Burkitt Lymphoma

Burkitt lymphoma is a neoplasm of B lymphocytes in lymphoid tissue. It was first reported in 1958 by an Irish anesthetist named Dennis Burkitt in Uganda. She observed cases of children with rapidly growing jaw or abdominal tumors. This type of lymphoma is:

• Commonest childhood cancer in tropical regions
• Fastest growing childhood tumor with a cell doubling time of 24-48 hours
• The first human tumor known to be associated with a virus (Epstein-Barr virus)
• The first human malignancy that responds satisfactorily to chemotherapy (Cyclophosphamide)
• One of the first tumors known to be associated with chromosomal translocation resulting in the activation of oncogenes
• The first lymphoma to be associated with HIV infection

Burkitt lymphoma (BL) exhibits the following epidemiological characteristics:

• BL has the highest incidence within latitude 10°N & 10°S of the equator.
• Burkitt Zone is also a Malaria Endemic Zone.
• This same area has an annual rainfall of > 50cm, ambient temperature of 16.6°C, and an altitude of about 1500m above sea level.

Incidence:

• The incidence is about 7-8 cases per 100,000.
• BL accounts for > 50% of all childhood malignancy in tropical Africa.
• Most BL occurs below the age of 14 years.
• 90% of patients are between the ages of 4-9 years; the peak age is about 4-7 years.
• It is rare before 1 year of age and after 20 years.
• Male-to-Female ratio (M:F) = 2:1

According to the World Health Organization (W.H.O), Burkitt lymphoma can be classified into three major clinical variants:

• Endemic Burkitt:
  • Seen in malaria endemic areas, such as Sub-Saharan Africa.
• Sporadic Burkitt lymphoma:
  • Occurs primarily in non-malarial areas, including Europe and North America.
• Burkitt lymphoma of immunodeficiency:
  • Occurs secondary to immunodeficiency states, such as HIV.

The etiology of Burkitt lymphoma is largely unknown, which is a common characteristic of most malignancies. However, there is a significant interplay between genetic and environmental factors in its development:

• BL is categorized as a neoplasm of B lymphocytes.
• Three key factors contribute to the concept of African Burkitt lymphoma:
  • Epstein Barr Virus Infection: This virus invades B cells due to its receptor interaction.
  • Intense and Chronic Plasmodium Falciparum Infestation: This infestation continuously activates B cells.
  • High Tendency for Chromosomal Translocation: Burkitt lymphoma is associated with frequent chromosomal translocations.

Several risk factors contribute to the development of Burkitt lymphoma:

Environmental Factors:

• Epstein Barr Virus (EBV): EBV plays a significant role in the evolution of endemic Burkitt lymphoma. The EBV genome is integrated into lymphocytes of individuals in the endemic zone, found in about 95% of cases. After integration, malarial infections prime lymphocytes, and multiple infections activate polyclonal B-lymphocytes, leading to malignancy.
• Recurrent malarial infections activate the c-myc oncogene located on chromosome 8's long arm. This activation perpetuates lymphocyte proliferation.

Genetic Abnormalities:

• An oncogene, c-myc, normally on chromosome 8, translocates to genetic loci on chromosomes 14, 2, or 22 that code for IgG. This results in uncontrolled proliferation of B-lymphocytes.
• As a result of these genetic changes, the tumor can arise anywhere in the body where B-lymphocytes are present.

Pre-existing Immunodeficient State:

• Burkitt lymphoma is a multi-centered cancer, not metastatic. It occurs at multiple points where lymphocytes are present.
• This can be due to a congenital or acquired immunodeficient state.

The clinical presentation of Burkitt lymphoma depends mainly on the location of the malignancy:

• Painless Jaw Swelling: This is the most common presentation, observed in up to 75% of patients. The maxilla is more frequently affected than the mandible, and it is common in younger age groups (1 – 5 years). In older children, abdominal tumors are more common.
• Exophthalmos: Involvement of the orbit by extension can lead to exophthalmos.
• Loss of Teeth or Loose Teeth: Burkitt lymphoma involving the jaw can cause tooth loss, loose or shaken teeth, and associated gingival swelling. This presentation may sometimes be confused with the normal physiological tooth eruption in children aged 1-5 years.
• Abdominal Swelling (Abdominal Burkitt): This presentation may account for up to 60% of cases. Some patients may have both jaw swelling and an abdominal mass. The abdominal Burkitt form can involve any abdominal organ, including the liver, spleen, ovaries, kidneys, and mesenteric lymph nodes.
• Paraplegia in CNS Burkitt: In around 30% of cases, the CNS may be involved, leading to paraplegia due to damage to vertebrae.
• Other Organs: Burkitt lymphoma can also affect other organs such as the breast, thyroid gland, or testis. Any glandular organ can be affected, and solitary, non-tender swelling of these organs may indicate Burkitt lymphoma.

To diagnose Burkitt lymphoma, the following steps and considerations are important:

• Rapidly Growing Tumor: A rapidly growing tumor of the jaw or abdomen (with a duration of less than 6 weeks) should raise suspicion of Burkitt lymphoma. The rapid growth rate is advantageous for early diagnosis, as parents tend to seek medical attention promptly due to the noticeable growth.
• Plain Radiograph: For Jaw Tumor, a lateral view of the jaw can reveal:
  • Soft tissue swelling
  • Dental mal-alignment or anarchy
  • Loss of 1 or 2 teeth
  • Loss of Lamina dura
  The "lucency" surrounding the base of the teeth (i.e., the cement of the teeth) is lost.
• Myelogram: If there is weakness of the limb, an increased vascularization in the area of the mass may be observed.
• Abdominal Ultrasound (USS): Abdominal ultrasound can help locate and characterize the tumor.
• Intravenous Urography (IVU): IVU is used if the tumor is related to the kidney:
  • For Burkitt lymphoma, the tumor is located within the kidney.
  • For Neuroblastoma (an adrenal/suprarenal mass), it is located above the kidney.
  • For Nephroblastoma, it is within the renal capsule, distorting the calyces.

Specific Diagnosis:

The diagnosis of Burkitt lymphoma is best confirmed through histological biopsy. Fine Needle Aspirate Cytology (FNAC) can also be used.

Histology:

• This method is more reliable and reassuring, although it takes about 2-3 days to obtain results.
• Advantage of histology over cytology: Histology takes a larger amount of tissue compared to cytology, allowing for a broader view of the tissue.

Histological Findings:

• Sheets of fairly uniform, monotonous cells measuring about 10-25 µm in diameter.
• The nuclei are round or oval, containing 2-5 prominent nucleoli.
• The cytoplasm is moderate, stains highly basophilic with small lipid vacuoles, and contains abundant mitotic elements.
• Scattered among these tumor cells are phagocytic macrophages with retracted cytoplasm, creating empty spaces between tumor cells and adjacent tissue, giving rise to the characteristic "STARRY SKY" appearance.

FNAC and Cytology:

Fine Needle Aspirate Cytology (FNAC) is diagnostic in more than 80% of cases. It is a simple procedure and provides rapid results.

Here's how FNAC is performed:

• Clean the skin over the mass.
• Use a wide-bore needle, preferably a 19G needle.
• Inject about 1-2ml of Normal Saline into the mass and then aspirate.
• Do not use water for injection, as it can cause osmolar swelling and subsequent lysis of the tumor cells.
• The aspirate is used to prepare a slide for cytology.

If the mass is not accessible, under ultrasonic guidance, introduce a needle into the mass and repeat the above procedure.

Results can be obtained within 1 or 2 hours.

Aside from FNAC and histology, additional investigations may be performed to aid in diagnosis:

• CT Scan or Myelogram: If there are symptoms of limb weakness or to assess intra- and extra-medullary tumors of the spinal column or CNS.
• Bone Marrow Aspiration for Cytology: Done to exclude involvement of the bone marrow.
• Lumbar Puncture: To obtain CSF cytology and determine evidence of malignant cells in CSF, which indicates extension to the central nervous system (CNS). CSF cytology could be positive in up to 50% of patients, even in those with clinical limb weakness.
• Serum Electrolyte and Urea: To assess evidence of tumor lysis.
• Blood and Urine Culture: Done to check for infections.
• Full Blood Count (FBC): To identify abnormalities such as anemia, thrombocytopenia, or leukocytosis.
• Liver Function Test: Important because all medications given are metabolized in the liver. Tests include ALT, AST, ALP, and others.

Modified Ziegler Staging:

This staging system uses the following categories:

• Stage A: A single extra-abdominal tumor site.
• Stage B: Multiple extra-abdominal tumor sites.
• Stage C: Intra-abdominal tumor without involvement of other sites.
• Stage D: Intra-abdominal tumor with involvement of extra-abdominal sites.
• Stage AR: Intra-abdominal tumor with over 90% of the tumor being surgically resectable. This refers to a stage C tumor that can be surgically removed.

Depending on the site of the tumor, the following conditions should be considered:

• Jaw tumor: Dental cyst, osteomyelitis of the jaw, jaw cellulitis, periodontitis.
• Orbital swelling or involvement: Rhabdomyosarcoma, retinoblastoma, metastatic neuroblastoma.
• Spinal tumor: Pott's disease, acute lymphoblastic leukemia, transverse myelitis, Schistosoma hematobium infection.
• Abdominal tumor: Abdominal tuberculosis, neuroblastoma, nephroblastoma, ovarian cysts.

For the treatment of Burkitt Lymphoma, we commonly use the Ziegler Regimen

• Burkitt Lymphoma responds well to chemotherapy, and combination therapy is the standard approach.
• If a single drug is to be used, Cyclophosphamide is the preferred choice.
• Cytotoxic drugs used in treatment include: Cyclophosphamide, Vincristine, Methotrexate, Cytosine-arabinoside, Melphalan.
• Newer drugs such as Etoposide and Ifosfamide may also be used.
• A combination of three drugs is usually employed, and they are given in a pulsatile manner. A standard regimen consists of six courses, with each course typically separated by two weeks.
• It's important to note that the more drugs used, the greater the cumulative side effects.

Regimen

• The most commonly used regimen includes the combination of Cyclophosphamide (CPA) + Methotrexate (MTX) + Vincristine (VCR).
• Alternatively, regimens could involve CPA + Cytosine Arabinoside (Ara-C) + VCR, or CPA + MTX + Ara-C + VCR.
• The child's surface area is typically used to calculate the dosage of cytotoxic drugs.
• Dosage:
• CPA: 1000mg/m²
• Given as a single dose, weekly for 6 weeks
• Each ampoule contains 500mg; dosage is calculated in mg/m²
• VCR: 1.4 mg/m²
• Given as a single dose, weekly for 6 weeks
• MTX: 1.5mg/m²
• Administered on day 1, 3, and 5
• If CNS is involved, ½ is given intrathecally (IT) and ½ intravenously (IV) after dilution
• Ara-C: 250 mg/m²
• Given on day 1, 3, and 5
• If CNS is involved, ½ is given IT and ½ IV
• Administration Process:
• Start the child on IV fluid
• Administer the cytotoxic drug
• Continue IV fluid after drug administration
• Before the next course:
• Perform a hemogram to ensure FBC, WBCC, and platelet count are normal
• If abnormalities are present, correct them before the next course
• Criteria: WBCC should not be < 2.2, PCV at least 30%, and platelet count at least 100,000

Adjunct Management

In addition to cytotoxic therapy, several adjunct measures are taken:

• Use of Allopurinol:
• Commenced 24-48 hours before starting cytotoxic drugs
• 50 mg t.d.s. (three times a day) for children < 5 years old, 100 mg t.d.s. for children > 5 years old
• Given throughout the duration of cytotoxic treatment (6 weeks)
• Allopurinol is used to prevent Tumor Lysis Syndrome (TLS), which could occur spontaneously or as a result of drug therapy
• If TLS occurs, appropriate management is implemented
• Antibiotics: Prescribed for secondary infections
• Ensuring Adequate Hydration:
• Administer IV fluids at 1 to 1.5 times the maintenance rate
• Encourage the child to consume liberal oral fluids to aid in the clearance of products of TLS through urine
• Surgical Debridement of Ulcerated Jaw Mass:
• Perform open dressing to prevent the growth of anaerobic organisms
• Followed by antiseptic treatment using 0.5% chlorhexidine or H2O2
• Reconstructive Surgery: Considered for some children
• Surgical Resection of Abdominal Mass:

The prognosis of Burkitt Lymphoma is influenced by several prognostic factors:

Prognostic Factors	Good Prognosis	Bad Prognosis
Tumor Burden (Size)	Smaller	Larger
Involvement of Sanctuaries	No	Yes
Involvement of CNS	No	Yes
Age	< 13 years	> 13 years
Time Relapse after Remission	Longer / Never	Shorter

Good News about Burkitt Lymphoma Chemotherapy:

By the time of the 2nd course, the tumor mass subsides, and parents may consider discontinuing the 3rd to 6th course.

This is also a bad news because:

By the end of the 2nd therapy, parents may want to discontinue therapy, assuming their child is doing fine.

• Tumor Lysis Syndrome (TLS)
• Obstruction of Gastrointestinal Tract (GIT) or Renal System
• Paraplegia
• Sterility
• Relapses and Treatment Resistance