The skinny on skin: The role of skin-aware professionals in skin cancer surveillance.

BACKGROUND: Licensed nonmedical, skin-aware professionals (e.g., hairdressers, massage therapists, etc.) have the potential to identify skin cancer, but baseline knowledge may not be sufficient to accomplish this goal. Following educational intervention, self-efficacy is one of the best surrogate metrics for behavior change. Curricula that increase knowledge and confidence levels can improve screening behaviors, but few have been tested for efficacy in this population AIMS: We assessed whether an online curriculum could reliably improve skin screening knowledge, attitudes, and behaviors of nonmedical professionals PATIENTS/METHODS: Skin-aware professionals were recruited through the Oregon Health Authority and IMPACT Melanoma TM. Participants completed a pre-survey, online training module, post-survey, and one-year follow-up survey. We evaluated participants' indicated levels of concern for suspicious and nonsuspicious lesions relative to "gold standard" physician ratings. We also assessed confidence and self-reported behavior change regarding talking to clients about skin cancer and recommending they see a provider to evaluate suspicious lesions RESULTS: The pre-survey was completed by 9872 skin-aware professionals; 5434 completed the post-survey, and 162 completed the one-year follow-up survey. Participants showed a significant improvement in ability to indicate the correct level of concern for all lesion types in concordance with "gold standard" physician ratings (p < 0.001). Participants reported increased comfort levels in discussing health-related topics with their clients posttraining CONCLUSIONS: Our training module effectively increased skin-aware professionals' knowledge, confidence, and concern for malignant lesions. Skin-aware professionals may serve as a valuable extension of the skin self-exam, but additional studies are needed to evaluate the impact of these curricula long-term, including potential downstream consequences.

The Causal Relationship Between Physical Activity and Skin Cancer Risk: An Univariable Mendelian Randomization Study.

Background: The existing observational research on the relationship between physical activity (PA) and skin cancer (SC) is contentious, which points to the intricate nature of their association and underscores the imperative for more nuanced research to untangle the causal dynamics at play. The aim of this article is to delve deeper into this complex relationship, seeking to clarify whether PA serves as a protective factor against SC, or contributes to its risk. Methods: We utilized data from the genome-wide association study (GWAS) of PA from GWAS Catalog (include self-reported moderate to vigorous PA (MVPA), self-reported vigorous PA (VPA), and accelerometer-based average-accelerated PA). The data of SC is from FinnGen. All of the participants are of European ancestry. We used two-sample Mendelian Randomization (TSMR) to analyze the causal relationship between PA and SC.The research was conducted using inverse variance weighted (IVW) method as the primary approach, and MR Egger regression as supplementary analytical method. To ensure the robustness of the results, Cochran's Q-test and MR pleiotropy residual sum and outlier (MR-PRESSO) global tests were used to measure sensitivity. Results: Our analysis indicated that average-accelerated PA was associated with an increased risk of SC (ORIVW = 0.94, 95% CI 0.93-0.96, P < 0.001). While neither MVPA (ORIVW = 0.99, 95% CI 0.67-1.47, P = 0.962) nor VPA (ORIVW = 0.80, 95% CI 0.29-2.18, P = 0.656) shows causal relationship on risk of SC. Conclusion: Our research suggests that PA is associated with a decrease in SC, provides a new perspective for future SC prevention. Our research findings bolster the hypothesis that increased levels of PA, characterized by average acceleration, are associated with a reduced risk of developing skin cancer. This has filled the gap of research on the causal relationship between PA and SC, and could pave the way for novel preventive strategies against skin cancer.

Changes in the Use of Hydrochlorothiazide and Other Antihypertensive Drugs in Switzerland in Association With the Swissmedic Safety Alert Regarding Non-melanoma Skin Cancer: An Interrupted Time-Series Analysis Using Swiss Claims Data.

PURPOSE: Long-term use of hydrochlorothiazide increases the risk of non-melanoma skin cancer. We aimed to evaluate potential changes in the use of hydrochlorothiazide in Switzerland after a direct healthcare professional communication (DHPC) in November 2018 by Swissmedic. METHODS: We performed interrupted time-series analyses using a large Swiss healthcare claims database (2015-2021). Within monthly intervals, we quantified the total number of claims and the total dispensed 'defined daily doses' (DDD) for preparations containing (1) hydrochlorothiazide, (2) angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II-receptor blockers (ARB), (3) calcium-channel blockers (CCB) and (4) thiazide-like diuretics per 10 000 persons. Using segmented linear regression, we quantified the pre-DHPC trend, the immediate change and the post-DHPC change in trend for total claims and DDD for the four drug classes weighted for the demographic distribution of the Swiss population. RESULTS: ACE inhibitors and ARB were the most frequently claimed antihypertensive drugs with 300-400 claims per 10 000 persons, which increased by 5.4% during the study period. The average number of hydrochlorothiazide claims (157/10 000 persons in 2015) declined by 35% between 2015 and 2021. The decrease started prior to the DHPC, but the DHPC was associated with an immediate 6.1% decline and an accelerated decline in claims over time after the DHPC (similar results for DDD). This coincided with a 23% increase in claims of CCB (dihydropyridine type) over 7 years, whereas use of other antihypertensives increased less. CONCLUSION: Our results suggest that the DHPC by Swissmedic in 2018 accelerated a pre-existing decline in the use of hydrochlorothiazide in Switzerland.

Recurrence of a dermatofibrosarcoma protuberans? Rare case.

Dermatofibrosarcoma protuberans (DFS) is a mesenchymal-origin skin tumor with intermediate malignancy. Though rare, it's not exceptional, comprising about 0.1% of malignant skin tumors. The authors discuss clinical, radiological, histopathological studies, and various therapeutic modalities for this tumor. Our 82-year-old patient presented with a 3 cm swelling on the right arm, initially undergoing biopsy followed by surgical excision of the mass. Adjuvant treatment with radiotherapy or chemotherapy is unnecessary unless recurrence or malignant transformation occurs. Histological analysis is crucial for diagnosis. The preferred treatment method is wide surgical excision. Prognosis primarily depends on malignancy, especially at the local level, with a high risk of recurrence. It's rare for a distinctly malignant sarcomatous transformation with metastasis to occur.

Clinical, Dermoscopic, and Molecular Features of Acantholytic Squamous Cell Carcinoma: A Systematic Review.

INTRODUCTION: Acantholytic squamous cell carcinoma (aSCC) is a rare clinicopathological subtype of cutaneous squamous cell carcinoma, accounting for approximately 4.9% of all SCC cases. However, there are currently no standardized criteria for the diagnosis of aSCC. This systematic review is the first to summarize the clinical and molecular features of aSCC. METHODS: A systematic search of Medline, Embase, Scopus, and PubMed was performed. All articles in English or French were included, with no restriction of publication date. All articles with original data pertaining to clinical or molecular characteristics of aSCC were included. Two reviewers screened articles and resolved conflicts. RESULTS: Our systematic review included 52 studies on the clinical and molecular features of aSCC, including a total of 482 patients (76% male, mean age at diagnosis 68.9 years): 430 cases assessed clinical features, while 149 cases assessed molecular features. The most common location of aSCC was the head and neck (n = 329/430; 76.5%). In terms of morphology, most lesions were described as nodules (n = 93/430, 21.6%), with common surface changes being hyperkeratosis (n = 6), erosion (n = 6), ulceration (n = 5), and crusting (n = 3). With regard to dermoscopy, only six cases were noted in the literature, including findings such as ulceration (n = 3), keratin clots (n = 2), and erosions (n = 2). Thirty-four studies discussed the molecular markers of aSCC, with the most prevalent markers being cytokeratins. CD15 negativity was noted in 23 cases, while common endothelial vascular markers such as CD34 (n = 16), CD31 (n = 15), factor VIII-related antigen (n = 10), and ERG (n = 1) were often not expressed. Finally, expression of intracellular adhesion molecules (i.e., E-cadherin, CD138) was markedly decreased compared to non-acantholytic invasive SCC. CONCLUSIONS: This systematic review summarizes the clinical characteristics and molecular features of aSCC. As clinical differentiation can be difficult, clinicopathological correlation with molecular markers may help ensure proper diagnosis.

The Mutational and Microenvironmental Landscape of Cutaneous Squamous Cell Carcinoma: A Review.

Cutaneous squamous cell carcinoma (cSCC) manifests through the complex interactions of UV-induced DNA damage, genetic mutations, and alterations in the tumor microenvironment. A high mutational burden is present in cSCC, as well as both cSCC precursors and normal skin, making driver genes difficult to differentiate. Despite this, several key driver genes have been identified, including TP53, the NOTCH family, CDKN2A, PIK3CA, and EGFR. In addition to mutations, the tumor microenvironment and the manipulation and evasion of the immune system play a critical role in cSCC progression. Novel therapeutic approaches, such as immunotherapy and EGFR inhibitors, have been used to target these dysregulations, and have shown promise in treating advanced cSCC cases, emphasizing the need for targeted interventions considering both genetic and microenvironmental factors for improved patient outcomes.

In Vitro Effect of Epigallocatechin Gallate on Heme Synthesis Pathway and Protoporphyrin IX Production.

Photodynamic therapy (PDT) treats nonmelanoma skin cancer. PDT kills cells through reactive oxygen species (ROS), generated by interaction among cellular O2, photosensitizer and specific light. Protoporphyrin IX (PpIX) is a photosensitizer produced from methyl aminolevulinate (MAL) by heme group synthesis (HGS) pathway. In PDT-resistant cells, PDT efficacy has been improved by addition of epigallocatechin gallate (EGCG). Therefore, the aim of this work is to evaluate the effect of EGCG properties over MAL-TFD and PpIX production on A-431 cell line. EGCG's role over cell proliferation (flow cytometry and wound healing assay) and clonogenic capability (clonogenic assay) was evaluated in A-431 cell line, while the effect of EGCG over MAL-PDT was determined by cell viability assay (MTT), PpIX and ROS detection (flow cytometry), intracellular iron quantification and gene expression of HGS enzymes (RT-qPCR). Low concentrations of EGCG (<50 µM) did not have an antiproliferative effect over A-431 cells; however, EGCG inhibited clonogenic cell capability. Furthermore, EGCG (<50 µM) improved MAL-PDT cytotoxicity, increasing PpIX and ROS levels, exerting a positive influence on PpIX synthesis, decreasing intracellular iron concentration and modifying HGS enzyme gene expression such as PGB (upregulated) and FECH (downregulated). EGCG inhibits clonogenic capability and modulates PpIX synthesis, enhancing PDT efficacy in resistant cells.

Feasibility Study on the Use of Infrared Cameras for Skin Cancer Detection under a Proposed Data Degradation Model.

Infrared thermography is considered a useful technique for diagnosing several skin pathologies but it has not been widely adopted mainly due to its high cost. Here, we investigate the feasibility of using low-cost infrared cameras with microbolometer technology for detecting skin cancer. For this purpose, we collected infrared data from volunteer subjects using a high-cost/high-quality infrared camera. We propose a degradation model to assess the use of lower-cost imagers in such a task. The degradation model was validated by mimicking video acquisition with the low-cost cameras, using data originally captured with a medium-cost camera. The outcome of the proposed model was then compared with the infrared video obtained with actual cameras, achieving an average Pearson correlation coefficient of more than 0.9271. Therefore, the model successfully transfers the behavior of cameras with poorer characteristics to videos acquired with higher-quality cameras. Using the proposed model, we simulated the acquisition of patient data with three different lower-cost cameras, namely, Xenics Gobi-640, Opgal Therm-App, and Seek Thermal CompactPRO. The degraded data were used to evaluate the performance of a skin cancer detection algorithm. The Xenics and Opgal cameras achieved accuracies of 84.33% and 84.20%, respectively, and sensitivities of 83.03% and 83.23%, respectively. These values closely matched those from the non-degraded data, indicating that employing these lower-cost cameras is appropriate for skin cancer detection. The Seek camera achieved an accuracy of 82.13% and a sensitivity of 79.77%. Based on these results, we conclude that this camera is appropriate for less critical applications.

The utility of artificial intelligence platforms for patient-generated questions in Mohs micrographic surgery: a multi-national, blinded expert panel evaluation.

BACKGROUND: Artificial intelligence (AI) and large language models (LLMs) transform how patients inform themselves. LLMs offer potential as educational tools, but their quality depends upon the information generated. Current literature examining AI as an informational tool in dermatology has been limited in evaluating AI's multifaceted roles and diversity of opinions. Here, we evaluate LLMs as a patient-educational tool for Mohs micrographic surgery (MMS) in and out of the clinic utilizing an international expert panel. METHODS: The most common patient MMS questions were extracted from Google and transposed into two LLMs and Google's search engine. 15 MMS surgeons evaluated the generated responses, examining their appropriateness as a patient-facing informational platform, sufficiency of response in a clinical environment, and accuracy of content generated. Validated scales were employed to assess the comprehensibility of each response. RESULTS: The majority of reviewers deemed all LLM responses appropriate. 75% of responses were rated as mostly accurate or higher. ChatGPT had the highest mean accuracy. The majority of the panel deemed 33% of responses sufficient for clinical practice. The mean comprehensibility scores for all platforms indicated a required 10th-grade reading level. CONCLUSIONS: LLM-generated responses were rated as appropriate patient informational sources and mostly accurate in their content. However, these platforms may not provide sufficient information to function in a clinical environment, and complex comprehensibility may represent a barrier to utilization. As the popularity of these platforms increases, it is important for dermatologists to be aware of these limitations.

Classification of melanocytic lesions using direct illumination multispectral imaging.

With rising melanoma incidence and mortality, early detection and surgical removal of primary lesions is essential. Multispectral imaging is a new, non-invasive technique that can facilitate skin cancer detection by measuring the reflectance spectra of biological tissues. Currently, incident illumination allows little light to be reflected from deeper skin layers due to high surface reflectance. A pilot study was conducted at the University Hospital Basel to evaluate, whether multispectral imaging with direct light coupling could extract more information from deeper skin layers for more accurate dignity classification of melanocytic lesions. 27 suspicious pigmented lesions from 23 patients were included (6 melanomas, 6 dysplastic nevi, 12 melanocytic nevi, 3 other). Lesions were imaged before excision using a prototype snapshot mosaic multispectral camera with incident and direct illumination with subsequent dignity classification by a pre-trained multispectral image analysis model. Using incident light, a sensitivity of 83.3% and a specificity of 58.8% were achieved compared to dignity as determined by histopathological examination. Direct light coupling resulted in a superior sensitivity of 100% and specificity of 82.4%. Convolutional neural network classification of corresponding red, green, and blue lesion images resulted in 16.7% lower sensitivity (83.3%, 5/6 malignant lesions detected) and 20.9% lower specificity (61.5%) compared to direct light coupling with multispectral image classification. Our results show that incorporating direct light multispectral imaging into the melanoma detection process could potentially increase the accuracy of dignity classification. This newly evaluated illumination method could improve multispectral applications in skin cancer detection. Further larger studies are needed to validate the camera prototype.

31-GEP (DecisionDx): a review of clinical utility and performance in a Mayo Clinic cohort.

BACKGROUND: Cutaneous melanoma (CM) is a significant health concern because of its high metastatic potential. Gene Expression Profile (GEP) testing, particularly the 31-GEP test (DecisionDx-Melanoma), has been increasingly used for risk stratification in CM patients. This study aimed to evaluate the clinical utility and performance of the 31-GEP test in a real-world setting. METHODS: Patients with CM who underwent 31-GEP testing from August 2014 to August 2022 at our institution were identified through searches of electronic health records. The study analyzed the influence of 31-GEP testing on clinical decision-making related to sentinel lymph node biopsy (SLNB), medical oncology referral, and postdiagnosis surveillance. Kaplan-Meier curves and Cox proportional hazard models were used to elucidate the test's performance, focusing on relapse-free survival (RFS) and melanoma-specific survival (MSS). RESULTS: The study included 65 CM patients. Dermatologists ordered more than 80% of 31-GEP tests. In 81.5% of cases, 31-GEP results did not alter standard clinical management. SLNB decisions were unaffected in 92% of patients with pre-SLNB 31-GEP results. Among patients with stage I-IIA melanoma, 25% of those with high-risk 31-GEP results were referred to medical oncology. Contrary to expectations, the rate of nodal metastasis was higher in low-risk than in high-risk 31-GEP cases. Survival analysis showed overlapping RFS and MSS curves between different 31-GEP classes, suggesting limited prognostic value. CONCLUSIONS: The 31-GEP test has a limited impact on clinical management decisions and shows limited prognostic value.

Cutaneous Oncology: Strategies for Melanoma Prevention, Diagnosis, and Therapy.

Skin cancer comprises one-third of all diagnosed cancer cases and remains a major health concern. Genetic and environmental parameters serve as the two main risk factors associated with the development of skin cancer, with ultraviolet radiation being the most common environmental risk factor. Studies have also found fair complexion, arsenic toxicity, indoor tanning, and family history among the prevailing causes of skin cancer. Prevention and early diagnosis play a crucial role in reducing the frequency and ensuring effective management of skin cancer. Recent studies have focused on exploring minimally invasive or non-invasive diagnostic technologies along with artificial intelligence to facilitate rapid and accurate diagnosis. The treatment of skin cancer ranges from traditional surgical excision to various advanced methods such as phototherapy, radiotherapy, immunotherapy, targeted therapy, and combination therapy. Recent studies have focused on immunotherapy, with the introduction of new checkpoint inhibitors and personalized immunotherapy enhancing treatment efficacy. Advancements in multi-omics, nanotechnology, and artificial intelligence have further deepened the understanding of the mechanisms underlying tumoral growth and their interaction with therapeutic effects, which has paved the way for precision oncology. This review aims to highlight the recent advancements in the understanding and management of skin cancer, and provide an overview of existing and emerging diagnostic, prognostic, and therapeutic modalities, while highlighting areas that require further research to bridge the existing knowledge gaps.

Basosquamous carcinoma: Comprehensive epidemiological, clinical, dermoscopic, and confocal features from a single center institution.

BACKGROUND: Basosquamous carcinoma (BSC) is a rare and aggressive nonmelanoma skin cancer (NMSC) that exhibits features of both BCC and squamous cell carcinoma (SCC). The gold standard for diagnosis is histopathological examination. BSC is often challenging to diagnose and manage due to its mixed histological features and potential for aggressive behavior AIM: To identify specific features aiding clinicians in differentiating BSCs using non-invasive diagnostic techniques. METHODS: We conducted a retrospective descriptive, monocentric study of the epidemiological clinical, dermoscopic, and reflectance confocal microscopy (RCM) features of histopathologically proven BSCs diagnosed between 2010 and 2023. A total of 192 cases were selected. RESULTS: The study population consisted of 17 men (60.9%). Total 95.8% of patients at the time of diagnosis were ≥50 years. BSC occurred in the head and neck area in 124 cases (63.1%) of which 65 (33.9%) were in the H-zone. For 47.4% of patients, BSC presented as a macule with undefined clinical margins (43.3%). Dermoscopic images were available for 98 cases: the most common parameter was the presence of whitish structureless areas (59 [60.2%]), keratin masses (58 [59.2%]), superficial scales, and ulceration or blood crusts (49 [50%] both). Vessels pattern analysis revealed hairpin vessels (exclusively) and linear irregular vessels as the most frequent (55 [56.1%] both). RCM examination was performed in 21 cases which revealed specific SCC features such as solar elastosis (19 [90.5%]), atypical honeycomb pattern (17 [89%]), proliferation of atypical keratinocytes (16 [80%]) combined with BCC' ones as bright tumor islands (12 [57.8%]), and cleft-like dark spaces (11 [53.4%]). DISCUSSION: Our study reflects the largest cohort of BSCs from a single institution. We described an incidence rate of 4.7%, higher than reported in the Literature, with the involvement of patients ≥50years in almost 96% of cases and an overall male predominance. At clinical examination, BSC was described as a hyperkeratotic macule with undefined clinical margins with one or more dermoscopic SCC' features, whereas the presence of typical BCC aspects was observed in less than 10% of cases, differently from what was previously reported. At RCM analysis, BSCs presented with an atypical honeycomb pattern with proliferation of atypical keratinocytes, hyperkeratosis, and in nearly 55% of patients, bright tumor islands with cleft-like dark spaces. CONCLUSION: The distinctive dermoscopic patterns, along with the RCM features aid in the differentiation of BSCs from other NMSCs.

Dermoscopy of skin metastases in advanced cancer-systemic (visceral, hematologic) and cutaneous.

Introduction: Skin metastases arise in 10% of cancer patients, but standardized dermoscopy diagnostic criteria for skin metastases remain poor. This study's objective was to analyze the dermoscopy features of skin metastases from advanced systemic and cutaneous cancers. Methods: A retrospective study on 715 dermoscopy images of skin metastases from 33 patients with various primary cancers (breast, ovary, melanoma, non-melanoma skin cancer, and chronic leukemia) attending two academic centers between 2013 and 2023 was performed. Four independent observers blindly analyzed patterns, colors, vessels, and elementary lesions for each metastasis (30 parameters in total). Results: The structureless white pattern was the most prominent indicator of cutaneous metastasis (81.26%, p < 0.001). Regardless of the primary tumor, colors pink, red, white, and tan were identified. Elementary lesions were infrequent, except for melanoma metastases that displayed dots (13.23%) and globules (11.11%). Breast cancer metastases presented: blue (41.48%) and red (34.32%) colors, irregular vessels (13.58%), and a blue-naevus pattern (22.22%). Melanoma metastases displayed: a blue-naevus pattern (61.38%), a blue color (85.71%), and a structureless-blue combination pattern (79.37%). Non-melanoma skin cancer metastases were characterized by vascular (42.11%) and angioma-like (31.58%) patterns, pink (57.89%) and red (57.89%) colors, irregular (57.89%), thin hairpin (47.37%), comma (47, 37%), and thick hairpin (26, 32%) vessels and a red, white and irregular vessels combination pattern (52, 63%). A pink structureless combination pattern was frequent (61.05%) in chronic leukemia metastases. Ovarian cancer metastases displayed a white and tan structureless combination pattern (100%) and frequently had dotted vessels (42.85%). Conclusion: Papules and nodules with a white structureless pattern suggest skin metastases, regardless of the primary tumor. A blue structureless lesion is indicative of melanoma metastasis and a vascular pattern with irregular vessels indicates a non-melanoma skin cancer metastasis. Dermoscopy stands as a reliable non-invasive diagnostic method for suspected cutaneous metastases in patients with a known cancer history.

Elastic Scattering Spectroscopy on Patient-Selected Lesions Concerning for Skin Cancer.

BACKGROUND: Access to dermatologists is limited in parts of the US, making primary care clinicians (PCCs) integral for early detection of skin cancers. A handheld device using elastic scattering spectroscopy (ESS) was developed to aid PCCs in their clinical assessment of skin lesions. METHODS: In this prospective study, 3 PCCs evaluated skin lesions reported by patients as concerning and scanned each lesion with the handheld ESS device. The comparison was pathology results or a 3-dermatologist panel examining high resolution dermatoscopic and clinical images. PCCs reported their diagnosis, management decision, and confidence level for each lesion. Evaluation of results included sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and Area Under the Curve (AUC). RESULTS: A total of 155 patients and 178 lesions were included in the final analysis. The most commonly patient-reported concerning feature was "new or changing lesion" (91.6%). Device diagnostic sensitivity and specificity were 90.0% and 60.7%, respectively, based on biopsy result or dermatologist panel reference standard; comparatively, PCC sensitivity was 40.0% and 84.8% specificity without the use of the device. Device NPV was 98.9%, and device PPV was 13.6%. The device recommended patient referral to dermatology with 88.2% concordance with the dermatologist panel. AUC for the device and PCCs were 0.815 and 0.643, respectively. CONCLUSIONS: The use of the ESS device by PCCs can improve diagnostic and management sensitivity for select malignant skin lesions by correctly classifying most benign lesions of patient concern. This may increase skin cancer detection while improving access to specialist care.

Association between cathepsins and skin cancers: A bidirectional two-sample Mendelian randomization study.

BACKGROUND: Several cathepsins have been identified as being involved in the development of cancer. Nevertheless, the connection between cathepsins and skin cancers remained highly elusive. METHODS: A bidirectional Mendelian randomization (MR) analysis was performed to investigate the causal association between cathepsins and skin malignancies. The genome-wide association studies (GWAS) data for cathepsins, malignant melanoma (MM), and basal cell carcinoma (BCC) were obtained from European research. The primary method employed was inverse variance weighted. In addition, MR-Egger, weighted median, weighted mode, and simple mode were also executed. Sensitivity analysis was performed using Cochran's Q test, MR-Egger, and MR-PRESSO. RESULTS: From univariable MR (UVMR), cathepsin H, and S were determined to have a causal relationship with BCC. Additionally, cathepsin H was identified as associated with MM. Multivariable MR (MVMR) showed that after correcting for risk factors of skin carcinoma, cathepsin H was detected to be protective against BCC, whereas cathepsin S has been observed as a risk factor for BCC. No substantial pleiotropy and heterogeneity were identified in the sensitivity analysis. CONCLUSION: This study was the first to establish a direct link between cathepsins and skin malignancies. Cathepsin H and S have the potential to serve as new biomarkers for BCC, offering valuable assistance in the prompt identification, treatment, and prevention of the disease. Nevertheless, additional clinical trials are required to validate our findings.