Pediatric Annals

Hodgkin's Disease

Charlotte T C Tan, MD; Ka Wah Chan, MBBS

Abstract

Hodgkin's disease occurs at a frequency of 5 per 1 million in children under 15 years of age and affects Caucasians and blacks at approximately equal rates. It is a disease of late childhood and adolescence and rarely occurs in children below four years of age. Although boys are affected more frequently in childhood, in teenage patients females exceed males in numbers (Figure 1).

The etiology of Hodgkin's disease remains obscure. Clustering of cases has been reported among students in high schools and also among relatives of patients. Higher incidences were noted in school teachers and physicians and this observation prompted the speculation of an environmental or infectious etiology in Hodgkin's disease. Further data suggesting viral etiology came from the observations that antibody titers against various antigens of Epstein-Barr virus were elevated in patients and there is increased risk of Hodgkin's disease among children with prior tonsillectomy and appendectomy. However, other studies have failed to confirm this report and the statistical methods by which the results were obtained were challenged. Presently, there is no indisputable evidence of time-stage clustering of Hodgkin's disease.

The distribution of some HLA antigens was found to be deviant from patients with Hodgkin's disease (namely, HLA-Al, BS1 and BI5) compared with the general population. However, it is not clear whether this finding represents increased disease susceptibility or resistance t o disease progression. A survey of 65 children at Memorial S loan-Ke tiering Cancer Center showed no abnormal distribution of HLA antigens (unpublished observation). Hodgkin's disease has been reported in individual children with ataxia-telangiectasia and congenital hypogammaglobulinemia. However, it is not a common malignancy among patients with congenital or acquired immunodeficiencies.

PATHOGENESIS

The neoplastic nature of mononuclear Hodgkin's cells and Reed-Sternberg cells has been clearly established in the past few years. These cells are capable of DNA synthesis and mitotic division and also have been shown to be aneuploid and heterotransplantable. It is possible to maintain these malignant cells in long-term culture and over 40% of them will demonstrate abnormal marker chromosomes. These cells lack T and B lymphocyte surface markers and do not synthesize endogenous immunoglobulins. On the other hand, they are able to form adhering clusters in culture and are shown to possess Fc and complement receptors. They are able to phagocytize Candida and other foreign substances; in some cases they stain positively for non-specific esterase and secret lysozyme. Therefore, the origin of mononuclear Hodgkin's cells and Reed-Sternberg cells seems to be from the monocyte-phagocyte system, rather than being of lymphoid lineage.

PATHOLOGY

The hallmark of Hodgkin's disease is the presence of Reed-Sternberg cells (large, multinucleated giant cells with basophilic inclusion-like nucleoli surrounded by a clear halo). They are thought to represent an end-stage, degenerative form of mononuclear Hodgkin's cells, which have similar nuclear and nucleolar characteristics. Mononuclear Hodgkin's cells are thought to be the actively proliferating component. However, the presence of Reed-Sternberg cells alone is not sufficient for a pathologic diagnosis of Hodgkin's disease, since they are sometimes found in lymph nodes of infectious mononucleosis, nodular histiocytic lymphoma, and graft vs host reactions.

The Rye histopathological classification of Hodgkin's disease is usually employed (Table 1 ) and is based on two principles. First, when the relative number of ReedSternberg cells and those of the other cellular elements is assessed, there is an inverse relationship between the number and variants of the malignant cells and the intensity of lymphocytic proliferation. According to the second principle, the lymph node architecture is usually effaced and there are two patterns of connective tissue reaction: diffuse fibrosis and nodular sclerosis.

With these criteria four different histologie subtypes of Hodgkin's…

Hodgkin's disease occurs at a frequency of 5 per 1 million in children under 15 years of age and affects Caucasians and blacks at approximately equal rates. It is a disease of late childhood and adolescence and rarely occurs in children below four years of age. Although boys are affected more frequently in childhood, in teenage patients females exceed males in numbers (Figure 1).

The etiology of Hodgkin's disease remains obscure. Clustering of cases has been reported among students in high schools and also among relatives of patients. Higher incidences were noted in school teachers and physicians and this observation prompted the speculation of an environmental or infectious etiology in Hodgkin's disease. Further data suggesting viral etiology came from the observations that antibody titers against various antigens of Epstein-Barr virus were elevated in patients and there is increased risk of Hodgkin's disease among children with prior tonsillectomy and appendectomy. However, other studies have failed to confirm this report and the statistical methods by which the results were obtained were challenged. Presently, there is no indisputable evidence of time-stage clustering of Hodgkin's disease.

The distribution of some HLA antigens was found to be deviant from patients with Hodgkin's disease (namely, HLA-Al, BS1 and BI5) compared with the general population. However, it is not clear whether this finding represents increased disease susceptibility or resistance t o disease progression. A survey of 65 children at Memorial S loan-Ke tiering Cancer Center showed no abnormal distribution of HLA antigens (unpublished observation). Hodgkin's disease has been reported in individual children with ataxia-telangiectasia and congenital hypogammaglobulinemia. However, it is not a common malignancy among patients with congenital or acquired immunodeficiencies.

PATHOGENESIS

The neoplastic nature of mononuclear Hodgkin's cells and Reed-Sternberg cells has been clearly established in the past few years. These cells are capable of DNA synthesis and mitotic division and also have been shown to be aneuploid and heterotransplantable. It is possible to maintain these malignant cells in long-term culture and over 40% of them will demonstrate abnormal marker chromosomes. These cells lack T and B lymphocyte surface markers and do not synthesize endogenous immunoglobulins. On the other hand, they are able to form adhering clusters in culture and are shown to possess Fc and complement receptors. They are able to phagocytize Candida and other foreign substances; in some cases they stain positively for non-specific esterase and secret lysozyme. Therefore, the origin of mononuclear Hodgkin's cells and Reed-Sternberg cells seems to be from the monocyte-phagocyte system, rather than being of lymphoid lineage.

PATHOLOGY

The hallmark of Hodgkin's disease is the presence of Reed-Sternberg cells (large, multinucleated giant cells with basophilic inclusion-like nucleoli surrounded by a clear halo). They are thought to represent an end-stage, degenerative form of mononuclear Hodgkin's cells, which have similar nuclear and nucleolar characteristics. Mononuclear Hodgkin's cells are thought to be the actively proliferating component. However, the presence of Reed-Sternberg cells alone is not sufficient for a pathologic diagnosis of Hodgkin's disease, since they are sometimes found in lymph nodes of infectious mononucleosis, nodular histiocytic lymphoma, and graft vs host reactions.

The Rye histopathological classification of Hodgkin's disease is usually employed (Table 1 ) and is based on two principles. First, when the relative number of ReedSternberg cells and those of the other cellular elements is assessed, there is an inverse relationship between the number and variants of the malignant cells and the intensity of lymphocytic proliferation. According to the second principle, the lymph node architecture is usually effaced and there are two patterns of connective tissue reaction: diffuse fibrosis and nodular sclerosis.

With these criteria four different histologie subtypes of Hodgkin's disease were defined and these subtypes were thought to have prognostic implications. However, with the advent of combination chemotherapy and high energy radiotherapy, the influence of histopathology on prognosis has become less significant with the exception of the lymphocyte-depleted subtype. Compared with adult patients, children have a higher proportion of nodular sclerosing and lymphocyte predominant subtypes of Hodgkin's disease, while the lymphocyte-depleted histology is seldom seen. During disease recurrence there may be a progressive deterioration of the histológica! feature, with gradual increase in the number of Reed-Sternberg cells and a loss of the lymphocyte population.

Involvement of extranodal sites of Hodgkin's disease is sometimes difficult to diagnose. The same histopathologic criteria should be adhered to, even if a primary diagnosis of Hodgkin's disease has not been made. However, when Hodgkin's disease has been confirmed by a lymph node biopsy, the presence of atypical malignant histiocytes and mononuclear cells, together with a polymorphous infiltrate of the portal tract, is acceptable as evidence of hepatic involvement. Similarly, foci of fibrosis and an infiltrate of ma lignant mononuclear cells, eosinophils and plasma cells in a bone marrow biopsy satisfies the criteria of bone marrow metastasis. However, if only fibrosis is seen, additional bone marrow biopsies should be done since marrow involvement in Hodgkin's disease may be focal. In general, liver and bone marrow involvement are very rarely present at diagnosis, especially in the absence of splenic disease.

Hodgkin's disease is believed to start from a single focus and to spread to neighboring echelons of lymph nodes. However, extralymphatic involvement is usually associated with involvement of adjacent or proximate lymph nodes or involvement of the spleen. Only 2% of patients show such a non-contiguous pattern of disease involvement at the time of diagnosis. This "contiguity theory" helped to explain the frequent association between I) lower cervical and mediastinal involvement, and 2) the unusual occurrence of bilateral neck involvement without concomitant mediastinal lymphadenopathy. The spread from lower cervical and supraclavicular regions to the para -aortic lymph nodes in the abdomen is probably the result of retrograde movement of malignant cells along the thoracic duct. Vascular involvement by Hodgkin's disease is found in less than 1 0% of spleens removed and is usually associated with hepatic and bone marrow disease. Early relapse often occurs and there is decreased length of survival in these patients.

Figure 1. Age and sex distribution of 303 children with Hodgkin's disease treated at The Memorial Sloan-Kettering Cancer Center.

Figure 1. Age and sex distribution of 303 children with Hodgkin's disease treated at The Memorial Sloan-Kettering Cancer Center.

SYMPTOMS AND SIGNS

Hodgkin's disease in children usually presents as indolent painless lymphadenopathy; the enlarged lymph nodes slowly progress in size but occasionally the size of the nodes may wax and wane. The neck is the most common site of presentation (Table 2) and about half of the patients also have concomitant but asymptomatic mediastinal lymphadenopathy, primary mediastinal involvement is uncommon. Obstructive symptoms due to compression of vital structures in the thorax may occur. However, the presence of symptoms of respiratory obstruction in children is usually due to non-Hodgkin's lymphoma, which is a more rapidly proliferative neoplasm. Extra-nodal involvement is rare at the time of diagnosis but may become more common at relapse. Systemic symptoms such as weight loss, fever and night sweats are present in 43% of the children we saw, and the frequency of systemic symptoms increases with advanced stages of Hodgkin's disease. Nearly all patients with disseminated involvement have one of the constitutional complaints.

Table

TABLE 1THE RYE HISTOPATHOLOGIC CLASSIFICATION OF HODGKIN'S DISEASE

TABLE 1

THE RYE HISTOPATHOLOGIC CLASSIFICATION OF HODGKIN'S DISEASE

Physical examination usually reveals rubbery firm, non-tender lymph nodes which may bediscrete or matted together. All lymph node areas should be palpated. However, some regions such as epitrochler nodes and Waldeyer's ring, are rarely affected. It is important to realize that the presence of shotty palpable lymph nodes in one or more areas is a common normal finding in children; thus, attention should be directed only to those lymph nodes which have enlarged in size recently. The liver and spleen are palpably enlarged in 10% to 40% of patients but are rarely massive in size. Facial edema, distended neck veins and pleural effusion may be associated with massive mediastinal involvement.

DIAGNOSTIC WORKUP

At Memorial Sloan-Kettering Cancer Center a child with newly diagnosed Hodgkin's disease undergoes laboratory and radiological evaluation as outlined in Table 3. The blood count is usually normal, with about 50% of the children showing neutrophilia, eosinophilia or thrombocytosis. The erythrocyte sedimentation rate, together with other acute phase reactants, are elevated. Serum copper level is abnormally high, but there is no correlation between the actual level of serum copper and the anatomic extent of disease. It is more useful to follow the serum copper level to detect early relapse. Determination of serum alkaline phosphatase is not as helpful as in adults. Its level is usually higher in adolescence. Bone involvement in Hodgkin's disease is usually lytic, causing minimal abnormalities of the alkaline phosphatase levels. Elevation of this enzyme due to hepatic infiltration occurs late, after liver involvement has become clinically evident.

A chest x-ray (Figure 2) will usually demonstrate mediastinal and hilar involvement, but a CT scan of the lungs is required to distinguish contiguous or metastatic pulmonary involvement. Mediastinal lymphadenopathy is frequently found in the nodular sclerosing variety of Hodgkin's disease especially in teenage girls, whereas patients with lymphocyte predominance histology rarely show mediastinal involvement. Skeletal survey and radionuclide bone scans are nearly always negative and have little place in the initial routine diagnostic workup. Similarly, the yield from liver and spleen scan is low and non-specific and there is little correlation between the size of the organs and the likelihood of disease involvement.

Bipedal lymphangiogram should be performed on all newly diagnosed patients unless contraindications exist ( Figure 3). It allows the visualization of the iliac and paraaortic lymph nodes up to the level of the renal pedicles and has a diagnostic sensitivity greater than 90%. Changes in the architecture of the lymph nodes, such as a foamy reticular appearance or filling defects, can be detected before actual enlargement occurs. It also helps in the planning of radiation fields.

The contrast dye injected during lymphangiography may still be visualized six to nine months after the procedure and its presence is useful to follow the response to therapy or to detect early recurrence. Lymphangiogram, however, cannot delineate celìac, porta hepatis, splenic pedicle and mesenteric nodes (which are rarely involved). Therefore, a negative lymphangiogram does not rule out abdominal involvement. Since early lymphangiographtc changes are non-specific, a false positive rate of up to 20% has been reported. False negative results, on the other hand, are rare.

Table

TABLE 2CHILDHOOD HODGKIN'S DISEASE: INITIAL CLINICAL FINDINGS IN 303 CHILDREN

TABLE 2

CHILDHOOD HODGKIN'S DISEASE: INITIAL CLINICAL FINDINGS IN 303 CHILDREN

Young age is not a contraindication to lymphangiography, although general anesthesia is sometimes required for the best results and interpretation may be more difficult. However, patients with massive mediasti nal and pulmonary involvement should be excluded from lymphangiography because of the high risk of pulmonary oil embolism (manifested as fever and dyspnea). Other risks associated with the procedure include increased incidence of hypothyroidism after neck irradiation, allergic reaction to the contrast dyes and local infection.

For those patients who are not candidates for lymphangiogram, ultrasound and CT scan of the abdomen might provide some clues to the extent of subdiaphragmatic involvement. These tests are noninvasive and are also useful during followup. The radionuclide gallium citrate is concentrated by lymphomatous tissue and may be useful for metastatic evaluation (Figure 4). It is most sensitive for supradiaphragmatic involvement but a false negative rate of up to 60% occurs for cases of Hodgkin 's disease affecting the abdomen. Reactive changes in the lymph nodes after lymphangiographic studies may give false positive results. Because of its non-invasiveness the gallium scan can be done repeatedly to follow treatment response and to detect a relapse. Gallium scans have been shown to be positive at a median of five months before clinical relapse (Figure 5).

IMMUNOLOGICAL ABNORMALITIES

Depression of cell mediated immunity has been found in 53% of patients with Hodgkin's disease, and its incidence progressively increases with advancing stages. Although there is no lymphopenia, varying frequency and degree of T lymphocyte dysfunction in vitro has been reported (Table 4). Evidence of T lymphocytedysfunction includes decreased response to various mitogens, impaired ability to form spontaneous sheep erythrocyte rosettes, and poor agglutination ability and cap formation with lectins. The etiology of these functional abnormalities remain unknown, although presence of various humoral inhibitors (including prostaglandin, apoferritin and cytotoxic antibodies) has been postulated.

Immunodeficiency is manifested in vivo by anergic responses to recall any chemical antigens, as well as by increased susceptibility to certain bacterial, viral and fungal infections. In particular, herpes zoster has been reported in 35% of patients in one series. However, there is .no relationship between anergy and the likelihood of achieving complete remission. Our studies showed that defects in functions of T lymphocytes are sometimes corrected after successful treatment of Hodgkin's disease in children; this finding is in contrast to findings in adults where the deficiencies of the T lymphocytes persist in spite of successful treatment. Humoral immunity is usually intact at diagnosis, although elevated levels of circulating immune complexes have been found.

Figure 2. A ten-year-old boy presented with fever, mediastinal and hilar mass, hepatosplenomegaly and generalized lymphadenopathy. Biopsy of cervical node showed Hodgkin's disease mixed cellularity type. He was treated as stage IV disease with multiple drug chemotherapy only. He has remained disease-free for 12+ years.

Figure 2. A ten-year-old boy presented with fever, mediastinal and hilar mass, hepatosplenomegaly and generalized lymphadenopathy. Biopsy of cervical node showed Hodgkin's disease mixed cellularity type. He was treated as stage IV disease with multiple drug chemotherapy only. He has remained disease-free for 12+ years.

Immunological deficits may also result from the treatment of the primary disease. Overwhelming bacterial sepsis and meningitis occurs in asplenic patients who have had splenectomy or splenic irradiation. Fatal graft vs host reaction has also been reported in patients after receiving unirradiated blood products following intensive chemotherapy, lymphoid radiation, or both.

STAGING

Newly diagnosed patients with Hodgkin's disease are usually staged according to the staging classification proposed at the Ann Arbor Conference (Table 5). A clinical stage (CS) can be assigned after diagnostic evaluation as outlined in the preceding section; however, it would require a surgical exploration to assess the lymphoid tissue inaccessible by these investigations. The surgical procedures required for pathological staging (PS) consist of splenectomy (including a search for accessory spleens), wedge liver biopsies, sampling of abnormal or suspicious lymph nodes as well as a representative member of each echelon of para-aortic nodes, open marrow biopsy, and transposition of the ovaries in the females. Complete staging is essential for determining the choice of treatment modalities, since as many as one-third of patients have their clinical stage changed after a laparotomy, mostly upgraded due to the finding of involvement of the spleen and/ or celiac lymph nodes. In 110 previously untreated children with Hodgkin's disease seen at Memorial Sloan-Kettering Cancer Center during the past ten years, all but five children were staged pathologically and the extent of the disease is shown in Table 6.

Figure 3. An eight-year-old boy. who was diagnosed with Hodgkin's disease in 1968 and was treated with irradiation. He was first seen at Memorial Hospital in May 1970 with disseminated disease. In addition to his recurrent disease in the mediastinum, as shown by chest x-ray, the lymphangiogram showed massive bilateral enlarged para-aortic nodes with filling defects. After treatment with chemotherapy (adriamycin) there was marked decrease in the size of the nodes within three weeks. This patient has remained disease-free for 12+ years.

Figure 3. An eight-year-old boy. who was diagnosed with Hodgkin's disease in 1968 and was treated with irradiation. He was first seen at Memorial Hospital in May 1970 with disseminated disease. In addition to his recurrent disease in the mediastinum, as shown by chest x-ray, the lymphangiogram showed massive bilateral enlarged para-aortic nodes with filling defects. After treatment with chemotherapy (adriamycin) there was marked decrease in the size of the nodes within three weeks. This patient has remained disease-free for 12+ years.

Figure 4. Gallium scan of a six-year-old boy who had a right neck node which was biopsied as Hodgkin's disease nodular sclerosi n g type. Surgical staging 1 A. He was given involved field irradiation and remained disease-free lor 10+ years.

Figure 4. Gallium scan of a six-year-old boy who had a right neck node which was biopsied as Hodgkin's disease nodular sclerosi n g type. Surgical staging 1 A. He was given involved field irradiation and remained disease-free lor 10+ years.

The Ann Arbor classification also carries prognostic implications. Patients with systemic symptoms do not fare as well as those who are asymptomatic. On the other hand, direct invasion of neighboring tissue by proximate lymph nodes is associated with a more favorable outcome, as compared with truly disseminated disease. However, there is improved prognosis with such localized disease only when the localized extralymphatic involvement can be treated definitively by irradiation. Results from treatment of adult patients has indicated that extensive abdominal involvement, with presence of positive para-aortic and iliac nodes in stage IHA Hodgkin's disease, has a worse prognosis than that for patients with limited upper abdominal involvement. There is no data on the results of treatment as related to such substaging in children with Hodgkin's disease.

Table

TABLE 3OUTLINE OF PROCEDURES FOR DIAGNOSTIC WORKUP OF THE CHILD WITH HODGKIN'S DISEASE

TABLE 3

OUTLINE OF PROCEDURES FOR DIAGNOSTIC WORKUP OF THE CHILD WITH HODGKIN'S DISEASE

In general, all patients who are candidates for definitive radiation therapy should undergo surgical staging to determine the stage of disease, especially to exclude patients in stage IUB or stage IV. Children less than five years of age have a high risk of overwhelming infection after splenectomy; they are, therefore, staged clinically without abdominal surgical exploration. Combination chemotherapy is used instead. When extensive mediastinal disease is present at diagnosis, lymphangiography and laparotomy should be postponed until a short course of radiotherapy (1500 to 2000 rad during a two-week period) is first given to the area of bulky disease.

TREATMENT

Radiotherapy

It has been shown that irradiation alone is curative for localized Hodgkin's disease, provided a high enough dose (3500 to 4000 rad) is given. With this dosage less than 4% of the patients will have local recurrence. Various irradiation fields have been employed; thus, the radiation portal may encompass only the area of clinically evidenced disease (involved field), or radiation may be given to the tumor-bearing site as well as the next echelons of lymph nodes (extended field). For the extended field approach, the least number of radiation fields are used, to avoid uneven dosage at junctions of overlap. The mantle field includes all the major chains of lymph nodes above the diaphragm, and the inverted Y covers the subdiaphragmatic nodes down to the pelvis. In patients with disease above and below the diaphragm, a combination of these two portals (mantle field and inverted Y) constitutes total nodal irradiation, with a single junction at Tl 1-12 where few lymph nodes reside.

Table

TABLE 4INCIDENCE OF IMMUNODEFICIENCY IN CHILDREN WITH HODGKIN'S DISEASE

TABLE 4

INCIDENCE OF IMMUNODEFICIENCY IN CHILDREN WITH HODGKIN'S DISEASE

Table

TABLE 5THE CLINICAL STAGES OF HODGKIN'S DISEASE

TABLE 5

THE CLINICAL STAGES OF HODGKIN'S DISEASE

Figure 5. A ten-year-old girl was treated as stage HIB Hodgkin's disease nodular sclerosing type. She developed pain in the left shoulder. A bone scan showed increased uptake on the left scapular. She then was given chemotherapy and the symptoms disappeared and the repeat bone scan was normal. She remains disease-free.

Figure 5. A ten-year-old girl was treated as stage HIB Hodgkin's disease nodular sclerosing type. She developed pain in the left shoulder. A bone scan showed increased uptake on the left scapular. She then was given chemotherapy and the symptoms disappeared and the repeat bone scan was normal. She remains disease-free.

Figure 6. Chemotherapy protocol used at The Memorial SloanKettering Cancer Center for children with advanced Hodgkin's disease.

Figure 6. Chemotherapy protocol used at The Memorial SloanKettering Cancer Center for children with advanced Hodgkin's disease.

At Memorial Sloan-Kettering Cancer Center patients with pathological stages IA and I1A are given involved field irradiation. Those with stage IUA disease have a high risk of recurrence after radiotherapy alone and are presently treated with both chemotherapy and radiotherapy. In other centers, extended field irradiation is used instead for these patients with early stages (stages IA and UA) of Hodgkin's disease.

Chemotherapy

Radiation alone is not adequate for patients with advanced stages of Hodgkin's disease, that is, stages IIIB and IV. Combination chemotherapy has greatly improved the prognosis of these patients. We use a protocol ( Figure 6) consisting of multiple chemotherapeutic agents and achieve continuous complete remission in 75% of these patients. Other combinations of antineoplastic drugs have produced comparable results. It has been shown that maintenance chemotherapy is of little benefit in these patients who have achieved complete remission following induction therapy.

Treatment With Combined Modalities

Local recurrence remains a problem for patients treated with combination chemotherapy alone. This finding led to the introduction of radiotherapy given to areas of bulky disease as part of the definitive treatment program. This combined modality program has resulted in further improvement of prognosis of patients with advanced disease and in those patients who have relapsed from previous therapy. However, these patients are not able to tolerate the usual high dose of chemotherapy due to the severe myelosuppression caused by giving both chemotherapy and radiotherapy. Also, retardation of body growth and development in children treated with high dose irradiation remains a concern. Accordingly, we have reduced the dose of irradiation used in the combined approach to 2000 to 2400 rad and have achieved similar results. Donaldson and associates at Stanford have also reduced their radiation dose in children given both radiotherapy and chemotherapy. Thus, children with bone age less than six years are given 1500 rad, children with bone age six to ten years are given 2000 rad, and children with bone age 1 1 to 1 4 years are given 2500 rad.

Some pediatrie oncologists use chemotherapy in an adjuvant fashion with involved field irradiation for patients with localized disease, and avoid surgical staging and splenectomy. Results of treatment are comparable to those of similar stages treated with extended field irradiation alone. It remains a controversy as to whether this approach is preferable, especially in view of the longterm adverse side effects reported with the use of combined modality therapy.

RELAPSES

Two-thirds of the relapses in childhood Hodgkin's disease occur within the first two years after diagnosis with less than 3% appearing more than four years after therapy. Most relapses are in the form of lymphatic involvement (65%) and extra nodal extension (35%). Recurrence may be heralded by constitutional symptoms or biochemical abnormalities, such as elevation of serum copper, serum ferritin levels, and increased sedimentation rate. Diagnosis of recurrent disease should be confirmed histologically, since the symptoms and laboratory findings may be secondary to the effects of previous therapy, such as radiation fibrosis or opportunistic infections. Complete evaluation of the patient should be done as with the initial workup, although a repeat lymphangiogram might be technically difficult. Laparotomy is not done since radiotherapy alone is seldom the therapeutic choice for recurrent disease.

Table

TABLE 6HISTOPATHOLOGICAL STAGE OF 110 CHILDREN WITH HODGKIN'S DISEASE

TABLE 6

HISTOPATHOLOGICAL STAGE OF 110 CHILDREN WITH HODGKIN'S DISEASE

The approach to recurrent Hodgkin's disease depends on the therapy previously given to the patient. If radiation alone was given, treatment with combination chemotherapy is indicated. Further local irradiation might be given to areas of bulky disease or if marginal miss is suspected. Children who have received chemotherapy previously can be retreated with a similar protocol, if more than nine to 12 months have elapsed since the previous treatment. In such cases, sensitivity to chemotherapy is presumably retained. However, for patients who had relapsed early, or those who failed to achieve complete remission, a change over to non-cross-resistant combinations of a chemotherapy regimen should be tried.

The results of treatment are less satisfactory, but 40% to 50% of patients are still expected to be free from disease five years after treatment. The presence of relapse seems to have prognostic significance. Patients who had a prolonged first remission and those with nodal relapse have the best response to repeat therapy.

SIDE EFFECTS

Complications may arise from diagnostic or therapeutic maneuvers. Intestinal obstruction and wound dehiscence occur, though rarely, after staging laparotomy. Acute respiratory distress may result from oil embolism following lymphangiography, especially in those patients with massive mediasi ina I involvement. Myelosuppression occurs with both combination chemotherapy and extended field irradiation. Up to 15% of the bone marrow volume in adults is included in the mantle radiation field while 50% of the marrow is radiated by the inverted Y portal. Myelosuppression following extended field radiotherapy may be less severe in children, however, because the bone marrow extends moredistally in the young.

Radiation pneumonitis and pericarditis may appear several months after localized radiotherapy or mediastinal or pulmonary disease and symptoms may be potentiated by abrupt withdrawal of steroids.

Overwhelming bacterial infections have been reported in splenectomized patients. Its incidence has varied widely in different series, but it is probably much lower than the 10% initially reported. Since the pathogens in overwhelming bacterial infections are usually pneumococci, the introduction of pneumococcal vaccines (Pneumovax) provides further protection to these patients. However, the antibody response to pneumococcal vaccines in children given cancer therapy is inferior to the antibody response of normal children. At the present time, it is recommended that the vaccine be given two weeks prior to spJenectomy and to continue penicillin prophylaxis to protect against possible streptococcal and meningococcal sepsis.

Clinical and biochemical hypothyroidism, characterized by depression of T4, with or without elevation of TSH, has been reported in 66% of patients six years after having been given mantle irradiation. Changes occur insidiously, less than 15% of cases of hypothyroidism were diagnosed in the first year after treatment. It has been suggested that lymphangiography induces hyperplasia of thyroid follicles and increases the susceptibility of the thyroid to the effect of subsequent irradiation. Monitoring of thyroid hormone levels is recommended every six months for the first five years after irradiation. Replacement therapy should be given even in cases of subclinical hypothyroidism so as to avoid enlargement of the pituitary and the continual stimulation of the thyroid glands, which may result in malignant transformation.

Growth and development of body tissue can be impaired in children undergoing radiotherapy. Hypoplasia of cerebral bodies occurs if they are irradiated in a child less than six years of age or during puberty. The ovaries and the testicles are affected by scattered irradiation, which may be manifested as secondary amenorrhea and subnormal fertility. I n ad o lesee n t males, both the germ cells and the interstitial cells of the testes are susceptible, and serum luteinizing hormone ( LH) and follicle stimulating hormone (FSH) levels are elevated, in addition to the presence of decreased testosterone levels. Gonadal dysfunction may also result from combination chemotherapy which includes alkylating agents; however, pre-pubertal children seem to show signs of gonadal dysfunction to a lesser extent. Recovery of reproductive function occurs at various periods of time after cancer treatment, and pregnancies resulting in normal infants have been reported. However, pubertal males should be offered the facilities of sperm banking before treatment is started.

The success of treatment of childhood Hodgkin's disease has been shadowed by the occurrence of secondary malignancies in presumably-cured patients. Osteosarcoma, soft tissue sarcoma and thyroid carcinoma have been related to irradiation. Acute myeloid leukemia (AML) develops in 4% of patients within seven years of diagnosis and the risk is highest in patients who had received both chemotherapy and radiotherapy (Table?). The medium time of onset of AML is five years after therapy and usually goes through a pre-leukemic phase, in which cytogenetic abnormalities are present. Response to treatment has been dismal. Non-Hod gkin's lymphoma, which is usually of the lymphoblastic or poorly differentiated variety occurs in 4.4% of patients, and risk may be three to four times higher for those who have received both radiation therapy and chemotherapy. NonHod gkin's lymphoma usually occurs in abdominal lymph nodes and in other sites in the bowel. It has recently been reported that the incidence of secondary malignancy is less in patients receiving the ABVD regimen (adriamycin, bleomycin, vinblastine, and dacarbazine), as compared to those who were treated by the MOPP chemotherapy regimen (nitrogen mustard, oncovin, prednisone and procarbazine).

PROGNOSIS

Despite all the complications of treatment, the outlook for children with Hodgkin's disease remains excellent. Since 1970, 76% of patients with previously untreated Hodgkin's disease seen in the Department of Pediatrics at Memorial S loan- Kette ring Cancer Center are in continuous, complete remission five years after diagnosis, with a total of 84% of all the children initially seen still living (Figure 7). Eighty-one percent stage 1, 76% stage II, 74% stage III and 69% stage IV patients are without evidence of disease five years after diagnosis (Figure 8). Similar results are obtained from several other pediatrie series.

Stage-for-stage children with Hodgkin's disease have an overall better response than adults with Hodgkin's disease. Patients with constitutional symptoms and the presence of a large mediastinal mass are less likely to have a prolonged remission. It has been reported that patients with advanced stage nodular sclerosmg histology are prone to late relapses despite chemotherapy. Although patients with lympohocyte-depleted histology and vascular invasion are likely to do poorly, the Rye histopathological classification is otherwise of little prognostic significance due to improvement of treatment results. Only patients with unilateral upper cervical lymphadenopathy are thought to have a better outlook than other patients with stage I disease.

Table

TABLE 7ACTUARIAL RISK OF LEUKEMIA FOLLOWING THERAPY FOR HODGKIN'S DISEASE

TABLE 7

ACTUARIAL RISK OF LEUKEMIA FOLLOWING THERAPY FOR HODGKIN'S DISEASE

Figure 7. Overall remission and survival duration in children with Hodgkin's disease. This graph shows the survival curves of 184 previously untreated children with Hodgkin's disease who were treated between 1960 and 1969 (o) and between 1970 and 1981 (x).

Figure 7. Overall remission and survival duration in children with Hodgkin's disease. This graph shows the survival curves of 184 previously untreated children with Hodgkin's disease who were treated between 1960 and 1969 (o) and between 1970 and 1981 (x).

Figure 8. Remission duration by stage: 106 previously untreated children from 1970 to 1981. This graph shows remission duration curves for 108 previously untreated children with Hodgkin's disease, classified according to stage of disease at time of diagnosis.

Figure 8. Remission duration by stage: 106 previously untreated children from 1970 to 1981. This graph shows remission duration curves for 108 previously untreated children with Hodgkin's disease, classified according to stage of disease at time of diagnosis.

SUMMARY AND CONCLUSIONS

Major advances have been made in the past decade in the treatment of childhood Hodgkin's disease. Complete staging and careful treatment planning should provide the best outcome with minimal side effects in these patients. It should be remembered that treatment strategy should not be reduced in intensity, despite the reports of serious side effects in some of the children given maximal doses of chemotherapy, radiotherapy, or both.

REFERENCES

1. Tan C, D'Angio GJ. Exelby PR. et al: The changing management of childhood Hodgkin's Disease. Cancer 1975; 35:808-816.

2. Tan C, Jereb B. Chan KW, et al: Hodgkin's disease in children; results of management between 1970-1981. Cancer, to be published.

3. Chan WC. Tan C, Martine? A. et at: Involved field radiation therapy for early stage Hodgkin's disease in children. Cancer 1976; 37:1625-1632.

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TABLE 1

THE RYE HISTOPATHOLOGIC CLASSIFICATION OF HODGKIN'S DISEASE

TABLE 2

CHILDHOOD HODGKIN'S DISEASE: INITIAL CLINICAL FINDINGS IN 303 CHILDREN

TABLE 3

OUTLINE OF PROCEDURES FOR DIAGNOSTIC WORKUP OF THE CHILD WITH HODGKIN'S DISEASE

TABLE 4

INCIDENCE OF IMMUNODEFICIENCY IN CHILDREN WITH HODGKIN'S DISEASE

TABLE 5

THE CLINICAL STAGES OF HODGKIN'S DISEASE

TABLE 6

HISTOPATHOLOGICAL STAGE OF 110 CHILDREN WITH HODGKIN'S DISEASE

TABLE 7

ACTUARIAL RISK OF LEUKEMIA FOLLOWING THERAPY FOR HODGKIN'S DISEASE

10.3928/0090-4481-19830401-04

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