Overview of Hodgkin lymphoma in children and

adolescents
Authors: Kenneth L McClain, MD, PhD, Kala Kamdar, MD, MS Epi
Section Editor: Julie R Park, MD
Deputy Editor: Alan G Rosmarin, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jan 2024. | This topic last updated: Nov 11, 2022.

INTRODUCTION

Hodgkin lymphoma (HL, formerly called Hodgkin's disease) is a malignant lymphoma

that accounts for approximately 7 percent of childhood cancers and 1 percent of
childhood cancer deaths in the United States ( table 1) [1]. The incidence of HL in
childhood varies by age such that HL is exceedingly rare in infants, but is the most
common childhood cancer in the 15- to 19-year-old age group. Children and
adolescents with HL have a five-year survival of 94 percent since 2002 compared with
an 81 percent survival in the early 1970s [2].

Few risk factors, other than those related to viral exposure and immune function,
have been convincingly identified. (See "Hodgkin lymphoma: Epidemiology and risk
factors".)

This topic will provide an overview of HL in children and adolescents. The

pathobiology of HL and its diagnosis and management in adults are presented
separately as is the care of the adult survivor of HL. (See "Approach to the adult
survivor of classic Hodgkin lymphoma" and "Clinical presentation and diagnosis of
classic Hodgkin lymphoma in adults".)

EPIDEMIOLOGY
Variation in the incidence, age, and sex distribution of HL occurs in different
populations according to geographic location, socioeconomic status, and
immunologic status. In the United States and other economically advantaged
countries, two incidence peaks exist: one in young adults and one in persons older
than 50 years; most patients are young adults ( figure 1) [1,3]. The estimated age-
related incidence rates are 29 cases per million per year in adolescents aged 15 to 19;
approximately 10 per million per year in 10- to 14-year-olds; 3.5 per million in 5- to 9-
year-olds; and 1 per million for ages 0 to 4 years. The bimodal age distribution of HL is
different in economically disadvantaged areas. An initial peak occurs in childhood for
boys, relatively low rates are found in young adults, and a late peak occurs in older
adults [4]. (See "Hodgkin lymphoma: Epidemiology and risk factors", section on 'Age
and race'.)

The overall incidence of HL in adolescents is greater in females than in males (male to

female ratio 0.8); however, boys under age 15 have higher incidence of HL, with up to
fivefold higher incidence of HL in boys than girls less than five years of age [5]. The
incidence of HL is similar among White American and African American children
younger than 10 years of age but is increased among White American children
relative to African American children older than 10 years (ratio of 1.4:1) [5].

● Immunodeficiency – Patients with primary immune deficiencies, such as ataxia

telangiectasia, chromosomal breakage syndromes, and the autoimmune
lymphoproliferative syndrome, have increased rates of HL as compared to
nonimmune-deficient individuals [6-8]. Likewise, individuals with HIV/AIDS and
after solid organ transplantation have an increased risk of HL [9,10].

● Familial – Familial HL has been estimated to represent 4.5 percent of all cases of
HL [11-13]. This familial association may include shared environmental factors,
exposure to viruses, and genetic influences, including inherited
immunodeficiency states. This is discussed in more detail separately. (See
"Hodgkin lymphoma: Epidemiology and risk factors", section on 'Familial risk' and
"Hyperimmunoglobulin M syndromes".)
BIOLOGY

The malignant cells of HL are clonal Hodgkin/Reed-Sternberg (HRS) cells ( picture 1

and picture 2), which usually constitute less than 1 percent of the cells in involved
lymph nodes. The rest of the lymph node contains a heterogeneous cellular infiltrate
consisting of lymphocytes, eosinophils, macrophages, plasma cells, and fibroblasts.
HRS cells are germinal center B cells that cannot synthesize immunoglobulin
molecules [14]. The infiltrating cells secrete an array of cytokines and chemokines that
are important for HRS cell survival and maintenance of the characteristic cellular
infiltrate. The biology of HRS cells and their role in HL are discussed separately. (See
"Pathogenesis of Hodgkin lymphoma".)

Epstein-Barr virus (EBV) infection is associated with many, but not all cases of HL.
When EBV is present, it can be detected in HRS cells, and is thought to play a role in
the pathogenesis of HL. Twenty-five to 50 percent of cases of classic HL in developed
countries are EBV positive; the incidence of EBV varies among histological subtypes.
(See "Hodgkin lymphoma: Epidemiology and risk factors".)

HISTOLOGIC CLASSIFICATION

HL comprises four subtypes of classic HL and a distinct category, labeled nodular

lymphocyte-predominant HL according to the World Health Organization 5th edition
(WHO5) [15] and nodular lymphocyte predominant B cell lymphoma in the
International Consensus Classification [16]. (See "Classification of hematopoietic
neoplasms", section on 'Hodgkin lymphoma (HL)'.)

Classic HL (cHL) — cHL accounts for 90 to 95 percent of cases of HL; cHL is

subdivided into four subtypes:

● Nodular sclerosis (NS) – This accounts for 80 percent of HL in older children and
adolescents, but 55 percent of HL in younger children in the United States [17].
Dense collagenous bands divide the lymph node into nodules. The
Hodgkin/Reed-Sternberg (HRS) cells may be a variant known as a lacunar cell.
 ● Mixed cellularity (MC) – This accounts for 20 percent of children younger than
10 years and half that in adolescents. Often with prominent eosinophils, it can be
confused with non-Hodgkin lymphoma.

● Lymphocyte depleted (LD) – This subtype is rare in children, often with bizarre
malignant cells, diffuse fibrosis, and necrosis [18].

● Lymphocyte rich (LR) – This subtype is rare in children. It has a nodular

appearance, but HRS cells express both CD15 and CD30. This is in contrast to HRS
cells of nodular lymphocyte-predominant HL, which do not express CD15 and
rarely express CD30.

Nodular lymphocyte-predominant HL (NLPHL) — This category of lymphoma is

called NLPHL in WHO5 [15], but it is labeled nodular lymphocyte predominant B cell
lymphoma (NLPBL) by the ICC [16].

The malignant cells in NLPHL, which are called LP cells ("popcorn cells"), have
distinctive characteristics that distinguish them from Reed-Sternberg cells of cHL
( table 2). (See "Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical
manifestations, diagnosis, and staging".)

CLINICAL PRESENTATION

Common presenting symptoms and signs of HL in children include lymphadenopathy,

systemic complaints, and mediastinal mass. Results of cooperative group studies
show that 80 to 85 percent of pediatric HL patients present with only lymph node
and/or splenic involvement (stage I to III) [19]. The remaining have liver, lung, or bone
marrow involvement and are stage IV.

Lymphadenopathy — Most children (80 percent) with HL present with painless

lymphadenopathy, usually cervical, supraclavicular, axillary, or, less often, inguinal.
The affected lymph nodes typically feel rubbery and more firm than inflammatory
adenopathy; they may be sensitive to palpation if they have grown rapidly. "Bulky
lymphadenopathy" (aggregates of lymph nodes ≥6 cm in diameter) are considered in
the risk stratification for therapy. (See 'Risk stratification' below and "Peripheral
lymphadenopathy in children: Evaluation and diagnostic approach", section on
'Lymph nodes'.)

Mediastinal mass — Up to 75 percent of children with HL have a mediastinal mass

on chest radiograph at the time of presentation. They are more common among
children older than 12 years of age, in whom approximately 30 percent have masses
greater than one-third the diameter of the intrathoracic cavity. Such "bulky"
mediastinal disease may cause dysphagia, dyspnea, orthopnea, cough, stridor, or the
superior vena cava syndrome. (See "Malignancy-related superior vena cava
syndrome".)

Children with intrathoracic HL may rarely present with hypertrophic osteoarthropathy,

characterized clinically by digital clubbing and painful periostosis of tubular bones
[20-22]. (See "Malignancy and rheumatic disorders", section on 'Hypertrophic
osteoarthropathy'.)

Systemic symptoms — Patients with HL may present with nonspecific systemic

symptoms including fatigue, anorexia, and weight loss. Fever (>38.0°C), drenching
night sweats, and weight loss (≥10 percent loss within six months before diagnosis),
classified as "B" symptoms, have important implications for staging and prognosis
( table 3) [23]. (See "Pretreatment evaluation, staging, and treatment stratification of
classic Hodgkin lymphoma", section on 'B symptoms'.)

As in adults, pruritus and alcohol-induced pain, which typically resolve with treatment,
have been described [24-28].

Other — Hepatic and/or splenic enlargement may be present in patients with

advanced stage HL. Rarely, patients present with autoimmune disorders such as
autoimmune hemolytic anemia, thrombocytopenia, or neutropenia [27]. Cases
presenting with nephropathy have also been described [29]. (See "Approach to the
child with an enlarged spleen".)

DIFFERENTIAL DIAGNOSIS
The presenting symptoms and signs suggestive of HL in children and adolescents
may be caused by a variety of diseases and the differential diagnosis includes other
malignant, infectious, and inflammatory diseases. They include non-Hodgkin
lymphoma, metastatic adenopathy from other primary tumors (eg, nasopharyngeal
carcinoma, soft tissue sarcoma), toxoplasmosis, typical and atypical mycobacterium
infections, Epstein-Barr virus (EBV) infection, systemic lupus erythematosus, and
disorders causing reactive hyperplasia of lymph nodes [30]. (See "Clinical presentation
and diagnosis of classic Hodgkin lymphoma in adults", section on 'Differential
diagnosis'.)

The diagnostic considerations in patients with mediastinal masses depend upon the
anatomic compartment in which the mass is located ( figure 2). In children, anterior
mediastinal mass must be distinguished from normal thymus, which attains maximal
size when the child reaches approximately 10 years of age [31]. (See "Approach to the
adult patient with a mediastinal mass".)

EVALUATION AND DIAGNOSIS

Clinical and laboratory evaluation and tissue biopsy are required for establishing the
diagnosis of HL.

Clinical and laboratory

● Clinical

• History – History should include presence of constitutional symptoms (ie,

fever, night sweats, weight loss), previous infections, family exposures to toxins
or occupational hazards, and evidence of underlying immune deficiencies and
familial cancer, including HL.

Patients who have a past medical history of recurrent infections, autoimmune

and inflammatory disorders, presentation at <5 years, or a family history of
immune deficiency should undergo a detailed immunologic evaluation. (See
"Approach to the child with recurrent infections".)
 • Examination – Physical examination includes assessment of general health,
measurement of height and weight, and documentation of the size and
location of lymphadenopathy ( figure 3), liver and spleen size, skin
infiltrations, pulmonary findings, and neurologic signs. The tonsils, base of the
tongue, and nasopharynx (ie, Waldeyer's ring) must be included in this
evaluation.

● Laboratory – Routine laboratory tests, including complete blood count (CBC) with
white blood cell differential count, erythrocyte sedimentation rate, renal and liver
function tests, lactate dehydrogenase (LDH), and urinalysis are obtained to assess
organ involvement and risk for relapse. (See "Pretreatment evaluation, staging,
and treatment stratification of classic Hodgkin lymphoma", section on 'Laboratory
studies'.)

Imaging — The goal of imaging is to define the extent of disease and guide tissue
biopsy. (See 'Diagnosis' below.)

The following imaging studies should be obtained:

● Chest radiograph (anteroposterior and lateral)

● Computed tomography (CT) with intravenous contrast of neck, chest, abdomen,

and pelvis

● 18-fluoro-2-deoxyglucose (FDG)-positron emission tomography (PET) scan (either

as an integrated PET/CT or as a separate PET study)

The chest radiograph provides immediate information about intrathoracic structures,

extent of mediastinal involvement, and patency of the airway. The CT provides
information about extranodal sites of disease, including pulmonary parenchyma,
chest wall, pleura, and pericardium [32,33]. PET is more sensitive for detecting both
nodular and diffuse disease, and may be more sensitive than bone marrow biopsy in
detecting bone marrow involvement [34,35]. (See "Pretreatment evaluation, staging,
and treatment stratification of classic Hodgkin lymphoma", section on 'PET/CT'.)

Bulk disease in children is defined below. (See 'Risk stratification' below.)

Diagnosis — The diagnosis of HL is established by histologic examination of a biopsy
specimen.

The preferred specimen is an excisional biopsy of an enlarged lymph node. An

incisional biopsy or multiple core needle biopsies may be acceptable, but fine needle
aspirates do not provide adequate amounts of material for proper histologic
classification nor for molecular studies needed in the evaluation of other lymphomas.

Biopsy of HL demonstrates "classic" Hodgkin/Reed-Sternberg (HRS) cells or their

variants, which may represent only a minority (usually <1 percent) of the cellular
infiltrate [36]. Subclassification of HL depends upon whether the tumoral architecture
is nodular, diffuse, or both, and whether "classic" or variant HRS cells are present, as
well as the composition of the cellular infiltrate (eg, non-neoplastic small
lymphocytes, eosinophils, plasma cells, fibroblasts, histiocytes, neutrophils, and
collagen fibers). (See "Hodgkin lymphoma: Epidemiology and risk factors" and
"Nodular lymphocyte-predominant Hodgkin lymphoma: Clinical manifestations,
diagnosis, and staging".)

Patients with a large mediastinal mass are at risk for acute respiratory compromise.
The evaluation and biopsy of these patients must be undertaken with special care.
These patients may have assumed an awkward seated position that allows them to
keep an open airway. Such patients should never be placed in a lying position. A
biopsy of a superficial node under local anesthesia may be required. Occasionally,
such patients need urgent systemic steroid administration and/or involved field
radiotherapy.

Bone marrow aspirates are recommended only for patients with advanced stage
disease (stage III, IV), B symptoms, or an abnormality on CBC that is suspicious for
bone marrow involvement (see 'Staging' below) [37]. Advances in diagnostic imaging
and the use of systemic chemotherapy in all pediatric HL treatment protocols have
made routine staging laparotomy unnecessary.

STAGING
Therapy and prognosis are based upon the stage of the disease, as defined by the
Ann Arbor staging system with Cotswolds modifications used both in children and
adults ( table 3). (See "Pretreatment evaluation, staging, and treatment stratification
of classic Hodgkin lymphoma".)

TREATMENT

Children with HL should be treated in a comprehensive pediatric oncology center

[38,39]. However, depending upon referral patterns and center-specific policies,
adolescents with HL may be treated with either adult or pediatric treatment protocols
[40]. Traditionally, management consists of a combination of chemotherapy and
radiotherapy. Because of high cure rates for HL and substantial secondary side effects
of therapies such as MOPP (mechlorethamine, vincristine, procarbazine, and
prednisone) and ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) [41-43],
modern pediatric cooperative group trials aim to appropriately risk-stratify patients to
reduce therapy (ie, eliminate radiotherapy) in patients with lower-stage disease or
disease rapidly responsive to chemotherapy.

Initial treatment

Classic Hodgkin lymphoma

Risk stratification — Most pediatric oncology centers use a risk-adapted

treatment approach, based on disease stage and the presence or absence of bulky
disease ( table 3). Note that for children, a nodal conglomerate ≥6 cm is considered
bulk disease; this differs from the definition of bulk disease in adults.

Although criteria for stratification may differ between centers and/or studies, we
suggest the following approach, based on the Children's Oncology Group criteria and
trial outcomes:

● Low-risk disease – Non-bulky stage IA or IIA disease (see 'Low-risk disease'

below)
 ● Intermediate-risk disease – Stage IB or IIB disease without bulk; bulky stage IA
or bulky stage IIA disease; stage IIAE and stage IIIA, regardless of bulk (see
'Intermediate-risk disease' below)

● High-risk disease – Stage IIB with bulk, stage IIIB, or stage IV disease (see 'High-
risk disease' below)

The treatment options for patients in each of these risk groups are described in the
sections that follow. Patients with nodular lymphocyte-predominant HL appear to
have a better outcome and require specific consideration. For all risk groups, a choice
among regimens with equivalent outcomes is largely made based upon physician
experience, cancer center preference, and expected toxicities ( table 4). (See
'Nodular lymphocyte-predominant HL' below.)

Low-risk disease — Children with non-bulky stage IA or IIA HL are considered to

have early stage, low-risk (no bulk; no B symptoms) disease; in some studies, selected
patients with stage IIIA are also included ( table 3). For children with stage I and IIA
(early) HL, the event-free survival (EFS) rates are approximately 92 percent with an
overall survival (OS) rate of approximately 98 percent with current treatment
protocols.

Most protocols use combination chemotherapy plus low dose involved field radiation
therapy (LD-IFRT). Commonly used regimens and clinical responses include:

● Four cycles of VAMP (vinblastine, doxorubicin, methotrexate, prednisone) plus LD-

IFRT administered after the second cycle of chemotherapy was associated with
EFS 89 percent and OS 100 percent [44].

● Four cycles of COPP (cyclophosphamide, vincristine, procarbazine,

prednisone)/ABV (doxorubicin, bleomycin, vinblastine) plus LD-IFRT was
associated with EFS 100 percent and OS 97 percent [19].

● ABVE (doxorubicin, bleomycin, vinblastine, etoposide), administered for two to

four courses depending on response, followed by LD-IFRT was associated with
EFS 91 percent and OS 98 percent [45,46].
 ● OEPA (vincristine, etoposide, prednisone, doxorubicin; for males) or OPPA
(vincristine, procarbazine, prednisone, doxorubicin; for females) followed by LD-
IFRT, depending upon the initial response to chemotherapy was associated with
EFS 94 to 97 percent and OS 97 percent [43,47].

Ongoing trials are evaluating whether early response to therapy can identify low-risk
patients for whom radiation may be eliminated without compromising survival. A
nonrandomized prospective international trial (GPOH-HD95) suggested that omission
of radiation did not compromise survival rates among children with early stage HL
who attained a complete response on CT or MRI following initial treatment with OEPA
or OPPA [43]. The Children's Oncology Group (COG) AHOD0431 trial investigated
whether doxorubicin, vincristine, prednisone, and cyclophosphamide (AVPC) without
radiotherapy would be curative in patients with complete remission at end of therapy.
Though preliminary data showed two-year OS to be 100 percent, two-year EFS was
just 65 percent in those patients with positron emission tomography (PET)-avid
disease after one cycle of therapy and who did not receive radiotherapy due to
complete remission at end of treatment [48]. Optimization of risk stratification in this
patient population is a subject for future clinical trials.

Intermediate-risk disease — The intermediate-risk group comprises patients

with stage IB or IIB disease without bulk; bulky stage IA or bulky stage IIA disease;
and stage IIAE or stage IIIA, regardless of bulk. Bulky stage IIB disease has been
variably classified as intermediate-risk or high-risk, depending on the cooperative
group and specific clinical trial. With current treatment strategies, the EFS rates in
intermediate-risk disease are approximately 85 percent with an OS rate of
approximately 93 percent.

Most protocols use more intensive combination chemotherapy plus LD-IFRT.

Commonly used regimens include:

● Six cycles of COPP (cyclophosphamide, vincristine, procarbazine, prednisone)/ABV

(doxorubicin, bleomycin, vinblastine) plus LD-IFRT (EFS 84 percent with IFRT, 78
percent without IFRT; OS 100 percent) [44].
 ● ABVE-PC (doxorubicin, bleomycin, vinblastine, etoposide, prednisone,
cyclophosphamide), administered for three to five courses depending upon
response, followed by LD-IFRT (EFS 84 percent; OS 95 percent) [45].

● Two cycles of OEPA (vincristine, etoposide, prednisone, doxorubicin; for males) or

OPPA (vincristine, procarbazine, prednisone, doxorubicin; for females), followed
by two cycles of COPP (cyclophosphamide, vincristine, procarbazine, prednisone;
for females) or COPDAC (cyclophosphamide, vincristine, prednisone, dacarbazine;
for males), plus LD-IFRT depending upon the initial response to chemotherapy
(EFS 88 percent; OS 98 percent) [43,47,49].

Some experts omit radiation therapy in children without bulky disease who achieve a
rapid early response after two cycles of ABVE-PC and a PET-negative complete
response after four cycles of ABVE-PC (ie, rapid early responders/complete
responders). Conversely, some escalate therapy in those who remain PET-positive
after the first two cycles (ie, slow early responders). Support for such dose
modifications comes from the COG AHOD0031 trial, in which 1712 children and
adolescents with newly diagnosed intermediate-risk HL were treated with two cycles
of ABVE-PC followed by response evaluation by CT scan with or without PET [50]. The
trial reported the following:

● Rapid early responders (≥60 percent reduction in the product of perpendicular

diameters by CT scan) received two additional cycles of ABVE-PC followed by a
PET/CT. Those who achieved a complete response (CR; ≥80 percent reduction by
CT and negative PET) after four cycles were randomly assigned to IFRT or no
additional therapy. Rapid early responders who did not achieve a CR after four
cycles proceeded with IFRT. Overall estimated four-year EFS and OS were 87 and
99 percent, respectively. Among those who achieved a CR, elimination of IFRT did
not significantly impact EFS. However, a later analysis revealed that patients with
bulky disease and anemia at diagnosis who did not receive IFRT had a worse
four-year EFS (77.9 percent) versus those who did receive radiation (89.3 percent)
[51].
 ● Slow early responders (all others) were randomly assigned to receive two
additional cycles of ABVE-PC with or without two cycles of DECA (dexamethasone,
etoposide, cisplatin, and cytarabine), each followed by IFRT. Overall estimated
four-year EFS and OS were 77 and 95 percent, respectively with no difference in
those assigned to the DECA arm. Among those with PET-positive disease after the
first two cycles of ABVE-PC, the addition of DECA resulted in superior EFS (71
versus 55 percent).

High-risk disease — Children with stage IIIB or IV disease are considered to have
high-risk or advanced stage HL; in some schemes, children with stage IIB bulky
disease or pleural effusions are included in this high-risk group.

For children with high-risk HL, we recommend dose-intensive treatment that includes
brentuximab vedotin (BV; anti-CD30 monoclonal antibody conjugate) plus
doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide, rather than
standard pediatric combination chemotherapy. This recommendation is based on a
phase 3 trial which reported that, compared with the standard pediatric regimen, the
BV-based regimen achieved superior three-year event-free survival (EFS) with no
increase in toxicity [52]. In settings where BV is not available, treatment using the
standard pediatric regimen is acceptable.

A multicenter, open-label trial randomly assigned 587 children (ages 2 to 21 years)

with high-risk cHL (stage IIB with bulk tumor or stage IIIB, IVA, or IVB) to treatment
using five cycles of BV, doxorubicin, vincristine, etoposide, prednisone, and
cyclophosphamide versus five cycles of a standard pediatric regimen (doxorubicin,
bleomycin, vincristine, etoposide, prednisone, cyclophosphamide) [52]. PET-CT was
performed after the second cycle of chemotherapy and 21 gray involved-site radiation
therapy (ISRT) was administered after the fifth cycle to children with slow-responding
lesions or large mediastinal adenopathy present at diagnosis. With median follow-up
of 42 months, three-year OS was 99 percent for both groups, but the BV-based
regimen achieved superior three-year EFS (disease progression, relapse, second
malignancy, or death; 92 versus 83 percent; hazard ratio [HR] 0.41 [95% CI 0.25-0.67])
and fewer relapses (8 versus 17 percent). The percentage of patients who received
ISRT did not differ substantially between the groups (53 and 57 percent, respectively).
Grade ≥3 adverse events (AEs) occurred in 74 percent of BV-treated children versus 68
percent of children treated with standard chemotherapy; grade ≥3 AEs included
febrile neutropenia in approximately one-third of both groups and peripheral
neuropathy in 7 and 6 percent, respectively.

Other commonly used regimens include:

● ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone,

cyclophosphamide), administered for three to five courses depending upon
response, followed by LD-IFRT (EFS 85 percent; OS 95 percent) [45].

● Two cycles of OEPA (vincristine, etoposide, prednisone, doxorubicin; for males) or

OPPA (vincristine, procarbazine, prednisone, doxorubicin; for females), followed
by four cycles of COPP (cyclophosphamide, vincristine, procarbazine, prednisone;
for females) or COPDAC (cyclophosphamide, vincristine, prednisone, dacarbazine;
for males), plus LD-IFRT depending upon the initial response to chemotherapy
(EFS 87 percent; OS 95 percent) [43,47,49].

● Four cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide,

vincristine, procarbazine, prednisone) with subsequent therapy dependent upon
response; rapid responders: four cycles of COPP/ABV without IFRT (females) or
two cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) with IFRT
(males); slow responders: four additional cycles of BEACOPP plus IFRT (EFS 94
percent; OS 97 percent) [53].

Other regimens that limit doses of alkylating agents, anthracyclines, and/or radiation
in children with advanced and unfavorable disease have led to inferior outcomes
compared with standard regimens [54-56].

Nodular lymphocyte-predominant HL — Nodular lymphocyte-predominant

Hodgkin lymphoma (NLPHL) is an uncommon subtype of HL found in 5 to 10 percent
of all pediatric cases and more often in children less than 10 years of age [57]. The
cells have multilobed nuclei and are referred to as "popcorn" cells that express CD19,
CD20, CD79A, sometimes CD30, and do not mark with anti-CD15 stains and may be
difficult to distinguish from progressive transformation of germinal centers or T cell
rich B cell lymphoma [57,58]. (See "Nodular lymphocyte-predominant Hodgkin
lymphoma: Clinical manifestations, diagnosis, and staging", section on 'Diagnosis'.)

NLPHL represents a more indolent disease than classic HL, and is therefore managed
uniquely. Patients with stage I/II NLPHL without B symptoms are treated with less
intensive therapy than patients with classic HL. In contrast, patients with stage III/IV
are treated in a similar fashion to patients with classic HL.

The current strategies for treating NLPHL in children are modest intensity
chemotherapy regimens, some without anthracyclines, with or without involved field
radiation. Since this disease is rare, most information concerning this approach has
come from reports of single institutions or pooled, multi-institutional retrospective
analyses in children and adults. These are described separately. (See "Treatment of
nodular lymphocyte-predominant Hodgkin lymphoma".)

Given the indolent nature of NLPHL and the potential toxicities of treatment, small
studies have evaluated the use of chemotherapy alone and the use of observation
without treatment following excision in children with stage I/II NLPHL. The latter
should be reserved for highly selected patients. The OS in most series is 100 percent,
with lower progression-free survival (PFS) and EFS in series with surgery alone (67 to
82 percent) [59,60] or CVP (cyclophosphamide, vincristine, prednisone) chemotherapy
(74 percent) [61].

Several pediatric study groups have evaluated treatment de-escalation in an attempt

to avoid toxicities that can be associated with treatment (eg, growth retardation,
infertility, hypothyroidism, cardiopulmonary complications, secondary malignancy)
[59,62,63]. As examples:

● A prospective COG trial observed 52 children with stage IA nonbulky single node
disease that had a negative PET/CT scan after complete resection [60]. At a
median follow-up of 56 months, 13 patients (25 percent) relapsed with a median
time to relapse 11.5 months (range, 1 to 79 months). One relapse was stage IIA
and the rest were IA, occurring at or near the initial site. Nine relapses were
treated on protocol with three cycles of AV-PC (adriamycin [doxorubicin],
vincristine, prednisone, cyclophosphamide) chemotherapy and attained a
 complete remission without radiation therapy. One of the nine had a second
relapse six months after treatment with AV-PC. The other four patients were
treated with chemotherapy off protocol. The five-year estimated EFS and OS rates
were 77 and 100 percent, respectively for the group as a whole.

This study also evaluated the use of three cycles of AV-PC chemotherapy in 135
children with nonbulky stage IA or IIA disease [60]. Following chemotherapy
alone, 124 children (92 percent) attained a complete remission and 11 children
had a partial remission that was successfully converted to a complete remission
after IFRT. At a median follow-up of 62 months, the five-year estimated EFS and
OS rates were 89 and 100 percent, respectively.

● The Stanford protocol for low-risk HL patients used four cycles of VAMP
(vincristine, adriamycin [doxorubicin] at 25 mg/m2, methotrexate, and
prednisone) [64]. Six of 32 patients with NLPHL histology failed this therapy but
were successfully treated with IFRT or additional chemotherapy.

● The European Network group reported data from 58 children (54 with stage IA
NLPHL) who were initially treated with resection alone [59]. After a median follow-
up of 43 months, all of the children were alive, with an estimated 50-month PFS of
67 percent. Of the stage IA patients who developed recurrence after initial
resection, all were restaged as either IA or IIA.

● The CCG-5942 study, using cyclophosphamide, vincristine, doxorubicin, and

procarbazine plus doxorubicin, bleomycin, and vinblastine (COPP/ABV), had
estimated EFS and OS rates of 97 and 100 percent [65]. However, this regimen
utilizes higher doses of alkylating agents and anthracycline than other modern
regimens, raising concerns for long-term chemotoxicity.

These data suggest that radiation therapy can be eliminated in those children who
achieve an early response to therapy. However, it is unclear if the long-term toxicities
of anthracycline based chemotherapy (eg, AV-PC) are less than those expected with
current radiation protocols.
NLPHL is CD20+ and rituximab (anti-CD20 antibody) has been effective for relapsed
disease; it has not been well-studied in front-line therapy for NLPHL.

Response assessment — At least three weeks from the end of chemotherapy or 8 to

12 weeks after radiation therapy, the clinical response should be documented by
history, physical examination, laboratory studies (complete blood count, erythrocyte
sedimentation rate, and biochemical profile), and imaging studies [66].

The protocol for follow-up imaging may vary between institutions, but a common
approach is PET at 6 and 12 months off-therapy and possibly 18 months off-therapy in
high-risk patients [67]. Disease response is determined using the International
Working Group response criteria ( table 5), which also uses the Deauville Scale for
response by PET criteria ( table 6). The immediate goal of initial treatment is the
attainment of a complete response. Failure to attain a complete response should
prompt further therapy for refractory disease.

TOXICITY

Acute effects of treatment for pediatric HL depend upon the specific

chemotherapeutic agents used, the total dose of radiation therapy, and the volume
irradiated.

Radiation — Acute radiation effects are a function of the total dose delivered and the
volume irradiated. The low dose involved-field radiation that is used in the treatment
of pediatric HL is usually well tolerated. Toxic effects, which are usually self-limited
and reversible, include:

● Erythema and/or hyperpigmentation of irradiated skin

● Transient hair thinning in exposed fields
● Mild gastrointestinal symptoms (see "Radiotherapy-induced nausea and
vomiting: Prophylaxis and treatment")
● Dry mouth or alteration in taste
● Neutropenia
● Thrombocytopenia
Chemotherapy — Children who receive multiple chemotherapeutic agents for the
treatment of HL may develop nausea and vomiting. These effects can be modulated
with serotonin receptor antagonist and substance P/neurokinin 1 (NK1) receptor
antagonist anti-emetics, as well as pretreatment with benzodiazepines. (See
"Prevention of chemotherapy-induced nausea and vomiting in adults".)

Reversible alopecia is another acute effect of HL chemotherapy regimens. Other acute

effects are related to particular agents. As examples, vincristine is associated with
neurotoxicity; bleomycin with pulmonary toxicity; and doxorubicin with cardiac
toxicity. (See "Overview of neurologic complications of conventional non-platinum
cancer chemotherapy", section on 'Vincristine' and "Bleomycin-induced lung injury"
and "Clinical manifestations, diagnosis, and treatment of anthracycline-induced
cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

Myelosuppression and immunosuppression — Myelosuppression is the most

common dose-limiting acute toxicity of multiagent chemotherapy. Granulocyte colony
stimulating factor and transfusions are commonly administered. Blood product
administration and empiric treatment of infections should be managed as in other
childhood cancers. (See "Red blood cell transfusion in infants and children: Selection
of blood products", section on 'Irradiated red blood cells' and "Transfusion-associated
graft-versus-host disease" and "Fever in children with chemotherapy-induced
neutropenia", section on 'Prompt initiation of antimicrobial therapy'.)

The cellular immune system, including decreased T cell and NK cell function, may be
impaired at baseline and further compromised by myelosuppression, increasing the
susceptibility to herpes zoster and varicella infections. Post-exposure prophylaxis can
be used to prevent development of varicella infection in children who did not receive
the varicella vaccine before undergoing chemotherapy. Antiviral therapy should be
promptly initiated in patients who develop varicella infection or varicella zoster. (See
"Post-exposure prophylaxis against varicella-zoster virus infection" and "Treatment of
herpes zoster".)

Patients who have undergone splenectomy or splenic irradiation are at particular risk
for acquisition of serious bacterial infection and should receive prophylactic
antibiotics and guidelines to follow during a febrile illness. Immunizations should be
administered prior to splenectomy/splenic irradiation and chemotherapy, when
possible. (See "Prevention of infection in patients with impaired splenic function".)

OUTCOME

Most children and adolescents with HL have an excellent prognosis with current
therapy. The overall five-year survival rate for early stage disease exceeds 90 percent,
regardless of the therapeutic regimen chosen [2,68-70]. Even high-risk disease has
cure rates above 85 percent with modern therapy, albeit with increased risk of late
effects.

PROGNOSTIC FACTORS

Studies have attempted to use prognostic factors to delineate a group of patients at

high risk for first relapse who may benefit from more intensive initial therapy.
Similarly, such factors may be able to identify a group of patients with an extremely
low risk of relapse for whom therapy may be minimized. The ability to identify risk
factors in ongoing trials is limited by low relapse rates achieved with modern therapy.

Factors that are commonly utilized in clinical practice as markers of worse outcome
are higher stage [71], presence of B symptoms [19,47], and presence of bulky disease
[72]. Other prognostic features that have been associated with worse outcome
include:

● Extranodal extension [19]

● Leukocytosis (white blood cell count greater than 13,500/microL) at diagnosis [71]
● Anemia (hemoglobin less than 11 g/dL) at diagnosis [71,72]
● Male sex [71,72]
● African American race was associated with inferior overall survival, due to
increased post-relapse mortality, in a pooled analysis that included 1605 patients
from three phase 3 trials [73]
Although definitions of "rapid early response" vary among different trials and disease
states, rapid early response to upfront therapy has been associated with favorable
outcome and may indicate need for less intensive therapy [46,53]. Preliminary data
from prospective trials [48,74] indicate that response assessment with positron
emission tomography (PET) imaging appears to be particularly useful as part of a risk
stratification scheme. As an example, patients with intermediate-risk Hodgkin
lymphoma who had rapid early response (>60 percent tumor shrinkage) and were
PET-negative after two cycles of therapy had equivalent three-year progression-free
survival whether they were randomized to receive radiation or not [74], indicating a
PET-defined cohort of intermediate-risk patients that may not need radiation therapy.

Scoring systems for childhood Hodgkin lymphoma have shown promise for
identifying patients at high risk of relapse [71] but have not yet been validated in
prospective clinical trials.

The above factors also have been found to predict for disease relapse in adults. (See
"Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin
lymphoma", section on 'International Prognostic Score (IPS)'.)

Late complications — Long-term survivors of HL may sustain an array of unwanted

side effects [75-80]. In a large retrospective study of 1876 pediatric HL survivors, the
estimated cumulative incidence rates of total (grade 1 to 5) and severe (grade 3 to 5)
chronic medical conditions were approximately 75 and 40 percent, respectively, at 25
years follow-up [81]. These complications have surfaced as significant causes of
increased mortality among HL survivors, with deaths related to toxicities exceeding
those from HL after long-term follow-up. (See "Approach to the adult survivor of
classic Hodgkin lymphoma".)

Late complications include:

● Impaired growth of soft tissue and bones

● Thyroid dysfunction
● Gonadal dysfunction
● Cardiopulmonary toxicity
● Second malignancies
 ● Functional impairment and reduced overall general health

Many of these long-term effects were described initially following treatment regimens
that are no longer used in children. As patients with HL have better longevity, side
effects from the chemotherapy, such as cardiopulmonary toxicity and second
malignancies, emerged as a competing cause of delayed mortality ( figure 4) [80,82-
84]. The combined modality therapy regimens that are currently given were designed
to be less intensive than the early therapies in an effort to decrease the incidence of
adverse late effects. (See "Second malignancies after treatment of classic Hodgkin
lymphoma".)

Rates of late mortality among survivors of childhood HL have improved over time as
therapy has evolved. One study evaluated late mortality among over 34,000 survivors
of childhood cancer treated from 1970 through 1999 with a median follow-up of 21
years, including 4332 patients who had survived at least five years after a diagnosis of
childhood HL [85]. In the group as a whole, later decades demonstrated a significant
decline in mortality rates, reflecting fewer deaths due to recurrence and long-term
toxicities. Among five-year survivors of childhood HL treated in the most recent
decade (1990 to 1994), an estimated 5.8 percent died within 15 years, with the cause
of death evenly split between progression (2.7 percent) and long-term toxicities (2.6
percent). The most common causes of treatment-related mortality included
subsequent neoplasm (1.3 percent at 15 years), cardiac toxicity (0.5 percent at 15
years), and pulmonary toxicity (0.5 percent at 15 years). Risk-adapted therapy has
been associated with a substantial reduction in late effects as well, with the omission
of radiation linked to a threefold reduction in late effects [86].

● Growth – Long-term effects on bone and soft-tissue growth among survivors of

childhood HL are related to the dose and volume of received radiation, as well as
the age of the child when the radiation was administered [87]. High dose
radiation can also cause narrowing of the thoracic apex with symmetric
narrowing of the clavicles and atrophy of the soft tissues of the neck.

● Thyroid dysfunction – Thyroid dysfunction (usually hypothyroidism) occurs

frequently in patients who have received radiation to the head and neck.
 Reported incidence varies from 4 to 79 percent, depending upon the radiation
dose [41,88,89]. Thyroid dysfunction occurs 1 to 10 years after radiation, and 20
to 30 percent of patients will need thyroid replacement therapy [77,80,90]; the
risk is probably life-long. Accordingly, survivors of childhood HL should be
screened annually with a free T4 and TSH. Symptomatic patients should be
evaluated sooner. (See "Acquired hypothyroidism in childhood and adolescence"
and "Endocrinopathies in cancer survivors and others exposed to cytotoxic
therapies during childhood", section on 'Thyroid disorders'.)

● Gonadal dysfunction – Gonadal dysfunction affects female as well as male

survivors of childhood HL. Use of alkylating agents (cyclophosphamide,
ifosfamide, procarbazine, or nitrogen mustard) greatly increases the likelihood of
gonadal toxicity. For this reason, most current HL treatment protocols include
lower doses of alkylating agents, or none at all; this is expected to reduce the risk
of ovarian or testicular failure.

• Pelvic radiation carries a high likelihood of ablation of ovarian function.

However, moving the ovaries out of the radiation field (oophoropexy) should
preserve their function [91-93]. In addition, the successful reimplantation of
cryopreserved ovarian cortical strips has been reported [94-96].

• The testes are sensitive to radiotherapy and chemotherapy [97]. Thus, in

postpubertal patients with advanced stage disease, sperm banking should be
offered, although decreased sperm quality has been documented before
therapy in some cases [98].

Children treated for HL before puberty should have annual ascertainment of

Tanner stage to determine whether the pubertal status and tempo of progression
are appropriate for age and height (see "Normal puberty"). Measurement of
serum luteinizing hormone (LH), follicle stimulating hormone (FSH), and sex
steroid levels (testosterone or estradiol) should be performed in children with
delayed or interrupted progression of puberty. (See "Endocrinopathies in cancer
survivors and others exposed to cytotoxic therapies during childhood", section on
'Disorders of luteinizing and follicle-stimulating hormones'.)
 The impact of treatment on long-term fertility was evaluated in a prospective
study of 467 female survivors of childhood HL treated on German protocols
between 1978 and 1995 who were in continuous complete remission without a
second malignant neoplasm with a median follow-up of 20 years [99].
Approximately half of these long-term survivors had at least one live birth (406
children born to 228 survivors). For those younger than age 40, the likelihood of a
successful full-term pregnancy was similar to an age-matched German
population. Factors associated with a decreased likelihood of successful
pregnancy included age over 40 years and receipt of pelvic radiation. It should be
noted that this study included patients in an era when more alkylating agents
were used in the treatment of HL.

● Cardiopulmonary and cardiovascular – The long-term cardiopulmonary and

cardiovascular complications of childhood HL therapy include cardiomyopathy,
functional valve injury, conduction defects, pericarditis, pulmonary fibrosis, and
accelerated atherosclerosis, with increased risk of stroke [100-105]. In one study
of 1279 persons with HL treated with mediastinal irradiation and followed for a
median of 14.7 years, estimated cumulative incidence rates of clinically significant
cardiac disease were 2, 5, 10, 16, and 23 percent at 5, 10, 15, 20, and 25 years,
respectively [106]. The greatest excess cardiovascular risk was seen in those
irradiated before the age of 20 years. The risk of cardiotoxicity may be lessened
by reducing the dose of anthracycline chemotherapy and radiation. This is
discussed in more detail separately. (See "Cardiotoxicity of radiation therapy for
breast cancer and other malignancies" and "Approach to the adult survivor of
classic Hodgkin lymphoma", section on 'Cardiovascular disease' and "Clinical
manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity"
and "Risk and prevention of anthracycline cardiotoxicity".)

Chronic pulmonary complications of therapy for childhood HL include pulmonary

fibrosis and spontaneous pneumothorax [107-109]. (See "Bleomycin-induced lung
injury" and "Radiation-induced lung injury" and "Spontaneous pneumothorax in
children".)
 We perform electrocardiogram, echocardiogram, and pulmonary function tests
every one to two years for the first five years after therapy and then every three
to five years if no abnormalities are detected.

● Second cancers – Data from the Childhood Cancer Survivor Study indicate that
the incidence of second malignancies among survivors of HL and soft-tissue
sarcomas is higher than that of other childhood cancers [75,110]. There is an
18.5-fold increased risk of developing a second cancer in HL patients compared
with the general population [80,111]. By 10 years after completing HL treatment,
10.6 percent will develop a second malignancy and 26.3 percent will by 30 years.
Breast cancer, thyroid cancer, acute myeloid leukemia, and soft tissue sarcomas
were the most common secondary malignances [111-115]. After HL therapy, the
latency for acute myeloid leukemia (AML) or myelodysplasia is 3.2 years and for
solid tumors is 14.3 years [116]. Breast cancer incidence is directly related to the
dose of radiation given with a 3.2-fold increased risk at 4 Gy and eightfold
increased risk when 40 Gy is given [117,118]. Treatment-related AML is associated
with the use of alkylating agents, anthracycline, and etoposide [119]. (See
"Second malignancies after treatment of classic Hodgkin lymphoma".)

Although uncommon, HL survivors are at increased risk of developing both

benign and malignant thyroid neoplasms. This risk is increased further in patients
greater than 10 years from therapy, females, and those who received radiation
doses greater than 25 Gy [120]. (See "Second malignancies after treatment of
classic Hodgkin lymphoma", section on 'Thyroid cancer'.)

Long-term follow-up — Specific long-term follow-up guidelines after treatment of

childhood cancer have been published by the Children's Oncology Group, and are
available at www.survivorshipguidelines.org. An overview to the care of the adult
survivor of classic HL is presented separately. (See "Approach to the adult survivor of
classic Hodgkin lymphoma".)

RELAPSED OR REFRACTORY DISEASE

Refractory (resistant) HL is defined as those patients who fail to obtain a complete
response with initial therapy or those who relapse within three months from the end
of initial therapy. In contrast, relapsed HL describes the reappearance of HL greater
than three months after the attainment of a complete response. The decision to use a
more aggressive treatment approach in relapsed or refractory HL is typically based on
the presence of predictors of poor outcome [121]. The following are predictors of
poor outcome in patients who relapse: B symptoms, relapse between 3 to 12 months
from the end of therapy, and poor response to second-line therapy [122-124]. Patients
who relapse later than 12 months from the end of initial therapy or who had reduced
dose chemotherapy and no radiotherapy have a better outcome when treated with
more intensive conventional chemotherapy [19,47].

Patients relapsing with early stage HL (stages IA, IIA with no bulky disease or B
symptoms) who had previously been treated with chemotherapy alone can have long
term responses to chemotherapy plus IFRT. Patients past puberty are sometimes
treated with radiotherapy alone, although this is currently less common due to
concern for potential late effects [125]. Patients initially treated for advanced stage HL
and those who relapse within three months of completing therapy need high dose
chemotherapy and autologous hematopoietic cell transplantation (HCT).

Approximately 30 to 50 percent of patients who relapse after chemotherapy and IFRT

will respond to second-line therapy. The response rate is probably higher for patients
who relapse after chemotherapy alone, particularly if the relapse is confined to a site
of initial disease involvement. The choice of chemotherapy regimen depends upon
prior therapy, but typically involves the use of non-cross-resistant combination
chemotherapy. A variety of chemotherapy protocols using agents not part of initial
treatment regimens include (see "Treatment of relapsed or refractory classic Hodgkin
lymphoma"):

● ICE (ifosfamide, carboplatin, and etoposide) [126]

● Ifosfamide and vinorelbine [127]

● Vinorelbine and gemcitabine [128]

 ● IEP/ABVD/COPP (ifosfamide, etoposide, prednisone/doxorubicin, bleomycin,
vinblastine, dacarbazine/cyclophosphamide, vincristine, procarbazine,
prednisone) [124]

● APE (cytarabine, cisplatin, etoposide) [129]

● EPIC (etoposide, prednisolone, ifosfamide, and cisplatin) [130]

● MIED (high dose methotrexate, ifosfamide, etoposide, and dexamethasone) [131]

● Rituximab (for patients with CD20-positive HL, such as NLPHL) alone or with other
second-line chemotherapy [132]

● Brentuximab vedotin (BV) is a monoclonal antibody that targets CD30 (which is

commonly expressed on HRS cells) conjugated with the antitubulin agent
monomethyl auristatin E. A phase I/II study of BV plus gemcitabine by the COG
(AHD1221, MCT01780662) reported 57 percent CR (24 of 42 patients) within the
first four cycles [133]. The overall CR rate was 67 percent, because 4 of 13 patients
with PR or stable disease later achieved Deauville scores ≤3. BV plus
bendamustine has shown excellent outcomes in adult patients with
refractory/relapsed HL and is now being studied in children with
refractory/relapsed HL [134]. BV for relapsed or refractory HL in adults is
discussed separately. (See "Treatment of relapsed or refractory classic Hodgkin
lymphoma".)

● PD-1 and PDL-1 inhibitors include nivolumab and pembrolizumab. HRS cells
evade immune detection by utilizing the programmed death 1 (PD-1) pathway.
PD-1 ligands are overexpressed in classic HL. PD-1 pathway inhibitors are being
evaluated for refractory/relapsed HL in children. Pembrolizumab is approved by
the US Food and Drug Administration (FDA) for treatment in children with
refractory classic HL or disease that has relapsed after ≥2 lines of therapy. Use of
PD-1 pathway inhibitors in adults is discussed separately. (See "Treatment of
relapsed or refractory classic Hodgkin lymphoma", section on 'PD-1 blockade'.)

If patients develop refractory disease during therapy or relapse <1 year after
completing therapy, second-line chemotherapy is followed by high dose
chemotherapy and subsequent autologous HCT [135,136]. Autologous HCT is
preferred over allogeneic HCT for most patients because of the increased transplant-
related mortality with the latter [137]. Survival rates of 45 to 70 percent and
progression-free survival rates of 30 to 89 percent have been reported. For patients
who fail autologous HCT or have chemotherapy resistant disease, an allogeneic HCT is
the best therapy. (See "Treatment of relapsed or refractory classic Hodgkin
lymphoma" and "Hematopoietic cell transplantation in classic Hodgkin lymphoma".)

Patients with primary refractory disease have poor outcomes with second-line
therapy even if HCT and radiation are employed. As examples:

● A study of 82 patients with refractory HL reported that aggressive second-line

therapy (high dose chemoradiotherapy) followed by autologous HCT resulted in a
five-year overall survival rate of 49 percent [138].

● In another study, patients with primary refractory HL treated with chemotherapy

plus radiation therapy had 10-year event-free and overall survival rates of 41
percent and 51 percent, respectively [124].

● Patients with primary refractory HL that is chemosensitive to standard dose

second-line chemotherapy have superior survival rates (66 percent overall
survival) than those who remain refractory (17 percent overall survival) [139].

Consolidation therapy with BV after autologous HCT may provide benefit for high-risk
refractory/relapse HL patients. In a randomized, controlled phase 3 trial involving 329
adult patients with refractory or unfavorable-risk relapsed HL, patients who received
16 cycles of BV after autologous HCT had improved progression-free survival (hazard
ratio 0.57, 95% CI 0.40-0.81) [140].

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and

regions around the world are provided separately. (See "Society guideline links:
Management of Hodgkin lymphoma".)
SUMMARY AND RECOMMENDATIONS
● Description – Hodgkin lymphoma (HL; formerly, Hodgkin's disease) is a
lymphoma derived from B lymphocytes, composed of malignant cells in a
background of reactive immune cells. There are four subtypes of classic HL (cHL;
listed below) and a distinct entity, nodular lymphocyte predominant HL (NLPHL).

● Epidemiology – HL accounts for approximately 7 percent of childhood cancers.

The incidence in childhood varies by age; HL is exceedingly rare in infants, but the
most common childhood cancer in children 15 to 19 years. (See 'Epidemiology'
above.)

● Pathogenesis – Epstein-Barr virus (EBV) infection is thought to play a role in

some cases. (See 'Biology' above.)

● Presentation – Clinical findings often include painless lymphadenopathy (almost

always above the diaphragm), systemic systems (eg, fever, sweats, weight loss),
and/or mediastinal mass. (See 'Clinical presentation' above.)

● Diagnosis – HL should be suspected in a child or adolescent with painless

lymphadenopathy, systemic symptoms, or respiratory compromise from a
mediastinal mass.

Diagnosis of cHL requires a lymph node biopsy that demonstrates the malignant
Hodgkin/Reed-Sternberg (HRS) cells ( picture 1 and picture 2) in a background
of reactive small lymphocytes, eosinophils, neutrophils, histiocytes, and plasma
cells. HRS cells have reduced expression of most B cell antigens (eg, CD20, CD791,
PAX5), and positive staining for CD30. (See 'Diagnosis' above.)

The corresponding malignant cell in NLPHL is called an LP cell (“popcorn” cell).

● Classification – There are four subtypes of cHL and a distinct category, called
nodular lymphocyte predominant HL (NLPHL) (See 'Histologic classification'
above.):

cHL subtypes are:

 • Nodular sclerosis

• Mixed cellularity

• Lymphocyte depleted

• Lymphocyte rich

● Staging – Disease stage is based on the Ann Arbor staging system with
Cotswolds modifications ( table 3). In children bulky disease is ≥6 cm. (See
'Staging' above.)

● Initial treatment – Treatment should be given at (or in consultation with) a

pediatric cancer center, when possible.

Initial treatment of cHL is risk-stratified by disease stage ( table 4),

constitutional symptoms, and/or bulky disease:

• Low-risk cHL – Children with low-risk cHL (ie, stage IA or IIA cHL without bulky
disease) are usually treated with combination chemotherapy. (See 'Low-risk
disease' above.)

• Intermediate-risk cHL – Intermediate-risk (stage IB or IIB cHL without bulk;

bulky stage IA or bulky stage IIA; stage IIAE, or stage IIIA) cHL is generally
treated with more intensive combination chemotherapy plus RT in selected
patients. (See 'Intermediate-risk disease' above and 'High-risk disease' above.)

• High-risk cHL – For children with high-risk HL (stage IIB with bulky disease,
stage IIIB, or stage IV), we recommend brentuximab vedotin (anti-CD30
antibody conjugate)-containing intensive combination chemotherapy rather
than other regimens (Grade 1B); RT is generally added for bulky or slowly-
responding disease. (See 'High-risk disease' above.)

Management of NLPHL is informed by disease stage and presence of bulky

disease. (See "Treatment of nodular lymphocyte-predominant Hodgkin
lymphoma".)
 ● Relapsed or refractory cHL – Treatment is with non-cross-resistant combination
chemotherapy, brentuximab vedotin, immune checkpoint inhibitors, sometimes
followed by autologous hematopoietic cell transplantation. (See 'Relapsed or
refractory disease' above.)

● Monitoring – Late effects include impaired growth of soft tissue and bones,
thyroid dysfunction, gonadal dysfunction, cardiopulmonary toxicity, second
malignancies, functional impairment, and reduced overall general health. (See
'Late complications' above.)

ACKNOWLEDGMENTS

The UpToDate editorial staff acknowledges Stephen M Gottschalk, MD and Stephen

Simko, MD, who contributed to earlier versions of this topic review.
REFERENCES

1. Ward E, DeSantis C, Robbins A, et al. Childhood and adolescent cancer statistics,

2014. CA Cancer J Clin 2014; 64:83.
2. Smith MA, Seibel NL, Altekruse SF, et al. Outcomes for children and adolescents
with cancer: challenges for the twenty-first century. J Clin Oncol 2010; 28:2625.
3. Ries LA, Kosary CL, Hankey BF, et al. (Eds). SEER cancer statistics review: 1973-199
4. NIH publ no. 97-2789. Bethesda: National Cancer Institute, 1997.
4. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/ca
ncer-facts-figures-2020.html (Accessed on March 23, 2021).
5. Percy CL, Smith MA, Linet M. Lymphomas and reticuloendothelial neoplasms. In: C
ancer Incidence and Survival among Children and Adolescents: United States SEER
Program, 1975-1995, Ries LA, Smith MA, Gurney JG, et al. (Eds), National Cancer In
stitute, Bethesda, MD 1999. p.35.
6. Robison LL, Stoker V, Frizzera G, et al. Hodgkin's disease in pediatric patients with
naturally occurring immunodeficiency. Am J Pediatr Hematol Oncol 1987; 9:189.
7. Straus SE, Jaffe ES, Puck JM, et al. The development of lymphomas in families with
autoimmune lymphoproliferative syndrome with germline Fas mutations and
 defective lymphocyte apoptosis. Blood 2001; 98:194.
8. Latour S, Winter S. Inherited Immunodeficiencies With High Predisposition to
Epstein-Barr Virus-Driven Lymphoproliferative Diseases. Front Immunol 2018;
9:1103.
9. Biggar RJ, Jaffe ES, Goedert JJ, et al. Hodgkin lymphoma and immunodeficiency in
persons with HIV/AIDS. Blood 2006; 108:3786.
10. Yanik EL, Smith JM, Shiels MS, et al. Cancer Risk After Pediatric Solid Organ
Transplantation. Pediatrics 2017; 139.
11. Ferraris AM, Racchi O, Rapezzi D, et al. Familial Hodgkin's disease: a disease of
young adulthood? Ann Hematol 1997; 74:131.
12. Linabery AM, Erhardt EB, Richardson MR, et al. Family history of cancer and risk of
pediatric and adolescent Hodgkin lymphoma: A Children's Oncology Group study.
Int J Cancer 2015; 137:2163.
13. Crump C, Sundquist K, Sieh W, et al. Perinatal and family risk factors for Hodgkin
lymphoma in childhood through young adulthood. Am J Epidemiol 2012;
176:1147.
14. Bräuninger A, Schmitz R, Bechtel D, et al. Molecular biology of Hodgkin's and
Reed/Sternberg cells in Hodgkin's lymphoma. Int J Cancer 2006; 118:1853.
15. Alaggio R, Amador C, Anagnostopoulos I, et al. The 5th edition of the World Health
Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms.
Leukemia 2022; 36:1720.
16. Campo E, Jaffe ES, Cook JR, et al. The International Consensus Classification of
Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee.
Blood 2022; 140:1229.
17. Bazzeh F, Rihani R, Howard S, Sultan I. Comparing adult and pediatric Hodgkin
lymphoma in the Surveillance, Epidemiology and End Results Program, 1988-2005:
an analysis of 21 734 cases. Leuk Lymphoma 2010; 51:2198.
18. Slack GW, Ferry JA, Hasserjian RP, et al. Lymphocyte depleted Hodgkin lymphoma:
an evaluation with immunophenotyping and genetic analysis. Leuk Lymphoma
2009; 50:937.
19. Nachman JB, Sposto R, Herzog P, et al. Randomized comparison of low-dose
involved-field radiotherapy and no radiotherapy for children with Hodgkin's
disease who achieve a complete response to chemotherapy. J Clin Oncol 2002;
20:3765.
20. Kebudi R, Ayan I, Erseven G, et al. Hypertrophic osteoarthropathy and
intrathoracic Hodgkin disease of childhood. Med Pediatr Oncol 1997; 29:578.
21. Atkinson MK, McElwain TJ, Peckham MJ, Thomas PP. Hypertrophic pulmonary
osteoarthropathy in Hodgkin's disease: reversal with chemotherapy. Cancer 1976;
38:1729.
22. Ansari N, Qureshi A, Hall GW. Images in haematology. Hypertrophic pulmonary
osteoarthropathy in mediastinal Hodgkin lymphoma in childhood. Br J Haematol
2010; 150:130.
23. Gobbi PG, Cavalli C, Gendarini A, et al. Reevaluation of prognostic significance of
symptoms in Hodgkin's disease. Cancer 1985; 56:2874.
24. Seymour JF. Splenomegaly, eosinophilia, and pruritus: Hodgkin's disease, or...?
Blood 1997; 90:1719.
25. Olsson H, Brandt L. Relief of pruritus as an early sign of spinal cord compression
in Hodgkin's disease. Acta Med Scand 1979; 206:319.
26. Stefanato CM, Reyes-Mugica M. Masked Hodgkin's disease: the pruriginous
disguise. Pediatr Hematol Oncol 1996; 13:293.
27. Cavalli F. Rare syndromes in Hodgkin's disease. Ann Oncol 1998; 9 Suppl 5:S109.
28. Callahan BC, Coe R, Place HM. Hodgkin disease of the spine presenting as alcohol-
related pain. A case report and review of the literature. J Bone Joint Surg Am 1994;
76:119.
29. Bergmann J, Buchheidt D, Waldherr R, et al. IgA nephropathy and hodgkin's
disease: a rare coincidence. Case report and literature review. Am J Kidney Dis
2005; 45:e16.
30. Sills RH. The spleen and lymph nodes. In: Oski's Pediatrics. Principles and Practice,
4th ed, McMillan JA, Feigin RD, DeAngelis C, Jones MD (Eds), Lippincott, Williams &
Wilkins, Philadelphia 2006. p.1717.
31. Heiberg E, Wolverson MK, Sundaram M, Nouri S. Normal thymus: CT
characteristics in subjects under age 20. AJR Am J Roentgenol 1982; 138:491.
32. Rostock RA, Siegelman SS, Lenhard RE, et al. Thoracic CT scanning for mediastinal
Hodgkin's disease: results and therapeutic implications. Int J Radiat Oncol Biol
Phys 1983; 9:1451.
33. Baker LL, Parker BR, Donaldson SS, Castellino RA. Staging of Hodgkin disease in
children: comparison of CT and lymphography with laparotomy. AJR Am J
Roentgenol 1990; 154:1251.
34. Robertson VL, Anderson CS, Keller FG, et al. Role of FDG-PET in the definition of
involved-field radiation therapy and management for pediatric Hodgkin's
lymphoma. Int J Radiat Oncol Biol Phys 2011; 80:324.
35. Sioka C. The utility of FDG PET in diagnosis and follow-up of lymphoma in
childhood. Eur J Pediatr 2013; 172:733.
36. World health organization classification of tumours of haematopoietic and lymph
oid tissues, revised 4th edition, Swerdlow SH, Campo E, Harris NL, et al. (Eds), IAR
C, Lyon 2017.
37. Mahoney DH Jr, Schreuders LC, Gresik MV, McClain KL. Role of staging bone
marrow examination in children with Hodgkin disease. Med Pediatr Oncol 1998;
30:175.
38. Murphy SB. The national impact of clinical cooperative group trials for pediatric
cancer. Med Pediatr Oncol 1995; 24:279.
39. Corrigan JJ, Feig SA, American Academy of Pediatrics. Guidelines for pediatric
cancer centers. Pediatrics 2004; 113:1833.
40. Foltz LM, Song KW, Connors JM. Hodgkin's lymphoma in adolescents. J Clin Oncol
2006; 24:2520.
41. Hudson MM, Donaldson SS. Hodgkin's disease. In: Principles and Practice of Pedia
tric Oncology, 5th ed, Pizzo PA, Poplack DG (Eds), Lippincott Williams & Wilkins, Phi
ladelphia 2006. p.695.
42. Yung L, Smith P, Hancock BW, et al. Long term outcome in adolescents with
Hodgkin's lymphoma: poor results using regimens designed for adults. Leuk
 Lymphoma 2004; 45:1579.
43. Dörffel W, Rühl U, Lüders H, et al. Treatment of children and adolescents with
Hodgkin lymphoma without radiotherapy for patients in complete remission after
chemotherapy: final results of the multinational trial GPOH-HD95. J Clin Oncol
2013; 31:1562.
44. Donaldson SS, Link MP, Weinstein HJ, et al. Final results of a prospective clinical
trial with VAMP and low-dose involved-field radiation for children with low-risk
Hodgkin's disease. J Clin Oncol 2007; 25:332.
45. Schwartz CL, Constine LS, Villaluna D, et al. A risk-adapted, response-based
approach using ABVE-PC for children and adolescents with intermediate- and
high-risk Hodgkin lymphoma: the results of P9425. Blood 2009; 114:2051.
46. Tebbi CK, Mendenhall NP, London WB, et al. Response-dependent and reduced
treatment in lower risk Hodgkin lymphoma in children and adolescents, results of
P9426: a report from the Children's Oncology Group. Pediatr Blood Cancer 2012;
59:1259.
47. Rühl U, Albrecht M, Dieckmann K, et al. Response-adapted radiotherapy in the
treatment of pediatric Hodgkin's disease: an interim report at 5 years of the
German GPOH-HD 95 trial. Int J Radiat Oncol Biol Phys 2001; 51:1209.
48. Keller FG, Nachman J, Constine L, et al. A phase III study for the treatment of
children and adolescents with newly diagnosed low risk Hodgkin lymphoma (HL).
Blood 2010; 116:A767.
49. Mauz-Körholz C, Hasenclever D, Dörffel W, et al. Procarbazine-free OEPA-COPDAC
chemotherapy in boys and standard OPPA-COPP in girls have comparable
effectiveness in pediatric Hodgkin's lymphoma: the GPOH-HD-2002 study. J Clin
Oncol 2010; 28:3680.
50. Friedman DL, Chen L, Wolden S, et al. Dose-intensive response-based
chemotherapy and radiation therapy for children and adolescents with newly
diagnosed intermediate-risk hodgkin lymphoma: a report from the Children's
Oncology Group Study AHOD0031. J Clin Oncol 2014; 32:3651.
51. Charpentier AM, Friedman DL, Wolden S, et al. Predictive Factor Analysis of
Response-Adapted Radiation Therapy for Chemotherapy-Sensitive Pediatric
Hodgkin Lymphoma: Analysis of the Children's Oncology Group AHOD 0031 Trial.
Int J Radiat Oncol Biol Phys 2016; 96:943.
52. Castellino SM, Pei Q, Parsons SK, et al. Brentuximab Vedotin with Chemotherapy
in Pediatric High-Risk Hodgkin's Lymphoma. N Engl J Med 2022; 387:1649.
53. Kelly KM, Sposto R, Hutchinson R, et al. BEACOPP chemotherapy is a highly
effective regimen in children and adolescents with high-risk Hodgkin lymphoma: a
report from the Children's Oncology Group. Blood 2011; 117:2596.
54. Friedmann AM, Hudson MM, Weinstein HJ, et al. Treatment of unfavorable
childhood Hodgkin's disease with VEPA and low-dose, involved-field radiation. J
Clin Oncol 2002; 20:3088.
55. Hudson MM, Krasin M, Link MP, et al. Risk-adapted, combined-modality therapy
with VAMP/COP and response-based, involved-field radiation for unfavorable
pediatric Hodgkin's disease. J Clin Oncol 2004; 22:4541.
56. Shankar A, Visaduraki M, Hayward J, et al. Clinical outcome in children and
adolescents with Hodgkin lymphoma after treatment with chemotherapy alone -
the results of the United Kingdom HD3 national cohort trial. Eur J Cancer 2012;
48:108.
57. Shankar A, Daw S. Nodular lymphocyte predominant Hodgkin lymphoma in
children and adolescents--a comprehensive review of biology, clinical course and
treatment options. Br J Haematol 2012; 159:288.
58. Kraus MD, Haley J. Lymphocyte predominance Hodgkin's disease: the use of bcl-6
and CD57 in diagnosis and differential diagnosis. Am J Surg Pathol 2000; 24:1068.
59. Mauz-Körholz C, Gorde-Grosjean S, Hasenclever D, et al. Resection alone in 58
children with limited stage, lymphocyte-predominant Hodgkin lymphoma-
experience from the European network group on pediatric Hodgkin lymphoma.
Cancer 2007; 110:179.
60. Appel BE, Chen L, Buxton AB, et al. Minimal Treatment of Low-Risk, Pediatric
Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the Children's
 Oncology Group. J Clin Oncol 2016; 34:2372.
61. Shankar A, Hall GW, Gorde-Grosjean S, et al. Treatment outcome after low
intensity chemotherapy [CVP] in children and adolescents with early stage nodular
lymphocyte predominant Hodgkin's lymphoma - an Anglo-French collaborative
report. Eur J Cancer 2012; 48:1700.
62. Pellegrino B, Terrier-Lacombe MJ, Oberlin O, et al. Lymphocyte-predominant
Hodgkin's lymphoma in children: therapeutic abstention after initial lymph node
resection--a Study of the French Society of Pediatric Oncology. J Clin Oncol 2003;
21:2948.
63. Murphy SB, Morgan ER, Katzenstein HM, Kletzel M. Results of little or no
treatment for lymphocyte-predominant Hodgkin disease in children and
adolescents. J Pediatr Hematol Oncol 2003; 25:684.
64. Metzger ML, Weinstein HJ, Hudson MM, et al. Association between radiotherapy vs
no radiotherapy based on early response to VAMP chemotherapy and survival
among children with favorable-risk Hodgkin lymphoma. JAMA 2012; 307:2609.
65. Appel BE, Chen L, Buxton A, et al. Impact of low-dose involved-field radiation
therapy on pediatric patients with lymphocyte-predominant Hodgkin lymphoma
treated with chemotherapy: a report from the Children's Oncology Group. Pediatr
Blood Cancer 2012; 59:1284.
66. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant
lymphoma. J Clin Oncol 2007; 25:579.
67. Rathore N, Eissa HM, Margolin JF, et al. Pediatric Hodgkin lymphoma: are we over-
scanning our patients? Pediatr Hematol Oncol 2012; 29:415.
68. Thomson AB, Wallace WH. Treatment of paediatric Hodgkin's disease. a balance of
risks. Eur J Cancer 2002; 38:468.
69. Johnston WT, Lightfoot TJ, Simpson J, Roman E. Childhood cancer survival: a report
from the United Kingdom Childhood Cancer Study. Cancer Epidemiol 2010;
34:659.
70. Pinkerton R, Wills RA, Coory MD, Fraser CJ. Survival from haematological
malignancy in childhood, adolescence and young adulthood in Australia: is the
 age-related gap narrowing? Med J Aust 2010; 193:217.
71. Smith RS, Chen Q, Hudson MM, et al. Prognostic factors for children with
Hodgkin's disease treated with combined-modality therapy. J Clin Oncol 2003;
21:2026.
72. Krasin MJ, Rai SN, Kun LE, et al. Patterns of treatment failure in pediatric and
young adult patients with Hodgkin's disease: local disease control with combined-
modality therapy. J Clin Oncol 2005; 23:8406.
73. Kahn JM, Kelly KM, Pei Q, et al. Survival by Race and Ethnicity in Pediatric and
Adolescent Patients With Hodgkin Lymphoma: A Children's Oncology Group Study.
J Clin Oncol 2019; 37:3009.
74. Friedman DI, Wolden S, Constine L, et al. AHOD0031: A Phase III Study of Dose-
Intensive Therapy for Intermediate Risk Hodgkin Lymphoma: A Report From the
Children's Oncology Group. Blood 2010; 116:Abstract 766.
75. Neglia JP, Friedman DL, Yasui Y, et al. Second malignant neoplasms in five-year
survivors of childhood cancer: Childhood cancer survivor study. J Natl Cancer Inst
2001; 93:618.
76. Ng AK, Bernardo MP, Weller E, et al. Long-term survival and competing causes of
death in patients with early-stage Hodgkin's disease treated at age 50 or younger.
J Clin Oncol 2002; 20:2101.
77. Mefferd JM, Donaldson SS, Link MP. Pediatric Hodgkin's disease: pulmonary,
cardiac, and thyroid function following combined modality therapy. Int J Radiat
Oncol Biol Phys 1989; 16:679.
78. Hudson MM, Mertens AC, Yasui Y, et al. Health status of adult long-term survivors
of childhood cancer: a report from the Childhood Cancer Survivor Study. JAMA
2003; 290:1583.
79. Kadan-Lottick NS, Zeltzer LK, Liu Q, et al. Neurocognitive functioning in adult
survivors of childhood non-central nervous system cancers. J Natl Cancer Inst
2010; 102:881.
80. Castellino SM, Geiger AM, Mertens AC, et al. Morbidity and mortality in long-term
survivors of Hodgkin lymphoma: a report from the Childhood Cancer Survivor
 Study. Blood 2011; 117:1806.
81. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult
survivors of childhood cancer. N Engl J Med 2006; 355:1572.
82. Donaldson SS, Hancock SL, Hoppe RT. The Janeway lecture. Hodgkin's disease--
finding the balance between cure and late effects. Cancer J Sci Am 1999; 5:325.
83. Schellong G. Pediatric Hodgkin's disease: treatment in the late 1990s. Ann Oncol
1998; 9 Suppl 5:S115.
84. Chow LM, Nathan PC, Hodgson DC, et al. Survival and late effects in children with
Hodgkin's lymphoma treated with MOPP/ABV and low-dose, extended-field
irradiation. J Clin Oncol 2006; 24:5735.
85. Armstrong GT, Chen Y, Yasui Y, et al. Reduction in Late Mortality among 5-Year
Survivors of Childhood Cancer. N Engl J Med 2016; 374:833.
86. Oeffinger KC, Stratton K, Hudson MM, et al. Risk-adapted therapy for pediatric
Hodgkin lymphoma (HL) results in lower risk of late effects: a report from the
Childhood Cancer Survivor Study (CCSS). J Clin Oncol (ASCO Annual Meeting
Abstracts) 2018; 36:10510.
87. Willman KY, Cox RS, Donaldson SS. Radiation induced height impairment in
pediatric Hodgkin's disease. Int J Radiat Oncol Biol Phys 1994; 28:85.
88. Constine LS, Donaldson SS, McDougall IR, et al. Thyroid dysfunction after
radiotherapy in children with Hodgkin's disease. Cancer 1984; 53:878.
89. Samaan NA, Schultz PN, Yang KP, et al. Endocrine complications after radiotherapy
for tumors of the head and neck. J Lab Clin Med 1987; 109:364.
90. Shafford EA, Kingston JE, Healy JC, et al. Thyroid nodular disease after
radiotherapy to the neck for childhood Hodgkin's disease. Br J Cancer 1999;
80:808.
91. Thibaud E, Ramirez M, Brauner R, et al. Preservation of ovarian function by ovarian
transposition performed before pelvic irradiation during childhood. J Pediatr 1992;
121:880.
92. Williams RS, Littell RD, Mendenhall NP. Laparoscopic oophoropexy and ovarian
function in the treatment of Hodgkin disease. Cancer 1999; 86:2138.
 93. Le Floch O, Donaldson SS, Kaplan HS. Pregnancy following oophoropexy and total
nodal irradiation in women with Hodgkin's disease. Cancer 1976; 38:2263.
94. Radford JA, Lieberman BA, Brison DR, et al. Orthotopic reimplantation of
cryopreserved ovarian cortical strips after high-dose chemotherapy for Hodgkin's
lymphoma. Lancet 2001; 357:1172.
95. Demeestere I, Simon P, Emiliani S, et al. Fertility preservation: successful
transplantation of cryopreserved ovarian tissue in a young patient previously
treated for Hodgkin's disease. Oncologist 2007; 12:1437.
96. Oktay K, Türkçüoğlu I, Rodriguez-Wallberg KA. Four spontaneous pregnancies and
three live births following subcutaneous transplantation of frozen banked ovarian
tissue: what is the explanation? Fertil Steril 2011; 95:804.e7.
97. Ben Arush MW, Solt I, Lightman A, et al. Male gonadal function in survivors of
childhood Hodgkin and non-Hodgkin lymphoma. Pediatr Hematol Oncol 2000;
17:239.
98. Botchan A, Hauser R, Gamzu R, et al. Sperm quality in Hodgkin's disease versus
non-Hodgkin's lymphoma. Hum Reprod 1997; 12:73.
99. Brämswig JH, Riepenhausen M, Schellong G. Parenthood in adult female survivors
treated for Hodgkin's lymphoma during childhood and adolescence: a
prospective, longitudinal study. Lancet Oncol 2015; 16:667.
100. Hancock SL, Donaldson SS, Hoppe RT. Cardiac disease following treatment of
Hodgkin's disease in children and adolescents. J Clin Oncol 1993; 11:1208.
101. Scholz KH, Herrmann C, Tebbe U, et al. Myocardial infarction in young patients
with Hodgkin's disease--potential pathogenic role of radiotherapy, chemotherapy,
and splenectomy. Clin Investig 1993; 71:57.
102. Hicks GL Jr. Coronary artery operation in radiation-associated atherosclerosis:
long-term follow-up. Ann Thorac Surg 1992; 53:670.
103. Adams MJ, Lipsitz SR, Colan SD, et al. Cardiovascular status in long-term survivors
of Hodgkin's disease treated with chest radiotherapy. J Clin Oncol 2004; 22:3139.
104. Bowers DC, McNeil DE, Liu Y, et al. Stroke as a late treatment effect of Hodgkin's
Disease: a report from the Childhood Cancer Survivor Study. J Clin Oncol 2005;
 23:6508.
105. Bhakta N, Liu Q, Yeo F, et al. Cumulative burden of cardiovascular morbidity in
paediatric, adolescent, and young adult survivors of Hodgkin's lymphoma: an
analysis from the St Jude Lifetime Cohort Study. Lancet Oncol 2016; 17:1325.
106. Galper SL, Yu JB, Mauch PM, et al. Clinically significant cardiac disease in patients
with Hodgkin lymphoma treated with mediastinal irradiation. Blood 2011;
117:412.
107. Donaldson SS, Kaplan HS. Complications of treatment of Hodgkin's disease in
children. Cancer Treat Rep 1982; 66:977.
108. Bossi G, Cerveri I, Volpini E, et al. Long-term pulmonary sequelae after treatment
of childhood Hodgkin's disease. Ann Oncol 1997; 8 Suppl 1:19.
109. Marina NM, Greenwald CA, Fairclough DL, et al. Serial pulmonary function studies
in children treated for newly diagnosed Hodgkin's disease with mantle
radiotherapy plus cycles of cyclophosphamide, vincristine, and procarbazine
alternating with cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine.
Cancer 1995; 75:1706.
110. O'Brien MM, Donaldson SS, Balise RR, et al. Second malignant neoplasms in
survivors of pediatric Hodgkin's lymphoma treated with low-dose radiation and
chemotherapy. J Clin Oncol 2010; 28:1232.
111. Bhatia S, Yasui Y, Robison LL, et al. High risk of subsequent neoplasms continues
with extended follow-up of childhood Hodgkin's disease: report from the Late
Effects Study Group. J Clin Oncol 2003; 21:4386.
112. Wolden SL, Lamborn KR, Cleary SF, et al. Second cancers following pediatric
Hodgkin's disease. J Clin Oncol 1998; 16:536.
113. Hudson MM, Poquette CA, Lee J, et al. Increased mortality after successful
treatment for Hodgkin's disease. J Clin Oncol 1998; 16:3592.
114. Lin HM, Teitell MA. Second malignancy after treatment of pediatric Hodgkin
disease. J Pediatr Hematol Oncol 2005; 27:28.
115. Guibout C, Adjadj E, Rubino C, et al. Malignant breast tumors after radiotherapy
for a first cancer during childhood. J Clin Oncol 2005; 23:197.
116. van Leeuwen FE, Klokman WJ, Veer MB, et al. Long-term risk of second malignancy
in survivors of Hodgkin's disease treated during adolescence or young adulthood.
J Clin Oncol 2000; 18:487.
117. Alm El-Din MA, Hughes KS, Finkelstein DM, et al. Breast cancer after treatment of
Hodgkin's lymphoma: risk factors that really matter. Int J Radiat Oncol Biol Phys
2009; 73:69.
118. Henderson TO, Amsterdam A, Bhatia S, et al. Systematic review: surveillance for
breast cancer in women treated with chest radiation for childhood, adolescent, or
young adult cancer. Ann Intern Med 2010; 152:444.
119. Le Deley MC, Leblanc T, Shamsaldin A, et al. Risk of secondary leukemia after a
solid tumor in childhood according to the dose of epipodophyllotoxins and
anthracyclines: a case-control study by the Société Française d'Oncologie
Pédiatrique. J Clin Oncol 2003; 21:1074.
120. Sklar C, Whitton J, Mertens A, et al. Abnormalities of the thyroid in survivors of
Hodgkin's disease: data from the Childhood Cancer Survivor Study. J Clin
Endocrinol Metab 2000; 85:3227.
121. Harker-Murray PD, Drachtman RA, Hodgson DC, et al. Stratification of treatment
intensity in relapsed pediatric Hodgkin lymphoma. Pediatr Blood Cancer 2014;
61:579.
122. Moskowitz CH, Nimer SD, Zelenetz AD, et al. A 2-step comprehensive high-dose
chemoradiotherapy second-line program for relapsed and refractory Hodgkin
disease: analysis by intent to treat and development of a prognostic model. Blood
2001; 97:616.
123. Gorde-Grosjean S, Oberlin O, Leblanc T, et al. Outcome of children and
adolescents with recurrent/refractory classical Hodgkin lymphoma, a study from
the Société Française de Lutte contre le Cancer des Enfants et des Adolescents
(SFCE). Br J Haematol 2012; 158:649.
124. Schellong G, Dörffel W, Claviez A, et al. Salvage therapy of progressive and
recurrent Hodgkin's disease: results from a multicenter study of the pediatric
DAL/GPOH-HD study group. J Clin Oncol 2005; 23:6181.
125. Wirth A, Corry J, Laidlaw C, et al. Salvage radiotherapy for Hodgkin's disease
following chemotherapy failure. Int J Radiat Oncol Biol Phys 1997; 39:599.
126. Cairo MS, Shen V, Krailo MD, et al. Prospective randomized trial between two
doses of granulocyte colony-stimulating factor after ifosfamide, carboplatin, and
etoposide in children with recurrent or refractory solid tumors: a children's cancer
group report. J Pediatr Hematol Oncol 2001; 23:30.
127. Bonfante V, Viviani S, Santoro A, et al. Ifosfamide and vinorelbine: an active
regimen for patients with relapsed or refractory Hodgkin's disease. Br J Haematol
1998; 103:533.
128. Cole PD, Schwartz CL, Drachtman RA, et al. Phase II study of weekly gemcitabine
and vinorelbine for children with recurrent or refractory Hodgkin's disease: a
children's oncology group report. J Clin Oncol 2009; 27:1456.
129. Wimmer RS, Chauvenet AR, London WB, et al. APE chemotherapy for children with
relapsed Hodgkin disease: a Pediatric Oncology Group trial. Pediatr Blood Cancer
2006; 46:320.
130. Shankar A, Hayward J, Kirkwood A, et al. Treatment outcome in children and
adolescents with relapsed Hodgkin lymphoma--results of the UK HD3 relapse
treatment strategy. Br J Haematol 2014; 165:534.
131. Sandlund JT, Pui CH, Mahmoud H, et al. Efficacy of high-dose methotrexate,
ifosfamide, etoposide and dexamethasone salvage therapy for recurrent or
refractory childhood malignant lymphoma. Ann Oncol 2011; 22:468.
132. Schulz H, Rehwald U, Morschhauser F, et al. Rituximab in relapsed lymphocyte-
predominant Hodgkin lymphoma: long-term results of a phase 2 trial by the
German Hodgkin Lymphoma Study Group (GHSG). Blood 2008; 111:109.
133. Cole PD, McCarten KM, Pei Q, et al. Brentuximab vedotin with gemcitabine for
paediatric and young adult patients with relapsed or refractory Hodgkin's
lymphoma (AHOD1221): a Children's Oncology Group, multicentre single-arm,
phase 1-2 trial. Lancet Oncol 2018; 19:1229.
134. LaCasce AS, Bociek G, Sawas A, et al. Brentuximab Vedotin Plus Bendamustine: A
Highly Active Salvage Treatment Regimen for Patients with Relapsed or Refractory
 Hodgkin Lymphoma. Blood (ASH Annual Meeting Abstracts) 2015; 126:3982.
135. Lieskovsky YE, Donaldson SS, Torres MA, et al. High-dose therapy and autologous
hematopoietic stem-cell transplantation for recurrent or refractory pediatric
Hodgkin's disease: results and prognostic indices. J Clin Oncol 2004; 22:4532.
136. Harris RE, Termuhlen AM, Smith LM, et al. Autologous peripheral blood stem cell
transplantation in children with refractory or relapsed lymphoma: results of
Children's Oncology Group study A5962. Biol Blood Marrow Transplant 2011;
17:249.
137. Peniket AJ, Ruiz de Elvira MC, Taghipour G, et al. An EBMT registry matched study
of allogeneic stem cell transplants for lymphoma: allogeneic transplantation is
associated with a lower relapse rate but a higher procedure-related mortality rate
than autologous transplantation. Bone Marrow Transplant 2003; 31:667.
138. Morabito F, Stelitano C, Luminari S, et al. The role of high-dose therapy and
autologous stem cell transplantation in patients with primary refractory Hodgkin's
lymphoma: a report from the Gruppo Italiano per lo Studio dei Linfomi (GISL).
Bone Marrow Transplant 2006; 37:283.
139. Moskowitz CH, Kewalramani T, Nimer SD, et al. Effectiveness of high dose
chemoradiotherapy and autologous stem cell transplantation for patients with
biopsy-proven primary refractory Hodgkin's disease. Br J Haematol 2004; 124:645.
140. Moskowitz CH, Nademanee A, Masszi T, et al. Brentuximab vedotin as
consolidation therapy after autologous stem-cell transplantation in patients with
Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised,
double-blind, placebo-controlled, phase 3 trial. Lancet 2015; 385:1853.

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