Burkitt Lymphoma

Overview

Burkitt lymphoma (BL) is a kind of non-Hodgkin lymphoma that is extremely aggressive (it grows quickly). Symptoms often appear fast, within a few days or weeks. Burkitt lymphoma causes multiple lymph nodes to expand in various regions of the body, and it frequently affects the belly and colon.

Other organs, such as the spleen and liver, may be impacted as well. This lymphoma can expand to the central nervous system and can be discovered in the bone marrow.

Burkitt Lymphoma definition

Burkitt lymphoma (BL) is a kind of non-Hodgkin B-cell lymphoma that is extremely aggressive. The condition is linked to Epstein Barr virus (EBV), HIV, and chromosomal translocations that result in the overexpression of the oncogene c-myc. BL is classified into three clinical categories by the World Health Organization (WHO): endemic, sporadic, and immunodeficiency-related.

Malaria and EBV have been associated to the endemic type. HIV and, to a lesser degree, organ donation are linked to the immunodeficiency-related variation. The illness prognosis is favorable in children but poor in adults with intensive chemotherapy treatment.

Epidemiology

Burkitt lymphoma accounts for from 1 percent to 5% of all non-Hodgkin lymphomas. Caucasians are more likely to have BL than those of African or Asian origin. BL, like most kinds of lymphoma, is more common in men, with a 3-4:1 male-to-female ratio. The distribution of endemic BL cases across Africa and Papua New Guinea conforms to malaria and Epstein Barr virus regions.

The frequency in children under the age of 18 is roughly 3 to 6 cases per 100,000 children per year. The typical age of diagnosis is six years. The sporadic variety is seen mostly in North America and Europe, with a median age of diagnosis of 45. Sporadic BL has a yearly estimated incidence of 4 per 1 million children under the age of 16, and 2.5 per 1 million adults. In pediatric patients, the typical age of diagnosis ranges from 3 to 12 years. In the United States, the immunodeficiency-associated variation occurs at a rate of 22 per 100,000 people.

Etiology

Epstein Barr virus is linked to Burkitt lymphoma (BL) (EBV). The precise mechanism underpinning EBV and B-cell malignancy is unknown. The EBNA1 protein is a latent EBV protein that is expressed in endemic BL. The deletion of the EBNA2 gene results in the expression of the EBNA3 genes . Tumor cells produced from these cell lines are resistant to apoptosis, suggesting that EBNA2 may provide a survival benefit to the neoplastic cells.

Burkitt lymphoma is seen in malaria-endemic locations such as Brazil, Papua New Guinea, and equatorial Africa. Several studies have found a link between endemic BL and higher Plasmodium falciparum antibody titers. Human immunodeficiency virus has been connected to immunodeficiency-associated BL (HIV). Contrary to popular belief, the risk of lymphoma is higher in patients with a CD4 count more than 200 and no opportunistic infection. It's unclear how HIV influences the risk of endemic BL. 

Pathophysiology

EBV latent proteins suppress apoptosis in B-cells bearing the C-MYC translocation through EBNA1 protein, BHRF1 protein, EBER transcripts, vIL-10, BZLF1, and LMP1 in endemic BL. The inhibition of apoptosis is most likely what causes the malignant clone of B-cells. EBV has been linked to genomic instability, telomere malfunction, and DNA damage. Plasmodium falciparum causes latent EBV to reactivate.

P. falciparum can also activate the toll-like receptor 9 (TLR9), causing immunoglobulin-MYC translocations. Cytidine deaminase permits B-cells to transition from IgM to other immunoglobulin subtypes expression. C-MYC translocation is associated with abnormal cytidine deaminase expression. In HIV-positive patients who do not have Burkitt lymphoma, the enzyme is not detectable.

Types of Burkitt lymphoma (BL)

There are 3 main subtypes of Burkitt lymphoma (BL) that include:

• Endemic (African): This is the most frequent lymphoma among African children, and it is linked to chronic malaria and the Epstein-Barr virus (EBV), a common virus that also causes glandular fever. It is most common in the jaw and other facial bones, although it can also arise in the belly, ovaries, kidney, or breast. Outside of Africa, endemic Burkitt lymphoma is uncommon.
• Sporadic (non-African): This subtype is found all over the world and accounts for 1-2 percent of adult lymphoma cases. The Epstein-Barr virus (EBV) is seen in 20% of individuals with sporadic BL, and the abdomen is the most prevalent location of occurrence, causing edema and pain. Burkitt lymphoma (BL) has the potential to migrate to the central nervous system (brain and spinal cord). Other organs and tissue, such as the thyroid and tonsils, as well as the facial bones, may be impacted.
• Immunodeficiency-associated: This subtype is especially frequent in patients who have HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome). Immunodeficiency-related Burkitt lymphoma (BL) can also arise in people who have hereditary immune abnormalities or who take immunosuppressive drugs to avoid organ transplant rejection.

Symptoms of burkitt's lymphoma

Because of the tumor's quick doubling time, patients frequently appear with a rapidly developing mass, high lactate dehydrogenase (LDH), and increased uric acid levels. The abdomen is the most common location of sporadic BL, however the head and neck can also be affected. Patients report with stomach discomfort, abdominal distention, nausea, vomiting, and gastrointestinal bleeding as a result of ileocecal illness.

Adult patients are more prone than pediatric ones to arrive with constitutional symptoms (i.e., fever, weight loss, night sweats). Patients with jaw or bone marrow involvement are uncommon. The mediastinum, central nervous system, testes, skin, thyroid gland, and breast are seldom affected by BL. Endemic BL is distinguished by an increasing jaw lesion, periorbital edema, or genitourinary involvement. Jaw involvement is most common in children.

Malnourishment is typical during the onset of sickness. If the patient has bone marrow involvement with more than 25% cellularity, the condition is classed as Burkitt leukemia. It is unusual to have a totally leukemic appearance.

Diagnosis

Adequate tissue is critical for diagnosis. Excisional biopsy is chosen because fine-needle aspiration may not yield enough tissue for diagnosis. For diagnosis, a sample of the superficial lymph node or pleural fluid may be taken. Microscopy or flow cytometry are used to suspect BL in developed nations, and immunohistochemistry and cytogenetics are used to confirm the diagnosis. Fine-needle aspiration and clinical correlation may be used to diagnose Burkitt's disease in locations where confirmatory testing is not available.

Following a tissue diagnosis, bone marrow aspiration and biopsy, as well as cerebrospinal fluid (CSF) analysis, should be conducted to determine the amount of involvement. Initially, computerized tomography (CT) images of the chest, abdomen, and pelvis are conducted. Whole-body PET/CT scans should be performed, but they should not be used to postpone therapy.

Complete blood count (CBC) with differential, ESR, complete metabolic panel (CMP), PT, PTT, serum lactate dehydrogenase, uric acid, hepatitis B serology, pregnancy testing in women, and HIV testing are all required lab tests. Ultrasonography may help in staging in regions with limited resources.

Patients may also be subjected to a series of baseline tests prior to the start of any treatment to assess organ function. These are frequently repeated throughout and after therapy to see whether the treatment has changed organ function. To assist control side effects, therapy and follow-up care may need to be altered at times. These might include:

• Physical examination
• Vital observations (blood pressure, temperature, & pulse rate)
• Heart scan
• Kidney scan
• Breathing tests
• Blood tests

It may take some time to perform all of the necessary biopsies and testing (an average of 1-3 weeks), but it is critical for clinicians to have a thorough picture of the lymphoma and the patient's overall health in order to make the best treatment recommendations.

Many of the staging and organ function tests are repeated after therapy to see whether the lymphoma treatment was effective and what effect it had on the body.

Treatment of burkitt's lymphoma

In affluent nations, the overall cure rate for sporadic Burkitt lymphoma in pediatric and young adult populations reaches 90%. Treatment is prioritized dependent on the patient's age and stage. It is suggested that pediatric patients with full surgical excision of illness get two rounds of moderate-intensity chemotherapy (i.e. cyclophosphamide, vincristine, prednisolone, doxorubicin). Overall survival in pediatric patients with stage I and II illness is more than 98 percent.

It is recommended that children with residual or stage III illness receive a minimum of four cycles of dose-intensive chemotherapy (i.e. two cycles of cyclophosphamide, vincristine, prednisolone, doxorubicin, and high-dose methotrexate). Following that, the patient will get two cycles of cytarabine and high-dose methotrexate.

Intrathecal treatment is used in conjunction with chemotherapy. Finally, it is recommended that pediatric patients with CNS or bone marrow involvement receive up to eight cycles of dose-intensive chemotherapy (two cycles of cyclophosphamide, vincristine, prednisolone, doxorubicin, and high-dose methotrexate) plus two courses of cytarabine and etoposide, as well as four courses of maintenance chemotherapy 

Intrathecal treatment, like residual or stage III illness, is provided along with chemotherapy.

Immunotherapy can help in treatment. Rituximab (anti-CD20) should be included in all therapy regimens since it is associated with a better prognosis. Ofatumumab and obinutuzumab, two newer anti-CD20 drugs, are being studied. Anti-CD19 monoclonal antibody linatumomab and anti-CD22 monoclonal antibody inotuzumab are being studied.

Histone acetylase inhibitors (e.g., rapamycin, valproic acid, tubacin) and mTOR inhibitors are among the experimental medications being tested to suppress the proliferation of BL B-cells by triggering apoptosis (i.e., temsirolimus). Anti-PD1 drugs inhibit tumor cells from evading the immune system through the PD1 pathway. Therapies that block the MYC oncogene are being researched. 

Highly active anti-retroviral therapy (HARRT) has enabled the treatment of immunodeficiency-related Burkitt lymphoma in HIV patients with high-dose chemotherapy. Because of the risk of organ failure and infection in this patient population, it is recommended that less toxic chemotherapy be utilized.

The prognosis for individuals with relapsing illness is often bad, and therapy will be determined by the exact clinical circumstance. However, the discovery of more effective chemotherapy medications (such as ifosfamide, carboplatin, and etoposide) is helping to improve patient outcomes. 

Toxicity and Side Effect Management

Tumor lysis syndrome is characterized by tumor cell cytolysis, which results in hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia.  Calcium can precipitate in the kidneys, resulting in acute renal damage (AKI). Calcium, phosphate, and potassium flow are linked to heart arrhythmias, CNS damage, and mortality. Because TLS can occur before therapy begins, prophylaxis should be undertaken as soon as possible.

Male patients are more prone to have tumor lysis syndrome, as are those with a history of renal illness, increased lactate dehydrogenase (LDH) or uric acid levels, or splenomegaly. Extensive hydration before and after chemotherapy, as well as allopurinol and rasburicase, have all been shown to enhance results. If the patient suffers from serious renal damage, hemodialysis is recommended.

Chemotherapy has considerable adverse effects, including hematologic damage and an increased risk of infection. Treatment in developing countries must take socioeconomic considerations into account. Supportive treatment is critical, especially for the prevention of tumor lysis syndrome, fever control, and nutritional supplements.

Many patients do not finish therapy due to the high expense, lack of access to medical care, and health illiteracy. The 1-year event-free survival rate in patients with endemic BL is used to predict long-term survival (risk of relapse is less than or equal to 5 percent after 1 year).

Differential Diagnosis

Other CD10 positive B-cell lymphomas in the differential diagnosis of BL include diffuse large B-cell lymphoma (DLBCL), high-grade follicular lymphoma, and B-cell acute lymphoblastic leukemia/lymphoma (B-ALL). DLBCL and high-grade follicular lymphoma usually feature bigger cells with higher pleomorphism than BL. BCL2 positive and a Ki67 proliferation score less than 90% support a non-BL diagnosis.

An MYC translocation is not diagnostic of BL; roughly 10% of DLBCL patients have a MYC translocation. B-ALL is similar in size to BL, but it contains finer chromatin. B-ALL will frequently display immature markers such as CD34 and/or TdT when examined using immunohistochemistry or flow cytometry.

Staging

For pediatric patients, the St. Jude staging system is typically employed, whereas the Ann Arbor and Murphy staging systems are commonly used for adults. The Ann Arbor system takes into consideration the patient's symptoms. Because of its emphasis on extranodal illness and for separating bone marrow involvement from central nervous system disease, the Murphy staging system is employed.

Because of the aggressive nature of the disease in adult patients, staging should be undertaken using bone marrow and lumbar puncture samples, and treatment should begin as soon as the diagnosis is confirmed.

St. Jude/Murphy Staging System (Children)

• Stage I: A single tumor (extranodal) or a single anatomical area (nodal) on the same side of the diaphragm, excluding the mediastinum or belly, or a tumor (extranodal) with regional node involvement.
• Stage II: A single extranodal tumor with regional node involvement, lymph node involvement on the same side of the diaphragm (two or more nodal areas or two single extranodal tumors with or without regional node involvement), or a primary gastrointestinal tract tumor (usually ileocecal) with or without associated mesenteric node involvement, grossly completely resected.
• Stage III: On both sides of the diaphragm (two or more nodal areas or two single extranodal tumors), all primary intrathoracic tumors (e.g., mediastinal or pleural thymic), all extensive primary intraabdominal disease; unresectable abdominal disease, even if only in one area; or all primary paraspinal or epidural tumors, regardless of other sites.
• Stage IV: Any of the foregoing with early involvement of the CNS or bone marrow (only if less than 25 percent of the marrow is composed of Burkitt cells).

Murphy System (Adult)

• Stage I: Single nodal or extranodal site excluding the mediastinum or abdomen.
• Stage II: Two or more nodal areas on one side of the diaphragm.
• Stage IIR: Completely resectable abdominal disease
• Stage III: Two or more nodal areas on opposite sides of the diaphragm, or a primary intrathoracic tumor, paraspinal or epidural tumors, extensive intra-abdominal disease
• Stage IIIA: Completely non-resectable abdominal disease
• Stage IIIB: Widespread multiorgan intra-abdominal disease
• Stage IV: Central nervous system or bone marrow involvement

Favorable: Stage I or IIR

Ann Arbor System (Adult)

• Stage 1: Single nodal or extranodal site
• Stage II: Two or more nodal areas on one side of the diaphragm, or localized involvement of an extra-lymphatic site and one or more sites on the same side of the diaphragm (IIE)
• Stage III: Two or more nodal areas on opposite sides of the diaphragm which may include/ involvement of the spleen (IIIs), or localized involvement of an extranodal site (IIIE)
• Stage IV: Diffuse or disseminated involvement of one or more extra-lymphatic sites, or two single extranodal tumors on opposite sides of the diaphragm

Favorable: Stage I, II, III

Prognosis

Clinical and histopathologic staging, particularly the degree of illness, influence prognosis. Younger individuals have a better prognosis in general. It is likely that pediatric kids can take more powerful chemotherapy better.

Poor response to cyclophosphamide, prednisolone, and vincristine, as well as the discovery of CNS illness upon presentation, are poor prognostic indications. Lactose dehydrogenase concentrations that are twice the upper limit of normal are related with bad outcomes. Additional cytogenetic abnormalities beyond the MYC translocation, such as a deletion of 13q, a gain of 7q, or complicated cytogenetics, may indicate a poor prognosis.

When BL recurs within 6 months of treatment completion, the prognosis is poor because to the scarcity of new medications for treatment, since most were exhausted during first therapy. In contrast, a higher percentage of children can be treated following recurrence in underdeveloped countries where therapy is less severe.

The stage of the illness and abdominal ultrasonography are utilized to evaluate prognosis in underdeveloped nations. To detect residual or recurring illness, fluorodeoxyglucose positron emission tomography (PET) scans are used. The predictive importance of early PET scans or CT scans for disease assessment is being studied.

Follow-up care

Following the completion of treatment, post-treatment staging scans are performed to assess how well the treatment worked. The scans will reveal to the doctor whether or not there has been a:

• Complete response (CR or no signs of lymphoma remain) or a
• Partial response (PR or there is still lymphoma present, but it has reduced in size)

If all goes well regular follow-up appointments will be made for every 3-6 months to monitor the below:  

• Review the effectiveness of the treatment
• Monitor any ongoing side effects from the treatment
• Monitor for any late effects from treatment over time
• Monitor signs of the lymphoma relapsing

These sessions are also crucial so that the patient may express any concerns they may have to the medical staff. These consultations also include a physical examination and blood testing. Scans are not normally performed unless there is a cause for them, save from soon following therapy to assess how well the treatment worked. Appointments for certain patients may become less frequent over time.

Relapsed or refractory Burkitt lymphoma (BL)

With first-line conventional therapy, a large percentage of persons establish remission from Burkitt lymphoma (BL). However, in certain circumstances, the lymphoma reappears (relapses) or, in rare cases, does not respond to first-line therapy (refractory). People with relapsed or refractory BL illness may have additional treatment choices (second-line therapy), such as:

• Other combination chemotherapy options
• Stem cell transplant (autologous or allogeneic)
• Biological medicines 
• Clinical trial participation

Conclusion 

Burkitt's lymphoma is a kind of lymphoma that is aggressive and affects the B-lymphocytes. It accounts for between 0.3 and 1.3 percent of all non-Hodgkin lymphomas. Untreated Burkitt's lymphoma progresses rapidly; however, with contemporary combination chemotherapy regimens, the response rate is quite high.

Regimes create the most effective and long-lasting effects. In order to prevent or treat Burkitt's lymphoma in the central nervous system, additional intrathecal chemotherapy is administered. In some cases, a monoclonal antibody may be used in conjunction with chemotherapy. When treating Burkitt's lymphoma, it is particularly critical to avoid treatment-related problems such as tumor lysis syndrome.

People will be given a stem cell transplant when it is suitable, either using their own stem cells (autologous) or those from a donor (allogeneic). New therapies for Burkitt's lymphoma are always being explored, and patients may be invited to participate in a clinical trial to evaluate a new treatment option.