Chromosomal imbalances and NF2 mutational analysis in a series of 10 spinal nerve sheath myxomas

AIMS: To report the demographic, clinical and molecular profile of a series of intraspinal nerve sheath myxomas. Nerve sheath myxomas are diagnostically challenging, mainly cutaneous spindle cell neoplasms exhibiting Schwann cell differentiation. They are frequently mistaken for neurothekeomas and their genetic features are essentially unknown. METHODS AND RESULTS: Ten spinal nerve sheath myxomas with a preferential location in the lumbar spine (70%) were investigated. Presenting symptoms consisted of sciatic pain (100%), muscle weakness and paraesthesia (60% each). Intraoperatively, all tumours were attached to a spinal nerve. Chromosomal imbalances by comparative genomic hybridization were found in 8/10 cases, consisting of -22q (80%) and -19 (30%). Polymerase chain reaction analysis of the NF2 gene (exons 1-16) revealed two tumours with mutations in exon 8 and 14, respectively. CONCLUSIONS: Although these 10 nerve sheath myxomas exhibited Schwann cell differentiation and frequently showed loss of chromosome 22q typically encountered in peripheral nerve tumours, only two cases demonstrated mutations of the NF2 gene. This may indicate involvement of other tumour suppressor genes on 22q in nerve sheath myxomas and shows that they are more closely related at the molecular level to sporadic schwannomas, underscoring the presumption that they are true nerve sheath tumours.     

Canine cutaneous spindle cell tumours with features of peripheral nerve sheath tumours: a histopathological and immunohistochemical study

In veterinary medicine, the term peripheral nerve sheath tumour is usually restricted to neoplasms that are closely associated with an identified nerve. Thirty-three cases of canine cutaneous tumours previously classified as spindle cell tumours with features resembling peripheral nerve sheath tumours were examined. Two histological patterns were identified: dense areas of spindle shaped cells resembling the Antoni A pattern and less cellular areas with more pleomorphic cells resembling the Antoni B pattern. Immunohistochemically, all tumours uniformly expressed vimentin and 15/33 (45.4%) had scattered and patchy expression of S-100. Laminin expression was found in 25/33 (75.7%) tumours and collagen IV labelling occurred in 14/33 (42.4%). Expression of protein gene product 9.5 was detected in 31/33 (93.9%) of tumours and neuron specific enolase labelling was present in 27/33 (81.8%). Glial fibrillary acidic protein was only expressed within the cytoplasm of some large multinucleated cells in one tumour. These findings suggest that any cutaneous tumour with one of the two histopathological patterns described above should be described as a cutaneous peripheral nerve sheath tumour and that expression of S-100, laminin and collagen IV may be used to define a schwannoma.     

What are the CD34+ cells in benign peripheral nerve sheath tumors? Double immunostaining study of CD34 and S-100 protein

To determine whether CD34 expression in nerve sheath lesions was found in a unique cell population or in a subset of nerve sheath cells, we performed double immunohistochemical staining using a standard avidinbiotin complex method with 2 separate color developing systems. We studied 40 neurofibromas and 16 neurilemomas. All lesions strongly expressed S-100 in nuclei and cytoplasm. CD34 was detected in cells having ameboid dendritic cytoplasm present in greatest numbers in Antoni B zones of neurilemomas, myxoid zones of neurofibromas, at the periphery of lobules in both tumor types, and condensed in apposition to perineurium. The CD34+ cells also were detected in normal nerves. They were infrequent in Antoni A zones of neurilemomas. No dual S-100 and CD34 expression was seen. This double immunostaining confirms the presence of a CD34-reactive non-Schwannian cell type in these neural neoplasms. As the CD34+, S-100-negative cell population is present also in normal nerves and infrequently seen in the areas of cellular neoplastic Schwann cells, CD34+, S-100-negative cells in peripheral nerve sheath tumors most likely are nonneoplastic and may have a supportive function.     

Peripheral nerve sheath differentiation in malignant soft tissue tumours: an ultrastructural and immunohistochemical study.

Thirteen soft tissue sarcomas with ultrastructural evidence of nerve sheath differentiation were investigated by immunohistochemistry. Three arose in a major nerve or nerve trunk and four patients had von Recklinghausen's neurofibromatosis. Ultrastructurally, 10 cases showed variable differentiation towards Schwann cells, two resembled perineurial cells and one tumour had features suggestive of both cell types. Immunostaining for S-100 protein was positive in eight Schwann cell tumours, negative in the other two Schwann cell tumours and negative in those with perineurial-like cells. No cases demonstrated epithelial membrane antigen, so that the existence of perineurial cells in malignant nerve sheath tumours remains immunohistochemically unsubstantiated; it may be that the perineurial-like cells are merely incompletely differentiated Schwann cells, with nerve sheath differentiation manifesting a continuous spectrum. Leu 7 was detected in four Schwann cell tumours, three of which were ultrastructurally well differentiated. Cytokeratin and desmin were demonstrated only in an undifferentiated pleomorphic area of one Schwann cell tumour. Electronmicroscopy can aid diagnosis by revealing nerve sheath differentiation in malignant soft tissue tumours without demonstrable S-100 protein.     

Monosomy 22 in a malignant peripheral nerve sheath tumour of the kidney in childhood: a genetic link with other malignant paediatric renal neoplasms?

A recurrent malignant spindle cell neoplasm of the kidney, occurring in a 11-year-old girl and corresponding to a malignant peripheral nerve sheath tumour is reported. The neurogenic differentiation was substantiated by the presence of PGP 9.5 neurofilament and S-100 protein positivity and by the ultrastructural features. Cytogenetic analysis revealed monosomy of chromosome 22 in the tumour while the constitutional karyotype was normal. Primary malignant peripheral nerve sheath tumour of the kidney is extremely rare and should, on morphology, be differentiated from stromal predominant Wilms' tumour and clear cell sarcoma of the kidney. Involvement of chromosome 22 has been described in a number of malignant renal tumours of childhood, such as Wilms' tumour (deletion), clear cell sarcoma (translocation), and rhabdoid tumour (deletion and translocation), thus suggesting common molecular mechanisms in pediatric malignant renal tumours.     

Normal and neoplastic Schwann cells in fish

Summary Peripheral nerve sheath (PNS) neoplasms, primarily neurofibromas, schwannomas and maliganant schwannomas, are among the most common tumors in fishes. Model systems involving PNS tumors in fishes are also valuable because mammalian models of PNS tumors are rare. Schwann cells, the primary cell type suspected of neoplastic transformation in these tumors, have been difficult to culture. We describe techniques for culturing normal and neoplastic Schwann cells from fish. We also present methods for preparing cells on culture dishes for electron microscopy which are especially useful when specific cells in a culture must be located for ultrastructural examination.Abbreviations PNS peripheral nerve sheath - SC Schwann cells     

Inflammatory pseudotumor of the peroneal nerve: case report and literature review

Inflammatory pseudotumors (IPTs) are a group of lesions of obscure etiology. Although they are presumably reactive, their exact pathogenesis is unknown. Inflammatory pseudotumors are identified in different organs; however, IPTs of the peripheral nerves have been rarely reported in the English literature. We report a 44-year-old woman who presented with left foot drop. Examination revealed a thickening in the posterolateral aspect of the popliteal fossa and features consistent with peroneal nerve palsy. Magnetic resonance imaging revealed a mass that may represent a Baker cyst or perineural sheath mass that was excised. After pathological examination, the case was diagnosed as IPT of peroneal nerve, and the patient received no further therapy. Inflammatory pseudotumors of the peripheral nerves, although rare, should always be of consideration in the differential diagnosis of peripheral nerve nodular mass lesions. They can mimic neoplastic nerve sheath lesions, clinically and radiologically. However, they are amenable to surgical cure with nerve-sparing surgery. Thus, despite their rarity, on dealing with neural S100 negative lesion, their inclusion is mandatory to avoid an unnecessary and a rather aggressive surgery.     

Gastric submucosal tumours of neurogenic origin with neuroaxonal and Schwann cell elements

Twelve cases of gastric submucosal tumours, originally diagnosed as leiomyoma and leiomyosarcoma, were investigated by staining with the neurogenic markers S-100 and neuron specific enolase (NSE). Three cases were, in addition, studied by electron microscopy. The tumours stained negatively for desmin, indicating that they were not of smooth muscle origin. All stained positively for S-100 and NSE. The ultrastructural features in the cases examined by electron microscopy were reminiscent of autonomic nerve structures normally present in the gastric wall. These included fine cytoplasmic processes of Schwann cells, wrapped with complete or incomplete basement membranes, and structures analogous to post-ganglionic neuroaxonal components. These tumours appear to represent a distinct type of gastric neoplasm originating from autonomic nerve elements in the stomach wall. They are different from previously described schwannomas or neurofibromas. In some of the tumours, identifiably neural elements are relatively a minor component, and the majority of the tumour cells are of undetermined origin. It is suggested that these cells may be poorly differentiated, lacking their antigenic determinants specific to neural differentiation.     

Mast cell and lymphoreticular infiltrates in neurofibromas. Comparison with nerve sheath tumors

Cellular heterogeneity produced by non-Schwannian elements may distinguish neurofibromas from other Schwann cell neoplasma and contribute to a different tumor biology. The present study compared cell counts of mast cells, T and B lymphocytes, and macrophages in 32 neurofibromas with those in 27 schwannomas, 9 malignant nerve sheath tumors, and 17 traumatic neuromas. Immunohistochemical and histochemical analyses were performed on formalin-fixed, paraffin-embedded tissues using two monoclonal antibodies against B-lymphocyte epitopes (LN-1 and LN-2), one monoclonal antibody against T-lymphocyte epitopes (UCHL-1), one polyclonal antibody recognizing alpha 1-antichymotrypsin (ACT), a macrophage/histiocytemarker, and toluidine blue O stains. Neurofibromas contained relatively high concentrations of mast cells significantly greater than the concentrations in other neoplastic or reactive nerve sheath tumors. Most neurofibromas also displayed moderate concentrations of LN-2 immunoreactive cells, similar to the concentrations in traumatic neuromas and not statistically different from cell counts in other tumor types. Limited, variable LN-1 and UCHL-1 immunoreactive infiltrates were detected in neurofibromas and some peripheral schwannomas. Rare or moderate ACT immunoreactivity was detected in the majority of neurofibromas, in contrast with the absence, or rare appearance, of ACT immunostaining in cranial and peripheral nerve schwannomas and moderate numbers of immunoreactive cells in many malignant nerve sheath tumors. Mast cells are an important cellular marker of neurofibromas and may participate in the pathogenesis of these neoplasms.     

Malignant peripheral nerve sheath tumor: pathology and genetics

Malignant peripheral nerve sheath tumors are soft tissue neoplasms that show differentiation toward cells of the nerve sheath. They often arise from peripheral nerves or preexisting benign nerve sheath tumors and are generally high-grade neoplasms, which behave aggressively with high incidence of distant metastases. Malignant peripheral nerve sheath tumor can be histologically diverse and is difficult to diagnose because of its morphological overlap with a variety of other sarcomas and its lack of specific immunohistochemical markers or genetic profile. We review the pathology of malignant peripheral nerve sheath tumor, with reference to etiology, molecular genetics, and clinical factors.     

An update on cutaneous tumours with neural differentiation

Cutaneous peripheral nerve sheath tumours are diverse proliferations of neuroectodermal origin ranging from benign, atypical to clearly malignant. In this update we review the clinico-pathological features supplemented by recent molecular genetic data of a variety of peripheral nerve sheath tumours arising primarily in the skin, including epithelial sheath neuroma, nerve sheath myxoma, schwannoma variants, neurofibroma variants, hybrid tumours, perineurioma, malignant melanotic schwannian tumour and malignant peripheral nerve sheath tumour (classical and epithelioid). Particular emphasis is also given to the differential diagnosis of these proliferations.     

Primary sarcomas of the lung: a clinicopathological and immunohistochemical study of 14 cases

The clinicopathological features and immunohistochemical findings in 14 primary sarcomas of the lung collected over a 30-year-period are presented. This represents one sarcoma per 550 bronchogenic carcinomas undergoing resection in this centre. The study group comprised six leiomyosarcomas, five malignant peripheral nerve sheath tumours, two haemangiopericytomas and one epithelioid haemangioendothelioma. The majority of cases occurred in men (nine males: five females), with mean age at presentation of 54 years for men and 47 years for women. All leiomyosarcomas were seen in men, whereas malignant peripheral nerve sheath tumours showed no particular sex preponderance. Leiomyosarcomas were larger tumours than malignant peripheral nerve sheath tumours, mean tumour diameter 15 cm (range 10–25 cm) compared to 9.5 cm (7–15 cm), respectively. All leiomyosarcomas were situated intraparenchymally whereas two of the five malignant peripheral nerve sheath tumours were endobronchial in site. Extrathoracic metastates were seen at death in two of the six leiomyosarcomas but not in any of the malignant peripheral nerve sheath tumours. Overall survival was 28 months although for the leiomyosarcoma/malignant peripheral nerve sheath tumour group alone survival was 8 months. Tumour grading appeared to be a more useful prognostic factor than tumour site (endobronchial/parenchymal) or tumour size. Haemangiopericytoma and epithelioid haemangioendothelioma were associated with a more favourable prognosis.     

Peripheral nerve sheath tumours--a short series with some uncommon variants

Peripheral nerve sheath tumours are rarely malignant (0.001%), such malignant peripheral nerve sheath tumours (MPNST) are more common in upper extremities than in head and neck. Chondroid differentiation in benign peripheral nerve sheath tumours and melanotic schwannoma are very uncommon. In a retrospective analysis of 25 peripheral nerve sheath tumours over a period of two years, we reported two MPNST one of which was in a parapharyngeal location while the other MPNST showed melanotic differentiation. Similar melanotic differentiation was also seen in another benign melanotic schwannoma. Chondroid differentiation in a schwannoma was also observed which is usually documented in MPNST.     

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.     

Primary pulmonary tumours of nerve sheath origin

Primary intrapulmonary tumours of nerve sheath origin are extremely rare. We describe the clinicopathological features of four such peripheral nerve sheath tumours, two benign and two malignant. Of the benign tumours, one was a typical schwannoma and the other an ancient or degenerated schwannoma. The typical schwannoma was endobronchial in origin, diagnosis being established by small bronchoscopic biopsy. The histological diagnosis of malignant peripheral nerve sheath tumour required immunohistochemical and/or ultrastructural evidence of nerve sheath differentiation. One malignant tumour arose in a patient with Von-Recklinghausen's disease. Both malignant tumours behaved aggressively with the development of multiple intrapulmonary metastases, despite the markedly different histological appearance of the two tumours. Flow cytometric analysis of nuclear DNA content was performed on the four tumours, all of which showed a diploid DNA profile.     

Genome‐wide transcriptome analyses reveal p53 inactivation mediated loss of miR‐34a expression in malignant peripheral nerve sheath tumours

Malignant peripheral nerve sheath tumours (MPNSTs) are aggressive soft tissue tumours that occur either sporadically or in patients with neurofibromatosis type 1. The malignant transformation of the benign neurofibroma to MPNST is incompletely understood at the molecular level. We have determined the gene expression signature for benign and malignant PNSTs and found that the major trend in malignant transformation from neurofibroma to MPNST consists of the loss of expression of a large number of genes, rather than widespread increase in gene expression. Relatively few genes are expressed at higher levels in MPNSTs and these include genes involved in cell proliferation and genes implicated in tumour metastasis. In addition, a gene expression signature indicating p53 inactivation is seen in the majority of MPNSTs. Subsequent microRNA profiling of benign and malignant PNSTs indicated a relative down‐regulation of miR‐34a in most MPNSTs compared to neurofibromas. In vitro studies using the cell lines MPNST‐14 (NF1 mutant) and MPNST‐724 (from a non‐NF1 individual) show that exogenous expression of p53 or miR‐34a promotes apoptotic cell death. In addition, exogenous expression of p53 in MPNST cells induces miR‐34a and other miRNAs. Our data show that p53 inactivation and subsequent loss of expression of miR‐34a may significantly contribute to the MPNST development. Collectively, our findings suggest that deregulation of miRNAs has a potential role in the malignant transformation process in peripheral nerve sheath tumours. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Reticular and plexiform perineurioma: clinicopathological and immunohistochemical analysis of two cases and review of perineurial neoplasms of skin and soft tissues

Perineurioma represents a recently described and relatively rare neoplasm in the spectrum of benign peripheral nerve sheath tumours composed of perineurial cells staining immunohistochemically positive for epithelial membrane antigen (EMA). In addition to intraneural, extraneural and sclerosing perineurioma, rare variants of perineurioma may occur, and their knowledge is important in the differential diagnosis of mesenchymal tumours of different lines of differentiation and clinically more aggressive neoplasms. We present a case of deep-seated reticular perineurioma arising on the upper arm of a 34-year-old female and a case of a dermal plexiform perineurioma arising on the lower lip of a 60-year-old female. The diagnosis was confirmed in both cases immunohistochemically; neoplastic cells stained positively for EMA and for the newly described perineurial markers, claudin-1 and glut-1. The morphological spectrum and the differential diagnosis of perineurial neoplasms of skin and soft tissues are discussed.     

Intra-abdominal spindle cell lesions: a review and practical aids to diagnosis

Intra-abdominal spindle cell lesions are uncommon and often present a diagnostic challenge. An important group of such lesions are the gastrointestinal stromal tumours. Other intra-abdominal spindle cell lesions include fibromatosis, various sarcomas-in particular, leiomyosarcoma, liposarcoma, and malignant peripheral nerve sheath tumour-and, in women, endometrial stromal sarcoma. Less common lesions are inflammatory myofibroblastic tumours, the mesenteric spindle cell reactive lesions, retroperitoneal fibrosis, and solitary fibrous tumour. A variety of intra-abdominal tumours of nonmesenchymal origin may have a spindle cell/sarcomatoid morphology; these include sarcomatoid carcinoma, malignant melanoma and, in women, sarcomatoid granulosa cell tumour. Finally, metastatic sarcomas from pelvic or extra-abdominal organs need also be considered. A set of practical aids to the diagnosis of intra-abdominal spindle cell lesions is presented to assist pathologists dealing with such lesions, particularly with regards to the consideration of differential diagnoses.