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Hodgkin lymphoma is a hematopoietic
malignancy with unique epidemiologic features that vary depending
on the geographic region of the patient. Genetic and environmental
contributions to the pathogenesis of the disease are not completely
understood and represent an active area of research. Progression
of Hodgkin lymphoma initially occurs along functionally contiguous
lymph nodes. If untreated, extranodal involvement eventually results
from hematogenous dissemination of neoplastic cells to the liver,
lungs, bones, bone marrow, and other tissues. The most common clinical
presentation is one of painless lymphadenopathy previously attributed
to infectious or inflammatory etiologies. Other signs and symptoms
vary based on the involved nodal sites and their compression of
adjacent organs and tissues. Cytokine production by malignant cells
results in constitutional symptoms including anorexia, pruritus, weight
loss, night sweats, and fever in some patients.
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Providing care for children with Hodgkin lymphoma challenges
the pediatric and radiation oncology team to accomplish the tandem
goals of optimizing disease control and limiting long-term morbidity.1 Historically,
treatment approaches mirrored those used for adults, but outcome
was compromised by unacceptable musculoskeletal hypoplasia resulting
from high dosage radiation of large volumes in physically immature
children. Pediatric patients are also more likely to experience
cardiovascular toxicity associated with anthracycline chemotherapy
and thoracic radiation, which may predispose them to early mortality
associated with cardiomyopathy and coronary artery disease.2 There
are also specific gender-related predispositions to treatment effects.
Boys are more vulnerable to gonadal toxicity following cumulative
doses of alkylating agent chemotherapy used in primary treatment regimens,
whereas girls generally maintain ovarian function unless chemotherapy
is combined with infradiaphragmatic radiation. Conversely, girls
treated with anthracycline chemotherapy, particularly if younger
than age 5 years, are more likely than boys to experience cardiotoxicity.
Likewise, young women treated with thoracic radiation during puberty
have a substantially increased risk of a breast malignancy that
is not observed in their male counterparts.3 Because of
these unique developmental and gender-related predispositions to
therapy effects, there is no single treatment method that is ideal
for all patients. Contemporary treatment uses a risk-adapted approach
that considers the prognostic features of the disease presentation
in the context of a patient’s predisposition to long-term
toxicity related to age and gender.
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Etiology and Epidemiology
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The epidemiologic, clinical, and histologic features of Hodgkin
lymphoma are different in economically developed and developing
countries.4 Epidemiologic studies support three distinct
forms of Hodgkin lymphoma attributable to interactions of environmental
and host factors.5 The childhood form (age 14 years or
younger) is characterized by a high incidence of the mixed cellularity
histologic subtype in children living in poorer socioeconomic environments.
The young adult form (ages 15 to 34 years) shows a predominance
of the nodular sclerosing histologic subtype in Caucasian adolescents
and young adults in developed countries. An older adult form (ages
55 to 74 years) produces the characteristic bimodal distribution
of incidence of the disease in industrialized countries. In developing
countries, the early peak occurs before adolescence.
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Hodgkin lymphoma is more common in males than in females in all
parts of the world. The gender ratio varies from 2:1 in Europe and America
to over 3.5:1 in Asia. The male predominance is most marked in patients
younger than age 10 years. In adolescents, the gender difference
in incidence is less conspicuous, particularly for the nodular sclerosing
histologic subtype. Beyond age 55, the gender difference in incidence
decreases and is similar across histologic subtypes. Hodgkin lymphoma
is rarely diagnosed in children younger than age 5 years in economically
developed countries.
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A genetic predisposition to Hodgkin lymphoma is suggested by
the incidence variation among racial and ethnic groups, familial
aggregation of the disease, and association with specific human
leukocyte antigens.4,6 In some groups, race and
ethnicity appear to predict the risk of Hodgkin lymphoma independent
of socioeconomic status. For example, Asians consistently have lower
incidence rates despite the marked international differences in
socioeconomic conditions. Many investigators have observed concordance
of Hodgkin lymphoma in first-degree relatives, including sibling
and parent–child pairs. In studies of concordant monozygotic
twins, the elevated risk of Hodgkin lymphoma ranges from threefold
among first-degree relatives to sevenfold in siblings. Hodgkin lymphoma
also develops more frequently in individuals with congenital or
acquired immunodeficiency, leading to the speculation that an inherited
subtle immune abnormality may predispose to the development of Hodgkin
lymphoma by increasing the risk of malignant transformation induced
by environmental factors.
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Characteristic epidemiologic features, including the bimodal
age incidence and socioeconomic influences, prompted the speculation
that an infectious agent may contribute to the pathogenesis of some
types of Hodgkin lymphoma.4 Epstein-Barr virus (EBV) was
indirectly implicated in epidemiologic studies demonstrating an
excess risk of Hodgkin lymphoma following infectious mononucleosis
and elevated anti-EBV titers in patients with Hodgkin lymphoma compared
to healthy controls. Supporting evidence of EBV association with
Hodgkin lymphoma includes the localization of viral genomes in the
Reed-Sternberg cells, expression of EBV-latent gene products in
the tumor specimens, and the demonstration of clonal infection.7 Clear
differences exist with the expression of EBV-associated antigens
in cases of Hodgkin lymphoma with respect to histologic subtype,
geographic region, and age. EBV-associated Hodgkin lymphoma occurs
more frequently in children in developing countries who present
with mixed cellularity histology. These data suggest that EBV may
be a cofactor in the pathogenesis of some cases of Hodgkin lymphoma.
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Hodgkin lymphoma is histologically characterized by the presence
of Reed-Sternberg cells within an inflammatory infiltrate of normal
lymphocytes, histiocytes, plasma cells, eosinophils, and neutrophils.
The neoplasm is unusual because the acknowledged malignant Hodgkin
and Reed-Sternberg (HRS) cells usually represent only 0.1 to 10% of
the cellular infiltrate of the tumor. Techniques such as microdissection
and single-cell polymerase chain reaction (PCR) have confirmed the
B-lymphoid origin of the disease through identification of clonal
immunoglobulin (Ig) rearrangements in enriched populations of HRS
cells removed from their benign polyclonal inflammatory background.8 Rarely,
the HRS cells have been found to contain T-cell receptor gene rearrangements,
suggesting that some of these tumors may be of T-lymphoid lineage,
but these cases remain controversial. Thus, Hodgkin lymphoma is
felt to represent a unique type of B-cell neoplasm. Consequently,
the currently used World Health Organization (WHO) classification
has abandoned the term Hodgkin’s disease,
thought to reflect the lack of knowledge regarding the true origin
of the HRS cells. Unlike other lymphoid neoplasms, cytogenetic abnormalities
characteristic of Hodgkin lymphoma have not been identified.
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The current WHO histologic classification of Hodgkin lymphoma
is largely based on the Rye modification of the Lukes and Butler
classification schema. The WHO classification recognizes two major subtypes
of Hodgkin lymphoma, classical Hodgkin lymphoma and nodular lymphocyte
predominance Hodgkin lymphoma, based on their biological and clinical
features.9 Classical Hodgkin lymphoma includes 4 histologic
subtypes that differ by tissue architecture, the presence of fibrosis,
and the features of the associated inflammatory infiltrate: nodular
sclerosis, mixed cellularity, lymphocyte rich, and lymphocyte depleted.
All histologic subtypes are responsive to therapy. Histologic subtyping
is valuable because of its association with clinical findings such
as sites of involvement, stage at presentation, and systemic symptoms.
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Clinical Manifestations
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The most common presentation of Hodgkin lymphoma is asymptomatic
cervical or supraclavicular lymphadenopathy. Two thirds of these patients
will also have involvement of mediastinal lymph nodes, which may
produce a nonproductive cough or other symptoms of tracheal or bronchial
compression. Rarely, patients may present with life-threatening
cardiovascular or respiratory decompensation as a result of tumor
infiltration of the pericardium, obstruction of superior vena cava
blood flow, or airway compression by bulky mediastinal lymphadenopathy.
Children present less frequently with axillary or inguinal lymphadenopathy.
Primary subdiaphragmatic nodal involvement is rare and occurs in
less than 10% of patients. In some cases, extension of
enlarged retroperitoneal lymph nodes through neural foramina produces
pain and para- or quadraparesis from spinal cord compression.
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About 30% of children exhibit constitutional symptoms
of fever, drenching night sweats, and unexplained weight loss within
the previous 6 months, which have a negative impact on prognosis
because of their association with more disseminated disease. “Pel-Ebstein” fevers are
typically associated with Hodgkin lymphoma and are characterized
by periodic febrile episodes (with our without night sweats) lasting
for several days, followed by afebrile periods of days or weeks.
Less commonly reported systemic symptoms such as pruritus and alcohol-induced
pain do not influence outcome.
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Nonspecific abnormalities of hematologic parameters may be observed
at diagnosis. Peripheral blood changes include neutrophilic leukocytosis,
lymphopenia, eosinophilia, and monocytosis. Elevations of erythrocyte
sedimentation, serum copper, ferritin, or C-reactive protein levels
reflect activation of the reticuloendothelial system and may be
used to monitor disease activity if they are abnormal at diagnosis.
Anemia usually indicates the presence of advanced disease and most
commonly results from impaired mobilization of iron stores. Coombs’ positive
hemolytic anemia associated with reticulocytosis and normoblastic hyperplasia
of the bone marrow has also been described at presentation of Hodgkin
lymphoma. Abnormalities of chemical parameters are infrequent in
Hodgkin lymphoma. Occasionally, levels of serum lactate dehydrogenase
will be elevated at diagnosis. Elevation of serum alkaline phosphatase
levels beyond that expected for age may be associated with the presence
of bony metastases. Liver function studies are generally unreliable
indicators of hepatic disease.
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Hodgkin lymphoma has been described in association with several
autoimmune diseases including immune thrombocytopenia purpura (ITP),
nephrosis, and hemolytic anemia. Of these, ITP is most frequently
observed and its prognosis for response to therapy is related to
the status of the underlying Hodgkin lymphoma. ITP presenting during
remission of Hodgkin lymphoma lacks prognostic significance. Patients
with Hodgkin lymphoma also exhibit immune system abnormalities at
diagnosis that may persist after therapy. These include abnormalities
of cell-mediated immunity resulting from enhanced sensitivity to
suppressor T-lymphocytes and reduction of natural killer cell cytotoxicity.
After treatment, humoral immunity may be transiently depressed.
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Other inflammatory causes of lymphadenopathy, especially those
with an indolent course (eg, atypical mycobacterium or toxoplasma
infections), should be considered in the differential diagnosis
of lymphadenopathy. Infectious agents producing lymphadenopathy
can often be distinguished from Hodgkin lymphoma by their characteristic
clinical presentations. Non-Hodgkin lymphoma may have similar presenting
signs and symptoms, but is typically associated with a more rapid
growth of affected lymph nodes. Also, children with non-Hodgkin
lymphoma more frequently exhibit elevations of serum uric acid and
lactate dehydrogenase levels. Although lymphadenopathy resulting
from bacterial or viral infection is more common than lymph node
enlargement from malignant infiltration, lymphadenopathy persisting
beyond 3 to 4 weeks should be considered for biopsy. Occasionally
the site, for example, in the supraclavicular region and character,
for example, firm, fixed painless lymphadenopathy, may indicate the
need for immediate biopsy. In such cases, an excisional lymph node
biopsy is the preferred procedure to establish a diagnosis as it
permits evaluation of the entire nodal architecture.
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Diagnosis and Clinical
Staging
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Biopsy is required to establish the diagnosis of Hodgkin lymphoma.
Lymph node excision represents the optimal method of diagnosis because
the malignant Hodgkin and Reed-Sternberg (HRS) cells can be evaluated
within the context of the nodal architecture unique to individual
histologic subtypes. If a noninvasive needle biopsy is planned,
multiple tissue passes should be performed to facilitate assessment
of nodal architecture.
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The goal of the staging evaluation is to identify sites and characteristics
of disease to permit as accurate a risk assessment as possible for
planning treatment. The routine use of systemic chemotherapy, coupled with
advances in diagnostic imaging technology that permitted more accurate
evaluation of abdominal and pelvic lymph node involvement, made
staging laparotomy used during the 1970s obsolete. Currently, surgical
staging is recommended in children only if the findings will significantly
alter the treatment plan. Table 452-1 summarizes the recommended steps in
the diagnostic workup for pediatric Hodgkin lymphoma. Table
452-2 outlines the Ann Arbor staging classification, which
has been the internationally accepted staging system for Hodgkin
lymphoma since 1971.
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Dramatic progress has been made in
the development of curative therapy for children and adolescents
with Hodgkin lymphoma over the past 50 years.1,10 Contemporary
treatment protocols for pediatric Hodgkin lymphoma produce long-term,
disease-free survival in 70% to 90% of patients
with advanced stage disease, and 85% to 100% of
patients with localized disease. The majority (60–80%)
of children with extranodal disease will also be cured of their
disease. This therapeutic success has provided the opportunity to
evaluate the long-term impact of treatment on morbidity and mortality.
Appreciation of treatment sequelae has prompted refinements in therapy
designed to reduce growth impairment, infertility, second malignancy,
and life-threatening organ dysfunction. Current treatment strategies
focus on reducing therapy for patients with favorable disease characteristics
and reserve more intensive treatment modalities for patients with
relapsed or refractory disease.
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Treatment options for children and adolescents with Hodgkin lymphoma
comprise multiagent chemotherapy alone or combined modality therapy
with chemotherapy and low-dose radiation therapy. The desire to avoid
radiation-induced growth inhibition of bones and soft tissues and
the induction of secondary solid tumor malignancies led to the abandonment
of the use of radiation therapy as a single modality in children with
Hodgkin lymphoma. Concerns about radiation-induced carcinogenesis
and cardiopulmonary toxicity, which are more prevalent following
standard-dose (35–44 Gy) than low-dose (15–25.5
Gy) levels, continue to significantly influence contemporary treatment
approaches.3
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Multiagent chemotherapy is still largely derived from the original
non-cross-resistant MOPP (mechlorethamine, vincristine [Oncovin],
prednisone, and procarbazine) and ABVD (doxorubicin [Adriamycin], bleomycin,
vinblastine, and dacarbazine) regimens.11,12 Treatment
sequelae following MOPP comprise an increased risk of acute myelogenous
leukemia and infertility, which have been correlated with the cumulative
dose of alkylating agents in the combination. The risk of secondary
leukemia can be reduced by limiting the total dose of alkylating
agents and substituting other less leukemogenic drugs, such as cyclophosphamide,
for mechlorethamine.
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ABVD is effective therapy for Hodgkin lymphoma that does not
produce an excess risk of secondary leukemia or infertility. However,
concerns regarding dose-related cardiac and pulmonary toxicity attributable
to doxorubicin and bleomycin in the combination have limited its
singular use in pediatric regimens. As a result, ABVD and similar
derivative combinations are commonly used in treatment regimens prescribing
fewer cycles of chemotherapy for patients with favorable disease
characteristics at presentation, or alternated with regimens containing
alkylating agents, for example, MOPP or COPP (cyclophosphamide vincristine,
procarbazine, and prednisone), in patients with advanced or unfavorable
disease.13,14
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Several trials have established the efficacy of treatment with
non-cross-resistant chemotherapy alone in pediatric Hodgkin lymphoma.13 Chemotherapy-alone
protocols offer advantages for children managed in centers lacking
radiation facilities and trained personnel, as well as diagnostic
imaging modalities needed for clinical staging. This treatment option
also avoids the potential long-term growth inhibition, organ dysfunction,
and solid tumor induction associated with radiation. On the other
hand, chemotherapy-alone treatment protocols usually prescribe higher
cumulative doses of alkylating agent and anthracycline chemotherapy,
which may produce acute and late treatment morbidity from myelosuppression,
cardiotoxicity, gonadal injury, and secondary leukemia.
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The desire to reduce the dose-related toxicity of agents in the
MOPP and ABVD regimens popularized the use of alternating, hybrid,
and derivative multiagent chemotherapy regimens (Table
452-3). Initially, standard-dose (35–44 Gy), extended-volume
radiation therapy was added to enhance local tumor control. The
efficacy of these regimens led to subsequent trials that demonstrated
excellent cure rates using fewer cycles of non-cross-resistant chemotherapy
with reduced radiation doses (15–25.5 Gy) and fields.
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Contemporary therapy planning utilizes a risk-adapted approach
based on the presenting features of the disease.1 Ongoing
trials for patients with favorable disease presentations are evaluating
the effectiveness of treatment with fewer cycles of combination
chemotherapy alone that limit doses of anthracyclines and alkylating
agents. For patients with unfavorable disease presentations, contemporary
trials are testing if chemotherapy and radiotherapy can be limited
in patients who achieve a rapid early response to dose-intensive chemotherapy
regimens. Table 452-4 provides general risk-adapted
treatment recommendations.
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Most relapses in patients with Hodgkin lymphoma occur within
the first 3 years, although some patients may relapse as long as
10 years after initial diagnosis.15 Treatment and ultimate
prognosis after relapse depend on the initial therapy type and time
of relapse. Standard multiagent chemotherapy and radiation therapy
may salvage 40% to 50% of children who maintained
initial remission for 1 or more years, but late treatment complications
such as second malignancies and cardiovascular disease may reduce
ultimate survival.16 Patients who develop refractory disease
during or within 1 year of completing therapy respond poorly to
conventional salvage therapy, as do patients with multiple relapses.
Consolidation with myeloablative therapy followed by hematopoietic
cell transplantation provides these high-risk patients the best
opportunity for a durable remission. Autologous hematopoietic stem
cell transplantation (HSCT) has been preferred for patients with
relapsed Hodgkin lymphoma because of the greater morbidity and mortality
associated with allogeneic HSCT. Overall survival after autologous
HSCT in pediatric patients with relapsed Hodgkin lymphoma ranges
from 30% to 60%. Reduced intensity or nonmyeloablative allogeneic
HSCT is under evaluation as a retrieval therapy for children with
recurrent/refractory disease after autologous HSCT.17 Nonmyeloablative
conditioning regimens most often use a nontoxic immunosuppression
with the goal of establishing a graft-versus-lymphoma effect that
provides a platform for adoptive cellular immunotherapy.
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Today, the majority of children and adolescents diagnosed with
Hodgkin lymphoma will enjoy long-term, disease-free survival. Consequently, ongoing
clinical trials are focusing on two primary objectives: (1) to maintain
cure rates and further reduce treatment sequelae in patients with favorable
disease presentations; and (2) to identify biologic and clinical
characteristics of patients with a high risk of treatment failure,
for whom treatment must be further intensified to improve outcome.
Because of the paucity of novel antineoplastic approaches with safer
toxicity profiles, alterations in the currently effective treatment strategies
must proceed cautiously to assure that disease-free survival is
not compromised.