Burkitt Lymphoma and Burkitt-like Lymphoma 

Updated: Dec 20, 2019
Author: Ali H Kanbar, MD; Chief Editor: Emmanuel C Besa, MD 

Overview

Practice Essentials

Burkitt lymphoma, or small noncleaved cell lymphoma, is a highly aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation and deregulation of the c-myc gene on chromosome 8.[1] The 2016 World Health Organization (WHO) classification of lymphoid neoplasms recognizes Burkitt-like lymphoma with 11q aberration as a new provisional entity that lacks MYC rearrangements but resembles Burkitt lymphoma morphologically, to a large extent phenotypically, and by gene expression profiling.[2] See the image below.

Computed tomography scan in a patient with a large Computed tomography scan in a patient with a large, left-sided axillary mass from which a biopsy was obtained. Biopsy findings were consistent with small noncleaved cell non-Hodgkin 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

  • 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)

Other

  • Bone marrow involvemen
  • Painless lymphadenopathy (adults > children)

See Presentation for more detail.

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. Expedite the staging workup.

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

The Ann Arbor system and St. Jude/Murphy staging (commonly used) consist of 4 stages.

Stage I is as follows:

  • Single tumor (extranodal)
  • Single anatomic area (nodal)

Stage II is as follows:

  • Single tumor (extranodal) with regional node involvement
  • Primary gastrointestinal tumor
  • Lymphoma involving nodal areas on the same side of the diaphragm

Stage IIR consists of completely resected intra-abdominal disease.

Stage III is as follows:

  • Lymphoma involving sites on opposite sides of the diaphragm
  • All primary intrathoracic tumors
  • All paraspinal or epidural tumors
  • Extensive intra-abdominal disease

Stage IV consists of any of the above, with CNS or bone marrow involvement (< 25%) at presentation.

The risk-adapted approach is used to treat most patients in the present-day clinical setting. Patients are divided into 2 broad groups, low- and high-risk patients. Low-risk patients have nonbulky disease (< 10 cm), early stage (I or II) disease, good performance status, and a normal lactate dehydrogenase (LDH) level. High-risk patients include all other patients.

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

See Workup for more detail.

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

See Treatment and Medication for more detail.

Background

Historically, Burkitt lymphoma was termed malignant small noncleaved lymphoma in patients presenting with a solid tumor or nodal mass, whereas patients who had greater than 25% bone marrow involvement were considered to have French American British (FAB) L3 type acute lymphoblastic leukemia (L3 ALL). The 2016 World Health Organization (WHO) classification of lymphoid neoplasms identifies Burkitt lymphoma, in which TCF3 or ID3 mutations are present in up to about 70% of cases, and Burkitt-like lymphoma with 11q aberration, a new provisional entity that closely resembles Burkitt lymphoma but lacks MYC rearrangement and has some other distinctive features.[2]

The dysregulation and mutation of the c-myc oncogene that characterizes Burkitt lymphoma often results from a translocation between chromosomes 8 and 14, t(8;14)(q24;q32). Other translocations are also reported to cause c-myc overexpression, including t(2;8)(p12;q24) and t(8;22)(q24;q11). However, according to the WHO classification of lymphoid neoplasms, diagnosis of Burkitt lymphoma can still be made even in the absence of c-myc rearrangement, if other clinical, morphologic, and immunophenotypic findings support that diagnosis.[2]

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 equatorial 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[3] as well as in congenital immunodeficiency patients.[4] Immunodeficiency-associated Burkitt lymphoma accounts for about 30% of lymphomas in HIV patients.[5]

Burkitt lymphoma was originally described in children, but this disease is also observed in adult patients. Burkitt lymphoma is one of the fastest growing malignancies in humans, with a growth fraction close to 100% and a doubling time of around 25 hours.[6]

Burkitt and Burkitt-like lymphomas have a rapid and aggressive clinical course, commonly presenting in children and young adults, with frequent bone marrow and central nervous system (CNS) involvement. These are considered to be medical emergencies and require immediate diagnostic and therapeutic intervention.

Historical information

Burkitt lymphoma is named after Dr. Dennis Burkitt, an Irish surgeon who worked in Kampala, Uganda, and noted a large number of African children affected with rapidly growing jaw tumors in areas where falciparum malaria was endemic. Dr. Burkitt described those tumors initially as a form of sarcoma.[7] It was not until 3 years later that the tumors were histologically identified by Burkitt and O’Conor as malignant lymphomas.[8] A few years later, Dr. Burkitt met and provided tumor samples to the pathologist Anthony Epstein. Dr. Epstein and his colleagues identified Epstein-Barr virus (EBV) from the lymphoma samples, which established a role for EBV in the pathogenesis of African Burkitt lymphoma.[9, 10, 11]

See also the following:

  • B-cell lymphoma

  • Mantle cell lymphoma (MCL)

  • Non-Hodgkin lymphoma

  • Pediatric Non-Hodgkin Lymphoma

  • Pathology of Primary Bone Lymphoma

Etiology and Pathophysiology

The exact cause and pathophysiologic mechanisms leading to the development of Burkitt lymphoma are not known. Several theories exist. Epstein-Barr virus (EBV) and malaria infection as well as C-myc oncogene activation are briefly discussed in this section.

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.[2]

Malaria infection also probably plays a role in the pathogenesis of eBL, as it can lead to inhibition of EBV-specific immune response.[2] 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.[12] EBV can be detected in 25-40% of immunodeficiency-associated cases.[2]

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.[13]

Genetic features

The classic t(8;14)(q24;q32) 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.[6] 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.[14, 15]

C-myc is a leucine zipper transcription factor that affects different pathways regulating cell cycle, growth, adhesion, differentiation, and apoptosis.[16, 17] It is overexpressed via its juxtaposition with immunoglobulin gene enhancers. Genes like cyclin D2, TRAP1, and HLA-DRB1 are 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.[18]

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. Furthermore, reduction of E2F1 expression led to decreased growth capacity in sBL cells in vitro.[19]

Mutations in the ID3 gene have been found in 34-68% of Burkitt lymphomas. The role of these inactivating ID3 mutations may be to significantly amplify the actions of the c-myc–immunoglobulin translocation, increas cell cycle progression and cellular proliferation in Burkitt lymphoma cells,[20, 21]  In a study that involved genetic sequencing of 59 Burkitt lymphoma tumors, ID3 was one of 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4.[20]  

Epidemiology

According to the SEER (Surveillance, Epidemiology and End Results) database, the yearly incidence of Burkitt lymphoma/leukemia in the United States across all ages, between 2001 and 2006 was 1759 cases. Most of these cases occurred in patients between ages 20 and 64 years. This disease constituted 0.4% of all lymphoid tumors.

About 30-40% of human immunodeficiency virus (HIV)–related non-Hodgkin lymphoma (NHL) cases are Burkitt lymphoma, and the rate did not seem to decrease with the advent of highly active anti-retroviral therapy (HAART), as Burkitt lymphoma typically affects patients with high CD4 counts (> 200/mm3).[22] This actually suggests that decreased immunity is not a risk factor in this variant of Burkitt lymphoma. (See HIV-1 Associated Opportunistic Neoplasms - CNS Lymphoma.)

Globally, Burkitt lymphoma is endemic in certain regions of equatorial Africa and other tropical locations between latitudes 10° south and 10° north. Incidence in these areas of endemic disease is 100 per million children. Epstein-Barr virus (EBV) infection is found in nearly all cases. In endemic areas, there seems to be a correlation with the geographic distribution of endemic malaria.[23, 24] (See Etiology and Pathophysiology.)

Although no racial predilection is reported, there is a sex and age predilection. Males are affected 2-3 times more often than females (male-to-female ratio, 2-3:1). According to the SEER database, between 2001 and 2006, the incidence of Burkitt lymphoma in adults (> 20 y) was roughly 5 times higher than the incidence of the disease in children (< 20 y).

The endemic form of the disease (eBL) is most common in children aged 4-7 years. Outside Africa, adults with the sporadic form (sBL) are typically younger than 35 years, whereas patients with Burkitt-like lymphoma (BLL) have a median age of 55 years.[25]

Prognosis

Approximately 90% of pediatric patients and up to 50-60% of adults with Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL) treated with current intensive chemotherapy regimens have long-term disease-free survival. Hvelange et al identified genetic differences between adult and pediatric Burkitt lymphomas, which suggests age-related heterogeneity in pathogenesis that may explain the poorer prognosis in adult patients.[26]

Children

The prognosis of Burkitt lymphoma (BL) in children correlates with the bulk of disease at the time of diagnosis, as outlined below. Before the advent of aggressive therapeutic programs, children with Burkitt lymphoma (BL) died rapidly. With appropriate management of the metabolic consequences of rapid cell turnover and with combination chemotherapy and central nervous system (CNS) prophylaxis, the survival rate has been improved significantly (≤ 60%).

  • Patients with limited (A, AR; stage I and II) disease have an excellent prognosis, with a survival rate greater than 90%

  • Patients with more extensive disease (stage III and IV), especially involvement of the bone marrow and CNS, have a worse prognosis, but long-term survival rates of 50-90% can be achieved with more aggressive chemotherapy regimens

  • Patients with relapse disease have a long-term survival rate of 20-50%

  • For those who experience relapse, as many as 25% of children may be able to achieve a long-term disease-free survival through high-dose therapy with autologous hematopoietic stem-cell transplantation (HSCT).[27] The addition of rituximab to this therapeutic regimen may further increase the response rate.[28]

Adults

Adults with Burkitt lymphoma (BL), particularly those with advanced stage disease, do more poorly than children with the disease.[6, 29, 30, 31, 32, 33, 34] In addition, bone marrow involvement with complex cytogenetics has been noted to carry a worse prognosis in a retrospective observation[35] ; such complex cytogenetics have been reported to be more common among elderly patients.[36]

A 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.[37] 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[37] :

  • 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

Complications

Complications from disease include the following:

  • The likelihood of complications increases with the extent of the disease

  • Because of the extremely fast growth rate of Burkitt tumor cells, massive acute destruction of the tumor cells during initial chemotherapy may result in tumor lysis syndrome requiring renal dialysis (See Tumor Lysis Syndrome and Pediatric Tumor Lysis Syndrome.)

  • In the abdominal form of the disease, rapid tumor growth may result in obstruction; renal failure may occur from tumor infiltration of the kidneys

  • External compression of the ureters may cause obstructive uropathy; compression of loops of bowel may cause bowel obstruction

Complications from chemotherapy include the following:

  • Tumor lysis syndrome

  • Cardiomyopathy (anthracycline related)

  • Infections (during neutropenia post chemotherapy)

  • Gonadal dysfunction (chemotherapy-related sterility)

  • Secondary leukemias (exposure to alkylating agents), a late potential complication generally occurring more than 5 years after alkylator therapy

Patient Education

Provide information and support about the disease and the adverse effects of the drugs used to treat Burkitt lymphoma (BL) to patients and the family members, such as the following:

  • Secondary leukemias and myelodysplastic syndrome
  • Infertility
  • Possible anaphylactic reactions
  • Serious and potentially fatal infections

Inform patients who require high-dose chemotherapy and stem-cell transplantation that long-term complications of higher doses of chemoradiotherapy and a mortality rate of 3-5% from the conditioning regimen are possible

Young patients should be referred for counseling regarding fertility preservation, before chemotherapy, if possible.

Clearly explain transfusions (both red blood cells and platelets) and their associated complications.

Emotional support is very helpful to patients with cancer. Educating the medical personnel directly involved in patient care and the family members about emotional support for the patient is very important.

Patients should also be educated about the following:

  • Febrile neutropenia
  • Postchemotherapy thrombocytopenia and the tendency to bleed with minimal trauma
  • Chemotherapy-associated alopecia
  • Avoidance of pregnancy in women of childbearing age
  • Chemotherapy-induced nausea and vomiting
  • Chemotherapy-associated menstrual dysregulation (females) and the possibility of sexual dysfunction
  • Fatigue
  • Sperm banking

For patient education information, see the Lymphoma Directory and Burkitt Lymphoma.

 

Presentation

History and Physical Examination

Burkitt lymphoma (BL) is a highly aggressive B-cell lymphoma. All the symptoms are caused by rapid turnover of the mature B lymphocytes and the involvement of extranodal sites and invasion of contiguous organs.

Because of the rapid growth of the Burkitt tumor, patients may quickly manifest significant metabolic derangement and renal function impairment. Less common presentations of Burkitt lymphoma (BL) include an epidural mass, skin nodules, central nervous system (CNS) symptoms, and bone marrow involvement.[5]

Burkitt lymphoma (BL) can also present as acute lymphocytic leukemia (L3-ALL), with fever, anemia, bleeding, and adenopathy.

eBL, sBL, and immunodeficiency-associated BL

The 3 different clinical variants of Burkitt lymphoma (BL) described (endemic, sporadic, and immunodeficiency related) may have varied clinical presentations.[2, 6, 38]

The endemic form of Burkitt lymphoma (eBL) is most commonly seen in patients in equatorial Africa, with jaw and facial bone (orbit) involvement occurring in more than 50% of cases. Patients most often present with swelling of the affected jaw or other facial bones, loosening of the teeth, and swelling of the lymph nodes, which are nontender and rapidly growing, in the neck or below the jaw. Other clinical presentations including abdominal masses (ileal, cecal, etc), as well as ovarian, gonadal, skeletal, and breast involvement have also been documented.

The sporadic forms (sBL) most often present with abdominal tumors with bone marrow involvement. Patients most commonly present with abdominal tumors that cause swelling and pain in the affected area. Some patients present with symptoms of bowel obstruction secondary to an ileal-cecal intussusception caused by tumor growth. However, generalized lymphadenopathy is rare. Approximately 90% of patients with sBL and 50% of patients with eBL have abdominal masses upon presentation.

Involvement of the Waldeyer ring (palatine and lingual tonsils, nasopharyngeal adenoid) and nodes is common in sBL, and may result in dysphagia, dyspnea, wheezing, and airway obstruction.[39] Jaw tumors are very rare in sBL.

Like eBL, sBL can involve the ovaries, kidneys, and breasts. Cases of Burkitt lymphoma presenting as acute pancreatitis, cardiac masses, bilateral ovarian masses, and even skin lesions have been reported.[40, 41, 42, 43]

Immunodeficiency-related Burkitt lymphoma usually presents as nodal involvement. Bone marrow involvement occurs frequently. Waldeyer ring and mediastinal nodes are rarely involved.

Burkitt-like lymphoma

Patients with Burkitt-like lymphoma (BLL) may have a variable presentation compared with those with classic Burkitt lymphoma (BL). Patients with BLL usually present in their fourth or fifth decade of life. More than 50% of affected patients present with widespread (nodal and extranodal) disease with frequent bone marrow and peripheral blood involvement. Some patients have a leukemic presentation.

After reviewing Southwest Oncology Group (SWOG) data, Braziel et al reported the following clinical features of BLL[44] : Median age was reported as 47 years (range, 28-69 y), and 70% of the patients presented with bulky advanced disease (stage II, III, or IV), with 60% of patients having two or more extranodal sites of lymphoma involvement.

Signs

Major signs of Burkitt lymphoma include a soft-tissue mass associated with the involvement of the jaw or other facial bones, rapidly enlarged cervical lymph nodes, abdominal masses, and ascites. The physical examination findings depend on the sites of extranodal involvement and may include the following:

  • Abdominal tenderness

  • Ascites

  • Abdominal mass

  • Hepatosplenomegaly

  • Palpable tumor of the mandibulomaxillary region

  • Ecchymosis and/or petechiae (as a result of thrombocytopenia)

  • Meningeal signs (from CNS disease)

  • Painless lymphadenopathy

Summary of common clinical manifestations

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 (TLS)

Mandibular or maxillary mass

  • Most common presentation in eBL

  • Maxillary tumors are more common (may involve the orbit)

  • Jaw involvement occurs much less frequently (15-20% of sBL cases)

CNS involvement

  • Meningeal infiltration, with or without cranial nerve (CN) involvement (frequently, CN III and CN VII); this is the 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

  • B systemic symptoms are uncommon but may be associated with other presenting symptoms, such as fever, weight loss, night sweats, fatigue.

Other

  • Bone marrow involvement is common in Burkitt lymphoma

  • Lymphadenopathy is more common in affected adults than in children

Staging

Patients with more than 25% bone marrow involvement are usually referred to as having Burkitt leukemia (BL). However, most patients will present with nodal or extranodal masses. Different staging systems, such as the National Cancer Institute (NCI) and Ann Arbor and St. Jude/Murphy staging systems, as well as a risk-adapted approach, have been proposed for these patients and are summarized below.

NCI staging system

See the list below:

  • 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

Ann Arbor system and St. Jude/Murphy staging (commonly used)

Stage I

  • Single tumor (extranodal)

  • Single anatomic area (nodal)

Stage II

  • Single tumor (extranodal) with regional node involvement

  • Primary gastrointestinal tumor

  • Lymphoma involving nodal areas on the same side of the diaphragm

Stage IIR

  • Completely resected intra-abdominal disease

Stage III

  • Lymphoma involving sites on opposite sides of the diaphragm

  • All primary intrathoracic tumors

  • All paraspinal or epidural tumors

  • Extensive intra-abdominal disease

Stage IV

  • Any of the above, with central nervous system (CNS) or bone marrow involvement (< 25%) at presentation

Around 30% of patients present with limited-stage disease (stage I or II), and 70% present with more extensive disease (stage III or IV). Bone marrow involvement is found in 30-38% of patients, and the CNS is involved in 13-17% of adult patients.

Risk-adapted approach

Currently, most patients are treated following a risk-adapted approach. In this classification, patients are broadly divided into two groups: low risk and high risk.

Low-risk patients are those who have nonbulky disease (< 10 cm), early stage (I or II) disease, good performance status, and a normal lactate dehydrogenase (LDH) level. High-risk patients include all other patients.

 

DDx

Diagnostic Considerations

Burkitt lymphoma (BL) must be distinguished from other primary abdominal tumors in childhood, including Wilms tumor, neuroblastoma, and peripheral neuroectodermal tumor. In the bone marrow, BL must be differentiated from B and T precursor and myeloid leukemias. Among peripheral B-cell lymphomas, the major difficulty is to differentiate BL from diffuse large B-cell lymphoma (DLBCL), lymphoblastic lymphoma, and blastic mantle cell lymphoma (MCL).

DLBCL

DLBCL typically has larger cells, but some Burkitt lymphoma (BL) cases might have centroblast-like (large) cells intermixed with the more common medium-sized monoclonal lymphocytes, resulting in some degree of a diagnostic dilemma, especially when considering that up to 15% of DLBCL cases might test positive for the c-myc translocation. Those borderline cases are categorized under Burkitt-like lymphoma (BLL). In the 2008 World Health Organization (WHO) classification system, these are referred to as "B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma."[2, 45] (See Histologic Features.)

Features that rule out the diagnosis of Burkitt lymphoma (BL) include bcl-6 gene rearrangement (independent from bcl-6 nuclear staining), bcl-2 positivity, presence of t(14;18), and a Ki67 staining of less than 95%.[46, 47]

Researchers have been able to define a specific genetic signature for Burkitt lymphoma (BL). Two different studies explored gene-expression profiling by microarray technology as a tool to accurately diagnose Burkitt lymphoma (BL) and differentiate it from DLBCL due to the significant difference in prognosis and treatment approaches for these diseases.[48, 49] Results showed that 17-34% of DLBCL cases diagnosed by expert pathologists had the typical Burkitt lymphoma (BL) genetic signature; likewise up to 4% of cases signed out as classic or atypical BL lacked the typical genetic signature.

In both studies, rare cases with the Burkitt signature were c-myc negative.[48, 49] Moreover, patients with a Burkitt lymphoma (BL) signature who were treated with CHOP-like (cyclophosphamide, hydroxydaunorubicin hydrochloride [doxorubicin hydrochloride], vincristine and prednisone) regimens had a worse prognosis than those patients who were treated with more intense chemotherapy regimens.[48, 49] Unfortunately, microarray analysis is not readily available in most clinical settings and remains a research tool.

Lymphoblastic and mantle cell lymphomas

Lymphoblastic lymphoma may be histologically similar to Burkitt lymphoma (BL), however, it is a T-cell lymphoma that expresses T-cell markers in addition to TdT, which are usually negative in BL cases. Similarly, mantle cell lymphoma cases can be easily distinguished from Burkitt lymphoma (BL) by immunohistochemistry and flow cytometry as they typically stain strongly for CD5 and cyclin D1, unlike BL.

Differential Diagnoses

 

Workup

Approach Considerations

The least invasive procedure should be used to establish the diagnosis, which usually involves pathologic evaluation of the involved tissue biopsy. The staging workup must be expedited, because Burkitt tumor grows rapidly, causing life-threatening complications.

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.

The detection of the classic reciprocal c-myc translocations as well as is not always feasible on routine cytogenetics studies; the use of fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) can be very helpful in detecting the presence of c-myc translocations in those cases.[50]

Flow cytometry of biopsied tissue or bone marrow may reveal expression of surface immunoglobulin M (IgM) (most common), as well as other mature B-cell markers, such as the following:

  • CD19
  • CD20
  • CD22
  • CD79a
  • CD10

In contrast, Tdt, CD5, CD23, and CD34 are negative.

Diagnostic Studies

General laboratory studies should include complete blood cell (CBC) count with differentials; a platelet count; serum levels of electrolytes, uric acid, lactate dehydrogenase (LDH), and creatinine; and liver function tests. All patients should also be checked for human immunodeficiency virus (HIV) and hepatitis B (HBV) infection.

CBC count and coagulation studies

CBC counts may reveal pancytopenia (anemia, thrombocytopenia, and/or leukopenia) due to the involvement of the bone marrow. Coagulation studies (prothrombin time [PT], partial thromboplastin time [PTT], and fibrinogen) should be performed to evaluate the presence of disseminated intravascular coagulopathy (DIC).

Serum chemistries

Electrolyte imbalances occur as a result of renal infiltration with lymphoma. The rapid turnover of the Burkitt lymphoma (BL) cells may cause primary tumor lysis, which is characterized by hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia—with resultant uric acid nephropathy and oliguric renal failure.

Serum lactate dehydrogenase (LDH) levels are almost always elevated, often to extreme levels. The diagnosis of Burkitt lymphoma (BL) should be considered in any patient with a marked elevation of LDH. This test is also a useful indicator of the patient's response to treatment and can be used as an early nonspecific indicator of disease relapse.

Liver function test results, if abnormal, may be indicative of visceral involvement with lymphoma.

Serum uric acid levels are often high and reflect the high-grade nature of the disease and correlate with the probability of tumor lysis syndrome with initiation of cytotoxic therapy.

Beta2 microglobulin is a predictor of the extent of disease and is used as a surrogate marker for early relapse.

Radiologic Studies

Imaging studies help assess tumor burden and measurement of tumor masses before therapy. Head or spinal computed tomography (CT) scanning or magnetic resonance imaging (MRI) is indicated if neurologic signs and symptoms are present (see the following images), whereas bone scanning and plain bone radiography are needed for patients with symptoms of bone involvement. These imaging studies are helpful in evaluating the extent of disease and used in assessing sites of relapse. Although complete staging is helpful in assessing the patient, treatment should not be delayed while extensive tests are performed.

Computed tomography scan in a patient with a large Computed tomography scan in a patient with a large, left-sided axillary mass from which a biopsy was obtained. Biopsy findings were consistent with small noncleaved cell non-Hodgkin lymphoma.
Postchemotherapy computed tomography scan in a pat Postchemotherapy computed tomography scan in a patient diagnosed with small noncleaved cell lymphoma (SNCCL) (same patient as in previous image). This image shows regression of a left axillary mass.
Coronal magnetic resonance imaging (MRI) section i Coronal magnetic resonance imaging (MRI) section in a patient with large neck mass (same patient as in previous image). Biopsy findings showed Burkitt-like non-Hodgkin lymphoma (NHL). MRI was performed to assess for cord involvement.
Sagittal magnetic resonance imaging (MRI) section Sagittal magnetic resonance imaging (MRI) section of the neck area showing a large mass invading the cervical spine with epidural encroachment (same patient as in the previous image). MRI was performed to rule out cord compression. The first image shows the gallium scan of this patient that correlates with the site of the tumor.
Right-sided pleural effusion in a patient with sma Right-sided pleural effusion in a patient with small noncleaved cell lymphoma (SNCCL) non-Hodgkin lymphoma.

Obtain a CT scan of the chest, abdomen, and pelvis with intravenous contrast. If the patient has evidence of renal insufficiency due to hyperuricemia, obstruction, or renal infiltration, then intravenous (IV) contrast medium should be omitted.

Positron emission tomography (PET) scanning has been reported to be very useful in staging non-Hodgkin lymphomas (NHL) and monitoring treatment response, but this modality is unlikely to alter management in Burkitt lymphoma (BL), therefore, it is reserved for use in clinical trials.

Cardiac imaging studies

Echocardiography (ECG) is indicated for possible arrhythmia resulting from cardiac involvement.

Multiple-gate acquisition (MUGA) scanning is used to evaluate the ejection fraction before chemotherapy treatment, especially if anthracyclines will be used, as these agents have a potential cardiotoxic effect.

Diagnostic Procedures and Associated Studies

The diagnosis of Burkitt lymphoma (BL) or Burkitt-like lymphoma (BLL) is made by obtaining a biopsy of the tumor mass for histopathology, immunochemistry, and flow cytometry (see the following image). Cytogenetic studies to identify c-myc mutation will aid in the diagnosis. The most suggestive lymph nodes should be selected for excisional biopsy. Frozen sections and needle biopsies are discouraged. Aspiration of bone marrow or effusions may provide the diagnosis and avoid lymph node biopsy.

A unilateral bone marrow aspirate and biopsy should be performed for every patient with Burkitt lymphoma (BL), because the frequent presence of unexpected bone marrow involvement has important implications for treatment planning. If lymphoma cells are present in the aspirate, flow cytometry/immunophenotyping should be ordered to further characterize the disease. Bone marrow is involved in 20% of sporadic cases and 8% of endemic cases of Burkitt lymphoma (eBL).

Lumbar puncture (LP) is considered part of the staging workup to evaluate for cerebrospinal fluid (CSF) involvement. This test should be deferred in the presence of significant thrombocytopenia or coagulation defects. The CSF should be sent for cytology and flow cytometry evaluation in addition to the usual studies. Intrathecal chemotherapy is usually given at the time of the initial lumbar puncture.

Paracentesis or thoracentesis may be needed for cytogenetic studies if ascites or pleural effusion is present.

Years ago, laparotomy was indicated for the initial diagnosis and for resection of the disease; this procedure is not recommended by current guidelines.

Histologic Features

Burkitt cells are homogeneous in size and shape, with round to oval nuclei and slightly coarse chromatin, with multiple nucleoli, and with intensely basophilic vacuolated cytoplasm that contains neutral fat. Extranodal involvement shows infiltration with monotonous cells of uniform size and shape. The cytoplasm is scanty, and the nucleus is round or slightly irregular with slightly coarse chromatin and several nucleoli.

Burkitt lymphoma

Histologically, Burkitt lymphoma (BL) is characterized by a monoclonal proliferation of medium-sized, noncleaved B-cells that are uniform in appearance and that produce a diffuse pattern of tissue involvement. These cells typically have a scant basophilic cytoplasm characterized by numerous lipid vacuoles, round nuclei with stippled chromatin and multiple small nucleoli.

Under the microscope, the hallmark of Burkitt lymphoma (BL) is the presence of a "starry sky" appearance (also observed in other highly proliferative lymphomas), imparted by scattered macrophages phagocytizing cell debris and apoptotic cells (tingible body macrophages) (see the image below).[2] However, the starry sky pattern is not pathognomonic for Burkitt lymphoma (BL) and may be observed in other highly proliferative lymphomas. Immunophenotype and cytogenetic studies aid in the diagnosis of Burkitt lymphoma (BL).[2, 45]

Hematoxylin and eosin (H&E) stain. Sheets of monot Hematoxylin and eosin (H&E) stain. Sheets of monotonous-appearing lymphoid cells with one or more prominent nucleoli and an area of pale staining resulting from the presence of benign macrophages reveal a starry sky pattern.

Burkitt lymphoma (BL) tumor cells are derived from mutated activated germinal center B-lymphocytes based on the fact that they share the same surface markers such as CD10, CD77, and bcl-6 (nuclear staining only) and the presence of somatic mutations in their immunoglobulins gene, similar to normal germinal center B cells.[51] They also express other B-cell antigens like CD10, CD19, CD20, CD22, as well as HLA-DR and surface immunoglobulin M (IgM) (see the image below). Ki67 staining usually approaches 100%. They typically lack CD5, CD23, TdT and are usually bcl-2 negative.[2] Expression of CD21 (Epstein-Barr virus [EBV]-C3d receptor) is present only in EBV-positive patients (endemic BL).[52]

The 2-dimensional flow cytometry demonstrates the The 2-dimensional flow cytometry demonstrates the highlighted cells to be CD5 negative and CD23 negative as well as lambda negative. Small noncleaved cell lymphoma (SNCCL) cells are typically CD19+, CD20+, CD22+, and CD10+.

Burkitt-like lymphoma

Burkitt-like lymphoma (BLL), a subcategory of Burkitt lymphoma (BL) in the World Health Organization (WHO) classification, has greater polymorphism in the nuclear size and shape, and the expression of surface markers is more variable. Morphologically, these tumors have features that are intermediate between diffuse large B-cell lymphoma (DLBCL) and classic Burkitt lymphoma (BL), with some large cells resembling DLBCL and other, smaller cells resembling typical BL cells. They are also characterized by a high proliferation rate, a starry-sky pattern, and an immunophenotype similar to classic Burkitt lymphoma (BL).[53]

The WHO describes cases that are morphologically typical of Burkitt lymphoma (BL) but that have an atypical immunophenotype or genetic features. Around 35-50% of these cases have 8q24/c-myc translocations, and approximately 15% have bcl-2 translocations (double hit lymphoma). Interestingly, not all c-myc translocations in Burkitt-like lymphoma (BLL) patients involve immunoglobulin loci (Non IG-MYC).[45]

 

Treatment

Approach Considerations

Burkitt lymphoma (BL) is a very fast growing tumor. Patients should be admitted to the hospital for rapid workup and diagnostic measures. Chemotherapy is the mainstay of treatment for this disease; consultation with a hematologist and oncologist should be obtained as soon as possible. No role exists for surgery or radiation therapy in the treatment of Burkitt lymphomaL).

It is critical to closely monitor serum chemistries in patients with Burkitt lymphoma (BL), especially during chemotherapy because of the high risk of tumor lysis syndrome and uric acid nephropathy. Prophylactic allopurinol and aggressive hydration with urine alkalinization should be administered.

Intravenous antibiotics should be administered for neutropenic fevers. Growth factors (granulocyte-macrophage colony-stimulating factor [GM-CSF] or granulocyte colony-stimulating factor [G-CSF]) are administered to help decrease the duration of neutropenia.

Transfusions (red blood cells or platelets) are administered as clinically indicated for anemia and thrombocytopenia. All blood products should be leukodepleted and irradiated.

Measures to prevent tumor lysis syndrome

Maintain adequate hydration through intravenous (IV) fluids, ideally starting 24 hours before administering chemotherapy. Note, however, that many patients require chemotherapy emergently and, in these patients, therapy should not be delayed.

Maintain high urine outflow (200-250 mL/m2/h), and monitor renal function closely.

Most patients with Burkitt lymphoma are considered at high risk for tumor lysis and meet the criteria for upfront treatment with rasburicase, which should be administered at a dose of 0.20 mg/kg IV daily for 5 days. Note that patients receiving rasburicase should not have alkalinization of the urine and that this agent is contraindicated in patients with glucose-6-phospate deficiency (G6PD). Lower-risk patients and those who cannot tolerate rasburicase can receive allopurinol, 300 mg twice daily

Close monitoring of the complete blood cell (CBC) count, coagulation studies, and at least twice-daily measurement of serum uric acid, potassium, calcium, phosphorus, magnesium, and creatinine levels is necessary for the first several days of treatment. Consider placing the patient on a cardiac monitor for the first few days. Liver function results should also be monitored.

Treatment should be performed at a facility where renal dialysis is available should it be necessary, particularly for patients with extensive disease.

Consultations

In addition to obtaining a consultation with a hematologist and hematopathologist should as soon as possible, various subspecialty consultations may be required as indicated by clinical situations, such as renal consultation for patients presenting with, or developing, renal failure (uric acid nephropathy) that may require dialysis and surgical consultation for excisional lymph node or tissue biopsy and central line/port placement

Transfer

Patients should be treated in a facility where the physicians are familiar with the use of intensive chemotherapy regimens. The facility should have access to hematopathology and physicians experienced in the prevention and treatment of renal failure from tumor lysis. Adequate blood product support should be available.

Diet and activity restrictions

Most centers advise a neutropenic diet, and patients with significant renal dysfunction should receive a renal diet.

Most patients with Burkitt lymphoma are acutely ill and in the hospital at diagnosis. Their activities will be extremely limited at this time. As the patient responds to therapy, they can increase their activity appropriately. Patients with significant anemia will be limited by fatigue. These patients should appropriately restrict activities that require intense concentration. Patients with significant thrombocytopenia should not perform strenuous activities.

Chemotherapy Overview

Intensive systemic chemotherapy is the treatment of choice for this aggressive disease in all its stages.[33] All clinical variants of Burkitt lymphoma are treated generally the same. The overall survival rate associated with Burkitt lymphoma depends upon the stage of the disease at initial diagnosis. Patients with localized disease respond well to chemotherapy and have an excellent survival rate. Patients with disseminated disease respond less well to chemotherapy and have a less favorable survival rate. Increasing age has also been associated with inferior outcome in most clinical trials.[6, 54] (See Staging and Prognosis.)

For patients who refuse, or are not candidates for clinical trials, short-duration, intensive, alkylator-based, multiagent chemotherapy regimens with adequate central nervous system (CNS) prophylaxis are necessary. Administration of less intensive chemotherapy regimens used in other non-Hodgkin lymphomas (NHL) (eg, CHOP [cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine and prednisone]) usually results in frequent relapses and inferior survival. Of particular importance is the rapid administration of successive cycles of intensive multidrug therapy to prevent tumor regrowth. Dose reduction should also be avoided if possible.[55]

Most adult Burkitt lymphoma regimens were initially adopted from the pediatric study protocols that used several known active agents, including cyclophosphamide, vincristine, methotrexate, doxorubicin, and cytarabine. The French (LMB 81, 84, 86, and 89) and the German (B-NHL 83, B-NHL 86) protocols as well as the CODOX-M/IVAC regimen (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate / ifosfamide, etoposide, high-dose cytarabine) were modified and used in adult patients with acceptable outcomes (2-y overall survival: 40-74%). Other protocols (hyper-CVAD [modified fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone], Cancer and Leukemia Group B [CALGB] 9251, etc) were evaluated primarily in adults.

A study by Todeschini et al found that intensive pediatric-based chemotherapy regimen increased remission and survival rates in both children and adults with Burtkitt lymphoma.[56]

Even though a standard regimen is not available yet, in general, three treatment approaches are available:

  • Intensive, short-duration regimens like CODOX-M/IVAC (Magrath regimen) and the CALGB 9251 protocol

  • Long-duration chemotherapy similar to acute lymphoblastic leukemia (ALL) treatment, like hyper-CVAD and the CALGB 8811 protocol

  • Combination regimens followed by autologous stem cell transplantation (SCT)

  • Most current regimens have added rituximab to previously established chemotherapy regimens

Despite the fact that no direct comparison has been done among these different approaches, the short-duration, more intense regimens are usually preferred in most US institutions, because they are faster to administer (ALL-type treatment may take up to 2 y and usually involves a maintenance arm) and less complicated than ALL-type treatment or SCT. The regimen most frequently used is CODOX-M/IVAC.

Toxicity

Each of the above mentioned regimens carries a 60-70% chance of prolonged progression-free and overall survival, but that is unfortunately associated with a significant toxicity profile. No toxic deaths were reported in the initial study by Magrath (CODOX-M/IVAC), but the rate of grade 3/4 neutropenia was 100%; thrombocytopenia, 96%; mucositis, 61%; and sepsis, 22%. Similar toxicities were seen on the CALGB 9251 protocol.

CNS prophylaxis

CNS prophylaxis using intrathecal methotrexate with or without cytarabine and hydrocortisone is included in most regimens. Without CNS prophylaxis, 30-50% of patients will develop CNS relapse. With the above mentioned regimens, the rate of CNS relapse drops to about 6-11%.[57] Use of prophylactic cranial irradiation causes increased neurologic toxicity; in the 2004 update of the CALGB 9251, the protocol was amended to restrict its use to patients with bone marrow involvement only. This did not significantly affect the rate of CNS relapse.

CODOX-M/IVAC Regimen (Magrath Regimen)

The CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate / ifosfamide, etoposide, high-dose cytarabine) regimen consists of 4 cycles, each cycle lasting until blood counts recover (absolute neutrophil count [ANC] > 1000/μL; platelets > 100,000/μL). Cycles 1 and 3 involve CODOX-M, and cycles 2 and 4 involve IVAC. Three cycles of CODOX-M are usually enough for low-risk patients, whereas high-risk patients receive 4 total cycles (2 cycles of CODOX-M, alternating with 2 cycles of IVAC).[29]

CODOX-M

The CODOX-M regimen is as follows:

  • Cyclophosphamide 800mg/m2 IV on day 1, followed by 200 mg/m2 IV on days 2-5

  • Doxorubicin 40 mg/m2 IV on day 1

  • Vincristine 1.5 mg/m2 IV (no capping of dose) on days 1 and 8 (cycle 1), as well as on days 1, 8, and 15 (cycle 3)

  • Methotrexate 1200 mg/m2 IV over 1 hour on day 10; then 240 mg/m2/h for the next 23 hours; leucovorin rescue begins 36 hours from the start of the methotrexate infusion

  • Intrathecal cytarabine 70 mg (patient older than age 3 y) on days 1 and 3

  • Intrathecal methotrexate 12 mg (patient older than age 3 y) on day 15

IVAC

The IVAC regimen is as follows:

  • Ifosfamide 1500 mg/m2 IV on days 1-5, with mesna protection

  • Etoposide 60 mg/m2 IV on days 1-5

  • Cytarabine 2 g/m2 IV every 12 hours on days 1-2

  • Intrathecal methotrexate 12 mg (patient older than age 3 y) on day 5

Administration of colony-stimulating factors is usually started 24 hours after completion of chemotherapy and continues until the ANC >1000/μL. See the Absolute Neutrophil Count calculator.

CNS involvement

If central nervous system (CNS) involvement is documented, patients are treated with a more intense intrathecal regimen during cycles 1 and 2. Cytarabine 70 mg (15 mg if administered into an Ommaya reservoir) is given on days 1, 3, and 5 of cycle 1 as well as on days 7 and 9 of cycle 2; in addition, intrathecal methotrexate 12.5 mg (2 mg if via Ommaya reservoir) on days 15 and 17 (cycle 1) and day 5 (cycle 2). For cycles 3 and 4, the usual prophylactic intrathecal doses of cytosine arabinoside (Ara-C) and methotrexate are given.

The MRC/NCRI LY1O trial investigated a modified dose of methotrexate (3 g/m2) and showed an overall survival of 67%, with decreased toxicity compared with the previous LY06 trial with full-dose methotrexate (6.7 g/m2).[58]

CALGB 9251 Regimen

The Cancer and Leukemia Group B (CALGB) launched a multidrug regimen pilot study (9251) of high-intensity, brief-duration chemotherapy. A brief schema of this protocol is discussed in this section.[59, 60]

Note: Courses II, IV, and VI and courses III, V, and VII are similar and described together. Courses II-VI are administered at 21-day intervals

Course I consists of cyclophosphamide 200 mg/m2/d IV on days 1-5; prednisone 60 mg/m2/d by mouth (PO) on days 1-7.

Courses II, IV, and VI comprise the following:

  • Ifosfamide 800 mg/m2 IV over 1 hour on days 1-5

  • Mesna 200 mg/m2 IV on days 1-5 (at 0, 4, and 8 h after ifosfamide)

  • Methotrexate 150 mg/m2 IV over 30 minutes on day 1, followed by 1.35 g/m2 IV over the next 23.5 hours (total dose: 1.5 g/m2)

  • Leucovorin 50 mg/m2 IV starting 36 hours after methotrexate, then 15 mg/m2 every 6 hours until serum methotrexate levels are < 5 × 10-8 M (0.05 μM)

  • Vincristine 2 mg IV bolus on day 1

  • Cytarabine (Ara-C) 150 mg/m2/day by continuous infusion over 48 hours (days 4-5)

  • Etoposide 80 mg/m2 IV over 1 hour on days 4-5

  • Dexamethasone 10 mg/m2 PO per day on days 1-5

Courses III, V, and VII comprise the following:

  • Cyclophosphamide 200 mg/m2 IV daily on days 1-5

  • Methotrexate 150 mg/m2 IV over 30 minutes on day 1, followed by 1.35 g/m2 IV over the next 23.5 hours (total dose: 1.5 g/m2)

  • Leucovorin 50 mg/m2 IV starting 36 hours after methotrexate, then 15 mg/m2 every 6 hours until serum methotrexate levels are < 5 × 10-8 M (0.05 μM)

  • Vincristine 2 mg IV bolus on day 1

  • Adriamycin (doxorubicin) 25 mg/m2 IV bolus on days 4-5

  • Dexamethasone 10 mg/m2 PO daily on days 1-5

Intrathecal chemotherapy consists of methotrexate 15 mg plus cytarabine 40 mg plus hydrocortisone 50 mg, all administered on day 1 of each course (II-VII).

Cranial radiation (amended in the 2004 update of the CALGB 9251: Only for those patients with previous bone marrow involvement): 2400 cGy in 12 fractions, administered at least 21 days after course VII.

Hyper-CVAD Regimen

The hyper-CVAD (modified fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) regimen consists of alternating A (1, 3, 5, and 7) and B (2, 4, 6, and 8) cycles. The second and subsequent cycles are administered when the patient's white blood cell (WBC) count is more than 3,000/mm3, and the platelet count is higher than 60,000/mm3 (between 14 and 21 d).

Cycle A comprises the following:

  • Cyclophosphamide 300 mg/m2 intravenously (IV) over 2 hours every 12 hours for 6 doses, on days 1-3

  • Mesna 600 mg/m2 by continuous IV infusion over 24 hours, starting 1 hour before cyclophosphamide and continuing for 12 hours after the last dose of cyclophosphamide

  • Vincristine 2 mg/dose IV push over 2-3 minutes for 2 doses on days 4 and 11

  • Doxorubicin 50 mg/m2 IV over 2 hours on day 4

  • Dexamethasone 40 mg/day orally (PO) or IV for 8 doses on days 1-4 and on days 11-14

  • Filgrastim 10 mcg/kg/day subcutaneously (SC) starting 24 hours after the last dose of chemotherapy and continuing until the WBC count is >3000/mm3

Cycle B comprises the following:

  • Methotrexate 1000 mg/m2 by continuous IV infusion over 24 hours on day 1

  • Cytarabine 3,000 mg/m2 IV over 2 hours every 12 hours for 4 doses, on days 2-3

  • Calcium leucovorin 50 mg IV over 20 minutes administered 12 hours after methotrexate infusion is completed, followed 6 hours later by leucovorin 15 mg IV every 6 hours for 8 total doses or until blood methotrexate concentration is < 0.1 µmol/L

  • Filgrastim 10 mcg/kg/day SC starting 24 hours after the last dose of chemotherapy and continuing until the WBC count is > 3000/mm3

Calcium leucovorin doses should be escalated to 50 mg IV every 6 hours if serum methotrexate concentrations are the following:

  • Greater than 20 µmol/L at the end of the methotrexate infusion (hour 24)

  • Greater than 1 µmol/L at 24 hours after the end of the methotrexate infusion (hour 48)

  • Greater than 0.1 µmol/L at 48 hours after the end of the methotrexate infusion (hour 72)

CNS prophylaxis

See the list below:

  • Methotrexate intrathecally on day 2 of each cycle, 12 mg/dose via lumbar puncture or 6 mg/dose via Ommaya reservoir

  • Cytarabine 100 mg/dose intrathecally via lumbar puncture or Ommaya reservoir administered on day 7 for 8 cycles

Rituximab

Rituximab is a recombinant antibody that targets CD20 on the surface of B lymphocytes. Many studies have incorporated rituximab into the treatment of Burkitt lymphoma. When Oriol et al investigated the addition of rituximab to an intense chemotherapy regimen containing methotrexate, cyclophosphamide, vincristine, ifosfamide, and teniposide (NHL2002 protocol from GMALL [German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia] study) in treating 36 patients, 19 (53%) of whom were HIV positive, complete remission (CR) rates were 88% for HIV-negative patients and 84% for HIV-positive patients.[61]

HIV-positive patients had a higher rate of mucositis and infectious diarrhea, but there was no statistically significant difference in 2-year overall survival between the 2 groups of patients.[61] The HIV-positive patients were all treated concurrently with highly active anti-retroviral therapy (HAART).[61] An improvement in the 3-year estimated survival, disease-free survival (DFS), and event-free survival (EFS) rates, particularly for the elderly, were seen in patients with Burkitt lymphoma receiving rituximab compared with historical controls who did not receive rituximab.

Rituximab has also been evaluated prospectively in small studies, in combination with hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone)[28] and dose-adjusted EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone).[62] Complete remissions were seen in 86-100% of patients. Rituximab is therefore recommended in the treatment of BL patients, probably to be started with cycle 2, in order to decrease the risk of tumor lysis with the first cycle. CALGB is currently recruiting for a trial looking specifically at the role of rituximab (CALGB 10002).

Evaluation of Treatment Response

After completion of chemotherapy, the response to treatment should be investigated. This should include patient history, physical examination, laboratory studies (complete blood cell (CBC) count, renal/liver profiles, and lactate dehydrogenase [LDH] levels) ,and posttherapy imaging, preferably computed tomography (CT) scans (see Workup).

A complete remission is achieved if the patient has no evidence of disease or disease-related symptoms and if all the masses or lymph nodes that were previously present have resolved on the posttreatment CT scan. If the bone marrow was involved before treatment, a repeat bone marrow biopsy should be normal.

Relapsed/Refractory Burkitt Lymphoma

The majority of relapses occur during the first year of treatment for Burkitt lymphoma. Failure to achieve complete remission is a very poor prognostic sign. Those who remain free from disease at 10-12 months are considered cured, although reports of delayed relapses have been described in the African population and in patients with concurrent human immunodeficiency virus (HIV) infection.

The best management approach to these patients is not well defined. Most patients in this group respond poorly to salvage therapy, although some patients are reported to have long-term survival.

The salvage regimen typically incorporates chemotherapeutic agents to which the patient has had no previous exposure. The DHAP (dexamethasone at 40 mg PO for 4 d, high-dose cytarabine [Ara-C] at 2000 mg/m2 IV q12h for 2 doses, and cisplatin at 100 mg/m2 IV for 1 dose) regimen is often used as salvage therapy. Among these patients, those whose disease demonstrates some chemosensitivity are then referred for high-dose chemotherapy and autologous stem cell transplantation (SCT)/bone marrow transplantation (or allogeneic SCT in clinical trials). Patients with chemoresistant disease are usually referred for best supportive care (see the Sweetenham et al reference[63] ).

Stem Cell Transplantation

The use of high-dose chemotherapy plus stem cell transplantation (SCT) has decreased because of the high rate of remission achieved with current treatment regimens.

High-dose chemotherapy plus autologous SCT may be considered for patients whose condition has not responded to (primary refractory) or who have relapsed after first-line conventional chemotherapy. The outcome for adult patients treated with a short, intensive regimen is less favorable than the outcome in children. Up to 40% of the patients treated on the LMB81 and LMB84 regimens experienced relapse; this rate is lower in patients treated with CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate / ifosfamide, etoposide, high-dose cytarabine).[29] Current indications for treatment of these patients with high-dose chemotherapy plus autologous SCT remain similar to those of the pediatric group.

Primary refractory disease

Patients with primary refractory disease do not respond well to high-dose chemotherapy plus autologous SCT. The duration of responses in these patients is often short, with eventual relapse in most reported series. Alternative approaches, including allogeneic SCT/bone marrow transplantation or salvage regimens in the setting of a clinical trial, should be considered in these cases.[6, 64]

Partial remission

Patients in first partial remission should be considered for high-dose chemotherapy plus autologous SCT. The outcome of treatment in these patients with conventional chemotherapy regimens is usually poor. In a report by Philip and Biron, the results of bone marrow transplantation in patients with Burkitt lymphoma (BL) in partial remission was a 70% survival rate at 2 years.[65]

Subsequent randomized studies in aggressive non-Hodgkin lymphoma (NHL) have failed to clearly show an advantage for high-dose chemotherapy plus autologous SCT. Currently, patients with Burkitt lymphoma (BL) whose disease demonstrates chemosensitivity and who achieve a good partial remission after front-line therapy should be considered for high-dose chemotherapy plus autologous SCT.[27]

Clinical remission

Patients in first clinical remission with poor prognostic features have been considered for consolidation therapy with high-dose chemotherapy plus autologous SCT. Published data to date do not support the use of this approach outside of a clinical trial.[66]

Relapse

A French group has reported improved survival rates in patients with relapsed aggressive NHL who were treated with high-dose chemotherapy plus autologous SCT.[67] The only significant prognostic factor noted was sensitivity to reinduction chemotherapy at the time of relapse. A 3-year survival rate of 36% in sensitive relapse (SR) versus 14% in resistant relapse (RR) was reported.[67] Subsequent studies have reported similar outcomes.

Patients with relapsed Burkitt lymphoma (BL) with chemosensitive disease should be considered for high-dose chemotherapy plus autologous SCT; alternative therapies should be considered for those with RR (see the Sweetenham et al reference[63] ).

SCT and graft vs leukemia effect

The role of allogeneic SCT and graft versus leukemia effect in Burkitt lymphom or Burkitt-like lymphoma remains investigational.[68, 69] Many transplant centers consider this option for patients at high risk and for those with refractory disease. There have also been case reports that suggested a possible role for nonablative and cord blood transplantation in relapsed heavily treated patients.[70]

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.

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.

Long-Term Monitoring

When patients with Burkitt lymphoma receive treatment in the clinic, close monitoring of their white blood cell (WBC) count, hemoglobin, platelet count, serum chemistry levels, and liver functions is needed.

After chemotherapy is completed, patients should be monitored at least every 2 months during the first year, then every 3 months the following year, and every 6 months thereafter.

During follow-up visits, a complete physical examination should be performed, and CBC count and serum electrolyte levels should be obtained. Lactate dehydrogenase (LDH) and beta2 microglobulin studies may be helpful in detecting early relapse.

Repeat staging with computed tomography (CT) scanning is performed during and after completion of treatment to ascertain disease response and document achievement of complete remission.

Special Considerations

Burkitt lymphoma and Burkitt-like lymphoma have an aggressive clinical course; therefore, management should be directed toward an expeditious diagnosis, followed by prompt institution of definitive therapy. Initial treatment should be started in an inpatient setting.

Patients with Burkitt lymphoma presenting with B symptoms should have a thorough examination, and a biopsy should be obtained immediately for any suspicious mass. Failure to diagnose this high-grade lymphoma can lead to long-term sequelae and, possibly, death.

Renal failure as a result of tumor lysis syndrome from therapy is a potential risk in all patients, especially those with a high tumor burden. Aggressive management of this potentially life-threatening complication should be clearly addressed. Early hemodialysis should be considered in these patients to prevent long-term renal dysfunction.

 

Guidelines

Guidelines Summary

Guidelines contributors: Priyank P Patel, MD, Hematology/Oncology Fellow, Roswell Park Cancer Institute, University at Buffalo; Francisco J Hernandez-Ilizaliturri, MD; Chief, Lymphoma and Myeloma Section; Professor of Medicine, Department of Medical Oncology; Director of The Lymphoma Translational Research Program; Associate Professor of Immunology, Roswell Park Cancer Institute 

Non-Hodgkin Lymphoma (NHL)  Classification Schemas

The three most commonly used classification schemas for non-Hodgkin lymphoma (NHL) are as follows:

  • National Cancer Institute’s Working Formulation (IWF)[71]

  • Revised European-American Classification of Lymphoid Neoplasms (REAL)[72]

  • World Health Organization (WHO) classification[2]

The Working Formulation, originally proposed in 1982, classified and grouped lymphomas by morphology and clinical behavior (ie, low, intermediate, or high grade) with 10 subgroups labeled A to J.[71] In 1994, the Revised European-American Lymphoma (REAL) classification attempted to apply immunophenotypic and genetic features in identifying distinct clinicopathologic NHL entities.[72]

The World Health Organization (WHO) classification, first introduced in 2001 and updated in 2008 and 2016, further elaborates upon the REAL approach. This classification divides NHL into two groups: those of B-cell origin and those of T-cell/natural killer (NK)–cell origin.[25, 2]

Although considered obsolete, the National Cancer Institute’s Working Formulation (IWF) classification is still used mainly for historical data comparisons.[71]

World Health Organization classification

The 2008 WHO modification of the REAL classification of NHL is based on morphology and cell lineage. The WHO classification identifies the following three clinical variants of Burkitt lymphoma (BL)[25] :

  • Endemic (eBL) – The most common form of childhood malignancy in equatorial Africa, associated with Epstein-Barr virus (EBV) infection

  • Sporadic (sBL) – The majority of cases are in the United States and Europe; up to 30% are associated with EBV

  • Immunodeficiency associated – Occurs in patients with HIV infection, post-transplantation immunosuppression, and congenital immunodeficiency

The 2016 revision of the WHO classification recognizes the following two molecular entities[2] :

  • Burkitt lymphoma - TCF3 or ID3 mutations in up to about 70% of cases
  • Burkitt-like lymphoma with 11q aberration - New provisional entity that closely resembles Burkitt lymphoma but lacks MYC rearrangement and has some other distinctive features

Diagnosis

In addition to its general guidance on diagnosis of lymphoma, the National Comprehensive Cancer Network (NCCN) recommends the following studies to establish a diagnosis of Burkitt lymphoma[73] :

  • Immunohistochemistry panel: CD45(LCA), CD20, CD3, BCL2, BCL6, Ki-67, TdT or

  • Cell surface marker analysis by flow cytometry: kappa/lambda, CD45, CD20, CD3, CD5, CD19, CD10, TdT

  • Fluorescence in situ hybridization (FISH) or cytogenetics for detection of t(8;14), MYC.

  • Epstein-Barr encoding region in situ hybridization (EBER-ISH) can be used to identify EBV

Risk stratification

A prognostic scoring system was developed in 2013 using the Surveillance, Epidemiology, and End Results (SEER) database. Risk factors and points assigned are as follows[74] :

  • 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 four risk groups based on the scoring system are as follows:

  • Low risk (0-1 point)

  • Low-intermediate risk (2 points)

  • High-intermediate risk (3 points)

  • High risk (≥4 points)

With this model, relative survival rates at 5 years are as follows:

  • Low risk - 71%

  • Low-intermediate - 55%

  • High-intermediate - 41%

  • High-risk - 29%

Treatment

Because of the complexity of the disease, NCCN guidelines recommend that treatment of Burkitt lymphoma be given at centers with expertise in the management of the disease. Recommended chemotherapy regimens include the following[73] :

  • Cancer and Leukemia Group B (CALGB) 10002 regimen

  • CODOX-M/IVAC (cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, high-dose cytarabine) – Original or modified, with or without addition of rituximab

  • Dose-adjusted EPOCH (etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, doxorubicin [hydroxydaunorubicin]), with rituximab (DA-EPOCH-R)

  • Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], dexamethasone alternating with high-dose methotrexate and cytarabine) with rituximab (R-hyper-CVAD)

Other treatment recommendations are as follows[73] :

  • Enrollment in available clinical trials for all patients

  • CHOP is not considered adequate therapy

  • Central nervous system prophylaxis with systemic and/or intrathecal chemotherapy with methotrexate and/or cytarabine

  • Prophylaxis for tumor lysis syndrome is mandatory

Follow-up

The NCCN recommends follow up every 2-3 months for the first year after complete response, then every 3 months for the next year, and every 6 months thereafter. Relapse is rare after 2 years.[73]

 

Medication

Medication Summary

Intensive systemic chemotherapy is the treatment of choice for this aggressive disease in all its stages.[33] Supportive medications are used to help control the adverse effects of chemotherapy, such as nausea, vomiting, tumor lysis syndrome, and infections.

Alkylating Agents

Class Summary

Alkylating agents inhibit cell growth and proliferation.

Cyclophosphamide (Cytoxan)

Cyclophosphamide is cell cycle nonspecific and involves hepatic metabolism. This agent is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and rapidly proliferating malignant cells.

Ifosfamide (Ifex)

Ifosfamide is chemically related to nitrogen mustards and is a synthetic analogue of cyclophosphamide. This agent requires metabolic activation in the liver. The alkylated metabolites of ifosfamide have been shown to react with cellular DNA. This agent inhibits DNA and protein synthesis and, thus, cell proliferation by causing DNA cross-linking and denaturation of double helix.

Vincristine (Oncovin)

The mechanism of action of vincristine is uncertain. This agent is cell cycle specific at the M and S phases and inhibits microtubule assembly at metaphase, resulting in cell division arrest. Approximately 80% of vincristine is excreted by the liver. This agent may cause a decrease in reticuloendothelial cell function or an increase in platelet production.

Methotrexate (Folex PFS)

Methotrexate is cell cycle S-phase specific. This agent inhibits enzyme dihydrofolate reductase (DHFR), resulting in decreased conversion of folic acid to tetrahydrofolate, which is essential for DNA synthesis. Methotrexate is metabolized in the liver, and most of the drug is excreted unchanged in urine. This agent crosses the blood-brain barrier and placenta.

Cytarabine (Ara-C)

Cytarabine (Ara-C) is cell-cycle S-phase specific, blocking the progression from G1 to S phase. This agent is converted intracellularly to the active compound cytarabine-5'-triphosphate, which inhibits DNA polymerase. This inhibition, in turn, halts viral replication.

Doxorubicin (Adriamycin)

Doxorubicin is an anthracycline antibiotic that can intercalate with DNA and affects many DNA functions, including synthesis. This agent forms DNA-cleavable complexes by interacting with topoisomerase II, which is responsible for the cytocidal activity of the drug.

Doxorubicin is administered intravenously and distributes widely into body tissues, including the heart, kidneys, lungs, liver, and spleen; however, it does not cross the blood-brain barrier and is excreted primarily in bile.

Rituximab (Rituxan)

Rituximab is a genetically engineered, chimeric, murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. This antibody is an immunoglobulin (Ig) G1 kappa immunoglobulin that contains murine light- and heavy-chain variable region sequences and human constant region sequences.

Glucocorticoids

Class Summary

The pharmacologic properties of glucocorticoid agents are therapeutically effective in various diseases, including neoplasms.

Prednisone (Sterapred)

Glucocorticoids have a lympholytic effect, although mechanism of this action is not clear.

Urate-Oxidase Enzymes

Class Summary

Urate-oxidase enzymes can be used to treat hyperuricemia associated with malignancy.

Rasburicase (Elitek)

Rasburicase is a recombinant form (derived from Saccharomyces cervisiae-synthesized, Aspergillus flavus) of the enzyme urate oxidase, which oxidizes uric acid to allantoin. This agent is indicated for the treatment and prophylaxis of severe hyperuricemia associated with the treatment of malignancy and has an elimination half-life of 18 hours. Hyperuricemia causes a precipitant in the kidneys, which leads to acute renal failure. Unlike uric acid, allantoin is soluble and easily excreted by the kidneys.

 

Questions & Answers

Overview

What is Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What are the signs and symptoms of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

How is Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL) diagnosed?

Which systems are used to stage Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

Which lab tests are performed in the workup of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

Which imaging studies are performed in the workup of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

Which invasive procedures are performed in the workup of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

Which medications are used in the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is included in the supportive treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

How is Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL) classified?

When was Burkitt lymphoma (BL) first identified?

What causes Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the role of Epstein-Barr Virus (EBV) and malaria infection in the etiology of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the role of genetics in the etiology of Burkitt lymphoma?

What is the US prevalence of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the global prevalence of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

Which patient groups have the highest prevalence of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the prognosis of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the prognosis of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL) in children?

What is the prognosis of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL) in adults?

What are the possible complications of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What are the possible complications of chemotherapy to treat Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is included in patient education about Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

Presentation

Which clinical history findings are characteristic of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

How does the clinical presentation of Burkitt lymphoma (BL) differ by variant?

Which physical findings are characteristic of Burkitt-like lymphoma (BLL)?

Which physical findings are characteristic of Burkitt lymphoma (BL)?

What are the most common clinical findings for Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the most commonly used staging system for Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

How is Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL) staged?

What is the NCI staging system for Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

How is risk determined in Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

DDX

Which condition are included in the differential diagnoses of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

How is Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL) differentiated from DLBCL?

How is Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL) differentiated from lymphoblastic and mantle cell lymphomas?

What are the differential diagnoses for Burkitt Lymphoma and Burkitt-like Lymphoma?

Workup

What is included in the diagnostic workup for Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the role of lab testing in the diagnostic workup for Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the role of CBC and coagulation studies in the diagnostic workup for Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the role of serum chemistries in the diagnostic workup for Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the role of imaging studies in the diagnostic workup for Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the role of cardiac imaging studies in the diagnostic workup for Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the role of biopsy in the diagnostic workup for Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

Which histologic findings are characteristic of Burkitt cells?

Which histologic findings are characteristic of Burkitt lymphoma (BL)?

Which histologic findings are characteristic of Burkitt-like lymphoma (BLL)?

Treatment

How is Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL) treated?

How is tumor lysis syndrome prevented in patients with Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

Which specialist consultations are beneficial to patients with Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

When is patient transfer indicated for the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

Which dietary modifications are used in the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

Which activity modifications are needed during the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the role of chemotherapy in the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What are the possible adverse reactions to chemotherapy for the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the role of CNS prophylaxis in the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the CODOX-M/IVAC regimen for the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the CODOX-M regimen for the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the IVAC regimen for the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

How is Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL) and CNS involvement treated?

What is the CALGB 9251 regimen for the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the hyper-CVAD regimen for the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the CNS prophylaxis when the hyper-CVAD regimen is used to treat Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the role of rituximab in the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

How is response to chemotherapy evaluated in patients with Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is salvage therapy for relapsed/refractory Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the role of stem cell transplantation (SCT) in the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the role of stem cell transplantation (SCT) in the treatment of primary refractory Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the role of stem cell transplantation (SCT) in the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL) with partial remission?

What is the role of stem cell transplantation (SCT) in the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL) with clinical remission?

What is the role of stem cell transplantation (SCT) in the treatment of relapsed Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the role of stem cell transplantation (SCT) and graft versus leukemia effect in the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the role of surgery in the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is included in the long-term monitoring of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

When is inpatient treatment indicated for Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the role of hemodialysis in the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

Guidelines

What are the most commonly used classification schemas for Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What is the WHO classification of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What are the NCCN diagnostic guidelines for Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

How is risk stratified for Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What are the NCCN treatment guidelines for Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

What are the NCCN guidelines for surveillance of patients with Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

Medications

What is the role of medications in the treatment of Burkitt lymphoma/Burkitt-like lymphoma (BL/BLL)?

Which medications in the drug class Urate-Oxidase Enzymes are used in the treatment of Burkitt Lymphoma and Burkitt-like Lymphoma?

Which medications in the drug class Glucocorticoids are used in the treatment of Burkitt Lymphoma and Burkitt-like Lymphoma?

Which medications in the drug class Alkylating Agents are used in the treatment of Burkitt Lymphoma and Burkitt-like Lymphoma?