-
Wellcome Open Research 2023Schwannoma is a nerve sheath tumour arising from differentiated Schwann cells, and melanocytic schwannoma (MS) is a rare variant where the Schwan cells produce melanin...
Schwannoma is a nerve sheath tumour arising from differentiated Schwann cells, and melanocytic schwannoma (MS) is a rare variant where the Schwan cells produce melanin pigment. MS is typically associated with spinal nerve roots and there have been only ~20 reports of cutaneous or subcutaneous MS to-date in humans. In canines, there have only been two reports of MS, both associated with spinal root nerves. In this report, we describe a 7-year-old Weimaraner cross breed dog that presented with two pigmented lesions on the eyelids. The lesions were surgically removed and histological analysis revealed well-circumscribed, non-encapsulated, expansile, neoplasms that were displacing most of the dermis and adnexa. The first lesion was composed of spindloid cells arranged in short interlacing streams with large amounts of pale eosinophilic cytoplasm that sometimes contained fine melanin granules. In areas there were spindle cells arranged in verocay bodies which led to a diagnosis of MS. In contrast, the second lesion was composed of polygonal cells arranged in thick sheets with large amounts of pale eosinophilic cytoplasm that sometimes contained fine melanin granules. The diagnosis was melanocytoma (which is one of the macroscopic differential diagnoses for MS). Whilst melanocytoma is a commonly occurring cutaneous lesion in canines and surgical removal is considered curative, due to little being known about MS in dogs, the outcome remained guarded, as MS in humans has an unpredictable nature, and recurrence and metastasis have been reported.
PubMed: 38911282
DOI: 10.12688/wellcomeopenres.19694.2 -
Cureus May 2024Pigmented lesions in the oral cavity can arise from the accumulation of external substances or internal pigments, resulting in black or brown discoloration. The etiology...
Pigmented lesions in the oral cavity can arise from the accumulation of external substances or internal pigments, resulting in black or brown discoloration. The etiology can be categorized as physiologic, reactive, neoplastic, idiopathic, or indicative of systemic illness. Several systemic drugs have been linked to the development of oral and/or cutaneous pigmentation, either by stimulating the production of melanin or by the accumulation of the drug or its byproducts. The medications most commonly associated with this condition include antimalarials, hormones, oral contraceptives, phenothiazines, chemotherapeutics, amiodarone, minocycline, zidovudine, clofazimine, and ketoconazole. The aim of this case report is to illustrate the drug-induced appearance of multiple melanotic macules in an 89-year-old female patient. The patient was referred to the Department of Oral Medicine and Pathology, School of Dentistry, Aristotle University of Thessaloniki, Greece, complaining of the recent and constant appearance of black spots in her oral cavity. Her medical history revealed a multitude of prescribed drugs, with citalopram being the most recently prescribed one, approximately one year prior to the examination. The clinical examination revealed multiple melanotic macules, on the upper and lower lip as well as on the hard and soft palate. Based on these findings, a biopsy of a melanotic macule of the lip was carried out. The histopathological examination showed that the basal layer of the stratified squamous epithelium exhibited hyperpigmentation (melanin-pigmented basal cells). In addition, scattered melaninophages were noted in lamina propria. Psychotropic drugs associated with cutaneous hyperpigmentation include citalopram. Therefore, our case constitutes an exception since citalopram induced intraoral and perioral, instead of cutaneous, hyperpigmentation.
PubMed: 38910786
DOI: 10.7759/cureus.60889 -
Clinics in Dermatology Jun 2024Artificial Intelligence (AI) has evolved to become a significant force in various domains, including medicine. We explore the role of AI in pathology, with a specific...
Artificial Intelligence (AI) has evolved to become a significant force in various domains, including medicine. We explore the role of AI in pathology, with a specific focus on dermatopathology and neoplastic dermatopathology. AI, encompassing Machine Learning (ML) and Deep Learning (DL), has demonstrated its potential in tasks ranging from diagnostic applications on Whole Slide Imaging (WSI) to predictive and prognostic functions in skin pathology. In dermatopathology, studies have assessed AI's ability to identify skin lesions, classify melanomas, and improve diagnostic accuracy. Results indicate that AI, particularly Convolutional Neural Networks (CNNs), can outperform human pathologists in terms of sensitivity and specificity. Moreover, AI aids in predicting disease outcomes, identifying aggressive tumors, and differentiating between various skin conditions. Neoplastic dermatopathology showcases AI's prowess in classifying melanocytic lesions, discriminating between melanomas and nevi, and aiding dermatopathologists in making accurate diagnoses. Studies emphasize the reproducibility and diagnostic aid that AI provides, especially in challenging cases. In inflammatory and lymphoproliferative dermatopathology, limited research exists, but studies show attempts to use AI to differentiate conditions like Mycosis Fungoides and eczema. While some results are promising, further exploration is needed in these areas. We highlight the extraordinary interest AI has garnered in the scientific community and its potential to assist clinicians and pathologists. Despite the advancements, we have stress edthe importance of collaboration between medical professionals, computer scientists, bioinformaticians, and engineers to harness AI's benefits while acknowledging its limitations and risks. The integration of AI into dermatopathology holds great promise, positioning it as a valuable tool rather than as a replacement for human expertise.
PubMed: 38909860
DOI: 10.1016/j.clindermatol.2024.06.010 -
Acta Neuropathologica Communications Jun 2024Neurofibromatosis Type 1 (NF1) is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs)....
snRNA-seq of human cutaneous neurofibromas before and after selumetinib treatment implicates role of altered Schwann cell states, inter-cellular signaling, and extracellular matrix in treatment response.
Neurofibromatosis Type 1 (NF1) is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs). Currently the only approved therapeutic for NF1 is selumetinib, a mitogen -activated protein kinase (MEK) inhibitor. The purpose of this study was to analyze the transcriptome of cNF tumors before and on selumetinib treatment to understand both tumor composition and response. We obtained biopsy sets of tumors both pre- and on- selumetinib treatment from the same individuals and were able to collect sets from four separate individuals. We sequenced mRNA from 5844 nuclei and identified 30,442 genes in the untreated group and sequenced 5701 nuclei and identified 30,127 genes in the selumetinib treated group. We identified and quantified distinct populations of cells (Schwann cells, fibroblasts, pericytes, myeloid cells, melanocytes, keratinocytes, and two populations of endothelial cells). While we anticipated that cell proportions might change with treatment, we did not identify any one cell population that changed significantly, likely due to an inherent level of variability between tumors. We also evaluated differential gene expression based on drug treatment in each cell type. Ingenuity pathway analysis (IPA) was also used to identify pathways that differ on treatment. As anticipated, we identified a significant decrease in ERK/MAPK signaling in cells including Schwann cells but most specifically in myeloid cells. Interestingly, there is a significant decrease in opioid signaling in myeloid and endothelial cells; this downward trend is also observed in Schwann cells and fibroblasts. Cell communication was assessed by RNA velocity, Scriabin, and CellChat analyses which indicated that Schwann cells and fibroblasts have dramatically altered cell states defined by specific gene expression signatures following treatment (RNA velocity). There are dramatic changes in receptor-ligand pairs following treatment (Scriabin), and robust intercellular signaling between virtually all cell types associated with extracellular matrix (ECM) pathways (Collagen, Laminin, Fibronectin, and Nectin) is downregulated after treatment. These response specific gene signatures and interaction pathways could provide clues for understanding treatment outcomes or inform future therapies.
Topics: Humans; Schwann Cells; Skin Neoplasms; Benzimidazoles; Extracellular Matrix; Signal Transduction; Neurofibroma; Female; Male; RNA-Seq; Middle Aged; Adult; Neurofibromatosis 1; Protein Kinase Inhibitors; Transcriptome
PubMed: 38907342
DOI: 10.1186/s40478-024-01821-z -
Archives of Dermatological Research Jun 2024High-frequency ultrasound has been used to visualize depth and vascularization of cutaneous neoplasms, but little has been synthesized as a review for a robust level of... (Review)
Review
High-frequency ultrasound has been used to visualize depth and vascularization of cutaneous neoplasms, but little has been synthesized as a review for a robust level of evidence about the diagnostic accuracy of high-frequency ultrasound in dermatology. A narrative review of the PubMed database was performed to establish the correlation between ultrasound findings and histopathologic/dermoscopic findings for cutaneous neoplasms. Articles were divided into the following four categories: melanocytic, keratinocytic/epidermal, appendageal, and soft tissue/neural neoplasms. Review of the literature revealed that ultrasound findings and histopathology findings were strongly correlated regarding the depth of a cutaneous neoplasm. Morphological characteristics were correlated primarily in soft tissue/neural neoplasms. Overall, there is a paucity of literature on the correlation between high-frequency ultrasound and histopathology of cutaneous neoplasms. Further studies are needed to investigate this correlation in various dermatologic conditions.
Topics: Humans; Skin Neoplasms; Ultrasonography; Skin; Dermoscopy; Melanoma
PubMed: 38904763
DOI: 10.1007/s00403-024-03179-7 -
International Journal of Surgery Case... Jul 2024Seborrheic keratosis (SK) is a common benign epidermal tumor usually presenting as small, non-pigmented lesions on the skin. However, giant SK presenting as a pigmented...
INTRODUCTION AND IMPORTANCE
Seborrheic keratosis (SK) is a common benign epidermal tumor usually presenting as small, non-pigmented lesions on the skin. However, giant SK presenting as a pigmented variant is a rare occurrences, with limited documented cases in medical literature.
CASE PRESENTATION
Here, we present a case report of a 70 year old female patient with an unusual giant warty cutaneous lesion prompting excisional biopsy. Histopathological examination revealed pigmented proliferative basaloid cell and pseudohorn cysts, characteristic of SK. Notably, the lesion exhibited pigmentation, adding to the rarity of the giant forms of SK case.
CLINICAL DISCUSSION
Giant pigmented seborrheic keratosis (GPSK) is an uncommon form that shares clinical and dermatoscopic features, frequently causing misdiagnosis as malignant melanoma.
CONCLUSION
Thus this report underscores the importance recognizing such atypical presentations of SK and highlights the need for histological evaluation to diagnose such variants.
PubMed: 38901381
DOI: 10.1016/j.ijscr.2024.109916 -
ELife Jun 2024Transport and localization of melanosome at the periphery region of melanocyte are depended on myosin-5a (Myo5a), which associates with melanosome by interacting with...
Transport and localization of melanosome at the periphery region of melanocyte are depended on myosin-5a (Myo5a), which associates with melanosome by interacting with its adaptor protein melanophilin (Mlph). Mlph contains four functional regions, including Rab27a-binding domain, Myo5a GTD-binding motif (GTBM), Myo5a exon F-binding domain (EFBD), and actin-binding domain (ABD). The association of Myo5a with Mlph is known to be mediated by two specific interactions: the interaction between the exon-F-encoded region of Myo5a and Mlph-EFBD and that between Myo5a-GTD and Mlph-GTBM. Here, we identify a third interaction between Myo5a and Mlph, that is, the interaction between the exon-G-encoded region of Myo5a and Mlph-ABD. The exon-G/ABD interaction is independent from the exon-F/EFBD interaction and is required for the association of Myo5a with melanosome. Moreover, we demonstrate that Mlph-ABD interacts with either the exon-G or actin filament, but cannot interact with both of them simultaneously. Based on above findings, we propose a new model for the Mlph-mediated Myo5a transportation of melanosomes.
Topics: Melanosomes; Myosin Type V; Animals; Mice; Adaptor Proteins, Signal Transducing; Protein Binding; Humans; Myosin Heavy Chains; Melanocytes
PubMed: 38900147
DOI: 10.7554/eLife.93662 -
Skin Research and Technology : Official... Jun 2024Transient Receptor Potential Mucolipin 1 (TRPML1) serves as a pivotal reactive oxygen species (ROS) sensor in cells, which is implicated in the regulation of autophagy....
BACKGROUND
Transient Receptor Potential Mucolipin 1 (TRPML1) serves as a pivotal reactive oxygen species (ROS) sensor in cells, which is implicated in the regulation of autophagy. However, its function in melanocyte autophagy under oxidative stress remains elusive.
METHODS
The expression and ion channel function of TRPML1 were investigated using immunofluorescence and calcium imaging in primary human melanocytes (MCs). After activating TRPML1 with MLSA1 (TRPML1 agonist), autophagy-related molecules were investigated via western blot. ROS level, apoptosis- and autophagy-related molecules were investigated after pretreatment with MLSA1. After interference with TRPML1 expression, mitochondrial structures were visualized by electron microscopy with hydrogen peroxide (HO)treatment.
RESULTS
TRPML1 was expressed and functionally active in primary human MCs, and its activation promotes elevated expression of LC3-II and reduced apoptosis and ROS levels under oxidative stress. TRPML1 downregulation caused mitochondrial swelling and disruption of cristae structures under oxidative stress in primary human MCs.
CONCLUSIONS
TRPML1 might mediate lysosomal autophagy in primary human MCs under oxidative stress, participating in mechanisms that maintain the oxidative and antioxidant systems in balance.
Topics: Humans; Oxidative Stress; Melanocytes; Reactive Oxygen Species; Autophagy; Apoptosis; Cells, Cultured; Transient Receptor Potential Channels; Mitochondria; Hydrogen Peroxide; Calcium
PubMed: 38899729
DOI: 10.1111/srt.13772 -
The Journal of Investigative Dermatology Jun 2024RAS proteins regulate cell division, differentiation and apoptosis via multiple downstream effector pathways. Oncogenic RAS variants are the commonest drivers in...
RAS proteins regulate cell division, differentiation and apoptosis via multiple downstream effector pathways. Oncogenic RAS variants are the commonest drivers in cancers, however they also drive many benign lesions predisposing to malignancy, such as melanocytic naevi, thyroid nodules, and colonic polyps. Reversal of these benign lesions could reduce cancer incidence, however the effects of oncogenic RAS have been notoriously difficult to target with downstream pathway inhibitors. Here we show effective suppression of oncogenic and currently undruggable NRAS in primary cells from melanocytic naevi using siRNA targeted to the recurrent causal variant. This results in striking reduction in expression of ARL6IP1, a known inhibitor of endoplasmic reticulum stress-induced apoptosis not previously linked to NRAS. We go on to show that a single dose of siRNA in primary cells triggers an apoptotic cascade, in contrast to treatment with a MEK inhibitor. Protective packaging of the targeted siRNA into lipid nanoparticles permits successful delivery into a humanised mouse model of melanocytic naevi, and results in variant NRAS knockdown in vivo. These data show that RAS-induced protection from apoptosis is involved in persistence of NRAS-driven melanocytic naevi and anticipate that targeted siRNA could form the basis of clinical trials for RAS-driven benign tumours.
PubMed: 38897541
DOI: 10.1016/j.jid.2024.04.031 -
BioRxiv : the Preprint Server For... Jun 2024Tanning bed users have a significantly increased risk of melanoma, but it remains unclear how indoor tanning drives melanomagenesis. Tanning bed radiation is often...
BACKGROUND
Tanning bed users have a significantly increased risk of melanoma, but it remains unclear how indoor tanning drives melanomagenesis. Tanning bed radiation is often thought of as a substitute for natural UV radiation despite differences in the maximum doses, UV content, body sites exposed, and patterns of melanoma that arise.
METHODS
To better understand the epidemiologic trends and etiology of melanoma associated with tanning bed use, we described the patterns of melanoma in patients with quantifiable tanning bed usage and performed exome sequencing of 182 melanocytes from normal skin of a subset of these patients.
RESULTS
Tanning bed users were more likely than non-users to have melanoma on body sites with low cumulative levels of sun damage and were more likely to have multiple melanomas. The melanocytes in normal appearing skin from tanning bed users had higher mutation burdens, a higher proportion of melanocytes with pathogenic mutations, and distinct mutational signatures. These differences were most prominent over body sites that experience comparatively less exposure to natural sunlight.
CONCLUSIONS
We conclude that tanning bed radiation induces melanoma by increasing the mutation burden of melanocytes and by mutagenizing a broader field of melanocytes than are typically exposed to natural sunlight. The unique signatures of mutations in skin cells of tanning users may be attributable to the distinct spectra of radiation emitted from solariums.
PubMed: 38895302
DOI: 10.1101/2024.06.04.597225