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Views and Perspectives of Cutaneous Squamous Cell Carcinoma

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

Deadline for manuscript submissions: 31 December 2024 | Viewed by 23244

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Special Issue Editors

Dr. Thomas Meyer

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Guest Editor

Department of Dermatology St. Josef Hospital, Ruhr-University Bochum, Gudrunstr. 56, 44791 Bochum, Germany
Interests: skin carcinogenesis; cancer immune surveillance; chronic skin inflammation; oncogenic virus; sexually transmitted infections

Dr. Alexandra Geusau

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Guest Editor

Department of Dermatology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
Interests: immuno-dermatology; infectious skin diseases / sexually transmitted infections; non-melanoma skin cancer (NMSC); skin disease(s) following organ transplantation; identification of clinical, genetic and immunosuppressive factors predisposing to NMSC in immunosuppressed; tumour markers for cutaneous squamous cell carcinoma

Special Issue Information

Dear Colleagues,

Cutaneous squamous cell carcinoma (cSCC) is the second most common type of skin cancer after basal cell carcinoma and represents about 20% of nonmelanoma skin cancer. Most cSCCs are treated successfully by surgical excision and have a good prognosis, but about 10% of these cancers show a more aggressive behavior. These cases of locally advanced and metastatic cSCC are associated with a high mortality rate. They are not amenable to local surgery or radiotherapy and require systemic therapy. In many countries, the incidence of cSCC is rising, and due to increasing sun exposure, outdoor leisure activities and life expectancy numbers are expected to increase further in the future, representing growing challenges for treatment and prevention.

In this Special Issue, we aim to compile papers addressing the importance of cSCC in public health regarding epidemiological aspects, prevention, and medical care. We are pleased to invite you to submit original research studies or reviews outlining future demands of cSCC management, which may also include your personal views and opinions. Research areas may include (but are not limited to) the following: epidemiology, risk factors, precancerous lesions, oncogenic mechanisms, diagnosis, and strategies for treatment and prevention of cSCC.

We look forward to receiving your contributions.

Dr. Thomas Meyer
Dr. Alexandra Geusau
Guest Editors

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Keywords

actinic keratosis
Morbus Bowen
UV exposure
immunosuppression
advanced cSCC
metastatic cSCC
cancer progression
cancer biomarker
immunotherapy
cancer prevention

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Published Papers (10 papers)

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Research

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24 pages, 5690 KiB

Open AccessArticle

PIK Your Poison: The Effects of Combining PI3K and CDK Inhibitors against Metastatic Cutaneous Squamous Cell Carcinoma In Vitro

by Jay R. Perry, Benjamin Genenger, Amarinder Singh Thind, Bruce Ashford and Marie Ranson

Cancers 2024, 16(2), 370; https://doi.org/10.3390/cancers16020370 - 15 Jan 2024

Cited by 2 | Viewed by 2018

Abstract

Cutaneous squamous cell carcinoma (cSCC) is a very common skin malignancy with poor prognosis for patients with locally advanced or metastatic cSCC (mcSCC). PI3K/AKT/mTOR and cell cycle signalling pathways are often dysregulated in mcSCC. A combination drug approach has been theorised to overcome the underwhelming clinical performance of targeted inhibitors as single agents. This study investigates the potential of targeted inhibition of the p110α−subunit of PI3K with PIK-75 or BGT226 (P13Ki), and of CDK1/2/5/9 with dinaciclib (CDKi) as single agents and in combination. The patient−derived mcSCC cell lines, UW-CSCC1 and UW-CSCC2, were used to assess cell viability, migration, cell signalling, cell cycle distribution, and apoptosis. PIK-75, BGT226, and dinaciclib exhibited strong cytotoxic potency as single agents. Notably, the non-malignant HaCaT cell line was unaffected. In 2D cultures, PIK-75 synergistically enhanced the cytotoxic effects of dinaciclib in UW-CSCC2, but not UW-CSCC1. Interestingly, this pattern was reversed in 3D spheroid models. Despite the combination of PIK-75 and dinaciclib resulting in an increase in cell cycle arrest and apoptosis, and reduced cell motility, these differences were largely negligible compared to their single-agent counterpart. The differential responses between the cell lines correlated with driver gene mutation profiles. These findings suggest that personalised medicine approaches targeting PI3K and CDK pathways in combination may yield some benefit for mcSCC, and that more complex 3D models should be considered for drug responsiveness studies in this disease. Full article

(This article belongs to the Special Issue Views and Perspectives of Cutaneous Squamous Cell Carcinoma)

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13 pages, 1710 KiB

Open AccessArticle

Sex as a Predictor of Response to Immunotherapy in Advanced Cutaneous Squamous Cell Carcinoma

by Nicholas Yeo, Benjamin Genenger, Morteza Aghmesheh, Amarinder Thind, Sarbar Napaki, Jay Perry, Bruce Ashford, Marie Ranson and Daniel Brungs

Cancers 2023, 15(20), 5026; https://doi.org/10.3390/cancers15205026 - 17 Oct 2023

Cited by 3 | Viewed by 1766

Abstract

Approximately 3–5% of patients with cutaneous squamous cell carcinoma (CSCC) develop advanced disease, accounting for roughly 1% of all cancer deaths in Australia. Immunotherapy has demonstrated significant clinical benefit in advanced CSCC in several key phase II studies; however, there are limited data for patients treated outside of clinical trials. This is particularly relevant in advanced CSCC, which is most often seen in elderly patients with significant comorbidities. Thus, we aim to describe our experience with immunotherapy in a cohort of patients with advanced CSCC in Australia. We retrospectively reviewed all advanced CSCC patients treated with immunotherapy within the Illawarra and Shoalhaven Local Health District. Among the 51 patients treated with immunotherapy, there was an objective response rate (ORR) of 53% and disease control rate (DCR) of 67%. Our most significant predictor of response was sex, with male patients more likely to have better responses compared to female patients (DCR 85% vs. 41%, p < 0.0001), as well as improved progression-free survival (HR 4.6, 95%CI 1.9–10.8, p = 0.0007) and overall survival (HR 3.0, 95%CI 1.3–7.1, p = 0.006). Differential expression analysis of 770 immune-related genes demonstrated an impaired CD8 T-cell response in female patients. Our observed ORR of 53% is similar to that described in current literature with durable responses seen in the majority of patients. Full article

(This article belongs to the Special Issue Views and Perspectives of Cutaneous Squamous Cell Carcinoma)

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13 pages, 1025 KiB

Open AccessArticle

Identification of Genetic Risk Factors for Keratinocyte Cancer in Immunosuppressed Solid Organ Transplant Recipients: A Case-Control Study

by Raute Sunder-Plassmann, Alexandra Geusau, Georg Endler, Wolfgang Weninger and Matthias Wielscher

Cancers 2023, 15(13), 3354; https://doi.org/10.3390/cancers15133354 - 26 Jun 2023

Cited by 1 | Viewed by 1656

Abstract

Because of long-term immunosuppression, solid organ transplant recipients are at increased risk for keratinocyte cancer. We matched solid organ transplant patients (n = 150), cases with keratinocyte cancers and tumor-free controls, considering the most important risk factors for keratinocyte cancer in solid organ transplant recipients. Using whole exome data of germline DNA from this patient cohort, we identified several genetic loci associated with the occurrence of multiple keratinocyte cancers. We found one genome-wide significant association of a common single nucleotide polymorphism located in EXOC3 (rs72698504). In addition, we found several variants with a p-value of less than 10⁻⁵ associated with the number of keratinocyte cancers. These variants were located in the genes CYB561, WASHC1, PITRM1-AS1, MUC8, ABI3BP, and THBS2-AS1. Using whole exome sequencing data, we performed groupwise tests for rare missense variants in our dataset and found robust associations (p < 10⁻⁶, Burden Zeggini test) between MC1R, EPHA8, EPO, MYCT1, ADGRG3, and MGME1 and keratinocyte cancer. Thus, overall, we detected genes involved in pigmentation/UV protection, tumor suppression, immunomodulation, intracellular traffic, and response to UV as genetic risk factors for multiple keratinocyte cancers in solid organ transplant recipients. We also grouped selected genes to pathways and found a selection of genes involved in the “cellular response to UV” to be significantly associated with multiple keratinocyte cancers. Full article

(This article belongs to the Special Issue Views and Perspectives of Cutaneous Squamous Cell Carcinoma)

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10 pages, 691 KiB

Open AccessArticle

Basal Proliferation and Acantholysis May Represent Histological High-Risk Factors for Progression into Invasive Squamous Cell Carcinoma: A Comparison Study in Solid Organ Transplant Recipients and Matched Immunocompetent Patients

by Conrad Falkenberg, Thomas Dirschka, Georgia Gilbert, Eggert Stockfleth, Bernhard Homey and Lutz Schmitz

Cancers 2023, 15(6), 1765; https://doi.org/10.3390/cancers15061765 - 14 Mar 2023

Cited by 2 | Viewed by 1789

Abstract

Histological risk factors of AKs cannot be directly determined. Recent studies indicate that AKs restricted to the lower third of the epidermis (AK I), with marked basal proliferation (PRO III) and acantholysis, are associated with an increased risk of progression to invasive squamous cell carcinoma (iSCC). To confirm the aforementioned histological risk factors, this study compared AKs from solid organ transplant recipients (sOTRs), known to carry an up to 250-fold higher risk for progression into iSCC, to a matched immunocompetent control group (ICG). In total, 111 AKs from 43 sOTRs showed more AKs (n = 54, 48.7%) graded as AK I compared to 35 AKs (31.5%) in the ICG (p = 0.009). In line with these findings, 89 AKs (80.2%) from sOTRs showed pronounced basal proliferation (PRO III) compared to 37 AKs (33.3%) in the ICG (p < 0.0001). Acantholysis was more frequent in sOTRs than the ICG (59.5% vs. 32.4%, p < 0.0001) and more frequently associated with advanced basal proliferation (p < 0.0001). In conclusion, this study showed that acantholytic AKs graded as AK I and PRO III are predominantly found in a population at high risk of iSCC. Thus, AKs with marked basal proliferation and acantholysis should be assumed to be histological high-risk factors for the progression into iSCC. Full article

(This article belongs to the Special Issue Views and Perspectives of Cutaneous Squamous Cell Carcinoma)

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20 pages, 3058 KiB

Open AccessArticle

Cumulative UV Exposure or a Modified SCINEXA™-Skin Aging Score Do Not Play a Substantial Role in Predicting the Risk of Developing Keratinocyte Cancers after Solid Organ Transplantation—A Case Control Study

by Liliane Borik-Heil, Georg Endler, Walther Parson, Andreas Zuckermann, Lisa Schnaller, Keziban Uyanik-Ünal, Peter Jaksch, Georg Böhmig, Daniel Cejka, Katharina Staufer, Elisabeth Hielle-Wittmann, Susanne Rasoul-Rockenschaub, Peter Wolf, Raute Sunder-Plassmann and Alexandra Geusau

Cancers 2023, 15(3), 864; https://doi.org/10.3390/cancers15030864 - 30 Jan 2023

Cited by 3 | Viewed by 2229

Abstract

The risk of keratinocyte cancer is determined by intrinsic and extrinsic factors, which also influence skin aging. Few studies have linked skin aging and UV exposure with the incidence of non-melanoma skin cancer (NMSC). We evaluated signs of actinic skin damage and aging, individual UV burden, and melanocortin-1 receptor (MC1R) variants. A total of 194 organ transplant recipients (OTR) who suffered from NMSC were compared to 194 tumor-free controls matched for gender, age, type of transplanted organ, post-transplantation (TX) period, and immunosuppressive therapy. Compared with the cases, the controls scored higher in all skin aging scores and there were no differences in UV burden except for intentional whole-body UV exposure for specific UV scenarios and periods of life in favor of cases. The number of NMSCs correlated with all types of skin aging scores, the extent of intentional sun exposure, older age, longer post-TX period, shorter interval from TX to first NMSC, and specific MC1R risk groups. Multivariable models revealed a 7.5-fold risk of developing NMSC in individuals with actinic keratosis; 4.1- or 3.6-fold in those with green or blue eyes, respectively; and a 1.9-fold increased risk in the MC1R medium- + high-risk group. In the absence of skin aging contributing to NMSC development, certain MC1R risk types may identify OTR at risk for high tumor burden. Full article

(This article belongs to the Special Issue Views and Perspectives of Cutaneous Squamous Cell Carcinoma)

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Review

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12 pages, 1443 KiB

Open AccessReview

Epidemiology of Keratinocyte Skin Cancer with a Focus on Cutaneous Squamous Cell Carcinoma

by Lena Nanz, Ulrike Keim, Alexander Katalinic, Thomas Meyer, Claus Garbe and Ulrike Leiter

Cancers 2024, 16(3), 606; https://doi.org/10.3390/cancers16030606 - 31 Jan 2024

Cited by 7 | Viewed by 2295

Abstract

Keratinocyte skin cancer, consisting of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), is by far the most common cancer in white-skinned populations, with rapid increases over the last 50 years. While the age-standardized incidence rates increase worldwide, the age-standardized mortality rates are variable. The incidence rates of keratinocyte skin cancer are much higher compared to those of melanoma, and are largely attributed to the raising exposure to ultraviolet (UV) radiation, the most important causal risk factor for skin cancer. Whereas the development of BCC is mainly due to intense UV exposure during childhood and adolescence, the development of SCC is related to chronic, cumulative UV exposure over decades. Although mortality rates are relatively low, SCC is an increasing problem for healthcare services, significantly causing morbidity, especially in older age groups. This review reports on the epidemiology of keratinocyte skin cancer, with a focus on SCC, in Australia, the United States, and the north of Europe, with an outlook on further challenges health systems will be confronted with in the next 20 years. Full article

(This article belongs to the Special Issue Views and Perspectives of Cutaneous Squamous Cell Carcinoma)

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12 pages, 982 KiB

Open AccessReview

Prevention and Treatment of HPV-Induced Skin Tumors

by Daniel Hasche and Baki Akgül

Cancers 2023, 15(6), 1709; https://doi.org/10.3390/cancers15061709 - 10 Mar 2023

Cited by 3 | Viewed by 2300

Abstract

Non-melanoma skin cancer (NMSC) is the most common cancer in humans with increasing incidence. Meanwhile, a growing body of evidence has provided a link between skin infections with HPV of the genus beta (betaHPV) and the development of cutaneous squamous cell carcinomas (cSCCs). Based on this association, the development of vaccines against betaHPV has become an important research topic. This review summarizes the current advances in prophylactic and therapeutic betaHPV vaccines, including progresses made in preclinical testing and clinical trials. Full article

(This article belongs to the Special Issue Views and Perspectives of Cutaneous Squamous Cell Carcinoma)

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25 pages, 554 KiB

Open AccessReview

Advanced or Metastatic Cutaneous Squamous Cell Carcinoma: The Current and Future Role of Radiation Therapy in the Era of Immunotherapy

by Gianluca Ferini, Paolo Palmisciano, Stefano Forte, Anna Viola, Emanuele Martorana, Silvana Parisi, Vito Valenti, Corrado Fichera, Giuseppe Emmanuele Umana and Stefano Pergolizzi

Cancers 2022, 14(8), 1871; https://doi.org/10.3390/cancers14081871 - 7 Apr 2022

Cited by 7 | Viewed by 3142

Abstract

Radiation therapy (RT) is an effective therapeutic option for small localized cutaneous squamous cell carcinoma (cSCC) among patients who are not eligible for or refuse surgery. RT also has a defined role as an adjuvant treatment in cases of adverse features that predispose to tumor recurrence after local excision. Since the development of cSCC is often a late consequence of chronic sun exposure, its occurrence is more common among elderly patients whose comorbidities may contraindicate surgical procedures. These could be impeded not only by frail medical conditions but also by technical issues. Indeed, an aggressive locoregional behavior of cSCC may culminate in unresectability due to widespread invasion of neighboring tissues. Moreover, cSCC could develop distant metastases. Both locally advanced and metastatic cSCCs carry a poor prognosis. In these scenarios, recent discoveries of tumor molecular targets are promoting the use of promising systemic therapies, especially immunotherapy, over RT. However, the results from using immunotherapy and, even more so, of chemotherapy are still not optimal. By contrast, advances in radiation delivery equipment can safely treat even large and complex-shaped cSCC targets in challenging body sites. In addition, RT could also have a role in metastatic cSCC settings by enhancing the effectiveness of concomitant immunotherapy. The aim of this review is to summarize and comment on the body of literature about the use of radiotherapy for operable and inoperable locally advanced cSCCs and for metastatic ones in an attempt to define its current and future role. Full article

(This article belongs to the Special Issue Views and Perspectives of Cutaneous Squamous Cell Carcinoma)

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8 pages, 3133 KiB

Open AccessOpinion

Where Artificial Intelligence Can Take Us in the Management and Understanding of Cancerization Fields

by Carmen Orte Cano, Mariano Suppa and Véronique del Marmol

Cancers 2023, 15(21), 5264; https://doi.org/10.3390/cancers15215264 - 2 Nov 2023

Cited by 2 | Viewed by 1410

Abstract

Squamous cell carcinoma and its precursor lesion actinic keratosis are often found together in areas of skin chronically exposed to sun, otherwise called cancerisation fields. The clinical assessment of cancerisation fields and the correct diagnosis of lesions within these fields is usually challenging for dermatologists. The recent adoption of skin cancer diagnostic imaging techniques, particularly LC-OCT, helps clinicians in guiding treatment decisions of cancerization fields in a non-invasive way. The combination of artificial intelligence and non-invasive skin imaging opens up many possibilities as AI can perform tasks impossible for humans in a reasonable amount of time. In this text we review past examples of the application of AI to dermatological images for actinic keratosis/squamous cell carcinoma diagnosis, and we discuss about the prospects of the application of AI for the characterization and management of cancerization fields. Full article

(This article belongs to the Special Issue Views and Perspectives of Cutaneous Squamous Cell Carcinoma)

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12 pages, 888 KiB

Open AccessSystematic Review

Cancer-Derived Extracellular Vesicles as Biomarkers for Cutaneous Squamous Cell Carcinoma: A Systematic Review

by Irene Tai-Lin Lee, Chin-Hsuan Shen, Feng-Chiao Tsai, Chun-Bing Chen and Kevin Sheng-Kai Ma

Cancers 2022, 14(20), 5098; https://doi.org/10.3390/cancers14205098 - 18 Oct 2022

Cited by 8 | Viewed by 3152

Abstract

Cutaneous squamous cell carcinoma (cSCC) as one of the most prevalent cancers worldwide is associated with significant morbidity and mortality. Full-body skin exam and biopsy is the gold standard for cSCC diagnosis, but it is not always feasible given constraints on time and costs. Furthermore, biopsy fails to reflect the dynamic changes in tumor genomes, which challenges long-term medical treatment in patients with advanced diseases. Extracellular vesicle (EV) is an emerging biological entity in oncology with versatile clinical applications from screening to treatment. In this systematic review, pre-clinical and clinical studies on cSCC-derived EVs were summarized. Seven studies on the genomics, transcriptomics, and proteomics of cSCC-derived EVs were identified. The contents in cSCC-derived EVs may reflect the mutational landscape of the original cancer cells or be selectively enriched in EVs. Desmoglein 2 protein (Dsg2) is an important molecule in the biogenesis of cSCC-derived EVs. Ct-SLCO1B3 mRNA, and CYP24A1 circular RNA (circRNA) are enriched in cSCC-derived EVs, suggesting potentials in cSCC screening and diagnosis. p38 inhibited cSCC-associated long intergenic non-coding RNA (linc-PICSAR) and Dsg2 involved in EV-mediated tumor invasion and drug resistance served as prognostic and therapeutic predictors. We also proposed future directions to devise EV-based cSCC treatment based on these molecules and preliminary studies in other cancers. Full article

(This article belongs to the Special Issue Views and Perspectives of Cutaneous Squamous Cell Carcinoma)

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