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Bilateral spinal neurofibromas in patients with neurofibromatosis 1
Brain & Development 34 (2012) 563–569 www.elsevier.com/locate/braindev
Original article
Bilateral spinal neurofibromas in patients with neurofibromatosis 1 Ignacio Pascual-Castroviejo a,⇑, Samuel-Ignacio Pascual-Pascual a, Juan Vian˜o b, Ramo´n Velazquez-Fragua a, Juan-Carlos Lo´pez-Gutierrez c a
Departament of Pediatric Neurology, University Hospital La Paz, Madrid, Spain b Image Unit, Hospital del Rosario, Madrid, Spain c Pediatric Plastic Section, University Hospital La Paz, Madrid, Spain
Received 18 April 2011; received in revised form 19 September 2011; accepted 20 September 2011
Abstract Neurofibromatosis 1 (NF1) is a neurocutaneous syndrome that can be inherited as autosomal dominant or may appear due to a de novo mutation. We present 8 patients (5 M and 3 F) with sporadic or non-familial spinal neurofibromatosis 1 (non-FSNF1) associated with bilateral spinal neurofibromas involving all of the paraspinal nerves. To our knowledge, this is the first series of such association described in the literature. Their ages ranged from 6 months to 20 years (average 9.8 years) at the time of radiological diagnosis. This presentation appears to be earlier than in familial spinal neurofibromas in NF1 (FSNF1). Predisposition to malignancy probably is greater in the non-FSNF1 type. MRI studies were performed routinely in all patients with NF1 and these were complemented with MRI enhanced with gadolinium and repeated at different ages in cases with paraspinal tumors. Coronal views provided the best evidence for the presence of neurofibromas in every spinal nerve. The size of the tumors and the clinical complications increased with advancing age in most patients. Giant plexiform tumors were often seen in the cervico-thoracic region. Malignant peripheral nerve sheath tumors (MPNST) were found in one patient with a sciatic tumor and another patient died suddenly at home without necropsy or pathological study. Voluminous paraspinal neurofibromas can be at risk for malignancy. More frequent neuroimaging studies may be necessary for an earlier detection. Early surgical treatment to anticipate the occurrence of MPNST during surveillance could be an option. Bilateral spinal neurofibromas are found in both patients who inherited the NF1 and in those due to de novo mutations. Ó 2011 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. Keywords: Neurofibromatosis type 1 (NF1); Plexiform neurofibromas; Spinal neurofibromas; Non-familial spinal neurofibromas (non-FSNF1); Malignant peripheral nerve sheath tumor (MPNST)
1. Introduction Neurofibromatosis 1 (NF1) (OMIM# 162200) is a common autosomal dominant disorder characterized by a broad phenotypic variability. The diagnosis of
⇑ Corresponding author. Address: University Hospital La Paz, Departament of Pediatric Neurology, 14 Orense Street, 10° E, 28020 Madrid, Spain. Tel.: +34 91 5550356; fax: +34 91 6236572. E-mail address: [email protected] (I. Pascual-Castroviejo).
NF1 is made using the NIH Consensus Development Conference Criteria [1]. The presence of wide, symmetrical distribution of spinal neurofibromas associated with NF1 is seldom reported, and still rarer is its occurrence in members of the same family in a special type of NF1, familial spinal NF1 (FSNF1) [2]. FSNF1 is characterized by multiple, extensive, bilateral spinal root neurofibromas at any level, without spinal cord symptoms, but with signs and symptoms of progressive, segmentally distributed nerve sheath neuropathy. Most patients commonly develop the spinal tumors during adulthood [2–4] and very seldom during
0387-7604/$ - see front matter Ó 2011 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. doi:10.1016/j.braindev.2011.09.011
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childhood [5]. The series of patients with spinal neurofibromas associated with NF1, although non-FSNF1, describe few patients and most often these don’t have the tumors in all the spinal roots at any level, whether the series include only children [6–9], patients of any age [10,11] or only adults [12]. Most reports of spinal neurofibromas associated with NF1 localize the tumors to only one spinal region, such as cervical [8–11], thoracic [10], abdomino-pelvic [13] or pelvic [14]. Description of isolated spinal neurofibromas limited to a small region or localized on only one side are often reported in individuals with NF1, and surgical treatment may be considered. The presence of plexiform, intra- or paraspinal neurofibromas located bilaterally in all spinal nerves from the highest cervical roots to the sacrococcygeal region in patients without FSNF1 is most uncommon. Sporadic generalized nerve tumors that involve bilaterally all of the paraspinal nerves were first described in a 14year-old adolescent girl [5]. Sporadic spinal neurofibromatosis with malignant peripheral nerve sheath tumors (MPNST) has been recently described in two adults [15]. Computerized tomography (CT) and especially magnetic resonance (MR) with or without contrast studies of the spine and paraspinal structures are necessary to visualize not only the presence of plexiform neurofibromas, but also to identify their location, size, continuity or not of the tumors following the course of the peripheral nerves, compression of the neighbouring organs, abnormal growth of some tumors with respect to the others, and irregularities of the tumor surface. All types of NF1 mutations can lead to spinal tumors in NF1 patients. We evaluate in this study the clinical and imaging features of 8 children and young adult patients with sporadic plexiform paraspinal tumors affecting all spinal roots symmetrically, associated with NF1, a very uncommon presentation. 2. Material and methods We reviewed the medical records, X-ray reports and MR images of patients with NF1 diagnosed between 1990 and 2004 and sporadic paraspinal neurofibromas, with ages ranging between 6 months and 20 years (average 9.8 years). The diagnosis of NF1 was made using the NIH Consensus Development Conference Criteria [1]. Paraspinal tumors were diagnosed by MR studies. Between 1990 and 2004 we examined 322 patients with NF1 who were 620 years of age at the time of their first visit. The entire spinal and paraspinal regions were studied by MR for the presence of paraspinal tumors. The radiological diagnosis was based on the presence of tumors on both sides of the spine of all nerves from the highest cervical region to the cauda equina. The examinations were performed using a 1.5-T apparatus, and T1- and T2-weighted images were obtained, with fat-suppression in some cases, and sagittal, coronal
and axial views with contrast enhancement. In some patients who showed kyphoscoliosis with some grade of spinal rotation that made difficult to demonstrate well both lateral sides of the column, it was necessary to visualize several planes. We attempted to classify the tumors as intramedullary, intradural extramedullary, intraforaminal, or extradural, based on their topographical location, but this was not always possible. Size, presence of some giant tumors that proliferated between the others, continuity of the spinal neurofibromas following the course of the peripheral nerves, and morphology were evaluated as well. Tumor changes were evaluated by MR follow-up studies performed in accordance with our surveillance protocol at regular intervals of ½ to 1 year following the diagnosis of plexiform neurofibromas in all patients while they were alive or until lost to follow-up (cases 1 and 8) or death (cases 2 and 3). At present 4 patients (cases 4, 5, 6 and 7) between 9 and 22-years of age are followed in our clinic. MR study was performed more than once in all 8 patients. 3. Results All 8 patients showed bilateral neurofibromas located in every spinal nerve of the cervical, dorsal, lumbar, sacral and coccygeal regions. The observed clinical and image abnormalities are described in the Table 1. Bilateral spinal neurofibromas appeared in patients who inherited the NF1 and in those due to de novo mutations. MR revealed spinal tumors in 19 patients (5.9%) of 322 patients with NF1, and in 8 (2.5%) the paraspinal tumors affected bilaterally all the paraspinal nerves. In the other 11 patients, the bilateral tumors affected a part of the spine or they were unilateral. Six patients were followed during more than 5 years and had more than two MR studies. This allowed us to observe the progressive increase in the size of the tumors from the time of their appearance and throughout their continuous growth. Two patients (cases 2 and 3) died. Case 2 died suddenly at home of unknown cause six years after the diagnosis of paraspinal tumors, one of which showed a voluminous size and was located in the left cervico-thoracic region (Fig. 1). The other patient (case 3) had a MPNST of the sciatic nerve and died 2 years following a diagnosis of paraspinal neurofibromas and MPNST (Fig. 2) (a benign neurofibroma was removed from a location adjacent to the MPNST). Case 4 of our series (Fig. 3) developed before nine years of age voluminous plexiform bilateral neurofibromas, two of which were located in the left thoracic cavity. In spite of this, the patient did not complain of symptoms, and showed no wasting, respiratory difficulties, motor, sensory or tendon reflex changes, and ten years later, she continues to be asymptomatic. The paraspinal tumors were already present in one patient (case 6) studied at
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Table 1 Clinical and neuroimaging features (all patients had external signs of NF1). Patient
Sex
Autosomal dominant transmission
Age at discovery of spinal tumors. Clinical features
Presence of voluminous paraspinal tumors
Presence of other peripheral neurofibromas
Treatment
Evolution
1
F
Non
Yes
Yes (generalized) Left optic nerve glioma
External anal and ureteral deviation at 22 yr
2
M
Yes
Yes
Yes (in several regions of the body)
No
3
M
Yes
Yes
Yes (left leg) Left optic nerve glioma
Yes (surgical removal MPNST of left sciatic nerve)
Progression in the number and size of tumors Lost to follow-up at 22 yr Malignancy of giant paraspinal tumor Death at 20 yr (MPNST) Death at 13 yr
4
F
Yes
Yes
Yes (occipital and both cervical nerves)
Yes (surgical removal of both tumors)
Followed for 19 yr Normal life
5
M
Yes
Yes
Yes (left palpebral)
No
Followed for 22 yr
6
M
No
Yes
Yes (in several regions)
Scoliosis at 8 yr
Followed for 9 yr
7
F
Yes
Yes
Yes (localized in many peripheral nerves)
No
Followed for 11 yr Normal life
8
M
No
14 yr Subcutaneous prominence of neurofibromas Pain 14 yr Subcutaneous prominence of neurofibromas 11 yr Cutaneous-subcutaneous plexiform neurofibroma on the neck 9 yr Generalizad subcutaneous neurofibromas 20 yr Generalizad subcutaneous neurofibromas 6 mo Cutaneous vascular malformation Plexiform neurofibroma on the neck Scoliosis Bilateral tibial dysplasia 5 yr Subcutaneous prominent neurofibromas 4 yr Subcutaneous prominent neurofibromas
Yes
Yes (plexiform neurofibromas in the right thigh)
No
Lost to follow-up at 12 yr
M = male; F = female; yr = years; mo = months; MPNST = malignant peripheral nerve sheath tumor.
Fig. 1. Patient 2 at 18-years of age. A male who showed only cutaneous signs of NF1 without neurological features. Coronal view of the MR enhanced with contrast medium shows bilateral neurofibromas in all the cervical nerves. Voluminous tumor in the left thoracic apex that enhances heterogeneously with contrast. He died suddenly at home at 20-years of age. Necropsy study was not done.
6 months of age. The tumors showed markedly increased growth vis a vis with the age in most patients, at least during several years, resulting in severe consequences for the intra-thoracic, intra-abdominal and intra-pelvic organs, and for peripheral nerve function, as occurred in case 1 of our series (Fig. 4), a woman with cutaneous signs of NF1 who was followed since 5-years of age and who developed paraspinal and generalized nerve sheath tumors between 9 and 14 years of age, with progressive loss of motor and sensory function until she was unable to walk without assistance since 14-years of age. The most frequent location of paraspinal voluminous neurofibromas was at the apex of the thoracic cavity on one or both sides, although preferentially on the left. The paraspinal tumors showed a progressive growth, not only following the trajectory of the nerve but also transversely causing enlargement of the nerves with the tumors. Paraspinal neurofibromas were excluded by MR studies in the parents of the five
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Fig. 2. Patient 3. MR enhanced with gadolinium at 11-years of age. (A) Coronal view of the lumbosacral region shows small, middle size bilateral plexiform neurofibromas of all paraspinal nerves. (B) Axial view of the gluteal region shows a malignant peripheral nerve sheath tumor (MPNST) involving the left sciatic nerve. Note the distinct types of signal within the MPNST tumor (arrow). This patient had been operated for a benign neurofibroma in a location adjacent to the last image at the same time as the malignant tumor.
Fig. 3. Patient 4 at 9-years of age. MR enhanced with contrast. (A) Coronal view shows two large plexiform neurofibromas in the superior left hemithorax. (B) Sagittal view shows two giant neurofibromas with intraspinal origin and neurofibromas in all the spinal foramina. (C) Axial view at the level of the upper thoracic region shows plexiform neurofibromas on both sides, with giant size on the left side that shows the original portion in the intraspinal region (arrow) compressing the spinal cord and eroding the vertebral body. A previous MR performed one year before showed tumors of similar size. The tumors did not receive any treatment, the patient continued a normal life and, at 19-years of age, she is asymptomatic, without any clinical features.
patients with inherited NF1.Two patients showed associated optic pathway gliomas. 4. Discussion About 40% of NF1 patients develop spinal tumors [16], most often neurofibromas that appear as isolated tumors. Spinal tumors form part of the clinical spectrum of NF1, but less than 2% are symptomatic, especially during childhood and adolescence. The diagnosis of
these tumors in patients with NF1 is frequently delayed or ignored because of the lack of clinical features, apart from the cutaneous signs of NF1 and of routine radiological studies of the spinal abnormalities in the periodic follow-up of these patients, especially in children who have no evident scoliosis. Intraspinal plexiform neurofibromas may present with clinical features related to size and location of the tumors [17]. However, asymptomatic plexiform lesions are frequently observed at least for several years during infancy, adolescence and early adult
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Fig. 4. Patient 1. (A) Post-contrast, fat-suppression coronal SE 3560/95 image shows enhancing tumors with nodular enlargement of all spinal nerves in a 14-year-old girl. (B) Coronal view of the pelvic region at 19-years of age shows a markedly increased size of the tumors and comparatively reduced size of rectum, uterus and bladder. (C) Axial view of the same study shows invasion of all the pelvic cavity, compressing rectum, uterus and bladder (arrow). (D) Coronal T2-weighted image of the lumbo-sacral region and both lower extremities shows multiple generalized tumors.
life [12]. The patients studied in the present series showed the tumors affecting bilaterally all the spinal regions from the highest cervical level to the sacrococcygeal region, and the paraspinal tumors followed the growth along the peripheral nerves. This presentation in non-familial form is very rare and the 8 patients presented in this paper constitute the first series published with bilateral neurofibromas that affect every spinal nerve from the first cervical segment to the cauda equina. Plexiform neurofibromas of the lumbosacral plexus can attain a large volume and cause multiple and severe complications, such as masses affecting the intra-abdominal and/or intra-pelvic organs. The small and large bowel can be affected by infiltration in cases of sarcomatous degeneration or by invasion of adjacent organs in cases with progressive growth without malignancy. In malignant and benign retroperitoneal tumors, the patients commonly present clinically with signs of bowel, rectal and/or ureteral obstruction, accompanied by fecal retention and hydroureteronephrosis that may require special maneuvers or specific medication to control sphincters, as was necessary in one of our patients
(case 1) despite an almost asymptomatic neurological course over a long time [12,13,18,19]. These tumors can show in CT and MR studies as well-differentiated fibromas, as appeared in our patients, or as an almost uniform mass of the involved organs [13]. Biondetti et al. [18] and Bass et al. [19] observed the symmetric homogeneous appearance of paraspinal plexiform neurofibromas. All the patients in our series had bilateral plexiform neurofibromas, but not all had homogeneous or symmetrical appearance or size. At least during the follow-up period, those located in the cervical and lumbosacral regions showed more similarities. However, most series report significant size differences among the neurofibromas located in the spinal region, being more frequent at the thoracic and lumbosacral levels, and less so in the cervical [20]. The largest asymmetries and the presence of most voluminous unilateral plexiform neurofibromas were found in the cervico-dorsal and highest dorsal regions in our series (cases 2 and 4). These voluminous tumors had the most rapid growth at any age, from the first years of life, although this was especially noticeable between 10 and 20 years of
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age. By contrast, the most rapid growth or even the onset of the growth in FSNF1 commonly is found years later, after 20 or 30 years, in most cases. Asymmetry in size and attenuation of a larger mass suggest the possibility of a MPNST [21], although this did not occur in our series in which with voluminous symmetrical or asymmetrical paraspinal plexiform neurofibromas did not develop malignancy, at least during more than 10 years of follow-up (cases 1 and 4). In our series, involvement of the sacral plexus extended into the sciatic nerve or even into all of the nerves of the lower extremities and involved of all the peripheral nerves. Malignancy of a plexiform neurofibroma that affected the sciatic nerve was seen in one patient (case 3). The diagnosis of MPNST at an early stage and resection of the malignant tumor with wide margins may achieve a better prognosis [21]. Unfortunately, this did not occur with the operated patient in our series (case 3) who survived less than two years after removal (probably in an incomplete form) of the MPNST. The risk of developing MPNST in patients with bilateral paraspinal plexiform neurofibromas may be twice that of patients with unilateral tumors, but it never has been reported either in non-FSNF1 or in FSNF1. NF1 microdeletion patients have a substantially higher risk for the development of MPNST compared with non-microdeletion NF1 individuals [22,23]. If this finding is confirmed, the routine testing of individuals with NF1 for the presence of a microdeletion and follow-up of NF1 microdeletion patients with a higher level of suspicion for MPNST would be appropriate [22]. Paraspinal neurofibromas present surgical challenges due to their anatomical relation to the spine, spinal cord, nerve roots, and major vasculature. Total resection of the tumor was achieved in 78.6% of cases with neurofibromas in the series of Cherqui et al. [24], but the patients did not have bilateral plexiform neurofibromas involving all paraspinal nerves. Microsurgical techniques are essential for identifying and, whenever possible, preserving non-involved roots [17], but the infiltration of multiple adjacent nerves and/or entire nerve plexus bilaterally, in conjunction with adjacent vascular and visceral organs, especially in the neck, the thorax and the pelvic regions, makes removal of these tumors difficult. The lack of a large series of FSNF1 and especially of non-FSNF1 involving all the spinal nerves does not allow sufficient experience in the most suitable treatment and the prognosis of the patients during adult life. To date, only voluminous tumors and especially those with malignant neuroradiological features, have been removed. MR coronal studies of the complete spine every two or three years, along with periodic clinical follow-up of patients with NF1 could detect these tumors sooner. Diagnosis and treatment of voluminous neurofibromas to anticipate the occurrence of
MPNST during the surveillance of NF1 patients appears a reasonable approach. References [1] Conference NIHCD. Neurofibromatosis: conference statement. Arch Neurol 1988;45:575–8. [2] Pascual-Castroviejo I, Pascual-Pascual SI, Velazquez-Fragua R, et al. Familial spinal neurofibromatosis. Neuropediatrics 2007;38: 105–8. [3] Pulst SM, Riccardi VM, Fain P, Korenberg JR. Familial spinal neurofibromatosis: clinical and DNA linkage analysis. Neurology 1991;41:1923–7. [4] Ars E, Kruyer H, Gaona P, et al. A clinical variant of neurofibromatosis type 1: familial spinal neurofibromatosis with a frameshift mutation in the NF1 gene. Am J Hum Genet 1998;62: 834–41. [5] Pascual-Castroviejo I, Pascual-Pascual SI, Vian˜o J, Martinez V. Generalized nerve sheath tumors in neurofibromatosis type 1 (NF1). A case report. Neuropediatric 2000;31:1–3. [6] Messiaen L, Riccardi V, Peltonen J, et al. Independent NF1 mutations in two large families with spinal neurofibromatosis. J Med Genet 2003;40:122–6. [7] Khong P-L, Goh WH, Wong VC, et al. MR imaging of spinal tumors in children with neurofibromatosis 1. AJR 2003;180: 413–7. [8] Chung CJ, Armfield KB, Mukherji SK, et al. Cervical neurofibromas in children with NF-1. Pediatr Radiol 1999;29:353–6. [9] Thakkar SD, Feigen U, Mautner V-F. Spinal tumours in neurofibromatosis type 1: an MRI study of frequency, multiplicity and variety. Neuroradiology 1999;41:625–9. [10] Schorry EK, Cawford AH, Egelhoff JC, et al. Thoracic tumors in children with neurofibromatosis-1. Am J Med Genet 1997;74: 533–7. [11] Leonard JR, Ferner RE, Thomas N, Gutmann DH. Cervical cord compression from plexiform neurofibromas in neurofibromatosis1. J Neurol Neurosurg Psychiatry 2007;78:14040–6. [12] Tonsgard JH, Kwak SM, Short MP, Dachman AH. CT imaging in adults with neurofibromatosis-1. Frequent asymptomatic plexiform lesions. Neurology 1998;50:1755–60. [13] Zacharia TT, Jaramillo D, Pousaint TY, Korf B. MR imaging of abdominopelvic involvement in neurofibromatosis type 1: a review of 43 patients. Pediatr Radiol 2005;35:317–22. [14] Pascual-Castroviejo I, Lopez-Pereira P, Savasta S, et al. Neurofibromatosis type 1 with external genitalia involvement. Presentation of 4 patients. J Pediatr Surg 2008;43:1998–2003. [15] Fauth C, Kehrer-Sawatzki H, Zatkova A, et al. Two sporadic spinal neurofibromatosis patients with malignant peripheral nerve sheath tumour. Eur J Med Genet 2009;52:409–14. [16] Alpadhyaya M, Spurlock G, Kluwe L, et al. The spectrum of somatic and germline NF1 mutations in NF1 patients with spinal neurofibromas. Neurogenetics 2009;10:251–63. [17] Pollack IF, Colak A, Fitz C, et al. Surgical management of spinal cord compression from plexiform neurofibromas in patients with neurofibromatosis 1. Neurosurgery 1998;43:248–56. [18] Biondetti PR, Vigo M, Fiore D, et al. CT appearance of generalized von Recklinghausen neurofibromatosis. J Comput Assist Tomogr 1983;7:866–9. [19] Bass JC, Korobkin M, Francis IR, et al. Retroperitoneal plexiform neurofibromas: CT findings. AJR 1994;163:617–20. [20] Conti P, Pansini G, Mouchaty H, et al. Spinal neurinomas: retrospective analysis and long-term outcome of 179 consecutively operated cases and review of the literature. Surg Neurol 2004;61: 35–44.
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[23] Kluwe L, Friedrich RE, Peiper M, et al. Constitutional NF1 mutations in neurofibromatosis 1 patients with malignant peripheral nerve sheath tumors. Hum Mutat 2003;22:420. [24] Cherqui A, Kim DH, Kim SH, et al. Surgical approaches to paraspinal nerve sheath tumors. Neurosurg Focus 2007;22:E9.
Original article
Bilateral spinal neurofibromas in patients with neurofibromatosis 1 Ignacio Pascual-Castroviejo a,⇑, Samuel-Ignacio Pascual-Pascual a, Juan Vian˜o b, Ramo´n Velazquez-Fragua a, Juan-Carlos Lo´pez-Gutierrez c a
Departament of Pediatric Neurology, University Hospital La Paz, Madrid, Spain b Image Unit, Hospital del Rosario, Madrid, Spain c Pediatric Plastic Section, University Hospital La Paz, Madrid, Spain
Received 18 April 2011; received in revised form 19 September 2011; accepted 20 September 2011
Abstract Neurofibromatosis 1 (NF1) is a neurocutaneous syndrome that can be inherited as autosomal dominant or may appear due to a de novo mutation. We present 8 patients (5 M and 3 F) with sporadic or non-familial spinal neurofibromatosis 1 (non-FSNF1) associated with bilateral spinal neurofibromas involving all of the paraspinal nerves. To our knowledge, this is the first series of such association described in the literature. Their ages ranged from 6 months to 20 years (average 9.8 years) at the time of radiological diagnosis. This presentation appears to be earlier than in familial spinal neurofibromas in NF1 (FSNF1). Predisposition to malignancy probably is greater in the non-FSNF1 type. MRI studies were performed routinely in all patients with NF1 and these were complemented with MRI enhanced with gadolinium and repeated at different ages in cases with paraspinal tumors. Coronal views provided the best evidence for the presence of neurofibromas in every spinal nerve. The size of the tumors and the clinical complications increased with advancing age in most patients. Giant plexiform tumors were often seen in the cervico-thoracic region. Malignant peripheral nerve sheath tumors (MPNST) were found in one patient with a sciatic tumor and another patient died suddenly at home without necropsy or pathological study. Voluminous paraspinal neurofibromas can be at risk for malignancy. More frequent neuroimaging studies may be necessary for an earlier detection. Early surgical treatment to anticipate the occurrence of MPNST during surveillance could be an option. Bilateral spinal neurofibromas are found in both patients who inherited the NF1 and in those due to de novo mutations. Ó 2011 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. Keywords: Neurofibromatosis type 1 (NF1); Plexiform neurofibromas; Spinal neurofibromas; Non-familial spinal neurofibromas (non-FSNF1); Malignant peripheral nerve sheath tumor (MPNST)
1. Introduction Neurofibromatosis 1 (NF1) (OMIM# 162200) is a common autosomal dominant disorder characterized by a broad phenotypic variability. The diagnosis of
⇑ Corresponding author. Address: University Hospital La Paz, Departament of Pediatric Neurology, 14 Orense Street, 10° E, 28020 Madrid, Spain. Tel.: +34 91 5550356; fax: +34 91 6236572. E-mail address: [email protected] (I. Pascual-Castroviejo).
NF1 is made using the NIH Consensus Development Conference Criteria [1]. The presence of wide, symmetrical distribution of spinal neurofibromas associated with NF1 is seldom reported, and still rarer is its occurrence in members of the same family in a special type of NF1, familial spinal NF1 (FSNF1) [2]. FSNF1 is characterized by multiple, extensive, bilateral spinal root neurofibromas at any level, without spinal cord symptoms, but with signs and symptoms of progressive, segmentally distributed nerve sheath neuropathy. Most patients commonly develop the spinal tumors during adulthood [2–4] and very seldom during
0387-7604/$ - see front matter Ó 2011 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. doi:10.1016/j.braindev.2011.09.011
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childhood [5]. The series of patients with spinal neurofibromas associated with NF1, although non-FSNF1, describe few patients and most often these don’t have the tumors in all the spinal roots at any level, whether the series include only children [6–9], patients of any age [10,11] or only adults [12]. Most reports of spinal neurofibromas associated with NF1 localize the tumors to only one spinal region, such as cervical [8–11], thoracic [10], abdomino-pelvic [13] or pelvic [14]. Description of isolated spinal neurofibromas limited to a small region or localized on only one side are often reported in individuals with NF1, and surgical treatment may be considered. The presence of plexiform, intra- or paraspinal neurofibromas located bilaterally in all spinal nerves from the highest cervical roots to the sacrococcygeal region in patients without FSNF1 is most uncommon. Sporadic generalized nerve tumors that involve bilaterally all of the paraspinal nerves were first described in a 14year-old adolescent girl [5]. Sporadic spinal neurofibromatosis with malignant peripheral nerve sheath tumors (MPNST) has been recently described in two adults [15]. Computerized tomography (CT) and especially magnetic resonance (MR) with or without contrast studies of the spine and paraspinal structures are necessary to visualize not only the presence of plexiform neurofibromas, but also to identify their location, size, continuity or not of the tumors following the course of the peripheral nerves, compression of the neighbouring organs, abnormal growth of some tumors with respect to the others, and irregularities of the tumor surface. All types of NF1 mutations can lead to spinal tumors in NF1 patients. We evaluate in this study the clinical and imaging features of 8 children and young adult patients with sporadic plexiform paraspinal tumors affecting all spinal roots symmetrically, associated with NF1, a very uncommon presentation. 2. Material and methods We reviewed the medical records, X-ray reports and MR images of patients with NF1 diagnosed between 1990 and 2004 and sporadic paraspinal neurofibromas, with ages ranging between 6 months and 20 years (average 9.8 years). The diagnosis of NF1 was made using the NIH Consensus Development Conference Criteria [1]. Paraspinal tumors were diagnosed by MR studies. Between 1990 and 2004 we examined 322 patients with NF1 who were 620 years of age at the time of their first visit. The entire spinal and paraspinal regions were studied by MR for the presence of paraspinal tumors. The radiological diagnosis was based on the presence of tumors on both sides of the spine of all nerves from the highest cervical region to the cauda equina. The examinations were performed using a 1.5-T apparatus, and T1- and T2-weighted images were obtained, with fat-suppression in some cases, and sagittal, coronal
and axial views with contrast enhancement. In some patients who showed kyphoscoliosis with some grade of spinal rotation that made difficult to demonstrate well both lateral sides of the column, it was necessary to visualize several planes. We attempted to classify the tumors as intramedullary, intradural extramedullary, intraforaminal, or extradural, based on their topographical location, but this was not always possible. Size, presence of some giant tumors that proliferated between the others, continuity of the spinal neurofibromas following the course of the peripheral nerves, and morphology were evaluated as well. Tumor changes were evaluated by MR follow-up studies performed in accordance with our surveillance protocol at regular intervals of ½ to 1 year following the diagnosis of plexiform neurofibromas in all patients while they were alive or until lost to follow-up (cases 1 and 8) or death (cases 2 and 3). At present 4 patients (cases 4, 5, 6 and 7) between 9 and 22-years of age are followed in our clinic. MR study was performed more than once in all 8 patients. 3. Results All 8 patients showed bilateral neurofibromas located in every spinal nerve of the cervical, dorsal, lumbar, sacral and coccygeal regions. The observed clinical and image abnormalities are described in the Table 1. Bilateral spinal neurofibromas appeared in patients who inherited the NF1 and in those due to de novo mutations. MR revealed spinal tumors in 19 patients (5.9%) of 322 patients with NF1, and in 8 (2.5%) the paraspinal tumors affected bilaterally all the paraspinal nerves. In the other 11 patients, the bilateral tumors affected a part of the spine or they were unilateral. Six patients were followed during more than 5 years and had more than two MR studies. This allowed us to observe the progressive increase in the size of the tumors from the time of their appearance and throughout their continuous growth. Two patients (cases 2 and 3) died. Case 2 died suddenly at home of unknown cause six years after the diagnosis of paraspinal tumors, one of which showed a voluminous size and was located in the left cervico-thoracic region (Fig. 1). The other patient (case 3) had a MPNST of the sciatic nerve and died 2 years following a diagnosis of paraspinal neurofibromas and MPNST (Fig. 2) (a benign neurofibroma was removed from a location adjacent to the MPNST). Case 4 of our series (Fig. 3) developed before nine years of age voluminous plexiform bilateral neurofibromas, two of which were located in the left thoracic cavity. In spite of this, the patient did not complain of symptoms, and showed no wasting, respiratory difficulties, motor, sensory or tendon reflex changes, and ten years later, she continues to be asymptomatic. The paraspinal tumors were already present in one patient (case 6) studied at
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Table 1 Clinical and neuroimaging features (all patients had external signs of NF1). Patient
Sex
Autosomal dominant transmission
Age at discovery of spinal tumors. Clinical features
Presence of voluminous paraspinal tumors
Presence of other peripheral neurofibromas
Treatment
Evolution
1
F
Non
Yes
Yes (generalized) Left optic nerve glioma
External anal and ureteral deviation at 22 yr
2
M
Yes
Yes
Yes (in several regions of the body)
No
3
M
Yes
Yes
Yes (left leg) Left optic nerve glioma
Yes (surgical removal MPNST of left sciatic nerve)
Progression in the number and size of tumors Lost to follow-up at 22 yr Malignancy of giant paraspinal tumor Death at 20 yr (MPNST) Death at 13 yr
4
F
Yes
Yes
Yes (occipital and both cervical nerves)
Yes (surgical removal of both tumors)
Followed for 19 yr Normal life
5
M
Yes
Yes
Yes (left palpebral)
No
Followed for 22 yr
6
M
No
Yes
Yes (in several regions)
Scoliosis at 8 yr
Followed for 9 yr
7
F
Yes
Yes
Yes (localized in many peripheral nerves)
No
Followed for 11 yr Normal life
8
M
No
14 yr Subcutaneous prominence of neurofibromas Pain 14 yr Subcutaneous prominence of neurofibromas 11 yr Cutaneous-subcutaneous plexiform neurofibroma on the neck 9 yr Generalizad subcutaneous neurofibromas 20 yr Generalizad subcutaneous neurofibromas 6 mo Cutaneous vascular malformation Plexiform neurofibroma on the neck Scoliosis Bilateral tibial dysplasia 5 yr Subcutaneous prominent neurofibromas 4 yr Subcutaneous prominent neurofibromas
Yes
Yes (plexiform neurofibromas in the right thigh)
No
Lost to follow-up at 12 yr
M = male; F = female; yr = years; mo = months; MPNST = malignant peripheral nerve sheath tumor.
Fig. 1. Patient 2 at 18-years of age. A male who showed only cutaneous signs of NF1 without neurological features. Coronal view of the MR enhanced with contrast medium shows bilateral neurofibromas in all the cervical nerves. Voluminous tumor in the left thoracic apex that enhances heterogeneously with contrast. He died suddenly at home at 20-years of age. Necropsy study was not done.
6 months of age. The tumors showed markedly increased growth vis a vis with the age in most patients, at least during several years, resulting in severe consequences for the intra-thoracic, intra-abdominal and intra-pelvic organs, and for peripheral nerve function, as occurred in case 1 of our series (Fig. 4), a woman with cutaneous signs of NF1 who was followed since 5-years of age and who developed paraspinal and generalized nerve sheath tumors between 9 and 14 years of age, with progressive loss of motor and sensory function until she was unable to walk without assistance since 14-years of age. The most frequent location of paraspinal voluminous neurofibromas was at the apex of the thoracic cavity on one or both sides, although preferentially on the left. The paraspinal tumors showed a progressive growth, not only following the trajectory of the nerve but also transversely causing enlargement of the nerves with the tumors. Paraspinal neurofibromas were excluded by MR studies in the parents of the five
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Fig. 2. Patient 3. MR enhanced with gadolinium at 11-years of age. (A) Coronal view of the lumbosacral region shows small, middle size bilateral plexiform neurofibromas of all paraspinal nerves. (B) Axial view of the gluteal region shows a malignant peripheral nerve sheath tumor (MPNST) involving the left sciatic nerve. Note the distinct types of signal within the MPNST tumor (arrow). This patient had been operated for a benign neurofibroma in a location adjacent to the last image at the same time as the malignant tumor.
Fig. 3. Patient 4 at 9-years of age. MR enhanced with contrast. (A) Coronal view shows two large plexiform neurofibromas in the superior left hemithorax. (B) Sagittal view shows two giant neurofibromas with intraspinal origin and neurofibromas in all the spinal foramina. (C) Axial view at the level of the upper thoracic region shows plexiform neurofibromas on both sides, with giant size on the left side that shows the original portion in the intraspinal region (arrow) compressing the spinal cord and eroding the vertebral body. A previous MR performed one year before showed tumors of similar size. The tumors did not receive any treatment, the patient continued a normal life and, at 19-years of age, she is asymptomatic, without any clinical features.
patients with inherited NF1.Two patients showed associated optic pathway gliomas. 4. Discussion About 40% of NF1 patients develop spinal tumors [16], most often neurofibromas that appear as isolated tumors. Spinal tumors form part of the clinical spectrum of NF1, but less than 2% are symptomatic, especially during childhood and adolescence. The diagnosis of
these tumors in patients with NF1 is frequently delayed or ignored because of the lack of clinical features, apart from the cutaneous signs of NF1 and of routine radiological studies of the spinal abnormalities in the periodic follow-up of these patients, especially in children who have no evident scoliosis. Intraspinal plexiform neurofibromas may present with clinical features related to size and location of the tumors [17]. However, asymptomatic plexiform lesions are frequently observed at least for several years during infancy, adolescence and early adult
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Fig. 4. Patient 1. (A) Post-contrast, fat-suppression coronal SE 3560/95 image shows enhancing tumors with nodular enlargement of all spinal nerves in a 14-year-old girl. (B) Coronal view of the pelvic region at 19-years of age shows a markedly increased size of the tumors and comparatively reduced size of rectum, uterus and bladder. (C) Axial view of the same study shows invasion of all the pelvic cavity, compressing rectum, uterus and bladder (arrow). (D) Coronal T2-weighted image of the lumbo-sacral region and both lower extremities shows multiple generalized tumors.
life [12]. The patients studied in the present series showed the tumors affecting bilaterally all the spinal regions from the highest cervical level to the sacrococcygeal region, and the paraspinal tumors followed the growth along the peripheral nerves. This presentation in non-familial form is very rare and the 8 patients presented in this paper constitute the first series published with bilateral neurofibromas that affect every spinal nerve from the first cervical segment to the cauda equina. Plexiform neurofibromas of the lumbosacral plexus can attain a large volume and cause multiple and severe complications, such as masses affecting the intra-abdominal and/or intra-pelvic organs. The small and large bowel can be affected by infiltration in cases of sarcomatous degeneration or by invasion of adjacent organs in cases with progressive growth without malignancy. In malignant and benign retroperitoneal tumors, the patients commonly present clinically with signs of bowel, rectal and/or ureteral obstruction, accompanied by fecal retention and hydroureteronephrosis that may require special maneuvers or specific medication to control sphincters, as was necessary in one of our patients
(case 1) despite an almost asymptomatic neurological course over a long time [12,13,18,19]. These tumors can show in CT and MR studies as well-differentiated fibromas, as appeared in our patients, or as an almost uniform mass of the involved organs [13]. Biondetti et al. [18] and Bass et al. [19] observed the symmetric homogeneous appearance of paraspinal plexiform neurofibromas. All the patients in our series had bilateral plexiform neurofibromas, but not all had homogeneous or symmetrical appearance or size. At least during the follow-up period, those located in the cervical and lumbosacral regions showed more similarities. However, most series report significant size differences among the neurofibromas located in the spinal region, being more frequent at the thoracic and lumbosacral levels, and less so in the cervical [20]. The largest asymmetries and the presence of most voluminous unilateral plexiform neurofibromas were found in the cervico-dorsal and highest dorsal regions in our series (cases 2 and 4). These voluminous tumors had the most rapid growth at any age, from the first years of life, although this was especially noticeable between 10 and 20 years of
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age. By contrast, the most rapid growth or even the onset of the growth in FSNF1 commonly is found years later, after 20 or 30 years, in most cases. Asymmetry in size and attenuation of a larger mass suggest the possibility of a MPNST [21], although this did not occur in our series in which with voluminous symmetrical or asymmetrical paraspinal plexiform neurofibromas did not develop malignancy, at least during more than 10 years of follow-up (cases 1 and 4). In our series, involvement of the sacral plexus extended into the sciatic nerve or even into all of the nerves of the lower extremities and involved of all the peripheral nerves. Malignancy of a plexiform neurofibroma that affected the sciatic nerve was seen in one patient (case 3). The diagnosis of MPNST at an early stage and resection of the malignant tumor with wide margins may achieve a better prognosis [21]. Unfortunately, this did not occur with the operated patient in our series (case 3) who survived less than two years after removal (probably in an incomplete form) of the MPNST. The risk of developing MPNST in patients with bilateral paraspinal plexiform neurofibromas may be twice that of patients with unilateral tumors, but it never has been reported either in non-FSNF1 or in FSNF1. NF1 microdeletion patients have a substantially higher risk for the development of MPNST compared with non-microdeletion NF1 individuals [22,23]. If this finding is confirmed, the routine testing of individuals with NF1 for the presence of a microdeletion and follow-up of NF1 microdeletion patients with a higher level of suspicion for MPNST would be appropriate [22]. Paraspinal neurofibromas present surgical challenges due to their anatomical relation to the spine, spinal cord, nerve roots, and major vasculature. Total resection of the tumor was achieved in 78.6% of cases with neurofibromas in the series of Cherqui et al. [24], but the patients did not have bilateral plexiform neurofibromas involving all paraspinal nerves. Microsurgical techniques are essential for identifying and, whenever possible, preserving non-involved roots [17], but the infiltration of multiple adjacent nerves and/or entire nerve plexus bilaterally, in conjunction with adjacent vascular and visceral organs, especially in the neck, the thorax and the pelvic regions, makes removal of these tumors difficult. The lack of a large series of FSNF1 and especially of non-FSNF1 involving all the spinal nerves does not allow sufficient experience in the most suitable treatment and the prognosis of the patients during adult life. To date, only voluminous tumors and especially those with malignant neuroradiological features, have been removed. MR coronal studies of the complete spine every two or three years, along with periodic clinical follow-up of patients with NF1 could detect these tumors sooner. Diagnosis and treatment of voluminous neurofibromas to anticipate the occurrence of
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