Search Results (180)

Background: Early and accurate differentiation between melanomas and benign nevi is essential for making proper clinical decisions. This study aimed to identify clinical, morphological, and histopathological variables most strongly associated with melanoma, using both statistical and machine learning approaches. Methods: This study evaluated 184 melanocytic lesions using clinical, morphological, and histopathological parameters. Univariable analyses were performed in XLStat statistical software, version 2014.5.03, while multivariable machine learning models were developed in Jamovi (version 2.4). Five supervised algorithms (random forest, partial least squares, elastic net regression, conditional inference trees, and k-nearest neighbors) were compared using repeated cross-validation, with performance evaluated by accuracy, Kappa, sensitivity, specificity, F1 score, and calibration. Results: Univariable analysis identified significant differences between melanomas and nevi in age, horizontal diameter, gender, lesion location, and selected histopathological features (cytological and extracellular matrix changes, epidermal interactions). However, several associations weakened in multivariable analysis due to collinearity and overlapping effects. Using glmnet, the most influential independent predictors were cytological changes, horizontal diameter, epidermal interactions, and extracellular matrix features, alongside age, gender, and lesion location. The model achieved high discrimination (AUC = 0.97, 95% CI: 0.93–0.99) and accuracy (training: 95.3%; test: 92.6%), confirming robustness. Conclusions: Structured demographic, morphological, and histopathological data—particularly age, lesion size, cytological and extracellular matrix changes, and epidermal interactions—can effectively support classification of melanocytic lesions. Machine learning approaches (the glmnet model in our study) provide a reliable framework to evaluate such predictors and offer practical diagnostic support in dermatopathology. Full article

Background and Objectives: Cutaneous melanoma (CM) is widely regarded as the most aggressive form of skin cancer worldwide, showing a rising global incidence. It develops from the uncontrolled transformation of pigment-producing melanocytes. The aim of this study is to characterize the cytotoxic and anti-proliferative properties of two 1-(2-aryl-adamantyl)piperazine derivatives, 6 and 7, with a specific emphasis on their impact on melanoma cells. Both compounds are synthesized based on the adamantane core structure which increases drug-like properties of the lead compound phencyclidine I, without increasing toxicity. Materials and Methods: This study describes concentration-dependent effects on cell viability and clonogenicity. Results: SRB assays, clonogenic (long-term) assays, and scratch assays reveal a significant anticancer activity of these two agents at low μΜ levels with a selective activity against melanoma cells. Furthermore, Western blot experiments indicate that both 6 and 7 induce LC3 accumulation, procaspase 3 decrease, and PARP cleavage, suggesting the implication of multiple death pathways in their anticancer mechanism of action. Conclusions: This study sheds light on the in vitro anticancer potential of two novel 1-(2-aryl-2-adamantyl)piperazine derivatives. It highlights their differential activity against melanoma and emphasizes their potential as lead candidates for further therapeutic exploration. Full article

The skin protects the body from damaging external stressors. The function of its outermost compartment, the epidermis, depends on high rates of protein synthesis and the production of protective molecules, both requiring amino acids as precursors. Conversely, the degradation of the epidermal barrier protein filaggrin releases free amino acids. Here, we review the epidermal amino acid metabolism, focusing on the metabolism of histidine, arginine and tyrosine, which are subjected to epidermal cell-specific control mechanisms. Histidine and arginine are metabolized by enzymes that are transcriptionally upregulated during terminal differentiation of keratinocytes, while tyrosine is specifically metabolized in melanocytes. Arginase converts arginine into ornithine and urea. While ornithine is decarboxylated to putrescine, a regulator of cellular proliferation, urea contributes to the moisturization of the skin surface. Histidase, also known as histidine ammonia lyase, converts histidine into urocanic acid (UCA) and ammonia. UCA is the main ultraviolet-absorbing molecule of the cornified layer of the epidermis, serving as a natural sunscreen of human skin. In melanocytes, tyrosinase initiates the polymerization of tyrosine to melanin, the main skin pigment that absorbs both visible light and ultraviolet radiation. The current evidence indicates that the metabolism of histidine, arginine, tyrosine and other amino acids critically influences normal and diseased skin. Full article

Background: Melanoma is one of the most aggressive types of skin cancer. Its diagnosis appears to be challenging due to morphological similarities to benign melanocytic lesions. Even though histopathological evaluation is the diagnostic gold standard, immunohistochemistry (IHC) proves to be useful in challenging cases. Preferentially Expressed Antigen in Melanoma (PRAME) has emerged as a promising diagnostic, prognostic, and therapeutic marker in melanoma. Methods: This review critically examines the role of PRAME across clinical domains. It presents an evaluation of PRAME’s diagnostic utility in differentiating melanomas from benign nevi, its prognostic significance across melanoma subtypes, and therapeutic applications in emerging immunotherapy strategies. An extensive analysis of the current literature was conducted, with a focus on PRAME expression patterns in melanocytic lesions and various malignancies, along with its integration into IHC protocols and investigational therapies. Results: PRAME demonstrates high specificity and sensitivity in distinguishing melanoma from benign melanocytic proliferations, particularly in challenging subtypes such as acral, mucosal, and spitzoid lesions. Its overexpression correlates with poor prognosis in numerous malignancies. Therapeutically, PRAME’s HLA class I presentation enables T-cell-based targeting. Early-phase trials show promising results using PRAME-directed TCR therapies and bispecific ImmTAC agents. However, immune evasion mechanisms (i.e., heterogeneous antigen expression, immune suppression in the tumor microenvironment, and HLA downregulation) pose significant challenges to therapy. Conclusions: PRAME is a valuable biomarker for melanoma diagnosis and a promising target for immunotherapy. Its selective expression in malignancies supports its clinical utility in diagnostic precision, prognostic assessment, and precision oncology. Ongoing research aimed at overcoming immunological barriers will be essential for optimizing PRAME-directed therapies and establishing their place in the personalized management of melanoma. Full article

Melanoma is a highly aggressive skin cancer with limited therapeutic response. Targeting intracellular signaling pathways and promoting tumor cell differentiation are promising therapeutic strategies. Pentoxifylline (PTX) and norcantharidin (NCTD) have demonstrated antitumor properties, but their combined mechanisms of action in melanoma remain poorly understood. The effects of PTX (30 and 60 mg/kg) and NCTD (0.75 and 3 mg/kg), administered alone or in combination, in a DBA/2J murine B16-F1 melanoma model via intraperitoneal and intratumoral (IT) routes were evaluated. Tumor growth was monitored, and molecular analyses included RNA sequencing and immunofluorescence quantification of PI3K, AKT1, mTOR, ERBB2, BRAF, and MITF protein levels, and molecular docking simulations were performed. In the final stage of the experiment, combination therapy significantly reduced tumor volume compared to monotherapies, with the relative tumor volume decreasing from 18.1 ± 1.2 (SD) in the IT Control group to 0.6 ± 0.1 (SD) in the IT combination-treated group (n = 6 per group; p < 0.001). RNA-seq revealed over 3000 differentially expressed genes in intratumoral treatments, with enrichment in pathways related to oxidative stress, immune response, and translation regulation (KEGG and Reactome analyses). Minimal transcript-level changes were observed for BRAF and PI3K/AKT/mTOR genes; however, immunofluorescence showed reduced total and phosphorylated levels of PI3K, AKT1, mTOR, BRAF, and ERBB2. MITF protein levels and pigmentation increased, especially in PTX-treated groups, indicating enhanced melanocytic differentiation. Docking analyses predicted direct binding of both drugs to PI3K, AKT1, mTOR, and BRAF, with affinities ranging from −5.7 to −7.4 kcal/mol. The combination of PTX and NCTD suppresses melanoma progression through dual mechanisms: inhibition of PI3K/AKT/mTOR signaling and promotion of tumor cell differentiation. Full article

Skin dullness contributes to a fatigued and aged appearance, often exceeding one’s biological age. It is a common dermatological concern influenced by aging and poor lifestyle habits, regardless of ethnicity or age. This study aimed to examine advanced glycation end products (AGEs) and their receptor (receptor for AGEs [RAGE]) as contributing factors to skin dullness. AGEs themselves have a yellowish hue, contributing to “yellow dullness.” Additionally, AGE–RAGE signaling promotes melanin production in melanocytes and impairs keratinocyte differentiation as a result of inflammation. Therefore, regulating the AGE–RAGE interaction may help reduce skin dullness. Through screening various natural ingredients, we found that peony root extract (PRE) inhibits AGE formation and blocks AGE–RAGE binding. Furthermore, the presence of PRE leads to the suppression of AGE-induced melanin production in melanocytes and the restoration of impaired keratinocyte differentiation in glycated basement membrane components. In a human clinical study, topical application of a 1% PRE-containing lotion for 2 weeks significantly reduced melanin content, with a trend toward decreased AGE accumulation and visible spots on the cheeks. These findings support the potential of PRE as a multifunctional cosmetic ingredient that comprehensively addresses skin dullness by modulating the AGE–RAGE interaction. Full article

Background and clinical significance: Trichoblastomas are rare, mixed epithelial tumors with a mesenchymal component and hair follicle differentiation. Case presentation: Herein, we present a case report of a 51-year-old female patient presenting to the obstetrics and gynecology department with complaints of edema and erythema of the right Bartholin gland, and a lesion measuring 2 cm on the right lateral edge of the mons pubis, towards the inguinal fold. Marsupialization of the Bartholin gland was performed, as well as an incision into the pubo-inguinal lesion, which the patient depicted as grossly resembling an ingrown hair. Upon incision into the pubic–inguinal lesion, it was dark brown in color and spontaneously popped out of the subcutis, without an attempt at enucleation. Histology and subsequent immunohistochemistry of the lesion showed a blue basaloid tumor with an extensive pigment component located deep in the dermis that was sharply demarcated from the surrounding tissues. Conclusion: Immunohistochemistry was diffusely and strongly positive for epithelial markers; melanocytic markers were positive only in dendritic melanocytes dispersed within the tumors, and the proliferative index was low. As such, the tumor was identified as melanotrichoblastoma. Full article

Background: Vitiligo, a chronic depigmentation disorder driven by oxidative stress and immune dysregulation, remains poorly understood mechanistically. The Keap1/NRF2/ARE pathway is critical for melanocyte protection against oxidative damage; however, the role of Cullin-3 (CUL3), a scaffold for E3 ubiquitin ligases that regulate NRF2 degradation, and its interplay with inflammatory mediators in vitiligo pathogenesis are underexplored. This study investigates CUL3, NRF2, and the associated regulatory networks in vitiligo, integrating clinical profiling and computational docking to identify therapeutic targets. Methods: A case-control study compared non-segmental vitiligo patients with age-/sex-matched controls. Lesional skin biopsies were analyzed by qRT-PCR for the expression of CUL3, NRF2, miRNA-146a, FOXP3, NF-κB, IL-6, TNF-α, and P53. Molecular docking was used to evaluate vitexin’s binding affinity to Keap1, validated by root mean square deviation (RMSD) calculations. Results: Patients with vitiligo exhibited significant downregulation of CUL3 (0.27 ± 0.03 vs. 1 ± 0.58; p = 0.013), NRF2 (0.37 ± 0.26 vs. 1 ± 0.8; p = 0.001), and FOXP3 (0.09 ± 0.2 vs. 1 ± 0.3; p = 0.001), alongside the upregulation of miRNA-146a (4.7 ± 1.9 vs. 1 ± 0.8; p = 0.001), NF-κB (4.7 ± 1.9 vs. 1 ± 0.5; p = 0.001), IL-6 (2.8 ± 1.5 vs. 1 ± 0.4; p = 0.001), and TNF-α (2.2 ± 1.1 vs. 1 ± 0.3; p = 0.001). P53 showed no differential expression (p > 0.05). Docking revealed a strong binding of vitexin to Keap1 (RMSD: 0.23 Å), mirroring the binding of the control ligand CDDO-Im. Conclusions: Dysregulation of the CUL3/Keap1/NRF2 axis and elevated miRNA-146a levels correlate with vitiligo progression, suggesting a role for oxidative stress and immune imbalance. Vitexin’s high-affinity docking to Keap1 positions it as a potential modulator of the NRF2 pathway, offering novel therapeutic avenues. This study highlights the translational potential of targeting the ubiquitin–proteasome and antioxidant pathways in the management of vitiligo. Full article

Background and Clinical Significance: Bilateral diffuse uveal melanocytic proliferation (BDUMP) is a rare paraneoplastic syndrome characterized by bilateral uveal melanocyte proliferation and progressive visual disturbance. While most commonly associated with solid tumors, its occurrence in hematologic malignancies is exceedingly rare. Case Presentation: We report a case of BDUMP in a 64-year-old male recently diagnosed with chronic myelomonocytic leukemia (CMML), who presented with subacute, painless bilateral blurred vision. Multimodal imaging revealed suggestive features of BDUMP, including orange-red subretinal patches, retinal pigment epithelium mottling, and diffuse choroidal thickening, consistent with early structural involvement despite preserved central vision. No intraocular mass or signs of inflammation were observed. The patient did not receive specific treatment for BDUMP, and visual acuity remained stable during follow-up. Conclusions: This case underscores the importance of considering BDUMP in the differential diagnosis of bilateral visual symptoms in patients with hematologic malignancies. Although rare, BDUMP may occur in the context of CMML. Recognition through multimodal imaging and interdisciplinary collaboration is essential, and further research is needed to clarify its pathogenesis and improve management strategies. Full article

Solar lentigines, commonly caused by prolonged ultraviolet exposure, raise the risk of skin disorders and remain challenging to manage due to their complex mechanisms. Understanding the molecular mechanisms driving the progression of solar lentigines is crucial for developing effective protective strategies. In this study, we introduced a novel method, Dynamic Network Driver (DND), which identifies upstream regulators that drive disease progression by integrating the Dynamic Network Biomarker (DNB) approach with network control theory. By applying DND to multi-omics data from solar lentigines subjects, we (1) identified the key drivers associated with solar lentigo progression, with their functions involved in differentiation and dermal–epidermal junction; and (2) highlighted ARNT2 and TBX2 as significant master factors supported by in vitro validation in melanocytes and pigmented 3D living skin equivalent models. These results demonstrate the potency of DND for uncovering the molecular mechanisms behind solar lentigines and informing therapeutic strategies. In summary, the DND approach identified novel drivers of solar lentigo progression, acting as new markers for spot mitigation in 3D spot mimic models. Full article

Background/Objectives: Cutaneous melanoma is one of the aggressive forms of skin cancer originating from melanocytes. The high incidence of melanoma metastasis continues to rise, partly due to the complex nature of the molecular mechanisms driving its progression. While melanomas generally arise from melanocytes, we investigated whether aberrant keratinocyte differentiation pathways—like cornified envelope formation—discriminate primary melanoma from metastatic melanoma, revealing novel biomarkers in progression. Methods: In the present study, we retrieved four datasets (GSE15605, GSE46517, GSE8401, and GSE7553) associated with primary and metastatic melanoma tissues and identified differentially expressed genes (DEGs). Thereafter, an integrated meta-analysis and functional enrichment analysis of the DEGs were performed to evaluate the molecular mechanisms involved in melanoma metastasis, such as immune cell deconvolution and protein-protein interaction (PPI) network construction. Hub genes were identified based on four topological methods, including ‘Betweenness’, ‘MCC’, ‘Degree’, and ‘Bottleneck’. We validated the findings using the TCGA-SKCM cohort. Drug-gene interactions were evaluated using the DGIdb, whereas structural druggability was assessed using the ProteinPlus and AlphaFold databases. Results: We identified a total of eleven hub genes associated with melanoma progression. These included members of the keratin gene family (e.g., KRT5, KRT6A, KRT6B, etc.). Except for the gene CDH1, all the hub genes were downregulated in metastatic melanoma tissues. From a prognostic perspective, these hub genes were associated with poor prognosis (i.e., unfavorable). Using the Human Protein Atlas (HPA), immunohistochemistry evaluation revealed mostly undetected levels in metastatic melanoma. Additionally, the cornified envelope formation was the most enriched pathway, with a gene ratio of 17/33. The tumor microenvironment (TME) of metastatic melanomas was predominantly enriched in NK cell–associated signatures. Finally, several hub genes demonstrated favorable druggable potential for immunotherapy. Conclusions: Through integrated meta-analysis, this study identifies transcriptional, immunological, and structural pathways to melanoma metastasis and highlights keratin family genes as promising biomarkers for therapeutic targeting. Full article

Amelanotic melanocytic nevi of the oral cavity are uncommon lesions that often present a diagnostic challenge for clinicians, primarily due to their nonspecific clinical appearance and the broad spectrum of possible differential diagnoses. These lesions can mimic a variety of benign and malignant conditions, requiring precise histopathological confirmation. The primary objective of this article is to present a comprehensive case report—tracing the course from initial presentation through diagnostic workup to final diagnosis—and to provide an overview of the current literature on oral amelanotic melanocytic nevi. We report the case of a 27-year-old female who presented with a small, exophytic mass located in the anterior mandibular gingival region. The lesion was asymptomatic and lacked pigmentation, adding to the diagnostic uncertainty. A range of differential diagnoses was considered, including pyogenic granuloma, peripheral ossifying fibroma, and squamous cell carcinoma. Due to the lesion’s limited size and accessibility, an excisional biopsy was performed under local anesthesia. Histopathological examination revealed an amelanotic melanocytic nevus, a rare variant characterized by the absence of melanin pigment, further complicating the clinical impression. The diagnosis was confirmed through immunohistochemical staining, which demonstrated melanocytic markers consistent with a nevus. The patient was followed up with for six months postoperatively, with no evidence of recurrence or malignant transformation. This case highlights the critical role of biopsy in achieving a definitive diagnosis, especially in lesions with atypical clinical presentations. It also underscores the importance of considering amelanotic melanocytic nevi in the differential diagnosis of nonpigmented oral lesions, as well as maintaining vigilance regarding the rare possibility of amelanotic melanoma. Full article

Lasers are widely employed in the treatment of melanocytic lesions. This scoping review evaluates 77 studies on the efficacy and safety of laser treatments for café-au-lait macules (CALMs), nevus of Ota (NOA), Becker’s nevus (BN), lichen planus pigmentosus (LPP), and other pigmented lesions. The Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG), particularly the 1064 nm, is the most frequently utilized laser, demonstrating strong efficacy for NOA and other dermal pigmentary disorders. Medium-wavelength lasers, including the Q-switched ruby and Alexandrite lasers, also show promise, though results vary based on lesion depth, skin type, and treatment protocols. Recurrence and adverse effects, including post-inflammatory hyperpigmentation (PIH) and hypopigmentation, are common, particularly in patients with darker skin tones. Future studies should standardize and optimize laser parameters across lesion types and skin tones, improve long-term efficacy, and prioritize inclusion of patients with diverse Fitzpatrick skin types to evaluate differential outcomes and promote equitable treatment efficacy. Full article

Background and clinical significance: Cutaneous melanomas sometimes display unusual histopathological features, reminiscent of various other malignancies, either primary or metastatic. However, due to the highly aggressive nature of cutaneous melanomas, an accurate and timely diagnosis is mandatory. This requires extensive histopathological and immunohistochemical analyses and molecular tests, if needed. Case presentation: In this respect, we present two cases of primary cutaneous melanomas exhibiting rhabdoid features and genuine divergent rhabdomyosarcomatous differentiation confirmed by immunoreactivity for myogenin and loss of positivity for some melanocytic markers. We discuss the diagnosis approach for these particularly rare entities, highlighting the most useful immunohistochemical panel. Additionally, we also provide an extensive review of all the previously reported similar lesions, focusing on the epidemiological, histopathological, immunohistochemical and molecular features, as well as discussing the prognostic and treatment options for rhabdomyosarcomatous cutaneous melanomas. Conclusions: These rare cases of primary cutaneous melanomas with rhabdomyosarcomatous differentiation underscore the diagnostic challenges posed by such unusual histopathological variants. In order to establish the correct diagnosis a comprehensive immunohistochemical workup, including both melanocytic and myogenic markers, is required. These findings are supported by a detailed review of the literature, emphasizing the importance of recognising these rare melanoma subtypes for providing the appropriate prognostic assessment, and therapeutic management. Full article

Background: With its incidence on the rise, a high mortality rate, and great costs associated with its treatment, melanoma represents an important challenge for healthcare systems, clinicians, and pathologists. Therefore, an emphasis should be placed on its early and correct diagnosis, as well as the appropriate assessment of prognostic and predictive factors. Immunohistochemistry (IHC) is an ancillary test that can provide invaluable information for diagnosing melanoma, especially in complex cases. Objective: The aim of this systematic review is to gather the available information regarding the use of IHC markers in the diagnosis, differential diagnosis, prognosis, staging, and treatment of melanoma in a format that is easy to access for clinicians and pathologists. Methods: A comprehensive search of the literature was conducted and resulted in one hundred and forty-seven studies being included in this systematic review. The results were grouped thematically by specific IHC markers. Results: The IHC markers specific to melanocytic differentiation, like S100, SOX10, and Melan-A/MART1, were consistent across studies as being positive in most cases of melanoma, with rare exceptions. HMB-45 and PRAME can provide additional information, especially for differential diagnoses between benign and malignant melanocytic lesions. MITF, Ki67, BRAF, and PD-L1 are associated with prognosis factors, like the Breslow thickness, tumour ulceration, type of inflammatory infiltrate, and response to treatment. Conclusions: IHC markers are an invaluable tool for the diagnosis and differential diagnosis of melanoma, especially in cases that lack the characteristic histopathological aspects. In addition, IHC provides prognostic factors and can help in predicting the tumour’s response to various treatments. Full article