INTRODUCTION — Burkitt lymphoma (BL) is a highly aggressive B cell non-Hodgkin lymphoma characterized by the translocation and deregulation of the MYC gene on chromosome 8. Three distinct clinical forms of BL are recognized: endemic (African), sporadic (non-endemic), and immunodeficiency-associated. Although they are histologically identical and have similar clinical behavior, there are differences in epidemiology, clinical presentation, and genetic features between the three forms as described below.
BL and Burkitt leukemia are considered different manifestations of the same disease in the 2016 World Health Organization (WHO) classification of hematologic malignancies. The current WHO classification also proposes three aggressive B cell lymphoma entities that resemble BL: "Burkitt-like lymphoma with 11q aberration"; "High-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement," and "High-grade B cell lymphoma, not otherwise specified" . Some tumors in this group were previously classified as "Burkitt-like" lymphoma . (See "Classification of hematopoietic neoplasms".)
The epidemiology, clinical features, pathology, and diagnosis of BL will be reviewed here. The pathobiology and treatment of BL are discussed separately, as is a general approach to the diagnosis, staging, and prognosis of the lymphomas. (See "Pathobiology of Burkitt lymphoma" and "Treatment of Burkitt leukemia/lymphoma in adults" and "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Pretreatment evaluation and staging of non-Hodgkin lymphomas".)
EPIDEMIOLOGY — The exact worldwide incidence of BL is not known, as collection of these types of epidemiologic data is limited by a lack of resources that are needed for case ascertainment and accurate diagnosis in the developing countries that have the highest apparent incidence (eg, equatorial Africa) . For epidemiologic and diagnostic purposes, cases of BL are generally divided into three distinct clinical forms: endemic (African), sporadic (non-endemic), and immunodeficiency-associated. The endemic and sporadic clinical variants of BL differ geographically.
●Endemic – The endemic variant is found in equatorial Africa and New Guinea. The incidence of BL in Africa is approximately 50-fold higher than that seen in the United States . BL accounts for 30 to 50 percent of all childhood cancer in equatorial Africa with an estimated incidence of 3 to 6 cases per 100,000 children per year . The peak incidence occurs in children age four to seven years, and the male:female ratio is approximately 2:1.
●Sporadic – The sporadic variant is seen in the United States and Western Europe. BL comprises 30 percent of pediatric lymphomas and <1 percent of adult non-Hodgkin lymphomas in the United States . This translates into an estimated incidence of approximately three cases per million persons per year in both children and adults. In Europe, the incidence is approximately 2.2 cases per million persons per year . The peak incidence occurs in children age 11 years. Among adults, sporadic BL is typically seen in patients less than 35 years of age, with a median age at diagnosis of 30 years [2,7]. Sporadic BL is more common among White Americans compared with African Americans or Asian Americans . Data suggest that it may be substantially more common in some areas of Central America (eg, Guatemala) . In all groups, the majority of patients are male with a 3 or 4:1 male:female ratio [5,9,10]. (See "Clinical manifestations and treatment of Epstein-Barr virus infection".)
●Immunodeficiency-associated – The immunodeficiency-associated variant is primarily seen in persons with human immunodeficiency virus (HIV) infection and less commonly in patients with other causes of immunodeficiency (eg, recipients of organ transplants). In HIV-positive patients, BL typically affects those with a relatively high CD4 count (eg, >200 cells/microL) and no opportunistic infections . In comparison to the majority of other HIV-associated lymphomas, the rate of BL in the HIV-positive population has not decreased with the advent of potent antiretroviral therapy (ART). This is presented in more detail separately. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology".)
PATHOGENESIS — BL is derived from germinal center B cells. The development of BL is dependent on the constitutive expression of the MYC proto-oncogene located at chromosome 8q24, which encodes the MYC protein transcription factor. This transcription factor modulates the expression of target genes that regulate many cell processes including cell growth and division, immortalization, Warburg metabolism, and cell death by apoptosis. (See "Pathobiology of Burkitt lymphoma".)
The MYC chromosomal translocation that characterizes BL has the molecular signature of a mistake that occurs during the attempted diversification of immunoglobulin gene segments in B cells. Chromosomal translocations involve non-homologous joining of the ends of DNA breaks that occur in at least two different places in the genome simultaneously. Cloning and sequencing of the genomic sequences where MYC is joined to Ig loci in BL clearly indicate that the DNA breaks in the involved Ig genes occur through processes that are normal for B cells, namely either attempted Ig V(D)J recombination or Ig class switch recombination. Some papers suggest that DNA breaks near MYC result from the recruitment of activation-induced cytosine deaminase (AID), an enzyme required for immunoglobulin class switching, to enhancer sites adjacent to the MYC gene body that are characterized by overlapping sense and antisense (convergent) transcription [12,13]. It is not known how the DNA breaks in MYC come to be spatially close to DNA breaks in the Ig locus in the interphase nucleus, which is a prerequisite for these DNA ends to be joined to form MYC translocations. The resulting dysregulation of MYC is complemented by additional mutations in oncogenes and tumor suppressors (described below); the basis for the genesis of these mutations is largely unknown.
Chronic Epstein-Barr virus (EBV) infection appears to play a role in virtually all cases of endemic (African) BL and a minority of sporadic and immunodeficiency-associated BL. Work in mouse models suggests that malaria selectively induces B cell lymphomas with chromosomal translocations involving MYC by causing protracted AID expression in germinal center B cells . (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology" and "HIV-related lymphomas: Clinical manifestations and diagnosis".)
CLINICAL FEATURES — Patients with BL present with rapidly growing tumor masses and often have evidence of spontaneous tumor lysis with a very high serum lactate dehydrogenase (LDH) concentration and elevated uric acid levels. The tumor doubling time is very short (eg, 25 hours).
Three distinct clinical forms of BL are recognized: endemic, sporadic, and immunodeficiency-associated . Although they are histologically identical and have similar clinical behavior, there are differences in epidemiology, clinical presentation, and genetic features between the three forms (table 1):
●The endemic (African) form presents as a jaw or facial bone tumor (picture 1) in 50 to 60 percent of cases. Primary involvement of the abdomen is less common. The primary tumor can spread to other extranodal sites, including mesentery, ovary, testis, kidney, breast, and meninges. Primary involvement of lymph nodes, mediastinum, and spleen are uncommon. Bone marrow involvement is seen in less than 10 percent of patients at the time of initial presentation but is a common complication of recurrent or treatment resistant disease.
●The non-endemic (sporadic) form usually has an abdominal presentation, most often with massive disease and ascites, involving the distal ileum, stomach (picture 2), cecum and/or mesentery, kidney, testis, ovary, breast, bone marrow, or central nervous system (CNS). Presenting symptoms can include those related to bowel obstruction or gastrointestinal bleeding, often mimicking acute appendicitis or intussusception. Approximately 25 percent of cases will have involvement of the jaw or facial bones. Lymphadenopathy, if present, is generally localized. Bone marrow and CNS involvement occurs in approximately 30 and 15 percent of cases, respectively, at the time of initial presentation, but are common complications of recurrent or treatment resistant disease .
●The presentation of patients with immunodeficiency-related BL is often accompanied by signs or symptoms related to the underlying immunodeficiency (eg, AIDS, congenital immunodeficiency, acquired immunodeficiency due to hematopoietic or solid organ transplantation). Immunodeficiency-related cases more often involve lymph nodes, bone marrow, and CNS. (See "HIV-related lymphomas: Clinical manifestations and diagnosis".)
The 2016 World Health Organization (WHO) classification of hematologic malignancies has recategorized some cases of BL . In the current scheme, a "leukemic" presentation (ie, extensive bone marrow and blood involvement) is not distinguished from other cases of BL; this was formerly described as acute lymphoblastic leukemia, L3 type in the now-obsolete French-American-British (FAB) group system. Aggressive lymphomas with morphological and genetic features intermediate between BL and diffuse large B cell lymphoma (DLBCL), which were previously classified as Burkitt-like lymphomas, are primarily described in the current WHO classification as "High-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement", and "High-grade B cell lymphoma, not otherwise specified."
Morphology — Biopsy of the tumor mass demonstrates complete effacement of the normal architecture by sheets of atypical lymphoid cells . At low power, the tumor has a "moth-eaten" appearance, often with interspersed areas of coagulative necrosis or hemorrhage. There is an extremely high rate of proliferation as well as a high rate of apoptotic cell death. A classic "starry-sky" pattern is usually present, imparted by numerous benign macrophages (histiocytes) that have ingested apoptotic tumor cells (ie, tingible body macrophages) (picture 3 and picture 4 and picture 5). The benign histiocytes ("the stars") are large with abundant, clear cytoplasm and are dispersed relatively evenly throughout a background of basophilic tumor cells ("the sky").
At higher power, BL tumor cells classically are monomorphic, medium-sized cells with round nuclei, multiple dark nucleoli, and basophilic cytoplasm (picture 6 and picture 7) . Cytologically, these cells resemble the small non-cleaved cells within normal germinal centers of the secondary lymphoid follicle. Prominent cytoplasmic lipid vacuoles are usually evident on air-dried imprints or smears. The interspersed benign histiocytes are large and irregularly shaped with abundant, clear cytoplasm, pale nuclei, and inconspicuous nucleoli.
The growth fraction of these lymphomas is very high, with frequent mitotic figures being seen and the fraction of Ki-67+ (MIB-1+) cells approaching 100 percent.
Several morphologic variants may be seen. Occasionally the tumor cells are associated with a marked granulomatous reaction, which may be so profound as to obscure the tumor cells lurking in the background. Other tumors may have single centrally placed nucleoli and eccentric cytoplasm, producing a plasmacytoid appearance. Another variant is marked by greater nuclear pleomorphism and more prominent nucleoli than are typical of "classic" forms of BL.
Immunophenotype — The tumor cells express surface immunoglobulin (Ig) of the IgM type and immunoglobulin light chains (kappa more often than lambda), B cell-associated antigens (CD19, CD20, CD22, CD79a), germinal center-associated markers (CD10 and BCL6), as well as HLA-DR and CD43 (picture 8) . They lack expression of CD5, B cell leukemia/lymphoma 2 (BCL2), TdT, and typically lack expression of CD23. BCL6 protein staining is in a nuclear pattern and independent of BCL6 gene rearrangement .
Expression of CD21, the Epstein-Barr virus (EBV)/C3d receptor, is dependent on EBV status of the tumors. Essentially all cases of endemic BL are EBV positive and express CD21, whereas the vast majority of non-endemic BL in non-immunosuppressed patients are EBV negative and lack CD21 expression. EBV involvement in BL occurring in the setting of immunodeficiency falls between these two extremes. For example, 25 to 40 percent of BL occurring in HIV-positive patients are EBV associated, as are a high fraction of BL associated with organ transplantation. BL generally lacks the adhesion molecules LFA-1 (CD11a/CD18), p150/95 (CD11c), and CD44. (See "Clinical manifestations and treatment of Epstein-Barr virus infection".)
The immunophenotype of the BL variants is very similar to BL, although expression of surface immunoglobulin (sIg), CD10, and CD21 is more variable. The immunophenotype of these variants as defined in the World Health Organization classification has not been determined in prospective studies.
Translocations involving the MYC oncogene — In virtually all studies, BL is associated with a translocation between the long arm of chromosome 8, the site of the MYC oncogene (8q24), and one of three locations on immunoglobulin (Ig) genes [17-22]:
●The Ig heavy chain gene on chromosome 14 (approximately 80 percent) – t(8;14)
●The kappa light chain gene on chromosome 2 (approximately 15 percent) – t(2;8)
●The lambda light chain gene on chromosome 22 (approximately 5 percent) – t(8;22)
In African (endemic) cases, the breakpoint on chromosome 14 involves the heavy chain joining region, while in non-endemic cases, the translocation involves the heavy chain switch region [18,23]. In endemic cases, the breakpoint in chromosome 8 usually lies adjacent to the MYC gene, while in sporadic cases it often lies within intron 1 of MYC. (See "Pathobiology of Burkitt lymphoma", section on 'MYC overexpression'.)
Cases with "double-hit" translocations involving MYC and BCL6, and rare "triple-hit" tumors with MYC, BCL2, and BCL6 rearrangements are better classified as "high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 translocations" . Such tumors are more common in older adults, are more likely to have atypical MYC rearrangements involving genes other than IgH, and sometimes appear to stem from transformation of an underlying lower grade B cell lymphoma, such as follicular lymphoma.
Other genetic abnormalities — Immunoglobulin heavy and light chain genes are rearranged. Studies of the immunoglobulin variable region genes show conflicting results: one study reported unmutated genes , while others report somatic mutations and intraclonal heterogeneity, consistent with ongoing mutations [25-27].
Mutations in the 5' noncoding region of the BCL6 gene, similar to those seen in diffuse large B cell lymphoma, have been reported in 25 to 50 percent of BL . Most African cases contain clonal EBV genomes, as do 25 to 40 percent of the cases associated with acquired immune deficiency syndrome (AIDS) .
In a study involving 33 children and 37 adults with BL, in which all subjects had translocations involving chromosome 8, additional abnormalities were present in 81 and 73 percent of the children and adults, respectively . The most commonly observed abnormalities involved chromosomes 1, 6, 13, 17, and 22. Of these, only abnormalities of chromosome 17 (the location of TP53) were poor prognostic features in adults.
The potential value of gene expression profiling (GEP) in diagnosing BL was illustrated in two large studies that identified a characteristic molecular signature that was able to differentiate BL from diffuse large B cell lymphoma [31,32]. While use of GEP has not found its way into clinical practice to establish the diagnosis of BL, new approaches that simplify the detection of RNA signature (eg, Nanostring analysis, which has been proposed as a means for sub-classification of diffuse large B cell lymphoma ) may make use of GEP more attractive in the future.
Next-generation sequencing studies of BL have revealed that all three subtypes are frequently associated with mutations in the transcription factor TCF3 (also known as E2A, 10 to 25 percent of cases) or a negative regulator of TCF3, ID3 (35 to 58 percent of cases) . Notably, the ID3 mutations are loss-of-function mutations, whereas most TCF3 mutations are gain-of-function mutations that abrogate ID3 binding to TCF3. Mutations in these genes are rare in diffuse large B cell lymphoma and other B cell lymphomas, suggesting that TCF3 gain of function is a defining lesion in BL. (See "Pathobiology of Burkitt lymphoma", section on 'Other genetic lesions'.)
DIAGNOSIS — The diagnosis of BL is based on the pathologic evaluation of involved tissue, usually an abdominal mass or some other extranodal site (eg, a jaw mass in endemic regions) (algorithm 1). Less commonly, involvement of typical extranodal sites of disease is absent and the diagnosis is made through pathologic evaluation of another tissue (eg, lymph node, lung, kidney, testicle). A discussion of tissue biopsy, including a general discussion of pathologic testing, is presented separately. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Lymph node and tissue biopsy'.)
Histology reveals monomorphic, medium-sized cells with basophilic cytoplasm and a high proliferation fraction with the Ki-67+ fraction approaching 100 percent. Cytogenetic analysis demonstrates a translocation involving the MYC gene on chromosome 8. Rearrangements involving MYC can usually be detected by routine cytogenetics, but can also be demonstrated by fluorescence in situ hybridization (FISH) using commercially available probes.
Whether MYC rearrangement is essential for the diagnosis has been questioned by studies showing that up to 5 percent of tumors with features that are otherwise typical of BL lack MYC rearrangements [31,35]. In the 2016 World Health Organization classification of lymphoid neoplasms, diagnosis of BL in the absence of MYC rearrangement is disfavored . Many of the cases that were previously categorized as BL in the absence of a MYC rearrangement are better classified as the new provisional entity "Burkitt-like lymphoma with 11q aberration" ; however, this remains a problematic diagnostic area since screening for 11q aberrations is not routine at most centers.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis for BL includes other tumors that can present as abdominal masses or facial tumors and other types of non-Hodgkin lymphoma. Among the other types of non-Hodgkin lymphoma that are the most difficult to differentiate from BL pathologically are lymphoblastic lymphoma, blastoid mantle cell lymphoma (which mimics the appearance of lymphoblastic lymphoma), and diffuse large B cell lymphoma (table 2). These are described in more detail below.
Other entities in the differential diagnosis depend largely upon the patient population and site of tumor:
●Intra-abdominal tumor – In children with an intra-abdominal tumor, the most common entities are Wilms' tumor and neuroblastoma; less commonly, other forms of lymphoma, leukemias with extensive extramedullary involvement, hepatic tumors, ovarian tumors, and soft tissue sarcomas may present as abdominal masses. Wilms' tumor and neuroblastoma occur more commonly in infants, whereas leukemic or lymphomatous involvement of the liver, spleen, or retroperitoneal lymph nodes occurs more commonly in older children. The differential diagnosis in adults includes both benign and malignant entities, such as colorectal cancer and ovarian cancer. (See "Presentation, diagnosis, and staging of Wilms tumor" and "Clinical presentation, diagnosis, and staging evaluation of neuroblastoma" and "Approach to the patient with an adnexal mass" and "Adnexal mass: Differential diagnosis" and "Epithelial carcinoma of the ovary, fallopian tube, and peritoneum: Clinical features and diagnosis" and "Clinical presentation, diagnosis, and staging of colorectal cancer".)
●Facial tumor – The differential diagnosis of facial tumors includes sarcomas, carcinomas, nerve sheath tumors, melanoma, salivary gland tumors, and benign entities such as paragangliomas. This is discussed in more detail separately. (See "Evaluation of a neck mass in adults" and "Differential diagnosis of a neck mass".)
It is highly unusual for a patient to present without tumor in at least one of these locations. The differential diagnosis of patients with a non-abdominal, non-facial presentation is dependent on the site of involvement and associated symptoms.
Diffuse large B cell lymphoma — Although most cases of BL are easily differentiated morphologically from diffuse large B cell lymphoma (DLBCL), some cases of BL have larger cells or an admixture of centroblast- or immunoblast-like cells, resulting in morphologic overlap between these two entities. These borderline cases are associated with a high degree of inter- and intra-observer variation among hematopathologists . In children and HIV-positive patients, these tumors often have MYC translocations and behave similarly to typical BL, while in adults without HIV infection these cases more often are "double-hit" lymphomas with MYC and BCL2 and/or BCL6 gene rearrangements and are thought to represent an aggressive variant of DLBCL that in some cases may arise from transformation of an underlying follicular lymphoma . Regardless of the context, accurate diagnosis of BL versus DLBCL is essential for choosing the most appropriate therapy.
The 2008 version of the World Health Organization (WHO) classification system provided an overlap category termed "B cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL" . The category encompassed several types of aggressive B cell lymphoma that are difficult to place into the BL or DLBCL categories. In the 2016 revision of the WHO classification system , this category was eliminated and the following was proposed instead:
●Tumors that show some atypical morphologic features but that have the immunophenotypic and genotypic features of BL should be categorized as BL.
●Most tumors that have rearrangements of MYC and BCL2 and/or BCL6 (so-called double or triple hit lymphomas) have been placed in a new category, "high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements," except for rare tumors that have these rearrangements but otherwise resemble lymphoblastic lymphoma or follicular lymphoma.
●Cases that have morphologic features intermediate between DLBCL and BL and lack rearrangements in MYC, BCL2, and BCL6 should be categorized as "high grade B cell lymphoma, not otherwise specified."
This remains a difficult and somewhat controversial diagnostic area and additional refinements are likely to be forthcoming.
Features that exclude the diagnosis of BL include the presence of additional cytogenetic/molecular abnormalities, such as rearrangements of BCL6 and/or BCL2, Ki-67 staining in less than 95 percent of the tumor cells, and immunohistochemical positivity for BCL2. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma".)
Lymphoblastic lymphoma — Lymphoblastic lymphoma is another highly aggressive lymphoma that resembles BL histologically. However, in contrast with BL cells, lymphoblastic lymphoma cells tend to have irregular nuclei, clumped "salt and pepper" chromatin, small nucleoli, and scant cytoplasm. Also, lymphoblastic lymphomas express TdT, are often of T cell phenotype, and when of B cell origin fail to express surface immunoglobulin. Thus, flow cytometry or immunohistochemistry can distinguish BL from lymphoblastic lymphoma with a high degree of certainty. (See "Clinical manifestations, pathologic features, and diagnosis of precursor T cell acute lymphoblastic leukemia/lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of B cell acute lymphoblastic leukemia/lymphoma".)
Mantle cell lymphoma, blastoid variant — Mantle cell lymphoma (MCL) is a lymphoma of adults and does not enter into the differential in children. However, cases of the blastoid variant of MCL may resemble BL morphologically. The blastoid variant of MCL is comprised of intermediate-sized cells with dispersed chromatin, irregular nuclear contours, and scant cytoplasm with a high mitotic rate. MCL can usually be distinguished from BL by its immunophenotype. While both entities express surface IgM and B cell-associated antigens, most cases of MCL express CD5 and do not express CD10 (unlike BL). In addition, nuclear staining for cyclin D1 is present in 95 percent of cases of MCL and is absent in BL. (See "Mantle cell lymphoma: Epidemiology, pathobiology, clinical manifestations, diagnosis, and prognosis".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lymphoma diagnosis and staging" and "Society guideline links: Management of Burkitt lymphoma".)
●Burkitt lymphoma (BL) is a highly aggressive B cell neoplasm that can present in one of three distinct clinical forms: endemic, sporadic, and immunodeficiency-associated. Although they are histologically identical and have similar clinical behavior, there are differences in epidemiology, clinical presentation, and genetic features between the three forms. (See 'Introduction' above.)
●BL comprises 30 percent of non-endemic pediatric lymphomas, but <1 percent of adult non-Hodgkin lymphomas. The endemic variant is found in equatorial Africa while the sporadic variant is seen in the United States and Western Europe. Endemic and sporadic BLs are both most common in children, and the majority of patients are male. (See 'Epidemiology' above.)
●Patients with BL present with rapidly growing tumor masses and often have evidence of tumor lysis. The endemic form presents as a jaw or facial bone tumor that spreads to extranodal sites while the non-endemic (sporadic) form has an abdominal presentation, most often with massive disease. Immunodeficiency-related cases more often involve lymph nodes. (See 'Clinical features' above.)
●BL tumor cells are monomorphic, medium-sized cells with round nuclei, multiple nucleoli, and basophilic cytoplasm (picture 6). Prominent cytoplasmic lipid vacuoles are usually evident on imprints or smears. There is an extremely high rate of proliferation, as well as a high rate of apoptotic cell death as evidenced by a Ki-67+ (MIB-1+) cells fraction approaching 100 percent and a "starry-sky" pattern. (See 'Morphology' above.)
●BL cells express surface IgM and B cell-associated antigens (CD19, CD20, CD22, CD79a), as well as CD10, HLA-DR, and CD43. They lack CD5, BCL-2, TdT, and typically lack CD23. (See 'Immunophenotype' above.)
●BL is strongly (but not uniformly) associated with a translocation between the long arm of chromosome 8, the site of the MYC oncogene (8q24), and one of three locations on Ig genes: t(8;14), t(2;8), or t(8;22). (See 'Genetic features' above.)
●The diagnosis of BL is based on the pathologic evaluation of involved tissue, usually an abdominal mass. (See 'Diagnosis' above.)
●The differential diagnosis for BL includes other tumors that can present as abdominal masses and other types of non-Hodgkin lymphoma. Among the other types of non-Hodgkin lymphoma, the most likely to be difficult to differentiate from BL are lymphoblastic lymphoma, the blastic variant of mantle cell lymphoma, and diffuse large B cell lymphoma (table 2). (See 'Differential diagnosis' above.)
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