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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 NHL, the 5-year survival rate 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 monitoring 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.[2,3]
The following factors affect the incidence of NHL in children and adolescents:
In sub-Saharan Africa, the incidence of Epstein-Barr virus (EBV)–induced Burkitt lymphoma/leukemia is tenfold to twentyfold higher than the incidence in the United States, resulting in a much higher incidence of NHL.
The incidence and age distribution of histologic types of NHL according to sex is described in Table 1.
Relatively little data on the epidemiology of childhood NHL have been published. However, known risk factors include the following:
Unlike adults with NHL who present most often with nodal disease, children typically have extranodal disease involving the mediastinum, abdomen, and/or head and neck, as well as the bone marrow or CNS. For example, in developed countries, Burkitt lymphoma/leukemia occurs in the abdomen in approximately 60% of cases, with 15% to 20% of cases arising in the head and neck.[12,13] This high incidence of extranodal disease substantiates the use of the Murphy staging system for pediatric NHL, instead of the Ann Arbor staging system.
The following tests and procedures are used to diagnose childhood NHL:
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 depends 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.[15,16,17]
International pediatric NHL response criteria have been proposed but require prospective evaluation. The clinical utility of these new criteria are under investigation.
Unlike in acute leukemia, in pediatric NHL, the prognostic value of minimal residual disease (MRD) after therapy is initiated remains uncertain and requires further investigation.
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.[18,20,27,28,29,30] Apart from this finding, the outcome by clinical stage, if the correct therapy is given, does not differ significantly.
A surrogate for tumor burden (i.e., elevated levels of LDH) has been shown to be prognostic in many studies.[18,28,31,32]
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.
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:
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 outcomes inferior to those of younger children.[12,14,49,50] 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.[14,50] On the other hand, for patients with Burkitt lymphoma/leukemia who were treated 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 patients with newly diagnosed anaplastic large cell lymphoma could be stratified into three risk groups, with a PFS of 28% (low risk), 68% (intermediate risk), and 93% (all remaining patients) (P < .0001).
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.[1,2,3] The World Health Organization (WHO) classifies NHL according to the following features:
On the basis of the WHO classification, the vast majority of NHL cases in childhood and adolescence fall into the following three categories:
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.[5,6,7,8,9] The exception is primary mediastinal B-cell lymphoma, which has had an inferior outcome with these regimens.[5,6,7,8,10,11]
For pediatric Burkitt lymphoma/leukemia patients, secondary cytogenetic abnormalities, other than MYC rearrangement, are associated with an inferior outcome,[12,13] and cytogenetic abnormalities involving gain of 7q or deletion of 13q appeared to have an inferior outcome on the FAB/LMB-96 chemotherapy protocol.[13,14] For pediatric patients with diffuse large B-cell lymphoma and chromosomal rearrangement at MYC (8q24), outcome appeared to be worse.
LBCL-IRF4 is included in the WHO 2017 classification as a provisional entity. LBCL-IRF4 cases 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.
For pediatric patients with T-cell lymphoblastic lymphoma, the Berlin-Frankfurt-Münster group reported that loss of heterozygosity (LOH) at chromosome 6q was observed in 12% of patients (25 of 217) and was associated with unfavorable prognosis (probability of event-free survival [pEFS], 27% vs. 86%, P < .0001).[16,17]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 LOH at 6q.
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.[18,19,20] 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 of failure.
Refer to the following sections of this summary for more information about the tumor biology and genomic alterations associated with each type of NHL:
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.[1,3]
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-type 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:
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 Children's 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 staging system is under investigation.
Role of Radiographic Imaging in Childhood NHL
Radiographic imaging is essential in the staging of patients with NHL. Ultrasonography may be the preferred method for assessment of an abdominal mass, but computed tomography (CT) scan and 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 fluorine F 18-fludeoxyglucose 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.[4,5]
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.[3,6,7] Data support that PET identifies more abnormalities than does 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.[5,9]
St. Jude Children's Research Hospital (Murphy) Staging
Stage I childhood NHL
In stage I childhood NHL, a single tumor or nodal area is involved, excluding the abdomen and mediastinum.
Stage II childhood NHL
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.
Stage III childhood NHL
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.
Stage IV childhood NHL
In stage IV childhood NHL, tumors involve the bone marrow and/or CNS, regardless of other sites of involvement.
Bone marrow involvement has been defined as 5% or more 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/μL 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 more than 2,500 patients. Overall, CNS involvement was diagnosed in 6% of patients. CNS involvement (percentage of patients) according to NHL subtype was as follows:
Many of the improvements in childhood cancer survival have been made by employing combinations of known and/or new agents aimed at improving 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 National Cancer Institute (NCI)–supported 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 the treatment of 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.
The treatment of NHL in childhood and adolescence has historically been based on the histologic subtype of the disease. A study by the Children's Cancer Group demonstrated that the outcome for lymphoblastic lymphoma was superior with longer acute lymphoblastic leukemia–like therapy, while nonlymphoblastic NHL (Burkitt lymphoma/leukemia) had superior outcome with short, intensive, pulsed therapy; the large cell lymphoma outcome was similar with either approach.
Outcomes for recurrent NHL in children and adolescents remain very poor, with the exception of anaplastic large cell lymphoma.[9,10,11,12,13] Patients or families who desire additional disease-directed therapy should consider entering trials of novel therapeutic approaches. Regardless of whether a decision is made to pursue disease-directed therapy at the time of progression, palliative care remains a central focus of management. This ensures that quality of life is maximized while attempting to reduce symptoms and stress related to the terminal illness.
Table 3 describes the treatment options for newly diagnosed and recurrent childhood NHL.
The most common potentially life-threatening clinical situations, seen most frequently in patients with lymphoblastic lymphoma and Burkitt or Burkitt-like lymphoma/leukemia, are the following:
Patients with large mediastinal masses are at risk of 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 for procedures such as computed tomography (CT) scans or echocardiograms.
Because of the risk of complications from 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.[15,16] The following procedures may be used:
In situations when the above procedures do not yield a diagnosis, the use of a CT-guided core-needle biopsy should be considered. This procedure can frequently be performed using light sedation and local anesthesia before more invasive procedures are undertaken. Care should be taken to keep patients out of a supine position. Most procedures, including CT and echocardiography, can be performed 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 complications from 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 complications from general anesthesia or heavy sedation is reduced.
Tumor lysis syndrome
Tumor lysis syndrome results from rapid breakdown of malignant cells, causing a number of metabolic abnormalities, most notably hyperuricemia, hyperkalemia, and hyperphosphatemia. Patients may present with tumor lysis syndrome 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.[18,19,20,21,22,23] In patients with G6PD deficiency, rasburicase may cause hemolysis or methemoglobinuria and should be avoided. 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 for pediatric NHL to support a finding that early response to therapy assessed by PET has prognostic value.
Diagnosing relapsed disease solely on the basis of imaging requires caution because false-positive results are common.[24,25,26] Data also demonstrate that PET scanning can produce false-negative results. A study of young adults with primary mediastinal B-cell lymphoma demonstrated that 9 of 12 patients who had residual mediastinal masses at the end of therapy had positive PET scans. Seven of these nine patients had the masses resected, but no viable tumor was found. Before changes in therapy are undertaken on the basis of residual masses noted by imaging, even if the PET scan is positive, a biopsy to prove residual disease is warranted.
Special Considerations for the Treatment of Children With Cancer
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 the 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 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 NCI-supported clinical trials is available from the NCI website.
In the United States, Burkitt lymphoma/leukemia account for about 40% of childhood non-Hodgkin lymphoma (NHL) and exhibit a consistent, aggressive clinical behavior.[1,2,3] 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).[2,4] (Refer to Table 1 for more information about the incidence of Burkitt lymphoma by age and sex distribution.)
Genomics of Burkitt lymphoma/leukemia
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 lymphomas/leukemias express 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 MYC oncogene and immunoglobulin (IG) locus regulatory elements, resulting in the inappropriate expression of MYC, a gene involved in cellular proliferation.[3,5,6] The presence of one of the variant translocations t(2;8) or t(8;22) does not appear to affect response or outcome.
Mapping of IGH-translocation breakpoints demonstrated that IG-MYC translocations in sporadic Burkitt lymphoma most commonly occur through aberrant class-switch recombination and less commonly through somatic hypermutation; translocations resulting from aberrant variable, diversity, and joining (VDJ) gene segment recombinations are rare. These findings are consistent with a germinal center derivation of Burkitt lymphoma.
While MYC translocations are present in all Burkitt lymphoma, cooperating genomic alterations appear to be required for lymphoma development. Some of the more commonly observed recurring mutations that have been identified in Burkitt lymphoma in pediatric and adult cases are listed below. The clinical significance of these mutations for pediatric Burkitt lymphoma remains to be elucidated.
A study that compared the genomic landscape of endemic Burkitt lymphoma with the genomics of sporadic Burkitt lymphoma found the expected high rate of Epstein-Barr virus (EBV) positivity in endemic cases, with much lower rates in sporadic cases. There was general similarity between the patterns of mutations for endemic and sporadic cases and for EBV-positive and EBV-negative cases; however, EBV-positive cases showed significantly lower mutation rates for selected genes/pathways, including SMARCA4, apoptosis, CCND3, and TP53.
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 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. BCL2 staining by immunohistochemistry is variable. The absence of a translocation involving the BCL2 gene does not preclude the diagnosis of Burkitt lymphoma/leukemia and has no clinical implications.
Burkitt-like lymphoma with 11q aberration was added as a provisional entity in the 2017 revised WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. In this entity, MYC rearrangement is absent, and the characteristic chromosome 11q finding (detected cytogenetically and/or with copy-number DNA arrays) is 11q23.2-q23.3 gain/amplification and 11q24.1-qter loss.[17,18] Most patients present in the adolescent and young adult age range with localized nodal disease, and outcomes appear favorable in the small number of cases identified. Cases show a very high proliferative index and can show a focal starry sky pattern. The mutational landscape of Burkitt-like lymphoma with 11q aberration is distinct from that of Burkitt lymphoma; mutations commonly observed in Burkitt lymphoma (e.g., ID3, TCF3, and CCND3) are uncommon in Burkitt-like lymphoma with 11q aberration. Conversely, mutations in GNA13 appear to be common (up to 50%) in patients with Burkitt-like lymphoma with 11q aberration and are less common in patients with Burkitt lymphoma.
The most common primary sites of disease are the abdomen and the lymphatic tissue of Waldeyer ring.[3,4] 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 are seen.
Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information about prognostic factors for Burkitt lymphoma/leukemia.
Standard treatment options for Burkitt lymphoma/leukemia
The treatment of Burkitt 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 lymphoma/leukemia or diffuse large B-cell lymphoma). Pediatric Burkitt lymphoma/leukemia and diffuse large B-cell lymphoma are clinically very aggressive and are treated with very intensive regimens.[19,20,21,22,23]
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 about 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 lymphoma.[19,21]
The following studies have contributed to the development of current treatment regimens for pediatric Burkitt 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]).[19,20,21,25]
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.
Standard treatment options for Burkitt lymphoma/leukemia and diffuse large B-cell lymphoma are described in Table 5.
Treatment options for recurrent Burkitt lymphoma/leukemia
There is no standard treatment option for patients with recurrent or progressive disease. For recurrent or refractory aggressive mature B-cell NHL, reported survival ranges between 10% to 50%, but in the largest series survival is about 20%.[21,31,32,33,34] Two large retrospective multivariable analyses identified prognostic factors for better survival to be:
Treatment options for recurrent Burkitt lymphoma/leukemia and diffuse large B-cell lymphoma include the following:
Chemoresistance makes remission difficult to achieve.
Evidence (treatment of recurrent Burkitt lymphoma/leukemia):
If remission can be achieved, high-dose therapy plus SCT remains the best option for survival. Patients not in remission at the time of transplant fare significantly worse.[35,38,41,43,44,45] The very poor outcome of patients whose disease is refractory to salvage chemotherapy suggests that a nonexperimental transplant option should not be pursued in these patients.[38,44,45] If a complete remission was reported, survival ranges between 30% to 75%, albeit all series have a small number of patients (i.e., fewer than 40).[38,41,42,44,46] The benefit of autologous versus allogeneic SCT remains unclear.[33,38,46,47]; [Level of evidence: 2A]; [Level of evidence: 3iiiDii]
(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 leukemia/lymphoma
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
Current Clinical Trials
Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.
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 an aggressive mature B-cell neoplasm that represents 10% to 20% of pediatric NHL.[2,3,49] Diffuse large B-cell lymphoma occurs more frequently during the second decade of life than during the first decade.[2,50] (Refer to Table 1 for more information on the incidence of diffuse large B-cell lymphoma by age and sex distribution.)
The World Health Organization (WHO) classification system categorizes diffuse large B-cell lymphoma on the basis of molecular characteristics into the germinal center B-cell subtype and the activated B-cell subtype, with the remaining classes being classified as diffuse large B-cell lymphoma, not otherwise specified (NOS).
Diffuse large B-cell lymphoma in children and adolescents differs biologically from diffuse large B-cell lymphoma in adults in the following ways:
Large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) was added as a provisional entity in the 2017 revision of the WHO classification of lymphoid neoplasms.
High-grade B-cell lymphoma, NOS is defined as a clinically aggressive B-cell lymphoma that lacks MYC plus BCL2 and/or BCL6 rearrangements and that does not meet criteria for diffuse large B-cell lymphoma, NOS or Burkitt lymphoma.
Pediatric diffuse large B-cell lymphoma may present in a manner clinically similar to that of Burkitt lymphoma/leukemia, although more often it is localized, and less often it involves the bone marrow or CNS.[49,50,64] (Refer to the Clinical presentation section in the Burkitt 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 about prognostic factors for diffuse large B-cell lymphoma.
Treatment options for diffuse large B-cell lymphoma
As with Burkitt lymphoma/leukemia, current treatment strategies are based on risk stratification, as described in Table 5. The treatment of diffuse large B-cell lymphoma is the same as the treatment of Burkitt lymphoma/leukemia. Refer to the Standard treatment options for Burkitt lymphoma/leukemia section of this summary for information about the treatment of diffuse large B-cell lymphoma.
Treatment options for recurrent diffuse large B-cell lymphoma
The treatment of recurrent diffuse large B-cell lymphoma is the same as the treatment of recurrent Burkitt lymphoma/leukemia. Refer to the Treatment options for recurrent Burkitt lymphoma/leukemia section of this summary for more information.
Treatment options under clinical evaluation for diffuse large B-cell lymphoma
Information about NCI-supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
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.[50,65,66,67]
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 World Health Organization (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:
Primary mediastinal B-cell lymphoma has a distinctive gene expression profile compared with diffuse large B-cell lymphoma; however, its gene expression profile has features similar to those seen in Hodgkin lymphoma.[69,70] Primary mediastinal B-cell lymphoma is also associated with a distinctive constellation of chromosomal aberrations compared with other NHL subtypes. Because primary mediastinal B-cell lymphoma is primarily a cancer of adolescents and young adults, the genomic findings are presented without regard to age.
As the name suggests, 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 superior vena cava 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
Treatment options for primary mediastinal B-cell lymphoma include the following:
Pediatric and adolescent patients with stage III primary mediastinal large B-cell lymphoma fared 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, in the NHL-BFM-95 trial, 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 rates.
Treatment options for refractory or relapsed primary mediastinal B-cell lymphoma
The U.S. Food and Drug Administration granted accelerated approval of pembrolizumab for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma or who have relapsed after two or more previous lines of therapy. The approval was based on data from 53 patients (median age, 33 years; range, 20–61 years). The overall response rate was 41%, which included 12% complete responses and 29% partial responses.
Treatment options under clinical evaluation for primary mediastinal B-cell lymphoma
Lymphoblastic lymphoma comprises approximately 20% of childhood non-Hodgkin lymphoma (NHL).[1,2,3] (Refer to Table 1 for more information about the incidence of lymphoblastic lymphoma by age and sex 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.[3,4]
As opposed to pediatric acute lymphoblastic leukemia, chromosomal abnormalities and the molecular biology of pediatric lymphoblastic lymphoma are not well characterized. The Berlin-Frankfurt-Münster 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 at 6q.[5,6]
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 about 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 acute lymphoblastic leukemia (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 centers on 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 about 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:
Equivalent outcomes were observed for arms A1, B1, A2, and B2.
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) rate higher than 90%.[13,14] 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.[9,10,11]
Patients with high-stage (stage III or stage IV) lymphoblastic lymphoma have long-term survival rates higher than 80%.[9,10,12] Mediastinal radiation is not necessary for patients with mediastinal masses, except in the emergency treatment of symptomatic superior vena cava 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 the treatment of patients with 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 cranial radiation therapy, which has been demonstrated not to be required in T-cell lymphoblastic lymphoma patients.[10,12] In this study, the benefit of adding the cardioprotectant dexrazoxane was tested in a randomized fashion. The addition of dexrazoxane did not affect the outcome and showed cardioprotective benefit on the basis of echocardiographic and laboratory assessments.[Level of evidence: 2A]
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.[12,18,19]
Treatment Options for Recurrent Lymphoblastic Lymphoma
For patients with recurrent or refractory lymphoblastic lymphoma, reports of survival range from 10% to 40%.[18,20]; [Level of evidence: 2A]; [22,23][Level of evidence: 3iiiA] As in patients 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
The following are examples of national and/or institutional clinical trials that are currently being conducted:
All lymphoma patients will receive a three-drug induction (dexamethasone, vincristine, and intravenous [IV] PEG-L-asparaginase) with intrathecal chemotherapy.
The objective for enrolled lymphoma patients is to collect biological data on B-cell lymphoblastic lymphoma and evaluate the effect of dose de-escalation on OS.
Anaplastic large cell lymphoma accounts for approximately 10% of childhood non-Hodgkin lymphoma (NHL) cases. (Refer to Table 1 for more information about the incidence of anaplastic large cell lymphoma by age and sex distribution.)
While the predominant immunophenotype of anaplastic large cell lymphoma is mature T-cell, null-cell disease (i.e., no T-cell, B-cell, or natural killer-cell surface antigen expression) does occur. The World Health Organization (WHO) classifies anaplastic large cell lymphoma as a subtype of peripheral T-cell lymphoma.
All anaplastic large cell lymphoma cases are CD30-positive. More than 90% of pediatric anaplastic large cell lymphoma cases have a chromosomal rearrangement involving the ALK gene. About 85% of these chromosomal rearrangements will be t(2;5)(p23;q35), leading to the expression of the fusion protein NPM-ALK; the other 15% of cases are composed of variant ALK translocations. Anti-ALK immunohistochemical staining pattern is quite specific for the type of ALK translocation. Cytoplasm and nuclear ALK staining is associated with NPM-ALK fusion protein, whereas cytoplasmic staining only of ALK is associated with the variant ALK translocations, as shown in Table 6.
In adults, ALK-positive anaplastic large cell lymphoma is viewed differently from other peripheral T-cell lymphomas because prognosis tends to be superior. Also, adult ALK-negative anaplastic large cell lymphoma patients have an inferior outcome compared with patients who have ALK-positive disease. In children, however, this difference in outcome between ALK-positive and ALK-negative disease has not been demonstrated. In addition, no correlation has been found between outcome and the specific ALK-translocation type.[7,8,9]
In a European 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 (hazard ratio, 2.0; P = .002). The prognostic implication of the small cell variant of anaplastic large cell lymphoma was also shown in the COG-ANHL0131 (NCT00059839) study, despite a different chemotherapy backbone.
Clinically, systemic anaplastic large cell lymphoma has a broad range of presentations. These include involvement of lymph nodes and a variety of extranodal sites, particularly skin and bone and, less often, gastrointestinal tract, lung, pleura, and muscle. Involvement of the central nervous system (CNS) and bone marrow is uncommon.
Anaplastic large cell lymphoma is often associated with systemic symptoms (e.g., fever, weight loss) and a prolonged waxing and waning course, making diagnosis difficult and often delayed. Patients with anaplastic large cell lymphoma may present with signs and symptoms consistent with hemophagocytic lymphohistiocytosis.
There is a subgroup of anaplastic large cell lymphoma patients who have leukemic peripheral blood involvement. These patients usually exhibit significant respiratory distress with diffuse lung infiltrates or pleural effusions and have hepatosplenomegaly.[11,12]
Refer to the Prognosis and Prognostic Factors for Childhood NHL section of this summary for information on prognostic factors for anaplastic large cell lymphoma.
Standard Treatment Options for Anaplastic Large Cell Lymphoma
Children and adolescents with high-stage (stage III or IV) anaplastic large cell lymphoma have a disease-free survival of approximately 60% to 75%.[13,14,15,16,17,18]
It is unclear which treatment strategy is best for anaplastic large cell lymphoma. Current data do not suggest superiority of one treatment regimen over another for these standard treatment options.
Commonly used treatment regimens include the following:
Evidence (treatment of anaplastic large cell lymphoma):
CNS involvement in anaplastic large cell lymphoma is rare at diagnosis. In an international study of systemic childhood anaplastic large cell lymphoma, 12 of 463 patients (2.6%) had CNS involvement, 3 of whom had isolated CNS disease (primary CNS lymphoma). For the CNS-positive group who received multiagent chemotherapy, including high-dose methotrexate, cytarabine, and intrathecal treatment, the EFS was 50% (95% confidence interval [CI], 25%–75%) and OS was 74% (95% CI, 45%–91%) at a median follow-up of 4.1 years. The role of cranial radiation therapy has been difficult to assess.
Treatment Options for Recurrent Anaplastic Large Cell Lymphoma
Unlike mature B-cell or lymphoblastic lymphoma, the prognosis for recurrent or refractory anaplastic large cell lymphoma is 40% to 60%.[25,26,27]
There is no standard approach for the treatment of recurrent/refractory anaplastic large cell lymphoma.
Treatment options for recurrent anaplastic large cell lymphoma include the following:
Although remissions can be achieved with single-agent therapy (e.g., vinblastine, brentuximab, or crizotinib), CNS progressions after therapy have been observed in patients with recurrent anaplastic large cell lymphoma. In one series, four of five patients who developed CNS progressions achieved complete remissions with either radiation therapy or high-dose methotrexate.
Chemotherapy, followed by autologous SCT or allogeneic SCT if remission can be achieved, has been employed in this setting.[26,27,33,34,36]
Evidence (chemotherapy and targeted therapy):
In one study, patients with recurrent anaplastic large cell lymphoma were treated with vinblastine alone, and the following was observed:[Level of evidence: 3iiiA]
In a phase II study of adults and adolescents with CD30-positive cancers, patients were administered a dose of 1.8 mg/kg of brentuximab vedotin every 3 weeks for approximately 1 year. The median age of patients was 52 years (range, 14–76 years). Sixteen of 58 patients (28%) had ALK-positive anaplastic large cell lymphoma, and 42 of 58 patients (72%) had ALK-negative anaplastic large cell lymphoma.
In a phase II study, 17 patients (median age, 11 years) were treated with brentuximab vedotin at a dose of 1.8 mg/kg every 21 days. Twelve patients were ALK positive and five were ALK negative. After treatment with brentuximab vedotin, nine patients then received either autologous or allogeneic transplant.[Level of evidence: 2Div]
Evidence (autologous vs. allogeneic SCT):
Treatment Options Under Clinical Evaluation for Anaplastic Large Cell Lymphoma
The incidence of lymphoproliferative disease or lymphoma is 100-fold higher in immunocompromised children than in the general population. The causes of such immune deficiencies include the following:
Non-Hodgkin lymphoma (NHL) associated with immunodeficiency is usually aggressive, with most cases occurring in extralymphatic sites and a higher incidence of primary central nervous system (CNS) involvement.[1,2,3,4]
Lymphoproliferative Disease Associated With Primary Immunodeficiency
Lymphoproliferative disease observed in primary immunodeficiency usually shows an aggressive mature B-cell phenotype and large cell histology. Mature T-cell lymphoma and anaplastic large cell lymphoma have been observed. Children with primary immunodeficiency and NHL are more likely to have high-stage disease and present with symptoms related to extranodal disease, particularly in the gastrointestinal tract and CNS.
Treatment options for lymphoproliferative disease associated with primary immunodeficiency
Treatment options for lymphoproliferative disease associated with primary immunodeficiency include the following:
Patients with primary immunodeficiency can achieve complete and durable remissions with standard chemotherapy regimens for NHL, although toxicity is increased.; [Level of evidence: 3iiiA] Recurrences in these patients are common and may not represent the same clonal disease. Immunologic correction through allogeneic SCT is often required to prevent recurrences.
NHL Associated With DNA Repair Defect Syndromes
The incidence of NHL is increased in patients with DNA repair syndromes, including ataxia-telangiectasia, Nijmegen breakage syndrome, and constitutional mismatch repair deficiency. Aggressive mature B-cell NHL accounts for the majority of NHL seen in patients with ataxia-telangiectasia (84%) and Nijmegen breakage syndrome (46%), and T-cell lymphoblastic lymphoma (81%) is observed in patients with constitutional mismatch repair deficiency.
Treatment options for NHL associated with DNA repair defect syndromes
Patients with DNA repair defects are particularly difficult to treat.[7,8] Overall 5-year to 10-year survival is poor, at 40% to 60%.[5,9]
Treatment options for NHL associated with DNA repair defect syndromes include the following:
Cytotoxic agents produce much more toxicity and greatly increase the risk of subsequent neoplasms in these patients. One review reported that dose reduction of chemotherapeutic drugs was effective and reduced toxic effects, but did not prevent subsequent neoplasms (10-year incidence, 25%).
NHL in children with HIV often presents with fever, weight loss, and symptoms related to extranodal disease, such as abdominal pain or CNS symptoms. Most childhood HIV-related NHL is of mature B-cell phenotype but with a spectrum, including primary effusion lymphoma, primary CNS lymphoma, mucosa-associated lymphoid tissue (MALT), Burkitt lymphoma/leukemia, and diffuse large B-cell lymphoma.[10,11]
HIV-associated NHL can be broadly grouped into the following three subcategories:
Highly active antiretroviral therapy has decreased the incidence of NHL in HIV-positive individuals, particularly for primary CNS lymphoma cases.[13,14]
Treatment options for HIV-associated NHL
Treatment options for HIV-associated NHL include the following:
In the era of highly active antiretroviral therapy, children with HIV and NHL are treated with standard chemotherapy regimens for NHL, but careful attention to prophylaxis against, and early detection of, infection is warranted.[1,13,14] Although the number of pediatric patients with HIV-associated NHL is too small to perform meaningful clinical trials, studies of adult patients support the addition of rituximab to standard regimens. Treatment of recurrent disease is based on histology using standard approaches.
Posttransplant Lymphoproliferative Disease (PTLD)
PTLD represents a spectrum of clinically and morphologically heterogeneous lymphoid proliferations. Essentially all PTLDs after HSCT are associated with EBV, but EBV-negative PTLD can be seen after solid organ transplant. While most PTLDs are of B-cell phenotype, approximately 10% are mature (peripheral) T-cell lymphomas. The B-cell stimulation by EBV may result in multiple clones of proliferating B cells, and both polymorphic and monomorphic histologies may be present in a patient, even within the same lesion of PTLD. Thus, histology of a single biopsied site may not be representative of the entire disease process.
The World Health Organization (WHO) has classified PTLD into the following three subtypes:
EBV lymphoproliferative disease posttransplant may manifest as isolated hepatitis, lymphoid interstitial pneumonitis, meningoencephalitis, or an infectious mononucleosis-like syndrome. The definition of PTLD is frequently limited to lymphomatous lesions (low stage or high stage), which are often extranodal (frequently in the allograft). PTLD may less commonly present as a rapidly progressive, high-stage disease that clinically resembles septic shock, which has a poor prognosis; however, the use of rituximab and low-dose chemotherapy may improve the outcome.[18,19] U.S. transplant and cancer registries show that PTLD accounts for about 3% of all pediatric NHL diagnoses; and that 65% of PTLDs are diffuse large B-cell lymphoma histology, and 9% are Burkitt histology.
Treatment options for PTLD
Treatment options for PTLD include the following:
First-line therapy for PTLD is to reduce immunosuppressive therapy as much as possible.[25,26] However, this may not be possible because of the increased risk of organ rejection or graft-versus-host disease (GVHD).
Rituximab, an anti-CD20 antibody, has been used in the posttransplant setting. In a study of 144 children and adults who developed post-HSCT PTLD, it was reported that approximately 70% of patients who received rituximab survived. Survival was also associated with reduction of immunosuppression, but older age, extranodal disease, and acute GVHD were predictors of poor outcome.[Level of evidence: 3iiiA] Rituximab as a single agent to treat PTLD after organ transplant has demonstrated efficacy in adult patients, but data are lacking in pediatric patients. (Refer to the Posttransplantation Lymphoproliferative Disorder (PTLD) section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)
Low-intensity chemotherapy has been effective in EBV-positive, CD20-positive B-lineage PTLD.[19,27] An event-free survival of 67% was demonstrated in a Children's Oncology Group study using rituximab plus cyclophosphamide and prednisone in children with PTLD after solid organ transplantation in whom immune suppression was reduced.[Level of evidence: 2A] Other studies suggest that modified conventional lymphoma therapy is effective for PTLD with MYC translocations and Burkitt histology.[23,24][Level of evidence: 3iiDiii] Patients with T-cell or Hodgkin-like PTLD are usually treated with standard lymphoma-specific chemotherapy regimens.[28,29,30,31]
Antirejection therapy is usually decreased or discontinued when chemotherapy is given to avoid excessive toxicity. There are no data to guide the re-initiation of immunosuppressive therapy after chemotherapy treatment. There is little evidence of benefit for chemotherapy after SCT.
Adoptive immunotherapy with either donor lymphocytes or ex vivo –generated EBV-specific cytotoxic T-cells have been effective in treating PTLD after blood or bone marrow transplant.[32,33] Although this approach has been demonstrated to be feasible in patients with PTLD after solid organ transplant, it has not been demonstrated to be as effective or practical.
Treatment options under clinical evaluation for PTLD
Low-grade or intermediate-grade mature B-cell lymphomas—such as small lymphocytic lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma, mantle cell lymphoma, myeloma, or follicular cell lymphoma—are rarely seen in children. The most recent World Health Organization (WHO) classification has identified pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma as entities separate from their adult counterparts.
In an attempt to learn more about the clinical and pathologic features of these rare types of pediatric non-Hodgkin lymphoma (NHL), the Children's Oncology Group (COG) opened a registry study (COG-ANHL04B1). This study banks tissue for pathobiology studies and collects limited data on clinical presentation and outcome of therapy.
Pediatric-type Follicular Lymphoma
Pediatric-type follicular lymphoma is a disease that genetically and clinically differs from its adult counterpart and is recognized by the WHO classification as a separate entity from follicular lymphoma observed commonly in adults. The genetic hallmark of follicular lymphoma is t(14;18)(q32;q21) involving BCL2; however, this translocation must be excluded to make the diagnosis of pediatric-type follicular lymphoma.[1,3,4,5] Pediatric-type follicular lymphoma predominantly occurs in males, is associated with a high proliferation rate, and is more likely to be localized disease.[3,6,7] In pediatric-type follicular lymphoma, a high-grade component (i.e., grade 3 with high proliferative index such as Ki-67 expression of >30%) resembling diffuse large B-cell lymphoma can frequently be detected at initial diagnosis but does not indicate a more aggressive clinical course in children. Unlike follicular lymphoma in adults, pediatric-type follicular lymphoma does not transform to diffuse large B-cell lymphoma.[1,3,5,7,8] Limited-stage disease is observed with pediatric-type follicular lymphoma, with cervical lymph nodes and tonsils as common sites, but disease has also occurred in extranodal sites such as the testis, kidney, gastrointestinal tract, and parotid gland.[3,4,5,8,9,10]
Pediatric-type follicular lymphoma appears to be molecularly distinct from follicular lymphoma that is more commonly observed in adults. The pediatric type lacks BCL2 rearrangements; BCL6 and MYC rearrangements are also not present. The TNFSFR14 mutations are common in pediatric-type follicular lymphoma, and they appear to occur with similar frequency in adult follicular lymphoma.[7,11] However, MAP2K1 mutations, which are uncommon in adults, are observed in as many as 43% of pediatric-type follicular lymphomas. Other genes (e.g., MAPK1 and RRAS) have been found to be mutated in cases without MAP2K1 mutations, suggesting that the MAP kinase pathway is important in the pathogenesis of pediatric-type follicular lymphoma.[12,13] Translocations of the immunoglobulin locus and IRF4, mutations in IRF8, and abnormalities in chromosome 1p have also been observed in pediatric-type follicular lymphoma.[11,14,15]
Treatment options for pediatric-type follicular lymphoma
Pediatric-type follicular lymphoma is rare in children, with only case reports and small case series to guide therapy. The outcome of pediatric-type follicular lymphoma is excellent, with an event-free survival (EFS) of about 95%.[3,5,6,7,8,10] Unlike in adult follicular lymphoma, the clinical course is not dominated by relapses.[3,5,8,9]
Treatment options for pediatric-type follicular lymphoma include the following:
Studies suggest that for children with stage I disease who had a complete resection, a watch-and-wait approach without chemotherapy may be indicated. Patients with higher-stage disease also have a favorable outcome with low-intensity and intermediate-intensity chemotherapy, with 94% EFS and 100% overall survival (OS) rates with a 2-year median follow-up.[2,3,6,7] Although the number of pediatric patients with pediatric follicular-type lymphoma is too small to perform meaningful clinical trials, studies of adult patients with follicular lymphoma support the addition of rituximab to standard regimens (refer to the Follicular Lymphoma section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information).
For patients with BCL2-rearranged tumors, treatment similar to that of adult patients with follicular lymphoma is administered (refer to the Follicular Lymphoma section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information).
Marginal Zone Lymphoma (Including MALT Lymphoma)
Marginal zone lymphoma is a type of indolent lymphoma that is rare in pediatric patients. Marginal zone lymphoma can present as nodal or extranodal disease and almost always as low-stage (stage I or stage II) disease. It is unclear whether the marginal zone lymphoma that is observed in pediatric patients is clinicopathologically different from the disease that is observed in adults. Most extranodal marginal zone lymphoma in pediatrics presents as MALT lymphoma and may be associated with Helicobacter pylori (gastrointestinal) or Chlamydophila psittaci (conjunctival), previously called Chlamydia psittaci.[16,17]
Treatment options for marginal zone lymphoma (including MALT lymphoma)
Treatment options for marginal zone lymphoma (including MALT lymphoma) include the following:
Most pediatric marginal zone lymphomas require no more than local therapy involving curative surgery and/or radiation therapy.[16,19] Treatment of MALT lymphoma of the gastric mucosa may also include antibiotic therapy, which is considered standard treatment in adults. However, the use of antibiotic therapy in children has not been well studied because there are so few cases.
Evidence (treatment of marginal zone lymphoma):
Although the number of pediatric patients with MALT lymphoma is too small to perform meaningful clinical trials, studies of adult patients support the use of rituximab with or without chemotherapy (refer to the Marginal Zone Lymphoma section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information).
Intralesional interferon-alpha for conjunctival MALT lymphoma has been described.
Primary Central Nervous System (CNS) Lymphoma
Other types of NHL that may be rare in adults and are exceedingly rare in pediatric patients include primary CNS lymphoma. Because of the small numbers of patients, it is difficult to ascertain whether the disease observed in children is the same as the disease observed in adults.
Reports suggest that the outcome of pediatric patients with primary CNS lymphoma (OS, 70%–80%) may be superior to that of adults with primary CNS lymphoma.[22,23,24,25]
Most children have diffuse large B-cell lymphoma, although other histologies can be observed.
Treatment options for primary CNS lymphoma
Treatment options for primary CNS lymphoma include the following:
Therapy with high-dose intravenous methotrexate and cytosine arabinoside is the most successful, and intrathecal chemotherapy may be needed only when malignant cells are present in the cerebrospinal fluid.
There is a case report of repeated doses of rituximab, both intravenous and intraventricular, being administered to a 14-year-old boy with refractory primary CNS lymphoma, with an excellent result. This apparently good outcome needs to be confirmed, and similar results have not been observed in adults. It is generally believed that rituximab does not cross the blood-brain barrier.
(Refer to the PDQ summary on Primary CNS Lymphoma Treatment for more information about treatment options for non–AIDS-related primary CNS lymphoma.)
Peripheral T-cell Lymphoma
Peripheral T-cell lymphoma, excluding anaplastic large cell lymphoma, is rare in children.
Mature T-cell/natural killer (NK)–cell lymphoma or peripheral T-cell lymphoma has a postthymic phenotype (e.g., terminal deoxynucleotidyl transferase negative), usually expresses CD4 or CD8, and has rearrangement of T-cell receptor genes, either alpha-beta and/or gamma-delta chains. The most common phenotype observed in children is peripheral T-cell lymphoma–not otherwise specified, although angioimmunoblastic lymphoma, enteropathy-associated lymphoma (associated with celiac disease), subcutaneous panniculitis-like lymphoma, angiocentric lymphoma, and extranodal NK/T-cell peripheral T-cell lymphoma have been reported.[28,29,30,31,32]
A Japanese study described extranodal NK/T-cell lymphoma–nasal type as the most common peripheral T-cell lymphoma subtype among Japanese children (10 of 21 peripheral T-cell lymphoma cases). In adults, extranodal NK/T-cell lymphoma–nasal type is generally Epstein-Barr virus (EBV) positive, and 60% of the cases observed in Japanese children were EBV positive.
Although very rare, gamma-delta hepatosplenic T-cell lymphoma may be seen in children. This tumor has also been associated with children and adolescents who have Crohn disease and have been treated with immunosuppressive therapy; this lymphoma has been fatal in all cases.
Treatment options for peripheral T-cell lymphoma
Optimal therapy for peripheral T-cell lymphoma is unclear for both pediatric and adult patients.
Treatment options for peripheral T-cell lymphoma include the following:
There have been four retrospective analyses of treatment and outcome for pediatric patients with peripheral T-cell lymphoma. The studies have reported the following:
Cutaneous T-cell Lymphoma
Primary cutaneous lymphomas are very rare in pediatric patients (1 case per 1 million person-years), but the incidence increases in adolescents and young adults. All histologies of NHL have been observed to involve the skin. More than 80% of cutaneous lymphomas are T-cell or NK-cell phenotype.
Subcutaneous panniculitic T-cell lymphomas are very rare lymphomas with panniculitis-like infiltration of subcutaneous tissue by cytotoxic T-cells.[36,37,38] Subcutaneous panniculitic T-cell lymphoma can be observed with malignant T cells, expressing alpha-beta chain T-cell receptor or gamma-delta T-cell receptor rearrangements.
In adults, the gamma-delta subtype of subcutaneous panniculitic T-cell lymphoma is associated with a more aggressive course and carries a worse prognosis than does the alpha-beta subtype of subcutaneous panniculitic T-cell lymphoma. Morbidity and mortality are frequently related to the development of hemophagocytic syndrome, which was reported in one series in adults to occur in 17% of patients with alpha-beta subcutaneous panniculitic T-cell lymphoma and in 45% of patients with gamma-delta subcutaneous panniculitic T-cell lymphoma. The 5-year OS rate is 82% for alpha-beta subcutaneous panniculitic T-cell lymphoma and 11% for gamma-delta subcutaneous panniculitic T-cell lymphoma. Subcutaneous panniculitic T-cell lymphoma is heterogeneous in the pediatric age group and does not necessarily follow the course observed in adults. In a series of 11 pediatric patients with subcutaneous panniculitis-like T-cell lymphoma, most presented with multifocal disease (often on the trunk) and systemic symptoms (fever), and there was a frequent association with hemophagocytic syndrome.
The diagnosis of primary cutaneous anaplastic large cell lymphoma can be difficult to distinguish pathologically from more benign diseases such as lymphomatoid papulosis. Primary cutaneous lymphomas are now thought to represent a spectrum of disorders, distinguished by clinical presentation.
Mycosis fungoides is rarely reported in children and adolescents,[42,43,44] accounting for about 2% of all cases. Patients present with low-stage disease, and it appears that the hypopigmented, CD8-positive variant of mycosis fungoides is more common in children than in adults.; [Level of evidence: 3iiiDii]
Treatment options for cutaneous T-cell lymphoma
Because of the rarity of cutaneous T-cell lymphoma, no standard treatments have been established. Management and treatment of cutaneous T-cell lymphoma should be individualized and, in some cases, watchful waiting may be appropriate. Treatment may only be necessary if hemophagocytic syndrome develops.
The best treatment for T-cell lymphomas with primarily pannicular involvement is not known. Treatment options include high-dose steroids, bexarotene, denileukin diftitox, multiagent chemotherapy, and hematopoietic SCT.[38,47,48,49,50,51,52]
An oral retinoid (bexarotene) has been reported to be active against subcutaneous panniculitis-like T-cell lymphomas in a series of 15 patients from three institutions. In a series of 11 pediatric patients, aggressive polychemotherapy was used in all patients. Nine of 11 patients sustained clinical remission, with a median follow-up of 3.5 years. In general, however, the optimal therapy for non–anaplastic large cell lymphoma cutaneous T-cell lymphoma in childhood is unclear.
Primary cutaneous anaplastic large cell lymphoma usually does not express ALK and may be treated successfully with surgical resection and/or local radiation therapy without systemic chemotherapy. There are reports of surgery alone also being curative for ALK-positive cutaneous anaplastic large cell lymphoma, but extensive staging and vigilant follow-up is required.[54,55]
Mycosis fungoides occurring in pediatric patients may respond to various therapies, including topical steroids, retinoids, radiation therapy, or phototherapy (e.g., narrow-band ultraviolet B treatment), but remission may not be durable.[45,56,57,58]
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Histopathologic and Molecular Classification of Childhood Non-Hodgkin Lymphoma (NHL)
Added text to state that less common entities of mature B-cell NHL included in the World Health Organization (WHO) 2017 classification that occur in children include Burkitt-like lymphoma with 11q alteration, high-grade B-cell lymphoma–not otherwise specified (NOS), and large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) (cited Swerdlow et al. as reference 4).
Added text to state that LBCL-IRF4 is included in the WHO 2017 classification as a provisional entity.
Aggressive Mature B-cell NHL
The Burkitt Lymphoma/Leukemia subsection was renamed from Burkitt and Burkitt-like Lymphoma/Leukemia.
Revised text to state that for recurrent or refractory aggressive mature B-cell NHL, reported survival ranges between 10% to 50%, but in the largest series survival is about 20%. Also revised text to add no failure in bone marrow as a prognostic factor for better survival (cited Cairo et al. as reference 36).
Added Rigaud et al. as reference 44. Also added text to state that if a complete remission was reported, survival ranges between 30% to 75%, albeit all series have a small number of patients.
Added text to state that the WHO classification system categorizes diffuse large B-cell lymphoma on the basis of molecular characteristics into the germinal center B-cell subtype and the activated B-cell subtype, with the remaining classes being classified as diffuse large B-cell lymphoma, NOS.
Added Ramis-Zaldivar as reference 54.
Added text about a report that included 31 pediatric patients with diffuse large B-cell lymphoma, NOS, in which most patients showed a germinal center phenotype, and the genomic alterations resembled those of adult germinal center B-cell diffuse large B-cell lymphoma. Among this group of patients, MYC rearrangements were detected in 3 patients, and 5 of 25 cases were Epstein-Barr virus positive.
Added text about the characteristics of large B-cell lymphoma with IRF4 rearrangement, which was added as a provisional entity in the 2017 revision of the WHO classification of lymphoid neoplasms (cited Pittaluga et al., Chisholm et al., and Liu et al. as references 59, 60, and 62, respectively).
Added text about the characteristics of high-grade B-cell lymphoma, NOS, which is defined as a clinically aggressive B-cell lymphoma that lacks MYC plus BCL2 and/or BCL6 rearrangements and that does not meet criteria for diffuse large B-cell lymphoma, NOS or Burkitt lymphoma (cited Kluin et al. as reference 63).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
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.
Reviewers and Updates
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).
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Non-Hodgkin Lymphoma Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Non-Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/lymphoma/hp/child-nhl-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389181]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.
Last Revised: 2020-03-20
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