Longitudinal study of neurofibromatosis 1 associated plexiform neurofibromas.

BACKGROUND: Plexiform neurofibromas are benign tumours that occur in more than half of people with neurofibromatosis 1 (NF1). These tumours can cause serious complications and can also progress to malignant peripheral nerve sheath tumours (MPNSTs), one of the leading causes of death among NF1 patients. Plexiform neurofibromas are clinically heterogeneous, and knowledge of their natural history is limited. In order to characterise the growth of plexiform neurofibromas better, we performed serial magnetic resonance imaging (MRI) in NF1 patients with such tumours. METHODS: MRI was done on 44 plexiform neurofibromas in 34 NF1 patients (median age 10 years; range 1-47 years). Each tumour was measured in two dimensions from the MRI scan, and the area and growth rate were calculated. The median length of follow-up was 6 years, with an average interval of 3 years between scans. RESULTS: 36 tumours remained stable in size throughout the period of follow-up. 8 tumours increased in size; all occurred in patients who were under 21 years of age when first studied. The single exception was a man who developed rapid tumour growth and pain in a plexiform neurofibroma that had been followed for 10 years. Biopsy showed the presence of an MPNST. CONCLUSION: Longitudinal MRI is a valuable means of monitoring the growth of plexiform neurofibromas in individuals with NF1.

Clinical relevance of positron emission tomography and magnetic resonance imaging in the progression of internal plexiform neurofibroma in NF1.

Neurofibromatosis type 1 (NF1) is a frequent and inherited disease with a predisposition for malignant peripheral nerve sheath tumor (MPNST) development. MPNST are soft tissue sarcomas that arise from peripheral nerves, being one of the most aggressive malignancies in humans with extremely poor prognosis. MPNST frequently arise from a previously undetected plexiform neurofibroma (PNF). The malignant transformation of an internal PNF to an MPNST is difficult to assess and requires advanced imaging techniques like magnetic resonance imaging or positron emission tomography. Despite the high quality of current diagnostics, the changing tumor biology inside a plexiform neurofibroma cannot currently be visualized accurately. We report 4 cases of NF1 patients with PNF who showed imaging findings suspicious for malignant degeneration, but proved to have MPNST in only one case. Three tumors might represent an intermediate type between PNF and MPNST. Ablative surgery and complete histological work-up of specimens is the only way to clarify tumor status, thereby enabling provision of adequate local treatment.

MRI growth patterns of plexiform neurofibromas in patients with neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with an incidence of 1:3000. Approximately 30% of NF1 patients develop plexiform neurofibromas (PNF) which often cause severe clinical deficits. We studied the growth patterns of 256 plexiform neurofibromas (PNF) by magnetic resonance imaging (MRI) and associated disfigurement and functional deficits to determine whether there are definable growth types of these tumors. Retrospectively, we evaluated MRI scans obtained during 1997 to 2003 of 256 plexiform neurofibromas from 202 patients with NF1. Clinical investigation was carried out at the same time as the MRI scans. We identified three growth patterns: superficial in 59, displacing in 76, and invasive growth in 121 tumors. The majority (52%) of invasive PNF were found in the face, head and neck area. While superficial PNF primarily caused aesthetic problems, displacing PNF led in most cases to aesthetic problems and pain, while invasive PNF led mainly to functional deficits and disfigurement. Our study demonstrates that PNF have different growth patterns that are associated with specific clinical features. Classification of PNF may open new opportunities in clinical management, especially regarding decisions and options associated with surgical intervention.

Malignant peripheral nerve sheath tumors (MPNST) in neurofibromatosis type 1 (NF1): diagnostic findings on magnetic resonance images and mutation analysis of the NF1 gene.

UNLABELLED: Plexiform neurofibroma (PNF) is a typical feature of neurofibromatosis 1 (NF1). About 10% of patients with NF1 develop malignant peripheral nerve sheath tumors (MPNST), usually arising from PNF, and this is the major cause of poor prognosis. A better prognosis can be achieved if the tumors are diagnosed at an early stage. Our objective was to establish magnetic resonance imaging (MRI) criteria for MPNST, and to test their usefulness in detecting early malignant changes in PNF and to correlate the findings with the mutations of the NF1 gene. PATIENTS AND METHODS: NF1 outpatients were diagnosed according to the NIH criteria. All patients underwent a complete dermatological, ophthalmological and neurological examination and ultrasound of the abdomen between 1997 and 2002. The study was approved by the Institutional Review Board and all patients gave informed consent to analyze clinical records and tumor material for scientific purposes. MRI was performed with devices at 1.5 Tesla field strength (Siemens Magnetom Symphony) or in some patients at 1.0 Tesla field strength (Siemens Impact Expert). T1- and T2-weighted sequences including STIR-sequences were acquired. Ultra-rapid image sequences with HASTE technique were performed for trunk imaging. In patients with no contraindication for the application of contrast media, Gadolinum-DTPA Magnevist was administered intravenously. RESULTS: MRI was performed on 50 patients with NF1 and nerve sheath tumors, of whom 7 had atypical pain, tumor growth or neurological deficits indicative of malignancy; the other 43 were asymptomatic. On MRI, all 7 symptomatic patients had inhomogeneous lesions, due to necrosis and hemorrhage and patchy contrast enhancement. In one patient, the multiplicity of confluent tumors with inhomogeneous areas in addition to central lesions did not allow the exclusion of malignancy. Only 3 of the 43 asymptomatic patients had comparable changes; the other 40 patients had tumors of relatively homogeneous structure on T1- and T2-weighted images before and after contrast enhancement. All 3 asymptomatic patients with inhomogeneous lesions were shown to have MPNST. Analysis of mutations of the NF1 gene of the 10 MPNST patients revealed a variety of mutations. Concerning the correlation of genetic findings and MPNST in NF1, the sample size of this study group was too small to define genotype-phenotype relations. In this cohort, all types of mutations were found. CONCLUSION: This study provides evidence for certain radiographic findings on MRI in PNF of NF1 patients that have to be considered as signs of malignancy, in particular indicating an MPNST. These findings are especially valuable in the long term follow-up control of patients with large tumors (plexiform neurofibromas).

Malignant peripheral nerve sheath tumours in neurofibromatosis type 1: MRI supports the diagnosis of malignant plexiform neurofibroma.

Plexiform neurofibroma (PNF) is a typical feature of neurofibromatosis 1 (NF1). About 10% of patients with NF1 develop malignant peripheral nerve-sheath tumours (MPNST), usually arising from PNF, and this is the major cause of poor survival. A better prognosis can be achieved if the tumours are diagnosed at an early stage. Our objective was to establish MRI criteria for MPNST and to test their usefulness in detecting early malignant change in PNF. MRI was performed on 50 patients with NF1 and nerve-sheath tumours, of whom seven had atypical pain, tumour growth or neurological deficits indicative of malignancy; the other 43 were asymptomatic. On MRI all seven symptomatic patients had inhomogeneous lesions, due to necrosis and haemorrhage and patchy contrast enhancement. In one patient, the multiplicity of confluent tumours with inhomogeneous areas in addition to central lesions did not allow exclusion of malignancy. Only three of the 43 asymptomatic patients had comparable changes; the other 40 patients had tumours being of relatively homogeneous structure on T1- and T2-weighted images before and after contrast enhancement. All three asymptomatic patients with inhomogeneous lesions were shown to have MPNST.

Growth type of plexiform neurofibromas in NF1 determined on magnetic resonance images.

This article describes some types of growth in plexiform neurofibroma (PNF) on magnetic resonance images (MRI). This tumor is almost exclusively associated with NF1. On MRI, the tumor is depicted as a hyperintensive area on T2-weighted images. We distinguished 3 patterns of tumor growth: first, the superficial and non-invasive tumors, that are restricted to the cutis and subcutis, only eventually having outgrowth to the muscles beneath and are slow growing. Second, the displacing PNF that develop in deeper layers of the skin or within the body. They can grow to a large extent but do not invade adjacent muscles or skin. Thirdly, the invasive type with no visible margins that cannot be resected without adjacent structures or organs. A combination of these tumors can sometimes be noted, e.g. a displacing tumorous nerve developing in a large lumpy, non-invasive PNF. These categories might be used as a current guideline for medical advice, surgical treatment planning and medication trials.

Identification of NF2 germ-line mutations and comparison with neurofibromatosis 2 phenotypes.

Neurofibromatosis 2 (NF2) is an autosomal inherited disorder that predisposes carriers to nervous system tumors. To examine genotype-phenotype correlations in NF2, we performed mutation analyses and gadolinium-enhanced magnetic resonance imaging of the head and full spine in 59 unrelated NF2 patients. In patients with vestibular schwannomas (VSs) or identified NF2 mutations, the mild phenotype was defined as < 2 other intracranial tumors and < or = 4 spinal tumors, and the severe phenotype as either > or = 2 other intracranial tumors of > 4 spinal tumors. Nineteen mutations were found in 20 (34%) of the patients and were distributed in 12 of the 17 exons of the NF2 gene, including intron-exon boundaries. Seven mutations were frameshift, six were nonsense, four were splice site, two were missense, and one was a 3-bp in frame deletion. The nonsense mutations included one codon 57 and two codon 262 C-->T transition in CpG dinucleotides. The frameshift and nonsense NF2 mutations occurred primarily in patients with severe phenotypes. The two missense mutations occurred in patients with mild phenotypes, and three of the four splice site mutations occurred in families with both mild and severe phenotypes. Truncating NF2 mutations are usually associated with severe phenotypes, but the association of some mutations with mild and severe phenotypes indicates that NF2 expression is influenced by stochastic, epigenetic, or environmental factors.

Spinal tumors in patients with neurofibromatosis type 2: MR imaging study of frequency, multiplicity, and variety.

OBJECTIVE: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder leading to various tumors of the CNS, with vestibular schwannomas being the hallmark of the disease. We have observed multiple asymptomatic spinal lesions in patients who have a single symptomatic spinal tumor. Accordingly, we studied the frequency, multiplicity, and variety of spinal tumors in all patients with NF2 to determine what is characteristic of the disease. SUBJECTS AND METHODS: MR images of the entire spinal canal were made in 73 patients aged 4-69 years with NF2. The number, location, morphology, signal characteristics, and contrast medium uptake of the spinal tumors as seen on MR images were recorded and analyzed. Histopathologic proof of 22 spinal tumors was obtained in 19 patients. RESULTS: Spinal tumors were found on MR images in 89% of the patients studied. No location in any part of the spine was preferred. MR imaging showed intramedullary tumors in 24 patients (33%) (three ependymomas pathologically proven). Extradural and intradural extramedullary tumors were found on MR imaging in the cervical spine of 36 patients, the thoracic spine of 40 patients, and the lumbar spine of 49 patients. These tumors were meningiomas, schwannomas, or neurofibromas, three categories that could not be differentiated on the basis of the neuroradiologic findings, with ten schwannomas, seven meningiomas, and two neurofibromas pathologically proven. Extradural extramedullary tumors were found on MR imaging in the cervical spine of 12 patients, the thoracic spine of five patients, and the lumbar spine of 18 patients. A syrinx associated with a tumor was found in two patients. In 19 patients the variety of tumor types was confirmed by histologic examination. CONCLUSION: Patients with NF2 frequently have spinal tumors, which are often multiple and of various histologic types. The presence of multiple and different pathologic types of spinal tumors is highly suggestive of NF2.

[Clinical relevance of signal-intense foci in cerebral magnetic resonance tomography in neurofibromatosis]. / Klinische Bedeutung signalintenser Herde in der zerebralen Magnetresonanztomographie bei Neurofibromatose.

37 patients with documented neurofibromatosis (15 children and 22 adults) had MR examination of the cerebrum. To determine the clinical relevance of signalintense foci in MRT EEG, BAEP and a neuropsychological test batteries was carried out. Our investigations showed that signalintense areas, which possibly represent dysplastic lesions, did not correlate with neurological deficits, epileptic seizures and cognitive disabilities. It remains unclear whether these lesions are of a potential malignancy.

[Cerebral MRT in neurofibromatosis: gliosis versus neoplasia?]. / Zerebrales MRT bei Neurofibromatose: Gliose versus Neoplasie?

15 patients aged 1-39 years with documented neurofibromatosis had MR examinations of the cerebrum within the scope of a basic diagnosis and therapy programme. Clinical examination did not lead to pathologic findings for 7 of the patients; 3 patients suffered from general developmental disabilities. A neurologico-psychiatric examination showed pathological findings in 5 patients. Signal-intense foci in proton density and T2-weighted MR images were found in the globus pallidus, thalamus, hippocampus, cerebellum and midbrain. In 2 patients, these foci could be found as well in T1-weighted images. Differentiation between gliosis areas and low grade astrocytomas was not possible in MR.