1. الرحيم الرحمن هللا بسم
Clinical presentation of Lymphoma
Unit prof/Ahmed alamen alsheikh
Mestr/Ahmed kamal
Presented by Mogahed ismail
2. lymphoid Structures
Lymph node:
A 2° lymphoid organ that has many afferents, 1 or more efferents. Encapsulated, with
trabeculae. Functions are nonspecific filtration by macrophages, storage of B and T
cells, and immune response activation.
1-Follicle :
Site of B-cell localization and proliferation. In outer cortex. 1° follicles are dense and
dormant. 2° follicles have pale central germinal centers and are active.
2-Medulla :
Consists of medullary cords (closely packed lymphocytes and plasma cells) and medullary
sinuses. Medullary sinuses communicate with efferent lymphatics and contain reticular cells
and macrophages.
3-Paracortex :
Houses T cells. Region of cortex between follicles and medulla. Contains high endothelial
venules through which T and B cells enter from blood. Not well developed in patients with
DiGeorge syndrome. Paracortex enlarges in an extreme cellular immune response (eg, viral
infection).
5. lymphoid Structures
SPLEEN:
Long, vascular channels in red pulp (red arrow
in A) with fenestrated “barrel hoop” basement
membrane. ƒ
T cells are found in the periarteriolar lymphatic
sheath (PALS) within the white pulp (white
arrow in A). ƒ
B cells are found in follicles within the white
pulp. ƒ
The marginal zone, in between the red pulp
and white pulp, contains macrophages and
specialized B cells, and is where
antigenpresenting cells (APCs) capture blood-
borne antigens for recognition by lymphocytes.
Macrophages found nearby in spleen remove
encapsulated bacteria.
6. Clinical note
Splenic dysfunction (eg, postsplenectomy, sickle cell disease): •decrease IgM lead to
decrease in complement activation which cuz decrease in C3b opsonization and thus
increaseŽsusceptibility to encapsulated organisms (Please SHINE my SKiS): ƒ
Pseudomonas aeruginosa
ƒStreptococcus pneumoniae ƒ
Haemophilus Influenzae type b ƒ
Neisseria meningitidis ƒ
Escherichia coli ƒ
Salmonella spp. ƒ
Klebsiella pneumoniae ƒ
Group B Streptococci
Postsplenectomy: ƒ
Howell-Jolly bodies (nuclear remnants) ƒTarget cells ƒThrombocytosis (loss of
sequestration and removal) ƒLymphocytosis (loss of sequestration)
8. Lymphoma
BASIC PRINCIPLES :
Neoplastic proliferation of lymphoid cells that forms a mass; may
arise in a lymph node or in exlranodal tissue .
Divided into non-Hodgkin lymphoma (NHL, 60%) and Hodgkin
lymphoma (HL, 40%) .
9. Hodgkin VS Non-Hodgkin
Hodgkin non-Hodgkin lymphoma
Localized, single group of nodes;
contiguous spread (stage is strongest
predictor of prognosis). Many patients
have a relatively good prognosis.
Multiple lymph nodes involved;
extranodal involvement common;
noncontiguous spread.
Characterized by Reed-Sternberg cells. Majority involve B cells; a few are of T-cell
lineage.
Bimodal distribution–young adulthood
and > 55 years; more common in men
except for nodular sclerosing type.
Can occur in children and adults.
Associated with EBV. May be associated with HIV and
autoimmune diseases.
Constitutional (“B”) signs/symptoms: low-
grade fever, night sweats, weight loss.
May present with constitutional
signs/symptoms.
10.
11. Hodgkin
BASIC PRINCIPLES :
A. Hodgkin lymphoma is a potentially curable lymphoma . Neoplastic proliferation of
Reed-Slernberg (RS) cells, which are large B cells with multilobcd nuclei and
prominent nucleoli ('owl-eyed nuclei'); classically positive for CD15 and CD30
B. RS cells secrete cytokines:
1. Occasionally results in 'B' symptoms (fever, chills, and night sweats)
2. Attract reactive lymphocytes, plasma cells, macrophages, and eosinophils
3. May lead to fibrosis
C. Reactive inflammatory cells make up a bulk of the tumor and form the basis for
classification of Hl„ Subtypes include
1. Nodular sclerosis 2. Lymphocyte-rich 3. Mixed cellularity
4. Lymphocyte-depleted
12. Hodgkin
D. Nodular sclerosis is the most common subtype of HI, (70% of all cases),
1.Classic presentation is an enlarging cervical or mediastinal lymph node in a young
adult, usually female.
E. Important considerations regarding other subtypes of HL
I. Lymphocyte-rich has the best prognosis of all types.
2. Mixed cellularity is often associated with abundant eosinophils (RS cells produce
IL-5).
3. Lymphocyte-depleted is the most aggressive of all types; usually seen in the elderly
and HIV-positive individuals.
13.
14. Hodgkin
History
Features of Hodgkin lymphoma include the following:
Asymptomatic lymphadenopathy may be present (above the diaphragm in 80% of
patients) Constitutional symptoms (eg, unexplained weight loss [>10% of total body
weight], unexplained fever, night sweats) are present in 40% of patients; collectively,
these are known as "B symptoms“ Intermittent fever is observed in approximately 35%
of cases; infrequently, the classic Pel-Ebstein fever is observed (high fever for 1-2 wk,
followed by an afebrile period of 1-2 wk) Chest pain, cough, shortness of breath, or a
combination of those may be present due to a large mediastinal mass or lung
involvement; rarely, hemoptysis occurs. Patients may present with pruritus.
Pain at sites of nodal disease, precipitated by drinking alcohol, occurs in fewer than
10% of patients but is specific for Hodgkin lymphoma.
Back or bone pain may rarely occur.
A family history is also helpful; in particular, nodular sclerosis Hodgkin lymphoma
(NSHL) has a strong genetic component and has often previously been diagnosed in
the family
15. Hodgkin
Physical examination
Palpable, painless lymphadenopathy can be seen in the cervical area (neck, 60-80%),
axilla (armpit, 6-20%), and, less commonly, in the inguinal area (groin, 6-20%)
Involvement of the Waldeyer ring (back of the throat, including the tonsils) or occipital
(lower rear of the head) or epitrochlear (inside the upper arm near the elbow) areas is
infrequently observed
Splenomegaly and/or hepatomegaly may be present
Superior vena cava syndrome may develop in patients with massive mediastinal
lymphadenopathy
Central nervous system (CNS) symptoms or signs may be due to paraneoplastic
syndromes, including cerebellar degeneration, neuropathy, Guillain-Barre syndrome,
or multifocal leukoencephalopathy
16. Hodgkin
Diagnostic Considerations
Other conditions to consider in the differential diagnosis of Hodgkin lymphoma
include the following:
Any disease presenting with lymphadenopathy and constitutional symptoms
Infection with human immunodeficiency virus (HIV)
Hypersensitivity reaction
Other solid tumors
Non-Hodgkin lymphoma, particularly diffuse large B cell lymphoma and anaplastic
large cell lymphoma, both of which may have CD30 expression
17. Hodgkin
Because Hodgkin lymphoma is considered a curable malignancy and the differential
diagnosis is broad, medicolegal problems may arise from failure to diagnose the disease in a
timely manner, possibly due to the following factors:
The misinterpretation of B symptoms
A lack of follow-up for abnormal chest radiographs or physical examination findings
A missed pathologic diagnosis because a needle biopsy was obtained rather than an
excisional lymph node biopsy
Occasionally, Hodgkin lymphoma can present as hemophagocytic syndrome
(hemophagocytic lymphohistiocytosis).
The hemophagocytic syndrome may be more prevalent in patients with Epstein-Barr virus
(EBV) antigen expression and has the following characteristics:
Pancytopenia
Fever
Hepatosplenomegaly with liver function test abnormalities
Elevated serum levels of ferritin and triglycerides
Phagocytosis of hematopoietic lineage cells by benign macrophages
21. Hodgkin
Lymph node is divided by bands of sclerosis on the right ; RS cells
are present in lake-like spaces (lacunar cells) on the left
22. Hodgkin
Very high magnification micrograph of nodular
lymphoctye predominant Hodgkin lymphoma
(NLPHL), with a popcorn-shaped Reed-
Sternberg cell (hematoxylin and eosin).
23. Hodgkin
Mixed cellularity Hodgkin
lymphoma showing both
mononucleate and binucleate Reed-
Sternberg cells in a background of
inflammatory cells (hematoxylin and
eosin, original magnification x200).
24. Hodgkin
Treatment:
Chemotherapy, radiotherapy.
In general, the management of Hodgkin lymphoma depends on the subtype. Most
clinicians divide classical Hodgkin lymphoma into the following three general groups:
• Early-stage favorable
• Early-stage unfavorable
• Advanced-stage disease
25. Hodgkin
However, favorable disease is defined differently by different groups.
The two most commonly used definitions are that of the European Organization for the
Research and Treatment of Cancer (EORTC) and the German Hodgkin Study Group (GHSG).
The EORTC definition uses the following patient criteria:
• Limited-stage disease
• Age younger than 50 years
• No bulky mediastinal adenopathy
• Erythrocyte sedimentation rate (ESR) less than 50 mm/h
• No B symptoms (or an ESR < 30 mm/h with B symptoms)
• Three or fewer sites of involvement
The GHSG definition uses the following criteria:
• No more than two sites of disease
• No extranodal extension
• No bulky mediastinal disease
• ESR < 50 mm/h (or < 30 mm/h if B symptoms present)
26. Hodgkin
Induction Chemotherapy Regimens eg :
MOPP (mechlorethamine, vincristine, procarbazine, prednisone).
Salvage Chemotherapy Regimens, eg:
ICE (ifosfamide, carboplatin, etoposide).
For treatment of classical Hodgkin lymphoma, radiation therapy is often administered in
combination with chemotherapy.
Treatment response criteria are defined as follows:
• Complete remission (CR): Disappearance of all evidence of disease as assessed by
computed tomography (CT) scanning, positron-emission tomography (PET) scanning,
history and physical examination, and bone marrow biopsy (if appropriate)
• Partial response: Achievement of at least a 50% regression in sites of measurable
disease and no new sites of disease
• Stable disease: Failure to achieve either of the above criteria, but not meeting criteria
for progressive disease
• Progressive disease: Any new lesion or an increase from a nadir of at least 50% in a
measurable lesion; if this occurs after a prior CR, it is called relapsed disease
27. Hodgkin
The most commonly used prognostic system is the International Prognostic System
(IPS), which uses the following variables to The most commonly used prognostic
system is the International Prognostic System (IPS), which uses the following variables
to determine prognosis:
• Serum albumin less than 4 g/dL
• Hemoglobin less than 10.5 g/dL
• Male sex
• Age of 45 years or older
• Stage IV disease (Ann Arbor classification)
• White blood cell (WBC) count greater than 15,000/mm 3
• Absolute lymphocyte count less than 600/mm 3, less than 8% of the total WBC
count, or both
28. Hodgkin
• Each of the previous variables is assigned 1 point. The total number of points for
prognostic factors is used to determine risk. When applied to a group of 5141
patients with Hodgkin lymphoma the IPS produced the following groups of 5-year
survival rates :
• 0 prognostic factors: 84%
• 1 prognostic factor: 77%
• 2 prognostic factors: 67%
• 3 prognostic factors: 60%
• 4 prognostic factors: 51%
• 5 or more prognostic factors: 42%
• However this scoring system is most applicable to patients with advanced-stage
disease (stages III and IV).
29.
30. non-Hodgkin
Non-Hodgkin lymphomas (NHLs) are tumors originating from lymphoid tissues, mainly
of lymph nodes.
These tumors may result from chromosomal translocations, infections, environmental
factors, immunodeficiency states, and chronic inflammation.
About 85% of all malignant lymphomas are NHLs. The median age at diagnosis is the
sixth decade of life, although Burkitt lymphoma and lymphoblastic lymphoma occur in
younger patients. NHL includes many clinicopathologic subtypes, each with distinct
epidemiologies; etiologies; morphologic, immunophenotypic, genetic, and clinical
features; and responses to therapy.
Individual subtypes of NHL are :
Burkitt lymphoma, Diffuse large B-cell lymphoma, Follicular lymphoma, Mantle cell
lymphoma, Primary central nervous system lymphoma, Adult T-cell lymphoma,
Mycosis fungoides/ Sézary syndrome
31. non-Hodgkin _ Etiology
Chromosomal translocations
Play an important role in the pathogenesis of many lymphomas and correlate with
histology and immunophenotype.
The t(14;18) translocation is the most common chromosomal abnormality associated
with NHL. This translocation occurs in 85% of follicular lymphomas and 28% of higher-
grade NHLs. This translocation results in the juxtaposition of the bcl-2 apoptotic
inhibitor oncogene at chromosome band 18q21 to the heavy chain region of the
immunoglobulin (Ig) locus within chromosome band 14q32.
The t(11;14) translocation has a diagnostic nonrandom association with mantle cell
lymphoma. This translocation results in the overexpression of bcl -1 (cyclin D1), a cell-
cycle regulator on chromosome band 11q13.
The 8q24 translocations lead to c-myc dysregulation. This is frequently observed in
high-grade small noncleaved lymphomas (Burkitt and non-Burkitt types), including
those associated with HIV infection.
32. non-Hodgkin
Infection:
Some viruses are implicated in the pathogenesis of NHL, probably because of their ability to
induce chronic antigenic stimulation and cytokine dysregulation, which leads to
uncontrolled B- or T-cell stimulation, proliferation, and lymphomagenesis. Epstein-Barr
virus (EBV) is a DNA virus that is associated with Burkitt lymphoma (especially the endemic
form in Africa), Hodgkin disease, lymphomas in immunocompromised patients (eg, from
HIV infection,[4] organ transplantation), and sinonasal lymphoma.
Human T-cell leukemia virus type 1 (HTLV-1) causes a latent infection via reverse
transcription in activated T-helper cells. This virus is endemic in certain areas of Japan and
the Caribbean islands, and approximately 5% of carriers develop adult T-cell leukemia or
lymphoma.
Hepatitis C virus (HCV) is associated with the development of clonal B-cell expansions and
certain subtypes of NHL (ie, lymphoplasmacytic lymphoma, Waldenström
macroglobulinemia), especially in the setting of essential (type II) mixed cryoglobulinemia.
Kaposi sarcoma–associated herpesvirus (KSHV) is associated with body cavity–based
lymphomas in patients with HIV infection
Helicobacter pylori infection is associated with the development of primary gastrointestinal
(GI) lymphomas, particularly gastric mucosa-associated lymphoid tissue (MALT) lymphomas.
33. non-Hodgkin
Environmental factors
Environmental factors linked to the development of NHL include chemicals (eg, solvents,
organic chemicals, hair dye), chemotherapy, and radiation exposure.
Immunodeficiency states
Congenital immunodeficiency states (eg, severe combined immunodeficiency disease
[SCID], Wiskott-Aldrich syndrome), acquired immunodeficiency states (eg, AIDS), and
induced immunodeficiency states (eg, immunosuppression) are associated with increased
incidence of NHL and are characterized by a relatively high incidence of extranodal
involvement, particularly of the GI tract, and with aggressive histology. Primary CNS
lymphomas can be observed in about 6% of patients with AIDS.
Celiac disease has been associated with an increased risk of malignant lymphomas. The risk
of lymphoproliferative malignancy in individuals with celiac disease depends on small
intestinal histopathology; no increased risk is observed in those with latent celiac disease.[5]
Chronic inflammation
The chronic inflammation observed in patients with autoimmune disorders, such as Sjögren
syndrome and Hashimoto thyroiditis, promotes the development of MALT and predisposes
patients to subsequent lymphoid malignancies.
Hashimoto thyroiditis is a preexisting condition in 23-56% of patients with primary thyroid
lymphomas which is marginal zone type.
34. non-Hodgkin
Diffuse large B-cell lymphoma
Usually older adults, but 20% in children
Most common type of non-Hodgkin lymphoma in adults.
Follicular lymphoma Adults
t(14;18)—translocation of heavy-chain Ig (14) and BCL-2 (18)
Indolent course; Bcl-2 inhibits apoptosis. Presents with painless “waxing and waning” lymphadenopathy. Follicular
architecture: small cleaved cells (grade 1), large cells (grade 3), or mixture (grade 2).
Mantle cell lymphoma
Adult males t(11;14)—translocation of cyclin D1 (11) and heavy-chain Ig (14)
Very aggressive, patients typically present with late-stage disease.
Primary central nervous system lymphoma
Adults Most commonly associated with HIV/ AIDS
Considered an AIDS-defining illness.
Variable presentation: confusion, memory loss, seizures. Mass lesion(s) on MRI, needs to be distinguished from
toxoplasmosis via CSF analysis or other lab tests.
Adult T-cell lymphoma
Occur in Adults Caused by HTLV (associated with IV drug abuse)
Adults present with cutaneous lesions; especially affects populations in Japan, West Africa, and the Caribbean. Lytic
bone lesions, hypercalcemia.
Mycosis fungoides/ Sézary syndrome
Adults Mycosis fungoides presents with skin patches, Plaques…see image (cutaneous T-cell lymphoma), characterized
by atypical CD4+ cells with “cerebriform” nuclei. May progress to Sézary syndrome (T-cell leukemia). See the images
below.
37. non-Hodgkin
History:
Low-grade lymphomas
Peripheral adenopathy that is painless and slowly progressive is the most common
clinical presentation in these patients.
Spontaneous regression of enlarged lymph nodes can occur in low-grade lymphoma,
potentially causing confusion with an infectious condition.
Primary extranodal involvement and B symptoms (ie, temperature >38°C, night
sweats, weight loss >10% from baseline within 6 mo) are not common at presentation,
but they are common in patients with advanced, malignant transformation (ie,
evolution from a low-grade to an intermediate- or high-grade lymphoma) or end-stage
disease.
Bone marrow is frequently involved and may be associated with cytopenia or
cytopenias.[1] Fatigue and weakness are more common in patients with advanced-
stage disease.
38. non-Hodgkin
Intermediate- and high-grade lymphomas
These types of lymphomas cause a more varied clinical presentation.
Most patients present with adenopathy.
More than one third of patients present with extranodal involvement; the most common sites are the
gastrointestinal (GI) tract (including the Waldeyer ring), skin, bone marrow, sinuses, genitourinary (GU)
tract, thyroid, and central nervous system (CNS).
B-symptoms are more common, occurring in approximately 30-40% of patients.
Lymphoblastic lymphoma, a high-grade lymphoma, often manifests with an anterior superior
mediastinal mass, superior vena cava (SVC) syndrome, and leptomeningeal disease with cranial nerve
palsies.
Patients with Burkitt lymphoma (occurring in the United States) often present with a large abdominal
mass and symptoms of bowel obstruction.
Obstructive hydronephrosis secondary to bulky retroperitoneal lymphadenopathy obstructing the
ureters can also be observed in these patients.
Primary CNS lymphomas are high-grade neoplasms of B-cell origin.
Most lymphomas originating in the CNS are large cell lymphomas or immunoblastomas, and they
account for 1% of all intracranial neoplasms.
These lymphomas are more commonly observed in patients who are immunodeficient because of
conditions such as Wiskott-Aldrich syndrome, transplantation, or AIDS
39. non-Hodgkin
Physical Examination
Low-grade lymphomas may produce peripheral adenopathy, splenomegaly, and
hepatomegaly.
Splenomegaly is observed in approximately 40% of patients; the spleen is rarely the
only involved site at presentation.
Intermediate- and high-grade lymphomas may produce the following physical
examination findings:
Rapidly growing and bulky lymphadenopathy
Splenomegaly
Hepatomegaly
Large abdominal mass : this usually occurs in Burkitt lymphoma
Testicular mass
Skin lesions: lesions are associated with cutaneous T-cell lymphoma (mycosis
fungoides),
40. non-Hodgkin
Complications
Potential disease-related complications include the following:
• Cytopenias (ie, neutropenia, anemia, thrombocytopenia) secondary to bone marrow
infiltration; alternatively, autoimmune hemolytic anemia is observed in some types of
NHL (eg, small lymphocytic lymphoma /chronic lymphocytic leukemia [SLL/CLL])
• Bleeding secondary to thrombocytopenia, disseminated intravascular coagulation (DIC),
or vascular invasion by the tumor
• Cardiac problems secondary to large pericardial effusion or arrhythmias secondary to
cardiac metastases
• Respiratory problems secondary to pleural effusion and/or parenchymal lesions
• Superior vena cava (SVC) syndrome secondary to a large mediastinal tumor
• Spinal cord compression secondary to vertebral metastases
• Neurologic problems secondary to primary CNS lymphoma or lymphomatous meningitis
• GI obstruction, perforation, and bleeding in a patient with GI lymphoma (may also be
caused by chemotherapy)
• Pain secondary to tumor invasion
• Leukocytosis (lymphocytosis) in leukemic phase of disease
41. non-Hodgkin _ Workup
CBC Count
In the early stage of disease, patients with NHL may have blood counts within the
reference range.
As the disease progresses, a CBC count with differential and platelet count in patients
with NHL may show the following:
• Anemia secondary to bone marrow infiltration, autoimmune hemolysis, bleeding,
anemia of chronic disease
• Thrombocytopenia, leukopenia, or pancytopenia secondary to bone marrow
infiltration or autoimmune cytopenias
• Lymphocytosis with circulating malignant cells (common in patients with low-
grade lymphomas)
• Thrombocytosis (paraneoplastic syndrome associated with lymphomas or reactive
secondary to blood loss)
42. non-Hodgkin
Serum chemistry studies
May show the following:
Elevated lactate dehydrogenase (LDH): indicates poor prognosis; correlates with
increased tumor burden
An elevated beta2-microglobulin level may be seen. Elevated levels correlate with a
poor prognosis.
CXR:
A chest radiograph yields positive information in approximately one fourth of patients
with NHLs. It may identify hilar or mediastinal adenopathy, pleural or pericardial
effusions, and parenchymal involvement
44. non-Hodgkin
(PA) chest radiograph in a 16-year-old
male adolescent with thoracic non-
Hodgkin lymphoma (NHL) shows subtle
enlargement of the lower paratracheal
lymph nodes.
45. non-Hodgkin
CT scan
Neck, chest, abdomen, and pelvis is used to detect enlarged lymph nodes,
hepatosplenomegaly, or filling defects in the liver and spleen. Currently, it is the most
widely used test for initial staging, assessing treatment response, and conducting follow-up
care
shows multiple enlarged lymph nodes in the prevascular space, in the right and left
paratracheal region.
Nodes in the left paratracheal region cause the trachea to be indented and narrowed on
the left side. Note the small, bilateral pleural effusion
46. non-Hodgkin
Biopsy
A well-processed hematoxylin and eosin (H&E)–stained section of an excised lymph
node is the mainstay of pathologic diagnosis. Excisional lymph node biopsy is required
because lymphoma diagnosis relies heavily on careful assessment of altered nodal
architecture accompanying lymphomatous infiltrates. Fine-needle aspiration (FNA) is
insufficient for establishing a diagnosis; needle-core biopsies have a limited role in
establishing a diagnosis of NHL.
47. non-Hodgkin - Ann Arbor staging system
Is the most commonly used staging system for patients with NHL.
This system divides NHL into 4 stages, as follows:
• Stage I NHL involves a single lymph node region (I) or localized involvement of a
single extralymphatic organ or site (IE)
• Stage II NHL involves 2 or more lymph node regions on the same side of the
diaphragm (II) or localized involvement of a single associated extralymphatic organ
in addition to criteria for stage II (IIE)
• Stage III involves lymph node regions on both sides of the diaphragm (III) that also
may be accompanied by localized involvement of an extralymphatic organ or site
(IIIE), spleen (IIIS), or both (IIISE)
• Stage IV represents disseminated or multifocal involvement of one or more
extralymphatic sites with or without associated lymph node involvement or
isolated extralymphatic organ involvement with distant (nonregional) nodal
involvement
48. non-Hodgkin - Treatment
Stage I and contiguous stage II NHL
Standard management consists of radiotherapy alone. Forty percent of patients with
limited-stage disease remained disease-free at 10 years after radiation
Noncontiguous stage II, III, and IV NHL
The use of rituximab, a monoclonal antibody targeting CD20 antigen present in benign
and malignant B-cells, in combination with systemic chemotherapy, has resulted in an
improved duration of remission and survival for patients with indolent B-cell
lymphomas when compared to chemotherapy.
Surgical Care
The role of surgery in the treatment of patients with NHL is limited. Surgery is useful in
selected situations (eg, GI lymphoma), particularly if the disease is localized or if risk of
perforation, obstruction, and massive bleeding is present. Orchiectomy is part of the
initial management of testicular lymphoma.
49. Burkitt Lymphoma
Burkitt lymphoma, or small noncleaved cell lymphoma, is a highly aggressive B-cell
non-Hodgkin lymphoma characterized by the translocation and deregulation of the
c-myc gene on chromosome 8.
Burkitt-like lymphoma (BLL) is considered to be a morphologic variant of Burkitt
lymphoma.
Three distinct forms of Burkitt lymphoma are identified:
(1) endemic (African), (2) sporadic, and (3) immunodeficiency-associated subtypes.
Although these forms differ in their clinical presentation and their epidemiology, they
share the same aggressive clinical behavior and are histologically identical.
The sporadic variant (sBL) is present in North America and Western Europe, and the
endemic variant (eBL) is observed in Africa.
Immunodeficiency-associated Burkitt lymphoma occurs most commonly in patients
with human immunodeficiency virus (HIV) infection, but it has also been reported in
the posttransplantation setting as well as in congenital immunodeficiency patients.
Immunodeficiency-associated Burkitt lymphoma accounts for about 30% of
lymphomas in HIV patients.[6]
50. Burkitt Lymphoma
Etiology and Pathophysiology
EBV and malaria infections:
EBV is a member of the herpesvirus family that has been strongly implicated in the endemic
form of Burkitt lymphoma (eBL).
Virtually all patients with eBL are EBV positive, whereas only about 20% of sporadic (sBL)
cases are associated with EBV.
EBV tends to cause a latent infection of B lymphocytes, some of which evade the T-cell-
mediated immune response and enter the germinal center.
This subsequently results in excessive B cell proliferation.
Malaria infection also probably plays a role in the pathogenesis of eBL, as it can lead to
inhibition of EBV-specific immune response.
The exact mechanism of EBV-mediated lymphomagenesis, however, is not well understood,
but evidence exists for a significant interaction between viral and cellular microRNA
(miRNA) interfering with normal gene expression and translation.
EBV can be detected in 25-40% of immunodeficiency-associated cases.
EBNA-1 (EBV nuclear antigen-1) and EBV-encoded RNAs have been shown to possess
modest anti-apoptotic properties. Furthermore, EBNA-3A and EBNA-3C can inhibit the
expression of the anti-apoptotic protein BCL-2.
51. Burkitt Lymphoma
C-myc oncogene activation
The classic t(8;14) reciprocal translocation (85% of cases) results in the transposition of the c-myc proto-
oncogene on chromosome 8 with one of the immunoglobulin heavy chain genes on chromosome 14,
which results in activation of the c-myc gene and is considered responsible for tumor proliferation.
Translocation t(8;14) is the most common, present in 80% of Burkitt lymphoma cases. In all the other
cases, c-myc has been translocated close to one of the immunoglobulin light chain genes on
chromosome 2 (kappa light chain) [t(8;2)] or 22 (lambda light chain) [t(8;22)].
Overproduction of the c-myc product may change the lymphocytes into cancer cells, but other gene
mutations may be responsible for the progression of Burkitt lymphoma.
Abnormalities in the p53 gene and in death-associated protein kinase (DAP-kinase) has been shown to
contribute to decreased apoptosis and to the pathogenesis of the disease.
C-myc is a leucine zipper transcription factor that affects different pathways regulating cell cycle,
growth, adhesion, differentiation, and apoptosis.
It is overexpressed via its juxtaposition with immunoglobulin gene enhancers.
Genes like cyclin D2, is induced with c-myc overexpression, whereas others like p21 and platelet-
derived growth factor receptor-alpha (PDGFR-alpha) are consistently repressed, possibly playing a role
in the pathogenesis of Burkitt lymphoma (BL).
E2F1 is a member of the E2F family of transcription factors that is involved in regulation of cell growth.
Interestingly, in recent years, E2F1 was found to be overexpressed in most sporadic cases of Burkitt
lymphoma (sBL). Furthermore, reduction of E2F1 expression led to decreased growth capacity in sBL
cells in vitro.[20]
52. Burkitt Lymphoma
Signs and symptoms
Burkitt and Burkitt-like lymphomas have a rapid and aggressive clinical course with frequent
bone marrow and central nervous system (CNS) involvement. These are considered to be
medical emergencies and require immediate diagnostic and therapeutic intervention.
Endemic (African) Burkitt lymphoma (eBL) most commonly involves the jaw and facial bone
(orbit) (>50% of cases). Sporadic Burkitt lymphoma (sBL) most often presents as abdominal
tumors with bone marrow involvement. Immunodeficiency-related Burkitt lymphoma cases
usually as with nodal involvement with frequent bone marrow involvement.
Common findings and symptoms in patients with Burkitt lymphoma are summarized below.
Abdominal masses, which can cause abdominal pain and distention andascites
Nausea and vomiting, Loss of appetite, change in bowel habits, or both, Gastrointestinal
bleeding, Signs and symptoms of acute abdomen
Intestinal perforation, Renal failure as a result of retroperitoneal disease and renal
involvement or secondary to tumor lysis syndrome
Mandibular or maxillary mass, Most common presentation in eBL (maxillary > mandibular).
May involve the orbit; jaw involvement occurs much less frequently (15-20%). CNS
involvement
53. Burkitt Lymphoma
Meningeal infiltration, with or without cranial nerve (CN) involvement (frequently, CN
III and CN VII); most common mode of presentation with CNS disease
Headaches, visual impairment, and paraplegia from spinal involvement; these may be
the initial presenting features in some cases
"B" systemic symptoms Uncommon but may be associated with other presenting
symptoms (eg, fever, weight loss, night sweats, fatigue)
Others are Bone marrow involvement, Painless lymphadenopathy (adults > children)
54. Burkitt Lymphoma
Diagnosis
The least invasive procedure used to establish the diagnosis usually involves pathologic
evaluation of the involved tissue biopsy.
Patients with more than 25% bone marrow involvement are usually referred to as having
Burkitt leukemia.
A diagnosis can sometimes be made by bone marrow aspiration and biopsy if the marrow is
involved.
If the marrow is not involved, diagnosis will require sampling lymph nodes or the involved
extranodal site.
Staging
Because most patients will present with nodal or extranodal masses, different staging
systems have been proposed.
The National Cancer Institute staging system is as follows:
A - Single solitary extra-abdominal site
AR - Intra-abdominal, more than 90% of tumor resected
B - Multiple extra-abdominal tumors
C - Intra-abdominal tumor
D - Intra-abdominal plus 1 or more extra-abdominal sites
OR BY The Ann Arbor system
55. Burkitt Lymphoma
Laboratory testing
Complete blood count with differentials and platelet count
Coagulation studies
Serum levels of electrolytes, uric acid, LDH, creatinine, beta2 microglobulin
Liver function tests
Tests for human immunodeficiency virus and hepatitis B
Histopathologic examination
Cytogenetic studies
Flow cytometry
Imaging studies
Head or spinal computed tomography (CT) scanning or magnetic resonance imaging: When neurologic signs/symptoms
are present
Bone scanning and plain bone radiography: When bone symptoms are present
Chest, abdominal and pelvic CT scanning with intravenous (IV) contrast (omit contrast medium in the presence of renal
insufficiency)
Echocardiography: For possible arrhythmias due to cardiac involvement
Multiple-gate acquisition scanning: For pre-chemotherapy evaluation of cardiac ejection fraction, particularly when
anthracyclines will be used
Procedures
Unilateral bone marrow aspirate and biopsy for every patient with Burkitt lymphoma
Lumbar puncture as part of staging workup for cerebrospinal fluid involvement (defer this procedure in the presence of
significant thrombocytopenia/coagulation defects)
Paracentesis or thoracentesis for cytogenetic studies of ascitic fluid or pleural effusion
56. Burkitt Lymphoma
Management
Chemotherapy is the mainstay of treatment for Burkitt lymphoma.
Administer IV antibiotics for neutropenic fevers, and growth factors (granulocyte-macrophage colony-
stimulating factor [GM-CSF] or granulocyte colony-stimulating factor [G-CSF]) to help decrease the
duration of neutropenia. Surgery or radiation therapy has no role in the treatment of Burkitt lymphoma.
In general, 3 chemotherapy approaches are available for Burkitt lymphoma, as follows:
• Intensive, short-duration regimens such as CODOX-M/IVAC (Magrath regimen) (cyclophosphamide,
vincristine, doxorubicin, high-dose methotrexate / ifosfamide, etoposide, high-dose cytarabine) and
the CALGB 9251 protocol
• Long-duration chemotherapy similar to acute lymphoblastic leukemia treatment, such as hyper-
CVAD (modified fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone) and the
Cancer and Leukemia Group B (CALGB) 8811 protocol
• Combination regimens followed by autologous stem cell transplantation
Most current regimens add rituximab to previously established chemotherapy regimens
Other medications that may be used in patients with Burkitt lymphoma include the following:
• Glucocorticoids (eg, prednisone)
• Urate-oxidase enzymes (eg, rasburicase)
• Supportive therapy
• Prophylactic allopurinol and aggressive hydration with urine alkalinization: To reduce the risk of
tumor lysis syndrome and uric acid nephropathy
• Transfusions of leukodepleted and irradiated red blood cells or platelets (as clinically indicated): For
anemia and thrombocytopenia
57. Surgical Intervention
In current clinical practice, effective and durable responses are observed with
combination chemotherapy, obviating the role of surgical debulking. Historically, most
patients with Burkitt lymphoma who presented with large masses, particularly
abdominal disease, underwent an exploratory laparotomy, at which time an effort was
made to debulk as well.
With newer, sophisticated interventional radiology approaches, an adequate diagnosis
can be reached in almost all patients without major surgical intervention.
Palliative surgery is considered only for patients with obstruction who cannot begin
chemotherapy immediately.
Tracheotomy is indicated if the patient's airway is compromised from the physical
pressure of a large tumor mass.
Exploratory laparotomy may be performed for bowel obstruction (often before the
diagnosis is made). Patients with uncontrolled gastrointestinal bleeding may also need
exploratory laparotomy or endoscopic procedures for hemostasis.
58. Pericardiocentesis is indicated for patients presenting with cardiac tamponade.
Paracentesis is indicated if large ascites is one of the presenting complaints.
An excisional lymph node biopsy is usually necessary to reach an accurate diagnosis.
A semi-permanent intravenous catheter such as a peripherally inserted central
catheter (PICC) line or medicine port should be arranged with interventional radiology
or surgery to aid administration of chemotherapy, medications, and blood products
and for fluid management.
59. Prognosis
prognostic scoring system developed in 2013 helps quantify the potential for cure in
newly diagnosed adult patients with Burkitt lymphoma and helps stratify participants
in future clinical trials.
Points are assigned as follows:
• Age 40-59 years or black race/ethnicity: 1 point
• Age 60-79 years or stage III/IV disease: 2 points
• Age 80 years and older: 4 points
The 4 risk groups based on the scoring system are as follows :
• Low-risk (5-year relative survival [RS]: 71%): 0-1 points
• Low-intermediate (5-year RS: 55%): 2 points
• High-intermediate (5-year RS: 41%): 3 points
• High-risk (5-year RS: 29%): 4 or more points
