Childhood Non-Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version

Histopathologic and Molecular Classification of Childhood NHL

In children, non-Hodgkin lymphoma (NHL) is distinct from the more common forms of lymphoma observed in adults. While lymphomas in adults are more commonly low or intermediate grade, almost all NHL that occurs in children is high grade.[1-3] The World Health Organization (WHO) classifies NHL according to the following features:[3]

Phenotype (i.e., B-lineage, T-lineage, or natural killer [NK] cell lineage).
Cell differentiation (i.e., precursor vs. mature).

On the basis of the WHO classification, the vast majority of NHL cases in childhood and adolescence fall into the following three categories:

Mature B-cell NHL: Burkitt and Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and primary mediastinal B-cell lymphoma.
Compared with treatments for adults, aggressive Burkitt regimens in pediatrics have been used to treat both Burkitt lymphoma/leukemia and large B-cell histologies, resulting in no difference in outcome based on histology.[4-8] The exception is primary mediastinal B-cell lymphoma, which has had an inferior outcome with these regimens.[4-7,9,10]
For pediatric Burkitt lymphoma/leukemia patients, secondary cytogenetic abnormalities, other than MYC rearrangement, are associated with an inferior outcome,[11,12] and cytogenetic abnormalities involving gain of 7q or deletion of 13q appeared to have an inferior outcome on the FAB/LMB-96 chemotherapy protocol.[12,13] For pediatric patients with diffuse large B-cell lymphoma and chromosomal rearrangement at MYC (8q24), outcome appeared to be worse.[12]
A subset of pediatric diffuse large B-cell lymphoma cases were found to have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci and has been associated with favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this finding.[14]
Lymphoblastic lymphoma: Primarily precursor T-cell lymphoma and, less frequently, precursor B-cell lymphoma.
For pediatric patients with T-cell lymphoblastic lymphoma, the Berlin-Frankfurt-Münster group reported that loss of heterozygosity (LOH) at chromosome 6q was observed in 12% of patients (25 of 217) and was associated with unfavorable prognosis (probability of event-free survival [pEFS], 27% vs. 86%, P < .0001).[15,16] NOTCH1 mutations were seen in 60% of patients (70 of 116) and were associated with favorable prognosis (pEFS, 84% vs. 66%; P = .021). NOTCH1 mutations were rarely seen in patients with LOH at 6q.[15]
Anaplastic large cell lymphoma: Mature peripheral T-cell/null-cell lymphomas. The null-cell variant is considered to be the same disease in which the cells have lost most of the T-cell antigens.
In adults, ALK-negative disease has an inferior outcome; however, in children, the difference in outcome between ALK-positive and ALK-negative disease has not been demonstrated.[17-19] In a series of 375 children and adolescents with systemic ALK-positive anaplastic large cell lymphoma, the presence of a small cell or lymphohistiocytic component was observed in 32% of patients and was significantly associated with a high risk of failure in the multivariate analysis, controlling for clinical characteristics.[20]
In the COG-ANHL0131 (NCT00059839) study, despite a different chemotherapy backbone, the small cell variant of anaplastic large cell lymphoma, as well as other histologic variants, had a significantly increased risk of failure.[19]

Refer to the following sections of this summary for more information about the tumor biology associated with each type of NHL:

WHO Classification for NHL

The WHO classification is the most widely used NHL classification and is shown in Table 2, with immunophenotype and common clinical and molecular findings in pediatric NHL.[1,3]

Table 2. Major Histopathological Categories of Non-Hodgkin Lymphoma in Children and Adolescentsa

ENLARGE

WHO Classification	Immunophenotype	Clinical Presentation	Chromosome Abnormalities	Genes Affected
CNS = central nervous system; LOH = loss of heterozygosity; TdT = terminal deoxynucleotidyl transferase; WHO = World Health Organization; + = positive.
aAdapted from Percy et al.[1]
Burkitt lymphoma	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)	MYC, TCF3, ID3, CCND3, TP53
Burkitt-like lymphoma with 11q aberration (provisional)	Mature B cell	Nodal	11q alteration, no MYC rearrangement
Large B-cell lymphoma with IRF4rearrangement	Mature B cell	Nodal (typically head and neck)	Cryptic IRF1rearrangement with IGH locus	IRF4
Diffuse large B-cell lymphoma	Mature B cell	Nodal, abdominal, bone, primary CNS (when associated with immunodeficiency), mediastinal	No consistent cytogenetic abnormality identified
Primary mediastinal (thymic) large B-cell lymphoma	Mature B cell, often CD30+	Mediastinal, but may also have other nodal or extranodal disease (i.e., abdominal, often kidney)	9p and 2p gains	CIITA, TNFAIP3, SOCS1, PTPN11, STAT6
ALK-positive large B-cell lymphoma		Generalized lymphadenopathy, bone marrow in 25%	t(2;5)(p23;q35); less common variant translocations involving ALK	ALK, NPM
T-lymphoblastic leukemia/lymphoma	T lymphoblasts (TdT, CD2, CD3, CD7, CD4, CD8)	Mediastinal mass, bone marrow
B-lymphoblastic leukemia/lymphoma	B lymphoblasts (CD19, CD79a, CD22, CD10, TdT)	Skin, soft tissue, bone, lymph nodes, bone marrow
Pediatric-type follicular lymphoma	Mature B cell	Nodal (typically head and neck)		TNFRSF14, MAP2K1
Pediatric nodal marginal zone lymphoma	Mature B cell	Nodal (typically head and neck)

Other types of lymphoma, such as the nonanaplastic large cell peripheral T-cell lymphomas (including T/NK lymphomas), cutaneous lymphomas, and indolent B-cell lymphomas (e.g., follicular lymphoma and marginal zone lymphoma), are more commonly seen in adults and occur rarely in children. The most recent WHO classification has designated pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma as distinct entities from the counterparts observed in adults.[3]

Refer to the following PDQ summaries for more information about the treatment of NHL in adult patients:

References

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 April 12, 2019.
Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996. [PUBMED Abstract]
Swerdlow SH, Campo E, Pileri SA, et al.: The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 127 (20): 2375-90, 2016. [PUBMED Abstract]
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. [PUBMED Abstract]
Cairo MS, Sposto R, Gerrard M, et al.: Advanced stage, increased lactate dehydrogenase, and primary site, but not adolescent age (≥ 15 years), are associated with an increased risk of treatment failure in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB LMB 96 study. J Clin Oncol 30 (4): 387-93, 2012. [PUBMED Abstract]
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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. [PUBMED Abstract]
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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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
Bonn BR, Rohde M, Zimmermann M, et al.: Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence. Blood 121 (16): 3153-60, 2013. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
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Alexander S, Kraveka JM, Weitzman S, et al.: Advanced stage anaplastic large cell lymphoma in children and adolescents: results of ANHL0131, a randomized phase III trial of APO versus a modified regimen with vinblastine: a report from the children's oncology group. Pediatr Blood Cancer 61 (12): 2236-42, 2014. [PUBMED Abstract]
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