Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood non-Hodgkin lymphoma. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.

Information about the following is included in this summary:

• Incidence.
• Cellular classification.
• Clinical presentation.
• Stage information.
• Treatment options.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

In the summary, treatments are described as “standard” or “conventional” and “under clinical evaluation.” These designations should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less-technical language, and in Spanish.

General Information

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.

Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. Refer to the PDQ Supportive 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.^[1] At these pediatric cancer centers, clinical trials are available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. 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 Late Effects of Treatment for Childhood Cancer summary for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.

Lymphoma (Hodgkin and non-Hodgkin [NHL]) is the third most common childhood malignancy, and NHL accounts for approximately 7% of cancers in children younger than 20 years.^[2][3] In the United States, about 800 new cases of NHL are diagnosed each year. The incidence is approximately 10 per 1,000,000. Although there is no sharp age peak, NHL occurs most commonly in the second decade of life, and occurs less frequently in children younger than 3 years. The incidence of NHL is increasing overall, and there is a slight increase in the incidence for those aged 15 to 19 years; however, the incidence of NHL for children younger than 15 years has remained constant over the past several decades.^[2] The incidence of NHL is higher in Caucasians than in African Americans, and NHL is more common in males than in females.^[2][4] Immunodeficiency, both congenital and acquired (HIV infection or posttransplant), increases the risk of NHL. Epstein-Barr virus (EBV) is associated with most cases of NHL seen in the immunodeficient population.^[2][3]

With current treatments, about 80% of children and adolescents with NHL will survive at least 5 years, though outcome is variable depending on a number of factors.^[4] The most important prognostic determinant, given optimal therapy, is the extent of disease at diagnosis as determined by pretreatment staging. Patients with localized 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.^[3][5][6] Patients with NHL arising in bone have an excellent prognosis regardless of histology,^[7][8] and testicular disease does not affect prognosis.^[9][10] Unlike adults, children and adolescents with nonlymphoblastic NHL involving the mediastinum have an inferior outcome, as compared with other sites of disease.^[4][11][12] Patients with intrathoracic or extensive intra-abdominal disease and patients with bone marrow or central nervous system involvement at diagnosis require intensive therapy.^{[3][4][6][13]} These intensive therapies have improved the outcome for patients with disseminated or advanced-stage disease.

Information about ongoing clinical trials is available from the NCI Web site.

References

Cellular Classification

Cellular Classification and Clinical Presentation

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] Classification of NHL in childhood and adolescence has historically been based on clinical behavior and response to treatment. A study by the Children’s Cancer Group (CCG) demonstrated that the outcome for lymphoblastic NHL was superior with longer leukemia-like therapy consisting of induction, consolidation, and maintenance, while nonlymphoblastic NHL (Burkitt and large cell) had superior outcome with short, intensive, pulsed therapy.^[3] In general, these treatment principles still apply.

The World Health Organization (WHO) has classified NHL on the basis of the following: (1) phenotype (i.e., B-lineage, T-lineage, or natural killer [NK] cell lineage); and (2) differentiation ( i.e., precursor versus mature/peripheral).^[1] On the basis of clinical response to treatment, NHL of childhood and adolescence currently falls into three therapeutically relevant categories: (1) B-cell NHL (Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma); (2) lymphoblastic lymphoma (primarily precursor T-cell lymphoma and, less frequently, precursor B-cell lymphoma); and (3) anaplastic large cell lymphoma (T-cell or null-cell lymphomas). NHL associated with immunodeficiency generally has a mature B-cell phenotype and is more often of large cell than Burkitt histology.^[2] Posttransplant lymphoproliferative diseases (PTLDs) are classified according to standard NHL nomenclature as (1) early lesions, (2) polymorphic, and (3) monomorphic.^[1]

Other types of lymphomas are more commonly seen in adults and occur rarely in children. (Refer to the PDQ summaries on the treatment of Adult Non-Hodgkin's Lymphoma, Primary CNS Lymphoma, and Mycosis Fungoides and the Sézary Syndrome for more information.)

Each type of childhood NHL is associated with distinctive molecular biological characteristics, which are outlined in the following table. The Revised European-American Lymphoma Classification (REAL) and the WHO ^[1] are the most current NHL classifications utilized and are shown below.^[2] The Working Formulation is also listed for reference. The WHO Classification applies the principles of the REAL Classification and focuses on the specific type of lymphoma for therapy purposes. The remainder of the categories, for the most part, do not pertain to pediatric NHL and are not shown.

Table 1: Major Histopathological Categories of Non-Hodgkin Lymphoma in Children and Adolescents*

Burkitt and Burkitt-like lymphoma/leukemia

Burkitt and Burkitt-like lymphoma/leukemia accounts for about 50% of childhood NHL and exhibits consistent, aggressive clinical behavior.^[2][4][5] The malignant cells show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase (TdT). These malignant cells usually express surface immunoglobulin, most bearing surface immunoglobulin M with either kappa or lambda light chains. A variety of additional B-cell markers (e.g., CD20, CD22) are usually present, and almost all childhood Burkitt/Burkitt-like lymphoma/leukemia express CALLA (CD10). About 25% contain Epstein-Barr virus (EBV) genomes. 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 gene to immunoglobulin locus regulatory elements, resulting in the inappropriate expression of c-myc, the gene involved in cellular proliferation. Pediatric Burkitt lymphoma patients whose tumors also contain cytogenetic abnormalities of 13q and 22q have a markedly poor survival on current chemotherapy protocols.^[2][6]

The distinction between Burkitt and Burkitt-like lymphoma/leukemia is controversial. Burkitt lymphoma consists of uniform, small, noncleaved cells, whereas Burkitt-like lymphoma is a highly disputed diagnosis among pathologists owing to features that are consistent with diffuse large B-cell lymphoma (DLBCL).^[1][2] A study assessing gene expression profiles compared to pathologic diagnosis by an expert panel demonstrated that the gene expression profile agreed with the pathologic review, with 19 of 20 Burkitt-like cases being molecularly similar to Burkitt lymphoma. Of 20 cases of pathologically called DLBCL, however, seven cases had gene expression profiles consistent with Burkitt lymphoma.^[2][7] Cytogenetic evidence of c-myc rearrangement is the gold standard for diagnosis of Burkitt lymphoma. For cases in which cytogenetic analysis is not available, the WHO has recommended that the Burkitt-like diagnosis be reserved for lymphoma resembling Burkitt lymphoma or with more pleomorphism, large cells, and a proliferation fraction (i.e., Ki-67[+] of at least 99%).^[1] Despite the histologic differences, Burkitt and Burkitt-like lymphoma/leukemia are clinically very aggressive and are treated with very aggressive regimens.

The two most common primary sites of disease are the abdomen and head and neck region.^[8] Other sites of involvement include testes, bone, peripheral lymph nodes, skin, bone marrow, and central nervous system (CNS).

Diffuse large B-cell lymphoma

DLBCL is a mature B-cell neoplasm that represents 10% to 20% of pediatric NHL. DLBCL occurs more frequently during the second decade of life than during the first.^[4][5][9] While classification systems have described morphologic variants (e.g., immunoblastic, centroblastic) of DLBCL, the WHO classification system for hematological malignancies does not recommend morphologic subclassification.^[1] Pediatric DLBCL may present clinically similar to Burkitt or Burkitt-like lymphoma, though it is more often localized and less often involves the bone marrow or CNS.^[5][10]

Nonmediastinal DLBCL in children and adolescents differs biologically from DLBCL in adults. Pediatric DLBCL belongs primarily to the germinal center B-cell type, as assessed by immunohistochemical analysis of selected proteins found in normal germinal center B cells.^[9] Unlike adult DLBCL of the germinal center B-cell type, in which the t(14;18) translocation involving the immunoglobulin heavy-chain gene and the BCL2 gene is commonly observed, pediatric DLBCL rarely demonstrates the t(14;18) translocation.^[2][9] Outcomes for children with DLBCL are more favorable than those observed in adults, with overall 5-year event-free survival (EFS) rates of approximately 90% in children.^{[11][12][13][14]}

About 20% of pediatric DLBCL presents as primary mediastinal disease (primary mediastinal B-cell lymphoma [PMBCL]). This presentation is more common in older children and adolescents and is associated with an inferior outcome compared with other pediatric DLBCL.^{[5][10][13][15][16]} PMBCL is associated with distinctive chromosomal aberrations (gains in chromosome 9p and 2p in regions that involve JAK2 and c-rel, respectively) ^[16] and commonly shows inactivation of SOCS1 by either mutation or gene deletion.^[17][18] PMBCL also has a distinctive gene expression profile in comparison with other DLBCL, suggesting a close relationship of PMBCL with Hodgkin lymphoma.^[19][20]

Lymphoblastic lymphoma

Lymphoblastic lymphoma makes up approximately 20% of childhood NHL.^[4][5] Lymphoblastic lymphomas are usually positive for TdT, with more than 75% having a T-cell immunophenotype and the remainder having a precursor B-cell phenotype.^[21] Chromosomal abnormalities are not well characterized in patients with lymphoblastic lymphoma.

Nearly 75% of patients with lymphoblastic lymphoma have an anterior mediastinal mass and may present with symptoms of dyspnea, wheezing, stridor, dysphagia, or swelling of the head and neck. Pleural 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, CNS, abdominal organs (but rarely bowel), and occasionally other sites such as lymphoid tissue of Waldeyer ring and testes. Abdominal involvement is rare compared with Burkitt lymphoma. Localized lymphoblastic lymphoma may occur in lymph nodes, bone, and subcutaneous tissue. Lymphoblastic lymphoma within the mediastinum is not considered localized disease.

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 leukemia, and those with fewer than 25% marrow blasts are considered to have lymphoma. It is not yet clear whether these arbitrary definitions are biologically distinct or relevant for treatment design.

Anaplastic large cell lymphoma

Anaplastic large cell lymphoma (ALCL) accounts for approximately 10% of childhood NHL.^[5] While the predominant immunophenotype of ALCL is mature T-cell, null-cell disease (i.e., no T-cell, B-cell, or NK-cell surface antigen expression) does occur. More than 90% of ALCL cases are CD30-positive and have the translocation t(2;5)(p23;q35) leading to the expression of the fusion protein NPM/ALK, though variant ALK translocations have been reported.^[22] Clinically, ALCL has a broad range of presentations, including 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 CNS and bone marrow is uncommon. However, in a retrospective subset analysis, there was evidence that submicroscopic bone marrow and peripheral blood involvement, detected by reverse transcriptase-polymerase chain reaction (RT-PCR) from NPM-ALK, were found in approximately 50% of patients and correlated with clinical stage;^[23] marrow involvement detected by PCR was associated with a 50% cumulative incidence of relapse. ALCL is often associated with systemic symptoms (e.g., fever, weight loss) and a prolonged waxing and waning course, making diagnosis difficult and often delayed. There is a subgroup of ALCL with leukemic peripheral blood involvement. These patients usually exhibit significant respiratory distress with diffuse lung infiltrates or pleural effusions and have hepatosplenomegaly. Most of these cases have an aberrant T-cell immunophenotype with frequent expression of myeloid antigens. Patients in this ALCL subgroup may require more aggressive therapy.^[24][25] Patients with ALCL may present with signs and symptoms consistent with hemophagocytic lymphohistiocytosis (HLH), but have mediastinal or other adenopathy that, when biopsied, is diagnostic of ALCL.^[26]

Lymphoproliferative disease associated with immunodeficiency in children

The incidence of lymphoproliferative disease or lymphoma is 100-fold higher in immunocompromised children than in the general population. The cause of such immune deficiencies may be a genetically inherited defect, secondary to HIV infection, or iatrogenic following transplantation (solid organ transplantation or allogeneic hematopoietic stem cell transplantation [HSCT]). EBV is associated with most of these tumors, but some tumors are not associated with any infectious agent.

NHL associated with HIV is usually aggressive, with most cases occurring in extralymphatic sites.^[27] HIV-associated NHL can be broadly grouped into three subcategories: systemic (nodal and extranodal), primary CNS lymphoma (PCNSL), and body cavity–based lymphoma, also referred to as primary effusion lymphoma (PEL). Approximately 80% of all NHL in HIV patients is considered to be systemic.^[27] PEL, a unique lymphomatous effusion associated with the human herpesvirus-8 (HHV8) gene or Kaposi sarcoma herpesvirus, is primarily observed in adults infected with HIV but has been reported in HIV-infected children.^[28] Highly active antiretroviral therapy has decreased the incidence of NHL in HIV-positive individuals, particularly for PCNSL cases.^[29] Most childhood HIV-related NHL is of mature B-cell phenotype but with a spectrum including PEL, PCSNL, mucosa-associated lymphoid tissue (MALT) ^[30], Burkitt lymphoma ^[31], and diffuse large cell lymphoma. Most NHL in children with HIV present with fever, weight loss, and symptoms related to extranodal disease, such as abdominal pain or CNS symptoms.^[27]

NHL observed in primary immunodeficiency usually shows a mature B-cell phenotype and large cell histology. Mature T-cell and anaplastic large cell lymphoma have been observed.^[32] Children with primary immunodeficiency and NHL are more likely to have disseminated disease and present with symptoms related to extranodal disease, particularly the gastrointestinal tract and CNS.^[32]

Posttransplant lymphoproliferative disease (PTLD) represents a spectrum of clinically and morphologically heterogeneous lymphoid proliferations. Essentially all PTLD following HSCT is associated with EBV, but EBV-negative PTLD can be seen following solid organ transplant. The WHO has classified PTLD into three subtypes: early lesions, polymorphic PTLD, and monomorphic PTLD.^[1] Early lesions show germinal center expansion but tissue architecture remains normal. Presence of infiltrating T cells, disruption of nodal architecture, and necrosis distinguish polymorphic PTLD from early lesions. Histologies observed in the monomorphic subtype are similar to those observed in NHL, with diffuse large B-cell lymphoma being the most common histology, followed by Burkitt lymphoma, with myeloma or plasmacytoma occurring rarely. The B-cell stimulation by EBV may result in multiple clones of proliferating B cells, and both polymorphous and monomorphous histologies may be present in a patient, even within the same lesion of PTLD.^[33] Thus, histology of a single biopsied site may not be representative of the entire disease process. Not all PTLD is B-cell phenotype.^[1] 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 (localized or diffuse), which are often extranodal (frequently in the allograft).^[34] Although less common, PTLD may present as a rapidly progressive, disseminated disease that clinically resembles septic shock, which almost always results in death despite therapy.^[35]

Rare non-Hodgkin lymphoma occurring in children

Mature T-cell and NK-cell NHL are much less common in children than in adults. Mature B-cell lymphomas such as small lymphocytic, MALT, mantle cell lymphoma, myeloma, or follicular cell lymphoma are also rarely seen in children. It is unclear whether these histologies observed in children are the same diseases as those seen in adults.^[36] For example, follicular lymphoma observed in children express bcl-2 only in a small number of cases.^[37] However, other diseases appear to reflect the disease observed in adult patients. For example, MALT lymphomas observed in pediatric patients usually present as localized disease and are associated with H. pylori and require no more than local therapy of surgery and/or radiation therapy to cure.^[36]

Other types of NHL may be rare in adults and are exceedingly rare in pediatric patients, such as primary cutaneous and primary CNS lymphomas. Due to small numbers, it is difficult to ascertain if the disease oberved in children is the same as in adults and, therefore, it is difficult to determine optimal therapy. Reports suggest that the outcome of pediatric patients with primary CNS lymphoma may be superior to that of adults with primary CNS lymphoma. These reports suggest that long-term survival can be achieved without cranial irradiation.^[38][39] One report showed that most of the children had diffuse large B-cell lymphoma or ALCL. Results of this study showed that therapy with high-dose intravenous methotrexate and cytosine arabinoside was most successful and that intrathecal chemotherapy may be needed only when malignant cells are present in the cerebral spinal fluid.^[39]

In an attempt to learn more about the clinical and pathologic features of these types of NHL seen rarely in children, the Children’s Oncology Group (COG) has opened a registry study—ANHL04B1. This study banks tissue for pathobiology studies and collects limited data on clinical presentation and outcome to therapy.

Stage Information

The most widely used staging scheme for childhood non-Hodgkin lymphoma (NHL) is that of the St. Jude Children’s Research Hospital (Murphy Staging).^[1]

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 bone marrow and/or central nervous system (CNS) disease 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 with 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 any other NHL, the definition of CNS disease is any malignant cell present in the CSF regardless of cell count. The Berlin-Frankfurt-Munster (BFM) Group analyzed the prevalence, clinical pattern, and outcome of CNS involvement in NHL in over 2,500 patients.^[2] Overall, CNS involvement was diagnosed in 6% of patients. Involvement by cell type was as follows:

• Burkitt lymphoma/leukemia: 8.8%
• Precursor B-cell lymphoblastic lymphoma: 5.4%
• Anaplastic large cell lymphoma: 3.3%
• T-cell lymphoblastic lymphoma: 3.7%
• Diffuse large B-cell lymphoma: 2.6%
• Primary mediastinal large B-cell lymphoma: 0%

The probability of event-free survival (EFS) at 6 years for CNS-positive patients was 64% compared with 86% for CNS-negative patients. Presence of CNS involvement did not impact outcome for T-cell lymphoblastic lymphoma patients, but had significant negative impact on patients with Burkitt lymphoma/leukemia.^[2]

As with histologic classification, there exist several different staging schemes for childhood NHL; none is perfect. For example, in the French Society of Pediatric Oncology and most recent international French-American-British study for B-lineage NHL, Group A is completely resected stage I and II disease; Group C is disease with leukemic disease (>25% marrow involvement) and/or CNS disease; and Group B consists of all other patients.^[3][4][5] For B-lineage NHL, the Berlin-Frankfurt-Munster group treats according to four risk groups: R1 is completely resected disease; R2 is unresected disease or stage III disease with lactate dehydrogenase (LDH) less than 500 u/L; R3 is stage III and LDH concentrations of 500 to 1,000 u/L or leukemic disease (>25% marrow disease) with LDH levels higher than 1,000 u/L; and R4 is stage III/IV disease or leukemic disease with LDH levels higher than 1,000 u/L and/or CNS involvement.^[6] In general, treatment for childhood NHL depends on localized versus disseminated disease. Localized disease is usually defined as stage I or II disease, while stage III or IV disease is generally considered disseminated.

Treatment Option Overview

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 Web site.

NHL in children is generally considered to be widely disseminated from the outset, even when apparently localized; as a result, combination chemotherapy is recommended for most patients.^[1] There are two potentially life-threatening clinical situations that are often seen in children with NHL: (1) superior vena cava syndrome (or mediastinal tumor with airway obstruction), most often seen in lymphoblastic lymphoma; and (2) tumor lysis syndrome, most often seen in lymphoblastic and Burkitt or Burkitt-like NHL. These emergent situations should be anticipated in children with NHL and addressed immediately.

Patients with large mediastinal masses are at risk of cardiac or respiratory arrest during general anesthesia or heavy sedation.^[2] Due to the risks of general anesthesia or heavy sedation, a careful physiologic and radiographic evaluation of the patient should be carried out and the least invasive procedure should be used to establish the diagnosis of lymphoma.^[3][4] Bone marrow aspirate and biopsy should always be performed early in the work up of these patients. If a pleural effusion is present, a cytologic diagnosis is frequently possible using thoracentesis. In those children who present with peripheral adenopathy, a lymph node biopsy under local anesthesia and in an upright position may be possible.^[5] In situations in which the above diagnostic procedures are not fruitful, consideration of a computed tomography–guided core needle biopsy should be contemplated. This procedure can frequently be carried out using light sedation and local anesthesia before proceeding to more invasive procedures. 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 localized radiation therapy should be considered. Since 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 are thought to be alleviated.

Tumor lysis syndrome results from rapid breakdown of malignant cells resulting in a number of metabolic abnormalities, most notably hyperuricemia, hyperkalemia, and hyperphosphatemia. Hyperhydration and allopurinol or rasburicase (urate oxidase) are essential components of therapy in all but patients with the most limited disease.^[6][7][8] An initial prephase consisting of low-dose cyclophosphamide and vincristine does not obviate the need for allopurinol or rasburicase and hydration. Gastrointestinal bleeding, obstruction, and (rarely) perforation may occur. Hyperuricemia and tumor lysis syndrome, particularly when associated with ureteral obstruction, frequently result in life-threatening complications. Patients with NHL should be managed only in institutions having pediatric tertiary care facilities.

Certain pediatric NHL clinical trials are based on immunophenotype and/or histopathology. Children with limited disease have an excellent prognosis when treated with chemotherapy. Radiation is not used as frontline therapy for children. Radiation therapy can serve an ancillary role (i.e., as emergency treatment) for involvement of the nervous system, or when there is a severe mass effect, as in superior vena caval compression or airway obstruction.^[9]

(Refer to the PDQ summary on Primary CNS Lymphoma Treatment for more information on treatment options for non–acquired immunodeficiency syndrome–related primary central nervous system lymphoma.)

The designations in PDQ that treatments are “standard” or “under clinical evaluation” are not to be used as a basis for reimbursement determinations.

References

Localized Non-Hodgkin Lymphoma in Children and Adolescents

Stage I and II patients with grossly resected (>90%) disease regardless of histology have an excellent prognosis, with 90% or better disease-free survival (DFS). A Children’s Cancer Group (CCG) study demonstrated that pulsed chemotherapy with cyclophosphamide, vincristine, methotrexate, and prednisone (COMP) administered for 6 months for localized nonlymphoblastic non-Hodgkin lymphoma (NHL) was equivalent to 18 months of therapy with radiation to sites of disease and that it produced more than 85% DFS and more than 90% overall survival.^[1][2] Patients with lymphoblastic lymphoma had a much inferior outcome. A Pediatric Oncology Group (POG) study tested 9 weeks of short, pulsed chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), with or without radiation to involved sites and with or without 24 weeks of maintenance chemotherapy.^[3] The results showed no benefit of radiation or maintenance chemotherapy, but the DFS for nonlymphoblastic lymphoma was superior to that of lymphoblastic lymphoma (90% vs. 60%).

For localized B-NHL, defined as risk group R1 (completely resected disease), the Berlin-Frankfurt-Munster (BFM) group has used a 5-day cytoreduction phase followed by two cycles of multiagent chemotherapy (BFM-90).^[4] In the most recent BFM study (BFM-95), it was shown that reducing the dose of methotrexate did not affect the results for localized disease.^[5] The French Society of Pediatric Oncology (SFOP) has treated all completely resected stage I and abdominal stage II (Group A) with two cycles of multiagent chemotherapy (LMB-89).^[6]

For localized lymphoblastic lymphoma (grossly resected, i.e., >90% stage I/II disease), about 60% of patients can achieve long-term DFS with short, pulsed chemotherapy.^[2][3] However, using a leukemia approach with induction, consolidation, and maintenance for a total of 24 months, the BFM group (BFM-90/95) has shown more than 90% DFS for localized lymphoblastic lymphoma.^[7][8]

For localized anaplastic large cell lymphoma (ALCL) (grossly resected, i.e., >90% stage I/II disease), the best results have come from using pulsed chemotherapy similar to B-NHL therapy. The SFOP group added methotrexate to the first two cycles following cytoreduction and added four more cycles of pulsed multiagent chemotherapy (HM-89/91).^[9] With an additional cycle of chemotherapy, the BFM group had shown results similar to those obtained with the BFM-90 regimen for B-NHL.^[10] Primary cutaneous ALCL presents a particular problem. The diagnosis can be difficult to distinguish from more benign diseases such as lymphoid papulosis.^[11] Many cutaneous ALCL are ALK-negative and may be treated successfully with surgical resection and/or local radiotherapy without systemic chemotherapy.^[12] There are reports of surgery alone being curative for ALK-positive cutaneous ALCL, but extensive staging and vigilant follow-up is required.

Standard treatment options are based on histology; however, current data do not suggest superiority between regimens listed below for a specific histology.

Standard Treatment Options

Large Cell Lymphoma: both diffuse large B-cell lymphoma (DLBCL) and anaplastic large cell lymphoma (ALCL)

• Vincristine, doxorubicin, cyclophosphamide, prednisone, mercaptopurine, and methotrexate.^[3]

DLBCL and Burkitt Lymphoma

• NHL-BFM-90 (B-NHL): dexamethasone, cyclophosphamide, methotrexate, cytarabine, prednisolone (IT), ifosfamide, etoposide, doxorubicin.^[5]
• LMB-89: cyclophosphamide, vincristine, doxorubicin, prednisone.^[6]

Lymphoblastic Lymphoma

• NHL-BFM-90/95 (Lymphoblastic): prednisone, vincristine, daunorubicin, L-asparaginase, cyclophosphamide, cytarabine, mercaptopurine, methotrexate (IV and IT).^[7][8]

Anaplastic Large Cell Lymphoma

• HM89/91: vincristine, cyclophosphamide, prednisone, methotrexate, doxorubicin, etoposide (vinblastine and bleomycin HM91).^[9]
• NHL-BFM-90 (ALCL): dexamethasone, cyclophosphamide, methotrexate, cytarabine, prednisolone (IT), ifosfamide, etoposide, doxorubicin.^[10]

Disseminated Childhood B-cell Non-Hodgkin Lymphoma

Patients with disseminated mature B-lineage non-Hodgkin lymphoma (NHL) (Burkitt or Burkitt-like lymphoma and diffuse large B-cell lymphoma [DLBCL]) have an 80% to 90% long-term survival.^[1][2][3][4]

For the Berlin-Frankfurt-Munster (BFM) group, disseminated mature B-lineage NHL defined by R2 is unresected disease or stage III disease with lactate deyhdrogenase (LDH) levels lower than 500 u/L; R3 is stage III disease and LDH concentrations between 500 u/L and 1,000 u/L or leukemic disease (>25% marrow disease) with LDH levels lower than 1,000 u/L; R4 is stage III/IV disease or leukemic disease with LDH levels higher than 1,000 u/L and/or central nervous system (CNS) involvement.^[2] R2 disease receives five cycles of intensive chemotherapy and has a disease-free survival (DFS) of more than 90%. The R3 group receives six cycles of intensive chemotherapy and has about 85% DFS. The R4 group receives seven cycles of intensive chemotherapy with approximately 80% DFS. For the French Society of Pediatric Oncology (FAB/LMB), Group B consists of all patients with unresected disease but excludes those with leukemic (>25% marrow involvement) and/or CNS involvement, while Group C patients have leukemic and/or marrow involvement.^[1] In an international randomized trial (FAB/LMB96), the outcome of Group B patients who had a greater than 20% response to prophase reduction was not affected by a reduction of the total dose of cyclophosphamide by 50% and elimination of one cycle of maintenance.^[3] In Group C patients, reduction of therapy resulted in inferior outcome.^[4] This study also demonstrated that patients with leukemic disease only, and no CNS disease, had a 3-year EFS of 90%.^[4] This study identified response to prophase reduction as the most significant prognostic factor with poor responders (i.e. less than 20% resolution of disease), having an EFS of 30%.^[4] As opposed to mature B-lineage NHL seen in adults, there is no difference in outcome based on histology with current therapy in pediatric trials.^[1][2][3][4] This improvement has developed through the use of short, intensive, pulsed chemotherapy with aggressive CNS-directed chemotherapy without cranial radiation. The use of high-dose methotrexate (>5 g/m²), cytarabine, and etoposide have appeared to be helpful.^[1][2][3][4] Even patients with CNS involvement can achieve a DFS of approximately 75% with current intensive therapy.^[1][2][4] Intrathecal methotrexate should be used in all patients, but prophylactic cranial radiation is not necessary.^[1][2][3][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 lymphoma.^[1][2][3][4] Testicular disease at diagnosis does not seem to confer poor prognosis.^[5] Poor prognostic factors include high levels of LDH,^[1][3][6] primary mediastinal disease,^[2][3] and age of more than 15 years, though this appears to mainly involve females with DLBCL.^[2][7] It appears that secondary cytogenetic abnormalities, other than c-myc rearrangement, are associated with an inferior outcome.^[8] Treating children with B-NHL with short, intensive, pulsed multiagent chemotherapy has markedly improved results, particularly in patients with extensive disease. All patients should be considered for entry into a clinical trial.

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 Treatment Option Overview section of this summary for more information.) For reduction of the complications of tumor lysis syndrome, current treatment regimens use a prephase of reduced intensity to cytoreduce patients;^[1][2][3][4] however, this does not obviate the use of hyperhydration and allopurinol or rasburicase (urate oxidase). Hyperuricemia and tumor lysis syndrome, particularly when associated with ureteral obstruction, frequently result in life-threatening complications. Gastrointestinal bleeding, obstruction, and (rarely) perforation may occur. Patients with NHL should be managed only in institutions having pediatric tertiary care facilities.^[9]

Rituximab is a mouse/human chimeric monoclonal antibody targeting the CD20 antigen. Among the lymphomas that occur in children, diffuse large B-cell NHL (DLBCL) and Burkitt lymphoma both express high levels of CD20.^[10] Data from adult clinical trials have demonstrated that rituximab is active against DLBCL.^[11][12] Rituximab has been safely combined with standard doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP) chemotherapy; in a randomized trial of adults with DLBCL comparing CHOP with CHOP plus rituximab, the rituximab arm demonstrated a superior outcome.^[13] In an adult study, rituximab has also been safely combined with an intensive chemotherapy regimen used to treat patients with Burkitt lymphoma.^[14] A Children’s Oncology Group pilot study (COG-ANHL01P1) is evaluating rituximab in combination with the intensive chemotherapy regimen based on the French LMB-89 protocol.

Standard Treatment Options

Current data do not suggest superiority for either of the following standard treatment options.

• FAB/ LMB 96: cyclophosphamide, vincristine, prednisone, methotrexate (IT), high-dose methotrexate, doxorubicin, cytarabine, etoposide. Reduced intensity arm for Group B, and full intensity for Group C.^[3][4]
• NHL-BFM 95: dexamethasone, cyclophosphamide, methotrexate, cytarabine, prednisolone (IT), ifosfamide, etoposide, vindesine, doxorubicin.^[2]

Treatment Options Under Clinical Evaluation

• ANHL01P1: addition of rituximab to FAB/ LMB-96–based therapy.

Information about ongoing clinical trials is available from the NCI Web site.

Disseminated Childhood Lymphoblastic Lymphoma

Patients with disseminated lymphoblastic lymphoma have long-term survival rates higher than 80%.^[1][2] As opposed to other pediatric non-Hodgkin lymphoma (NHL), it has been shown that lymphoblastic lymphoma responds much better to leukemia therapy with 2 years of therapy than with shorter, intensive, pulsed chemotherapy regimens.^[1] A Pediatric Oncology Group (POG) randomized trial (POG 8704) showed that patients receiving a weekly high-dose asparaginase regimen for 20 weeks had a superior outcome.^[3] The best results to date come from the Berlin-Frankfurt-Munster (BFM) group. In NHL-BFM-90, the 5-year disease-free survival (DFS) was 90%, and there was no difference in outcome between stage III and IV patients.^[2] Precursor B-cell lymphoblastic lymphoma appears to have similar results using the same therapy.^[4] In NHL-BFM-95, the prophylactic cranial radiation was omitted, and the intensity of induction therapy was decreased slightly. There were no significant increases in central nervous system (CNS) relapses, suggesting cranial radiation may be reserved for patients with CNS disease at diagnosis.^[5] Of interest, event-free survival (EFS) was worse in BFM-95 than in BFM-90 (90% vs. 82%). Although this difference was not statistically different, the omission of prophylactic cranial radiation and the reduction of asparaginase and/or doxorubicin in induction may have affected outcome. It was proposed that the major difference in EFS between BFM-90 and BFM-95 resulted from the increased number of secondary malignancies observed in BFM-95.^[5] The reason for this is unclear, but it has been shown that patients treated for lymphoblastic lymphoma have a higher incidence of secondary malignancy than do patients treated for other pediatric NHL (10% vs. 2% at age 20 years).^[6]

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 leukemia, and those with fewer than 25% marrow blasts are classified as having lymphoma. It is not yet clear whether these arbitrary definitions are biologically distinct or relevant for treatment design. All current therapies for advanced-stage lymphoblastic lymphoma have been derived from regimens designed for the treatment of acute lymphoblastic leukemia.

Mediastinal radiation is not necessary for patients with mediastinal masses, except in the emergency treatment of symptomatic superior vena caval obstruction or airway obstruction, where low-dose radiation is usually employed. (Refer to the Treatment Option Overview section of this summary for more information on such complications.) Because of the complexities of optimal therapeutic regimens and the possibility of toxic side effects, patients should be offered the opportunity to enter into a clinical trial. Information about ongoing clinical trials is available from the NCI Web site.

Standard Treatment Options

Current data do not suggest superiority for the following standard treatment options.

• NHL-BFM-90: prednisone, dexamethasone, vincristine, daunorubicin, doxorubicin, L-asparaginase, cyclophosphamide, cytarabine, methotrexate, 6-mercaptopurine, 6-thioguanine, CNS radiation therapy.^[1]
• NHL-BFM-95: prednisone, dexamethasone, vincristine, daunorubicin, doxorubicin, L-asparaginase, cyclophosphamide, cytarabine, methotrexate, 6-mercaptopurine, 6-thioguanine, CNS radiation therapy for CNS-positive patients only.^[2]

Treatment Options Under Clinical Evaluation

• COG A-5971: A Children’s Oncology Group (COG) trial comparing the NHL-BFM-95 regimen (which utilizes high-dose methotrexate during interim maintenance for CNS prophylaxis) with the COG BFM-modified leukemia regimen (which uses oral methotrexate during interim maintenance and intensive intrathecal methotrexate for CNS prophylaxis). A second randomization compares standard BFM four-drug induction to the New York induction with high-dose daunorubicin and a single dose of cyclophosphamide during the first 3 days of therapy, in conjunction with vincristine, steroid, and L-asparaginase. The study has met accrual for the randomization. The study recently closed and is awaiting final analysis.

Disseminated Childhood Anaplastic Large Cell Lymphoma

Children and adolescents with disseminated anaplastic large cell lymphoma (ALCL) have a disease-free survival (DFS) of approximately 60% to 75%.^[1][2][3][4] It is unclear which strategy is best for the treatment of disseminated ALCL. The French Society of Pediatric Oncology has treated patients with a cytoreduction phase followed by six cycles of intensive, pulsed chemotherapy (HM89/91).^[1] The German Berlin-Frankfurt-Munster (BFM) group has also used six cycles of intensive pulsed therapy, similar to their B-NHL therapy (NHL-BFM-90).^[2] The Pediatric Oncology Group (POG) trial POG 9317 demonstrated no benefit to methotrexate and high-dose cytarabine added to 52 weeks of cyclic chemotherapy.^[3] The Italian Association of Pediatric Hematology/Oncology used a leukemia-like regimen for 24 months in LNH-92.^[4] Although uncommon, when leukemic peripheral blood involvement is present, it appears to be associated with an unfavorable prognosis.^[5][6] One study suggested that the amount of tumor involvement as measured by polymerase chain reaction in the marrow is predictive for relapse.^[7]

Standard Treatment Options

Current data do not suggest superiority for the following standard treatment options.

• HM89/91: vincristine, cyclophosphamide, prednisone, methotrexate, doxorubicin, etoposide (vinblastine and bleomycin HM91).^[1]
• NHL-BFM-90 (ALCL): dexamethasone, cyclophosphamide, methotrexate, cytarabine, prednisolone (IT), ifosfamide, etoposide, doxorubicin.^[2]
• APO: doxorubicin, prednisone, vincristine.^[3]
• LNH-92: cyclophosphamide, vincristine, dexamethasone, daunorubicin, thioguanine, cytarabine, asparaginase, methotrexate, and intrathecal methotrexate/cytarabine/prednisolone.

Treatment Options Under Clinical Evaluation

• ANHL0131:^[8] The Children's Oncology Group is evaluating the contribution of vinblastine when added to standard therapy for children with newly diagnosed stage III and IV ALCL. Patients are randomly assigned to receive standard chemotherapy, which includes doxorubicin, prednisone, and vincristine (APO); or to receive the same chemotherapy, substituting weekly vinblastine for vincristine during the consolidation phase of therapy. Vinblastine has been shown to be active as a single agent in patients with relapsed ALCL.^[5]
• International ALCL 99: dexamethasone, cyclophosphamide, methotrexate, cytarabine, prednisolone (IT), ifosfamide, high-dose methotrexate, etoposide, doxorubicin, vincristine.

Recurrent Childhood Non-Hodgkin Lymphoma

For recurrent or refractory B-lineage non-Hodgkin lymphoma (NHL) or lymphoblastic lymphoma, survival is generally 10% to 20%.^{[1][2][3][4][5]} For recurrent or refractory anaplastic large cell lymphoma, as many as 60% of patients can achieve long-term survival.^[3] There is no current standard treatment option for patients with recurrent or progressive disease. The first goal is to try to control the disease. A Children’s Cancer Group study (CCG-5912) was able to achieve complete remission in 40% of NHL patients.^[6] Radiation therapy may have a role in treating patients who have not had a complete response to therapy. If remission can be achieved, high-dose therapy and stem cell transplantation are usually pursued. The benefit of autologous versus allogeneic stem cell transplantation is unclear.^{[3][7][8][9][10][11]} All patients with primary refractory or relapsed NHL should be considered for clinical trials.

Standard Treatment Options

• Allogeneic or autologous bone marrow transplantation.^{[3][7][8][9][10][11]}
• DECAL: dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase.^[6]
• ICE: ifosfamide, carboplatin, and etoposide.^[12][13]

Treatment Options Under Clinical Evaluation

• ANHL0121:^[14] Rituximab, ifosfamide, carboplatin, and etoposide (mature B-cell only). This trial (COG-ANHL0121) is closed to new patient accrual.

Information about ongoing clinical trials is available from the NCI Web site.

Lymphoproliferative Disease Associated With Immunodeficiency in Children

Regardless of the etiology of the immune defect, immunodeficient children with lymphoma have a worse prognosis than does the general population with non-Hodgkin lymphoma (NHL).^[1][2][3] If the disease is localized and amenable to complete surgical resection and/or radiation therapy, the outcome is quite favorable; however, most NHL in this population is disseminated and requires systemic cytotoxic therapy. These patients usually tolerate cytotoxic therapy poorly, with increased morbidity and mortality due to increased infectious complications and often increased end-organ toxicities. However, more indolent low-grade lymphomas (e.g., mucosa-associated lymphoid tissue [MALT] lymphomas) have developed in patients with common variable immunodeficiency or other immunodeficient states.^[4][5] (Refer to the PDQ summary on the treatment of Adult Non-Hodgkin's Lymphoma for more information about MALT lymphomas.)

In the era of highly active antiretroviral therapy, children with HIV and NHL should be treated with standard chemotherapy regimens for NHL, but careful attention to prophylaxis against and early detection of infection is warranted.^[1][6] Patients with primary immunodeficiency can achieve complete and durable remissions with standard chemotherapy regimens for NHL, though again toxicity is increased.^[2] Recurrences in these patients are common and may not represent the same clonal disease.^[7] Immunologic correction through allogeneic stem cell transplantation is often required to prevent recurrences. In posttransplant lymphoproliferative disease (PTLD), first-line therapy is the reduction of immunosuppression, as much as can be tolerated.^[3][8] Rituximab, an anti-CD20 antibody, has been used with some success, but data for its use in children are sparse. In one study, ten children with PTLD were treated with standard chemotherapy regimens for pediatric NHL, and 70% were disease-free survivors (DFS).^[9] Another study treated 36 children with PTLD who had failed other therapies with a low-dose chemotherapy regimen, resulting in 70% DFS.^[6]

Standard Treatment Options

• Standard chemotherapy regimens for specific histology.^[1][2][7][9]
• Low-dose cyclophosphamide and prednisone.^[3]

Treatment Options Under Clinical Evaluation

• COG ANHL0221: Addition of rituximab to low-dose cyclophosphamide and prednisone.
• Adoptive immunotherapy with either donor lymphocytes of ex vivo–generated Epstein-Barr virus–specific cytotoxic T-cells have been effective in treating PTLD following blood or bone marrow transplant;^[10][11] however, this has not been shown to be as effective or practical in patients with PTLD following solid organ transplant.

Information about ongoing clinical trials is available from the NCI Web site.

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Changes to This Summary (02/19/2008)

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.

Cellular Classification

Added text to state that in a retrospective subset analysis, there was evidence that submicroscopic bone marrow and peripheral blood involvement were found in approximately 50% of patients and correlated with clinical stage; marrow involvement detected by PCR was associated with a 50% cumulative incidence of relapse (cited Damm-Welk et al. as reference 23).

Added Grewal et al. as reference 25.

Added text to state that one report of children with primary CNS lymphoma showed that most patients had diffuse large B-cell lymphoma or ALCL and that therapy with high-dose intravenous methotrexate and cytosine arabinoside was most successful; intravenous chemotherapy may be needed only when malignant cells are present in the cerebral spinal fluid.

Stage Information

Added text about the prevalence, clinical pattern, and outcome of CNS involvement in NHL patients (cited Salzburg et al. as reference 2).

Disseminated Childhood Anaplastic Large Cell Lymphoma

Added Grewal et al. as reference 6.

Added text to state that one study suggested that the amount of tumor involvement as measured by PCR in the marrow is predictive for relapse (cited Damm-Welk as reference 7).