Overview of Childhood Hodgkin Lymphoma
Epidemiology
Pathobiology
Clinical Presentation

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

Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ Supportive Care ¹ 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 pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[1] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare 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. ²

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ Late Effects of Treatment for Childhood Cancer ³ for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Childhood Hodgkin lymphoma is one of the few pediatric malignancies that shares aspects of its biology and natural history with an adult cancer. When treatment approaches for children were modeled after those used for adults, substantial morbidities (primarily musculoskeletal growth inhibition) resulted from the unacceptably high radiation doses. Thus, new strategies utilizing chemotherapy and lower-dose radiation were developed. Approximately 90% to 95% of children with Hodgkin lymphoma can be cured, prompting increased attention to devising nonmorbid therapy for these patients. Contemporary treatment programs use a risk-adapted approach in which patients receive multiagent chemotherapy with or without low-dose involved-field irradiation. Prognostic factors used in determining chemotherapy intensity include stage, presence or absence of B symptoms and/or bulk disease. The option of omitting radiation following chemotherapy is only considered in patients achieving complete response to initial chemotherapy.

Hodgkin lymphoma comprises 6% of childhood cancers. In the United States, the incidence of Hodgkin lymphoma is age-related and is highest among 15 to 19 year olds (29 per million per year), with children ages 10 to 14 years, 5 to 9 years, and 0 to 4 years having approximately threefold, eightfold, and 30-fold lower rates, respectively.[2] In non-European Union countries, there is a similar rate in young adults but a much higher incidence in childhood.[3,4] The male to female ratio varies markedly by age in the pediatric population. Children younger than 5 years show a strong male predominance (M/F = 5.3) and children aged 15 to 19 show a slight female predominance (M/F = 0.8).[5]Lymphomas and reticuloendothelial neoplasms (ICCC II) ⁴ For children and adolescents in the United States, there is an increased risk of Hodgkin lymphoma in families with higher parental incomes and higher education level. There is a lower incidence of Hodgkin lymphoma in families with large numbers of children.[4]

Hodgkin lymphoma is characterized by a variable number of characteristic multinucleated giant cells (Reed-Sternberg [R-S] cells) or large mononuclear cell variants (lymphocytic and histiocytic [L & H] cells) in an inflammatory milieu. This inflammatory milieu consists of small lymphocytes, histiocytes, epithelioid histiocytes, neutrophils, eosinophils, plasma cells, and fibroblasts in different proportions depending on the histologic subtype. It has been conclusively shown that R-S cells and/or L & H cells represent a clonal population. Almost all cases of Hodgkin lymphoma arise from preapoptotic germinal center B cells that cannot synthesize immunoglobulin.[6,7] The R-S cell appears to be resistant to apoptotic stimuli. Deregulation of the nuclear transcription factor NFkB in the R-S cells may explain this resistance to apoptosis.

Epstein-Barr virus (EBV) genetic material can be detected in R-S cells from some patients with Hodgkin lymphoma. EBV positivity is most commonly observed in tumors with mixed-cellularity histology and is almost never seen in patients with lymphocyte-predominant histology.[8-12] EBV positivity is more common in children younger than 10 years [8,12] compared to adolescents and young adults.[9,10] The incidence of EBV tumor cell positivity for Hodgkin lymphoma in developed countries is 15% to 25% in adolescents and young adults.[11-13] There is a very high incidence of mixed-cellularity histology in childhood Hodgkin lymphoma seen in developing countries, and these cases are generally EBV-positive (approximately 90%). EBV serologic status is not a prognostic factor for failure-free survival in pediatric and young adult Hodgkin lymphoma patients.[8,11-14] Patients with a prior history of serologically confirmed infectious mononucleosis have a fourfold increased risk of developing EBV-positive Hodgkin lymphoma; these patients are not at increased risk for EBV-negative Hodgkin lymphoma.[15] Although rare, Hodgkin lymphoma can be familial.

Approximately 80% of patients present with painless adenopathy, commonly in the supraclavicular or cervical area. Enlarged nodes are generally firm and have a rubbery texture. Mediastinal disease is present in about 75% of adolescents and young adults, and may be asymptomatic. In contrast, only about 35% of young children with Hodgkin lymphoma have mediastinal presentation, in part, reflecting the tendency of these patients to have either mixed cellularity or lymphocyte-predominant histology. Approximately 25% of patients may have systemic symptoms such as fever, night sweats, and weight loss that are secondary to release of lymphokines and cytokines by R-S cells. Approximately 20% of patients will have bulky adenopathy (maximum mediastinal diameter greater than one-third of the chest diameter and/or a node or nodal aggregate larger than 10 cm). Approximately 80% to 85% of children and adolescents with Hodgkin lymphoma have involvement of lymph nodes and/or the spleen only (stages I–III). The remaining 15% to 20% of patients will have noncontiguous extranodal involvement (stage IV). The most common sites of extranodal involvement are the lung, liver, bones, and bone marrow.[16,17]

References

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2. Ries LAG, Harkins D, Krapcho M, et al.: SEER Cancer Statistics Review, 1975-2003. Bethesda, Md: National Cancer Institute, 2006. Also available online ⁵. Last accessed July 31, 2008. 
   
   
3. Macfarlane GJ, Evstifeeva T, Boyle P, et al.: International patterns in the occurrence of Hodgkin's disease in children and young adult males. Int J Cancer 61 (2): 165-9, 1995.  [PUBMED Abstract]
   
   
4. Grufferman S, Gilchrist GS, Pollock BH, et al.: Socioeconomic status, the Epstein-Barr virus and risk of Hodgkin's disease in children. [Abstract] Leuk Lymphoma 42 (Suppl 1): P-054, 40, 2001. 
   
   
5. Ries LA, Kosary CL, Hankey BF, et al., eds.: SEER Cancer Statistics Review 1973-1995. Bethesda, Md: National Cancer Institute, 1998. 
   
   
6. Bräuninger A, Schmitz R, Bechtel D, et al.: Molecular biology of Hodgkin's and Reed/Sternberg cells in Hodgkin's lymphoma. Int J Cancer 118 (8): 1853-61, 2006.  [PUBMED Abstract]
   
   
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8. Armstrong AA, Alexander FE, Cartwright R, et al.: Epstein-Barr virus and Hodgkin's disease: further evidence for the three disease hypothesis. Leukemia 12 (8): 1272-6, 1998.  [PUBMED Abstract]
   
   
9. Araujo I, Bittencourt AL, Barbosa HS, et al.: The high frequency of EBV infection in pediatric Hodgkin lymphoma is related to the classical type in Bahia, Brazil. Virchows Arch 449 (3): 315-9, 2006.  [PUBMED Abstract]
   
   
10. Makar RR, Saji T, Junaid TA: Epstein-Barr virus expression in Hodgkin's lymphoma in Kuwait. Pathol Oncol Res 9 (3): 159-65, 2003.  [PUBMED Abstract]
    
    
11. Herling M, Rassidakis GZ, Medeiros LJ, et al.: Expression of Epstein-Barr virus latent membrane protein-1 in Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma: associations with presenting features, serum interleukin 10 levels, and clinical outcome. Clin Cancer Res 9 (6): 2114-20, 2003.  [PUBMED Abstract]
    
    
12. Claviez A, Tiemann M, Lüders H, et al.: Impact of latent Epstein-Barr virus infection on outcome in children and adolescents with Hodgkin's lymphoma. J Clin Oncol 23 (18): 4048-56, 2005.  [PUBMED Abstract]
    
    
13. Jarrett RF, Stark GL, White J, et al.: Impact of tumor Epstein-Barr virus status on presenting features and outcome in age-defined subgroups of patients with classic Hodgkin lymphoma: a population-based study. Blood 106 (7): 2444-51, 2005.  [PUBMED Abstract]
    
    
14. Herling M, Rassidakis GZ, Vassilakopoulos TP, et al.: Impact of LMP-1 expression on clinical outcome in age-defined subgroups of patients with classical Hodgkin lymphoma. Blood 107 (3): 1240; author reply 1241, 2006.  [PUBMED Abstract]
    
    
15. Hjalgrim H, Askling J, Rostgaard K, et al.: Characteristics of Hodgkin's lymphoma after infectious mononucleosis. N Engl J Med 349 (14): 1324-32, 2003.  [PUBMED Abstract]
    
    
16. Nachman JB, Sposto R, Herzog P, et al.: Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. J Clin Oncol 20 (18): 3765-71, 2002.  [PUBMED Abstract]
    
    
17. Rühl U, Albrecht M, Dieckmann K, et al.: Response-adapted radiotherapy in the treatment of pediatric Hodgkin's disease: an interim report at 5 years of the German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys 51 (5): 1209-18, 2001.  [PUBMED Abstract]