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Recent Progress in the Diagnosis and Treatment of Melanoma and Other Skin Cancers

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 27598

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Dr. Reinhard Dummer

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Guest Editor

Department of Dermatology, University Hospital Zurich, 8091 Zurich, Switzerland
Interests: skin cancer immunology; immunotherapy; targeted therapy; melanoma; non-melanoma skin cancer; cutaneous lymphoma

Dr. Florentia Dimitriou

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Guest Editor

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Dear Colleagues,

The treatment landscape of early and advanced melanoma has changed dramatically in recent years. Key advances in molecular biology and tumor genetics have led to the application of immune-checkpoint inhibitors (ICIs) and BRAF/MEK inhibitors in the treatment of advanced melanoma with increased efficacy and durability of response in a subset of patients. Currently, these treatments have been shown to reduce the risk of recurrence when used in the adjuvant or neo-adjuvant setting. Following the paradigm in advanced melanoma, the development of ICIs and targeted therapies has also shifted the management of other skin cancers, including cutaneous squamous cell, basal cell, and Merkel cell carcinoma, and the future of the drug development is still bright. Despite these significant improvements, many patients still develop treatment resistance, which can be observed either initially (primary resistance) or secondarily (acquired resistance), and further research in this field is required. Strategies to reduce toxicities and overcome resistance, as well as predictive and prognostic biomarkers to guide patient selection, are fundamental in this rapidly evolving treatment landscape.

This Special Issue of Cancers will focus on recent updates in the diagnosis and treatment of melanoma and other skin cancers.

Dr. Reinhard Dummer
Dr. Florentia Dimitriou
Guest Editors

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Keywords

skin cancer
melanoma
non-melanoma skin cancer
immunotherapy
targeted therapy
toxicity

Published Papers (10 papers)

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Editorial

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3 pages, 201 KiB

Open AccessEditorial

Recent Progress in the Diagnosis and Treatment of Melanoma and Other Skin Cancers

by Laura Pawlik, Sarah Morgenroth and Reinhard Dummer

Cancers 2023, 15(6), 1824; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15061824 - 17 Mar 2023

Cited by 3 | Viewed by 1315

Abstract

In this Special Issue, the reader will find nine papers regarding recent progress in diagnosis and treatment to optimize the clinical management of melanoma and non-melanoma skin cancer [...] Full article

(This article belongs to the Special Issue Recent Progress in the Diagnosis and Treatment of Melanoma and Other Skin Cancers)

Research

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18 pages, 3381 KiB

Open AccessArticle

Clinical Presentation and Prognostic Features in Patients with Immunotherapy-Induced Vitiligo-like Depigmentation: A Monocentric Prospective Observational Study

by Nicola Hermann, Lara Valeska Maul, Milad Ameri, Stephan Traidl, Reihane Ziadlou, Karolina Papageorgiou, Isabel Kolm, Mitchell Levesque, Julia-Tatjana Maul and Marie-Charlotte Brüggen

Cancers 2022, 14(19), 4576; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194576 - 21 Sep 2022

Cited by 6 | Viewed by 2612

Abstract

Vitiligo-like depigmentation (VLD) is an immune-related adverse event (irAE) of checkpoint-inhibitor (CPI) treatment, which has previously been associated with a favourable outcome. The aim of this study was to explore clinical, biological and prognostic features of melanoma patients with VLD under CPI-treatment and to explore whether they exhibit a characteristic immune response profile in peripheral blood. Melanoma patients developing VLD under CPI were included in a prospective observational single-center cohort study. We collected and analysed clinical parameters, photographs and serum from 28 VLD patients. They received pembrolizumab (36%), nivolumab (11%), ipilimumab/nivolumab (32%) or clinical trial medications (21%). We performed a high-throughput proteomics assay (Olink), in which we identified a distinct proteomic signature in VLD patients in comparison to non-VLD CPI patients. Our clinical assessments revealed that VLD lesions had a predominantly symmetrical distribution pattern, with mostly smaller “freckle-like” macules and a preferential distribution in UV-exposed areas. Patients with previous targeted therapy showed a significantly longer time lapse between CPI initiation and VLD onset compared to non-pre-treated patients (12.5 vs. 6.25 months). Therapy responders exhibited a distinct proteomic profile when compared with non-responders in VLD such as upregulation of EDAR and downregulation of LAG3. ITGA11 was elevated in the VLD-group when compared to non-VLD-CPI-treated melanoma patients. Our findings demonstrate that on a proteomic level, VLD is characterized by a distinct immune signature when compared to CPI-treated patients without VLD and that therapy responsiveness is reflected by a characteristic immune profile. The pathomechanisms underlying these findings and how they could relate to the antitumoral response in melanoma remain to be elucidated. Full article

(This article belongs to the Special Issue Recent Progress in the Diagnosis and Treatment of Melanoma and Other Skin Cancers)

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Graphical abstract

12 pages, 2193 KiB

Open AccessArticle

The Prognostic Value of a Single, Randomly Timed Circulating Tumor DNA Measurement in Patients with Metastatic Melanoma

by Aurelio Boerlin, Elisa Bellini, Patrick Turko, Phil F. Cheng, Mitchell P. Levesque, Reinhard Dummer and Egle Ramelyte

Cancers 2022, 14(17), 4158; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14174158 - 27 Aug 2022

Cited by 5 | Viewed by 1957

Abstract

Melanoma currently lacks validated blood-based biomarkers for monitoring and predicting treatment efficacy. Circulating tumor DNA (ctDNA), originating from tumor cells and detectable in plasma, has emerged as a possible biomarker in patients with metastatic melanoma. In this retrospective, single-center study, we collected 129 plasma samples from 79 patients with stage IIIB–IV melanoma as determined by the American Joint Committee on Cancer (AJCC, 8th edition). For the determination of ctDNA levels, we used eight different assays of droplet digital polymerase chain reaction (ddPCR) to detect the most common hotspot mutations in the BRAF and NRAS genes. The aim of the study was to investigate the association of the detectability of ctDNA at a non-prespecified time point in a patient’s treatment with tumor progression, and to correlate ctDNA with commonly used biomarkers (protein S100, LDH, and CRP). Patients with detectable ctDNA progressed more frequently in PET-CT within 12 months than those without detectable ctDNA. Detectability of ctDNA was associated with shorter OS in univariate and multivariate analyses. ctDNA was detectable in a statistically significantly larger proportion of patients with distant metastases (79%) than in patients with no distant metastases or only intracranial metastases (32%). Elevated protein S100 and CRP correlated better with detectable ctDNA than LDH. This study supports the potential of ctDNA as a prognostic biomarker in patients with metastatic melanoma. However, additional prospective longitudinal studies with quantitative assessments of ctDNA are necessary to investigate the limitations and strengths of ctDNA as a biomarker. Full article

(This article belongs to the Special Issue Recent Progress in the Diagnosis and Treatment of Melanoma and Other Skin Cancers)

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21 pages, 3949 KiB

Open AccessArticle

Over-Detection of Melanoma-Suspect Lesions by a CE-Certified Smartphone App: Performance in Comparison to Dermatologists, 2D and 3D Convolutional Neural Networks in a Prospective Data Set of 1204 Pigmented Skin Lesions Involving Patients’ Perception

by Anna Sophie Jahn, Alexander Andreas Navarini, Sara Elisa Cerminara, Lisa Kostner, Stephanie Marie Huber, Michael Kunz, Julia-Tatjana Maul, Reinhard Dummer, Seraina Sommer, Anja Dominique Neuner, Mitchell Paul Levesque, Phil Fang Cheng and Lara Valeska Maul

Cancers 2022, 14(15), 3829; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14153829 - 07 Aug 2022

Cited by 19 | Viewed by 3317

Abstract

The exponential increase in algorithm-based mobile health (mHealth) applications (apps) for melanoma screening is a reaction to a growing market. However, the performance of available apps remains to be investigated. In this prospective study, we investigated the diagnostic accuracy of a class 1 CE-certified smartphone app in melanoma risk stratification and its patient and dermatologist satisfaction. Pigmented skin lesions ≥ 3 mm and any suspicious smaller lesions were assessed by the smartphone app SkinVision^® (SkinVision^® B.V., Amsterdam, the Netherlands, App-Version 6.8.1), 2D FotoFinder ATBM^® master (FotoFinder ATBM^® Systems GmbH, Bad Birnbach, Germany, Version 3.3.1.0), 3D Vectra^® WB360 (Canfield Scientific, Parsippany, NJ, USA, Version 4.7.1) total body photography (TBP) devices, and dermatologists. The high-risk score of the smartphone app was compared with the two gold standards: histological diagnosis, or if not available, the combination of dermatologists’, 2D and 3D risk assessments. A total of 1204 lesions among 114 patients (mean age 59 years; 51% females (55 patients at high-risk for developing a melanoma, 59 melanoma patients)) were included. The smartphone app’s sensitivity, specificity, and area under the receiver operating characteristics (AUROC) varied between 41.3–83.3%, 60.0–82.9%, and 0.62–0.72% according to two study-defined reference standards. Additionally, all patients and dermatologists completed a newly created questionnaire for preference and trust of screening type. The smartphone app was rated as trustworthy by 36% (20/55) of patients at high-risk for melanoma, 49% (29/59) of melanoma patients, and 8.8% (10/114) of dermatologists. Most of the patients rated the 2D TBP imaging (93% (51/55) resp. 88% (52/59)) and the 3D TBP imaging (91% (50/55) resp. 90% (53/59)) as trustworthy. A skin cancer screening by combination of dermatologist and smartphone app was favored by only 1.8% (1/55) resp. 3.4% (2/59) of the patients; no patient preferred an assessment by a smartphone app alone. The diagnostic accuracy in clinical practice was not as reliable as previously advertised and the satisfaction with smartphone apps for melanoma risk stratification was scarce. MHealth apps might be a potential medium to increase awareness for melanoma screening in the lay population, but healthcare professionals and users should be alerted to the potential harm of over-detection and poor performance. In conclusion, we suggest further robust evidence-based evaluation before including market-approved apps in self-examination for public health benefits. Full article

(This article belongs to the Special Issue Recent Progress in the Diagnosis and Treatment of Melanoma and Other Skin Cancers)

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14 pages, 2034 KiB

Open AccessArticle

Contribution of the Skin–Gut Axis to Immune-Related Adverse Events with Multi-System Involvement

by Alyce M. Kuo, Lukas Kraehenbuehl, Stephanie King, Donald Y. M. Leung, Elena Goleva, Andrea P. Moy, Mario E. Lacouture, Neil J. Shah and David M. Faleck

Cancers 2022, 14(12), 2995; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14122995 - 17 Jun 2022

Cited by 5 | Viewed by 1838

Abstract

Immune-related adverse events (irAEs) frequently complicate treatment with immune checkpoint blockade (ICB) targeting CTLA-4, PD-1, and PD-L1, which are commonly used to treat solid and hematologic malignancies. The skin and gastrointestinal (GI) tract are most frequently affected by irAEs. While extensive efforts to further characterize organ-specific adverse events have contributed to the understanding and management of individual toxicities, investigations into the relationship between multi-organ toxicities have been limited. Therefore, we aimed to conduct a characterization of irAEs occurring in both the skin and gut. A retrospective analysis of two cohorts of patients treated with ICB at Memorial Sloan Kettering Cancer Center was conducted, including a cohort of patients with cutaneous irAEs (ircAEs) confirmed by dermatologists (n = 152) and a cohort of patients with biopsy-proven immune-related colitis (n = 246). Among both cohorts, 15% (61/398) of patients developed both skin and GI irAEs, of which 72% (44/61) patients had ircAEs preceding GI irAEs (p = 0.00013). Our study suggests that in the subset of patients who develop both ircAEs and GI irAEs, ircAEs are likely to occur first. Further prospective studies with larger sample sizes are needed to validate our findings, to assess the overall incidence of co-incident irAEs, and to determine whether ircAEs are predictors of other irAEs. This analysis highlights the development of multi-system dermatologic and gastrointestinal irAEs and underscores the importance of oncologists, gastroenterologists, and dermatologists confronted with an ircAE to remain alert for additional irAEs. Full article

(This article belongs to the Special Issue Recent Progress in the Diagnosis and Treatment of Melanoma and Other Skin Cancers)

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14 pages, 1536 KiB

Open AccessArticle

Pilot Trial of Arginine Deprivation Plus Nivolumab and Ipilimumab in Patients with Metastatic Uveal Melanoma

by Lukas Kraehenbuehl, Aliya Holland, Emma Armstrong, Sirinya O’Shea, Levi Mangarin, Sara Chekalil, Amanda Johnston, John S. Bomalaski, Joseph P. Erinjeri, Christopher A. Barker, Jasmine H. Francis, Jedd D. Wolchok, Taha Merghoub and Alexander N. Shoushtari

Cancers 2022, 14(11), 2638; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14112638 - 26 May 2022

Cited by 12 | Viewed by 5358

Abstract

Metastatic uveal melanoma (UM) remains challenging to treat, with objective response rates to immune checkpoint blockade (ICB) being much lower than in primary cutaneous melanoma (CM). Besides a lower mutational burden, the overall immune-excluded tumor microenvironment of UM might contribute to the poor response rate. We therefore aimed at targeting deficiency in argininosuccinate synthase 1, which is a key metabolic feature of UM. This study aims at investigating the safety and tolerability of a triple combination consisting of ipilimumab and nivolumab immunotherapy and the metabolic therapy, ADI-PEG 20. Nine patients were enrolled in this pilot study. The combination therapy was safe and tolerable with an absence of immune-related adverse events (irAE) of special interest, but with four of nine patients experiencing a CTCAE grade 3 AE. No objective responses were observed. All except one patient developed anti-drug antibodies (ADA) within a month of the treatment initiation and therefore did not maintain arginine depletion. Further, an IFNg-dependent inflammatory signature was observed in metastatic lesions in patients pre-treated with ICB compared with patients with no pretreatment. Multiplex immunohistochemistry demonstrated variable presence of tumor infiltrating CD8 lymphocytes and PD-L1 expression at the baseline in metastases. Full article

(This article belongs to the Special Issue Recent Progress in the Diagnosis and Treatment of Melanoma and Other Skin Cancers)

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12 pages, 3504 KiB

Open AccessArticle

Eight Years of Real-Life Experience with Smoothened Inhibitors in a Swiss Tertiary Skin Referral Center

by Lara E. Grossmann, Egle Ramelyte, Mirjam C. Nägeli and Reinhard Dummer

Cancers 2022, 14(10), 2496; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14102496 - 19 May 2022

Cited by 8 | Viewed by 2218

Abstract

Background: The hedgehog inhibitors vismodegib and sonidegib are approved for the treatment of advanced basal cell carcinoma. This study reports the experiences with these therapies in a tertiary skin referral center in daily practice. Methods: A retrospective, observational, single-center study analyzing medical records of patients with aBCC treated with a smoothened (SMO) inhibitor outside a clinical trial for at least one month between 2013 and 2021. Results: In total, 33 patients were included: 21 (64%) patients were treated with vismodegib, 3 (9%) patients with sonidegib and 9 (27%) patients with both treatments subsequently. With vismodegib, the best overall response was complete response (CR) in 33% cases, and partial response (PR) in 33% cases. Under sonidegib, 42% patients achieved CR and 17% PR. Mean duration to next treatment was 33 and 14 months for vismodegib and sonidegib, respectively. Adverse events varied in frequency between continuous and intermittent dosing and they were the most common reason for therapy discontinuation. Conclusions: Our real-world data illustrate the pitfalls and benefits of HhIs as well as the impact of different dosing regimens on adverse events, patient adherence and response. Treatment duration remains limited by adverse events and resistance. Additional treatment options, including immunotherapy and drug combinations, are needed. Full article

(This article belongs to the Special Issue Recent Progress in the Diagnosis and Treatment of Melanoma and Other Skin Cancers)

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15 pages, 2444 KiB

Open AccessArticle

Effects of COVID-19 Lockdown on Melanoma Diagnosis in Switzerland: Increased Tumor Thickness in Elderly Females and Shift towards Stage IV Melanoma during Lockdown

by Lisa Kostner, Sara Elisa Cerminara, Gustavo Santo Pedro Pamplona, Julia-Tatjana Maul, Reinhard Dummer, Egle Ramelyte, Johanna Mangana, Nikolaus Benjamin Wagner, Antonio Cozzio, Saskia Kreiter, Angelika Kogler, Markus Streit, Anja Wysocki, Alfred Zippelius, Heinz Läubli, Alexander Andreas Navarini and Lara Valeska Maul

Cancers 2022, 14(10), 2360; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14102360 - 10 May 2022

Cited by 11 | Viewed by 2173

Abstract

At the early stages of the COVID-19 outbreak in 2020, Switzerland was among the countries with the highest number of SARS-CoV2-infections per capita in the world. Lockdowns had a remarkable impact on primary care access and resulted in postponed cancer screenings. The aim of this study was to investigate the effects of the COVID-19 lockdown on the diagnosis of melanomas and stage of melanomas at diagnosis. In this retrospective, exploratory cohort study, 1240 patients with a new diagnosis of melanoma were analyzed at five tertiary care hospitals in German-speaking Switzerland over a period of two years and three months. We compared the pre-lockdown (01/FEB/19–15/MAR/20, n = 655) with the lockdown (16/MAR/20–22/JUN/20, n = 148) and post-lockdown period (23/JUN/20–30/APR/21, n = 437) by evaluating patients’ demographics and prognostic features using Breslow thickness, ulceration, subtype, and stages. We observed a short-term, two-week rise in melanoma diagnoses after the major lift of social lockdown restrictions. The difference of mean Breslow thicknesses was significantly greater in older females during the lockdown compared to the pre-lockdown (1.9 ± 1.3 mm, p = 0.03) and post-lockdown period (1.9 ± 1.3 mm, p = 0.048). Thickness increase was driven by nodular melanomas (2.9 ± 1.3 mm, p = 0.0021; resp. 2.6 ± 1.3 mm, p = 0.008). A proportional rise of advanced melanomas was observed during lockdown (p = 0.047). The findings provide clinically relevant insights into lockdown-related gender- and age-dependent effects on melanoma diagnosis. Our data highlight a stable course in new melanomas with a lower-than-expected increase in the post-lockdown period. The lockdown period led to a greater thickness in elderly women driven by nodular melanomas and a proportional shift towards stage IV melanoma. We intend to raise awareness for individual cancer care in future pandemic management strategies. Full article

(This article belongs to the Special Issue Recent Progress in the Diagnosis and Treatment of Melanoma and Other Skin Cancers)

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16 pages, 3710 KiB

Open AccessArticle

Line-Field Confocal Optical Coherence Tomography: A New Tool for the Differentiation between Nevi and Melanomas?

by Sandra Schuh, Cristel Ruini, Maria Katharina Elisabeth Perwein, Fabia Daxenberger, Charlotte Gust, Elke Christina Sattler and Julia Welzel

Cancers 2022, 14(5), 1140; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14051140 - 23 Feb 2022

Cited by 25 | Viewed by 2686

Abstract

Until now, the clinical differentiation between a nevus and a melanoma is still challenging in some cases. Line-field confocal optical coherence tomography (LC-OCT) is a new tool with the aim to change that. The aim of the study was to evaluate LC-OCT for the discrimination between nevi and melanomas. A total of 84 melanocytic lesions were examined with LC-OCT and 36 were also imaged with RCM. The observers recorded the diagnoses, and the presence or absence of the 18 most common imaging parameters for melanocytic lesions, nevi, and melanomas in the LC-OCT images. Their confidence in diagnosis and the image quality of LC-OCT and RCM were evaluated. The most useful criteria, the sensitivity and specificity of LC-OCT vs. RCM vs. histology, to differentiate a (dysplastic) nevus from a melanoma were analyzed. Good image quality correlated with better diagnostic performance (Spearman correlation: 0.4). LC-OCT had a 93% sensitivity and 100% specificity compared to RCM (93% sensitivity, 95% specificity) for diagnosing a melanoma (vs. all types of nevi). No difference in performance between RCM and LC-OCT was observed (McNemar’s p value = 1). Both devices falsely diagnosed dysplastic nevi as non-dysplastic (43% sensitivity for dysplastic nevus diagnosis). The most significant criteria for diagnosing a melanoma with LC-OCT were irregular honeycombed patterns (92% occurrence rate; 31.7 odds ratio (OR)), the presence of pagetoid spread (89% occurrence rate; 23.6 OR) and the absence of dermal nests (23% occurrence rate, 0.02 OR). In conclusion LC-OCT is useful for the discrimination between melanomas and nevi. Full article

(This article belongs to the Special Issue Recent Progress in the Diagnosis and Treatment of Melanoma and Other Skin Cancers)

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Review

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Open AccessReview

Recent Advances in the Diagnosis and Management of High-Risk Cutaneous Squamous Cell Carcinoma

by Clio Dessinioti and Alexander J. Stratigos

Cancers 2022, 14(14), 3556; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14143556 - 21 Jul 2022

Cited by 7 | Viewed by 2736

Abstract

High-risk cSCC is defined as invasive cSCC staged as N0 (without detectable regional lymph nodes) and M0 (without distant metastasis), that has features associated with a higher risk of poorer prognosis. The focus of this review is on the recent advances in the diagnosis and management of high-risk cSCC. The interest in high-risk cSCC relies on its higher risk of progression to advanced cSCC, as it represents the main pool of cSCCs that give rise to advanced tumors. Assessment of the risk is thus particularly relevant for common cSCC to identify the few with a high-risk risk of local recurrence, metastasis, or disease-specific death among all other low-risk tumors. The timely diagnosis and effective treatment of high-risk cSCCs may halt their further progression and aim to prevent and lower the incidence of advanced cSCCs. Clearance of the tumor with negative surgical margins is the main goal of surgery, which is the primary treatment of cSCC. It seems that it is difficult to discern the group of high-risk cSCCs that may benefit from adjuvant RT, as a universal beneficial effect for a cSCC with any high-risk factor which was resected with clear surgical margins has not been established. In the case of a high-risk cSCC with positive margins after surgery, and re-excision not feasible, post-operative radiotherapy is performed when possible. Recommendations on further management are discussed. Regarding the follow-up of patients diagnosed with high-risk cSCC, factors to consider regarding the frequency and intensity of the follow-up schedule include the risk and possible time of occurrence of metastasis from cSCC. Full article

(This article belongs to the Special Issue Recent Progress in the Diagnosis and Treatment of Melanoma and Other Skin Cancers)

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