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Childhood Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Childhood Hodgkin Lymphoma Treatment (PDQ®)–Health Professional Version - National Cancer Institute

National Cancer Institute

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

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General Information About Childhood Hodgkin Lymphoma

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%. For Hodgkin lymphoma, the 5-year survival rate has increased over the same time from 81% to more than 95% for children and adolescents.[1]

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 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 lessens long-term morbidity for these patients. Contemporary treatment programs use a risk-based and response-adapted approach in which patients receive multiagent chemotherapy with or without low-dose involved-field or involved-site radiation therapy. Prognostic factors used in determining chemotherapy intensity include stage, presence or absence of B symptoms (fever, weight loss, and night sweats), bulky disease, extranodal involvement, and/or erythrocyte sedimentation rate.

Epidemiology

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 1 million per year); children aged 10 to 14 years, 5 to 9 years, and 0 to 4 years have approximately threefold, eightfold, and 30-fold lower rates, respectively, than do adolescents.[2] In developing countries, there is a similar incidence rate in young adults but a much higher incidence rate in childhood.[3]
Hodgkin lymphoma has the following unique epidemiological features:
  • Bimodal age distribution. 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.[4]
  • Male to female ratio. 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).[5,6]
  • Age cohorts. Hodgkin lymphoma can be segregated into the following three age cohorts because of the variation in etiologies and histological subtypes (refer to Table 1):
    • Children: Individuals aged 14 years and younger have a higher prevalence of nodular lymphocyte-predominant disease and Epstein-Barr virus (EBV)–associated mixed-cellularity disease.
      Early exposure to common infections in early childhood appears to decrease the risk of Hodgkin lymphoma, most likely by maturation of cellular immunity.[7,8]
      There are more males than females affected in the younger age cohort, especially in children younger than 10 years. EBV-associated Hodgkin lymphoma increases in prevalence in association with larger family size and lower socioeconomic status.[4]
    • Adolescent and young adult: Hodgkin lymphoma in individuals aged 15 to 34 years is associated with a higher socioeconomic status in industrialized countries, increased sibship size, and earlier birth order.[9] 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.[7]
      Nodular-sclerosing Hodgkin lymphoma is the most common subtype, followed by mixed cellularity.
    • Older adult: Hodgkin lymphoma most commonly presents in individuals aged 55 to 74 years. This group has a higher risk of lymphocyte-depleted Hodgkin lymphoma. The treatment of older adults is not discussed in this summary.
  • Family history. A family history of Hodgkin lymphoma in siblings or parents has been associated with an increased risk of this disease.[10,11] In a population-based study that evaluated risk of familial classical Hodgkin lymphoma by relationship, histology, age, and sex, the cumulative risk of Hodgkin lymphoma was 0.6%, representing a 3.3-fold increased risk compared with the general population risk.[12] The risk in siblings was significantly higher than the risk in parents and/or offspring. The risk in sisters was higher than the risk in brothers or siblings of opposite sex. The lifetime risk of Hodgkin lymphoma was higher when first-degree relatives were diagnosed before age 30 years.
Table 1. Epidemiology of Hodgkin Lymphoma (HL) Across the Age Spectruma
VariablesChildhood HLAYA HLAdult HLOlder Adult HL
Age Range≤14 y15–35 y≥35 y≥55 y
Prevalence of HL10%–12%50%35%
Gender (Male-to-Female Ratio)2–3 to 11 to 1–1.3 to 11.2 to 1–1 to 1.1
Histology: 
 Nodular sclerosing40%–45%65%–80%35%–40%
 Mixed cellularity30%–45%10%–25%35%–50%
 NLPHL8%–20%2%–8%7%–10%
EBV Associated27%–54%20%–25%34%–40%50%–56%
Advanced Stage30%–35%40%55%
B Symptoms25%30%–40%50%
Relative Survival: Rates at 5 Years94% (age <20 y)90% (age <50 y)65% (age >50 y)
AYA = adolescent and young adult; EBV = Epstein-Barr virus; NLPHL = nodular lymphocyte-predominant Hodgkin lymphoma.
aAdapted from Punnett et al.[13]

Epstein-Barr virus (EBV) and Hodgkin lymphoma

EBV has been implicated in the causation of some cases of Hodgkin lymphoma. Patients with Hodgkin lymphoma may have high EBV titers, suggesting that a previous infection with 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, most commonly in those with mixed-cellularity disease.[14] In children and adolescents with intermediate-risk Hodgkin lymphoma, EBV DNA in cell-free blood correlated with the presence of EBV in the tumor; EBV DNA 8 days after the initiation of therapy predicted an inferior event-free survival (EFS).[14]
The incidence of EBV-associated Hodgkin lymphoma also shows the following distinct epidemiological features:
  • Histology. EBV positivity is most commonly observed in tumors with mixed-cellularity histology and is almost never seen in patients with lymphocyte-predominant histology.[15,16]
  • Age. EBV positivity is more common in children younger than 10 years than in adolescents and young adults.[15,16]
  • Developing countries. The incidence of EBV tumor cell positivity for Hodgkin lymphoma in developed countries ranges from 15% to 25% in adolescents and young adults.[15-17] A high incidence of mixed-cellularity histology in childhood Hodgkin lymphoma is seen in developing countries, and these cases are generally EBV positive (approximately 80%).[18]
EBV serologic status is not a prognostic factor for failure-free survival in young adult patients with Hodgkin lymphoma,[15-17,19,20] but plasma EBV DNA has been associated with an inferior outcome in adults.[21] However, this is not the case in children, with better outcomes described for intermediate-risk patients with higher levels of EBV DNA at diagnosis,[14] which also correlates with better outcomes for patients with mixed-cellularity disease treated with dose-dense chemotherapy (ABVE-PC [doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide]). Patients with a previous history of serologically confirmed infectious mononucleosis have a fourfold increased risk of developing EBV-positive Hodgkin lymphoma; these patients are not at increased risk of developing EBV-negative Hodgkin lymphoma.[22]

Immunodeficiency and Hodgkin lymphoma

Among individuals with immunodeficiency, the risk of Hodgkin lymphoma is increased,[23] although the risk of non-Hodgkin lymphoma is even higher.
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.[23]
  • The risk of Hodgkin lymphoma increases as much as 50-fold over the general population in patients with autoimmune lymphoproliferative syndrome.[24]
  • Although it is not an AIDS-defining malignancy, the incidence of Hodgkin lymphoma appears to be increased in HIV-infected individuals, including children.[25,26]
  • Compared with the general population, the risk of Hodgkin lymphoma is increased in recipients of solid organ transplant who are maintained on chronic immunosuppressive medications.[27]
  • Hodgkin lymphoma is the second most common cancer type in children who have undergone solid organ transplant.[28]

Clinical Presentation

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 and cell signaling within the tumor microenvironment:[29]
  • 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 involvement, reflecting the greater prevalence of mixed-cellularity and lymphocyte-predominant histology versus nodular-sclerosing histology in this age cohort.
  • Nonspecific constitutional symptoms including fatigue, anorexia, weight loss, pruritus, night sweats, and fever occur in approximately 25% of patients.[30,31]
  • Three specific constitutional symptoms (B symptoms) that 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—are commonly used to assign risk in clinical trials.[32]
  • Female patients with large mediastinal masses and B symptoms are most likely to present with pericardial effusions.[33][Level of evidence: 3iiC]
Fifteen percent 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.[30,31]

Prognostic Factors

As the treatment of Hodgkin lymphoma improved, factors associated with outcome became 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 collinear.

Pretreatment factors

Pretreatment factors associated with an adverse outcome in one or more studies include the following:
  • Advanced stage of disease.[34,35]
  • Presence of B symptoms.[30,31,35]
  • Presence of bulky disease.[30,35]
  • Presence of a pericardial effusion.[33][Level of evidence: 3iiC]
  • Presence of a pleural effusion.[36][Level of evidence: 2A]
  • Elevated erythrocyte sedimentation rate.[37]
  • Leukocytosis (white blood cell count of 11,500/mm3 or higher).[34]
  • Anemia (hemoglobin lower than 11.0 g/dL).[34]
  • Hypoalbuminemia.[35]
  • Male sex.[31,34]
  • Response to initial treatment with chemotherapy.[38,39]
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 sex were adverse prognostic factors for EFS on multivariate analysis.[31]
  • In 320 children with clinically staged Hodgkin lymphoma treated in the Stanford-St. Jude-Dana Farber Cancer Institute consortium, male sex; 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.[34]
  • In the CCG-5942 study, the combination of B symptoms and bulky disease was associated with an inferior outcome.[30]
  • Factors associated with adverse outcome, many of which are collinear, were evaluated by multivariable analysis using the COG trial AHOD0031 (NCT00025259) for children with intermediate-risk Hodgkin lymphoma. This study enrolled 1,734 patients. The most robust predictors of outcome in this homogeneously treated cohort were stage IV disease, fever, a large mediastinal mass, and low albumin (<3.4 g/dL). The Childhood Hodgkin International Prognostic Score, highly predictive of EFS, was derived by giving a point for each adverse factor;[35] however, it requires further prospective validation.
  • Pleural effusions have been shown to be an adverse prognostic finding in patients treated for low-stage Hodgkin lymphoma.[36][Level of evidence: 2A] The risk of relapse was 25% in patients with an effusion, as opposed to less than 15% in patients without an effusion. Patients with effusions were more often older (15 years vs. 14 years) and had nodular-sclerosing histology.
A single-institution study showed that African American patients had a higher relapse rate than did white patients, but OS was similar.[40] A Children’s Oncology Group (COG) analysis showed no difference in EFS by race or ethnicity. However, compared with non-Hispanic whites, Hispanic and non-Hispanic black children had an inferior OS because of an increased postrelapse mortality rate.[41][Level of evidence: 1iiA]

Response to initial chemotherapy

The rapidity of response to initial cycles of chemotherapy also appears to be prognostically important.[38,39,42] Response evaluation in previous generations of trials relied on computed tomography and gallium uptake; more recent trials have employed positron emission tomography (PET) scanning to assess early response in pediatric Hodgkin lymphoma.[43] Fluorine F 18-fludeoxyglucose PET avidity after two cycles of chemotherapy for Hodgkin lymphoma in adults has been shown to predict treatment failure and progression-free survival.[44-46] Reduction in PET avidity after one cycle of chemotherapy was associated with a favorable EFS outcome in children with limited-stage classical Hodgkin lymphoma.[37] Additional studies in children are ongoing to assess the role of early PET-based response in modifying therapy and predicting outcome.
Prognostic factors will continue to change because of risk stratification and choice of therapy, with parameters such as disease stage, bulk, systemic symptomatology, and early response to chemotherapy used to stratify therapeutic assignment.
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