Figure 4 - uploaded by Reinhard E Friedrich
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Example of double labelling with antibodies against smooth muscle actin and protein gene product 9.5 (PGP9.5). Red: Smooth muscle actin in an arterial wall (chromogen fast red); brown: PGP9.5 labelling of innervating nerve fibres (black arrows) and distant nerve fibres (grey arrow) (chromogen diaminobenzidine (DAB); scale bar=20 μm.
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Neurofibroma constitutes a heterogeneous group of solid tumours occurring sporadically or in association with syndromes. The aspect of these peripheral nerve sheath tumours may vary considerably, with disseminated tumours covering various parts of the body or nodular/diffuse plexiform neurofibroma that can grow to an impressive size. A...
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Context 1
... vessel innervation was highest in skin samples (13.24%) and lowest in plexiform-diffuse neurofibroma (4.71%). However, univariate ANOVA and t-test revealed no significant differences of this parameter between histological subtypes and controls (Figures 4 and 5) because of large variations between the cases. ...
Citations
... Non-NF1-related lesions showed decreased signals under 526 nm LED illumination compared to NF1-related lesions. According to previous research, nevi have decreased blood vessel density values when compared to the surrounding skin [32], while neurofibromas' blood vessel density is comparable to that of normal skin [20,33]. Therefore, if hemoglobin was in the background of a different reflectance signal under 526 nm illumination for certain neurofibromas and nevi, the difference would have been inverted-neurofibromas would have had, on average, a lower intensity due to higher absorbance. ...
Neurofibromatosis type 1 (NF1) is a rare disease, affecting around 1 in 3500 individuals in the general population. The rarity of the disease contributes to the scarcity of the available diagnostic and therapeutic approaches. Multispectral imaging is a non-invasive imaging method that shows promise in the diagnosis of various skin diseases. The device utilized for the present study consisted of four sets of narrow-band LEDs, including 526 nm, 663 nm, and 964 nm for diffuse reflectance imaging and 405 nm LEDs, filtered through a 515 nm long-pass filter, for autofluorescence imaging. RGB images were captured using a CMOS camera inside of the device. This paper presents the results of this multispectral skin imaging approach to distinguish the lesions in patients with NF1 from other more common benign skin lesions. The results show that the method provides a potential novel approach to distinguish NF1 lesions from other benign skin lesions.
... There was increased vascular endothelial growth factor immunoreactivity, suggesting their angiogenic potential. However, studies by Friedrich et al. have shown variable vascular density in cutaneous and plexiform neurofibroma associated with NF1 that is not significantly different from normal human skin [62]. ...
The first description of histopathological variants of neurofibroma dates back to 1994. Over the years, many individual case reports elucidating unusual histologic features in neurofibroma have been added to the literature, some of which have defined criteria, with the others falling under the roof of benign neural neoplasms. These unusual features, which sometimes may lead to pauses in identifying a common benign tumor such as neurofibroma. Awareness of these variants may help dermatopathologists avoid misinterpretation. Thus, this review aims to summarize all novel and unusual histopathological variants of cutaneous neurofibroma reported to date, in addition to any unusual variants that we encountered in our practice.
... The presence of peripheral innervation has been found in other types of tumors, as well as the presence of neurotrophic factors that could benefit them, such is the case of ameloblastomas [73], papillary thyroid carcinoma [74], and among others, some benign tumors such as cutaneous neurofibromas, where a greater number of nerve fibers was found in the evaluated neoplastic tissues, compared to the control tissue [75]. For the most part, the abundance of nerves in newly formed tissues is associated with malignancy and the nerve phenotypes mainly reported correspond to adrenergic innervation, although it is important to note that there is nerve variation in the different histological classifications of primary tumors of the same cell line. ...
The involvement of the nervous system in the development of cancer is controversial. Several authors have shown opinions and conflicting evidence that support the early effect of the nervous system on the carcinogenic process. For about a century, research has not been enough, questions remain open, ideas are not discarded, and although more research is still needed to answer all the questions, there is now enough evidence to support the theories and give hope of finding one more possible form of treatment. It is clear that malignant neoplasms have endogenous characteristics that allow them to establish and progress. Some of these characteristics known as hallmarks of cancer, are damage mechanisms in the pathology but necessary during other physiological processes which show some nerve dependence. The nervous system communicates with the whole organism, regulating physiological processes necessary to respond to external stimuli and for the maintenance of homeostasis. The modification of nerve activity could generate an overload and deregulate the state of cellular and tissue homeostasis; this could drive cancer development. In this review, we will address the issue in an evidence-oriented manner that supports that the nervous system is able to participate in the initial and progressive process of carcinogenesis by inducing biochemical, physiological, and cellular modifications involved in the hallmarks of cancer.
... The f correlates with blood volume and the D* theoretically correlates with blood flow 18 , suggesting that PNs have a higher total blood volume but slower overall blood flow 19 . These data are consistent with pathological reports of biopsy samples taken from PN subjects when stained for smooth muscle actin, with diffuse plexiform neurofibromas demonstrating the highest vessel density compared to other subtypes of neurofibromas 20 . Although the qualitative detection of PNs compared to background normal tissue is not usually difficult for a trained expert on STIR images, the ability of IVIM to quantitatively differentiate PNs from background tissue may be an alternative approach to aid the neuroradiologist in determining optimal treatment planning and response to therapy. ...
We assessed the accuracy of semi-automated tumor volume maps of plexiform neurofibroma (PN) generated by a deep neural network, compared to manual segmentation using diffusion weighted imaging (DWI) data. NF1 Patients were recruited from a phase II clinical trial for the treatment of PN. Multiple b-value DWI was imaged over the largest PN. All DWI datasets were registered and intensity normalized prior to segmentation with a multi-spectral neural network classifier (MSNN). Manual volumes of PN were performed on 3D-T2 images registered to diffusion images and compared to MSNN volumes with the Sørensen-Dice coefficient. Intravoxel incoherent motion (IVIM) parameters were calculated from resulting volumes. 35 MRI scans were included from 14 subjects. Sørensen-Dice coefficient between the semi-automated and manual segmentation was 0.77 ± 0.016. Perfusion fraction (f) was significantly higher for tumor versus normal tissue (0.47 ± 0.42 vs. 0.30 ± 0.22, p = 0.02), similarly, true diffusion (D) was significantly higher for PN tumor versus normal (0.0018 ± 0.0003 vs. 0.0012 ± 0.0002, p < 0.0001). By contrast, the pseudodiffusion coefficient (D*) was significantly lower for PN tumor versus normal (0.024 ± 0.01 vs. 0.031 ± 0.005, p < 0.0001). Volumes generated by a neural network from multiple diffusion data on PNs demonstrated good correlation with manual volumes. IVIM analysis of multiple b-value diffusion data demonstrates significant differences between PN and normal tissue.
... Conversely, neurofibromas are positive for CD34 and Factor XIIIa, while schwannomas are not (Gray et al. 1990;Hirose et al. 2003). There is some controversy on whether neurofilament protein staining can be used as a differential diagnostic marker, being positive for neurofibromas (Friedrich et al. 2015). In theory, schwannomas are believed to develop eccentrically from the surface of nerves and therefore not to contain axons, but this concept has been disputed (Nascimento and Fletcher 2007). ...
Schwann cells generate myelin sheaths around the axons of the peripheral nervous system, thus facilitating efficient nerve impulse propagation. Two main tumor types can arise from peripheral nerves, schwannomas and neurofibromas, which are sometimes difficult to distinguish and may require the use of diagnostic biomarkers. Here, we characterize a new marker for Schwann cells and its potential use as a diagnostic marker for schwannomas. Immunohistochemistry for Glu-tubulin, a posttranslational modification of α-tubulin, was performed in mouse and human tissues. This technique labels Schwann cells but not oligodendrocytes. All peripheral nerves were immunoreactive for this antibody, including large nerve trunks, thin myelinated nerves, as well as the myenteric and submucous plexus of the digestive tract. In the mouse brain, many neurons were immunoreactive for Glu-tubulin but oligodendrocytes were negative. During embryo development, immunoreactive nerves were already found at E10. In Schwann cells, the staining is restricted to the myelin sheaths and is not present in the perinuclear cytoplasm or the Ranvier nodes. Primary cultures of fibroblasts and Schwann cells were established from mouse sciatic nerves, and Western blot analysis showed that Glu-tubulin immunoreactivity was found in the Schwann cells but not in the fibroblasts. Clinical specimens of schwannomas (n = 20) and neurofibromas (n = 20) were stained with anti-Glu-tubulin antibodies. Schwannomas presented a strong staining in all tumor cells, whereas neurofibromas had a light speckled staining pattern, easily distinguishable from the one found in schwannomas. In conclusion, Glu-tubulin can be used as a marker of Schwann cells and can help in diagnosing peripheral nerve tumors.
Neovascularization is a critical process in tumor progression and malignant transformation associated with neurofibromatosis type 1 (NF1). Indeed, fibroblasts are known to play a key role in the tumoral microenvironment modification by producing an abundant collagenous matrix, but their contribution in paracrine communication pathways is poorly understood. Here, we hypothesized that NF1 heterozygosis in human dermal fibroblasts could promote angiogenesis through exosomes secretion. The purposes of this study are to identify the NF1 fibroblast‐derived exosome protein contents and to determine their proangiogenic activity. Angiogenic proteome measurement confirmed the overexpression of VEGF and other proteins involved in vascularization. Tube formation of microvascular endothelial cells was also enhanced in presence of exosomes derived from NF1 skin fibroblasts. NF1 tissue‐engineered skin (NF1‐TES) generation showed a significantly denser microvessels networks compared to healthy controls. The reduction of exosomes production with an inhibitor treatment demonstrated a drastic decrease in blood vessel formation within the dermis. Our results suggest that NF1 haploinsufficiency alters the dermal fibroblast function and creates a pro‐angiogenic signal via exosomes, which increases the capillary formation. This study highlights the potential of targeting exosome secretion and angiogenesis for therapeutic interventions in NF1. image
Zusammenfassung
Hintergrund und Zielsetzung
Klinisch‐pathologische Merkmale angeborener kutaner Neurofibrome, die sich bei Patienten mit Neurofibromatose Typ 1 (NF1) als große, unregelmäßig geformte „Café‐au‐lait“‐Flecken (CALM) präsentieren, sind noch nicht gut charakterisiert. Unser Ziel war, große „atypische“ CALM bei Kindern mit NF1 histopathologisch zu analysieren.
Patienten und Methoden
In dieser retrospektiven Beobachtungsstudie haben wir histopathologische und immunhistochemische Merkmale von 21 Biopsaten untersucht, die innerhalb der ersten Lebensmonate aus 18 großen hyperpigmentierten Flecken (mit oder ohne Hypertrichose) bei Kindern mit NF1 entnommen wurden.
Ergebnisse
Von den 21 Biopsaten zeigten zehn ein diffuses Neurofibrom, vier weitere hatten Charakteristika eines plexiformen Neurofibroms (PNF). Bei zwölf Proben fanden sich spindelförmige, linear angeordnete Zellen wie bei einem dünnen Nervenstrang mit abnormer Morphologie. Zwei dieser Läsionen wurden mit zunehmendem Alter erneut biopsiert und zeigten eine Transformation hin zu einem plexiformen Muster. In 17 Proben wurden vermehrt Zellen im interstitiellen Raum festgestellt, bei 16 waren die Zellen um ekkrine Drüsen konzentriert sowie bei zwölf Proben um Haarfollikel und Gefäßstrukturen. Alle diese Zellen exprimierten S100‐Protein und CD68, 15 Proben auch Melan‐A.
Schlussfolgerung
Die klinisch‐pathologischen Merkmale angeborener kutaner Neurofibrome liefern schon früh diagnostische Hinweise auf NF1 und sind hoch relevant für die Nachverfolgung der Patienten.
Background and objective
Clinicopathological features of cutaneous neurofibromas presenting as large irregularly shaped congenital café‐au‐lait macules (CALM) in Neurofibromatosis type 1 (NF1) patients have not been well characterized. We aimed to analyze the histopathological findings of large “atypical” CALM in children with NF1.
Patients and Methods
In this retrospective observational study we analyzed histopathological and immunostaining features of 21 biopsy specimens from 18 large hyperpigmented macules with irregular borders with or without hypertrichosis present during the first months of life in NF1 diagnosed children.
Results
Of the 21 biopsies, ten showed a diffuse neurofibroma pattern and four exhibited characteristics of plexiform neurofibroma (PNF). In twelve specimens we observed groups of fusiform cells arranged linearly mimicking a small caliber nerve trunk with abnormal morphology. Repeated biopsies from two of these lesions performed at different ages showed transformation to a plexiform pattern. An increased interstitial cellularity was observed in 17 samples that was more evident around eccrine glands in 16 or accompanying hair follicles and vascular structures in twelve samples. All these cells had immunoreactivity for S100‐protein, CD68 and were Melan‐A positive in 15 samples.
Conclusion
Clinicopathological findings of congenital cutaneous neurofibromas provide early diagnostic clues of NF1 with high relevance for monitoring of these patients.
