Meissner Corpuscles Research Articles

Cutaneous somatic and autonomic nerve TDP-43 deposition in amyotrophic lateral sclerosis.

To evaluate the involvement of the sensory and autonomic nervous system in amyotrophic lateral sclerosis (ALS) and to determine whether TDP-43/pTDP-43 deposits in skin nerve fibers signify a valuable biomarker for ALS. Eighteen patients with ALS and 18 age- and sex-matched control subjects underwent physical examinations, in addition to donating skin biopsies from the distal leg. The density of epidermal, Meissner's corpuscle (MC), sudomotor, and pilomotor nerve fibers were measured. Confocal microscopy was used to determine the cutaneous somatic and autonomic nerve fiber density and TDP-43/pTDP-43 deposition. Intraepidermal nerve fiber density (IENFD) was reduced in individuals with ALS (P < 0.001). MC density (MCD) (P = 0.001), sweat gland nerve fiber density (SGNFD) (P < 0.001), and pilomotor nerve fiber density (PNFD) (P < 0.001) were all reduced in ALS patients. The SGNFD correlated with the small-fiber neuropathy Symptoms Inventory Questionnaire (SFN-SIQ), VAS and age. The SFN-SIQ was higher in ALS with sensory symptoms than without sensory symptoms (P = 0.000). Furthermore, the SFN-SIQ was higher in ALS with autonomic symptoms than without autonomic symptoms (P = 0.002). SFN-SIQ was higher in ALS patients that were pTDP-43 positive than pTDP-43 negative (P = 0.04), respectively. We established in the peripheral nervous system that higher SFN-SIQ and VAS was involved in ALS, indicating the loss of SGNF. The deposition of TDP-43/pTDP-43 in ALS nerve fibers may indicate an important role in the underlying pathogenesis of ALS. This observation might be used as a potential biomarker for diagnosing ALS.

Exploring of the Unpredicted Effects of Olfactory Network Injuries on Mammary Gland Degeneration: A Preliminary Experimental Study

ABSTRACTPurpose of the study: Hypofunctioning breasts are typically considered a dysfunction of higher brain centers that regulate hormonal feedback, and olfactory information has been proposed as a triggering factor for lactation in the maternal body. However, there are no substantive studies regarding whether olfaction disorders and/or loss of olfactory sense may result in breast gland atrophy by causing diminished olfactory stimulation. To fill this gap in the literature, we studied the histologic features of breast glands as a sample model in animals that had undergone an olfactory bulb lesion (OBL). Materials and methods: This study was conducted on 22 rats. Six, eight, and six of them were used as control, SHAM, and OBL groups, respectively. After 10 weeks, the animals were decapitated. Olfactory bulbs and breast glands were stained with Hematoxylin-eosin and tunnel dye. Specimens were analyzed stereologically to evaluate the loss in volume of the olfactory bulbs, total breast follicle volume (TBFV) and Meissner's corpuscles per cubic centimeter, and these two senior metrics were compared with each other statistically. Results: Olfactory bulb volume loss and breast gland atrophy were both detected in study group. Mean TBFV and OB volumes were measured as: (296 ± 89) × 106 µm3/cm3 and 4.43 ± 0.98 mm3 in control (Group I); (264 ± 63) × 106 µm3/cm3 and 3.86 ± 0.81 mm3 in SHAM (Group II) and (194 ± 52) × 106 µm3/cm3 and 1.52 ± 0.36 mm3 in OBL group (Group III). It was noted that the TBFV was significantly diminished, with apoptotic degradation in the olfactory bulbs and breast glands of OBL-applied animals (p < 0.001). Conclusion: It seems that diminished milk secretion is attributable to the degradation of breast glands that results from olfaction loss in OBL animals.

85. Digital acuity measured by “the bumps” device correlates with degeneration of digital mechanoreceptors in peripheral neuropathies

“The bumps” is a sensitive test to quantify tactile threshold of fingerpads. We tested its ability to detect distal axonal degeneration in peripheral neuropathies. The bumps device is a checkerboard-like surface divided into squares. Each square includes 5 colored circles, one of which contains a round bump (height range 2.5–14 μm) to identify using the fingerpad. For each subject, we defined the height of the lowest bump such that it and the next 2 highest were detected. Functional data were compared to the density of Meissner corpuscles (MC) in fingertip skin biopsies processed and quantified according to standard procedures. Study population included 86 subjects (M/F = 51/35; age = 52.3 ± 15.1) affected by peripheral neuropathy and 15 subjects (M/F = 9/6; age = 50.4 ± 13.9) affected by CNS pathology as control group. Average threshold in the neuropathy group was 7.0 ± 4.4 μm, average MC density was 9.3 ± 7.3/mm2. Average threshold in the CNS pathology group was 7.4 ± 5.1 μm and average density of MC was 10.5 ± 6.8/mm2. Digital acuity threshold correlated with the density of Meissner corpuscles in the neuropathy group (r = 0.353; p < 0.01), but not in the CNS pathology group (r = 0.048; p = 0.865). The Bumps is a sensitive and easy-to-use tool, suitable to detect degeneration of sensory endings in peripheral neuropathies.

Merkel cells and Meissner's corpuscles in human digital skin display Piezo2 immunoreactivity.

The transformation of mechanical energy into electrical signals is the first step in mechanotransduction in the peripheral sensory nervous system and relies on the presence of mechanically gated ion channels within specialized sensory organs called mechanoreceptors. Piezo2 is a vertebrate stretch-gated ion channel necessary for mechanosensitive channels in mammalian cells. Functionally, it is related to light touch, which has been detected in murine cutaneous Merkel cell-neurite complexes, Meissner-like corpuscles andlanceolate nerve endings. To the best of our knowledge, the occurrence of Piezo2 in human cutaneous mechanoreceptors has never been investigated. Here, we used simple and double immunohistochemistry toinvestigate the occurrence of Piezo2 in human digital glabrous skin. Piezo2 immunoreactivity was detected in approximately 80% of morphologically and immunohistochemically characterized (cytokeratin 20+ , chromogranin A+ and synaptophisin+ ) Merkel cells. Most of them were in close contact with Piezo2- nerve fibre profiles. Moreover, the axon, but not the lamellar cells, of Meissner's corpuscles was also Piezo2+ , but other mechanoreceptors, i.e. Pacinian or Ruffini's corpuscles, were devoid of immunoreactivity. Piezo2 was also observed in non-nervous tissue, especially the basal keratinocytes, endothelial cells and sweat glands. The present results demonstrate the occurrence of Piezo2 in cutaneous sensory nerve formations that functionally work as slowly adapting (Merkel cells) and rapidly adapting (Meissner's corpuscles) low-threshold mechanoreceptors and are related to fine and discriminative touch but not to vibration or hard touch. These data offer additional insight into the molecular basis of mechanosensing in humans.

Loss of cutaneous large and small fibers in naive and l-dopa-treated PD patients.

To study small and large fiber pathology in drug-naive and l-dopa-treated patients affected by Parkinson disease (PD) in early phases, before the occurrence of neuropathic electrophysiologic abnormalities. We enrolled 85 patients with idiopathic PD (male/female 49/36, age 61.3 ± 9.7 years) without electrophysiologic signs of neuropathy, including 48 participants naive to l-dopa treatment. All patients underwent clinical, functional, and morphologic assessment of sensory and autonomic nerves through dedicated questionnaires, quantitative sensory testing, sympathetic skin response, dynamic sweat test, and punch biopsies from glabrous and hairy skin. Sensory and autonomic innervation was visualized with specific antibodies and analyzed by confocal microscopy. Data were compared with those obtained from sex- and age-comparable healthy controls. In 35 patients, skin biopsies were performed bilaterally to evaluate side-to-side differences. Intraepidermal nerve fiber density was lower in patients compared to controls in all the examined sites (p < 0.001). The loss was higher in the more affected side (p < 0.01). A loss of autonomic nerves to vessels, sweat glands, and arrector pili muscles and of Meissner corpuscles and their myelinated endings in glabrous skin was found (p < 0.001). Patients showed increased tactile and thermal thresholds, impairment of mechanical pain perception, and reduced sweat output (p < 0.001). The naive and l-dopa-treated groups differed only for Meissner corpuscle density (p < 0.001). Both large and small fiber pathology occurs in the early stages of PD and may account for the sensory and autonomic impairment. l-Dopa affects the 2 populations of fibers differently.

In-vivo reflectance confocal microscopy of Meissner's corpuscles in diabetic distal symmetric polyneuropathy

ObjectiveTo evaluate in-vivo reflectance confocal microscopy (RCM) of Meissner's corpuscles (MC) in diabetic distal symmetric polyneuropathy (DSP). MethodsForty-three adults with diabetes and 21 control subjects underwent RCM of MC density at the fingertip of digit V, thenar eminence (TE), and arch of the foot, ankle skin biopsy for epidermal nerve fiber density (ENFD), electrophysiological studies, monofilament threshold testing, and timed vibration at the toe. Subjects with diabetes were subdivided into groups with and without clinical DSP using the American Academy of Neurology (AAN) case definition and neuropathy outcomes were compared across groups. ResultsBoth diabetic groups (with and without AAN clinical DSP criteria) had objective evidence of peripheral sensory involvement using conventional sensory measures, although those with clinical DSP criteria had greater abnormalities. MC densities were lower in the entire diabetic group at the TE and digit V relative to controls. MC densities at all imaging sites were associated with corresponding conventional sensory measures. MC densities were reduced in subjects without AAN clinical DSP criteria at the TE and digit V compared to controls whereas conventional upper limb sensory measures did not differ between these groups. ConclusionsIn-vivo RCM of MC density at digit V is a non-invasive, painless, objective marker in diabetes that offers a window into early large fiber sensory nerve terminal loss. Further studies are needed to determine whether RCM of MCs can identify quantitative changes in DSP associated with disease progression or treatment.

Human Digital Meissner Corpuscles Display Immunoreactivity for the Multifunctional Ion Channels Trpc6 and Trpv4.

Ion channels are at the basis of the sensory processes including mechanosensing. Some members of the transient receptor potential (TRP) ion channel superfamily have been proposed as mechanosensors, but their putative role in mechanotransduction is controversial. Among them there are TRP canonical 6 (TRPC6) and TRP vanilloid 4 (TRPV4) ion channels, which are known to cooperate in mechanical hyperalgesia. Here, we investigated the occurrence, distribution, and possible colocalization of TRPC6 and TRPV4 in human digital Meissner sensory corpuscles using immunohistochemistry and double immunofluorescence (associate with markers for specific corpuscular constituents). TRPC6 immunoreactivity was restricted to the axon of Meissner corpuscles, whereas TRPV4 was detected in the axon but also in the lamellar cells. Moreover, axonal colocalization of TRPV4 and TRPC6 was found in the digital Meissner corpuscles. Present results demonstrate for the first time the occurrence and colocalization of two ion channels candidates to mechanosensors in human cutaneous mechanoreceptors. The functional significance of these ion channels in that place remains to be clarified, but should be related to different properties of mechanosensitivity. Anat Rec, 300:1022-1031, 2017. © 2016 Wiley Periodicals, Inc.

Immunoreactivity to Meissner corpuscles and dermal nerves in a bullous arthropod bite reaction

Immunoreactivity to Meissner corpuscles and dermal nerves in a bullous arthropod bite reaction

Peripheral neuropathic changes in pachyonychia congenita.

We compared patterns of intraepidermal nerve fibers and mechanoreceptors from affected and unaffected plantar skin from patients with pachyonychia congenita (PC) and control subjects. Plantar biopsies from 10 genetically confirmed patients with PC (with a mutation in KRT6A) were performed at the ball of the foot (affected skin) and the arch (unaffected) and were compared to biopsies from corresponding locations in 10 control subjects. Tissue was processed to visualize intraepidermal nerve fibers (IENF) (PGP9.5), subsets of IENF (CGRP, substance P, tyrosine hydroxylase), myelinated nerve fiber (neurofilament H, NFH), blood vessels (CD31), Meissner corpuscles, and Merkel cells (MCs). Structures were quantified using stereology or validated quantification methods. We observed that PC-affected plantar skin had significantly lower sweat gland innervation (sweat gland nerve fiber density) and reduced numbers of Meissner corpuscles compared to PC-unaffected or anatomically matched control skin. In contrast, Merkel cell densities and blood vessel counts were higher in PC-affected skin compared to either control or PC-unaffected skin. There were no differences in myelinated nerve fiber densities, SP, or CGRP between the groups. Pressure pain thresholds in PC-affected skin were lower compared to PC-unaffected and anatomically matched control skin. Additionally, MC densities in callused plantar skin from healthy runners with callus and one subject with a nonpainful palmoplantar keratoderma (AQP5 mutation) were similar to PC-unaffected and control skin consistent with callus alone not being sufficient to increase MC number. These findings suggest that alterations in PC extend beyond keratinocytes and may provide strategies to study neuropathic pain in PC.

47. Early sensory and autonomic involvement in drug-naive Parkinson

Small fiber pathology has been demonstrated in Parkinson Disease (PD). To verify if it is among the early non-motor features of PD, unrelated to Levodopa therapy, we assessed function and morphology of cutaneous sensory and autonomic nerves in 32 consecutive drug-naive PD patients (M/F = 16/16; age 57.3 ± 11.1 years) and 64 age and sex matched controls. Fifty-micron-thick sections of skin samples from thigh, leg and fingertip were processed by indirect immunofluorescence techniques. Digital images were acquired using a non-laser confocal microscope. Density of intrapapillar myelinated endings (IME), Meissner’s corpuscles (MC) and epidermal nerve fibers (ENFs) was calculated. Sudomotor, pilomotor and vasomotor nerves were assessed semi-quantitatively. Further evaluation included sural nerve conduction study, sympathetic skin response, quantitative sensory testing and dynamic sweat test. Nerve conduction was normal in all patients. Morphological analysis showed: a significant loss (p

Acquired Melanocytic Nevus: An Unusual Case Presentation

Acquired Melanocytic Nevi (AMV) are common benign pigmented skin lesions. There are three types which include junctional nevus, compound nevus and Intradermal Melanocytic Nevus (IMN). IMN are characterized clinically by dome-shaped, soft, fleshy papules and are seen commonly in adults. Herein we reported a case with an unusual large IMN. A 35 years old otherwise healthy male presented with history of asymptomatic skin lesion on his scalp of several years duration that started to get bigger within the previous few months prior presenting to us. Skin examination revealed solitary firm skin colored nodule measuring 1.5×1.5 cm on his scalp. Exccesional skin biopsy revealed sharply-defined intradermal tumor composed of nests and fascicles of nevus cells. The tumor cells in superficial dermis are composed of epithelioid cells arranged singly and in clusters with heavy pigmentation in the superficial part. The deeper portion of the tumor is composed of bland looking spindle cells. No atypia or mitosis has been seen. Nerve corpuscles resembling Meissner corpuscles have also been seen in the deeper portions of the tumor. Histochemical analysis showed positivity for S100 and HMB-45. On the basis of the above clinicopathological findings, the diagnosis of intradermal melanocytic nevus was made and the patient was reassured.

Non-motor involvement in amyotrophic lateral sclerosis: new insight from nerve and vessel analysis in skin biopsy.

To assess cutaneous sensory and autonomic nerves and the vascular bed in amyotrophic lateral sclerosis (ALS). We enrolled 41 patients (M = 20, aged 63.5 ± 11.8 years), and 41 age- and gender-matched healthy volunteers (M = 20, aged 63.5 ± 11.8 years). Disease severity and sensory and autonomic symptoms were scored using dedicated rating scales. Skin biopsies obtained from thigh, leg and fingertip were processed using indirect immunofluorescence. Intraepidermal nerve fibres, Meissner corpuscles (MCs), intrapapillary myelinated endings, cholinergic and noradrenergic pilomotor nerves and dermal vessels were quantified on confocal images. Intraepidermal nerve fibres, pilomotor nerves and vessels were also assessed on distal leg skin samples of 10 spinal cord injury patients to compare our findings with those of a chronic hypomobility condition. Compared to healthy controls skin biopsies showed: (i) non-length-dependent loss of intraepidermal nerve fibres (P < 0.01) and loss of MCs (P < 0.01); (ii) reduced (P < 0.01) density of pilomotor nerves involving cholinergic and noradrenergic fibres and (iii) a reduced (P < 0.01) vascular bed. Autonomic nerve and dermal vessel densities were higher in patients with higher disease progression rate (P < 0.01). Moreover, we observed signs of nerve regeneration coexisting with nerve degeneration and increased complexity of the dermal vessels. In patients with posttraumatic spinal cord injury, the density of intraepidermal nerve fibres, pilomotor nerves and of the vascular bed did not differ from controls (P > 0.05). We demonstrated a cutaneous sensory and autonomic denervation in ALS and a previously undescribed relationship between autonomic and vascular involvement that appeared to be linked to the disease progression rate.

Two-Photon Imaging of DiO-Labelled Meissner Corpuscle in Living Mouse's Fingertip.

Meissner corpuscles are the fast adapting type I (FA-I) mechanoreceptor that locates at the dermal papillae of skin. The Meissner corpuscle is well known for its complex structure, consisting of spiral axons, lamellar cells, and a collagen capsule. Fluorescent microscopy has become a convenient method for observing the Meissner corpuscle and its inner structure. This method requires preparing samples with fingertip cross-sections and performing antibody staining before observation. Various kinds of microscopy can be used for observation, such as confocal microscopy, transmission electron microscopy (TEM), or scanning electron microscopy (SEM). Although the anatomical shape, distribution, and components of Meissner corpuscle are recognized, they have been mostly determined from observations of fixed tissues. Therefore, knowledge of mechanical transduction is limited by the lack of in vivo experiments and individual differences among samples. In this study, we propose a novel less invasive imaging method that incorporates a staining technique with lipophilic carbocyanine [Formula: see text] and two-photon microscopy. This combination allows us to repetitively observe the Meissner corpuscle in a living mouse.

Involvement of sensory innervation in the skin of SOD1(G93A) ALS mice.

Sensory alterations have been described in both amyotrophic lateral sclerosis (ALS) patients and mouse models. While involvement of intraepidermal and subepidermal axons has been shown in skin biopsies of ALS patients, it is unclear if the SOD1(G93A) mouse presents similar alterations. We analyzed the epidermal and dermal innervation, based on PGP9.5 immunostaining, of SOD1(G93A) mice at different stages. The results showed a marked reduction of intraepidermal nerve fibers, Meissner's corpuscles, and subepidermal nerve density already at 4 weeks. This loss of innervation progressed over time. Dermal axonal density decreased at a later stage of the disease. There was a gradient of axonal loss, with a more severe decline in the epidermis compared with deeper structures, indicating a distal axonal neuropathy as the mechanism of degeneration. These findings suggest that the analysis of the cutaneous sensory innervation may be an accessible and useful tool to assess the neurodegeneration process in motoneuron diseases.

Cutaneous sensory and autonomic denervation in CADASIL.

To assess the involvement of the peripheral nervous system in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) by means of immunofluorescence and confocal analysis of punch skin biopsies. We recruited 14 unrelated patients with CADASIL (M/F = 9/5; age 53.9 ± 10.5 years) and 52 healthy controls (M/F = 31/21; age 53.8 ± 9.8). Patients underwent clinical and neuroradiologic assessment. Three-millimeter punch skin biopsies were taken from the fingertip, the thigh, and the distal leg and processed using indirect immunofluorescence and a panel of primary antibodies to mark vessels and sensory and autonomic nerve fibers. Intraepidermal nerve fibers (IENF), Meissner corpuscles (MC), and sudomotor, vasomotor, and pilomotor nerves were assessed using confocal microscopy. In patients, compared to controls, we found a severe loss of IENF at the distal leg (p < 0.01), at the thigh (p < 0.01), and at the fingertip (p < 0.01) with a non-length-dependent pattern and a loss of MC (p < 0.01). A severe sudomotor, vasomotor, and pilomotor nerve fiber loss was found by semiquantitative evaluation. Along with nerve loss, a severe derangement of the vascular bed was observed. In our patient population, sensory and autonomic denervation did not correlate with age, sex, type of mutation, or MRI involvement. We found an involvement of the peripheral nervous system in patients with CADASIL through the assessment of cutaneous somatic and autonomic nerves. The neurovascular derangement observed in the skin may reflect, although to a lesser extent, what happens in the CNS.

Vibrotactile stimulation of fast-adapting cutaneous afferents from the foot modulates proprioception at the ankle joint.

It has previously been shown that cutaneous sensory input from across a broad region of skin can influence proprioception at joints of the hand. The present experiment tested whether cutaneous input from different skin regions across the foot can influence proprioception at the ankle joint. The ability to passively match ankle joint position (17° and 7° plantar flexion and 7° dorsiflexion) was measured while cutaneous vibration was applied to the sole (heel, distal metatarsals) or dorsum of the target foot. Vibration was applied at two different frequencies to preferentially activate Meissner's corpuscles (45 Hz, 80 μm) or Pacinian corpuscles (255 Hz, 10 μm) at amplitudes ∼3 dB above mean perceptual thresholds. Results indicated that cutaneous input from all skin regions across the foot could influence joint-matching error and variability, although the strongest effects were observed with heel vibration. Furthermore, the influence of cutaneous input from each region was modulated by joint angle; in general, vibration had a limited effect on matching in dorsiflexion compared with matching in plantar flexion. Unlike previous results in the upper limb, we found no evidence that Pacinian input exerted a stronger influence on proprioception compared with Meissner input. Findings from this study suggest that fast-adapting cutaneous input from the foot modulates proprioception at the ankle joint in a passive joint-matching task. These results indicate that there is interplay between tactile and proprioceptive signals originating from the foot and ankle.

Nerve endings in rat periodontal ligament: an immunofluorescence study

Periodontal ligament is a structure between tooth root and alveolar bone. A few morphological study on the sensory innervation of periodontal ligament are available. Although there has been controversy over the distribution and shape of the sensory nerve terminals, researchers largely agree on the presence of two types of nerve endings: free endings and organized structures as Ruffini-like and Meissner corpuscles. Ruffini-like are slowly adapting receptors and give informations about the intensity and duration of the mechanical stimulus applied to the periodontal ligament; Meissner’s corpuscles are rapidly adapting receptors and give informations about direction of mechanical stimuli to the tissue. In the present study we investigated, by immunofluorescence for protein gene product PGP 9.5, the distribution of nerve endings among the different regions of periodontal ligament both of incisors and molars of rat. We found a variety of nerve endings morphology and several difference about their distribution between incisors and molars periodontal ligament. Moreover, we found that the morphology of nerve endings changes depending on the modification of the force applied to periodontal ligament, highlighting its importance in regulation of muscle activity.

Tactile display with rigid coupling based on soft actuator

The tactile display is a device which physically stimulates the human skin to reproduce the feel of touch. This paper presents a novel tactile display device driven by a dielectric elastomer actuator. The device adopts an indirect actuation method by using a rigid coupling, which aims to avoid direct contact of the human skin with the actuator. The rigid coupling is made of silicone to transmit the movement of the actuator to the touch layer located on the top surface of the coupling and provides the feeling of softness on contact. The device produces displacement about 350–140 μm at 0.3–10 Hz, which meets frequency requirements for simulating the Merkel cells as well as Meissner corpuscle. The force to simulate the fingertips can be exerted over 44 mN. This work describes its design, analysis and fabrication method in details with its experimental evaluations.

Charcot-Marie-Tooth disease: New insights from skin biopsy.

To evaluate, by skin biopsy, dermal nerve fibers in 31 patients with 3 common Charcot-Marie-Tooth (CMT) genotypes (CMT1A, late-onset CMT1B, and CMTX1), and rarer forms of CMT caused by mutations in RAB7 (CMT2B), TRPV4 (CMT2C), and GDAP1 (AR-CMT2K) genes. We investigated axonal loss by quantifying Meissner corpuscles and intrapapillary myelinated endings and evaluated morphometric changes in myelinated dermal nerve fibers by measuring fiber caliber, internodal, and nodal gap length. The density of both Meissner corpuscles and intrapapillary myelinated endings was reduced in skin samples from patients with CMT1A and all the other CMT genotypes. Nodal gaps were larger in all the CMT genotypes though widening was greater in CMT1A. Perhaps an altered communication between axons and glia may be a common feature for multiple forms of CMT. Internodal lengths were shorter in all the CMT genotypes, and patients with CMT1A had the shortest internodes of all our patients. The uniformly shortened internodes in all the CMT genotypes suggest that mutations in both myelin and axon genes may developmentally impede internode formation. The extent of internodal shortening and nodal gap widening are likely both important in determining nerve conduction velocities in CMT. This study extends the information gained from skin biopsies on morphologic abnormalities in various forms of CMT and provides insights into potential pathomechanisms of axonal and demyelinating CMT.

Malignant peripheral nerve sheath tumor (MPNST) arising in diffuse-type neurofibroma: clinicopathologic characterization in a series of 9 cases.

Diffuse-type neurofibroma, an uncommon variant of neurofibroma, is associated with neurofibromatosis type 1 in ∼60% of cases. Typically presenting in young adults as ill-defined plaque-like dermal/subcutaneous thickening, most cases are located on the trunk or the head and neck region. Malignant transformation is extremely rare. Nine cases of malignant peripheral nerve sheath tumor (MPNST) arising in diffuse-type neurofibroma (identified in consult files) are described, including clinicopathologic features and follow-up. Five patients were male and 4 female, aged 31 to 59 years (median 49 y). All diffuse-type neurofibromas contained Meissner corpuscles, with tumor sizes ranging between 3.6 and 45 cm (median, 7.4 cm). Five patients had a clinical history of neurofibromatosis type 1, and 1 had Klippel-Trénaunay-Weber syndrome. Six tumors arose on the trunk and 1 each on the leg, arm, and scalp. Increased cellularity, nuclear atypia, and mitoses (range, 1 to 63/50 high-power fields) indicated transition to MPNST, classified as low grade in 5, intermediate to high grade in 1, and high grade in 3 cases, 1 of which exhibited heterologous angiosarcomatous differentiation. S-100 expression was quite strong and diffuse in the neurofibroma components and less extensive or weaker in MPNST. Follow-up, available for all patients (median, 80.5 mo, except 1 recent case), revealed that 1 patient developed local recurrence after 9 months; 1 with metastases at the time of initial diagnosis died 1 month after tumor resection. All other patients were alive without evidence of disease at 15 to 145 months (median, 83 mo). Diffuse-type neurofibroma may show transformation to MPNST in very rare instances. It is important to be aware of possible malignant change, requiring thorough sampling of resection specimens and long-term clinical follow-up of patients with unexcised lesions.