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 primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (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 potentially better therapy with therapy that is currently accepted as standard. 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 Web site.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has 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 88% in children younger than 15 years and from 47% to 77% 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.)
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.[3,4] In the United States, about 800 new cases of NHL are diagnosed each year. The incidence is approximately ten cases per million people per year. The incidence of NHL observed in children and adolescents varies depending on age, histology, gender, and race. 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-Munster [BFM] trials from 1986 to 2002). The incidence of NHL is increasing overall, which is accounted for 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.
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.[3,6] A review of Surveillance, Epidemiology, and End Results (SEER) data on Burkitt lymphoma diagnosed in the United States between 1992 and 2008 revealed 2.5 cases/million person-years 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.
The incidence and age distribution of specific types of NHL according to gender is described in Table 1.
|Incidence of NHL per million person-years|
|ALCL = anaplastic large cell lymphoma; DLBCL = diffuse large B-cell lymphoma; NHL = non-Hodgkin lymphoma.|
|aAdapted from Percy et al.|
|bIn older adolescents, indolent and aggressive histologies (more commonly seen in adult patients) are beginning to be found.|
|Other (mostly ALCL)||2.3||3.3||4.3||7.8b||1.5||1.6||2.8||3.4b|
The incidence of NHL is higher in whites than in African Americans, and Burkitt lymphoma is more frequent in non-Hispanic whites (3.2 cases/million person-years) than in Hispanic whites (2.0 cases/million person-years).
Relatively little is known of the epidemiology of childhood NHL. However, immunodeficiency, both congenital and acquired (human immunodeficiency virus infection [HIV] or posttransplant immunodeficiency), increases the risk of NHL. Epstein-Barr virus (EBV) is associated with most cases of NHL seen in the immunodeficient population. Although 85% or more of Burkitt lymphoma is associated with the EBV in endemic Africa, approximately 15% of cases in Europe or the United States will have EBV detectable in the tumor tissue.
NHL presenting as a secondary malignancy is rare in pediatrics. A retrospective review of the German Childhood Cancer Registry identified 11 (0.3%) of 2,968 newly diagnosed children older than 20 years with NHL as having a secondary malignancy. In this small cohort, outcome was similar to patients with de novo NHL when treated with standard therapy.
Prognostic Factors for Childhood NHL
With current treatments, more than 80% of children and adolescents with NHL will survive at least 5 years, though outcome is variable depending on a number of factors, including clinical stage and histology.
Prognostic factors for childhood NHL include the following:
Age: NHL in infants is rare (1% in Berlin-Frankfurt-Munster [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.[10-13] A review of survival for various subtypes of NHL in children and adolescents between 1986 and 2007 has been reported by the BFM group. Event-free survival (EFS) was 79% for adolescents and 85% for children. This adverse affect of age appears to be most pronounced for adolescents with T-cell lymphoblastic lymphoma and diffuse large B-cell lymphoma compared with children with these diagnoses. The poorer outcome of patients older than 15 years appears to be attributable primarily to patients with diffuse large B-cell lymphoma. On the other hand, for patients with Burkitt and Burkitt-like lymphoma on the FAB LMB 96 (COG-C5961) clinical trial, adolescent age (≥ 15 years) was not an independent risk factor for inferior outcome, with 3-year EFS of 89% ± 1.0% for children younger than 15 years and 84% ± 3.4% for patients aged 15 years and older.
Site of disease: 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.[15-20] Patients with NHL arising in bone have an excellent prognosis, regardless of histology.[21,22] Testicular involvement does not affect prognosis.[16,17,23] As opposed to adults, mediastinal involvement in children and adolescents with nonlymphoblastic NHL results in an inferior outcome.[10,14,15,18] For patients with primary mediastinal B-cell lymphoma, 3-year EFS is 50% to 70%,[14,15,18,24] and for patients with central nervous system (CNS) disease at presentation, the 3-year EFS is 70%.[14,18,25]
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. An immune response against the ALK protein (i.e., anti-ALK antibody titer) appears to correlate with lower clinical stage and absence of these clinical risk features (mediastinal and visceral organ involvement) and predicts relapse risk but not overall survival. However, in the CCG-5941 study for anaplastic large cell lymphoma patients, only bone marrow involvement predicted inferior progression-free survival.[Level of evidence: 2A] Patients with leukemic involvement (>25% blasts in marrow) or CNS involvement at diagnosis require intensive therapy.[17,25,29] Although these intensive therapies have improved the outcome for patients with high-stage (stage III or IV) or advanced-stage disease, patients who present with CNS disease have the worst outcome.[17,25,29,30] The combination of CNS involvement and marrow disease appears to impact outcome the most for Burkitt lymphoma/leukemia. Patients with leukemic disease only, and no CNS disease, had a 3-year EFS of 90%, while patients with CNS disease at presentation had a 70% 3-year EFS.
Chromosomal abnormalities: Though data for cytogenetics is less robust than for childhood leukemia, some chromosomal abnormalities have been reported to have prognostic value.
- For pediatric Burkitt lymphoma patients, secondary cytogenetic abnormalities, other than c-myc rearrangement, are associated with an inferior outcome,[31,32] and cytogenetic abnormalities involving gain of 7q or deletion of 13q appear to have an inferior outcome on current chemotherapy protocols.[32,33]
- For pediatric patients with diffuse large B-cell lymphoma and chromosomal rearrangement at MYC (8q24), outcome appears to be lower.
- The BFM group reported that in pediatric patients with T-cell lymphoblastic lymphoma, loss of heterozygosity at chromosome 6q was observed in 12% (25 of 217) of patients and was associated with unfavorable prognosis (probability of EFS [pEFS], 27% vs. 86%, P <.0001).[34,35] NOTCH1 mutations were seen in 60% (70 of 116) of patients 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.
Tumor burden: A surrogate for tumor burden (i.e., elevated levels of lactate dehydrogenase) has been shown to be prognostic in many studies.[14,15,18,24]
More recently, detection of minimal disease at diagnosis or minimal residual disease (MRD) appears to be prognostic in most subtypes of childhood NHL. In a retrospective subset analysis, there was evidence that submicroscopic bone marrow and peripheral blood involvement, detected by reverse transcription-polymerase chain reaction (RT-PCR) from NPM-ALK, was found in approximately 50% of patients and correlated with clinical stage; marrow involvement detected by PCR was associated with a 50% cumulative incidence of relapse. The prognostic role of MRD in the treatment of Burkitt leukemia remains unclear.[37-39]
- Response to therapy: One of the most important predictive factors for Burkitt lymphoma/leukemia is response to the initial prophase treatment; poor responders (i.e., <20% resolution of disease) had an EFS of 30%. Results from two studies suggest inferior outcome for patients with Burkitt leukemia that had detectable MRD after induction chemotherapy.[37,38]
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