Color Doppler sonography of focal lesions of the skin and subcutaneous tissue.
We evaluated with color Doppler sonography 71 visible and palpable nodules of the skin and subcutaneous tissue from 51 patients. The nodules were classified as avascular (type I), hypovascular with a single vascular pole (type II), hypervascular with multiple peripheral poles (type III), and hypervascular with internal vessels (type IV). Of the 32 malignant nodules, 9% showed a type I pattern, 50% had a type III pattern, and 41% had a type IV pattern; of the 39 benign nodules, 86% showed a type I pattern and 14% had a type II pattern. The sensitivity and specificity of hypervascularity in malignant lesions were 90% and 100%, respectively, whereas the sensitivity and specificity of hypovascularity in benign lesions were 100% and 90%, respectively. The authors conclude that color Doppler sonography is able to increase the specificity of ultrasonography in the evaluation of nodular lesions of the skin. (+info
Extreme lateral transcondylar approach to the skull base.
In this study, the authors present their experience of using extreme later transcondylar approach (ELTC) for treating 7 patients with lesions in the anterolateral foramen magnum, upper cervical spine and cerebellopontine angle reaching upto jugular foramen. The tumours included meningiomas, neurofibromas (2 cases each), chondrosarcoma, epidermoid and aneurysmal bone cyst (one case each). The approach was used alone, in combination with retrolabyrinthine presigmoid approach in a patient with lower cranial nerve neurofibroma extending extracranially through the jugular foramen, or in combination with partial C1-C3 laminectomy in two patients with meningiomas situated anterolateral to the cord from the foramen magnum to C3. In two patients with extradural vertebral artery (VA) entrapment by a chondrosarcoma and aneurysmal bone cyst respectively, the vertebral artery was ligated distal to the tumour. The tumours were totally excised in five cases and partially in two. There was no preoperative mortality. The major complications included cerebrospinal fluid leak from the wound (3 cases) and increase in lower cranial nerve paresis (2 cases). At follow up, ranging from 6 months to 2 years, 5 patients showed no tumour recurrence. There was improvement in neurological status. One patient, with a partially excised aneurysmal bone cyst, showed no added deficits or increase in the tumour size. However, there was a massive regrowth in the patient with chondrosarcoma after 6 months. This technique provided a wide surgical exposure with direct visualization of the tumour-anterior cord interface, early proximal control of the VA and preservation of lower cranial nerves. (+info
Deletions of the INK4A gene occur in malignant peripheral nerve sheath tumors but not in neurofibromas.
The INK4A gene, a candidate tumor suppressor gene located on chromosome 9p21, encodes two protein products, p16 and p19(ARF). p16 is a negative cell cycle regulator capable of arresting cells in the G1 phase by inhibiting cyclin-dependent kinases 4 (Cdk4) and 6 (Cdk6), thus preventing pRB phosphorylation. p19(ARF) prevents Mdm2-mediated neutralization of p53. Loss of INK4A is a frequent molecular alteration involved in the genesis of several neoplasms, including tumors of neuroectodermal origin. This study investigated the frequency of INK4A gene alterations in a series of malignant peripheral nerve sheath tumors (MPNSTs) and neurofibromas (NFs). INK4A gene and the p19(ARF)-specific exon 1beta were studied in 11 MPNST samples from 8 patients and 7 neurofibromas. Presence of INK4A deletions was assessed by Southern blotting hybridization and by a multiplex polymerase chain reaction (mPCR). INK4A point mutations were examined by single-strand conformation polymorphism (SSCP) and sequencing. The p16 promoter methylation status was determined by PCR amplification of bisulfite-treated DNA. Homozygous deletions of exon 2, thus affecting both p16 and p19(ARF), were identified in MPNSTs from 4 of 8 patients. Deletions, mutations, or silencing by methylation were not identified in the neurofibromas analyzed. Based on our results, we conclude that INK4A deletions are frequent events in MPNSTs and may participate in tumor progression. Silencing of p16 by methylation, which occurs often in several tumor types, is uncommon in MPNSTs. (+info
Malignant transformation of neurofibromas in neurofibromatosis 1 is associated with CDKN2A/p16 inactivation.
Patients with neurofibromatosis 1 (NF1) are predisposed to develop multiple neurofibromas (NFs) and are at risk for transformation of NFs to malignant peripheral nerve sheath tumors (MPNSTs). Little is known, however, about the biological events involved in the malignant transformation of NFs. We examined the CDKN2A/p16 gene and p16 protein in NFs and MPNSTs from patients with NF1. On immunohistochemical analysis, all NFs expressed p16 protein. The MPNSTs, however, were essentially immunonegative for p16, with striking transitions in cases that contained both benign and malignant elements. None of the benign tumors had CDKN2A/p16 deletions, whereas three of six MPNSTs appeared to have homozygous CDKN2A/p16 deletions. Methylation analysis and mutation analysis of CDKN2A/p16 in MPNSTs did not reveal any abnormalities. These results show that malignant transformation of NF is associated with loss of p16 expression, which is often secondary to homozygous deletion of the CDKN2A/p16 gene. The findings suggest that CDKN2A/p16 inactivation occurs during the malignant transformation of NFs in NF1 patients and raises the possibility that p16 immunohistochemistry may provide ancillary information in the distinction of NF from MPNST. (+info
Expression of p27(kip) and other cell cycle regulators in malignant peripheral nerve sheath tumors and neurofibromas: the emerging role of p27(kip) in malignant transformation of neurofibromas.
There is little information regarding the status of cell cycle regulators in malignant peripheral nerve sheath tumors (MPNSTs) and neurofibromas (NFs). In this study, we investigated patterns of expression of p53 and pRB, cyclin-dependent kinase inhibitors (CKIs) p21 and p27, as well as cyclins D1 and E, in a cohort of 35 well-characterized MPNSTs and 16 NFs. These phenotypes were correlated with proliferative index, as assessed by Ki-67, as well as clinicopathological parameters of poor outcome. p53 nuclear overexpression was found in 10 of 35 (29%) MPNSTs, and it was lacking in NFs (P = 0.02). There were no differences in the patterns of expression of pRB, cyclin D1, and p21 between MPNSTs and NFs. However, p27 nuclear expression was present in most NFs, but it was absent in the majority of MPNSTs, which displayed cytoplasmic staining (P < 0.001). Nuclear cyclin E expression was more pronounced in MPNSTs than in NFs. We observed inverse patterns of expression for nuclear p27 and nuclear cyclin E expression. The staining profiles of cytoplasmic p27 and nuclear cyclin E expression were found to be statistically associated (P = 0.01). High Ki-67 expression was found in 20 of 34 (59%) MPNSTs but was absent in NFs (P < 0.001). Furthermore, detection of cytoplasmic p27 expression was found to be a prognostic factor for poor survival in MPNSTs (P = 0.03, relative risk = 2.4). (+info
Evaluation of (18)fluorodeoxyglucose positron emission tomography ((18)FDG PET) in the detection of malignant peripheral nerve sheath tumours arising from within plexiform neurofibromas in neurofibromatosis 1.
OBJECTIVES: The ability of (18)fluorodeoxyglucose positron emission tomography ((18)FDG PET) to detect malignant change in plexiform neurofibromas from patients with neurofibromatosis 1 (NF1) was evaluated. METHODS: Eighteen NF1 patients who presented with pain, increase in size, or neurological deficit associated with a plexiform neurofibroma were assessed. Magnetic resonance imaging determined the site and extent of the lesion. Qualitative(18)FDG PET was performed and the standard uptake value (SUV) measured the regional glucose metabolism. Histological confirmation of the diagnosis was obtained in 10 patients. RESULTS: Twenty three plexiform neurofibromas were detected in 18 patients. Seven malignant peripheral nerve sheath tumours, four high grade and three low grade tumours, occurred in five patients. In one patient the clinical and radiological characteristics of the tumour suggested malignancy, but histology was inconclusive. Fifteen benign plexiform neurofibromas were identified in 12 patients and these findings were confirmed histologically in five lesions from four patients. Ten plexiform neurofibromas occurring in eight patients were considered benign on(18)FDG PET and the patients did not undergo surgery. They remained stable or their symptoms improved on clinical follow up (median 9 months). The results of qualitative (18)FDG PET were interpreted as indicating that 13 plexiform neurofibromas were benign and 10 were malignant. No malignant tumours were classified as benign, but two benign tumours were reported as malignant. The SUV was calculated for 20 tumours and was significantly higher in five malignant tumours 5.4 (SD 2.4), than in 15 benign tumours 1.54 (SD 0.7), p=0.002. There was an overlap between benign and malignant tumours in the SUV range 2.7-3.3. CONCLUSIONS: (18)FDG PET is helpful in determining malignant change in plexiform neurofibromas in NF1. Increased separation between benign and malignant lesions could be obtained by calculating the SUV at about 200 minutes after injection of (18)FDG, when the peak activity concentration is obtained in malignant tumours. (+info
Melanotic neurofibroma in a steer.
A melanotic neurofibroma in a steer was investigated histologically, immunohistochemically and ultrastructurally. A very large tumor mass was located in the region of the head and right cheek. The tumor tissue consisted of an admixture of cells resembling Schwann cells and spindle-shaped cells, and they frequently contained melanin granules. Neoplastic Schwann cells were positive for S100 protein, with variation in intensity of staining, but most spindled cells were S100 negative. The tumor cells displayed ultrastructural features similar to those of Schwann cells or perineurial cells. The presence of melanosomes in varying stages of melanization in both cell types suggests that they have a common origin. This is a tumor of neural crest origin showing schwannian and perineurial differentiation, with ectopic production of melanin granules. (+info
Genetic and cellular defects contributing to benign tumor formation in neurofibromatosis type 1.
Neurofibromatosis type 1 (NF1) is a common inherited cancer predisposition syndrome. The NF1 gene product, neurofibromin, is hypothesized to function as a tumor suppressor and nearly all NF1 patients develop benign peripheral nerve tumors. These neurofibromas presumably arise from NF1 inactivation in S100(+)Schwann cells, but there is no formal proof for this mechanism. We demonstrate that fibro-blasts isolated from neurofibromas carried at least one normal NF1 allele and expressed both NF1 mRNA and protein, whereas the S100(+)cells typically lacked the NF1 transcript. Our findings further indicate that additional molecular events aside from NF1 inactivation in Schwann cells and/or other neural crest derivatives contribute to neurofibroma formation. (+info