Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. 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 pediatric patients with cancer have been outlined by the American Academy of Pediatrics. 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.
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For Hodgkin lymphoma, the 5-year survival rate has increased over the same time from 81% to more than 94% for children and adolescents. 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 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.)
Overview of Childhood Hodgkin Lymphoma
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 therapy that produces less long-term morbidity for these patients. Contemporary treatment programs use a risk-adapted approach in which patients receive multiagent chemotherapy with or without low-dose involved-field radiation therapy. Prognostic factors used in determining chemotherapy intensity include stage, presence or absence of B symptoms (fever, weight loss, and night sweats), and/or bulky disease.
Hodgkin lymphoma comprises 6% of childhood cancers. In the United States, the incidence of Hodgkin lymphoma is age-related and is highest among adolescents aged 15 to 19 years (29 cases 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. In non-European Union countries, there is a similar rate in young adults but a much higher incidence in childhood.
Hodgkin lymphoma has the following unique epidemiological features:
- Hodgkin lymphoma has a bimodal age distribution that differs geographically and ethnically in industrialized countries; the early peak occurs in the middle to late 20s and the second peak after age 50 years. In developing countries, the early peak occurs before adolescence.
- The male-to-female ratio varies markedly by age. Children younger than 5 years show a strong male predominance (M:F = 5.3) and children aged 15 to 19 years show a slight female predominance (M:F = 0.8).[6,7]
- There are three distinct forms of Hodgkin lymphoma:
- Childhood form—occurs in individuals aged 14 years and younger. The childhood form of Hodgkin lymphoma increases in prevalence in association with larger family size and lower socioeconomic status. Early exposure to common infections in early childhood appears to decrease the risk of Hodgkin lymphoma, most likely by maturation of cellular immunity.[8,9]
- Young adult form—effects individuals aged 15 to 34 years. The young adult form is associated with a higher socioeconomic status in industrialized countries, increased sibship size, and earlier birth order. The lower risk of Hodgkin lymphoma observed in young adults with multiple older, but not younger, siblings, is consistent with the hypothesis that early exposure to viral infection (which the siblings bring home from school, for example) may play a role in the pathogenesis of the disease.
- Older adult form—most commonly presents in individuals aged 55 to 74 years.
- A family history of Hodgkin lymphoma in siblings or parents has been associated with an increased risk of this disease.
Epstein-Barr virus and Hodgkin lymphoma
Epstein-Barr virus (EBV) has been implicated in the causation of Hodgkin lymphoma. A large proportion of patients with Hodgkin lymphoma have high EBV titers, suggesting that an enhanced activation of EBV may precede the development of Hodgkin lymphoma in some patients. EBV genetic material can be detected in Reed-Sternberg cells from some patients with Hodgkin lymphoma.
The incidence of EBV-associated Hodgkin lymphoma also shows the following distinct epidemiological features:
- EBV positivity is most commonly observed in tumors with mixed-cellularity histology and is almost never seen in patients with lymphocyte-predominant histology.[12-16]
- EBV positivity is more common in children younger than 10 years [12,16] compared with adolescents and young adults.[13,14]
- The incidence of EBV tumor cell positivity for Hodgkin lymphoma in developed countries is 15% to 25% in adolescents and young adults.[15-17] There is a high incidence of mixed-cellularity histology in childhood Hodgkin lymphoma seen in developing countries, and these cases are generally EBV-positive (approximately 80%).
EBV serologic status is not a prognostic factor for failure-free survival in pediatric and young adult Hodgkin lymphoma patients.[12,15-17,19] 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.
Immunodeficiency and Hodgkin lymphoma
Among individuals with immunodeficiency, the risk of Hodgkin lymphoma is increased, although not as high as the risk of non-Hodgkin lymphoma.
Characteristics of Hodgkin lymphoma presenting in the context of immunodeficiency are as follows:
- Hodgkin lymphoma usually occurs at a younger age and with histologies other than nodular sclerosing in patients with primary immunodeficiencies.
- The risk of Hodgkin lymphoma increases as much as 50-fold over the general population in patients with autoimmune lymphoproliferative syndrome.
- Although it is not an AIDS-defining malignancy, the incidence of Hodgkin lymphoma appears to be increased in HIV-infected individuals, including children.[23,24]
The following presenting features of Hodgkin lymphoma result from direct or indirect effects of nodal or extranodal involvement and/or constitutional symptoms related to cytokine release from Reed-Sternberg cells.
- Approximately 80% of patients present with painless adenopathy, most commonly involving the supraclavicular or cervical area.
- 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 20% of patients will have bulky adenopathy (maximum mediastinal diameter one-third of the chest diameter or greater and/or a node or nodal aggregate larger than 10 cm).
- Based on data from large cooperative group cohorts, 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.[25,26]
- Nonspecific constitutional symptoms including fatigue, anorexia, weight loss, pruritus, night sweats, and fever occur in approximately 25% of patients.[25,26]
- Only three specific constitutional (B) symptoms have been correlated with prognosis—unexplained fever (temperature above 38.0°C orally), unexplained weight loss (10% of body weight within the 6 months preceding diagnosis), and drenching night sweats.
As the treatment of Hodgkin lymphoma has improved, factors that are associated with outcome have become more difficult to identify. Several factors, however, continue to influence the success and choice of therapy. These factors are interrelated in the sense that disease stage, bulk, and biologic aggressiveness are frequently codependent. Further complicating the identification of prognostic factors is their use in determining the aggressiveness of therapy. For example, in a report from the German-Austrian Pediatric multicenter trial DAL-HD-90, bulky disease was not a prognostic factor for outcome on multivariate analysis. However, in this study, boost irradiation doses were given to patients who had postchemotherapy residual disease, which could have obfuscated the relevance of bulky disease at presentation. This underscores the complexity in determining prognostic factors.
Pretreatment factors associated with an adverse outcome in one or more studies include the following:
- Advanced stage of disease.
- Presence of B symptoms.[25,26]
- Presence of bulky disease.
- Extranodal extension.
- Elevated erythrocyte sedimentation rate.
- Leukocytosis (white blood cell count 11,500/mm3 or higher).
- Anemia (hemoglobin lower than 11.0 g/dL).
- Male gender.[26,29]
- Response to initial treatment with chemotherapy.[23,30,31]
Prognostic factors identified in selected multi-institutional studies include the following:
- In the Society for Paediatric Oncology and Haematology (Gesellschaft für Pädiatrische Onkologie und Hämatologie [GPOH]) GPOH-95 study, B symptoms, histology, and male gender were adverse prognostic factors for event-free survival on multivariate analysis.
- In 320 children with clinically staged Hodgkin lymphoma treated in the Stanford-St. Jude-Dana Farber Cancer Institute consortium, male gender; stage IIB, IIIB, or IV disease; white blood cell count of 11,500/mm3 or higher; and hemoglobin lower than 11.0 g/dL were significant prognostic factors for inferior disease-free survival and overall survival (OS). Prognosis was also associated with the number of adverse factors.
- In the CCG-5942 study, the combination of B symptoms and bulky disease was associated with an inferior outcome.
- One single-institutional study showed that African American patients had a higher relapse rate than white patients, but OS was similar.
The rapidity of response to initial cycles of chemotherapy also appears to be prognostically important and is being used in the research setting to determine subsequent therapy.[30,31,33] Positron emission tomography (PET) scanning is being evaluated as a method to assess early response in pediatric Hodgkin lymphoma. Fluorodeoxyglucose-PET avidity after two cycles of chemotherapy for Hodgkin lymphoma in adults has been shown to predict treatment failure and progression-free survival.[35-37] Further studies in children are required to assess the role of early response based on PET. The value of PET avidity to predict outcome and whether improved outcome can be achieved by altering the therapeutic strategy based on early PET response is to be determined.
Although prognostic factors will continue to change because of risk stratification and choice of therapy, parameters such as disease stage, bulk, systemic symptomatology, and early response to chemotherapy are likely to remain relevant to outcome.
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