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Skin Cancers as a Paradigm Shift: From Pathobiology to Treatment

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 30 August 2024 | Viewed by 10034

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Dr. Ioannis D. Bassukas

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Department of Skin and Venereal Diseases, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
Interests: keratinocyte skin cancer; minimally invasive treatment modalities

Dr. Panagiota Spyridonos

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Guest Editor

Faculty of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina, Greece
Interests: medical image analysis; machine learning; computer aided skin diagnostics; treatment evaluation
Special Issues, Collections and Topics in MDPI journals

Dr. Georgios Gaitanis

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Guest Editor

Department of Skin and Venereal Diseases, Faculty of Medicine, School of Health Sciences, University of Ioannina, 45100, Ioannina, Greece
Interests: minimally invasive treatment and diagnostics; medical photography

Special Issue Information

Dear Colleagues

We are pleased to announce this Special Issue in Cancers which has the scope to provide a comprehensive update on the current knowledge pertaining to skin cancers, as delineated by the title and the relevant aims.

It is well-established that in humans, compared to other body tissues and organs, most malignant and non-malignant neoplasms affect the skin and, in particular, the epidermis. Additionally, the development of malignant skin cancers is relatively slower and has a comparatively better prognosis than cancers of other tissue origins. Histogenetically, malignant skin neoplasms originate predominately from the permanently residing cells of the skin epithelium (keratinocytes, melanocytes, Merkel cells), and less commonly from the transiently cycling populations of Langerhans cells and lymphocytes, as well as from cellular components of the dermal and subdermal compartments of the skin, including the endothelia. On the other hand, ultraviolet radiation (UVR) is an established complete carcinogen for the skin, responsible for >90% of all skin cancers and with a particular impact on epidermal cancers. Notably, most skin carcinogenesis occurs in a spatially restricted tissue niche, the single cell layer of the basal epidermis, which, however, is expanded on the whole skin surface and is thus subjected to a significantly varying degree to the environmental carcinogen UVR during life. Thus, human skin neoplasms, particularly UVR-induced keratinocyte skin cancers, are a suitable model for studying two key dogmas of contemporary oncology: Multifocal carcinogenesis within cutaneous cancerization fields and multistage carcinogenesis. Furthermore, the relatively slow progression of the majority of the ensuing cutaneous pre-cancers and cancers, as well as the accessibility of the skin to medical interventions, emphasize the role of dermato-oncology as an ideal scientific and clinical area for the evaluation of emerging concepts of innovative non- to minimally invasive modalities for the diagnosis, treatment, and follow-up of cancer.

This Special Issue aims to:

Update the current knowledge on the epidemiology and pathobiology of skin cancers;
Address recent developments in the non-invasive imaging-based approaches to the diagnosis, treatment evaluation, and follow-up of skin cancer, also incorporating novel advents from the field of artificial intelligence;
Investigate the potential of minimally invasive therapeutic modalities for treating selected types of skin neoplasms or addressing the specific treatment demands of certain patient populations.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following: epidemiology, pathobiology of skin cancer, minimally invasive diagnostics and treatment, artificial intelligence/machine learning in dermato-oncology, and therapeutic issues in selected populations (e.g., immunocompromised, older-old, etc.)

We look forward to receiving your contributions.

Dr. Ioannis D. Bassukas
Dr. Panagiota Spyridonos
Dr. Georgios Gaitanis
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

skin cancer
pathobiology
diagnosis
artificial intelligence
machine learning
treatment

Published Papers (8 papers)

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Research

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36 pages, 17669 KiB

Open AccessArticle

Type I Diabetes Mellitus Suppresses Experimental Skin Carcinogenesis

by Maria Giakoumaki, George I. Lambrou, Dimitrios Vlachodimitropoulos, Anna Tagka, Andreas Vitsos, Maria Kyriazi, Aggeliki Dimakopoulou, Vasiliki Anagnostou, Marina Karasmani, Heleni Deli, Andreas Grigoropoulos, Evangelos Karalis, Michail Christou Rallis and Homer S. Black

Cancers 2024, 16(8), 1507; https://doi.org/10.3390/cancers16081507 - 15 Apr 2024

Viewed by 356

Abstract

This study explores the previously uncharted territory of the effects of ultraviolet (UV) radiation on diabetic skin, compared to its well-documented impact on normal skin, particularly focusing on carcinogenesis and aging. Employing hairless SKH-hr2, Type 1 and 2 diabetic, and nondiabetic male mice, the research subjected these to UV radiation thrice weekly for eight months. The investigation included comprehensive assessments of photoaging and photocarcinogenesis in diabetic versus normal skin, measuring factors such as hydration, trans-epidermal water loss, elasticity, skin thickness, melanin, sebum content, stratum corneum exfoliation and body weight, alongside photo documentation. Additionally, oxidative stress and the presence of hydrophilic antioxidants (uric acid and glutathione) in the stratum corneum were evaluated. Histopathological examination post-sacrifice provided insights into the morphological changes. Findings reveal that under UV exposure, Type 1 diabetic skin showed heightened dehydration, thinning, and signs of accelerated aging. Remarkably, Type 1 diabetic mice did not develop squamous cell carcinoma or pigmented nevi, contrary to normal and Type 2 diabetic skin. This unexpected resistance to UV-induced skin cancers in Type 1 diabetic skin prompts a crucial need for further research to uncover the underlying mechanisms providing this resistance. Full article

(This article belongs to the Special Issue Skin Cancers as a Paradigm Shift: From Pathobiology to Treatment)

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9 pages, 238 KiB

Open AccessArticle

Delay in Cutaneous Squamous Cell Carcinoma Diagnosis Due to Interrupted Services Is Associated with Worse Prognoses and Modified Surgical Approaches

by Filippo Taccioli, Claudio Gio Francesco Blessent, Alessia Paganelli, Francesca Fagioli, Johanna Mary Chester, Shaniko Kaleci, Matteo Costantini, Barbara Ferrari, Chiara Fiorentini, Giorgio De Santis and Cristina Magnoni

Cancers 2024, 16(8), 1469; https://doi.org/10.3390/cancers16081469 - 11 Apr 2024

Viewed by 405

Abstract

Background: The delayed diagnosis of skin tumors is associated with a worsened prognosis. The impact of the interruption of clinical and surgical health services during the COVID-19 pandemic lockdowns has been documented among many pathologies. The impact of delayed diagnoses on patients with cutaneous squamous cell carcinomas (cSCCs) is poorly defined. Objective: To compare patient and lesion characteristics and the surgical management of excised cSCCs prior to the pandemic shutdown of services (2018–2019) with the phase following the pandemic’s second wave (2021–2022). Methods: An observational, single-center, cross-sectional study of 416 surgically excised cSCCs over the course of two years was performed. Only patients with histologically confirmed cSCC were enrolled. Data collection included patient demographics and lesion characteristics, time to surgery, surgical approach, and histological data. Results: More cSCC lesions were excised prior to the interruption of services (n = 312 vs. n = 186). Lesions were significantly larger (1.7 ± 1.2 vs. 2.1 ± 1.5 cm; p = 0.006) and more invasive (52% vs. 89%; p < 0.001), in the period 2021–2022. Surgical reconstructive techniques were significantly different (p = 0.001). Metastatic involvement was confirmed in three subjects (one in 2018–2019 and two in 2021–2022). There were no significant differences in the time to surgery or patient characteristics. Multivariable regression analysis identified a 4.7-times higher risk of tumor invasion (OR 4.69, 95%CI 2.55–8.16, p < 0.001), a two-times higher chance of dermo-epidermal grafts (OR 2.06, 95%CI 1.09–3.88, p = 0.025), and a 3.2-times higher risk of positive surgical margins (OR 3.21, 95%CI 1.44–7.17, p = 0.004). Conclusions: Diagnostic delays of cutaneous SCCs associated with reduced patient access to clinical and diagnostic services are associated with a 4.7-times increased risk of more severe invasion, a three-times increased risk of positive surgical margins, and a significant impact on surgical management, compared to the pre-pandemic period. Comparable patient cohort characteristics and time to surgery remained unchanged. Full article

(This article belongs to the Special Issue Skin Cancers as a Paradigm Shift: From Pathobiology to Treatment)

19 pages, 2870 KiB

Open AccessArticle

Real-World Data on Clinical Outcomes and Treatment Management of Advanced Melanoma Patients: Single-Center Study of a Tertiary Cancer Center in Switzerland

by Ramon Staeger, Julia M. Martínez-Gómez, Patrick Turko, Egle Ramelyte, Lukas Kraehenbuehl, Valerio Del Prete, Omar Hasan Ali, Mitchell P. Levesque, Reinhard Dummer, Mirjam C. Nägeli and Joanna Mangana

Cancers 2024, 16(5), 854; https://doi.org/10.3390/cancers16050854 - 20 Feb 2024

Viewed by 769

Abstract

Background: Immune checkpoint inhibitors (ICIs) and BRAF/MEK inhibitors (BRAF/MEKi) have drastically changed the outcomes of advanced melanoma patients in both the resectable/adjuvant and unresectable/metastatic setting. In this follow-up analysis of real-world data, we aimed to investigate the clinical management and outcomes of advanced melanoma patients in a tertiary referral center in Switzerland approximately a decade after the introduction of ICIs and BRAF/MEKi into clinical use. Moreover, we aimed to compare the results with seminal phase 3 trials and to identify areas of high unmet clinical need. Methods: This single-center retrospective cohort study analyzed the melanoma registry of the University Hospital Zurich, a tertiary cancer center in Switzerland, and included patients treated in the resectable/adjuvant (n = 331) or unresectable/metastatic setting (n = 375). Results: In the resectable setting, adjuvant anti-PD1 or BRAF/MEKi showed a 3-year relapse-free survival (RFS) of 53% and 67.6%, respectively, and the overall median RFS was 50 months. Patients with lymph node plus in-transit metastases or with distant metastases prior to commencing adjuvant treatment had a significantly reduced overall survival (OS). In 10.9% of patients, the treatment was stopped due to toxicity, which did not affect RFS/OS, unless the duration of the treatment was <3 months. Following a relapse of the disease during the first adjuvant treatment, the median progression-free survival (PFS2) was only 6.6 months; outcomes were particularly poor for relapses that were unresectable (median PFS2 3.9 months) or occurred within the first 2 months (median PFS2 2.7 months). A second adjuvant treatment for patients with resectable relapses still showed efficacy (median RFS2 43.7 months). Elevated LDH levels in patients with an unresectable relapse was correlated with a strong reduction in OS2 (HR 9.84, p = 0.018). In the unresectable setting, first-line anti-PD1, anti-CTLA4/PD1 combination, or BRAF/MEKi showed a 5-year OS of 46.5%, 52.4%, and 49.2%, respectively. In a multivariate analysis, elevated LDH levels or the presence of brain metastases substantially shortened OS (HR > 1.78, p < 0.035). There was a non-significant trend for the improved survival of patients treated with anti-CTLA4/PD1 compared to anti-PD1 (HR 0.64, p = 0.15). After a progression on first-line therapy, the median OS2 was reduced to below two years. Elevated LDH (HR 4.65, p < 0.001) levels and widespread disease with at least three metastatic sites, particularly bone metastases (HR 2.62, p = 0.026), affected OS2. Conclusion: Our study offers real-world insights into the clinical management, treatment patterns, and outcomes of advanced melanoma patients in both the adjuvant and unresectable setting. Early relapses in patients undergoing adjuvant treatment pose a particular challenge but these patients are generally excluded from first-line trials. The approved first-line metastatic treatments are highly effective in the real-world setting with 5-year OS rates around 50%. However, outcomes remain poor for patients with brain metastases or who fail first-line treatment. Full article

(This article belongs to the Special Issue Skin Cancers as a Paradigm Shift: From Pathobiology to Treatment)

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17 pages, 6928 KiB

Open AccessArticle

Internet of Things-Assisted Smart Skin Cancer Detection Using Metaheuristics with Deep Learning Model

by Marwa Obayya, Munya A. Arasi, Nabil Sharaf Almalki, Saud S. Alotaibi, Mutasim Al Sadig and Ahmed Sayed

Cancers 2023, 15(20), 5016; https://doi.org/10.3390/cancers15205016 - 17 Oct 2023

Cited by 2 | Viewed by 1280

Abstract

Internet of Things (IoT)-assisted skin cancer recognition integrates several connected devices and sensors for supporting the primary analysis and monitoring of skin conditions. A preliminary analysis of skin cancer images is extremely difficult because of factors such as distinct sizes and shapes of lesions, differences in color illumination, and light reflections on the skin surface. In recent times, IoT-based skin cancer recognition utilizing deep learning (DL) has been used for enhancing the early analysis and monitoring of skin cancer. This article presents an optimal deep learning-based skin cancer detection and classification (ODL-SCDC) methodology in the IoT environment. The goal of the ODL-SCDC technique is to exploit metaheuristic-based hyperparameter selection approaches with a DL model for skin cancer classification. The ODL-SCDC methodology involves an arithmetic optimization algorithm (AOA) with the EfficientNet model for feature extraction. For skin cancer detection, a stacked denoising autoencoder (SDAE) classification model has been used. Lastly, the dragonfly algorithm (DFA) is utilized for the optimal hyperparameter selection of the SDAE algorithm. The simulation validation of the ODL-SCDC methodology has been tested on a benchmark ISIC skin lesion database. The extensive outcomes reported a better solution of the ODL-SCDC methodology compared with other models, with a maximum sensitivity of 97.74%, specificity of 99.71%, and accuracy of 99.55%. The proposed model can assist medical professionals, specifically dermatologists and potentially other healthcare practitioners, in the skin cancer diagnosis process. Full article

(This article belongs to the Special Issue Skin Cancers as a Paradigm Shift: From Pathobiology to Treatment)

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17 pages, 4707 KiB

Open AccessArticle

The Promise of Semantic Segmentation in Detecting Actinic Keratosis Using Clinical Photography in the Wild

by Panagiotis Derekas, Panagiota Spyridonos, Aristidis Likas, Athanasia Zampeta, Georgios Gaitanis and Ioannis Bassukas

Cancers 2023, 15(19), 4861; https://doi.org/10.3390/cancers15194861 - 05 Oct 2023

Viewed by 784

Abstract

AK is a common precancerous skin condition that requires effective detection and treatment monitoring. To improve the monitoring of the AK burden in clinical settings with enhanced automation and precision, the present study evaluates the application of semantic segmentation based on the U-Net architecture (i.e., AKU-Net). AKU-Net employs transfer learning to compensate for the relatively small dataset of annotated images and integrates a recurrent process based on convLSTM to exploit contextual information and address the challenges related to the low contrast and ambiguous boundaries of AK-affected skin regions. We used an annotated dataset of 569 clinical photographs from 115 patients with actinic keratosis to train and evaluate the model. From each photograph, patches of 512 × 512 pixels were extracted using translation lesion boxes that encompassed lesions in different positions and captured different contexts of perilesional skin. In total, 16,488 translation-augmented crops were used for training the model, and 403 lesion center crops were used for testing. To demonstrate the improvements in AK detection, AKU-Net was compared with plain U-Net and U-Net++ architectures. The experimental results highlighted the effectiveness of AKU-Net, improving upon both automation and precision over existing approaches, paving the way for more effective and reliable evaluation of actinic keratosis in clinical settings. Full article

(This article belongs to the Special Issue Skin Cancers as a Paradigm Shift: From Pathobiology to Treatment)

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12 pages, 2625 KiB

Open AccessArticle

Image Perceptual Similarity Metrics for the Assessment of Basal Cell Carcinoma

by Panagiota Spyridonos, Georgios Gaitanis, Aristidis Likas, Konstantinos Seretis, Vasileios Moschovos, Laurence Feldmeyer, Kristine Heidemeyer, Athanasia Zampeta and Ioannis D. Bassukas

Cancers 2023, 15(14), 3539; https://doi.org/10.3390/cancers15143539 - 08 Jul 2023

Viewed by 890

Abstract

Efficient management of basal cell carcinomas (BCC) requires reliable assessments of both tumors and post-treatment scars. We aimed to estimate image similarity metrics that account for BCC’s perceptual color and texture deviation from perilesional skin. In total, 176 clinical photographs of BCC were assessed by six physicians using a visual deviation scale. Internal consistency and inter-rater agreement were estimated using Cronbach’s α, weighted Gwet’s AC2, and quadratic Cohen’s kappa. The mean visual scores were used to validate a range of similarity metrics employing different color spaces, distances, and image embeddings from a pre-trained VGG16 neural network. The calculated similarities were transformed into discrete values using ordinal logistic regression models. The Bray–Curtis distance in the YIQ color model and rectified embeddings from the ‘fc6’ layer minimized the mean squared error and demonstrated strong performance in representing perceptual similarities. Box plot analysis and the Wilcoxon rank-sum test were used to visualize and compare the levels of agreement, conducted on a random validation round between the two groups: ‘Human–System’ and ‘Human–Human.’ The proposed metrics were comparable in terms of internal consistency and agreement with human raters. The findings suggest that the proposed metrics offer a robust and cost-effective approach to monitoring BCC treatment outcomes in clinical settings. Full article

(This article belongs to the Special Issue Skin Cancers as a Paradigm Shift: From Pathobiology to Treatment)

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Review

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21 pages, 2354 KiB

Open AccessReview

Cutaneous Side Effects of Modern Targeted Therapy and Immunotherapy in Patients with Dermatological Malignancies

by Kerasia-Maria Plachouri, Vaia Florou, Vasileios Georgiou and Sophia Georgiou

Cancers 2023, 15(12), 3126; https://doi.org/10.3390/cancers15123126 - 09 Jun 2023

Cited by 1 | Viewed by 1461

Abstract

The advent of immunotherapy and targeted therapies in treating dermatological malignancies has dramatically changed the landscape of dermato-oncology in recent years. Their superior efficacy compared to previous therapeutic options, such as chemotherapy, has resulted in their use in treating devastating malignancies, such as melanoma or unresectable/metastatic basal cell and squamous cell carcinoma. Skin toxicity is a critical safety consideration, among other adverse reactions, that can occur under treatment with these agents. This article aims to summarize the cutaneous side effects of immune checkpoint inhibitors and targeted dermato-oncological therapies. Although the skin side effects of these agents are primarily mild, they can occasionally affect the decision for treatment continuation and the quality of life of the affected patients. Therefore, physicians must be acquainted with the specific cutaneous toxicity profile of such treatments to mitigate their impact on the patients and optimize the overall outcome of dermato-oncological therapy. Full article

(This article belongs to the Special Issue Skin Cancers as a Paradigm Shift: From Pathobiology to Treatment)

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20 pages, 2055 KiB

Open AccessReview

Merkel Cell Carcinoma—Update on Diagnosis, Management and Future Perspectives

by Eleni Zaggana, Maria Polina Konstantinou, Gregor Herrmann Krasagakis, Eelco de Bree, Konstantinos Kalpakis, Dimitrios Mavroudis and Konstantinos Krasagakis

Cancers 2023, 15(1), 103; https://doi.org/10.3390/cancers15010103 - 23 Dec 2022

Cited by 8 | Viewed by 3221

Abstract

MCC is a rare but highly aggressive skin cancer. The identification of the driving role of Merkel cell polyomavirus (MCPyV) and ultraviolet-induced DNA damage in the oncogenesis of MCC allowed a better understanding of its biological behavior. The presence of MCPyV-specific T cells and lymphocytes exhibiting an ‘exhausted’ phenotype in the tumor microenvironment along with the high prevalence of immunosuppression among affected patients are strong indicators of the immunogenic properties of MCC. The use of immunotherapy has revolutionized the management of patients with advanced MCC with anti-PD-1/PD L1 blockade, providing objective responses in as much as 50–70% of cases when used in first-line treatment. However, acquired resistance or contraindication to immune checkpoint inhibitors can be an issue for a non-negligible number of patients and novel therapeutic strategies are warranted. This review will focus on current management guidelines for MCC and future therapeutic perspectives for advanced disease with an emphasis on molecular pathways, targeted therapies, and immune-based strategies. These new therapies alone or in combination with anti-PD-1/PD-L1 inhibitors could enhance immune responses against tumor cells and overcome acquired resistance to immunotherapy. Full article

(This article belongs to the Special Issue Skin Cancers as a Paradigm Shift: From Pathobiology to Treatment)

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