Classical Hodgkin’s Lymphoma and Related Lesions

Incidence

HL accounts for approximately 15% to 25% of all malignant lymphomas. With current diagnostic criteria, approximately 95% of HLs fall into the CHL category; the remaining cases are NLPHLs. The age-adjusted annual incidence rate of HL in Western countries is approximately 2 to 4 per 100,000 population. In recent decades, a decrease in incidence has been observed among older adults; however, this can be attributed mainly to the misdiagnosis of NHL as HL in previous years. In contrast, there has been a slight increase of the nodular sclerosis subtype in young adults. The incidence of CHL is higher in affluent, industrialized nations than in developing countries.

Age and Sex Distribution

In industrialized countries, CHL shows a bimodal age distribution: the first, higher peak occurs in early adulthood (15 to 35 years of age), with a second peak in those older than 55 years. CHL is rare in children and is an exceptional occurrence in those younger than 3 years. The overall male-to-female ratio is approximately 1.5:1. Although males predominate in childhood cases and among older adults, the male-to-female ratio is balanced or even slightly reversed in the early adulthood peak. The distribution of histologic subtypes varies with age. Although the nodular sclerosis subtype predominates in young adults, especially in females, there is a higher percentage of the mixed-cellularity subtype in children and older patients. Developing countries show a distinct epidemiologic pattern: the first incidence peak occurs in childhood, with a predominance of the mixed-cellularity subtype, and there is no peak in young adulthood.

Nodular sclerosis CHL in young adults is associated with a higher socioeconomic status and smaller family size, factors thought to favor a delayed exposure to common childhood viruses. Paradoxically, the early adulthood cases show the lowest frequency of Epstein-Barr virus (EBV) positivity, the only infectious agent so far shown to be associated with CHL. EBV is most often identified in CHL in children and older adults and in association with human immunodeficiency virus (HIV) infection.

Familial cases of HL have been reported frequently, and siblings of HL patients have a moderately increased risk for developing the disease. A markedly increased risk for CHL was reported for monozygotic twins in a single study. There seems to be a weak but consistent increase in the relative risk for CHL among certain human leukocyte antigen (HLA) types. Interestingly, carriers of HLA-A*02, known to be involved in the cytotoxic response to latency proteins of EBV, are underrepresented in EBV-positive CHL.

Association with Immunodeficiency Disorders

The risk for developing CHL is increased in patients with some types of immunodeficiency. HIV-infected persons have a 6-fold to 20-fold increased risk for developing CHL. In the setting of acquired immunodeficiency syndrome (AIDS), CHL shows a predominance of unfavorable histologies (mixed-cellularity and lymphocyte-depleted) and advanced-stage disease, and it is almost universally associated with EBV. The incidence of CHL seems to increase in the first months after initiation of highly active antiretroviral therapy.

A significantly increased risk for CHL has been described in recipients of solid organs and allogeneic bone marrow grafts. In either setting, CHL occurs late after transplantation, is almost always EBV positive, and is mainly of the mixed-cellularity subtype. The clinical presentation and outcome of CHL in allograft recipients is similar to that in non-immunocompromised patients (see later).

Functional Consequences of Infection

LMP-1, which is strongly expressed by the neoplastic cells in HL, is the only viral protein with proven oncogenic properties. LMP-1 induces an array of phenotypic changes in infected cells, including upregulation of activation antigens and antiapoptotic genes, as well as induction of various cytokines; it can also induce an RS-like phenotype in germinal-center B cells. LMP-1 functions as a constitutively activated tumor necrosis factor (TNF) receptor and induces a variety of downstream effects, such as constitutive activation of nuclear factor-κB (NF-κB) and JAK/STAT signaling pathways and upregulation of antiapoptotic genes. Of note, virtually all cases of CHL with so-called crippling IGH mutations are EBV positive, emphasizing the importance of EBV-related genes for rescuing CHL precursor cells from apoptosis. However, there is no clear-cut correlation between EBV positivity and tissue expression of genes known to be regulated by LMP-1 in vitro, and the gene-expression profiles of HRS cells are very similar irrespective of EBV status, indicating that the main impact of EBV infection of CHL pathogenesis may lie in the early stage of disease development and in the interaction with the immune system.

Strains and Variants

Two common strains of EBV, types A and B (or 1 and 2), exist in a worldwide distribution. EBV type A transforms lymphocytes more efficiently and is found in the majority of CHL cases in non-immunosuppressed patients. Type B is encountered more often in HIV-associated CHL but has also been found in a higher proportion of cases from Latin America, indicating that geographic variations in the prevalence of viral strains can influence their distribution in EBV-associated lymphomas.

In addition to these two viral strains, a number of variations of the EBV genome have been described. Among these, deletions in the carboxyterminal part of the LMP-1 gene have received the greatest attention. Although initial findings suggested an increased occurrence in cases with aggressive morphologic features, further studies demonstrated that the deletion variant is not associated with any specific histologic or prognostic features; its frequency in EBV-associated CHL reflects its prevalence in healthy carriers from the same geographic region, with the possible exception of higher frequencies of deletion variants in HIV-associated CHL. Of note, CHL cases with EBV type B contain the LMP-1 deletion very frequently, indicating that this deletion might be necessary for the transforming capacity of this less virulent strain.

Epidemiology of Epstein-Barr Virus–Associated Classical Hodgkin's Lymphoma

The frequency of the association between EBV and CHL in non-immunosuppressed patients is influenced by histologic subtype, age at presentation, geographic and ethnic origin, and possibly socioeconomic factors. Mixed-cellularity CHL is EBV positive in approximately 75% of cases, whereas EBV positivity in the nodular sclerosis subtype ranges from 10% to 25%. Reported rates for both lymphocyte-depleted and lymphocyte-rich CHL are variable, probably reflecting differences in diagnostic criteria. However, when stringent criteria are used, lymphocyte-depleted CHL is usually EBV positive. Children and older adults are more likely to have EBV-positive CHL, as are males. Developing countries generally show a higher incidence of EBV-associated disease, reaching almost 100% in childhood cases. A history of infectious mononucleosis and atypical prediagnosis EBV serology are associated with an increased risk for EBV-positive, but not EBV-negative CHL, further supporting the pathogenetic role of EBV.

Epstein-Barr Virus–Negative Classical Hodgkin's Lymphoma

Based on observations in EBV-positive Burkitt's lymphoma cell lines, it has been proposed that the virus might be lost during the malignant progression of CHL once it is no longer required for propagation of the malignant clone. Although a single study reported detection of defective, rearranged EBV in a fraction of CHLs that were EBER negative, results from other groups have not provided evidence for this “hit and run” theory. Searches for other candidate viruses, such as human herpesvirus 6 or 8, have failed to provide evidence for their involvement in the pathogenesis of CHL.

Laboratory Findings

Laboratory findings are mostly non-specific and include leukocytosis, elevated erythrocyte sedimentation rate, and increased lactate dehydrogenase. Eosinophilia can be observed in approximately 20% of patients, and lymphopenia is present in advanced disease stages. However, most patients with CHL exhibit demonstrable defects in cell-mediated immunity, regardless of stage. A decrease in CD4-positive cells in the peripheral blood is already detectable at an early stage. T lymphocytes from HL patients show a weaker response to T-cell mitogens and a decrease in cytokine production upon stimulation. Clinically, this anergy can manifest as an increased susceptibility to infections and a lack of reactivity in the tuberculin skin test. It is still unclear whether these immune abnormalities are preexistent and may contribute to disease development or are secondary phenomena, possibly due to immunosuppressive cytokines secreted by the neoplastic population.

Extranodal Manifestations

Although CHL is almost always a node-based lymphoma, practically any site and organ of the body can be involved during the course of the disease or, much rarer, as a primary manifestation. Although the spleen, bone marrow, and liver are frequently involved in advanced disease, isolated involvement of these organs is rare. Thymic involvement is frequent in mediastinal disease. Rarely, if lymph node involvement is not apparent, CHL can simulate other neoplasms of the thymus radiologically, prompting surgical removal of the thymic mass. The affected thymus gland frequently shows cystic degeneration. CHL is rare in mucosa-associated lymphoid tissue, including the tonsils and Waldeyer's ring. Apart from the liver, the lung is probably the most frequently involved non-lymphoid organ, usually as an extension of mediastinal disease. Primary pulmonary disease is rare. The same is true for primary gastrointestinal CHL. Further, many cases from earlier series probably represent NHLs such as polymorphic large B-cell NHL or enteropathy-type T-cell lymphoma. Interestingly, primary CHL of the gastrointestinal tract was initially reported in association with a history of inflammatory bowel disease or immunosuppression. These cases would today probably be classified as EBV-associated lymphoproliferation with Hodgkin-like features, specifically as EBV-associated mucocutaneous ulcer. Many other extranodal primary sites of CHL have been reported, mainly in anecdotal form. An especially problematic organ is the skin, owing to the morphologic and phenotypic overlap between CHL and CD30-positive lymphoproliferative disorders of the skin, including cutaneous anaplastic large-cell lymphoma (ALCL) and lymphomatoid papulosis. Only a few well-documented cases of apparently primary cutaneous CHL have been reported. Central nervous system involvement with CHL is very rare but may occur as primary disease.