Categories
ORGAN SYSTEMS

Burkitt lymphoma (BL)

Introduction

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
f2.large_
Bowzyk Al-Naeeb, A., Ajithkumar, T., Behan, S., & Hodson, D. J. (2018). Non-Hodgkin lymphoma. BMJ, 362, k3204. https://doi.org/10.1136/bmj.k3204

History

urncambridge.orgidbinary20180518072006985-0419s0954422417000117s0954422417000117_fig7t
Denis Parsons Burkitt FRS (1911 – 1993) was a surgeon who made significant advances in health, such as the etiology of a pediatric cancer, now called Burkitt’s lymphoma, and the finding that the rates of colorectal cancer is higher in those who eat limited dietary fiber.

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.

gr1
Molyneux, E. M., Rochford, R., Griffin, B., Newton, R., Jackson, G., Menon, G., … Bailey, S. (2012). Burkitt’s lymphoma. The Lancet, 379(9822), 1234–1244. https://doi.org/10.1016/S0140-6736(11)61177-X

Classification

  • 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.
Endemic Sporadic HIV‐associated
Distribution Equatorial belt of Africa and Papua New Guinea Worldwide Worldwide
EBV association 98% 5−10% 30−40%
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

 

Aetiology

  • 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)
1750-9378-8-35-1
Pathogenesis model of Burkitt lymphoma (BL) showing progression from a naïve B cell through a necessary pre-malignant stage involving chromosomal translocation of MYC on chromosome 8 into the vicinity of promoter elements of immunoglobulin genes on chromosome 14, 2, or 22 and progression of translocation-positive B cells to a clone of malignant BL. The first stage is indicated by letter a and the second stage by letter b. The transit times for these stages are unknown, but several assumptions are possible. First, exogenous exposures linked to high risk of BL, such as infection with malaria, Epstein-Barr virus, and human immunodeficiency virus (HIV) – in the West – may act by increasing the absolute number (load) of translocation-positive B cells, which would increase the number of initiated cells that can progress to BL and, hence, population incidence of BL. Second, the rate-limiting step of BL is the apoptosis feedback loop in translocation-positive B cells. Thus, exposures that increase the survival, i.e., circumvent apoptosis feedback loops in translocation-positive B cells until the abnormal cells develop capacity for self-perpetuation will increase the individual risk of BL. | Mbulaiteye S. M. (2013). Burkitt Lymphoma: beyond discoveries. Infectious agents and cancer, 8(1), 35. doi:10.1186/1750-9378-8-35

Pathophysiology

Genetic hallmark: Reciprocal translocation t(8:14) (75-85% cases)

  • Less commonly: t(8;22) or t(2;8)

burkitt

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.

cp47977.f1
Pathogenesis of Burkitt lymphoma | Brady, G., MacArthur, G. J., & Farrell, P. J. (2007). Epstein-Barr virus and Burkitt lymphoma. Journal of clinical pathology, 60(12), 1397–1402. doi:10.1136/jcp.2007.047977
  • “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:

41572_2019_132_fig1_html
B cell lymphomas are cancers that develop from the malignant transformation of B lymphocytes at various stages of ontogeny. Most are of mature B cell origin, and revolve around the germinal centre (GC) reaction, a critical step in which B cells are subject to intense proliferation and genomic remodelling processes — namely, somatic hypermutation and class-switch recombination — to generate memory B cells and plasma B cells that produce high-affinity antibodies. From naive B cells to memory B cells, most differentiation steps are associated with a malignant B cell subtype (defined as the cell of origin (COO)) on the basis of classic histological definitions and gene expression profiling. The COO assumes that B cell malignancies are ‘frozen’ at a given B cell differentiation stage arising in a particular location of the B cell follicle. For example, follicular lymphoma (FL) is a follicle-related B cell lymphoma that is considered the malignant counterpart of normal ‘frozen’ GC B cells. Unmutated mantle cell lymphoma (UM-MCL) originates from mantle zone B cells, marginal zone lymphoma (MZL) resembles marginal zone B cells whereas Burkitt lymphoma (BL) resembles dark zone B cells. Based on the COO, distinct diffuse large B cell lymphoma (DLBCL) molecular subtypes are defined as not otherwise specified DLBCL (DLBCL NOS), whereas, the GC B cell-like DLBCL corresponds to B cells that are arrested at various stages of the GC transit (from dark zone to light zone B cells) and the activated B cell-like DLBCL seems to derive from GC B cells en route to plasma cell differentiation, resembling plasmablasts. BCR, B cell receptor; FDC, follicular dendritic cell; M-MCL, mutated mantle cell lymphoma; MHC, major histocompatibility complex; TCR, T cell receptor; TFH, follicular T helper. | Basso, K. & Dalla-Favera, R. Germinal centres and B cell lymphomagenesis. Nat. Rev. Immunol. 15, 172–184 (2015). Return to ref 44 in article

Clinical features

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

Immunodeficiency-related BL:

  • Lymph nodes, bone marrow, and CNS
  • Underlying immunodeficiency symptoms
  • Burkitt leukaemia (advanced-stage BL): Extensive bone marrow and blood involvement

B symptoms:

  • Fevers, chills, night sweats or unexplained weight loss >10% of body weight
  • Frequent in patients with advanced-stage or bulky disease
non-hodgkin-lymphoma
The Calgary Guide | http://calgaryguide.ucalgary.ca/

 

Complications

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)

Diagnosis

Blood tests:

  • Pancytopenia (bone marrow infiltration)
  • Hyperuricemia (↑ cell turnover)
  • Hypercalcaemia
  • ↑↑ 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-).
ahmt-8-011fig2
Diagnostic pathology of BL: low magnification (×10, ×40) hematoxylin/eosin staining of BL sample involving the gastrointestinal tract, showing monotonous proliferation of medium-sized basophilic lymphoid cells punctuated by lightly colored macrophages (“starry sky” pattern) (A and B); immunohistochemistry, demonstrating staining for B-cell antigens including CD20 and the early CD10 antigen, with concurrent c-MYC and BCL6 expression and high proliferative rate (Ki67) (C–H). | Dozzo, M., Carobolante, F., Donisi, P. M., Scattolin, A., Maino, E., Sancetta, R., … Bassan, R. (2016). Burkitt lymphoma in adolescents and young adults: management challenges. Adolescent health, medicine and therapeutics, 8, 11–29. doi:10.2147/AHMT.S94170

Staging

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

Differential diagnosis

  • 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)

Management

Treatment must begin within 48 hours.

Combination chemotherapy:

  • 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)
f1.medium
A young boy in Monrovia, Liberia shows his before and after face a month into starting treatment for his endemic Burkitt’s Lymphoma. | Akhter, S. (2018). About Face: The Miracle of Chemotherapy in Endemic Burkitt’s Lymphoma in Liberia. Pediatrics, 142(1 MeetingAbstract), 539 LP – 539. https://doi.org/10.1542/peds.142.1_MeetingAbstract.539

Prognosis

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

Leave a Reply