1Department of Internal Medicine I, Hematology-Oncology, University of Cologne, Germany 2Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York
Hodgkin lymphoma is a malignancy of the lymphatic system with an incidence of about 3 cases per 100,000 persons per year in developed countries. In 2014 approximately 9,190 new cases of Hodgkin lymphoma will be diagnosed, and 1,180 deaths will occur. Over the past 4 decades, advances in radiation therapy and the advent of combination chemotherapy have tripled the cure rate of patients with Hodgkin lymphoma. At present, more than 80% of all newly diagnosed patients can expect a normal, disease-free life span.
The male-to-female ratio of Hodgkin lymphoma 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.
Hodgkin lymphoma 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 Hodgkin lymphoma 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.
Hodgkin lymphoma 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 Hodgkin lymphoma 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 Hodgkin lymphoma, as is involvement of Waldeyer's ring and occipital, epitrochlear, posterior mediastinal, and mesenteric sites.
About 30% of patients experience systemic symptoms, so-called B symptoms. They include fever, drenching night sweats, and weight loss. These symptoms occur more frequently in older patients and have a negative impact on prognosis (see section on "Staging and prognosis").
Hodgkin lymphoma 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 Hodgkin lymphoma 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. Hodgkin lymphoma 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 Hodgkin lymphoma. The prognostic significance of CD20-positive R-S cells in classic Hodgkin lymphoma 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.
Nodular lymphocyte–predominant Hodgkin lymphoma (NLPHL) accounts for about 5% of Hodgkin lymphoma cases. It differs from the histologic subtypes of classic Hodgkin lymphoma in terms of immunophenotype, clinical presentation, and course. The malignant lymphocyte-predominant cells consistently express CD20, which is only infrequently found in classic Hodgkin lymphoma. In contrast to classic Hodgkin lymphoma, NLPHL is mostly diagnosed in early favorable stages, often in peripheral nodes, and rarely involves the mediastinum. These patients are often sufficiently treated with limited-field radiotherapy alone (Chen RC et al, J Clin Oncol, 2010). Patients presenting with more advanced disease are usually treated in a manner very similar to that for classic Hodgkin lymphoma, with an excellent long-term outcome (Nogová L et al, J Clin Oncol, 2008). However, regular follow-up is mandatory even in the case of long-term remission, as NLPHL patients tend to have late relapses more often than classic Hodgkin lymphoma patients and, with a rate of up to 30% at 20 years, transformation into aggressive B-cell non-Hodgkin lymphoma is more common than previously reported (Al-Mansour M et al, J Clin Oncol, 2010).
According to the present World Health Organization classification, there are four histologic subtypes of classic Hodgkin lymphoma.
As the most common subtype, nodular sclerosis is typically seen in young adults 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 older 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 Hodgkin lymphoma
Lymphocyte-rich classic Hodgkin lymphoma has morphologic similarity to NLPHL (see below). However, the R-S cells have a classic morphology and phenotype (CD30-positive, CD15-positive, and the surrounding lymphocytes are reactive T cells) and should be managed like other classic Hodgkin lymphoma histologies.
Lymphocyte-depleted Hodgkin lymphoma
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-Hodgkin lymphomas. 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 Hodgkin lymphoma
This is an infrequent form of Hodgkin lymphoma 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 named lymphocyte-predominant cells 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 Hodgkin lymphoma.
This finding has led investigators to propose that lymphocyte-predominant Hodgkin lymphoma is a B-cell malignancy with a mature B-cell phenotype, distinct from the other four histologic types of Hodgkin lymphoma. Lymphocyte-predominant Hodgkin lymphoma is often clinically localized, is usually treated effectively with limited-field irradiation alone at early stages, and may relapse late (a clinical feature reminiscent of low-grade non-Hodgkin 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.