2. A TYPICAL CLINICAL CASE
PRESENTATION
In February 2020, an asymptomatic 5-year-old boy underwent a pediatric examination for a left
submandibular swelling that gradually increased in size, with a hard-elastic consistency and was not
painful on palpation. Blood tests, prescribed by the pediatrician and performed in a private medical
center, were normal: the blood count with the leukocyte formula and the inflammation indexes such as
ESR and PCR were not altered, LDH was normal and anti-CMV IgM were negative, anti-EBV VCA and
anti-toxoplasma IgM. The child underwent an ultrasound of the neck which showed numerous lymph
nodes increased in size in the left submandibular site; The pediatrician prescribed amoxicillin / clavulanic acid
therapy for six days and despite taking antibiotics, the swelling had increased in size. In March the boy
came to our hospital for further diagnostic information; he repeated the blood tests, which were normal,
and underwent an ultrasound of the cervical, axillary and inguinal lymph nodes, testicles and complete
abdomen. The ultrasound of the neck showed in the left submandibular seat a coarse lymph node of the
size of 38x30 mm, with a markedly and unevenly hypoechoic echostructure and anarchic
vascularization at the colour doppler.
3. TABLE OF CONTENT
BACKGROUND
INTRODUCTION
EPIDEMIOLOGY
PATHOGENESIS
MALARIA ASSOCIATED AND AIDS ASSOCIATED LYMPHOMA
INCIDENCE
CCLINICAL FEATURES
DIAGNOSIS
STAGING
DIFFERENTIAL DIAGNOSIS
TREARMENT
PROGNOSIS
REFERENCES
5. Burkitt’s Lymphoma: Background
• Burkitt's lymphoma (BL) is a tumor which
was first described in 1958 by Denis Burkitt,
a surgeon working in Africa.
• It is a solid tumor of B lymphocytes which
form part of the white cell population in the
blood and lymph glands.
• It is one form of non-Hodgkin's lymphoma.
The type of cell affected in Burkitt's
lymphoma is the B lymphocyte which is
normally involved in fighting infection by
producing antibodies.
6. Endemic Burkitt lymphoma(BL) is the
most common childhood cancer in
Africa .
The first description of Burkitt
lymphoma (BL) was probably that of
Albert Cook, the first missionary doctor
in Uganda, who founded Mengo
Hospital and subsequently Mulago
Hospital, initially a centre for the
treatment of tuberculosis, which
eventually became the University
Hospital of Makerere University.
6
7. INTRODUCTION
One of Cook’s patients was a child with a
large jaw tumour, and his illustration of the
appearance in his meticulous notes leaves
little doubt that this was a case of BL.
In the first half of the 20th century, a number
of European pathologists working in
equatorial Africa noted the high frequency of
jaw tumours or of lymphomas in children
(Smith & Elmes, 1934; Davies, 1948; De
Smet, 1956; Edington, 1956; Thijs, 1957).
7
8. INTRODUCTION
But it was Denis Burkitt who
provided the first detailed
clinical description of the
tumour in 1958 while working
at Mulago Hospital (Burkitt,
1958).
He recognized a number of
different clinical presentations
of tumours in children,
including jaw tumours and
intra-abdominal tumours,
that could occur either alone
or together, and it was this
8
9. Denis Parsons Burkitt
9
Born 1911, Ireland; Died 1993
Lost his right eye at the age of
11 in an accident.
Trained as a surgeon in Trinity
College, Dublin.
Went to East Africa (Kenya,
Somaliland, then Uganda) in World
War II. Joined the colonial service
in Uganda in 1946 as GP in Lira,
then became a surgeon in Mulago
Hospital, Kampala.
Saw his first case of jaw tumor in a
boy of 5 in the children’s ward in
1957, then a second a few weeks
later. Surgery not possible: both
children died soon after.
10. Recognition of Burkitt Lymphoma
1958
Denis Burkitt
Describes a
Clinical Syndrome..
1910:
Albert Cooke
Describes Jaw Tumor in
Mengo Hospital.
1934-57:
Descriptions of Jaw
Tumors and High Frequency
of Lymphomas in African
Children.
O’Connor
1960-61:
Burkitt 1962:
Climatic
10
11. Milestones in endemic burkitt lymphoma
[bl] research
Endemic Burkitt's lymphoma: a polymicrobial disease?
Rosemary Rochford, Martin J. Cannon & Ann M. Moormann
Nature Reviews Microbiology 3, 182-187 (February 2005)
13. Epidemiology: clues to the pathogenesis of
Burkitt lymphoma
The two major epidemiological clues to the
pathogenesis of Burkitt lymphoma (BL) are:
1. the geographical association with
malaria – BL incidence relates to the
malaria transmission rate – and:
2. early infection by Epstein–Barr virus
(EBV).
Both agents cause B cell hyperplasia, which
is almost certainly an essential component of
lymphomagenesis in BL.
14. Epidemiology: clues to the pathogenesis of
Burkitt lymphoma [contd.]
The critical event in lymphomagenesis is the creation of
a MYC translocation, bringing the MYC gene into
juxtaposition with immunoglobulin genes and causing
its ectopic expression, thereby driving the proliferation
of BL cells.
It is highly likely that such translocations are mediated
by the activation-induced cytidine deaminase (AID)
gene, which is responsible for hypervariable region
mutations as well as class switching. Stimulation of the
Toll-like receptor 9 by malaria-associated agonists
induces AID, providing a mechanism whereby malaria
could directly influence BL pathogenesis.
15. Epidemiology: clues to the pathogenesis
of Burkitt lymphoma [contd.]
EBV-containing cells must reach the memory cell
compartment in order to survive throughout the life of the
individual, which probably requires traversal of the
germinal centre. Normally, cells that do not produce high
affinity antibodies do not survive this passage, and are
induced to undergo apoptosis.
EBV, however, prevents this, and in doing so may also
enhance the likelihood of survival of rare translocation-
containing cells.
16. In 1964, the Epstein-Barr virus [EBV] was
recognized in electron micrographs of BL-cells.
This led to the finding that BL-patients had high
antibody titres to EBV antigens.
Apart from this, it was shown that over 80% of
tumors contain multiple copies of EBV-DNA
genome.
It is also established that over 80% of African
children under 5 years of age were infected
with EBV whilst studies in Ugandan children
demonstrated that those who had high EBV
antibodies subsequently developed BL.
All this evidence pointed to EBV as a
possible caustive agent.
16
18. Malaria Association with BL
1964: Dalldorf suggests climatic distribution
could relate to holoendemic malaria.
Geographic distribution of malaria and BL
very similar (NB. Zanzibar – formerly free of
both).
BL has higher incidence in regions of intense
malarial infection (some exceptions).
De Thé: chloroquine prophylaxis in Mara
Masai region: decrease (?) in incidence of BL
Sickle cell trait protects against malaria trend
to protection against BL, but insufficient data.
18
19. Malaria Association with BL [contd.]
The so-called lymphoma
belt (black) extending
across equatorial Africa.
It extends approximately
100 –150 north and south
of the equator with a
prolongation to the south
on the east coast.
Altitude is usually not
above 1500 meters.
Annual rainfall is not less
than 50cm.
Ambient temperatures not
below 26.6 0C.
19
21. Malaria: Possible Pathogenetic Mechanisms
Malaria has also been postulated as a co-factor,
by priming the lymphatic system for a causative
agent.
Malaria could promote BL in various ways, but
probably acts primarily through its ability to
increase the fraction of cells infected by EBV.
It could also alter the cell types infected by EBV
– e.g., permit infection of immature cells
The malarial attack is said to activate
polyclonal B-cells.Polyclonal not monoclonal
21
22. Malaria: Possible Pathogenetic
Mechanisms [contd.]
Advances in cytogenics have thrown more light on
the pathogenesis of BL.
C-MYC, an oncogene located on the long arm of
chromosome 8, has been observed to be
translocated to the genetic loci on chromosome 14,
2 or 22 that code for immunoglobulins.
Uncontrolled proliferation of B-lymphocytes results,
probably representing the critical step in the
oncogenesis of BL.
The fact that the tumour can arise wherever B-
lymphocytes are found in the body probably
explains that varied presenting sites and clinical
features.
22
23. Evidence for Importance of Deregulated Myc
Myc not expressed in normal germinal
follicle cells
Multiple types of translocation (8;14, 2;8
and 8;22 as well as (rarely) non-Ig
translocations are associated with major
structural changes or mutations (regulatory
region or coding region) in Myc.
Myc translocations also present in B cell
neoplasms in mice and rats.
23
24. Burkitt’s Lymphoma -
Karyotype:
* Here is an actual karyotype (courtesy of Janet Finan and C.
M. Croce) of a cell from the tumor of a patient with Burkitt's
lymphoma. The long (q) arm of the resulting chromosome 8 is
shorter (8q-) than its normal homologue; the long arm of
25. Burkitt’s Lymphoma -
* In most
(approximately 90%)
of the cases of
Burkitt's lymphoma,
a reciprocal
translocation has
moved the proto-
oncogene c-myc
from its normal
position on
chromosome 8 to a
location close to the
enhancers of the
26. AIDS-associated Burkitt lymphoma
Ziegler et al (1984) described the increased incidence
of NHLs in homosexual males and subsequently, the
association of BL with HIV seropositivity was reported
(Wiggill et al, 2011).
Since then, the relationship between NHL and HIV
infection has been confirmed in many parts of the
world, including, for example, South Africa.
It remains uncertain, however, how much HIV
infection predisposes to BL in equatorial Africa. In
fact, the relationship is tenuous at best, at least in
children as, although a few percent of children with
BL are HIV positive, this is similar to the frequency of
HIV infection in children in the normal population.
26
27. AIDS-associated Burkitt lymphoma
[contd.]
Similarly, although HIV infection is more prevalent in adults,
the degree to which it predisposes to adult BL in equatorial
Africa is uncertain (Parkin et al, 2000; Mutalima et al, 2010).
HIV is known to alter the immune response to malaria,
resulting in increased prevalence and severity of clinical
malaria (Flateau et al, 2011), and this could, in turn, result in
an increased predisposition to BL. HIV infection also causes
B-cell hyperplasia, and, like malaria, increases the
proportion of circulating EBV-containing cells, resulting from
the reactivation of EBV infection, thus increasing the EBV
load in HIV-infected individuals (Bonnet et al, 2006; Richard
et al, 2010). However, the memory B cell population is
reduced in HIV infection, and other B cells may become the
primary EBV reservoir (Richard et al, 2010).
27
28. AIDS-associated Burkitt lymphoma
[contd.]
Thus, even though HIV+ individuals have a
higher EBV load than HIV) persons, the lack of
an obvious connection between HIV infection
and predisposition to BL, at least in children, may
be indicative of differences in the pathogenesis
of HIV+ and HIV) BL in Africa that have yet to be
determined.
28
29. Burkitt’s Lymphoma: Incidence
The incidence of Burkitt's lymphoma [BL]
shows great geographical variation.
It is the most common childhood tumor in
equatorial Africa but is very rare in children in
Western countries.
BL accounts for over half of all malignant
tumours in tropical Africa.
Over 90% of patients present between the
ages of 4 and 9 years.
Peak age being 5 years.
30. Age distribution of Burkitt lymphoma in
Africa (a) and the United States (b).
30
Jaw and orbital tumours are particularly common in young
children in African Burkitt lymphoma (fraction of patients
with jaw tumours is indicated by the red column in (a)) but
not in Burkitt lymphoma in the United States.
31. Burkitt’s Lymphoma: Incidence
[contd.]
No cases have been reported under one
year of age.
Rarely cases have been reported above 20
years.
Males are twice more likely to suffer from
this disorder as opposed to females.
MALES
Recently Burkitt's lymphoma has been
diagnosed in around 2% of AIDS patients.
33. Clinical Features of Burkitt
Lymphoma
1. The jaw * is the
part of the body
most affected,
often presenting
as a swelling in
75 % of patients,
with the maxilla
being more
affected than the
mandible.
34. Clinical Features of Burkitt Lymphoma
[contd].
Note:
* In African [endemic] Burkitt's lymphoma
the jaw is the commonest site where it
causes visible swelling of the cheek and
loosening of the teeth.
* In non-African Burkitt’s lymphoma the
tumor commonly arises in the abdomen
where it causes swelling and discomfort.
35. Clinical Features of Burkitt
Lymphoma [contd].
2. The maxillary
tumor often
spreads to
involve the
orbit, causing
exophthalmos.
The swelling is
often painless.
36. Clinical Features of Burkitt
Lymphoma [contd].
3. Early in the
course of the
illness,
looseness of
the teeth may
occur, with
gingival
swelling [which
on a radiograph
of the jaw may
show loss of
lamina dura].-
37. Clinical Features of Burkitt
Lymphoma [contd].
4. Abdominal
masses
involving the
ovaries,
kidneys,
mesenteric
nodes and
peritoneum are
also
encountered.
38. Clinical Features of Burkitt
Lymphoma [contd].
5. Patients may also present with
paraplegia, which indicates involvement of
the CNS, secondary to damage to the
vertebral body.
6. BL is one of the commonest causes of
paraplegia in the African child.Tryto r/o Tb
spine
7. Abnormal CSF cytology or cranial nerve
palsy may be the only evidence of CNS
39. Clinical Features of Burkitt Lymphoma
[contd].
8. Other organs occasionally involved
include the breast, thyroid and testis.
40. Clinical Features of Burkitt
Lymphoma [contd].
9. An unusual feature of BL is presentation
as leukemia.
This is considered a pre-terminal event and
is seen in patients with extensive tumour
burden and in cases of relapse.
Bone marrow infiltration can occur in 15-20%
of patients.
42. Burkitt’s Lymphoma –
Diagnosis
*A rapidly growing tumor of the jaws or
abdomen should raise the suspicion of a
BL.
* Loose teeth and involvement of other
organs should strengthen this suspicion.
• The rate of growth of the tumour is so rapid
that the patient can present within one or
two weeks of the onset.
• A longer history makes the suspicion less.
43. Burkitt’s Lymphoma –
Diagnosis
* Burkitt's lymphoma is diagnosed from a biopsy
sample of the tumor. A small piece of the tumor is
removed by surgery and the sample, stained by
specific dyes, is examined under the microscope
by a pathologist.
* Burkitt's lymphoma can be differentiated from other
tumors by the distinctive pattern of tumor cells
which is known as a “starry-sky” pattern.
* It is possible to use specialized laboratory
44. Burkitt’s Lymphoma –
Diagnosis … cont’d
* Biopsies of
Burkitt’s
Lymphoma
patients show
a ‘starry sky’
pattern like
the one seen
to the left.
45. The tumor cells
A diagnosis can be confirmed by biopsy
and histology.
Histologically, BL in the African child is
the same as in the sporadic cases
elsewhere.
BL [high-grade, small non-cleaved cell
lyphoma as per the Working Formulation]
being a malignancy of B-cell origin,
characteristically bears surface
46. The description of the tumor cells
The tumour consists of sheets
of fairly uniform rather
monotonous cells of about 10-
25 um in diameter.
The nuclei are round to oval,
and contain multiple [2-5]
prominent nucleoli.
The cytoplasm is moderate,
lightly basophilic or
amphophilic, and is intensely
pyrinophilic; i.e., it stains
intensely with methly green
pyronine.
47. “starry sky” appearance
Scattered diffusely
amongst the tumour
cells are benign
phagocytic
macrophages with
retracted cytoplasm,
thereby creating
empty spaces
between the cells
and the adjacent
tissue.
This striking feature
48. About the “starry sky” appearance.....
This “starry sky” appearance is not
pathognomonic for BL, as it is seen in
other rapidly dividing lymphoreticular
malignancies.
49. Burkitt’s Lymphoma – Diagnosis [contd.]
Other investigations include:
Plain radiographs of affected bones.
Intravenous urograms [IVU].
Intra- or extra-medullary tumours of the spinal
column can be diagnosed with myelograms.
CT scans can be of immense help in CNS
involvement.
Bone marrow infiltration can occur in 15-20% of
patients and makes bone marrow aspiration with
histology and peripheral blood smears necessary.
CSF cytology at 1st visit [since > 50% of patients may
have CNS involvement at some time in the course of
the disease].
50. Staging of Burkitt Lymphoma
50
Staging: This is a description of the extent of
tumor spread in the body and is useful in
determining the form of treatment and outcome.
It should therefore be carried out as early as
possible.
Two methods can be used.
51. Staging of Burkitt Lymphoma: [method 1]
Stag
e
Definition
I. Disease limited to one anatomical area
II. a. Disease limited to two contiguous areas
b. Disease present in two or more non-adjacent
areas, but on the same side of the diaphragm.
III. a. Disease involves structures on both sides of
the diaphragm
b. Disease involves structures on both sides of
the diaphragm, but also with presence of
tumour cells in the bone marrow or blood
stream.
52. Staging of Burkitt Lymphoma: [method 2]
Method 2: For a simple evaluation, patients can be
divided into two groups:
Those with small tumour burdens [stages A,B,AR].
Those with large tumour burden [stages C and D].
53. Staging of Burkitt Lymphoma: [method 2]
Stag
e
Definition
A. A single Extra-abdominal tumour site
B. Multiple Extra-abdominal tumour site
AR. Completely [> 90%] resected Intra-abdominal
tumour
C. Intra-abdominal tumour without involvement of
other sites
D. Intra-abdominal and Extra-abdominal tumour
sites.
55. Differential Diagnosis of Burkitt Lymphoma
A. [In cases of jaw swelling]: dental cysts;
osteomyelitis of the jaw bones.
B. [In orbital swelling]: advanced
retinoblastoma; metastatic
neuroblastoma; rhabdomyosarcoma.
C. [In ovarian tumours]: neuro-abdominal
swelling.
D. Tuberculosis of the spine [Potts’s
disease] should always be borne in mind
when the patient presents with paraplegia.
57. Burkitt’s Lymphoma –
Treatment
• Although Burkitt's lymphoma is a very rapidly
growing tumor it responds well to aggressive
treatment.
• In African children the drug cyclophosphamide is the
treatment of choice. This drug is so effective that
one dose may be enough to cause the tumor to
disappear. However, it is very important to complete
the course of treatment in order to prevent the tumor
recurring.
* In AIDS patients treatment is less successful
because of the underlying HIV infection. In addition
to drugs, these patients are usually given X-rays
which cause the tumor to shrink.
58. Burkitt’s Lymphoma –
Treatment [contd.]
• The drugs that have been found to be effective
are cyclophosphamide, methotrexate,
cytosine arabinoside, vincristine and
melphalan. ;[+prednisolone].
• A single large dose of drugs is preferred to
smaller doses of a larger amount over a longer
period.
• The disease stage is more important than the
size of the tumour.
59. Burkitt’s Lymphoma – Treatment
[contd.]
• Cyclophosphamide: 30-40mg/kg, repeated at
2-3 weekly intervals.
• Vincristine: 1.4mg/m2 iv on the first day of a
four day schedule.
• Methotrexate: 15mg.m2, and
• Cytosine arabinoside 250mg/m2 are given in a
daily infusion for 3 days.
• [Methotrexate and cytosine arabinoside are
available for intra-thecal administration and
many centers use them prophylactically, with
beneficial results, especially against relapse.
60. Burkitt’s Lymphoma – Treatment
[contd.]
• It is necessary to follow the blood parameters
with a weekly full blood count.
• A satisfactory urinary output before the
onset of chemotherapy should be ensured
with adequate fluid intake.
• In anticipation of the hyperuricemia that
usually follows chemotherapy, allopurinol
[100mg thrice daily], is usually given.
61. • Fungating or ulcerating tumours of the jaw
can be treated with chlorhexidine [0.5%] in
water as a mouth wash or spray.
• Radiotherapy is not very effective,
probable because of the rapid growth of
the tumour.
64. Need to Improve Access to Care for More Children
3.5
weeks
Total
cost of
chemo ~
$200
INCTR African BL Treatment
Project
64
65. Burkitt’s Lymphoma – Prognosis
• Factors considered important for prognosis
include:
The extent of the tumour burden;
Bone marrow involvement;
Peripheral manifestation;
CNS involvement
Presentation above the age of 13 years.
• Although the overall response of BL to
chemotherapy is about 90%, the relapse rate is
up to 50%.
• Relapse shortly after remission has a poorer
prognosis, but younger patients survive better.
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