Hodgkin lymphoma (HL) is a malignancy of the lymphatic system with an incidence of about 3 cases per 100,000 persons per year in developed countries. It is estimated that in 2012, a total of 9,060 men and women in the United States were diagnosed with Hodgkin lymphoma and 1,190 died from the disease. Over the past 4 decades, advances in radiation therapy and the advent of combination chemotherapy have tripled the cure rate of patients with HL. At present, more than 80% of all newly diagnosed patients can expect a normal, disease-free life span.
The male-to-female ratio of HL is 1.3:1.
The age-specific incidence of the disease is bimodal, with the greatest peak in the third decade of life and a second, smaller peak after the age of 50 years.
HL occurs less commonly in African-Americans (2.3 cases per 100,000 persons) than in Caucasians (3 per 100,000 persons).
The age-specific incidence of HL differs markedly in various countries. In Japan, the overall incidence is low, and the early peak is absent. In some developing countries, there is a downward shift of the first peak into childhood.
The cause of HL remains unknown, and there are no well-defined risk factors for its development. However, certain associations have been noted that provide clues to possible etiologic factors.
Same-sex siblings of patients with HL have a 10 times higher risk of developing the disease. Patient-child combinations are more common than spouse pairings. Higher risk for HL is associated with few siblings, single-family houses, early birth order, and fewer playmates—all of which decrease exposure to infectious agents at an early age. The monozygotic twin sibling of a patient with HL has a 99 times higher risk of developing HL than a dizygotic twin sibling of a patient with HL. These associations suggest a genetic predisposition and/or a role for an infectious or environmental agent during childhood or early adolescence in the etiology of the disease.
Studies of young adult HL developing in one of a pair of monozygotic twins suggest a common T helper (Th) cell type 2 (Th2) cytokine profile in each twin, with elevated interleukin (IL)-6 levels and decreased IL-12 levels compared with controls. This inherited cytokine phenotype may increase the likelihood of HL development.Environmental factors also may play a role. The hygiene hypothesis explains a propensity for atopy with an associated lack of a healthy Th cell type 1 (Th1) response to antigenic challenge noted among patients having decreased fecal-oral exposure during early childhood. Monozygotic twins developing HL showed less fecal-oral exposure and more atopy than did unaffected twins of the same pairs.Thus, genetic and environmental factors may contribute to a Th2 milieu that favors HL development.
Familial aggregation may imply genetic factors, but other epidemiologic findings mentioned previously suggest an abnormal response to an infective agent. Both factors may play a role in the pathogenesis of the disease. The Epstein-Barr virus (EBV) has been implicated in the etiology of HL by both epidemiologic and serologic studies, as well as by the detection of the EBV genome in 20% to 80% of tumor specimens.
There have been no conclusive studies regarding the possible increased frequency of HL in patients with human immunodeficiency virus (HIV) infection. However, HL in HIV-positive patients is associated with an advanced stage and poor therapeutic outcome. (For further discussion of HL in patients with HIV infection, see the "AIDS-Related Malignancies" chapter.)
The incidence of HL is increased by approximately 2-fold in smokers.
HL is a lymph node–based malignancy and commonly presents as an asymptomatic lymphadenopathy that may progress to predictable clinical sites.
Location of Lymphadenopathy
More than 80% of patients with HL present with lymphadenopathy above the diaphragm, often involving the anterior mediastinum; the spleen may be involved in about 30% of patients. Less than 10% to 20% of patients present with lymphadenopathy limited to regions below the diaphragm. The commonly involved peripheral lymph nodes are located in the cervical, supraclavicular, and axillary areas; para-aortic pelvic and inguinal areas are involved less frequently. Disseminated lymphadenopathy is rare in patients with HL, as is involvement of Waldeyer's ring and occipital, epitrochlear, posterior mediastinal, and mesenteric sites.
About 30% of patients experience systemic symptoms. They include fever, drenching night sweats, or weight loss (so-called B symptoms) and chronic pruritus. These symptoms occur more frequently in older patients and have a negative impact on prognosis (see section on "Staging and prognosis").
HL may affect extranodal tissues by direct invasion (contiguity; the so-called E lesion) or by hematogenous dissemination (stage IV disease). The most commonly involved extranodal site is the lungs. Liver, bone marrow, and bone may also be involved.
The initial diagnosis of HL can only be made by biopsy. Because reactive hyperplastic nodes may be present, multiple biopsies of a suspicious site may be necessary. Needle aspiration is inadequate because the architecture of the lymph node is important for diagnosis and histologic subclassification.
In a biopsied lymph node, the Reed-Sternberg (R-S) cell is the diagnostic tumor cell that must be identified within the appropriate cellular milieu of lymphocytes, eosinophils, and histiocytes. HL is a unique malignancy pathologically in that the tumor cells constitute a minority of the cell population, whereas normal inflammatory cells are the major cell component. As a result, it may be difficult to identify R-S cells in some specimens. Also, other lymphoproliferations may have cells resembling R-S cells.
The R-S cell is characterized by its large size and classic binucleated structure with large eosinophilic nucleoli. Two antigenic markers are thought to provide diagnostic information: CD30 and CD15. These markers are present on R-S cells and their variants but not on background inflammatory cells. It is also important to obtain a stain for CD20, since it may be positive in the minority of patients with classic HL. The prognostic significance of CD20-positive R-S cells in classic HL is controversial.
Studies have confirmed the B-cell origin of the R-S cell. Single-cell polymerase chain reaction (PCR) analysis of classic R-S cells shows a follicular center B-cell origin for these cells with clonally rearranged but crippled V heavy-chain genes, presumably leading to inhibition of apoptosis. Also, high levels of the nuclear transcription factor-kappa-B (NF-kB) have been found in R-S cells; these high NF-kB levels may play a role in pathogenesis by interfering with apoptosis. A molecular link between R-S cells and tumor cells of mediastinal diffuse large B-cell lymphoma has been recently found in gene-profiling studies.
Sidebar: An analysis of long-term outcome in a cohort of 164 French patients with nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) confirmed an excellent outcome regardless of treatment strategy, with a 15-year overall survival of 89% (Biasoli I et al: Cancer 116:631–639, 2010). Studies have shown that treatment, such as radiation or combined-modality therapy, compared with "watch and wait" reduces relapses (10-year progression-free survival rate of 66% vs 41%, respectively; P = .002), but does not yield improved overall survival; 15-year overall survival was 89% in both groups. Some investigators argue that radiation-based treatment increases the chances of cure. A recent retrospective analysis of radiation treatment in 93 patients with stages I and II NLPHL showed a 10-year progression-free survival of 85% and 61%, respectively, for patients with stage I disease. However, due to late relapses and the long indolent natural history of NLPHL, one must not overinterpret these results as definitive for the curative potential of radiation therapy (Chen RC et al: J Clin Oncol 28:136–141, 2010). Histologic transformation to T-cell/histiocyte-rich diffuse large B-cell lymphoma can also occur; it was reported in 12% of patients from one series and was associated with a lower survival rate (76%) at 10 years. This supports aggressive early diagnosis by biopsy of patients with new rapidly growing disease. These results reflect the variable albeit usually indolent behavior of NLPHL and indicate that the treatment strategy should be tailored to the clinical situation.
According to the Rye classification (based on the number and appearance of R-S cells, as well as the background cellular milieu), there are four histologic subtypes of classic HL.
As the most common subtype, nodular sclerosis is typically seen in young adults (more commonly in females) who have early-stage supradiaphragmatic presentations. Its distinct features are the presence of (1) broad birefringent bands of collagen that divide the lymphoid tissue into macroscopic nodules and (2) an R-S cell variant, the lacunar cell.
This is the second most common histology. It is more often diagnosed in males, who usually present with generalized lymphadenopathy or extranodal disease and with associated systemic symptoms. R-S cells are frequently identified; bands of collagen are absent, although fine reticular fibrosis may be present; and the cellular background includes lymphocytes, eosinophils, neutrophils, and histiocytes.
Sidebar: Because of the limited treatment outcome predictability of current models based on pretreatment clinical factors, new predictive models have been developed using molecular and other biological markers. A model using gene expression of 10 genes determined from paraffin-embedded biopsies integrating four gene signatures (cell cycle, apoptosis, NF-kB, and monocyte-macrophage) has been found to predict 5-year freedom from progression (Sánchez-Espiridión B et al: Blood 116: e12-e17, 2010). Gene-expression profiling identified a gene signature of tumor-associated macrophages in Hodgkin lymphoma biopsy specimens that was associated with primary treatment failure. An increased number of these macrophages that were CD68-positive in pretreatment biopsy samples was associated with a decreased disease-specific survival and outperformed the International Prognostic Score in multivariate analysis (Steidl C et al: N Engl J Med 362:875–885, 2010).
The World Health Organization (WHO) classification recognizes a new subtype of lymphocyte-rich classic HL that has morphologic similarity to nodular lymphocyte-predominant HL. However, the R-S cells have a classic morphology and phenotype (CD30-positive, CD15-positive, and the surrounding lymphocytes are reactive T cells). This disease subtype does not show a tendency toward late relapse and should be managed like other classic HL histologies.
This is a rare diagnosis, particularly since the advent of antigen marker studies, which led to the recognition that many such cases represented T-cell non-HLs (NHLs). R-S cells are numerous, the cellular background is sparse, and there may be diffuse fibrosis and necrosis. Patients usually have advanced-stage disease, extranodal involvement, an aggressive clinical course, and a poor prognosis.
This is an infrequent form of HL in which few R-S cells or their variants may be identified. The cellular background consists primarily of lymphocytes in a nodular or sometimes diffuse pattern. The R-S variants express a B-cell phenotype (CD20-positive, CD30-negative, CD15-negative). B-cell clonality has also been demonstrated by PCR of the immunoglobulin heavy-chain genes in single R-S variant cells in biopsy material from patients with lymphocyte-predominant HL.
This finding has led investigators to propose that lymphocyte-predominant HL is a B-cell malignancy with a mature B-cell phenotype, distinct from the other four histologic types of HL. Lymphocyte-predominant HL is often clinically localized, is usually treated effectively with irradiation alone at early stages, and may relapse late (a clinical feature reminiscent of low-grade lymphoma). The 15-year disease-specific survival is excellent (> 90%). However, the definitive role of these novel markers remains to be proven in large prospective series.