Pathologic Features

CHL is characterized by the presence of mononuclear Hodgkin and multinucleated Reed-Sternberg cells. Hodgkin and Reed-Sternberg cells are usually in the minority, residing in a reactive infiltrate of a variable mixture of nonneoplastic lymphocytes, eosinophils, neutrophils, plasma cells, fibroblasts, and collagen fibers present in response to cytokines produced by the tumor. The Reed-Sternberg cells are large cells with abundant, slightly basophilic cytoplasm and have at least two nuclear lobes or nuclei containing a prominent inclusionlike eosinophilic nucleolus. Diagnostic Reed-Sternberg cells must have at least two nuclei in two separate lobes. Mononuclear variants are termed Hodgkin cells and often have a more intense basophilic cytoplasm. Microdissection techniques have enabled the isolation of Reed-Sternberg cells from frozen sections and the investigation of their lineage commitment. In more than 98% of cases, Reed-Sternberg cells are B cells, as defined by monoclonal immunoglobulin gene rearrangements. Only a few cases have shown clonal T-cell receptor (TCR) gene rearrangement in the Reed-Sternberg cells, suggesting T-cell origin. Reed-Sternberg cells of CHL express the B-lineage antigens CD20 and CD79a in variable proportions, whereas the B-cell–specific activator protein (BSAP), a product of the PAX5 gene, is expressed in about 90% of cases. Reed-Sternberg cells are almost invariably positive for the CD30 antigen and usually express the CD15 antigen, whereas the expression of the epithelial membrane antigen (EMA) is rare. In Epstein-Barr virus (EBV)–positive cases of CHL, the Reed-Sternberg cells express the EBV latency type II pattern latent membrane (LMP) protein 1 and Epstein-Barr nuclear antigen (EBNA) 1, but without EBNA2.

Based on the characteristics of the reactive infiltrate and the morphology of the Reed-Sternberg cells, four subtypes of classic Hodgkin lymphoma are distinguished in the WHO classification : lymphocyte-rich Hodgkin lymphoma (LRHL), lymphocyte-depleted Hodgkin lymphoma (LDHL), mixed-cellularity Hodgkin lymphoma (MCHL), and nodular sclerosis Hodgkin lymphoma (NSHL). The immunophenotypic and genetic features of the Reed-Sternberg cells are identical in these histologic subtypes, whereas they differ in clinical features and association with EBV. CHL is associated with overexpression and an abnormal pattern of cytokines and chemokines and their receptors by Reed-Sternberg cells and the cells of the reactive background. The abnormal cytokine and chemokine expression most likely accounts for the abundant admixture and pattern of inflammatory cells in CHL lesions as well as for distinct clinical features.

The NSHL subtype is characterized by a nodal growth pattern with collagen bands that surround at least one nodule, the formation of clusters of Reed-Sternberg cells, and so-called lacunar cells (mononuclear Hodgkin cells with only moderately prominent nucleoli). NSHL can be grade 1 or 2, mainly depending on the number of Reed-Sternberg cells in distinct nodules. The EBV-encoded LMP1 antigen is less commonly expressed than in other subtypes.

The MCHL subtype is characterized by scattered classic Reed-Sternberg cells in a diffuse or vaguely nodular mixed inflammatory background without sclerosis. Partial involvement of the lymph node can be observed in MCHL, described as interfollicular disease. The EBV-encoded LMP1 antigen is more commonly expressed than in NSHL.

The LRHL and LDHL subtypes are relatively rare in children. The LRHL subtype contains scattered Reed-Sternberg cells and a nodular or diffuse background of small lymphocytes but with an absence of neutrophils and eosinophils. The LDHL subtype is a diffuse form of CHL, rich in Reed-Sternberg cells and/or depleted of nonneoplastic lymphocytes and is often sarcomatoid in appearance.

In some patients, distinction between true Hodgkin lymphoma and certain subtypes of NHL can be difficult. Grey-zone lymphomas are those that do not fit into a single disease entity. The WHO classification includes the entity of “B-cell lymphoma, unclassifiable with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classic Hodgkin lymphoma,” although this entity is exceptionally rare in children.

Molecular and Cellular Biology

The cell of origin of the malignant cells in CHL was long a matter of controversy because of the low incidence of Reed-Sternberg cells in the tumors and their unusual immunophenotype in that they lack expression of immunoglobulins and other B-cell markers; rather, they express markers characteristic of dendritic cells, granulocytes, monocytes, and T cells. However, the identification of immunoglobulin gene rearrangement and somatic hypermutation in microdissected Reed-Sternberg cells in almost all cases of CHL has demonstrated that these cells derive from postgerminal B cells. In addition these studies have demonstrated that about 25% of CHL cases carry crippling immunoglobulin-gene rearrangements that destroy the function of the immunoglobulin protein. These nonfunctional rearrangements typically induce rapid apoptosis in normal B cells, suggesting that Hodgkin lymphoma may originate from germinal-center B cells that have escaped apoptosis. Analysis of TCR rearrangements has shown that despite the common expression of T-cell markers, CHL originates from T cells in only 1% to 2% of cases.

In NLPHL, the malignant popcorn cells show expression of B-cell markers such as CD20 and CD79a, suggesting a B-cell origin for these tumors as well. As in CHL, the analysis of immunoglobulin genes in microdissected tumors has shown clonal and somatically mutated gene rearrangements. In addition, 50% of cases have shown evidence of ongoing somatic hypermutation, which strongly suggests that they derive from germinal center B cells.

Epidemiology and Causative Factors

The epidemiology of Hodgkin lymphoma is complex, with variation across geographic regions and with age, sex, and socioeconomic status. Data from cancer incidence surveys conducted in five continents have suggested that Hodgkin lymphoma has a bimodal peak at ages 15 to 34 years and a second peak in those older than 60 years. In Asian populations the overall incidence is only half that of the incidence in Europe. In all regions, Hodgkin lymphoma occurs rarely in children younger than 5 years of age ( Fig. 53-2 ).

Age- and gender-specific incidence rates (per 100,000) of Hodgkin lymphoma during childhood in Germany, 2000 to 2004.

(Modified from Kaatsch P, Spix C: Annual report, 2005: German Childhood Cancer Registry , Mainz, Germany, 2007, Institut für Medizinische Biometrie, Epidemiologie, und Informatik, p 52.)

Hodgkin lymphoma occurring in patients younger than 15 years of age, referred to as childhood Hodgkin lymphoma, has several unique features compared with the more common disease of older adolescents and young adults. In childhood disease there is a 2 to 3 : 1 male preponderance, whereas in older patients the disease is almost equal in males and females. Within the younger age group, mixed cellularity and nodular lymphocyte-predominant histologies are more common. In addition, in childhood Hodgkin lymphoma increasing family size and lower socioeconomic status are risk factors for disease. Conversely, in Hodgkin lymphoma in adolescents and young adults, higher socioeconomic status and smaller family size are risk factors for disease.

The role of EBV as an etiologic agent for Hodgkin lymphoma has been the source of much study. In 1966 MacMahon was the first to suggest an infectious cause of Hodgkin lymphoma, and in 1974 Rosdahl and colleagues reported an increased risk of Hodgkin lymphoma in people with a history of infectious mononucleosis. Molecular studies identified monoclonal EBV genomes in Reed-Sternberg cells, implying that they were infected before malignant transformation. Subsequent studies showed EBV genome sequences associated with Reed-Sternberg cells in 59% of cases. The proportion of EBV-positive Hodgkin lymphoma cases varies, how­ever, according to geographic region, age, and histologic subtype. The proportion of EBV-positive Hodgkin lymphoma cases is higher in children than adults. It is most prevalent in mixed cellularity histology and more common in boys. The incidence is higher in the developing world including parts of Africa, Asia, and South America, with an incidence of EBV-positive Hodgkin lymphoma as high as 90% in Peru.

Familial aggregation of Hodgkin lymphoma was first described by Razis and coworkers in 1959 and is now well documented. The familial risk of Hodgkin lymphoma ranks among the highest in the population-based Swedish Family Cancer Database. In an analysis of 28 reports of familial Hodgkin lymphoma there is only one major peak between 15 and 34 years of age for familial Hodgkin lymphoma instead of the classic bimodal age distribution of sporadic Hodgkin lymphoma. This corresponds to the findings of two large studies of an increased sevenfold risk in siblings of cases diagnosed at ages younger than 45 and 35 years of age, respectively, but little or no increased risk in siblings of cases diagnosed at older ages. Strong evidence for a role for genetic susceptibility was provided by the finding that monozygotic twins of patients with Hodgkin lymphoma have a 99-fold increased risk, whereas no increased risk in dizygotic twins was observed.

Familial aggregation of Hodgkin lymphoma may in part reflect inherited abnormalities of the immune response. A familial or personal history of autoimmune conditions and sarcoidosis is associated with an increased risk for Hodgkin lymphoma. A 51-fold increased risk for Hodgkin lymphoma was found in kindreds predisposed to autoimmune lymphoproliferative syndrome, a disorder of lymphocyte homeostasis usually associated with germline FAS gene mutations. In patients with ataxia-telangiectasia mutation (ATM), the risk of Hodgkin lymphoma was increased, but its risk was much lower than the risk of NHL. In 1975 Svejgaard and coworkers first described an association of certain human leukocyte antigen (HLA) loci with an increased risk of Hodgkin lymphoma, suggesting a disease susceptibility gene within or near the histocompatibility region on chromosome 6. Since then, numerous studies have confirmed the association of particular HLA loci in the susceptibility to Hodgkin lymphoma, including HLAs A1, B5, B8, B15, B27, B35, and B37. In a large study on familial Hodgkin lymphoma, Chakravarti and colleagues have found strong evidence for a recessive mode of inheritance for susceptibility to Hodgkin lymphoma, and approximately 60% of associations were caused by an HLA-linked susceptibility gene. Recent genetic studies have identified disruption of KLHDC8B in the germline of a family with several cases of Hodgkin lymphoma and a germline frameshift mutation in the NPAT gene in a family with four cases of NLPHL. Finally a genome-wide association study has identified risk loci at 2p16.1 ( REL ), 8q24.21 ( PVT1 ), and 10p14 ( GATA3 ) and confirmed the strong HLA association with this disease.

Clinical Characteristics

The most common clinical presentation of Hodgkin lymphoma in children and adolescents is a persistently enlarged node in the cervical or supraclavicular region. Characteristically the lymph nodes involved with Hodgkin lymphoma are not painful and have a “rubbery” firmness on palpation. Enlarged nodes have often been present for weeks or months, increasing and decreasing in size irrespective of whether antibiotic therapy has been given. Although the majority of patients have painless cervical adenopathy, the clinical presentation varies considerably, ranging from life-threatening airway compression to the coincidental detection of an enlarged node during an otherwise routine examination. Approximately 80% of children have disease in one or both sides of the upper or lower neck. Of those with cervical adenopathy, more than two thirds have intrathoracic disease, most commonly in the anterosuperior mediastinum, paratracheal, and tracheobronchial lymph node groups. Pulmonary parenchymal involvement is rarely observed in the absence of hilar disease. Pleural effusions are uncommon; they are usually an indication of lymphatic obstruction from bulky central disease rather than a sign of advanced-stage disease. Pericardial effusion may occur in cases with pericardial involvement and occurs most often in the setting of bulky mediastinal disease. Hodgkin lymphoma has a strong tendency for contiguous spread along adjacent lymph-node regions. Although about 30% of patients have supradiaphragmatic and infradiaphragmatic disease, Hodgkin lymphoma limited to infradiaphragmatic sites is rare.

Systemic symptoms including fatigue and anorexia are common in patients with Hodgkin lymphoma. At the time of diagnosis, approximately 30% of patients have constitutional signs referred to as B symptoms and defined as the presence of fever (temperature higher than 38° C [100.4° F]) for 3 consecutive days, drenching night sweats and unexplained body weight loss of 10% or more over the preceding 6 months. Classically the fever associated with Hodgkin lymphoma, called the Pel-Epstein fever, occurs in the evening and becomes more pronounced with time. Severe and unexplained pruritus is associated with Hodgkin lymphoma, sometimes preceding the development of adenopathy. A poorly understood and relatively unusual sign of Hodgkin lymphoma is pain at the sites of disease with alcohol ingestion.

Laboratory findings are often nonspecific with mild anemia and elevated erythrocyte sedimentation rate (ESR) being the most common findings. Nonspecific hematologic laboratory findings include neutrophilia, monocytosis, lymphopenia, and eosinophilia. Acute-phase reactants including C-reactive protein, ferritin, and serum copper may be elevated. High levels of alkaline phosphatase can be associated with bone involvement.

Rarely patients with Hodgkin have findings suggestive of paraneoplastic syndromes such as nephritic syndrome, polymyositis, idiopathic cholestasis and autoimmune hemolytic anemia, neutropenia, and thrombocytopenia, or combinations of these. Limbic encephalitis or subacute cerebellar degeneration have also been reported as very rare paraneoplastic syndromes in patients with Hodgkin lymphoma.

At the time of diagnosis patients may exhibit altered immune function characterized by reduced cellular immunity, whereas humoral immunity is usually relatively intact. The nature of the immune defect is unclear. The severity of the impairment increases with advanced stage, disease progression, and recurrence and after treatment with radiotherapy and chemotherapy. T-cell deficits may persist for a prolonged period in successfully treated patients.

Diagnosis and Staging

Biopsy to provide pathologic tissue for examination is required for the diagnosis of Hodgkin lymphoma. Excisional biopsy of an enlarged node is preferred. Samples from needle biopsies are often insufficient for the diagnosis of Hodgkin lymphoma because of the importance of the information provided by the nodal architecture and background stroma, as well as the need to identify the relatively rare Reed-Sternberg cell. In a case series, one third of children who ultimately were diagnosed with Hodgkin lymphoma and who underwent core needle biopsies of their mediastinal masses were not able to be diagnosed from these initial samples. Needle biopsy should be restricted to situations in which surgery and general anesthesia may carry undue risks for the patient. If needle biopsy is performed, multiple biopsy samples should be taken to augment diagnostic potential.

The purpose of a staging evaluation is to identify all sites and characteristics of Hodgkin lymphoma in each patient to permit accurate stratification of therapy based on risk, the definition of areas to be included in potential radiation fields, and to inform follow-up imaging studies. Table 53-2 gives an overview of suggested evaluations.

A plain film of the chest is useful in providing preliminary information about mediastinal involvement and is an essential evaluation in a patient who will undergo anesthesia for cervical node biopsy ( Fig. 53-3 ). Computed tomography (CT) of the neck, chest, abdomen, and pelvis are standard initial staging evaluations. In the past, imaging of the neck was considered not necessary given the ability to detect cervical node by physical examination. Imaging of the neck, however, can be of significant importance to current care, because it allows for the most accurate radiation field planning, avoiding potential overtreatment of the neck, and providing baseline data for the measurement of disease response. CT of the chest provides detailed information about sites of disease involvement including the mediastinum, pulmonary parenchyma, pleura, and pericardium. Sites of disease in the abdomen and pelvis are visualized with CT done with oral and intravenous (IV) contrast. Alternatively, magnetic resonance imaging (MRI) or ultrasound can also be used for staging abdominal and pelvis disease.

Chest x-ray of a patient with Hodgkin lymphoma and involvement of the mediastinal nodes and hilum.

Functional nuclear imaging is an important component to initial staging though perhaps has an even more significant role in assessment of disease response (see later). Gallium-67 imaging has largely been replaced by 18-fluorodeoxyglucose positron emission tomography (FDG-PET) because of increased sensitivity and specificity. Increased F-FDG uptake in lymphoma is based on elevated glycolysis and the longer residence time of ¹⁸ F-FDG in malignant cells compared with most normal tissues. Numerous studies in adults with Hodgkin lymphoma have demonstrated that PET is able to detect an additional number of Hodgkin lymphoma lesions compared with conventional imaging studies, in particular CT and bone marrow biopsy, resulting in a modification of staging in 15% to 20% of patients, with an impact on disease management in 5% to 15% of cases. The data in children are more limited. A review of a single-center experience showed that the findings from the diagnostic FDG-PET were more sensitive than conventional imaging and that the findings altered the involved-field radiation treatment fields in 17% of patients. Prospective studies are required to assess whether FDG-PET done at the time of diagnosis has on impact on outcome or on treatment burden.

Historically, surgical staging including splenectomy was considered standard for patients with Hodgkin lymphoma. Staging splenectomy is associated with significant risks. In the German-Austrian experience of 1181 children with Hodgkin lymphoma, the survival was poorer for children younger than age 10 years because of episodes of infection and death caused by sepsis in splenectomized children. With the availability of cross-sectional imaging techniques, routine staging laparotomy has now been abandoned. In the relatively rare circumstance of imaging findings that are ambiguous in defining disease involvement or noninvolvement, and when this information affects therapeutic decision making and in particular radiation fields, then staging biopsy may still be warranted.

Until recently bone marrow biopsy has been considered a standard component of the initial staging evaluation for any child with cytopenias at presentation and all patients except for those with stage 1A or 2A disease. Retrospective investigations have suggested that the impact of the findings from diagnostic bone marrow biopsies had a minimal effect on patient-risk assignment and subsequent therapy. FDG-PET is a sensitive and specific method for detection of bone marrow disease. Two recent studies provide data to support the idea that FDG-PET can replace bone marrow biopsies for staging purposes in an analogous fashion to cross-sectional imaging of the abdomen replacing staging laparotomy in the past.

The Ann Arbor staging classification for Hodgkin lymphoma, adopted in 1971, was based on the recognized orderly spread of the disease between contiguous lymph nodes, which predominates until late in the course of the disease ( Table 53-3 ). The distinct lymph node regions recognized by the Ann Arbor classification system are shown in Figure 53-4 . The substage classifications A, B, and E amend each stage based on distinct features. Stage A designates asymptomatic disease; B indicates the presence of any one of the three B symptoms as defined in Table 53-3 ; and extralymphatic disease is designated as E, referring to limited extranodal extensions that easily can be encompassed within a radiotherapy portal. Extralymphatic disease is further designated as L (lung), P (pleura), and O (osseous) according to this system. The decision to classify extralymphatic disease either as substage E or as stage IV is based on the clinician’s judgment and often depends on whether the extralymphatic disease can be adequately covered in a radiotherapy treatment portal. Multiple E lesions are automatically considered to be stage IV.

Distinct nodal regions according to the Ann Arbor staging classification for Hodgkin lymphoma.

(Modified from Dörffel W, Schellong G: Morbus Hodgkins. In Gadner H, Gaedicke G, Niemeyer C, Ritter J, editors: Paediatrische Haematologie und Onkologie , Heidelberg, Germany, 2006, Springer, p. 770–776.)

Treatment

Centers treating children with Hodgkin lymphoma should have extensive experience and a dedicated multidisciplinary team, including a pediatric surgeon, radiation oncologist, pediatric oncologist, pathologist, and diagnostic radiologist. If such a team is not available at the facility at which the child is initially seen, prompt referral to a comprehensive childhood cancer center is essential.

Treatment and Outcomes.

In the 1960s extended-field radiation with doses of 35 to 44 Gy were shown to be curative in a significant portion of patients with Hodgkin lymphoma. In children, the negative sequelae of high-dose extended-field radiation quickly became apparent. Soon thereafter the MOPP combination was created by Devita and coworkers to treat patients with Hodgkin lymphoma. The basic rationale was to combine single drugs with proven efficacy but different mechanisms of action and resistance that had few overlapping toxicities to maximize antitumor effect and limit side effects caused by use of moderate doses of the individual drugs. The second important combination chemotherapy regimen for the treatment of Hodgkin lymphoma was doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD), which was developed by Bandanna and coworkers. Variations of these two regimens have formed the cornerstone of almost all subsequent chemotherapy regimens.

Combined-modality therapy using both chemotherapy and radiation has emerged as the standard of care for most children and adolescents diagnosed with Hodgkin lymphoma. The use of six cycles of MOPP chemotherapy combined with involved-field radiotherapy (IFRT) was pioneered by the Stanford investigators in children with pathologically staged disease. This pivotal trial has served as the model for combined-modality treatment programs in children.

Subsequent studies evaluated regimens with modifications incorporated designed to minimize risks of late effects while maintaining efficacy. Changes have included both the substitution of drugs the use of which is associated with lower risks of specific long term toxicities as well as limiting the cumulative dose of drugs that are associated with risks of late sequelae in a dose dependent manner. Some modifications have been gender specific. Table 53-5 gives an overview of chemotherapy combinations. With most of these multiagent combinations, comparable high disease-free survival rates have been achieved.

TABLE 53-5

Combination Chemotherapy Courses for Treatment of Hodgkin Lymphoma

Course	Drugs	Dosage and Route	Days
MOPP	Mechlorethamine	6.0 mg/m 2 , IV	1, 8
	Vincristine (Oncovin)	1.4 mg/m 2 , IV	1, 8
	Procarbazine	100 mg/m 2 , PO	1-15
	Prednisone	40 mg/m 2 , PO	1-15
MOPP Derivatives
COPP	Cyclophosphamide	600 (500) mg/m 2 , IV	1, 8
	Vincristine (Oncovin)	1.4 mg/m 2 , IV (max 2 mg)	1, 8
	Procarbazine	100 mg/m 2 , PO	1-15
	Prednisone	40 mg/m 2 , PO	1-15
COMP	Cyclophosphamide	600 mg/m 2 , IV	1, 8
	Vincristine (Oncovin)	1.4 mg/m 2 , IV (max 2 mg)	1, 8
	Methotrexate	40 mg/m 2 , IV	1, 8
	Prednisone	40 mg/m 2 , PO	1-15
COP	Cyclophosphamide	600 mg/m 2 , IV	1, 8
	Vincristine (Oncovin)	1.4 mg/m 2 , IV (max 2 mg)	1, 8
	Procarbazine	100 mg/m 2 , PO	1-14
ABVD	Doxorubicin (Adriamycin)	25 mg/m 2 , IV	1, 15
	Bleomycin	10 U/m 2 , IV	1, 15
	Vinblastine	6 mg/m 2 , IV	1, 15
	Dacarbazine	375 mg/m 2 , IV	1, 15
MOPP-ABVD Hybrids and Derivatives
OPPA	Vincristine (Oncovin)	1.5 mg/m 2 , IV (max 2 mg)	1, 8, 15
	Procarbazine	100 mg/m 2 , PO	1-15
	Prednisone	60 mg/m 2 , PO	1-15
	Doxorubicin (Adriamycin)	40 mg/m 2 , IV	1, 15
OPA	Vincristine (Oncovin)	1.5 mg/m 2 , IV (max 2 mg)	1, 8, 15
	Prednisone	60 mg/m 2 , PO	1-15
	Doxorubicin (Adriamycin)	40 mg/m 2 , IV	1, 15
OEPA	Vincristine (Oncovin)	1.5 mg/m 2 , IV (max 2 mg)	1, 8, 15
	Etoposide	125 mg/m 2 , IV	3-6
	Prednisone	60 mg/m 2 , PO	1-15
	Doxorubicin (Adriamycin)	40 mg/m 2 , IV	1, 15
ChlVPP	Chlorambucil	6 mg/m 2 , PO	1-14
	Vinblastine	6 mg/m 2 , PO	1, 8
	Procarbazine	100 mg/m 2 , PO	1-14
	Prednisone	40 mg/m 2 , PO	1-14
VAMP	Vinblastine	6 mg/m 2 , IV	1, 15
	Doxorubicin (Adriamycin)	25 mg/m 2 , IV	1, 15
	Methotrexate	20 mg/m 2 , IV	1, 15
	Prednisone	40 mg/m 2 , PO	1-14
VBVP	Vinblastine	6 mg/m 2 , IV	1, 8
	Bleomycin	10 mg/m 2 , IV	1
	Etoposide (VP-16)	100 mg/m 2 , IV	1-5
	Prednisolone	40 mg/m 2 , PO	1-8
COPP-ABV	Cyclophosphamide	600 mg/m 2 , IV	0
	Vincristine (Oncovin)	1.4 mg/m 2 , IV	0
	Procarbazine	100 mg/m 2 , PO	0-6
	Prednisolone	40 mg/m 2 , PO	0-13
	Doxorubicin (Adriamycin)	35 mg/m 2 , IV	7
	Bleomycin	10 U/m 2 , IV	7
	Vinblastine	6 mg/m 2 , IV	7
ABC	A
	Cytarabine	3 g/m 2 , IV over 3 hr, q12h	0, 1
	Etoposide	200 mg/m 2 , IV over 1 hr, q12h	0, 1
	G-CSF	5 µg/kg, SC	Starting on day 2
	B
	COPP-ABVD	See COPP/ABVD	21-27
	G-CSF	5 µg/kg, SC	Starting on day 28
	C
	Vincristine	1.4 mg/m 2 , IV	42
	Cyclophosphamide	1200 mg/m 2 , IV	42-43
	Doxorubicin	25 mg/m 2 /day, continuous infusion	42-44
	Methylprednisolone	250 mg/m 2 , IV q6h	42
	Prednisone	60 mg/m 2 , PO	43-46
	G-CSF	5 µg/kg, SC	Starting on day 46
BEACOPP	Bleomycin	10 U/m 2 , IV	8
	Etoposide	200 mg/m 2 , IV	1-3
	Doxorubicin (Adriamycin)	35 mg/m 2 , IV	1
	Cyclophosphamide	1200 mg/m 2 , IV	1
	Vincristine (Oncovin)	2 mg/m 2 (max 2 mg), IV	8
	Procarbazine	100 mg/m 2 , PO	1-7
	Prednisone	40 mg/m 2 , PO	1-14
DBVE	Doxorubicin	25 mg/m 2 , IV	1, 15
	Bleomycin	10 mg/m 2 , SC	1, 15
	Vincristine	1.5 mg/m 2 (max,] 2 mg), IV	1, 15
	Etoposide	100 mg/m 2 , IV over 1 hr	1-5
Stanford V	Mechlorethamine	6 mg/m 2 , IV	1
	Vinblastine	6 mg/m 2 , IV	1, 15
	Doxorubicin	25 mg/m 2 , IV	1, 15
	Etoposide	60 mg/m 2 , IV	15, 16
	Vincristine	1.4 mg/m 2 (max 2 mg), IV	8, 22
	Bleomycin	5 U/m 2 , IV	8, 22
	Prednisone	40 mg/m 2 , PO	Every other day
ABVD-PC	Doxorubicin (Adriamycin)	25 mg/m 2 IV	1, 2
	Bleomycin	10 IU/m 2 * IV	1, 8
	Vincristine	1.4 mg/m 2 IV (max 2.8)	1, 8
	Etoposide	125 mg/m 2 IV	1-5
	Prednisone	40 mg/m 2 , PO	1-7
	Cyclophosphamide	800 mg/m 2 IV	1
	G-CSF	5 µg/kg SC	Starting day 6

 

G-CSF, Granulocyte colony-stimulating factor; IV, intravenous; PO, per os; SC, subcutaneous

* Modified to 5 IU/m ² on day 0 mid-study.

The balance of efficacy and late risk of the combined-modality of chemotherapy and radiotherapy adopted by the German-Austrian study group has been investigated over a series of trials ( Table 53-6 ). Modifications investigated have included reduction of the cumulative dose of alkylating agents and replacement of mechlorethamine of MOPP with doxorubicin (vincristine [Oncovin], prednisone, procarbazine, and doxorubicin [OPPA]) and cyclophosphamide (cyclophosphamide, vincristine [Oncovin], procarbazine, and prednisone [COPP]); reduction of radiotherapy (volume, dose, and number of patients who receive radiotherapy); and replacement of procarbazine by etoposide for boys. The seventh of the sequential studies built on findings of the previous six trials. In this study the primary aim was to evaluate modifications of therapy to maintain good outcomes for boys but to do so with less gonadotoxic therapy. In this study procarbazine was replaced with higher dose etoposide in the first two cycles and with dacarbazine in the subsequent two to four cycles. The outcomes for boys and girls on this study were superimposable, supporting the efficacy of this regimen.

TABLE 53-6

Development of Treatment Strategy and Outcome for Children and Adolescents with Hodgkin Lymphoma in Seven Sequential Trials of the German-Austrian Multicenter Study Group

Study	No. of Patients (EFS)	Therapy Group 1			Therapy Group 2			Therapy Group 3
		Stages (% of patients) EFS	Chemotherapy	Radiotherapy	Stages (% of patients) EFS	Chemotherapy	Radiotherapy	Stages (% of patients) 5-yr EFS	Chemotherapy	Radiotherapy
DAL-HD78	170 (92%)	I, IIA (43%) 95%	OPPA ×2	EF, 36-40 Gy	>IIA (57%) 89%	OPPA ×2 COPP ×4	EF, 36-40 Gy	Included in TG2
DAL-HD82	203 (96%)	I, IIA (49%) 99%	OPPA ×2	IF, 35 Gy	IIB, IIIA (26%) 96%	OPPA ×2 COPP ×2	IF, 30 Gy *	IIIB, IV (25%) 87%	OPPA ×2 COPP ×4	25 Gy *
DAL-HD85	103 (77%)	I, IIA (58%) 59%	OPA ×2	IF, 35 Gy	IIB, IIIA (20%) 62%	OPPA ×2 COMP ×2	IF, 30 Gy *	IIIB, IV (22%) 62%	OPA ×2 COMP ×4	25 Gy *
DAL-HD87	204 (85%)	I, IIA (51%) 84%	OPA ×2	IF, 30 Gy *	IE, IIEA IIB, IIIA (17%) 82%	OPPA ×2 COPP ×2	25 Gy *	IIIB, IV (28%) 89%	OPPA ×2 COPP ×4	25 Gy *
DAL-HD90	578 (91%)	I, IIA (46%) 94%	OPPA ×2 † OEPA ×2 ‡	IF, 25 Gy *	IE, IIEA IIB, IIIA (21%) 93%	OPPA ×2 † COPP ×2 OEPA ×2 ‡ COPP ×2	25 Gy *	IIEB, IIIEA IIIB, IV (31%) 86%	OPPA ×2 † COPP ×4 OEPA ×2 ‡ COPP ×4	20 Gy *
GPOH-HD95	1018 (88%)	I, IIA (40%) 94%	OPPA ×2 † OEPA ×2 ‡	CR: no RT (28%) § ; non-CR: IF, 20 Gy *	IE, IIEA IIB, IIIA (26%), 87%	OPPA ×2 † COPP ×2 OEPA ×2 ‡ COPP ×2	CR: no RT (19%) § ; non-CR: IF 20 Gy *	IIEB, IIIEA; IIIB, IV (33%) 83%	OPPA ×2 † COPP ×4 OEPA ×2 ‡ COPP ×4	CR: no RT (17%) § ; non-CR: IF, 20 Gy *
GPOH-HD02	573 (89%)	1A/B, IIA (34%) 92%	OPPA ×2 † OE*PA ×2 ‡	CR: no RT (33%) § ; non-CR: IF, 20 Gy *	IE, IIEA, IIB, IIIA (24%) 93%	OPPA ×2 † COPP ×2 OEPA ×2 ‡ COPDAC ×2	20 Gy *	IIEB, IIIEA; IIIB, IV (42%) 87%	OPPA, ×2 † COPP ×4 OEPA ×2 ‡ COPDAC ×4	20 Gy *

 

COMP, Cyclophosphamide, vincristine (Oncovin), methotrexate, and prednisone; COPDAC, cyclophosphamide, vincristine (Oncovin), prednisone, and dacarbazine; COPP, cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone; CR, complete remission; DAL-HD, Deutsche Arbeitsgemeinschaft fir Leukamiefarschung-Hodgkin disease; EF, extended field; EFS, event-free survival; GPOH-HD, German Society for Pediatric Oncology and Hematology–Hodgkin disease; IF, involved field; OEPA, vincristine (Oncovin), etoposide, prednisone, and doxorubicin (Adriamycin); OE*PA, vincristine (oncovin) etoposide, prednisone and doxorubicin (adriamycin); OPA, vincristine (Oncovin), prednisone, doxorubicin (Adriamycin); OPPA , vincristine (Oncovin), prednisone, procarbazine, and doxorubicin (Adriamycin); RT, radiotherapy; TG2, therapy group 2.

* Boost to residual tumor to 30-35 Gy.

† Female.

‡ Male.

§ Percentage of patients in the treatment subgroup who did not receive radiotherapy.

The second strategy that is of critical importance in trying to maximize efficacy and minimize toxicity is the stratification of treatment intensity based on the patient’s risk for relapse. Cooperative group trials of pediatric and adolescent Hodgkin lymphoma have generally divided patients into low-, intermediate-, and high-risk groups (see Table 53-4 ). In addition to stratification by stage, studies have also evaluated modifications of therapy based on early disease response. Many reports from these therapeutic studies are confined to a distinct risk group of patients. Comparisons among trials confined to patient subsets need to be done with caution, because the risk group definitions vary both based on the patient characteristics at the time of initial staging and the criteria of disease response.

Table 53-7 summarizes treatment strategy and results of therapeutic studies in the patient subgroup defined as low risk. Patients at low risk in general are those with stage I and II disease without B symptoms and without bulky disease. These patients have been shown to have excellent outcomes with sequential trials using two to four cycles of multiagent chemotherapy and low-dose involved-field radiation. These regimens have been designed to minimize exposure to anthracyclines, alkylators, and epipodophyllotoxins in order to minimize risks of cardiac dysfunction, infertility, and secondary acute myelogenous leukemia (AML), respectively.

TABLE 53-7

Combined-Modality Treatment Strategy and Results for Low-Risk Patients with Hodgkin Lymphoma in Selected Multicenter Trials

Group or Institution	No. of Patients	Stage	Chemotherapy *	Radiation (Gy), Field	EFS or RFS Overall (%)	Survival (%)
GPOH-HD95	281	I, IIA	Female: OPPA ×2 Male: OEPA ×2	CR † : no RT (22%); non-CR: IF, 20 Gy; residual tumor, 30-35 Gy	94	NR
GPOH-HD02	195	IA/B, IIA	Female: OPPA ×2 Male: OE*PA ‡ ×2	CR † : no RT (33%); no-CR: IF, 20 Gy; residual tumor, 30-35 Gy	92	99
French Society of Pediatric Oncology	202	I, II I, II	4 VBVP, good responders; 4 VBVP + 1 or 2 OPPA, poor responders	20, IF 20, IF	91 and 78 §	97.5
Stanford-St. Jude-Boston Consortium	88	1, II ‖	4 VAMP	CR post 2 cycles, no IF No CR: 25.5 Gy	90 (2 yr)	99
CCG5942	294	I + IIA without ¶	COPP-ABV × 4	CR, ** random: IF 21 Gy vs. no RT; PR, 21 Gy IF	95 (3 yr)	100
POG9226	51	I, IIA, IIIA1	4 DBVE	25, IF	91(6 yr)	98

 

CCG, Children’s Cancer Study Group; COPP-ABV, cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone–doxorubicin (Adriamycin), bleomycin, and vinblastine; CR, complete remission; DBVE, doxorubicin, bleomycin, vincristine, etoposide; EFS, event-free survival; GPOH-HD, German Society for Pediatric Oncology and Hematology–Hodgkin disease; IF, involved field; NR, not reported; OEPA, vincristine (Oncovin), etoposide, prednisone, and doxorubicin (Adriamycin); OPPA, vincristine (Oncovin), prednisone, procarbazine, and doxorubicin (Adriamycin); POG, Pediatric Oncology Group; PR, partial remission; RFS, relapse-free survival; RT, radiotherapy; VAMP, vinblastine, doxorubicin (Adriamycin), methotrexate, and prednisone; VBVP, vinblastine, bleomycin, etoposide (VP-16), prednisolone.

* For the composition of combination chemotherapy courses, see Table 53-8 .

† CR defined as reduction of tumor volume of >95% and residual mass <2 mL.

‡ OE*PA includes higher dose of etoposide than OEPA.

§ For good and poor responders respectively.

‖ Less than 3 nodal sites, no B symptoms, no mediastinal bulk, no extranodal extension.

¶ Peripheral nodal disease, <6 cm, mediastinal tumor smaller than one third of intrathoracic diameter, absence of extranodal involvement.

** CR defined as >70% reduction of initial tumor volume and gallium-negative if initially gallium-positive.

Table 53-8 summarizes the treatment strategy and results of selected therapeutic studies in patients considered to have intermediate- or high-risk disease. Chemotherapy for these groups generally consists of combinations of ABVD and MOPP or hybrid regimens. Most regimens contain four to six cycles of chemotherapy followed by involved-field radiation with some including high-dose radiation to bulky or residual sites of disease.

TABLE 53-8

Combined-Modality Treatment Strategy and Results for Patients with Intermediate- and High-Risk Hodgkin Lymphoma in Selected Multicenter Trials

Group or Institution	No. of Patients	Stage	Chemotherapy	Radiation (Gy), Field	EFS at 5 years	Overall Survival (%)
DAL-HD90 (high risk)	179	IIEB, IIIEA, B, IIIB, IVA, B	2 OEPA-OPPA + 4 COPP	IF, 20-25 Gy residual tumor 30-35 Gy	86%	94%
GPOH-HD95 3-5 ABVD-PC	265	IIEA, IIIEA, B, IIIB, IVA, B	2 OPPA/OEPA + 4 COPP	CR * : no RT (22%); non-CR: IF, 20 Gy; residual tumor, 30-35	79% DFS no IFRT 91% DFS with IFRT	NR
GPOH-HD02 (intermediate risk)	139	IAE, IB, IIAE, IIB, IIIA	2 OPPA + 2 COPP † 2 OE*PA +2 COPAD ‡	IF, 20 Gy; residual tumor, 30-35	93%	98%
GPOH-HD02 (highest risk)	239	IIBE, IIIAE, IIIB, IVA, IVB, IVE	2 OPPA + 4 COPP † 2 OE*PA + 4 COPAD ‡	IF, 20 Gy; residual tumor, 30-35	87% EFS	95% 5 yrs
Stanford-St. Jude-Boston Consortium	159	I-II unfavorable, § III, IV	3 VAMP/3 COP	15-25.5 Gy, ‖ IF	76 at 5 yr	93% at 5 yr
POG	179	IIB, IIIA2, IIIB, IV	4 MOPP, 4 ABVD	21 Gy total nodal	79%	92%
POG	216	IB, IIA/IIIA with bulk, IIB, IIIB, IV	3-5 ABVD-PC	21 Gy IF	84% at 5 yr	95% at 5 yr
CCG	394	I/IIB, IIB, III	6 COPP-ABV	CR: randomized to 21 Gy vs. no IFRT, no CR 21 Gy IFRT	87%	95%
CCG	141	IV	COPP-ABV + CHOP + Ara-C	CR: randomized to 21 Gy vs. no IFRT, no CR 21 Gy IFRT	90%	100%
COG	98	IIB with bulk, ¶ IIIB with bulk, IV	BEACOPP × 4 then one of: COPP/ABV × 4 ‡ ABVD × 2 † BEACOPP × 4 #	Female, RER ** : no RT Male or SER: 21 Gy Residual tumor, 35 Gy	94% EFS	97% 5 yr

 

ABV, Doxorubicin (Adriamycin), bleomycin, and vinblastine; ABVD, doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine; Ara-C, cytarabine; BEACOPP, bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine, procarbazine, and prednisone; CCG, Children’s Cancer Study Group; CHOP, cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin) and prednisone; COG, Children’s Oncology Group; COPAD, cyclophosphamide, vincristine (Oncovin), prednisolone, and doxorubicin; COP, cyclophosphamide, vincristine, prednisone; COPP, cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone; CR, complete remission; DAL-HD, Deutsche Arbeitsgemeinschaft fir Leukamiefarschung-Hodgkin disease; DFS, disease-free survival; EFS, event-free survival; GPOH-HD, German Society for Pediatric Oncology and Hematology–Hodgkin disease; IF, involved field; IFRT, involved-field radiotherapy; MOPP, mechlorethamine, vincristine (Oncovin), procarbazine, and prednisone; NR, not reported; OEPA, vincristine (Oncovin), etoposide, prednisone, and doxorubicin (Adriamycin); OE*PA, vincristine (oncovin) etoposide, prednisone and doxorubicin (adriamycin); OPPA, vincristine (Oncovin), prednisone, procarbazine, and doxorubicin (Adriamycin); PC, prednisone, cyclophosphamide; POG, Pediatric Oncology Group; RER, rapid early responder; RT, radiotherapy; SER, slow early responder; VAMP, vinblastine, doxorubicin (Adriamycin), methotrexate, and prednisone

* CR defined as reduction of tumor volume of >95% and residual mass <2 mL.

† Males.

‡ Females.

§ Defined as presence of one or more of the following: bulky disease, peripheral nodal disease 6 cm or larger, and/or mediastinal tumor one third of intrathoracic diameter or larger; and B symptoms.

‖ 15 Gy for nonbulky sites and complete response after two cycles of chemotherapy.

¶ Bulk defined as mediastinal mass greater than intrathoracic diameter at level of T5 or extrathoracic nodal mass greater than 10cm.

# Slow early responders.

** SER, partial response not meeting criteria for RER; RER, >70%reduction in tumor volume and gallium negative post 4 cycles.

Prognostic information for patients with Hodgkin lymphoma is based on information available at the time of the child’s initial evaluation. Additionally the importance of the kinetics of disease response to chemotherapy has been shown to be a predictive factor for this disease, as it has been for pediatric leukemias. The premise is that those with more robust responses to initial chemotherapy have more favorable disease and that responsiveness can be included in the factors that are used to decide the intensity of therapy, including whether irradiation is indicated. The definition of a favorable response to chemotherapy, including the timing of assessment of response, the intensity of the chemotherapy regimen used to get the response, and the tools used to measure response have varied widely between study groups and over time. Table 53-9 describes the criteria for disease response evaluations in recent cooperative group trials.

TABLE 53-9

Definitions of Favorable Response to Therapy in Selected Multicenter Trials in Children and Adolescents with Hodgkin Lymphoma

Study	Definition of Favorable Response	Timing of Assessment	Treatment Modification for Those with Favorable Response
CCG5942	>70% reduction in initial tumor volume and gallium negative	At completion of chemotherapy	Randomized to IFRT or no IFRT
GPOH-HD02	≥95% reduction in tumor volume	After 2, 4, or 6 cycles of chemotherapy depending on disease group	No IFRT for patients with low-stage disease only (TG1)
Stanford-St. Jude-Boston Consortium	≥75% reduction in perpendicular diameters of measurable lesions, or return no normal size and gallium or PET negative	After 2 cycles of VAMP	No IFRT
COG	Disappearance of all clinical and disease-related symptoms and PET negative	After 2 cycles of ABVD-PC	All get IFRT; Less than good response: chemo intensified with additional 2 cycles ifos/vinolebine

 

ABVD-PC, Doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine–prednisone, cyclophosphamde; CCG, Children’s Cancer Study Group; COG, Children’s Oncology Group; GPOH-HD, German Society for Pediatric Oncology and Hematology–Hodgkin disease; IFRT, involved-field radiotherapy; PET, positron emission tomography; TG1, therapy group 1; VAMP, vinblastine, doxorubicin (Adriamycin), methotrexate, and prednisone.

Cross-sectional imaging can define response based on a percentage decrease in size. In Hodgkin lymphoma, a significant proportion of patients have residual masses at the time of disease response assessment and at the end of therapy. Functional imaging methods such as gallium scanning and PET are able to assess metabolically active tissue associated with residual disease ( Fig. 53-5 ). A series of studies primarily performed in adults with Hodgkin lymphoma where therapy was not changed based on interim radiographic results have shown that PET scans performed after two cycles of chemotherapy are highly predictive of outcome. The accuracy of PET to predict treatment outcome is higher early in the course of treatment as compared with the end of chemotherapy. Both the German-Austrian study GPOH-HD2002 and the Children’s Oncology Group (COG) studies of intermediate- and high-risk disease addressed the strength of early PET obtained after two cycles of chemotherapy; however the results are still pending.

PET scan at diagnosis and after two cycles of ABVD-PC chemotherapy in an adolescent with advanced-stage Hodgkin lymphoma.

Several cooperative group studies have focused on modifications of regimens to avoid gender-specific toxicities. The COG evaluated a strategy of stratifying patients with high-risk disease based both on response and gender. All patients received escalated bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) therapy for 4 cycles. Patients with a rapid early response, defined as a 70% tumor reduction and having a negative gallium scan after four cycles, were then assigned to subsequent therapy based on gender. Boys received two additional cycles of ABVD designed to minimize risks of infertility and involved field radiation. Girls received four cycles of COPP/doxorubicin (Adriamycin), bleomycin, and vinblastine (ABV) and no radiation in order to avoid the risks of secondary breast cancer. Those with disease that met the criteria for slow early response received an additional 4 cycles of BEACOPP. Seventy-seven percent of girls avoided radiotherapy, whereas 68% of boys avoided alkylating agents during consolidation. The EFS and OS rates remained excellent.

The German GPOH-HD2002 study also evaluated sex-based modifications of therapy but did not use patient response for treatment allocation. Boys received two cycles of dose-intensified vincristine, etoposide, prednisone, and doxorubicin (Adriamycin; OEPA) therapy followed by two (for those with intermediate-risk disease) or four (for those with high-risk disease) cycles of cyclophosphamide, vincristine (Oncovin), prednisone, and dacarbazine (COPDAC) designed to attempt to limit gonadal toxicity. Girls received the same number of cycles but of OPPA followed by COPP. EFS and OS rates did not differ between the two sexes with the regimens employed.

The Pediatric Oncology Group (POG) evaluated response-based modifications of therapy without modifications for sex in patients with intermediate- and high-risk disease. In this study patients were evaluated for response after three cycles of therapy. Those with a rapid early response defined as a greater-than-70% reduction in disease and gallium negative, received 21 Gy IFRT. Those who were slow responders received an additional two cycles followed by radiation. With this strategy the 5-year EFS rate was the same in both groups, and the OS rate was 95%.

Whether radiotherapy can be omitted from treatment for at least some children and adolescents with Hodgkin lymphoma is one of the important questions in recent and ongoing clinical trials. Three cooperative group trials in the low-risk group each evaluated the removal of IFRT in a subset of patients with largely successful results. In the Stanford-St.Jude-Boston protocol, patients with a complete response, defined as greater than 75% reduction of the sum of the perpendicular of all lesions after two cycles of vinblastine, doxorubicin (Adriamycin), methotrexate (methotrexate), and prednisone (VAMP) chemotherapy were nonrandomly assigned to no radiation. All patients received four cycles of VAMP chemotherapy. Fifty three percent of patients met criteria for complete response. The 2-year EFS rates of this group were no different from those who did receive radiation, at 89% and 92% respectively. The GPOH-HD 2002 study also nonrandomly assigned patients at low risk with a complete response after two cycles, defined as more than 95% volume reduction, to no radiation. Thirty three percent of patients met this criterion, did not receive radiation, and had an outcome identical to those who did receive IFRT, with EFS rates at 5 years of 93% and 91% respectively. The Children’s Cancer Group (CCG) study 5942 randomly assigned patients who obtained a complete remission (CR), defined as 70% mass reduction of tumor volume and negative gallium scan, to radiation or no radiation after four cycles of COPP/ABV therapy. The EFS rates for randomized patients at 3 years were significantly different at 97% versus 91%; however, the OS rate at 3 years in both groups was 100%.

Omission of radiation has also been investigated in subgroups of patients with intermediate- and high-risk disease with mixed results. In the POG trial 8725, patients with stages IIB, IIIA2, IIIB, and IV were randomized to receive eight alternating cycles of MOPP/ABVD chemotherapy followed by total nodal irradiation (21 Gy) or no radiotherapy in cases of CR. There was no difference in EFS or OS between patient groups who did or did not receive radiation. In the GPOH-HD95 trial patients who achieved a complete response received no further therapy, whereas those who did not received 20 to 35 Gy of IFRT. In the intermediate- and high-risk groups, omission of radiation was associated with a significantly decreased EFS rate of 77% for those treated with chemotherapy only versus 92% for those who received combined modality therapy.

The CCG5942 trial included subjects with all disease stages. Based on their risk-group assignment, patients received either four or six cycles of COPP/ABV or six cycles of the mutiagent ABC regimen chemotherapy. Patients with at least a 70% tumor-volume reduction and negative gallium scan at the completion of chemotherapy were randomized to receive or not receive IFRT with 21 Gy. This randomized trial was stopped because of a significantly higher number of relapses in the no-IFRT arm. Most of the relapses were at sites of initial disease. Patients who did not receive IFRT had an EFS rate at 3 years from the time of randomization of 87% compared with 92% ( P = .057) for patients treated with IFRT in the intent-to-treat analysis. Importantly, longer term follow-up study of this cohort has shown that the OS in the two arms is no different. At 10 years postrandomization, the EFS of those treated or not treated with IFRT were 91.2% and 82.9% ( P = .004), respectively, whereas the OS of the two groups were 97.2% and 95.5% ( P = .5), respectively.

Radiation remains a critical component of therapy for the majority of children and adolescents with Hodgkin lymphoma. Radiotherapy planning involves decision making about both dosage and field, with the goals of maximizing efficacy but limiting late effects. Radiation fields have evolved over time ( Fig. 53-6 ). IFRT, used in the majority of contemporary protocols, generally involves radiation of the entire lymph-node region that includes the pathologically enlarged node. One major implication of the change from mantle-field radiation to IFRT for cervical disease is the exclusion of the axilla, which significantly reduces the exposure of lung and breast tissue. Investigations of further limitations to radiation fields are ongoing. The dosages in most contemporary studies used in combination with chemotherapy are generally no greater than 21 Gy, with some studies using higher dosages to sites of bulky or residual disease.

Radiation fields for treating Hodgkin lymphoma.

A, Total nodal irradiation. B, Mantle field. C, Involved field. D, Radiation field individualized to the patient’s local disease, taking into account the tolerance of involved or adjacent extranodal organs.

(Courtesy of Dr. W. Dörffel, Berlin, Germany.)

Disease Surveillance after Completion of Therapy

Driven both by required studies as part of clinical trials and as part of standard of care in some pediatric oncology settings, children and adolescents routinely undergo surveillance imaging with CT scans at regular intervals after completion of therapy. Given increasing awareness of the potential risks secondary to imaging-related radiation exposure, recent work has examined the utility of CT imaging as compared with clinical findings in the detection of disease recurrence. A retrospective review of patients treated in a POG study showed that the majority of relapses occurred within the first year and were detected by clinical findings. For the patients with late relapse, detection by either by clinical symptoms or surveillance imaging did not change the OS rate. These authors suggest limiting surveillance-CT imaging to the first 12 months after completion of therapy. FDG-PET scanning, which has utility in staging newly diagnosed patients and in the assessment of disease response (see above) has no established role in off-therapy surveillance. More widespread use of MRI as a replacement for CT may also allow for reduction of radiation exposure in lymphoma patients in the future.

Pathologic Features

NLPHL is a monoclonal B-cell neoplasm. The histology is characterized by effacement of the lymph node architecture by a nodular or nodular and diffuse infiltrate of small lymphocytes, with an associated follicular dendritic network and scattered or clustered large cells referred to as lymphocytic and histiocytic (L&H) cells . NLPHL corresponds to Hodgkin paragranuloma of the classification of Jackson and Parker from 1947 and to lymphocyte-predominant Hodgkin lymphoma of the Rye modification of Lukes and Butler. Differentiation of NLPHL from the lymphocyte-rich subtype of classic Hodgkin lymphoma can be difficult in some cases. However, the phenotype of L&H cells (also termed popcorn cells because of their often multilobed nuclei) is different than classic Reed-Sternberg cells of the CHL subtypes in that they express CD45 and usually retain most normal markers of B-cell differentiation, such as CD20, CD79a, and the B-cell specific transcription factors BOB.1 and Oct-2, but do not express CD30 and CD15 (see Table 53-1 ). Also, markers of EBV infection are consistently absent from L&H cells of NLPLH. In some patients with NLPHL, progressively transformed germinal centers are observed in association with NPLHL. However, it remains uncertain whether these lesions are truly preneoplastic, because most patients with such lesions in reactive lymph-node hyperplasia do not develop a lymphoma.

Clinical Features

NLPHL comprises between 5% and 8% of Hodgkin lymphoma in children and adolescents and accounts for an even higher percentage of prepubertal patients. Unlike in patients with CHL, there is a significant male preponderance in those with NLPHL. The disease course is more indolent, and a higher proportion of patients have low-stage disease, most often presenting as localized peripheral adenopathy, most commonly in the neck and less commonly in the inguinal area. Mediastinal involvement is relatively rare. Unlike CHL, where contiguous nodal spread is the norm, in NLPHD noncontiguous spread is observed in those with high-stage disease. The pattern of relapse of disease also differs from CHL, with relapses occurring late and often repeatedly. An additional unique feature of NLPHL is the increased risk of transformation to NHL occurring in 5% to 12% of cases, whereas this is very rarely observed in CHD.

Diagnostic evaluation should include excisional node biopsy. Fine-needle aspirate is often inadequate and can lead to the misdiagnosis of reactive nodal tissue. Staging of patients with NLPHL uses the Ann Arbor system as used for CHL, and staging evaluations to be considered are the same as those for a patient with CHL except that bone marrow biopsies are rarely indicated. The only consistent prognostic factor for patients with NLPHL is stage of disease, although some data suggest that a ratio of lymphocyte count to monocyte count at the time of diagnosis may also have prognostic value.

Treatment and Outcomes

Historically patients with NLPHL have been included in most therapeutic studies of childhood and adolescent Hodgkin lymphoma. Uncertainty remains about optimal therapy for these patients. Given the favorable prognosis and the burden of late effects from therapy, the evaluation of less intensive regimens has been undertaken.

The majority of patients with NLPHL have low-stage disease, which is sometimes amenable to complete resection. One of the unique features of NLPHD is that a portion of children with low-stage disease treated with resection alone are cured of their disease. Studies of patients treated in this fashion have reported relapse-free survival rates of 67% to 100%. All of the recurrences in patients with relapse were low stage, and the OS has been reported as 100%. For pediatric patients with NLPHD, a watchful waiting approach for those who are in CR after initial surgery is appropriate. However, a careful postoperative staging and meticulous follow-up observation is essential. Other strategies for patients with low-stage disease are the use of radiotherapy alone or low-intensity alkylator-based chemotherapy regimens.

Data to evaluate the best therapy for patients with advanced stage NLPHL are relatively scarce. Outcome of these patients is similar to those with CHL, and the usual recommendation is that they receive therapy similar to those with advanced-stage CHL. Investigation of the possible role for therapy with rituximab as a single agent or as part of combination therapy for this disease are ongoing.