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. 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.
Epidemiology
Gender
The male-to-female ratio of HL is 1.3:1.
Age
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.
Race
HL occurs less commonly in African-Americans (2.3 cases per 100,000 persons) than in Caucasians (3.0 per 100,000 persons).
Geography
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.
Etiology and risk factors
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.
Familial factors
Same-sex siblings of patients with HL have a 10 times higher risk for 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 when 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 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.
Viruses
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 chapter 24.)
Smoking
The incidence of HL is increased by approximately 2-fold in smokers.
Signs and symptoms
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.
Systemic symptoms
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").
Extranodal involvement
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.
Diagnosis
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.
Pathology
Reed-Sternberg (R-S) cell
In a biopsied lymph node, the 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 (Ber-H2) and CD15 (Leu-M1). 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.
Histologic subtypes
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.
Nodular sclerosis
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(Drug information on collagen) that divide the lymphoid tissue into macroscopic nodules and (2) an R-S cell variant, the lacunar cell.
Mixed cellularity
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.
Lymphocyte-rich HL
The WHO classification recognizes a new subtype of lymphocyte-rich classic HL that has morphologic similarity to nodular lymphocyte-predominant HL (see sidebar). However, the R-S cells have a classic morphology and phenotype (CD30-positive, CD15-positive, CD20-negative), 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.
Lymphocyte depletion
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.
Lymphocyte-predominant HL
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, 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 three 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.
