Highly aggressive, rapidly growing B cell non-Hodgkin lymphoma, which manifests in several subtypes including sporadic, endemic, and immunodeficiency-associated forms.
- M/rapidly progressive human tumour (cell doubling time: 25 hours)
- M/aggressive non-Hodgkin lymphoma (NHL)
- Age-defining lymphoma
- Other age-defining lymphomas: Kaposi sarcoma, CNS lymphoma, cervical cancer
Burkitt Lymphoma (BL) was first described in African children by Dennis Burkitt . Within less than 10 years, Burkitt’s report of an obscure tumour in Africa had a dramatic impact on epidemiology, virology, immunology and oncology, spawning over 10,000 publications within a few decades of its description in 1958. Originally considered peculiar to Africa, characterization of histochemical and cytological properties of BL led to the recognition of cases worldwide and the realization that the discovery had a universal relevance. Notable geographic differences in BL incidence were apparent and suggested aetiology by a vectored virus. They also suggested an intuitive classification of the types of BL as “endemic BL “when occurring at a high incidence and “sporadic BL” when occurring at low incidence.
Study of BL led to a quick succession of seminal discoveries. Epstein-Barr virus (EBV) was discovered in 1964 in tumour cells cultured from an African case examined by electron microscopy. Dramatic response to chemotherapy and a cure of BL was reported and replicated in trial and error efforts. Chromosomal translocations involving light and heavy chain immunoglobulin genes and MYC were discovered in BL tumours, unlocking new ways to study tumour biology. The study of mouse tumours with analogous translocations – plasmacytomas -became an important resource for developing monoclonal antibodies. In 1969, after epidemiological studies confirmed that EBV, the virus found in BL tumours, was not transmitted by a vector, Dennis Burkitt proposed recurrent infection with Plasmodium falciparum (Pf) as co-factor in BL aetiology. Today, BL is considered a model disease to understand the poly-microbial and the genetic basis of cancer. Specifically, a pathogenesis model can be constructed, where the nodes of risk comprise of exposures to infections that may increase the risk of developing chromosomal translocation and exposures that confer longevity to translocation-positive B cells by circumventing apoptosis feedback loops induced by overexpression of c-MYC.
- Sporadic (American) BL (sBL) (30–50% of pediatric lymphomas):
- GI symptoms, paraaortic/preaortic lymphadenopathy
- Endemic (African) BL (eBL) (74% of all childhood cancer in equatorial Africa)
- Jaw tumours
- Immunodeficiency-associated BL:
- HIV-infection (M/C)
- Allograft recipients
- Congenital immunodeficiency.
|Distribution||Equatorial belt of Africa and Papua New Guinea||Worldwide||Worldwide|
|Co‐factors||EBV, malaria infection||–||HIV infection|
|Incidence||5–10/100 000||0.01/100 000||Variable|
|MYC breakpoint||Often >1 kb upstream from 1st coding exon||Exon 1/intron 1 of MYC gene||Exon 1/intron 1 of MYC gene|
|Ig breakpoint||Joining (J) region, switch (S)μ in some cases||Sμ, Sα or J region||Sμ region|
|Progenitor cell||GC, late GC or memory B cell||GC B cell||GC, late GC or memory B cell|
|Frequent site of occurrence||Most frequently jaw. Abdomen, kidneys and ovaries may also be involved||Most frequently abdomen. Kidneys, bone marrow and ovaries may also be involved||Lymph nodes, abdomen, bone marrow, CNS|
- Ebstein-Barr virus (EBV) infection (95% cases)
- EBV has the potential to transform normal human B lymphocytes into continuously growing immortalized cells such as BL and B-lymphoblastoid cells.
- HIV infection
- eBL: Endemic Plasmodium falciparum malaria (hyperstimulation of B cells and suppression of T-cell activity by malaria allow for reactivation of EBV in infected B cells, which consequently increase in numbers)
Genetic hallmark: Reciprocal translocation t(8:14) (75-85% cases)
- Less commonly: t(8;22) or t(2;8)
Reciprocal translocation t(8:14)
(Translocation of the MYC proto-oncogene to an immunoglobulin (Ig) locus)
Upregulation of the c-myc protein transcription factor
Upregulation of cell proliferation.
- “Double hit” lymphoma: MYC and BCL–2 (or less commonly BCL–6) rearrangements
- “Triple-hit” lymphoma: MYC, BCL–2, and BCL–6 rearrangements.
Origin of mature B cell lymphomas:
Patients present rapidly growing tumour masses and often have signs of rapid tumour turnover with high serum lactate dehydrogenase (LDH) concentration and elevated uric acid.
Endemic (African) BL (eBL):
- Jaw/facial bone tumour (50–60% cases)
- Other sites: mesentery, ovary, testis, kidney, breast, and meninges, spreading to lymph nodes, mediastinum, and spleen (less frequently)
- Bone marrow involvement (<10%, but common in recurrence/treatment resistance)
Sporadic (American) BL (sBL):
- Abdominal presentation (91%) with massive disease and ascites, involving distal ileum, stomach, cecum and/or mesentery, kidney, testis/ovary (6%), and breast
- Bone marrow (20%) and/or CNS involvement (14%)
- Involvement more common with recurrent or resistant disease
- Presenting symptoms: Bowel obstruction or gastrointestinal bleeding, mimicking acute appendicitis or intussusception.
- Localized lymphadenopathy
- Lymph nodes, bone marrow, and CNS
- Underlying immunodeficiency symptoms
- Burkitt leukaemia (advanced-stage BL): Extensive bone marrow and blood involvement
- Fevers, chills, night sweats or unexplained weight loss >10% of body weight
- Frequent in patients with advanced-stage or bulky disease
Tumour lysis syndrome (TLS):
Potential complication of therapy due to rapid growth rates of tumor cells caused by release of cellular products overwhelming the kidneys’ excretory capacity.
- Kidney damage → Electrolyte imbalances (hyperkalemia, hyperphosphatemia, hyperuricemia) → Kidney failure
- ℞: IV hydration, hypouricemic agents (allopurinol, rasburicase) & dialysis (if indicated)
- Pancytopenia (bone marrow infiltration)
- Hyperuricemia (↑ cell turnover)
- ↑↑ LDH
- Serum protein electrophoresis: M spikes
Core-needle/excisional biopsy (no FNAC):
- Cytoplasm lipid vacuoles
- Very high mitotic figures (highest rate of cell division for any known tumour)
- Starry-sky pattern (imparted by numerous benign macrophages that have ingested apoptotic tumor cells)
- Immunophenotype: B cell-associated antigens (CD19, CD20, CD22, CD79a), germinal center-associated markers (CD10 & BCL-6), & CD43, BCL-2 (20% cases), lack expression of (CD23-, CD5- & Tdt-).
Ann Arbor staging system with Cotswolds modification:
Staging system for lymphomas, both in Hodgkin’s lymphoma (formerly designated Hodgkin’s disease) and non-Hodgkin lymphoma (abbreviated NHL)
- Principal stages (determined by location):
- Stage I: Single site (nodal/extranodal)
- Stage II: ≥ 2 LN on same side of diaphragm (number of anatomic sites should be indicated in a suffix: e.g. II2)
- Stage III: LN/structures on both sides of diaphragm:
- III1: With/without splenic, hilar, celiac or portal nodes
- III2: With paraaortic, iliac or mesenteric nodes
- Stage IV: Diffuse, disseminated, several extranodal ± nodal involvement
- Modifiers (can be appended to some stages):
- A: No B symptoms
- B: B symptoms present
- S (spleen)
- E “extranodal”
- X (largest deposit is >10 cm large (“bulky disease”), or whether the mediastinum is wider than ⅓ of the chest on a chest X-ray)
St.Jude’s/Murphy classification: Pediatric NHL
- Diffuse large B-cell lymphoma (DLBCL)
- Unclassifiable BL/DLBCL (extremely poor prognosis)
- Grey-zone lymphomas (other tumors with histomorphological and immunohistochemical features intermediate between BL and DLBCL)
Treatment must begin within 48 hours.
- Cyclophosphamide (adv effect: hemorrhagic cystitis)
- Key component
- R-CHOP regimen not effective
- Prophylactic therapy to the CNS is mandatory (as chemotherapy does not cross BBB)
International prognostic index (IPI):
- Age > 60 years
- ↑ Serum lactate dehydrogenase (LDH)
- Performance status ≥ 2 (ECOG) or ≤70 (Karnofsky)
- Ann Arbor Stage III/IV
- ≥ 2 sites of extranodal involvement