International Journal of Surgery Case Reports 2 (2011) 36–39
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Case report
Spinal schwannomatosis in the absence of neurofibromatosis: A very rare condition A. Landi ∗ , D.E. Dugoni, N. Marotta, C. Mancarella, R. Delfini Department of Neurological Science, Division of Neurosurgery, University of Rome Sapienza, Roma, Italy
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Article history: Received 12 November 2010 Received in revised form 3 December 2010 Accepted 9 December 2010 Available online 22 December 2010 Keywords: Spinal schwannoma NF1 NF2 Neurofibromatosis Laminectomy Spinal neuromas
a b s t r a c t Schwannomatosis is defined as an extremely rare tumors syndrome characterized by the presence of multiple schwannomas in the absence of typical signs of NF1 and NF2 syndromes. The genetic and molecular analysis performed on these tumors makes it possible to name schwannomatosis as distinct clinical and genetic syndrome. The treatment in the case of symptomatic lesions is surgical removal; if the lesions are asymptomatic it is better to perform serial MRI studies. Given the high incidence of developing additional lesions in patients with schwannomatosis, it remains imperative to perform serial brain and spinal cord MRI studies during follow-up. The differential diagnosis is important including clinical and radiological criteria plus molecular genetic analysis of tumor cells and lymphocyte DNA. We report a rare case of spinal schwannomatosis in which genetic analysis performed on surgical samples showed two different mutations in the cells of the two lesions. © 2010 Surgical Associates Ltd. Elsevier Ltd. Open access under CC BY-NC-ND license.
1. Introduction Schwannomas are encapsulated and slow growing benign peripheral nerve tumors. They represent about one third of all benign primary spinal tumors.1 Most schwannomas occur as isolated lesions, but it is possible to find multiple localization involving one or more nerves.2,3 The presence of multiple schwannomas in a single patient is suggestive of a genetic predisposition to tumor genesis and a possible association with syndromes such as neurofibromatosis (NF). Among the different variants of NF only for NF1 and NF2 National Institute of Health (NIH)4,5 have established the guidelines for the diagnosis as described in the literature. NF1 is the most common form, with an incidence at birth of 1/2500. The gene for NF1 maps to the chromosome band 17q11.1. NF2, much less common (incidence at birth of approximately 1/33,000) and is associated with significant morbidity and mortality due to the frequent localization of the lesions in the brain and in the spinal cord. The mutation in the NF2 gene maps to chromosome band 22q12.6 The most important finding for the diagnosis of NF2 is the presence of bilateral schwannomas involving the eighth cranial nerve, with an incidence of about 95% of patients. Individuals with NF2 also have an increased risk of developing single or multiple meningiomas and schwannomas of peripheral nerves. Lately, a small subset of patients with multiple schwannomas without any
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clinical signs and without any radiological evidence of vestibular lesions or other characteristic features of NF2 has been identified. The genetic and molecular analysis performed on the tumors of these patients, revealed that it is possible to name schwannomatosis as a distinct clinical and genetic syndrome.7,8 Schwannomatosis is defined, therefore, as an extremely rare tumors syndrome characterized by the presence of multiple schwannomas in the absence of typical signs of NF1 and NF2 syndromes. Usually, patients with schwannomatosis develop cranial, spinal or peripheral nerve schwannomas but do not develop vestibular lesions (VS), typical of NF2. Even the genetic features are different with respect to neurofibromatosis, allowing one to classify the disease as a distinct nosological entity. We report a rare case of spinal schwannomatosis in which genetic analysis performed on surgical samples showed two different mutations in the cells of the two lesions. 2. Case report A 41-year-old man with a 10 years history of low back pain presented with 2 years of worsening pain especially on awakening, that improved partially during the day. An MRI without contrast of the lumbosacral column showed the presence of two small rounded areas of altered signal, slightly hyperintense on T2 and hypointense on T1 at T12 and L2–L3 levels (see Fig. 1). He was referred because of these findings. A more detailed diagnosis was performed with contrast-enhanced MRI of the brain and spinal cord in its entirety. This examination confirmed the presence of the two areas of altered signal at T12 and L2–L3 levels with homogeneous
2210-2612 © 2010 Surgical Associates Ltd. Elsevier Ltd. Open access under CC BY-NC-ND license. doi:10.1016/j.ijscr.2010.12.001
A. Landi et al. / International Journal of Surgery Case Reports 2 (2011) 36–39
Fig. 3. Intraoperative picture of the L2–L3 lesion after durotomy.
Fig. 1. Preoperative T1 and T2 weighted sagittal images: presence of two nodular lesions at T12 and L2–L3.
contrast enhancement that looked like the neuroma (Figs. 1 and 2). The study of the brain was negative. Because of the severity of low back pain that limited the daily activities of the patient it was decided to remove both the lesions surgically, by double laminectomy centered on tumors (Figs. 3 and 4). Removal of both lesions was performed by microsurgical technique, with preservation of the root. The entire procedure was performed under neurophysiological monitoring, in particular electromyography. Histological examination confirmed the previous diagnosis of schwannoma, for both lesions. A genetic study was performed that showed two different mutations for the two lesions: in particular a mutation in exon 4 in the NF2 locus with loss of heterozygosity for the gene NF2CA3 for the lesion at T12 level, and a mutation at nucleotide 441 in exon 4 of the NF2 locus, with loss of heterozygosity for the gene NF2CA3 for the lesion at L2–L3 level. A contrast-enhanced MRI control performed 3 months after surgery, showed the complete removal of the lesions without any sign of recurrence (Fig. 5). A follow-up with spinal and brain MRI every year has been planned.
Fig. 4. Intraoperative picture of T12 lesion after durotomy.
Fig. 2. Preoperative T1 with Gd-DTPA administration axial images: omogeneous enhancing of the lesions.
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A. Landi et al. / International Journal of Surgery Case Reports 2 (2011) 36–39
Fig. 5. Postoperative MRI with Gd-DTPA administration: complete removal of the lesions.
3. Discussion An important aspect for the classification of schwannomatosis is the differential diagnosis with NF. Schwannomatosis is a syndrome which can be defined as characterized by multiple schwannomas in the absence of VS, having no characteristic of NF1 or NF2, having no familiarity and, having no constitutional mutations of specific gene, as like 17q11.1 in NF1 and 22q12 in NF2.9 The NF2 is caused by a “de novo” mutation at 22q12 in more than 50% of patients. It is a tumor suppressor gene with a molecular weight of 110 kb, it consists of 16 consecutive exons and alternatively spliced exon. The protein encoded by NF2 gene is called Merlin. The Merlin has a similar structure to the family of proteins that link cell surface glycoproteins to actin cytoskeleton. Schwannomatosis was first described in 1973 as neurofibromatosis type 3.10 The characteristic of this syndrome was the presence of multiple skin and spinal’s schwannomas in the absence of vestibular involvement or other relevant features of NF1 and NF2. Over time, several authors have reported cases of patients with multiple schwannomas without vestibular lesions, suggesting the existence of a distinct syndrome from the NF. At this time there are no NIH diagnostic criteria for schwannomatosis. Jacobi et al.7 have proposed clinical criteria for diagnosis of schwannomatosis: the presence of two or more schwannomas in the absence of radiological evidence of vestibular lesions in patients older than 18 years, is definitely indicative of schwannomatosis. Michael et al.4 have proposed an integration of these diagnostic criteria, indicating the MRI exam as a fundamental instrument to exclude the presence of vestibular schwannomas and, more important is the absence of constitutional NF2 mutations. The first major challenge to the diagnosis of schwannomatosis is the presence of two or more non-intradermal schwannomas in patients older than 30 years, in the absence of vestibular lesions shown on the brain MRI with contrast enhancement and in the absence constitutional NF2 mutations.11 A second important aspect is the presence of firstdegree relative(s) with a confirmed diagnosis of schwannomastosis in a patient with multiple schwannomas; these aspects have to be shown in the absence of vestibular lesions resulting on MRI imaging and genetic analysis. In the case of presence of first-degree relative there is no any limit of age for the diagnosis. Several authors have studied the schwannomatosis molecular genetics. Jacobi and MacCollins12 analyzed alterations in the NF2 locus in patients with schwannomatosis revealing in the tumor
cell, a typical truncating mutations at NF2 gene, with loss of heterozygosity of chromosome 22. In patients with NF2, no mutation at NF2 locus was found in non-pathological tissues. In our case, genetic analysis has included the study of the DNA of lymphocytes taken from the patient’s peripheral blood and the study of the DNA of cancer cells. There was a noticeable absence of constitutional mutations in lymphocyte DNA, whereas in the DNA of tumor cells were observed two distinct mutations, each one belonging to the cell population of a schwannoma. In particular, the T12 lesion had a mutation in exon 4 of the NF2 locus with loss of heterozygosity of the NF2CA3 gene, whereas the lesion at L2–L3 level had a mutation at nucleotide 441 in exon 4 of the NF2 locus, with loss of heterozygosity of the NF2CA3 gene. In our case the absence of specific signs of NF1 or NF2 mutations associated with the absence of constitutional mutation of lymphocytes DNA, characterize the schwannomatosis as a syndrome, distinct from neurofibromatosis. Clearly, the treatment in case of symptomatic lesions is surgical removal13 performed by laminotomy or laminectomy centered on the lesion, followed by longitudinal durotomy and removal of the lesion with preservation of the root as soon as possible. The use of neurophysiological monitoring is extremely useful for the surgical procedure because it prevents any neurological damage. In the case of asymptomatic lesions it is important to perform serial MRI. Moreover, given the high incidence of developing additional lesions in patients with schwannomatosis, it remains imperative to perform serial MRI studies during follow-up. 4. Conclusion Schwannomatosis fits as a different syndrome from neurofibromatosis. The differential diagnosis includes clinical and radiological criteria plus molecular genetic analysis of tumor cells and lymphocyte DNA. The treatment consists in surgical removal of symptomatic lesions with preservation of the root as early as possible. Serial MRIs to keep under control additional lesions frequently seen in these patients is mandatory. Conflict of interest statement None declared. Funding None. Ethical approval Written informed consent was obtained from the patient for publication of this case report and accompanying images. References 1. Mautner VF, Tatagiba M, Lindenau M, Funsterer C, Pulst SM, Baser ME, et al. Spinal tumors in patients with neurofibromatosis type 2: MR imaging study of frequency, multiplicity, and variety. AJNR Am J Roentgenol 1995;165(4):951–5. 2. Daras M, Koppel BS, Heise CW, Mazzeo MJ, Poon TP, Duffy KR. Multiple spinal intradural schwannomas in the absence of Von Recklinghausens disease. Spine 1993;18:2556–9. 3. Javalkar VK, Pigott T, Pal P, Findlay G. Multiple schwannomas: report of two cases. Eur Spine J 2007;16(Suppl. 3):287–92 [Epub.]. 4. Michael EB, Friedman JM, Gareth D, Evans R. Increasing the specificity of diagnostic criteria for schwannomatosis. Neurology 2006;66:730–2. 5. Mulvihill JJ, Parry DM, Shermann JL, Pikus A, Kaiser-Kupfer MI, Eldridge R. NIH conference. Neurofibromatosis 1 and neurofibromatosis 2. An update. Ann Intern Med 1990;113:39–52. 6. Rouleau GA, Merel P, Lutchman M, Sanson M, Zucman J, Marineau C, et al. Alteration in a new gene encoding a putative membrane-organizing protein causes neurofibromatosis type 2. Nature 1993;363:515–21.
A. Landi et al. / International Journal of Surgery Case Reports 2 (2011) 36–39 7. Jacoby LB, Jones D, Davis K, Kronn D, Short MP, Gusella J, et al. Molecular analysis of the NF2 tumor-suppressor gene in schwannomatosis. Am J Hum Genet 1997;61:1293–302. 8. Seppala MT, Saino MA, Haltia MJ, Kinnunen JJ, Setala KH, Jaaskelainen JE. Multiple schwannomas: schwannomatosis or neurofibromatosis 2. J Neurosurg 1998;89:36–41. 9. Jason H, Huang JH, Simon SL, Nagpal S, Nelson PT, Zager EL. Management of patients with schwannomatosis: report of six cases and review of the literature. Surg Neurol 2004;62(October (4)):353–61, discussion 361. 10. Nimura M. Neurofibromatosis. Rinsho Derma 1973;15:653–63.
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11. MacCollin M, Chicocca EA, Evans DG, et al. Diagnostic criteria for schwannomatosis. Neurology 2005;64:1838–45. 12. MacCollin M, Willet C, Heinrich B, Jacoby LB, Acierno Jr JS, Perry A, et al. Familial schwannomatosis. Exclusion of the NF2 locus as the germ line event. Neurology 2003;60:1968–74. 13. Conti P, Pansini G, Mouchaty H, Capuano C, Conti R. Spinal neurinomas: retrospective analysis and long-term outcome of 179 consecutively operated cases and review of the literature. Surg Neurol 2004;61(January (1)):34–43, discussion 44 (review).
