EuropeanJournalof

Eur J Pediatr (1991) 150 : 789-792 034061999100166E

Pediatrics

9 Springer-Verlag1991

Familial neural crest tumours C. M. Robertson 1, J. C. Tyrrell 2, and J. Pritchard 1 1Department of Haematology and Oncology, The Hospital for Sick Children, Great Ormond Street, London WCIN 3JH, United Kingdom 2Department of Paediatrics, Northampton General Hospital, Billing Road, Northampton NN1 5AD, United Kingdom Received November 28, 1990 / Accepted March 8, 1991

Abstract. It is known that some cases of neural crest tumours are hereditary. We report the clinical and cytogenetic findings in a three-generation, extended family, four m e m b e r s of which developed single or multiple neural crest tumours (ganglioneuroma, ganglioneuroblastoma or neuroblastoma). To our knowledge, this is the first report of a family with three generations affected. No constitutional cytogenetic abnormality was found in the two m e m b e r s tested. We also review the literature on familial neural crest tumours, with emphasis on those affecting m o r e than one generation. It is important that a detailed family history, with particular reference to tumours, is obtained in all cases of childhood cancer.

Key words: Neural crest tumours - N e u r o b l a s t o m a Ganglioneuroblastoma - Ganglioneuroma - Multiple tumours

one or m o r e somatic cells in the offspring. This theory conforms with the finding that: (a) the familial neural crest turnouts tend to cluster in the earlier years of life and (b) the incidence of multiple tumours is higher than in non-familial cases [15, 16].

Case reports Case 1. A 5-year-old, previously fit girl, (Fig. 1, IV, 1) an only child, presented in September 1987 with a 2-month history of limb pain, malaise, fever and weight loss. She was found to have a hard mass in the left loin and dullness to percussion, with decreased air entry, over the right upper throax. Chest and abdominal X-ray films showed speckled calcification in the left hypochondrium and a left lower thoracic paravertebral mass extending through the diaphragm and a separate, large extra-

1/~ Introduction Though most neural crest tumours (neuroblastoma, ganglioneuroblastoma and ganglioneuroma) are apparently sporadic, several familial cases have been reported [2, 4 - 6 , 8, 10-13, 16-19, 21-23]. The pedigrees affecting two generations suggest an autosomal dominant m o d e of inheritance [2, 4 - 6 , 8, 11, 22, 23]. (Another type of neural crest tumour, p h a e o c h r o m o c y t o m a , can be inherited as part of multiple endocrine neoplasia type 2a, but this is a separate entity). In 1972, Knudson and Strong postulated a two mutation model to explain the occurrence of hereditary and non-hereditary neuroblastoma [15]. In non-hereditary cases two somatic mutations must occur in one cell to give rise to a single turnout. In hereditary cases the first mutation occurs in a parental germ cell and a second mutation then occurs in Offprint requests to: C. M. Robertson, Childhood Cancer Research Group, 57 Woodstock Road, Oxford OX2 6HJ, United Kingdom Abbreviations: OPEC = oncovin, Cis-platinum, cyclophos-

phamide and teniposide

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0 =Female 1 [7 =Male IV or0 =Affected /(~/orJ=Dead Fig. 1. Pedigree of family

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790 Initial treatment was with 3 weekly courses of O P E C Oncovin, cis-platinum, cyclophosphamide and teniposide (VM26) [20]. The abdominal tumour became smaller with the chemotherapy but the size and configuration of the thoracic tumours were unchanged. After six courses of OPEC, repeat staging showed a 'good partial remission' with no measurable 'active' metastatic disease. The residual abdominal mass was then removed: histology confirmed ganglioneuroblastoma (the histological pattern characteristic of tumours resected after 'induction' therapy such as OPEC). Consolidation treatment was with high dose melphalan and total body irradiation, with autologous bone marrow transplantation. Despite this intensive therapy she relapsed, 5 months later, at multiple sites and died soon afterwards. Case 2. In 1986, at the age of 30 years, the father of case 1 (Fig. 1, III, 7) had been investigated for abdominal pain and a chest X-ray film had revealed a large right sided mediastinal mass and a smaller left paravertebral mass. These findings were confirmed by computerised axial tomography. The right sided mass was resected and histology showed a ganglioneuroblastoma. A Chest X-ray film 7 months after surgery showed a normal right hemithorax but the left paravertebral mass was unchanged. At present he is alive and well; his urinary catecholamine metabolite excretion is normal.

Fig. 2. Case 1. Chest X-ray film demonstrating a large extrapleural mass at the right apex and a separate left paravertebral mass extending from the abdomen

Fig. 3. Case 1. A section of the C A T scan abdomen demonstrating the partly calcified tumour of the left adrenal gland pleural mass at the right apex (Fig. 2). Computerised axial tomography confirmed that there was no anatomical continuity between the two thoracic masses and demonstrated a large calcified left supra-renal mass with enlarged para-aortic nodes (Fig. 3). A 99mTc bone scan showed increased uptake in the metaphyseal regions around the knees and also in L1, the tenth left rib, the skull and both humeri. An n3I-meta-iodobenzylguanidine scan showed uptake at multiple skeletal sites and in the abdominal mass, but not into either thoracic mass. Urinary catecholamine metabolite (vanillylmandelic acid and homovanillic acid) excretion was grossly raised. Bone marrow aspirates and trephine biopsies contained malignant cells positive to anti-neural monoclonal antibodies [1]. 'Trucut' biopsy of the right upper chest mass showed ganglioneuroblastoma (Fig. 4) whilst biopsy of the supra-renal mass revealed neuroblastoma (Fig. 5). It was concluded that the child had multiple primary neural crest tumours, consisting of an adrenal neuroblastoma with multipie metastases (stage 4) and two thoracic tumours, one proven histologically to be a ganglioneuroblastoma.

Case 3. In 1956, at the age of 25 years, the paternal grandmother of case 1 (Fig. 1., II, 6), had been found to have a pelvic tumour on ante-natal examination. As a consequence her son, (case 2) was delivered by caesarian section. Subsequently a labarotomy was performed and the tumour was described as 'firm and closely adherent to the sacrum'. It was not resected and the biopsy taken contained only 'fibro-fatty tissue'. The description of this tumour was compatible with a diagnosis of pelvic ganglioneuroma or ganglioneuroblastoma. She is, now, still alive and well; her urinary catecholamine metabolite excretion is normal. Case 4. In 1951, at the age of 14 years, the paternal great uncle of case 1 (Fig. 1., II, 3) had died of multiple and disseminated tumours. He had presented with neck and back pain, followed by a progressive weakness of his lower limbs. On examination he had a complete paraplegia, with a sensory level at T8 and a large firm abdominal mass in the right hypochondrium. Spinal and chest Xray films revealed destructive lesions in many vertebrae and also bilateral thoracic paravertebral masses. Open biopsy of the adominal mass was performed and the histology was reported as 'ganglioneuroma'. The patient was then transferred to the care of the neurosurgeons who performed a thoracic laminectomy with partial removal of extrathecal and extravertebral tumour. Histology reports described this tumour as 'less differentiated' and 'much more celluar' than the abdominal tumour. It also stated that the 'specimen consists for the most part of masses of clumps of cells in fibrous and fibrillary tissue' and 'some of them (cells) are arranged in groups suggesting ill-formed rosettes'. It was thought to be a 'ganglioneuroblastoma' or 'differentiated sympatheticoblastoma' (i.e. differentiated neuroblastoma). The laminectomy did not produce any clinical improvement and his overall condition deteriorated, despite 'a few small doses of X-ray therapy'. He died 4 months after his initial presentation. The post-mortem report described firm masses either side of the thoracic vertebrae which had invaded the spinal cord. There was also a tumour in the right loin close to the adrenal gland. Other deposits were found in the omentum, next to the lumbar spine and also in the wall of the pelvis. The histological specimens from this case were unobtainable for further review. Case 5. In 1980, aged 2 years, the second cousin of case 1 (on her paternal grandfathers' side) (Fig. 1, IV, 2) died of neuroblastoma. He had presented a few weeks previously with a right sided abdominal mass and anaemia but no other constitutional symptoms. Ultrasound scan and intravenous pyelogram confirmed a mass arising from the right kidney. There was no evidence of pulmonary

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Fig. 4. Case 1. Histological section of the biopsy of thoracic mass, showing ganglioneuroblastoma

Fig. 5. Case 1. Histological section of the biopsy of suprarenal mass, showing neuroblastoma metastases on chest X-ray film. Laparotomy was therefore performed to resect a presumed Wilms' tumour. A large tumour of renal origin, which had invaded the liver and diaphragm was found along with some enlarged para-aortic lymph nodes. As the tumour was mobilised the patient became severely hypertensive and then suffered a cardiovascular collapse and died during the operation. The histopathological diagnosis was intra-renal neuroblastoma. The result of the urinary catecholamine metabolite excretion became available only after surgery: the levels of both were grossly raised. Post-mortem did not reveal any other tumours. A detailed family tree was obtained and the pedigree is shown in Fig. 1. There was no relevant history on the maternal side of the family of case 1. Chromosome preparations using standard air-drying procedures were made from peripheral blood lymphocytes from case 1 and her father. Trypsin-Giemsa banded karyotypes [9] were prepared and no obvious structural chromosome abnormalities de-

tected in either case. Special attention was paid to the short arm of chromosome 1 (see discussion). Case 2 was shown to be heterozygous for the relatively common polymorphic heterochromatic region on the long arm of chromosome 1, 1 qh. Case 1 had inherited 1 qh from her father.

Discussion T h e histology of this g r o u p of n e u r a l crest t u m o u r s varies f r o m n e u r o b l a s t o m a to m o r e b e n i g n forms such as g a n g l i o n e u r o b l a s t o m a or g a n g l i o n e u r o m a . T h e r e are n o w m a n y r e p o r t s of familial n e u r a l crest t u r n o u t s a n d these have b e e n r e v i e w e d by K n u d s o n a n d Strong [15] a n d K u s h n e r et al. [16] b u t only in s e v e n of these reports is t h e r e m o r e t h a n o n e g e n e r a t i o n affected [2, 4, 5, 8, 11, 22, 23]. T h e r e are five p r e v i o u s reports in which

792 parents of children with n e u r o b l a s t o m a a p p a r e n t l y had g a n g l i o n e u r o b l a s t o m a or g a n g l i o n e u r o m a [4, 5, 8, 11, 23] and one which described a father with an unresectable ' n e u r o b l a s t o m a ' w h o r e m a i n e d well after low dose r a d i o t h e r a p y [2]; this t u m o u r p r e s u m a b l y regressed or ' m a t u r e d ' . W o n g et al. r e p o r t e d two children with n e u r o b l a s t o m a whose father was f o u n d to have raised urinary c a t e c h o l a m i n e metabolites, but with no detectable t u m o u r , suggestive of a t u m o u r that has ' m a t u r e d ' [22]. It is interesting to n o t e that, of these seven reports, five describe the o c c u r r e n c e of multiple t u m o u r s in a single individual [5, 8, 11, 22, 23]. To o u r k n o w l e d g e the family, r e p o r t e d here, is the first family with three generations affected by neural crest t u m o u r s . Cases 1, 2 and 4 d e m o n s t r a t e one of the recognised features of familial t u m o u r s in that all of t h e m had multiple primaries. H o w e v e r , the two children (case 1 and 4) p r e s e n t e d with t u m o u r at ages of 5 and 14 years (relatively late for n e u r o b l a s t o m a ) which does not support the t h e o r y of familial t u m o u r s occurring at an earlier age than non-familial tumours. Case 5 (Fig. 1, IV, 5), a l t h o u g h interesting, is f r o m a separate part of the family and m a y be no m o r e t h a n coincidental. It is interesting that case 1 p r e s e n t e d with stage 4 n e u r o b l a s t o m a at the same time as having two relatively benign t u m o u r s in the chest. It is possible that w h e n t h e y first d e v e l o p e d , the thoracic t u m o u r s were also n e u r o b lastomas. If this is the case it is interesting to speculate w h y the thoracic t u m o u r s had ' m a t u r e d ' whilst the abd o m i n a l t u m o u r progressed and metastasised. It is well k n o w n that neural crest t u m o u r s have a t e n d e n c y to maturation and regression [14]. P e r h a p s an additional genetic 'hit' h a d o c c u r r e d only in the a b d o m i n a l t u m o u r . I n the c h r o m o s o m e analysis of case 1 and 2, special attention was paid to the short a r m of c h r o m o s o m e 1 because of the d e m o n s t r a t i o n of its fl:equent i n v o l v e m e n t in r e a r r a n g e m e n t s in n e u r o b l a s t o m a cells [7]. T h o u g h no constitutional l p c h r o m o s o m a l a b n o r m a l i t y has b e e n d e t e c t e d in patients with neural crest t u m o u r s , as in case 1 and her father, a m o r e subtle 'sub-microscopic' m u t a tion might be present and D N A f r o m the surviving affected family m e m b e r s and f r o m case 1, has b e e n stored for future studies. A d v a n c e s in the cytogenetics and molecular genetics of t u m o u r s are rapid, so identification o f ' c a n c e r ' families by epidemiological studies is of critical importance. In case 1, it was k n o w n f r o m the outset that her father was affected b y a similar t u m o u r . H o w e v e r , the m o r e e x t e n d e d positive family history was only obtained a considerable time afterwards. This case d e m o n strates the i m p o r t a n c e of obtaining an initial, detailed family history, with particular reference to t u m o u r s , in all cases of childhood cancer. A s t h e r a p y for neurob l a s t o m a i m p r o v e s and m o r e children survive to adulth o o d [3] there iwill be m o r e o p p o r t u n i t y to study their offspring. B y analogy with the m u c h m o r e Commonly inherited r e t i n o b l a s t o m a , cytogenetic analysi~ of these rare familial cases m a y eventually lead to t h e identification of the gene or genes whose a b e r r a n t expression or function m a y be involved in the d e v e l o p m e n t of b o t h hereditary and sporadic n e u r o b l a s t o m a .

Acknowledgements. We thank the family for allowing us to investigate their family history. Dr. Marion Malone kindly provided the photographs of the histology. Dr. John Cowell performed the cytogenetic work. Dr. Jon Pritchard received funding from the Imperial Cancer Research Fund.

References 1. Allen PM, Garson JA, Harper E, Asset V, Coakham HB, Brownell B, Kemshead JT (1983) Biological characterisation and clinical applications of a monoclonal antibody recognizing an antigen restricted to neuroectodermal tissues. Int J Cancer 31 : 591-598 2. Arenson EB, Hutter J J, Restuccia RD, Holton CP (1976) Neuroblastoma in father and son. JAMA 235 : 727-729 3. Birch JM, Marsden HB, Morris Jones PH, Pearson D, Blair V (1988) Improvements in survival from childhood cancer; resuits of a population based survey over 30 years. Br Med J 296 : 1372-1376 4. Bond JV (1976) Familial neuroblastoma and ganglioneuroblastoma (letter) JAMA 236 : 561-562 5. Carlsen NLT (1986) Epidemiological investigations on neuroblastomas in Denmark 1943 : 1980. Br J Cancer 54: 977-988 6. Chatten J, Voorhess ML (1967) Familial neuroblastoma. N Engl J Med 277:1230-1236 7. Christiansen H, Lampert F (1988) Tumour karyotype discriminates between good and bad prognostic outcome in neuroblastoma. Br J Cancer 57 : 121-126 8. Clausen N, Andersson P, Tommerup N (1989) Familial occurrence of neuroblastoma, Von Recklinghausen's neurofibromatosis, Hirschprung's agangliosis and jaw-winking syndrome. Acta Paediatr Scand 78 : 736-741 9. Cowell JK (1980) Consistent chromosome abnormalities associated with mouse bladder epithelial cell lines transformed in vitro. J Natl Cancer Inst 65 : 955-961 10. Feingold M, Gheradi GJ, Simons C (1971) Familial neuroblastoma and trisomy 13 (letter) Am J Dis Child 121 : 451 11. Gerson JM, Chatten J, Eisman S (1974) Familial neuroblastoma - a follow-up. N Engl J Med 290: !487 12. Griffin ME, Bolande RP (1969) Familial neuroblastoma with regression and maturation to ganglioneurofibroma. Pediatrics 43 : 377-382 13. Hardy PC, Nesbit ME (1972) Familial neuroblastoma: Report of a kindred with a high incidence of infantile tumours. J Pediatr 80 : 74-77 14. Knudson AG, Meadows AT (1976) Developmental genetics of neuroblastoma. J Natl Cancer Inst 57: 675-682 15. Knudson AG, Strong LC (1972) Mutation and cancer: neuroblastoma and phaeochromocytoma. Am J Hum Genet 24: 514-532 16. Kushner BH, Gilbert F, Helson L (1986) Familial neuroblastoma; case reports, literature review and etiologic considerations. Cancer 57 : 1887-1893 17. Leape LL, Lowman JT, Loveland GC (1978) Multifocal nondisseminated neuroblastoma: report of two cases in siblings. J Pediatr 92: 75-77 18. Mancini AF, Rosito P, Faldella G, Serra L, Vallicelli R, Vechi V, Vivarelli F, Paolucci G (1982) Neuroblastoma in a pair of identical twins. Med Pediatr Oncol 10: 45-51 19. Pegelow CH, Ebbin AJ, Powars D, Towner JW (1975) Familial neuroblastoma. J Pediatr 87 : 763-765 20. Shafford EA, Rogers DW, Pritchard J (1984) Advanced neuroblastoma: improved response rate using a multiagent regimen (OPEC) including sequential cisplatin and VM-26. J Clin Oncol 2: 742-747 21. Wagget J, Aherne G, Aherne W (1973) Familial neuroblastoma: report of two sib pairs. Arch Dis Child 48:63-66 22. Wong KY, Hanenson IB, Lampkin BC (1971) Familial neuroblastoma. Am J Dis Child 121:415-416 23. Zimmermann J (1951) Ganglioneuroblastome als erbliche Systemerkrankung des sympathicus. Beitr Anat Pathol 111: 355-372

Familial neural crest tumours.

It is known that some cases of neural crest tumours are hereditary. We report the clinical and cytogenetic findings in a three-generation, extended fa...
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