ABSTRACT: Burkitt lymphoma is a unique B-cell malignancy with a high proliferation rate and characteristic genetic changes involving the c-myc oncogene. Burkitt lymphoma is common in children but also occurs in adults, where distinction from diffuse large B-cell lymphoma may pose a problem. The development of brief, very intensive chemotherapy regimens has led to a very high cure rate in children with Burkitt lymphoma. The use of these regimens in adults, often in combination with the antibody rituximab (Rituxan), has also made the cure of a majority of adults possible. Burkitt lymphoma in adults cannot be treated effectively with the common regimens used for diffuse large B-cell lymphoma such as CHOP-R (cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone, rituximab). Prompt diagnosis and initiation of appropriate therapy with attention to the possibility of tumor lysis syndrome are necessary for optimal results.
Burkitt lymphoma (BL) is a unique B-cell lymphoma characterized by a high proliferation rate and cytogenetic changes related to c-myc proto-oncogene overexpression. Burkitt lymphoma is a highly aggressive B-cell lymphoma that is most frequently seen in children and young adults in endemic areas. As a result of the worldwide epidemic of acquired immunodeficiency syndrome (AIDS), the number of cases of adult BL has increased substantially in the past 3 decades.
The challenge of correctly distinguishing BL in an individual patient becomes particularly critical when the clinician is confronted with a treatment decision. Burkitt lymphoma is rapidly fatal if not treated appropriately with brief intensive chemotherapy, which has yielded an excellent result. However, when patients with BL are treated with regimens for diffuse large B-cell lymphoma (DLBCL), the outcome is usually poor.[1-4] On the other hand, brief intensive therapy is not the favored choice for DLBCL since it is associated with significant adverse effects (Table 1). Therefore, use of more advanced modalities to establish an accurate diagnosis is crucial, to avoid undertreatment or overtreatment of patients. The aim of this review is to discuss adult BL and emphasize controversial topics in diagnosis and treatment.
Historical Background and Epidemiology
Burkitt lymphoma was first described by Dr. Dennis Burkitt, an Irish surgeon who was working for the Colonial Medical Service in Uganda. He noted a high incidence of rapid-growing tumors affecting the jaws of African children in the endemic areas of malaria. At that time, Dr. Burkitt described the tumor as a form of sarcoma. Three years later, the tumor was recognized histologically as a malignant lymphoma by Burkitt and O’Conor when they studied a series of cases—involving extranodal sites in African children—that shared the geographic distribution, histologic features, and high incidence of jaw involvement.
Burkitt lymphoma accounts for over half of all childhood cancers in endemic areas, and 40% to 50% of childhood non-Hodgkin lymphomas (NHLs) in nonendemic areas (America and Western Europe). BL is a rare lymphoma in adults, except in human immunodeficiency virus (HIV)-positive patients. It constitutes 1% to 2% of all non-HIV adult lymphomas in Western Europe and the United States.
The World Health Organization (WHO) classified BL on the basis of geographic distribution and clinical presentation into three subtypes: endemic, sporadic, and immunodeficiency-associated BL (Table 2). These subtypes share the same morphologic and immunohistologic features.
The endemic variant is the prototype and the most common form. It describes cases that have been observed in children in equatorial Africa and Papua New Guinea, with a geographic distribution pattern that corresponds with endemic falciparum malaria. The highest risk of BL is seen between 10° north and south of the equator. The disease has a tendency to occur in low, warm, and humid lands, and it is an important health issue in areas such as the Middle East, North Africa, and parts of South America. It is characterized by a high incidence of jaw and other facial bone involvement. Central nervous system (CNS) and bone marrow involvement in children has been reported in 12% and 22% of cases, respectively. Nearly all endemic cases are associated with EBV infection.
In contrast, the sporadic form describes cases that occur outside the endemic distribution of the disease and is seen in industrialized nations such as North America and Europe. It accounts for a minor percentage of adult lymphomas, and its peak incidence occurs in the second and third decades.
Sporadic BL is a highly aggressive disease with a propensity to invade bone marrow and CNS, with a reported incidence of 30% to 38% and 13% to 17% of cases, respectively. Lymph node involvement is more common among adults than children. Whereas the jaw is the most common affected site in the endemic form, it is infrequently involved in sporadic Burkitt. The abdomen is the most common site in sporadic cases, particularly the terminal ileum, cecum, and intra-abdominal lymph nodes. However, it also occurs in sites such as the ovary, kidney, pancreas, liver, omentum, Waldeyer’s ring, and breast. Breast involvement is observed almost exclusively in girls at the onset of puberty and in lactating women.
One-third of patients have B symptoms at presentation (unexplained fever higher than 38°C (100.4°F) in the prior month, unexplained weight loss greater than 10% in the past 6 months, and recurrent drenching night sweats in the prior month). Patient with abdominal disease usually present with abdominal mass or pain, bowel obstruction, gastrointestinal bleeding, or a syndrome mimicking appendicitis. In the sporadic form, 15% to 30% neoplastic cells are EBV-positive.
The third group is immunodeficiency-associated BL which is seen in HIV-positive patients, to a lesser extent in posttransplant recipients,[19,20] and in some individuals with congenital immunodeficiency. Burkitt lymphoma occurs over a thousand times more often in HIV-positive individuals than in the general population. It accounts for 30% to 40% of all HIV-associated NHLs. Compared to other AIDS-associated NHLs, BL occurs in younger patients with higher CD4 counts. Since the introduction of highly active antiretroviral therapy (HAART), the prognosis of HIV-associated NHL has improved significantly with standard chemotherapy protocols, except for BL, which continues to carry an unsatisfied prognosis with current chemotherapy.
The majority of patients are diagnosed with stage III or IV disease (Table 3). Relapse with CNS involvement tends to occur early in the course of the disease. Posttransplant BL tends to occur after a relatively long interval following the transplant (average interval was 4.5 years in one series).
Pathology and Pathobiology
Histologically, classic BL is characterized by a uniform proliferation of medium-sized cells with round nuclei, stippled chromatin, and multiple small, membrane-associated nucleoli (Table 4). The cells have a moderate amount of basophilic cytoplasm, with numerous lipid vacuoles in smears and touch preparations. The hallmark of BL is the presence of a “starry sky” appearance seen at low-power magnification. This appearance is created by numerous macrophages containing ingested fragments of tumor cells as a consequence of rapid proliferation and a high rate of apoptosis (Figure 1). The rate of cell division is extremely high, as reflected by the presence of numerous mitotic figures and a high fraction of proliferating cells (> 95%) as demonstrated by Ki-67 stains. This classic form of BL is seen in most endemic cases and in most sporadic pediatric cases.
The WHO classification has identified Burkitt lymphoma and leukemia as a single entity of mature B-cell lymphoma with two related morphologic variants in addition to the classic form: BL with plasmacytoid differentiation and atypical BL/Burkitt-like lymphoma. These variants share the genetic and immunophenotypic features of classic BL, but they have atypical morphologic features. Atypical Burkitt lymphoma (ABL) has morphologic features intermediate between BL and DLBCL, with greater pleomorphism in nuclear size and shape, cells with more prominent central nucleoli, and the presence of large centroblasts admixed, and it is seen more frequently in sporadic adult cases (Figure 1). The revised European-American lymphoma (REAL) classification gave ABL a provisional status, which was a confusing entity for clinicians, who often found it difficult to choose between treating the disease as BL or as DLBCL. The Southwest Oncology Group reported that ABL is an entity of high-grade lymphoma much closer to BL than DLBCL, which can be differentiated by its characteristic phenotypic and molecular features, and a higher proliferation index than is usually seen in DLBCL. The WHO classification resolved this dilemma by recognizing ABL as a morphologic variant of BL that requires intensive therapy.
BL with plasmacytoid differentiation is seen frequently in AIDS patients. It is distinguished by features of ABL and the presence of monotypic cytoplasmic immunoglobulin.
The features of BL are consistent with a germinal center-cell stage of differentiation, based on the presence of somatically mutated immunoglobulin heavy chain variable-region genes and the expression of characteristic GC B-cell surface markers such as CD10 and Bcl-6.[30-32] Some cases of endemic BL show evidence of ongoing somatic hypermutation, which supports its germinal center-cell origin.
The cells of BL typically express monotypic surface IgM, CD19, CD20, CD22, CD10, Bcl-6, and CD79a, and are negative for CD5, CD23, Bcl-2, and nuclear terminal deoxyribonucleotide transferase (TdT).[8,34] Lack of surface immunoglobulin has been reported in a few cases. The presence of CD10 and Bcl-6 expression supports the germinal center-cell stage of differentiation. A remarkable feature of BL is the high growth fraction (> 95%) as demonstrated by Ki-67. The leukemic cells of BL express a mature immunophenotype that distinguishes it from precursor B-cell acute lymphoblastic leukemia (ALL).
Atypical BL demonstrates more phenotypic diversity and may exhibit a lower proliferation rate compared to the classic form and more frequent expression of Bcl-2.[37,38] On the other hand, some cases of DLBCL exhibit an overlapping immunophenotype with BL including a high proliferation rate, which makes the distinction of ABL from DLBCL difficult based on immunophenotypic characteristics alone. Expression of CD21—the EBV receptor—is seen in EBV-positive cases. It is present in the vast majority of endemic cases of BL.
C-myc encodes a transcriptional factor. It has a marked influence on cell proliferation, growth, cellular differentiation, and apoptosis. Dysregulation of the gene is the key element in BL pathogenesis at the molecular level.
Translocation of the c-myc oncogene is universal in BL. This abnormality juxtaposes the c-myc oncogene location at 8q24 and one of three immunoglobulin loci. The most common translocation is (8;14), which is seen in 80% of BL cases; it occurs between the c-myc oncogene and Ig heavy chain gene (IgH). About 15% of BL cases have a t(2;8) rearrangement, where the translocation occurs between c-myc and kappa light chain gene, and the remaining 5% have an (8;22) translocation between c-myc and lambda light chain gene. The detection of translocations is not always feasible by performing a routine cytogenetic assessment. Fluorescence in situ hybridization (FISH) using a break-apart probe or long-segment polymerase chain reaction increases the chance of identifying the presence of these translocations.
The position of the breakpoint in relation to c-myc gene at chromosome 8 and IgH at chromosome 14 is not variable. Studies have found a correlation between the site of the breakpoint and the geographic distribution of BL. In the endemic form, the breakpoint on chromosome 8 tends to occur upstream of the c-myc gene, while the breakpoint in the IgH locus is usually located within the joining segment. In sporadic as well as AIDS-associated cases, the translocation breakpoint often falls within the c-myc gene on chromosome 8 and in the IgH switch region in chromosome 14.[41,43-45] This may imply a diverse pathogenesis for the variants of BL, which may explain the clinical variations between the endemic and sporadic subtypes.
Making BL diagnosis more challenging, c-myc was found to be sometimes overexpressed in DLBCL, as 5% to 15% of DLBCL cases harbor this rearrangement.[34,46] Considering that 40% of NHLs are DLBCL and 10% of these cases involve c-myc translocation, in contrast to BL, which constitutes 2% of NHLs with all cases having the translocation, the majority of NHLs with c-myc translocations are not BL. Some reported cases of ABL also lacked the c-myc translocation.[47,48]
Both (8;14)(q24;q32) and (14;18)(q32;q21) translocations can occur in the same malignant cells. Tumors harboring this combination have more aggressive disease, present in more advanced stages, and have a worse prognosis.[49,50] The t(14;18) causes overexpression of Bcl-2, which promote cell survival through apoptosis inhibition.[51,52] Dual translocation has been reported in BL cases, especially ABL,[49,53,54] but also DLBCL. More complex cases of BL with triple translocations have been reported, and this has also been linked to poor prognosis.[54-56] The management approach in such complex translocation cases is not well defined. Whether “double-hit” DLBCL responds better to intensive therapy or CHOP-R (cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone, rituximab [Rituxan]) is a question that has not yet been answered.
The pathogenesis of BL is not exclusively explained by c-myc dysregulation; other genetic aberrancies have been found to occur frequently. A p53 mutation was observed in 30% to 40% of BL cases in two reports,[57,58] and the 6q deletion was detected in 30% of cases in another study.
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