Hodgkin Lymphoma

Richard S. Stein

David S. Morgan

Hodgkin lymphoma (HL) is a lymphoproliferative malignancy that accounts for approximately 1% of cancers in the United States. Most patients present with disease limited to lymph nodes or to lymph nodes and the spleen. The bone marrow is involved in approximately 5% of cases. HL generally spreads in a contiguous fashion, making the use of radiation therapy (RT) feasible for many patients. The average age at presentation is 32 years with a bimodal incidence curve; one peak occurs before age 25 years and the other at age 55 years.

Most patients with HL are cured with primary therapy. Patients with advanced disease can be cured with combination chemotherapy, while those with limited disease can be cured either with limited combination chemotherapy and limited RT, or with more extensive RT alone. A major focus of HL therapy in the last 40 years has been the recognition of and the attempt to limit long-term side effects of therapy. Thus, the recent trend has been away from extensive RT alone for limited-stage disease.

While HL is highly curable at presentation, a significant minority will not respond or will relapse after initial treatment. Many of these patients can be cured by salvage therapy. Salvage chemotherapy may produce cures in patients initially treated with RT. Readministration of standard-dose chemotherapy or, more commonly, the administration of high-dose chemotherapy in conjunction with autologous stem cell transplantation may produce cures in patients initially treated with combination chemotherapy. Nevertheless, the potential for cure should not lead clinicians and patients to lose sight of the fact that approximately 20% to 25% of patients with HL eventually die of the disease.

For most cancers, disease-free survival (DFS) is a valuable surrogate marker for overall survival and thus evaluating DFS is a useful method for choosing optimal initial therapy. However, for HL, the success of salvage therapy means that the treatment options that are associated with superior DFS may not necessarily produce superior overall survival when the results of salvage therapy are considered, and this makes the selection of initial therapy somewhat subtler. In fact, because radiation and chemotherapy have significant long-term consequences such as secondary malignancies (associated with larger RT fields) or acute leukemia (associated with combined-modality therapy), DFS may overestimate the value of a specific therapy. Therefore, for each stage of HL, more than one rational therapeutic option may exist.

I. DIAGNOSIS AND PATHOLOGY

The diagnosis of HL requires excisional biopsy of an involved node and review of the material by a hematopathologist. Lymph node biopsy is recommended for any patient with lymphadenopathy greater than 1 cm in diameter and persisting for more than 4 weeks. Lymphoma, including HL, may be suspected when the nodes are freely movable and rubbery rather than stony hard. However, these clinical features are not specific for HL or for lymphoma in general. Key features of the histopathology of HL include the presence of Reed-Sternberg (RS) cells (or variants) in a mixed inflammatory background. The RS cells of classical HL (see subsequent discussion) are of B-cell origin, stain for CD15 and CD30, and are negative for CD45 and CD20. Whenever the diagnosis of HL is made in a patient presenting at an extranodal site or at a nodal site below the diaphragm, the diagnosis should be subjected to greater than usual scrutiny.

The current World Health Organization classification divides HL into two major groups: classical HL and nodular lymphocyte predominant HL (NLPHL). Classical HL includes the four subtypes: nodular sclerosis HL (approximately 70% of cases), mixed cellularity HL (approximately 20%), lymphocyte-rich HL (less than 5%), and lymphocyte depletion HL (less than 5%). NLPHL (5% of all HL) is a B-cell neoplasm characterized by variant RS cells (“L and H cells” or “popcorn cells”) that are positive for CD20 and negative for CD30 and CD15. In immunophenotype and behavior, NLPHL bears similarities to low-grade non-HL.

In the past, much was made of the prognostic significance of the subtypes of classical HL. Most of the difference is explained by the fact that stage covaries with histology. For instance, the average patient with mixed cellularity HL presents at a more advanced stage than the average patient with the nodular sclerosis HL. Thus it is generally true that patients with nodular sclerosis HL do better than patients with mixed cellularity HL. However, when one stratifies patients by stage, the impact of histopathology on prognosis is minimal.

II. STAGING

Accurate staging is critical to determining the optimal therapy for the patient with HL. It also provides a baseline so that the completeness of a response can be determined when therapy has been completed.

A. Cotswold staging system

The Cotswold modification of the Ann Arbor Staging System (Table 21.1) is used for patients with HL. Clinically, patients are placed in one of four stages based on anatomic extent of disease and are further classified as to the absence, “A,” or presence, “B,” of systemic symptoms (see subsequent discussion). In addition, the subscript E (e.g., II_E) may be used to denote involvement of an
extralymphatic site primarily or, more commonly, to denote direct extension into an organ, such as a large mediastinal mass extending into the lung. Stage III HL is subdivided into two substages, stages III₁ and III₂, based on the extent of intra-abdominal disease. However, as current treatment recommendations are the same for both substages, this distinction is of little clinical relevance.

TABLE 21.1 Cotswold Modification of the Ann Arbor Staging System for HL

Stage I	Involvement of a single lymph node region
Stage II	Involvement of two or more lymph nodes regions on the same side of the diaphragm
Stage III₁	Involvement of lymph node regions on both sides of the diaphragm. Abdominal disease is limited to the upper abdomen (i.e., spleen, splenic hilar, celiac, and/or porta hepatis nodes).
Stage III₂	Involvement of lymph node regions on both sides of the diaphragm. Abdominal disease includes para-aortic, mesenteric, iliac, or inguinal nodes, with or without disease in the upper abdomen.
Stage IV	Diffuse or disseminated involvement of one or more extralymphatic tissues or organs, with or without associated lymph node involvement
A	No symptoms
B	Fever, drenching sweats, weight loss
X	Bulky disease greater than one-third widening of the mediastinum
E	Involvement of a single extranodal site contiguous to a nodal site

B. Prognostic score for advanced HL (International Prognostic Score [IPS]) In 1998, Hasenclever and Diehl created a prognostic model for advanced HL based on a multivariate analysis of patients. Seven factors were identified as having prognostic value: serum albumin <4 gm/dL, hemoglobin <10.5 gm/dL, male sex, stage IV disease, age ≥45 years, white cell count ≥15,000/μL, and lymphocyte count either <600/μL or <8% of the white cell count. In the paper presenting the model, the prognostic score correlated with both freedom from progression and overall survival rate. However, the utility of the IPS is limited by the fact that most patients had a score of 0 to 3, with only 12% of patients having a score of 4 and only 7% of patients having a score of 5 to 7.
C. Staging tests

Before the advent of modern radiographic and nuclear medicine techniques, clinicians made use of the knowledge that HL tends to spread in a contiguous manner, and elegant and detailed descriptions ofpatterns of disease were made. For instance, it was recognized that because the thoracic duct makes the left supraclavicular area and the abdomen contiguous sites, abdominal disease is found in 40% of patients with left supraclavicular presentations and in only 8% of patients with right supraclavicular presentations. While such
fascinating associations were useful before modern imaging was available, today they are largely superseded by computed tomography (CT) and positron emission tomography (PET) scans. Procedures used in the staging of HL are as follows.
- 1. History taking. As with any patient, the staging of the patient with HL begins with a history and a physical exam. Special attention should be given to symptoms such as bone pain that might signal a specific extranodal site of disease. The symptoms that are considered “B symptoms” are fever, night sweats, and weight loss greater than 10% of body weight. Fever in HL can have any pattern. The pattern of days of high fever separated by days without fever, so-called Pel-Ebstein fever, has been associated with HL for over a century but is quite rare in modern times when the diagnosis of HL is usually made early in the course of disease and effective therapy is initiated. Pain at the site of HL in association with alcohol ingestion is a rare finding but may give hints as to visceral sites of involvement.
- 2. Complete physical examination. Attention must be paid to all lymph node regions and the spleen. Splenomegaly is seen at presentation in approximately 10% of patients with HL and does not necessarily indicate splenic involvement by HL.
- 3. Laboratory tests. Complete blood counts, erythrocyte sedimentation rate (ESR), serum alkaline phosphatase, and tests of liver and kidney function should be obtained. Hepatic enzymes may be elevated “nonspecifically” in patients with HL and do not necessarily indicate hepatic involvement by HL.
- 4. Chest radiographs and CT scans of the neck, chest, abdomen, and pelvis are routinely obtained in patients with HL.
- 5. PET scans, especially PET/CT fusion scans, have been shown to be highly sensitive in HL and may “upstage” patients in comparison to CT scans alone. The PET scan is also useful for detecting relapse and persistent disease and therefore should be obtained at baseline for comparison with later scans. The PET scan is especially helpful when the posttreatment CT scan shows a residual mass, which could be either an inactive residual mass or persistent HL. The value of PET has been shown in many studies and was most clearly shown in a study by Gallamini and associates in which the PET scan was repeated after two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy. Therapy was not changed based on the PET findings (i.e., ABVD was continued). Two-year progression-free survival was 13% for patients who were PET-positive as compared to 95% in patients who had become PET-negative (p < 0.0001). Whether or not changing the chemotherapy in patients with a positive PET can alter the poor prognosis of those patients is the subject of ongoing clinical trials.
- 6. Bone marrow biopsy. The test is rarely positive except in patients who are found to have at least stage III disease by other tests. However, because of the potential use of autologous bone marrow transplantation (ABMT) or stem cell transplantation as salvage therapy, a bone marrow biopsy is a reasonable baseline study in all patients with HL. Alternatively, if chemotherapy is planned and if blood counts are normal, the test may be omitted until the time that stem cell transplantation is considered.
- 7. Staging laparotomy. With the widespread availability of PET scans, and the tendency to treat even limited disease with chemotherapy, staging laparotomy is of historical interest only.

III. THERAPY OF HODGKIN LYMPHOMA

A. General considerations

Therapy of HL must be considered on a stage-by-stage basis. The incidence of various stages of HL is presented in Table 21.2, which also presents an estimated cure rate for each stage. Historically, potentially curative RT was available before curative chemotherapy was defined, and therefore there has been a traditional bias to use radiation as the sole modality of therapy or as part of combination therapy whenever possible. Thus, RT has been used for limited-stage HL, and even stage IIIa HL in the recent past, even after more effective, and safer, chemotherapy had been advocated for use in HL. Indeed, there are only limited data for the use of chemotherapy alone in stage I and II HL.

Late complications of RT for HL include breast cancer, lung cancer, hypothyroidism, thyroid cancer, musculoskeletal atrophy or growth deficit, coronary artery disease, cardiomyopathy, and valvular heart disease. While the incidence of each of these complications is fairly low, the cumulative risk of death from all of these complications may be as much as 15% at 15 years following treatment. It is therefore reasonable to consider decreasing the field and dose of RT or eliminating it entirely as an approach to limited-stage disease. We now have numerous reports of combined modality therapy for limited-stage HL showing excellent DFS; however, there are no data showing that the overall survival of patients with limited-stage HL can be improved with this alteration of therapy. Studies designed to illustrate the superiority of combined modality therapy with respect to the incidence of late side effects may require 15 to 20 years of follow-up. Thus, after decades of general agreement that RT was the optimal approach to limited-stage HL, there has been a shift to incorporating chemotherapy in the treatment of limited-stage HL.

TABLE 21.2 HL: Incidence of Stages and Results of Therapy

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