Brain, Vol. 126, No. 1, 152-160,
January 2002
© 2002 Guarantors of Brain
doi: 10.1093/brain/awg016
Prognostic factors of CNS tumours in Neurofibromatosis 1 (NF1)
A retrospective study of 104 patients
1 INSERM Unité 421, Faculté de Médecine and Services 2 de Neurologie, 3 de Santé Publique et 4 de Dermatologie, Hôpital Henri Mondor, Créteil, 5 Service d’Oncologie Pédiatrique, Institut Gustave Roussy, Villejuif, 6 Service de Neurologie Pédiatrique, Hôpital Saint Vincent de Paul, 7 Service d’Oncologie Pédiatrique, Institut Curie, 8 Service de Neurochirurgie Pédiatrique, Hôpital Necker, 9 Service de Neurologie, Groupe Hospitalier Pitié-Salpêtrière, Paris and 10 Service de Dermatologie, Hôpital Hôtel Dieu, Nantes, France
Correspondence to: Alain Créange, Service de Neurologie, Hôpital Henri Mondor, 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France E-mail: alain.creange{at}hmn.ap-hop-paris.fr
Received April 2, 2002. Revised July 11, 2002. Accepted July 15, 2002.
 |
Summary |
|---|
 Top Summary IntroductionPatients and methodsResultsDiscussionReferences |
|---|
In addition to multiple peripheral neurofibromas, Neurofibromatosis 1 (NF1) predisposes to CNS tumours. Most of them are pilocytic astrocytomas, arise in children and are located in the optic pathways or in the brainstem. The majority are indolent, but factors predictive of poor prognosis have yet to be identified. Furthermore, the incidence and natural history of gliomas of a higher grade, arising in adults or involving other locations are largely unknown in NF1. In order to address these issues, we performed a retrospective study of 104 patients followed in seven French centres between 1982 and 2000. Inclusion criteria were a diagnosis of NF1, according to the National Institutes of Health criteria, and the presence of a CNS tumour, regardless of type, location or age of onset. The series included 88 children (age range 3 months to 17 years) and 16 adults (age range 19–52 years). The median follow-up was 5.6 years. One hundred and twenty-seven CNS tumours were observed in the 104 patients. Eighty-four (66%) were optic pathway tumours (OPT) and 43 (34%) extra-optic pathway tumours (extra-OPT) (brainstem: n = 21; other locations: n = 22). Twenty-one patients (20%) had multiple CNS tumours. OPT were symptomatic in 50 patients and extra-OPT in 19. Main clinical findings at presentation included visual loss (n = 29; 58%) and precocious puberty (n = 5; 10%) for OPT, increased intracranial pressure (n = 9; 48%) for extra-OPT. Fourteen out of the 27 symptomatic tumours with histology were pilocytic astrocytomas. The overall survival rate was 90% at 5 years (95% confidence interval 82–95%). Extra-optic location, tumour diagnosis in adulthood and symptomatic tumours were independent factors associated with shorter survival time (P < 0.05, Cox model). Radiotherapy for OPT was associated with vascular complications (ischaemic strokes) and growth hormone deficiency in 32 and 46% of patients, respectively. In conclusion, mortality is high in extra-OPT, particularly in adults, whereas OPT are only exceptionally life-threatening. Radiotherapy of OPT is associated with an important morbidity in NF1.
Keywords: brainstem glioma; Neurofibromatosis 1; optic pathway glioma
Abbreviations: NF1 = Neurofibromatosis 1; OPT = optic pathway tumour; UBO = unidentified bright object
|
Introduction |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Neurofibromatosis 1 (NF1) is a common genetic disorder, with an incidence of one per
3500 births (Riccardi, 1991
; Friedman, 1999). The NF1 gene, a tumour-suppressor gene located on chromosome 17q11.2, encodes neurofibromin, a negative regulator of the Ras oncogene, the inactivation of which leads to cell proliferation and tumour development (Seizinger, 1993; Rasmussen and Friedman, 2000). NF1 predisposes mainly to tumours developed from peripheral or central nerve tissue (Sorensen et al., 1986; Huson et al., 1988; Friedman and Birch, 1997; Gutmann et al., 1997; McGaughran et al., 1999). Tumours of the peripheral nervous system are the most frequent tumours of NF1, and malignant peripheral nerve sheath tumours are the major cause of mortality in adult patients (Créange et al., 1999). Although less frequent than peripheral nervous system tumours, CNS tumours are important because they may lead to major morbidity and mortality, despite the fact that most of them are grade I pilocytic astrocytomas (Sorensen et al., 1986; Matsui et al., 1993; Listernick et al., 1999a).
Optic pathway (Listernick et al., 1994) and brainstem (Pollack et al., 1996) gliomas are prevalent CNS tumours in NF1. Most of the studies, carried out in children, showed that these tumours were less aggressive than their counterparts in non-NF1 patients (Listernick et al., 1995; Molloy et al., 1995; Deliganis et al., 1996; Pollack and Mulvihill, 1996). However, few data are available for tumours located outside optic pathways and brainstem, and for tumours arising in adults, even though we have recently suggested that brainstem gliomas could lead to an unusual mortality in NF1 adults (Guillamo et al., 2001). Moreover, asymptomatic or low symptomatic tumours are increasingly revealed by systematic MRI, raising new prognostic queries and difficulties in patient management (Aoki et al., 1989; Bonawitz et al., 1998; DiMario and Ramsby, 1998).
It therefore appears preferable to identify prognostic factors for patients with CNS tumours and NF1, in addition to, or, in most cases, as an alternative to histological criteria. The present multicentric retrospective study, based on a large NF1 population including both children and adults with CNS tumours, has been set up in order to address these issues.
|
Patients and methods |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Patients
Records were collected for patients with NF1 according to the criteria of the National Institute of Health (National Institutes of Health Consensus Development Conference, 1988
) and with CNS tumours referred to four Neurofibromatosis clinics: Henri Mondor (n = 14); Saint-Vincent de Paul (n = 16); Necker-Enfants Malades (n = 14); and Hôtel-Dieu de Nantes (n = 13); and three departments of oncology: Gustave-Roussy (n = 33); Curie (n = 9); and Pitié-Salpêtrière (n = 5), during the period from 1982 to 2000. Computed tomography (CT) scan at diagnosis was mandatory before 1987, and MRI after 1987. A list of 111 records was drawn up; 104 were available for the study (five records were not included because of incomplete clinical and/or radiological data, and two patients did not meet NF1 criteria). Patients aged >18 years at tumour diagnosis were defined as adults.
Tumour diagnosis
The diagnosis of CNS tumour was based on pathological confirmation except for infiltrating tumours of the optic pathways or the brainstem, in which diagnosis was based on radiological criteria (Listernick et al., 1997). In the case of asymptomatic tumours, the diagnosis of CNS tumour was considered in presence of two or more of the following radiological features: expansive lesion, contrast enhancement or mass effect. The differential diagnosis, unidentified bright object (UBO), was considered in non-expansive T2-weighted MRI lesions without contrast enhancement or mass effect (Ferner et al., 1993; DeBella et al., 2000). In the case of asymptomatic tumours, metastases were excluded on the basis of clinical history, absence of a known cancer, and clinical and radiological follow-up. Meningiomas that are not intrinsic tumours of the CNS and constitute a distinct entity in terms of embryological origin were excluded from the study.
Classification of tumours
Tumours were classified according to their location in two groups: optic pathway tumours (OPT) and extra-optic pathway tumours (extra-OPT). OPT included tumours of the optic nerves, chiasma and retrochiasmatic pathways. Extra-OPT included brainstem tumours and tumours of other locations (i.e. cerebral lobes, basal ganglia, cerebellum and spinal cord). Multiple tumours were defined as distinct lesions, i.e. lesions without an anatomical link. Histology of tumours was classified according to the World Health Organization (WHO) classification (Kleihues and Cavenee, 2000).
Record review and data collection
The medical record of each patient was reviewed by one of us (J.-S.G.). The following data were collected: demographic information (age, sex, familial history of NF1), date of tumour diagnosis, circumstances of diagnosis and age at onset, location and number of tumours, radiological features, histology when available, treatment, clinical and radiological course, and complications (including treatment complications).
Statistical analyses
Survival time was measured from the date of onset of symptoms or from the date of diagnosis for asymptomatic tumours, to the date of last follow-up visit or death. Survival time was estimated by the Kaplan–Meier method (Kaplan and Meier, 1958). The factors that may influence survival time (sex, age at tumour diagnosis, location of the tumour, symptoms at diagnosis, multiple tumours) were tested by comparing survival curves with the log rank test. Cox’s proportional hazards model was used to take into account simultaneously all potential prognostic factors over time (Cox, 1972). Variables included in the final multivariate model were those emerging from univariate models with a P value <0.15. Hazard ratios and their two-sided 95% confidence interval (CI) were estimated. All tests were two-tailed, a P value of <0.05 indicated statistical significance. Data were analysed using the Biomedical Statistical Package (BMDP) software (University of California, Berkeley). Percentages were compared with the Fisher’s exact test.
|
Results |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Patients and tumours
One hundred and four patients were included in the study (male : female, 54 : 50). Fifty-nine patients had sporadic NF1, 38 patients had a familial form; familial status was not available in seven. Eighty-eight patients were children (median age 5.2 years; range 3 months to 17 years) and 16 were adults (median age 28.8 years; range 19–52 years). The median follow-up was 5.6 years (range 4.5 months to 18 years; mean 6.3 years).
One hundred and twenty-seven tumours were observed in the 104 patients included in the study. Their locations are summarized in Fig. 1. Twenty-one (20%) patients had either two (n = 19) or three (n = 2) CNS tumours. Nine patients had both an OPT and a brainstem tumour.
|
Characteristics of OPT
Age and clinical features at diagnosis
OPT were diagnosed in 84 patients (74 children and 10 adults; Fig. 2A). Thirty-four tumours were asymptomatic and were diagnosed on systematic imaging (24 out of 74 in children, and 10 out of 10 in adults). Fifty tumours were symptomatic (50 out of 74 in children, and zero out of 10 in adults). Symptoms at diagnosis are summarized in Table 1. Visual loss (58%) and precocious puberty (10%) were the most frequent symptoms. Fifteen children out of 50 with symptomatic OPT were diagnosed after the age of 6 years. All were under 9 years of age. Of these 15 OPT in older children, four progressed after diagnosis and required specific treatment.
|
|
Location
OPT represented 66% of CNS tumours. OPT locations are summarized in Fig. 3. Anterior OPT were the most frequent tumours (84% of OPT).
|
Radiological features
Radiological examinations of OPT, based either on CT scans (n = 21) or MRI (n = 63), showed a mass effect on adjacent structures in 23 (27%) tumours and a cystic component in four (5%). Thirty-six (56%) of the 64 tumours with contrast infusion showed contrast enhancement.
Pathological features
Pathological examination was available in eight progressive OPT (all in children). Five were pilocytic astrocytomas (grade I) and three were low-grade astrocytomas (grade II).
Treatment and complications
Twenty-eight asymptomatic and 13 symptomatic OPT were not treated. One patient had spontaneous regression of the tumour during follow-up. Six asymptomatic (three of them progressed after diagnosis) and 37 symptomatic OPT had treatment. Treatment consisted of surgical resection (n = 9), cerebrospinal fluid shunt (n = 7), radiotherapy (n = 28) and chemotherapy (n = 11). Among the 28 OPT treated with radiotherapy, 17 tumours enlarged on radiological examinations before treatment. Of these 17 OPT, four had partial responses, 11 stable diseases and two progressive diseases after radiotherapy. Only one out of nine severely affected patients (visual acuity <2 out of 10) improved after radiotherapy.
Twenty-four patients had precocious puberty: five at the time of tumour diagnosis, 19 during the follow-up and among them, nine after radiotherapy (P = 0.17; Fisher’s exact test). Fourteen patients had growth hormone deficiency and among them, 13 after radiotherapy within a median interval of 23 months (46% of OPT with radiotherapy) compared with only one who had no radiotherapy (P < 0.001; Fisher’s exact test). Nine patients (32% of OPT with radiotherapy) had presumed radiation related ischaemic strokes within a median interval of 28 months.
Characteristics of extra-OPT
Age and clinical features at diagnosis
Extra-OPT were diagnosed in 43 patients (33 children and 10 adults; Fig. 2B). Twenty-four tumours were asymptomatic and diagnosed on systematic imaging (20 out of 33 in children and four out of 10 in adults). Nineteen tumours were symptomatic (13 out of 33 in children and six out of 10 in adults). Symptoms at diagnosis are summarized in Table 1. Increased intracranial pressure (48%) was the most frequent clinical presentation.
Location
Extra-OPT locations are summarized in Fig. 1. Brainstem tumours were the most frequent tumours (49% of extra-OPT).
Radiological features
Radiological examinations of extra-OPT based either on CT scans (n = 4) or MRI (n = 39) showed a mass effect on adjacent structures in 19 (44%) tumours and a cystic component in nine (21%). Twenty-seven (82%) tumours out of the 33 with contrast infusion showed contrast enhancement.
Pathological features
Pathological examination was available in 19 progressive extra-OPT. Nine were pilocytic astrocytomas (grade I; eight children, one adult), five were low-grade astrocytomas (grade II; four children, one adult), two were anaplastic astrocytomas (grade III; one child, one adult), two were glioblastomas (grade IV; one child, one adult) and one was a dysplastic neuroepithelial tumour (one child).
Treatment and complications
Nineteen asymptomatic and one symptomatic extra-OPT were not treated. Five asymptomatic (four in children and one in an adult that progressed after diagnosis) and 18 symptomatic extra-OPT had treatment. Treatment consisted of surgical resection (n = 14), cerebrospinal fluid shunt (n = 4), radiotherapy (n = 15) and chemotherapy (n = 13).
There was no endocrinological complication or radiation-induced stroke in patients with extra-OPT in this series. Leptomeningeal dissemination was observed for three tumours.
Other associated tumours and UBOs
Other associated tumours included multiple meningiomas (n = 2), malignant peripheral nerve sheath tumour (sarcoma) (n = 1), rhabdomyosarcoma of the bladder (n = 1), compressive spinal cord neurofibroma (n = 3) and plexiform neurofibroma (n = 3). UBOs were observed in 73% of patients with MRI, all in children, except for the youngest adult (aged 19 years).
Survival analysis
Twelve (11%) out of the 104 patients died during follow-up. Causes of death are presented in Table 2. Death was related to glioma progression in 10 patients and to another tumour (sarcoma) in two patients with stable OPT. The survival curve of the population is shown in Fig. 4. The survival rate was 90% at 5 years (95% CI 82–95%) and 82% at 10 years (95% CI 70–90%).
|
|
Survival according to the location of the tumour, age at diagnosis and the presence of symptoms at diagnosis is shown in Fig. 5. Survival time of patients with extra-OPT was significantly shorter than patients with OPT (P < 0.0001). Adult patients had a significantly worse prognosis than children (P < 0.0001), even for extra-OPT only (P = 0.002). Asymptomatic patients tended to have a better survival than symptomatic patients, but the difference did not reach significance in univariate analysis (P = 0.08). There was no difference in survival between patients with a single tumour and patients with multiple CNS tumours (P = 0.66) or between males and females (P = 0.77).
|
In multivariate analyses, extra-optic location, tumour diagnosis at adulthood and symptoms at diagnosis were independently associated with a higher mortality (P < 0.05; Cox’s proportional hazards model; Table 3).
|
|
Discussion |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
This study included CNS tumours in NF1, whatever their location or histological type, or the age of the patient. The use of definite criteria of NF1, the median follow-up of 5.6 years and the large proportion of MRI examinations allowed a good overview of the spectrum of CNS tumours in NF1. This population included a high proportion of tumours located outside the optic pathways (34%) and a high proportion of patients with multiple CNS tumours (20%). The overall prognosis was good, with a 5-year survival rate of 90% and a 10-year survival rate of 82%. However, this study also showed that mortality was independently associated with extra-optic location, symptomatic tumours and adult patients.
Astrocytomas are the major type of CNS tumours in NF1, and pilocytic astrocytoma (WHO grade I) the main histological subtype (Stern et al., 1980; Listernick et al., 1997). Pilocytic astrocytomas are usually characterized by a stable or a very slow progressive course that may account for the overall good prognosis of CNS tumours in NF1. Interestingly, a high proportion of progressive tumours in our series were not pilocytic astrocytomas but higher grade astrocytomas (grade II, III and IV), an observation consistent with previous data from NF1 brainstem gliomas (Molloy et al., 1995; Pollack et al., 1996) suggesting that symptomatic/progressive tumours may be associated with a more aggressive histological subtype. Therefore, in cases of symptomatic and progressive tumours, particularly when located outside the optic pathways, histological specification can be useful for treatment adjustment and prognosis. Although other rare types of CNS tumours have been reported in NF1, including ependymomas (Es et al., 1996), medulloblastomas (Matsui et al., 1993) and dysplastic neuroepithelial tumours (Lellouch-Tubiana et al., 1995), only one of these rare tumours was observed in the present series, suggesting that either the incidence of these tumours in NF1 is very low or that they should not be considered as NF1 associated tumours.
Not surprisingly, the majority of tumours were OPT (66%). In large population-based studies or in studies with systematic radiological evaluation, OPT are observed in 5–20% of NF1 patients, most being asymptomatic (Lewis et al., 1984; Sorensen et al., 1986; Listernick et al., 1994; Friedman and Birch, 1997). Previous studies have shown that the age distribution and location of optic pathway gliomas are different in patients with NF1 and without NF1, and that optic pathway gliomas are associated with a better prognosis in patients with NF1 (Listernick et al., 1995; Deliganis et al., 1996; Kornreich et al., 2001). However, in the present series, the age limit for symptomatic and progressive OPT was 9 years, a slightly older limit than previously considered (Listernick et al., 1997). Secondly, our data showed that although OPT were exceptionally life threatening in NF1, they were associated with a significant morbidity related either to the tumour itself (visual loss, precocious puberty) or to the treatment. Although the high proportion of symptomatic OPT (58%) in our study was probably related to inclusion bias of patients from NF clinics and oncological departments, it is a real concern in the overall population of NF1 patients. The utility of screening neuroimaging for the improvement of clinical outcome of OPT has been questioned. Our data show that all the adults and a majority of children with OPT did not progress after detection. For those whose OPT progressed and required treatment, abnormal visual findings could be detected by ophthalmological examination. Consistent with the conclusions of the Neurofibromatosis Task Force on Optic Pathway Glioma (Listernick et al., 1997), these results do not support recommendation of screening neuroimaging for detection of OPT in NF1. However, systematic annual eye examinations are highly recommended to detect OPT in NF1 children, particularly in very young children, in whom complaints of visual loss are rare (Listernick et al., 1997; Pinson et al., 2001).
In the past, various doses of radiotherapy have been used to treat OPT (Bataini et al., 1991; Jenkin et al., 1993; Grill et al., 2000). Tumour control is obtained in up to 80–90% of NF1 patients (Bataini et al., 1991; Jenkin et al., 1993; Tao et al., 1997). Despite this high rate of control, systematic use of radiotherapy has been questioned, since it has been associated with serious delayed toxicity in NF1 (Grill et al., 1999). Main complications include radiation-induced stroke and growth hormone deficiency (32 and 46%, respectively, of patients in our series), although these two complications can be exceptionally observed in absence of radiotherapy. These data support the restricted use of treatment, the modalities of which should be carefully discussed, only in cases of symptomatic and progressive tumours. In this setting, given the high rate of delayed toxicity, there is virtually no role for radiotherapy in childhood OPT with NF1. Chemotherapy is currently a recommended alternative to radiotherapy, although there are few published data in NF1 to date (Packer et al., 1997; Listernick et al., 1999b).
The present series included a high proportion of extra-OPT. Extra-optic location was an independent prognostic factor for death. Brainstem gliomas are the second most frequent tumours in NF1 after OPT. As a rule, brainstem gliomas behave much less aggressively in NF1 patients than in other patients (Raffel et al., 1989; Molloy et al., 1995; Pollack et al., 1996). Although most of them remained asymptomatic or did not progress clinically without treatment, our study clearly demonstrated that brainstem gliomas may also become life-threatening in NF1 patients, both in children (three out of seven deaths) and adults (two out of five deaths). Other symptomatic extra-OPT, including cerebral and cerebellar tumours, were associated with a poor prognosis. Extra-optic tumours were the only cause of death in adults.
Twenty per cent of patients in this series had multiple CNS tumours. This is in keeping with a previous study in which 18% of patients had multiple tumours (whatever the type and location) and 14% of patients had multiple CNS tumours (Sorensen et al., 1986). In a recent neuroradiological series with MRI, 40% of patients with a brainstem glioma had a concurrent OPT (Bilaniuk et al., 1997). Not surprisingly, the most frequent association was an OPT and a brainstem tumour that usually combined one asymptomatic and one symptomatic tumour. The life prognosis of patients with multiple tumours was not different from the prognosis of patients with a single tumour. This result highlights the existence of tumours compatible with long survival, an assessment especially true when tumours are diagnosed in children, develop in the optic nerve and remain asymptomatic. Multiple tumours are therefore a core feature of NF1, even when only CNS tumours are considered.
Adulthood was an independent prognostic factor for shorter survival, and was associated with the development of malignant CNS tumours located outside the optic pathways. In a previous study, we had shown that life-threatening neurological complications were rare in adults, except malignant peripheral nerve sheath tumours (Créange et al., 1999). Non-neoplastic neurological manifestations of NF1 are more severe in childhood than in adulthood (Créange et al., 1999). This assessment is also true for OPT, but it cannot be extended to the other cerebral tumours. The increased risk for malignant tumours with ageing could well result from additional genetic alterations arising randomly over time. Although, malignant peripheral nerve sheath tumours in the peripheral nervous system arise from plexiform and subcutaneous neurofibromas (Leroy et al., 2001), our study does not address the question of possible degeneration from asymptomatic benign CNS tumours. In our series, only one adult patient with an asymptomatic cerebral lesion experienced a rapid progression of the tumour, 9 years after detection.
In conclusion, survival of patients with CNS tumours and NF1 is dependent on age of onset, the presence of tumour related symptoms, and the presence of extra-optic tumours. Decision making for NF1 patients with CNS tumours should be facilitated by these results.
|
References |
|---|
|
TopSummaryIntroductionPatients and methodsResultsDiscussionReferences |
|---|
Aoki S, Barkovich AJ, Nishimura K, Kjos BO, Machida T, Cogen P, et al. Neurofibromatosis types 1 and 2: cranial MR findings. Radiology 1989; 172: 527–34.
Bataini JP, Delanian S, Ponvert D. Chiasmal gliomas: results of irradiation management in 57 patients and review of literature. [Review]. Int J Radiat Oncol Biol Phys 1991; 21: 615–23.[ISI][Medline]
Bilaniuk LT, Molloy PT, Zimmerman RA, Phillips PC, Vaughan SN, Liu GT, et al. Neurofibromatosis type 1: brain stem tumours. Neuroradiology 1997; 39: 642–53.[CrossRef][ISI][Medline]
Bonawitz C, Castillo M, Chin CT, Mukherji SK, Barkovich AJ. Usefulness of contrast material in MR of patients with neurofibromatosis type 1. AJNR Am J Neuroradiol 1998; 19: 541–6.[Abstract]
Cox DR. Regression models and life table. J R Stat Soc 1972; 34: 187–220.
Créange A, Zeller J, Rostaing-Rigattieri S, Brugieres P, Degos JD, Revuz J, et al. Neurological complications of neurofibromatosis type 1 in adulthood. Brain 1999; 122: 473–81.
DeBella K, Poskitt K, Szudek J, Friedman JM. Use of ‘unidentified bright objects’ on MRI for diagnosis of neurofibromatosis 1 in children. Neurology 2000; 54: 1646–51.
Deliganis AV, Geyer JR, Berger MS. Prognostic significance of type 1 neurofibromatosis (von Recklinghausen disease) in childhood optic glioma. Neurosurgery 1996; 38: 1114–8; discussion 1118–9.[CrossRef][ISI][Medline]
DiMario FJ Jr, Ramsby G. Magnetic resonance imaging lesion analysis in neurofibromatosis type 1. Arch Neurol 1998; 55: 500–5.
Es SV, North KN, McHugh K, Silva MD. MRI findings in children with neurofibromatosis type 1: a prospective study. Pediatr Radiol 1996; 26: 478–87.[CrossRef][ISI][Medline]
Ferner RE, Chaudhuri R, Bingham J, Cox T, Hughes RA. MRI in neurofibromatosis 1. The nature and evolution of increased intensity T2 weighted lesions and their relationship to intellectual impairment. J Neurol Neurosurg Psychiatry 1993; 56: 492–5.
Friedman JM. Epidemiology of neurofibromatosis type 1. [Review]. Am J Med Genet 1999; 89: 1–6.[CrossRef][ISI][Medline]
Friedman JM, Birch PH. Type 1 neurofibromatosis: a descriptive analysis of the disorder in 1,728 patients. Am J Med Genet 1997; 70: 138–43.[CrossRef][ISI][Medline]
Grill J, Couanet D, Cappelli C, Habrand JL, Rodriguez D, Sainte-Rose C, et al. Radiation-induced cerebral vasculopathy in children with neurofibromatosis and optic pathway glioma. Ann Neurol 1999; 45: 393–6.[CrossRef][ISI][Medline]
Grill J, Laithier V, Rodriguez D, Raquin MA, Pierre-Kahn A, Kalifa C. When do children with optic pathway tumours need treatment? An oncological perspective in 106 patients treated in a single centre. Eur J Pediatr 2000; 159: 692–6.[CrossRef][ISI][Medline]
Guillamo JS, Monjour A, Taillandier L, Devaux B, Varlet P, Haie-Meder C, et al. Brainstem gliomas in adults: prognostic factors and classification. Brain 2001; 124: 2528–39.
Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, et al. The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. [Review]. JAMA 1997; 278: 51–7.[Abstract]
Huson SM, Harper PS, Compston DA. Von Recklinghausen neurofibromatosis. A clinical and population study in south-east Wales. Brain 1988; 111: 1355–81.
Jenkin D, Angyalfi S, Becker L, Berry M, Buncic R, Chan H, et al. Optic glioma in children: surveillance, resection, or irradiation? Int J Radiat Oncol Biol Phys 1993; 25: 215–25.[ISI][Medline]
Kaplan EL, Meier P. Non parametric estimation for incomplete observations. J Am Stat Assoc 1958; 53: 457–81.[CrossRef][ISI]
Kleihues P, Cavenee WK, editors. Pathology and genetics of tumours of the nervous system. Lyon: IARC Press; 2000.
Kornreich L, Blaser S, Schwarz M, Shuper A, Vishne TH, Cohen IJ, et al. Optic pathway glioma: correlation of imaging findings with the presence of neurofibromatosis. AJNR Am J Neuroradiol 2001; 22: 1963–9.
Lellouch-Tubiana A, Bourgeois M, Vekemans M, Robain O. Dysembryoplastic neuroepithelial tumors in two children with neurofibromatosis type 1. Acta Neuropathol (Berl) 1995; 90: 319–22.[Medline]
Leroy K, Dumas V, Martin-Garcia N, Falzone MC, Voisin MC, Wechsler J, et al. Malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1: a clinicopathologic and molecular study of 17 patients. Arch Dermatol 2001; 137: 908–13.
Lewis RA, Gerson LP, Axelson KA, Riccardi VM, Whitford RP. von Recklinghausen neurofibromatosis. II. Incidence of optic gliomata. Ophthalmology 1984; 91: 929–35.[ISI][Medline]
Listernick R, Charrow J, Greenwald M, Mets M. Natural history of optic pathway tumors in children with neurofibromatosis type 1: a longitudinal study. J Pediatr 1994; 125: 63–6.[CrossRef][ISI][Medline]
Listernick R, Darling C, Greenwald M, Strauss L, Charrow J. Optic pathway tumors in children: the effect of neurofibromatosis type 1 on clinical manifestations and natural history. J Pediatr 1995; 127: 718–22.[CrossRef][ISI][Medline]
Listernick R, Louis DN, Packer RJ, Gutmann DH. Optic pathway gliomas in children with neurofibromatosis 1: consensus statement from the NF1 Optic Pathway Glioma Task Force. Ann Neurol 1997; 41: 143–9.[CrossRef][ISI][Medline]
Listernick R, Charrow J, Gutmann DH. Intracranial gliomas in neurofibromatosis type 1. [Review]. Am J Med Genet 1999a; 89: 38–44.[CrossRef][ISI][Medline]
Listernick R, Charrow J, Tomita T, Goldman S. Carboplatin therapy for optic pathway tumors in children with neurofibromatosis type-1. J Neurooncol 1999b; 45: 185–90.[CrossRef][Medline]
Matsui I, Tanimura M, Kobayashi N, Sawada T, Nagahara N, Akatsuka J. Neurofibromatosis type 1 and childhood cancer. Cancer 1993; 72: 2746–54.[CrossRef][ISI][Medline]
McGaughran JM, Harris DI, Donnai D, Teare D, MacLeod R, Westerbeek R, et al. A clinical study of type 1 neurofibromatosis in north west England. J Med Genet 1999; 36: 197–203.
Molloy PT, Bilaniuk LT, Vaughan SN, Needle MN, Liu GT, Zackai EH, et al. Brainstem tumors in patients with neurofibromatosis type 1: a distinct clinical entity. Neurology 1995; 45: 1897–902.
National Institutes of Health Consensus Development Conference. Neurofibromatosis. Conference statement. Arch Neurol 1988; 45: 575–8.[ISI][Medline]
Packer RJ, Ater J, Allen J, Phillips P, Geyer R, Nicholson HS, et al. Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg 1997; 86: 747–54.[ISI][Medline]
Pinson S, Créange A, Barbarot S, Stalder JF, Chaix Y, Rodriguez D, et al. Neurofibromatosis 1: recommendations for management. [Review]. [French]. Ann Dermatol Venereol 2001; 128: 567–75.[ISI][Medline]
Pollack IF, Mulvihill JJ. Special issues in the management of gliomas in children with neurofibromatosis 1. [Review]. J Neurooncol 1996; 28: 257–68.[Medline]
Pollack IF, Shultz B, Mulvihill JJ. The management of brainstem gliomas in patients with neurofibromatosis 1. [Review]. Neurology 1996; 46: 1652–60.
Raffel C, McComb JG, Bodner S, Gilles FE. Benign brain stem lesions in pediatric patients with neurofibromatosis: case reports. Neurosurgery 1989; 25: 959–64.[ISI][Medline]
Rasmussen SA, Friedman JM. NF1 gene and neurofibromatosis 1. [Review]. Am J Epidemiol 2000; 151: 33–40.
Riccardi VM. Neurofibromatosis: past, present, and future. N Engl J Med 1991; 324: 1283–5.[ISI][Medline]
Seizinger BR. NF1: a prevalent cause of tumorigenesis in human cancers? Nature Genet 1993; 3: 97–9.[CrossRef][ISI][Medline]
Sorensen SA, Mulvihill JJ, Nielsen A. Long-term follow-up of von Recklinghausen neurofibromatosis. Survival and malignant neoplasms. N Engl J Med 1986; 314: 1010–5.[Abstract]
Stern J, Jakobiec FA, Housepian EM. The architecture of optic nerve gliomas with and without neurofibromatosis. Arch Ophthalmol 1980; 98: 505–11.[ISI][Medline]
Tao ML, Barnes PD, Billett AL, Leong T, Shrieve DC, Scott RM, et al. Childhood optic chiasm gliomas: radiographic response following radiotherapy and long-term clinical outcome. Int J Radiat Oncol Biol Phys 1997; 39: 579–87.[CrossRef][ISI][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||