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1672 Part XI: Malignant Lymphoid Diseases Chapter 102: Burkitt Lymphoma 1673

ETIOLOGY AND PATHOGENESIS and BL only rarely occurs with other forms of immunosuppression.
BL is different from other EBV-associated lymphoproliferative dis-
MOLECULAR GENETICS orders that occur with advanced HIV, yet is otherwise comparable
to EBV-positive posttransplantation lymphoproliferative disorders
Myc Overexpression and Gene-Expression Profiling (PTLDs) that arise in severely immunosuppressed solid-organ
The unifying feature of all three types of BL is activation of the MYC allograft recipients. Rather, the clinical course and pathogenesis of
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gene via an Ig translocation leading to high levels of MYC protein, immunodeficiency-associated BL more closely parallels that of spo-
which activates transcription of a variety of genes involved in cell radic BL in the immunologically intact patient. In eBL, the underly-
growth. Translocations are thought to occur via double-stranded DNA ing immune alteration is probably multifactorial, may be influenced
breaks that occur during normal class-switch reaction and somatic by chronic malnutrition, and may stem from chronic immune acti-
hypermutation in mature B-cell development, which, in turn, depends vation to various stimuli including holoendemic malaria, EBV, and
on activation-induced cytidine deaminase. In addition, somatic point possibly other environmental agents. 27,28
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mutation of growth-regulatory genes (such as MYC) which are also
caused by activation-induced cytidine deaminase may also play an
important role. The dominant role of MYC activation in BL patho- Epstein-Barr Virus and Malaria
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genesis is emphasized by the results of multiple independent gene- The clear epidemiologic and immunologic link to malaria and
expression studies. GEP analysis is capable of distinguishing BL from EBV-infection has led several investigators to characterize eBL as a
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diffuse large B-cell lymphoma (DLBCL), and this finding is predicated “polymicrobial” disease. Numerous biological mechanisms have
on identifying cases with highly expressed target genes of MYC, as well been proposed to explain the etiologic link between eBL and each
as markers of germinal center B cells, and lower expression of target infection. For example, EBV may play a role prior to the MYC translo-
genes of the nuclear factor (NF)-κB pathway. In a separate study, a cation event, simultaneously inducing proliferation (via Epstein-Barr
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core group of eight cases of pediatric BL (fulfilling World Health Orga- nuclear antigen [EBNA]-2) and inhibiting apoptosis (via EBNA3A- and
nization [WHO] criteria) were used to generate a molecular signature, EBNA3C-induced epigenetic silencing of proapoptotic protein Bim
and tumors that matched this expression pattern were termed “molecu- [Bcl-2-interacting mediator of cell death], a key defender of MYC-in-
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lar BL” (mBL). Additional characteristics of this group included lower duced tumorigenesis). Alternatively, inhibition of apoptosis may be
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cytogenetic complexity (including near total absence of translocations sustained in BL tumor cells as a result of EBNA-1 expression (the only
involving BCL6 and/or IGH-BCL2) and the presence of MYC translo- latency-associated viral protein consistently expressed in BL), noncod-
cations involving Ig genes, rather than non-Ig partners, features which, ing viral RNAs (including Epstein-Barr virus-encoded RNA [EBER]
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again, distinguish BL from DLBCLs and other high-grade NHLs. and microRNAs), or possibly as a result of epigenetic reprogramming.
Precise mechanisms for the role of malaria in eBL are less clear, but
Next Generation Sequencing and ID3/TCF3 Mutations it has been shown that Plasmodium species can stimulate B cells in a
Advanced sequencing analysis at the level of the whole genome, polyclonal fashion, 32,33 the effects of which may modulate EBV tran-
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exome, and transcriptome has provided a more complete view of the scriptional programs within infected B cells. Malaria infection also
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spectrum of somatic mutations that occur in Burkitt lymphomagen- modulates virus-specific T-cell responses to EBV. By simultaneously
esis and identified several recurring and previously unappreciated expanding EBV-infected B cells, which may dysregulate the activation
determinants of molecular pathogenesis. In addition to mutations in induced cytidine deaminase function and thereby increase the chance
MYC, as many as 70 additional genes were found to be recurrently of acquiring a MYC translocation, while at the same time perturbing
mutated in BL. Mutations in ID3, TCF3, and CCND3 are among the host’s antiviral immune response, malaria infection may serve as a
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the most common seen in multiple independent studies. 23–25 ID3 is critical facilitator that brings together these otherwise disparate patho-
a member of the inhibitor of DNA binding (ID) protein family, and logic events in a manner that predisposes specific populations to devel-
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it is a negative regulator of transcription factor TCF3. The presence oping eBL. Overall, these findings suggest that BL emerges in the
of biallelic inactivating mutations and/or deletions of ID3 suggests setting of chronically altered but fundamentally intact immune system.
it serves as a tumor suppressor. TCF3, conversely, was shown to be
essential for BL cell viability, and the presence of monoallelic muta-
tions that result in substitutions among highly conserved amino acid CLINICAL FEATURES
residues suggests gain of function mutations in TCF3 may result.
Overall, the mutational landscape for BL differs significantly from The endemic (African) form often presents as a jaw or facial bone tumor.
DLBCL. For example, relatively few ID3 mutations were found It may spread to extranodal sites, especially to the marrow and menin-
among other B-cell lymphomas, even in those with Ig-MYC translo- ges. Almost all cases are EBV-positive. The nonendemic or American
cations. ID3 and/or TCF3 mutations were also common among all form presents as an abdominal mass in approximately 65 percent of
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three epidemiologic subtypes of BL. CCND3 mutations were rare in cases, often with ascites. Extranodal sites, such as the kidneys, gonads,
eBL, but abundant in the other two subtypes. 25 breast, marrow, and CNS, may be involved. Involvement of the marrow
and CNS is much more common in the nonendemic form. Patients with
ALTERED IMMUNE STATUS AND INFECTION more than 25 percent marrow involvement with malignant cells often
are referred to as having Burkitt cell leukemia (see Blood and Marrow
HIV-Associated and Endemic Disease below). In addition, in contrast to the endemic form, only 15 percent of
Underlying immune alteration likely plays a role in at least two the nonendemic cases are EBV-positive.
epidemiologic subtypes of BL (endemic and immunodeficien- Immunodeficiency-related cases often involve the lymph nodes
cy-associated), although teasing apart the precise role of immune and are associated with EBV in 30 percent of the cases. Staging using
function in BL pathogenesis has proven challenging. Immunodefi- the system modified for childhood BL (Murphy staging system,
ciency-associated BL occurs predominantly in HIV-positive patients. Table 102–1) may be used rather than the Ann Arbor system, given that BL
Its occurrence does not directly correlate with CD4+ T cell status, is largely an extranodal lymphoma.

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