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Overview of Hodgkin lymphoma in children and adolescents

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
Literature review current through: Dec 2022. | 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 and African-American children younger than 10 years of age but is increased among White children relative to African Americans 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 in the immunocompetent host".)

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 gender [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.

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Topic 6246 Version 43.0

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