INTRODUCTION — Hodgkin lymphomas (HL; formerly called Hodgkin's disease) are lymphoid neoplasms in which the malignant cells are admixed with a heterogeneous population of non-neoplastic inflammatory cells.
HL is divided into two major subgroups, based on morphology and immunophenotype [1] (table 1):
●Classic HL (cHL), which is further categorized according to histology:
•Nodular sclerosis cHL (NSCHL)
•Mixed cellularity cHL (MCCHL)
•Lymphocyte rich cHL (LRCHL)
•Lymphocyte depleted cHL (LDCHL)
●Nodular lymphocyte predominant HL (NLPHL)
This topic will review the epidemiology and risk factors for cHL and NLPHL.
Clinical presentation and diagnosis, and pretreatment evaluation, staging, and prognosis of cHL are discussed separately.
●(See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults".)
●(See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma".)
Clinical manifestations, diagnosis, and treatment of NLPHL are presented separately. (See "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging" and "Treatment of nodular lymphocyte-predominant Hodgkin lymphoma".)
The pathogenesis of HL and the role of Epstein-Barr virus in HL are discussed separately. (See "Pathogenesis of Hodgkin lymphoma".)
EPIDEMIOLOGY
Subtypes — Classic HL (cHL) accounts for approximately 90 percent of Hodgkin lymphoma, while nodular lymphocyte-predominant HL (NLPHL) accounts for the remainder of cases [2]. However, the distribution of histologic subtypes of cHL varies based on geography, socioeconomic factors, race/ethnicity, and age.
In the United States, Europe, and other economically developed regions, HL accounts for approximately 10 percent of all lymphomas (the remainder being non-Hodgkin lymphomas), 0.5 percent of all cancers, and 0.2 percent of all cancer deaths [3-5]. The incidence of HL in such settings has been stable at 2 to 3 cases per 100,000 persons for decades; in the United States, this corresponds to approximately 8500 new cases of HL annually, but the approximately 1000 annual deaths indicates a decreasing mortality rate.
The distribution of cHL subtypes in economically developed settings is [1]:
●Nodular sclerosis cHL (NSCHL): 70 percent
●Mixed cellularity cHL (MCCHL): 20 to 25 percent
●Lymphocyte rich cHL (LRCHL): 5 percent
●Lymphocyte depleted cHL (LDCHL): <1 percent
The distribution of cHL subtypes differs in other settings, and contributing factors include socioeconomic factors, age of exposure to Epstein-Barr virus (EBV), and prevalence of HIV/AIDS, as described below. (See 'Risk factors' below.)
Age and race — HL is most common among young adults (20 to 34 years); the median age at diagnosis is 39 years in the United States [6]. There is a bimodal age distribution with some histologic subtypes or geography (figure 1). The age distribution of patient ages varies with the histologic subtype:
●Nodular lymphocyte-predominant HL (NLPHL) has a peak incidence in the fourth and fifth decades of life, but is also seen in children [2]. NLPHL is more common in males than in females. Other aspects of the epidemiology of NLPHL are discussed separately. (See "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations, diagnosis, and staging", section on 'Epidemiology'.)
●Classic Hodgkin lymphoma (cHL) – The age and sex distribution varies with the cHL subtype. NSCHL has a peak incidence between ages 15 and 35 years, whereas MCCHL has a bimodal distribution with the peak in young adults and a second peak in older adults [1]. For NSCHL the incidence is comparable between males and females, but there is a male predominance for other subtypes of cHL [7,8].
The incidence of HL varies by race. As an example, from the SEER database, the incidence is equal in White and Black Americans in the United States (3.1 cases per 100,000 males), but it is lower in Hispanic Americans (2.6), Asians/Pacific Islanders, Native Americans, and Alaska natives [9]. In one population-based study (also using SEER), the peak incidence was in young adulthood among White and Black Americans and Asian/Pacific Islanders, but the peak in Hispanic Americans was in older individuals [10]. Compared to non-Hispanic White children, Hispanic children had an increased risk of HL (OR 2.43; 95% CI 1.14-5.17) and, in particular, were more often diagnosed with MCCHL [11].
RISK FACTORS
Overview — The incidence and distribution of HL histologic subtypes is influenced by geography, socioeconomic factors, HIV infection, and family history. Although Epstein-Barr virus (EBV) has been linked to the pathogenesis of HL, the virus is detected in only a subset of cases, and the absolute risk for HL after EBV infection is very small. (See 'Epstein-Barr virus' below.)
Importantly, there is an association between several of the risk factors for HL. As an example, compared with economically developed regions, there are higher rates of mixed cellularity classic HL (MCCHL) and lymphocyte-depleted classic HL (LDCHL) in geographic regions with lower socioeconomic development; these subtypes are more commonly associated with EBV-positive HL and higher rates of HIV infection [12-17].
Epstein-Barr virus — Detection of EBV in Hodgkin/Reed-Sternberg (HRS) cells varies with the histologic subtype, geography, and immunocompetence of the patient. EBV is most often associated with MCCHL and LDCHL subtypes, is more common in resource-limited settings, and is nearly always detected in HL of HIV-infected patients. The biology of EBV and mechanisms by which it may contribute to the pathogenesis of HL are discussed separately. (See "Virology of Epstein-Barr virus" and "Pathogenesis of Hodgkin lymphoma", section on 'Epstein-Barr virus'.)
Only a very small minority of patients infected with EBV will develop HL. Approximately 90 to 95 percent of adults worldwide are EBV seropositive, but the age of infection varies with socioeconomic conditions [18]. EBV is the cause of infectious mononucleosis (IM), and one study estimated that the absolute risk of developing HL after IM was approximately 1 in 1000 [19]. In this case-control study, there was an increased relative risk (RR) of developing EBV-positive HL after IM (RR 4.0; 95% CI 3.4-4.5), but no increased risk for EBV-negative HL [19]. There may be at higher risk of developing EBV-positive cHL in patients with certain genetic features. (See 'Genetic features' below.)
Epidemiologic, serologic, and pathologic data have identified the following associations of EBV with HL:
●Histologic subtype – EBV positivity varies among the various histological categories of cHL: approximately 10 to 25 percent of NSCHL, 40 percent of LRCHL, 70 percent of MCCHL, and close to 100 percent of LDCHL [20,21]. EBV is rarely, if ever, found in NLPHL. Most cases of HL that carry inactivating mutations of immunoglobulin genes are EBV positive [22].
●Geography – EBV is detected in the malignant cells of 20 to 50 percent of cases of classic HL (cHL) in North America and Europe, but nearly all cases of cHL are EBV positive in tropical and economically developing regions [12-17].
●HIV/AIDS and other immunosuppressive conditions – Almost all HL cases occurring in patients with HIV infection or other immunosuppressive conditions are EBV positive, as discussed below. (See 'Immunosuppression' below.)
Other infections — There is controversy regarding a possible role for human herpesvirus 6 (HHV6) in HL pathogenesis, but there is currently no persuasive evidence that other types of infections play a causal role in HL [23].
HHV6 was detected in HRS cells of approximately half of NSCHL specimens in one study, based on immunodetection and molecular techniques on microdissected cells; HHV6 was more commonly found in younger patients with EBV-negative disease [24]. Other studies have also reported associations with HHV6 based on serologic and other techniques, but its contribution to the pathogenesis of HL is unclear [25-27].
There is no evidence that cytomegalovirus, human herpesviruses 7 and 8, polyoma JC virus, adenovirus types 5 and 12, human T cell lymphotropic virus 1 and 2, and human retrovirus 5 are present in HRS [28,29]. Certain childhood infectious illnesses, including chickenpox, measles, mumps, rubella, and pertussis, are negatively associated with the risk of HL [30]. A large population-based case-control study from Sweden reported an association between HL and certain infections (eg, sinusitis, tuberculosis, encephalitis, herpes zoster), but this may reflect an underlying immunodeficiency related to HL rather than a causal role for these infections [31]. (See 'Immunosuppression' below.)
Geography and socioeconomic status — The distribution of HL subtypes varies with geography and certain socioeconomic factors.
The distribution of histologic subtypes and age appears to parallel the level of industrial development in various geographic locales:
●In the United States, Europe, and other economically advantaged countries, the highest incidence of HL is in older adolescents/young adults and there is a smaller peak in older adults (approximately age 65 years) (figure 1) [32]. Lymphomas are the most common cancer in adolescents (21 percent of new cancer diagnoses in those 15 to 19 years old) in such settings, and HL comprises approximately two-thirds of those cases [3].
●In contrast, in economically disadvantaged areas, there is an initial peak in childhood for boys, relatively low rates in young adults, and a prominent peak in older adults [16,17,33].
●An intermediate pattern with peaks of incidence both in childhood and in the second decade of life has been described in early industrialized or transitional economies [33-35].
In the developing world, MCCHL and LDCHL are relatively common HL subtypes whereas, in economically advantaged settings, NSCHL is the predominant subtype and LDCHL is rare [36,37]. The risk for MCCHL is inversely related to socioeconomic factors that are indicative of a higher standard of living, such as single family housing and small family size [38-40]. Among lower socioeconomic groups in economically advantaged settings, the predominant subtypes are MCCHL and LDCHL [41]. In Brazil, MCCHL is more common in rural regions, whereas NSCHL is more common in urban areas [42]. A population-based study in Israel reported a higher risk for NSCHL in Israeli-born individuals compared with immigrants (HR 1.59; 95% CI 1.32-1.92), which may reflect socioeconomic factors [43].
The associations between socioeconomic factors and disease incidence are generally taken to suggest that the development of HL is related to exposure to a common environmental or infectious agent, but the specific agent and/or exposure is not clear [28,44-49].
Other environmental factors — Although other environmental factors have been associated with the incidence of HL, no causal relationship has been proven and some of these factors may be associated with socioeconomic status. (See 'Geography and socioeconomic status' above.)
●Diet, body weight: There is an increased risk of HL in association with obesity, based on population-based studies and a meta-analysis [50-52]. High intake of meat or sweets has been associated with an increased risk of cHL [53]. A positive association between physical inactivity and risk of HL was reported in 87 patients with HL compared with cancer-free controls [54].
●Aspirin: A protective effect of aspirin for HL development has been reported, but results have varied across studies. In a case-control study of 565 patients with HL and 679 control subjects regular use of aspirin, but not other nonsteroidal anti-inflammatory drugs (NSAID), was associated with a lower risk of HL (odds ratio 0.60; 95% CI 0.42-0.85) [55]. A population-based study from northern Denmark reported a more modest, but not statistically significant, protective effect of aspirin [56]. The inverse association with aspirin consumption may reflect its effect on inhibiting NF-kB signaling, which is thought to play a key role in HL pathogenesis. (See "Pathogenesis of Hodgkin lymphoma", section on 'Pathogenesis of cHL'.)
●Birth weight/breast feeding: High birthweight (after adjusting for birth order, maternal age at the age of the time of delivery, and paternal age) was associated with an increased risk of pediatric HL (OR 1.23; 95% CI 1.02-1.48) [57]. A protective effect of breastfeeding has been shown in multiple studies, but it is not known if this is related to transmitted maternal antibodies [58,59].
●Cigarette smoking: A meta-analysis that analyzed 50 studies with nearly 5000 cases of HL reported that a history of ever-smoking was associated with increased risk for HL (pooled-effect estimate = 1.15, 95% CI 1.02-1.30); sizeable associations were observed regarding both NSCHL and MCCHL subtypes [60]. Several individual studies using various methodologies have reported an association between smoking and HL incidence [61-65].
Immunosuppression — The incidence of HL is increased in patients infected with HIV and in other settings associated with immunodeficiency. HL in these populations is almost universally positive for EBV. Although there is an increased incidence of HL in people infected with AIDS, HL is not considered an AIDS-defining malignancy. (See "HIV infection and malignancy: Epidemiology and pathogenesis", section on 'Non-AIDS-defining cancers'.)
The relative risk of HL has been reported to be increased 5- to 25-fold among patients infected with HIV [66-70]. In the United States, HIV infection is present in a substantial proportion of non-Hispanic Black, Hispanic, and middle-aged men with LDCHL and MCCHL [71]. The risk for HL is also increased in patients after solid organ transplantation, hematopoietic cell transplantation, and treatment with immunosuppressive drugs (eg, for autoimmune diseases) [72-76]. Rarely, cHL can arise as a Richter's transformation of chronic lymphocytic leukemia, and this occurrence may be related to immunosuppressive therapy (eg, fludarabine) or EBV [77]. Almost all HL cases occurring in the setting of HIV infection are EBV positive and many cases are LDCHL [78].
The risk for HL in immunosuppressed individuals is less striking than the risk for non-Hodgkin lymphomas (NHLs) [73,75]. The peak incidence of HL is four or more years after transplantation, in contrast to NHL, which most commonly occurs in the first year after transplantation. The CD4 T cell count associated with HIV-associated HL is typically higher than in other EBV-associated lymphomas. Further discussion of the association of immunosuppression and lymphomas is presented separately. (See "HIV-related lymphomas: Epidemiology, risk factors, and pathobiology" and "Malignancy after solid organ transplantation" and "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders".)
Autoimmune disorders — Patients with a history of autoimmune disorders are at increased risk for the development of HL, but it is unclear if this is directly related to these conditions or if it increased by the immunosuppressive agents used to treat them.
A population-based study of nearly 900,000 Swedes reported an increased standardized incidence ratio (SIR) for all subtypes of cHL (SIR 2.0; 95% CI 1.8-2.0) among patients with autoimmune illnesses, including polyarteritis nodosa, polymyositis/dermatomyositis, Behçet's disease, Sjögren's disease, polymyalgia rheumatica, and psoriasis [79]. A large population-based registry data study from Sweden and Denmark reported a strong association of HL with a personal or family history of autoimmune conditions [80]. Another population-based study reported an increased risk for HL in Danish patients with rheumatoid arthritis, but not with atopic diseases [81].
Familial risk — There is a familial predisposition to HL, but it is unclear how much of this effect is genetic versus environmental. The increased risk in close relatives of patients with HL is approximately three- to fivefold greater than the expected rate overall, but the risk may vary with the subtype [82-85]. In a registry-based study, the SIR for cHL was 5.3 (95% CI, 3.0 to 8.8) and SIR for NLPHL was 19 (95% CI, 8.8 to 36) in first-degree relatives of patients with HL [86]. The risk is stronger for HL in siblings than in parents [82,87-89].
Studies that reported increased familial risk for HL have used a variety of methodologies:
●Case-control studies – A large Scandinavian case-control study reported a 3.3 odds ratio (OR) for HL in individuals of family history of HL [90]. Some smaller studies have reported larger ORs for HL [91,92].
●Cohort studies – A cohort study of 3.5 million people in Sweden family history was associated with 7.2 and 8.5-fold increased risk of HL in children and young adults, respectively [87]. Another cohort study reported a sixfold increase for siblings [93].
●Registry-based studies – A registry study from Sweden and Denmark reported a 3.1-fold increased risk (95% CI 1.8-5.3) [82,83]. In other registry-based studies, the risk of HL in first-degree relatives of HL probands ranged from 1.2 to 5.8-fold [88,89,94].
●Monozygotic twins – In one study, compared to background rates, the SIR for HL in monozygotic twins was 99 (95% CI 48-182) [95]. Another study reported a 57-fold increased risk for HL in same sex twins [85].
Genetic features — The most consistent genetic association with risk for HL is variation at major histocompatibility complex (MHC)/human leukocyte antigen (HLA) loci. However, the increased risk for HL is most likely due to co-inheritance of multiple risk alleles, some which are likely to be common, rather than a single genetic determinant [96].
Variations at specific MHC/HLA loci are associated with an increased risk of developing HL. There is a consistent association with HLA-A1, and to a lesser extent, HLA-B5, HLA-B8, and HLA-B18 [97-103]. Genome-wide association studies (GWAS) identified specific MHC variants that were independently associated with both EBV-negative and EBV-positive cHL, while certain MHC variants that were independently associated with only EBV-positive cHL and other variants were only associated with EBV-negative cHL [103,104].
There has not been consistent identification of other genetic loci as risk factors for HL. A systematic review and meta-analysis of 21 studies identified some associations with various HLA loci, but no reproducible associations with candidate genes such as immune function/response, carcinogen metabolism enzymes, folate metabolism enzymes, DNA repair proteins, and others [96]. Some genes that have been reported to increase the risk for HL include REL, EOMES, ERAP1, IL13, PVT1, GATA3 and TCF3 [104-110].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of Hodgkin lymphoma".)
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●Basics topics (see "Patient education: Hodgkin lymphoma in adults (The Basics)")
●Beyond the Basics topics (see "Patient education: Hodgkin lymphoma in adults (Beyond the Basics)")
SUMMARY
●Hodgkin lymphomas (HL), formerly called Hodgkin's disease, are lymphoid neoplasms in which malignant cells are admixed with a large, heterogeneous population of non-neoplastic inflammatory cells. HL is divided into two major subgroups, based on morphology and immunophenotype:
-Classic HL (cHL), which accounts for approximately 90 percent of HL:
-Nodular sclerosis cHL (NSCHL)
-Mixed cellularity cHL (MCCHL)
-Lymphocyte rich cHL (LRCHL)
-Lymphocyte depleted cHL (LDCHL)
•Nodular lymphocyte-predominant HL (NLPHL) accounts for the remainder of HL
●Epidemiology – The distribution of HL subtypes varies with geography and the level of economic development. In economically developed settings, NSCHL is the predominant subtype, followed by MCCHL, while LRCHL and LDCHL are uncommon. (See 'Subtypes' above.)
●Age distribution – HL is most common among young adults (20 to 34 years) with a median of 39 years. HL has a bimodal age distribution with some histologic subtypes or geography (figure 1). (See 'Age and race' above.)
●Epstein-Barr virus (EBV) is associated with the development of HL, but EBV is found in only a subset of cases of HL; involvement by EBV varies by age, geography, ethnicity, and histologic subtype. EBV infection is more common in resource-poor settings and is almost universally associated with HL in immunodeficient individuals (eg, HIV/AIDS). (See 'Epstein-Barr virus' above.)
●Other risk factors that have been associated with HL include socioeconomic status, immunosuppression, and familial/genetic risks, as discussed above. (See 'Risk factors' above.)
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