Burkitt lymphoma is common in children and adolescents, but represents only 1 to 2% of non-Hodgkin lymphomas in adults.1 People with Burkitt lymphoma often have a dramatic clinical presentation, warranting immediate evaluation, given the characteristic rapidity of lymphoma growth and spread to extranodal anatomical sites, including intra-abdominal organs and the central nervous system (CNS).
A high index of clinical suspicion is required for rapid diagnosis and early initiation of treatment. Studies of Burkitt lymphoma have led to fundamental discoveries about the viral role in tumor development and the distinctive translocation of the MYC oncogene. Genomic studies have demonstrated the presence of mutations in p53 and along the phosphatidylinositol 3-kinase (PI3K) signaling pathway that contribute to oncogenesis.2,3
More than 90% of children and adolescents are cured with very intensive doses of chemotherapy, while adults are more susceptible to the toxic effects of the treatment; Prospective trials have shown that only 75 to 85% of adults have long-term remission. Studies suggest that clinical benefit from high-dose chemotherapy may be achieved by administering low-intensity chemotherapy infusions; Lower peak drug concentrations significantly reduce the toxic effects of treatment.4,5
Although first-line therapy is highly effective, almost all cases of relapsed or refractory disease are fatal. Retrospective population-based studies of Burkitt lymphoma have shown that the incidence of treatment failure among adults can be as high as 35%.6 Newer, safer therapies are needed.
| History of Burkitt lymphoma |
Burkitt’s lymphoma is named after Irish surgeon Denis P. Burkitt, who in 1958 described 38 Ugandan children with rapidly growing facial tumors that were uniformly fatal.7 He postulated that these tumors were round cell sarcomas and noted the unique combination of involvement mandibular and orbital and a predilection for extranodal spread to adrenal glands, kidneys, liver, thyroid, pancreas, stomach and ovaries. Later, it was observed that the histological appearance was identical to that of lymphomas, characterized by abdominal masses, confirming its lymphoid origin.8
A key clinical observation was that cases were limited to defined geographic areas in equatorial Africa, strongly implying an environmental association with an infectious cause.9 In this context, virologists Michael A. Epstein and Yvonne M. Barr successfully cultured tumor cells from a patient with Burkitt lymphoma and observed the presence of intracellular particles in electron microscopy that had the characteristic morphological features of a virus.10
The eponymous Epstein-Barr virus (EBV) thus became the first virus implicated as a factor in the cause of human cancer.11 Characteristic abnormalities involving additional bands on the long arm of chromosome 14 were found in Burkitt’s lymphoma, with corresponding loss of material on the long arm of chromosome 8.12 This observation led to the discovery of reciprocal translocations juxtaposing the MYC oncogene on chromosome 8 and the immunoglobulin loci on chromosomes 2, 14, or 22, resulting in deregulated expression of MYC and uncontrolled tumor proliferation.13
The geographic distribution of Burkitt lymphoma was also correlated with regions that are holoendemic for Plasmodium falciparum malaria and areas with successful malaria eradication programs did not report this tumor.14
It is now recognized that activation-induced deregulated expression of cytidine deaminase within germinal center B cells leads to MYC chromosomal translocations.
Plasmodium infections in mouse models cause prolonged germinal center reactions and enhanced chromosome breaks caused by activation-induced cytidine deaminase; Chromosomal breaks potentially explain the elevated risk of Burkitt lymphoma in malaria-endemic regions.15
| Epidemiological variants |
Three variants of Burkitt lymphoma are currently recognized: endemic, sporadic and associated with immunodeficiency.
The three variants share morphological and immunophenotypic characteristics but have different epidemiological and clinical characteristics (Table 1).16
The endemic variant occurs in geographic areas where malaria is holoendemic, and Burkitt lymphoma is the most common pediatric cancer in these regions. Historically, endemic Burkitt lymphoma affected the jaw, orbit, or both, but contemporary studies show that abdominal involvement is now more common.17
It is postulated that jaw involvement is related to poor dentition, allowing EBV to enter the medullary cells of the jaw. Bone marrow may be involved, but frank leukemia is rare.
CNS involvement occurs in less than 10% of cases, typically manifesting as cranial nerve palsies or spinal cord compression. Endemic Burkitt lymphoma is almost always associated with EBV infection, and high titers of anti-EBV antibodies are associated with increased risk.18
The median age of presentation among people with sporadic Burkitt lymphoma is 10 years, with additional incidence peaks at ages 40 years and 75 years.19 Patients older than 60 years represent only 20% of cases, but the incidence in this population is increasing.19 Men are affected 3 to 4 times more than women, without any racial or ethnic predisposition.
Sporadic Burkitt lymphoma can affect virtually any organ but often manifests as a rapidly growing abdominal mass, with involvement of the ileocecal region that simulates acute appendicitis or intestinal obstruction .
Involvement of both breasts is rare and may mimic the inflammation of breast cancer. CNS involvement occurs in up to 20% of cases, and the bone marrow is involved in 30 to 35% of cases. EBV is associated with 20 to 30% of cases of sporadic Burkitt lymphoma, most frequently in patients older than 50 years of age.
The median age of patients with immunodeficiency-associated Burkitt lymphoma is 40 to 45 years, and cases are equally distributed between the sexes. This variant most commonly arises in patients infected with the human immunodeficiency virus (HIV) and was the first lymphoma described associated with it.20
Burkitt lymphoma accounts for almost 40% of lymphomas arising in HIV-infected patients and, in particular, occurs in those with relatively normal CD4 counts.21
The clinical manifestation of HIV-associated Burkitt lymphoma often involves the gastrointestinal tract and bone marrow. CNS involvement occurs in 20 to 30% of cases of immunodeficiency-associated Burkitt lymphoma, and EBV is detected in 25 to 40% of cases.
| Pathological features |
The pathological features of Burkitt lymphoma are similar in all variants, and the diagnosis is based on morphological, immunophenotypic, and molecular features that arise in a characteristic clinical context. It is essential to distinguish Burkitt lymphoma from diffuse large B-cell lymphoma and other high-grade B-cell lymphomas that may carry a MYC translocation.22,23 Tumor biopsy specimens are characterized by medium-sized monomorphic B cells with nuclei round, prominent nucleoli and numerous mitotic figures.
The cytoplasm is deeply basophilic and often contains lipid vacuoles. The proliferation rate is almost 100%, and the sample may have a "starry sky" pattern with numerous benign macrophages that have ingested apoptotic debris.
The tumor cells show the immunophenotype of a mature germinal center B cell; They typically express strong membrane IgM with light chain restriction; they are positive for CD19, CD20, CD79A, PAX5, CD10 and BCL6; and are generally negative for CD5, BCL2 and TdT. Strong expression of BCL2 is rare, and the level of expression can be used to distinguish Burkitt lymphoma from other high-grade B-cell lymphomas.
The molecular hallmark of Burkitt lymphoma is the t(8;14) translocation of MYC from chromosome 8 to the immunoglobulin heavy chain region of chromosome 14 in 70 to 80% of cases; the t(2;8) translocation from chromosome 8 to the immunoglobulin kappa locus on chromosome 2 in 15% of cases; or the t(8;22) translocation from chromosome 8 to the immunoglobulin lambda locus on chromosome 22 in 5% of cases.16
MYC translocations are almost universal in all Burkitt lymphoma variants, but are also seen in other high-grade B-cell lymphomas. Furthermore, these translocations cannot always be detected with standard fluorescence in situ hybridization, and cryptic MYC insertions in the immunoglobulin heavy chain have been described.24 BCL2 translocations do not occur in Burkitt lymphoma.
A provisional entity known as Burkitt-type lymphoma with 11q aberrations has been introduced into the classification system of lymphoid cancers.16 These cases do not carry a MYC translocation and have proximal gains or telomeric losses of chromosome 11q. Additional studies have shown that this entity has a mutational landscape that, unlike mutations in Burkitt lymphoma, resembles diffuse large B-cell lymphoma of germinal center origin.25,26
| Molecular biological characteristics |
The distinctive translocation that places MYC under the control of an immunoglobulin gene enhancer is present in more than 90% of Burkitt lymphoma cases, and arises from cytidine deaminase-mediated immunoglobulin class switch recombination. somatic activation or hypermutation.27 However, MYC deregulation alone is generally not sufficient for lymphomagenesis, and cooperating genetic alterations are common.2,27
Early genetic studies showed that TP53 mutations in Burkitt lymphoma inactivate the tumor suppressor p53, and these lesions may be enriched in chemotherapy-refractory cases.28,29 Loss of p53 promotes MYC-induced transformation by blocking apoptosis that occurs when the MYC oncoprotein is expressed in primary B cells.30 In addition to lesions in TP53, Burkitt lymphomas inactivate the tumor suppressors ARF (encoded in the CDKN2A locus) and USP7, increasing the degradation of p53 mediated by MDM2.31,32 The tumor suppressor DDX3X is also frequently mutated or deleted in Burkitt lymphoma, promoting early MYC transformation by reducing MYC-induced proteotoxic stress early in the disease. 2,3,33
Subsequently, malignant cells increase expression of the DDX3Y paralog encoded on the Y chromosome, restoring full protein synthesis, which may partly explain the higher prevalence of Burkitt lymphoma among men.33 Another regulator of MYC that is inactive in Burkitt lymphoma is SIN3A, which deacetylates MYC and decreases its activity as a transcriptional activator.34
A critical role for activation of B cell receptor (BCR)-dependent PI3K signaling has emerged from high-throughput sequencing studies in Burkitt lymphoma.2,35-38
Mutations targeting the transcription factor TCF3 or its negative regulator ID3 occur in up to 70% of cases and disrupt the binding of ID3 to TCF3, thus releasing TCF3 to transactivate the genes encoding immunoglobulin heavy and light chains, as well as BCR signaling subunits CD79A and CD79B.39 Furthermore, TCF3 directly represses PTPN6, which encodes SHP-1, a negative regulator of BCR signaling.2 Therefore, mutations in TCF3 and ID3 promote the constitutive activity of the BCR, which is essential to maintain the viability of malignant cells.2
BCR signaling activates PI3K and mammalian target of rapamycin (mTOR) signaling, which is increased by mutations targeting PTEN and FOXO1 and by amplification of the MIR17HG locus encoding microRNAs that block PTEN.2 expression, 40.41
Additional recurrent mutations in Burkitt lymphoma activate cyclin D3 (CCND3) or inactivate p16 (CDKN2A), thereby promoting the exuberant proliferation characteristic of this lymphoma.2 Inactivation of the G protein-coupled receptor P2RY8 and its downstream signaling mediator Gα13 (GNA13) alters the motility and spread of Burkitt lymphoma cells.42
Finally, genetic inactivation of several chromatin regulators alters the epigenetic landscape and differentiation potential of Burkitt lymphoma.2,3,27-29,35-37 FBXO11 is included in this category, as it is an E3 ubiquitin ligase of BCL6 and targets BCL6 for proteasomal degradation.43 Inactivation of FBXO11 in Burkitt lymphoma increases BCL6,44 blocking the malignant cell in the highly proliferative germinal center B cell state and preventing terminal plasmacytic differentiation.45
Two key questions are whether Burkitt lymphoma can be subdivided into distinct molecular types and whether clinical variants, age, EBV status, or therapeutic vulnerabilities are related to biologically classified subtypes. Gene expression studies have confirmed that Burkitt lymphoma has a characteristic molecular profile that distinguishes it from other germinal center-derived lymphoma subtypes, but transcriptional differences across clinical variants are modest.22,23,46
Studies have shown that EBV status is a better way to separate Burkitt lymphoma into biological subgroups than geographic origin (locally endemic vs. non-endemic).3,47
EBV-associated Burkitt lymphoma is characterized by substantially elevated expression of activation-induced cytidine deaminase, a mutator, and consequently has a much higher mutational burden than the other Burkitt lymphoma variants. However, compared with EBV-positive Burkitt lymphoma, EBV-negative tumors more frequently activate cyclin D3 and inactivate p53, either directly by mutating TP53 or indirectly by inactivating ARF or USP7.3 Together, these findings show that EBV infection exerts a powerful influence on the Burkitt lymphoma genome, which could influence the therapeutic response.
| Staging and risk stratification |
The clinical manifestation of Burkitt lymphoma is often dramatic, and a marked elevation in serum lactate dehydrogenase (LDH) levels may indicate spontaneous tumor lysis.
The diagnostic and staging study is determined based on the patient’s age and the availability of health resources.
A large-bore central needle or surgical biopsy is necessary to distinguish Burkitt lymphoma from other aggressive lymphomas; Fine needle aspiration is not an appropriate diagnostic procedure. Surgical reduction is unnecessary and tumor resection should be avoided, as recovery from surgery may delay the initiation of systemic therapy, which is urgently needed in this rapidly growing tumor.
Staging procedures include bone marrow biopsy and aspiration, as well as lumbar puncture for analysis of cerebrospinal fluid (CSF), the results of which influence treatment. Flow cytometry should be performed on freshly collected CSF to identify low-volume disease that requires more aggressive CNS-directed therapy.48
Laboratory tests include complete blood count, comprehensive metabolic panels, measurement of LDH and uric acid levels, and screening for HIV infection, hepatitis B and C, and in selected cases, malaria. Imaging studies include a total body computed tomography (CT) scan; positron emission tomography more easily detects extranodal disease.
Ultrasound or magnetic resonance imaging (MRI) scans can be substituted for CT in children to avoid radiation. MRI of the brain, spinal cord, or both is indicated in patients with neurological symptoms. The effects of evaluation and treatment on fertility should be discussed with patients as appropriate.
In children and adolescents, the St. Jude staging system has largely been replaced by the International Pediatric Non-Hodgkin Lymphoma Staging System (Table 2).49 Risk stratification in children and adolescents incorporates the extent of the burden tumor, along with baseline LDH level and status with respect to CNS involvement
(Table 3).
The Ann Arbor staging system is often used for risk stratification in adults, although it is poorly suited to the task.50 Patient-related factors such as age, coexisting conditions, and performance status must be weighed along with risk factors. disease: tumor burden, LDH level and status with respect to bone marrow and CNS involvement.
Analysis of data from a large retrospective series identified four factors independently associated with clinical outcomes in adults treated with standard regimens: age 40 years or older, performance status of 2 or greater, LDH level 3 times higher than limit of the normal range and CNS involvement.51 The International Burkitt Lymphoma Prognostic Index, which is based on these four risk factors, showed that patients without any of the factors (18%) had an overall survival rate at 3 years of 96 to 98%, while patients with two or more factors (46%) had an overall 3-year survival rate of only 58 to 64% (Table 4).51
Older age has been associated with poor clinical outcomes from high-dose intensive therapy, but it is unclear whether poor outcomes are due to biologically higher-risk diseases, treatment-associated adverse effects, or both. Indeed, the study of an intensive high-dose pediatric regimen used in adults showed that age ≥ 33 years was associated with lower overall survival.52
A recent prospective clinical study showed that a risk-adapted approach with adjusted doses of etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (DA-EPOCH-R) was safe and the outcome was not associated with age.5 Thus Similarly, HIV infection has historically been associated with poor outcomes, but with improvements in antiretroviral therapy, advances in supportive care, and the use of lower-intensity regimens, HIV infection is no longer prognostic.4 ,5,53
CNS involvement occurs in 15 to 20% of patients and remains a serious clinical problem, particularly in adults.54 Outcomes in children and adolescents with CNS involvement have improved with intensification of systemic and intrathecal chemoimmunotherapy, but this This approach is not always feasible in adults due to treatment-related toxic effects.55
CNS involvement is often associated with a poor performance state, and intensification of chemotherapy increases the risk of premature death from toxicity. Furthermore, even with regimens that incorporate intensive CNS-targeted therapy, outcomes are poor for patients with baseline CNS involvement, with a CNS relapse rate of 5% to 10%.54,56
| Clinical management |
Clinical signs suggestive of Burkitt lymphoma should be considered a medical emergency, and intensive supportive care designed to prevent sepsis, intestinal perforation, and tumor lysis syndrome should be initiated immediately.
Vigorous intravenous hydration and correction of electrolyte imbalances are critical, as spontaneous tumor lysis syndrome may worsen with therapy. Allopurinol should be administered before initiating chemotherapy, and recombinant urate oxidase (rasburicase) may be necessary as prophylaxis against hyperuricemia.57
Intestinal or biliary obstruction is often safely managed conservatively, as systemic therapy will rapidly relieve the obstruction. Unnecessary delays can lead to multisystem organ failure and premature death from toxicity. If supportive care resources are limited and hemodialysis is not immediately available, referral to a higher level of care should be considered. Burkitt lymphoma is very sensitive to combination chemotherapy, but the conventional dose of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) is inadequate . The general treatment approach is the same for all clinical variants and does not depend on EBV status.
In children and adolescents, risk-adapted approaches involve short-course, high-dose intensive chemotherapy regimens designed to achieve high maximal drug concentrations; chemotherapy includes agents that penetrate the CNS.58-61 These regimens require a prolonged hospital stay, robust transfusion support, and antibiotic prophylaxis. A regimen alternates cycles of cyclophosphamide, vincristine, doxorubicin, and methotrexate (CODOX-M) with cycles of mesna and ifosfamide, etoposide, and cytarabine (IVAC), plus intrathecal cytarabine and methotrexate.60
The FAB (French–American–British) regimen and the BFM (Berlin–Frankfurt–Münster) regimen are similar, and each serves as the backbone for risk-stratified treatment of pediatric patients. Low-risk patients receive two to four courses of chemotherapy, while high-risk groups receive five or six courses, with CNS-directed therapy such as high-dose methotrexate or cytarabine along with intrathecal therapy. High-risk patients, such as those with CNS involvement or extensive leukemic disease, receive higher doses of CNS-penetrating agents, along with more intensive intrathecal therapy regimens. Rituximab improves overall survival and should be administered to all patients.62
Adults have conventionally received these intensive, high-dose regimens, which were originally adopted from pediatric protocols, but the adverse event profile worsens with increasing age. Cranial irradiation is particularly toxic and is associated with unacceptably high rates of severe neurotoxicity.63 To complete therapy, reductions in chemotherapy doses are often necessary.64
Still, these regimens are effective for adults for whom the adverse event profile is acceptable, with 2-year event-free survival rates ranging from 65 to 80%. Risk-adapted approaches minimize toxic effects through shorter duration of therapy and low-risk patients can be effectively treated with as few as three cycles of CODOX-M with rituximab. A randomized study showed that the addition of rituximab to the standard FAB regimen in HIV-negative adults with Burkitt lymphoma significantly improved the 3-year event-free survival rate, increasing it by approximately 15%. Rituximab should be considered as standard therapy in all patients.65-68
A multicenter prospective study showed that the risk-adapted DA-EPOCH-R regimen achieved a 4-year event-free survival rate of approximately 85% and was effective for adults, regardless of age and HIV status.4, 5 This approach tested the hypothesis that prolonged drug exposure with chemotherapy infusions would avoid the toxic effects associated with high peak drug concentrations while maintaining efficacy. Low-risk patients were effectively treated with three cycles without CNS prophylaxis.
High-risk patients received six treatment cycles with intrathecal therapy as CNS prophylaxis or active therapy. Appropriate staging requires careful evaluation of CSF with multiparameter flow cytometry prior to DA-EPOCH-R therapy, as patients with active CNS disease are treated with a more intensive schedule of intrathecal therapy.5
Patients with brain parenchymal lesions are not suitable candidates for DA-EPOCH-R. In a randomized trial comparing DA-EPOCH-R with CODOX-M and IVAC plus rituximab in high-risk adult patients without CNS involvement, enrollment was recently completed and preliminary results were reported.69 No significant differences in survival were observed. observed between the two groups, but CODOX-M with IVAC and rituximab was associated with excessive toxic effects and prolonged hospitalization. The relatively low toxicity and high efficacy of DA-EPOCH-R make it the preferred choice for most adults without CNS involvement. The appropriate treatment approach for adults with CNS disease remains undefined and should be the focus of future clinical trials.
| Specific patient populations |
Treatment in resource-limited areas often relies on less intensive chemotherapy, but outcomes are better with more intensive regimens.70 Lack of resources in supportive care makes it difficult to provide intensive, high-dose chemotherapy.17
Lower-dose combination regimens have been the mainstay of treatment for high- and low-risk patients, with rituximab often omitted due to cost. Patients with HIV-associated Burkitt lymphoma used to have an unacceptable high rate of adverse events when treated with standard regimens, but both DA-EPOCH-R and CODOX-M have been shown to be safe and effective in patients with HIV infection. 5.65
| Management of recurrent disease and new objectives |
Children and adults with relapsed or refractory disease have a poor prognosis, with standard approaches to salvage chemotherapy, followed by consolidation with autologous or allogeneic stem cell transplantation, resulting in a survival rate of less than 20%.71,72 To overcome resistance to chemotherapy, targeted pathway inhibitors and immunotherapy are being tested, and patients with relapsed or refractory disease should be given preference in clinical trials.
Pathogenic BCR signaling is a universal feature of aggressive B-cell lymphomas, with different modes of BCR signaling across lymphoma subtypes.
Burkitt lymphoma is characterized by constitutive and antigen-independent BCR signaling through the PI3K pathway to activate AKT and mTOR. This oncogenic pathway can be targeted with the use of inhibitors of the proximal BCR kinases LYN and SYK, as well as PI3Kδ, AKT, and mTOR complex 1 (mTORC1) inhibitors.2,73 Additionally, inhibition of the metabolic enzyme serine hydroxymethyltransferase 2 disrupts BCR signaling through autophagic degradation of TCF3 and is a rational therapeutic target.74
New immunotherapeutic approaches such as chimeric antigen receptor T-cell therapy (CAR-T) also overcome resistance to chemotherapy and have demonstrated preliminary efficacy in children with relapsed Burkitt lymphoma. In a series of five patients, all had at least a transient response to CAR-T therapy, including 3 with a complete response.75
Other rational therapeutic targets include BCL6 inhibitors and degraders, which may be more effective in cases with FBXO11 mutations. 44 Finally, cyclin D3-dependent cell cycle progression in Burkitt lymphoma could be blocked with the use of CDK6 inhibitors such as palbociclib.2 None of these agents are currently approved for use in patients with Burkitt lymphoma, and new clinical trials will be needed to determine their clinical efficacy.
| Conclusions |
The clinical outcomes of Burkitt lymphoma are excellent in children and adolescents, but improvements are needed for adults with CNS involvement.
Intensive supportive care is required at the first recognition of possible Burkitt lymphoma to prevent premature death from toxicity and organ involvement. Molecular subtypes have been identified that may have unique therapeutic susceptibilities.
Greater understanding of the biological basis of treatment resistance is necessary to move beyond chemotherapy with new pathway inhibitors and immunotherapy.
Comment
|
Table 1. Epidemiological and clinical characteristics of Burkitt lymphoma variants.*
| Characteristic _ | Endemic variant | Sporadic variant | Variant associated with immunodeficiency |
| Incidence | 3–6 cases per 1000 children; 30–50% of all childhood cancers and approximately 90% of lymphomas in high-risk areas | 30 to 50% of childhood lymphomas; 1-2% of lymphomas in adults | 40% of lymphomas are associated with HIV; antiretroviral therapy has not reduced this risk |
| Geographical distribution | Equatorial Africa and Papua New Guinea; Incidence was correlated with regions where Plasmodium falciparum malaria is holoendemic. | world | world |
| Age | Median: 6–9 years | It predominantly affects children and adolescents; incidence peaks occur at ages 10, 40, and 75 years | Median: 40–45 years |
| Man:woman relationship | 2:1 | 3:1 | 1:1 |
| anatomical sites | Previously, mandible and orbit; currently abdomen thyroid, ovaries, kidneys, adrenal glands, breasts; often spares the lungs and spleen | Common large abdominal masses; ileocecal region most common site; It can also be present in the head and neck, affecting the paranasal sinuses or oropharynx; ovaries, kidneys, breasts | More lymph node involvement than other variants; The most common sites of extranodal involvement are the gastrointestinal tract and bone marrow. |
| CNS involvement | <10% of cases; cranial nerve palsy or leg paralysis | 10 to 20% of cases, mostly leptomeninges | 20-30% of cases |
| Bone marrow involvement | Occasional; uncommon leukemia | 30-35% of cases | Frequent |
| Associated with EBV | 95-100% of cases | 20-30% of cases; higher incidence among older adults | 25-40% of cases |
*The World Health Organization currently recognizes three variants of Burkitt lymphoma for epidemiological reasons. The variants have identical morphological and immunophenotypic characteristics, with differences in clinical characteristics. The treatment approach is similar in all variants, and the choice of therapy is based on the patient’s age, risk stratification, and availability of supportive care resources. CNS: denotes central nervous system, EBV: Epstein-Barr virus and HIV: human immunodeficiency virus.
Table 2. International staging system for pediatric non-Hodgkin lymphoma*
| Stadium | Extension of the disease |
| Yo | Single tumor that does not affect the mediastinum or abdomen; extranodal (bone or skin) or nodal |
| II | Single tumor with regional lymph node involvement ≥2 lymph node areas on the same side of the diaphragm. Completely resectable primary gastrointestinal tumor with or without regional nodes |
| III | ≥2 extranodal tumors above or below the diaphragm ≥2 nodal tumors above or below the diaphragm Any intrathoracic tumor Intra-abdominal or retroperitoneal disease (i.e., liver, spleen, kidney, ovary), excluding primary gastrointestinal tumor completely resectable with or no regional nodes Any paraspinal or epidural tumor A single bone lesion with concomitant extranodal or non-regional lymph node involvement |
| IV | Involvement of the CNS, bone marrow, or both |
| *Adapted from Rosolen et al.49 | |
Table 3. Risk stratification in children and adolescents.*
| At-risk group | Resection status | Disease stage and initial serum LDH |
| BFM risk stratification | ||
| R1 | Complete resection | |
| R2 stage I or II | Incomplete or no resection | Stage I or II disease |
| R2 stage III | Incomplete or no resection | Stage III disease and LDH <2 × ULN |
| R3 | Incomplete or no resection | Stage III disease and LDH ≥2 × ULN but <4 × ULN or stage IV disease and LDH <4 × ULN; without CNS involvement |
| R4 | Incomplete or no resection | Stage III disease and LDH ≥4 × ULN or stage IV disease and LDH ≥4 × ULN; without CNS involvement |
| R4 CNS | Incomplete or no resection | Stage IV disease and CNS involvement |
| FAB risk stratification | ||
| TO | Complete resection | Stage I or II disease |
| B low risk | Incomplete or no resection | Stage I, II, or III disease and LDH <2 × ULN |
| B high risk | Incomplete or no resection | Stage III or IV disease and LDH ≥2 × ULN |
| c | Incomplete or no resection | Leukemic disease with >25% blasts, CNS involvement, or both |
| * BFM: Berlin-Frankfurt-Münster, FAB: French-American-British, LDH: lactate dehydrogenase and LSN: Upper limit of normal range | ||
Table 4. Risk stratification in adults according to the International Prognostic Index for Burkitt’s Lymphoma*
| Risk factor |
| CNS involvement LDH >3 × ULN ECOG performance status score ≥2 Age ≥40 years |
| Risk category |
| Low risk: No risk factors Intermediate risk: 1 risk factor High risk: ≥2 risk factors |
| *Data are from Olszewski et al.51 ECOG denotes Eastern Cooperative Oncology Group; Scores are evaluated on a 6-point scale, with higher scores indicating greater disability |
