Elsevier

The Lancet

Volume 379, Issue 9822, 31 March–6 April 2012, Pages 1234-1244
The Lancet

Seminar
Burkitt's lymphoma

https://doi.org/10.1016/S0140-6736(11)61177-XGet rights and content

Summary

Burkitt's lymphoma is a highly aggressive B-cell non-Hodgkin lymphoma and is the fastest growing human tumour. The disease is associated with Epstein-Barr virus and was one of the first tumours shown to have a chromosomal translocation that activates an oncogene (c-MYC). Burkitt's lymphoma is the most common childhood cancer in areas where malaria is holoendemic. The incidence is very high in immunosuppressed patients in non-endemic areas, especially when associated with HIV infection. Outcome with intensive chemotherapy has improved and is now excellent in children, but the prognosis is poor in elderly adults. The success of intensive treatment relies on good supportive care. The therapy offered in oncology units in low-income countries is not as aggressive as in centres in high-income countries and outcomes are less successful. Adjuvant monoclonal antibody therapy with rituximab shows promise for improved outcomes and reduced toxic effects in the future.

Section snippets

Introduction and history

Burkitt's lymphoma has had an important role in the understanding of tumorigenesis. It was the first human tumour to be associated with a virus,1 one of the first tumours shown to have a chromosomal translocation that activates an oncogene,2, 3 and the first lymphoma reported to be associated with HIV infection.4 Burkitt's lymphoma is the fastest growing human tumour, with a cell doubling time of 24–48 h, and was the first childhood tumour to respond to chemotherapy alone.5 It is the most

Classification

The WHO classification of Burkitt's lymphoma describes three clinical variants: endemic, sporadic (the predominant type found in non-malarial areas), and immunodeficiency-related.20 These types are similar in morphology, immunophenotype, and genetic features. The endemic variant is associated with malaria endemicity and EBV is found in almost all cases. The sporadic type occurs mainly throughout the rest of the world (predominantly North America and Europe), with no special climatic or

Epidemiology

The distribution of endemic Burkitt's lymphoma across Africa and Papua New Guinea corresponds to areas of holoendemic malaria and the early acquisition of EBV.13, 26, 27, 28, 29, 30, 31, 32 The annual incidence has been estimated at 40–50 per million children younger than 18 years.33 In these high-risk areas endemic Burkitt's lymphoma comprises about half of all childhood cancer diagnoses and up to 90% of lymphoma diagnoses. Incidence peaks at age 6 years and the disease is twice as common in

Epstein-Barr virus

Several observations suggest a direct causative role for EBV in endemic Burkitt's lymphoma. For example, EBV is consistently present in these tumours;37 infection of malignant B cells precedes tumorigenesis;38 EBV induces immortalisation of B cells in culture; and very high EBV antibody titres are recorded in children before development of the disease.39 However, the underlying mechanism linking EBV infection of B cells to the emergence of malignancy remains undiscovered.

Although EBV encodes

Clinical presentation

The most common site of presentation in sporadic Burkitt's lymphoma is the abdomen (60–80%).21 Presenting symptoms include abdominal pain (25% of patients have ileocaecal disease—either a right lower quadrant mass or pain from intussusception), distension, nausea and vomiting, and gastrointestinal bleeding.86, 87 The next most common site is the head and neck, including lymphadenopathy and involvement of the nasal or oropharynx, tonsils, or sinuses. The jaw is infrequently implicated. Bone

Histopathology and immunocytochemistry

Burkitt's lymphoma is a highly aggressive B-cell non-Hodgkin lymphoma characterised by monomorphic medium-sized cells with a very high proliferation rate (figure 4). The cells are intermediate in size and contain coarse chromatin and prominent basophilic nucleoli. Some plasmacytoid and atypical variants show more nuclear pleiomorphism. In tissue sections, typically the cells seem to be moulded and the cytoplasm is deeply basophilic with squared-off cytoplasmic margins. The proliferation index

Cytogenetics and molecular studies

The translocation t(8;14)(q24;q32) is the hallmark of Burkitt's lymphoma and occurs in 70–80% of patients. The variant translocations, t(2;8)(p12;q24) and t(8;22)(q24;q11), occur in 10–15% of patients.93, 94, 95 The molecular consequence of the three translocations is deregulated expression of the MYC oncogene, which has an essential role in cell cycle control. Deregulated expression arises as a result of juxtaposition of MYC to the enhancer elements of one of the immunoglobulin genes: the

High-income countries

Diagnosis of Burkitt's lymphoma should be confirmed by microscopy and immunocytological analysis (figure 5). The recommended approach is to remove and examine the most accessible disease-containing tissue. This sample could be a superficial lymph node or malignant pleural fluid. Excision biopsy of a lymph node is preferable to fine-needle aspiration, which does not provide sufficient tissue for all the investigations required. In some cases a laparotomy or laparoscopy is necessary to obtain

Prognostic markers

Therapy is guided partly by clinical and histopathological staging with biological features beginning to inform therapeutic strategies. Clinically, prognosis is determined by staging, which includes extent of disease.106 The St Jude/Murphy classification for Burkitt's lymphoma is the most common staging system used (panel).107 Cytogenetic analysis is important in diagnosis to identify MYC deregulation and the presence of additional cytogenetic abnormalities, some of which have been shown to

High-income countries

Treatment of Burkitt's lymphoma in most centres is guided by the FAB LMB study (cooperative study between the Children's Cancer Group, the Société Française d'Oncologie Pédiatrique, and the UK Children's Cancer Study Group)86, 87 or Berlin–Frankfurt–Münster protocols. The former consists of initial cytoreduction with cyclophosphamide, prednisolone, and vincristine, followed by more intensive chemotherapy in varying combinations. The risk of pronounced tumour lysis is high in the first few days

Outcome

The outcome for sporadic Burkitt's lymphoma in high-income countries is excellent with an overall cure rate of roughly 90%. In most studies all B-cell non-Hodgkin lymphomas and B-cell leukaemias are treated similarly. Separate subanalyses of children with Burkitt's lymphoma are not always published. Children with resected stage I and II disease have event-free survival and overall survival above 98%.17 Those with stage III and IV disease do less well if lactose dehydrogenase concentrations are

Adult Burkitt's lymphoma

Burkitt's lymphoma in adults is uncommon with an annual incidence of about 1200 patients in the USA. The disease occurs at any age, although 59% of patients are older than 40 years. As in children, in adults the disease can be associated with HIV infection or other immunodeficiencies.126 Outcome in adult patients has been poor, but is improving. No randomised therapeutic trials have been done for adult Burkitt's lymphoma.

Adults present with rapidly developing disease, commonly in the abdomen,

Future

In low-income countries better diagnostic testing is needed. When only morphology is available, tumours are probably incorrectly classified as Burkitt's lymphoma. Additionally, a high standard of supportive care and medical infrastructure is necessary to deliver the most effective therapy. New, effective, and inexpensive therapies are needed for low-income countries. One possibility is to use compounds with histone deacetylase inhibitor activity as adjuvant therapy.135 These agents stimulate

Search strategy and selection criteria

We searched for articles in English on Medline and Embase with the search terms “Burkitt lymphoma” and “Burkitt's lymphoma”, together with the terms “paediatric”, “pediatric”, “children”, “adult”, “sporadic”, “epidemiology”, “co factor”, “HIV”, “malaria”, “EBV”, “pathology”, “immunology”, “treatment”, and “outcome”. We also searched the reference lists of articles identified by this strategy. We did not limit ourselves by date so as to provide historical context.

Contributors

All the authors

References (137)

  • C Bellan et al.

    Immunoglobulin gene analysis reveals 2 distinct cells of origin for EBV-positive and EBV-negative Burkitt lymphomas

    Blood

    (2005)
  • A Chene et al.

    Endemic Burkitt's lymphoma as a polymicrobial disease: new insights on the interaction between Plasmodium falciparum and Epstein-Barr virus

    Semin Cancer Biol

    (2009)
  • CL Yone et al.

    Persistent Epstein-Barr viral reactivation in young African children with a history of severe Plasmodium falciparum malaria

    Trans R Soc Trop Med Hyg

    (2006)
  • KM Lam et al.

    Circulating Epstein-Barr virus-carrying B cells in acute malaria

    Lancet

    (1991)
  • S Yawetz et al.

    Elevated serum levels of soluble CD23 (sCD23) precede the appearance ofacquired immunodeficiency syndrome-associated non-Hodgkin's lymphoma

    Blood

    (1995)
  • CA van den Bosch

    Is endemic Burkitt's lymphoma an alliance between three infections and a tumour promoter?

    Lancet Oncol

    (2004)
  • T Aya et al.

    Chromosome translocation and c-MYC activation by Epstein-Barr virus and Euphorbia tirucalli in B lymphocytes

    Lancet

    (1991)
  • C Patte et al.

    The Societe Francaise d'Oncologie Pediatrique LMB89 protocol: highly effective multiagent chemotherapy tailored to the tumor burden and initial response in 561 unselected children with B-cell lymphomas and L3 leukemia

    Blood

    (2001)
  • A Bernheim et al.

    Cytogenetic studies on African Burkitt's lymphoma cell lines: t(8;14), t(2;8) and t(8;22) translocations

    Cancer Genet Cytogenet

    (1981)
  • B Shiramizu et al.

    Patterns of chromosomal breakpoint locations in Burkitt's lymphoma: relevance to geography and Epstein-Barr virus association

    Blood

    (1991)
  • MS Lindstrom et al.

    Role of genetic and epigenetic changes in Burkitt lymphoma

    Semin Cancer Biol

    (2002)
  • F Lovisa et al.

    IGH and IGK gene rearrangements as PCR targets for pediatric Burkitt's lymphoma and mature B-ALL MRD analysis

    Lab Invest

    (2009)
  • L Zech et al.

    Characteristic chromosomal abnormalities in biopsies and lymphoid-cell lines from patients with Burkitt and non-Burkitt lymphomas

    Int J Cancer

    (1976)
  • G Manolov et al.

    Marker band in one chromosome 14 from Burkitt lymphomas

    Nature

    (1972)
  • D Burkitt

    Etiology of Burkitt's lymphoma—an alternative hypothesis to a vectored virus

    J Natl Cancer Inst

    (1969)
  • DM Parkin et al.

    Cancer in Africa: epidemiology and prevalence. Burkitt lymphoma

    IARC Scientific Publications

    (2003)
  • GW Kafuko et al.

    Burkitt's lymphoma and malaria

    Int J Cancer

    (1970)
  • JN Davies

    Pathology of central African natives; Mulago Hospital post-mortem studies

    East Afr Med J

    (1948)
  • BG Elmes et al.

    Malignant disease in Nigeria; an analysis of a thousand tumours

    Ann Trop Med Parasitol

    (1947)
  • A Thijs

    Malignant tumors of Belgium Congo and Ruanda-Urundi natives; 2,536 case reports

    Ann Soc Belg Med Trop (1920)

    (1957)
  • D Burkitt

    A sarcoma involving the jaws in African children

    Br J Surg

    (1958)
  • GT O'Connor et al.

    Malignant tumors in African children. With special reference to malignant lymphoma

    J Pediatr

    (1960)
  • D Burkitt

    A “tumour safari” in east and central Africa

    Br J Cancer

    (1962)
  • M Gerrard et al.

    Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study

    Br J Haematol

    (2008)
  • R Rochford et al.

    Endemic Burkitt's lymphoma: a polymicrobial disease?

    Nat Rev Microbiol

    (2005)
  • ES Jaffe

    The 2008 WHO classification of lymphomas: implications for clinical practice and translational research

    Hematology Am Soc Hematol Educ Program

    (2009)
  • SM Mbulaiteye et al.

    Sporadic childhood Burkitt lymphoma incidence in the United States during 1992–2005

    Pediatr Blood Cancer

    (2009)
  • O Martinez-Maza et al.

    B-cell activation and lymphoma in patients with HIV

    Curr Opin Oncol

    (2002)
  • R Newton et al.

    A case-control study of human immunodeficiency virus infection and cancer in adults and children residing in Kampala, Uganda

    Int J Cancer

    (2001)
  • JA Ferry

    Burkitt's lymphoma: clinicopathologic features and differential diagnosis

    Oncologist

    (2006)
  • D Burkitt

    Determining the climatic limitations of a children's cancer common in Africa

    BMJ

    (1962)
  • D Burkitt

    A children's cancer dependent on environment

  • D Burkitt

    A lymphoma syndrome dependent on environment. ii. epidemiological features

    (1964)
  • P Cook-Mozaffari et al.

    The geographical distribution of Kaposi's sarcoma and of lymphomas in Africa before the AIDS epidemic

    Br J Cancer

    (1998)
  • AH Cardy et al.

    Burkitt's lymphoma: a review of the epidemiology

    Kuwait Med J

    (2001)
  • JJ Rainey et al.

    Spatial distribution of Burkitt's lymphoma in Kenya and association with malaria risk

    Trop Med Int Health

    (2007)
  • J Orem et al.

    Burkitt's lymphoma in Africa, a review of the epidemiology and etiology

    Afr Health Sci

    (2007)
  • OW Mwanda et al.

    Burkitt's lymphoma in Kenya: geographical, age, gender and ethnic distribution

    East Afr Med J

    (2004)
  • DP Burkitt

    Epidemiology of Burkitt's lymphoma

    Proc R Soc Med

    (1971)
  • A Geser et al.

    Final case reporting from the Ugandan prospective study of the relationship between EBV and Burkitt's lymphoma

    Int J Cancer

    (1982)
  • Cited by (0)

    View full text