Multinodular and vacuolating neuronal tumors in epilepsy: dysplasia or neoplasia?

Multinodular and vacuolating neuronal tumor (MVNT) is a new pattern of neuronal tumour included in the recently revised WHO 2016 classification of tumors of the CNS. There are 15 reports in the literature to date. They are typically associated with late onset epilepsy and a neoplastic vs. malformative biology has been questioned. We present a series of ten cases and compare their pathological and genetic features to better characterized epilepsy-associated malformations including focal cortical dysplasia type II (FCDII) and low-grade epilepsy-associated tumors (LEAT). Clinical and neuroradiology data were reviewed and a broad immunohistochemistry panel was applied to explore neuronal and glial differentiation, interneuronal populations, mTOR pathway activation and neurodegenerative changes. Next generation sequencing was performed for targeted multi-gene analysis to identify mutations common to epilepsy lesions including FCDII and LEAT. All of the surgical cases in this series presented with seizures, and were located in the temporal lobe. There was a lack of any progressive changes on serial pre-operative MRI and a mean age at surgery of 45 years. The vacuolated cells of the lesion expressed mature neuronal markers (neurofilament/SMI32, MAP2, synaptophysin). Prominent labelling of the lesional cells for developmentally regulated proteins (OTX1, TBR1, SOX2, MAP1b, CD34, GFAPδ) and oligodendroglial lineage markers (OLIG2, SMI94) was observed. No mutations were detected in the mTOR pathway genes, BRAF, FGFR1 or MYB. Clinical, pathological and genetic data could indicate that MVNT aligns more with a malformative lesion than a true neoplasm with origin from a progenitor neuro-glial cell type showing aberrant maturation.

18F-FDG PET/CT diagnosis of vagus nerve neurolymphomatosis.

A 62-year-old woman was in remission from previously treated stage IV diffuse large B-cell lymphoma with cranial involvement. She presented with new-onset hoarseness of voice and choking; MRI of the brain showed disease recurrence in the left cavernous sinus. She was subsequently referred for F-FDG PET/CT with contrast for further evaluation of lymphomatous recurrence. F-FDG PET/CT not only revealed hypermetabolic activity in the left cavernous sinus correlating to the MRI findings but also showed an interesting manifestation explaining the patient's hoarseness of voice, being neurolymphomatosis along the left vagus nerve.

Morbidity and functional status of patients with pelvic neurogenic tumors after wide excision.

BACKGROUND: We previously reported that over the last 10 years our practice has evolved in the treatment of neurogenic tumors of the pelvis to include a multispecialty team of surgeons, a factor that might decrease morbidity and improve recurrence, survival, and function. QUESTIONS/PURPOSES: Therefore, we (1) assessed the morbidity associated with surgical excision in patients with neurogenic tumors of the pelvis; (2) determined the function of these patients; and (3) determined the rates of local recurrence, metastasis, and overall survival with this new approach. METHODS: We reviewed the records of all 38 patients who had surgery for a pelvic plexus tumor between 1994 and 2005. Twenty one were male. The mean age of all patients was 38 years and median follow up was 2.1 years. Twelve patients had a malignant tumor. We recorded demographic data, postoperative complications, tumor-specific recurrence, and determined survival. RESULTS: Postoperative complications occurred in nine of the 38 patients (23%): hematoma (n = 3), wound infection or deep abscess (n = 3), and deep venous thrombosis (n = 3). Surgical complications occurred more frequently in patients with malignant disease. Patients with benign tumors had a mean MSTS score of 94%, while survivors of malignant disease had a mean of 57%. For malignant tumors, the 5-year rate of local recurrence was 40%, the estimated 5-year rate of metastasis was 67% and 5-year survival rate was 50%. CONCLUSION: Using a team approach, surgical excision provided high functional scores for patients with benign disease with a low rate of complications. In patients with malignant tumors, intentional wide resection is associated with higher morbidity but yields acceptable functional scores.

The diagnostic value of vestibular-evoked myogenic potential in patients with vestibular schwannoma.

OBJECTIVE: This study examined the diagnostic value of the vestibular-evoked myogenic potential (VEMP) in comparison with the caloric test in patients with vestibular schwannoma (VS). METHODS: Data were retrospectively collected from 803 consecutive patients who visited our vertigo clinic and underwent vestibular tests. Amongst them, 78 patients were diagnosed as having untreated unilateral VS. VEMP was performed using click and short-tone burst stimulation. The caloric test was performed using ice water. The sensitivity and specificity of each test were evaluated. RESULTS: Of the 78 patients with VS, 63 had abnormal VEMPs as well as abnormal caloric responses. Of the 725 patients without VS, 382 had normal VEMPs and 416 had normal caloric responses. The sensitivity and specificity of VEMP were 80.8% (95% CI: 72.0-89.5%) and 52.7% (95% CI: 49.1-56.3%), respectively; those of the caloric test were 80.8% (95% CI: 72.0-89.5%) and 57.4% (95% CI: 53.8-61.0%), respectively. CONCLUSIONS: The sensitivity and specificity of VEMP and the caloric test showed no significant differences. SIGNIFICANCE: In patients with VS, although the specificity of VEMP was not very high, its sensitivity was high and comparable to that of the caloric test.

Magnetic resonance perfusion imaging in neuro-oncology.

Recent advances in magnetic resonance imaging (MRI) have seen the development of techniques that allow quantitative imaging of a number of anatomical and physiological descriptors. These techniques have been increasingly applied to cancer imaging where they can provide some insight into tumour microvascular structure and physiology. This review details technical approaches and application of quantitative MRI, focusing particularly on perfusion imaging and its role in neuro-oncology.

Centrosome dysfunction in Drosophila neural stem cells causes tumors that are not due to genome instability.

Genome instability (GI) and centrosomal alterations are common traits in human cancer [1, 2]. It is suspected that centrosome dysfunction may cause tumors by bringing about GI, but direct experimental proof is still lacking [3]. To explore the possible functional link between centrosome function and overgrowth, we have assayed the tumorigenic potential of a series of mutants that affect different centrosomal proteins in Drosophila. We have found that a significant number of such mutant conditions are tumorigenic in larval brain tissue, where self-renewing asymmetric division of neural stem cells is frequent, but not in symmetrically dividing epithelial cells. We have also found that mutations that increase GI without causing centrosome dysfunction are not tumorigenic in our assay. From these observations, we conclude that the tumors caused by centrosome dysfunction cannot be explained solely by the resulting genome instability. We propose that such tumors might be caused by impaired asymmetric division of neural stem cells [4]. These results show that centrosome loss, far from being innocuous, is a potentially dangerous condition in flies.

Neuropeptide Y in neural crest-derived tumors: effect on growth and vascularization.

Neuropeptide Y (NPY) is a sympathetic neurotransmitter recently found to be a potent growth and angiogenic factor. The peptide and its receptors are abundant in neural crest-derived tumors, such as sympathetic neuroblastomas and pheochromocytomas, as well as parasympathetic Ewing's sarcoma family of tumors. NPY regulates their growth directly, by an autocrine activation of tumor cell proliferation or apoptosis, and indirectly, by its angiogenic activity. The overall effect of the peptide on tumor growth depends on a balance between these processes and the type of receptors expressed in the tumor cells. Thus, NPY and its receptors may become targets for the treatment of neural tumors, directed against both tumor cell proliferation and angiogenesis.

Atypical ganglion cell tumor of the sciatic nerve.

CONTEXT: Although herniation of a lumbosacral intervertebral disk is a major cause of sciatic distribution pain, relentlessly progressive symptoms or signs should alert one to the possibility of a tumor involving the nerve. OBJECTIVE: To describe the clinical, neurophysiological, and histological features of a pathologically unique tumor involving the sciatic nerve. SETTING: Tertiary referral university hospital. PATIENT: A 36-year-old woman was seen with a 6-year history of increasingly severe symptoms in the distribution of the left sciatic nerve. RESULTS: Electromyography indicated a sciatic nerve lesion in the region of the greater sciatic notch. Magnetic resonance imaging demonstrated a tumor involving the left sciatic nerve in this area. Light microscopy, electron microscopy, and immunohistochemistry results confirmed the presence of an atypical ganglion cell tumor of the sciatic nerve that exhibited prognostically conflicting clinical and histological features. CONCLUSIONS: To our knowledge, this is the first report of an atypical ganglion cell tumor affecting the sciatic nerve, and illustrates the value of detailed neurophysiological examination in localizing the site of peripheral nerve injury to facilitate focused neuroimaging when standard investigations are uninformative. Longer follow-up is required to determine the true biologic potential of this lesion.

Sympathectomy does not affect the early ectopic discharge from myelinated fibres in ferret inferior alveolar nerve neuromas.

Ectopic neural activity from damaged axons is thought to contribute to the development of sensory disorders following nerve injury. Here we have studied the role of sympathetic fibres in the generation or potentiation of this abnormal activity by determining the effect of predegenerating these fibres. Twelve adult ferrets were used in the study and six of them underwent sympathectomy by removal of the left superior cervical ganglion. Electrophysiological recordings were made from myelinated axons in fine filaments dissected from the inferior alveolar nerve, 3 days after it had been ligated further distally, and the level of spontaneous activity and mechanical sensitivity was determined. There was no significant difference between the level or characteristics of spontaneous activity, or the level of mechanical sensitivity, in the two groups of animals. We conclude that, in this animal model, the absence of sympathetic nerve fibres does not affect the development or characteristics of ectopic neural activity in the early period following nerve injury.

Pathophysiology of glial growth factor receptors.

Activation and proliferation of glial cells are common events in the pathology of the nervous system. Although we are only beginning to understand the molecular signals leading to glial activation in vivo, there is increasing evidence that growth factors and their receptors may play an important part. In this paper we summarize the data on the pathophysiology of glial growth factor receptors and their ligands in the central and peripheral nervous systems.

Reduced P3b category response in prefrontal patients.

Several studies have implicated a frontal/prefrontal contributor to P3b. We hypothesized that prefrontal involvement may be necessary to the processing of novel contextual information, as suggested by selective reduction of P3a in prefrontal patients. ERPs were recorded from 12 controls and 12 unilateral prefrontal lesion patients. In two target-detection tasks, subjects/patients viewed randomly-ordered stimuli drawn from differentially probable categories: numbers (standard, 90%) and letters (deviant, 10%). Topographic and midline analyses were applied to examine target and category effects on P3b. Low-probability targets evoked distinct P3bs in each group. Control subjects' P3bs were additionally enhanced to deviant targets and nontargets. Patients' P3s were enhanced to deviant nontargets but were unaffected by deviant targets. This is consistent with the view that target- and nontarget-evoked P300s are functionally distinct, and suggests that a prefrontal contributor to P3b supports attention to contextual attributes among task-relevant stimuli.

Nerve growth factor and neural oncology.

The precise role of the nerve growth factor protein (NGF) during the growth and development of the human nervous system is not determined. Although it appears to influence a number of neural functions, its mechanism of action is poorly understood. A number of researchers have proposed that NGF may be involved in several pathological conditions including cancer. It has been shown that NGF is secreted by certain sarcoma (23), neuroblastoma (113), and glioma (7,102,136) cell lines and can bind to neuroblastoma and metastatic melanoma cell lines (42). Neuroblastoma (136,181) and pheochromocytoma (165) cells in vitro can be induced by NGF to differentiate toward a morphologically "more benign" state and appropriate NGF treatment of rats can reduce the number of chemically induced gliomas and neurinomas (174,178). NGF can also reduce the growth of intracerebrally inoculated anaplastic glioma cells (172). Anti-NGF treatment of rats (178) and mice (179) can alter the tumor distribution observed following ethylnitrosourea or benzo(a)pyrene treatment (10). In humans, it has been reported that serum levels of NGF are usually elevated in persons "at risk" for neurofibromatosis (156). The precise nature of the NGF role is not known in these instances. Further understanding of the action of NGF could be of clinical importance.

APUD cells and the apudomas. A concept relevant to anaesthesia and endocrinology.

A variety of cells found in the pituitary and pineal glands, sympathetic nervous system and adrenal glands, the gut, pancreas, thyroid (C-cells), chemoreceptors (type I-Cells), lungs (P-cells), skin (melanocytes) and the urogenital tract have a common origin from the neural crest. These cells are programmed for neuro-endocrine function and, as a group, can be regarded as one of the physiological control systems. They secrete a variety of amine and peptide hormones and have common cytochemical characteristics from which the term APUD cell is derived. Tumours of these cells are referred to as 'apudomas' and may synthesise not only their own hormones but also those which are normally produced by other APUD cells. The relevant physiological properties of some of the peptides which have been described relatively recently are discussed and the principal clinical syndromes produced by the APUDomas are described.

Electrophysiological properties of ethylnitrosourea-induced, neoplastic neurogenic rat cell lines cultured in vitro and in vivo.

A comparative analysis was performed on the electrophysiological properties of 11 neoplastic neurogenic cell culture lines and five other cell lines of different origin (HV1C, rat bile duct carcinoma; BICR/M1RK, rat mammary tumor; HeLa, human cervix carcinoma; 3T3, mouse embryo; REe, rat embryo). Neurogenic lines were derived either from N-ethyl-N-nitrosourea-induced neoplasms of the nervous system or from cultured fetal rat brain cells that had undergone neoplastic transformation in vitro after exposure to N-ethyl-N-nitrosourea in vivo. Electrical membrane excitability was lacking in all neurogenic cells analyzed. Their membrane potential and input resistance values were similar to those of the nonneurogenic lines. Intercellular ionic coupling was consistently observed between cells of a fibroblastoid shape or cells bearing multiple cytoplasmic processes (i.e., all neurogenic lines HV1C, BICR/M1RK, and 3T3). Epithelioid cells (i.e., HeLa, REe, an NV1C subpopulation, and a GV1C1 variant) showed no such intercellular communication. In vivo monolayer cultures on glass coverslips were obtained by a modified i.p. diffusion chamber technique. Under these conditions, the cells (with the exception of a glioma-derived cell line) retained the morphological appearance and electrophysiological properties observed in vitro.

[Hematopoiesis in children with retroperitoneal neurogenic tumors]. / O krovetvorenii u detei s zabriushinnymi neirogennymi opukholiami

Under observation were 140 children with retroperitoneal neurogenic tumors. In 69 of 125 patients with malignant neoplasms metastases were detected. Hemographic and myelographic findings were analysed depending on the degree of malignancy and tumor spread. Anemia usually moderate and normochromatic was observed only in neuroblastomas. This group of patients is also characterized by frequent shifts to the left leucograms and high sedimentation test, contrary to benigh tumors. The investigation of bone marrow allows one to reveal the suppression, and more rarely irritation of various blood stems.