This treatment information summary on childhood Hodgkin's disease is an overview of prognosis, diagnosis, classification, and treatment. The National Cancer Institute created the PDQ database to increase the availability of new treatment information and its use in treating patients. Information and references from the most recently published literature are included after review by pediatric oncology specialists. Cancer in children is rare. A team approach that incorporates the skills of the local physician, pediatric surgeon, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, and social workers is imperative to ensure that patients receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. For advances to be made in treating these patients, therapy should be delivered in the context of a clinical trial at a major medical center that has expertise in treating children. Only through entry of all eligible children into appropriate, well-designed clinical trials will progress be made against these diseases. Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.
Hodgkin's disease is a lymphoma characterized by a pleomorphic cellular infiltrate with multinucleated giant cells (Reed-Sternberg cells). These Reed-Sternberg cells are considered to be the malignant cell of Hodgkin's disease, but their normal counterparts have not been definitively identified. Most cases of Hodgkin's disease probably arise from germinal center B cells that are unable to synthesize immunoglobulin. Clinically, patients usually present with painless adenopathy, commonly in the supraclavicular or cervical area. The enlarged nodes are typically firmer than inflammatory nodes and have a rubbery texture. Many patients have some degree of mediastinal involvement at presentation. Patients may have systemic symptoms such as fever, night sweats, and weight loss that are perhaps secondary to the lymphokines released by the Hodgkin's cells.
In the United States, there is a bimodal age distribution of Hodgkin's disease with an early peak in the mid to late 20s and a second peak in late adulthood. Hodgkin's disease is rare before 5 years of age, and in children younger than 10 years of age the incidence is much higher in boys. The majority of cases in developing countries and about one third of those in the United States are associated with the presence of Epstein-Barr virus in the Reed-Sternberg cells. Although rare, Hodgkin's disease can be familial. While Hodgkin's disease occurs in various age groups, children with the disease should be treated in multidisciplinary pediatric oncology institutions with experience treating children with cancer. The problems that arise in treatment and follow-up of childhood Hodgkin's disease can differ from those in adults, and pediatric specialty care can best deal with these problems.
It is generally thought that Hodgkin's disease spreads contiguously via the lymphatics from one adjacent nodal area to another. A pattern of "skip areas" is unusual until late stages of advanced disease. The current Ann Arbor stage classification listed in the staging section rests on this assumption.
More than 90% of all children and adolescents with newly diagnosed Hodgkin's disease are curable with modern therapy. Since the selection of treatment is influenced by the stage of disease and the potential long-term effects of treatment, careful clinical and/or pathologic evaluation is essential. Treatment planning by a multidisciplinary team of cancer specialists is required to determine optimal therapy for patients with this disease.
Patients with stage I or II disease may well be cured with radiotherapy alone, although most would consider chemotherapy with low-dose radiation the standard of care in growing children. Patients with B symptoms, regardless of stage, should be treated with chemotherapy. Treatment strategies depend on a number of factors including the presence of B symptoms, the histologic subtype, gender, and sexual maturity. Adolescents are often treated as adults when these factors are taken into consideration. Those whose disease recurs after radiation alone may still achieve cure with combination chemotherapy. Although second remissions are obtained in the majority of these patients, late relapses do occur. Patients with advanced disease, stages III and IV, are generally treated initially with chemotherapy with subsequent possible radiation to bulky disease.
In the patient who is still growing (that is, patients who are younger than 13 years of age or who have not attained sexual maturity), every attempt is made to preserve the integrity of bony and connective tissue structures. The risk of sterility, damage to the heart and lungs, and second malignancies must be considered. Hematopoietic malignancies (such as acute myeloid leukemia and non-Hodgkin's lymphoma) have been associated with chemotherapy and solid tumors (such as sarcomas and breast cancer) have been associated with radiotherapy. The risk of breast cancer for girls between the ages of 10 and 16 years who are treated with radiotherapy is especially high and is dose-related. Consequently, the dose of radiation administered to patients in the younger age group is lower than that classically given to adult patients and combination chemotherapy may be used as part of the treatment or, in selected cases, as the only treatment of early-stage disease.
Changes in therapy to reduce late effects while maintaining high cure rates have been the goal of pediatric oncologists. Radiation therapy has been decreased in dose, duration, and fields. Chemotherapy regimens have been developed which limit alkylating agents and anthracyclines to decrease the risk of second neoplasms, loss of fertility, and late cardiopulmonary toxicity.
Because of the significant long-term risk of bacterial sepsis, which may occur in as many as 20% of patients who have undergone a splenectomy or who have received radiation to the spleen, the Advisory Committee on Immunization LCPractices recommends immunization with polyvalent pneumococcal vaccine, hemophilus influenza type B conjugate vaccine, and meningococcal vaccine. This patient group should be vaccinated prior to and 2 years after therapy, with a booster dose every 6 years thereafter. Whether all patients with Hodgkin's disease should receive this vaccine is controversial. In administering the vaccine, it should be kept in mind that patients with Hodgkin's disease have essentially normal responses to vaccine administered 10-14 days prior to therapy and 2 years after therapy. Impaired responses may be observed in patients who receive the vaccine at other times in relation to their treatment. In many patients, administration of vaccine at less than optimal times may be unavoidable, but it is anticipated that with fewer patients undergoing splenectomy, the incidence of serious bacterial sepsis will decrease.
CELLULAR CLASSIFICATION
The current histologic classification for childhood Hodgkin's disease used by pathologists is the Rye modification of the Lukes and Butler classification.
Rye classification:
lymphocyte predominance
nodular sclerosis
mixed cellularity
lymphocyte depletion
unclassified
Patients with lymphocyte predominant Hodgkin's disease generally have localized disease, are usually asymptomatic, and appear to be curable with less intensive therapy than other subtypes. Increased risk of second malignancy in this group suggest minimizing therapy associated with secondary malignancies in Hodgkin's disease. Nodular sclerosing is the most common histologic subtype. With effective multiagent chemotherapy, histologic subtype does not influence outcome.
STAGE INFORMATION
Stage has a critical role in the selection of treatment. The stage is based on a combination of clinical staging (history, physical examination, x-rays, including computed tomographic (CT) scans of chest, abdomen, and pelvis, gallium scan, and laboratory studies). In the past, lymphangiograms were commonly used to evaluate the nature of the involvement of abdominal lymph nodes with Hodgkin's disease; however, there are more false-positives in children than in adults and the studies are technically more difficult to perform. Currently, these studies are rarely included in the staging of children.
Patients with large mediastinal masses are at risk of cardiac or respiratory arrest during general anesthesia or heavy sedation. Due to the risks of general anesthesia or heavy sedation, a careful physiologic and radiographic evaluation of the patient should be carried out and the least invasive procedure should be used to establish the diagnosis of lymphoma. Bone marrow aspirate and biopsy should always be performed early in the work up of these patients and if a pleural effusion is present, a thoracentesis should be performed as cytologic diagnosis is frequently possible. In those children who present with peripheral adenopathy, a lymph node biopsy under local anesthesia and in an upright position may be possible.
In situations in which the above diagnostic procedures are not fruitful, consideration of a CT guided core needle biopsy should be contemplated. This procedure can frequently be carried out using light sedation and local anesthesia before proceeding to more invasive procedures. Mediastinoscopy, anterior mediastinotomy or thoracoscopy are the procedures of choice when other diagnostic modalities fail to establish the diagnosis. A formal thoracotomy is rarely if ever indicated for the diagnosis or treatment of childhood lymphoma. Occasionally it will not be possible to perform a diagnostic operative procedure because of the risk of general anesthesia or heavy sedation. In these situations preoperative treatment with steroids or localized radiation therapy should be considered. Since preoperative treatment may affect the ability to obtain an accurate tissue diagnosis, a diagnostic biopsy should be obtained as soon as the risk of general anesthesia or heavy sedation are thought to be alleviated.
Pathologic staging requires laparotomy with splenectomy and biopsies of lymph nodes, liver, and bone marrow, unless a diagnosis of disseminated disease has already been established by some other technique. Except in patients for whom radiation therapy alone is being considered, staging laparotomy is important to both plan proper radiation portals and to assess as accurately as possible the stage of disease. Certain clinical features such as pulmonary hilar adenopathy on chest CT scan are highly predictive of splenic involvement, as are changes on the splenic surface or involvement of lymph nodes at the splenic hilus/pancreatic tail when directly visualized at laparotomy. Splenectomy may be avoided if lymph node biopsy specimen is positive.
During staging laparotomy, placement of titanium clips at the splenic hilum is strongly recommended to facilitate planning radiation therapy to shield the left kidney when the para-aortic nodes are to be irradiated. In girls, if pelvic irradiation is anticipated, oophoropexy with transposition of the ovaries to a midline position should be performed. In all cases, there should be consultation between the pediatric oncologist, radiation oncologist, and surgeon prior to the staging operation.
Patients who have had a splenectomy are susceptible to sepsis with encapsulated organisms. They should be given HIB and Pneumovax before splenectomy, if possible, and daily prophylactic penicillin thereafter. Also, in some ages, the risk of secondary leukemia is more common in patients who have had splenectomy than in those who have not.
The staging classification that is currently used for Hodgkin's disease was adopted at the Ann Arbor Conference held in 1971.
Subclassification of stage
Stages I, II, III, and IV childhood Hodgkin's disease can be subclassified into A and B categories and subcategory E: A for those patients who are asymptomatic and B for those patients with any of the following specific symptoms:
unexplained loss of more than 10% of body weight in the 6 months before diagnosis
unexplained fever with temperatures above 38 degrees C for more than 3 days
drenching night sweats
The subclassification E denotes minimal extralymphatic disease from direct extension. Extralymphatic disease presents confusing problems in staging. The designation "E" is not appropriate for cases of widespread disease, which should be considered stage IV. Only if the extralymphatic disease is very limited, adjacent to a lymph-node bearing area, and can be encompassed by a potentially curative radiotherapy portal should the substage "E" be applied.
If pathologic proof of involvement of one or more extralymphatic sites has been documented, the symbol for the site of involvement, followed by a plus sign (+), is listed. Current practice is to assign a clinical stage (CS) based on the findings of the clinical evaluation and a pathologic stage (PS) based on the findings made as a result of the staging laparotomy. For example, a patient with disease in the chest and neck, with systemic symptoms, and a negative lymphangiogram, might be found at laparotomy to have involvement of the spleen, liver, and bone marrow. Thus, the precise stage of such a patient would be CS IIB, PS IVB (S+).
Stage I
Stage I Hodgkin's disease means the involvement of a single lymph node region or, in the case of stage I(E), extension from that node to an adjacent extralymphatic region.
Stage II
Stage II Hodgkin's disease means the involvement of two or more lymph node regions (number to be stated) on the same side of the diaphragm, or extension from these lymph nodes to an extralymphatic adjacent organ, or stage II(E).
Stage III
Stage III Hodgkin's disease means the involvement of lymph node regions on both sides of the diaphragm, which may also be accompanied by extension to an adjacent extralymphatic organ, stage III(E), or by involvement of the spleen, stage III(S+), or both, stage III(E+S).
Stage IV
Stage IV Hodgkin's disease means there is diffuse or disseminated (multifocal) involvement of one or more extralymphatic organs or tissues with or without associated lymph node enlargement, or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement by spread through the blood stream as opposed to spread by the lymphatics.
The extent of disease in stage IV patients is identified further by specifying sites according to the following notation:
