Childhood Lymphoma
Summary of Key Points
Incidence
• Malignant lymphoma, which comprises both Hodgkin lymphoma and non-Hodgkin lymphoma (NHL), is the third most common malignancy in childhood.
• Among children younger than age 15 years, there is a slight predominance of NHL, whereas HL is more frequent among children up to age 18 years.
• There are approximately 500 newly diagnosed cases of pediatric NHL in the United States each year.
Etiology/Epidemiology
• NHL is more common in boys than girls and in white children than black.
• There are geographic differences with respect to the frequency of histologic subtypes of NHL. Burkitt lymphoma is the predominant subtype in equatorial Africa and northeast Brazil, where it is associated with Epstein-Barr virus in the majority of cases, in contrast to the infrequent association observed in the United States and Western Europe.
• Children with immunodeficiency conditions are at increased risk of developing NHL. These include those with ataxia-telangiectasia (A-T), Wiskott-Aldrich syndrome, and X-linked lymphoproliferative syndrome (XLP). Children with acquired immunodeficiency disorders, including the acquired immunodeficiency syndrome (AIDS), and those receiving immunosuppressive therapy following bone marrow or organ transplantation are also at increased risk.
Pathology/Biology
• The most common subtypes of NHL in children are Burkitt lymphoma, lymphoblastic lymphoma, anaplastic large-cell lymphoma, and diffuse large B-cell lymphoma (including the mediastinal subtype).
• Burkitt lymphoma is a mature B-cell lymphoma of germinal center origin, characterized by a very high proliferation rate, resulting from the activation of the c-myc oncogene as a result of juxtaposition to one of the immunoglobulin genes, through one of three characteristic balanced chromosomal translocations, that is, t(8;14), t(2;8), and t(8;22).
• Lymphoblastic lymphoma is typically of precursor T-cell immunophenotype, and may be associated with reciprocal translocations involving a T-cell receptor gene. Rare cases may be of precursor B-cell lineage.
• Anaplastic large-cell lymphoma is a peripheral (postthymic) T-cell lymphoma, characterized by large anaplastic (“hallmark”) cells expressing CD30 and, in the vast majority of pediatric cases, anaplastic lymphoma kinase (ALK), as a result of a balanced translocation involving the ALK gene, for example, t(2;5).
• Diffuse large B-cell lymphomas are a biologically heterogeneous category of mature B-cell lymphomas of germinal center or postgerminal center origin, composed predominantly of large cells, with a diffuse growth pattern.
Clinical Findings
• The clinical features at diagnosis are determined by primary sites of disease, which vary according to histologic subtype.
• Children with Burkitt lymphoma usually present with an abdominal mass and associated gastrointestinal symptoms, whereas those with advanced-stage lymphoblastic lymphoma typically present with a mediastinal mass associated with a spectrum of respiratory symptoms.
• Children with large-cell lymphoma or HL may present with disease in either the abdomen or mediastinum.
Diagnosis and Differential Diagnosis
• Infectious processes, such as bacterial adenitis, histoplasmosis, tuberculosis, and Epstein-Barr virus infection, may simulate lymphoma.
• A comprehensive characterization of the biological features of tissue will help distinguish NHL from other small round blue cell tumors, including Ewing sarcoma, neuroblastoma, and rhabdomyosarcoma.
Initial Workup and Staging
• The workup should include a history and physical examination, complete blood count, chemistry panel (including electrolytes, blood urea nitrogen, creatinine, uric acid, phosphorus, calcium, and lactate dehydrogenase [LDH]), diagnostic imaging studies (computed tomographic scan of chest, abdomen and pelvis, nuclear imaging with a PET scan), and HIV screen.
• For children with NHL, stage is usually assigned according to the St. Jude system, whereas children with HL are staged using the Ann Arbor system.
Primary Therapy
• The treatment plan is determined on the basis of histology, stage, immunophenotype, and in some cases, clinical symptoms such as fever, weight loss, and night sweats.
• Children with advanced-stage Burkitt lymphoma are generally treated with intensive cyclophosphamide-based regimens given over a relatively short period of time, whereas children with lymphoblastic lymphoma are generally treated with regimens derived from strategies for children with acute lymphoblastic leukemia (ALL).
• Among children with large-cell lymphoma, the treatment plan varies with respect to tumor cell immunophenotype.
• Involved-field radiation therapy has a role in certain cases of HL but is rarely indicated for children with NHL.
Salvage Therapy
• Children with refractory or recurrent disease are generally considered to have a poor prognosis and are therefore candidates for intensive or novel salvage treatment regimens.
• Those with chemosensitive disease are potential candidates for an intensification phase with hematopoietic stem cell rescue.
1. Which of the following treatment regimens has been shown to be superior in the treatment of pediatric anaplastic large-cell lymphoma (ALCL)?
2. Which of the following agents has been shown to be active in recurrent ALCL?
3. Which of the following statements regarding pediatric follicular lymphoma (as defined by the most recent WHO Classification) is correct?
1. Answer: C. APO and ALCL-99 have resulted in comparable treatment outcomes (~70% 3-year EFS). However, the risks associated with each regimen are different and should be considered in determining therapy. APO is longer (~1 year of therapy) but generally requires fewer hospital admissions compared to the more intensive ALCL-99. The risk for long-term cardiac toxicity should be considered in determining treatment strategies for children with NHL. In this regard, the total anthracycline exposure is greater with APO.
2. Answer: D. Single-agent vinblastine has been shown to be active in patients with recurrent ALCL; however, when introduced into frontline therapy, it has not improved the EFS. SGN-35 (brentuximab vedotin) is an antibody drug conjugate that links auristatin to anti-CD30. It has been shown to be active in adults with CD30+ lymphomas; studies in children are ongoing. Crizotinib is a small-molecule inhibitor that targets ALK. It has been shown to be active in adults with ALK-positive ALCL; studies in children are ongoing.
3. Answer: A. Pediatric follicular lymphoma is defined by the WHO Classification 2008 as a variant of follicular lymphoma unique to the pediatric age group and characterized by distinctive clinical features. This lymphoma, while consisting histologically of a lymphoid proliferation with follicular architecture similar to the adult-type follicular lymphoma, is usually characterized by a CD10+/BCL6+/BCL2– immunophenotype, rendering the distinction from benign reactive follicular hyperplasia more difficult. The absence of BCL2 overexpression correlates with a lack of t(14;18) that leads to overexpression of the BCL2 gene due to juxtaposition to the IGH gene in the adult type of follicular lymphoma. Additionally, although most cases show a predominance of large centroblastic cells in the neoplastic germinal centers (similar to the grade 3 of 3 adult follicular lymphoma), they characteristically have an indolent clinical course, in some cases even without therapy. Therefore this histologic feature does not correlate with a more aggressive clinical course in pediatric follicular lymphoma.
