Pediatric Hodgkin Lymphoma 

Hodgkin disease (Hodgkin's disease) is a highly curable malignancy. Over the past few decades, the understanding and insight into the biology of Hodgkin-Reed-Sternberg (HRS) cells as B-cell derived have led to the classification of Hodgkin disease as a lymphoma or Hodgkin lymphoma.^[1]

Hodgkin lymphoma was the first cancer to be cured with radiation therapy alone or with a combination of several chemotherapeutic agents, even before understanding of the biology of Hodgkin lymphoma improved (although its biology is still not fully understood). Since then, the cure rate for children and adolescents with Hodgkin lymphoma has steadily improved, particularly with the introduction of combined radiation and multiagent chemotherapy.^[2]

This therapeutic success has come at the price of serious long-term toxicities, such that a 30-year survivor of Hodgkin lymphoma is more likely to die of therapy-related complications than from Hodgkin lymphoma. Therefore, the therapeutic paradigm has shifted toward reducing treatment-associated toxicity while maintaining high cure rates. This new paradigm has lead to the current risk-adapted, response-based approach to the treatment of Hodgkin lymphoma (see Treatment).

See also the Medscape Reference topic Hodgkin Disease.

Hodgkin lymphoma is a germinal center, B-cell malignant disorder that affects the reticuloendothelial and lymphatic systems.^[14] Disease extension is predictable, is contagious, and can affect other organs and systems. Organs that are predominantly affected include the lungs, bone, bone marrow, liver parenchyma, and, rarely, the central nervous system.

Epidemiologic data suggest that environmental, genetic, and immunologic factors are involved in the development of Hodgkin lymphoma. Clustering of cases in families or racial groups supports the idea of a genetic predisposition or a common environmental factor.

In identical twins of patients with Hodgkin lymphoma, the risk of developing Hodgkin lymphoma is higher than that of other first-degree relatives. Subjects with acquired or congenital immunodeficiency disorders also have an increased risk of developing Hodgkin lymphoma.

Findings from several epidemiologic studies have suggested links between Hodgkin lymphoma and certain viral illnesses. The strongest case to date is a relationship to Epstein-Barr virus (EBV), in that EBV viral DNA can be found in HRS cells. Infants and children aged 0-14 years with Hodgkin lymphoma have EBV DNA in their HRS cells more often than young adults aged 15-39 years with Hodgkin lymphoma.

In addition, the prevalence of EBV-positive classic Hodgkin lymphoma tumors differs geographically. The rate of EBV positivity is 50% in Great Britain, Jordan, Egypt, and South Africa; 91% in Greece; and 100% in Kenya. In general, EBV is most common in mixed-cellularity Hodgkin lymphoma, in young children, and in developing countries.

In EBV-positive Hodgkin lymphoma, EBV-encoding genes play a role in preventing apoptosis. Latent membrane protein-1 (LMP-1) expressed in EBV-positive HRS cells mimics an activated CD40 receptor, activating the antiapoptotic nuclear factor–kappa-B (NF-κB) pathway.

Advances in techniques to isolate HRS cells, immunohistochemical and molecular biology techniques, have helped to clearly identify 2 immunophenotypes for HRS cells. Immunophenotype I is characterized by CD20 positivity, J-chain rearrangements, and, in general, CD30 and CD15 negativity, which is typical of nodular lymphocyte predominant Hodgkin lymphoma. Immunophenotype II is characterized by CD30 positivity, absence of J chains, and frequent expression of CD15, which is consistent with classic Hodgkin lymphoma.^[8]

The clinical manifestations of Hodgkin lymphoma result from the mass effect that is mostly due to the reactive tissue surrounding HRS cells, as well as cytokine production by HRS cells. Systemic symptoms have been attributed to the production of interleukin (IL)–6, whereas some of the histopathological characteristics, such as eosinophilia and collagen sclerosis, have been attributed to cytokine production, such as IL-4, IL-5 exotoxin, IL-6, IL-7, tumor necrosis factor (TNF), lymphotoxin, transforming growth factor β (TGF-β), and basic fibroblast growth factor.

A paracrine activation of NF-κB in Hodgkin lymphoma is observed; both HRS cells and the surrounding supporting cells produce cytokines that upregulate several members of the TNF receptor superfamily, including CD30, CD40, or EBV latent membrane protein-1 (LMP-1).

The production of the ligand for these receptors is responsible for the phosphorylation and translocation to the nucleus of NF-κB. The constitutive translocation of NF-κB to the nucleus of HRS cells is essential for the malignant transformation of HRS cells. It leads to inhibition of apoptosis, proliferation, and secretion of proinflammatory cytokines.^[9]

The etiology of Hodgkin lymphoma is believed to be multifactorial, including the following:

• Infectious agents
• Genetic predisposition
• Socioeconomic factors
• Immune dysregulation
• Environment

Several studies have documented a link between Hodgkin lymphoma and EBV. EBV DNA can be identified in HRS cells in approximately 50% of patients in the United States and in Western Europe and in 90% or more of patients in developing countries.

Clustering in families suggests a genetic predisposition, with an increased incidence especially among same-sex siblings, monozygotic twins, and parent-child pairs. Familial Hodgkin lymphoma has been associated with specific human leukocyte antigens (HLAs). Familial cases account for 4.5% of all cases.

Socioeconomic factors in the United States like parental income and parental education level are inversely related to the incidence of Hodgkin lymphoma.

The increased susceptibility to Hodgkin lymphoma in patients with T-cell immunodeficiency, human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS), or congenital immunodeficiency syndromes suggest a role for immune dysregulation in the development of Hogdgkin lymphoma.

Clustering of cases in families or racial groups supports the idea of a common environmental link. At present, no conclusive association is recognized between dietary habits and the development of Hodgkin lymphoma or other common environmental factos other than EBV infection. Limited evidence suggests increased incidence in higher socioeconomic status and smaller families.^[15] This lends support to the hypothesis that protection from early exposure to other children may contribute to the development of Hodgkin lymphoma in high-income countries.

The age-adjusted standardized rate (ASR) of Hodgkin lymphoma in North America, western Europe, and Oceania is usually just below 7 cases per million. For children and adolescents younger than 15 years, the incidence is 5.5 cases per million. For individuals aged 15-20 years, the incidence is 12.1 cases per million. These rates are in contrast to those in western Asia (from the Mediterranean to northwest India), where the ASR is consistently higher than 7 cases per million.

Differences are observed among countries with different levels of economic development, with highest incidences among young children in developing countries. Over time, these differences have become less pronounced.

In the United States and in Western Europe, the childhood rate is lower than the young-adult rate. In Eastern Europe, the young-adult rate is similar to that observed in the United States and Western Europe, but the childhood rate is higher. Latin American countries have patterns of incidence approaching those of the United States.

The incidence is relatively low in Asia, with the exception of South Asia, where the incidence is relatively high. Nodular sclerosis Hodgkin lymphoma is the most common type in developed countries, whereas in some developing countries, mixed cellularity Hodgkin lymphoma is the most common histologic type.

Race-, sex-, and age-related differences in incidence

In the United States, the incidence among whites and blacks is essentially the same. However, the ratio is 1.4:1 in children older than 10 years.^[4] A significant male-to-female predominance of 3:1 is observed in children younger than 10 years. In older children and adults, the male-to-female ratio is about 1:1.

The incidences of Hodgkin lymphoma by age show a bimodal distribution. In developed nations, the first peak occurs at approximately age 20, and the second peak is observed in patients aged 55 years or older. Hodgkin lymphoma is uncommon before age 5 years. However, in developing countries, the first peak is shifted into childhood, usually before adolescence.

In developed countries, the 5-year overall survival (OS) for Hodgkin lymphoma of all stages is very high. Patients with stage I or II disease have OS greater than 90%, whereas those with stage II or IV disease have OS as low as 70%. Survival in developing countries may be lower, depending on availability of care, medications, distance to the treating centers, and number of patients who abandon therapy before completion.

Most acute and late complications are due to treatment-related toxicities. Hypothyroidism after neck and chest irradiation is prevalent and affects as many as 50% of patients who survive pediatric Hodgkin lymphoma 10 years after treatment. In particular, white female patients are at greater risk than male patients and black patients.

Cardiac and pulmonary complications after radiotherapy depend on the cumulative doses of anthracyclines (cardiac effects) and bleomycin (pulmonary effects) and on the radiation dose.

Girls and especially boys are at high risk for infertility later in life after they receive regimens containing high doses of alkylators. Therefore, male patients should receive counseling about storing their sperm in a sperm bank, as appropriate, before such a regimen is started.

As many as 30% of patients who survive pediatric Hodgkin lymphoma develop a secondary malignancy 30 years after their Hodgkin lymphoma is diagnosed. The most common secondary malignancies are thyroid cancer, breast cancer, nonmelanoma skin cancer, non-Hodgkin lymphoma, and acute leukemia.

Long-term survivors of Hodgkin lymphoma are more likely to die from treatment-related complications 30 years after diagnosis than from Hodgkin lymphoma.^[10]

Before the initiation of treatment, patients with Hodgkin lymphoma should be counseled about the potential complications of Hodgkin lymphoma therapy. Depending on the therapeutic modality, this may include the risk of cardiac disease, lung toxicity, infertility, infection, and secondary cancers. All patients should be counseled on health habits that may help reduce the risk of cancer and cardiovascular disease, including avoidance of smoking, control of lipids, and the use of sunscreen.

Patients should understand the risk of psychosocial problems that may affect survivors of Hodgkin lymphoma. Consultations with social workers, psychologists, and psychiatrists may be helpful to manage some of these issues.

For patient education information, see the Blood and Lymphatic System Center, as well as Lymphoma.