Vascular wall cells contribute to tumourigenesis in cutaneous neurofibromas of patients with neurofibromatosis type 1. A comparative histological, ultrastructural and immunohistochemical study.

UNLABELLED: Neurofibromas are benign nerve sheath tumours. They occur sporadically, singly or few in number, and in neurofibromatosis type 1 (NF1), an autosomal inherited disease. These tumours are composed of different cell types, e.g. nerve cells (axons and axon sheaths), Schwann cells, mast cells, and fibroblasts. The local control of tumour growth in NF1 is poorly understood. Identification of cell markers could provide new information on the processes that are involved in tumour growth. MATERIALS AND METHODS: NF1 patients were diagnosed according to the revised NF1 diagnostic criteria proposed by the US National Institute of Health. Fifteen cutaneous neurofibromas from eight patients (origin: trunk and face) were excised, immediately immersion-fixed in Bouin's fixative and embedded in paraffin. Six micrometre thin sections were incubated with a variety of neuronal markers, connective tissue and glial cell markers, neurotrophic factors and their receptors. In addition, material was fixed, embedded and further processed for light and electron microscopic studies. RESULTS: The tumours were composed of different cell types, e.g. nerve cells (axons and axon sheaths), Schwann cells, mast cells, compartmentalising cells and fibroblasts. Neuronal markers were identified in axons (neuron-specific protein gene product 9.5, PGP9.5), in several cell types (neurofilament protein-200 kDa, NF-200) and glial cells (protein S-100, S-100). In glial cells the immunoreactivity for fibroblast surface protein (FSP) was scanty, low for cyclic 2,3-nucleotide 3'-phosphodiesterase (CNPase), strong for glucose transporter 1 (Glut-1) but lacking for glial fibrillary acidic protein (GFAP). Schwann cells and so-called compartmentalising cells exhibited immunoreactivity for neurotrophin receptor protein TrkA (TrkA) and glial cell-derived neurotrophic factor (GDNF). GDNF receptor α-1 (GFR-α1) exhibited distinct immunoreactivity in single axons, in Schwann cells, and with lower intensity in some perineurial sheet cells. No immunoreactivity was observed for the low-affinity neurotrophin receptor protein p75(NTR), high-affinity receptor protein TrkB (TrkB), high-affinity receptor protein TrkC (TrkC), the neurotrophin 3 (NT-3), and the brain-derived neurotrophic factor (BDNF). CONCLUSION: Human cutaneous neurofibromas displayed a pattern of neurotrophic factors and their receptor immunoreactivity, which is characteristic of differentiated non-malignant tumours, and exhibited some differences from that established in developing and differentiated control Schwann cells (probably involved in the pathogenesis of the neurofibromas), as well as tumour cells in the process of differentiation. Neurofibromas are highly vascularized tumours and possess activated endothelial cells and pericytes. We presume that most of the hyperplastic structural components of a neurofibroma are generated from activated pericytes and smooth muscle cells of the small tumour vessels which possess qualities of adult stem cells.

Hybrid peripheral nerve sheath tumor of the nasal cavity showing schwannomatous, neurofibromatous, and perineuriomatous areas.

Soft tissue hybrid peripheral nerve sheath tumors (PNST), including schwannoma-perineurioma or neurofibroma-perineurioma, have recently been described. However, there are no reports on hybrid PNST arising in the nasopharyngeal area. In this article, we report such a case. A 58-year-old Japanese man presented with nasal obstruction and was found to have bilateral polypoid lesions in the middle meatus of the nose. Subsequently, nasal polypectomy was performed. Histologically, the tumor consisted of three components including schwannoma, neurofibroma, and perineurioma. Immunohistochemically, schwannoma, neurofibroma, and perineurioma components were positive for S-100 protein, CD34, and epithelial membrane antigen, respectively. In conclusion, this is the first case of hybrid PNST reported to occur in the nasopharyngeal area. Pathologists should be aware of the possibility that hybrid PNST may present outside soft tissue.

Primary localised pleural neurofibroma: expanding the spectrum of spindle cell tumours of the pleura.

AIMS: Primary localised pleural neoplasms are a rare group of thoracic tumours, with solitary fibrous tumour representing the most frequently encountered entity. Two cases of localised pleural neurofibromas involving the pleura are described. METHODS AND RESULTS: The patients were both female: 78 and 29 years of age. In the former a pleural-based lesion was identified on a chest radiograph after she presented with shoulder pain. The second patient was known to have neurofibromatosis type I, and the pleural lesion was found incidentally during excision of a metastatic malignant peripheral nerve sheath tumour of the lung. Both tumours were localised and composed histologically of bland neoplastic spindle cells embedded in a loose collagenous matrix. There was variable immunoreactivity for S100 and CD34, while ultrastructure examination in the two cases showed a mixture of nerve sheath cell types. CONCLUSION: To the best of the authors' knowledge, localised neurofibromas have not been previously reported within the pleura. The presence of a bland spindle cell pleural neoplasm immunoreactive for CD34 may potentially be mistaken for a solitary fibrous tumour. While distinction is usually achieved on close attention to the histological features, staining with S100 protein, especially in small biopsies, should be considered to exclude a neurofibroma.

Olfactory ensheathing cell tumor with neurofibroma-like features: a case report and review of the literature.

A 32-year-old man had seizure attack since April 2008 and radiographic examination revealed a heterogeneous enhancing mass at the left subfrontal region. He underwent craniotomy for tumor removal on October 1, 2008. The tumor, which was grayish white with glistening appearance and rubbery consistency, was traced to the proximal part of left olfactory tract. Histopathological examination revealed a hypocellular tumor with dense hyalinization in most areas. The tumor cells had ovoid to elongate and often comma-shaped nucleus. Myxoid change of the stroma was apparent in places. Most of the tumor cells were immuno-reactive for S-100 protein. Staining for Leu 7 (CD57 or HNK-1) was negative. Bodian method illustrated many axons within the tumor. Ultrastructural study of the tumor cells showed features compatible with those of olfactory ensheathing cell. The tumor was designated as olfactory ensheathing cell tumor with neurofibroma-like features. There have been 14 nerve sheath tumors arising from the olfactory nerve reported in the literature; all of them had the morphology of schwannoma. Our case, which had the morphology simulating neurofibroma was the first of its kind to be recorded.

Localized, plexiform, diffuse, and other variants of neurofibroma in 12 dogs, 2 horses, and a chicken.

In humans, neurofibroma and schwannoma are distinct entities within the group of benign peripheral nerve sheath tumors. In the veterinary literature, these tumors are often classified together simply as benign peripheral nerve sheath tumors, and diagnostic criteria for their subclassification are not well established. We describe peripheral nerve sheath tumors with microscopic, immunohistologic, and ultrastructural features similar to those in subtypes of human neurofibroma in 12 dogs, 2 horses, and 1 chicken. Dogs were of different breeds and were aged 2 months to 15 years. The canine tumors were located in the skin, peripheral nerve, tongue, and large intestine. The 2 horses were 11 and 12 years old. The equine tumors were located in the subcutis of the neck and axilla. The chicken was a mature white Leghorn chicken with an ocular neoplasm. Neurofibromas of this study had localized, plexiform, diffuse and combined plexiform and diffuse growth patterns, and microscopic features similar to those in classic, collagenous, cellular, myxoid, and pigmented neurofibromas of humans. One diffuse neurofibroma contained areas of schwannian differentiation (hybrid neurofibroma-schwannoma). Two plexiform neurofibromas occurred together with diffuse ganglioneuromatosis in the large intestine of young dogs, as has also been reported in humans. This investigation shows the existence of identical subtypes of neurofibroma in animals and humans and identifies similarities in tumor location and patient age between animals and humans. This report will allow a more discriminating classification of benign peripheral nerve sheath tumors and probably has a bearing on epidemiology, pathogenesis and prognosis.

Neurofibroma central de la mandíbula: informe de un caso / Central neurofibroma of the mandible: report of a case

El neurofibroma raramente aparece como una lesión solitaria, excepto cuando está presente en los huesos maxilares. Por el contrario, múltiples lesiones se observan en la neurofibromatosis de Von Recklinhausen. El neurofibroma central ha sido informado tanto en mandíbula como en maxilar; sin embargo, esta última ubicación es la más común. Presentamos un caso de neurofibroma central de la mandíbula.

Neurofibroma solitario de la región preauricular: presentación de un caso clínico / Solitary neurofibroma of the preauricular region: report of a clinical case

EL neurofibroma es un tumor benigno que deriva de las células de Schwann y de los fibroblastos perineurales de los nervios periféricos. Dentro de los tumores de cabeza y cuello, presenta una frecuencia muy baja, pero es el tumor más frecuente de origen neurógeno. Se presentan solitarios o formando parte de la neurofibromatosis múltiples tipo 1 (enfermedad de Von Recklinghausen). El diagnóstico prequirúrgico es dificultoso. Se llega ala diagnóstico definitivo tras el estudio histopatológico de la pieza quirúrgica. Se presenta un caso clínico y se realiza la revisión bibliográfica correspondiente

Neurofibroma solitario de la región preauricular: presentación de un caso clínico / Solitary neurofibroma of the preauricular region: report of a clinical case

EL neurofibroma es un tumor benigno que deriva de las células de Schwann y de los fibroblastos perineurales de los nervios periféricos. Dentro de los tumores de cabeza y cuello, presenta una frecuencia muy baja, pero es el tumor más frecuente de origen neurógeno. Se presentan solitarios o formando parte de la neurofibromatosis múltiples tipo 1 (enfermedad de Von Recklinghausen). El diagnóstico prequirúrgico es dificultoso. Se llega ala diagnóstico definitivo tras el estudio histopatológico de la pieza quirúrgica. Se presenta un caso clínico y se realiza la revisión bibliográfica correspondiente (AU)

Somatostatinoma: collision with neurofibroma and ultrastructural features.

The clinical presentation, histopathology and immunoelectron microscopic features of two cases of duodenal somatostatinoma are described, one of which is a hitherto unreported example of a collision tumour with a neurofibroma. Ultrastructural morphometric immunoelectron microscopy studies revealed the presence of four types of cells in both tumours, but there was no difference in the proportions of these cells between the collision tumour and the non-collision tumour. Neurosecretory granules ranging in size from 255-815 nm were generally larger than those previously reported for somatostatinomas and somatostatin was identified in granules of all sizes across this range. Neither tumour was associated with the somatostatinoma syndrome comprising associated diabetes mellitis, steatorrhoea and cholelithiasis.

Isolated neurofibroma of the orbit with extensive myxoid changes: a clinicopathologic study including MRI and electron microscopic findings.

Isolated orbital neurofibroma (INO) without systemic neurofibromatosis is rare. Previous reports including MRI with elaboration of the ultrastructural features of the cellular and extracellular components in INO do not exist. A 44-year-old male presented with painless, slowly progressive proptosis (6 mm) and downward displacement (3 mm) of the left eye of two years duration. MRI revealed a suprabulbar mass hypointense to fat, isointense to brain on T1-weighted images with small hyperintense areas following contrast enhancement. T2-weighted images showed a predominantly hyperintense mass with a few hypointense islands. The lesion was excised using an anterior superior transseptal orbitotomy. Histopathologically, large areas of a paucicellular myxoid stroma containing mucopolysaccharides made up approximately three-quarters of the mass. Focal hypercellular areas showed marked collagen deposition. Blood vessels were distributed at the periphery of the lesion and in association with nodules of nerve sheath cells. Ultrastructurally, perineural and fibroblast-like cells were loosely arranged in a myxoid stroma. Schwann cells were embedded in a dense collagenous matrix. Variable differentiation of Schwann cells, perineural cells and fibroblast-like cells associated with a more solid (collagenous) or loose (myxoid) extracellular matrix may determine the characteristic, though not specific, MRI features in isolated neurofibromas of the orbit.

Comparative ultrastructural and immunohistochemical study of perineurioma and neurofibroma of the oral mucosa.

In the course of assessing the cellular composition of intraoral neurofibroma (NF), we encountered a unique gingival tumor of putative perineurial (PN) origin. The lesion showed the ordinary light microscopic NF pattern, but the ultrastructural features of well-differentiated PN cells as well as an epithelial membrane antigen (EMA)-positive, S-100 protein-negative immunoprofile confirmed the diagnosis of soft tissue perineurioma (STP). In our small series of NF, there were three ultrastructural subtypes: Type I (common Schwann cell type), Type II (NF with a high content of PN cells) and Type III (predominantly fibroblastic NF), although inhomogeneous and overlapping assembly of cellular elements. A significant number of tumor cells in Type II showed the substantial reactivity for EMA, whereas many CD34-positive cells were noted in Type III. The present results confirm previous findings that PN lineage is an important constituent in the formation of NF and reinforce the value of electron microscopy in the diagnosis of peripheral nerve sheath tumors.

[Melanotic neurofibroma, clinical and histopathologic diagnosis. Case report]. / Neurofibromul melanocitar, diagnostic clinic si histopatologic. Caz clinic.

Melanotic neurofibroma is a rare benign tumor, derived from peripheral nerve sheath, whose originality consists in the presence of melanic pigment. The clinical diagnosis is difficult to establish, requiring the histopathological exam to make the difference between melanotic neurofibroma and the other pigmented tumors. Although, sometimes neither the anatomopathological exam can establish the final diagnosis, requiring supplementary studies. Melanotic neurofibroma has a good prognosis and the malignization is rare. The elective treatment is surgical, represented by the complete excision of the tumor.

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.

Ribosome-lamella complexes in the perineurial cells of neurofibromatosis.

Ribosome-lamella complexes are occasionally seen in neoplastic disorders of the hematopoietic system, particularly in hairy cell leukemia. However, these structures are rare in epithelial and mesenchymal cells. In this report three tumors from a patient with neuro-fibromatosis (von Recklinghausen's disease) are examined by electron microscopy. Ribosome-lamella complexes were seen in the perineurial cells. This may be the first report of these complexes in nerve sheath tumors.

[Neurofibroma of the larynx]. / Neurofibroma krtani.

During the years 1986--90 about 480 patients with tumors of the larynx were treated in Cracow Otolaryngological Clinic. In this group were two cases of neurofibroma of the larynx. These patients were treated upon by various types of surgically operations.

[Neurofibroma of the lower lip]. / Neurofibroma de labio inferior.

Reporting a nervous tumor diagnosed as Neurofibroma, which owing to its localisation, on the lower lip, and its possible origin, from a salivary gland, should be considered an extraordinary rarity. The AA, make a bibliographic review of the commonest sites of the growth, the histological description and consider some possible differential diagnosis with special emphasis to the schwannoma and the Recklinghausen's disease.

Clinical and pathological aspects of solitary spinal neurofibroma.

Four cases are described of solitary spinal neurofibroma, a rare tumour of the spinal cord or nerve roots. Computerised tomography provided an accurate topographical definition of the tumour. Magnetic resonance imaging showed an increased T2-weighted signal and multiple areas of decreased T1- and T2-weighted signals centrally. The MR signals matched the histological examination which showed hyperplastic interfascicular connective tissue, pleomorphic cells, and tightly packed nerve fibres compressed by the surrounding loose connective tissue. Electron microscopy showed three types of cell: Schwann cells, fibroblast-like cells, and mast cells. The histological findings suggests that solitary spinal neurofibroma is a distinct pathological entity which could be diagnosed preoperatively from the MR images.

The ultrastructure of peripheral neurofibroma: the role of mast cells and their interaction with perineurial cells.

The authors analyze the ultrastructure of mast cells and perineurial cells when both are present in neurofibroma of the nerve sheath. Samples of pathologic tissue taken from three patients with neurofibroma of a peripheral nerve sheath were analyzed by light and transmission electron microscopy. The observations document the characteristics of the tumor cells (Schwann cells and perineurial cells) as well as the presence of numerous mast cells, typically in close contact with the perineurial cells and never with the Schwann cells. Many electron-dense vesicles were found between the cells; these vesicles are created when the cell membrane of the mast cell buds, and then they come into contact with the adjacent perineurial cell. Endocytosis vesicles are often present in the cytoplasm of perineurial cells. Analysis of these observations led the authors to assume the existence of a metabolic interaction between the two cell type in contact with each other and an active role of the mast cells in the evolution of the tumor. The following two theories are plausible: either the mast cells actively stimulate tumor growth, or they alter the phenotype of the tumor cell. These findings could have interesting clinical applications. The use of treatment protocols which inhibit mast cell activity could, in theory, stop either the proliferation of the neurofibroma or its malignant transformation.