Burkitt’s Lymphoma- Clinicopathologic Features and Differen

Burkitts Lymphoma: Clinicopathologic Features and Differen Burkitts,lymphoma,#8226;,Immunophenotype,#8226;,c-myc,#8226;,Outcome,#8226;,Differential,diagnosisLEARNING OBJECTIVESAfter completing this course, the reader will be able to:Describe the events leading to the initial identification and description of Burkitts lymphoma and the discovery of its association with the Epstein-Barr virus.Outline the WHO Classification of Burkitts lymphoma, including the clinical and pathological variants of this lymphoma.Discuss the treatment strategies used for treating Burkitts lymphoma.List the criteria for establishing a diagnosis of Burkitts lymphoma and discuss the entities that may enter its differential diagnosis.ABSTRACTBurkitts lymphoma is a highly aggressive lymphoma identified and described in the last century by Denis Burkitt in Africa, in areas endemic for malaria. Since its description in African children, it has been recognized outside areas with endemic malaria, frequently also in children as well as among individuals with an underlying immunodeficiency. Since its initial designation as Burkitts lymphoma, this type of lymphoma and lymphomas closely resembling it have received a variety of names in different classifications of lymphomas and leukemias: undifferentiated lymphoma, Burkitts and non-Burkitts type in the modified Rappaport Classification, malignant lymphoma, small non-cleaved cell, Burkitts type in the Working Formulation, Burkitts lymphoma and high-grade B-cell lymphoma, Burkitt-like in the REAL Classification, and acute lymphoblastic leukemia, L3 type in the FAB Classification. With the publication of the WHO Classification of Haematopoietic and Lymphoid Tumors, the nomenclature of this lymphoma has come full circle, and it is once again known simply as Burkitts lymphoma. In recent years, efforts have focused on improving therapy for this rapidly proliferating neoplasm while minimizing, to the extent possible, treatment-associated toxicity. These efforts have led to the development of high-intensity, short-duration combination chemotherapy that has proven extremely effective for a high proportion of Burkitts lymphoma patients. The differential diagnosis of Burkitts lymphoma is broad, and precise diagnosis based on histologic, immunophenotypic, and genetic features remains the critical first step in planning appropriate therapy.HISTORICAL BACKGROUNDIn the middle of the last century, when Denis Burkitt, a surgeon, was working in central Africa in Kampala, he noted children with grossly distorted faces, with lesions involving one or both sides of the face and upper and lower jaws, sometimes accompanied by proptosis. He noted that some children had huge abdominal masses, sometimes accompanied by disease in the facial bones, although there was usually no lymph node involvement. This malignancy, initially thought to be a sarcoma 13 and later established to be a lymphoma and given the name Burkitts lymphoma, was the most common tumor in children in that area 2. This lymphoma was found to occur throughout tropical Africa except at high altitudes or in areas where the climate was relatively cool. Occurrence was greater in areas with greater rainfall. These geographic and climatic associations suggested an association with falciparum malaria. In 1961, Burkitt made the acquaintance of Epstein, an experimental pathologist, and shared samples of the lymphoma with him. Within these lymphomas, Epstein and colleagues identified the virus that has come to be known as Epstein-Barr virus (EBV); this was the first description of a virus involved in the pathogenesis of a tumor in humans. In the setting of the florid reactive lymphoid hyperplasia that occurs in response to malaria, it was proposed that EBV could be oncogenic 2. Although only limited chemotherapeutic agents were available at that time and in that place, an excellent response could be obtained, eventually attaining up to 80% long-term survival 2. In present-day Africa, Burkitts lymphoma continues to account for most childhood malignancies 4. A second form of Burkitts lymphoma is now found in Africa: HIV-associated Burkitts lymphoma, occurring mainly in adults 4.PATHOLOGIC FEATURESIn the World Health Organization (WHO) Classification, three clinical variants of Burkitts lymphoma are described: endemic, sporadic, and immunodeficiency-associated types. Endemic Burkitts lymphoma refers to those cases occurring in African children, usually 47 years old, with a male:female ratio of 2:1, involving the bones of the jaw and other facial bones, as well as kidneys, gastrointestinal tract, ovaries, breast, and other extranodal sites 5. The incidence is estimated to be 50 times higher than in the U.S. 6. EBV is found in nearly all cases. Sporadic Burkitts lymphoma occurs worldwide; it includes those cases occurring with no specific geographic or climatic association. It accounts for 1%2% of lymphoma in adults and up to 40% of lymphoma in children in the U.S. and western Europe 6. The abdomen, especially the ileocecal area, is the most common site of involvement; the ovaries, kidneys, omentum, Waldeyers ring, and other sites may also be involved (Fig. 1 and Fig. 2). Bilateral involvement of the breasts may occur in association with the onset of puberty or with lactation 5. Lymph node involvement is more common among adults than among children 7. Patients may also have malignant pleural effusions or ascites 5, 7. Rarely, patients present with disease that is primarily leukemic (classified as acute lymphoblastic leukemia ALL, L3 type in the French-American-British FAB Classification). Neoplastic cells are EBV+ in 15%30% of cases, or fewer in some series 8. Immunodeficiency-associated Burkitts lymphoma occurs mainly in patients infected with HIV (Fig. 3) but also occurs in allograft recipients 9, 10 and individuals with congenital immunodeficiency. In the early years of the AIDS epidemic, several cases of Burkitts lymphoma were described in homosexual men 11, 12; these were the first descriptions of non-Hodgkins lymphoma arising in association with what was later recognized as HIV infection. Information accumulated since that time indicates that Burkitts lymphoma accounts for 30%40% of non-Hodgkins lymphoma in HIV+ patients 6, 13, 14. In a study performed before widespread use of highly active antiretroviral therapy (HAART), Burkitts lymphoma was estimated to be 1,000 times more common in HIV+ individuals than in the general population 14. Compared with other HIV+ patients with non-Hodgkins lymphoma of the diffuse large B-cell type, those with Burkitts lymphoma are younger, less often carry a prior diagnosis of AIDS, and have higher mean CD4 counts (usually 200 cells/µl). The diagnosis of Burkitts lymphoma in an HIV+ individual often represents the first AIDS-defining criterion 14, 15. HIV-associated Burkitts lymphoma shares some pathogenetic features with endemic Burkitts lymphoma. HIV infection, analogous to malaria, leads to polyclonal B-cell activation, and permits poorly controlled proliferation of EBV+ B cells. The genetic instability of the EBV+/, aberrantly regulated B cells leads to a greater risk of c-myc rearrangement, and then to lymphoma. HIV is not directly involved in lymphomagenesis but is indirectly involved via cytokine deregulation, chronic antigenic stimulation, and decreased immune surveillance 14, 15. Lymphoma often involves lymph nodes, bone marrow, and extranodal sites, most often in the abdomen 14. Burkitts lymphoma occurring in transplant recipients tends to occur after a relatively long interval post-transplant (mean, 4.5 years in one series) 9. Most patients are solid organ recipients, but recipients of stem cells are rarely affected as well. EBV is commonly but not uniformly present 9, 10.With respect to morphology, the WHO Classification describes classic Burkitts lymphoma and two variants: Burkitts lymphoma with plasmacytoid differentiation and atypical Burkitts/Burkitt-like lymphoma 5. Classic Burkitts lymphoma is found in cases of endemic Burkitts lymphoma and most cases of sporadic Burkitts lymphoma affecting children (Fig. 1) but in only a minority of sporadic and immunodeficiency-associated adult cases. Neoplastic cells are uniform and medium-sized (their nuclei are no larger than the nuclei of admixed histiocytes), with round nuclei and several or multiple small basophilic nucleoli. Cytoplasm is moderately abundant, and with formalin fixation there may be slight cytoplasmic retraction, leading to squared-off edges between neighboring cells. The RNA-rich cytoplasm is deep blue on Giemsa or Wright stain and usually shows multiple vacuoles (Fig. 3) because of the presence of lipid, when marrow aspirates or Wright-stained touch preps are available. The mitotic rate is unusually high. Characteristically there are numerous admixed tingible body macrophages, phagocytosing abundant apoptotic debris, creating a starry-sky pattern 5. Many cases of sporadic Burkitts lymphoma occurring in adults have Burkitt-like morphology. Those with plasmacytoid differentiation tend to occur in association with immunodeficiency. Burkitt-like lymphoma and Burkitts lymphoma with plasmacytoid differentiation both tend to have greater nuclear pleomorphism than classic Burkitts lymphoma, and both tend to have a smaller number of more prominent nucleoli (Fig. 2). The plasmacytoid variant has, in addition, monotypic cytoplasmic immunoglobulin. Burkitts lymphoma, regardless of subtype, typically expresses monotypic surface IgM, pan-B-cell antigens, including CD19, CD20, CD22, and CD79a, and coexpresses CD10, Bcl-6, CD43, and p53, but not CD5, CD23, Bcl-2, CD138, or TdT. The proliferation fraction is very nearly 100% 5, 16; accordingly, the doubling time of the tumor is very short, between 24 and 48 hours. Rare cases have been reported that lack surface immunoglobulin 8, including some occurring in allograft recipients 9. The immunophenotype suggests follicle center origin for this lymphoma.A defining feature of Burkitts lymphoma is the presence of a translocation between the c-myc gene and the IgH gene (found in 80% of cases t(8;14) or between c-myc and the gene for either the kappa or lambda light chain (IgL) in the remaining 20% t(2;8) or t(8;22), respectively. Other specific lymphoma-associated translocations, such as IgH/bcl-2 and translocations involving bcl-6, are absent. The myc/Ig translocation may not be detected by routine cytogenetics; performing fluorescence in situ hybridization (FISH) or long-segment polymerase chain reaction may increase the chance of identifying the translocation 8. In endemic Burkitts lymphoma, the break point in c-myc is more than 100 kb upstream from the first coding exon, and the break point in the IgH gene is in the joining segment. In sporadic and HIV-associated Burkitts lymphoma, the break point in myc is between exons 1 and 2, and the break point in IgH is in the switch (Sµ) region, suggesting a different pathogenesis and suggesting that neoplastic transformation affects B cells at different maturational stages for these subtypes of Burkitts lymphoma 5, 17. It should be noted however, that results have not been uniform; in a study of sporadic Burkitts lymphoma, most presenting as leukemia, one third of cases had chromosomal break points in the joining region of IgH 8.Proliferating tissues typically express at least one member of the myc family, most often c-myc. myc is downregulated when cells are terminally differentiated (or when lymphoid cells become memory lymphocytes) 18. c-myc rearrangement is a pivotal event in lymphomagenesis; it results in a perpetually proliferative state. It has wide ranging effects on progression through the cell cycle, cellular differentiation, apoptosis, and cell adhesion 6. c-myc rearrangement is an early event; lymphomagenesis most likely involves accumulation of other genetic events as well. p53 gene mutation, for example, is common in Burkitts lymphoma, occurring in immunocompetent and immunosuppressed patients, including HIV+ individuals and transplant recipients 9, 19.STAGING, TREATMENT, AND OUTCOMEStaging is performed using the Ann Arbor or, more often, the St Jude/Murphy staging system 5, 6, 13, 20. Approximately 30% of patients present with limited-stage disease (I or II), while 70% present with widespread disease (stage III or IV) 5. Patients often present with bulky disease, frequently with an elevated lactate dehydrogenase (LDH) level. Patients with any of the three clinical variants are at risk for spread to the central nervous system (CNS) and bone marrow. The bone marrow is positive in 30%38%, and the CNS is involved in 13%17% of adult cases 6. In a study of children with disseminated disease, 12% had CNS involvement, and 22% had marrow involvement 21.Sporadic and immunodeficiency-associated Burkitts lymphoma do not share endemic Burkitts lymphomas exquisite sensitivity to chemotherapy, so that historically the prognosis had been poor, particularly among adults. Short-duration, high-intensity chemotherapy, sometimes combined with CNS prophylaxis, yields excellent survival in children: patients with localized disease have a 90% 5-year survival rate 21, and children with widespread disease(including leukemic presentation)mayachievea90% complete response (CR) rate, with an event-free survival (EFS) rate at 4 years of 65% in patients with leukemic presentation, and 79% for those presenting with stage IV lymphoma reported in one series 22. When similar aggressive chemotherapeutic regimens have been administered to adults, good outcomes have been achieved, with CR rates of 65%100% and overall survival (OS) rates of 50%70% 6, 13, 23. The institution of the CODOX-M/IVAC regimen (Magrath protocol)two cycles of CODOX-M (cyclophosphamide, vincristine, doxorubicin, high-dose metho-trexate, and intrathecal therapy) alternating with IVAC (ifosfamide, etoposide, high-dose cytarabine, and intrathecal therapy)for high-risk disease, and for those with low-risk disease (e.g., one extranodal site or completely resected abdominal disease with normal LDH), three cycles of CODOX-M, represented a major step forward in the treatment of Burkitts lymphoma. Children and adults treated with this regimen had similar outcomes; the EFS rate at 2 years was 92% for the group as a whole 23. However, there were significant associated toxicities, including frequent myelosuppression, mucositis, neuropathy, and some treatment-related deaths 6, 13. In addition, because of the rapid, effective tumor cell killing with this aggressive protocol, careful monitoring is required to avoid the complication of tumor lysis syndrome 5. Some modifications have been suggested to minimize the significant toxicities associated with the CODOX-M/IVAC protocol. The United Kingdom Lymphoma Group, for example, used this protocol with slight modifications, such as decreases in vincristine, achieving a 2-year EFS rate of 65% overall (83% in the low-risk cohort and 60% in the high-risk cohort) 13, 24. The Dana-Farber Cancer Institute has treated patients with a modified Magrath protocol, aimed at decreasing toxicity while maintaining good outcome. In this modification, the schedule of fractionated cyclophosphamide was altered and the vincristine dose was capped, but the dose of doxorubicin was escalated. In this cohort, there were no treatment-related deaths, one instance of severe mucositis, and no severe neurotoxicity. The 2-year EFS rate was 64% for all patients, 100% for low-risk patients, and 60% for high-risk patients 13, 25. When relapses occur, it is usually within 1 year of diagnosis, so those who survive 2 years without recurrence can be considered cured 5.Rituximab, a monoclonal anti-CD20 antibody, may improve outcome; a study of a small series from the M.D. Anderson Cancer Center used rituximab in conjunction with hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), with CNS prophylaxis, and achieved a complete remission rate of 89%; most patients had advanced-stage disease, and some were HIV+ 13, 26. These results are promising, but additional investigation is required to determine the role of rituximab in the treatment of Burkitts lymphoma 13. Similarly, the role of autologous or allogeneic stem cell transplantation for possible consolidation or salvage therapy is not established 6. Although in recent years tremendous progress has been made, new therapies are required to minimize toxicities, especially in older patients. Relapses remain a problem, particularly among higher-risk patients 13. Novel therapies that have not been tested but could be useful include those targeted against the c-myc gene, DNA methyltransferase inhibitors, proteasome inhibitors, cyclin-dependent kinase inhibitors, and others 6.Although the most important prognostic features have yet to be determined, some features that have been associated with adverse outcome in adults and children include older age, advanced stage, poor performance status, bulky disease, high LDH, and CNS or marrow involvement 6, 27. Among pediatric patients, a poorer prognosis is associated with age over 15 years 27. A good prognosis is associated with resectable abdominal disease 5. Failure to achieve a CR is a very poor prognostic sign 6, 27. A granulomatous response to the lymphoma has been associated with localized disease and a favorable outcome in cases of sporadic Burkitts lymphoma 28, 29.A minority of patients with Burkitts lymphoma presents with leukemic disease, previously classified as ALL, L3 type. Therapy traditionally used to treat lymphoblastic leukemia worked poorly in Burkitts patients, but newer chemotherapeutic regimens are associated with better outcome, although they too are associated with serious toxicities 13.HIV+ patients may be treated with intensive therapy but require especially close observation, with transfusion support and antibiotic therapy as needed. HAART may improve outcome, allowing patients a better chance of being able to tolerate full-dose chemotherapy 13. Patients developing Burkitts lymphoma in a post-transplant setting may also be difficult to treat, but may show a good response to therapy that includes a combination of chemotherapy, decreased immunosuppression, and rituximab 9, although mortality appears to be high among the small numbers of cases reported 9, 10, with three of five patients in one series succumbing to complications of therapy 10.