Symposium on Advances in Treatment of Cancer
Neuroblastoma and Wilms' Tumor Allen D. Schwartz, M.D. ,;,
From 1920 to 1950, malignant diseases were not included as one of the ten major fatal illnesses in children. Today, however, cancer is second only to accidents as the cause of death in children between the ages of 1 and 14 years. This is not because of a significant increase in the incidence of malignancies, but because of a reduction of fatalities from infectious diseases and the development of better surgical techniques to correct previously lethal congenital anomalies. Leukemia is by far the most common malignant disease of childhood. Neuroblastoma and Wilms' tumor are of nearly equal incidence and are exceeded only by malignancies of the brain as a cause of death from solid tumors in young children in the United States.
NEUROBLASTOMA The neuroblastoma originates from neural crest cells that give rise to the adrenal medulla and the sympathetic ganglia. It may present anywhere that sympathetic neural tissue normally occurs. The disease is diagnosed in the majority of patients prior to 5 years of age, with a peak incidence at age 2 years. The disease has been diagnosed in a number of children at birth. Over half the children have their primary tumor in the retroperitoneal region, arising either within the adrenal medulla or a sympathetic ganglion. A roentgenogram of the abdomen often reveals calcifications in the tumor. An intravenous pyelogram usually demonstrates displacement of the kidney if the neuroblastoma arises in the adrenal gland, with little or no distortion of the calyceal system (Fig. 1), in contrast to the distorted calyces usually seen with an intrarenal mass such as Wilms' tumor. A paravertebral tumor may displace one ureter laterally, sometimes causing ureteral compression and hydronephrosis. The tumor also commonly occurs in the posterior mediastinum, and may cause increasing dyspnea or pulmonary infection because of airway obstruction. When the neoplasm arises from a paraspinal sympathetic ganglion it has an unusual tendency to grow into the intervertebral *Associate Professor of Pediatrics and Head, Division of Pediatric Hematology and Oncology, University of Maryland Hospital, Baltimore, Maryland
Medical Clinics of North America- Vo!. 61, No. 5, September 1977
1053
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Figure 1. Suprarenal neuroblastoma with downward displacement of kidney. Note calcifications and lack of distortion of the calyceal system. (Courtesy of Herbert Kaiser, M.D.)
foramina causing spinal cord compression (Fig. 2). Careful periodic neurologic evaluation should be performed on the child with a paraspinal neuroblastoma since cord compression may necessitate emergency surgical decompression. The late recognition of this complication has resulted in permanent paraplegia. Involvement of the cervical symphathetic ganglion may cause Horner's syndrome. This may also occur as a complication of surgical removal of the tumor mass. Because the sympathetic nervous system is associated with the development and maintenance of normal eye color, neuroblastoma affecting the ophthalmic sympathetic nerves may result in heterochromia iridis, a difference in color between the two irises. 28 Metastatic disease is often the first sign of neuroblastoma, especially during the neonatal period. Subcutaneous nodules, often bluish in color, have been reported to occur in one third of neonates with neuroblastoma. 43 The liver often bears the brunt of metastatic dissemination, especially in the infant, with the tumor presenting as a rapidly growing hepatic neoplasm. The first signs of illness may be due to widespread disease with weight loss, irritability, fever, anemia, and bone pain from skeletal me-
NEUROBLASTOMA AND WILMS' TUMOR
1055
Figure 2. Posterior mediastinal neuroblastoma in a child who presented with difficulty in walking. Note the blockage of contrast material (arrow) from the intraspinal portion of the tumor.
tastases. Bone lesions appear roentgenographically as small, lytic defects with irregular margins and some periosteal reaction. They may be confused with primary bone tumors, histiocytosis, lymphoreticular malignancies, or an osteomyelitis. Retrobulbar soft tissue involvement may cause periorbital edema and proptosis. The presence of periorbital ecchymosis in a child with an abdominal mass should make one strongly suspicious of metastatic neuroblastoma (Fig. 3). Intracranial metastatic involvement commonly involves the meninges, but intracerebral metastases are unusual. Over half the children with neuroblastoma have bone marrow involvement, even in the absence of roentgenographic findings in the bones. The tumor cells are usually distinguishable from leukemic infiltration because they appear in small clusters, but the differentiation may be difficult when there is extensive marrow replacement. The cell arrangement in rosettes and the presence of neurofibrils, although characteristic of neuroblastoma, are often absent, and one cannot rely on marrow morphology alone to distinguish neuroblastoma from other malignancies that invade the bone marrow. Several children with neuroblastoma have been reported whose sole presenting symptom was persistent, intractable diarrhea which dramatically abated following surgical removal of the tumor.22 It is believed that the diarrhea is due to excessive secretion by the tumor of one or more catecholamines or their metabolic end products. Hypertension, however, seldom occurs, even in the presence of elevated urinary catecholamines.
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Figure 3. Periorbital ecchymosis in a child with metastatic neuroblastoma.
The association of acute myoclonic encephalopathy and neuroblastoma has been described by numerous authors. This usually consists of rapid multidirectional eye movements (opsoclonus), myoclonus, and truncal ataxia in the absence of increased intracranial pressure. In many instances neurologic improvement has followed tumor removal. The encephalopathy was at one time thought to be due to toxic neurologic effects of catecholamine catabolites, but neurologic symptoms have developed months following the removal of the tumor and the return to normal of previously elevated levels of urinary catecholamines.8 It has been suggested that an autoimmune factor, possibly an antibody directed against a neuroblastoma antigen, crossreacts with a common antigen in the cerebellar cells resulting in cerebellar damage. 5 The excellent prognosis for survival in patients with opsomyoclonus lends credence to such a mechanism. 1
Biochemical Abnormalities Studies in children with neuroblastoma have shown elevated urine levels of norepinephrine, its biochemical precursors, and its metabolites, including DOP A, dopamine, normetanephrine, homovanillic acid (RV A), and vanillylmandelic acid (VMA).46 According to Williams and Geer, 95 per cent of patients have increased urinary excretion of VMA, RVA, or both. 48 In occasional cases, however, there is no elevation of catecholamines. 47 It is therefore important to measure urinary catechola-
1057
NEUROBLASTOMA AND WILMS' TUMOR
mines in a child prior to surgical removal of a neuroblastoma or initiation of therapy in order to determine whether or not it is a catecholamine-producing tumor. This unique property of the neoplasm not only aids in diagnosis but is a useful means of assessing the response to therapy or detection of recurrence of tumor. LaBrosse33 has shown that periodic assays of the urinary excretion of VMA and HV A during the course of the disease is of prognostic value, with 80 to 90 per cent reliability (Table 1). By contrast, when only the excretion in the initial urine specimens is considered, the survival rate is the same for patient with normal and with elevated values. Urinary excretion of cystathionine is detectable in most children with neuroblastoma. 25 This intermediate metabolite in the conversion of methionine to cysteine has also been reported in patients with hepatoblastoma and other childhood neoplasms. 25 This lack of specificity limits its use diagnostically. Plasma carcinoembryonic antigen (CEA) levels are elevated in patients with neuroblastoma as well as those with a number of malignant and clinically active nonmalignant diseases. CEA determinations have little to offer diagnostically, but are useful in monitoring the response of disease to therapy.19
Pathology The neuroblastoma is a highly cellular tumor composed of small round cells with scant cytoplasm. Diagnosis by light microscopy is often difficult because of similarities between neuroblasts, lymphocytes, and other small round cell malignancies such as lymphomas, embryonal rhabdomyosarcoma, and Ewing's sarcoma. Occasionally, when a child presents with disseminated disease composed of primitive neuroblasts and no evidence of a primary tumor, the diagnosis can be made only on the basis of urinary catecholamine elevations. The ganglioneuroma, a more benign counterpart, is composed of large, mature ganglion cells with abundant cytoplasm, while the ganglioneuroblastoma is intermediate in the degree of cellular differentiation. The histologic appearance of an individual tumor, however, may show various degrees of cellular maturation. Although attempts have been made to correlate prognosis with the degree of tumor maturation,7 there appears to be a much better correlation between prognosis and both clinical staging of the disease and the patient's age at the time of diagnosis. Electron microscopy has been used to differentiate the neuroblasTable 1. Survival and Urinary Excretion ofVMA and HVA in Serial Specimens from Patients with Neuroblastoma 33
Normal ---> Normal Normal ---> Elevated Elevated --> Normal Elevated --> Elevated
VMA
HVA
SURVIVED
SURVIVED
31% 8% 82% 4%
71% 0% 80% 5%
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toma from other small round cell tumors. 37 The neuroblastoma has typical peripheral dendritic processes that contain longitudinally oriented microtubules. One notable feature is the presence of small, spherical, membrane-bound granules with electron-dense cores. The granules represent cytoplasmic accumulations of catecholamines. Electron microscopy has also been helpful in the identification of neuroblastoma cells in the marrow. 38 Staging and Prognosis The chance of survival of a patient with neuroblastoma appears to be inversely correlated with the age of the child at the time of diagnosis. Breslow and McCann6 reported a 74 per cent survival rate for children diagnosed between 0 and 11 months of age, a 26 per cent survival for those diagnosed between 12 and 23 months, and only a 12 per cent survival in those diagnosed at age 2 or over. The site of origin of the tumor also appears to be a factor that influences survival. A more favorable prognosis has been observed in children whose primary tumor is in the mediastinum. 16 The major reason, however, is that there is usually less dissemination at the time of diagnosis in patient with tumors arising above the diaphragm. Other factors reported to correlate with a good prognosis are increased numbers of bone marrow lymphoblasts,t4 and the feature of opsomyoclonus. 1 There is no significant difference between black and white children in regard to median duration of survival or percentage of long-term survivors,9 in contrast to the reports of a poorer survival in black children as compared to white children with acute lymphocytic leukemia. Evans and co-workersl2 proposed the following clinical staging system for children with neuroblastoma, and it appears to be helpful in predicting the patient's prognosis: Stage I. Tumors confined to the organ or structure of origin. Stage ll. Tumors extending in continuity beyond the organ or structure of origin, but not crossing the midline. Regional lymph nodes on the ipsilateral side may be involved. Stage Ill. Tumors extending in continuity beyond the midline. Regional lymph nodes may be involved bilaterally. Stage IV. Remote disease involving the skeleton, organs, soft tissues, or distant lymph node groups. Patients with a greater degree of spread tend to have a poorer prognosis, and those with Stage IV disease usually die of their malignancy. The few long-term survivors who had skeletal metastases were usually under a year of age at the time of diagnosis. 40 One unique group of patients with disseminated disease had such a good prognosis that a separate category called Stage IV-S was described to distinguish them from other patients with widespread involvement. These children had remote spread of tumor involving the liver, skin, and/or bone marrow but did not have roentgenographic evidence of bone metastases on complete skeletal survey. This metastatic pattern occurs most commonly during infancy. In one large series 7 the 2 year survival of those with Stage IV-S disease was 84 per cent as compared to a 5 per cent survival in those with Stage IV disease. This association
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NEUROBLASTOMA AND WILMS' TUMOR
between age at diagnosis, clinical staging, and survival is shown in Table 2. A number of other clinical staging systems have been used but the one proposed by Evans and colleagues is the one most commonly used at the present time. A number of children with neuroblastoma have been reported to have experienced spontaneous regression of their tumor. The diagnosis of neuroblastoma was made before the age of 6 months in 21 of 29 such cases collected by Everson and Cole. 15 The remainder were diagnosed between 6 and 24 months of age. This relationship of spontaneous regression to age has also been noted by Evans et al.,t3 who found that the majority of those with tumor regression were under 6 months of age and were usually those with Stage Il or IV-S disease. Spontaneous regression of tumor in patients with Stage I disease could not be evaluated because the tumor was usually surgically resected. In other instances malignant neuroblastomas have apparently undergone maturation into benign ganglioneuromas. 23 Most reviews indicate that 2 year survival in a child with neuroblastoma without evidence of disease is equivalent to cure. Fatal recurrences, however, have been reported beyond this period and have led to death more than 10 years after the initial diagnosis and apparent complete regression. 27 Treatment Evaluation of therapy for neuroblastoma is often difficult because of the tumor's unpredictable course with occasional spontaneous maturation or regression. Bodian4 reported that massive doses of vitamin BI2 led to cure, but a later evaluation of the collected experience of others failed to confirm his observations. 34,42 One likely explanation for Bodian's successful results was that his series was heavily weighted with young patients who experienced spontaneous remission. Reports that surgical assault on the primary tumor may be responsible for regression of distant metastases3I must also be interpreted with caution in view of the natural history of the disease. Complete surgical removal of the tumor may be accomplished in patients with Stage I and Il disease, but is often hazardous or impossible in those with Stage III disease. If complete tumor removal cannot be accomplished without endangering the life of the patient, residual tumor should be outlined with metal clips to guide the radiation therapist if this form of therapy is later chosen. Table 2. Two Year Survival of 234 Children with Neuroblastoma 7 AGE
STAGE
(MONTHS)
Neuroblastoma and Wilms' Tumor Allen D. Schwartz, M.D. ,;,
From 1920 to 1950, malignant diseases were not included as one of the ten major fatal illnesses in children. Today, however, cancer is second only to accidents as the cause of death in children between the ages of 1 and 14 years. This is not because of a significant increase in the incidence of malignancies, but because of a reduction of fatalities from infectious diseases and the development of better surgical techniques to correct previously lethal congenital anomalies. Leukemia is by far the most common malignant disease of childhood. Neuroblastoma and Wilms' tumor are of nearly equal incidence and are exceeded only by malignancies of the brain as a cause of death from solid tumors in young children in the United States.
NEUROBLASTOMA The neuroblastoma originates from neural crest cells that give rise to the adrenal medulla and the sympathetic ganglia. It may present anywhere that sympathetic neural tissue normally occurs. The disease is diagnosed in the majority of patients prior to 5 years of age, with a peak incidence at age 2 years. The disease has been diagnosed in a number of children at birth. Over half the children have their primary tumor in the retroperitoneal region, arising either within the adrenal medulla or a sympathetic ganglion. A roentgenogram of the abdomen often reveals calcifications in the tumor. An intravenous pyelogram usually demonstrates displacement of the kidney if the neuroblastoma arises in the adrenal gland, with little or no distortion of the calyceal system (Fig. 1), in contrast to the distorted calyces usually seen with an intrarenal mass such as Wilms' tumor. A paravertebral tumor may displace one ureter laterally, sometimes causing ureteral compression and hydronephrosis. The tumor also commonly occurs in the posterior mediastinum, and may cause increasing dyspnea or pulmonary infection because of airway obstruction. When the neoplasm arises from a paraspinal sympathetic ganglion it has an unusual tendency to grow into the intervertebral *Associate Professor of Pediatrics and Head, Division of Pediatric Hematology and Oncology, University of Maryland Hospital, Baltimore, Maryland
Medical Clinics of North America- Vo!. 61, No. 5, September 1977
1053
1054
ALLEN
D.
SCHW ARTZ
Figure 1. Suprarenal neuroblastoma with downward displacement of kidney. Note calcifications and lack of distortion of the calyceal system. (Courtesy of Herbert Kaiser, M.D.)
foramina causing spinal cord compression (Fig. 2). Careful periodic neurologic evaluation should be performed on the child with a paraspinal neuroblastoma since cord compression may necessitate emergency surgical decompression. The late recognition of this complication has resulted in permanent paraplegia. Involvement of the cervical symphathetic ganglion may cause Horner's syndrome. This may also occur as a complication of surgical removal of the tumor mass. Because the sympathetic nervous system is associated with the development and maintenance of normal eye color, neuroblastoma affecting the ophthalmic sympathetic nerves may result in heterochromia iridis, a difference in color between the two irises. 28 Metastatic disease is often the first sign of neuroblastoma, especially during the neonatal period. Subcutaneous nodules, often bluish in color, have been reported to occur in one third of neonates with neuroblastoma. 43 The liver often bears the brunt of metastatic dissemination, especially in the infant, with the tumor presenting as a rapidly growing hepatic neoplasm. The first signs of illness may be due to widespread disease with weight loss, irritability, fever, anemia, and bone pain from skeletal me-
NEUROBLASTOMA AND WILMS' TUMOR
1055
Figure 2. Posterior mediastinal neuroblastoma in a child who presented with difficulty in walking. Note the blockage of contrast material (arrow) from the intraspinal portion of the tumor.
tastases. Bone lesions appear roentgenographically as small, lytic defects with irregular margins and some periosteal reaction. They may be confused with primary bone tumors, histiocytosis, lymphoreticular malignancies, or an osteomyelitis. Retrobulbar soft tissue involvement may cause periorbital edema and proptosis. The presence of periorbital ecchymosis in a child with an abdominal mass should make one strongly suspicious of metastatic neuroblastoma (Fig. 3). Intracranial metastatic involvement commonly involves the meninges, but intracerebral metastases are unusual. Over half the children with neuroblastoma have bone marrow involvement, even in the absence of roentgenographic findings in the bones. The tumor cells are usually distinguishable from leukemic infiltration because they appear in small clusters, but the differentiation may be difficult when there is extensive marrow replacement. The cell arrangement in rosettes and the presence of neurofibrils, although characteristic of neuroblastoma, are often absent, and one cannot rely on marrow morphology alone to distinguish neuroblastoma from other malignancies that invade the bone marrow. Several children with neuroblastoma have been reported whose sole presenting symptom was persistent, intractable diarrhea which dramatically abated following surgical removal of the tumor.22 It is believed that the diarrhea is due to excessive secretion by the tumor of one or more catecholamines or their metabolic end products. Hypertension, however, seldom occurs, even in the presence of elevated urinary catecholamines.
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Figure 3. Periorbital ecchymosis in a child with metastatic neuroblastoma.
The association of acute myoclonic encephalopathy and neuroblastoma has been described by numerous authors. This usually consists of rapid multidirectional eye movements (opsoclonus), myoclonus, and truncal ataxia in the absence of increased intracranial pressure. In many instances neurologic improvement has followed tumor removal. The encephalopathy was at one time thought to be due to toxic neurologic effects of catecholamine catabolites, but neurologic symptoms have developed months following the removal of the tumor and the return to normal of previously elevated levels of urinary catecholamines.8 It has been suggested that an autoimmune factor, possibly an antibody directed against a neuroblastoma antigen, crossreacts with a common antigen in the cerebellar cells resulting in cerebellar damage. 5 The excellent prognosis for survival in patients with opsomyoclonus lends credence to such a mechanism. 1
Biochemical Abnormalities Studies in children with neuroblastoma have shown elevated urine levels of norepinephrine, its biochemical precursors, and its metabolites, including DOP A, dopamine, normetanephrine, homovanillic acid (RV A), and vanillylmandelic acid (VMA).46 According to Williams and Geer, 95 per cent of patients have increased urinary excretion of VMA, RVA, or both. 48 In occasional cases, however, there is no elevation of catecholamines. 47 It is therefore important to measure urinary catechola-
1057
NEUROBLASTOMA AND WILMS' TUMOR
mines in a child prior to surgical removal of a neuroblastoma or initiation of therapy in order to determine whether or not it is a catecholamine-producing tumor. This unique property of the neoplasm not only aids in diagnosis but is a useful means of assessing the response to therapy or detection of recurrence of tumor. LaBrosse33 has shown that periodic assays of the urinary excretion of VMA and HV A during the course of the disease is of prognostic value, with 80 to 90 per cent reliability (Table 1). By contrast, when only the excretion in the initial urine specimens is considered, the survival rate is the same for patient with normal and with elevated values. Urinary excretion of cystathionine is detectable in most children with neuroblastoma. 25 This intermediate metabolite in the conversion of methionine to cysteine has also been reported in patients with hepatoblastoma and other childhood neoplasms. 25 This lack of specificity limits its use diagnostically. Plasma carcinoembryonic antigen (CEA) levels are elevated in patients with neuroblastoma as well as those with a number of malignant and clinically active nonmalignant diseases. CEA determinations have little to offer diagnostically, but are useful in monitoring the response of disease to therapy.19
Pathology The neuroblastoma is a highly cellular tumor composed of small round cells with scant cytoplasm. Diagnosis by light microscopy is often difficult because of similarities between neuroblasts, lymphocytes, and other small round cell malignancies such as lymphomas, embryonal rhabdomyosarcoma, and Ewing's sarcoma. Occasionally, when a child presents with disseminated disease composed of primitive neuroblasts and no evidence of a primary tumor, the diagnosis can be made only on the basis of urinary catecholamine elevations. The ganglioneuroma, a more benign counterpart, is composed of large, mature ganglion cells with abundant cytoplasm, while the ganglioneuroblastoma is intermediate in the degree of cellular differentiation. The histologic appearance of an individual tumor, however, may show various degrees of cellular maturation. Although attempts have been made to correlate prognosis with the degree of tumor maturation,7 there appears to be a much better correlation between prognosis and both clinical staging of the disease and the patient's age at the time of diagnosis. Electron microscopy has been used to differentiate the neuroblasTable 1. Survival and Urinary Excretion ofVMA and HVA in Serial Specimens from Patients with Neuroblastoma 33
Normal ---> Normal Normal ---> Elevated Elevated --> Normal Elevated --> Elevated
VMA
HVA
SURVIVED
SURVIVED
31% 8% 82% 4%
71% 0% 80% 5%
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toma from other small round cell tumors. 37 The neuroblastoma has typical peripheral dendritic processes that contain longitudinally oriented microtubules. One notable feature is the presence of small, spherical, membrane-bound granules with electron-dense cores. The granules represent cytoplasmic accumulations of catecholamines. Electron microscopy has also been helpful in the identification of neuroblastoma cells in the marrow. 38 Staging and Prognosis The chance of survival of a patient with neuroblastoma appears to be inversely correlated with the age of the child at the time of diagnosis. Breslow and McCann6 reported a 74 per cent survival rate for children diagnosed between 0 and 11 months of age, a 26 per cent survival for those diagnosed between 12 and 23 months, and only a 12 per cent survival in those diagnosed at age 2 or over. The site of origin of the tumor also appears to be a factor that influences survival. A more favorable prognosis has been observed in children whose primary tumor is in the mediastinum. 16 The major reason, however, is that there is usually less dissemination at the time of diagnosis in patient with tumors arising above the diaphragm. Other factors reported to correlate with a good prognosis are increased numbers of bone marrow lymphoblasts,t4 and the feature of opsomyoclonus. 1 There is no significant difference between black and white children in regard to median duration of survival or percentage of long-term survivors,9 in contrast to the reports of a poorer survival in black children as compared to white children with acute lymphocytic leukemia. Evans and co-workersl2 proposed the following clinical staging system for children with neuroblastoma, and it appears to be helpful in predicting the patient's prognosis: Stage I. Tumors confined to the organ or structure of origin. Stage ll. Tumors extending in continuity beyond the organ or structure of origin, but not crossing the midline. Regional lymph nodes on the ipsilateral side may be involved. Stage Ill. Tumors extending in continuity beyond the midline. Regional lymph nodes may be involved bilaterally. Stage IV. Remote disease involving the skeleton, organs, soft tissues, or distant lymph node groups. Patients with a greater degree of spread tend to have a poorer prognosis, and those with Stage IV disease usually die of their malignancy. The few long-term survivors who had skeletal metastases were usually under a year of age at the time of diagnosis. 40 One unique group of patients with disseminated disease had such a good prognosis that a separate category called Stage IV-S was described to distinguish them from other patients with widespread involvement. These children had remote spread of tumor involving the liver, skin, and/or bone marrow but did not have roentgenographic evidence of bone metastases on complete skeletal survey. This metastatic pattern occurs most commonly during infancy. In one large series 7 the 2 year survival of those with Stage IV-S disease was 84 per cent as compared to a 5 per cent survival in those with Stage IV disease. This association
1059
NEUROBLASTOMA AND WILMS' TUMOR
between age at diagnosis, clinical staging, and survival is shown in Table 2. A number of other clinical staging systems have been used but the one proposed by Evans and colleagues is the one most commonly used at the present time. A number of children with neuroblastoma have been reported to have experienced spontaneous regression of their tumor. The diagnosis of neuroblastoma was made before the age of 6 months in 21 of 29 such cases collected by Everson and Cole. 15 The remainder were diagnosed between 6 and 24 months of age. This relationship of spontaneous regression to age has also been noted by Evans et al.,t3 who found that the majority of those with tumor regression were under 6 months of age and were usually those with Stage Il or IV-S disease. Spontaneous regression of tumor in patients with Stage I disease could not be evaluated because the tumor was usually surgically resected. In other instances malignant neuroblastomas have apparently undergone maturation into benign ganglioneuromas. 23 Most reviews indicate that 2 year survival in a child with neuroblastoma without evidence of disease is equivalent to cure. Fatal recurrences, however, have been reported beyond this period and have led to death more than 10 years after the initial diagnosis and apparent complete regression. 27 Treatment Evaluation of therapy for neuroblastoma is often difficult because of the tumor's unpredictable course with occasional spontaneous maturation or regression. Bodian4 reported that massive doses of vitamin BI2 led to cure, but a later evaluation of the collected experience of others failed to confirm his observations. 34,42 One likely explanation for Bodian's successful results was that his series was heavily weighted with young patients who experienced spontaneous remission. Reports that surgical assault on the primary tumor may be responsible for regression of distant metastases3I must also be interpreted with caution in view of the natural history of the disease. Complete surgical removal of the tumor may be accomplished in patients with Stage I and Il disease, but is often hazardous or impossible in those with Stage III disease. If complete tumor removal cannot be accomplished without endangering the life of the patient, residual tumor should be outlined with metal clips to guide the radiation therapist if this form of therapy is later chosen. Table 2. Two Year Survival of 234 Children with Neuroblastoma 7 AGE
STAGE
(MONTHS)
