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MD Consult: Books: Goldman: Cecil Medicine: Chapter 197 – HODGKIN’S LYMPHOMA

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier

Chapter 197 – HODGKIN’S LYMPHOMA

Joseph M. Connors

Definition

Hodgkin’s lymphoma, formerly called Hodgkin’s disease, is one of the B-cell lymphomas. It has a characteristic neoplastic cell, the Reed-Sternberg cell, a distinct natural history, and most importantly, an excellent response to treatment, with the large majority of patients being cured. Its management, which requires careful multidisciplinary cooperation, serves as a paradigm for the successful application of modern oncologic concepts. Highly effective chemotherapy is the cornerstone of treatment. Carefully selected patients may require the addition of radiation or, if the lymphoma recurs after primary treatment, high-dose chemoradia-tion therapy and autologous hematologic stem cell transplantation (HDC/HSCT). The current challenge to clinicians managing this neoplasm is not only to cure it but also to do so with the least burden of long-term toxicity.

Epidemiology

The incidence of Hodgkin’s lymphoma varies substantially around the world. The highest rates occur in the United States, Canada, Switzerland, and northern Europe. Intermediate rates are seen in southern and eastern Europe and low rates in eastern Asia. No clear explanation for this variation in incidence has been found. Postulated reasons include differences in the age at onset or genotype of any associated Epstein-Barr virus (EBV) infection, crowding during childhood as a result of lower socioeconomic status predisposing to passage of an as yet undiscovered infectious vector, or intrinsic genetic differences in susceptibility.

Approximately 20,000 new cases are seen annually in North America and Europe. The age-adjusted incidence of Hodgkin’s lymphoma has declined modestly but significantly over the past 20 years at a rate of approximately 0.9% per year and is now approximately 2.7 per 100,000. Age-adjusted annual mortality is 0.5 per 100,000. Hodgkin’s lymphoma occurs slightly more often in men and is seen more frequently in whites than African-Americans and much less frequently in Asian populations. Much of the difference in incidence between whites and blacks in North America can be attributed to the higher incidence seen in higher socioeconomic classes. The cumulative lifetime risk for development of Hodgkin’s lymphoma is approximately 1 in 250 to 1 in 300 in North America.

The incidence of Hodgkin’s lymphoma rises from a very low level in childhood to a plateau in early adulthood and then remains stable. In the Western world, only about 5% of cases occur in persons younger than 15 years and 5% in persons older than 70 years. In contrast, however, the age distribution in the Indian subcontinent is strongly shifted into childhood.

Pathobiology

The cause of Hodgkin’s lymphoma remains unclear. Hodgkin’s lymphoma is not associated with exposure to radiation, chemicals, biocidal agents, working in health care–related professions, or previous tonsillectomy. The leading suspect remains EBV based on much suggestive evidence but no definitive proof.

Epstein-Barr Virus

EBV is a large B-lymphocyte tropic herpesvirus ( Chapter 400 ). Approximately 90% of the general population acquires infection with EBV by early adulthood. In the developing world, this infection usually occurs in childhood, but in developed countries, infection is often delayed into the teens, when it is associated with the syndrome of infectious mononucleosis in up to 30% of new cases. A history of infectious mononucleosis increases the likelihood for subsequent Hodgkin’s lymphoma three-fold. Antibodies to the viral capsid antigen reach higher levels in patients with Hodgkin’s lymphoma than in controls, and these higher levels appear several years before the neoplasm. In situ hybridization studies have demonstrated that the Reed-Sternberg cells in approximately 50% of cases of Hodgkin’s lymphoma contain EBV-encoded small RNA (EBER), and in these cases virtually all the Reed-Sternberg cells are positive for the virus. The EBV genome is amplified 50-fold or more in Reed-Sternberg cells and is monoclonal in an individual patient’s Reed-Sternberg cells. In some populations, virtually all cases of Hodgkin’s lymphoma occur in EBV-positive individuals, but up to 50% of patients in developed countries do not have EBV in their Reed-Sternberg cells. Thus, although EBV may play an important role in the development of Hodgkin’s lymphoma, that role is neither straightforward nor universal.

Genetic Factors

Circumstantial evidence for a genetic contribution to the etiology of Hodgkin’s lymphoma comes from studies showing that Hodgkin’s lymphoma is almost 100-fold more likely to develop in the monozygotic twin of an affected individual than in a dizygotic twin. First-degree relatives of individuals with the disease have up to a five-fold increased risk for development of the lymphoma. Perhaps genetically predisposed individuals react differently to EBV, thereby increasing the chance that a lymphoid neoplasm will develop.

Polymerase chain reaction–based genotypic analysis has demonstrated the clonal derivation of Reed-Sternberg cells, including identical p53 mutations from multiple Reed-Sternberg cells extracted from a single biopsy specimen, thereby unequivocally establishing clonality. The presence of clonal immunoglobulin gene rearrangements from multiple cells in the same biopsy specimen also confirms a B-cell origin. Only a few rare cases with a T-cell genotype have been reported but are obviously exceptional. The presence of clonal somatic mutations provides proof of the germinal center origin of the neoplastic cells. Finally, identification of cells with identical immunoglobulin gene rearrangements both at diagnosis and at relapse verify that the B-cell clonality of the disease is preserved over time.

Despite their B-cell origin, the neoplastic cells of Hodgkin’s lymphoma are incapable of making intact antibodies, perhaps because they lack the ability to make the transcription factors necessary to activate the immunoglobulin promoter. B cells that are incapable of manufacturing antibody should undergo apoptosis, but the Hodgkin/Reed-Sternberg cells avoid this self-destruction. The observation that the anti-apoptotic nuclear transcription factor NFκB is constitutively activated in these cells may provide an explanation.

Classic cytogenetics has been unrevealing in Hodgkin’s lymphoma. Aneuploidy and hyperploidy consistent with the multinucleated nature of Hodgkin’s/Reed-Sternberg cells are frequent, but no consistent translocations have been detected.

Clinical Manifestations

Hodgkin’s lymphoma is usually manifested as lymphadenopathy ( Chapter 174 ), typically in the cervical, axillary, or mediastinal areas, and only about 10% of the time as nodal disease below the diaphragm. Although peripherally located nodes seldom reach large size, very large mediastinal masses or, less often, retroperitoneal masses can develop with only modest symptoms. Lymph node involvement in Hodgkin’s lymphoma is usually painless, but an occasional patient notes discomfort in involved nodal sites immediately after drinking alcohol.

Approximately 25% of patients with Hodgkin’s lymphoma have constitutional symptoms. The classic B symptoms, significant weight loss (>10% of baseline), night sweats, or persistent fever, usually signal widespread or locally extensive disease and imply a need for systemic treatment. Generalized pruritus, occasionally severe, can antedate the diagnosis of Hodgkin’s lymphoma by up to several years. Some patients have symptoms suggestive of a growing mass lesion, such as cough or stridor as a result of tracheobronchial compression from mediastinal disease or bone pain secondary to metastatic involvement. Because Hodgkin’s lymphoma can involve the bone marrow extensively, an occasional patient has symptomatic anemia or incidentally noted pancytopenia. Paraneoplastic neurologic or endocrine syndromes have been reported with Hodgkin’s lymphoma but are rare.

Diagnosis

The diagnosis of Hodgkin’s lymphoma is based on recognition of Reed-Sternberg cells ( Fig. 197-1 ) or Hodgkin’s cells (or both) in an appropriate cellular background in tissue sections from a lymph node or extralymphatic organ, such as bone marrow, lung, or bone. Fine-needle aspiration biopsy is not adequate for the diagnosis of Hodgkin’s lymphoma. Open biopsy and standard histochemical staining are required to establish the diagnosis unequivocally and to determine the histologic subtype. Immunohistochemical studies can prove helpful in difficult cases or to distinguish special subtypes such as lymphocyte-rich classic Hodgkin’s lymphoma and the nodular lymphocyte-predominant type. In classic Hodgkin’s lymphoma, scattered large Reed-Sternberg cells are either multinucleated or have a large polyploid nucleus. Variations include mononuclear cells that are similar to the usual polylobated or multinuclear cells but have only one large nucleus with a prominent nucleolus, as well as lacunar cells, which are Reed-Sternberg variants with abundant cytoplasm that has retracted as an artifact of formalin fixation. The infrequent Reed-Sternberg cells are usually present in a background mixture of polyclonal lymphocytes, eosinophils, neutrophils, plasma cells, fibroblasts, and histiocytes. Occasionally, granulomas form with a prominent histiocytic component.

FIGURE 197-1  Nodular sclerosing Hodgkin’s lymphoma. This figure shows a typical case of classic nodular sclerosing Hodgkin’s lymphoma with many lacunar cells, occasional diagnostic Reed-Sternberg cells, and the characteristic background of lymphocytes and eosinophils.  (Photomicrograph courtesy of Randy D. Gascoyne, MD, British Columbia Cancer Agency.)

Hodgkin’s lymphoma can typically be classified into one of five well-described subtypes ( Table 197-1 ). Reproducibility of the distinctions among these subtypes has been confirmed in the current widely accepted World Health Organization classification of lymphoid neoplasms. With addition of the new category of lymphocyte-rich classic Hodgkin’s lymphoma, this newest classification scheme permits confident identification of nodular lymphocyte-predominant Hodgkin’s lymphoma as a separate entity. The most common subtype is nodular sclerosing, which has characteristic course bands of sclerosis surrounding nodules composed of typical Reed-Sternberg cells in the usual background mixture of reactive and inflammatory cells.


TABLE 197-1   — 
WORLD HEALTH ORGANIZATION CLASSIFICATION OF HODGKIN’S LYMPHOMA SUBTYPES

Subtype Name Frequency (%)[*]
Classic Hodgkin’s lymphoma
Nodular sclerosis 65
Lymphocyte rich 3
Mixed cellularity 12
Lymphocyte depleted 2
Nodular lymphocyte-predominant Hodgkin’s lymphoma 6
Hodgkin’s lymphoma, not otherwise classifiable 12

* Frequency based on all new cases (N = 302) seen in British Columbia since January 1998 when the category of lymphocyte-rich classic Hodgkin’s lymphoma became well established.

The immunophenotype of the neoplastic cells in Hodgkin’s lymphoma can help identify the specific subtype. Typically, the Hodgkin/Reed-Sternberg cells stain positively for CD30 (80 to 100% of cases), CD15 (75 to 85% of cases), and B-cell–specific activating protein (BSAP), which is the product of the PAX5 gene (>90% of cases). However, often only a minority of the malignant cells stain positively for the CD15 and BSAP markers. CD20, a generally reliable marker of B-cell lineage, is positive in about 40% of cases of classic Hodgkin’s lymphoma, but usually only a minority of cells are positive, and the staining can be weak. In contrast, nodular lymphocyte-predominant Hodgkin’s lymphoma almost always stains strongly positive for CD20 and for the specialized B-cell markers CD79a and CD45, but it is negative for CD30 and CD15. Nodularity signals the diagnosis of nodular lymphocyte-predominant Hodgkin’s lymphoma. Finally, anaplastic large cell lymphoma ( Chapter 196 ) is reliably negative for CD15, CD20, and CD79a but frequently positive for anaplastic lymphoma kinase (ALK).

Differential Diagnosis

Depending on the site of occurrence and associated symptoms, the differential diagnosis of Hodgkin’s lymphoma includes non-Hodgkin’s lymphoma ( Chapter 196 ), germ cell tumors ( Chapter 210 ), thymoma ( Chapter 448 ), sarcoidosis ( Chapter 95 ), and tuberculosis ( Chapter 345 ). However, the specific diagnosis is readily determined by obtaining an adequate biopsy specimen for review by an experienced hematopathologist. Proceeding to such a biopsy early in the assessment of patients with lymphadenopathy ( Chapter 174 ), especially of the mediastinum, often saves time and spares the patient needless testing and delay in diagnosis.

With the widespread availability of computed tomography (CT) and appropriate biopsy procedures to investigate enlarged central thoracic or intra-abdominal lymph nodes, the diagnosis of Hodgkin’s lymphoma seldom presents difficulty. The immunophenotype can also help distinguish Hodgkin’s lymphoma from other diseases. For example, T cell–rich B-cell lymphoma ( Chapter 196 ) is distinguished from classic Hodgkin’s lymphoma by being CD30 and CD15 negative but positive for CD20 and CD45. However, T cell–rich B-cell lymphoma ( Chapter 196 ) can be very difficult to distinguish from nodular lymphocyte-predominant Hodgkin’s lymphoma because both are negative for CD30 and CD15 but positive for CD45. This distinction is best made by focusing on the histologic pattern of the neoplastic cells. In fact, the combination of appropriate immunohistopathologic evaluation by an expert hematopathologist and clinical assessment has virtually eliminated difficulties with the differential diagnosis. Problems mostly arise when inadequate or improperly processed material is all that is available for diagnosis.

Staging

Physical Examination

Given its tendency to spread in an orderly fashion, usually from initially involved lymph nodes, the stage of Hodgkin’s lymphoma can be established by using readily available imaging and laboratory tests ( Fig. 197-2 and Table 197-2 ). The evaluation should start with a careful history to search for the presence of localizing signs, such as bone pain, or the constitutional symptoms of fever, weight loss, or night sweats. The history may also reveal comorbid conditions that may affect the safe delivery of planned treatment. The physical examination may identify lymphadenopathy or organomegaly.

FIGURE 197-2  Anatomic definition of lymph node regions for staging of Hodgkin’s disease.  (From Kaplan HS, Rosenberg SA: The treatment of Hodgkin’s disease. Med Clin North Am 1966;50:1591-1610.)


TABLE 197-2   — 
TESTS REQUIRED FOR STAGING OF HODGKIN’S LYMPHOMA

   Complete history to search for B symptoms (fever, weight loss, night sweats) or other symptomatic problems suggesting more advanced disease
   Physical examination for lymphadenopathy or organomegaly
   Complete blood count plus erythrocyte sedimentation rate
   Serum creatinine, alkaline phosphatase, lactate dehydrogenase, bilirubin, and protein electrophoresis (including albumin level)
   Chest radiograph, posteroanterior and lateral views
   Computed tomography scan of the neck, thorax, abdomen, and pelvis
   Certain tests are required only for specific manifestations
Manifestation/Condition Test
B symptoms or WBC count <4.0 × 109/L, Hgb <120 g/L (women) or 130 g/L (men), or platelets <125 × 109/L Bone marrow biopsy and aspiration
Stage IA or IIA disease with upper cervical lymph node involvement (supra-hyoid) ENT examination

ENT = ear, nose, and throat; Hgb = hemoglobin; WBC = white blood cell.

Laboratory Testing

Laboratory testing should include blood cell counts and the erythrocyte sedimentation rate, assessment of liver and renal function, serologic testing for hepatitis B and hepatitis C if liver enzyme abnormalities are detected, human immunodeficiency virus (HIV) antibody testing if the history indicates an increased risk or if the sites of disease are unusual, an albumin level, and serum protein electrophoresis. Bone marrow aspiration and biopsy are most useful for the minority of patients with constitutional (B) symptoms or those with lower than normal peripheral blood counts at diagnosis.

Imaging

Imaging techniques to evaluate Hodgkin’s lymphoma continue to evolve ( Fig. 197-3 ). All patients should undergo contrast-enhanced CT scanning of the thorax, abdomen, and pelvis with slices at intervals of 1 cm or less. Magnetic resonance imaging is occasionally useful when the extent of bone or soft tissue involvement must be determined precisely or for a patient with an absolute contraindication to the use of intravenous contrast agents. Gallium scanning adds little to what can be learned with CT scanning and is prone to false-negative and false-positive results.

FIGURE 197-3  Imaging of Hodgkin’s lymphoma. Bulky Hodgkin’s disease as seen on chest radiograph (A), computed tomography (CT) of the chest (B), gallium scan (C), and positron emission tomography (PET) (D). The arrows indicate sites of disease. Note that the PET and CT scans provide more detailed information than the chest radiograph and gallium scan.

Positron Emission Tomography

Positron emission tomography (PET) is more sensitive and specific than CT or gallium scanning both for staging and for assessment of residual masses after treatment. However, it has not been proved that the addition of PET to standard staging imaging tests for Hodgkin’s lymphoma will actually improve outcome, so whether PET could replace other studies is not clear. The greatest usefulness of PET presently appears to be the assessment of residual masses during or after planned treatment so that the minority of patients who should receive altered or additional therapy can be identified.

The Ann Arbor staging system with the Cotswold modification ( Table 197-3 ) categorizes patients into four stages. The first three indicate the expanding extent of lymph node disease (see Fig. 197-2 ): stage I, a single nodal area; stage II, two or more nodal areas but still on one side of the diaphragm; and stage III, nodal disease on both sides of the diaphragm. The spleen and the lymphoid tissue of Waldeyer’s ring each count as nodal sites in this system. Stage IV is reserved for extranodal disease, which for all practical purposes is disease in the bone marrow, lung, bone, or liver. Hodgkin’s lymphoma at any other extranodal site should prompt questioning of the diagnosis or a search for HIV infection.


TABLE 197-3   — 
MODIFIED ANN ARBOR STAGING SYSTEM FOR HODGKIN’S LYMPHOMA

Stage Involvement
I Single lymph node region (I) or one extralymphatic site (IE)
II Two or more lymph node regions, same side of the diaphragm (II), or local extralymphatic extension plus one or more lymph node regions, same side of the diaphragm (IIE)
III Lymph node regions on both sides of the diaphragm (III); may be accompanied by local extralymphatic extension (IIIE)
IV Diffuse involvement of one or more extralymphatic organs or sites
A No “B” symptoms
B Presence of at least one of the following:
  Unexplained weight loss >10% of baseline during 6 months before staging
  Recurrent unexplained fever >38°C
  Recurrent night sweats

Bulky disease is defined as the presence of any tumor mass with the largest diameter greater than 10 cm or a mediastinal mass with a transverse diameter exceeding a third of the largest transverse transthoracic diameter. Now that CT scanning is widely available, use of the mediastinal mass ratio is obsolete, and the term bulky is best assigned to tumors exceeding 10 cm in largest single diameter.

The E lesion designation identifies patients whose limited extranodal extension of Hodgkin’s lymphoma could be included in a reasonable involved field of irradiation. After staging, patients are further subdivided into those with or without fever, night sweats, or weight loss (B symptoms).

Treatment

Over the past 50 years, Hodgkin’s lymphoma has been transformed from a nearly uniformly fatal illness to one that is usually cured. This remarkable success has provided a paradigm on which much of modern oncologic treatment is based. The principles underlying combined-modality treatment and multiagent chemotherapy, the mainstays of today’s successful treatment of many malignancies, were first demonstrated to be effective with Hodgkin’s lymphoma. The essential involvement of a multidisciplinary team, including pathologists, experts in diagnostic imaging, medical and radiation oncologists, nurses, and support staff, has served as a model for all cancer. The necessity to balance greater efficacy of initial treatment, which often requires an increase in intensity and therefore toxicity, against troublesome and occasionally fatal late complications has encouraged a long-term perspective.

From a practical therapeutic viewpoint, patients with stage III or IV disease, bulky disease, or B symptoms are defined as having advanced disease, whereas patients without these characteristics have limited-stage disease. In Europe, patients with limited disease are further subdivided into those with favorable and unfavorable outcomes, but cure rates exceed 90 to 95% for all patients with nonbulky stage IA or IIA (limited) disease. However, for patients with advanced-stage disease, independent predictors of progression include gender, age, stage, hemoglobin level, white blood cell count, lymphocyte count, and serum albumin level ( Table 197-4 ). For the 80% of patients with no more than three factors, the likelihood of progression-free survival is 70%. For the 20% who have four or more factors, the progression-free survival rate falls to less than 50%. A straightforward plan of treatment for the 90% of patients in whom Hodgkin’s lymphoma is diagnosed between the ages of 16 and 70 can be based on clinical stage, the presence of B symptoms, and bulk of the largest tumor mass ( Table 197-5 ).


TABLE 197-4   — 
RATES OF PROGRESSION IN 5 YEARS IN PATIENTS WITH ADVANCED-STAGE HODGKIN’S LYMPHOMA

Number of Factors[*] Frequency (%) Percentage with Progression-Free Survival at 5 Years
0–3 81 70
4–7 19 47

* Male sex, age older than 45 years, stage IV, hemoglobin level less than 10.5 g/dL, white blood cell count greater than 15,000/mL, lymphocyte count less than 600/mL or less than 8% of the white cell count, or serum albumin less than 4 g/dL.


TABLE 197-5   — 
TREATMENT PLAN FOR ADULT PATIENTS WITH HODGKIN’S LYMPHOMA

Stage Prognostic Category Treatment
IA or IIA, no bulky disease[*] ≤3 adverse factors[] ABVD[] × 4 if CR after 2 cycles or ABVD × 2 + IRRT
IB, IIB, or any stage III or IV, but no bulky disease ≤3 adverse factors ABVD[] until 2 cycles past CR (minimum 6, maximum 8)
Bulky disease, any stage ≥4 adverse factors Stanford V[] or BEACOPP[]
    ABVD × 6 + IRRT

* Bulky refers to disease with the largest diameter of any single mass equal to or greater than 10 cm.
See Table 197-4 .
See text for drugs in each regimen. Optimal dosing must be individualized. CR = complete response; IRRT = involved-region radiation therapy.

Treatment of Limited-Stage Hodgkin’s Lymphoma

Most of the 35% of patients with Hodgkin’s lymphoma initially seen with-limited stage disease can be cured regardless of the site of occurrence, the presence of disease above or below the diaphragm, or the histologic subtype. The greatest challenge is to achieve this goal with the least toxicity and cost.

Two cycles of ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine) chemotherapy followed by involved-field irradiation cures nearly 95% of patients with limited-stage disease and nearly completely eliminates the risk for infertility, premature menopause, and leukemia and minimizes cardiopulmonary toxicity. [1] [2] The chemotherapy in the combined-modality treatment of limited-stage Hodgkin’s lymphoma eradicates subclinical disease and allows smaller fields of irradiation to be used. However, a substantial proportion of the excess, long-term mortality in patients with limited-stage Hodgkin’s lymphoma is due to cardiovascular disease and second neoplasms that are closely related to the use of irradiation. In a randomized trial that compared four to six cycles of ABVD chemotherapy alone versus irradiation, either alone or augmented with two cycles of ABVD chemotherapy, the strategy of chemotherapy alone proved equivalent to irradiation-based treatment in terms of event-free and overall survival, although the irradiation-based approach did produce a modest improvement in progression-free survival.[3] Longer follow-up will be necessary to see whether the goal of a reduction in cardiovascular events and second neoplasms was accomplished. This trial suggests that more than 90% of patients with limited-stage Hodgkin’s lymphoma can be treated with four to six cycles of ABVD alone; for the minority whose lymphoma does not completely regress after two cycles, probably best assessed by PET scanning, the addition of radiation may be optimal.

Treatment of Advanced-Stage Hodgkin’s Lymphoma

In advanced-stage Hodgkin’s lymphoma (stages IIIA, IIIB, IVA, and IVB), both ABVD and MOPP (mechlorethamine, Oncovin [vincristine], procarbazine, and prednisone)/ABVD are superior to MOPP alone in terms of progression-free survival. Today, ABVD is the most widely used regimen for patients with advanced-stage Hodgkin’s lymphoma. The addition of radiation therapy significantly improves progression-free survival at 10 years in patients with advanced-stage Hodgkin’s lymphoma, but it does not improve overall survival[4] because it causes significantly more deaths unrelated to lymphoma. Even the addition of radiation therapy for patients in complete remission after chemotherapy for advanced-stage Hodgkin’s lymphoma has no significant impact.[5] The adverse long-term effects of radiation therapy and its lack of improvement in overall survival appear to outweigh any benefits for the usual patient with advanced-stage disease. The ability of PET scanning to distinguish between residual fibrosis and persistent lymphoma may provide a mechanism to identify selected patients who might benefit from localized radiation therapy.

Recently devised regimens for patients with advanced Hodgkin’s lymphoma are the Stanford V regimen (doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone) and escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and procarbazine) (see Table 197-5 ). As originally described, both include postchemotherapy irradiation to sites of initial or residual tumor bulk (≥5 cm). In phase II testing, the Stanford V regimen provided 91% freedom from progression at 8 years with an overall survival rate of 95%; fertility was maintained. BEACOPP plus radiation therapy provides better progression-free and overall survival at a median follow-up of 6.9 years than COPP/ABVD plus radiation therapy despite a higher rate of hematologic toxicity and infertility.[6]

About 50% of patients who are not cured by primary chemotherapy can be effectively treated with HDC/HSCT ( Chapter 184 ). For the 80% of patients with zero to three adverse prognostic factors, who have a 70% chance of cure with primary chemotherapy, the most widely used approach is to start with ABVD. For the 30% of these low-risk patients in whom progressive lymphoma develops despite primary treatment, HDC/HSCT ( Chapter 184 ) should be offered. Such a strategy confines the high cost and toxicity of intensified treatment to the minority of patients whose disease demands it. Conversely, for the 20% of high-risk patients who have four or more adverse factors and less than a 50% likelihood of cure with primary chemotherapy, more intense initial treatment with the Stanford V or BEACOPP protocol is reasonable.

Management of Refractory or Relapsed Hodgkin’s Lymphoma

HDC/HSCT has become the established treatment for most patients whose Hodgkin’s lymphoma persists or recurs despite primary chemotherapy.[7] However, the treatment-related mortality, high levels of toxicity, and cost associated with HDC/HSCT demand that it be reserved for patients in whom it clearly increases the chance of cure over alternative treatments; such patients include those whose disease progresses during or within approximately 3 months of initial multiagent chemotherapy (refractory Hodgkin’s lymphoma) and those who relapse more than 3 months after completing a full course of multiagent chemotherapy (relapsed Hodgkin’s lymphoma). For relapsed lymphoma, controversy remains, however, for two special subgroups: patients who relapse solely in originally involved but unirradiated lymph nodes and without B symptoms or extranodal disease, who may obtain up to a 40 to 50% cure rate with wide-field irradiation, and patients who relapse without B symptoms more than 1 year after completion of primary chemotherapy, who may achieve up to a 30 to 40% cure rate with additional chemotherapy with or without irradiation. However, even these two subgroups may achieve up to an 80% 10-year disease-free survival rate after HDC/HSCT. Thus, data suggest that standard treatment for patients with progressive Hodgkin’s lymphoma after primary chemotherapy for advanced-stage disease should be HDC/HSCT regardless of the characteristics of the relapse.

Despite the effectiveness of HDC/HSCT for refractory or relapsed Hodgkin’s lymphoma, randomized trials of HDC/HSCT for patients with adverse prognostic factors in complete or partial remission after primary chemotherapy for advanced Hodgkin’s lymphoma failed to show a difference in outcome.[8] Based on present evidence, HDC/HSCT should be reserved for patients who have progressive lymphoma after primary chemotherapy.

Management of Complications

Follow-up and Late Complications of Treatment

Most adult patients with Hodgkin’s lymphoma are cured and experience minimal long-term toxicity from their treatment. However, the risk for certain predictable and occasional rare and less predictable late effects warrants careful but not intrusive follow-up and selective intervention ( Table 197-6 ). First, at the conclusion of treatment a thorough reassessment of the initial sites of lymphoma should be completed to provide post-treatment baseline measurements. Patients should be seen by a specialist knowledgeable in the management of lymphoma, preferably about every 3 months for 2 years, then every 6 months for 3 years, then annually. Patients should be strongly encouraged to refrain from smoking, to perform careful breast and skin examinations on a regular basis, and to undergo regular immunizations for influenza annually, pneumococcus at diagnosis and 5 years after treatment, and diphtheria and tetanus every 10 years ( Chapter 16 ). Patients who have received radiation to the head or neck area should follow a vigorous program of dental prophylaxis in anticipation of the deleterious effect of reduced saliva production and have their thyroid-stimulating hormone level checked annually in recognition of about a 50% risk for eventual hypothyroidism.

Special Problems in the Management of Hodgkin’s Lymphoma

 

Hodgkin’s Lymphoma during Pregnancy

Between 0.5 and 1.0% of cases of Hodgkin’s lymphoma occur coincident with pregnancy ( Chapter 258 ). When the lymphoma is discovered during pregnancy, it is almost always possible to control the lymphoma and allow the pregnancy to go to full term.

Standard staging tests (see Table 197-2 ) should be completed, except that imaging requiring radiation must be minimized. For example, abdominal ultrasonography can identify bulky retroperitoneal disease, and a single posteroanterior radiograph of the chest, with proper shielding, can identify bulky mediastinal disease.

More than 50% of patients can continue the pregnancy to term without any treatment of the lymphoma. If symptomatic or progressive disease develops, systemic chemotherapy can be given in the second and third trimester with very small risk of injuring the fetus. An alternative is intermittent single-agent vinblastine, given in the lowest dose that can control symptoms until delivery, followed by a full course of six to eight cycles of multiagent chemotherapy after delivery.

Hodgkin’s Lymphoma and Acquired Immunodeficiency Syndrome

In patients with HIV infection, the incidence of Hodgkin’s lymphoma is increased as much as 5- to 10-fold, and the lymphoma is manifested differently and pursues a more aggressive natural history ( Chapter 416 ). Hodgkin’s lymphoma in HIV-positive individuals is almost always associated with EBV within Hodgkin’s/Reed-Sternberg cells. The histology is much more likely to be mixed cellularity or lymphocyte depleted. The disease most commonly develops in extranodal sites, especially the bone marrow. More than 80% of patients have advanced-stage disease, and most patients have B symptoms.

Patients are prone to opportunistic infections, and the interaction of chemotherapeutic agents with other medications may compromise the patient’s ability to tolerate treatment. The best approach is a combination of vigorous supportive care with antiviral and antifungal agents, neutrophil-stimulating growth factors, and their usual highly active antiretroviral agents ( Chapter 412 ) along with standard multiagent chemotherapy. With appropriate supportive care, regimens such as ABVD[9] and EBVP (epirubicin, bleomycin, vinblastine, and prednisone) can be delivered. However, worse than normal toxicity must be anticipated, and cure rates are much lower than in the non–HIV-infected population. Median survival is typically 1 to 2 years.

Hodgkin’s Lymphoma in the Elderly

Elderly patients with Hodgkin’s lymphoma have a worse outcome. For example, the 5-year overall survival rate falls from 80% in patients younger than 65 years to less than 50% in patients older than 65. Explanations include more advanced stage at diagnosis, comorbid diseases, delay in diagnosis, incomplete staging, inadequate adherence to treatment protocols, and failure to maintain full dose intensity.

Of note is that elderly patients achieve outcomes equivalent to those of younger patients when they receive similar doses of chemotherapy. The best approach for elderly patients is to attempt to treat them in a manner similar to younger patients, with the addition of neutrophil growth factors if necessary to enable safe delivery of full doses. For patients with preexisting pulmonary or cardiac disease, it might be necessary to reduce or eliminate bleomycin or doxorubicin, respectively.


TABLE 197-6   — 
MONITORING AFTER SUCCESSFUL PRIMARY TREATMENT OF HODGKIN’S LYMPHOMA

Risk/Problem Incidence/Response
Relapse Ten percent to 30% of patients relapse. Careful attention should be directed to lymph node sites, especially if previously involved with disease and not treated with radiation. New persistent focal symptoms such as bone pain should be investigated with appropriate laboratory and imaging studies.
Dental caries Neck or oropharyngeal irradiation may cause decreased salivation. Patients should have regular dental care and should make their dentist aware of the previous irradiation.
Hypothyroidism After external beam thyroid irradiation at doses sufficient to cure Hodgkin’s lymphoma, at least 50% of patients eventually become hypothyroid. All patients who have been exposed to neck irradiation should have an annual TSH level determined. Patients whose TSH level becomes elevated should be treated with lifelong thyroxine replacement in doses sufficient to suppress TSH levels to low normal ( Chapter 244 ).
Infertility ABVD is not known to cause permanent gonadal toxicity, although temporary oligospermia or irregular menses may persist for 1 to 2 years after treatment. Direct or scatter radiation to gonadal tissue may cause infertility, amenorrhea, or premature menopause, but this adverse event seldom occurs with the current fields used for the treatment of Hodgkin’s lymphoma. In general, women who continue menstruating are fertile, but men require semen analysis to provide a specific answer.
Secondary neoplasms Though uncommon, certain secondary neoplasms occur with increased frequency in patients who have been treated for Hodgkin’s lymphoma: acute myelogenous leukemia; thyroid, breast, lung, cervical, and upper gastrointestinal carcinoma; and melanoma. It is appropriate to “be vigilant” for these neoplasms for the remainder of the patient’s life because they may have a lengthy induction period.

ABVD = Adriamycin, bleomycin, vinblastine, and dacarbazine; TSH = thyroid-stimulating hormone.

Future Directions

The ability to profile multigene expression patterns and identify genetic polymorphisms associated with specific malignancies may provide better insight into the molecular genesis of Hodgkin’s and other lymphomas.

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