Childhood Non-Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version
- General Information About Childhood Non-Hodgkin Lymphoma (NHL)
- Histopathologic and Molecular Classification of Childhood NHL
- Stage Information for Childhood NHL
- Treatment Option Overview for Childhood NHL
- Mature B-cell NHL
- Lymphoblastic Lymphoma
- Anaplastic Large Cell Lymphoma
- Lymphoproliferative Disease Associated With Immunodeficiency in Children
- Rare NHL Occurring in Children
- Changes to This Summary (08/11/2016)
- About This PDQ Summary
- View All Sections
General Information About Childhood Non-Hodgkin Lymphoma (NHL)
Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
- Primary care physicians.
- Pediatric surgical surgeons.
- Radiation oncologists.
- Pediatric medical oncologists/hematologists.
- Rehabilitation specialists.
- Pediatric nurse specialists.
- Social workers.
- Child life professionals.
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of children with cancer have been outlined by the American Academy of Pediatrics. At these pediatric cancer centers, clinical trials are available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare therapy that is accepted as the best currently available therapy (standard therapy) with potentially better therapy. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. For non-Hodgkin lymphoma (NHL), the 5-year survival rate has increased over the same time period from 45% to 87% in children younger than 15 years and from 48% to 82% for adolescents aged 15 to 19 years. Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on the Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
On the basis of immunophenotype, molecular biology, and clinical response to treatment, the vast majority of NHL cases occurring in childhood and adolescence fall into three categories:
- Mature B-cell NHL (Burkitt and Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and primary mediastinal B-cell lymphoma).
- Lymphoblastic lymphoma.
- Anaplastic large cell lymphoma.
Other rare types of pediatric NHL include the following:
Lymphoma (Hodgkin lymphoma and NHL) is the third most common childhood malignancy, and NHL accounts for approximately 7% of cancers in children younger than 20 years in high-income countries.[3,4]
The following factors affect the incidence of NHL in children and adolescents:
- Geographic location: In the United States, about 800 new cases of NHL are diagnosed each year. The incidence is approximately ten cases per 1 million people per year.In sub-Saharan Africa, the high incidence of Epstein-Barr virus (EBV)-induced Burkitt lymphoma/leukemia is tenfold to twentyfold higher, resulting in a much higher incidence of NHL.
- Age: Although there is no sharp age peak, childhood NHL occurs most commonly in the second decade of life, and occurs infrequently in children younger than 3 years. NHL in infants is very rare (1% in Berlin-Frankfurt-Münster [BFM] trials from 1986 to 2002). The incidence of NHL is increasing overall because of a slight increase in the incidence for those aged 15 to 19 years; however, the incidence of NHL in children younger than 15 years has remained constant over the past several decades.
- Race: The incidence of NHL is higher in whites than in African Americans, and Burkitt lymphoma/leukemia is more frequent in non-Hispanic whites (3.2 cases/million person-years) than in Hispanic whites (2.0 cases/million person-years).
- Gender: Childhood NHL is more common in males than in females, with the exception of primary mediastinal B-cell lymphoma, in which the incidence is almost the same in males and females.[3,8] A review of Surveillance, Epidemiology, and End Results (SEER) data revealed that 2.5 cases per 1 million person-years of Burkitt lymphoma/leukemia were diagnosed in the United States between 1992 and 2008, with more cases in males than in females (3.9:1.1). The incidence of diffuse large B-cell lymphoma increases with age in both males and females. The incidence of lymphoblastic lymphoma remains relatively constant across ages for both males and females.
- Histology: The incidence and age distribution of histologic type of NHL according to gender is described in Table 1.
Relatively little data have been published on the epidemiology of childhood NHL. However, known risk factors include the following:
- EBV: EBV is associated with most cases of NHL seen in the immunodeficient population. Almost all Burkitt lymphoma/leukemia is associated with EBV in endemic Africa; however, approximately 15% of cases in Europe or the United States will have EBV detectable in the tumor tissue.
- Immunodeficiency: Immunodeficiency, both congenital and acquired (human immunodeficiency virus infection [HIV] or posttransplant immunodeficiency), increases the risk of NHL.[3,4]
- Previous neoplasm: NHL presenting as a subsequent neoplasm is rare in pediatrics. A retrospective review of the German Childhood Cancer Registry identified 2,968 children who were newly diagnosed with cancer, 11 of whom (0.3%) were later diagnosed with NHL as a subsequent neoplasm before the age of 19 years. In this small cohort, outcome was similar to patients with de novo NHL when treated with standard therapy.
Unlike adults with NHL who most often present with nodal disease, children typically have extranodal disease involving the mediastinum, abdomen, and/or head and neck, as well as marrow or CNS. For example, in developed countries, Burkitt lymphoma/leukemia occurs in the abdomen (approximately 60% of cases), with 15% to 20% of cases arising in the head and neck.[11,12] This high incidence of extranodal disease substantiates use of the Murphy staging system for pediatric NHL, as opposed to the Ann Arbor staging system.
The following tests and procedures are used to diagnose childhood NHL:
- History and physical exam.
- Pathologic examination of tumor cells.
- Immunophenotyping by immunohistochemistry and/or flow cytometry.
- Cytogenetics and/or fluorescence in situ hybridization (FISH).
- Bone marrow biopsy and aspiration.
- Lumbar puncture.
- Total-body imaging (e.g., computed tomography scan, positron emission tomography, and magnetic resonance imaging).
- Serum electrolytes, uric acid, blood urea nitrogen (BUN), and creatinine.
- Liver function tests.
Prognosis and Prognostic Factors for Childhood NHL
In high-income countries and with current treatments, more than 80% of children and adolescents with NHL will survive at least 5 years, although outcome is variable depending on a number of factors, including clinical stage and histology.
Prognostic factors for childhood NHL include the following:
Response to therapy
Response to therapy in pediatric lymphoma is one of the most important prognostic markers. Regardless of histology, pediatric NHL that is refractory to first-line therapy has a very poor prognosis.[14-16]
- Burkitt lymphoma/leukemia: One of the most important predictive factors is response to the initial prophase treatment; poor responders (i.e., <20% resolution of disease) had an event-free survival (EFS) of 30%.[17,18] Failure to achieve a complete remission after the initial induction courses has also been shown to adversely affect survival in Burkitt lymphoma/leukemia.[17,18]
- Lymphoblastic lymphoma: The presence of a residual mediastinal mass at day 33 or at the end of induction was not found to be associated with a decreased survival in the BFM 90-95 studies, but all patients with less than 70% reduction at end induction had therapy intensified.
International pediatric NHL response criteria have been proposed and require prospective evaluation. However, the clinical utility of these new criteria are under investigation.
As opposed to acute leukemia, the prognostic value of minimal residual disease (MRD) following initiation of the therapy in pediatric NHL remains uncertain and requires further investigation.
- Burkitt lymphoma/leukemia: One study suggests inferior outcome for patients with Burkitt lymphoma/leukemia that had detectable MRD after induction chemotherapy, but a positive MRD at end induction was not prognostic in B-cell NHL in 32 MDD-positive patients, possibly because of the low number of relapses.
- T-lymphoblastic lymphoma: In a small study, one of ten patients had measurable MRD at end induction and this was the only patient who relapsed.
- Anaplastic large cell lymphoma: A retrospective analysis of a collaborative European study showed that after induction, MRD-negative patients had a relapse risk of approximately 20% and an overall survival (OS) rate of approximately 90%. By contrast, MRD-positive patients had a relapse risk of 81% and an OS rate of 65% (P < .001). The presence of MRD is significantly associated with uncommon histologic subtypes containing small cell and/or lymphohistiocytic components.[Level of evidence: 2A]
Stage at diagnosis/minimal disseminated disease (MDD)
In general, patients with low-stage disease (i.e., single extra-abdominal/extrathoracic tumor or totally resected intra-abdominal tumor) have an excellent prognosis (a 5-year survival rate of approximately 90%), regardless of histology.[17,19,25-28] Apart from this, the outcome by clinical stage, if the correct therapy is given, does not differ significantly, except for stage IV patients with CNS disease.
A surrogate for tumor burden (i.e., elevated levels of lactate dehydrogenase [LDH]) has been shown to be prognostic in many studies.[17,26,29,30]
MDD is generally defined as submicroscopic bone marrow involvement that is present at diagnosis. MDD is generally detected by sensitive methods such as flow cytometry or reverse transcription–polymerase chain reaction (RT-PCR). Patients with morphologically involved bone marrow with more than 5% lymphoma cells are considered to have stage IV disease.
- Burkitt lymphoma/leukemia: The role of MDD remains to be defined. One study suggests MDD to be predictive of outcome, while another study does not.
- T-lymphoblastic lymphoma: A Children's Oncology Group (COG) study demonstrated the 2-year EFS for patients who had an MDD level by flow cytometry of less than 1% was 91% compared with 68% if the MDD level was more than 1%, and 52% if the MDD was 5% and greater.
- Anaplastic large cell lymphoma: In a retrospective subset analysis of children with anaplastic large cell lymphoma, MDD detected by RT-PCR for the NPM-ALK gene, could be found in 57% of patients at diagnosis and correlated with clinical stage. The presence of MDD was associated with a 46% cumulative incidence of relapse compared with a 15% cumulative incidence of relapse in patients with no marrow involvement. Patients with MDD who achieved MRD negative status before their second course of therapy had an intermediate EFS (69%) compared with MDD-negative patients (82%) and compared with patients with both MDD and positive MRD status (19%).The presence of MDD is significantly associated with uncommon histologic subtypes containing small cell and/or lymphohistiocytic components.
Sites of disease at diagnosis
In pediatric NHL, some sites of disease appear to have prognostic value, including the following:
- Bone marrow and CNS: In general, patients with leukemic involvement (>25% blasts in marrow) or CNS involvement at diagnosis require more intensive therapy.[18,19,34] Although these intensive therapies have improved outcome, patients who present with CNS disease continue to have the worst outcome.[18,19,34,35] Patients with mature B-cell lymphoma/leukemia with CNS disease at presentation have a 3-year EFS of around 70%, while those with marrow involvement alone have a 3-year EFS of 90%.[18,26,30] The combination of CNS involvement and marrow disease appears to impact outcome the most.
- Mediastinum: As opposed to adults, mediastinal involvement in children and adolescents with nonlymphoblastic NHL results in an inferior outcome.[13,17,26,30] In children and young adults with primary mediastinal B-cell lymphoma, series have reported a 3-year EFS of 50% to 70%.[26,29,30,36] However, a recent study from the NCI that utilized the dose-adjusted (DA)-EPOCH protocol (etoposide, prednisone, vincristine, and doxorubicin) with rituximab achieved an EFS close to 90%.
- Viscera: In anaplastic large cell lymphoma, a retrospective study by the European Intergroup for Childhood NHL (EICNHL) found a high-risk group of patients defined by involvement of mediastinum, skin, or viscera. In a subsequent study analysis from EICNHL utilizing biologic risk factors, the clinical risk features were not found to be significant. In the CCG-5941 study for anaplastic large cell lymphoma patients, these clinical risk factors could not be confirmed and only bone marrow involvement predicted inferior progression-free survival (PFS).[Level of evidence: 2A]
- Bone: Although previously thought to be a poor prognostic site, patients with NHL arising in bone have an excellent prognosis, regardless of histology.[41,42]
- Testicle: Testicular involvement does not affect prognosis.[19,25,43]
- Head and Neck: For mature B-cell NHL, OS is comparable to that observed for patients with primary tumors at other sites. Head and neck primary tumors are associated with higher rates of disseminated and CNS disease and lower rates of LDH levels that were more than twofold above the upper limit of normal. Childhood NHL of the head and neck site was not associated with inferior OS.
- Skin: The prognostic implication of skin involvement is limited to anaplastic large cell lymphoma and depends on whether the disease is localized to skin. ALK-negative, skin-limited anaplastic large cell lymphoma appears to have an excellent prognosis. However, studies from EICNHL and the COG have demonstrated that skin involvement in systemic anaplastic large cell lymphoma does not appear to have positive prognostic value.[39,40]
- Mature B-cell lymphoma: Compared with treatments for adults, aggressive Burkittregimens in pediatrics have been used to treat both Burkitt lymphoma/leukemia and large B-cell histologies, resulting in no difference in outcome based on histology.[13,17,26,27,30] The exception is primary mediastinal B-cell lymphoma, which has had an inferior outcome with these regimens.[13,17,26,29,30,36]For pediatric Burkitt lymphoma/leukemia patients, secondary cytogenetic abnormalities, other than c-myc rearrangement, are associated with an inferior outcome,[44,45] and cytogenetic abnormalities involving gain of 7q or deletion of 13q appeared to have an inferior outcome on the FAB 96 chemotherapy protocol.[45,46] For pediatric patients with diffuse large B-cell lymphoma and chromosomal rearrangement at MYC (8q24), outcome appears to be worse.A subset of pediatric diffuse large B-cell lymphoma cases were found to have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci and has been associated with favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this finding.
- T-lymphoblastic lymphoma: For pediatric patients with T-cell lymphoblastic lymphoma, the BFM group reported that loss of heterozygosity at chromosome 6q was observed in 12% of patients (25 of 217) and was associated with unfavorable prognosis (probability of EFS [pEFS], 27% vs. 86%, P <.0001).[48,49] NOTCH1 mutations were seen in 60% of patients (70 of 116) and were associated with favorable prognosis (pEFS, 84% vs. 66%; P = .021). NOTCH1 mutations were rarely seen in patients with loss of heterozygosity in 6q16.
- Anaplastic large cell lymphoma: In adults, ALK-negative disease has an inferior outcome; however, in children, the difference in outcome between ALK-positive and ALK-negative disease has not been demonstrated.[50-52] In a series of 375 children and adolescents with systemic ALK-positive anaplastic large cell lymphoma, the presence of a small cell or lymphohistiocytic component was observed in 32% of patients and was significantly associated with a high risk of failure in the multivariate analysis, controlling for clinical characteristics.In the COG-ANHL0131 (NCT00059839) study, despite a different chemotherapy backbone, the small cell variant of anaplastic large cell lymphoma, as well as other histologic variants, had a significantly increased risk for failure.
NHL in infants is rare (1% in BFM trials from 1986 to 2002). In this retrospective review, the outcome for infants was inferior compared with the outcome for older patients with NHL.
Adolescents have been reported to have inferior outcome compared with younger children.[11,13,54,55] This adverse effect of age appears to be most pronounced for adolescents with diffuse large B-cell lymphoma, and to a lesser degree T-cell lymphoblastic lymphoma, compared with younger children with these diagnoses.[13,55] On the other hand, for patients with Burkitt and Burkitt-like lymphoma/leukemia on the FAB LMB 96 (COG-C5961) clinical trial, adolescent age (≥15 years) was not an independent risk factor for inferior outcome.
Immune response to tumor
An immune response against the ALK protein (i.e., anti-ALK antibody titer) appeared to correlate with lower clinical stage and predicted relapse risk but not OS. A study by the EICNHL, which combined the level of anti-ALK antibody with MDD, demonstrated that newly diagnosed anaplastic large cell lymphoma patients could be reliably stratified into three risk groups (low, intermediate, and all remaining patients), with a PFS of 28%, 68% and 93%, respectively (P < .0001).
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