Introduction
Background
Hodgkin disease (Hodgkin's disease) is a highly curable malignant disease. The recent understanding and insight into the biology of Hodgkin-Reed-Sternberg (HRS) cells as B-cell derived have lead to the classification of Hodgkin disease as a lymphoma or Hodgkin lymphoma (HL). 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. 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.1
However, 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 to reduce 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.
Pathophysiology
Hodgkin lymphoma is a B-cell malignant disorder that affects the reticuloendothelial and lymphatic systems. Invasion can affect other organs and systems, predominantly the lungs, bone, bone marrow, liver parenchyma, and, rarely, the CNS. 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 Hodgkin-Reed-Sternberg (HRS) cells. Infants and children aged 0-14 years with Hodgkin disease 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 geographically differs. 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 (NF)–kappa-B pathway.
Frequency
United States
The age-adjusted standardized rate (ASR) 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.
International
Differences are observed among countries with different levels of economic development, with highest incidences among young children in developing countries. Over time, this observation is becoming less pronounced than it is now. 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.
Mortality/Morbidity
In developed countries, the 5-year overall survival (OS) for Hodgkin lymphoma of all stages is of 90% or greater. 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% (see Staging). 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.
Race
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.
Sex
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.
Age
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.
Clinical
History
Most patients with Hodgkin disease (Hodgkin's disease) present with persistent painless adenopathy, unresponsive to antibiotic therapy. More than 70% of patients with Hodgkin lymphoma (HL) present with cervical lymphadenopathy. Patients with mediastinal adenopathy may present with respiratory symptoms such as shortness of breath, chest pain, or cough. These patients are at risk for respiratory failure, especially if they undergo sedation or anesthesia for diagnostic procedures. Clinicians must use care when recommending diagnostic biopsies in these patients. Performing a diagnostic biopsy under local analgesia is preferable; if this is not possible, these patients must be carefully evaluated by an anesthesiologist. These patients may be difficult to intubate or, if intubated, may be unable to be taken off respirator support. A large mediastinal mass may also cause superior vena cava syndrome.
Patients with Hodgkin lymphoma may present with symptoms that are associated with advanced disease and adverse prognosis. The Ann Arbor staging system recognizes the following 3 symptoms as having prognostic significance (see Staging):
- Unexplained fever with temperatures above 38°C for 3 consecutive days
- Unexplained weight loss of 10% or more in the previous 6 months
- Drenching night sweats
Patients may have other symptoms that relate to the cytokines produced by Hodgkin-Reed-Sternberg (HRS) cells or the supporting environment within the affected lymph nodes, such as pruritus, urticaria, and fatigue.
Several immune-mediated paraneoplastic syndromes, such as immune thrombocytopenic purpura and autoimmune hemolytic anemia, can be associated with Hodgkin lymphoma. These paraneoplastic syndromes can present before, after, or at the time of presentation of Hodgkin lymphoma.
Physical
Physical examination is important in the evaluation of patients with Hodgkin lymphoma because it allows the clinician to monitor the response to treatment. Careful evaluation of all lymph node stations, hepatosplenomegaly, and involvement of Waldeyer or tonsillar tissues should always be performed and the findings should be documented.
Patients may have firm, nontender lymphadenopathy. This lymphadenopathy is cervical in 70-80% of patients and axillary in 25%. Other sites are supraclavicular, inguinal, and, less often, epitrochlear or popliteal. A mediastinal mass may cause superior vena cava obstruction, respiratory symptoms, or both. Splenomegaly, hepatomegaly, or both may be present.
Causes
The etiology of Hodgkin lymphoma is believed to be multifactorial. Several studies have documented a link between Hodgkin lymphoma and Epstein-Barr virus (EBV). EBV DNA can be identified in HRS cells in approximately 50% of patients in developed countries and in ³ 90% of patients in developing countries. 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 CD30 positive and has absence of J chains with frequent expression of CD15, a pattern consistent with classic Hodgkin lymphoma histological subtypes as defined by the World Health Organization classification of lymphomas.2
The clinical manifestations of Hodgkin lymphoma may be a direct result of cytokine production by HRS cells or the surrounding cells within the affected lymph nodes. 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 (TNF-β), and basic fibroblast growth factor. The constitutive translocation of nuclear factor κB (NF-κB) to the nucleus of HRS cells is essential for the malignant transformation of HRS cells.
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, which, in turn, leads to inhibition of apoptosis, proliferation, and secretion of proinflammatory cytokines.
Other factors include the following:
- Genetic predisposition: 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.
- Infectious agents: EBV is found in approximately 50% of cases of Hodgkin lymphoma in the United States and in western Europe.
- Socioeconomic factors: In the United States, parental income and parental education level are inversely related to the incidence of Hodgkin lymphoma.
- Immune dysregulation: Patients may have T-cell immunodeficiency, human immunodeficiency syndrome (HIV) infection or acquired immunodeficiency syndrome (AIDS), or congenital immunodeficiency syndromes.
- Diet: At present, no conclusive association is recognized between dietary habits and the development of Hodgkin disease.
- Environment: Clustering of cases in families or racial groups has supported the idea of a common environmental link.
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| Treatment & Medication: Hodgkin Disease |
| Follow-up: Hodgkin Disease |
| Multimedia: Hodgkin Disease |
| References |
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Further Reading
Keywords
Hodgkin disease, HD, Hodgkin's disease, Hodgkin lymphoma, nodular sclerosis HD, nodular sclerosis Hodgkin disease, nodular sclerosis Hodgkin's disease, NS HD, mixed cellularity HD, mixed cellularity Hodgkin disease, mixed cellularity Hodgkin's disease, MC HD, lymphocyte-rich HD, lymphocyte-rich Hodgkin disease, lymphocyte-rich Hodgkin's disease, LR HD, lymphocyte-depleted HD, lymphocyte-depleted Hodgkin disease, lymphocyte-depleted Hodgkin's disease, LD HD, nodular lymphocyte–predominant HD, nodular lymphocyte–predominant Hodgkin disease, nodular lymphocyte–predominant Hodgkin's disease, NLP HD, Epstein-Barr virus, superior vena cava syndrome, pruritus, urticaria, fatigue, thrombocytopenic purpura, autoimmune hemolytic anemia, hepatosplenomegaly
