Original Article
25
Ganglioneuroma: To Operate or Not to Operate Alba Sánchez-Galán1 Saturnino Barrena1 Alejandra Vilanova-Sánchez1 Sara Hernández A. Martín1 Sergio Lopez-Fernandez1 Purificación García2 Manuel Lopez-Santamaria1 Leopoldo Martínez1 Juan A. Tovar1 1 Department of Pediatric Surgery, Hospital Universitario La Paz,
Madrid, Spain 2 Department of Pediatric Oncology, Hospital Universitario La Paz, Madrid, Spain
Address for correspondence Juan A. Tovar, PhD, Department of Pediatric Surgery, Hospital Universitario La Paz, P° La Castellana 261, Madrid 28046, Spain (e-mail: [email protected]).
Abstract
Keywords
► ganglioneuroma ► ganglioneuroblastoma ► neuroblastoma ► resection/expectant ► complications
received May 20, 2013 accepted after revision September 16, 2013 published online December 10, 2013
Introduction Ganglioneuroma (GN) is a benign, differentiated variety of neurogenic tumor. It is often asymptomatic and may be diagnosed by serendipity. Surgical removal is the treatment of choice. However, it has been suggested that postoperative complications and sequelae might outweigh the benefits of this approach. The purpose of the present study was to examine these issues in a large experience of neural tumors. Methods Patients treated between 1992 and 2012 were retrospectively reviewed. Modern imaging, measurement of catecholamine metabolite excretion and metaiodobenzylguanidine were used for workup. Surgical treatment aimed at complete resection. Complications and sequelae were recorded. Literature was searched for regrowth or malignant transformation of GN. Results Of 227 patients with neural tumors, 24 were GN patients (12 abdominal, 11 thoracic and 1 cervical with 8 dumbbell extensions). Six children were symptomatic (three with abdominal pain and mass, one with stridor or dysphonia, and one each with anisocoria and opsomyoclonus). However, 18 (75%) were asymptomatic and the diagnosis was incidental. Several tumors were large and involved more than one body space. There were no neurologic symptoms in eight cases with dumbbell extension. Complete resection was achieved in 20 children (83%) whereas gross residual was left in four. Postoperative complications were: Horner syndrome (3 patients), mild scoliosis (1 patient), adhesive bowel obstruction (1 patient) and acute urinary retention (1 patient). There was no evidence of either regrowth or malignant behavior in residual masses left in place after follow-up of 84 (1–194) months. Conclusions There were a limited number of general minor complications in this series that did not include cases of regrowth or malignant transformation. However, these unfavorable events were occasionally reported in the literature. Since diagnosis of GN cannot be ascertained before removal of the mass, this should remain the aim of the treatment, although limiting the chances of complications to a minimum even if incomplete resection is the price to pay. Nonoperative attitudes should not be recommended in all cases, but they are certainly justified in some.
© 2014 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0033-1358790. ISSN 0939-7248.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Eur J Pediatr Surg 2014;24:25–30.
Ganglioneuroma
Sánchez-Galán et al.
Introduction Peripheral neuroblastic tumors are the most common solid extracranial malignancies in infancy and childhood, and include the histotypes: neuroblastoma (NB), ganglioneuroblastoma (GNB), and ganglioneuroma (GN).1 These tumors of neural crest origin arise from the sympathetic ganglia or adrenal medulla and represent a continuous spectrum of differentiation and neuronal maturation.2 NB is the most common and highly malignant variety, with a histologic pattern of abundant neuroblasts and scarce stroma. GNB contains neuroblastic and stromal elements and can be divided into two forms: nodular, with malignant potential and unfavorable prognosis, and intermixed (stroma-rich) with favorable prognosis.3 Finally, GN represents the benign and less frequent form. It is a stroma-predominant tumor, with more or less mature ganglion cells. Immature elements, such as neuroblasts, intermediate cells, and mitotic figures are not part of pure GN.4,5 GN is probably always the end-result of the maturation of fetal or postnatal NB or GNB. It is most times asymptomatic and it is often diagnosed by serendipity. However, in some instances it can attain large size and displace or compress the neighboring organs.2 In contrast with NB, GN does not respond to chemotherapy and surgical removal after presumptive diagnosis based on imaging, absence of amine uptake or catecholamine excretion has been the treatment of choice for many years. This is apparently in contradiction with the need for tissue diagnosis required for application of protocols for neural tumors. However, some studies showed that this attitude was not devoid of risks of complications, permanent sequelae or even death. In a collective Italian series of 139 children operated upon for GN, 22 (15%) had surgical complications, 7 of which were severe enough as to be lethal in 2 instances.3 Furthermore, a series of 23 children having complete or nearcomplete removal of GN, the occurrence of 7 (30%) complications like Horner’s syndrome, chylothorax, pneumothorax, arm pain or adhesive intestinal obstruction6 led the authors, from one of the leading institutions in Europe, to cast some doubts on the pertinence of this management strategy for a benign tumor.6 The aim of this study was to examine these issues on the basis of an extensive experience with neural tumors.
Methods Neural tumors treated at our institution between 1992 and 2012, were retrospectively reviewed. The diagnosis of GN was established histologically on the basis of the International Neuroblastoma Pathology Classification.4,5 Tumors with immature, neuroblastic elements or those resulting from maturation after treatment of NB were excluded. Clinical features including gender, age, weight, location and size of tumors, symptoms at diagnosis, histology, treatment and complications were recorded. Laboratory tests included urinary excretion of vanillylmandelic (VMA) and homovanillinic acid (HVA); serum neuron-specific enolase (NSE); ferritin and European Journal of Pediatric Surgery
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lactate dehydrogenase (LDH). N-myc amplification and 1p36 deletion were ruled out when possible. All patients had conventional imaging and metaiodobenzylguanidine (MIBG) studies. Tumor volume in mL was estimated on the basis of measurements of the pathology specimen using the following formula: π/6 length width height. Data were expressed as medians and ranges. Surgical treatment was performed in all cases bearing in mind that likely mature, benign tumors do not require radical, risky procedures. Complete resection was achieved when possible using occasionally combined approaches (two body spaces, laminotomy), but avoiding vital risks or damage to other organs. Resection was defined as complete when all macroscopic tumor bulk was excised and incomplete when macroscopic residual was left in place. Complications appearing in the first three postoperative months where considered as early ones, whereas complications or sequelae persisting beyond that point were considered as late or permanent. Patients were followed up closely in the first postoperative year and annually ever since.
Results Out of 227 patients with peripheral neural tumors, 24 (10%), 13 males and 11 females, had GN and were included in the study. The median age at diagnosis was 60 (range 36–168) months or 5 (range 3–14) years. Patients weighed 21 (range 13–58) Kg. Twelve tumors (50%) were abdominal (two adrenal, one pelvic, and two with extension to the thorax); 11 (46%) were thoracic (►Fig. 1) (three with cervical involvement [►Fig. 2]); and one (4%) was cervical. Eight cases (33%) had dumbbell intraspinal extension (►Fig. 3). The tumors were equally distributed on the left and the right sides (11 on each side) and two were medial or bilateral. Most patients were asymptomatic and the diagnosis was made incidentally. Only six (25%) had symptoms (three abdominal mass and pain, one with stridor or dysphonia, one anisocoria, and one opsomyoclonus) (►Table 1). None of the children with invasion of the spinal canal had symptoms of either cord or radicular compression. Three children were referred to us after receiving some form of chemotherapy elsewhere without response. Complete primary resection was achieved in 20 patients (two required a second operation), and only incomplete removal was possible in four. The median volume of the removed tumor was 63 (12.2–299.5) mL. Either laminotomy or foramen enlargement were necessary in two of the eight cases with intraspinal extension in order not to leave bulky tumor mass. There were complications in six patients (25%) in whom complete resection was achieved. These are summarized in ►Table 2. Early complications were: one adhesive bowel obstruction requiring laparotomy, one acute urinary retention resolved spontaneously, and one cerebrospinal fluid leak requiring intercostal drainage after transthoracic, intraspinal approach. Late complications were minimal scoliosis in one case and persistent Horner syndrome in three. In none of the four patients with incomplete resection, regrowth of the
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26
Sánchez-Galán et al.
Fig. 1 Coronal (A) and sagittal (B) MRI corresponding to a large upper thoracic GN on a 3-year-old asymptomatic girl. After complete removal, the patient developed Horner syndrome. GN, ganglioneuroma; MRI, magnetic resonance imaging.
Fig. 2 (A, B) A huge cervicothoracic ganglioneuroma in a 6-year-old girl with a palpable neck mass. (C) MRI showed how the mass displacement of the airway to the right. Complete removal was performed through a cervicosternotomy. Later the patient presented a Horner syndrome. MRI, magnetic resonance imaging.
Fig. 3 A 12-year-old girl with anisocoria; MRI revealed a huge upper thoracic GN (A) with invasion of the spinal canal (B) through four foramina. Incomplete resection was performed. GN, ganglioneuroma; MRI, magnetic resonance imaging.
European Journal of Pediatric Surgery
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Ganglioneuroma
Ganglioneuroma
Sánchez-Galán et al.
Table 1 Clinical features in 24 patients with GN treated between 1992 and 2012 Patient
Age (mo)
Gender
Tumor location
Tumor volume (mL)
Dumbbell extension
Symptoms
1
36
F
Thoracic
104.7
Yes
Asymptomatic
2
36
F
Thoracic (cervical component)
15.7
No
Asymptomatic
3
36
M
Cervical
N.A.
No
Stridor/dysphonia
4
48
M
Thoracic
14
No
Asymptomatic
5
48
F
Abdominal (pelvic)
N.A.
No
Asymptomatic
6
48
M
Abdominal
155.5
Yes
Abdominal pain
7
48
M
Abdominal
207.3
No
Asymptomatic
8
48
F
Thoracic
201.6
No
Asymptomatic
9
52
M
Abdominal
164.9
No
Asymptomatic
10
53
M
Abdominal (adrenal)
19.6
No
Asymptomatic
11
59
F
Thoracic
23.6
Yes
Asymptomatic
12
60
F
Thoracic
15.7
Yes
Asymptomatic
13
60
M
Abdominal (thoracic component)
37.7
No
Opsomyoclonus
14
65
F
Thoracic (cervical component)
125.7
No
Asymptomatic
15
84
M
Abdominal (thoracic component)
55.6
Yes
Asymptomatic
16
84
M
Abdominal
34.5
Yes
Asymptomatic
17
84
M
Abdominal
63.4
No
Asymptomatic
18
96
F
Abdominal (adrenal)
N.A.
No
Asymptomatic
19
108
M
Thoracic
12.2
No
Asymptomatic
20
132
F
Thoracic
62.8
Yes
Asymptomatic
21
132
F
Thoracic (cervical component)
240.9
Yes
Anisocoria
22
144
F
Abdominal
299.5
No
Abdominal pain
23
156
M
Thoracic
N.A.
No
Asymptomatic
24
168
M
Abdominal
73.3
No
Abdominal pain
Abbreviations: F, female; GN, ganglioneuromas; M, male; N.A., not available.
residual mass left in place was observed upon 0.5 to 16 years of follow-up. No malignant transformation was observed either in any case. The overall follow-up was 84 (1–194) months or 7 (1–16) years.
Discussion The present series represents a large neural tumor experience and confirms most features observed in other studies2,3,6: late age at diagnosis, more or less balanced distribution between male and female patients, some preference for thoracic location and constantly benign behavior. The proportion of complications in these studies was comparable although it should be pointed out that most of them were relatively minor if not irrelevant (the most frequent one was Horner syndrome that can appear also before operation). The more severe complications were observed in a collective multi-institutional study in which the standards of surgical care were necessarily uneven.3 Observation alone would therefore appear as an acceptable attitude for GN. However, it would be dangerous to European Journal of Pediatric Surgery
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ignore that (1) imaging and biological markers might not be enough to ascertain this diagnosis, (2) malignant transformation of a verified GN is definitely possible, and (3) large size, invasion of other body spaces and metastases may pose particular problems. The present study cannot answer the question of whether reliable diagnosis of GN is possible without tissue studies. Inclusion criteria involved retrospective histological diagnosis of GN, absence of either biological activity or amine uptake and no biological predictors of malignity. The same can be said about the series of study by Retrosi et al.6 In fact, it is difficult to rule out the presence of neuroblastic elements in GN based upon biopsies and even after histological assessment of the entire operative specimen. Retrospective review of the pathology of 76 GN in the Italian collaborative study permitted to reclassify one-third of them as GNBs.3 The process of differentiation and maturation of neuroblastic tumors may not be homogeneous and cell clusters at different stages may coexist in the same tumor. Up to 93% of 49 GN studied by Geoerger et al had “slightly immature” neuroblasts.2 In the same study, 39% of these patients had increased
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28
Ganglioneuroma
Sánchez-Galán et al.
29
Patient
Resection
Observations
Early complications
Sequelae
1
C
Preoperative chemotherapy elsewhere
No
No
2
C
Tumor involved the stellate ganglion
Horner syndrome
Horner syndrome
3
I
Retropharyngeal residual mass
No
No
4
C
Thoracoscopy
No
No
5
I
Preoperative chemotherapy and radiotherapy elsewhere, three attempts for resection and ureteral diversion
No
No
6
I
Complete resection in a second time. Ureteral diversion and neurosurgery
No
No
7
C
Preoperative chemotherapy elsewhere
No
No
8
C
–
No
No
9
I
Residual mass attached to the vena cava
No
No
10
C
Retroperitoneoscopy
Urinary retention
No
11
C
–
Horner syndrome
Horner syndrome
12
C
Neurosurgery
CSF leak
Scoliosis
13
C
–
No
No
14
C
Cervicosternotomy
Horner syndrome
Horner syndrome
15
C
–
No
No
16
I
Adrenalectomy. Complete resection in a second time
No
No
17
C
–
No
No
18
C
–
No
No
19
C
Thoracoscopy
No
No
20
C
–
No
No
21
I
Costovertebral residual mass
No
No
22
C
Adrenalectomy
Intestinal obstruction
No
23
C
–
No
No
24
C
–
No
No
Abbreviations: C, complete; GN, ganglioneuromas; I, incomplete.
levels of catecholamines and 57% had some degree of MIBG uptake. Increased catecholamine levels were observed in some GNs by other investigators.7 On the other hand, normal catecholamine excretion8–11 and/or absent MIBG uptake does not formally rule out the presence of neuroblastic elements in the tumor.12 Therefore, diagnosis based only on imaging, age, location, absence of MIBG uptake or metabolite excretion or biopsy alone can be misleading (and dangerous) in a limited number of cases. The present study cannot answer either the question of whether reactivation of a dormant GN and malignant transformation into NB is at all possible. These events were present neither in comparable series from a single institution13 nor in a large German registry.2 Probably, the relative rarity of pure GN and the likely long time span necessary for malignant transformation to occur make most series useless for this purpose. Large multinational studies able to determine prevalence of these events are lacking and a multi-institutional
series of 139 GNs only reported one regrowth that remained stable after biopsy and two unrelated ovarian and thyroid malignancies appearing at adult age.3 However, it would be foolish to ignore that malignant transformation of GN into NB has been occasionally reported14,15 and that other neural malignancies like peripheral nerve sheath tumors16–20 or nonneural ones like rhabdomyosarcoma21 developed in previously diagnosed GNs have also been observed. Nonoperative attitudes for large GNs, particularly when they involve more than one body space and, particularly when they invade the spinal canal, are hard to embrace. These benign and generally inert masses occasionally displace vital structures like the trachea or the genitourinary tract interfering with breathing (one of the cases herein reported), bladder emptying or childbearing.22 They can also cause intestinal obstruction,23 neck stiffness24 or scoliosis.25 Some rare cases have metastases containing fully mature tissue that attest that they were originally fetal or postnatal European Journal of Pediatric Surgery
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Table 2 Surgical features and complications appeared in 24 patients with GN treated in our hospital between 1992 and 2012
Ganglioneuroma
Sánchez-Galán et al.
silent NBs subsequently differentiated.26–28 Finally, intraspinal extensions of dumbbell GNs are particularly prone to be surgically removed. No patient in the present series had spinal cord or radicular compression, but these have been occasionally reported.29,30 In conclusion, there are no enough convincing arguments to prone nonoperative treatment for all GNs. Although neither the present study nor other similar ones3,6 showed evidence of regrowth, malignant transformation, or severe symptoms of GN, there are reports in the literature showing that all these are possible. GN deserves an individualized approach: complete removal should be the aim of treatment only if it can be achieved without major risk for the patient and/or for neighboring structures. Imaging-based estimation of the surgical risk factors used in current staging of NB1 should be used when planning operations for GN. The surgeon should minimize the risks of complications. If necessary, incomplete resection is warranted and safe in view of the good prognosis of these tumors. In some particular cases, nonoperative management of GN may be justified.
12
13
14
15
16
17
18
19
Conflict of Interest The authors report no conflict of interest. 20
References 1 Cecchetto G, Mosseri V, De Bernardi B, et al. Surgical risk factors in
2
3 4
5
6
7
8 9
10
11
primary surgery for localized neuroblastoma: the LNESG1 study of the European International Society of Pediatric Oncology Neuroblastoma Group. J Clin Oncol 2005;23(33):8483–8489 Geoerger B, Hero B, Harms D, Grebe J, Scheidhauer K, Berthold F. Metabolic activity and clinical features of primary ganglioneuromas. Cancer 2001;91(10):1905–1913 De Bernardi B, Gambini C, Haupt R, et al. Retrospective study of childhood ganglioneuroma. J Clin Oncol 2008;26(10):1710–1716 Shimada H, Ambros IM, Dehner LP, et al. The International Neuroblastoma Pathology Classification (the Shimada system). Cancer 1999;86(2):364–372 Shimada H, Umehara S, Monobe Y, et al. International neuroblastoma pathology classification for prognostic evaluation of patients with peripheral neuroblastic tumors: a report from the Children’s Cancer Group. Cancer 2001;92(9):2451–2461 Retrosi G, Bishay M, Kiely EM, et al. Morbidity after ganglioneuroma excision: is surgery necessary? Eur J Pediatr Surg 2011;21(1): 33–37 Lucas K, Gula MJ, Knisely AS, Virgi MA, Wollman M, Blatt J. Catecholamine metabolites in ganglioneuroma. Med Pediatr Oncol 1994;22(4):240–243 Voorhess ML. Neuroblastoma with normal urinary catecholamine excretion. J Pediatr 1971;78(4):680–683 LaBrosse EH, Comoy E, Bohuon C, Zucker JM, Schweisguth O. Catecholamine metabolism in neuroblastoma. J Natl Cancer Inst 1976;57(3):633–638 Worthington DJ, Hammond EM, Eldeeb BB, et al. Neuroblastoma— when are urinary catecholamines and their metabolites ’normal’? Ann Clin Biochem 1988;25(Pt 6):620–626 Cotterill SJ, Pearson AD, Pritchard J, et al. Clinical prognostic factors in 1277 patients with neuroblastoma: results of The European
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Neuroblastoma Study Group ’Survey’ 1982-1992. Eur J Cancer 2000;36(7):901–908 Claudiani F, Stimamiglio P, Bertolazzi L, et al. Radioiodinated metaiodobenzylguanidine in the diagnosis of childhood neuroblastoma. Q J Nucl Med 1995;39(4, Suppl Suppl 1):21–24 Retrosi G, Sebire NJ, Bishay M, et al. Brain lipid-binding protein: a marker of differentiation in neuroblastic tumors. J Pediatr Surg 2011;46(6):1197–1200 Moschovi M, Arvanitis D, Hadjigeorgi C, Mikraki V, TzortzatouStathopoulou F. Late malignant transformation of dormant ganglioneuroma? Med Pediatr Oncol 1997;28(5):377–381 Kulkarni AV, Bilbao JM, Cusimano MD, Muller PJ. Malignant transformation of ganglioneuroma into spinal neuroblastoma in an adult. Case report. J Neurosurg 1998;88(2):324–327 Chandrasoma P, Shibata D, Radin R, Brown LP, Koss M. Malignant peripheral nerve sheath tumor arising in an adrenal ganglioneuroma in an adult male homosexual. Cancer 1986;57(10): 2022–2025 Fletcher CD, Fernando IN, Braimbridge MV, McKee PH, Lyall JR. Malignant nerve sheath tumour arising in a ganglioneuroma. Histopathology 1988;12(4):445–448 Damiani S, Manetto V, Carrillo G, Di Blasi A, Nappi O, Eusebi V. Malignant peripheral nerve sheath tumor arising in a “de novo” ganglioneuroma. A case report. Tumori 1991;77(1):90–93 Drago G, Pasquier B, Pasquier D, et al. Malignant peripheral nerve sheath tumor arising in a “de novo” ganglioneuroma: a case report and review of the literature. Med Pediatr Oncol 1997;28(3): 216–222 Meng ZH, Yang YS, Cheng KL, Chen GQ, Wang LP, Li W. A huge malignant peripheral nerve sheath tumor with hepatic metastasis arising from retroperitoneal ganglioneuroma. Oncol Lett 2013; 5(1):123–126 Kimura S, Kawaguchi S, Wada T, Nagoya S, Yamashita T, Kikuchi K. Rhabdomyosarcoma arising from a dormant dumbbell ganglioneuroma of the lumbar spine: a case report. Spine 2002;27(23): E513–E517 Kurzel RB, Durso N. Pelvic ganglioneuroma during pregnancy. A case report. J Reprod Med 1990;35(3):286–288 Cronin EM, Coffey JC, Herlihy D, et al. Massive retroperitoneal ganglioneuroma presenting with small bowel obstruction 18 years following initial diagnosis. Ir J Med Sci 2005;174(2): 63–66 Gary C, Robertson H, Ruiz B, Zuzukin V, Walvekar RR. Retropharyngeal ganglioneuroma presenting with neck stiffness: report of a case and review of literature. Skull Base 2010; 20(5):371–374 Velyvis JH, Durbhakula S, Wurapa R, Carl AL. Ganglioneuroma with scoliosis of the thoracic spine: a case report. Spine J 2005;5(4): 457–460 Garvin JH Jr, Lack EE, Berenberg W, Frantz CN. Ganglioneuroma presenting with differentiated skeletal metastases. Report of a case. Cancer 1984;54(2):357–360 Srinivasan R, Koliyadan KS, Krishnand G, Bhat SS. Retroperitoneal ganglioneuroma with lymphnode metastasis: a case report. Indian J Pathol Microbiol 2007;50(1):32–35 Jung HR, Kang KJ, Kwon JH, Kang YN. Adrenal ganglioneuroma with hepatic metastasis. J Korean Surg Soc 2011;80(4):297–300 Duhem-Tonnelle V, Vinchon M, Defachelles AS, Cotten A, Dhellemmes P. Mature neuroblastic tumors with spinal cord compression: report of five pediatric cases. Childs Nerv Syst 2006;22(5): 500–505 Skaggs DL, Roberts JM, Codsi MJ, Meyer BC, Moral LA, Masso PD. Mild gait abnormality and leg discomfort in a child secondary to extradural ganglioneuroma. Am J Orthop 2000;29(2):111–114
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Ganglioneuroma: To Operate or Not to Operate Alba Sánchez-Galán1 Saturnino Barrena1 Alejandra Vilanova-Sánchez1 Sara Hernández A. Martín1 Sergio Lopez-Fernandez1 Purificación García2 Manuel Lopez-Santamaria1 Leopoldo Martínez1 Juan A. Tovar1 1 Department of Pediatric Surgery, Hospital Universitario La Paz,
Madrid, Spain 2 Department of Pediatric Oncology, Hospital Universitario La Paz, Madrid, Spain
Address for correspondence Juan A. Tovar, PhD, Department of Pediatric Surgery, Hospital Universitario La Paz, P° La Castellana 261, Madrid 28046, Spain (e-mail: [email protected]).
Abstract
Keywords
► ganglioneuroma ► ganglioneuroblastoma ► neuroblastoma ► resection/expectant ► complications
received May 20, 2013 accepted after revision September 16, 2013 published online December 10, 2013
Introduction Ganglioneuroma (GN) is a benign, differentiated variety of neurogenic tumor. It is often asymptomatic and may be diagnosed by serendipity. Surgical removal is the treatment of choice. However, it has been suggested that postoperative complications and sequelae might outweigh the benefits of this approach. The purpose of the present study was to examine these issues in a large experience of neural tumors. Methods Patients treated between 1992 and 2012 were retrospectively reviewed. Modern imaging, measurement of catecholamine metabolite excretion and metaiodobenzylguanidine were used for workup. Surgical treatment aimed at complete resection. Complications and sequelae were recorded. Literature was searched for regrowth or malignant transformation of GN. Results Of 227 patients with neural tumors, 24 were GN patients (12 abdominal, 11 thoracic and 1 cervical with 8 dumbbell extensions). Six children were symptomatic (three with abdominal pain and mass, one with stridor or dysphonia, and one each with anisocoria and opsomyoclonus). However, 18 (75%) were asymptomatic and the diagnosis was incidental. Several tumors were large and involved more than one body space. There were no neurologic symptoms in eight cases with dumbbell extension. Complete resection was achieved in 20 children (83%) whereas gross residual was left in four. Postoperative complications were: Horner syndrome (3 patients), mild scoliosis (1 patient), adhesive bowel obstruction (1 patient) and acute urinary retention (1 patient). There was no evidence of either regrowth or malignant behavior in residual masses left in place after follow-up of 84 (1–194) months. Conclusions There were a limited number of general minor complications in this series that did not include cases of regrowth or malignant transformation. However, these unfavorable events were occasionally reported in the literature. Since diagnosis of GN cannot be ascertained before removal of the mass, this should remain the aim of the treatment, although limiting the chances of complications to a minimum even if incomplete resection is the price to pay. Nonoperative attitudes should not be recommended in all cases, but they are certainly justified in some.
© 2014 Georg Thieme Verlag KG Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0033-1358790. ISSN 0939-7248.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Eur J Pediatr Surg 2014;24:25–30.
Ganglioneuroma
Sánchez-Galán et al.
Introduction Peripheral neuroblastic tumors are the most common solid extracranial malignancies in infancy and childhood, and include the histotypes: neuroblastoma (NB), ganglioneuroblastoma (GNB), and ganglioneuroma (GN).1 These tumors of neural crest origin arise from the sympathetic ganglia or adrenal medulla and represent a continuous spectrum of differentiation and neuronal maturation.2 NB is the most common and highly malignant variety, with a histologic pattern of abundant neuroblasts and scarce stroma. GNB contains neuroblastic and stromal elements and can be divided into two forms: nodular, with malignant potential and unfavorable prognosis, and intermixed (stroma-rich) with favorable prognosis.3 Finally, GN represents the benign and less frequent form. It is a stroma-predominant tumor, with more or less mature ganglion cells. Immature elements, such as neuroblasts, intermediate cells, and mitotic figures are not part of pure GN.4,5 GN is probably always the end-result of the maturation of fetal or postnatal NB or GNB. It is most times asymptomatic and it is often diagnosed by serendipity. However, in some instances it can attain large size and displace or compress the neighboring organs.2 In contrast with NB, GN does not respond to chemotherapy and surgical removal after presumptive diagnosis based on imaging, absence of amine uptake or catecholamine excretion has been the treatment of choice for many years. This is apparently in contradiction with the need for tissue diagnosis required for application of protocols for neural tumors. However, some studies showed that this attitude was not devoid of risks of complications, permanent sequelae or even death. In a collective Italian series of 139 children operated upon for GN, 22 (15%) had surgical complications, 7 of which were severe enough as to be lethal in 2 instances.3 Furthermore, a series of 23 children having complete or nearcomplete removal of GN, the occurrence of 7 (30%) complications like Horner’s syndrome, chylothorax, pneumothorax, arm pain or adhesive intestinal obstruction6 led the authors, from one of the leading institutions in Europe, to cast some doubts on the pertinence of this management strategy for a benign tumor.6 The aim of this study was to examine these issues on the basis of an extensive experience with neural tumors.
Methods Neural tumors treated at our institution between 1992 and 2012, were retrospectively reviewed. The diagnosis of GN was established histologically on the basis of the International Neuroblastoma Pathology Classification.4,5 Tumors with immature, neuroblastic elements or those resulting from maturation after treatment of NB were excluded. Clinical features including gender, age, weight, location and size of tumors, symptoms at diagnosis, histology, treatment and complications were recorded. Laboratory tests included urinary excretion of vanillylmandelic (VMA) and homovanillinic acid (HVA); serum neuron-specific enolase (NSE); ferritin and European Journal of Pediatric Surgery
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lactate dehydrogenase (LDH). N-myc amplification and 1p36 deletion were ruled out when possible. All patients had conventional imaging and metaiodobenzylguanidine (MIBG) studies. Tumor volume in mL was estimated on the basis of measurements of the pathology specimen using the following formula: π/6 length width height. Data were expressed as medians and ranges. Surgical treatment was performed in all cases bearing in mind that likely mature, benign tumors do not require radical, risky procedures. Complete resection was achieved when possible using occasionally combined approaches (two body spaces, laminotomy), but avoiding vital risks or damage to other organs. Resection was defined as complete when all macroscopic tumor bulk was excised and incomplete when macroscopic residual was left in place. Complications appearing in the first three postoperative months where considered as early ones, whereas complications or sequelae persisting beyond that point were considered as late or permanent. Patients were followed up closely in the first postoperative year and annually ever since.
Results Out of 227 patients with peripheral neural tumors, 24 (10%), 13 males and 11 females, had GN and were included in the study. The median age at diagnosis was 60 (range 36–168) months or 5 (range 3–14) years. Patients weighed 21 (range 13–58) Kg. Twelve tumors (50%) were abdominal (two adrenal, one pelvic, and two with extension to the thorax); 11 (46%) were thoracic (►Fig. 1) (three with cervical involvement [►Fig. 2]); and one (4%) was cervical. Eight cases (33%) had dumbbell intraspinal extension (►Fig. 3). The tumors were equally distributed on the left and the right sides (11 on each side) and two were medial or bilateral. Most patients were asymptomatic and the diagnosis was made incidentally. Only six (25%) had symptoms (three abdominal mass and pain, one with stridor or dysphonia, one anisocoria, and one opsomyoclonus) (►Table 1). None of the children with invasion of the spinal canal had symptoms of either cord or radicular compression. Three children were referred to us after receiving some form of chemotherapy elsewhere without response. Complete primary resection was achieved in 20 patients (two required a second operation), and only incomplete removal was possible in four. The median volume of the removed tumor was 63 (12.2–299.5) mL. Either laminotomy or foramen enlargement were necessary in two of the eight cases with intraspinal extension in order not to leave bulky tumor mass. There were complications in six patients (25%) in whom complete resection was achieved. These are summarized in ►Table 2. Early complications were: one adhesive bowel obstruction requiring laparotomy, one acute urinary retention resolved spontaneously, and one cerebrospinal fluid leak requiring intercostal drainage after transthoracic, intraspinal approach. Late complications were minimal scoliosis in one case and persistent Horner syndrome in three. In none of the four patients with incomplete resection, regrowth of the
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Sánchez-Galán et al.
Fig. 1 Coronal (A) and sagittal (B) MRI corresponding to a large upper thoracic GN on a 3-year-old asymptomatic girl. After complete removal, the patient developed Horner syndrome. GN, ganglioneuroma; MRI, magnetic resonance imaging.
Fig. 2 (A, B) A huge cervicothoracic ganglioneuroma in a 6-year-old girl with a palpable neck mass. (C) MRI showed how the mass displacement of the airway to the right. Complete removal was performed through a cervicosternotomy. Later the patient presented a Horner syndrome. MRI, magnetic resonance imaging.
Fig. 3 A 12-year-old girl with anisocoria; MRI revealed a huge upper thoracic GN (A) with invasion of the spinal canal (B) through four foramina. Incomplete resection was performed. GN, ganglioneuroma; MRI, magnetic resonance imaging.
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Ganglioneuroma
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Sánchez-Galán et al.
Table 1 Clinical features in 24 patients with GN treated between 1992 and 2012 Patient
Age (mo)
Gender
Tumor location
Tumor volume (mL)
Dumbbell extension
Symptoms
1
36
F
Thoracic
104.7
Yes
Asymptomatic
2
36
F
Thoracic (cervical component)
15.7
No
Asymptomatic
3
36
M
Cervical
N.A.
No
Stridor/dysphonia
4
48
M
Thoracic
14
No
Asymptomatic
5
48
F
Abdominal (pelvic)
N.A.
No
Asymptomatic
6
48
M
Abdominal
155.5
Yes
Abdominal pain
7
48
M
Abdominal
207.3
No
Asymptomatic
8
48
F
Thoracic
201.6
No
Asymptomatic
9
52
M
Abdominal
164.9
No
Asymptomatic
10
53
M
Abdominal (adrenal)
19.6
No
Asymptomatic
11
59
F
Thoracic
23.6
Yes
Asymptomatic
12
60
F
Thoracic
15.7
Yes
Asymptomatic
13
60
M
Abdominal (thoracic component)
37.7
No
Opsomyoclonus
14
65
F
Thoracic (cervical component)
125.7
No
Asymptomatic
15
84
M
Abdominal (thoracic component)
55.6
Yes
Asymptomatic
16
84
M
Abdominal
34.5
Yes
Asymptomatic
17
84
M
Abdominal
63.4
No
Asymptomatic
18
96
F
Abdominal (adrenal)
N.A.
No
Asymptomatic
19
108
M
Thoracic
12.2
No
Asymptomatic
20
132
F
Thoracic
62.8
Yes
Asymptomatic
21
132
F
Thoracic (cervical component)
240.9
Yes
Anisocoria
22
144
F
Abdominal
299.5
No
Abdominal pain
23
156
M
Thoracic
N.A.
No
Asymptomatic
24
168
M
Abdominal
73.3
No
Abdominal pain
Abbreviations: F, female; GN, ganglioneuromas; M, male; N.A., not available.
residual mass left in place was observed upon 0.5 to 16 years of follow-up. No malignant transformation was observed either in any case. The overall follow-up was 84 (1–194) months or 7 (1–16) years.
Discussion The present series represents a large neural tumor experience and confirms most features observed in other studies2,3,6: late age at diagnosis, more or less balanced distribution between male and female patients, some preference for thoracic location and constantly benign behavior. The proportion of complications in these studies was comparable although it should be pointed out that most of them were relatively minor if not irrelevant (the most frequent one was Horner syndrome that can appear also before operation). The more severe complications were observed in a collective multi-institutional study in which the standards of surgical care were necessarily uneven.3 Observation alone would therefore appear as an acceptable attitude for GN. However, it would be dangerous to European Journal of Pediatric Surgery
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ignore that (1) imaging and biological markers might not be enough to ascertain this diagnosis, (2) malignant transformation of a verified GN is definitely possible, and (3) large size, invasion of other body spaces and metastases may pose particular problems. The present study cannot answer the question of whether reliable diagnosis of GN is possible without tissue studies. Inclusion criteria involved retrospective histological diagnosis of GN, absence of either biological activity or amine uptake and no biological predictors of malignity. The same can be said about the series of study by Retrosi et al.6 In fact, it is difficult to rule out the presence of neuroblastic elements in GN based upon biopsies and even after histological assessment of the entire operative specimen. Retrospective review of the pathology of 76 GN in the Italian collaborative study permitted to reclassify one-third of them as GNBs.3 The process of differentiation and maturation of neuroblastic tumors may not be homogeneous and cell clusters at different stages may coexist in the same tumor. Up to 93% of 49 GN studied by Geoerger et al had “slightly immature” neuroblasts.2 In the same study, 39% of these patients had increased
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Ganglioneuroma
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29
Patient
Resection
Observations
Early complications
Sequelae
1
C
Preoperative chemotherapy elsewhere
No
No
2
C
Tumor involved the stellate ganglion
Horner syndrome
Horner syndrome
3
I
Retropharyngeal residual mass
No
No
4
C
Thoracoscopy
No
No
5
I
Preoperative chemotherapy and radiotherapy elsewhere, three attempts for resection and ureteral diversion
No
No
6
I
Complete resection in a second time. Ureteral diversion and neurosurgery
No
No
7
C
Preoperative chemotherapy elsewhere
No
No
8
C
–
No
No
9
I
Residual mass attached to the vena cava
No
No
10
C
Retroperitoneoscopy
Urinary retention
No
11
C
–
Horner syndrome
Horner syndrome
12
C
Neurosurgery
CSF leak
Scoliosis
13
C
–
No
No
14
C
Cervicosternotomy
Horner syndrome
Horner syndrome
15
C
–
No
No
16
I
Adrenalectomy. Complete resection in a second time
No
No
17
C
–
No
No
18
C
–
No
No
19
C
Thoracoscopy
No
No
20
C
–
No
No
21
I
Costovertebral residual mass
No
No
22
C
Adrenalectomy
Intestinal obstruction
No
23
C
–
No
No
24
C
–
No
No
Abbreviations: C, complete; GN, ganglioneuromas; I, incomplete.
levels of catecholamines and 57% had some degree of MIBG uptake. Increased catecholamine levels were observed in some GNs by other investigators.7 On the other hand, normal catecholamine excretion8–11 and/or absent MIBG uptake does not formally rule out the presence of neuroblastic elements in the tumor.12 Therefore, diagnosis based only on imaging, age, location, absence of MIBG uptake or metabolite excretion or biopsy alone can be misleading (and dangerous) in a limited number of cases. The present study cannot answer either the question of whether reactivation of a dormant GN and malignant transformation into NB is at all possible. These events were present neither in comparable series from a single institution13 nor in a large German registry.2 Probably, the relative rarity of pure GN and the likely long time span necessary for malignant transformation to occur make most series useless for this purpose. Large multinational studies able to determine prevalence of these events are lacking and a multi-institutional
series of 139 GNs only reported one regrowth that remained stable after biopsy and two unrelated ovarian and thyroid malignancies appearing at adult age.3 However, it would be foolish to ignore that malignant transformation of GN into NB has been occasionally reported14,15 and that other neural malignancies like peripheral nerve sheath tumors16–20 or nonneural ones like rhabdomyosarcoma21 developed in previously diagnosed GNs have also been observed. Nonoperative attitudes for large GNs, particularly when they involve more than one body space and, particularly when they invade the spinal canal, are hard to embrace. These benign and generally inert masses occasionally displace vital structures like the trachea or the genitourinary tract interfering with breathing (one of the cases herein reported), bladder emptying or childbearing.22 They can also cause intestinal obstruction,23 neck stiffness24 or scoliosis.25 Some rare cases have metastases containing fully mature tissue that attest that they were originally fetal or postnatal European Journal of Pediatric Surgery
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Table 2 Surgical features and complications appeared in 24 patients with GN treated in our hospital between 1992 and 2012
Ganglioneuroma
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silent NBs subsequently differentiated.26–28 Finally, intraspinal extensions of dumbbell GNs are particularly prone to be surgically removed. No patient in the present series had spinal cord or radicular compression, but these have been occasionally reported.29,30 In conclusion, there are no enough convincing arguments to prone nonoperative treatment for all GNs. Although neither the present study nor other similar ones3,6 showed evidence of regrowth, malignant transformation, or severe symptoms of GN, there are reports in the literature showing that all these are possible. GN deserves an individualized approach: complete removal should be the aim of treatment only if it can be achieved without major risk for the patient and/or for neighboring structures. Imaging-based estimation of the surgical risk factors used in current staging of NB1 should be used when planning operations for GN. The surgeon should minimize the risks of complications. If necessary, incomplete resection is warranted and safe in view of the good prognosis of these tumors. In some particular cases, nonoperative management of GN may be justified.
12
13
14
15
16
17
18
19
Conflict of Interest The authors report no conflict of interest. 20
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3 4
5
6
7
8 9
10
11
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