Epidemiology and Risk Factors¹

Hodgkin’s disease accounts for less than 1% of cancers diagnosed in the United States each year.^2,3 There is a slight male predominance. The median age at the time of diagnosis is 26 to 30 years. The disease is uncommon in children younger than 10 years and the age-adjusted incidence is bimodal.⁴ Both peaks, at ages 20 to 24 and 75 to 84, show an annual incidence of approximately 5.5 cases per 100,000. A recent decline in the height of the incidence peak for older adults may be attributed to improved diagnostic accuracy and the ability to differentiate mixed cellularity or lymphocyte depletion Hodgkin’s disease from diffuse large-cell or anaplastic large-cell lymphomas.

There are no well-defined risk factors related to the development of Hodgkin’s disease.⁵ Older reports associating an increased risk with tonsillectomy have been refuted. There are no definite associations between Hodgkin’s disease and human leukocyte antigen (HLA) loci. The slight increased risk associated with small sibship size and higher degree of education has not been explained, but contributes to the hypothesis of an infectious cause. A relationship between Hodgkin’s disease and prior infection with Epstein-Barr virus (EBV) has been proposed. Components of the EBV genome have been detected in the cellular deoxyribonucleic acid (DNA) of Reed-Sternberg cells,⁶ and elevated levels of immunoglobulin G and immunoglobulin A against the EBV capsid antigen and elevated levels of antibody against the EBV nuclear antigen and early antigen D have been detected in the serum of patients who later develop Hodgkin’s disease.⁷ The risk for developing Hodgkin’s disease appears to be higher in the presence of a prior history of infectious mononucleosis.⁸ Evidence of prior EBV infection is most common in mixed cellularity Hodgkin’s disease and in pediatric Hodgkin’s disease in underdeveloped countries.⁹

Anatomy

Hodgkin’s disease arises primarily in lymph nodes. Solitary extralymphatic involvement in the absence of nodal disease is exceedingly rare. There is a general axial distribution of lymph node involvement. More than 80% of patients have cervical lymph node involvement at presentation, and more than half have mediastinal disease. The most common site of extranodal disease is the spleen.

Pathologic Conditions^10,11

The diagnostic cell of Hodgkin’s disease is the Reed-Sternberg cell; however, these cells account for less than 1% of the cells in a lymph node infiltrated by Hodgkin’s disease. The majority of the cells are lymphocytes, eosinophils, and plasma cells. The Reed-Sternberg cell has a classic appearance that is binucleate, with two prominent nucleoli. There is a well-demarcated nuclear membrane, and eosinophilic cytoplasm with a perinuclear halo.

The cell of origin of the Reed-Sternberg cell is likely a precursor B cell. In most instances, the Reed-Sternberg cells stain positively for CD30 and CD15. They also express the interleukin 2 receptor (TAC) and HLA-DR antigens. They stain negatively with the leukocyte common antigen; occasionally, they are positive for pan–B cell markers such as CD20.^12,13 However, the lymphocytic (L) and histiocytic (H) cells (Reed-Sternberg equivalents) in lymphocyte-predominant Hodgkin’s disease are strongly positive for CD20 and CD45, but negative for CD15.¹⁴ There are five histologic subtypes of Hodgkin’s disease, according to the World Health Organization modification of the Lukes and Butler system. These include nodular lymphocyte predominant Hodgkin’s disease and four subtypes of classical Hodgkin’s disease: nodular sclerosis, lymphocyte-rich, mixed cellularity, and lymphocyte depletion.¹⁵

Nodular lymphocyte predominance (Fig. 60-1) is characterized by an abundance of normal-appearing lymphocytes and a paucity of abnormal cells. Patients frequently present with limited disease (stage I-II), and systemic symptoms are uncommon (<10%). The natural history of lymphocyte predominance is the most favorable among the histologic subtypes. In some reports, it demonstrates a pattern of late relapse similar to that of the low-grade lymphomas.¹⁶ However, the degree to which management programs should be influenced by this observation is not clear. In addition, these patients are at increased risk to develop transformation to other B-cell lymphomas, such as diffuse large-cell lymphoma. These observations, coupled with the different staining characteristics of the L and H cells of nodular lymphocyte-predominant Hodgkin’s disease, suggest that this entity may actually be a form of B-cell non-Hodgkin’s lymphoma.^14,16

FIGURE 60-1 • Nodular lymphocyte predominance. The abnormal large cells have pale-staining nuclei with lobulations that resemble popcorn (lymphocytic and histiocytic cells). The background is dominated by normal small lymphocytes admixed with occasional epithelioid histiocytes.

(Courtesy Roger A. Warnke, MD.)

Patients affected by lymphocyte-predominant Hodgkin’s disease may have a history of a peculiar form of reactive hyperplasia termed progressive transformation of germinal centers. Progressive transformation of germinal centers may also occur concurrently with a subsequent diagnosis of nodular lymphocyte-predominant Hodgkin’s disease.

Lymphocyte-rich, classic Hodgkin’s disease was previously considered a diffuse variant of lymphocyte predominance. However, unlike true lymphocyte predominance, lymphocyte-rich, classic Hodgkin’s disease includes Reed-Sternberg cells with the usual staining characteristics. The histologic characteristic of this variant is marked by a diffuse effacement of the node by normal-appearing lymphocytes and occasional Reed-Sternberg cells.

Nodular sclerosis Hodgkin’s disease (Fig. 60-2 and Fig. 60-3) is the most common histologic subtype in the United States (>70%). Involved nodes are traversed by broad bands of birefringent collagen surrounding nodules of cells that include lymphocytes, eosinophils, plasma cells, tissue histiocytes, and a variable proportion of atypical mononuclear cells and Reed-Sternberg cells. Women are more commonly affected than men, and the median age is younger than for other histologic subtypes. Clinically, the mediastinum and neck are often involved. One-third of patients have B symptoms. The natural history is somewhat less favorable than that of lymphocyte-predominant Hodgkin’s disease.

FIGURE 60-2 • Nodular sclerosis. This low magnification of a lymph node replaced by nodular sclerosis shows sclerosis of the capsule at the top and well-demarcated nodules at the center surrounded by pale-staining collagen bands.

(Courtesy Roger A. Warnke, MD.)

FIGURE 60-3 • Nodular sclerosis. At high magnification, scattered neoplastic cells, some of which have multiple nuclei, are seen to be surrounded by a clear retraction space (lacunar cells). The non-neoplastic background is largely composed of normal lymphocytes and histiocytes.

(Courtesy Roger A. Warnke, MD.)

Mixed-cellularity Hodgkin’s disease (Fig. 60-4) is characterized by a diffuse effacement of lymph nodes by lymphocytes, eosinophils, and plasma cells, and there are relatively abundant atypical mononuclear and Reed-Sternberg cells. Patients with mixed-cellularity Hodgkin’s disease tend to present with more advanced disease and tend to be slightly older than those with nodular sclerosing or lymphocyte-predominant disease. The natural history of mixed-cellularity Hodgkin’s disease is less favorable than that of nodular sclerosing Hodgkin’s disease.

FIGURE 60-4 • Mixed cellularity. This example shows a mixed inflammatory background of lymphocytes and histiocytes together with small numbers of eosinophils and plasma cells. A Reed-Sternberg cell is seen at the center of the field.

(Courtesy Roger A. Warnke, MD.)

Lymphocyte-depletion Hodgkin’s disease is characterized by a paucity of normal-appearing cells and an abundance of abnormal mononuclear cells, Reed-Sternberg cells, and Reed-Sternberg variants. It may occasionally be difficult to distinguish lymphocyte-depletion Hodgkin’s disease from anaplastic large-cell lymphoma. It is the least common histologic subtype, tends to occur in older individuals, and is more likely to be associated with advanced disease and B symptoms. It has the worst prognosis of all histologic subtypes.

Interfollicular Hodgkin’s disease refers to a pattern of focal involvement of a lymph node in which there is a small focus of Hodgkin’s disease in the interfollicular zone. It is easy to confuse these cases with reactive lymphoid hyperplasia.¹⁷

Table 60-1 summarizes the characteristics of 2590 patients treated at Stanford University from 1968 to 2001, according to histologic subtype. Other large centers in the United States and western Europe report a similar distribution of cases. However, the distribution of histologic subtypes from South America, Asia, Africa, Eastern Europe, and even some parts of the United States includes a greater proportion of unfavorable histologic types with a more aggressive clinical behavior.¹⁸

Clinical Presentation and Routes of Spread

Patients with Hodgkin’s disease usually present with painless lymphadenopathy. Some patients report systemic symptoms including unexplained fevers, drenching night sweats, weight loss, generalized pruritus, or alcohol-induced pain (in tissues infiltrated by Hodgkin’s disease). Occasionally, the diagnosis arises from an incidental finding noted on a routine chest x-ray examination.

Assuming contiguity between the supraclavicular lymph nodes and upper paraortic nodes–celiac axis–spleen (via the thoracic duct), 90% of patients with Hodgkin’s disease present with contiguous sites of involvement.¹⁹ The pattern of relapse among patients treated with irradiation alone also supports the concept of contiguity.²⁰ Visceral involvement may be secondary to direct extension (especially lung, bone, or soft tissue) or hematogenous spread (such as to liver or multifocal bone).

The mechanism of spread of disease to the spleen is unclear. However, there is a correlation between the burden of disease identified in the spleen and the likelihood of hematogenous dissemination. Nearly all patients with hepatic or bone-marrow involvement by Hodgkin’s disease have (or had) extensive involvement of the spleen.²¹

Hodgkin’s disease only rarely involves the lymphoid tissues of the Waldeyer ring and Peyer patches. In addition, although visceral involvement by Hodgkin’s disease may be identified in the lungs, liver, bone marrow, and skeletal system, it uncommonly involves other organ systems such as the upper aerodigestive tract, central nervous system, skin, and gastrointestinal tract.²²

The rapidity of growth and spread of Hodgkin’s disease is variable. On occasion, a slow evolution of disease can be demonstrated on serial radiographs or suspected by clinical evolution over a period of several years. It is unusual for disease to progress during the evaluation and staging process.

One-third of patients present with fever, night sweats, or weight loss (B symptoms). Fevers may have a classic intermittent Pel-Ebstein pattern. The night sweats may be drenching. The presence of B symptoms often signals more extensive disease; however, even patients with only one or two involved lymph node regions may have significant B symptoms. Patients who have both weight loss and fevers may have a particularly poor prognosis.²³

The pattern of presentation for lymphocyte-predominant Hodgkin’s disease is unique. It is seen most commonly in adolescent boys, presenting in a peripheral nodal site such as the high neck, axilla, or inguinal region. Mediastinal disease is uncommon and sytemic symptoms are rare.

Patient age may have an effect on the natural history of the disease. In the elderly, the presence of intercurrent illness often affects the selection of staging and treatment procedures.²⁴

Hodgkin’s disease may be diagnosed during pregnancy, and it is common for pregnancy to follow successful treatment. However, there is no evidence that pregnancy has any effect on the natural history of Hodgkin’s disease in these women.^25,26

Although patients infected with human immunodeficiency virus (HIV-1) do not appear to be at increased risk for the development of Hodgkin’s disease, patients infected with HIV-1 who develop Hodgkin’s disease display an unusual natural history. The disease tends to present in a more advanced stage, is more likely to be associated with systemic symptoms, and often has unusual patterns of involvement.²⁷ Treatment is challenging because these patients have a poor tolerance for chemotherapy and opportunistic infections are common.

Diagnostic and Staging Studies^28,29

Staging procedures commonly employed for Hodgkin’s disease are listed in Table 60-2. Routine hematologic evaluation may reveal a mild anemia, lymphopenia, leukopenia, leukocytosis, or thrombocytosis. These may reflect paraneoplastic effects, but in some cases may be indicative of bone marrow involvement. The erythrocyte sedimentation rate and alkaline phosphatase and lactate dehydrogenase levels may be elevated and serve as useful markers to assess response to treatment and subsequent disease activity.³⁰ Serum albumin levels, white blood cell counts, and lymphocyte counts are all important prognostic factors, especially in advanced disease.³¹

Table 60-2 Staging Procedures in Hodgkin’s Disease

CBC, Complete blood cell count; CT, computed tomography; ESR, erythrocyte sedimentation rate; ¹⁸FDG-PET, 2-fluoro-2-deoxy-d-glucose positron emission tomography; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging.

Radiographic evaluation should include posterior-anterior and lateral chest radiographs. A convenient means for measuring the extent of mediastinal adenopathy is to divide the maximum single width of the mediastinal mass by the maximum intrathoracic diameter (near the level of the diaphragm), as shown in Fig. 60-5. When this ratio exceeds 1 : 3, the disease is defined as bulky.³² Other measurements have also been used to define bulky mediastinal disease, including mass diameters that exceed 10 cm. A computed tomography (CT) scan of the chest should also be obtained if there is mediastinal disease, because it provides ancillary information regarding the extent of intrathoracic disease and assists in treatment planning and follow-up assessment.³³

FIGURE 60-5 • Mediastinal mass size. The most useful definition of mediastinal mass size is the ratio of the maximal width of the mediastinal mass divided by the maximal intrathoracic diameter (usually near the level of the diaphragm) on a standing posterior-anterior chest radiograph. In this case, the ratio is 0.51 (15.0 : 29.3). Masses with a ratio greater than 1 : 3 have a worse prognosis when treated with single-modality therapy than masses with a ratio less than 1 : 3.

Abdominal and pelvic CT scans should be obtained with special attention paid to the retroperitoneal area, spleen, and liver. Lymph nodes are generally considered to be enlarged on a CT scan if their short axis measurement exceeds 1 to 1.5 cm. Splenomegaly or hepatomegaly alone does not equate with involvement by Hodgkin’s disease, because enlarged spleens are often uninvolved at the time of splenectomy; however, the presence of nodules visible on CT scan is considered indicative of involvement. The overall accuracy rate for detection of Hodgkin’s disease in the spleen by CT was reported to be only 58% in a laparotomy series.³⁴ However, these data, obtained at a time when staging laparotomy was routine, may underestimate the detection rate with current CT scanning technology.

In the last several years,³⁵ positron emission tomography (PET) using 2-fluoro-2-deoxy-d-glucose (¹⁸FDG) has been acknowledged as an important initial staging study in Hodgkin’s disease. FDG-PET is more sensitive than CT scanning³⁶ or gallium imaging³⁷ and is more convenient than gallium as a staging procedure because of the shorter interval between injection and scanning (1 hour versus 48 to 72 hours). PET scanning will identify additional sites of disease, beyond those identified by other clinical evaluation and imaging, in 10% to 15% of patients. PET scanning has proved to be highly useful as an early response indicator. When repeated early in the course of therapy, its prognostic value exceeds that of other well-established prognostic factors.³⁸ PET is also useful as a follow-up study to evaluate residual masses present on CT scan.³⁹

Magnetic resonance imaging (MRI) may be an alternative to chest or abdominopelvic CT scanning for initial staging, but has not been employed widely. Its main value may be in the staging evaluation of pregnant women with Hodgkin’s disease.⁴⁰

A posterior iliac crest needle bone marrow biopsy should be performed in selected patients. Because the yield is exceedingly low in asymptomatic patients with stage I and II disease, it can be restricted to patients who have B symptoms or stage III or IV disease. The overall frequency of bone marrow involvement in Hodgkin’s disease is only 5%.

Staging System^41–44

The Ann Arbor staging system for Hodgkin’s disease is outlined in Table 60-3.⁴⁵ The lymphoid regions used in this system are displayed in Fig. 60-6. The designation of clinical stage (CS) is based on results of the initial biopsy and clinical staging studies, whereas the pathologic stage (PS) is based on the results of any subsequent biopsies, including bone marrow biopsy and laparotomy and splenectomy. In the postlaparotomy era, the distinction between CS and PS is rarely noted. Significant systemic (B) symptoms include fevers, night sweats, and weight loss. Other systemic symptoms of Hodgkin’s disease, including pruritus, alcohol-induced pain, and fatigue, should be noted, but are not considered B symptoms. The E designation indicates extralymphatic disease, although the concept is very poorly defined. In practical clinical terms, an E lesion is often considered to be a direct extension from involved lymph nodes and encompassable by a curative radiation field; however, the original description includes as an example “multiple nodules in the lung limited to one lobe.” In addition, the Ann Arbor system fails to deal with the possibility of multiple E lesions, which can be identified quite clearly in the chest with the careful use of contemporary imaging studies such as CT and MRI. Some authors’ inclusion of these patients in stage IV has led to a great deal of confusion in the literature. Another deficiency of the Ann Arbor system is its failure to consider bulk of disease. This has been shown to be important, especially in the mediastinum. The presence of bulky disease in the mediastinum should be noted, together with the stage.

Table 60-3 Ann Arbor Staging Classification System

The absence or presence of fever, night sweats, or unexplained loss of 10% or more of body weight in the 6 months before diagnosis is denoted by the suffix letter A or B, respectively.

Patients are assigned a clinical stage based on the initial biopsy and all subsequent nonsurgical staging studies. A pathologic stage is assigned based on all clinical studies as well as subsequent surgical staging procedures such as bone marrow biopsy, staging laparotomy, and splenectomy.

From Carbone PP, Kaplan HS, Mushoff K, et al: Report of the committee on Hodgkin’s disease staging classification, Cancer Res 31:1860, 1971.

FIGURE 60-6 • Ann Arbor lymphoid regions. Note that the cervical, supraclavicular, occipital, and preauricular areas compose a single region and that the mediastinum and bilateral hilar areas constitute three regions.

In addition to Ann Arbor stage, other indicators may be helpful in predicting prognosis or selecting therapy. An international study evaluated prognosis in advanced Hodgkin’s disease by analyzing prognostic features among 5141 patients.³¹ Seven factors were identified, each of which had a similar prognostic affect. These are summarized in Table 60-4.

Table 60-4 A Prognostic Score for Advanced Hodgkin’s Disease

Standard Therapeutic Approaches