Hodgkin lymphoma (HL) is one of the most curable cancers in both pediatric and adult patients. The primary disease carries an excellent prognosis with an estimated 5-year survival rate of more than 98% [1]; however, long-term overall survival remains poor because of relapsed or refractory (R/R) disease and the late effects of treatment regimens. The current American Cancer Society statistics report that the 5-year relative survival rate for all patients diagnosed with HL is now about 87% [2].

HL is named after the English physician Thomas Hodgkin, who first described the disorder in 1832 [3]. In his publication, he noted that the unknown ailment was characterized by painless lymph node enlargement [3]. More than two decades later, in 1856, Samuel Wilks noted that splenomegaly was also a common symptom in patients with the disorder [4]. Finally, at the turn of the century, two pathologists (Carl Sternberg and Dorothy Reed) working independently of each other described the distinctive, multinucleated cells which now bear their names (Reed–Sternberg [RS] cells) and are pathognomonic for classical HL (cHL) [5]. Their discovery helped dispel the notion—commonly held within the medical community at the time—that Hodgkin’s disease was merely a form of tuberculosis (because both disorders commonly present with night sweats, weight loss, fever, and lymphadenopathy) [6].

HL is a rare malignancy of lymphoid origin that accounts for about 15% of all lymphoma diagnoses. The disease is characterized by unique, mononucleated Hodgkin cells and giant, multinucleated RS cells—collectively known as Hodgkin–Reed–Sternberg (HRS) cells—surrounded by inflammation ^[7][8][7,8]. The classical presentation involves supra-diaphragmatic lymphadenopathy, often associated with systemic (constitutional) B symptoms comprised of unexplained, high-grade fever; drenching night sweats; weight loss of at least 10% of body weight; and fatigue [9].

HL is sometimes incorrectly classified as being primarily a malignancy of adulthood. This is likely partially due to its bimodal age distribution, which consists of an incidence peak in young adults (ages 20–34 years) and a second peak in older adults (older than 55 years). The average age at diagnosis is 39 years [10]; however, HL is actually relatively common in the pediatric population as well [11]. In fact, HL accounts for approximately 7% of childhood cancers overall and 1% of childhood cancer deaths in the United States [10]. Additionally, it is the most common childhood cancer in the 15-to-19-year-old age group [12].

The World Health Organization broadly categorizes HL into two classes based on histopathological differences [13]: classical Hodgkin lymphoma (cHL) and nodular lymphocyte-predominant HL (NLPHL). cHL, which has four subclasses (described later in the classification section), is much more common and accounts for approximately 95% of HL cases, whereas NHLPL accounts for only 5% ^[8][14][8,14].

The conventional treatment of HL, which has been developed over the past several decades, consists of stage-driven chemotherapy with or without radiation and achieves a cure rate of about 80%. Alternate high-dose chemotherapies and hematopoietic stem cell transplantation (SCT) are the only second-line therapies available for R/R cases ^{[8][15][16][17]}[8,15,16,17].

Despite the significant cure rates achieved using traditional therapies, about 20% of patients with cHL experience R/R disease, which carries a dismal prognosis; only half of such patients are cured via intensive second-line therapies ^[7][11][18][7,11,18]. Moreover, the potential late effects of treatment continue to be concerning, warranting the need for improvement in the field ^[1][19][1,19].

In clinical studies for R/R HL, novel methods such as monoclonal antibodies (i.e., brentuximab vedotin [BV, an anti-CD30 monoclonal antibody], nivolumab, and pembrolizumab) and immunomodulatory medications have produced outstanding results and are now being incorporated into front-line treatment regimens ^[20][21][20,21].

2. Epidemiology

Every year, HL accounts for approximately 10% of newly diagnosed lymphoma cases (2.6 cases per 100,000 population) in the United States, or 2% to 2.5% of total cancer diagnoses. The American Cancer Society estimated that, in the United States in 2022, 8540 of the 89,010 lymphoma cases were HL; that HL would cause about 920 deaths (0.3% of all cancer deaths) [2]; and that HL would represent approximately 7% of childhood cancers overall and 1% of childhood cancer deaths [2]. According to the National Cancer Institute, from 2010 to 2020, the age-adjusted rate of new HL cases fell an average of 1.6% per year, while the age-adjusted death rate fell an average of 4.0% per year [22]. Whereas the incidence of most lymphomas increases with advancing age, HL is distinguishable because of its bimodal age distribution [22]. HL occurs most frequently in adolescents and young adults (aged 15–35 years) and in older adults (over the age of 55 years); the average age at diagnosis is 39 years [22]. HL is exceptionally rare in infants, toddlers, and pre-pubertal patients [22]. It remains the most common cancer diagnosed in adolescents aged 15 to 19 years [2]. With regard to race, HL incidence rates vary by region across the United States [23]. However, in general, non-Hispanic whites have slightly higher rates of the disease and American Indians/Alaska Natives and Asians/Pacific Islanders have lower rates ^[23][24][23,24]. In terms of sex predilection, in adults, HL is only slightly more common in men than in women; however, in pediatric patients, the difference between the sexes is significantly higher, and approximately 85% of patients are boys [25].

3. Risk Factors and Etiology

There is no clearly defined etiology for HL, but there are numerous risk factors that may predispose an individual to develop the malignancy [26]. For instance, individuals with immunodeficiencies, such as acquired immunodeficiency syndrome (AIDS), and those on chronic immunosuppression because of solid-organ or stem-cell transplants are at higher risk of developing HL ^[26][27][26,27] (although individuals with immunodeficiencies actually have a greater risk of developing non-HL than HL, and HL is not considered an AIDS-defining malignancy) ^[28][29][28,29]. Epstein–Barr virus (EBV) positivity has also been identified as a causative factor in HL ^[26][30][26,30]. In fact, EBV genetic material has been detected in the RS cells of some HL patients [30]. EBV affects 90% to 95% of adults worldwide and is associated with approximately 1% of all cancers and one-third of all HL cases ^[31][32][31,32]. However, only a small percentage of individuals infected with EBV actually develop lymphoma [32]. Therefore, it is likely that other biological or epidemiological determinants besides the virus itself play a role in the development of this disease ^[32][33][32,33]. Family history also appears to be a determinant in the development of HL [34]. Multiple population-based cohort studies in European countries have demonstrated that a family history of HL is an independent risk factor for the development of childhood HL [35]. One study found that the overall lifetime cumulative risk of HL in the first-degree relatives of a patient with HL was three times higher than that in the general population [36].

4. Pathophysiology and Molecular Biology of HL

HL is a complex, multifactorial malignancy that primarily involves B cells (although 1–2% of cases involve T cells) [37]. These lymphocytes originate in the germinal center of lymph nodes [38]. The disease is characterized by the presence of unique, mononucleated Hodgkin cells, and large, multinucleated RS cells, collectively known as HRS cells, and are rare amidst the extensive and complex inflammatory background. Though both Hodgkin and RS cells are abnormal lymphocytes, their morphological appearance differs, and both are highly specific to HL. RS cells continually develop from the Hodgkin cells as a result of incomplete cytokinesis and re-fusion [39]. Nonetheless, HRS cells are the hallmark of cHL, and are characteristically unable to express B-cell-specific genes, most notably the immunoglobulin (Ig) heavy-chain gene, and are thus unable to produce antibodies [37]. Various mechanisms (such as EBV infection) activate the anti-apoptotic nuclear factor kappa B (NF-κB) transcription factor signaling pathway [40]. Activation of this pathway prevents the apoptosis of the defective lymphocytes and promotes the proliferation of RS cells ^[37][40][37,40]. HRS cells of cHL exhibit a perplexing co-expression of markers from different hematopoietic cell types, including expression of the B-cell transcription factor PAX5 ^[39][41][39,41]. Genetic analysis studies confirmed that HRS cells are transformed B cells, as they possess Ig heavy- and light-chain V gene rearrangements specific to B cells, along with somatic mutations associated with germinal center (GC)-experienced B cells ^[39][42][43][39,42,43]. Furthermore, the detection of destructive mutations in IgV genes indicated the derivation of HRS cells from pre-apoptotic GC B cells [43]. Notably, a small subset of cHL cases may be attributed to T-cell origin [44]. HRS cells express the CD30 marker and show key features similar to normal CD30+ B cells, including mutated IgV genes, class switching, and expression of MYC [45]. Although the transformation process of pre-apoptotic GC B cells into HRS cells remains poorly understood, evasion of programmed cell death appears to be a crucial early event [39]. Interestingly, cases with mutations impairing BCR expression are often associated with EBV infection. Furthermore, EBV-infected HRS cells exhibit lower mutation loads, suggesting that viral gene expression substitutes for oncogene and tumor suppressor gene mutations, supporting the pathogenic role of EBV in EBV+ cHL [46]. The downregulation of the B-cell program in HRS cells involves multiple factors, including the dysregulation of transcription factors, immune evasion, and epigenetic silencing [39]. Notably, cHL lacks a defining genetic lesion, and the combination of genetic alterations may contribute to the uniqueness of this disease. HRS cells rely on aberrant, constitutive activity in several signaling pathways, including NF-κB, JAK/STAT, and PI3K/AKT, with the high constitutive activity of the NF-κB pathway being critical for HRS cell survival ^[39][47][48][39,47,48]. The most frequent mutations found in cHL cases are those involving regulators of these signaling pathways, including NF-κB factor REL, TNFAIP3, SOCS1, and STAT6 ^[39][48][39,48]. Multiple receptors, such as CD30 and CD40, transmit pro-survival and pro-proliferative signals via NF-κB, highlighting their potential involvement in HRS cell signaling [39].