Benign Peripheral Nerve Tumors Research Articles

Plexiform and Dermal Neurofibromas and Pigmentation Are Caused by Nf1 Loss in Desert Hedgehog-Expressing Cells

Neurofibromatosis type 1 (Nf1) mutation predisposes to benign peripheral nerve (glial) tumors called neurofibromas. The point(s) in development when Nf1 loss promotes neurofibroma formation are unknown. We show that inactivation of Nf1 in the glial lineage in vitro at embryonic day 12.5 + 1, but not earlier (neural crest) or later (mature Schwann cell), results in colony-forming cells capable of multilineage differentiation. In vivo, inactivation of Nf1 using a DhhCre driver beginning at E12.5 elicits plexiform neurofibromas, dermal neurofibromas, and pigmentation. Tumor Schwann cells uniquely show biallelic Nf1 inactivation. Peripheral nerve and tumors contain transiently proliferating Schwann cells that lose axonal contact, providing insight into early neurofibroma formation. We suggest that timing of Nf1 mutation is critical for neurofibroma formation.

Expressions of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in malignant peripheral nerve sheath tumor

Background Matrix metalloproteinase-9 (MMP-9) can degrade collagen IV (the main structural ingredient of basilar membrane), and it also plays an important role in tumor vascularization, tumor cell progression, formation of metastatic focus, etc. Tissue inhibitor of metalloproteinase-1 (TIMP-1) can bind with MMP-9 to form 1:1 compound and inhibit its activity, and can negatively regulate the tumor progression and metastasis. Objective To analyze the relationship of MMP-9 and TIMP-1 expressions with the pathological grade, metastasis and prognosis of malignant peripheral nerve sheath tumor (MPNST). Design An observational comparative experiment. Setting Heze Medical College. Participants Fifty-eight surgical pathological samples, which were clearly diagnosed to be MPNST, were collected from the pathological laboratory archives in the Department of Pathology, Heze Municipal Hospital from January 1988 to December 2003. The MPNST pathological types were common tumor in 53 cases, malignant triton tumor in 2 cases, epithelial MPNST in 2 cases and MPNST with gland differentiation in 1 case. The pathological grade was grade 1 in 11 cases, grade 2 in 24 cases and grade 3 in 23 cases. Besides, the resected tumor samples of 20 patients with benign peripheral nerve tumor (10 cases of nerve sheath tumor and 10 cases of neurofibromatosis) and the normal peripheral nerves (by-products of some surgeries) of 5 patients were also collected. The samples were used with the approval of the patients. Rat-anti-human MMP-9, TIMP-1 monoclonal antibody and S-P kit were purchased from Fuzhou Maixin Biotechnology, Co., Ltd. Methods The documented paraffin blocks were again prepared to sections of 5 μm. The expressions of MMP-9 and TIMP-1 in the samples were detected with mmunohistochemical S-P method. The relationships of the MPNST severity, recurrence, metastasis and survival rate with the expressions of MMP-9 and TIMP-1 were analyzed. Main outcome measures Relationships of MMP-9 and TIMP-1 expressions with the MPNST severity and prognosis. Results ▪ Expressions of MMP-9 and TIMP-1 in three tissues: MMP-9 and TIMP-1 stainings were mainly observed in cytoplasm. Among the 58 MPNST patients, the MMP-9 expression was significantly higher than those in normal peripheral nerve and benign tumor ( P < 0.05), while the TIMP-1 expression in MPNST was lower than those in normal peripheral nerve and benign tumor ( P < 0.05). ▪ Relationship of MMP-9 and TIMP-1 expressions with the severity and prognosis of MPNST: The expressions of both proteins were observed in the four subtypes. The positive expression of MMP-9 in the MPNST patients of grades 2–3 was significantly higher than that in the MPNST patients of grade 1 ( P < 0.05), while the expression of MMP-9 was significantly lower than that in the MPNST patients of grade 1 ( P < 0.05). The metastatic rate was positively correlated with MMP-9 expression ( r = 1.696, P < 0.05), but negatively correlated with TIMP-1 expression ( r = –2.125, P < 0.05). Conclusion MMP-9 and TIMP-1 are associated with MPNST pathological grades and metastasis, and can be used as the indicators for judging the severity and prognosis of MPNST.

Major-nerve schwannomas versus intramuscular schwannomas

A schwannoma is a benign peripheral nerve tumor. Predicting the involvement of a nerve on symptoms or magnetic resonance (MR) findings is crucial to the diagnostic process. To compare symptoms, MR findings, and histological findings between major-nerve schwannomas and intramuscular schwannomas. Thirty-four patients with 36 palpable schwannomas (29 major-nerve schwannomas and seven intramuscular schwannomas) surgically excised and proven histologically were retrospectively reviewed. Frequencies of the Tinel-like sign, split-fat sign, entering and exiting nerve, and low-signal margin indicate the presence of a nerve, and were significantly higher in major-nerve schwannomas than in intramuscular schwannomas. In tumor morphological patterns (target sign, inhomogeneous and homogeneous pattern), there were no significant differences between major-nerve schwannomas and intramuscular schwannomas. Schwannomas showing the target sign histologically tended to be less degenerative. All major-nerve schwannomas and five of the intramuscular schwannomas produced some characteristic symptoms and/or MR findings, but two intramuscular schwannomas did not have any characteristic symptoms and findings. In major-nerve schwannomas, the Tinel-like sign, split-fat sign, entering and exiting nerve, and low-signal margin are commonly observed and useful for diagnosis. In intramuscular schwannomas, these characteristic findings are less common, which makes diagnosis difficult.

Experimental therapeutic approaches to peripheral nerve tumors

Discovery that the Schwann cell is the primary cell type responsible for both the neurofibroma as well as the schwannoma has proven to represent a crucial milestone in understanding the pathogenesis of peripheral nerve tumor development. This information and related findings have served as a nidus for research aimed at more fully characterizing this family of conditions. Recent discoveries in the laboratory have clarified an understanding of the molecular mechanisms underlying the pathogenesis of benign peripheral nerve tumors. Similarly, the mechanisms whereby idiopathic and syndromic (NF1- and NF2-associated) nerve sheath tumors progress to malignancy are being elucidated. This detailed understanding of the molecular pathogenesis of peripheral nerve tumors provides the information necessary to create a new generation of therapies tailored specifically to the prevention, cessation, or reversal of pathological conditions at the fundamental level of dysfunction. The authors review the data that have helped to elucidate the molecular pathogenesis of this category of conditions, explore the current progress toward exploitation of these findings, and discuss potential therapeutic avenues for future research.

A Solitary Neurofibroma as a Cause of Nasal Obstruction: Report of a Rare Case

Neurogenic tumors form a very small percentage of all neoplastic lesions of the head and neck region. However, the head and neck region is by far the most common location for benign peripheral nerve tumors. Several cases involving the nose have been sporadically documented throughout the medical literature.

Intramuscular Neurilemoma of the Lower Limb

Objectives: Neurilemoma (schwannoma) is a benign tumor of peripheral nerves, usually arising from spinal nerve roots or larger peripheral nerves. We report a case of intramuscular neurilemoma in the quadriceps femoris muscle, which is a rare site for this tumor. Diagnostic appearance and differential diagnosis are discussed.

A peripheral nerve sheath tumour as a cause of nasal obstruction

Neurogenic tumours form a very small percentage of all neoplastic lesions of the head and neck region. However, the head and neck region is by far the most common location for benign peripheral nerve tumours. Several cases involving the nose have been sporadically documented throughout the medical literature. We present a rare case of a solitary neurofibroma arising from the lateral nasal wall of a 68-year-old woman. En bloc surgical resection of the mass was achieved by the lateral rhinotomy approach. The clinical significance of this case report is due to its rare site. In recent medical literature, there has been only one report concerning a solitary neurofibroma arising from the inferior turbinate. This case also highlights the importance of considering this clinical entity in the differential diagnosis when encountering a unilateral soft tissue mass in the nasal cavity.

Tumors of the peripheral nerves and plexuses

Peripheral nerve tumors are a diverse group of lesions histologically and in their clinical behavior. The genetic disorders neurofibromatosis type 1 and 2 and schwannomatosis are significant risk factors for the development of peripheral nerve tumors. An understanding of these disorders is important in allowing appropriate management. Active treatment of peripheral nerve tumors is reserved for lesions that are malignant or causing neurologic dysfunction, pain, compressive symptomatology, or cosmetic concern. The mainstay of treatment is surgical intervention, the nature of which will vary with the type of tumor and anatomical location. In the case of malignant tumors, adjuvant chemotherapy and radiotherapy are commonly used. Developments in the understanding of the genetics and molecular biology of peripheral nerve tumors are opening up potentially exciting new avenues of treatment. The prognosis of benign peripheral nerve tumors is excellent, with a recurrence rate of just 5% or less after successful surgery. Malignant tumors have proven to be more challenging, with a much higher recurrence rate and a 5-year survival rate of 64%.

Perinatal Epidermal Growth Factor Receptor Blockade Prevents Peripheral Nerve Disruption in a Mouse Model Reminiscent of Benign World Health Organization Grade I Neurofibroma

Benign peripheral nerve tumors called neurofibromas are a major source of morbidity for patients with neurofibromatosis type 1. Some neurofibroma Schwann cells aberrantly express the epidermal growth factor receptor (EGFR). In a mouse model in which the CNPase promoter drives expression of human EGFR in Schwann cells, nerves develop hypertrophy, mast cell accumulation, collagen deposition, disruption of axon-glial interactions, characteristics of neurofibroma and are hypoalgesic. Administration of the EGFR antagonist cetuximab (IMC-C225) for 2 weeks beginning at birth in CNPase-hEGFR mice normalized all pathologies at 3 months of age as evaluated by hotplate testing or histology and by electron microscopy. Mast cell chemoattractants brain-derived neurotrophic factor, monocyte chemoattractant protein-1, and transforming growth factor-beta1, which may account for mast cell accumulation and fibrosis, were reduced by cetuximab. Later treatment was much less effective. A birth to 2-week pulse of cetuximab blocked hEGFR phosphorylation and Schwann cell prolifera-tion in perinatal mutant nerve, so CNPase-hEGFR Schwann cell numbers correlate with the cetuximab effect. A >250-fold enlarged population of EGFR(+)/p75(+) cells was detected in newborn Nf1(+/-) mouse nerves. These results suggest the existence of an EGFR(+) cell enriched in the perinatal period capable of driving complex changes characteristic of neurofibroma formation.

Gene-Targeted Deletion of Neurofibromin Enhances the Expression of a Transient Outward K+Current in Schwann Cells: A Protein Kinase A-Mediated Mechanism

Mutations in the neurofibromatosis type 1 gene predispose patients to develop benign peripheral nerve tumors (neurofibromas) containing Schwann cells (SCs). SCs from neurofibromatosis type-1 gene (Nf1) null mutant mice showed increased levels of Ras-GTP and cAMP. The proliferation and differentiation of SCs are regulated by Ras-GTP and cAMP-mediated signaling, which have been linked to expression of K+ channels. We investigated the differential expression of K+ currents in Nf1 null mutant SCs (Nf1-/-) and their wild-type (Nf1+/+) counterparts and determined the mechanisms underlying the differences. The current densities of the sustained component of K+ currents were similar in the two genotypes. However, Nf1-/- SCs showed a significant increase (approximately 1.5-fold) in a 4-aminopyridine-sensitive transient outward K+ current (I(A)). Nonstationary fluctuation analysis revealed a significant increase in the number of functional channels in the null mutant cells. When the involvement of the Ras pathway in the modulation of the K+ current was examined using adenoviral-mediated gene transfer of a dominant-negative H-Ras N17 or the known H-Ras inhibitor (L-739,749), an additional increase in I(A) was observed. In contrast, protein kinase A (PKA) inhibitors, H89 and [PKI(2-22)amide] attenuated the enhancement of the current in the Nf1-/- cells, suggesting that the increase in I(A) was mediated via activation of protein kinase A. The unitary conductance of the channel underlying I(A) was unaltered by inhibitors of PKA. Activation of I(A) is thus negatively regulated by Ras-GTP and positively regulated by PKA.

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.

Neurofibromatosis Type 1: Genetic and Cellular Mechanisms of Peripheral Nerve Tumor Formation

Neurofibromatosis type 1 (NF1) is among the most common inherited human diseases. The NF1 protein is a Ras-GTPase activating protein, positioning NF1 in important intracellular signaling pathways. Patients with mutations in the NF1 gene can develop benign peripheral nerve tumors (neurofibromas), learning disabilities, and/or benign optic nerve gliomas, in addition to abnormalities unassociated with the nervous system. The NF1 gene is believed to act as a tumor suppressor. How NF1 mutations relate to benign features of NF1 is the subject of active investigation. Studies using transgenic mice with NF1 mutations and cells derived from these mice have yielded exciting new data, implicating multiple cell types mutant at NF1 and possibly factors in the environment in the pathogenesis of benign neurofibromas. NEUROSCIENTIST 3:412-420, 1997

Primary Tumors of the Middle and Posterior Mediastinum

Mediastinal cysts and neurogenic neoplasms are common primary middle and posterior mediastinal masses. Foregut cysts are a relatively frequent cause of a middle mediastinal mass and may progressively enlarge or rarely rupture, while pericardial cysts are infrequent lesions which rarely produce complications or symptoms. Schwannomas and neurofibromas are benign peripheral nerve tumors and are the most common mediastinal neurogenic neoplasms. Malignant tumors of nerve sheath origin are rare. Tumors arising in sympathetic ganglia typically occur in children and young adults and include ganglioneuroma, ganglioneuroblastoma and neuroblastoma. Mediastinal paragangliomas are rare. Lateral thoracic meningocele is the most common cause of a posterior mediastinal mass in a patient with neurofibromatosis.

Nerve-sheath myxoma (neurothekeoma) of the oral cavity: A case report and review of the literature

Nerve-sheath myxoma (NSM) is a benign tumor of peripheral nerves,’ which was first described by Harkin and Reed2 in 1969. In 1980, Gallager and Helwig3 used the term neurothekeoma for the same tumor. The lesion is often located in the dermis and subcutis of the head and neck region and the shoulders.’ Intraoral NSM is extremely rare. We describe a case of NSM of the posterior hard palate, and review all previously reported intraoral lesions.

Cytogenetic and histologic correlation of peripheral nerve sheath tumors of soft tissue

Cytogenetic analysis was performed on 11 peripheral nerve sheath tumors of soft tissue from 10 patients. They include 6 benign and 5 malignant schwannomas. Five cases which include two benign, one cellular and two malignant schwannomas had a known association with a nerve, but only one patient with malignant schwannoma has clinically documented neurofibromatosis type I. All the patients had a normal diploid constitutional karyotype. Two cases of celluaar schwannoma were analyzed by routine cytogenetic analysis and fluorescence in situ hybridization (FISH). One tumor was karyotyped as 45,XX,−13,−22 +mar; and the other case had a 45,X,−Y,t(1;17)(p12;q11.2) karyotype. In the latter, the breakpoint in 17q occurred below the centromere and is at or in the region of the Neurofibromatosis Type 1 (NF1) gene. Four benign tumors had a normal diploid karyotype. One hypodiploid malignant schwannoma with myxoid features demonstrated monosomy of chromosomes 17 and 22 by FISH analysis. The rest of the malignant schwannomas showed a wide range of numerical and structural aberrations, with frequent loss of 22q and gains of chromosomes 2 and 7. Loss of a sex chromosome was observed in cellular as well as malignant schwannomas. Regional karyotypic evolution was noted in one malignant schwannoma. Cytogenetic analysis may prove to be useful in identifying tumors, such as cellular schwannomas, which, because of their histologic features may be inadvertently categorized as malignant. Simultaneous involvement of NF1 and NF2 genes, which are located on chromosomes 17q and 22q, respectively, should be investigated at a molecular level in both benign and malignant tumors of peripheral nerves.

The use of MRI in the diagnosis of benign peripheral nerve tumours of the upper extremity

The use of MRI in the diagnosis of benign peripheral nerve tumours of the upper extremity

Cellular schwannoma. A clinicopathologic, DNA flow cytometric, and proliferation marker study of 70 patients.

A clinicopathologic study of 70 cases of cellular schwannoma was performed to assess their distribution, response to therapy, and rate of recurrence relative to modern prognostic indicators. Seventy-one cellular schwannomas from 70 patients were retrieved from the files of the Mayo Clinic Tissue Registry. The significance of mitotic index, proliferative marker staining (proliferating cell nuclear antigen and MIB1), immunochemical p53 expression, and DNA ploidy were assessed relative to tumor behavior, particularly recurrence. All parameters were subject to statistical analysis (Student's t test). Cellular schwannomas represented 4.6% of benign peripheral nerve tumors operated on at the Mayo Clinic. In 15% of the cases, an initial diagnosis of malignancy had been made. The median patient age was 47.7 years (range, 15-80 years) and the female-to-male ratio was 1.6:1. The principle tumor locations were the para- and intraspinal regions, including the sacrum (64%), extremities (25%), and intracranial space (8%). All tumors consisted primarily of hypercellular, compact, Antoni A tissue. Mitoses (< or = 4/10 hPF]) were observed in 71% of the cases. Foci of necrosis were noted in 11% of cases. Ultrastructural studies and immunohistochemistry clearly demonstrated features of schwannian differentiation. Surgery was the treatment in all cases. Excision was intralesional to gross total in the majority; total resection with wide margins was undertaken in three tumors, each of which had initially been considered malignant. Follow-up in 47 patients (67%) ranged from 1 to 29 years (mean, 7.7 years) and revealed recurrences in 11 patients (23.4%): no patient experienced metastasis or died of tumor. Although no correlation existed between recurrence and DNA ploidy, percent S-phase determinations, proliferation marker (PCNA, MIB1) staining, or the frequency of p53 immunoreactivity, a statistically significant correlation (P < 0.001) was observed, however, between recurrence and mitotic indices. Proliferation indices, as defined by immunochemical analysis, are not useful predictors of recurrence in cellular schwannoma. In lesions not completely resected, tumor recurrence is significantly correlated with mitotic count. The significant overall frequency of recurrence in this series is attributable to a high proportion of intraspinal and intracranial tumors. Our study confirms the benign nature of cellular schwannoma and underscores the necessity of distinguishing them from malignant peripheral nerve sheath tumors, lesions that often require adjuvant therapy.

Neural sheath tumors of major nerves.

Over a 22-year period, operations were performed on 263 patients for 288 primary benign tumors of major peripheral nerves. The tumors included 85 schwannomas, 197 neurofibromas, and six plexiform neurofibromas. Total removal was achieved in 83 of the 85 schwannomas, and 76 of these patients were available for follow-up evaluation. Motor function either improved or was unchanged in 87% of these patients and 85% of those with pain in the distribution of the involved nerve had either total or partial resolution of their symptoms. Of the neurofibromas, 123 occurred in 121 patients without von Recklinghausen's disease. All tumors within this group were completely excised using a fascicular approach to the tumor. Of the 99 patients available for follow-up evaluation, 90% had either improved or unchanged motor function and 88% had partial or complete resolution of pain syndromes. Fifty-nine patients with von Recklinghausen's disease had 80 tumors removed: 74 fusiform tumors (58 of which were completely removed) and six plexiform tumors. Forty-eight of the 58 patients with gross total removal of fusiform tumors were available for follow-up evaluation, of whom 83% had improved or unchanged motor function and 74% had partial or complete resolution of pain syndromes. All six patients with plexiform tumors had progression of symptoms postoperatively. One brachial plexus schwannoma recurred and was re-excised without subsequent recurrence at the 5-year follow-up evaluation. Several incompletely excised plexiform neurofibromas have recurred with a symptomatic presentation.

Frequent expression of 75 kDa nerve growth factor receptor and phosphotyrosine in human peripheral nerve tumours: an immunohistochemical study on paraffin-embedded tissues.

One hundred and three benign, and 10 malignant peripheral nerve tumours were examined immunohistochemically for expression of 75 kDa nerve growth factor receptor (NGFR). In benign tumours NGFR was demonstrated at 61% in neurinoma, 71% in neurofibroma, 93% in neurofibromatosis and 90% in traumatic neuroma. Malignant neurogenic tumours were 100% positive for NGFR. Phosphotyrosine-immunoreactivity was detected in 76% of NGFR-positive tumours but the frequency of immunostained tumour cells was low. These results suggest that both benign and malignant peripheral nerve tumours express 75 kDa NGFR. The receptor seems to serve as growth signal transduction of the tumour cells in terms of phosphorylation of the tyrosine residue of the receptor or the target protein of the NGFR protein tyrosine kinase.

Comparison of various basement membrane components in benign and malignant peripheral nerve tumours

Immunohistochemical methods were used to analyse benign and malignant tumours of peripheral nerve tissue. We tested for the distribution of basement membrane (BM) components collagen IV, laminin, heparan sulphate proteoglycan, fibronectin, for S100 protein and for the presence of interstitial collagens III and V. Laminin was generally noted in association with Schwann cells, but collagen IV occurred with perineural cells. When tested for BM components, fibroblasts were notably non-reactive except for fibronectin. Three specific area-dependent BM patterns were observed in the benign tumours: (a) Schwann cell-like, in fascicular areas (Antoni A areas of schwannoma, central fibrous bundles of plexiform neurofibromas and central areas of cutaneous neurofibroma), (b) perineural cell-like (capsular structures of schwannoma) and (c) fibroblast-like (myxoid and fibrously transformed areas). Most malignant tissues showed a variably fragmentary focal deposition of laminin. Other BM components were present only in well-differentiated areas. Poorly differentiated tumours demonstrated fibronectin reactivity alone. Our results provide evidence that the specific staining pattern for BM components helps to differentiate the various cellular proliferations in neurogenic tumours. Schwann cells are not only distinguishable from perineural cells by S100 protein staining, but also by their specific BM staining. In addition, perineural cells can be separated from fibroblasts, which do not express BM material. The "tropism" of laminin in normal nerves and benign neural tumours--which persists in neurogenic sarcomas--indicates preferential Schwann cell differentiation in these cells.