shows the distribution
indicate the most frequent breakpoints affecting the switch regions of the of MYC mutations along the MYC protein and its sites of phosphorylation and
constant elements of IGHA and IGHM, respectively. Translocations are assumed acetylation. The MYC protein consists of two MYC BOX (MBI and MBII), helix–
to derive from aberrant CSR (fusing the switch regions of IGHM with one of the loop–helix DNA-binding domain (HLH) and leucine zipper, Myc (Myc-LZ).
switch regions of the upstream constant regions encoding IGHA, IGHG and IGHE) Note, the MYC mutations in BL cluster close to known phosphorylation sites.
or aberrant somatic hypermutation (SHM) (affecting mostly the IGHV regions). eBL, endemic BL; iBL, immunodeficiency-associated BL; sBL, sporadic BL;
b, The MYC locus on chromosome 8 contains three exons (blue) located in 8q24, SNVs, single nucleotide variants. Adapted from ref.101, CC BY 4.0 (https://
with the thickness indicating the coding part (thicker parts) and the untranslated creativecommons.org/licenses/by/4.0/).
regions (smaller parts). The protein is shown below in part c. MYC contains two

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and sphingosine-1-phosphate signalling (Fig. 6). Highly recurrent altera- autophagic degradation of TCF3, suggesting SHMT2 as a potential
tions involving the transcription factor TCF3 and its negative regula- drug target in BL138.
tor ID3, which are essentially absent in other germinal centre-derived In addition to genomic translocation, MYC is the top altered gene
B cell lymphomas, indicate an important role for BCR signalling in BL in BL being affected by single nucleotide variants, with mutations
pathogenesis132–134. Inactivating somatic mutations in ID3 have been occurring in 70% of patients132–134. The mutations mainly affect the MYC
identified in 50–60% of patients with BL101,132–134. ID3 mutations cluster transactivation domain and are enriched in target motifs of the SHM
in SHM motifs within exon 1 and intron 1, encoding the HLH domain, machinery132–134. Moreover, the MYC mutations are clustered around
abrogating ID3 function133. TCF3-activating mutations, identified in phosphorylation sites101, which can prevent the degradation of MYC and
10–25% of patients with BL, affect the basic helix–loop–helix (B-HLH) enhance its stability. MYC alterations not only cooperate in proliferation,
DNA binding and dimerization domain of TCF3 splice isoform E47 but but can also enhance BCR signalling via activation of PI3K signalling by
not isoform E12 (ref.132). E47 and E12 isoforms have been found to be inducing expression of the MIR17HG cluster139,140. PI3K signalling is also
upregulated and downregulated, respectively, in BL compared with modulated by mir-19a and mir-19b, which decrease expression of PTEN,
control GCBs101. In addition, the E47 isoform is highly expressed in BL a negative regulator of PI3K activity141,142.
that lacks ID3 mutations compared with BL with ID3 mutations101. Hence, Inactivating mutations in the tumour suppressor gene TP53 and
differential TCF3 splicing can be an alternative mechanism to deregu- activating mutations in CCND3 have been identified in 40% and 50% of
late TCF3 activity. TCF3 protein is dysregulated via hypomethylation, BL, respectively132–134. The presence of mutations deregulating both
resulting in high TCF3 expression in BL135. In line with these findings, genes can explain the high rate of tumour cell in BL, as TP53 inactiva-
TCF3 overexpression has been observed in paediatric BL, correlating tion and altered TP53 expression in tumour cells are well established
with a poor prognosis136. Similarly, EBV infection is associated with to lead to growth and survival advantages, such as increased prolif-
an increase in methylation in the ID3 promoter resulting from DNA eration and evasion of apoptosis143,144. Disruption of CCND3 in mice
methyltransferase activity mediated by LMP1, consequently silencing blocks the formation and expansion of the germinal centres145. In
ID3 (ref.137). In addition, the enzyme serine hydroxymethyltransferase addition, cyclin-dependent kinase inhibitor p16 encoded by CDKN2A,
2 (SHMT2) is a relevant modulator of TCF3, and its inhibition generates a negative regulator of CCND3, is deleted or inactivated in 10% of BL132.
a Tumour localization and jaw manifestation b Affected body parts in BL patients

in endemic BL
Orbit
Jaw
Thyroid
Lymph node
Swollen eyes
Heart and
pericardium
Loose teeth
Breast
Swollen face
Liver
Spleen
Kidney
Swollen
abdomen
Kidney
Peyer patches
Swollen (in the ileum
testicles of the small
intestine)
Ovary/testes
Bone
Fig. 5 | Involved anatomical sites in Burkitt lymphoma. Tumour localization endemic BL and jaw manifestations. b, Affected body sites in patients with BL,
of Burkitt lymphoma (BL) including nodal and extranodal localizations, including nodal and extranodal involvement. Adapted from ref.101, CC BY 4.0
highlighting the specific sites affected in endemic BL. a, Tumour localization in (https://creativecommons.org/licenses/by/4.0/).

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a
B cell receptor P2RY8 S1PR2
10–20% 3%
Cell membrane CD79
Syk
Cytoplasm
SRK
9
GNA13 15–20%
15% FOXO1 PI3K PTEN 5%
GTP
ARHGEF1
SHP-1 7% Akt
4 RHOA 10%
mTOR MIR17HG 10%
GDP GTP
Activation
Proliferation Survival Cell migration
Nucleus 3
MYC 60–80%
5 8
TP53 30–40%
2 1 SWI–SNF complex
50–60% ID3 TCF3 10–25%
MDM2 USP7 8–10% BCL11 4% BCL7 6%
4% ARID1B ARID1A SMARCA4 30–40%
6 7
DNA 30%
20–50% CCND3 CDKN2A 10%
CDK6
Loss of function Gain of function Differences between SNVs or indels SVs or CNAs Epigenetic changes
EBV+ and EBV– BL or alternative splicing
b
Sphingosine-1-phosphatase signalling
BCR signalling Proliferation and survival SWI/SNF complex Others
80
70
60
50
Frequency
40
30
20
10
0
#
P7 #
3
F3
YC
53
12
1*
11
X
X7
8
ID
XO
ND
A1
CA
AP
X3
O
D1
L7
RY
BP
TC
TP
XO
M
US
RH
RF
TF
BC
GN
GN
DD
AR
FO
I
CC
PC
P2
AR
FB
SM
Genes EBV+ EBV–

Fig. 6 | Molecular pathways altered in Burkitt lymphoma. a, The figure pathways are labelled (1) to (9), corresponding to TCF3–ID3 modul ((1) and (2)),
illustrates the prevalence of somatic alterations and the types of aberration in cell cycle and proliferation ((3) to (7)), the SWI–SNF complex ((8)), and sphingosine-
specific genes. The single nucleotide variants (SNVs) and small insertions and 1-phosphate signalling ((9)). b, The graph displays the frequencies of somatic
deletions (indels) are labelled with dark blue circles; the structural variants (SVs) genes affected in BL based on the EBV status obtained published data18,19,101
and copy number aberrations (CNAs) are labelled with gold hexagons; and the (the alteration frequencies of the two genes labelled with an asterisk are available
epigenetic changes and alternative splicing are labelled with blue triangles. Gain- in only two studies18,101). The altered genes are ordered by pathway. The genes
of-function mutations are labelled in blue and loss-of-function mutations in red. included in the display are those recurrently altered in at least 10% of cases and
The altered genes occurring with different frequencies between EBV+ and EBV− identified in more than one study. BCR, B cell receptor; EBV, Epstein–Barr virus.
Burkitt lymphoma (BL) are indicated with a dark border. The altered genes and

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Hence, aberrations in CCND3 or CDKN2A may cooperate to perturb sphingosine-1-phosphate signalling could promote dissemination.
the cell cycle. Of note, mutual exclusivity between TP53 and CDKN2A Overall, MYC activation in BL leads to an avalanche of differential
aberrations has been described in B cell lymphoma146. Similarly, BL gene expression. For example, CXCR4 is highly expressed by BL cells, a
with TP53 alterations has increased expression of CDKN2A101. Addi- feature shared with primary central nervous system (CNS) lymphoma,
tional altered genes involved in proliferation and survival of BL include which could explain the brain as a target of BL but also point to new
HECW2 (ref.101), USP7 and RFX7 (refs.18,101). All three genes are linked to therapeutic modalities156–160.
regulation of TP53 (refs.147–149). The transcription factor RFX7 has also Several studies have sought to clarify the differing clinical behav-
been found to regulate MYC and IGHG1 (refs.147,150). Overall, several iour of paediatric and adult mature B cell lymphomas. Comparison of
genes involved in the cell cycle and proliferation are recurrently altered genetic alterations in paediatric and adult patients with BL identified
in BL contributing to its aggressiveness. a subset of mutations that was more frequently altered in the specific
Alterations of the SWI–SNF chromatin remodelling complex have age groups161. Mutations in ID3, DDX3X, ARID1A and SMARCA4 were
been identified as a key pathway in BL pathogenesis. Two compo- more prevalent in the paediatric group, which is probably connected
nents of this pathway, SMARCA4 and ARID1A, are frequently altered in to the higher frequency of EBV+ BL in adults36. By contrast, alterations
BL133–135. SMARCA4 mutations are present in ~40% of BL and preferen- in BCL2 and YY1AP1 were almost exclusively detected in BL diagnosed
tially target the helicase domain135. High expression of the inactivated in adult patients. Interestingly, the study also suggested a biological
SMARCA4 protein is found in BL, which is accompanied by decreased transition of the BL mutational profile between patients diagnosed at
DNA methylation and active promoters at the SMARCA4 locus135. Bind- age 25 years and those diagnosed at age 40 years36.
ing of the helicase-deficient mutated SMARCA4 to its target genes has In summary, a quite conserved set of molecular complexes and
been suggested to be associated with demethylation of its binding pathways is deregulated at the DNA, epigenomic and/or transcriptomic
sites but lack of expression of its target genes as a consequence of levels in all types of BL, and changes at different cellular levels can
the retained binding competence in the absence of the helicase activ- substitute for each other. EBV+ and EBV− BL show deregulation of the
ity135. SMARCA4 mutations are mutually exclusive with alterations of same set of complexes and pathways, but by different cellular means.
other members of the SWI–SNF complex, including ARID1A, ARID1B
and SMARCB1 (refs.101,135). Truncating ARID1A mutations have been Role of EBV infection in lymphomagenesis
described in 20–30% of BL101,151. ARID1A has been implicated as a tumour Since the discovery of EBV in BL biopsy samples10, research into the
suppressor in solid tumours152,153, and functional analysis supports this contribution of EBV to lymphomagenesis has been fraught with para-
role153. Further genomic mutations of other members of the SWI–SNF doxical observations. For example, EBV infection persists in a latent
complex have been identified in BL, including in BCL7A, CHD4 and form in most of the world’s population but only some of those who
BCL11B, although they are uncommon135. are infected develop cancer. In addition, although EBV encodes sev-
Sphingosine-1-phosphate signalling is deregulated in BL as a result eral latent proteins that are essential for B cell immortalization, only
of mutations and altered DNA methylation. RHOA mutations are pre- one latent protein, Epstein–Barr nuclear antigen 1 (EBNA1), is consist-
sent in ~10% of BL154, and mutations in GNA13, GNAI1 and GNAI2 are less ently expressed in BL. To understand the role of EBV in the aetiopatho-
frequent18,101,132,133. Furthermore, differentially methylated regions in genesis of BL, it is worth focusing on what has been learnt from studies
key components corresponding to PDGFRB, GNA11, S1PR1 and GNA12 of EBV in eBL in children. In 1978, a seminal Ugandan population-based
have been identified in BL compared with control GCBs135. S1PR2 is study found that elevation of antibodies against the EBV viral cap-
frequently inactivated by mutations promoting increased AKT and sid antigen occurred before emergence of the tumour, supporting a
migratory activity155. Overall, mutations and differential DNA methyla- causal role of EBV in eBL162. Later studies showed elevated antibod-
tion contribute together to inactivate Gα13 and increase AKT signalling ies to EBV lytic antigens were observed in patients with BL but not in
and migration activity. healthy individuals163–165. The EBV genome, which is episomal but can
Despite the overlap of many altered genes in sBL and eBL, some be integrated into the nuclear tumour genome, is detected in most
differences in mutational frequency exist18–20. eBL has higher mutation patients with eBL166,167. The viral genome was found to be clonal and,
counts but a lower number of variants of genes that are highly altered therefore, infection of the malignant B cell preceded transformation,
in sBL, including MYC, ID3, TCF3, DDX3X, CCND3 and TP53 (refs.20,132). further substantiating a role for EBV in contributing to malignant
EBV+ BL is characterized by increased PI3K activity via downregulation transformation168. Also, loss of the EBV genome from BL cell lines
of PTEN, followed by mTORC1 activation19. By contrast, the TCF3 path- results in apoptotic cell death169,170.
way is more activated in EBV− BL. This observation is highly supported An emerging consensus for one role of EBV in lymphomagen-
by the mutational landscape, as the key drivers, including ID3, TCF3 esis is that EBV genes subvert the apoptotic pathways in B cells171,172
and CCND3, have higher frequencies of mutations in EBV− BL than in (Fig. 3). Consistent with this model, the promoter of BCL2L11 that
EBV+ BL19–22. In addition, AID activity is higher in EBV+ BL than in EBV− encodes BIM protein (BCL-2 interacting mediator of cell death), is
BL, displaying an enrichment of mutations affecting AICDA recogni- highly methylated in BL172. Of note, BIM is required for programmed cell
tion sites (RGYW) in EBV+ BL18. BL may also have different patterns of death when wild-type MYC is overexpressed169. Interestingly, in some
mutational profiles based on the type of EBV. BL with EBV type 2 was patients with BL, EBV genomes with a deletion of EBNA2 with concomi-
found to have significantly higher numbers of altered genes than BL tant expression of other latent genes, EBNA3A, EBNA3B, EBNA3C and
with EBV type 1 (ref.19). However, these findings were not supported EBNALP, from the Wp latent promoter have been detected173,174. These
by another study integrating genomic and transcriptomic data from Wp-restricted BLs also express the viral BCL-2 homologue, BHRF1,
106 patients with BL18. which was shown to provide a survival advantage175,176. Expression of
Cell cycle dysregulation together with MYC activation could EBNA2 cannot occur with deregulated MYC expression, suggesting
explain the highly proliferative nature of BL cells. Moreover, BCR sig- a selection of an EBV genome that loses EBNA2 (ref.174). EBV encodes
nalling activation enhances tumour survival, and dysregulation of the BART microRNAs (miRNAs); loss of the EBV genome in BL results

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in apoptosis but expression of BART miRNAs can rescue these cells177, Tumour microenvironment
providing a potential explanation for how EBV− BL can emerge from an To date, few studies have focused on the role of the tumour micro
EBV-infected MYC-translocated cell. environment in BL. The few existing studies suggest only a minor role in
It is intriguing to consider whether the geographical patterns of BL very aggressive and rapidly evolving lymphomas such as BL, in which
are an epidemiological manifestation of different EBV variants circulat- the genetic alterations render growth and survival of the tumour cells
ing in regions with high or low BL rates29; however, whether patients widely (though probably not completely) independent of the non-
with BL have unique EBV variants compared with control populations tumoural microenvironment197,198. Nevertheless, one characteristic
has not yet been conclusively demonstrated. Two types of EBV (type 1 histological feature of BL is the presence of many tumour-associated
and type 2) exist, which are genotypically and phenotypically different. macrophages (TAMs). Polarization towards an M2 phenotype of TAMs,
EBV type 1 has been observed more commonly in eBL than EBV type 2 independent of BL subtype, that is characterized by pro-tumoural
(ref.178) but more studies are needed to confirm this observation. properties has been observed199. However, the same research group
A variant of the promoter for the immediate early protein, Zta, a protein characterized four EBV+ BL with a granulomatous reaction showing
required to initiate the lytic cycle, has also been found more frequently an M1–Th1-polarized microenvironment associated with controlled
in patients with BL than in healthy control individuals179, pointing to a growth and spontaneous regression200. Further studies are needed
possible role for lytic reactivation of EBV in eBL pathogenesis. to elucidate the potential effect of the tumour environment in BL
P. falciparum transmission is a cofactor in EBV infection in eBL pathogenesis.
aetiopathogenesis based on ecological overlap between EBV+ BL and
endemic malaria based on case–control studies demonstrating ele- Diagnosis, screening and prevention
vated antimalaria antibodies in patients with BL compared with control Diagnostic evaluation and delivery of BL treatment require an inte-
patients diagnosed with other cancers60,180. Several studies have identi- grated multidisciplinary approach that is currently well developed in
fied potential roles for malaria including T cell exhaustion, polyclonal HICs and rudimentary in other countries, especially in regions with
B cell activation, induction of EBV reactivation and AID activation181. As high incidence of BL.
children are repeatedly infected in regions where P. falciparum malaria
is endemic, this might indicate additional pathways in which malaria Clinical variants and presentation
modulates EBV to increase the risk for eBL. BL can have unusual protean manifestations such as cardiac manifes-
EBV, HIV and P. falciparum malaria have all been shown to induce tations201 or peri-appendiceal masses202 (Fig. 5b). The clinical pres-
expression of AID182, an enzyme involved in inducing point mutations entation of most BL is dramatic due to highly proliferating tumour
and immunoglobulin gene class switching in normal GCB. AID dys- cells with a predilection for disseminating to extranodal anatomical
regulation might be a key aetiopathogenic event in the pathogenesis sites. Suspicion of BL should be considered a medical emergency and
of BL, although the absolute number of somatic variants attribut- the diagnostic and staging evaluation needs to be completed with
able to AID activity is lower in BL than in many other GCB-derived urgency. Supportive care measures, including intravenous hydration,
lymphomas18,101,183. Nevertheless, the finding that AID induces a MYC prophylaxis for tumour lysis syndrome (for example, with rasburicase
translocation in a TP53−/− mouse model supports this hypothesis184, or allopurinol), correction of electrolyte imbalances and treatment
suggesting that chronic immune activation leading to aberrant AID of concomitant infections, should be initiated immediately and such
expression may be the driver of MYC translocation185. Dysregulated disorders corrected before confirming the diagnosis203. In selected
AID expression has been reported in populations at risk of BL185–187. patients, a short course of steroids may be considered before chemo-
In addition, EBV+ tumours have a higher AID mutation burden than therapy to improve the performance status of the patient and/or to
EBV− tumours18. improve organ dysfunction; however, steroids should be used with
Immune control of EBV is mediated through both CD4+ and CD8+ caution, as they may induce tumour lysis syndrome.
T cell pathways188. As EBNA1 is not processed by the proteasomal machin- Children with eBL classically present with rapidly growing masses
ery due to its structural features, the suggestion arose that cytotoxic in the jaw or periorbital region, and extranodal sites, such as the intes-
T cell responses cannot be mounted against EBNA1 (ref.189). With the tine, gonads, kidney and breasts, are commonly involved204,205 (Fig. 5).
discovery of CD4+ cytotoxic T lymphocytes targeting EBNA1 (ref.190), Leptomeningeal involvement often manifests as cranial nerve palsies,
an explanation has to be found for the lack of immune response to BL but may be less common in eBL205.
expressing EBNA1. A lack of EBNA1-elicited IFNγ response was found in Patients with sBL commonly present with a mass in the ileocaecal
Kenyan patients with eBL, consistent with a model of immune escape region that may mimic acute appendicitis or with a fast-growing mass
by BL191. EBV-induced lymphomas in a humanized mouse model xeno- in the head and neck region206,207. It is critical for clinicians to recognize
grafted with human lymphocytes revealed expression of PDL1 and these presentations as possible BL, as complete resection of the mass is
PDL2 on lymphoma cells, blocking T cell control of the lymphoma192. In neither curative nor necessary. Bone marrow involvement commonly
addition, BL typically shows downregulated MHC class I, providing an occurs in sBL and includes leukaemia with extensive blasts (>25%) in the
additional pathway for immune escape193. A final paradox to consider is marrow. CNS involvement is found in 5–20% of patients at diagnosis and
the existence of both EBV+ and EBV− BL. Whether EBV− and EBV+ BL have is typically leptomeningeal or associated with spinal cord compression,
different aetiologies remains unclear. So-called traces of EBV infection and is only rarely brain parenchymal207–209.
were seen in BL that were considered EBV− based on lack of expression The iBL variant often occurs in patients with a CD4 count of
of EBV-encoded small RNAs194,195, suggesting that EBV infection is an >200 cells/mm3 and the incidence of HIV-associated BL has not sub-
initiating event in lymphomagenesis in otherwise EBV− BL. However, stantially declined despite the widespread use of highly active antiret-
evidence of ongoing SHM in EBV+ BL but not in EBV− BL18,196 suggests roviral therapy (HAART)75,210. Patients with HIV-associated BL present
that EBV− BL arises from different pathogenetic mechanisms unrelated with a very high rate of dissemination to extranodal sites including the
to EBV infection. CNS (20–30%), bone marrow (~30%), breasts, gonads and adrenals211.

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Diagnosis and staging consistently negative for the haematopoietic development marker
The diagnostic and staging work-up is similar across clinical BL variants LMO2 (refs.117,214–218). They usually show strong expression of IgM, but
and determined mostly by the age of the patient and available health- in ~10% of patients, they express IgA alone and in a few patients they are
care resources. To establish a preliminary diagnosis of BL, a minimally negative for surface immunoglobulin BCR. Intense MYC expression in
invasive diagnostic procedure may be sufficient, but it is important >80% cells is noted in almost all patients with BL, although MYC expres-
to note that fine-needle biopsy may not yield sufficient diagnostic sion can very rarely be absent despite the presence of MYC rearrange-
material for all tests23. A Tru-Cut needle biopsy or an open biopsy is ment due to mutations or alternative mechanisms of MYC regulation.
preferred to obtain adequate amount of material23. The characteristic Demonstration of a MYC translocation or IG::MYC fusion is not manda-
morphological features of BL are monomorphic B cells of medium size, tory for BL diagnosis but the definitive lack of these genetic changes
with finely clumped and dispersed chromatin, and multiple basophilic excludes a diagnosis of BL (Table 2). The Ki-67 proliferative index is
paracentrally located nucleoli16 (Fig. 7). The cytoplasm is deeply baso- typically >95%, reflecting high proliferation rates in BL. Cytoplasmic
philic and usually contains lipid vacuoles that are best seen in imprint lipid vacuoles can be demonstrated in paraffin sections by staining
preparations on fine needle aspiration cytology. The cells display some with an adipophilin antibody219. BL cells are usually negative for CD5,
cohesion. The tumour has an extremely high proliferation rate with CD23, CD138, BCL-2, CD44 and terminal deoxynucleotidyl transferase
many mitotic figures, as well as a high rate of spontaneous cell death (TdT)220–222. However, weak BCL-2 expression, seen in ~20% of patients,
(apoptosis). A ‘starry sky’ pattern is usually present, resulting from the is still acceptable for the diagnosis of BL. Patients presenting with these
presence of interspersed tingible body macrophages23. Rarely, a florid morphological and immunophenotypic features, particularly with
granulomatous reaction that may mask the tumour can be observed. In demonstrable MYC expression in >80% of B cells and a Ki-67 index of
these patients, BL is characterized by a pro-inflammatory microenvi- 95%, can be diagnosed with BL223. According to the present Fifth Edi-
ronment and typically presents as limited stage disease, an especially tion of the WHO classification, desirable but not mandatory diagnostic
good prognosis sometimes showing spontaneous regression200,212,213. criteria are a starry-sky pattern, cohesive growth pattern, BCL-6 and
The characteristic phenotype of BL is expression of all B cell anti- CD38 expression in the absence of TdT, and as well as lack of BCL2
gens (CD19, CD20, CD79a, CD22 and PAX5) and many germinal centre and BCL6 rearrangements (mainly required in adult BL)23.
antigens (for example, CD10, BCL-6, CD38, HGAL and MEF2B)23. The Staging procedures in BL include clinical history and physical
neoplastic cells are variably positive for the germinal centre marker examination, including assessment of the cranial nerves. Laboratory
GCET1, which is inversely correlated to EBV− association, but are tests include complete blood count, liver and renal function tests,
a b
c d e f
Fig. 7 | Morphology of classic Burkitt lymphoma. Haematoxylin and macrophages. Typical cytoplasmic lipid vacuoles can be seen in cytological
eosin-stained (part a) and Giemsa-stained (part b) tumour sections show the preparations (part a, inset). Neoplastic cells are typically present with a CD10+
morphological features of classic Burkitt lymphoma: diffuse proliferation immunophenotype (part c) or a BCL-6+ immunophenotype (part d), with
of monomorphic B cells of medium size, with finely clumped and dispersed strong MYC expression in >90% of the cells (part e) and a high proliferation rate
chromatin, multiple basophilic paracentrally located nucleoli (black arrow) demonstrated by Ki-67 expression in 95% of cells (part f). All images, ×20.
and starry sky presentation due to the presence of interspersed tangible body

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Table 2 | Differential diagnosis of Burkitt lymphoma
Diagnosis Morphology Immunophenotype Genomic features
BL Cohesive monomorphic, medium- B cells positive for CD10, BCL-6, CD38 and IG::MYC fusion due to CSR or SHM in all
sized cells with multiple small nucleoli MYC; Ki-67 >95%; negative for BCL-2, TdT, patients (direct BCL6::MYC fusion extremely
and basophilic cytoplasma CD44 and cyclin D1 rare); absence of BCL2 or BCL6 translocation
B lymphoblastic Fine nuclear chromatin; nucleoli often Uniform expression of TdT in most patients; IG::MYC translocation due to V(D)J
leukaemia/lymphoma with less conspicuous; scanty cytoplasm CD34 expression in some recombination in all patients; some patients
IG::MYC fusion also show IGH::BCL2 fusion
Diffuse large B cell or high- Variable; intermediate between BL Most express BCL-2; some express TdT Structural chromosomal variant of BCL2
grade B cell lymphoma and DLBCL or blastoid (mostly IGH::BCL2) in addition to MYC
with MYC and BCL2 fusion with immunoglobulin gene or
rearrangements non-immunoglobulin gene partners
High-grade B cell Medium to large cells; variation in Most express BCL-2; variable MYC Isolated MYC, isolated BCL2, or BCL2 and
lymphoma, not otherwise nuclear size and nucleolar content; expression dependent on MYC BCL6 translocations possible; simultaneous
specified cohesive growth usually absent abnormalities BCL2 and MYC rearrangements or 11q
aberration absent
High-grade B cell Resemblance to BL, but often more Variable MYC expression Gain in 11q23.3 and minimal region of
lymphoma with 11q pleomorphism with some variation loss (or LOH) at 11q24.1-qter; lack of MYC
aberration in nuclear shape and/or size and translocation
presence of larger nucleoli
Diffuse large B cell Large cells; nucleoli more prominent; Most express BCL-2; can lack CD10, Most lack MYC translocation; variable
lymphoma, not otherwise peripherally located nucleoli; BCL-6, CD38 or MYC expression; can presence of BCL2 or BCL6 translocations;
specified pleomorphism show expression of CD44 simultaneous MYC and BCL6 rearrangements
constitute a subgroup
Paediatric-type follicular Intermediate to large blastoid cells; B cells positive for CD10 and BCL-6; Ki-67 Absence of MYC, BCL2, BCL6 and IRF4
lymphomab cytologically between centrocytes and >30%; BCL-2 negative or weak; negative translocations
centroblasts; follicular pattern may not for MYC and cyclin D1; CD21/CD23-positive
be apparent in a needle core biopsy follicular dendritic cell meshworks
BL, Burkitt lymphoma; CSR, class switch recombination; DLBCL, diffuse large B cell lymphoma; LOH, loss of heterozygosity; SHM, somatic hypermutation; TdT, terminal deoxynucleotidyl
transferase. aMorphology is quite uniform across the different epidemiological subtypes. bParticularly in a needle core biopsy.
and detection of serum uric acid and lactate dehydrogenase (LDH). immunostains; phase 2, three additional immunostains; and phase 3,
Screening of all patients for HIV infection is recommended, and adult FISH217. The availability of an antibody for robust assessment of MYC
patients should be screened for hepatitis B and hepatitis C (which expression in paraffin-embedded tissue samples now greatly aids in
is routine in patients who might receive transfusions of blood prod- the diagnosis of BL. Using the immunohistochemistry threshold of
ucts), and tested for malaria in endemic areas. Imaging procedures to ≥80% of tumour cells being MYC-positive, a MYC rearrangement can
determine the extent of disease should include the neck, and thoracic, be predicted in ~99% of patients with BL23,223,227,228.
abdominal and pelvic regions. Imaging modalities differ according to Of note, not all BL exhibit the classic morphology. Some may show
the age of the patient and local availability. In children and adolescents, increased nuclear pleomorphism and the nucleoli may be more promi-
ultrasonography or MRI are preferred to avoid unnecessary radiation nent and fewer in number. In other patients, particularly in adults with
exposure, whereas adults are commonly staged with whole-body CT. As immunodeficiency, the tumour cells can exhibit plasmacytoid differen-
BL commonly affects extranodal sites, ultrasonography of the testes, tiation with eccentric basophilic cytoplasm and often a single central
PET–CT, bone marrow aspirates and examination of the cerebrospinal nucleolus47. In these instances, FISH studies to interrogate the status
fluid (CSF) with flow cytometry analysis should be performed when of MYC, BCL2 and BCL6 (ideally together with immunoglobulin genes)
available. Brain MRI is usually reserved for patients with cranial nerve are required for a precise diagnosis of BL. As long as the typical BL
palsies, CSF involvement or neurological symptoms suggestive of brain phenotype, along with MYC rearrangement or even preferred IG::MYC
involvement. Staging of paediatric BL is defined in Box 2. juxtaposition and lack of BCL2 and BCL6 rearrangements, is present, a
In resource-restricted areas, the basic evaluation of patients with diagnosis of BL can be made. These morphological features are in line
suspected BL includes complete medical history and physical examina- with gene expression profile studies suggesting that the morphologi-
tion, laboratory tests, including serum LDH quantification, along with cal spectrum of BL is broader than previously expected118. Details on
chest X-ray and ultrasonography224. However, accurate risk stratifica- differential diagnoses of different BL types are presented in Table 2.
tion is challenging in this setting given the limited assessment capacity.
As a result, the pathological diagnosis of childhood lymphoma includ- Screening
ing BL in Uganda has been noted to have a high probability of errors The association between BL and infections, notably type 1 carcinogens
compared with diagnosis in HICs225. Imaging and other procedures, EBV and HIV229, and the type 2A carcinogen P. falciparum230, suggested
such as CSF analysis and bone marrow biopsies, are often only available the theoretical possibility of reducing BL morbidity or mortality by tar-
in selected centres226. geting associated infections231. Because BL is a rapidly growing tumour,
Several algorithms have been proposed to assist in the diagnosis with a short clinical history of 4–8 weeks before presentation due to
of BL in settings of limited resources. One algorithm is based on a scor- doubling its mass every 28–48 h, screening for early detection is often
ing system comprising three phases: phase 1, morphology with three not possible and is, therefore, not recommended to reduce mortality,

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particularly in HICs where BL accounts for ~1–2% of non-Hodgkin lym- Increased funding of global health, including for BL, optimism for
phomas (NHL) and ≤20% of patients are EBV+18,33. The BL cure rate with precision medicine and increasing access to omics analyses should be
chemotherapy in these settings is high at 90–100%45,232. However, the harnessed to generate data needed to evaluate promising biomarkers
possible importance of screening for early detection to reduce mortal- for BL screening235. A case–control study of the EBV antibody responses to
ity in BL endemic areas deserves careful consideration and study. In 202 peptide sequences representing 86 EBV proteins in 150 Ghanaian
these regions, BL is the first or second most common childhood cancer children with BL identified 33 IgG markers with markedly elevated
and >50% of patients die from the disease53,233 due to late presenta- titres compared with those in matched controls165. Replication of these
tion, diagnostic delays and less-effective treatments50. The fact that results is needed to prioritize markers that could be evaluated as a
BL — and indeed any other childhood cancer — is not a major public serological test to screen for early disease.
health concern in African countries according to current internationally eBL is nearly consistently associated with EBV18, and many
established development and public health priorities, as it accounts reports indicate that children with eBL have high levels of EBV DNA
for a small proportion of childhood morbidity and mortality234, has in the blood239,240. Although, EBV DNA assays are perceived to have
discouraged research to investigate new screening approaches49. How- poor specificity as EBV can be detected at fairly high levels in blood
ever, the goal of epidemiologists studying BL should be to balance and saliva from people without eBL, the determination of the most
the interest in understanding the aetiology of BL and the real population appropriate sample medium (plasma, peripheral blood mononuclear
interest in decreasing disease incidence and mortality. Investigating cells or saliva) and the threshold for diagnosis or screening remains
the link between eBL and EBV and P. falciparum is motivated by the of research interest237. The characterization of unique molecular
need to discover biomarkers that could be applied for screening and abnormalities in BL18,132,133,241 provides opportunities to use circulating
early detection of BL49,235. The perception that tests based on EBV or tumour cells or cell-free tumour DNA from liquid biopsies for screen-
P. falciparum detection alone have poor specificity, as both infections ing or as early diagnosis markers for BL242. Another new approach has
are likely to be detected at high levels even in children without BL, is been developed to identify EBV in fine-needle aspiration samples
based on early studies using single-antigen assays165 and unfounded without DNA extraction based on loop-mediated isothermal ampli-
extrapolation of the lessons learned from nasopharyngeal carcinoma fication (LAMP)243. Clearly, the identification of suitable biomarkers
(NPC), another EBV-associated cancer with different clinical, tissue, and development and validation of screening assays will be challeng-
ethnicity and epidemiological properties236,237. Measurements of EBV ing, but the opportunity to reduce the morbidity and mortality of BL
copy number in plasma may be useful in identifying children with eBL, in populations in which it is endemic should be a strong moral and
opening up a promising area for future research to differentiate a high scientific motivation49,235.
EBV copy number associated with tumour from a high EBV copy number
associated with asymptomatic parasitaemia237. In addition, EBV has Risk stratification
been detected at much higher quantities (two-log copies higher) in Common parameters of current paediatric protocols for risk stratifica-
plasma from children with eBL than in plasma from children without tion are the status of lymphoma resection and the pretreatment level
eBL238, suggesting that a plasma-based EBV DNA quantitative assay of serum LDH, which is an indicator of tumour volume and stage of
holds promise as an early detection and/or diagnostic assay237,239,240. disease. The St. Jude staging system which was used in earlier years244
Box 2
International Paediatric Non-Hodgkin Lymphoma Staging System245

Stage I •• Two or more nodal tumours above and below the diaphragm.
•• A single tumour (extranodal) or single anatomical area (nodal) •• Any intrathoracic tumour (mediastinal, hilar, pulmonary, pleural
with exclusion of the mediastinum and abdomen (skin (S), or thymic).
extranodal-bone (EN-B), extranodal-skin (EN-S))245. •• Intra-abdominal and retroperitoneal disease, including liver,
spleen, kidney and/or ovary localizations, regardless of degree
Stage II of resection (except primary gastrointestinal tract tumour (usually
•• A single tumour with regional node involvement. in ileocaecal region) and/or involvement of associated mesenteric
•• Two or more nodal areas on the same side of the diaphragm. nodes that is completely resectable).
•• A primary gastrointestinal tract tumour (usually in the ileocaecal •• Any paraspinal or epidural tumour, regardless of whether other
area), with or without involvement of associated mesenteric sites are involved.
nodes, that is completely resectable (if malignant ascites or •• A single bone lesion with concomitant involvement of extranodal
extension of tumour to adjacent organs are present, it should be and/or non-regional nodal sites.
regarded as stage III).
Stage IV
Stage III •• Any of the above findings with initial involvement of the central
•• Two or more extranodal tumours (including EN-B or EN-S) above nervous system (stage IV CNS), bone marrow (stage IV BM) or both
and/or below the diaphragm. (stage IV combined) based on conventional methods.

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Table 3 | Risk-stratification groups in paediatric Burkitt is crucial given the need for pretreatment supportive measures. The
lymphoma main focus is on prevention of tumour lysis syndrome using simple
measures, such as alkaline hydration and allopurinol prophylaxis,
Risk group Resection Stage and initial serum LDH level
similar to approaches in HICs248. Additional considerations for eBL
status
include assessment of baseline nutritional status, anaemia, endemic
NHL-BFM48 infections, worm infestation and HIV status to enable the provision of
R1 Complete Not applicable effective treatment and favourable long-term outcomes.
R2 I/II Incomplete Stage I–II
Prevention
R2 III Incomplete Stage III and LDH <2 × ULN
There are currently no recommended prevention strategies for BL.
R3 Incomplete Stage III and LDH ≥2 × ULN but <4 × ULN To date, only one study has investigated whether malaria suppression
Stage IV/leukaemic disease and results in a reduction in BL. Starting in 1978, children <10 years of age
LDH <4 × ULN and CNS-negative received bi-weekly chloroquine through mass distribution249. Malaria
R4 Incomplete Stage III and LDH ≥4 × ULN parasitaemia prevalence decreased from 48% in 1976 to 13% in 1978
during the intervention period but not in the control communities,
Stage IV/leukaemic disease and
LDH ≥4 × ULN and CNS-negative and BL incidence decreased from an average of ~4 to ~1 per 100,000
during the intervention period249. However, failures in drug distribu-
R4 CNS-positive Incomplete Stage IV/leukaemic disease and
tion and development of chloroquine resistance led to ambiguous
CNS-positive
results. An alternative explanation for the reduction in BL incidence
LMB-FAB48
than chloroquine-induced suppression of malaria was suggested in
A Complete Stage I–II a 2008 study using a mouse model, in which chloroquine induced
B low Non-resected Stage I–III and LDH <2 × ULN tumour cell death through activation of stress-response pathways250.
This hypothesis has not been investigated in humans, but BL may be
B high Not applicable Stage III–IV and LDH ≥2 × ULN
susceptible to chemoprevention using chloroquine or its improved
C Not applicable Leukaemic with >25% blasts and/or CNS versions. Strengthened malaria control has since led to considerable
disease
declines in malaria burden in many countries251. Demonstrating a con-
CNS, central nervous system; LDH, lactate dehydrogenase; LMB-FAB, mature B cell lymphoma,
comitant reduction in BL rates could provide ecological support to
French–American–British; NHL-BFM, non-Hodgkin lymphoma, Berlin–Frankfurt–Münster;
ULN, upper limit of normal.
the prevention of BL by strengthening malaria control programmes. The
WHO recommendation of the first malaria vaccine in 2021 is anticipated
to be another measure in controlling BL in LMIC. Concerted efforts to
has largely been replaced by the International Paediatric Non-Hodgkin develop an EBV vaccine will also be useful in preventing BL.
Lymphoma Staging System since 2015 (ref.245) (Box 2). HIV is an established risk factor for AIDS-related BL, and survival
In adults, risk stratification is based on disease-related factors has increased with access to HAART252, with similar outcomes expected
at diagnosis, including serum LDH levels, tumour bulk, leukaemic in HIV+ and HIV− patients with BL45. However, in the USA, the incidence
disease and CNS involvement, in addition to patient-related factors, of BL seemed to increase during the period 1996–2012 despite wide-
such as age, presence of comorbid conditions and performance status spread access to combination antiretroviral therapy252, suggesting that
(Table 3). Four factors that are most closely associated with prognosis simple reversal of immunosuppression without eliminating chronic
have been identified, including CNS involvement, serum LDH more HIV viraemia may not be sufficient to prevent BL78.
than three times the upper limit of normal, Eastern Cooperative Oncol-
ogy Group performance status ≥2 and age ≥40 years246. According to Management
the Burkitt Lymphoma International Prognostic Index (BL-IPI), patients The general treatment approach to BL is similar across all variants and
with two or more risk factors have a 3-year progression-free survival of is not modified by the presence of EBV or well-controlled HIV infec-
only 53% compared with 92% in patients with none of these risk factors. tion. A patient presenting with suspected BL should prompt initia-
Of note, in the context of low-intensity chemotherapy, patient age and tion of supportive care before confirmation of the diagnosis (Fig. 8).
comorbid conditions, such as HIV infection, are not prognostic, sug- The choice of first-line regimen should be risk-stratified and based
gesting that these prognostic factors are more closely associated with on the age of patient, disease-related risk factors, ability to tolerate
toxic effects of the treatment regimen than high-risk disease biology45. the intensity of treatment, and availability of adequate supportive
Regardless of the first-line regimen, patients with CNS involvement are care resources247,253,254. The main management differences between
at high risk of treatment failure and represent an unmet clinical need BL variants relate to supportive care and the dosing of methotrexate.
in the treatment of adult BL45,208. Patients with eBL may not have access to comprehensive medical care
Although risk stratification is an important component of treat- and patients with iBL require careful monitoring for opportunistic
ment approaches, it may not be uniformly applied in SSA as assessment infections and immune recovery after treatment.
of prognostic factors is challenging in this setting. The assumption
is that the clinical characteristics of eBL have remained unchanged First-line treatment
in Africa; however, subtle changes in these characteristics seem to Children and adolescents. Historically, two established regimens for the
have occurred in some instances over time, although confirmation is treatment of paediatric patients with BL have been used: the French LMB
still required247. Nevertheless, the proportion of children presenting regimen (malignant B cell lymphoma; later FAB, French–American–British
with a hepatic mass, malignant pleocytosis and advanced-stage BL is (LMB-FAB)) and the German BFM regimen (Berlin–Frankfurt–Muenster,
fairly high56, and creating implementable risk stratification criteria non-Hodgkin lymphoma (NHL-BFM)) (Supplementary Tables 1–3).

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Treatment consists, in part after a prophase, of two to six short but by mucositis, infections and haematological toxic effects232,255. All pro-
intense courses of chemotherapy based on corticosteroids, methotrex- tocols include several doses of intrathecal treatment for CNS prophy-
ate and cytarabine, cyclophosphamide and ifosfamide, vinca alkaloids, laxis or treatment. Current trials address the role of rituximab as a
anthracyclines, and etoposide and rituximab, in some protocols with window before standard chemotherapy256, (randomly) added to chem-
added intrathecal treatment48 (Fig. 8). These regimens have been otherapy for advanced BL232, or as a substitute for components of stand-
optimized in subsequent randomized clinical trials and have served ard chemotherapy in patients with low-risk or intermediate-risk BL
as the backbone for modified variants in several clinical trial groups (ongoing trial NCT03206671)257.
worldwide. Risk-stratified chemotherapy, refined by incorporation
of rituximab, has led to overall survival of 90% in children and adoles- Adults. The traditional treatment approach to BL in adults involves
cents with B cell lymphoma. Local treatment approaches, including short courses of dose-intense combination chemotherapy together
local radiotherapy and surgical resection, have no role in standard with rituximab. These regimens were developed in children and young
treatment. Surgical debulking or resection is unnecessary for control adults with acute leukaemia, and incorporate alternating courses
of disease and may delay the initiation of definitive chemotherapy. and rapid cycling of chemotherapy and hyperfractionation of cyclo-
First-line treatment consists of short courses with intense chemo- phosphamide, and include agents that specifically penetrate the
therapy using high-dose methotrexate and corticosteroids. The total CNS, including methotrexate and cytarabine258,259. These paediatric
number of courses and the intensity of the regimen is stratified accord- regimens induce a very high rate of remission but they are associated
ing to risk group (Table 3). Around half of the patients fall into the low- with considerable acute and long-term toxic effects that make them
risk groups (LMB-FAB A and B low, or NHL-BFM R1 and R2) and receive challenging to administer in patients with advanced age or comorbid
two to four courses of chemotherapy, usually accompanied by limited conditions. Indeed, the patient’s ability to tolerate the toxic effects
acute and long-term effects. The other half of the patients fall into the associated with paediatric regimens is an important determinant in
advanced disease risk groups, and receive a pre-phase with steroids and the choice of first-line regimen51,206,260,261 (Fig. 8). In the past decade,
five to six courses of chemotherapy with high-dose methotrexate a reduced-intensity approach using a pharmacodynamically dose-
and high-dose cytarabine. These regimens are commonly complicated adjusted chemotherapy regimen was shown to cure most patients
Approach to ‘possible’ Burkitt lymphoma Children and adolescents

• Rapid diagnosis
• Urgent staging with CSF evaluation Adults
• Tumour lysis prophylaxis
• Consider referral for enhanced supportive care
• Consider ‘pre-phase’ steroids
Low-risk disease High-risk disease Low-risk disease High-risk High-risk disease,

• LMB-FAB A • LMB-FAB B high • Stage I or II disease, low-risk high-risk for
Risk • LMB-FAB B low • LMB-FAB C • LDH normal for toxicity toxicity
assessment • NHL-BFM R1 • NHL-BFM R3 • No tumour bulk • Leukaemic • Older age
outcome • NHL-BFM R2 • NHL-BFM R4 • Good performance bone marrow • HIV positive
status involvement • Comorbid
• CNS conditions
involvement • Poor performance
Resource-restricted status
Resource-restricted
Paediatric
chemotherapy DA-EPOCH-R ×
Pre-phase + regimen + 6 cycles with IT
Risk-adapted 5–6 courses of rituximab MTX
frontline intensive or or
treatment chemotherapy + DA-EPOCH-R× Modified paediatric
COM/COMP 2–4 courses of CNS-directed COM/COMP DA-EPOCH-RR 6 cycles with IT regimen +
×2–4 cycles chemotherapy therapy ×6 cycles ×3 cycles MTX rituximab
Fig. 8 | Risk-adapted treatment approach to Burkitt lymphoma in children, In resource-restricted areas, lower-intensity regimens such as COM or COMP can
adolescents and adults. Rapid diagnosis is essential in all patients with be used. Adult patients with high-risk disease, including those with leukaemia
suspected Burkitt lymphoma. Supportive care measures, including those and/or CNS involvement, who can tolerate intensive chemotherapy can be
designed to prevent tumour lysis syndrome, should be implemented before treated with high dose-intensity regimens similar to those used in paediatric
diagnosis confirmation. Paediatric patients with low-risk disease can be treated protocols or DA-EPOCH-R for six cycles with intrathecal methotrexate. Most
with two to four courses of chemotherapy but, in resource-limited settings, older patients or those with comorbid conditions should be treated with
lower-intensity regimens may be used due to lack of supportive care resources. DA-EPOCH-R, but some patients may be able to tolerate paediatric regimens
In paediatric patients with high-risk disease treatment with a short course of with dose modifications. CNS, central nervous system; COM, cyclophosphamide,
steroids may be considered before chemotherapy followed by five or six courses vincristine, methotrexate; COMP, cyclophosphamide, vincristine, methotrexate,
of high dose-intensity chemotherapy along with CNS-directed therapy. Adult prednisone; CSF, cerebrospinal fluid; IT, intrathecal; LDH, lactate dehydrogenase;
patients with low-risk disease can be treated with three cycles of dose-adjusted LMB-FAB, mature B cell lymphoma, French–American–British; MTX, methotrexate;
etoposide, vincristine and doxorubicin with prednisone, cyclophosphamide NHL-BFM, non-Hodgkin lymphoma, Berlin–Frankfurt–Münster.
and two doses of rituximab (DA-EPOCH-RR) and no CNS prophylaxis.

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irrespective of age and comorbid conditions45,46. In adult patients and patients are at risk of early death from toxic effects. Common
with low-risk BL, dose-adjusted chemotherapy with rituximab is cura- treatment complications include sepsis, multisystem organ failure,
tive with as few as three cycles and without the use of CNS-directed tumour lysis syndrome and gastric perforation. Lower-intensity
prophylaxis45. Preliminary results from a randomized trial compar- approaches with dose-adjusted chemotherapy seem to have lower rates
ing dose-adjusted chemotherapy with high dose-intensity regimens of acute treatment-related toxic effects, but this observation needs
demonstrate no difference in survival but excessive toxic effects confirmation in a randomized trial.
with dose-intense approaches262. In patients without CNS involvement,
dose-adjusted chemotherapy is the preferred approach although some Relapsed or refractory disease
patients may still be treated with paediatric regimens with chemo- Survival is poor in children and adolescents with refractory or relapsed
therapy dose modifications. The optimal approach to the treatment disease269. Only two prospective clinical trials with cohorts of ~20 chil-
of adult patients with CNS disease remains undefined, but they should dren or adolescents with relapsed or refractory B cell NHL have been
be treated with either paediatric chemotherapy regimens with ritux- reported270,271, but none specifically in patients with BL. Retrospective
imab or dose-adjusted chemotherapy with intensified intrathecal series of national or international groups have confirmed poor survival
chemotherapy. in patients with relapsed and refractory BL and have shown an associa-
tion with intensity of first-line therapy, time to relapse, bone marrow
Considerations for resource-restricted regions. The approach to status, CNS status, sites of relapse and response to second-line ther-
front-line treatment in SSA is still primarily based on the successes of apy272–279. Salvage chemotherapy with courses that are recommended
pioneering trials from the 1970s with cyclophosphamide as the back- for the treatment of high-risk B cell NHL275,277 seem outdated for use in
bone agent263. In HICs, the prognosis in patients with BL has improved most patients with relapsed BL as more effective re-induction regimens
considerably with the introduction of short, intensive chemotherapeu- have become available. Frequently used re-induction regimens include
tic regimens. Most improvements and developments of new therapies rituximab, ifosfamide, carboplatin and etoposide (RICE) or rituximab,
for BL have focused on adult sBL globally. However, these advances vincristine, ifosfamide, carboplatin, idarubicin and dexamethasone
have not benefited most of the African population affected by BL, (RVICI), followed by consolidation with either autologous or alloge-
who are mainly children and adolescents. Nevertheless, the biggest neic haematopoietic stem cell transplantation (HSCT)270,271,278. Data on
hurdle to potential benefit from highly dose-intensive chemotherapy graft versus lymphoma effect which is restricted to allogeneic HSCT in
is the lack of supportive care resources required for optimal delivery patients with BL are limited280–284. Thus, allogeneic HSCT is not generally
of this treatment247,263. Low-dose therapy has been the mainstay of preferred over autologous HSCT in patients with BL, but has a role in
treatment since the initial trials in Africa for both patients with low- enabling dose-dense second-line treatment without haematological
risk BL and patients with high-risk BL in Africa, with the most common recovery in patients from whom haematological stem cells have not
combinations being cyclophosphamide, vincristine and doxorubicin been previously harvested for autologous HSCT. Each disease progres-
(COM), or cyclophosphamide, doxorubicin, vincristine and prednisone sion in BL is associated with additional chemoresistance transferred by
(COMP), or cyclophosphamide, vincristine and prednisone (COP)264 increasing genetic alterations and clonal evolution in the lymphoma
(Fig. 8). Several trials investigating high dose-intensity combinations, cells91,98. In addition, survival of patients who had received rituximab
such as cyclophosphamide, vincristine, doxorubicin and high-dose during first-line therapy is even worse than that of patients who had
methotrexate, alternating with ifosfamide, etoposide and cytarabine not received rituximab at the time of relapse232,278.
(CODOX-M/IVAC), have produced mixed results mainly due to lack of Further intensification of re-induction treatment with cytostatic
adequate supportive therapy263. The current approach for patients agents either by increasing their dose or by adding additional cytostatic
with high-risk BL in resource-limited areas is based on clinical risk drugs to current second-line treatment cannot solve the problem of
stratification (tumour stage, completeness of resection of abdominal resistant disease at relapse. To overcome these resistances, agents
disease and LDH level) especially where clinical information is acces- with new mechanisms of action are required. An interdisciplinary
sible263. Availability of supportive therapy and infrastructure is a key committee of experts have identified CAR T cells, T cell engagers,
determinant of treatment choice. Rituximab is often omitted from antibody–drug conjugates and immune checkpoint inhibitors as medi-
the treatment of BL in SSA as standard of care, mainly due to cost265. cal products with the greatest probability of being beneficial. Future
Data addressing prognosis in patients with HIV-associated BL living efforts and clinical trials will enable prioritization of these agents to
in Africa are currently sparse266. Both adults and children with HIV- increase survival of patients with relapsed and refractory BL269.
associated BL based in Africa are reported to have a good initial
response but poor overall treatment outcomes248. Both adults and pae- Quality of life
diatric patients with BL and HIV positivity in Africa are reported to have Traditional regimens for BL have relied on short durations of chemo-
a good initial response but poor overall treatment outcomes. This could therapy that reach very high dose levels and require inpatient adminis-
relate to more advanced disease in HIV-positive patients as well as poor tration. The safe use of these regimens requires a prolonged inpatient
tolerance of chemotherapy in the absence of HAART. hospital stay of 3–6 months and intensive supportive care resources,
including transfusion support and prophylactic antibiotics. Conse-
Acute treatment-related toxic effects. Paediatric regimens rely quently, these regimens have a substantial effect on the quality of life
on short durations of high dose-intensity chemotherapy to achieve of the patients experiencing these forms of acute treatment-related
very high peak levels of drug and are, therefore, associated with con- effects, as well as long-term and late adverse effects that emerge months
siderable myelosuppression247,267,268. As a result, all these regimens or even years after therapy. Lower-intensity regimens have been intro-
require administration in the inpatient setting to provide transfusion duced that have similar efficacy to traditional regimens derived from
support and parenteral nutrition owing to the resulting mucositis. paediatric protocols and are associated with fewer acute and long-term
Treatment-related complications often occur early during treatment toxic effects.

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In SSA, efforts to translate and culturally validate such tools in children

Box 3 are scarce. Studies comparing quality of life between patients with
different subtypes of BL are not readily available292.
Experience of paediatric Burkitt Patient experiences

Anecdotal patient experiences are a good starting point for obser-
lymphoma, from patient to vation of the quality of life effects of BL and its management. The
doctor experiences of three patients with BL are presented here (Boxes 3–5);
all three patients report considerable emotional effects, especially
during the treatment phase. Broader socioeconomic dimensions are
“Burkitt lymphoma survivor” sounds great and today, 15 years most prominent for a patient from a LIC in terms of delayed diagnosis
after diagnosis, it feels like that. Looking back evokes mixed and initiation of treatment. These are probably factors that immedi-
feelings. Of course, on the one hand, I remember terrible adverse ately influence quality of life in this setting. Apart from a mention of
effects, most of all the mucositis. On the other hand, I feel happy possible neurological sequelae, no major negative experiences are
and honoured to be alive. Each year, in addition to my birthday, described. Nevertheless, the successful completion of treatment and
I celebrate day of diagnosis and last day of chemotherapy. I do not being disease-free had the most lasting positive effects on quality of life
regret suffering from cancer, because this experience also formed in all three patients. The positive stories of their experience and their
me into the woman I am today. I am 26 years old and enjoy being determination to face life seem to override all negative aspects of
healthy. As assistant doctor, I work in paediatric oncology. The their experience293. The building of a strong personality, sense of pur-
first question I often get is “why?”. The answer is simple: I always pose, career path in science and advocacy is needed as part of workforce
wanted to become a doctor. Shortly after my diagnosis my plans to overcome the scourge. Finally, the joy of being alive with hope of
changed because I could not imagine ‘afflicting’ patients would building a family .
make me happy. With time and distance to therapy, my interest Small differences in effects on quality of life seem to exist
and fascination in oncology grew. I reconsidered: the doctors between well-resourced settings and low-resource settings. In well-
did not torture me, they rescued me. I wanted to become the resourced settings, adverse effects of treatment and effects on
same — not only a survivor. I started to study medicine and loved livelihood that occur early in the treatment phase matter most. In
it. In my doctoral thesis, I am writing about the clonal evolution low-resource settings, socioeconomic dimensions are most affected.
of Burkitt lymphoma and I have just published my first paper in However, in the long term, all three patients mention positive effects
Leukaemia. I like putting energy into research and management of on personality, and restored sense of value and purpose, irrespective
my patients. My own experience helps me to deal empathically with of the setting.
each patient. Nevertheless, lymphoma showed me what is most
important: to live and even more to enjoy each moment of life.
Box 4
Long-term effects
Outcomes in patients with BL have improved dramatically over the Experience of adult Burkitt
past decades. Although few late effects have been reported, they are
most likely related to chemotherapy, especially alkylating agents, and lymphoma in the USA
radiotherapy. Long-term experience in survivors of B cell NHL provides
some insights into late effects, such as increased mortality, subsequent The treatment overall was fairly easy, mainly due to all the support
malignant neoplasms, chronic health conditions, and limited physical I got from the staff. They did a great job of preparing me for any
and mental function285. In paediatric patients with B cell NHL including adverse effects that I might have while undergoing therapy, as
BL, most relevant long-term effects are an increased risk of second- well as remaining positive and reassuring that the outcome of the
ary malignancies, acute leukaemias and solid tumours, and increased treatment was going to be successful. That made any adverse
risks of death and neurocognitive and psychosocial effects286,287. So effects that I had much easier to tolerate. At the beginning, there
far, no comparable data are available for patients with BL, and long- were some rough days and I had to deal with nausea and some
term outcomes of disease, its treatment and survival, and quality of life neuropathy, but I never had any vomiting and I only had to spend
indicators are required. Objective data could be obtained by using the one night in the hospital when I needed help getting enough
Quality of Life Scale (QOLS). The QOLS was created for use in adults with sleep. Most of the adverse effects have all gone away, but I do have
chronic illness to correlate disease burden and health status, but has some issues with my nerves occasionally when it gets really hot
gained applicability in malignancies288. Most studies of quality of life or really cold. While I received treatment, I continued to work but
measurement in patients with haematological malignancies included at a reduced schedule. I would work 2 or 3 days each week during
adults only, and their long-term physical and psychosocial sequelae treatment for about four hours a day. It was really helpful that I could
have been well studied. Long-term survivors of childhood NHL tend to continue working around my treatment. Currently, I am 24 years
have a good overall health status289,290. Exploration of other domains, old, live independently and have a new dog that I am busy training.
such as patient social groups, community and culture, are areas of I have not tried to have children yet, but I look forward to that
current interest. For example, the PROMIS-25 and EORTC QLQ-C30 opportunity down the road.
instruments are commonly used in the USA and Europe, respectively291.

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genomic information and the resulting functions is important. Such

Box 5 studies might not only help identify molecular markers for diagnosis,
risk stratification and targeted therapy but also disclose the normal
B cell counterpart of BL cells.
Experience of paediatric Burkitt The common mucosal presentation, as well as epidemiological
evidence and some molecular features, point to a possible role
lymphoma in Africa of mucosal immunity, probably IgA-mediated, in the pathogenesis of
BL101,121–123,125–127,205,207. If this postulation can be confirmed, further inves-
As an 8-year-old, I was staying with my grandmother. One evening tigation of the role of the microbiome, including that of the gut, would
on my way back home after playing football, my left leg couldn’t be warranted. Well-known sex differences in microbiomes294–296 could
touch the ground. I spoke to my grandmother and it wasn’t taken determine part of the sex differences in the incidence of BL. Thus, future
seriously. Then, I developed a fever. For 3 weeks we treated the epidemiological, pathogenetic and clinical studies should take advan-
fever with no change and that is when my grandmother wrote to my tage of including comprehensive microbiome studies in their agendas.
mother who at the time was studying at Nsambya hospital. Several In turn, systematic determination of the antigen specificity of the BCR
tests were carried out at the Nsambya hospital and they found that expressed by BL cells in different areas of the world might help identify
my vertebrae were rotting, so an operation was required. After common antigens, and this search should extend beyond antigens
2 months of recovery from the operation, my left jaw started provided by human cells. All these efforts together and innovative
swelling so we had to head back to the hospital where they referred approaches in EBV and malaria research could lead to novel concepts
us to the cancer ward of Mulago hospital. Tests were carried out of BL prevention that, depending on the antigenic stimuli identified,
and they discovered that I had Burkitt lymphoma. I was then put on could range from newborn nutrition to oral immunization. Such studies
a trial drug. The biggest challenge that I found was the fact that, at should be integrated with the germline genomic risk scores to identify
the time, both adults and children all were in the same ward only persons at risk of BL and new methods for early detection based on
separated by cubicles. By the age of 5 and 6, I had lost both an liquid biopsies using ctDNA242 or innovative EBV tests, such as the LAMP
uncle and an aunt, which meant that it was mentally hard for me test243 to screen for early disease. In addition, a major effort has been
when I saw a body being carried out because I thought that I would made to develop an EBV vaccine297–301. In theory, such an EBV prophy-
be next. It was also expensive to buy supportive drugs for treatment lactic vaccine combining, for example EBV gH/gL, gB and gp350, should
but, luckily, family played a critical part in helping my mum meet be a promising approach to preventing EBV infection and, therefore,
the expenses for treatment. In 2000, I was declared cancer free and EBV-associated diseases including BL302.
embarked on giving back to fight cancer after my university time. Finally, treatment approaches might benefit from characteriza-
Currently, I am an advocate for cancer in children and working with tion of the BL molecular universe, although the focus seems to remain
Uganda Child Cancer Foundation as team lead. on MYC. Although targeting MYC at the protein level has been dif-
ficult303–305, other genomic approaches, such as epigenome or epi-
genome editing, might open new avenues. Thus, although we know
some of the main drivers of BL, including MYC, EBV and P. falciparum,
Outlook further characterization of BL aetiopathogenesis will enable improved
BL has been a frontrunner in many aspects of cancer research, includ- prevention, management and outcomes of this disease.
ing epidemiology, oncogenic viruses, chromosomal aberrations and
oncogene identification. In addition to the high BL cure rates in the Published online: xx xx xxxx
paediatric population, this history of extraordinary success in research
might give the impression that all major questions in BL have been References
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lymphoma and mature acute leukemia: a report from the French LMB study. Pediatr. Blood The studies of the authors on Burkitt lymphoma have been supported by the German Ministry
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(2020). by the BMBF-funded Heidelberg Center for Human Bioinformatics (HD-HuB) within the
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Cancers (Basel) 13, 2075 (2021). Cancer Institute, National Institutes of Health, Department of Health and Human Services
280. Grigg, A. & Ritchie, D. Graft-versus-lymphoma effects: clinical review, policy proposals, contracts HHSN261201100063C and HHSN261201100007I. C.L. is supported by postdoctoral
and immunobiology. Biol. Blood Marrow Transplant. 10, 579–590 (2004). Beatriu de Pinós from Secretaria d’Universitats i Recerca del Departament d’Empresa i
281. Petersen, S. L. Alloreactivity as therapeutic principle in the treatment of hematologic Coneixement de la Generalitat de Catalunya and by the Marie Sklodowska-Curie COFUND
malignancies. Studies of clinical and immunologic aspects of allogeneic hematopoietic program from H2020 (2018-BP-00055). B.B. and the NHL-BFM study group are supported by
cell transplantation with nonmyeloablative conditioning. Dan. Med. Bull. 54, 112–139 the German Cancer Aid and the Deutsche Kinderkrebsstiftung. The authors thank J. Ferlay
(2007). of the International Agency for Research on Cancer for assisting with access to data files. The
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283. Giulino-Roth, L. et al. Ten-year follow-up of pediatric patients with non-Hodgkin giving them their BL data from Africa for 2018. The authors thank M. Hyer, E. Carver and J.
lymphoma treated with allogeneic or autologous stem cell transplantation. Pediatr. Lyman of Information Management Systems (Rockville, MD) for preparing the files for analysis
Blood Cancer 60, 2018–2024 (2013). and drawing the maps.

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Author contributions Peer review information Nature Reviews Disease Primers thanks A. Gloghini, M. A. Piris, L.
Introduction (R.S. and C.L.); Epidemiology (S.M.M. and M.D.O.); Mechanisms/pathophysiology Sterlin Young and the other, anonymous, reviewer(s) for their contribution to the peer review
(C.L. and R.R.); Diagnosis, screening and prevention (J.K.C.C., L.L. and S.M.M.); Management of this work.
(B.B., J.O. and M.R.); Quality of life (B.B., J.O. and M.R.); Outlook (R.S. and C.L.); Overview of the
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This is a U.S. Government work and not under copyright protection in the US; foreign copyright
Correspondence should be addressed to Reiner Siebert. protection may apply 2022
1
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. 2Institute of Human Genetics, Ulm University and Ulm University
Medical Center, Ulm, Germany. 3Non-Hodgkin’s Lymphoma Berlin-Frankfurt-Münster (NHL-BFM) Study Center and Paediatric Hematology, Oncology
and BMT, University Hospital Muenster, Muenster, Germany. 4Department of Pathology, Queen Elizabeth Hospital, Hong Kong SAR, China. 5Section of
Pathology, Department of Medical Biotechnology, University of Siena, Siena, Italy. 6Division of Cancer Epidemiology and Genetics, National Cancer
Institute, National Institutes of Health, US Department of Health and Human Services, Bethesda, MD, USA. 7EMBLEM Study, St. Mary’s Hospital, Lacor,
Gulu, Uganda. 8Uganda Cancer Institute, Kampala, Uganda. 9Department of Immunology and Microbiology, University of Colorado School of Medicine,
Aurora, CO, USA. 10Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda,
MD, USA.

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Burkitt Lymphoma: Disease Primers

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Burkitt lymphoma (BL) is an aggressive form of B cell lymphoma that Introduction

confounded by the frequency of EBV positivity. Subtyping into EBV+

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0.02 Fig. 2 | Multimodal age-specific incidence rates of Burkitt

Mechanisms/pathophysiology subtype of B lymphoblastic leukaemia/lymphoma characterized by

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P. falciparum Epigenomic or genomic alterations sBL/EBV –

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IGH regions and B cell Enhancer Constant CSR or SHM

128.749 mb 128.750 mb 128.753 mb

MBI MBII Myc-amino terminal region HLH Myc-LZ

Phosphorylation Mutation Acetylation

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a Tumour localization and jaw manifestation b Aﬀected body parts in BL patients

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Genes EBV+ EBV–

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Table 2 | Differential diagnosis of Burkitt lymphoma

Diagnosis Morphology Immunophenotype Genomic features

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International Paediatric Non-Hodgkin Lymphoma Staging System245

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Approach to ‘possible’ Burkitt lymphoma Children and adolescents

Low-risk disease High-risk disease Low-risk disease High-risk High-risk disease,

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In SSA, efforts to translate and culturally validate such tools in children

Experience of paediatric Burkitt Patient experiences

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genomic information and the resulting functions is important. Such

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