The incidence of Hodgkin lymphoma is greatest in white populations with age and gender distributions as described above [2]. However, differences in incidence between white and black populations predominantly exist in the 15–24 age groups and disappear with advancing age through the young adult continuum. The incidence is lower among Hispanic populations, with these differences persisting through the entirety of the adolescent and young adult age ranges. Given the uncommon nature of Hodgkin lymphoma and high overall cure rates, it is not possible to reliably detect differences in mortality by ethnicity.

New understandings of the etiology and pathogenesis of Hodgkin lymphoma have evolved over the past 5 years [5, 6]. Central to these understandings are the pathognomonic feature of the disease, the Hodgkin and Reed-Sternberg (HRS) cell of classic Hodgkin lymphoma (see Sect. 5.4, Pathology), and the role of the Epstein-Barr virus (EBV) [5, 7, 8]. The etiology of Hodgkin lymphoma remains uncertain and, like most cancers, likely includes a range of molecular subtypes that lead to common histologic appearances. The association of EBV with Hodgkin lymphoma has been known for decades [8]; recent observations show population-based heterogeneity in this association. In the Western world, 40 % of patients with classical Hodgkin lymphoma demonstrate infection of HSR cells with EBV; in contrast, 90 % of pediatric cases in Central America are infected [5, 8].

Hodgkin lymphoma is unusual in that the up to 99 % of the cancerous tissue is comprised of surrounding non-malignant cells that make up the tumor microenvironment [6]. The microenvironment includes neutrophils and macrophages, lymphocytes and plasma cells, and dendritic and mast cells. In classical Hodgkin lymphoma, as few as 1 % of the cellular material is comprised of malignant HRS cells. These HRS cells are germinal B-cells (GBCs) that, after acquiring unfavorable somatic mutations, undergo transformative molecular events that rescue these cells from apoptosis [5, 7]. This transformative process may be in association with EBV infection. The transformed HRS cells commonly overexpress the transcription factor NF kappa B (NFKB), with multiple molecular alterations in NFKB regulation described [5]. The dysregulation of the NFKB pathway promotes HRS cell survival and may be crucial to the pathogenesis of Hodgkin lymphoma. In addition to the NFKB pathway, other molecular pathways may be affected; alterations of the JAK/STAT pathway are commonly described and may be associated with changes in the tumor microenvironment that contribute to loss of immunosuppression, which permits HRS cell survival [5, 7].

Together these molecular findings are consistent with three main risk factors associated with Hodgkin lymphoma: previous EBV infection, immunosuppressive disorders including human immunodeficiency virus infection, and a family history of Hodgkin lymphoma. Family clustering of Hodgkin lymphoma is well described and may be a result of somatic mutations that facilitate the transformative molecular events that lead to HRS cells and their survival.

The current pathologic classification of Hodgkin lymphoma is based on the Revised European American Lymphoma classification schema of 1994 [9], which was updated in the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues in 2008 [10]. Hodgkin lymphoma is subdivided into two major forms: classical Hodgkin lymphoma and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). The diagnosis of classical Hodgkin lymphoma requires demonstration of HRS cells and comprises 95 % of cases. Classical Hodgkin lymphoma includes four histologic subtypes: nodular sclerosis, mixed cellularity, lymphocyte rich, and lymphocyte depleted. The nodular sclerosing subtype is most common, especially in adolescents (approximately 85 % in adolescents and 65–75 % in adults) [11, 12]. In comparison with adults, the incidence of mixed cellularity histology is less frequent in the adolescent population (20 % vs. 10 %).

About 5 % of Hodgkin lymphoma patients, both adolescents and adults, are diagnosed with the NLPHL subtype, which is associated with demonstration of lymphocyte-predominant (LP) cells [11]. In contrast to classical Hodgkin lymphoma, the pathogenesis of NLPHL does not include the same association with EBV as LP cells are rarely infected with the virus [5]. Separating classical Hodgkin lymphoma from NLPHL is integral to patient management as the clinical course, treatment, and prognosis include important differences.

While the pathognomonic HRS cell typically differentiates classical Hodgkin lymphoma from various forms of non-Hodgkin lymphoma, diagnostic uncertainties can exist, including histologic and molecular resemblances of the two diseases that overlap into the entity of grey zone lymphomas. Gray-zone lymphomas likely represent distinct genetic variants of lymphoproliferative cancers and need to be distinguished from the diagnostic challenges associated with differentiating forms of classical Hodgkin lymphoma from anaplastic large cell lymphoma and primary mediastinal large B-cell lymphoma (Sect. 5.6.1, Diagnosis).

The presenting features of patients with Hodgkin lymphoma can be considered in two main categories: those who present with painless lymphadenopathy and those who present with other symptoms. Those presenting with other symptoms typically have one of the B symptoms associated with clinical staging (Table 5.4), which include fever, weight loss, and/or night sweats [13]. Approximately 35 % of patients will present with B symptoms, with no clear differences in symptom patterns observed between pediatric, adolescent, and adult populations [11, 12, 14].

The anatomical distribution of adenopathy includes supradiaphragmatic nodes in 95 % of cases; adenopathy limited to a subdiaphragmatic distribution is seen in less than 5 % of cases and is disproportionately associated with NLPHL pathology. The most common sites of adenopathy include the posterior triangle of the neck, the axilla, and the mediastinum. Across all age groups, mediastinal adenopathy is observed in 60 % of cases [11, 12, 14]. Among those with mediastinal adenopathy, half will have bulky disease, historically defined as a mass with a diameter that exceeds one-third of the thoracic diameter on standard imaging. These patients commonly present with persistent cough and less commonly with chest pain and shortness of breath. As with B symptoms, no differences in mediastinal involvement or presence of bulky disease are observed in adolescent versus adult populations. Rarely patients will present with distinct symptoms associated with Hodgkin lymphoma: two well-described syndromes are intractable pruritus and pain in a region affected by adenopathy associated with alcohol intake. For those patients with intractable pruritus and no palpable adenopathy, evaluations assessing for mediastinal adenopathy are crucial.

Given the most common presentation of painless adenopathy, differential diagnoses include infectious etiologies, including EBV, noninfectious inflammatory etiologies, and malignancies. The differential diagnosis of EBV infection is more common in the adolescent and young adult population given the incidence of infectious mononucleosis in this age group.

Standard baseline investigations are listed in Table 5.5. Additional evaluations as prompted by patient specifics may also be applicable.

As Hodgkin lymphoma includes an element of contiguous spread according to the anatomy of the lymphoid system and radiation therapy was historically the primary treatment modality, anatomical staging has, and continues to be, essential in determining prognosis and therapy. The Ann Arbor classification [18], modified at the Cotswolds meeting [13] and recently validated at the Lugano meeting [16], remains standard (Table 5.4). In contrast to non-Hodgkin lymphoma, the presence of B symptoms carries important implications for management. In addition, disease bulk, historically defined as a mediastinal mass greater than one-third of the chest diameter on standard imaging or of 10 cm in any dimension and now defined as any mass of 7 cm, carries therapeutic implications.

In addition to anatomic staging, the International Prognostic Index [15] has been used to stratify patients into risk categories (Table 5.6). This index has been of particular importance in clinical trials, both in reporting baseline characteristics of the populations studied and in developing therapeutic approaches for risk-specific populations. The elements of the index are nonspecific indicators associated with prognosis as determined through mathematical modeling. No direct biomarkers related to Hodgkin lymphoma biology have yet been shown to be predictive in that the presence or absence of the biomarker can be used to direct therapy in individual patients [19].