Predictors of Local Invasion in Infiltrative Basal Cell Carcinoma: Tumour Budding Outperforms the WHO Subtyping.

Tumour budding (TB) correlates with increased local invasion in various neoplasms. Certain basal cell carcinomas (BCCs) exhibit local aggressiveness. Detecting adverse prognostic factors in partial biopsies could aid in identifying cases with heightened local risk. The absolute number of TB (≤ 3 tumour cells) in excision specimens of 271 infiltrative BCCs (0: absent; 1: 1-2 foci; 2: ≥ 3 foci; 3: ≥ 10 foci), the histopathological subtype and depth of infiltration, perineural invasion, and other histological features were evaluated. A significant correlation was found between TB and both depth of infiltration (rho 0.445, p < 0.001) and perineural invasion (p = 0.009). In the multivariate analysis of depth and perineural invasion (multiple regression, stepwise), TB was identified as a significant covariate together with diameter, inflammation, and perineural invasion for the former, and depth for the latter. Conversely, no correlation existed between the WHO histological subtypes (infiltrating, sclerosing, and micronodular), and depth of infiltration or perineural invasion. This study demonstrates the value of TB as a biomarker for local invasiveness in BCC. In routine practice, a count of ≥ 3 TB foci in lesions incompletely excised or with narrow tumour-free surgical margins would be a straightforward and reproducible method to guide BCC treatment.

Multicenter proteome-wide Mendelian randomization study identifies causal plasma proteins in melanoma and non-melanoma skin cancers.

This study addresses the diagnostic and therapeutic challenges in malignant melanoma (MM) and non-melanoma skin cancers (NMSC). We aim to identify circulating proteins causally linked to MM and NMSC traits using a multicenter Mendelian randomization (MR) framework. We utilized large-scale cis-MR to estimate the impact of numerous plasma proteins on MM, NMSC, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). To ensure robustness, additional analyses like MR Steiger and Bayesian colocalization are conducted, followed by replication through meta-analytical methods. The associations between identified proteins and outcomes are also validated at the tissue level using Transcriptome-Wide Association Study methods. Furthermore, a protein-protein interaction analysis is conducted to explore the relationship between identified proteins and existing cancer medication targets. The MR analysis has identified associations of 13 plasma proteins with BCC, 2 with SCC, and 1 with MM. Specifically, ASIP and KRT5 are associated with BCC, with ASIP also potentially targeting MM. CTSS and TNFSF8 are identified as promising druggability candidates for BCC. This multidimensional approach nominates ASIP, KRT5, CTSS, and TNFSF8 as potential diagnostic and therapeutic targets for skin cancers.

Nevi - when to refer.

PURPOSE OF REVIEW: Congenital melanocytic nevi (CMN) and acquired nevi are prevalent in pediatric populations, with distinct characteristics and management considerations. This chapter aims to equip pediatricians with knowledge to discern between benign and high-risk nevi, facilitating appropriate referrals and management within primary care settings. Risk factors associated with malignant melanoma (MM) underscore the importance of vigilant monitoring and early referral to dermatology for suspicious lesions. RECENT FINDINGS: Recent findings highlight the variability in CMN presentation and the evolving diagnostic strategies, emphasizing the need for multidisciplinary approaches to optimize patient outcomes. SUMMARY: Management of CMN involves tailored surveillance and intervention strategies, with an emphasis on early identification of high-risk features for MM and neurocutaneous melanosis (NCM). Pediatricians play a crucial role in advocating for sun protection practices and facilitating timely referrals, thereby contributing to the overall well being of pediatric patients with nevi.

Benefits of dermoscopy in primary care.

ABSTRACT: Skin cancer is the most common cancer in the United States, with an estimated 9,500 new diagnoses made each day. Dermoscopy (also called dermatoscopy) is an established clinical approach to improving skin cancer evaluation. However, only 8% to 9% of primary care physicians use it, and no data are available for physician associate/assistant or NP use. This article reports a dermoscopy algorithm that primary care providers can use to increase the detection of skin cancer and reduce unnecessary referrals and biopsies.

Automated cutaneous squamous cell carcinoma grading using deep learning with transfer learning.

INTRODUCTION: Histological grading of cutaneous squamous cell carcinoma (cSCC) is crucial for prognosis and treatment decisions, but manual grading is subjective and time-consuming. AIM: This study aimed to develop and validate a deep learning (DL)-based model for automated cSCC grading, potentially improving diagnostic accuracy (ACC) and efficiency. MATERIALS AND METHODS: Three deep neural networks (DNNs) with different architectures (AlexNet, GoogLeNet, ResNet-18) were trained using transfer learning on a dataset of 300 histopathological images of cSCC. The models were evaluated on their ACC, sensitivity (SN), specificity (SP), and area under the curve (AUC). Clinical validation was performed on 60 images, comparing the DNNs' predictions with those of a panel of pathologists. RESULTS: The models achieved high performance metrics (ACC>85%, SN>85%, SP>92%, AUC>97%) demonstrating their potential for objective and efficient cSCC grading. The high agreement between the DNNs and pathologists, as well as among different network architectures, further supports the reliability and ACC of the DL models. The top-performing models are publicly available, facilitating further research and potential clinical implementation. CONCLUSIONS: This study highlights the promising role of DL in enhancing cSCC diagnosis, ultimately improving patient care.

Leukomelanoderma Resembling Hyperpigmented Mycosis Fungoides.

Acquired circumscribed hyperpigmented patches and plaques have various differential diagnoses, including post-inflammatory hyperpigmentation and mycosis fungoides (MF). Leukomelanoderma is an uncommon cutaneous condition in which the pathogenesis is not fully elucidated. It has been reported that leukomelanoderma occurs after allergic contact dermatitis from hydroquinone or acute cutaneous graft-versus-host disease (1,2). Hyperpigmented MF is a cutaneous T-cell lymphoma with a frequent CD8+ phenotype (3). Herein, we report a case of leukomelanoderma clinically and histologically resembling hyperpigmented MF. A 55-year-old Japanese woman was referred to our department for evaluation of reticulate pigmentation with pruritic erythema on the face. She had used commercially available depigmenting cosmetic reagents for 20 years and ointment containing 10% hydroquinone for 3 months. Physical examination revealed diffuse hyperpigmentation and demarcated hypopigmented macules on the face and neck (Figure 1, a). Dermoscopy showed depigmented spots and reticulated plus dotted hyperpigmentation; it presented a pseudo-pigment network (Figure 1, b). Histological examination of a tissue specimen biopsied from the lesion showed superficial band-like lymphocytic infiltration in dermis accompanying single cells or small clusters in epidermis (Figure 1, c). Interface changes were observed together with melanophages in the dermis. Melan-A-positive melanocytes were absent. Immunohistochemical analysis demonstrated that the epidermotropic lymphocytes were CD3+CD7-, and they had predominance of CD8+ cells (Figure 1, d). These immunohistochemical results mimicked MF. However, PCR analysis of the T-cell receptor g-gene rearrangement was negative. Closed patch test result with hydroquinone (5% pet.) was graded D2 (+?) and D3 (+). Ten months after discontinuing cosmetic reagents and hydroquinone, the pigmentary changes showed improvement. The pathomechanism of leukomelanoderma is unclear. Although post-inflammatory pigmentation due to allergic or contact dermatitis together with direct depigmenting effects from hydroquinone use has been suggested (1), the immunophenotype of T-cells has not been examined. As observed in our patient, interface changes with melanophages, in addition to frequent CD8+ phenotype of the epidermotropism and dermal infiltrate of lymphocytes, were characteristic for hyperpigmented MF (3). Moreover, minimal CD7 expression was a specific finding for MF (4). T-cell receptor clonality was negative in our patient, but the clonality appears to be detected by PCR in up to 50% of the patients with early MF (3). In contrast, the closed patch test was positive for hydroquinone in our patient, and it is reported that CD8+ T-cells are recruited to the interphase between the epidermis and the dermis of the patients with allergic contact dermatitis (5). CD8+ T-cells might contribute to acute cutaneous graft-versus-host disease-like interface changes and destroy melanocytes in the leukomelanoderma lesion. Allergic contact dermatitis presenting as leukomelanoderma was thus suggested in our patient. However, further reports and studies are required to support this issue. Therefore, we considered it necessary to follow the patient, since MF was not absolutely eliminated.

Copper nitroprusside analogue nanoparticles against melanoma: detailed in vitro and in vivo investigation.

Melanoma is the most invasive and lethal form of skin cancer that arises from the malignant transformation of specialized pigment-producing cell melanocytes. Nanomedicine represents an important prospect to mitigate the difficulties and provide significant benefits to cure melanoma. In the present study, we investigated in vitro and in vivo therapeutic efficacies of copper nitroprusside analogue nanoparticles (abbreviated as CuNPANP) towards melanoma. Initially, in vitro anti-cancer activities of CuNPANP towards melanoma cells (B16F10) were evaluated by several experiments such as [methyl-3H]-thymidine incorporation assay, cell cycle and apoptosis assays using FACS analysis, ROS generation using DCFDA, DHE and DAF2A reagents, internalization of nanoparticles through ICP-OES analysis, co-localization of the nanoparticles using confocal microscopy, JC-1 staining to investigate the mitochondrial membrane potential (MMP) and immunofluorescence studies to analyze the expressions of cytochrome-c, Ki-67, E-cadherin as well as phalloidin staining to analyze the cytoskeletal integrity. Further, the in vivo therapeutic effectiveness of the nanoparticles was established towards malignant melanoma by inoculating B16F10 cells in the dorsal right abdomen of C57BL/6J mice. The intraperitoneal administration of CuNPANP inhibited tumor growth and increased the survivability of melanoma mice. The in vivo immunofluorescence studies (Ki-67, CD-31, and E-cadherin) and TUNEL assay further support the anti-cancer and apoptosis-inducing potential of CuNPANP, respectively. Finally, various signaling pathways and molecular mechanisms involved in anti-cancer activities were further evaluated by Western blot analysis. The results altogether indicated the potential use of copper-based nanomedicines for the treatment of malignant melanoma.

Dermotoscope assisted diagnosis of adolescent bullous pilomatricoma: six case reports.

BACKGROUND: Pilomatricoma (PM) is a cutaneous benign neoplasm derived from the hair matrix. It clinically presents as a solitary and firm nodule overlying normal epidermis and is usually not easy to be noticed at early stage. Nevertheless, when special bullous lesion occurs in a short time or even ulcerates, preoperative diagnosis by a dermatologist is often challenging especially when the pediatric patients refuse biopsy. CASE PRESENTATION: We present six bullous PM cases and particularly conduct correlation analysis on the dermotoscopy and histopathology detection data. The basic information, medical history, symptoms and lesion morphology results of the patients were also provided. We found that the incidence of bullous PM was higher in females than in males, and most patients were adolescents and the predilection location seem to be consistent in the vaccine injection site. The dermatoscopic features of bullous PM reported were luminous yellow structure below, with gray-blue homogeneous areas and branched capillary. The histological features were consistent with PM, and evident epidermis bullae were above the tumor with extraordinary dilation of lymphangion in the upper dermis. The patients described in this study were Chinese patients in Han population included 4 females and 2 males, coincidentally, they are almost teen-age, respectively are 5,11,17,19,21,22 year-old. CONCLUSIONS: This study reported and analyzed the dermotoscopy and clinical characteristics of bullous PM, dermotoscopy may guide as a rapid and reliable technique in bullous PM diagnosis.

Multi-Wavelength Raman Differentiation of Malignant Skin Neoplasms.

Raman microspectroscopy has become an effective method for analyzing the molecular appearance of biomarkers in skin tissue. For the first time, we acquired in vitro Raman spectra of healthy and malignant skin tissues, including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), at 532 and 785 nm laser excitation wavelengths in the wavenumber ranges of 900-1800 cm-1 and 2800-3100 cm-1 and analyzed them to find spectral features for differentiation between the three classes of the samples. The intensity ratios of the bands at 1268, 1336, and 1445 cm-1 appeared to be the most reliable criteria for the three-class differentiation at 532 nm excitation, whereas the bands from the higher wavenumber region (2850, 2880, and 2930 cm-1) were a robust measure of the increased protein/lipid ratio in the tumors at both excitation wavelengths. Selecting ratios of the three bands from the merged (532 + 785) dataset made it possible to increase the accuracy to 87% for the three classes and reach the specificities for BCC + SCC equal to 87% and 81% for the sensitivities of 95% and 99%, respectively. Development of multi-wavelength excitation Raman spectroscopic techniques provides a versatile non-invasive tool for research of the processes in malignant skin tumors, as well as other forms of cancer.

Multiple Trichoepitheliomas: A Disfiguring Lesion Successfully Treated with Excision and Skin Grafting.

BACKGROUND: Multiple trichoepitheliomas are rare benign adnexal tumours that present a unique challenge both to the patient and the managing physician. The multiple nature of the lesion and face being a common location often causes cosmetic concern and psychosocial challenges. Physicians on the other hand face the challenge of providing an ideal treatment with a satisfactory outcome. Dermabrasion and laser therapy have been used to treat this lesion successfully, though they require multiple sessions, and recurrence is common. These options are however either not available or unaffordable in low-resource countries such as Nigeria. Surgical excision though an option, has rarely been advocated due to scarring, leading some experts to offer no treatment at all in developing nations. We report a challenging case of sporadic multiple trichoepitheliomas successfully treated with surgical excision and full-thickness skin graft. METHOD: Following diagnosis, the patient was counselled on the procedure, the risks and benefits. She had en-bloc excision of the lesion, and full-thickness skin graft harvested from the right groin was transplanted and anchored with Monocryl 5-0. All wounds were dressed, and the graft site was reviewed on day 10. She was discharged for outpatient follow-up. RESULT: Graft take was 95%. Epidermolysis which was seen on postoperative day 10 resolved. Hypertrophic scar on the ala nasi is softening on scar massage, and the patient is very satisfied with the outcome. CONCLUSION: Surgical excision can be a valuable tool in low-resource settings for the management of multiple trichoepitheliomas.

CONTEXTE: Les trichoépithéliomes multiples sont des tumeurs annexielles bénignes rares qui présentent un défi unique à la fois pour le patient et le médecin traitant. La nature multiple de la lésion et le visage étant un site commun entraînent souvent des préoccupations esthétiques et des défis psychosociaux. Les médecins, de leur côté, sont confrontés au défi de fournir un traitement idéal avec un résultat satisfaisant. La dermabrasion et la thérapie au laser ont été utilisées avec succès pour traiter cette lésion, bien qu'elles nécessitent plusieurs séances et que la récidive soit fréquente. Ces options ne sont cependant pas disponibles ou abordables dans les pays à faibles ressources tel que le Nigeria. L'exérèse chirurgicale, bien qu'une option, a rarement été préconisée en raison des cicatrices, conduisant certains experts à ne proposer aucun traitement du tout dans les pays en dével oppement . Nous rappor tons un cas difficile de trichoépithéliomes multiples sporadiques traités avec succès par exérèse chirurgicale et greffe de peau totale. MÉTHODE: Après le diagnostic, la patiente a été informée de la procédure, des risques et des avantages. Elle a subi une exérèse en bloc de la lésion, et une greffe de peau totale prélevée dans l'aine droite a été transplantée et fixée avec du Monocryl 5-0. Toutes les plaies ont été habillées, et le site de la greffe a été examiné le 10e jour. Elle a été renvoyée pour un suivi en consultation externe. RÉSULTAT: La prise de greffe était de 95 %. L'épidermolyse observée le 10e jour postopératoire a disparu. La cicatrice hypertrophique sur l'aile du nez s'assouplit avec le massage de la cicatrice, et la patiente est très satisfaite du résultat. CONCLUSION: L'exérèse chirurgicale peut être un outil précieux dans les contextes à faibles ressources pour la prise en charge des trichoépithéliomes multiples. MOTS-CLÉS: Trichoépithéliomes multiples, Thérapie au laser, Électrocautérisation, Exérèse chirurgicale, Greffe de peau totale.

Cutaneous T-cell Lymphoma Diagnostic and Therapeutic Trends amidst the COVID-19 Pandemic.

is missing (Short communication).

Reverse causation bias: A simulation study comparing first- and second-line treatments with an overlap of symptoms between treatment indication and studied outcome.

BACKGROUND: Reverse causation is a challenge in many drug-cancer associations, where the cancer symptoms are potentially mistaken for drug indication symptoms. However, tools to assess the magnitude of this type of bias are currently lacking. We used a simulation-based approach to investigate the impact of reverse causation on the association between the use of topical tacrolimus and cutaneous T-cell lymphoma (CTCL) in a multinational, population-based study using topical corticosteroids (TCS) as comparator. METHODS: We used a multistate model to simulate patients' use over time of a first- (TCS) and second-line treatment (topical tacrolimus), onset of atopic dermatitis (indication for drugs) and CTCL (the studied outcome). We simulated different scenarios to mimic real-life use of the two treatments. In all scenarios, it was assumed that there was no causal effect of the first- or second-line treatment on the occurrence of CTCL. Simulated data were analysed using Cox proportional hazards models. RESULTS: The simulated hazard ratios (HRs) of CTCL for patients treated with tacrolimus vs. TCS were consistently above 1 in all 9 settings in the main scenario. In our main analysis, we observed a median HR of 3.09 with 95% of the observed values between 2.11 and 4.69. CONCLUSIONS: We found substantial reverse causation bias in the simulated CTCL risk estimates for patients treated with tacrolimus vs. TCS. Reverse causation bias may result in a false positive association between the second-line treatment and the studied outcome, and this simulation-based framework can be adapted to quantify the potential reverse causation bias.

Melanoma progression and prognostic models drawn from single-cell, spatial maps of benign and malignant tumors.

Melanoma clinical outcomes emerge from incompletely understood genetic mechanisms operating within the tumor and its microenvironment. Here, we used single-cell RNA-based spatial molecular imaging (RNA-SMI) in patient-derived archival tumors to reveal clinically relevant markers of malignancy progression and prognosis. We examined spatial gene expression of 203,472 cells inside benign and malignant melanocytic neoplasms, including melanocytic nevi and primary invasive and metastatic melanomas. Algorithmic cell clustering paired with intratumoral comparative two-dimensional analyses visualized synergistic, spatial gene signatures linking cellular proliferation, metabolism, and malignancy, validated by protein expression. Metastatic niches included up-regulation of CDK2 and FABP5, which independently predicted poor clinical outcome in 473 patients with melanoma via Cox regression analysis. More generally, our work demonstrates a framework for applying single-cell RNA-SMI technology toward identifying gene regulatory landscapes pertinent to cancer progression and patient survival.

3D models for mohs micrographic surgery: a review on its use in patient education.

The use of a 3D model for patient education has shown encouraging results in surgical specialties like plastic surgery and neurosurgery, amongst many others; however, there is limited research on the clinical application of 3D models for Mohs Micrographic Surgery. This study delves into the utilization of 3D models for patient education in Mohs Surgery by juxtaposing different 3D modalities, highlighting their differences, and exploring potential avenues for future integration of 3D models into clinical practice. A literature search in the scientific database MEDLINE through PubMed and OVID and on the ProQuest Health & Medical Collection database was performed on the use of a 3D model for patient education. We limited the search to articles available in English and considered those mentioning the educational use of 3D models, especially for patient education, after excluding duplicate titles. We did not exclude articles based on publication year due to limited availability of literature. Utilizing 3D models for patient education within the framework of Mohs Micrographic surgery, including a 3D multicolored clay model and a 3D model accompanied by an educational video intervention, presents substantial advantages. 3D models offer a visual and tactile means to improve patients' comprehension of the Mohs procedure, the affected area, and possible outcomes. They hold the potential to reduce patient anxiety and improve decision-making. Currently, literature on the use of 3D models for patient education in Mohs Micrographic Surgery is limited, warranting further research in this area.

[To assess the effectiveness of treatment methods for patients of different age groups with basal cell cancer of the skin of the nose and ears].

The relevance of the problems of diagnosis and treatment of skin cancer is currently determined not only by the high incidence rate, but by the existing difficulties in differential diagnosis and treatment with traditional methods. For localizations of basal cell skin cancer (BCSC) that are "inconvenient" for treatment, such as the external auditory canal, auricle, and wing of the nose, treatment is associated with certain difficulties and the possible appearance of a cosmetic defect, therefore, when choosing a treatment method, the anatomical features of these organs are taken into account. It has been determined that the effectiveness of treatment for primary BCSC of the nose and auricles is higher than recurrent one, and among the various treatment methods, the most effective and radical is the surgical method. The immediate results of treatment of BCSC in the form of PR by surgical method were 86.7%, which is statistically significant compared with other types of treatment (p < 0.05). Long-term treatment results with the surgical method are also higher (77%) compared to other methods, which is also statistically significant (p < 0.05).

CoPheScan: phenome-wide association studies accounting for linkage disequilibrium.

Phenome-wide association studies (PheWAS) facilitate the discovery of associations between a single genetic variant with multiple phenotypes. For variants which impact a specific protein, this can help identify additional therapeutic indications or on-target side effects of intervening on that protein. However, PheWAS is restricted by an inability to distinguish confounding due to linkage disequilibrium (LD) from true pleiotropy. Here we describe CoPheScan (Coloc adapted Phenome-wide Scan), a Bayesian approach that enables an intuitive and systematic exploration of causal associations while simultaneously addressing LD confounding. We demonstrate its performance through simulation, showing considerably better control of false positive rates than a conventional approach not accounting for LD. We used CoPheScan to perform PheWAS of protein-truncating variants and fine-mapped variants from disease and pQTL studies, in 2275 disease phenotypes from the UK Biobank. Our results identify the complexity of known pleiotropic genes such as APOE, and suggest a new causal role for TGM3 in skin cancer.