Clinical Manifestations

Pediatric patients most commonly present with painless cervical or supraclavicular lymphadenopathy. Mediastinal lymphadenopathy occurs in up to 66% of patients and may be associated with a nonproductive cough or other symptoms of tracheal or bronchial compression. Axillary or inguinal lymphadenopathy is less frequently seen as the first presenting sign. Primary infradiaphragmatic disease is rare in pediatric patients and occurs in fewer than 5% of cases. Splenic involvement occurs in 30% to 40% of pediatric patients with Hodgkin’s lymphoma, whereas hepatic involvement is exceedingly rare. The pulmonary parenchyma, chest wall, pleura, and pericardium are the most commonly involved extranodal sites of disease. Bone marrow involvement at the time of initial presentation of Hodgkin’s lymphoma is also uncommon in children. Approximately 65% of children have stage I and II disease and 35% have stage III and IV disease (Table 72-1).

TABLE 72-1 Pediatric Hodgkins Lymphoma: Demographic and Clinical Characteristics at Presentation

* Data taken from Ruhl et al⁴⁹ and Nachman et al.⁴⁸

† Data taken from Cleary et al.¹³⁶

‡ Data derived from both pathologically and clinically staged patients.

Nonspecific systemic symptoms are often associated with lymphadenopathy and may include fatigue, anorexia, mild weight loss, and pruritus. The prognostically significant constitutional or B symptoms that are included in the staging assignment are unexplained fever with temperatures taken orally that are higher than 38° C, unexplained weight loss of 10% within 6 months preceding diagnosis, and drenching night sweats. B symptoms occur in approximately 33% of patients (see Table 72-1). Laboratory changes observed at presentation are nonspecific but may provide clues about the extent of disease. Hematologic abnormalities may include anemia, neutrophilic leukocytosis, lymphopenia, eosinophilia, and monocytosis. Anemia may be associated with the presence of advanced disease and may result from impaired mobilization of iron stores or, less commonly, from hemolysis. Several autoimmune disorders have been reported in patients with Hodgkin’s lymphoma, including nephrotic syndrome, autoimmune hemolytic anemia, autoimmune neutropenia, and immune thrombocytopenia.³² These conditions typically remit as the lymphoma is responding to therapy. Several acute phase reactants, including erythrocyte sedimentation rate and serum copper, ferritin, and C-reactive protein levels, may be elevated at diagnosis and useful in follow-up evaluations.

Patient Evaluation

Posteroanterior and lateral thoracic radiographs should be performed as soon as Hodgkin’s lymphoma becomes part of the differential diagnosis to assess mediastinal involvement, airway patency, and other intrathoracic structures. This is particularly important if sedation is planned for diagnostic procedures. An excisional lymph node biopsy is the preferred diagnostic procedure because it permits evaluation of the malignant Hodgkin’s Reed-Sternberg cells within the background of characteristic architectural changes of the specific histologic subtypes. All nodal regions, including Waldeyer’s ring, should be assessed by careful physical examination. An upright chest radiograph should be obtained to assess mediastinal bulk that is defined by mediastinal lymphadenopathy measuring 33% or more of the maximum intrathoracic cavity. CT is most frequently used to evaluate the nodal regions in the neck, axilla, thoracic and abdominal cavities, and pelvis. Administration of both oral and intravenous contrast agents is required for CT to accurately distinguish lymphadenopathy from other infradiaphragmatic structures. Organ size is an unreliable indicator of lymphomatous involvement in the liver or spleen, because tumor deposits may be less than 1 cm in diameter and not visualized by diagnostic imaging modalities. Increased size of either organ can, of course, be caused by nonmalignant causes. The presence of hypodense lesions by CT and/or abnormal functional avidity by PET scanning provides stronger evidence of tumor infiltration in these organs.

Functional nuclear imaging studies are appropriately used in patients with Hodgkin’s lymphoma as a diagnostic and monitoring modality. PET scanning uses uptake of the radioactive glucose analog ¹⁸fluoro-2-deoxyglucose (FDG) as a correlate of tumor activity. PET scanning is now widely available and is a standard part of the staging workup and assessment of response to therapy. Fused PET/CT offers the advantage of integrating functional and anatomic tumor characteristics. Residual or persistent gallium or FDG avidity is useful in predicting prognosis and the need for additional therapy in post-treatment evaluation.33,34,35,36,37 Moreover, PET may be useful in evaluating abnormalities that become clinically manifest or appear on imaging in order to assess recurrence.³⁸ The utility of PET for follow-up is being studied because reports suggest low rates of diagnosing relapsed disease and problems with a high degree of false-positive findings.^39,40,41

Because extranodal disease involving the bones and bone marrow is relatively uncommon in children, these staging evaluations can be omitted in patients presenting with localized and asymptomatic disease. Bone pain should be evaluated with plain radiographs. PET scanning is supplanting technetium-99 (⁹⁹Tc) bone scans, which historically have been performed for an elevated serum alkaline-phosphatase concentration beyond that expected for age, or extranodal disease identified by other staging evaluations. A bone marrow biopsy should be performed in any patient with clinical stage III or IV disease or B symptoms. Because the pattern of infiltration in the bone marrow may be diffuse or focal and is often accompanied by reversible marrow fibrosis, a bone marrow aspirate alone is inadequate to assess the marrow for disease.

Staging

Physical examination and diagnostic imaging evaluations are used to designate a clinical stage according to the Ann Arbor staging system.⁴² In the past, pathologic staging, based on the findings of a staging laparotomy, including splenectomy, was routinely used to assess infradiaphragmatic disease. The increasing use of systemic therapy in children and the development of more accurate diagnostic imaging modalities led to the routine use of clinical staging and abandonment of surgical staging except to assess equivocal findings. Currently, surgical staging—most typically, nodal sampling without splenectomy—is pursued only if the anticipated findings will significantly alter the treatment plan.

Risk-Adapted Treatment Approach

Contemporary treatment for children and adolescents with Hodgkin’s lymphoma involves a risk-adapted approach based on the patient’s presenting features at diagnosis.* Factors included in the risk assessment vary across studies, but they most often include the presence of B symptoms, mediastinal and peripheral lymph node bulk, extranodal extension of disease to contiguous structures, number of involved nodal regions, Ann Arbor stage, and gender. A favorable clinical presentation is typically characterized as localized (stage I/II) nodal involvement in the absence of B symptoms and bulky disease. Although the historical definition of mediastinal bulk was based on a ratio greater than one-third between the transverse dimension of the mediastinal mass to the intrathoracic cavity on an upright chest radiograph, some trials have moved to use a simple size criteria on cross-sectional imaging as used for peripheral lymph node bulk. That definition, however, is highly variable across studies, ranging from 4 to 10 cm as a minimal threshold. Moreover, there is additional subjectivity in the definition of bulk when there are multiple matted or adjacent nodes, contributing to confusion on such risk stratification in practice. Fewer than three or four involved nodal regions are considered favorable.

In some risk-adapted treatment protocols, patients with localized disease presenting with unfavorable features are designated intermediate in risk and treated similarly to those with advanced-stage disease, whereas in others a therapy intermediate in intensity is prescribed. The criteria for unfavorable clinical presentations have also differed among studies, but the criteria most often used are B symptoms, bulky lymphadenopathy, hilar lymphadenopathy, more than three to four involved nodal regions, extranodal extension to contiguous structures, and advanced-stage (IIIB to IV) disease. The results of contemporary trials indicate that children and adolescents with early-stage or favorable presentations of Hodgkin’s lymphoma are excellent candidates for reduced therapy.44,47,48,49 Ongoing trials are evaluating whether intensification of therapy improves outcomes in patients with intermediate-risk and high-risk presentations.

Although not widely used to guide therapy assignment in pediatric trials, other factors such as gender, age at diagnosis, and histologic findings are considered in individual patients. The trials organized by the German-Austrian Pediatric Oncology Group (GPOH) and one trial by the Children’s Cancer Group (now integrated in the Children’s Oncology Group—COG) have been unique in their aims to prospectively evaluate gender-based therapy.^49,51 Long-term follow-up of the GPOH 90 and 95 studies demonstrate that the substitution of etoposide for procarbazine in the vincristine, prednisone, procarbazine, and doxorubicin (OPPA) regimen does not compromise disease-free survival rates and provides less potential risk for gonadal toxicity.^45,49 Although age at presentation has not been used as a criterion to assign therapy in prospective trials, reports describing outcomes after treatment with chemotherapy alone stress the benefits of this approach in younger children at higher risk of radiation-related toxicity.^46,48

Lastly, retrospective reports of excellent outcome in patients with completely resected nodular lymphocyte-predominant disease have motivated prospective studies prescribing observation alone.^52,53 At the same time, early-stage nodular lymphocyte-predominant Hodgkin’s lymphoma responds well to chemotherapy alone, IFRT alone, or combined-modality therapy. As an example of the later, VAMP (vinblastine, Adriamycin [doxorubicin], methotrexate, and prednisone) plus low-dose IFRT (LDRT) in a series of 33 patients had a 100% 10-year survival rate and EFS rate.⁵⁴ Because data supporting the effectiveness of IFRT alone are based on full-dose RT (e.g., ≥30 Gy), it is not considered appropriate for children who are not fully grown.

A summary of trials in children with early-stage and advanced-stage Hodgkin’s lymphoma is provided in Tables 72-2 and 72-3 (a more complete tabulation is available in the Expert Consult online version of this chapter).

Response-Based Therapy

The response to chemotherapy, either early in its course or at its completion, is known to be an important prognostic factor in Hodgkin’s lymphoma.¹³ This knowledge has led to a hypothesis that modifications in therapy may be based on the initial response to chemotherapy in a similar fashion to the management of acute lymphoblastic leukemia. Based on rapidity of a complete response to chemotherapy, a reduction or augmentation of therapy may be possible, a concept under cautious investigation in clinical trials. Response-based approaches titrate the overall duration of chemotherapy and/or the need for radiotherapy by assessing the early response to chemotherapy. Two Pediatric Oncology Group trials (POG 8725 and 8625) comparing chemotherapy alone versus chemoradiotherapy supported this idea that a rapid early response (RER) to chemotherapy reflects the chemosensitivity of a patient’s Hodgkin’s lymphoma and is a predictor of good long-term control.^7,14 The implication is that treatment can be reduced in intensity or duration for those with RER in order to mitigate toxicity, or increased for those with a slow early response (SER) in order to improve disease control.

The augmentation in therapy for SER can be an increased radiotherapy dose or additional chemotherapy, or both. The French Society of Pediatric Oncology MDH90 treated 202 children with stage I or II Hodgkin’s lymphoma with four cycles of vinblastine, bleomycin, etoposide, and prednisone (VBVP). Good responders received 20 Gy IFRT alone, while poor responders were given an additional one to two cycles of OPPA and then either 20 Gy IFRT (good responders at second evaluation) or 40 Gy IFRT (poor responders). The 5-year overall survival (OS) and EFS rates were 97.5% and 91.1%, respectively.⁴⁷ In the German trial, GPOH HD-95, early-stage patients who had a complete response to chemotherapy (two cycles of OPPA for girls or two cycles of OEPA for boys) did not receive adjuvant radiotherapy. OPPA/OEPA chemotherapy alone produced a 5-year disease-free survival rate of 88%, which was not significantly different from that observed in patients who received radiotherapy (92%).⁴⁵ In this trial, higher-risk patients who received radiotherapy were prescribed radiation doses of up to 35 Gy if a complete response was not achieved. The use of higher-dose radiotherapy with simple anterior-posterior beams is certainly known to cause undesirable musculoskeletal toxicities and the potential for increased cardiopulmonary injury and secondary cancers, such that augmentation of chemotherapy or more conformal radiotherapy may be better approaches for nonresponders. POG 9425 administered three versus five cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) chemotherapy and 21-Gy regional radiotherapy for rapid and slow responders, respectively.⁵⁵ The 2-year EFS rate was 88.2%, with no statistical difference between early and slow responders. These studies suggest that interim or early response-adapted therapy may be useful in identifying patients with favorable disease, who can be treated with lower radiotherapy doses or abbreviated chemotherapy regimens.

A recently closed COG intermediate-risk Hodgkin’s lymphoma study may provide additional data on response-based strategies, including when it may be safe to eliminate radiotherapy for some patients. Children with stage IA/IIA bulky disease or IB, IIB, IIIA, or IVA disease receive two cycles of ABVE-PC prior to response evaluation with CT imaging. Those with RER, and who go on to a complete response after an additional two cycles of the same chemotherapy, are randomized to 21 Gy of IFRT or no additional treatment. Patients with an SER to two cycles of chemotherapy are randomized to either standard therapy (an additional two cycles of ABVE-PC plus 21-Gy IFRT) or intensified therapy (standard therapy plus two additional cycles of chemotherapy—dexamethasone, etoposide, cytarabine, and cisplatin [DECA]—before IFRT). This trial will provide useful data regarding the selection of patients who may avoid radiotherapy and the value of chemotherapy intensification among those with an SER.

Although most completed trials have used CT, with or without gallium or PET to determine response, it is becoming increasingly clear that PET scanning after the initial (one or two) chemotherapy cycles will better identify good-prognosis patients and facilitate treatment intensification.13,36,56,57 Whether radiotherapy can be omitted among patients with a negative PET scan after chemotherapy is unknown and should be considered investigational at the present. The corollary problem is how to define a response by PET criteria because low levels of residual FDG activity after therapy are common. Another unresolved problem is the interpretation of splenic or hepatic involvement by Hodgkin’s lymphoma given the physiologic uptake of FDG in these organs. A consensus panel has promulgated PET-based response criteria known as the International Harmonization Project.^58,59

Chemotherapy Regimens and Radiation Therapy