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CHAPTER 102 and other regions of the world where malaria is endemic. It typically
presents in the jaw or maxilla, and is associated with Epstein-Barr virus
BURKITT LYMPHOMA (EBV) infection at an early age. Although there are reports dating to
as early as 1910, it was Denis Burkitt who is credited with describing
this malignancy in 1958 as a common tumor in children of Uganda.
2,3
Originally thought by Burkitt to be a sarcoma of the jaw, it was a pathol-
Andrew G. Evans and Jonathan W. Friedberg ogist named George O’Connor who, in 1960, concluded it was a lym-
phoma. In 1964, while studying BL samples by electron microscopy,
4
Sir Michael Anthony Epstein, Yvonne Barr, and Bert Achong discov-
SUMMARY ered EBV when they recognized viral particles were present in tumor
5
cells, thus helping to launch the nascent field of tumor virology. Fur-
Burkitt lymphoma is one of the highly aggressive B-cell lymphomas. It was the ther studies of BL over many years led to epidemiologic associations
with both EBV and malaria in Africa. Tumors of a similar histologic
6,7
first tumor to be etiologically associated with (1) a virus, specifically Epstein- appearance were subsequently identified in the United States, Middle
Barr virus, (2) a specific translocation involving the MYC oncogene, and (3) one East, and elsewhere (i.e., nonendemic regions) and termed sporadic
of the first cancers shown to be curable by chemotherapy alone. It presents BL. Sporadic cases were found to occur in older individuals, typically
in three clinically distinct forms: endemic, sporadic, and immunodefi- presented in the abdomen rather than the orofacial region, and were
ciency-associated. Burkitt lymphoma is an uncommon form of lymphoma infrequently associated with EBV. In 1985, a third class of BL was iden-
8
in adults, with an incidence of approximately 1200 patients per year in the tified in immunosuppressed patients, most commonly as a result of
United States. Over the last decade, the definition of Burkitt lymphoma has infection with HIV. BL was referred to as “small noncleaved cell lym-
9
been refined, largely as a consequence of improvements in immunohis- phoma” according to the Kiel classification system proposed by Karl
tochemical, cytogenetic, and molecular diagnostic techniques. Transcriptional Lennert in 1977, but this designation is no longer used. In the mid-
profiling has more clearly defined Burkitt lymphoma at the molecular level, 1970s, recurrent chromosomal translocations involving chromosomes
10,11
while whole-genome sequencing has expanded our understanding of the 8 and 14 were described in BL, paving the way for the identification
of MYC as an important human oncogene when it was shown to be the
mutational landscape that underlies this disease. Despite these refinements in translocation partner involved with immunoglobulin (Ig) heavy-chain
diagnostic criteria, the differential diagnosis includes several high-grade lym- and light-chain translocations. 12,13 Evolution in the diagnosis and treat-
phomas, including a group of patients with a diagnosis defined by the World ment of BL has occurred over the past few decades. High cure rates are
Health Organization as intermediate between Burkitt lymphoma and diffuse now achieved among pediatric and young adult populations in health-
large B-cell lymphoma. Burkitt lymphoma is a highly curable malignancy care settings capable of delivering intensive combined chemotherapy
in the modern therapeutic era. The majority of younger patients are cured regimens, both with and without B-cell–directed monoclonal antibody
with intensive chemotherapeutic regimens, and increasing efficacy has been therapy (i.e., rituximab). In 2006, a “molecular signature” for BL was
14
demonstrated in older patients with reduced intensity treatments. Remaining developed from gene-expression profiling (GEP) data, and in 2012 the
15
challenges include the optimal management of older patients, the develop- first whole-genome sequences were published. Despite these scien-
ment of therapy for patients with relapsed or refractory disease, and the trans- tific and technologic advances in our understanding of this historically
lation of gains made in treatment to the management of endemic disease. important disease, translation of this information into specific targeted
therapeutics for BL (i.e., inhibitors of known dysregulated pathways or
mutated gene products) has yet to be realized.

DEFINITION AND HISTORY EPIDEMIOLOGY

Burkitt lymphoma (BL) may present in three distinct forms: endemic
(African), sporadic, and immunodeficiency-associated. The endemic The endemic form of BL is found in equatorial Africa (as well as Brazil,
1
form (eBL) is the most common pediatric tumor in sub-Saharan Africa Papua New Guinea, and other malaria-endemic regions), with a peak
age incidence at 4 to 7 years, and is nearly twice as frequent in boys as
in girls. In Africa it accounts for 20 percent of cancers in newborns to
14-year-olds, and for the majority of non-Hodgkin lymphomas (NHLs)
16
Acronyms and Abbreviations: B-ALL, acute B-cell lymphoblastic leukemia; BCL-U, in all age groups. Infection by EBV is found in nearly 100 percent of
7
B-cell lymphoma–unclassifiable; BL, Burkitt lymphoma; B-LBL, B-cell lymphoblastic patients with eBL, and higher titers are linked to increase risk of eBL.
lymphoma; CODOX-M/IVAC, cyclophosphamide, doxorubicin, vincristine, methotrex- Although not as close, there is an epidemiologic association with
16
17
ate, ifosfamide, etoposide and high-dose cytarabine, with intrathecal cytarabine malaria, in addition to other environmental factors. Sporadic BL,
and methotrexate; DHL, double-hit lymphoma; DLBCL, diffuse large B-cell lym- defined as cases outside of endemic African regions, accounts for 1 to
phoma; EBER, Epstein-Barr virus-encoded RNA; eBL, endemic Burkitt lymphoma; 2 percent of NHL, is higher in males than in females, and has a median
EBNA, Epstein-Barr nuclear antigen; EBV, Epstein-Barr virus; FISH, fluorescence in age of 30 years. In the United States, BL exhibits a primarily a bimodal
situ hybridization; GEP, gene-expression profiling; HAART, highly active antiretroviral age distribution, with at least two incidence peaks of approximately 10
therapy; hyper-CVAD, fractionated cyclophosphamide, vincristine, doxorubicin, and 75 years of age (median age of approximately 30 years), as com-
dexamethasone; Ig, immunoglobulin; LDH, lactate dehydrogenase; NHL, non-Hodgkin pared to other NHLs, which generally increase from childhood through
18
lymphoma; PTLD, posttransplantation lymphoproliferative disease; R-EPOCH, adulthood. Immunodeficiency-related BL increased in incidence dur-
etoposide, vincristine and doxorubicin, with bolus rituximab, cyclophosphamide and ing the AIDS epidemic; however, with improved antiretroviral therapy,
steroids; WHO, World Health Organization. the incidence has decreased in the United States and countries with
access to effective therapy for HIV.

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