National Cancer Institute
Posted Date: Oct 5, 2015
Expert-reviewed information summary about the treatment of childhood non-Hodgkin lymphoma.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood non-Hodgkin lymphoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Childhood NHL Treatment
Childhood Non-Hodgkin Lymphoma Treatment
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:
(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:
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.
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. 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.
- 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. 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.
- Stage at diagnosis/presence of minimal disseminated disease (MDD).
- Sites of disease at diagnosis.
- Tumor biology.
- Immune response to tumor.
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.
- 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%. Failure to achieve a complete remission after the initial induction courses has also been shown to adversely affect survival in Burkitt lymphoma/leukemia.
- 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]
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. 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.
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 transcriptionâpolymerase 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.
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. Although these intensive therapies have improved outcome, patients who present with CNS disease continue to have the worst outcome. 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%. 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. In children and young adults with primary mediastinal B-cell lymphoma, series have reported a 3-year EFS of 50% to 70%. 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.
- Testicle: Testicular involvement does not affect prognosis.
- 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.
- Mature B-cell lymphoma: Compared with treatments for adults, aggressive Burkitt regimens 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. The exception is primary mediastinal B-cell lymphoma, which has had an inferior outcome with these regimens. For pediatric Burkitt lymphoma/leukemia patients, secondary cytogenetic abnormalities, other than c-myc rearrangement, are associated with an inferior outcome, and cytogenetic abnormalities involving gain of 7q or deletion of 13q appeared to have an inferior outcome on the FAB 96 chemotherapy protocol. 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). 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. 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. 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. On the other hand, for patients with Burkitt and Burkitt-like lymphoma/leukemia on the FAB LMB 96 (COG-C5961) clinical trial, adolescent age (â¥15 years) was not an independent risk factor for inferior outcome.
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).
Histopathologic and Molecular Classification of Childhood NHL
In children, non-Hodgkin lymphoma (NHL) is distinct from the more common forms of lymphoma observed in adults. While lymphomas in adults are more commonly low or intermediate grade, almost all NHL that occurs in children is high grade. The World Health Organization (WHO) classifies NHL according to the following features:
Based on the WHO classification, the vast majority of NHL cases in childhood and adolescence fall into the following three categories:
Refer to the following sections of this summary for more information about the tumor biology associated with each type of NHL:
- Burkitt and Burkitt-like lymphoma/leukemia.
- Diffuse large B-cell lymphoma.
- Primary mediastinal B-cell lymphoma.
WHO Classification for NHL
The WHO classification is the most widely used NHL classification and is shown in Table 2, with immunophenotype and common clinical and molecular findings in pediatric NHL.
Other types of lymphoma, such as the nonanaplastic large cell peripheral T-cell lymphomas (including T/NK lymphomas), cutaneous lymphomas, and indolent B-cell lymphomas (e.g., follicular lymphoma and marginal zone lymphoma), are more commonly seen in adults and occur rarely in children. The most recent WHO classification has designated pediatric follicular lymphoma and pediatric nodal marginal zone lymphoma as distinct entities from the counterparts observed in adults.
Refer to the following PDQ summaries for more information about the treatment of NHL in adult patients:
- Adult Non-Hodgkin Lymphoma Treatment.
- Primary CNS Lymphoma Treatment.
- Mycosis Fungoides and the Sézary Syndrome Treatment.
Stage Information for Childhood NHL
The Ann Arbor staging system is used for all lymphomas in adults and for Hodgkin lymphoma in pediatrics. However, the Ann Arbor staging system has less prognostic value in pediatric non-Hodgkin lymphoma (NHL), primarily because of the high incidence of extranodal disease. Therefore, the most widely used staging schema for childhood NHL is that of the St. Jude Childrenâs Research Hospital (Murphy Staging). A new staging system defines bone marrow and central nervous system (CNS) involvement using modern techniques to document the presence of malignant cells. However, the basic definitions of bone marrow and CNS disease are essentially the same. The clinical utility of this new staging system is under investigation.
Role of Radiographic Imaging in Childhood NHL
Radiographic imaging is essential in the staging of patients with NHL. Ultrasound may be the preferred method for assessment of an abdominal mass, but computed tomography (CT) scan and, more recently, magnetic resonance imaging (MRI) have been used for staging. Radionuclide bone scans may be considered for patients in whom bone involvement is suspected.
The role of functional imaging in pediatric NHL is controversial. Gallium scans have been replaced by fluorodeoxyglucose positron emission tomography (PET) scanning, which is now routinely performed at many centers. A review of the revised International Workshop Criteria comparing CT imaging alone or CT together with PET imaging demonstrated that the combination of CT and PET imaging was more accurate than CT imaging alone.
While the International Harmonization Project for PET (now called the International Working Group) response criteria have been attempted in adults, the prognostic value of PET scanning for staging pediatric NHL remains under investigation. Data support that PET identifies more abnormalities than CT scanning, but it is unclear whether this should be used to upstage pediatric patients and change therapy. The International Working Group has updated their response criteria for malignant lymphoma to include PET, immunohistochemistry, and flow cytometry data.
St. Jude Children's Research Hospital (Murphy) Staging
In stage I childhood NHL, a single tumor or nodal area is involved, excluding the abdomen and mediastinum.
In stage II childhood NHL, disease extent is limited to a single tumor with regional node involvement, two or more tumors or nodal areas involved on one side of the diaphragm, or a primary gastrointestinal tract tumor (completely resected) with or without regional node involvement.
In stage III childhood NHL, tumors or involved lymph node areas occur on both sides of the diaphragm. Stage III NHL also includes any primary intrathoracic (mediastinal, pleural, or thymic) disease, extensive primary intra-abdominal disease, or any paraspinal or epidural tumors.
In stage IV childhood NHL, tumors involve bone marrow and/or CNS, regardless of other sites of involvement.
Bone marrow involvement has been defined as 5% malignant cells in an otherwise normal bone marrow, with normal peripheral blood counts and smears. Patients with lymphoblastic lymphoma who have more than 25% malignant cells in the bone marrow are usually considered to have leukemia and may be appropriately treated on leukemia clinical trials.
CNS disease in lymphoblastic lymphoma is defined by criteria similar to that used for acute lymphocytic leukemia (i.e., white blood cell count of at least 5/Î¼L and malignant cells in the cerebrospinal fluid [CSF]). For other types of NHL, the definition of CNS disease is any malignant cell present in the CSF regardless of cell count. The Berlin-Frankfurt-Münster group analyzed the prevalence of CNS involvement in NHL in over 2,500 patients. Overall, CNS involvement was diagnosed in 6% of patients. CNS involvement (percentage of patients) according to NHL subtype was as follows:
- Burkitt lymphoma/leukemia: 8.8%
- Precursor B-cell lymphoblastic lymphoma: 5.4%
- T-cell lymphoblastic lymphoma: 3.7%
- Anaplastic large cell lymphoma: 3.3%
- Diffuse large B-cell lymphoma: 2.6%
- Primary mediastinal large B-cell lymphoma: 0%
Treatment Option Overview for Childhood NHL
Many of the improvements in childhood cancer survival have been made using combinations of known and/or new agents that have attempted to improve the best available, accepted therapy. Clinical trials in pediatrics are designed to compare potentially better therapy with therapy that is currently accepted as standard. This comparison may be done in a randomized study of two treatment arms or by evaluating a single new treatment and comparing the results with those previously obtained with standard therapy.
All children with non-Hodgkin lymphoma (NHL) should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists with experience treating tumors of childhood is strongly recommended to determine, coordinate, and implement treatment to achieve optimal survival. Children with NHL should be referred for treatment by a multidisciplinary team of pediatric oncologists at an institution with experience in treating pediatric cancers. Information about ongoing clinical trials is available from the NCI website.
NHL in children is generally considered to be widely disseminated at diagnosis, even when the tumor is apparently localized; as a result, combination chemotherapy is recommended for most patients. Exceptions to this treatment strategy include the following:
In contrast to the treatment of adults with NHL, the use of radiation therapy is limited in children with NHL. Study results include the following:
Radiation therapy may have a role in treating patients who have not had a complete response to chemotherapy. Data to support limiting the use of radiation therapy in pediatric NHL come from the Childhood Cancer Survivor Study. This analysis demonstrated that radiation was a significant risk factor for subsequent neoplasms and death in long-term survivors.
Treatment of NHL in childhood and adolescence has historically been based on histologic subtype of the disease. A study by the Childrenâs Cancer Group demonstrated that the outcome for lymphoblastic lymphoma was superior with longer acute lymphoblastic leukemiaâlike therapy, while nonlymphoblastic NHL (Burkitt lymphoma/leukemia) had superior outcome with short, intensive, pulsed therapy, whereas the large cell lymphoma outcome was similar with either approach.
Outcome for recurrent NHL in children and adolescents remains very poor, with the exception of anaplastic large cell lymphoma. All patients with primary refractory or relapsed NHL should be considered for clinical trials.
Table 3. Treatment Options for Childhood Non-Hodgkin Lymphoma (NHL)
The most common potentially life-threatening clinical situations, most often seen in lymphoblastic lymphoma and Burkitt or Burkitt-like lymphoma/leukemia, are the following:
- Mediastinal masses.
- Tumor lysis syndrome.
Patients with large mediastinal masses are at risk for tracheal compression, superior vena caval compression, large pleural and pericardial effusions, and right and left ventricular outflow compression. Thus, cardiac or respiratory arrest is a significant risk, particularly if the patient is placed in a supine position.
Because of the risks of general anesthesia or heavy sedation, a careful physiologic and radiographic evaluation of the patient should be completed, and the least invasive procedure should be used to establish the diagnosis of lymphoma. The following procedures may be used:
- Bone marrow aspirate and biopsy.
- Thoracentesis. If a pleural or pericardial effusion is present, a cytologic diagnosis is frequently possible using thoracentesis, with confirmation of the diagnosis and cell lineage by flow cytometry.
- Lymph node biopsy. In children who present with peripheral adenopathy, a lymph node biopsy under local anesthesia and in an upright position may be possible.
In situations when the above procedures do not yield a diagnosis, use of a computed tomography (CT)-guided core-needle biopsy should be considered. This procedure can frequently be performed using light sedation and local anesthesia before proceeding to more invasive procedures. Care should be taken to keep patients out of a supine position. Most procedures, including CT scans and echocardiograms, can be done with the patient on his or her side or prone. Mediastinoscopy, anterior mediastinotomy, or thoracoscopy are the procedures of choice when other diagnostic modalities fail to establish the diagnosis. A formal thoracotomy is rarely, if ever, indicated for the diagnosis or treatment of childhood lymphoma.
Occasionally, it will not be possible to perform a diagnostic operative procedure because of the risk of general anesthesia or heavy sedation. In these situations, preoperative treatment with steroids or, less commonly, localized radiation therapy should be considered. Because preoperative treatment may affect the ability to obtain an accurate tissue diagnosis, a diagnostic biopsy should be obtained as soon as the risk of general anesthesia or heavy sedation is reduced.
Tumor lysis syndrome results from rapid breakdown of malignant cells, causing a number of metabolic abnormalities, most notably hyperuricemia, hyperkalemia, and hyperphosphatemia. Tumor lysis syndrome may present before the start of therapy.
Hyperhydration and allopurinol or rasburicase (urate oxidase) are essential components of therapy in all patients, except those with the most limited disease. In patients with G6PD deficiency, rasburicase may cause hemolysis or methemoglobinuria. An initial prephase consisting of low-dose cyclophosphamide and vincristine does not obviate the need for allopurinol or rasburicase and hydration.
Hyperuricemia and tumor lysis syndrome, particularly when associated with ureteral obstruction, frequently result in life-threatening complications.
Although the use of positron emission tomography (PET) to assess rapidity of response to therapy appears to have prognostic value in Hodgkin lymphoma and some types of NHL observed in adult patients, it remains under investigation in pediatric NHL. To date, there are insufficient data in pediatric NHL to support that early response to therapy assessed by PET has prognostic value.
Diagnosing relapsed disease based solely on imaging requires caution because false-positive results are common. There are also data demonstrating that PET scanning can produce false-negative results. A study of young adults with primary mediastinal B-cell lymphoma demonstrated that among 12 patients who had residual mediastinal masses at the end of therapy, 9 of the 12 had positive PET scans. Seven of these nine patients had the masses resected, but no viable tumor was found. Before undertaking changes in therapy based on residual masses noted by imaging, a biopsy to prove residual disease is warranted.
Mature B-cell NHL
Burkitt and Burkitt-like Lymphoma/Leukemia
Burkitt and Burkitt-like lymphoma/leukemia in the United States accounts for about 40% of childhood non-Hodgkin lymphoma (NHL) and exhibits a consistent, aggressive clinical behavior. The overall incidence of Burkitt lymphoma/leukemia in the United States is 2.5 cases per 1 million person-years and is higher among boys than girls (3.9 vs. 1.1). (Refer to Table 1 for more information on the incidence of Burkitt lymphoma by age and gender distribution.)
The malignant cells show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase. These malignant cells usually express surface immunoglobulin, most bearing a clonal surface immunoglobulin M with either kappa or lambda light chains. A variety of additional B-cell markers (e.g., CD19, CD20, CD22) are usually present, and most childhood Burkitt and Burkitt-like lymphoma/leukemia express CALLA (CD10).
Burkitt lymphoma/leukemia expresses a characteristic chromosomal translocation, usually t(8;14) and more rarely t(8;22) or t(2;8). Each of these translocations juxtaposes the c-myc oncogene and immunoglobulin locus regulatory elements, resulting in the inappropriate expression of c-myc, a gene involved in cellular proliferation. The presence of one of the variant translocations t(2;8) or t(8;22) does not appear to affect response or outcome.
The distinction between Burkitt and Burkitt-like lymphoma/leukemia is controversial. Burkitt lymphoma/leukemia consists of uniform, small, noncleaved cells, whereas the diagnosis of Burkitt-like lymphoma/leukemia is highly disputed among pathologists because of features that are consistent with diffuse large B-cell lymphoma.
Cytogenetic evidence of c-myc rearrangement is the gold standard for diagnosis of Burkitt lymphoma/leukemia. For cases in which cytogenetic analysis is not available, the World Health Organization (WHO) has recommended that the Burkitt-like diagnosis be reserved for lymphoma resembling Burkitt lymphoma/leukemia or with more pleomorphism, large cells, and a proliferation fraction (i.e., MIB-1 or Ki-67 immunostaining) of 99% or greater.
Studies have demonstrated that the vast majority of Burkitt-like or atypical Burkitt lymphoma/leukemia has a gene expression signature similar to Burkitt lymphoma/leukemia. Additionally, as many as 30% of pediatric diffuse large B-cell lymphoma cases will have a gene signature similar to Burkitt lymphoma/leukemia.
The most common primary sites of disease are the abdomen and the lymphatic tissue of Waldeyer ring. Other sites of involvement include testes, bone, skin, bone marrow, and central nervous system (CNS). While lung involvement does not tend to occur, pleural and peritoneal spread is seen.
Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information on prognostic factors for Burkitt lymphoma/leukemia.
The treatment of Burkitt and Burkitt-like lymphoma/leukemia is the same as treatment for diffuse large B-cell lymphoma. The following discussion is pertinent to the treatment of both types of childhood NHL.
Unlike mature B-lineage NHL seen in adults, there is no difference in outcome based on histology (Burkitt or Burkitt-like lymphoma/leukemia or diffuse large B-cell lymphoma). Pediatric Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma are clinically very aggressive and are treated with very intensive regimens.
Tumor lysis syndrome is often present at diagnosis or after initiation of treatment. This emergent clinical situation should be anticipated and addressed before treatment is started. (Refer to the Tumor lysis syndrome section in the Treatment Option Overview for Childhood NHL section of this summary for more information.)
Current treatment strategies are based on risk stratification as described in Table 4. Involvement of the bone marrow may lead to confusion as to whether the patient has lymphoma or leukemia. Traditionally, patients with more than 25% marrow blasts are classified as having mature B-cell leukemia, and those with fewer than 25% marrow blasts are classified as having lymphoma. It is not clear whether these arbitrary definitions are biologically distinct, but there is no question that patients with Burkitt leukemia should be treated with protocols designed for Burkitt leukemia.
The following studies have contributed to the development of current treatment regimens for pediatric Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma.
Both the BFM and FAB/LMB studies demonstrated that omission of craniospinal irradiation, even in patients presenting with CNS disease, does not affect outcome (COG-C5961 [FAB/LMB-96] and NHL-BFM-90 [GER-GPOH-NHL-BFM-90]).
Rituximab is a mouse/human chimeric monoclonal antibody targeting the CD20 antigen. Burkitt lymphoma/leukemia and diffuse large B-cell lymphoma both express high levels of CD20. Rituximab has been safely combined with standard doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP) chemotherapy and has been shown to improve outcome in a randomized trial of adults with diffuse large B-cell lymphoma (CAN-NCIC-LY9). In children, a single-agent phase II study of rituximab performed by the BFM group showed activity in Burkitt lymphoma/leukemia.[Level of evidence: 2Div] A Children's Oncology Group (COG) pilot study (COG-ANHL01P1) added rituximab to baseline chemotherapy with FAB/LMB-96 therapy in patients with stage III and stage IV B-cell NHL. Compared with chemotherapy-only protocols, toxicity was similar, despite a trend toward higher peak rituximab levels in younger patients.; [Level of evidence: 3iiiA] The contribution of rituximab in pediatric B-cell lymphoma is being evaluated in an international randomized phase III trial.
Standard treatment options for Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma are described in Table 5.
There is no standard treatment option for patients with recurrent or progressive disease.
Treatment options for recurrent Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma include the following:
For recurrent or refractory B-lineage NHL, survival is generally 10% to 20%. Chemoresistance makes remission difficult to achieve.
Evidence (rituximab therapy):
If remission can be achieved, high-dose therapy and SCT remains the best option for survival. However, the benefit of autologous versus allogeneic SCT is unclear.; [Level of evidence: 2A]; [Level of evidence: 3iiiDii]
Patients not in remission at time of transplant do significantly worse. The very poor outcome of patients whose disease is refractory to salvage chemotherapy suggests that a transplant option should not be pursued in these patients.
(Refer to the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation).
Evidence (SCT therapy):
Treatment options under clinical evaluation for Burkitt and Burkitt-like lymphoma/leukemia include the following:
- COG-ANHL1131 (Combination Chemotherapy With or Without Rituximab in Treating Younger Patients With Stage IIIâIV Non-Hodgkin Lymphoma or B-Cell Acute Leukemia): This randomized study of patients with high-risk disease (defined as group B with high LDH and group C) examines the addition of rituximab to the standard FAB LMB 96 (COG-C5961) chemotherapy regimen. Additionally, the dose-adjusted EPOCH-R regimen (etoposide, prednisone, vincristine, doxorubicin, and rituximab) will be tested in a single-arm, phase II trial for pediatric patients with primary mediastinal B-cell lymphoma.
Information about ongoing clinical trials is available from the NCI website.
Diffuse Large B-cell Lymphoma
Primary mediastinal B-cell lymphoma, previously considered a subtype of diffuse large B-cell lymphoma, is now a separate entity in the most recent WHO classification. (Refer to the Primary Mediastinal B-cell Lymphoma section of this summary for more information.)
Diffuse large B-cell lymphoma is a mature B-cell neoplasm that represents 10% to 20% of pediatric NHL. Diffuse large B-cell lymphoma occurs more frequently during the second decade of life than during the first decade. (Refer to Table 1 for more information on the incidence of diffuse large B-cell lymphoma by age and gender distribution.)
The WHO classification system does not recommend subclassification of diffuse large B-cell lymphoma based on morphologic variants (e.g., immunoblastic, centroblastic).
Diffuse large B-cell lymphoma in children and adolescents differs biologically from diffuse large B-cell lymphoma in adults in the following ways:
- The vast majority of pediatric diffuse large B-cell lymphoma cases have a germinal center B-cell phenotype, as assessed by immunohistochemical analysis of selected proteins found in normal germinal center B cells, such as the BCL6 gene product and CD10. The age at which the favorable germinal center subtype changes to the less favorable nongerminal center subtype was shown to be a continuous variable.
- Pediatric diffuse large B-cell lymphoma rarely demonstrates the t(14;18) translocation involving the immunoglobulin heavy-chain gene and the BCL2 gene that is seen adults.
- As many as 30% of patients younger than 14 years with diffuse large B-cell lymphoma will have a gene signature similar to Burkitt lymphoma/leukemia.
- In contrast to adult diffuse large B-cell lymphoma, pediatric cases show a high frequency of abnormalities at the MYC locus (chromosome 8q24), with approximately one-third of pediatric cases showing MYC rearrangement and with approximately one-half of the nonrearranged cases showing MYC gain or amplification.
- A subset of pediatric diffuse large B-cell lymphoma cases was found to have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci. Diffuse large B-cell lymphoma cases with an IRF4 translocation were significantly more frequent in children than adults (15% vs. 2%), were germinal centerâderived B-cell lymphomas, and were associated with favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this abnormality.
Pediatric diffuse large B-cell lymphoma may present in a manner clinically similar to Burkitt or Burkitt-like lymphoma/leukemia, although it is more often localized and less often involves the bone marrow or CNS. (Refer to the Clinical presentation section in the Burkitt and Burkitt-like Lymphoma/Leukemia section of this summary for more information.)
Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information on prognostic factors for diffuse large B-cell lymphoma.
As in Burkitt and Burkitt-like lymphoma/leukemia, current treatment strategies are based on risk stratification, as described in Table 4. The treatment of diffuse large B-cell lymphoma is the same as the treatment of Burkitt and Burkitt-like lymphoma/leukemia. Refer to the Standard treatment options for Burkitt and Burkitt-like lymphoma/leukemia section of this summary for information on the treatment of diffuse large B-cell lymphoma.
The treatment of recurrent diffuse large B-cell lymphoma is the same as treatment of recurrent Burkitt and Burkitt-like lymphoma/leukemia. Refer to the Treatment options for recurrent Burkitt and Burkitt-like lymphoma/leukemia section of this summary for more information.
The treatment options under clinical evaluation for diffuse large B-cell lymphoma are the same as those for the treatment of Burkitt and Burkitt-like lymphoma/leukemia. Refer to the Treatment options under clinical evaluation for Burkitt and Burkitt-like lymphoma/leukemia section of this summary for more information.
Primary Mediastinal B-cell Lymphoma
In the pediatric population, primary mediastinal B-cell lymphoma is predominantly seen in older adolescents, accounting for 1% to 2% of all pediatric NHL cases.
Primary mediastinal B-cell lymphoma was previously considered a subtype of diffuse large B-cell lymphoma, but is now a separate entity in the most recent WHO classification. These tumors arise in the mediastinum from thymic B-cells and show a diffuse large cell proliferation with sclerosis that compartmentalizes neoplastic cells.
Primary mediastinal B-cell lymphoma can be very difficult to distinguish morphologically from the following types of lymphoma:
- Diffuse large B-cell lymphoma: Cell surface markers are similar to the ones seen in diffuse large B-cell lymphoma, such as CD19, CD20, CD22, CD79a, and PAX-5. Primary mediastinal B-cell lymphoma often lacks cell surface immunoglobulin expression but may display cytoplasmic immunoglobulins. CD30 expression is commonly present.
- Hodgkin lymphoma: This type of lymphoma may be difficult to clinically and morphologically distinguish from Hodgkin lymphoma, especially with small mediastinal biopsies because of extensive sclerosis and necrosis.
Primary mediastinal B-cell lymphoma is associated with distinctive chromosomal aberrations (gains in chromosome 9p and 2p in regions that involve JAK2 and c-rel, respectively) and commonly shows inactivation of SOCS1 by either mutation or gene deletion. Primary mediastinal B-cell lymphoma has a distinctly different gene expression profile from diffuse large B-cell lymphoma, but its gene expression profile has features similar to those seen in Hodgkin lymphoma.
As the name would suggest, primary mediastinal B-cell lymphoma occurs in the mediastinum. The tumor can be locally invasive (e.g., pericardial and lung extension) and can be associated with the superior vena caval syndrome. The tumor can disseminate outside the thoracic cavity with nodal and extranodal involvement, with predilection to the kidneys; however, CNS and marrow involvement are exceedingly rare.
Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information on prognostic factors for primary mediastinal B-cell lymphoma.
Treatment options for primary mediastinal B-cell lymphoma include the following:
Pediatric and adolescent patients with stage III primary mediastinal large B-cell lymphoma did significantly worse on the FAB/LMB-96 (NCT00002757) study, with a 5-year EFS of 66% compared with 85% for adolescents with nonmediastinal diffuse large B-cell lymphoma.[Level of evidence: 2A] Similarly on NHL-BFM-95, patients with primary mediastinal B-cell lymphoma had an EFS of 50% at 3 years. However, a study of young adults treated with DA-EPOCH-R showed excellent disease-free survival.
Treatment options under clinical evaluation for primary mediastinal B-cell lymphoma include the following:
- COG-ANHL1131 (Combination Chemotherapy With or Without Rituximab in Treating Younger Patients With Stage IIIâIV Non-Hodgkin Lymphoma or B-Cell Acute Leukemia): This randomized study of patients with high-risk disease (defined as group B with high LDH and group C) examines the addition of rituximab to the standard FAB LMB 96 (COG-C5961) chemotherapy regimen. Additionally, the DA-EPOCH-R regimen will be tested in a single-arm, phase II trial for pediatric patients with primary mediastinal B-cell lymphoma.
Information about ongoing clinical trials is available from the NCI website.
Lymphoblastic lymphoma comprises approximately 20% of childhood non-Hodgkin lymphoma (NHL). (Refer to Table 1 for more information on the incidence of lymphoblastic lymphoma by age and gender distribution.)
Lymphoblastic lymphomas are usually positive for terminal deoxynucleotidyl transferase, with more than 75% having a T-cell immunophenotype and the remainder having a precursor B-cell phenotype.
As opposed to pediatric acute lymphoblastic leukemia (ALL), chromosomal abnormalities and the molecular biology of pediatric lymphoblastic lymphoma are not well characterized. The Berlin-Frankfurt-Münster (BFM) group reported that loss of heterozygosity at chromosome 6q was observed in 12% of patients and NOTCH1 mutations were seen in 60% of patients, but NOTCH1 mutations are rarely seen in patients with loss of heterozygosity in 6q16.
As many as 75% of patients with T-cell lymphoblastic lymphoma will present with an anterior mediastinal mass, which may manifest as dyspnea, wheezing, stridor, dysphagia, or swelling of the head and neck.
Pleural and/or pericardial effusions may be present, and the involvement of lymph nodes, usually above the diaphragm, may be a prominent feature. There may also be involvement of bone, skin, bone marrow, central nervous system (CNS), abdominal organs (but rarely bowel), and occasionally other sites, such as lymphoid tissue of Waldeyer ring, testes, bone, or subcutaneous tissue. Abdominal involvement is less than what is observed in Burkitt lymphoma/leukemia.
Involvement of the bone marrow may lead to confusion as to whether the patient has lymphoma with bone marrow involvement or leukemia with extramedullary disease. Traditionally, patients with more than 25% marrow blasts are considered to have T-cell ALL, and those with fewer than 25% marrow blasts are considered to have stage IV T-cell lymphoblastic lymphoma. The World Health Organization (WHO) classifies lymphoblastic lymphoma as the same disease as ALL. The debate remains as to whether they truly represent the same disease. It is not yet clear whether these arbitrary definitions are biologically distinct or relevant for treatment design.
Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information on prognostic factors for lymphoblastic lymphoma.
Standard Treatment Options for Lymphoblastic Lymphoma
Current data do not suggest superiority for the following treatment options.
Standard treatment options for lymphoblastic lymphoma include the following:
Patients with low-stage (stage I or stage II) lymphoblastic lymphoma have long-term disease-free survival (DFS) rates of about 60% with short, pulsed chemotherapy followed by 6 months of maintenance, with an overall survival (OS) greater than 90%. However, with the use of an ALL approach and induction, consolidation, and maintenance therapy for a total of 24 months, DFS rates higher than 90% have been reported for children with low-stage lymphoblastic lymphoma.
Patients with high-stage (stage III or stage IV) lymphoblastic lymphoma have long-term survival rates higher than 80%. Mediastinal radiation is not necessary for patients with mediastinal masses, except in the emergency treatment of symptomatic superior vena caval obstruction or airway obstruction. In these cases, either corticosteroid therapy or low-dose radiation is usually employed. (Refer to the Mediastinal masses section of the Treatment Option Overview for Childhood NHL section of this summary for more information.)
Evidence (high-stage treatment regimens for lymphoblastic lymphoma):
The Pediatric Oncology Group conducted a trial to test the effectiveness of the addition of high-dose methotrexate in T-cell ALL and T-cell lymphoblastic lymphoma. In the lymphoma patients, high-dose methotrexate did not demonstrate benefit. In the small cohort (n = 66) of lymphoma patients who did not receive high-dose methotrexate, the 5-year EFS was 88%.[Level of evidence: 1iiA] Of note, all of these patients received prophylactic craniospinal radiation therapy, which has been demonstrated not to be required in T-cell lymphoblastic lymphoma patients.
In addition to the NHL-BFM-95 trial, a single-center study reported that patients treated for lymphoblastic lymphoma had a higher incidence of subsequent neoplasms than did patients treated for other pediatric NHL. However, studies from the Children's Oncology Group (COG) and the Childhood Cancer Survivor Study Group do not support this finding.
Treatment Options for Recurrent Lymphoblastic Lymphoma
For recurrent or refractory lymphoblastic lymphoma, reports of survival range from 10% to 40%.; [Level of evidence: 3iiiA] As with Burkitt lymphoma/leukemia, chemoresistant disease is common.
There are no standard treatment options for patients with recurrent or progressive disease.
Treatment options for recurrent lymphoblastic lymphoma include the following:
Evidence (treatment of recurrent lymphoblastic lymphoma):
Treatment Options Under Clinical Evaluation for Lymphoblastic Lymphoma
Treatment options under clinical evaluation for lymphoblastic lymphoma include the following:
- NCI-2014-00712; AALL1231 (NCT02112916) (Combination Chemotherapy With or Without Bortezomib in Treating Younger Patients With Newly Diagnosed T-Cell ALL or Stage IIâIV T-Cell Lymphoblastic Lymphoma): This phase III trial is utilizing a modified augmented BFM regimen for patients aged 1 to 30 years with T-cell ALL. Patients are classified into one of three risk groups (standard, intermediate, or very high) based on morphologic response at day 29, minimal residual disease (MRD) status at day 29 and end of consolidation, and CNS status at diagnosis. Age and presenting leukocyte count are not used to stratify patients. The objectives of the trial include the following:To compare EFS in patients who are randomly assigned to receive or not to receive bortezomib on a modified augmented BFM backbone. For those randomly assigned to receive bortezomib, it is given during the induction phase (four doses) and again during the delayed intensification phase (four doses).To determine the safety and feasibility of modifying standard COG therapy for T-cell ALL by using dexamethasone instead of prednisone during the induction and maintenance phases and additional doses of PEG-asparaginase during the induction and delayed intensification phases.To determine whether prophylactic cranial radiation can be omitted in 85% to 90% of T-cell ALL patients (nonâvery high risk, non-CNS3) without an increase in relapse risk, compared with historic controls.To determine the proportion of patients with end consolidation MRD >0.1% who become MRD-negative after intensification therapy using three high-risk BFM blocks that include high-dose cytarabine, high-dose methotrexate, ifosfamide, and etoposide.
- COG-AALL0932 (Risk-Adapted Chemotherapy in Younger Patients With Newly Diagnosed Standard-Risk ALL or Localized B-lineage Lymphoblastic Lymphoma): This trial subdivides standard-risk patients into two groups: low risk and average risk. Low risk is defined as the presence of all of the following: NCI-standard risk age/white blood cell count, favorable genetics (e.g., double trisomies or ETV6-RUNX1), CNS1 at presentation, and low MRD (<0.01% by flow cytometry) at day 8 (peripheral blood) and day 29 (marrow). Average risk includes other NCI standard-risk patients excluding those with high day 29 MRD morphologic induction failure or other unfavorable presenting features (e.g., CNS3, iAMP21, low hypodiploidy, MLL translocations, and BCR-ABL).All patients will receive a three-drug induction (dexamethasone, vincristine, and intravenous [IV] PEG-L-asparaginase) with intrathecal chemotherapy. For postinduction therapy, low-risk patients will be randomly assigned to receive one of the following:A regimen based on POG-9904, including six courses of intermediate-dose methotrexate (1 g/m2) but without any alkylating agents or anthracyclines.A modified BFM backbone including two interim maintenance phases with escalating doses of IV methotrexate (no leucovorin) and one delayed intensification phase.The objective is not to prove superiority of either regimen, but rather, to determine whether excellent outcomes (at least 95% 5-year DFS) can be achieved.All average-risk patients will receive a modified BFM backbone as postinduction treatment. For these patients, the study is comparing, in a randomized fashion, two doses of weekly oral methotrexate during the maintenance phase (20 mg/m2 and 40 mg/m2) to determine whether the higher dose favorably impacts DFS. Average-risk patients are also eligible to participate in a randomized comparison of two schedules of vincristine/dexamethasone pulses during maintenance (delivered every 4 weeks or every 12 weeks). The objective of this randomization is to determine whether vincristine/dexamethasone pulses can be delivered less frequently without adversely impacting outcome.
Information about ongoing clinical trials is available from the NCI website.
Check the list of NCI-supported cancer clinical trials that are now accepting patients with stage I childhood lymphoblastic lymphoma, stage II childhood lymphoblastic lymphoma, stage III childhood lymphoblastic lymphoma, stage IV childhood lymphoblastic lymphoma and recurrent childhood lymphoblastic lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI website.
Anaplastic Large Cell Lymphoma
Anaplastic large cell lymphoma accounts for approximately 10% of childhood non-Hodgkin lymphoma (NHL) cases. (Refer to Table 1 for more information on the incidence of anaplastic large cell lymphoma by age and gender distribution.)
While the predominant immunophenotype of anaplastic large cell lymphoma is mature T-
October 03, 2014
November 25, 2015