AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

Section 2 of 11  

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Background

Hodgkin disease (HD) is a highly curable malignant disease. The recent understanding and insight into the biology of Hodgkin and Reed Sternberg (H-RS) Cells as B-cell derived have lead to the classification of HD as a lymphoma or Hodgkin lymphoma (HL). HL was the first cancer to be cured with radiation therapy alone or with a combination of several chemotherapeutic agents even before our understanding of the biology of HL improved. Since then, the cure rate for children with HL has steadily improved, particularly with the introduction of combined radiation therapy and multiagent chemotherapy.

However, this therapeutic success has come at the price of serious long-term toxicities such that a 30-year survivor of HL is more likely to die of therapy-related complication than from HL. Therefore, the therapeutic paradigm has shifted to reduce treatment-associated toxicity while maintaining high cure rates. This new paradigm has lead to the current risk-adapted, response-based approach to the treatment of HL.

Pathophysiology

HL is predominantly a B-cell malignant disorder that affects the reticuloendothelial and lymphatic systems. Invasion can affect other organ and systems, predominantly the lungs, bone, bone marrow, liver parenchyma, and CNS. Epidemiologic data suggest that environmental, genetic and immunologic factors are involved in the development of HL. Clustering of cases in families or racial groups supports the idea of a genetic predisposition or a common environmental factor. In identical twins of patients with HL, the risk of developing HL is as much as 7 times higher than that of other first-degree relatives. Subjects with acquired or congenital immunodeficiency disorders also have an increased risk of developing HL.

Findings from several epidemiologic studies have suggested links between HL and certain viral illnesses. The strongest case to date was related to Epstein-Barr virus (EBV) in that viral DNA was noted in Reed-Sternberg cells. Infants and children aged 0-14 years with HL have EBV more often than young adults aged 15-39 years with HL.

In addition, the prevalence of EBV geographically differs. The rate of EBV positivity is 50% in Great Britain, Jordan, Egypt, and South Africa; 91% in Greece; and 100% in Kenya. In general, EBV is most common in mixed-cellularity HL, in young children and in developing countries. In EBV-positive HL, EBV-encoding genes play a role in preventing apoptosis. Latent membrane protein-1 (LMP-1) expressed in EBV-positive H-RS cells mimic an activated CD40 receptor, activating the antiapoptotic nuclear factor (NF)–kappa-B pathway.

Frequency

United States

The age-adjusted standardized rate (ASR) in North America, western Europe, and Oceania is usually just below 7 cases per million. For children and adolescents younger than 15 years, the incidence is 5.5 cases per million. For individuals aged 15-20 years, the incidence is 12.1 cases per million. These rates are in contrast to those in western Asia (from the Mediterranean to northwest India), where the ASR is consistently higher than 7 cases per million.

International

Differences exist among countries with different levels of economic development, with highest incidences among young children of relatively undeveloped countries. Over time, this observation is becoming less pronounced than it is now. In the United States and in western Europe, the childhood rate is lower than the young-adult rate. In eastern Europe, the young-adult rate is similar to that observed in the United States and Western Europe, but the childhood rate is higher. Latin American countries have patterns of incidence approaching those of the United States. The incidence is relatively low in Asia, with the exception of south Asia, where the incidence is relatively high. Nodular sclerosis HL is the most common type in developed countries.

Mortality/Morbidity

The 5-year survival rate for HL of all stages is 91%. Patients with stage I or II disease (see Staging below) have survival rates greater than 90%, whereas those with stage II or IV disease have survival rates as low as 70%.

Race

In the United States, the incidence among Caucasians and African Americans is essentially the same. However, the ratio is 1.4:1 in children older than 10 years.

Sex

A significant male-to-female predominance of 3:1 is observed in children younger than 10 years. In older children and adults, the male-to-female ratio is about 1:1.

Age

The incidences of HL by age show a bimodal distribution. In industrialized nations, the first peak occurs in at approximately 20 years of age, and the second peak is observed in patients aged 55 years or older. HL is uncommon before the age of 5 years. However, in low-income countries, the first peak is shifts into childhood, usually before adolescence.

CLINICAL

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History

• Peripheral lymphadenopathy - Persistent painless adenopathy, unresponsive to antibiotic therapy
• Mediastinal mass
• • Shortness of breath, cough or chest pain
  • Superior vena cava syndrome
• Systemic symptoms, ie, B symptoms
• • Unexplained fever with temperatures above 38°C for 3 consecutive days
  • Unexplained weight loss of 10% or more in the previous 6 months
  • Drenching night sweats
• Other systemic symptoms - Pruritus, urticaria, and fatigue

Physical

Physical examination is important in the evaluation of patients with HL, as it allows the clinician to monitor the response to treatment. Careful evaluation of all lymph-node stations, hepatosplenomegaly, and involvement of Waldeyer or tonsillar tissues should always be performed and the findings documented.

• Patients may have firm, nontender lymphadenopathy. This lymphadenopathy is cervical in 70-80% of patients and axillary in 25%. Other sites are supraclavicular, inguinal, and, less often, epitrochlear or popliteal.
• A mediastinal mass may cause superior vena cava (SVC) obstruction and/or respiratory symptoms.
• Splenomegaly and/or hepatomegaly may be present.

Causes

The etiology of HL is believed to be multifactorial.

• Genetic predisposition: Clustering in families suggests a genetic predisposition, with an increased incidence especially among same-sex siblings, monozygotic twins, and parent-child pairs. Familial HL has been associated with specific human leukocyte antigens (HLAs). Familial cases account for 4.5% of all cases.
• Infectious agents: EBV is found in approximately 50% of cases of HL in the United States and in western Europe.
• Socioeconomic factors: In the United States, parental income and parental education level are inversely related to the incidence of HL.
• Immune dysregulation: Patients may have T-cell immunodeficiency, HIV infection or AIDS, congenital immunodeficiency syndromes.
• Diet: At present, no conclusive association is recognized between dietary habits and the development of Hodgkin disease.
• Environment: Clustering of cases in families or racial groups has supported the idea of a common environmental link.

DIFFERENTIALS

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Other Problems to be Considered

Fibrosing Mediastinitis
Atypical Mycobacteria
AIDS

WORKUP

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Lab Studies

• The CBC count may reveal the following:
• • Hemolytic anemia (Coombs positive), anemia of chronic disease, and/or anemia secondary to involvement of the bone marrow
  • Leukocytosis, lymphopenia, eosinophilia, and/or monocytosis
  • Thrombocytopenia and/or an idiopathic thrombocytopenia purpura (ITP)–type picture
• Assessment of acute-phase reactants may involve the erythrocyte sedimentation rate (ESR) and C-reactive protein, serum copper, and ferritin levels.
• A full serum chemistry panel may aid in evaluating levels of serum electrolytes, lactate dehydrogenase levels (LDH, which reflects bulk of disease), alkaline phosphatase (which indicates bony metastasis), as well as liver and kidney function.
• Urinalysis may demonstrate proteinuria. Nephrotic syndrome may be associated with HL.

Imaging Studies

• Chest radiography is performed with anteroposterior and lateral projections to assess the bulk of the mediastinal mass. Mediastinal mass with a thoracic ratio of 33% or greater is of prognostic importance.
• CT or MRI of neck, chest, abdomen, and/or pelvis may be indicated To assess sites of disease: nodal and extranodal sites of involvement, as well as to assess liver and spleen involvement.
• Ultrasonography can be used to assess the abdominal and pelvic structures. in centers with limited resources where CT or MRI is not available.
• On positron emission tomography (PET), uptake of the radioactive glucose analog 2-[18F]fluoro-2-deoxy-D-glucose (FDG) is correlated with proliferative activity in tumors undergoing anaerobic glycolysis.
• Gallium scanning is rarely used and has been replaced by PET scanning.
• Bone scan is necessary only when bony metastases are suspected because of an elevated alkaline phosphatase level. However, the same information may be obtained with PET scanning.

Procedures

• Staging laparotomy is no longer advocated in pediatric HL.
• Lymph node biopsy may be helpful.
• • Histopathologic studies consist of hematoxylin and eosin staining and special immunohistochemical staining for surface markers such as CD15, CD20, CD30, and CD45.
  • Consider other immunohistochemical staining to make sure they are negative and rule out non-HLs, like CD3 and anaplastic lymphoma kinase (ALK).
• Fine-needle aspiration is not recommended because of lack of stromal tissue and the difficulty of classifying the HL into 1 of the classic subtypes versus the nodular lymphocyte–predominant (NLP) subtype.
• Bilateral bone marrow biopsy is necessary in all patients with suspected involvement of the bone marrow and in those with stage IIB, III, or IV disease.

Histologic Findings

Classification

The most recent and currently accepted classification is the Revised European-American Lymphoma (REAL) classification that the World Health Organization (WHO) has adopted reflects the distinction of NLP HL from classic HL. The system is as follows:

• Classic nodular sclerosing: This class is notable for fibrous bands that result in a nodular pattern and lacunar-type H-RS cells wherein the cytoplasm in formalin-fixed specimens retracts, forming a lacuna around the nucleus. This is the most common type in all age groups (77% of adolescents and 72% of adults), though it affects only 44% of younger children.
• Classic mixed cellularity: This class may have interstitial fibrosis, but fibrous bands are not observed. H-RS cells are classic in appearance or mononuclear. Lymphocytes may predominate in the cellular background. This subtype is more common in young children (33%) than in adolescents (11%) or adults (17%).
• Classic lymphocyte rich: This class has classic or lacunar-type H-RS cells with rare or absent eosinophils on a cellular background. This type is extremely rare.
• Classic lymphocyte depleted: This class has large numbers of H-RS cells with sarcomatous variants and a hypocellular background because of fibrosis and necrosis. This type is also extremely rare.
• NLP: This form may be nodular, but fibrosis is unusual. The H-RS cell variants are known as lymphocytic and histiocytic (L&H) or popcorn cells. The nuclei are multilobed and vesicular with small nucleoli. The characteristic halo of the classic H-RS cell is absent. The background consists of histiocytes and lymphocytes with a B-cell predominance in contrast to the cellular background in classic HD, which has a T-cell predominance.

Immunophenotyping

The classic subtypes of HL are positive for CD15 and CD30 and may be positive for CD20, whereas NLP HL is negative for CD15 and CD30 but positive for CD20 and CD45.

Staging

• After a tissue diagnosis is made, the disease is staged by using imaging studies, evaluating the bone marrow evaluation, and assessing for B symptoms (see History above).
• The most widely used staging system is the Ann Arbor staging system.
• • Stage I - Single lymph node region or single extranodal site
  • Stage II - Two or more lymph node regions on the same side of the diaphragm
  • Stage III - Lymph node regions on both sides of the diaphragm
  • Stage IV - Diffuse or disseminated involvement of 1 or more extralymphatic organs (liver, bone marrow, lung) or tissues with or without associated lymph node involvement (The spleen is considered a nodal site.)
• A or B designations are also used.
• • B is the presence of at least 1 of the following symptoms: drenching night sweats, unexplained fevers with temperature >38°C, and >10% loss of body weight in the past 6 months.
  • A is the absence of symptoms described above.
• The E designation is extension or contiguous involvement of extranodal sites by large mediastinal masses that are not considered metastatic or stage IV.

TREATMENT

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Medical Care

Children with HL should be treated at a pediatric oncology center where pediatric oncologists, radiation therapists, and full ancillary services are available for children with malignancies.

HL is one of the most curable malignancies of childhood and adolescence. HL can be cured with radiation therapy alone, chemotherapy alone, or a combination of both. However, acute and late toxicities vary substantially according to the treatment modality used. Therefore, most modern pediatric treatment strategies focus on reducing late effects of therapy while maintaining excellent cure rates with risk-adapted chemotherapy alone or response-adjusted combined-modality regimens.

Placement of a peripheral intravenous catheter or other central venous catheter for chemotherapy and supportive care is suggested but not required. The decision to place a central venous catheter should be based on the intensity of the treatment, the level of supportive care anticipated, the state of the patient's peripheral venous access, and the patient's preference.

• Radiation therapy: Radiation therapy was the first curative modality used for HL. However, the doses and fields used for the treatment of adult HL causes profound musculoskeletal retardation, cardiac toxicity, and increased incidence of secondary malignancies in the radiation field (eg, breast cancer in female survivors). Therefore, risk-adapted or response-based, low-dose, involved- or extended-field radiation is currently used as an adjuvant treatment after chemotherapy.
• Chemotherapy: With rare exceptions, all children and adolescents are treated with chemotherapy alone or combined with radiation therapy. Chemotherapy alone is effective and prevents radiation-associated treatment complications. This approach is recommended especially in centers were pediatric radiation therapy is not feasible but where chemotherapy can be reliably administered. However, in pediatric oncology centers with well-developed pediatric radiation programs, combined-modality therapy is preferred to avoid the high cumulative doses of alkylating agents, bleomycin, and anthracyclines used in chemotherapy-only protocols. Although combined chemotherapy and radiation broadens the spectrum of potential toxicities, the incidence and severity of individual drug or radiation-related toxicities are generally reduced because of the lowered doses of chemotherapy and radiation.
• • Regimens that contain alkylating agents without anthracyclines include the following:
    • Mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)
    • Cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)
    • Cyclophosphamide, vincristine, methotrexate, and prednisone (COMP)
    • Cyclophosphamide, vinblastine, procarbazine, and prednisone (CVPP)
    • Chlorambucil, vinblastine, procarbazine, and prednisone (ChVPP)
  • Regimens that contain anthracyclines without alkylating agents are the following:
    • Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD)
    • Adriamycin, bleomycin, vincristine, and etoposide (ABVE)
    • Vincristine (Oncovin), etoposide, prednisone, and doxorubicin (Adriamycin) (OEPA)
    • Vincristine, doxorubicin (Adriamycin), methotrexate, and prednisone (VAMP)
    • Vinblastine, bleomycin, etoposide, and prednisone (VBVP)
  • Regimens that contain alkylating agents and anthracyclines include the following:
    • Doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC)
    • Bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP)
    • Cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin (Adriamycin), bleomycin, and vinblastine (COPP/ABV)
    • Vincristine, procarbazine, prednisone, and doxorubicin (Adriamycin) (OPPA)
    • Doxorubicin (Adriamycin), vinblastine, nitrogen mustard, vincristine, bleomycin, etoposide, and prednisone (Stanford V)
  • Standard treatment regimens for pediatric HL are as follows:
    • For early or favorable disease (stage IA or IIA with <3 nodal sites) - Four chemotherapy cycles without alkylators (VAMP; etoposide, bleomycin, vinblastin, and prednisone [EBVP]; OEPA; or ABVE) plus low-dose, involved-field radiation of 15-30 Gy or 6 chemotherapy cycles (alternating COPP and ABVD or derivatives of these regimens) and no irradiation
    • For intermediate-risk disease (stage IA, IIA, or IIA bulky disease with extension or >3 nodal sites) - Four to six chemotherapy cycles (OPPA and COPP, Stanford V) plus low-dose, involved-field radiation of 15-30 Gy or 6 chemotherapy cycles (alternating COPP and ABVD or their derivatives) or a dose-intense, hybrid regimen (eg, Stanford V, ABVE-PC, or BEACOPP) and no irradiation
    • For advanced or unfavorable disease (stages IIB, IIIB, or IV) - Six to eight chemotherapy cycles (OPPA and/or COPP, ABVE-PC, BEACOPP) plus low-dose involved-field radiation 15-30 Gy or 6-8 chemotherapy cycles (alternating COPP and ABVD or their derivatives) or a dose-intense, hybrid regimen (ABVE-PC or BEACOPP) and no irradiation

Surgical Care

Staging laparotomy and splenectomy are no longer routinely performed in patients with HL. In patients with suspicious lesions on imaging performed for staging, biopsy is sometimes necessary if the findings might alter the treatment regimen.

Consultations

• Radiation oncologist
• Psychosocial specialists to provide support for the family

Diet

No special diet is required.

Activity

Activity is unrestricted.

MEDICATION

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Several chemotherapeutic agents in various combinations are used to treat HL. The combinations vary by the stage of disease and by the treating institution. In patients with relapsing or unresponsive disease, autologous stem-cell transplantation significantly prolongs disease-free survival. A variety of drug combinations has been used with stem-cell rescue.

Although the intended target is the malignant cells of HL, the effects of chemotherapy on normal cells of the body are considerable and account for the adverse effects observed with these agents. Because most patients with HL are long-term survivors, one of the goals of current therapy is to decrease the long-term adverse effects while maintaining excellent cure rates. The use of different therapeutic agents with nonoverlapping toxicities is 1 way to achieve this goal. Various combinations of the drugs presented below are used to treat HL.

Although adverse effects vary with each drug, some are common to many drugs. These adverse effects include nausea, vomiting, alopecia, bone marrow suppression, and, less commonly, secondary malignancies.

Drug Category: Antineoplastics agents

Cancer chemotherapy is based on an understanding of tumor cell growth and of how drugs affect this growth. After cells divide, they enter a period of growth (ie, phase G1), followed by DNA synthesis (ie, phase S). The next phase is a premitotic phase (ie, G2), then finally a mitotic cell division (ie, phase M).

Cell-division rates vary for different tumors. Most common cancers grow slowly compared with normal tissues, and the growth rate may be decreased in large tumors. This difference allows normal cells to recover more quickly than malignant ones after chemotherapy and is the rationale behind current cyclic dosage schedules.

Antineoplastic agents interfere with cell reproduction. Some agents are specific to phases of the cell cycle, whereas others (eg, alkylating agents, anthracyclines, cisplatin) are not. Cellular apoptosis (ie, programmed cell death) is another potential mechanism of many antineoplastic agents.

FOLLOW-UP

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Further Inpatient Care

• Initial evaluation, staging, and subsequent treatment can be performed on an outpatient basis.
• Admission is sometimes indicated for supportive medical care.

Further Outpatient Care

• The patient requires regular monitoring to assess his or her response to therapy and to check for adverse effects of treatment.

In/Out Patient Meds

• Antiemetics
• • Ondansetron
  • Diphenhydramine (Benadryl)
• Pain relievers
• • Codeine
  • Gabapentin (for neuropathic pain secondary to vinca alkaloids)
• Other drugs - Ranitidine while patient is receiving steroids

Deterrence/Prevention

• During periods of decreased blood cell counts due to bone marrow suppressive effects of treatment, neutropenic and thrombocytopenic precautions should be observed.

Complications

• Most acute and late complications are due to treatment-related toxicities.
• Hypothyroidism after neck and chest irradiation is prevalent and affects as many as 50% of patients who survive pediatric HL 10 years after treatment. In particular, Caucasian female patients are at greater risk than male patients and African Americans.
• Cardiac and pulmonary complications after radiotherapy depend on the cumulative doses of anthracyclines (cardiac effects) and bleomycin (pulmonary effects) and on the radiation dose. Therefore, patients need to be monitored periodically.
• Girls and especially boys are at high risk for infertility later in life after they receive regimens containing high doses of alkylators. Therefore, male patients should receive counseling about storing their sperm in a sperm bank, as appropriate, before such a regimen is started.
• As many as 30% of patients who survive pediatric HL develop a secondary malignancy 30 years after their HL is diagnosed. The most common secondary malignancies are thyroid cancer, breast cancer, nonmelanoma skin cancer, non-HL disease, and acute leukemia.
• Monitoring for disease recurrence should occur on a regular basis.
• At 20 years after HL is initially diagnosed, patients are more likely to die from treatment-related complications than from HL.

Prognosis

• The overall 5-year survival rate for HL is 91%.
• Patients with localized disease have a higher rate than those with advanced-stage disease (>90% vs as low as 70%).

Patient Education

• Refer the patient and family for psychosocial counseling.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to obtain an accurate and timely diagnosis before the start of therapy
• Failure to obtain informed consent for procedures and therapy
• Failure to appropriately monitor patients for toxicities of therapy

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Mixed cellularity Hodgkin disease showing both mononucleate and binucleate Reed-Sternberg cells in a background of inflammatory cells (hematoxylin and eosin, original magnification X200).
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Media type:  Photo

REFERENCES

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• Arky R. Physicians' Desk Reference. 53rd ed. Montvale, NJ:. Thomson Medical Economics;1999.
• Arya LS, Dinand V. Current strategies in the treatment of childhood Hodgkins disease. Indian Pediatr. Nov 2005;42(11):1115-28. [Medline].
• Balis FM, Holcenberg JS, Poplack DG. General Practices of Chemotherapy. In: Principles and Practice of Pediatric Oncology. 3rd ed. Philadelphia, Pa:. Lippincott Williams & Wilkins;1997:215-72.
• Carbone PP, Kaplan HS, Musshoff K, et al. Report of the Committee on Hodgkin''s Disease Staging Classification. Cancer Res. Nov 1971;31(11):1860-1. [Medline].
• Harris NL. Hodgkin's disease: classification and differential diagnosis. Modern Pathology. 1999;12:159-175. [Medline].
• Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. Sep 1 1994;84(5):1361-92. [Medline].
• Howard SC, Metzger ML, Hudson MM. Pediatric Hodgkin Lymphoma. In: Antillon FA, Bernaola E, Sierrasesumaga L, eds. Pediatric Oncology. Pearson Education;. 2006.
• Hudson MM, Donaldson SS. Hodgkin's disease. In: Principles and Practice of Pediatric Oncology. 3rd ed. Philadelphia, Pa:. Lippincott Williams & Wilkins;1997:523-43.
• Jackson H, Parker F. Hodgkin's Disease and Allied Disorders. London, England: Oxford University Press;. 1947.
• Lukes R, Butler J, Hicks E. Natural History of Hodgkin's disease as related to its pathologic picture. In: Cancer. Vol. 19. 1966: 317-44.
• Munker R, Hasenclever D, Brosteanu O, et al. Bone marrow involvement in Hodgkin''s disease: an analysis of 135 consecutive cases. German Hodgkin''s Lymphoma Study Group. J Clin Oncol. Feb 1995;13(2):403-9. [Medline].
• Percy CL, Smith MA, Linet M, et al. Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995: Lymphomas and Reticuloendothelial Neoplasms [Surveillance, Epidemiology, and End Results Web site]. November 5, 1999. Bethesda, MD: National Cancer Insti. 35-49:[Full Text].
• Re D, Thomas RK, Behringer K, Diehl V. From Hodgkin disease to Hodgkin lymphoma: biologic insights and therapeutic potential. Blood. Jun 15 2005;105(12):4553-60. [Medline].

Article Last Updated: Jul 19, 2006