Quantitative Analysis of Superb Microvascular Imaging versus Color-Coded Doppler Sonography for Preoperative Evaluation of Vascularization of Schwannomas.

PURPOSE: Comparison of vascularization of schwannomas, benign peripheral nerve sheath tumors, using color-coded Doppler sonography (CCDS) and the Toshiba monochrome Superb Microvascular Imaging (mSMI) (Minato, Tokyo, Japan) technique. METHODS: In a retrospective single-center analysis, 16 patients were identified with histologically confirmed schwannomas. Between March and June 2018, all of them underwent ultrasonography using mSMI and CCDS before surgery. Schwannoma vascularization was quantitatively measured using ImageJ, an open platform for scientific image analysis. As the diagnostic gold standard, magnetic resonance imaging was mandatory. RESULTS: The mSMI and CCDS vascularization showed a moderate agreement between the techniques (κ = 0.5556; p = 0.0066). The quantitative visual assessment of the vascularization revealed no difference (25.3 ± 8.2 vs. 18.2 ± 3.8; p = 0.0532). Significant differences were found for the quantitative assessment of CCDS with ImageJ (26.8 ± 8.8 vs. 19.3 ± 2.8; p = 0.0368). However, in a subanalysis of highly vascularized schwannomas, mSMI revealed significant differences to slightly vascularized schwannomas (32.0 ± 8.2 vs. 21.3 ± 6.1; p = 0.0065) but not between moderately and slightly vascularized types (p = not significant). CONCLUSION: The mSMI mode is qualitatively superior to conventional CCDS; however, quantitative analysis of the vascularization of schwannomas revealed no significant quantitative advantage for mSMI. Nevertheless, the mean ImageJ values showed a positive trend toward a better representation of the vascularization degree of schwannomas with mSMI.

Anti-VEGF treatment improves neurological function in tumors of the nervous system.

Research of various diseases of the nervous system has shown that VEGF has direct neuroprotective effects in the central and peripheral nervous systems, and indirect effects on improving neuronal vessel perfusion which leads to nerve protection. In the tumors of the nervous system, VEGF plays a critical role in tumor angiogenesis and tumor progression. The effect of anti-VEGF treatment on nerve protection and function has been recently reported - by normalizing the tumor vasculature, anti-VEGF treatment is able to relieve nerve edema and deliver oxygen more efficiently into the nerve, thus reducing nerve damage and improving nerve function. This review aims to summarize the divergent roles of VEGF in diseases of the nervous system and the recent findings of anti-VEGF therapy in nerve damage/regeneration and function in tumors, specifically, in Neurofibromatosis type 2 associated schwannomas.

Acute presentation of brachial plexus schwannoma secondary to infarction.

Schwannomas of the brachial plexus are rare and typically present as slowly growing masses. We describe a case of a 37-year-old female who presented with acute onset of severe left upper extremity pain. Magnetic resonance imaging (MRI) showed a 2.3 × 2.1 cm peripherally enhancing centrally cystic lesion in the left axilla, along the cords of the left brachial plexus, with significant surrounding edema and enhancement. The mass was surgically removed. Pathology was consistent with a schwannoma with infarction. The pain completely resolved immediately after surgery.

Vascular endothelial growth factor, basic fibroblast growth factor and epithelial growth factor receptor in peripheral nerve sheath tumors of neurofibromatosis type 1.

BACKGROUND/AIM: Neurofibromas, benign tumors of the nerve sheaths, are the hallmark of neurofibromatosis type 1 (NF1), an autosomal-dominant inherited tumor predisposition syndrome. Malignant tumors arising from nerve sheath cells are an important factor influencing the life expectancy of NF1 patients. Expression of growth factors and growth factor receptors play a key role in the development of tumors. Therapy of peripheral nerve sheath (PNS) tumors is predominantly surgical. The outcome in malignant entities of NF1-affected patients remains poor, despite many efforts to implement pharmacological therapy into the treatment modalities. Growth of peripheral nerve sheath tumors is finely-adjusted by growth factors and PNS tumors express growth factor receptors. However, quantification of receptor expression and comparison to the expression of other related factors are not available. The aim of the present study was to determine growth factor expression relevant for growth control in neurofibromas of NF1. MATERIALS AND METHODS: Fifty-eight dermal, dermal/diffuse and plexiform neurofibromas and malignant peripheral nerve sheath tumors (MPNST) of NF1-affected patients were analyzed immunohistochemically for the expression of growth factors relevant for angiogenesis: vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and epithelial growth factor receptor (EGFR). The vessel density was also determined quantitatively by light microscopy. RESULTS: Plexiform neurofibroma revealed a higher expression level for VEGF compared to dermal/diffuse neurofibroma. However, statistical significant differences for VEGF expression and of all other proteins investigated were found in comparison to MPNST only. EGFR expression was remarkably high in NF1 patients in their first decade of life. However, this result has to be interpreted with caution in view of the high number of young patients with MPNST in this age group. Vessel density correlated with tumor type. Vessel density increased significantly comparing benign nerve sheath tumors and MPNST (p<0.05). DISCUSSION/CONCLUSION: This study revealed the presence of factors and receptors involved in angiogenesis as a prerequisite for tumor development and maintenance of PNS in NF1. These factors are highly expressed in all tumors of this study. This study reveals these relevant factors in nerve sheath tumors and also described the significant increase of vessel density in MPNST compared to benign counterparts. Anti-angiogenic drugs are presently investigated for application in NF1 tumor treatment, in particular for patients with a surgically-intractable high tumor burden. Drugs capable of blocking the EGFR receptor-mediated pathway are promising tools within the pharmacological repertoires to treat these patients.

Study of neurinomas with ultrasound contrast media: review of a case series to identify characteristic imaging patterns.

PURPOSE: The aim of this study was to evaluate whether there exists a characteristic distribution pattern of vessels within neurinomas that may be used to characterise this type of lesion by employing a contrast-specific ultrasound technique. MATERIALS AND METHODS: Between January 2003 and May 2010, 66 suspected neurinomas were evaluated according to their sonographic features (solid fusiform mass with well-defined margins located in direct continuity with the nerve that was not always discernible and heterogeneous as a result of the presence of small cystic areas or calcifications). The lesions were examined using a sonographic contrast medium consisting of sulphur hexafluoride microbubbles and equipment with dedicated contrast-specific software [contrast tuned imaging (CnTI)]. Of these lesions, five were excluded from the analysis because the definitive diagnosis was not available (in two cases, the follow-up was still in progress, whereas in the remaining three, there was no follow-up). Our study, therefore, is based on 61 surgically excised lesions that were confirmed to be neurinomas by histology, which is regarded as the gold standard. RESULTS: In 41/61 cases (67.2%), we identified an enhancement pattern that we termed reticular owing to the interweaving of blood vessels, of which two subtypes were identified depending on whether the interwoven vessels were densely or sparsely packed: loose-knit reticular in 18/41, and tight-knit reticular in 23/41. In 20/61 (32.8%) cases, we observed a vascular pattern of diffuse heterogeneous enhancement, which was divided into two subtypes based on the presence of one (7/20) or more (13/20) avascular areas. CONCLUSIONS: Results showed that all neurinomas studied could be divided into two groups according to the type of enhancement pattern observed: reticular or diffuse heterogeneous.

Paraganglioma of the cauda equina: a highly vascular tumour.

Paragangliomas uncommonly occur in the cauda equina region. This type of tumour may be misdiagnosed pre-operatively as a neurinoma or an ependymoma. Paragangliomas are highly vascular tumours. We report three patients with paraganglioma of the cauda equina. The first patient had many dilated vessels resembling an arteriovenous malformation, which were seen during surgery. The second patient had a post-operative haemorrhage without any residual tumour. The third patient had a selective angiogram with dense tumour staining.

Cervical sympathetic chain schwannoma masquerading as a carotid body tumour with a postoperative complication of first-bite syndrome.

Carotid body tumours (CBT) are the most common tumours at the carotid bifurcation. Widening of the bifurcation is usually demonstrated on conventional angiography. This sign may also be produced by a schwannoma of the cervical sympathetic plexus. A 45-year-old patient presented with a neck mass. Investigations included contrast-enhanced CT, MRI and magnetic resonance arteriography with contrast enhancement. Radiologically, the mass was considered to be a CBT due to vascular enhancement and splaying of the internal and external carotid arteries. Intraoperatively, it was determined to be a cervical sympathetic chain schwannoma (CSCS). The patient had a postoperative complication of first-bite syndrome (FBS).Although rare, CSCS should be considered in the differential diagnosis for tumours at the carotid bifurcation. Damage to the sympathetic innervation to the parotid gland can result in severe postoperative pain characterised by FBS and should be considered in all patients undergoing surgery involving the parapharyngeal space.

An orthotopic xenograft model of intraneural NF1 MPNST suggests a potential association between steroid hormones and tumor cell proliferation.

Malignant peripheral nerve sheath tumors (MPNST) are the most aggressive cancers associated with neurofibromatosis type 1 (NF1). Here we report a practical and reproducible model of intraneural NF1 MPNST, by orthotopic xenograft of an immortal human NF1 tumor-derived Schwann cell line into the sciatic nerves of female scid mice. Intraneural injection of the cell line sNF96.2 consistently produced MPNST-like tumors that were highly cellular and showed extensive intraneural growth. These xenografts had a high proliferative index, were angiogenic, had significant mast cell infiltration and rapidly dominated the host nerve. The histopathology of engrafted intraneural tumors was consistent with that of human NF1 MPNST. Xenograft tumors were readily examined by magnetic resonance imaging, which also was used to assess tumor vascularity. In addition, the intraneural proliferation of sNF96.2 cell tumors was decreased in ovariectomized mice, while replacement of estrogen or progesterone restored tumor cell proliferation. This suggests a potential role for steroid hormones in supporting tumor cell growth of this MPNST cell line in vivo. The controlled orthotopic implantation of sNF96.2 cells provides for the precise initiation of intraneural MPNST-like tumors in a model system suitable for therapeutic interventions, including inhibitors of angiogenesis and further study of steroid hormone effects on tumor cell growth.

Multiple filum terminale hemangioblastomas symptomatic during pregnancy. Case report.

Hemangioblastomas are low-grade, highly vascular tumors commonly associated with von Hippel-Lindau (VHL) syndrome and most often appearing in the cerebellum. They very rarely occur in the spinal nerve roots, and an origin in the filum terminale is exceptional with no instances of multiple hemangioblastomas of the filum terminale reported in the literature. Because of their vascular nature, these lesions can enlarge and become symptomatic in the context of the changes that take place during pregnancy, as has been noted with cerebellar hemangioblastomas. In any case, the evolution of spinal hemangioblastomas during pregnancy is not well known given its rarity. The conjunction of both processes--that is, multiple hemangioblastomas arising in the filum terminale and pregnancy--is unique. The authors describe the case of a 41-year-old woman with multiple hemangioblastomas of the filum terminale and no other evidence of VHL syndrome, in whom pregnancy precipitated symptoms. The interruption of gestation led to a remission of the symptoms. The literature concerning filum terminale hemangioblastomas and pregnancy is also reviewed.

Hemangioblastoma of filum terminale associated with arteriovenous shunting.

BACKGROUND: Spinal arteriovenous shunt typically presents in middle age or in the elderly with a strong male predilection. The clinical presentation is usually progressive neurological deficits such as paraparesis or incontinence due to cord edema, although back pain is also a common presentation. Progress of neurological deficit is typically stopped by occlusion of the shunt (surgically or endovascularly), but the return of loss of function may be found in less than half of these patients. In contrast, spinal hemangioblastomas usually occur in adults, and the most common presentation is pain with radiculopathy. Location in the filum terminale is very rare. CASE DESCRIPTION: After a review of the medical literature, we identified 7 cases of hemangioblastomas arising from the filum terminale (Am J Neuroradiol. 2005;26:936-945; Acta Neurochir [Wien]. 2000;142:1059-1062; J Neurosurg Sci. 2001;45:58-62; J Clin Neurosci. 2006;13:285-288; Neurosurgery. 1999;44:220-223; Clin Neurol Neurosurg. 1985;87:55-59). We report an additional case of a filum terminale hemangioblastoma occurring in a 64-year-old man with 1 month exacerbation of chronic low back pain. Preoperatively, it was misdiagnosed as filum terminale arteriovenous fistula. CONCLUSION: Even with modern imaging, preoperative diagnosis can still be difficult.

A patient with a VEGF and endostatin producing gastrointestinal autonomic nerve tumour.

Tumour associated neovascularisation has been characterised as chaotic and insufficient. This report details the results of the analysis of angiogenic factors in tumour cyst fluid, pleural fluid, and blood from a patient with a gastrointestinal autonomic nerve tumour. The tumour produced vascular endothelial growth factor and endostatin in large quantities, which may explain the dysfunctional angiogenesis and tendency to bleeding seen in this tumour type.

In vivo angiogenic activity of neuroblastoma correlates with MYCN oncogene overexpression.

Neuroblastoma (NB) is the most common malignant solid tumor in early childhood. Amplification of the MYCN oncogene is associated with a more malignant course of disease and poor outcome. The role that MYCN plays in the regulation of angiogenesis in NB remains unclear. To better elucidate this matter, fresh biopsy samples from 21 patients, 10 with MYCN-amplified tumors (defined as having >10 copies of the oncogene) and 11 with nonamplified tumors, were tested for their angiogenic capacity using the chick embryo chorioallantoic membrane assay, a useful model for such investigation. Moreover, using the same experimental model, conditioned media obtained from 5 different human NB cell lines MYCN-amplified (HTLA-230, LAN-5 and GI-LI-N) or nonamplified (ACN and SH-SY5Y) and biopsy fragments obtained from xenografts derived from 4 NB cell lines (HTLA-230, GI-LI-N, ACN and SH-SY5Y) injected in nude mice were assayed for angiogenic potential. Our results clearly demonstrated that MYCN amplification parallels angiogenesis in NB. When fresh biopsy samples from patients, CM derived from NB cell lines and biopsy fragments derived from xenografts of the same cell lines injected in nude mice were tested, the response was univocal: the angiogenic response, evaluated both macroscopically and microscopically, was significantly higher in the MYCN-amplified specimens compared to the nonamplified ones.

Ischemia and failed regeneration in chronic experimental neuromas.

Neuromas are generally considered to be swollen uniform collections of uncontrolled aberrantly sprouting axons. In early experimental neuromas, there are substantial rises in local blood flow associated with their formation, but human studies of chronic lesions have suggested that neuromas develop ischemia and become impediments to regeneration. The issue is important because traumatically severed human nerves are frequently considered for repair some time after injury, when neuroma formation has occurred. In this work, we examined local perfusion, axon penetration and other characteristics of long-term (6 month) experimental neuromas created by sciatic nerve transection and resection of the distal sciatic nerve and its branches. The scenario was designed to model prior transection in a human nerve, where late surgical reconnection might be contemplated. Local blood flow in the extrinsic plexus of neuromas, examined using a laser Doppler flowmetry probe, declined in distal portions of the stump to values considerably lower than observed in intact nerves. Intrinsic blood flow near the stump tip, examined using microelectrode hydrogen clearance polarography was highly nonuniform and included zones with very low perfusion. Correlated with these findings were nonuniform histological features with zones of absent axons and blood vessels, progressive distal disorganization, marked declines in distal axon penetration, nonremodelled microfascicles and persistent expression of 'regenerative' axon and Schwann cell markers. Uncontrolled axon sprouting was not a feature. Longstanding neuromas include zones of relative ischemia and limited axon penetration that develop in the absence of nerve trunk reconnection. These features would limit their suitability for later repair.

Paraganglioma of the cauda equina: MR findings. One case.

Paraganglioma of the filum terminale is a rare tumor but well described in the neurosurgery and pathology literature. Few MRI reports are mentioned. Paraganglioma, often misdiagnosed with ependymoma or schwannoma on MRI images, must be kept in mind, when a highly vascular lesion with serpentine vessels is observed.

Exogenous opioids influence the microcirculation of injured peripheral nerves.

Local microvessels of peripheral nerve trunks (vasa nervorum) dilate following capsaicin-induced inflammation or local nerve trunk injury. In previous work, we observed that morphine blocked capsaicin-induced dilation of vasa nervorum presumably through the action of local opioid receptors. In the present work, we studied injury-related hyperemia of the rat sciatic vasa nervorum using laser Doppler and hydrogen clearance microelectrode measurements of local perfusion. Systemic morphine reversed hyperemia by vasoconstricting both extrinsic and intrinsic microvessels supplying 48-h-old "neuroma" preparations or crush zones of peripheral nerve trunks. Morphine did not constrict microvessels of contralateral uninjured or sham exposed but uninjured sciatic nerves. In contrast to the injured nerves, contralateral uninjured nerves exposed to morphine frequently had a rise in local perfusion, indicating vasodilation. The vasoconstrictive actions of morphine were blocked by pretreatment with naloxone and were not mimicked by saline injections alone. Systemic doses of selective opioid agonists to mu-, kappa-, and delta-receptors also selectively constricted microvessels of injured nerves. Local blood flow in older experimental neuromas at 7 days had partial sensitivity to morphine, whereas at 14 days perfusion flow was not influenced by morphine. Exogenous opioids dampen early but not later inflammatory microvasodilation and could have important influences on the nerve regenerative milieu.

Proliferative activity, angiogenesis, and necrosis in peripheral nerve sheath tumors: a quantitative evaluation for prognosis.

Malignant peripheral nerve sheath tumors (MPNSTs) are distinguished from a control group of typical benign schwannomas and neurofibromas on the basis of a set of quantitatively evaluated parameters, i.e., the cell density; the number of mitoses and apoptotic bodies; the nuclear area and shape; the number and absolute and relative areas of silver-staining nucleolar organizer regions; necrosis; and angiogenesis. Only the extent of tumor necrosis, the mitotic rate, and the parameters related to silver-staining nucleolar organizer regions discriminate between less aggressive MPNSTs (disease-free patients after 4 years of follow-up) and more aggressive MPNSTs (with recurrences or metastases during the first 4 years of follow-up).

Evidence for CGRP accumulation and activity in experimental neuromas.

Calcitonin gene-related peptide (CGRP) is a potent vasodilator and widely distributed neuropeptide that may participate in the injury response of peripheral nerve. We examined evidence for the presence of CGRP immunoreactivity (IR) and its activity in experimental neuromas of Sprague-Dawley rats created by sectioning the midsciatic nerve with resection of 2-3 cm of its distal portion and branches. CGRP activity was evaluated by measuring local blood flow in neuromas using hydrogen polarography and laser-Doppler flowmetry. At all time points studied after nerve section (24 h, 48 h, 7 days, 14 days) there was a rise in local blood flow in the neuroma stumps. At 48 h the hyperemia was maximum but was reversed by topical application of human CGRP(8--37), a specific CGRP-receptor antagonist. CGRP presence was evaluated by immunohistochemistry and radioimmunoassay (RIA). At 24 and 48 h, CGRP IR was intense and distributed in a globular and diffuse pattern apparently not confined to discrete axonlike profiles. At 7 and 14 days, CGRP IR remained prominent and was associated with disorganized axonlike profiles, sometimes directed in a circumferential pattern around the outside of the neuroma. RIA confirmed rises in CGRP content at 24 and 48 h that accompanied the changes in local blood flow and altered distribution of CGRP IR. CGRP accumulates in a time-related fashion within experimental neuromas, where it induces among other possible actions prominent local vasodilatation. CGRP may be important in the regenerative milieu of injured nerves.

Accumulation and degranulation of mast cells in experimental neuromas.

Mast cell accumulation and degranulation occur within the endoneurium of injured peripheral nerves. We investigated the time course of mast cell accumulation and degranulation in experimental neuromas of the sciatic nerve in rats. Mast cell accumulation and degranulation were significant only after the first week following neuroma creation and were prominent at 14 days within the neuroma stump. Mast cell degranulation could account for microvascular changes within neuromas after the first week following injury.