Spontaneous regression of disseminated neuroblastoma

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December 1974 The J o u m a l o f P E D I A T R I C S

Spontaneous regression of disseminated neuroblastoma Two infants with disseminated neuroblastoma experienced spontaneous regression and recovery without the benefit of therapy. A review o f present knowledge o f this disease indicates that children under one year of age with a specific pattern o f metastatic involvement may have a good chance of experiencing a spontaneous regression. The authors' suggest that these infants be observed for a perDd of time before a decision is made to initiate therapy.

Allen D. Schwartz, M.D.,* Mahboubeh Dadash-Zadeh, M.D., Hahng Lee, M.D., and Jerry J. Swaney, M.D., Chicago, IlL

N E U R O B L A S T O M A is a m a l i g n a n t n e o p l a s m w h i c h arises f r o m primitive s y m p a t h e t i c neuroblasts. It is the s e c o n d m o s t c o m m o n solid t u m o r in y o u n g children, e x c e e d e d in i n c i d e n c e only by brain tumors. W e recently cared for two children with disseminated neuroblastoma who spontaneously recovered without any f o r m of treatment. This e x p e r i e n c e suggests that treatm e n t in selected cases may not always be indicated, and t h e child should be o b s e r v e d for a period of t i m e b e f o r e a decision is m a d e to initiate therapy. CASE REPORTS Case I. N. G., a one-week-old black girl, was referred to Children's Memorial Hospital because of hepatomegaly. Her liver was palpated to the level of the umbilicus. A liver-spleen scan demonstrated abnormal radionuclide localization in the right hepatic lobe (Fig. 1, A). Biopsy of the liver yielded tissue diagnostic of neuroblastoma. Intravenous pyelogram, bone marrow examination, and roentgenographic examinations of the chest and skeleton were normal. Urinary excretion of VMA measured at 12 days of age was elevated to 240 t~g/mg of From the Department o f Pediatrics, Northwestern University Medical School and the Children "sMemorial Hospital. Supported in part by Grant CA-O7431from the National Cancer Institute, by United States Public Health Grant RR-054 75 and by the Otho S.A. Sprague Memorial Institute. *Reprintaddress:The Children'sMemorial Hospital, 2300 Children'sPlaza, Chicago,IlL 60614.

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creatinine (normal: 20 #g/mg creatinine or less). A diagnosis of neuroblastoma was made which involved the liver, although the location of the primary tumor was undetected. No therapy was administered, and the child was carefully followed as an outpatient. The liver slowly decreased to normal size over the ensuing months. On liver-spleen scans performed at 2 and 3 months of age there was only minimal localization of radionuclide in the right lobe. On a scan done at 9 months there was no evidence of localization (Fig. 1, B). During this period of time the urinary VMA values decreased progressively to 147, 25, 21, and 10 t~g/mg of creatinine at one, two, three, and five months, respectively. At one year of age the child is well with no clinical, roentgenographic, or chemical evidence of tumor. Abbreviation used VMA: vanilmandelic acid

I

Case II. M. L., a two-month-old Caucasian girl, was referred to Children's Memorial Hospital with a chief complaint of "lumps in the skin" since birth. The lesions were purple and blanched with pressure. A biopsy of one of the skin lesions was diagnostic of neuroblastoma. Results of a bone marrow examination, liver-spleen scan, and roentgenograms of the chest and skeleton were normal. An intravenous pyelogram revealed lateral displacement of the left ureter suggesting a left paravertebral mass. Urinary VMA excretion was elevated to 90 v.g/mg of creatinine. A diagnosis of disseminated neuroblastoma was made, the primary tumor probably arising from a left paravertebral sympathetic ganglion in the abdomen. No therapy was administered and the child was followed as an outpatient. The skin lesions completely resolved by 4 months of age (Fig. 2), at

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0'0

2 MONTHS

2 ~ MONTHS

3112 MONTHS

3 MONTHS

4 MONTHS

Fig. 2. Spontaneous resolution of the skin lesions of Case II.

Fig. 1. ,4, 99mTcsulfur colloid liver-spleen scan demonstrating abnormality in the right hepatic lobe of Case I. B, Repeat scan eight months later with no evidence of the defect. which time a repeat intravenous pyelogram was normal with no evidence of the paravertebral mass. The urinary excretion of VMA decreased to 8 p,g/mg of creatinine. At 6 months of age the child appears well and has no evidence of neuroblastoma. DISCUSSION W h e n d i s s e m i n a t i o n of n e u r o b l a s t o m a occurs the m a l i g n a n c y is often fatal. However, a n u m b e r of children have been reported to have experienced spontaneous regression of this tumor despite the presence of metastases. Those who eventually recover usually have certain characteristics in c o m m o n ; the two most important predictive features are the age of the child at the

time of diagnosis and the pattern of organ involvement. The diagnosis was made before the age of 6 months in 21 of 29 cases of neuroblastoma collected by Everson and Cole 1 in which spontaneous regression occurred. The r e m a i n d e r were diagnosed b e t w e e n 6 a n d 24 months of age. This relationship of prognosis to age has been noted by others. 24 T h e i n c i d e n c e of s p o n t a n e o u s regression may, in fact, be more common than is clinically evident, as suggested by the observations of Beckwith and Perrin. 5 These investigators detected the presence of microscopic in situ neuroblastomas in the adrenal glands of a significant n u m b e r of infants under the age of 3 months with no clinical evidence of tumor upon whom postmortem examinations were performed. They estimated the incidence of neuroblastoma in situ to be about 40 times greater than the n u m b e r of cases of clinically diagnosed disease. Based upon their findings, they proposed that the great majority of these tumors either degenerated or underwent differentiation to normal tissue. The site of origin also has been considered to be a factor influencing survival, and a more favorable prognosis has been observed in children with mediastinal n e u r o b l a s t o m a . 3,6 A n e v a l u a t i o n by E v a n s and coworkers 7 of 100 cases confirmed this observation, but it was felt that the prognosis was good because such patients seldom had metastatic disease. Based on their findings, these investigators proposed a clinical staging for children with neuroblastoma which appeared to be

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helpful in estimating the ultimate prognosis. Those patients with r e m o t e m e t a s t a s e s i n v o l v i n g s k e l e t o n , organs, soft tissues, or d i s t a n t l y m p h nodes were classified as having Stage IV disease and had the worst prognosis. One group of patients with disseminated disease had such a good prognosis, however, that a separate category called Stage IV S was proposed to dist i n g u i s h t h e m from o t h e r p a t i e n t s with w i d e s p r e a d involvement. This special group of children had remote spread of tumor involving the liver, skin, and/or bone m a r r o w w i t h o u t r o e n t g e n o g r a p h i c e v i d e n c e of b o n e metastases. The favorable prognosis of this pattern of dissemination is well documented, and the pattern appears to occur most commonly in infancy. Eighteen of twenty infants under the age of one year with Stage IV S disease collected by D'Angio and associates 8 appeared to be cured of their disease. The two year survival of all of those with Stage IV S disease was 84% as compared to 5% survival in those with Stage IV disease. The response of neuroblastoma to chemotherapy is o f t e n d r a m a t i c ; the two m o s t c o m m o n l y e m p l o y e d drugs are vincristine sulfate and cyclophosphamide. 9"13 The most impressive results appear to occur in children under the age of one year. 13"15 Yet despite the welldocumented initial regression of tumor, present evidence indicates that the addition of chemotherapy has done little to improve survival in this disease. 15,16 The unpredictable course of neuroblastoma with its occasional spontaneous maturation or regression makes the tumor not only unusual, b u t causes difficulty in evaluating the effect of therapeutic intervention. The impressive collection of cases reported by Bodian 17suggested that massive doses of vitamin B12led to cure, but subsequent evaluation of the collected experience of others failed to confirm these observations. 18 A review of Bodian's 32 patients who experienced clinical remission revealed that 21 were under one year of age and seven were from one to two years of age. Two of the rem a i n i n g four had c o m p l e t e surgical r e m o v a l of the tumor. Thus only two older patients, both with localized mediastinal disease, had some tumor remaining following surgery and were treated with vitamin B12 alone. One likely explanation for Bodian's observations is that his series was heavily weighted with young patients who experienced spontaneous regression. The complications of therapy, considered an acceptable hazard in most children with neuroblastoma, must be considered very carefully before initiating treatment in the child considered to have a good prognosis. This is especially true if such therapy has yet to be of proved value. A 6% operative nortality rate was reported by Lingley and associates 19in 50 patients, and 12 operative

The Journal of Pediatrics December 1974

deaths were noted in 134 patients by Koop and Johnson. 2~Such risk apperas justified if the surgical attempt is to remove a tumor which might otherwise be fatal. This 6% to 9% case fatality rate may not be acceptable in the infant with Stage IV S disease who has a 90% chance of survival. 4 The observation that surgical assault on the p r i m a r y t u m o r may i n f l u e n c e r e g r e s s i o n o f d i s t a n t metastases 4 must be interpreted with caution in view of the natural history of the disease. The problems resulting from uncontrolled studies have already been demonstrated by the possible misinterpretation of the effectiveness of vitamin B12. The use of therapeutic agents is also not without risk. The death of an eight-month-old child with disseminated neuroblastoma due to bone marrow suppression resulting from radiation therapy was reported by Griffin and Bolande. 22 A second child in the same family with disseminated disease had a spontaneous cure after the parents refused all therapy becuase of their previous experience. The long-term effects of such drugs must also be considered, such as the complications of cyclophosphamide therapy on the gonad, 21 if one is expecting a high rate of survival. The authors do not suggest that all patients with neuroblastoma be treated in a conservative manner. The extremely high fatality rate in older children with regional extension or disseminated disease warrants an aggressive approach with further evaluation of newer therapeutic agents. An exception, however, should be considered in the management of the infant with the special pattern of metastases classed as Stage IV S disease. The very nature of spread makes complete surgical removal or radiation to all tumor sites a most difficult and often impossible task. There is also little reason to believe that chemotherapy with vincristine and cyclophosphamide is responsible for the good prognosis of the child with Stage IV S disease, since these drugs have not made an impact on the survival of children with Stage III or IV disease. Is Our present policy is to withhold treatment in children under the age of one year with Stage IV S disease unless mechanical problems arise because of large tumor masses. The n u m b e r of patients who u n d e r g o s p o n t a n e o u s r e m i s s i o n w i t h o u t t h e r a p y is u n k n o w n , and c u r r e n t e x p e r i e n c e is too l i m i t e d to a l l o w e s t a b l i s h m e n t o f g u i d e l i n e s for therapeutic intervention. To date, however, our policy of a preliminary period of observation in selected instances appears to be justified. The authors wish to express their appreciation to Dr. John G. Raffensperger for his helpful advice in the preparation of this manuscript.

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REFERENCES 1. Everson TC, and Cole WH: Spontaneous regression of cancer: A study and abstract of reports in the world medical literature and of personal communications concerning spontaneous regression of malignant disease, Philadelphia, 1966, W. B. Saunders Company, pp. 88-163. 2. Dargeon HW: Neuroblastoma, J PEDIATR61:456, 1962. 3. deLorimier AA, Bragg KU, and Linden G: Neuroblastoma in childhood, Am J Dis Child 118:441, 1969. 4. D'Angio GJ, Evans AE, and Koop CE: Special patterns of widespread neuroblastoma with a favorable prognosis, Lancet 1:1046, 1971. 5. Beckwith JB, and Perrin EV: In situ neuroblastoma: A contribution to the natural history of neural crest tumors, Am J Pathol 43:1089, 1963. 6. Filler RM, Traggis DG, Jaffe N, and Vawter GF: Favorable outlook for children with mediastinal neuroblastoma, J Pediatr Surg 7:136, 1972. 7. Evans AE, D'Angio GJ, and Randolph J: A proposed staging for children with neuroblastoma, Cancer 27:374, 1971. 8. D'Angio GJ, Evans AE, and Koop CE: Special pattern of widespread neuroblastoma with a favourable prognosis, Lancet 1:1046, 1971. 9. Sullivan MP, Nora AH, Kulapongs P, Lane DM, Windmiller J, and Thurman WG: Evaluation of vincristine sulfate and cyclophosphamide chemotherapy for metastatic neuroblastoma, Pediatrics 44:685, 1969. 10. Pinkel D, Pratt C, Holton C, James D. Wrenn E, and Hustu HO: Survival of children with neuroblastoma treated with combination chemotherapy, J PEDIATR 73:928, 1968. 11. Windmiller J, Berry DH, Haddy TB, Vietti TJ, and Sutow WW: Vincristine sulfate in the treatment of neuroblastoma in children, Am J Dis Child 111:75, 1966. 12. Thurman WG, Fernbach DJ, and Sullivan MP: Cyclo-

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