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Epithelioid malignant peripheral nerve sheath tumor (MPNST) is a rare subtype of MPNST composed of epithelioid cells with abundant cytoplasm. Currently, strong and diffuse immunostaining for S100 protein and SOX10 is generally regarded as a characteristic feature of epithelioid MPNST. However, malignant tumors with epithelioid morphology that arise from a peripheral nerve or a pre-existing benign nerve sheath tumor should be regarded as epithelioid MPNSTs when they do not show characteristic features that definitively lead to other specific diagnoses. Here, we describe 3 cases of epithelioid MPNST in the peripheral nerve or schwannoma that was negative for S100 protein and SOX10 expression. Instead, these tumors were positive for EMA, GLUT1, claudin 1, and cytokeratin to varying degrees, while all of them retained SMARCB1 and H3K27me3 by immunohistochemistry. EMA, GLUT1, and claudin 1 are known markers of perineurial cell differentiation; thus, they could possibly represent epithelioid MPNST with perineurial cell differentiation.

BackgroundIn temporal arteries (TAs) from patients with giant cell arteritis, varicella zoster virus (VZV) is seen in perineurial cells that surround adventitial nerve bundles and form the peripheral nerve-extrafascicular tissue barrier (perineurium). We hypothesized that during VZV reactivation from ganglia, virus travels transaxonally and disrupts the perineurium to infect surrounding cells.MethodsMock- and VZV-infected primary human perineurial cells (HPNCs) were examined for alterations in claudin-1, E-cadherin, and N-cadherin. Conditioned supernatant was analyzed for a soluble factor(s) mediating these alterations and for the ability to increase cell migration. To corroborate in vitro findings, a VZV-infected TA was examined.ResultsIn VZV-infected HPNCs, claudin-1 redistributed to the nucleus; E-cadherin was lost and N-cadherin gained, with similar changes seen in VZV-infected perineurial cells in a TA. VZV-conditioned supernatant contained increased interleukin 6 (IL-6) that induced E-cadherin loss and N-cadherin gain and increased cell migration when added to uninfected HPNCs; anti-IL-6 receptor antibody prevented these changes.ConclusionsIL-6 secreted from VZV-infected HPNCs facilitated changes in E- and N-cadherin expression and cell migration, reminiscent of an epithelial-to-mesenchymal cell transition, potentially contributing to loss of perineurial cell barrier integrity and viral spread. Importantly, an anti-IL-6 receptor antibody prevented virus-induced perineurial cell disruption.

Hypomyelination, a neurological condition characterized by decreased production of myelin sheets by glial cells, often has no known etiology. Elucidating the genetic causes of hypomyelination provides a better understanding of myelination, as well as means to diagnose, council, and treat patients. Here, we present evidence that YIPPEE LIKE 3 (YPEL3), a gene whose developmental role was previously unknown, is required for central and peripheral glial cell development. We identified a child with a constellation of clinical features including cerebral hypomyelination, abnormal peripheral nerve conduction, hypotonia, areflexia, and hypertrophic peripheral nerves. Exome and genome sequencing revealed a de novo mutation that creates a frameshift in the open reading frame of YPEL3, leading to an early stop codon. We used zebrafish as a model system to validate that YPEL3 mutations are causative of neuropathy. We found that ypel3 is expressed in the zebrafish central and peripheral nervous system. Using CRISPR/Cas9 technology, we created zebrafish mutants carrying a genomic lesion similar to that of the patient. Our analysis revealed that Ypel3 is required for development of oligodendrocyte precursor cells, timely exit of the perineurial glial precursors from the central nervous system (CNS), formation of the perineurium, and Schwann cell maturation. Consistent with these observations, zebrafish ypel3 mutants have metabolomic signatures characteristic of oligodendrocyte and Schwann cell differentiation defects, show decreased levels of Myelin basic protein in the central and peripheral nervous system, and develop defasciculated peripheral nerves. Locomotion defects were observed in adult zebrafish ypel3 mutants. These studies demonstrate that Ypel3 is a novel gene required for perineurial cell development and glial myelination., Author summary The study of congenital rare diseases allows the identification of new gene variants involved in development. Genetic and sequence analysis of a patient with a novel complex phenotype including hypomyelination, enlarged peripheral nerves, and motor defects implicated a de novo mutation in the YPEL3 gene as potentially causative. YPEL3 had not previously been associated with disease. Using CRISPR technology, we created a zebrafish model carrying a DNA lesion similar to that of the affected patient. Homozygous mutant embryos display weak and variable peripheral nerve phenotypes and are viable. Because ypel3 transcripts are present from fertilization, we generated maternal zygotic mutants. Analysis of these mutants revealed hypomyelination, defective axonal wrapping, and swimming defects. Time-lapse video lineage analysis showed that ypel3 is required for proper development of oligodendrocytes, Schwann cells, and perineurial cells. These results identify YPEL3 as a new regulator of glial cell development and support the conclusion that the de novo YPEL3 mutation is responsible for the patient’s disease.

Made available in DSpace on 2022-04-28T19:41:32Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-10-22 Individuals with orofacial asymmetry due to mucosal overgrowths, ipsilateral bone and dental aberrations with perineurial hyperplasia and/or perineuriomatous pseudo-onion bulb proliferations, comprise a recognizable clinical entity. In this article, we describe three individuals with this clinical entity and mosaic PIK3CA variants c.3140A>G (p. His1047Arg), c.328_330delGAA (p. Glu110del), and c.1353_1364del (p.Glu453_Leu456del). We conclude that the identification of these mosaic variants in individuals with orofacial asymmetry presenting histopathologically perineurial hyperplasia and/or intraneural pseudo-onion bulb perineurial cell proliferations supports the inclusion of this clinical entity in the PIK3CA-related overgrowth spectrum. Division of Oral and Maxillofacial Pathology University of Minnesota São Paulo State University (Unesp) Institute of Science and Technology, São José dos Campos King Saud University Medical Genomics and Metabolic Genetics Branch National Human Genome Research Institute Genetic Diagnostic Laboratory University of Pennsylvania Perelman School of Medicine São Paulo State University (Unesp) Institute of Science and Technology, São José dos Campos

Background Molecular composition and topography of the extracellular matrix (ECM) influence regenerative cell migration following peripheral nerve injury (PNI). Advanced tissue engineering strategies for the repair of neurotmesis-type PNI include the development of nanofiber-containing implantable scaffolds that mimic features of the ECM to orchestrate regenerative growth. Reliable and quantifiable in vitro assays are required to assess the ability of such substrates to influence migration of the cell types of interest. However, most popular migration assays monitor cell migration into a cell exclusion zone (CEZ) but have dubious abilities to preserve the molecular and topographical cues of the substrate. New method Elastic band spacers (EBS), a simple, economical and standardized technique for the generation of well-defined CEZ based on the use of commercially available elastic bands, are introduced. Results EBS could sufficiently preserve ECM-derived molecular and poly(e-caprolactone) (PCL) nanofiber-derived topographical cues. The application of EBS in the absence and presence of nanofiber-derived topographical cues was validated using perineurial cells and Schwann cells, both known to play key roles in peripheral nerve regeneration. Comparison with existing methods In contrast to EBS, commercial silicone inserts and the popular scratch assay caused substantial ECM substrate disruption, thereby preventing these techniques from being included in further investigations employing deposition of PCL nanofibers and cell migration analysis. Conclusions EBS represent a useful addition to the existing repertoire of migration assays offering significant benefits in terms of substrate preservation. The simplicity and economy of the approach make it immediately accessible to research groups at minimal extra expense.

Hybrid peripheral nerve sheath tumors (PNSTs), which show hybrid features of more than one cell type normally found in a peripheral nerve sheath, are recently recognized clinical entities. Various composite tumors have been reported; however, granular cell tumor/perineurioma is a rare combination [1-4]. Since perineurial cells may be found in other types of PNSTs, it is important to determine if those are reactive, remnantal, or true neoplastic when a perineurial component of the PNST is identified. Main differential diagnoses include granular perineurioma and granular cell tumor with reactive perineurial cell hyperplasia, which show a lack of immunopositivity for S-100 in the granular cells and prominent perineurial cell proliferation throughout the tumor, respectively.

Colorectal perineuriomas are characterized by a mucosal proliferation of benign stromal cells expressing perineurial markers leading to separation and/or disorganization of the crypts that frequently display a serrated/hyperplastic architecture. Previous studies demonstrated a high prevalence of a BRAF p.V600E mutation in perineuriomas with serrated crypts and suggested that perineuriomas without crypt serration may represent an unrelated, different type of polyp. Yet, these molecular analyses included only 2 cases of perineuriomas without crypt serration. In fact, no previous studies can be found in the literature that have separately analyzed serrated and nonserrated perineuriomas and made a comparison between them. We retrospectively evaluated the clinical, histologic, immunohistochemical, and molecular features of 15 perineuriomas without and 45 with crypt serration (NSPs and SPs, respectively). No significant differences were found between the groups with regard to sex, age, location, and size. Histologically, the perineurial proliferation in SPs and NSPs demonstrated similar features with fascicles or bundles of bland, plump spindle cells surrounding and separating the crypts. All lesions showed expression with at least 2 of 4 perineurial cell markers (epithelial membrane antigen, claudin-1, GLUT-1, and collagen type IV). Molecular analysis performed in 20 cases (8 SPs and 12 NSPs) identified BRAF mutation of codon 600 in 5 (62%) SPs including 3 with p.V600E (c.1799T>A) and 2 with p.V600R (c.GT1798_99GT>AG). In contrast, no case of NSPs harbored BRAF mutations (p value 0.004). Our findings confirm that BRAF mutations originate in the serrated epithelium of SPs and demonstrate that SPs and NSPs have similar clinical and endoscopic characteristics and similar stroma, suggesting that they might represent 2 variants of a single lesion.

A 55-year-old man with typical clinical and electrodiagnostic findings of carpal tunnel syndrome complained of progression of his symptoms. Since repeated surgical interventions did not provide any relief, sonographic examination was performed and depicted a massive median nerve enlargement with hyperechoic perineurial tissue (figure, A). Beyond postoperative perineural fibrosis, the findings were suspicious for an underlying tumor. MRI revealed a tumorous nerve swelling and surgical neurolysis of hypertrophic fascicles followed (figure, B and C). Histopathology confirmed the diagnosis of intraneural perineurioma, a rare, benign, slow-growing peripheral nerve sheath tumor of perineurial cell origin (figure, D and E).1 Nerve sonography is recommended in therapy-refractory cases, as it might uncover unusual causes of entrapment syndromes.2

Soft tissue neoplasms with features of both schwannoma and perineurioma (hybrid schwannoma-perineurioma) have been increasingly recognized in recent years. To date, only a single case of this entity has been documented in the gastrointestinal tract (sigmoid colon). We herein describe 2 new cases of this entity. For comparison, we reevaluated 12 classic gastrointestinal schwannomas for the perineurial cell component. The 2 hybrid schwannoma-perineuriomas were detected incidentally in the gastric antrum and the vermiform appendix in a 50-year-old woman and a 17-year-old man during surgery for gastric GIST and appendicitis-like symptoms, respectively. None of the patients had neurofibromatosis 1 or 2. Patients were alive with no evidence of recurrence or new tumors at 8 and 12 months, respectively. The tumors measured 1.2 cm and 1.5 cm in size. Histologically, they showed prominent storiform, lamellar, and fascicular patterns. Notably, both lacked peripheral lymphoid cuffs and the trabecular pattern of gastrointestinal schwannomas. Both tumors coexpressed protein S100 (≥80%), CD34 (80%), and the perineurial cell markers (20% to 40% of tumor cells). The perineurial cell component formed alternating fascicles with S100-positive cells throughout the neoplasm. Reevaluation of 12 classic gastrointestinal schwannomas showed isolated claudin-1/epithelial membrane antigen-positive cells. However, 4 schwannomas (33%) strongly expressed glucose transporter-1 in most of the tumor cells indicating its limited specificity in this setting. Compared with gastrointestinal schwannomas, CD34 expression was stronger and more diffuse in hybrid schwannoma-perineuriomas. We conclude that hybrid schwannoma-perineuriomas are distinct from gastrointestinal schwannoma, both histologically and immunohistochemically.

Intraneural perineurioma is a benign peripheral nerve sheath tumor of perineurial cell origin. We present the case of an intraneural perineurioma of the median nerve in a 23-year-old woman which posed a diagnostic challenge. Ultrasonography was found to be a quick, easy, and effective screening tool for identifying the source of the deficit followed by MRI to further elucidate the lesion. We discuss surgical management options for optimizing functional outcomes when addressing such lesions.

An intraneural perineurioma arising in the tongue of a 34-year-old woman is presented. Histologically, the tumor was composed of numerous pseudo-onion bulb structures, formed by whorled proliferation of spindle cells around axons. Immunohistochemically, the spindle cells were positive for epithelial membrane antigen (EMA) but negative for S-100 protein, indicating that the tumors cells were derived from perineurial cells.

A 5-year-old National Show horse mare presented with a soft mass on the left dorsolateral aspect of the tongue. Over the next 2 years, the mare developed numerous, similar, coalescing masses that extended along the left dorsolateral aspect to the tip of the tongue. Microscopically, the bases for these masses were slender, fusiform, mesenchymal cells that formed compact whorls around myelinated and unmyelinated nerves. These cells were labeled by antibodies directed against vimentin but not by S-100. Ultrastructurally, multiple, concentrically arranged, long, slender cell processes, with discontinuous external laminae and many pinocytotic vesicles, helped to accurately phenotype the proliferative element. Whether this unusual perineurial cell proliferative disorder is neoplastic or not remained a matter of conjecture.

Cutaneous neurofibromas consist of axonal processes, Schwann cells, fibroblasts, perineurial cells, mast cells, and abundant extracellular matrix. The distribution and role of perineurial cells in neurofibromas has been uncertain, partly because there has not been a specific immunohistochemical marker for perineurial cells. In this study, tight junctions (TJs) of 16 neurofibromas from 12 patients with neurofibromatosis type 1 (NF1) were analyzed using electron microscopy, immunohistochemistry, and Western transfer analysis. Cell-cell contacts with typical ultrastructural morphology of TJs were seen between adjacent perineurial cells surrounding the small nerves and between contacting perineurial cell processes embedded in tumor stroma. Immunohistochemistry showed expression of claudin-1, claudin-3, and ZO-1 in the intercellular junctions of a subpopulation of tumor cells. Occludin was present mainly in perineurium and claudin-5 localized to the blood vessels. Double immunolabelings were used to identify the cell types expressing claudin-1. The results showed that claudin-1 positive cells were also positive for type IV collagen and epithelial membrane antigen but not for S-100 protein. This labeling pattern is consistent with perineurial cell phenotype. Using claudin-1 as a marker, our results showed that clusters of perineurial cells are distributed around the rudimentary nerves within cutaneous neurofibromas and at the periphery of some neurofibromas.

Intraneural perineurioma is an extremely rare condition characterized by perineurial cell proliferation within peripheral nerve (PN) sheaths. In the veterinary field, this entity has been reported only in a dog. We examined multiple enlargements of PNs in 11 chickens ( Gallus gallus domesticus) (9 Japanese bantams and 2 specific pathogen-free White Leghorn), which were inoculated with an avian leukosis virus (ALV) causing so-called fowl glioma. All chickens clinically exhibited progressive leg paralysis. Lumbosacral plexus, brachial plexus, and/or spinal ganglion were commonly affected, and these nerves contained a diffuse proliferation of spindle cells arranged concentrically in characteristic onion bulb-like structures surrounded by residual axons and myelin sheaths. The spindle cells were immunohistochemically negative for S-100α/β protein. Electron microscopy revealed that these cells were characterized by short bipolar cytoplasmic processes, occasional cytoplasmic pinocytotic vesicles, and discontinuous basal laminae. These features are consistent with those of intraneural perineurioma. Furthermore, the specific sequence of the ALV was detected in the PN lesions of 8/11 (73%) birds by polymerase chain reaction. These results indicate that the multiple intraneural perineuriomas of chicken may be associated with the ALV-A causing fowl glioma.

Aquaporin 1 (AQP1) is an isoform of membrane water channels. We examined the distribution of AQP1 in peripheral nerves. Immunofluorescence microscopy with specific antibodies to AQP1 was performed in the tissue sections of the rat tongue, esophagus, trachea, and sciatic nerve. AQP1 was present in the perineurium of nerve fiber bundles in the sciatic nerve and nerve fiber bundles in the tongue, esophagus, and trachea. Laser confocal microscopy of the double-labeled specimens for AQP1 and sugar transporter GLUT1 revealed that AQP1 was localized in the outer layer(s) of the perineurial cell layers, whereas GLUT1 was present throughout the entire perineurial cell layers. AQP1 and GLUT1 were also present in blood vessels inside the nerve fiber bundle. They were rarely found in the same blood vessels, namely, AQP1 was hardly detectable in GLUT1-positive blood vessels and GLUT1 was hardly detectable in AQP1-positive vessels. AQP1 in these sites of the blood-nerve barrier may participate in the water transfer across the barrier and contribute to the maintenance of the milieu of the nerve. In addition, we showed the presence of AQP1 in the perichondrium of the tracheal cartilage suggesting a possible role in water transfer between the cartilage and surrounding connective tissues.

The effect of nerve growth factor (NGF) on ontogenesis of frog mast cells was investigated in vivo by histochemical, morphometric, and ultrastructural analysis. Three groups of tadpoles at various stages of development were used. In the first group, the larvae received i.p. injections of 1 ng NGF/g; the second group received 10 ng NGF/g, while the control group received only the vehicle. The first recognizable mast cells arose symmetrically in the tongue at stage 26 of Witschi's standard table. At stages 26 and 29, the mast cell number in the NGF-injected tadpoles was significantly higher than the control group. From stage 29 onward, the mast cell number rapidly increased in all groups. No significant differences in mast cell number were observed between the control group and the NGF-injected groups at stages 31 and 33. Electron microscopy revealed that at metamorphic climax (stage 33), the mast cells in the NGF-treated groups were more mature than those in the control group. Therefore, nerve growth factor at early stages of tadpole development is likely to induce differentiation of mast cell precursors, while at later stages it is likely to induce maturation of immature mast cells. The close anatomical association between mast cells and perineurium, observed during nerve development, is intriguing. Already in the early stages of nerve development, the mast cells form a network around Schwann cell–axon complexes, together with the perineurial cells. At climax, the mast cells are located between the perineurial layers, suggesting that they may play a role in the tissue-nerve barrier of the perineurium. Nerve growth factor also seems to induce perineurial cell maturation. Microsc. Res. Tech. 62:439–450, 2003. © 2003 Wiley-Liss, Inc.

Background: Although benign tumors derived from the nerve sheath perineurial cell have been described from a variety of anatomic sites and are known to be a component of a number of benign neoplasms, malignant nerve sheath tumors of perineurial origin are exceedingly uncommon. Methods: We report an unusual case of a 70-year-old male who presented with a rapidly growing mass of the left arm, subsequently shown to be a malignant nerve sheath tumor with perineurial differentiation. A brief microscopic differential diagnosis and review of the literature are discussed. Results: Histologic sections show a partially circumscribed tumor of atypical spindle cells arranged in sweeping fascicles embedded in a myxoid matrix with focal whorling. Nuclear pleomorphism was evident among scattered typical and atypical mitotic figures (mean mitotic index of 7/10 high-power fields). The immunophenotypic profile consisted of only vimentin and epithelial membrane antigen (EMA) positivity, while antibodies to S-100, CD34, smooth muscle actin, and pankeratins were negative. Ultrastructural features included spindle cells with long cytoplasmic processes invested by interrupted basal lamina and pinocytotic vesicles, consistent with perineurial differentiation. Conclusions: While the histogenic source of the benign perineurioma, the perineurial cell has only rarely been described in conjunction with malignant tumors. All cases to date have shown EMA-positive and S-100-negative atypical spindled cells arranged in fascicles embedded in a myxoid matrix. In addition to immunohistochemistry, ultrastructural examination may be necessary to support the diagnosis. The diagnostic differential includes melanoma, spindle cell squamous cell carcinoma, atypical fibroxanthoma, leiomyosarcoma, and conventional malignant peripheral nerve sheath tumor, most commonly of Schwannian differentiation. Recognizing perineurial differentiation is important since few cases have been reported to date and the biological potential of these neoplasms is not known.

A case of dermatofibrosarcoma protuberans (DFSP) with epithelial membrane antigen (EMA)-positive cells is described. The tumor was excised from the left groin of a 28-year-old woman. It showed characteristic histologic features of DFSP with typical diffuse immunohistochemical positivity for CD34. Moreover, scattered neoplastic cells expressed EMA, suggesting perineural cell differentiation. Ultrastructural study found perineurial cell features, such as thin long bipolar cytoplasmic processes, pinocytotic vesicles, fragments of external lamina and/or external lamina-like material, attachment plaques, and desmosome-like junctions. This observation, together with previous immunohistochemical findings of EMA-positive cells in a subset of DFSPs, strongly suggests perineurial cell differentiation in these tumors. DFSP should be included in the differential diagnosis of EMA-positive spindle cell lesions of superficial soft tissue and skin.

The perineurium is composed of multiple concentric single-cell layers enclosing individual nerve fascicles. Each layer has a thickness equivalent to the width of a perineurial cell. Groups of these cells join by means of tight junctions and desmosomes to form layers that function as a barrier against diffusion of particles across them. Perineurial internal layers have more of these specialized unions among perineurial cells, which are proximal to nerve fascicles.

Among 99 cases of neurofibroma (NF), eight tumors (8%) contained epithelial membrane antigen (EMA)-positive perineurial cells inside the lesions. These cells were numerous and represented a significant part of the tumor cell population. In case 7, EMA-positive cells represented approximately half of the tumor. These patients' ages ranged from 23 to 73 years (average 51 years). Six patients were females and two were males. Neurofibromatosis type 1 was present in one case. The histological types of neurofibromas with EMA-positive cells were as follows: cutaneous, well-circumscribed, localized type in four cases; cutaneous diffuse type in one case; subcutaneous, well-circumscribed type in two cases; and subcutaneous plexiform type in one case. Perineurial cell differentiation was suspected by examining routinely stained sections in four cases; it was unsuspected in four cases. The perineurial cells were arranged in a pattern similar to that of "pure" perineurioma. They possessed thin bipolar processes and were arranged in laminar fascicles and whorls. In cellular areas, the cytoplasm was more eosinophilic and cell borders were poorly visible. In contrast, when the stroma was myxoid, it accentuated the shape of individual cells. As these morphological features of perineurial cell differentiation in NF are not entirely specific, EMA staining is recommended to prove the perineurial cell differentiation in neurofibromas. An additional immunohistochemical result of this study is the presence of numerous CD34-positive cells in all neurofibromas, which is similar to previous studies.

Aim: The relationship between perineurial collagen IV content and fascicle size was determined in diabetic and control human peripheral nerve. Methods and results Age-matched diabetic and control sural nerve samples were immunostained using antibodies to collagen IV. The number of cell layers and the perimeter of the fascicle were measured and the collagen IV content of the perineurium determined. Using this method, a comparison could be made of collagen IV content in the perineuria of fascicles of different size. A positive linear relationship was found between fascicle size and the amount of collagen IV per unit of perineurium. The number of perineurial cell layers and the collagen IV content of the diabetic nerve did not differ from control values. Conclusions The linear relationship between fascicle size and perineurial collagen IV content per unit of perineurium underlines the importance of taking fascicle size into account when determining changes in basement membrane components associated with neuropathy. The results indicate that increased deposition of collagen IV is not involved in the early changes in the perineurial cell basement membrane and is thus not the primary factor involved in altered nerve function associated with diabetic neuropathy.

We describe two examples of soft tissue perineurioma, a hard tumor, 1.7 cm in diameter, involving the dermis and superficial subcutaneous tissue of the left thumb, and the other a massive, lobulated lesion of the pelvis. Both occurred in 49-year-old men. Both were mobile and well demarcated but unencapsulated. Their cut surfaces were white and collagenous. Microscopically, each consisted of spindle-shaped or epithelioid tumor cells in a dense stroma of haphazardly oriented collagen bundles. Spindle-shaped cells were individually distributed, whereas epithelioid cells were often arranged in cords or clusters. Cytologic atypia was conspicuous in the massive tumor, but no mitotic activity was observed. Immunostains showed diffuse reactivity for vimentin, membrane pattern staining for epithelial membrane antigen and type IV collagen, as well as patchy CD34 reactivity. Stains for S-100 protein, Leu-7, smooth muscle actin, desmin, and cytokeratin were negative. Ultrastructural studies showed perineurial cell characteristics, including slender cytoplasmic processes, numerous pinocytotic vesicles, occasional tight junctions, and discontinuous surface basement membrane. Perineuriomas featuring marked stromal sclerosis often occur in the hands of young adults, as has recently been reported; the authors considered it a clinicopathologic variant. Herein we report two sclerotic perineuriomas, one a small tumor of the thumb and the other a centrally situated, massive pelvic tumor with sclerosis and degenerative cytologic atypia. We believe that exaggerated collagen deposition in perineuriomas, occasionally associated with degenerative nuclear changes, is not a manifestation of a unique, clinically relevant tumor variant but rather a manifestation of chronicity akin to that seen in “ancient schwannoma” and ‘atypical neurofibroma.’

The feasibility of peripheral nerve allograft pretreatment utilizing cold storage (5°C in the University of Wisconsin Cold Storage Solution) or freeze-thawing to prevent rejection was investigated. Regeneration across cold-stored (3 or 5 weeks) or freeze-thawed (FT), 3.0-cm sciatic nerve allografts were compared to fresh auto- and allografts in an inbred rat model. At 16-week post-engraftment, only FT allografts appeared similar to autografts on gross inspection; FT grafts were neither shrunken nor adherent to the surrounding tissue as seen in the other allograft groups. Qualitatively, the pattern of regeneration in the graft segments of the fresh allograft and to a lesser extent of pretreated allografts was inferior to that of autografts as evidenced by a disruption in the perineurium, more extrafascicular axons, smaller and fewer myelinated axons, increased intrafascicular collagen deposition, and the persistence of perineurial cell compartmentation and perivascular infiltrates. Distal to these grafts, the regeneration became more homogenous between groups, although areas of ongoing Wallerian degeneration, new regeneration as well as compartmentation, were more prevalent in fresh and pretreated allografts. Although the number of myelinated fibres was equivalent to autografts, the fibre diameters, the number of large diameter fibres, and the G-ratio were significantly decreased in the allograft groups, which, in part, accounted for the significant decrease in conduction velocity in the 3-week stored and fresh allograft, and the slight decrease in the 5-week stored and FT allograft groups. There was a small return in the Sciatic Function Index towards normal, but no consistent differences between groups were found. Prolonged cold storage and freeze-thawing of nerve allografts resulted in regeneration that was better than fresh allografts, but inferior to autografts. With the concomitant use of host immunosuppression or other immunotherapies, these storage techniques can provide a means of transporting nerve allografts between medical centres and for converting urgent into elective procedures.

Structural abnormalities of the perineurium from six spontaneously diabetic dogs (diabetes duration 4-8 years and six control animals were quantified using detailed electron microscopic morphometric methods on superficial peroneal nerve biopsy specimens. Total perineurial sheath thickness (microm) was significantly increased in diabetic (8.8+/-0.6) compared to control animals (6.2+/-0.3) (P < 0.02). This was attributed to a significant increase in the mean perineurial lamellar width in diabetic (0.49+/-0.03) compared to control (0.40+/-0.01) (P < 0.04) animals. The number of lamellae also showed a non-significant increase in diabetic animals (7.8+/-0.4) compared to controls (6.9+/-0.13) (P < 0.06). There was no change in the mean interlamellar space in diabetic (0.7+/-0.05) compared to control (0.6+/-0.06) (P = 0.15) animals. The total interlamellar space was increased in diabetic (5.7+/-0.5) compared to control (4.1+/-0.36) (P < 0.04) animals. The perineurial cell basement membrane thickness (nm) was significantly increased in diabetic (126.9+/-9.8) compared to control (62.8+/-6.1) (P < 0.005) animals. The current study has demonstrated significant abnormalities of the perineurium in the spontaneously diabetic dog, which may have relevance to the pathogenesis of diabetic neuropathy.

Observations have been made on the rabbit sciatic nerve distal to a transection, with survival periods of up to 26 mo and prevention of reinnervation. It was confirmed that the nerve becomes compartmented by fibroblast processes and that a zone of fine collagen fibrils develops around the Schwann cell columns that constitute the Büngner bands. The Schwann cells become progressively more atrophic but after 6 mo of denervation still expressed low affinity p75 nerve growth factor receptor (NGFR), the latest stage at which this was examined. NGFR was also expressed by the processes of the fibroblasts producing the endoneurial compartmentation. By 26 mo after transection the site of previous nerve fibres was indicated by sharply demarcated domains of approximately circular outline in transverse section consisting of densely packed longitudinally oriented collagen fibrils. Some of these domains still possessed centrally situated Schwann cells or residual basal lamina but many were acellular. The central collagen fibrils in these domains were of smaller diameter than those situated peripherally but were of larger size than those that form around the Büngner bands during wallerian degeneration. The peripherally located fibrils in the domains were of the same calibre as for normal endoneurial collagen. The collagen domains were encircled by fibroblast processes or at times enclosed in a perineurial cell ensheathment. Long-standing axonal loss therefore leads to a striking reorganisation of the internal architecture of peripheral nerve trunks. The findings may be relevant for the interpretation of the appearances in chronic peripheral neuropathies in man.

The authors report a malignant peripheral nerve sheath tumor (MPNST) that developed in the body of the pancreas of a 76-year-old woman. The well-demarcated tumor, 4.5 x 3.5 cm in size, was composed of spindle-shaped cells arranged in a storiform pattern or sweeping fascicles. Ultrastructurally, the tumor cells had elongated cytoplasmic processes with numerous pinocytotic vesicles, and were covered with discontinuous basal lamina-like substances. Immunohistochemically, tumor cells were diffusely positive for epithelial membrane antigen, vimentin, and CD34, but negative for S-100 protein and Leu 7. It was therefore concluded that the tumor was a MPNST with perineurial cell differentiation. Primary MPNST of the pancreas is extremely rare and the immunohistochemical and ultrastructural studies are necessary for its diagnosis.