AUTHOR INFORMATION

Section 1 of 12

Authored by Pedro A de Alarcon, MD, William H Albers Professor and Chair, Department of Pediatrics, University of Illinois College of Medicine at Peoria

Coauthored by Kaveri Suryanarayan, MD, Assistant Professor, Department of Pediatrics, Division of Hematology-Oncology, University of Maryland Medical Center; Monika Metzger, MD, MSc, Assistant Professor, University of Tennessee School of Medicine; Consulting Staff, Department of Hematology/ Oncology, Division of Leukemia, St Jude Children's Research Hospital

Pedro A de Alarcon, MD, is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American Federation for Clinical Research, American Pediatric Society, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, Eastern Society for Pediatric Research, International Society for Experimental Hematology, International Society of Hematology, International Society on Thrombosis and Haemostasis, Medical Society of the State of New York, National Hemophilia Foundation, New York Academy of Sciences, Society for Pediatric Research, Southern Society for Pediatric Research, and Virginia Pediatrics Society

Edited by Kathleen Sakamoto, MD, Professor, Department of Pediatrics, Division of Hematology-Oncology and Pathology and Laboratory Medicine, Mattel Children's Hospital, David Geffen School of Medicine, University of California at Los Angeles; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland, CA; Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University; and Robert J Arceci, MD, PhD, King Fahd Professor, Division of Pediatric Oncology, Johns Hopkins University School of Medicine

Author's Email:	Pedro A de Alarcon, MD
Editor's Email:	Kathleen Sakamoto, MD

eMedicine Journal, July 19 2006, VOLUME 7, Number 7

INTRODUCTION

Section 2 of 12

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:

• In the US: 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.

• Internationally: 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

Section 3 of 12

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

Section 4 of 12

Acute Lymphoblastic Leukemia
Brucellosis
Catscratch Disease
Cytomegalovirus Infection
Histoplasmosis
Lymph Node Disorders
Lymphadenitis
Lymphadenopathy
Lymphoproliferative Disorders
Mononucleosis and Epstein-Barr Virus Infection
Non-Hodgkin Lymphoma
Toxoplasmosis
Tuberculosis

Other Problems to be Considered:

Fibrosing Mediastinitis
Atypical Mycobacteria
AIDS

WORKUP

Section 5 of 12

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.

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

Section 6 of 12

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

Section 7 of 12

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.

Drug Name	Mechlorethamine (Mustargen, nitrogen mustard, HN2) -- Alkylating agent. Component of MOPP.
Pediatric Dose	6 mg/m2 IV on days 1 and 8 of each cycle
Contraindications	Documented hypersensitivity; active infection
Interactions	May decrease immune response to live virus vaccines
Pregnancy	D - Unsafe in pregnancy
Precautions	Avoid inhalation or contact with skin or eyes (potent vesicant, use extravasation precautions); associated with renal, hepatic, and bone marrow toxicity; infertility and increased incidence of secondary malignancy

Drug Name	Bleomycin (Blenoxane) -- Classified as antibiotic. Induces free radical–mediated breaks in strands of DNA. Part of ABVD regimen.
Pediatric Dose	5-10 U/m2 IV/IM/SQ on days 1 and 15 of each cycle
Contraindications	Documented hypersensitivity; clinically significant renal impairment; compromised pulmonary function
Interactions	May decrease plasma levels of digoxin and phenytoin; cisplatin may increase toxicity when administered systemically; may decrease immune response to live virus vaccines
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in renal impairment; possibly secreted in breast milk; may cause mutagenesis and pulmonary toxicity (10%); idiosyncratic reactions similar to anaphylaxis (1%) may occur; monitor for adverse effects during and after treatment; vaso-occlusive phenomenon with distal necrosis of digit; permanent damage to nail matrix may occur

Drug Name	Vinblastine (Velban) -- Vinca alkaloid that inhibits mitosis because of interactions with tubulin.
Pediatric Dose	6 mg/m2 IV on days 1 and 15 of each cycle
Contraindications	Documented hypersensitivity; granulocytopenia; intrathecal use
Interactions	May reduce phenytoin plasma levels when administered concomitantly; with mitomycin may substantially increase pulmonary toxicity; cytochrome P450 (CYP) 3A4 inhibitors (eg, itraconazole, erythromycin, quinupristin/dalfopristin) may decrease elimination, increasing toxicity; may decrease immune response to live virus vaccines
Pregnancy	D - Unsafe in pregnancy
Precautions	Hyperbilirubinemia; associated with bone marrow suppression; caution in impaired liver function and neurotoxicity (modify dose); monitor closely for shortness of breath and bronchospasm when patient is receiving mitomycin C

Drug Name	Dacarbazine (DTIC-Dome) -- Alkylating agent. Inhibits DNA, RNA, and protein synthesis. Inhibits cell replication in all phases of cell cycle.
Pediatric Dose	375 mg/m2 IV on days 1 and 15 of each cycle
Contraindications	Documented hypersensitivity
Interactions	May decrease immune response to live virus vaccines
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause nausea, vomiting, fever, or myalgias; caution in bone marrow suppression and renal and/or hepatic impairment; avoid extravasation

Drug Name	Etoposide (Toposar, VP-16) -- Epipodophyllotoxin that induces DNA strand breaks by disrupting topoisomerase II activity.
Pediatric Dose	75 mg/m2 IV on days 1-5 of each cycle
Contraindications	Documented hypersensitivity
Interactions	May prolong effects of warfarin and increase clearance of methotrexate; with cyclosporine, has additive effects in cytotoxicity of tumor cells; may decrease response to live virus vaccines
Pregnancy	D - Unsafe in pregnancy
Precautions	May cause nausea, vomiting, alopecia, anaphylaxis, or secondary malignancy; consider dosage reduction in patients with low serum albumin, bone marrow suppression, or renal impairment

Drug Name	Vincristine (Oncovin) -- Vinca alkaloid with mechanism of action similar to that of vinblastine.
Pediatric Dose	1.4 mg/m2 IV on days 1 and 8 of each cycle
Contraindications	Documented hypersensitivity; patients with demyelinating form of Charcot-Marie-Tooth syndrome; hyperbilirubinemia; intrathecal administration (universally fatal)
Interactions	Acute pulmonary reaction may occur with concurrent mitomycin-C; asparaginase, CYP3A4 inhibitors (eg, itraconazole, quinupristin-dalfopristin, sertraline, ritonavir), granulocyte-macrophage colony-stimulating factors (GM-CSF, eg, sargramostim, filgrastim), or nifedipine increase toxicity; CYP3A4 inducers (eg, carbamazepine, phenytoin, phenobarbital, rifampin) may decrease effects; may decrease immune response to live virus vaccines
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in severe cardiopulmonary disease, hepatic impairment (adjust dose), or preexisting neuromuscular dysfunction; can cause peripheral neuropathy, constipation, foot drop, and joint pain

Drug Name	Procarbazine (Matulane) -- Alkylating agent with mechanism of action similar to that of dacarbazine.
Pediatric Dose	100 mg/m2/d PO on days 1-15 of each cycle
Contraindications	Documented hypersensitivity; preexisting bone marrow aplasia
Interactions	Sympathomimetic amines, barbiturates, phenothiazines, alcohol, and other CNS depressants can increase toxicity; because of weak monoamine oxidase (MAO) properties, foods containing high amounts of tyramine or coadministration with MAO inhibitors (MAOIs) can increase toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in preexisting renal or hepatic disease (reduce dose); associated with hepatic, renal, and bone marrow toxicity; associated with mucositis and hypersensitivity reactions

Drug Name	Prednisone (Deltasone, Meticorten, Orasone, Sterapred) -- Corticosteroid used to treat leukemias and lymphomas because of its lympholytic activity.
Pediatric Dose	40 mg/m2/d PO on days 1-15 of each cycle
Contraindications	Documented hypersensitivity; serious infections (excluding meningitis and septic shock); fungal or varicella infections
Interactions	Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics; coadministration with anticoagulants or antiplatelets may increase risk of GI bleeding
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Name	Cyclophosphamide (Cytoxan) -- Alkylating agent. Chemically related to nitrogen mustards. Mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
Pediatric Dose	500-800 mg/m2/d IV on days 1 and 8 of each cycle
Contraindications	Documented hypersensitivity; severe hemorrhagic cystitis; severely depressed bone marrow function
Interactions	Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; toxicity may increase with chloramphenicol; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia; coadministration with succinylcholine may increase neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy	D - Unsafe in pregnancy
Precautions	Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis (administer with mesna)

Drug Name	Methotrexate -- Antimetabolite that inhibits dihydrofolate reductase necessary for conversion of folate to biologically active tetrahydrofolate.
Pediatric Dose	40 mg/m2 IV on days 1 and 8 of each cycle
Contraindications	Documented hypersensitivity
Interactions	Nonsteroidal anti-inflammatory drugs (NSAIDs) may increase or prolong levels; may decrease clearance of theophylline; penicillins may decrease renal excretion; broad-spectrum PO antibiotics may decrease bioavailability; large doses of folate may decrease efficacy; additional folate antagonists (eg, cotrimoxazole) may have additive myelosuppression
Pregnancy	X - Contraindicated in pregnancy
Precautions	Mucositis, hepatic failure, acute pulmonary disease, and bone marrow toxicity; high doses require leucovorin rescue; monitor CBC counts monthly and liver and renal function q1-3mo during therapy (more frequently during initial dosing, dose adjustments, or if levels might be elevated [eg, in dehydration]); toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if blood counts substantially decrease; fatal reactions reported when administered concurrently with NSAIDs

Drug Name	Doxorubicin (Adriamycin) -- Anthracycline that functions as DNA intercalator. Inhibits topoisomerase II and produces free radicals, which may destroy DNA. Combination of the 2 events can inhibit growth of neoplastic cells.
Pediatric Dose	25-30 mg/m2/d IV on days 1 and 15 of each cycle
Contraindications	Documented hypersensitivity; myocardial damage; cumulative anthracycline dose in excess of 450 mg/m2 is a relative contraindication
Interactions	May decrease phenytoin and digoxin plasma levels; phenobarbital may decrease plasma levels; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity; cyclophosphamide increases cardiac toxicity; streptozocin increases half-life, increasing toxicity (decrease dose); may decrease immune response to live virus vaccines
Pregnancy	D - Unsafe in pregnancy
Precautions	May cause mucositis or hyperbilirubinemia; irreversible cardiac toxicity and myelosuppression may occur; extravasation may result in severe local tissue necrosis; reduce dose in impaired hepatic function

FOLLOW-UP

Section 8 of 12

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

Section 9 of 12

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

TEST QUESTIONS

Section 10 of 12

CME Question 1: Which factor or factors are currently thought to contribute most to the development of Hodgkin disease?

A: Genetic predisposition alone
B: Diet alone
C: Immune dysregulation alone
D: A and C
E: A, B, and C

The correct answer is D: At present, no conclusive association is recognized between dietary habits and the development of Hodgkin disease. Clustering of cases in families or racial groups has supported the idea of a genetic predisposition or a common environmental link.

CME Question 2: Which study is not commonly part of the initial evaluation of Hodgkin disease?

A: Chest radiography
B: Biopsy
C: Lumbar puncture
D: Bone marrow aspirate and biopsy
E: Bone scanning

The correct answer is C: Lumbar puncture for cytology is performed if neurologic symptoms are present, but the CSF is rarely a site of disease.

Pearl Question 1 (T/F): The popcorn cell is observed in nodular sclerosis Hodgkin disease.

The correct answer is False: The popcorn cell is observed in nodular lymphocyte–predominant Hodgkin disease.

Pearl Question 2 (T/F): Mixed cellularity HL is more common in young children than in adolescents.

The correct answer is True: Nodular sclerosing HL is the most common form of HL in all age groups (around 70%). Mixed-cellularity HL is more common in young children (33%) than in adolescents (11%).

Pearl Question 3 (T/F): Cytomegalovirus is found in approximately 50% of patients with Hodgkin disease in the United States.

The correct answer is False: Epstein-Barr virus is found in approximately 50% of patients with Hodgkin disease in the United States.

Pearl Question 4 (T/F): A pruritic rash is a B symptom of Hodgkin disease.

The correct answer is False: B symptoms consist of unexplained fever with a temperature above 38°C for 3 consecutive days, unexplained weight loss of 10% or more in the previous 6 months, and drenching night sweats.

PICTURES

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Caption: Picture 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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BIBLIOGRAPHY

Section 12 of 12

• 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 2005 Nov; 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 1971 Nov; 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 1994 Sep 1; 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 1995 Feb; 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 2005 Jun 15; 105(12): 4553-60[Medline].

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