Pediatric Hodgkin Lymphoma: Past, Present and Future

Aaron Weiss; Michelle Neier; Richard A Drachtman

Pediatr Health. 2009;3(6):593-606.

Abstract and Introduction

Abstract

The history of treatment of Hodgkin lymphoma in children and young adults has been one of increasing success, with the focus shifting in recent years from cure, regardless of the cost, to an increasing concern regarding late effects and other consequences of treatment. Ongoing protocols continue to explore the use of risk-based therapy, further delineating the ability to individualize therapy in an effort to decrease morbidity and mortality, while preserving excellent cure rates.

Introduction

Prior to the differentiation of pediatric oncology as a separate specialty, children with Hodgkin lymphoma (HL) were treated as small adults, using adult paradigms. Radiotherapy alone was the initial mainstay of therapy, with cure possible in patients with limited disease. There was, however, a significant incidence of side effects due to irradiation, some of which were not appreciated until decades later, such as the increasing incidence of secondary malignancies in the radiation fields and cardiac disease, as well as relatively more acute effects, such as hypothyroidism and musculoskeletal growth arrest in the irradiated areas. The incorporation of systemic therapy enabled the degree of toxicity seen as a result of any one drug or modality to be reduced, and allowed patients to undergo clinical staging and to forgo staging laparatomy. While there are currently no identified biologic features unique to children, the current trend in the pediatric population is towards minimizing therapy while not sacrificing quality of life or ultimate survival.^[1,2]

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Cite this: Pediatric Hodgkin Lymphoma: Past, Present and Future - Medscape - Dec 01, 2009.

Abstract and Introduction
Epidemiology
Pathobiology & Classification
Clinical Presentation, Staging & Diagnostic Evaluation
History of Treatment
Current Therapy
Relapsed & Refractory Disease
Late Effects
Prognosis
Conclusion
Future Perspective
References
Sidebar

Table 1. Common chemotherapy regimens in Hodgkin lymphoma.
Chemotherapy regimen	Agents	Comments
VAMP	Vinblastine, doxorubicin, methotrexate, prednisone; involved field radiation therapy for stage I–II	Stanford–Dana Farber–St Jude study group for early-stage Hodgkin lymphoma
AV-PC	Doxorubicin, vincristine, prednisone and cyclophosphamide	Children's Oncology Group study; eliminates radiation for patients with complete response to initial therapy
MOPP-ABVD	Mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine and dacarbazine	Non-crossresistant chemotherapy
OEPA ± COPP (males) OPPA ± COPP (females)	Vincristine, etoposide/procarbazine, prednisone, doxorubicin, cyclophosphamide, vincristine, prednisone and procarbazine	Etoposide instead of procarbazine to preserve male fertility
BEACOPP	Bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and procarbazine	German Hodgkin Study Group showed excellent response with increased toxicity

Box 1. Pediatric Hodgkin lymphoma histological classification (incidence).
Classical Hodgkin lymphoma (95%) Nodular sclerosis (75–85%) Mixed cellularity (15–25%) Lymphocyte depleted (6%) Lymphocyte rich (1%) Nodular lymphocyte-predominant Hodgkin lymphoma (5%)

Box 2. Clinical presentation, diagnostic evaluation and staging of pediatric Hodgkin lymphoma.
*Clinical presentation* Adenopathy Typically located in cervical and supraclavicular regions Characteristics: firm, matted and painless Mediastinal mass (present in the majority of nodular sclerosis subtypes) B symptoms Fever (> 38°C for more than 3 days during the last month) Weight loss (unexplained loss of > 10% of bodyweight over the past 6 months) Drenching night sweats *Diagnostic evaluation* Biopsy (open biopsy preferred) Plain chest radiograph Computed tomography scan of the neck, chest, abdomen and pelvis Gallium scintigraphy or positron emission tomography scan Bilateral bone marrow biopsy Bone scan (only if B symptoms or symptomatic bone pain) *Staging & risk classification* Stage I: limited to involvement of a single lymph node region Stage II: two or more lymph node regions on the same side of the diaphragm Stage III: lymph node involvement on both sides of the diaphragm Stage IV: disseminated disease Most common sites: lung, liver, bone and bone marrow B symptoms (designated A if absent) Bulky disease Extralymphatic extension

Sidebar

Executive Summary

Epidemiology

Hodgkin lymphoma (HL) represents 6% of all pediatric cancers.
There is a bimodal age-distribution pattern with peaks between 15 and 35 years of age and after 55 years of age.
Nodular sclerosis (NS) HL is the most common histologic subtype across all age groups.
Incidence is influenced by numerous familial, environmental, socioeconomic and infectious factors.

Pathobiology & classification

HL is characterized by the identification of multinucleated giant cells known as Reed–Sternberg (R–S) cells within an inflammatory milieu.
Resistance by the R–S cells to apoptotic stimuli appears to be an important event in tumor cell pathogenesis.
Classical HL (cHL) is the most common subtype representing 95% of all HL cases.
Nodular lymphocyte-predominant HL (NLPHL) is a less common and pathologically distinct subtype.
Immunophenotyping in cHL typically demonstrates CD15 and CD30 positivity.
There appears to be a causal association between Epstein–Barr virus and certain subtypes of HL.

Clinical presentation, staging & diagnostic evaluation

The majority of patients present with disease in the cervical or supraclavicular regions.
A quarter of patients have B symptoms at presentation.
NLPHL patients typically present with asymptomatic, localized disease.
Numerous diagnostic studies are required to determine the extent of disease.
Disease staging incorporates anatomical and clinical criteria.

Current therapy

Treatment is risk based and emphasizes chemotherapy or combined modality treatments.
Early-stage disease typically receives two to four cycles of chemotherapy with or without radiation.
Treatment of patients with intermediate- and advanced-stage HL requires more intensified combined modality therapy.
Most patients with NLPHL are successfully treated with surgery alone.

Relapsed & refractory disease

A consensus regarding standard therapy for patients with relapsed or refractory disease has not been reached.
Numerous effective salvage regimens exist with excellent outcome achieved for select subgroups of patients.
Autologous or allogeneic stem cell transplant is an option for high-risk patients.
Novel therapeutics are currently reserved for patients with multiply relapsed or refractory disease.

Late effects

Therapy-related toxicity has become a significant challenge in the management of patients with HL.
HL patients are most at risk for cardiac toxicity, gonadal toxicity, thyroid disease and secondary malignancies.
Current therapy goals are to reduce toxicity through risk-adapted therapy.

Prognosis

Overall survival for HL across all stages is 87–100%.
Numerous prognostic risk factors impacting outcome have been identified.
NLPHL patients demonstrate superior outcomes with limited therapy compared with those with cHL.

Future perspective

Excellent survival rates in most patients will continue to shift focus to limiting toxicity and late effects.
New agents are needed for patients with refractory disease.
Positron emission tomography may play a more significant role in staging and response evaluations.

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