Burkitt lymphoma (BL) may present in three distinct forms: endemic (African), sporadic, and immunodeficiency-associated.¹ The endemic form (eBL) is the most common pediatric tumor in sub-Saharan Africa 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 (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 pathologist named George O’Connor who, in 1960, concluded it was a lymphoma.⁴ In 1964, while studying BL samples by electron microscopy, Sir Michael Anthony Epstein, Yvonne Barr, and Bert Achong discovered EBV when they recognized viral particles were present in tumor cells,⁵ thus helping to launch the nascent field of tumor virology. Further studies of BL over many years led to epidemiologic associations with both EBV and malaria in Africa.^6,7 Tumors of a similar histologic appearance were subsequently identified in the United States, Middle East, and elsewhere (i.e., nonendemic regions) and termed sporadic BL. Sporadic cases were found to occur in older individuals, typically presented in the abdomen rather than the orofacial region, and were infrequently associated with EBV.⁸ In 1985, a third class of BL was identified in immunosuppressed patients, most commonly as a result of infection with HIV.⁹ BL was referred to as “small noncleaved cell lymphoma” according to the Kiel classification system proposed by Karl Lennert in 1977, but this designation is no longer used. In the mid-1970s, recurrent chromosomal translocations involving chromosomes 8 and 14 were described in BL,^10,11 paving the way for the identification of MYC as an important human oncogene when it was shown to be the translocation partner involved with immunoglobulin (Ig) heavy-chain and light-chain translocations.^12,13 Evolution in the diagnosis and treatment of BL has occurred over the past few decades. High cure rates are now achieved among pediatric and young adult populations in healthcare settings capable of delivering intensive combined chemotherapy regimens, both with and without B-cell–directed monoclonal antibody therapy (i.e., rituximab). In 2006, a “molecular signature” for BL was developed from gene-expression profiling (GEP) data,¹⁴ and in 2012 the first whole-genome sequences were published.¹⁵ Despite these scientific and technologic advances in our understanding of this historically 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.

The endemic form of BL is found in equatorial Africa (as well as Brazil, 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) in all age groups.¹⁶ Infection by EBV is found in nearly 100 percent of patients with eBL, and higher titers are linked to increase risk of eBL.⁷ Although not as close, there is an epidemiologic association with malaria,¹⁷ in addition to other environmental factors.¹⁶ Sporadic BL, defined as cases outside of endemic African regions, accounts for 1 to 2 percent of NHL, is higher in males than in females, and has a median age of 30 years. In the United States, BL exhibits a primarily a bimodal age distribution, with at least two incidence peaks of approximately 10 and 75 years of age (median age of approximately 30 years), as compared to other NHLs, which generally increase from childhood through adulthood.¹⁸ Immunodeficiency-related BL increased in incidence during the AIDS epidemic; however, with improved antiretroviral therapy, the incidence has decreased in the United States and countries with access to effective therapy for HIV.

MOLECULAR GENETICS

Myc Overexpression and Gene-Expression Profiling

The unifying feature of all three types of BL is activation of the MYC gene via an Ig translocation leading to high levels of MYC protein, which activates transcription of a variety of genes involved in cell growth. Translocations are thought to occur via double-stranded DNA breaks that occur during normal class-switch reaction and somatic hypermutation in mature B-cell development, which, in turn, depends on activation-induced cytidine deaminase.¹⁹ In addition, somatic point mutation of growth-regulatory genes (such as MYC) which are also caused by activation-induced cytidine deaminase may also play an important role.²⁰ The dominant role of MYC activation in BL pathogenesis is emphasized by the results of multiple independent gene-expression studies. GEP analysis is capable of distinguishing BL from diffuse large B-cell lymphoma (DLBCL), and this finding is predicated on identifying cases with highly expressed target genes of MYC, as well as markers of germinal center B cells, and lower expression of target genes of the nuclear factor (NF)-κB pathway.²¹ In a separate study, a core group of eight cases of pediatric BL (fulfilling World Health Organization [WHO] criteria) were used to generate a molecular signature, and tumors that matched this expression pattern were termed “molecular BL” (mBL).²² Additional characteristics of this group included lower cytogenetic complexity (including near total absence of translocations involving BCL6 and/or IGH-BCL2) and the presence of MYC translocations involving Ig genes, rather than non-Ig partners, features which, again, distinguish BL from DLBCLs and other high-grade NHLs.

Next Generation Sequencing and ID3/TCF3 Mutations

Advanced sequencing analysis at the level of the whole genome, exome, and transcriptome has provided a more complete view of the spectrum of somatic mutations that occur in Burkitt lymphomagenesis and identified several recurring and previously unappreciated determinants of molecular pathogenesis. In addition to mutations in MYC, as many as 70 additional genes were found to be recurrently mutated in BL.²³ Mutations in ID3, TCF3, and CCND3 are among the most common seen in multiple independent studies.^23,24,25 ID3 is a member of the inhibitor of DNA binding (ID) protein family, and it is a negative regulator of transcription factor TCF3. The presence of biallelic inactivating mutations and/or deletions of ID3 suggests it serves as a tumor suppressor. TCF3, conversely, was shown to be essential for BL cell viability, and the presence of monoallelic mutations that result in substitutions among highly conserved amino acid residues suggests gain of function mutations in TCF3 may result. Overall, the mutational landscape for BL differs significantly from DLBCL. For example, relatively few ID3 mutations were found among other B-cell lymphomas, even in those with Ig-MYC translocations.²⁴ ID3 and/or TCF3 mutations were also common among all three epidemiologic subtypes of BL. CCND3 mutations were rare in eBL, but abundant in the other two subtypes.²⁵

ALTERED IMMUNE STATUS AND INFECTION

HIV-Associated and Endemic Disease

Underlying immune alteration likely plays a role in at least two epidemiologic subtypes of BL (endemic and immunodeficiency-associated), although teasing apart the precise role of immune function in BL pathogenesis has proven challenging. Immunodeficiency-associated BL occurs predominantly in HIV-positive patients. Its occurrence does not directly correlate with CD4+ T cell status, and BL only rarely occurs with other forms of immunosuppression. BL is different from other EBV-associated lymphoproliferative disorders that occur with advanced HIV, yet is otherwise comparable to EBV-positive posttransplantation lymphoproliferative disorders (PTLDs) that arise in severely immunosuppressed solid-organ allograft recipients.²⁶ Rather, the clinical course and pathogenesis of immunodeficiency-associated BL more closely parallels that of sporadic BL in the immunologically intact patient. In eBL, the underlying immune alteration is probably multifactorial, may be influenced by chronic malnutrition, and may stem from chronic immune activation to various stimuli including holoendemic malaria, EBV, and possibly other environmental agents.^27,28

Epstein-Barr Virus and Malaria

The clear epidemiologic and immunologic link to malaria and EBV-infection has led several investigators to characterize eBL as a “polymicrobial” disease.²⁹ Numerous biological mechanisms have been proposed to explain the etiologic link between eBL and each infection. For example, EBV may play a role prior to the MYC translocation event, simultaneously inducing proliferation (via Epstein-Barr nuclear antigen [EBNA]-2) and inhibiting apoptosis (via EBNA3A- and EBNA3C-induced epigenetic silencing of proapoptotic protein Bim [Bcl-2-interacting mediator of cell death], a key defender of MYC-induced tumorigenesis).³⁰ Alternatively, inhibition of apoptosis may be sustained in BL tumor cells as a result of EBNA-1 expression (the only latency-associated viral protein consistently expressed in BL), noncoding viral RNAs (including Epstein-Barr virus-encoded RNA [EBER] and microRNAs), or possibly as a result of epigenetic reprogramming.³¹ Precise mechanisms for the role of malaria in eBL are less clear, but it has been shown that Plasmodium species can stimulate B cells in a polyclonal fashion,^32,33 the effects of which may modulate EBV transcriptional programs within infected B cells.³⁴ Malaria infection also modulates virus-specific T-cell responses to EBV.³⁵ By simultaneously expanding EBV-infected B cells, which may dysregulate the activation induced cytidine deaminase function and thereby increase the chance of acquiring a MYC translocation, while at the same time perturbing the host’s antiviral immune response, malaria infection may serve as a critical facilitator that brings together these otherwise disparate pathologic events in a manner that predisposes specific populations to developing eBL.³⁶ Overall, these findings suggest that BL emerges in the setting of chronically altered but fundamentally intact immune system.

The endemic (African) form often presents as a jaw or facial bone tumor. It may spread to extranodal sites, especially to the marrow and meninges. Almost all cases are EBV-positive. The nonendemic or American form presents as an abdominal mass in approximately 65 percent of cases, often with ascites. Extranodal sites, such as the kidneys, gonads, breast, marrow, and CNS, may be involved. Involvement of the marrow and CNS is much more common in the nonendemic form. Patients with more than 25 percent marrow involvement with malignant cells often are referred to as having Burkitt cell leukemia (see Blood and Marrow below). In addition, in contrast to the endemic form, only 15 percent of the nonendemic cases are EBV-positive.

Immunodeficiency-related cases often involve the lymph nodes and are associated with EBV in 30 percent of the cases. Staging using the system modified for childhood BL (Murphy staging system, Table 102–1) may be used rather than the Ann Arbor system, given that BL is largely an extranodal lymphoma.

BLOOD AND MARROW

Patients with bulky disease may have Burkitt cells in marrow and blood with accompanying suppression of normal blood counts. Characteristic pathologic features of BL on smear preparation are intermediate-size cells with round nuclei, multiple nucleoli, strongly basophilic cytoplasm (a consequence of the abundant polyribosomes), and the presence of lipid-filled cytoplasmic vesicles, some of which overlie the nucleus (Fig. 102–1

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