General Information About Childhood Non-Hodgkin Lymphoma (NHL)

The National Cancer Institute (NCI) 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.

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of children with cancer have been outlined by the American Academy of Pediatrics.[2] At these pediatric cancer centers, clinical trials are available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For non-Hodgkin lymphoma (NHL), the 5-year survival rate has increased over the same time period from 45% to 88% in children younger than 15 years and from 47% to 77% for adolescents aged 15 to 19 years.[1] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on the Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Epidemiology

Lymphoma (Hodgkin lymphoma and NHL) is the third most common childhood malignancy, and NHL accounts for approximately 7% of cancers in children younger than 20 years.[3,4] In the United States, about 800 new cases of NHL are diagnosed each year. The incidence is approximately ten cases per million people per year. The incidence of NHL observed in children and adolescents varies depending on age, histology, gender, and race.[3] Although there is no sharp age peak, childhood NHL occurs most commonly in the second decade of life, and occurs infrequently in children younger than 3 years.[3] NHL in infants is very rare (1% in Berlin-Frankfurt-Munster [BFM] trials from 1986 to 2002).[5] The incidence of NHL is increasing overall, which is accounted for because of a slight increase in the incidence for those aged 15 to 19 years; however, the incidence of NHL in children younger than 15 years has remained constant over the past several decades.[3]

Childhood NHL is more common in males than in females, with the exception of primary mediastinal B-cell lymphoma, in which the incidence is almost the same in males and females.[3,6] A review of Surveillance, Epidemiology, and End Results (SEER) data on Burkitt lymphoma diagnosed in the United States between 1992 and 2008 revealed 2.5 cases/million person-years with more cases in males than in females (3.9:1.1). The incidence of diffuse large B-cell lymphoma (DLBCL) increases with age in both males and females. The incidence of lymphoblastic lymphoma remains relatively constant across ages for both males and females.

The incidence and age distribution of specific types of NHL according to gender is described in Table 1.

Table 1. Incidence and Age Distribution of Specific Types of NHL^a

	Incidence of NHL per million person-years
ALCL = anaplastic large cell lymphoma; DLBCL = diffuse large B-cell lymphoma; NHL = non-Hodgkin lymphoma.
a Adapted from Percy et al.[3]
b In older adolescents, indolent and aggressive histologies (more commonly seen in adult patients) are beginning to be found.
	Males	Females
Age (y)	<5	5–9	10–14	15–19	<5	5–9	10–14	15–19
Burkitt	3.2	6	6.1	2.8	0.8	1.1	0.8	1.2
Lymphoblastic	1.6	2.2	2.8	2.2	0.9	1.0	0.7	0.9
DLBCL	0.5	1.2	2.5	6.1	0.6	0.7	1.4	4.9
Other (mostly ALCL)	2.3	3.3	4.3	7.8b	1.5	1.6	2.8	3.4b

The incidence of NHL is higher in whites than in African Americans, and Burkitt lymphoma is more frequent in non-Hispanic whites (3.2 cases/million person-years) than in Hispanic whites (2.0 cases/million person-years).[7]

Relatively little is known of the epidemiology of childhood NHL. However, immunodeficiency, both congenital and acquired (human immunodeficiency virus infection [HIV] or posttransplant immunodeficiency), increases the risk of NHL. Epstein-Barr virus (EBV) is associated with most cases of NHL seen in the immunodeficient population.[3] Although 85% or more of Burkitt lymphoma is associated with the EBV in endemic Africa, approximately 15% of cases in Europe or the United States will have EBV detectable in the tumor tissue.[8]

NHL presenting as a secondary malignancy is rare in pediatrics. A retrospective review of the German Childhood Cancer Registry identified 11 (0.3%) of 2,968 newly diagnosed children older than 20 years with NHL as having a secondary malignancy.[9] In this small cohort, outcome was similar to patients with de novo NHL when treated with standard therapy.[9]

Prognostic Factors for Childhood NHL

With current treatments, more than 80% of children and adolescents with NHL will survive at least 5 years, though outcome is variable depending on a number of factors, including clinical stage and histology.[10]

Prognostic factors for childhood NHL include the following:

• Age: NHL in infants is rare (1% in Berlin-Frankfurt-Munster [BFM] trials from 1986 to 2002).[5]In this retrospective review, the outcome for infants was inferior compared with the outcome for older patients with NHL.[5]

  Adolescents have been reported to have inferior outcome compared with younger children. A review of survival for various subtypes of NHL in children and adolescents between 1986 and 2007 has been reported by the BFM group.[11] Event-free survival (EFS) was 79% for adolescents and 85% for children. This adverse affect of age appears to be most pronounced for adolescents with T-cell lymphoblastic lymphoma and DLBCL compared with children with these diagnoses.[11] The poorer outcome of patients older than 15 years appears to be attributable primarily to patients with DLBCL.[10]

• Site of disease: In general, patients with low-stage disease (i.e., single extra-abdominal/extrathoracic tumor or totally resected intra-abdominal tumor) have an excellent prognosis (a 5-year survival rate of approximately 90%), regardless of histology.[12,13,14,15,16,17]Patients with NHL arising in bone have an excellent prognosis, regardless of histology.[18,19]Testicular involvement does not affect prognosis.[13,14,20]As opposed to adults, mediastinal involvement in children and adolescents with nonlymphoblastic NHL results in an inferior outcome.[10,12,15]For patients with primary mediastinal B-cell lymphoma, 3-year EFS is 50% to 70%,[12,15,21]and for patients with central nervous system (CNS) disease at presentation, the 3-year EFS is 70%.[15,22]

  In ALCL, a retrospective study by the European Intergroup for Childhood NHL (EICNHL) found a high-risk group of patients defined by involvement of mediastinum, skin, or viscera.[23] An immune response against the ALK protein (i.e., anti-ALK antibody titer) appears to correlate with lower clinical stage and absence of these clinical risk features (mediastinal and visceral organ involvement) and predicts relapse risk but not overall survival.[24] However, in the CCG-5941 study for ALCL patients, only bone marrow involvement predicted inferior progression-free survival.[25][Level of evidence: 2A] Patients with leukemic involvement (>25% blasts in marrow) or CNS involvement at diagnosis require intensive therapy.[14,22,26] Although these intensive therapies have improved the outcome for patients with high-stage (stage III or IV) or advanced-stage disease, patients who present with CNS disease have the worst outcome.[14,22,26] The combination of CNS involvement and marrow disease appears to impact outcome the most for Burkitt lymphoma/leukemia.[22] Patients with leukemic disease only, and no CNS disease, had a 3-year EFS of 90%, while patients with CNS disease at presentation had a 70% 3-year EFS.[22]

• Chromosomal abnormalities: Though data for cytogenetics is less robust than for childhood leukemia, some chromosomal abnormalities have been reported to have prognostic value. For pediatric Burkitt lymphoma patients, secondary cytogenetic abnormalities, other thanc-mycrearrangement, are associated with an inferior outcome,[27,28]and cytogenetic abnormalities involving gain of 7q or deletion of 13q appear to have an inferior outcome on current chemotherapy protocols.[28,29]Outcome appears to be lower for pediatric patients with DLBCL who have chromosomal rearrangement atMYC(8q24).[28]

  One study of patients with T-cell lymphoblastic lymphoma demonstrated that loss of heterozygosity on chromosome 6q was associated with an increased risk of relapse.[30]

• Tumor burden: A surrogate for tumor burden (i.e., elevated levels of lactate dehydrogenase) has been shown to be prognostic in many studies.[12,15,21]

  More recently, detection of minimal disease at diagnosis or minimal residual disease (MRD) appears to be prognostic in most subtypes of childhood NHL. In a retrospective subset analysis, there was evidence that submicroscopic bone marrow and peripheral blood involvement, detected by reverse transcription-polymerase chain reaction (RT-PCR) from NPM-ALK, was found in approximately 50% of patients and correlated with clinical stage;[31] marrow involvement detected by PCR was associated with a 50% cumulative incidence of relapse. The prognostic role of MRD in the treatment of Burkitt leukemia remains unclear.

• Response to therapy: One of the most important predictive factors for Burkitt lymphoma/leukemia is response to the initial prophase treatment; poor responders (i.e., <20% resolution of disease) had an EFS of 30%.[12]Results from two studies suggest inferior outcome for patients with Burkitt leukemia that had detectable MRD after induction chemotherapy.[32]

References:

1.	Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.
2.	Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.
3.	Percy CL, Smith MA, Linet M, et al.: Lymphomas and reticuloendothelial neoplasms. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649., pp 35-50. Also available online. Last accessed March 29, 2012.
4.	Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996.
5.	Mann G, Attarbaschi A, Burkhardt B, et al.: Clinical characteristics and treatment outcome of infants with non-Hodgkin lymphoma. Br J Haematol 139 (3): 443-9, 2007.
6.	Jaffe ES, Harris NL, Stein H, et al.: Introduction and overview of the classification of the lymphoid neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 157-66.
7.	Mbulaiteye SM, Biggar RJ, Bhatia K, et al.: Sporadic childhood Burkitt lymphoma incidence in the United States during 1992-2005. Pediatr Blood Cancer 53 (3): 366-70, 2009.
8.	Gutiérrez MI, Bhatia K, Barriga F, et al.: Molecular epidemiology of Burkitt's lymphoma from South America: differences in breakpoint location and Epstein-Barr virus association from tumors in other world regions. Blood 79 (12): 3261-6, 1992.
9.	Landmann E, Oschlies I, Zimmermann M, et al.: Secondary non-Hodgkin lymphoma (NHL) in children and adolescents after childhood cancer other than NHL. Br J Haematol 143 (3): 387-94, 2008.
10.	Burkhardt B, Zimmermann M, Oschlies I, et al.: The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol 131 (1): 39-49, 2005.
11.	Burkhardt B, Oschlies I, Klapper W, et al.: Non-Hodgkin's lymphoma in adolescents: experiences in 378 adolescent NHL patients treated according to pediatric NHL-BFM protocols. Leukemia 25 (1): 153-60, 2011.
12.	Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007.
13.	Link MP, Shuster JJ, Donaldson SS, et al.: Treatment of children and young adults with early-stage non-Hodgkin's lymphoma. N Engl J Med 337 (18): 1259-66, 1997.
14.	Reiter A, Schrappe M, Ludwig WD, et al.: Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood 95 (2): 416-21, 2000.
15.	Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005.
16.	Gerrard M, Cairo MS, Weston C, et al.: Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Br J Haematol 141 (6): 840-7, 2008.
17.	Seidemann K, Tiemann M, Schrappe M, et al.: Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 97 (12): 3699-706, 2001.
18.	Lones MA, Perkins SL, Sposto R, et al.: Non-Hodgkin's lymphoma arising in bone in children and adolescents is associated with an excellent outcome: a Children's Cancer Group report. J Clin Oncol 20 (9): 2293-301, 2002.
19.	Zhao XF, Young KH, Frank D, et al.: Pediatric primary bone lymphoma-diffuse large B-cell lymphoma: morphologic and immunohistochemical characteristics of 10 cases. Am J Clin Pathol 127 (1): 47-54, 2007.
20.	Dalle JH, Mechinaud F, Michon J, et al.: Testicular disease in childhood B-cell non-Hodgkin's lymphoma: the French Society of Pediatric Oncology experience. J Clin Oncol 19 (9): 2397-403, 2001.
21.	Reiter A, Schrappe M, Tiemann M, et al.: Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 94 (10): 3294-306, 1999.
22.	Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007.
23.	Le Deley MC, Reiter A, Williams D, et al.: Prognostic factors in childhood anaplastic large cell lymphoma: results of a large European intergroup study. Blood 111 (3): 1560-6, 2008.
24.	Ait-Tahar K, Damm-Welk C, Burkhardt B, et al.: Correlation of the autoantibody response to the ALK oncoantigen in pediatric anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with tumor dissemination and relapse risk. Blood 115 (16): 3314-9, 2010.
25.	Lowe EJ, Sposto R, Perkins SL, et al.: Intensive chemotherapy for systemic anaplastic large cell lymphoma in children and adolescents: final results of Children's Cancer Group Study 5941. Pediatr Blood Cancer 52 (3): 335-9, 2009.
26.	Salzburg J, Burkhardt B, Zimmermann M, et al.: Prevalence, clinical pattern, and outcome of CNS involvement in childhood and adolescent non-Hodgkin's lymphoma differ by non-Hodgkin's lymphoma subtype: a Berlin-Frankfurt-Munster Group Report. J Clin Oncol 25 (25): 3915-22, 2007.
27.	Onciu M, Schlette E, Zhou Y, et al.: Secondary chromosomal abnormalities predict outcome in pediatric and adult high-stage Burkitt lymphoma. Cancer 107 (5): 1084-92, 2006.
28.	Poirel HA, Cairo MS, Heerema NA, et al.: Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Leukemia 23 (2): 323-31, 2009.
29.	Nelson M, Perkins SL, Dave BJ, et al.: An increased frequency of 13q deletions detected by fluorescence in situ hybridization and its impact on survival in children and adolescents with Burkitt lymphoma: results from the Children's Oncology Group study CCG-5961. Br J Haematol 148 (4): 600-10, 2010.
30.	Burkhardt B, Moericke A, Klapper W, et al.: Pediatric precursor T lymphoblastic leukemia and lymphoblastic lymphoma: Differences in the common regions with loss of heterozygosity at chromosome 6q and their prognostic impact. Leuk Lymphoma 49 (3): 451-61, 2008.
31.	Damm-Welk C, Busch K, Burkhardt B, et al.: Prognostic significance of circulating tumor cells in bone marrow or peripheral blood as detected by qualitative and quantitative PCR in pediatric NPM-ALK-positive anaplastic large-cell lymphoma. Blood 110 (2): 670-7, 2007.
32.	Mussolin L, Pillon M, Conter V, et al.: Prognostic role of minimal residual disease in mature B-cell acute lymphoblastic leukemia of childhood. J Clin Oncol 25 (33): 5254-61, 2007.

Cellular Classification of Childhood NHL

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.[1,2,3] The World Health Organization (WHO) has classified NHL on the basis of the following: (1) phenotype (i.e., B-lineage and T-lineage or natural killer [NK] cell lineage) and (2) differentiation (i.e., precursor vs. mature).[4]

On the basis of clinical response to treatment, NHL of childhood and adolescence currently falls into the following three therapeutically relevant categories:

1.	Mature B-cell NHL (Burkitt and Burkitt-like lymphoma/leukemia and diffuse large B-cell lymphoma [DLBCL]).
2.	Lymphoblastic lymphoma (primarily precursor T-cell lymphoma and, less frequently, precursor B-cell lymphoma).
3.	Anaplastic large cell lymphoma (ALCL) (mature 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.[5] Posttransplant lymphoproliferative diseases (PTLDs) are classified according to WHO nomenclature as (1) early lesions, (2) polymorphic, and (3) monomorphic.[6] While the majority of PTLDs are of B-cell phenotype, approximately 10% are mature (peripheral) T-cell lymphomas.[6]

Other types of lymphoma, such as peripheral T-cell lymphoma (PTCL), T/NK lymphomas, cutaneous lymphomas, and indolent B-cell lymphomas (e.g., follicular lymphoma), are more commonly seen in adults and occur rarely in children. Refer to the following PDQ summaries for more information:

• Adult Non-Hodgkin Lymphoma.
• Primary CNS Lymphoma.
• Mycosis Fungoides and the Sézary Syndrome.

Each type of childhood NHL is associated with distinctive molecular biological characteristics, which are outlined in the following table. The Revised European-American Lymphoma (REAL) classification and the WHO classification 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. For the most part, the remaining categories do not pertain to pediatric NHL and are not shown.

Table 2. Major Histopathological Categories of Non-Hodgkin Lymphoma in Children and Adolescents^a

Category (WHO Classification/ Updated REAL)	Category (Working Formulation)	Immuno-phenotype	Clinical Presentation	Chromosome Translocation	Genes Affected
CNS = central nervous system; ML = malignant lymphoma; REAL = Revised European-American Lymphoma; WHO = World Health Organization.
a Adapted from Percy et al.[2]
Burkitt and Burkitt-like lymphomas	ML small noncleaved cell	Mature B cell	Intra-abdominal (sporadic), head and neck (non-jaw, sporadic), jaw (endemic), bone marrow, CNS	t(8;14)(q24;q32), t(2;8)(p11;q24), t(8;22)(q24;q11)	C-MYC,IGH,IGK,IGL
Diffuse large B-cell lymphoma	ML large cell	Mature B cell; maybe CD30+	Nodal, abdominal, bone, primary CNS (when associated with immunodeficiency), mediastinal	No consistent cytogenetic abnormality identified
Lymphoblastic lymphoma, precursor T-cell leukemia, or precursor B-cell lymphoma	Lymphoblastic convoluted and non-convoluted	Pre-T cell	Mediastinal, bone marrow	MTS1/p16ink4a; DeletionTAL1t(1;14)(p34;q11), t(11;14)(p13;q11)	TAL1, TCRAO, RHOMB1, HOX11
		Pre-B cell	Skin, bone, mediastinal
Anaplastic large cell lymphoma, systemic	ML immunoblastic or ML large	CD30+ (Ki-1+)	Variable, but systemic symptoms often prominent	t(2;5)(p23;q35); less common variant translocations involvingALK	ALK,NPM
		T cell or null cell
Anaplastic large cell lymphoma, cutaneous		CD30+ (Ki-usually)	Skin only; single or multiple lesions	Lacks t(2;5)
		T cell

Burkitt and Burkitt-like lymphoma/leukemia

Burkitt and Burkitt-like lymphoma/leukemia in the United States accounts for about 30% of childhood NHL and exhibits consistent, aggressive clinical behavior.[2,3,7] The overall incidence of Burkitt lymphoma is 2.5 cases per million person-years and is higher among boys than girls (3.9 vs. 1.1).[2,8] The most common primary sites of disease are the abdomen and the lymph nodes, especially of the head and neck region.[3,8] Other sites of involvement include testes, bone, skin, bone marrow, and central nervous system (CNS).

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). Burkitt lymphoma/leukemia expresses a characteristic chromosomal translocation, usually t(8;14) and more rarely t(8;22) or t(2;8). Each of these translocations juxtaposes the c-myc oncogene and immunoglobulin locus regulatory elements, resulting in the inappropriate expression of c-myc, a gene involved in cellular proliferation.[3]

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 because of features that are consistent with DLBCL.[9] 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 ≥99%).[7] Studies have demonstrated that the vast majority of Burkitt-like or "atypical Burkitt" lymphomas have a gene expression signature similar to Burkitt lymphoma.[10] Additionally, as many as 30% of pediatric DLBCL cases will have a gene signature similar to Burkitt lymphoma.[10,11] Despite the histologic differences, Burkitt and Burkitt-like lymphoma/leukemia are clinically very aggressive and are treated with very aggressive regimens.[12,13,14,15]

Diffuse large B-cell lymphoma

DLBCL is a mature B-cell neoplasm that represents 10% to 20% of pediatric NHL.[2,3,16] DLBCL occurs more frequently during the second decade of life than during the first decade.[2,17,18] The WHO classification system does not recommend morphologic subclassification based on morphologic variants (e.g., immunoblastic, centroblastic) of DLBCL.[19] 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.[16,17,20]

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 has been associated with an inferior outcome compared with other pediatric DLBCL.[13,14,17,21,22,23] PMBCL is associated with distinctive chromosomal aberrations (gains in chromosome 9p and 2p in regions that involve JAK2 and c-rel, respectively) [22,23] and commonly shows inactivation of SOCS1 by either mutation or gene deletion.[24,25] PMBCL also has a distinctive gene expression profile in comparison with other DLBCL, suggesting a close relationship of PMBCL with Hodgkin lymphoma.[26,27]

With the exception of PMBCL, DLBCL in children and adolescents differs biologically from DLBCL in adults. The vast majority of pediatric DLBCL cases have a germinal center B-cell phenotype, as assessed by immunohistochemical analysis of selected proteins found in normal germinal center B cells, such as the BCL6 gene product and CD10.[18,28,29] 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.[18] As many as 30% of patients younger than 14 years with DLBCL will have a gene signature similar to Burkitt lymphoma.[10] A subset of pediatric DLBCL cases were found to have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci. DLBCL cases with an IRF4 translocation were significantly more frequent in children than adults (15% vs. 2%), were germinal center–derived B-cell lymphomas, and were associated with favorable prognosis compared with DLBCL cases lacking this abnormality.[30]

Lymphoblastic lymphoma

Lymphoblastic lymphoma comprises approximately 20% of childhood NHL.[2,3,17] 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.[3,31] Chromosomal abnormalities are not well characterized in patients with lymphoblastic lymphoma.

As many as 75% of patients with 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 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 less than observed in Burkitt lymphoma. Low-stage lymphoblastic lymphoma may occur in lymph nodes, bone, testes, or subcutaneous tissue. Lymphoblastic lymphoma within the mediastinum is not considered low-stage 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.[17] 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. The WHO classification system classifies ALCL as a peripheral T-cell lymphoma (PTCL).[4] Many view ALK-positive ALCL differently than other PTCL because prognosis tends to be superior to other forms of PTCL.[32] All ALCL cases are CD30-positive and more than 90% of pediatric ALCL 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 comprised of variant ALK translocations.[33] 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.[33] There is no correlation between outcome and ALK translocation type.[34] In a series of 375 children and adolescents with systemic ALK-positive ALCL, 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).[35]

Clinically, systemic 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. 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. Patients with ALCL may present with signs and symptoms consistent with hemophagocytic lymphohistiocytosis.[36] 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 patients have an aberrant T-cell immunophenotype with frequent expression of myeloid antigens. Patients in this ALCL subgroup may require more aggressive therapy.[37,38]

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 human immunodeficiency virus (HIV) infection, or iatrogenic following transplantation (solid organ transplantation or allogeneic hematopoietic stem cell transplantation [HSCT]). Epstein-Barr virus (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.[39] HIV-associated NHL can be broadly grouped into three subcategories: (1) systemic (nodal and extranodal), (2) primary CNS lymphoma (PCNSL), and (3) 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.[39] 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.[40] Highly active antiretroviral therapy has decreased the incidence of NHL in HIV-positive individuals, particularly for PCNSL cases.[41] Most childhood HIV-related NHL is of mature B-cell phenotype but with a spectrum, including PEL, PCNSL, mucosa-associated lymphoid tissue (MALT),[42] Burkitt lymphoma,[43] and DLBCL. NHL in children with HIV often presents with fever, weight loss, and symptoms related to extranodal disease, such as abdominal pain or CNS symptoms.[39]

NHL observed in primary immunodeficiency usually shows a mature B-cell phenotype and large cell histology.[5] Mature T-cell lymphoma and ALCL have been observed.[5] Children with primary immunodeficiency and NHL are more likely to have high-stage disease and present with symptoms related to extranodal disease, particularly the gastrointestinal tract and CNS.[5]

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.[44] The WHO has classified PTLD into the following three subtypes:[6]

• Early lesions – Early lesions show germinal center expansion, but tissue architecture remains normal.
• Polymorphic PTLD – Presence of infiltrating T cells, disruption of nodal architecture, and necrosis distinguish polymorphic PTLD from early lesions.
• Monomorphic PTLD – Histologies observed in the monomorphic subtype are similar to those observed in NHL, with DLBCL 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.[45] Thus, histology of a single biopsied site may not be representative of the entire disease process. Not all PTLD is B-cell phenotype.[6] 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).[44] Although less common, PTLD may present as a rapidly progressive, high-stage disease that clinically resembles septic shock, which almost always results in death despite therapy.[46,47]

Rare NHL occurring in children

Low- or intermediate-grade mature B-cell lymphomas, such as small lymphocytic lymphoma, MALT lymphoma, mantle cell lymphoma, myeloma, or follicular cell lymphoma, are rarely seen in children. The most recent WHO classification has identified pediatric follicular lymphoma (FL) and pediatric nodal marginal zone lymphoma as unique entities.[1]

Pediatric follicular lymphoma is a disease that differs from the adult counterpart genetically and clinically. The genetic hallmark of adult FL, the translocation of t(14;18)(q32;q21), is typically not detectable in pediatric FL. The outcome of pediatric FL is excellent, and in contrast to adult FL, the clinical course is not dominated by relapses, if the BFM protocols for DLBCL and BL are used. In pediatric FL, a simultaneous DLBCL can frequently be detected at initial diagnosis but does not indicate a more aggressive clinical course in children.[48,49]

Other diseases appear to reflect the disease observed in adult patients. For example, MALT lymphomas observed in pediatric patients usually present as low-stage (stage I or II) disease and are associated with H. pylori and require no more than local therapy involving curative surgery and/or radiation therapy.[50]

Other types of NHL may be rare in adults and are exceedingly rare in pediatric patients, such as primary CNS lymphoma (PCNSL). Due to small numbers, it is difficult to ascertain if the disease observed 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 PCNSL (overall survival 70%–80%) may be superior to that of adults with PCNSL. These reports suggest that long-term survival can be achieved without cranial irradiation.[51,52,53,54] Most children have DLBCL or ALCL. Therapy with high-dose intravenous methotrexate and cytosine arabinoside is most successful and intrathecal chemotherapy may be needed only when malignant cells are present in the cerebral spinal fluid.[52,54] There is a case report of repeated doses of rituximab, both intravenous and intraventricular, being administered to a 14-year-old boy with refractory PCNSL, with an excellent result.[55] This apparently good outcome needs to be confirmed, especially since similar results have not been observed in adults. (Refer to the PDQ summary on Primary CNS Lymphoma Treatment for more information on treatment options for nonacquired immunodeficiency syndrome–related primary CNS lymphoma.)

Peripheral T-cell lymphoma (PTCL), excluding ALCL, is rare in children. Mature T-cell/NK-cell lymphoma or PTCL has a postthymic phenotype (e.g., TdT negative), usually expresses CD4 or CD8, and has rearrangement of T-cell receptor (TCR) genes, either alpha/beta and/or gamma/delta chains. The most common phenotype observed in children is PTCL-not otherwise specified (NOS), although angioimmunoblastic lymphoma (AITL), enteropathy-associated lymphoma (EATL) (associated with celiac disease), subcutaneous panniculitis-like lymphoma, angiocentric lymphoma, and extranodal NK/T-cell PTCL have been reported.[56,57,58] Mycosis fungoides has rarely been reported in children and adolescents.[59] A Japanese study described extranodal NK/T-cell lymphoma, nasal type as the most common PTCL subtype among Japanese children (10 of 21 PTCL cases). In adults, extranodal NK/T-cell lymphoma, nasal type is generally EBV-positive, and 60% of the cases observed in Japanese children were EBV-positive.[60] Though very rare, hepatosplenic T-cell lymphoma is associated with children and adolescents who have Crohn disease and have been on immunosuppressive therapy; this lymphoma has been fatal in all cases.[61]

Optimal therapy for PTCL is unclear, even for adult patients. There have been three retrospective analyses of treatment and outcome for pediatric patients with PTCL. The United Kingdom Children's Cancer Study Group (UKCCSG) reported on 25 children diagnosed over a 20-year period with PTCL, with an approximate 50% 5-year survival rate.[56] The UKCCSG also observed that the use of acute lymphoblastic leukemia (ALL)–like therapy, instead of NHL therapy, produced a superior outcome. The Children's Oncology Group (COG) reported 20 patients older than 8 years treated on Pediatric Oncology Group NHL trials.[57] Eight of ten patients with low-stage disease achieved long-term disease-free survival compared to only four of ten patients with high-stage disease. A study of Japanese children with PTCL (N = 21) reported a 5-year overall survival rate of 85.2%. Treatment for PTCL was not consistent in this study and included chemotherapy (n = 18), radiation (n = 2), and autologous (n = 2) and allogeneic (n = 9) stem cell transplantation.[60]

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

References:

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5.	Seidemann K, Tiemann M, Henze G, et al.: Therapy for non-Hodgkin lymphoma in children with primary immunodeficiency: analysis of 19 patients from the BFM trials. Med Pediatr Oncol 33 (6): 536-44, 1999.
6.	Swerdlow SH, Webber SA, Chadburn A: Post-transplant lymphoproliferative disorders. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 343-9.
7.	Leoncini L, Raphael M, Stein H: Burkitt lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 262-4.
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9.	Kluin PM, Harris NL, Stein H: B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 265-6.
10.	Klapper W, Szczepanowski M, Burkhardt B, et al.: Molecular profiling of pediatric mature B-cell lymphoma treated in population-based prospective clinical trials. Blood 112 (4): 1374-81, 2008.
11.	Dave SS, Fu K, Wright GW, et al.: Molecular diagnosis of Burkitt's lymphoma. N Engl J Med 354 (23): 2431-42, 2006.
12.	Sevilla DW, Gong JZ, Goodman BK, et al.: Clinicopathologic findings in high-grade B-cell lymphomas with typical Burkitt morphologic features but lacking the MYC translocation. Am J Clin Pathol 128 (6): 981-91, 2007.
13.	Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005.
14.	Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007.
15.	Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007.
16.	Reiter A, Klapper W: Recent advances in the understanding and management of diffuse large B-cell lymphoma in children. Br J Haematol 142 (3): 329-47, 2008.
17.	Burkhardt B, Zimmermann M, Oschlies I, et al.: The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol 131 (1): 39-49, 2005.
18.	Oschlies I, Klapper W, Zimmermann M, et al.: Diffuse large B-cell lymphoma in pediatric patients belongs predominantly to the germinal-center type B-cell lymphomas: a clinicopathologic analysis of cases included in the German BFM (Berlin-Frankfurt-Munster) Multicenter Trial. Blood 107 (10): 4047-52, 2006.
19.	Stein H, Warnke RA, Chan WC: Diffuse large B-cell lymphoma (DLBCL), NOS. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 233-7.
20.	Lones MA, Perkins SL, Sposto R, et al.: Large-cell lymphoma arising in the mediastinum in children and adolescents is associated with an excellent outcome: a Children's Cancer Group report. J Clin Oncol 18 (22): 3845-53, 2000.
21.	Seidemann K, Tiemann M, Lauterbach I, et al.: Primary mediastinal large B-cell lymphoma with sclerosis in pediatric and adolescent patients: treatment and results from three therapeutic studies of the Berlin-Frankfurt-Münster Group. J Clin Oncol 21 (9): 1782-9, 2003.
22.	Bea S, Zettl A, Wright G, et al.: Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood 106 (9): 3183-90, 2005.
23.	Oschlies I, Burkhardt B, Salaverria I, et al.: Clinical, pathological and genetic features of primary mediastinal large B-cell lymphomas and mediastinal gray zone lymphomas in children. Haematologica 96 (2): 262-8, 2011.
24.	Melzner I, Bucur AJ, Brüderlein S, et al.: Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line. Blood 105 (6): 2535-42, 2005.
25.	Mestre C, Rubio-Moscardo F, Rosenwald A, et al.: Homozygous deletion of SOCS1 in primary mediastinal B-cell lymphoma detected by CGH to BAC microarrays. Leukemia 19 (6): 1082-4, 2005.
26.	Rosenwald A, Wright G, Leroy K, et al.: Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med 198 (6): 851-62, 2003.
27.	Savage KJ, Monti S, Kutok JL, et al.: The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 102 (12): 3871-9, 2003.
28.	Miles RR, Raphael M, McCarthy K, et al.: Pediatric diffuse large B-cell lymphoma demonstrates a high proliferation index, frequent c-Myc protein expression, and a high incidence of germinal center subtype: Report of the French-American-British (FAB) international study group. Pediatr Blood Cancer 51 (3): 369-74, 2008.
29.	Gualco G, Weiss LM, Harrington WJ Jr, et al.: Nodal diffuse large B-cell lymphomas in children and adolescents: immunohistochemical expression patterns and c-MYC translocation in relation to clinical outcome. Am J Surg Pathol 33 (12): 1815-22, 2009.
30.	Salaverria I, Philipp C, Oschlies I, et al.: Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults. Blood 118 (1): 139-47, 2011.
31.	Neth O, Seidemann K, Jansen P, et al.: Precursor B-cell lymphoblastic lymphoma in childhood and adolescence: clinical features, treatment, and results in trials NHL-BFM 86 and 90. Med Pediatr Oncol 35 (1): 20-7, 2000.
32.	Savage KJ, Harris NL, Vose JM, et al.: ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 111 (12): 5496-504, 2008.
33.	Duyster J, Bai RY, Morris SW: Translocations involving anaplastic lymphoma kinase (ALK). Oncogene 20 (40): 5623-37, 2001.
34.	Stein H, Foss HD, Dürkop H, et al.: CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood 96 (12): 3681-95, 2000.
35.	Lamant L, McCarthy K, d'Amore E, et al.: Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: results of the ALCL99 study. J Clin Oncol 29 (35): 4669-76, 2011.
36.	Sevilla DW, Choi JK, Gong JZ: Mediastinal adenopathy, lung infiltrates, and hemophagocytosis: unusual manifestation of pediatric anaplastic large cell lymphoma: report of two cases. Am J Clin Pathol 127 (3): 458-64, 2007.
37.	Onciu M, Behm FG, Raimondi SC, et al.: ALK-positive anaplastic large cell lymphoma with leukemic peripheral blood involvement is a clinicopathologic entity with an unfavorable prognosis. Report of three cases and review of the literature. Am J Clin Pathol 120 (4): 617-25, 2003.
38.	Grewal JS, Smith LB, Winegarden JD 3rd, et al.: Highly aggressive ALK-positive anaplastic large cell lymphoma with a leukemic phase and multi-organ involvement: a report of three cases and a review of the literature. Ann Hematol 86 (7): 499-508, 2007.
39.	McClain KL, Joshi VV, Murphy SB: Cancers in children with HIV infection. Hematol Oncol Clin North Am 10 (5): 1189-201, 1996.
40.	Jaffe ES: Primary body cavity-based AIDS-related lymphomas. Evolution of a new disease entity. Am J Clin Pathol 105 (2): 141-3, 1996.
41.	Kirk O, Pedersen C, Cozzi-Lepri A, et al.: Non-Hodgkin lymphoma in HIV-infected patients in the era of highly active antiretroviral therapy. Blood 98 (12): 3406-12, 2001.
42.	Ohno Y, Kosaka T, Muraoka I, et al.: Remission of primary low-grade gastric lymphomas of the mucosa-associated lymphoid tissue type in immunocompromised pediatric patients. World J Gastroenterol 12 (16): 2625-8, 2006.
43.	Fedorova A, Mlyavaya T, Alexeichik A, et al.: Successful treatment of the HIV-associated Burkitt lymphoma in a three-year-old child. Pediatr Blood Cancer 47 (1): 92-3, 2006.
44.	Loren AW, Porter DL, Stadtmauer EA, et al.: Post-transplant lymphoproliferative disorder: a review. Bone Marrow Transplant 31 (3): 145-55, 2003.
45.	Chadburn A, Cesarman E, Liu YF, et al.: Molecular genetic analysis demonstrates that multiple posttransplantation lymphoproliferative disorders occurring in one anatomic site in a single patient represent distinct primary lymphoid neoplasms. Cancer 75 (11): 2747-56, 1995.
46.	Collins MH, Montone KT, Leahey AM, et al.: Autopsy pathology of pediatric posttransplant lymphoproliferative disorder. Pediatrics 107 (6): E89, 2001.
47.	Picarsic J, Jaffe R, Mazariegos G, et al.: Post-transplant Burkitt lymphoma is a more aggressive and distinct form of post-transplant lymphoproliferative disorder. Cancer 117 (19): 4540-50, 2011.
48.	Oschlies I, Salaverria I, Mahn F, et al.: Pediatric follicular lymphoma--a clinico-pathological study of a population-based series of patients treated within the Non-Hodgkin's Lymphoma--Berlin-Frankfurt-Munster (NHL-BFM) multicenter trials. Haematologica 95 (2): 253-9, 2010.
49.	Lorsbach RB, Shay-Seymore D, Moore J, et al.: Clinicopathologic analysis of follicular lymphoma occurring in children. Blood 99 (6): 1959-64, 2002.
50.	Claviez A, Meyer U, Dominick C, et al.: MALT lymphoma in children: a report from the NHL-BFM Study Group. Pediatr Blood Cancer 47 (2): 210-4, 2006.
51.	Abla O, Sandlund JT, Sung L, et al.: A case series of pediatric primary central nervous system lymphoma: favorable outcome without cranial irradiation. Pediatr Blood Cancer 47 (7): 880-5, 2006.
52.	Abla O, Weitzman S: Primary central nervous system lymphoma in children. Neurosurg Focus 21 (5): E8, 2006.
53.	Shah AC, Kelly DR, Nabors LB, et al.: Treatment of primary CNS lymphoma with high-dose methotrexate in immunocompetent pediatric patients. Pediatr Blood Cancer 55 (6): 1227-30, 2010.
54.	Abla O, Weitzman S, Blay JY, et al.: Primary CNS lymphoma in children and adolescents: a descriptive analysis from the International Primary CNS Lymphoma Collaborative Group (IPCG). Clin Cancer Res 17 (2): 346-52, 2011.
55.	Akyuz C, Aydin GB, Cila A, et al.: Successful use of intraventricular and intravenous rituximab therapy for refractory primary CNS lymphoma in a child. Leuk Lymphoma 48 (6): 1253-5, 2007.
56.	Windsor R, Stiller C, Webb D: Peripheral T-cell lymphoma in childhood: population-based experience in the United Kingdom over 20 years. Pediatr Blood Cancer 50 (4): 784-7, 2008.
57.	Hutchison RE, Laver JH, Chang M, et al.: Non-anaplastic peripheral t-cell lymphoma in childhood and adolescence: a Children's Oncology Group study. Pediatr Blood Cancer 51 (1): 29-33, 2008.
58.	Wang ZY, Li YX, Wang WH, et al.: Primary radiotherapy showed favorable outcome in treating extranodal nasal-type NK/T-cell lymphoma in children and adolescents. Blood 114 (23): 4771-6, 2009.
59.	Kim ST, Sim HJ, Jeon YS, et al.: Clinicopathological features and T-cell receptor gene rearrangement findings of mycosis fungoides in patients younger than age 20 years. J Dermatol 36 (7): 392-402, 2009.
60.	Kobayashi R, Yamato K, Tanaka F, et al.: Retrospective analysis of non-anaplastic peripheral T-cell lymphoma in pediatric patients in Japan. Pediatr Blood Cancer 54 (2): 212-5, 2010.
61.	Rosh JR, Gross T, Mamula P, et al.: Hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn's disease: a cautionary tale? Inflamm Bowel Dis 13 (8): 1024-30, 2007.

Stage Information for Childhood NHL

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), 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 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%
• T-cell lymphoblastic lymphoma: 3.7%
• Anaplastic large cell lymphoma: 3.3%
• Diffuse large B-cell lymphoma (DLBCL): 2.6%
• Primary mediastinal large B-cell lymphoma: 0%

Mature B-cell NHL (Burkitt lymphoma and DLBCL) patients have been treated based on features of the disease, other than stage.

Table 3. FAB/LMB and BFM Staging Schemas for B-cell NHL

	Stratum	Disease Manifestation
ALL = acute lymphoblastic leukemia; BFM = Berlin-Frankfurt-Munster; CNS= central nervous system; FAB = French-American-British; LDH = lactate dehydrogenase; NHL = non-Hodgkin lymphoma.
FAB/LMB International Study[3,4,5]	A	Completely resected stage I and abdominal stage II
	B	Multiple extra-abdominal sites
		Nonresected stage I and II, III, IV (marrow <25% blasts, no CNS disease)
	C	Mature B-cell ALL (>25% blasts in marrow) and/or CNS disease
BFM Group[6]	R1	Completely resected stage I and abdominal stage II
	R2	Nonresected stage I/II and stage III with LDH <500 IU/L
	R3	Stage III with LDH 500–999 IU/L
		Stage IV, B-ALL (>25% blasts), no CNS disease, and LDH <1,000 IU/L
	R4	Stage III, IV, B-cell ALL with LDH >1,000 IU/L
		Any CNS disease

References:

1.	Murphy SB, Fairclough DL, Hutchison RE, et al.: Non-Hodgkin's lymphomas of childhood: an analysis of the histology, staging, and response to treatment of 338 cases at a single institution. J Clin Oncol 7 (2): 186-93, 1989.
2.	Salzburg J, Burkhardt B, Zimmermann M, et al.: Prevalence, clinical pattern, and outcome of CNS involvement in childhood and adolescent non-Hodgkin's lymphoma differ by non-Hodgkin's lymphoma subtype: a Berlin-Frankfurt-Munster Group Report. J Clin Oncol 25 (25): 3915-22, 2007.
3.	Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007.
4.	Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007.
5.	Gerrard M, Cairo MS, Weston C, et al.: Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Br J Haematol 141 (6): 840-7, 2008.
6.	Reiter A, Schrappe M, Tiemann M, et al.: Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 94 (10): 3294-306, 1999.

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]

In contrast to the treatment of adults with NHL, the use of radiation therapy is limited in children with NHL. Early studies demonstrated that the routine use of radiation had no benefit for low-stage (I or II) NHL.[2] It has been demonstrated that prophylactic central nervous system (CNS) radiation can be omitted in lymphoblastic lymphoma.[3,4] It has also been demonstrated that CNS radiation can be eliminated for patients with anaplastic large cell lymphoma and B-cell NHL, even for patients who present with CNS disease.[5,6] Further data to support the limited use of radiation in pediatric NHL comes from the Childhood Cancer Survivor Study.[7] This analysis demonstrated that radiation was a significant risk factor for secondary malignancy and death in long-term survivors.

Treatment 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 demonstrated that the outcome for lymphoblastic NHL was superior with longer acute lymphoblastic leukemia–like therapy, while nonlymphoblastic NHL (Burkitt lymphoma) had superior outcome with short, intensive, pulsed therapy.[8]

Superior Mediastinal Syndrome (Anterior Mediastinal Mass)

There are two potentially life-threatening clinical situations that are often seen in children with NHL: (1) superior mediastinal tumor with airway compression 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.[9] 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.[10,11] Bone marrow aspirate and biopsy should always be performed early in the workup 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.[12] In situations in which the above diagnostic procedures are not fruitful, consideration of a computed tomography (CT)–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. Care should be taken to keep patients out of a supine position. Most procedures, including CT scans, can be done with the patient on their side or prone. Mediastinoscopy, anterior mediastinotomy, or thoracoscopy are the procedures of choice when other diagnostic modalities fail to establish the diagnosis. A formal thoracotomy is rarely, if ever, indicated for the diagnosis or treatment of childhood lymphoma. Occasionally, it will not be possible to perform a diagnostic operative procedure because of the risk of general anesthesia or heavy sedation. In these situations, preoperative treatment with steroids or 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 is thought to be alleviated.

Tumor Lysis Syndrome

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 patients except those with the most limited disease.[13,14,15,16] 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.

Role of Radiographic Imaging in Childhood NHL

Radiographic imaging is essential in the staging of patients with NHL. Ultrasound may be the preferred method for assessment of an abdominal mass, but CT scan and, more recently, magnetic resonance imaging (MRI) have been used for staging. Radionucleotide bone scans should be considered for patients where bone involvement is suspected.

The role of functional imaging in pediatric NHL is controversial. Gallium scans have been replaced by fluorodeoxyglucose positron emission tomography (PET) scanning, which is now routinely performed at many centers.[17] 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.[18,19] While the International Harmonization for PET had been attempted in adults, it has yet to be evaluated in pediatric populations.[17,20]

The value of PET scanning for staging pediatric NHL is under investigation, but there are no data that support the use of PET to upstage a patient.

The use of 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, and this is also under investigation in pediatric NHL. However, there are no data in pediatric NHL to support the hypothesis that early response to therapy assessed by PET has prognostic value.

Caution should be used in making the diagnosis of relapsed disease based solely on imaging because false-positive results are common.[21,22,23,24] There are also data demonstrating that PET scanning can produce false-negative results.[25] Before undertaking changes in therapy based on residual masses noted by imaging, a biopsy to prove residual disease is warranted.

References:

1.	Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996.
2.	Link MP, Shuster JJ, Donaldson SS, et al.: Treatment of children and young adults with early-stage non-Hodgkin's lymphoma. N Engl J Med 337 (18): 1259-66, 1997.
3.	Burkhardt B, Woessmann W, Zimmermann M, et al.: Impact of cranial radiotherapy on central nervous system prophylaxis in children and adolescents with central nervous system-negative stage III or IV lymphoblastic lymphoma. J Clin Oncol 24 (3): 491-9, 2006.
4.	Sandlund JT, Pui CH, Zhou Y, et al.: Effective treatment of advanced-stage childhood lymphoblastic lymphoma without prophylactic cranial irradiation: results of St Jude NHL13 study. Leukemia 23 (6): 1127-30, 2009.
5.	Seidemann K, Tiemann M, Schrappe M, et al.: Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 97 (12): 3699-706, 2001.
6.	Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007.
7.	Bluhm EC, Ronckers C, Hayashi RJ, et al.: Cause-specific mortality and second cancer incidence after non-Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood 111 (8): 4014-21, 2008.
8.	Anderson JR, Jenkin RD, Wilson JF, et al.: Long-term follow-up of patients treated with COMP or LSA2L2 therapy for childhood non-Hodgkin's lymphoma: a report of CCG-551 from the Childrens Cancer Group. J Clin Oncol 11 (6): 1024-32, 1993.
9.	Azizkhan RG, Dudgeon DL, Buck JR, et al.: Life-threatening airway obstruction as a complication to the management of mediastinal masses in children. J Pediatr Surg 20 (6): 816-22, 1985.
10.	King DR, Patrick LE, Ginn-Pease ME, et al.: Pulmonary function is compromised in children with mediastinal lymphoma. J Pediatr Surg 32 (2): 294-9; discussion 299-300, 1997.
11.	Shamberger RC, Holzman RS, Griscom NT, et al.: Prospective evaluation by computed tomography and pulmonary function tests of children with mediastinal masses. Surgery 118 (3): 468-71, 1995.
12.	Prakash UB, Abel MD, Hubmayr RD: Mediastinal mass and tracheal obstruction during general anesthesia. Mayo Clin Proc 63 (10): 1004-11, 1988.
13.	Pui CH, Mahmoud HH, Wiley JM, et al.: Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients With leukemia or lymphoma. J Clin Oncol 19 (3): 697-704, 2001.
14.	Goldman SC, Holcenberg JS, Finklestein JZ, et al.: A randomized comparison between rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor lysis. Blood 97 (10): 2998-3003, 2001.
15.	Cairo MS, Bishop M: Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 127 (1): 3-11, 2004.
16.	Cairo MS, Coiffier B, Reiter A, et al.: Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol 149 (4): 578-86, 2010.
17.	Juweid ME, Stroobants S, Hoekstra OS, et al.: Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 25 (5): 571-8, 2007.
18.	Brepoels L, Stroobants S, De Wever W, et al.: Hodgkin lymphoma: Response assessment by revised International Workshop Criteria. Leuk Lymphoma 48 (8): 1539-47, 2007.
19.	Cheson BD, Pfistner B, Juweid ME, et al.: Revised response criteria for malignant lymphoma. J Clin Oncol 25 (5): 579-86, 2007.
20.	Cheson BD: The International Harmonization Project for response criteria in lymphoma clinical trials. Hematol Oncol Clin North Am 21 (5): 841-54, 2007.
21.	Nasr A, Stulberg J, Weitzman S, et al.: Assessment of residual posttreatment masses in Hodgkin's disease and the need for biopsy in children. J Pediatr Surg 41 (5): 972-4, 2006.
22.	Levine JM, Weiner M, Kelly KM: Routine use of PET scans after completion of therapy in pediatric Hodgkin disease results in a high false positive rate. J Pediatr Hematol Oncol 28 (11): 711-4, 2006.
23.	Rhodes MM, Delbeke D, Whitlock JA, et al.: Utility of FDG-PET/CT in follow-up of children treated for Hodgkin and non-Hodgkin lymphoma. J Pediatr Hematol Oncol 28 (5): 300-6, 2006.
24.	Meany HJ, Gidvani VK, Minniti CP: Utility of PET scans to predict disease relapse in pediatric patients with Hodgkin lymphoma. Pediatr Blood Cancer 48 (4): 399-402, 2007.
25.	Picardi M, De Renzo A, Pane F, et al.: Randomized comparison of consolidation radiation versus observation in bulky Hodgkin's lymphoma with post-chemotherapy negative positron emission tomography scans. Leuk Lymphoma 48 (9): 1721-7, 2007.

Low-Stage Childhood NHL Treatment

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Patients with stage I and II disease have an excellent prognosis, regardless of histology. A Children's Cancer Group study demonstrated that pulsed chemotherapy with cyclophosphamide, vincristine, methotrexate, and prednisone (COMP) administered for 6 months for low-stage (stage I or II) nonlymphoblastic non-Hodgkin lymphoma (NHL) was equivalent to 18 months of therapy with radiation to sites of disease, resulting in more than 85% disease-free survival (DFS) and more than 90% overall survival (OS). However, patients with lymphoblastic lymphoma had a much inferior outcome.[1,2] 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 low-stage mature B-cell NHL (Burkitt lymphoma or diffuse large B-cell lymphoma [DLBCL]), DFS is about 95%. The Berlin-Frankfurt-Munster (BFM) group has treated risk group R1 (completely resected disease) with two cycles of multiagent chemotherapy (GER-GPOH-NHL-BFM-90 and GER-GPOH-NHL-BFM-95).[4,5] For unresected stage I/II disease (R2), patients received a cytoreductive phase followed by five cycles of chemotherapy.[4,5] In the NHL-BFM-90 study, it was shown that reducing the dose of methotrexate did not affect the results for low-stage disease.[4] In NHL-BFM-95, it was demonstrated for low-stage disease that prolonging the duration of methotrexate infusion did not improve outcome.[5] The French Society of Pediatric Oncology (SFOP) and French-American-British (FAB) studies have treated all completely resected stage I and abdominal stage II (group A) with two cycles of multiagent chemotherapy, without intrathecal chemotherapy (COG-C5961 [FAB/LMB-96]).[6][Level of evidence: 2A] For unresected stage I/II disease (group B), the above-mentioned FAB study demonstrated that reducing the duration of therapy to four cycles of chemotherapy following a cytoreduction phase and reducing the cumulative doses of cyclophosphamide and doxorubicin did not affect outcome.[7]

For low-stage lymphoblastic lymphoma (stage I/II disease), about 60% of patients can achieve long-term DFS with short, pulsed chemotherapy.[2,3] However, using an acute lymphoblastic leukemia approach with induction, consolidation, and maintenance for a total of 24 months, the BFM group (NHL-BFM-90/95) has shown more than 90% DFS for low-stage lymphoblastic lymphoma.[8,9]

For low-stage anaplastic large cell lymphoma (ALCL), the best results have come from using pulsed chemotherapy similar to mature B-cell NHL therapy. In the POG study for low-stage lymphoma using three cycles of CHOP, a 5-year event-free survival (EFS) of 88% for large cell lymphoma (ALCL and DLBCL) patients was reported.[3] The BFM group has used three cycles of chemotherapy following a cytoreductive prophase for completely resected stage I/II disease.[10] The FRE-IGR-ALCL99 trial used three cycles of chemotherapy following cytoreductive prophase for patients with stage I completely resected disease. The minority of stage I patients had complete resections (6 out of 36) but there were no treatment failures for these six patients. The therapy for patients without complete resection was the same as the therapy for patients with disseminated disease and the 3-year EFS (81%) and OS (97%) were not statistically different from the outcomes for patients with higher stage disease.[11][Level of evidence: 2A]

Primary cutaneous ALCL presents a particular problem. The diagnosis can be difficult to distinguish from more benign diseases such as lymphoid papulosis.[12] Primary cutaneous ALCL usually does not express ALK and may be treated successfully with surgical resection and/or local radiation therapy without systemic chemotherapy.[13] There are reports of surgery alone being curative for ALK-positive cutaneous ALCL, but extensive staging and vigilant follow-up is required.

Follicular lymphoma is rare in children, with only case reports and case series to guide therapy. Case series reporting a variety of chemotherapy approaches have resulted in good outcomes.[14]

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

Table 4. Standard Treatment Options for Low-Stage Non-Hodgkin Lymphoma

Disease	Treatment Options
Burkitt lymphoma or diffuse large B-cell lymphoma (DLBCL) (completely resected)	GER-GPOH-NHL-BFM-95 (R1): Two cycles of chemotherapy.[5]
	COG-C5961 (FAB/LMB-96)(Group A): Two cycles of chemotherapy.[6]
Burkitt lymphoma or DLBCL (nonresected stage I/II)	GER-GPOH-NHL-BFM-95 (R2): Prephase + four cycles of chemotherapy (4-hour methotrexate infusion).[5]
	COG-C5961 (FAB/LMB-96)(Group B): Prephase + four cycles of chemotherapy (reduced-intensity arm).[7]
	POG-8314/POG-8719: Three cycles of chemotherapy (no radiation or maintenance therapy).[3]
Lymphoblastic lymphoma	GER-GPOH-NHL-BFM-95: Induction, consolidation, intensification, and maintenance therapy (2 years of total therapy); ALL-type induction and consolidation, high-dose methotrexate courses × 4, and ALL-type maintenance therapy (2 years of total therapy).[8,9]
Anaplastic large cell lymphoma	POG-8314/POG-8719: Three cycles of chemotherapy (no radiation or maintenance therapy).[3]
	GER-GPOH-NHL-BFM-90: Prephase + three cycles of chemotherapy (only for completely resected disease).[10]
	FRE-IGR-ALCL99: Prephase + six cycles of chemotherapy (for disease not completely resected).[11]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I childhood large cell lymphoma, stage I childhood small noncleaved cell lymphoma, stage I childhood lymphoblastic lymphoma, stage I childhood anaplastic large cell lymphoma, stage II childhood large cell lymphoma, stage II childhood small noncleaved cell lymphoma, stage II childhood lymphoblastic lymphoma and stage II childhood anaplastic large cell lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1.	Meadows AT, Sposto R, Jenkin RD, et al.: Similar efficacy of 6 and 18 months of therapy with four drugs (COMP) for localized non-Hodgkin's lymphoma of children: a report from the Childrens Cancer Study Group. J Clin Oncol 7 (1): 92-9, 1989.
2.	Anderson JR, Jenkin RD, Wilson JF, et al.: Long-term follow-up of patients treated with COMP or LSA2L2 therapy for childhood non-Hodgkin's lymphoma: a report of CCG-551 from the Childrens Cancer Group. J Clin Oncol 11 (6): 1024-32, 1993.
3.	Link MP, Shuster JJ, Donaldson SS, et al.: Treatment of children and young adults with early-stage non-Hodgkin's lymphoma. N Engl J Med 337 (18): 1259-66, 1997.
4.	Reiter A, Schrappe M, Tiemann M, et al.: Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 94 (10): 3294-306, 1999.
5.	Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005.
6.	Gerrard M, Cairo MS, Weston C, et al.: Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Br J Haematol 141 (6): 840-7, 2008.
7.	Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007.
8.	Reiter A, Schrappe M, Ludwig WD, et al.: Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood 95 (2): 416-21, 2000.
9.	Burkhardt B, Woessmann W, Zimmermann M, et al.: Impact of cranial radiotherapy on central nervous system prophylaxis in children and adolescents with central nervous system-negative stage III or IV lymphoblastic lymphoma. J Clin Oncol 24 (3): 491-9, 2006.
10.	Seidemann K, Tiemann M, Schrappe M, et al.: Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 97 (12): 3699-706, 2001.
11.	Attarbaschi A, Mann G, Rosolen A, et al.: Limited stage I disease is not necessarily indicative of an excellent prognosis in childhood anaplastic large cell lymphoma. Blood 117 (21): 5616-9, 2011.
12.	Kumar S, Pittaluga S, Raffeld M, et al.: Primary cutaneous CD30-positive anaplastic large cell lymphoma in childhood: report of 4 cases and review of the literature. Pediatr Dev Pathol 8 (1): 52-60, 2005 Jan-Feb.
13.	Hinshaw M, Trowers AB, Kodish E, et al.: Three children with CD30 cutaneous anaplastic large cell lymphomas bearing the t(2;5)(p23;q35) translocation. Pediatr Dermatol 21 (3): 212-7, 2004 May-Jun.
14.	Kumar R, Galardy PJ, Dogan A, et al.: Rituximab in combination with multiagent chemotherapy for pediatric follicular lymphoma. Pediatr Blood Cancer 57 (2): 317-20, 2011.

High-Stage Childhood B-cell NHL Treatment

Patients with high-stage (stage III or stage IV) 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] Unlike mature B-lineage NHL seen in adults, there is no difference in outcome based on histology (Burkitt or Burkitt-like lymphoma or DLBCL) with current therapy in pediatric trials.[1,2,3]

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.[1,3]

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 subsection in 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 prophase of reduced intensity to cytoreduce patients;[1,2,3] 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.[4]

In the NHL-BFM-95 trial, it was shown that when the dose of methotrexate was reduced for R1 and R2 patients, outcome was not inferior; however, reducing the infusion time of methotrexate from 24 hours to 4 hours for R3 and R4 group patients resulted in less mucositis, but inferior outcome.[1] Event-free survival (EFS) with best therapy in NHL-BFM-95 was more than 95% for R1 and R2 group patients and was 93% for R3 and R4 group patients. Inferior outcome was observed for patients with primary mediastinal B-cell lymphoma (50% 3-year EFS) and CNS disease at presentation (70% 3-year EFS).[5] In the COG-C5961 (FAB/LMB-96) study, the outcome of group B patients, who had a greater than 20% response to cytoreductive prophase, was not affected by a reduction of the total dose of cyclophosphamide by 50% and elimination of one cycle of maintenance therapy.[2] The 3-year EFS was 98% for stage I/II, 90% for stage III, and 86% for stage IV (CNS-negative) patients, while patients with primary mediastinal B-cell lymphoma had a 3-year EFS of 70%.[2] In group C patients, reduction in cumulative dose of therapy and number of maintenance cycles resulted in inferior outcome.[3] Patients with leukemic disease only, and no CNS disease, had a 3-year EFS of 90%, while patients with CNS disease at presentation had a 70% 3-year EFS.[3] This study identified response to prophase reduction as the most significant prognostic factor, with poor responders (i.e., <20% resolution of disease) having an EFS of 30%.[3] Both the Berlin-Frankfurt-Munster (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]).[1,2,3,5]

Rituximab is a mouse/human chimeric monoclonal antibody targeting the CD20 antigen. Among the lymphomas that occur in children, DLBCL and Burkitt lymphoma both express high levels of CD20.[6] Rituximab has been safely combined with standard doxorubicin, cyclophosphamide, vincristine, and prednisone (CHOP) chemotherapy and has been shown to improve outcome in a randomized trial of adults with DLBCL (CAN-NCIC-LY9).[7,8] In an adult study, rituximab has also been safely combined with an intensive chemotherapy regimen used to treat patients with Burkitt lymphoma.[9] In children, a single-agent phase II study of rituximab performed by the BFM group showed activity in Burkitt leukemia and lymphoma.[10][Level of evidence: 2Div] A Children's Oncology Group (COG) pilot study (COG-ANHL01P1) to test the toxicity of adding rituximab to FAB/LMB-96 (COG-C5961) has completed accrual and results are pending.

Standard Treatment Options

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

Table 5. Standard Treatment Options for High-Stage B-cell NHL

	Stratum	Disease Manifestations	Treatment
ALL = acute lymphoblastic leukemia; BFM = Berlin-Frankfurt-Munster; CNS = central nervous system; LDH = lactate dehydrogenase; NHL= non-Hodgkin lymphoma.
FAB/LMB-96 International Study COG-C5961 (FAB/LMB-96)[2,3]	B	Multiple extra-abdominal sites	Prephase + four cycles of chemotherapy (reduced intensity arm)[2]
		Nonresected stage I and II, III, IV
		Marrow <25% blasts
		No CNS disease
	C	Mature B-cell ALL (>25% blasts in marrow) and/or CNS disease	Prephase + eight cycles of chemotherapy (full intensity arm)[3]
BFM Group[1,5]	R2	Nonresected stage I/II and stage III with LDH <500 IU/L	Prephase + four cycles of chemotherapy (4 h methotrexate infusion)[1]
	R3	Stage III with LDH 500–999 IU/L	Prephase + five cycles of chemotherapy (24 h methotrexate infusion)[1]
		Stage IV, B-cell ALL (>25% blasts) and LDH <1,000 IU/L
		No CNS disease
	R4	Stage III, IV, B-cell ALL with LDH >1,000 IU/L	Prephase + six cycles of chemotherapy (24 h methotrexate infusion)[1]
		Any CNS disease

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III childhood large cell lymphoma, stage III childhood small noncleaved cell lymphoma, stage IV childhood large cell lymphoma and stage IV childhood small noncleaved cell lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1.	Woessmann W, Seidemann K, Mann G, et al.: The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 105 (3): 948-58, 2005.
2.	Patte C, Auperin A, Gerrard M, et al.: Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 109 (7): 2773-80, 2007.
3.	Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007.
4.	Cairo MS, Bishop M: Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol 127 (1): 3-11, 2004.
5.	Reiter A, Schrappe M, Tiemann M, et al.: Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: A report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 94 (10): 3294-306, 1999.
6.	Perkins SL, Lones MA, Davenport V, et al.: B-Cell non-Hodgkin's lymphoma in children and adolescents: surface antigen expression and clinical implications for future targeted bioimmune therapy: a children's cancer group report. Clin Adv Hematol Oncol 1 (5): 314-7, 2003.
7.	Coiffier B, Lepage E, Briere J, et al.: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346 (4): 235-42, 2002.
8.	Pfreundschuh M, Trümper L, Osterborg A, et al.: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7 (5): 379-91, 2006.
9.	Thomas DA, Faderl S, O'Brien S, et al.: Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer 106 (7): 1569-80, 2006.
10.	Meinhardt A, Burkhardt B, Zimmermann M, et al.: Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-Hodgkin's lymphoma and Burkitt leukemia. J Clin Oncol 28 (19): 3115-21, 2010.

High-Stage Childhood Lymphoblastic Lymphoma Treatment

Patients with high-stage (stage III or IV) lymphoblastic lymphoma have long-term survival rates higher than 80%.[1] Unlike 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.[1,2,3]

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 (ALL).

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 either corticosteroid therapy or 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.

The best results to date come from the Berlin-Frankfurt-Munster (BFM) group. In the GER-GPOH-NHL-BFM-90 study, the 5-year disease-free survival was 90%, and there was no difference in outcome between stage III and stage IV patients.[1] Precursor B-cell lymphoblastic lymphoma appears to have similar results using the same therapy.[4] In the GER-GPOH-NHL-BFM-95 study, 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.[3] Of interest, the probability of 5-year event-free survival (EFS) rates was worse in NHL-BFM-95 than in NHL-BFM-90 (82% vs. 90%, respectively). Although this difference was not statistically different, NHL-BFM-95 had a reduction of asparaginase and doxorubicin in induction, which may have affected outcome. It was proposed that the major difference in EFS between NHL-BFM-90 and NHL-BFM-95 resulted from the increased number of secondary malignancies observed in NHL-BFM-95.[3] A single-center study suggests that patients treated for lymphoblastic lymphoma have a higher incidence of secondary malignancy than do patients treated for other pediatric NHL; however, studies from the Children's Oncology Group and the Childhood Cancer Survivor Study Group do not support this finding.[5,6,7]

The Pediatric Oncology Group conducted a trial to test the effectiveness of the addition of high-dose methotrexate in T-cell ALL and T-cell lymphoblastic lymphoma. In the lymphoma patients, high-dose methotrexate did not demonstrate benefit. However, in the small cohort (n = 66) of lymphoma patients who did not receive high-dose methotrexate, the 5-year EFS was 88%.[8][Level of evidence: 1iiA] Of note, all of these patients received prophylactic craniospinal radiation therapy, which has been demonstrated not to be required in T-cell lymphoblastic lymphoma patients.[3]

Standard Treatment Options

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

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

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III childhood lymphoblastic lymphoma and stage IV childhood lymphoblastic lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1.	Reiter A, Schrappe M, Ludwig WD, et al.: Intensive ALL-type therapy without local radiotherapy provides a 90% event-free survival for children with T-cell lymphoblastic lymphoma: a BFM group report. Blood 95 (2): 416-21, 2000.
2.	Anderson JR, Jenkin RD, Wilson JF, et al.: Long-term follow-up of patients treated with COMP or LSA2L2 therapy for childhood non-Hodgkin's lymphoma: a report of CCG-551 from the Childrens Cancer Group. J Clin Oncol 11 (6): 1024-32, 1993.
3.	Burkhardt B, Woessmann W, Zimmermann M, et al.: Impact of cranial radiotherapy on central nervous system prophylaxis in children and adolescents with central nervous system-negative stage III or IV lymphoblastic lymphoma. J Clin Oncol 24 (3): 491-9, 2006.
4.	Burkhardt B, Zimmermann M, Oschlies I, et al.: The impact of age and gender on biology, clinical features and treatment outcome of non-Hodgkin lymphoma in childhood and adolescence. Br J Haematol 131 (1): 39-49, 2005.
5.	Leung W, Sandlund JT, Hudson MM, et al.: Second malignancy after treatment of childhood non-Hodgkin lymphoma. Cancer 92 (7): 1959-66, 2001.
6.	Abromowitch M, Sposto R, Perkins S, et al.: Shortened intensified multi-agent chemotherapy and non-cross resistant maintenance therapy for advanced lymphoblastic lymphoma in children and adolescents: report from the Children's Oncology Group. Br J Haematol 143 (2): 261-7, 2008.
7.	Bluhm EC, Ronckers C, Hayashi RJ, et al.: Cause-specific mortality and second cancer incidence after non-Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood 111 (8): 4014-21, 2008.
8.	Asselin BL, Devidas M, Wang C, et al.: Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404). Blood 118 (4): 874-83, 2011.

High-Stage Childhood Anaplastic Large Cell Lymphoma Treatment

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Children and adolescents with high-stage (stage III or IV) anaplastic large cell lymphoma (ALCL) have a disease-free survival of approximately 60% to 75%.[1,2,3,4,5] It is unclear which strategy is best for the treatment of high-stage ALCL. The German Berlin-Frankfurt-Munster (BFM) group used six cycles of intensive pulsed therapy, similar to their B-cell non-Hodgkin lymphoma (NHL) therapy (GER-GPOH-NHL-BFM-90 [NHL-BFM-90]).[2]; [6][Level of evidence: 1iiA] Building on these results, the European Intergroup for Childhood NHL (EICNHL) group conducted the FRE-IGR-ALCL99 study (based on the GER-GPOH-NHL-BFM-90 regimen). First, this randomized study demonstrated that methotrexate 1 g/m² infused over 24 hours plus intrathecal methotrexate and methotrexate 3 g/m² infused over 3 hours without intrathecal methotrexate yielded similar outcomes.[7][Level of evidence: 1iiC] However, methotrexate 3 g/m² over 3 hours had less toxicity than methotrexate 1 g/m² over 24 hours.[7]; [6][Level of evidence: 1iiDi] Secondly, FRE-IGR-ALCL99 randomly assigned patients to limited vinblastine versus prolonged (1 year) vinblastine exposure. Patients receiving the vinblastine plus chemotherapy regimen had a better event-free survival (EFS) in the first year after therapy (91%) than those not receiving vinblastine (74%); however, after 2 years of follow-up, the EFS was 73% for both groups.[8][Level of evidence: 1iiDi] Of note, the Pediatric Oncology Group (POG) trial (POG-9317) demonstrated no benefit of adding methotrexate and high-dose cytarabine to 52 weeks of the APO (doxorubicin, prednisone, and vincristine) regimen.[3] The Italian Association of Pediatric Hematology/Oncology group has used a leukemia-like regimen for 24 months in LNH-92, with similar results as other regimens.[4] The CCG-5941 study tested an approach similar to LNH-92, with more intensive induction and consolidation with maintenance for 1 year total duration of therapy, with similar outcome, but significant hematologic toxicity was observed.[5][Level of evidence: 2A]

Standard Treatment Options

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

• APO: doxorubicin, prednisone, and vincristine.[3]This regimen can be administered in the outpatient setting. The duration of therapy is 52 weeks and the cumulative dose of doxorubicin in 300 mg/m².
• FRE-IGR-ALCL99: dexamethasone, cyclophosphamide, ifosfamide, etoposide, doxorubicin, IV methotrexate (3 g/m² arm), cytarabine, prednisolone, and vinblastine.[6]This regimen usually requires hospitalization for administration. The total duration of therapy is 5 months and the cumulative dose of doxorubicin is 150 mg/m².

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III childhood anaplastic large cell lymphoma and stage IV childhood anaplastic large cell lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1.	Brugières L, Deley MC, Pacquement H, et al.: CD30(+) anaplastic large-cell lymphoma in children: analysis of 82 patients enrolled in two consecutive studies of the French Society of Pediatric Oncology. Blood 92 (10): 3591-8, 1998.
2.	Seidemann K, Tiemann M, Schrappe M, et al.: Short-pulse B-non-Hodgkin lymphoma-type chemotherapy is efficacious treatment for pediatric anaplastic large cell lymphoma: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 97 (12): 3699-706, 2001.
3.	Laver JH, Kraveka JM, Hutchison RE, et al.: Advanced-stage large-cell lymphoma in children and adolescents: results of a randomized trial incorporating intermediate-dose methotrexate and high-dose cytarabine in the maintenance phase of the APO regimen: a Pediatric Oncology Group phase III trial. J Clin Oncol 23 (3): 541-7, 2005.
4.	Rosolen A, Pillon M, Garaventa A, et al.: Anaplastic large cell lymphoma treated with a leukemia-like therapy: report of the Italian Association of Pediatric Hematology and Oncology (AIEOP) LNH-92 protocol. Cancer 104 (10): 2133-40, 2005.
5.	Lowe EJ, Sposto R, Perkins SL, et al.: Intensive chemotherapy for systemic anaplastic large cell lymphoma in children and adolescents: final results of Children's Cancer Group Study 5941. Pediatr Blood Cancer 52 (3): 335-9, 2009.
6.	Brugières L, Le Deley MC, Rosolen A, et al.: Impact of the methotrexate administration dose on the need for intrathecal treatment in children and adolescents with anaplastic large-cell lymphoma: results of a randomized trial of the EICNHL Group. J Clin Oncol 27 (6): 897-903, 2009.
7.	Wrobel G, Mauguen A, Rosolen A, et al.: Safety assessment of intensive induction therapy in childhood anaplastic large cell lymphoma: report of the ALCL99 randomised trial. Pediatr Blood Cancer 56 (7): 1071-7, 2011.
8.	Le Deley MC, Rosolen A, Williams DM, et al.: Vinblastine in children and adolescents with high-risk anaplastic large-cell lymphoma: results of the randomized ALCL99-vinblastine trial. J Clin Oncol 28 (25): 3987-93, 2010.

Recurrent Childhood NHL Treatment

Outcome for recurrent non-Hodgkin lymphoma (NHL) in children and adolescents depends on histologic subtype. A Children's Cancer Group study (CCG-5912) was able to achieve complete remission (CR) in 40% of NHL patients.[1] A Pediatric Oncology Group study showed a 70% response rate and 40% CR rate.[2] Radiation therapy may have a role in treating patients who have not had a complete response to chemotherapy. All patients with primary refractory or relapsed NHL should be considered for clinical trials.

For recurrent or refractory B-lineage NHL, survival is generally 10% to 20%.[3,4,5,6,7] Chemoresistance is a major problem, making remission difficult to achieve. There is no standard treatment option for patients with recurrent or progressive disease. The use of single-agent rituximab, as well as rituximab combined with standard cytotoxic chemotherapy, has shown activity in the treatment of B-cell lymphoma patients.[8][Level of evidence: 3iiiDii] A Children's Oncology Group (COG) study using rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) to treat relapsed/refractory B-cell NHL (diffuse large B-cell lymphoma [DLBCL] and Burkitt lymphoma) showed a CR/partial remission (PR) rate of 60%.[9][Level of evidence: 3iiA] If remission can be achieved, high-dose therapy and stem cell transplantation (SCT) may be pursued. The benefit of autologous versus allogeneic SCT is unclear.[5,10,11,12]; [13][Level of evidence: 2A]; [14][Level of evidence: 3iiiDii] An analysis of the Center for International Blood and Marrow Transplant Research (CIBMTR) data demonstrated no difference using either autologous or allogeneic donor stem cell sources, with 2-year event-free survival (EFS) to be 30% for DLBCL and 50% for Burkitt lymphoma. This analysis also showed patients not in remission at time of transplant do significantly worse.[12,13] For patients who have a second relapse after initial autologous SCT, an allogeneic SCT was found to be a promising treatment in a study of adults with DLBCL.[15]

For recurrent or refractory lymphoblastic lymphoma, survival in the literature ranges from 10% to 40%.[5,16]; [17,18][Level of evidence: 3iiiA] As with Burkitt lymphoma, chemoresistant disease is common. There is no standard treatment option for patients with recurrent or progressive disease. A COG phase II study of nelarabine (compound 506U78) as a single agent demonstrated a response rate of 40%.[19] The CIBMTR analysis demonstrated that EFS was significantly worse using autologous (4%) versus allogeneic (40%) donor stem cell source, with all failures resulting from progressive disease.[12]

For recurrent or refractory anaplastic large cell lymphoma (ALCL), 40% to 60% of patients can achieve long-term survival.[5,20,21] There is no standard approach for recurrent/refractory ALCL; standard chemotherapy, followed by autologous SCT or allogeneic SCT, if remission can be achieved, have all been employed in this setting.[5,12,20,21]; [13][Level of evidence: 2A] In a retrospective study of relapsed or refractory ALCL in patients who received Berlin-Frankfurt-Muenster–type first-line therapy, reinduction chemotherapy followed by autologous stem cell transplant resulted in 59% 5-year EFS and 77% overall survival.[21][Level of evidence: 2A] However, outcome of patients with bone marrow or central nervous system involvement, relapse during first-line therapy, or CD3-positive ALCL was poor. These patients may benefit from allogeneic transplantation.[21] Several additional studies suggest that allogeneic SCT may result in better outcome for refractory/relapsed ALCL.[12,22] Vinblastine is active as a single agent in recurrent/refractory ALCL, inducing CR in 25 (83%) of 30 evaluable patients in one study.[23] Nine of 25 patients treated with vinblastine alone remained in CR with median follow-up of 7 years since the end of treatment.[23][Level of evidence: 3iiiA] Brentuximab vedotin has been evaluated in adults with ALCL. A phase I study in adults with CD30-positive cancers identified a recommended phase II dose of 1.8 mg/kg, administered every 3 weeks; two of two patients with ALCL achieved CR.[24] A phase II trial in adults with relapsed ALCL (N = 58 with 72% ALK-negative) showed a CR rate of 57% and a PR rate of 29%.[25] The number of pediatric patients treated with brentuximab vedotin is not sufficient to determine whether they respond differently than adult patients.

Treatment Options

Burkitt lymphoma and DLBCL

• DECAL: dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase.[1]
• ICE (ifosfamide, carboplatin, and etoposide) plus rituximab (for B-cell lymphoma).[9]
• Allogeneic or autologous bone marrow transplantation (BMT).[12]

Lymphoblastic lymphoma

• DECAL: dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase.[1]
• ICE: ifosfamide, carboplatin, and etoposide.[2]
• Allogeneic BMT.[12]

ALCL

• DECAL: dexamethasone, etoposide, cisplatin, cytarabine, and L-asparaginase.[1]
• ICE: ifosfamide, carboplatin, and etoposide.[2]
• Vinblastine (for ALCL).[23]
• Allogeneic or autologous BMT.[12]

Treatment Options Under Clinical Evaluation

The following is an example of a national or international clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• COG-ADVL0912(Crizotinib in Treating Young Patients With Relapsed or Refractory Solid Tumors or ALCL): TheALKinhibitor, crizotinib, is under phase I evaluation in children. The study has a stratum for children withALKand ALCL.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood non-Hodgkin lymphoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1.	Kobrinsky NL, Sposto R, Shah NR, et al.: Outcomes of treatment of children and adolescents with recurrent non-Hodgkin's lymphoma and Hodgkin's disease with dexamethasone, etoposide, cisplatin, cytarabine, and l-asparaginase, maintenance chemotherapy, and transplantation: Children's Cancer Group Study CCG-5912. J Clin Oncol 19 (9): 2390-6, 2001.
2.	Kung FH, Harris MB, Krischer JP: Ifosfamide/carboplatin/etoposide (ICE), an effective salvaging therapy for recurrent malignant non-Hodgkin lymphoma of childhood: a Pediatric Oncology Group phase II study. Med Pediatr Oncol 32 (3): 225-6, 1999.
3.	Cairo MS, Sposto R, Perkins SL, et al.: Burkitt's and Burkitt-like lymphoma in children and adolescents: a review of the Children's Cancer Group experience. Br J Haematol 120 (4): 660-70, 2003.
4.	Atra A, Gerrard M, Hobson R, et al.: Outcome of relapsed or refractory childhood B-cell acute lymphoblastic leukaemia and B-cell non-Hodgkin's lymphoma treated with the UKCCSG 9003/9002 protocols. Br J Haematol 112 (4): 965-8, 2001.
5.	Attarbaschi A, Dworzak M, Steiner M, et al.: Outcome of children with primary resistant or relapsed non-Hodgkin lymphoma and mature B-cell leukemia after intensive first-line treatment: a population-based analysis of the Austrian Cooperative Study Group. Pediatr Blood Cancer 44 (1): 70-6, 2005.
6.	Cairo MS, Sposto R, Hoover-Regan M, et al.: Childhood and adolescent large-cell lymphoma (LCL): a review of the Children's Cancer Group experience. Am J Hematol 72 (1): 53-63, 2003.
7.	Cairo MS, Gerrard M, Sposto R, et al.: Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 109 (7): 2736-43, 2007.
8.	Attias D, Weitzman S: The efficacy of rituximab in high-grade pediatric B-cell lymphoma/leukemia: a review of available evidence. Curr Opin Pediatr 20 (1): 17-22, 2008.
9.	Griffin TC, Weitzman S, Weinstein H, et al.: A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell (CD20+) non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group. Pediatr Blood Cancer 52 (2): 177-81, 2009.
10.	Ladenstein R, Pearce R, Hartmann O, et al.: High-dose chemotherapy with autologous bone marrow rescue in children with poor-risk Burkitt's lymphoma: a report from the European Lymphoma Bone Marrow Transplantation Registry. Blood 90 (8): 2921-30, 1997.
11.	Sandlund JT, Bowman L, Heslop HE, et al.: Intensive chemotherapy with hematopoietic stem-cell support for children with recurrent or refractory NHL. Cytotherapy 4 (3): 253-8, 2002.
12.	Gross TG, Hale GA, He W, et al.: Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents. Biol Blood Marrow Transplant 16 (2): 223-30, 2010.
13.	Harris RE, Termuhlen AM, Smith LM, et al.: Autologous peripheral blood stem cell transplantation in children with refractory or relapsed lymphoma: results of Children's Oncology Group study A5962. Biol Blood Marrow Transplant 17 (2): 249-58, 2011.
14.	Andion M, Molina B, Gonzalez-Vicent M, et al.: High-dose busulfan and cyclophosphamide as a conditioning regimen for autologous peripheral blood stem cell transplantation in childhood non-Hodgkin lymphoma patients: a long-term follow-up study. J Pediatr Hematol Oncol 33 (3): e89-91, 2011.
15.	van Kampen RJ, Canals C, Schouten HC, et al.: Allogeneic stem-cell transplantation as salvage therapy for patients with diffuse large B-cell non-Hodgkin's lymphoma relapsing after an autologous stem-cell transplantation: an analysis of the European Group for Blood and Marrow Transplantation Registry. J Clin Oncol 29 (10): 1342-8, 2011.
16.	Abromowitch M, Sposto R, Perkins S, et al.: Shortened intensified multi-agent chemotherapy and non-cross resistant maintenance therapy for advanced lymphoblastic lymphoma in children and adolescents: report from the Children's Oncology Group. Br J Haematol 143 (2): 261-7, 2008.
17.	Mitsui T, Mori T, Fujita N, et al.: Retrospective analysis of relapsed or primary refractory childhood lymphoblastic lymphoma in Japan. Pediatr Blood Cancer 52 (5): 591-5, 2009.
18.	Burkhardt B, Reiter A, Landmann E, et al.: Poor outcome for children and adolescents with progressive disease or relapse of lymphoblastic lymphoma: a report from the berlin-frankfurt-muenster group. J Clin Oncol 27 (20): 3363-9, 2009.
19.	Berg SL, Blaney SM, Devidas M, et al.: Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group. J Clin Oncol 23 (15): 3376-82, 2005.
20.	Mori T, Takimoto T, Katano N, et al.: Recurrent childhood anaplastic large cell lymphoma: a retrospective analysis of registered cases in Japan. Br J Haematol 132 (5): 594-7, 2006.
21.	Woessmann W, Zimmermann M, Lenhard M, et al.: Relapsed or refractory anaplastic large-cell lymphoma in children and adolescents after Berlin-Frankfurt-Muenster (BFM)-type first-line therapy: a BFM-group study. J Clin Oncol 29 (22): 3065-71, 2011.
22.	Woessmann W, Peters C, Lenhard M, et al.: Allogeneic haematopoietic stem cell transplantation in relapsed or refractory anaplastic large cell lymphoma of children and adolescents--a Berlin-Frankfurt-Münster group report. Br J Haematol 133 (2): 176-82, 2006.
23.	Brugières L, Pacquement H, Le Deley MC, et al.: Single-drug vinblastine as salvage treatment for refractory or relapsed anaplastic large-cell lymphoma: a report from the French Society of Pediatric Oncology. J Clin Oncol 27 (30): 5056-61, 2009.
24.	Younes A, Bartlett NL, Leonard JP, et al.: Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 363 (19): 1812-21, 2010.
25.	Seattle Genetics, Inc.: ADCETRIS (Brentuximab Vedotin): Prescribing Information. Bothell, Wa: Seattle Genetics, 2012. Available online. Last accessed March 29, 2012.

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).[1,2,3,4] One potential exception is the more indolent low-grade lymphomas (e.g., mucosa-associated lymphoid tissue [MALT] lymphomas), which have developed in patients with common variable immunodeficiency or other immunodeficient states.[5,6] 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 high-stage (stage III or IV) 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. (Refer to the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information about MALT lymphomas.)

In the era of highly active antiretroviral therapy, children with human immunodeficiency virus and NHL should be treated with standard chemotherapy regimens for NHL, but careful attention to prophylaxis against and early detection of infection is warranted.[1,7] 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.[8] Immunologic correction through allogeneic stem cell transplantation is often required to prevent recurrences. Patients with DNA repair defects (e.g., ataxia-telangiectasia) are particularly difficult to treat.[4,9] Cytotoxic agents produce much more toxicity and greatly increase the risk of secondary malignancies in these patients. Survival is rare at 5 years postdiagnosis.

In posttransplant lymphoproliferative disease (PTLD), first-line therapy is the reduction of immunosuppression as can be tolerated, although it has been reported that immediate use of lymphoma-directed therapy results in an improved outcome for patients with either the monomorphic or the Burkitt lymphoma form of PTLD.[3,10,11] Rituximab, an anti-CD20 antibody, has been used with some success, but data for its use in children are sparse. Rituximab plus low-intensity chemotherapy may also be effective, even in PTLDs with the t(8;14) Burkitt lymphoma marker.[12][Level of evidence: 3iiDiii] Patients with T-cell or Hodgkin-like PTLD are usually treated with standard lymphoma-specific chemotherapy regimens.[13,14,15,16]

Standard Treatment Options

• Standard chemotherapy regimens for specific histology.[1,2,8,17]
• Low-dose chemotherapy.[3,12][Level of evidence: 3iiDiii]

Treatment Options Under Clinical Evaluation

The following is an example of a national or international clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• Adoptive immunotherapy with either donor lymphocytes orex vivo –generated Epstein-Barr virus–specific cytotoxic T-cells have been effective in treating PTLD following blood or bone marrow transplant.[18,19]Though this approach has been demonstrated to be feasible in patients with PTLD following solid organ transplant, it has not been demonstrated to be as effective or practical.

References:

1.	McClain KL, Joshi VV, Murphy SB: Cancers in children with HIV infection. Hematol Oncol Clin North Am 10 (5): 1189-201, 1996.
2.	Seidemann K, Tiemann M, Henze G, et al.: Therapy for non-Hodgkin lymphoma in children with primary immunodeficiency: analysis of 19 patients from the BFM trials. Med Pediatr Oncol 33 (6): 536-44, 1999.
3.	Gross TG, Bucuvalas JC, Park JR, et al.: Low-dose chemotherapy for Epstein-Barr virus-positive post-transplantation lymphoproliferative disease in children after solid organ transplantation. J Clin Oncol 23 (27): 6481-8, 2005.
4.	Dembowska-Baginska B, Perek D, Brozyna A, et al.: Non-Hodgkin lymphoma (NHL) in children with Nijmegen Breakage syndrome (NBS). Pediatr Blood Cancer 52 (2): 186-90, 2009.
5.	Aghamohammadi A, Parvaneh N, Tirgari F, et al.: Lymphoma of mucosa-associated lymphoid tissue in common variable immunodeficiency. Leuk Lymphoma 47 (2): 343-6, 2006.
6.	Ohno Y, Kosaka T, Muraoka I, et al.: Remission of primary low-grade gastric lymphomas of the mucosa-associated lymphoid tissue type in immunocompromised pediatric patients. World J Gastroenterol 12 (16): 2625-8, 2006.
7.	Kirk O, Pedersen C, Cozzi-Lepri A, et al.: Non-Hodgkin lymphoma in HIV-infected patients in the era of highly active antiretroviral therapy. Blood 98 (12): 3406-12, 2001.
8.	Hoffmann T, Heilmann C, Madsen HO, et al.: Matched unrelated allogeneic bone marrow transplantation for recurrent malignant lymphoma in a patient with X-linked lymphoproliferative disease (XLP). Bone Marrow Transplant 22 (6): 603-4, 1998.
9.	Sandoval C, Swift M: Treatment of lymphoid malignancies in patients with ataxia-telangiectasia. Med Pediatr Oncol 31 (6): 491-7, 1998.
10.	Green M, Michaels MG, Webber SA, et al.: The management of Epstein-Barr virus associated post-transplant lymphoproliferative disorders in pediatric solid-organ transplant recipients. Pediatr Transplant 3 (4): 271-81, 1999.
11.	Picarsic J, Jaffe R, Mazariegos G, et al.: Post-transplant Burkitt lymphoma is a more aggressive and distinct form of post-transplant lymphoproliferative disorder. Cancer 117 (19): 4540-50, 2011.
12.	Windebank K, Walwyn T, Kirk R, et al.: Post cardiac transplantation lymphoproliferative disorder presenting as t(8;14) Burkitt leukaemia/lymphoma treated with low intensity chemotherapy and rituximab. Pediatr Blood Cancer 53 (3): 392-6, 2009.
13.	Yang F, Li Y, Braylan R, et al.: Pediatric T-cell post-transplant lymphoproliferative disorder after solid organ transplantation. Pediatr Blood Cancer 50 (2): 415-8, 2008.
14.	Williams KM, Higman MA, Chen AR, et al.: Successful treatment of a child with late-onset T-cell post-transplant lymphoproliferative disorder/lymphoma. Pediatr Blood Cancer 50 (3): 667-70, 2008.
15.	Dharnidharka VR, Douglas VK, Hunger SP, et al.: Hodgkin's lymphoma after post-transplant lymphoproliferative disease in a renal transplant recipient. Pediatr Transplant 8 (1): 87-90, 2004.
16.	Goyal RK, McEvoy L, Wilson DB: Hodgkin disease after renal transplantation in childhood. J Pediatr Hematol Oncol 18 (4): 392-5, 1996.
17.	Hayashi RJ, Kraus MD, Patel AL, et al.: Posttransplant lymphoproliferative disease in children: correlation of histology to clinical behavior. J Pediatr Hematol Oncol 23 (1): 14-8, 2001.
18.	Papadopoulos EB, Ladanyi M, Emanuel D, et al.: Infusions of donor leukocytes to treat Epstein-Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N Engl J Med 330 (17): 1185-91, 1994.
19.	Rooney CM, Smith CA, Ng CY, et al.: Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients. Blood 92 (5): 1549-55, 1998.

Changes to This Summary (03 / 29 / 2012)

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 of Childhood Non-Hodgkin Lymphoma (NHL)

Added Picarsic et al. as reference 47.

Lymphoproliferative Disease Associated With Immunodeficiency in Children

Revised text to state that in posttransplant lymphoproliferative disease (PTLD), first-line therapy is the reduction of immunosuppression as can be tolerated, although it has been reported that immediate use of lymphoma-directed therapy results in an improved outcome for patients with either the monomorphic or the Burkitt lymphoma form of PTLD (cited Picarsic et al. as reference 11).

About This PDQ Summary

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:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

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:

• Robert J. Arceci, MD, PhD (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
• Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
• Thomas G. Gross, MD, PhD (Nationwide Children's Hospital)
• Kenneth L. McClain, MD, PhD (Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital)
• Arthur Kim Ritchey, MD (Children's Hospital of Pittsburgh of UPMC)
• Nita Louise Seibel, MD (National Cancer Institute)
• Malcolm Smith, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. 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.

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Childhood Non-Hodgkin Lymphoma Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/child-non-hodgkins/HealthProfessional. Accessed <MM/DD/YYYY>.

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Last Revised: 2012-03-29