Hodgkin Lymphoma
The 5 Minute Pediatric Consult
Deborah L. Kramer
DEFINITION
A malignant enlargement of lymph nodes characterized by a pleomorphic cellular infiltrate with multinucleated giant cells (Reed-Sternberg cells)
PATHOPHYSIOLOGY
- Exact cause unknown
- Reed-Sternberg cells are the malignant cells of Hodgkin lymphoma; however, their normal counterparts have not been definitively identified. They may originate from activated B or T lymphocytes or from an antigen-presenting cell. Histologically, Reed-Sternberg cells are dispersed among apparently normal reactive cells including lymphocytes, plasma cells, and eosinophils.
- The Rye classification histologically divides the disease into four categories: lymphocyte predominant, mixed cellularity, lymphocyte depleted, and nodular sclerosis.
- Unicentric in origin with spread mostly by contiguity from one chain of lymph nodes to another.
GENETICS
- Familial clustering suggests the role of both genetic and environmental factors in pathogenesis:
- three- to sevenfold increased risk of disease among siblings, in families where twins are concordant
- reports in parent-child pairs have been noted
EPIDEMIOLOGY
- Incidence shows bimodal age distribution:
- Early peak, before adolescence in developing countries, mid to late 20s in United States
- Second peak, late adulthood >50 years of age
- Childhood cases, rare before 5 years of age, males > females less than 10 years of age, more common in white race >15 years of age
- Infections with Epstein-Barr virus, cytomegalovirus, and herpesvirus 6 may play role in transmission of disease
- patients with history of EBV infection have a threefold increased risk of disease
COMPLICATIONS
- Acute toxicity of treatment
- Radiation effects are generally reversible and not serious. They are a function of total dose and volume irradiated and include erythema with or without hyperpigmentation of involved skin, nausea, fatigue, and possibly myelosuppression. Lhermitte syndrome, a sensation of “electric shock” radiating down the back into the extremities, may occasionally be seen.
- Chemotherapy regimens will cause nausea, vomiting, and reversible alopecia to some degree. Transfusions may be required for anemia and thrombocytopenia. Each individual agent also has a list of toxicities that must be reviewed before using alone or in combination. Most important of these include cardiac toxicity with Adriamycin, neurotoxicity with vincristine, and pulmonary toxicity with bleomycin.
- Infection
- Most common dose-limiting acute toxicity of chemotherapy is myelosuppression. Patients may have to be admitted for antibiotics if fever develops during neutropenia. Prophylactic antibiotics and vaccines have reduced the incidence of serious bacterial infections in the splenectomized host.
PROGNOSIS
- With current therapy including chemotherapy and/or radiation, five-year disease-free survival ranges from:
- 88–100% in low stage disease
- 54–94% in advanced stage disease
- Infection is most common cause for acute lymphadenopathy.
- Bacterial (Staphylococcus aureus, b-hemolytic streptococcus, TB, atypical mycobacteria)
- Other (EBV, CMV, Cat-scratch disease, toxo, HIV, histoplasmosis)
- Malignancy is more common with chronic adenopathy.
- Non-Hodgkin lymphoma, neuroblastoma, leukemia, rhabdomyosarcoma
- Mediastinal masses divided anatomically:
- Anterior: lymphoid and thyroid tumors, bronchogenic cysts, aneurysms, lipomas
- Middle: lymphoid tumors, angiomas, pericardial cysts, teratomas, esophageal lesions, hernias
- Posterior: neurogenic tumors, cysts, thoracic meningocele, sarcomas
HISTORY
- Nonspecific clinical findings probably result from cytokine production
- Fatigue, anorexia, weight loss in one-third of patients
- “B” symptoms (part of staging classification) include one of the following:
- Unexplained fever with temp >38°C for at least 3 days
- Unexplained weight loss >10% body weight in previous 6 months
- Drenching night sweats
- “A” disease (asymptomatic)
- Pruritis or pain that worsens with ingestion of alcohol seen in some patients
- Painless lymphadenopathy most common
- Nodes are usually firmer and less mobile than inflammatory nodes
- Mediastinal mass in two-thirds of patients, may cause nonproductive cough or difficulty breathing
- Hepatosplenomegaly and bone tenderness in advanced stages
- Unusual signs and symptoms: nephrotic syndrome, dermatomyositis, and acute dysautonomia
- CBC, ESR
- Liver and renal function studies
- Serum copper, fibrinogen
- Baseline thyroid functions (preradiotherapy)
- Baseline echocardiogram and pulmonary function tests
PATHOLOGY
- Lymph node biopsy for definitive diagnosis
RADIOLOGIC STUDIES
- Chest x-ray (PA and lateral), looks for mediastinal mass
- CT scan (chest, abdomen, pelvis), to rule out disseminated disease
- CT or MRI of spine (if bony tenderness or symptoms of cord compression suspected)
SPECIAL TESTS
- Bone marrow biopsy
- Gallium scan (detects residual disease in the mediastinum)
- Bone scan (evaluates bone involvement, optional)
- Lymphangiogram (evaluates retroperitoneal adenopathy, optional)
- Cardiac Troponin-T levels (elevated after myocardial damage possibly due to therapy, investigational)
STAGING
- Staging laparotomy is indicated in patients with equivocal abdominal findings from clinical staging or in patients with radiotherapy treatment only.
- I: Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (IE) by direct extension
- II: Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm (IIE)
- III: Involvement of lymph node regions on both sides of the diaphragm (III), which may be accompanied by involvement of the spleen (IIIS) or by localized involvement of an extralymphatic organ or site (IIIE) or both (IIIES)
- IV: Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node involvement
- Staging is further subclassified “A” or “B” according to absence or presence of symptoms (listed above), respectively.
RADIOTHERAPY (XRT)
- Exquisitely responsive to XRT
- Decisions to use XRT based on patient age, tumor burden, and potential complications
- Standard dose XRT, 3500 cGy; low dose, 2500 cGy; total dose given to all involved areas
- Doses administered in fractions, 150–200 cGy per day/five times a week
CHEMOTHERAPY
Multiple agents allow different mechanisms of action (to circumvent resistance) and nonoverlapping toxicities so that full doses can be given.
- MOPP: mechlorethamine + vincristine (Oncovin) + procarbazine + prednisone
- COPP: cyclophosphamide substituted for mechlorethamine in MOPP
- COMP: methotrexate substituted for procarbazine in COPP
- ABVD: doxorubicin (Adriamycin) + bleomycin + vinblastine + dacarbazine
- DBVE: doxorubicin + bleomycin + vincristine + etoposide
- DBVE-PC: DBVE + prednisone and cyclophosphamide
- Each cycle consists of 21–28 days, dependent on toxicity. Some regimens alternate therapy (i.e., MOPP alternating with ABVD), or use growth factor support to intensify schedule.
- Stages IA, IIA
- Attained full growth; no unfavorable signs: standard-dose XRT alone
- Still growing, bulky disease, or E lesions: (see staging) low dose XRT + two to four courses multiagent chemotherapy
- Stages IB, IIB, IIIA/B, IVA/B
- Attained full growth; no unfavorable signs: combined modality therapy with three to five courses multiagent chemotherapy + low-dose XRT
- Still growing or large mediastinal mass: low-dose XRT + chemotherapy (same as above)
- Office visits monthly with CBC
- CT scan of involved areas every 3 months for first 2 years, then every 6 months for 3 years
- Special studies as needed for toxicity-related complications
- Relapse of disease usually occurs within first 3 years. Some may relapse as late as 10 years after initial diagnosis.
PITFALLS
- Late effects
- Pulmonary damage (radiation-induced and/or chemotherapy-bleomycin): pneumonitis, pulmonary fibrosis, decreased pulmonary function, pneumothorax
- Cardiac damage (XRT-induced and/or chemotherapy-Adriamycin): cardiomyopathy resulting in CHF, arrhythmias with conduction defects, pericarditis, valvular damage, coronary heart disease, and myocardial infarction
- Radiation nephritis
- Azoospermia induced by alkylating agents is almost always permanent in postpubertal boys
- Amenorrhea occurs in 20% of patients under 25 years using the MOPP regimen. Radiation-induced ovarian damage can be avoided by performing oophoropexy during laparotomy.
- Hypothyroidism results from XRT.
- Damage to soft tissue and bone growth can occur with high doses of XRT (>3500 cGy), resulting in a disproportionate alteration in sitting height versus standing height. Risk is highest during active bone growth (under 6 years of age and puberty).
- Secondary malignant neoplasms are a major concern in selecting therapy. The risk of developing leukemia (AML) is highest when both radiotherapy and alkylating agents are used. One study showed the risk of second neoplasm 15 years after diagnosis was 7%, with breast cancer as the most common solid tumor. Other secondary neoplasms associated with treatment are thyroid and skin carcinomas, brain tumor, and malignant fibrous histiocytoma.
| COMMON QUESTIONS AND ANSWERS |
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Q: Is my child at risk for other cancers?
A: Yes. Although the incidence is low, children with Hodgkin disease are primarily at risk for cancers resulting from their treatment. Breast cancer is the most common solid tumor and can occur decades after therapy. Therefore, long term follow-up is essential.
Q: Will my child be infertile following treatment?
A: It depends on the therapy he/she received. Certain chemotherapy agents are associated with a higher risk of infertility (alkylating agents). Radiation to the gonads is also associated with infertility.
ICD-9-CM 201.9
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Bhatia S, Robinson LL, Oberlin O, et al. Breast cancer and other second neoplasms after childhood Hodgkin Disease. N Engl J Med 1996;334:745–751.
Lanzkowsky P. Hodgkin’s disease. Manual of pediatric hematology and oncology. New York: Churchill Livingstone, 1989:251–269.
Leventhal BG, Donaldson SS. Hodgkin disease. In: Pizzo PA, Poplack DG, eds. Principles and practice of pediatric oncology, 2nd ed. Philadelphia: JB Lippincott, 1993:577–594.
Mack TM, Cozen W, Shibata DK, et al. Concordance for Hodgkin’s disease in identical twins suggesting genetic susceptibility to the young-adult form of the disease. N Engl J Med 1995;332:413–418.
Ottlinger ME, Sallan SE, Rifai N, Sacks DB, Lipshultz SE. Myocardial damage in doxorubicin-treated children: a study of serum cardiac troponin-T. Proc Am Soc Clin Oncol 1995;14:345.
Copyright © 2000 Lippincott Williams & Wilkins
M. William Schwartz, Louis M. Bell, Jr., Peter M. Bingham, Esther K. Chung, David F. Friedman and Andrew E. Mulberg, The 5 Minute Pediatric Consult