Grover's Disease Association with Cutaneous Keratinocyte Cancers: More than a Coincidence?

Better mechanistic understanding of desmosome disruption and acantholysis in Grover's disease (GD) may improve management of this disease. Recent molecular studies highlighted promising pathways to be explored by directly comparing GD and selected features of associated skin diseases. The association between GD and cutaneous keratinocyte carcinomas, the most prevalent non-melanoma skin cancers (NMSC), is not completely characterized. To review the medical literature regarding GD-associated cutaneous keratinocyte cancers, focusing on molecular features, pathophysiological mechanisms, and disease associations, to help guide future research and patient management. GD has been associated with a variety of skin conditions, but its association with skin cancers has been rarely reported. Between 1983 and 2024, only nine scientific papers presented data supporting this association. Interestingly, we found that GD may mimic multiple NMSCs, as few authors reported GD cases misdiagnosed as multiple cutaneous squamous cell carcinomas for more than 4 years or the presence of superficial basal cell carcinoma-like areas associated with focal acantholysis. In conclusion: (a) GD may be an imitator of multiple NMSCs, and (b) the relationship between GD and NMSCs may reveal promising pathways for the mechanistic understanding of desmosome disruption and acantholysis in GD and may even lead to its reclassification as a distinctive syndrome.

Transcriptional and signalling regulation of skin epithelial stem cells in homeostasis, wounds and cancer.

The epidermis and skin appendages are maintained by their resident epithelial stem cells, which undergo long-term self-renewal and multilineage differentiation. Upon injury, stem cells are activated to mediate re-epithelialization and restore tissue function. During this process, they often mount lineage plasticity and expand their fates in response to damage signals. Stem cell function is tightly controlled by transcription machineries and signalling transductions, many of which derail in degenerative, inflammatory and malignant dermatologic diseases. Here, by describing both well-characterized and newly emerged pathways, we discuss the transcriptional and signalling mechanisms governing skin epithelial homeostasis, wound repair and squamous cancer. Throughout, we highlight common themes underscoring epithelial stem cell plasticity and tissue-level crosstalk in the context of skin physiology and pathology.

The promotion of cell proliferation and invasion in cutaneous squamous cell carcinomas after ARNT downregulation is associated with CXCL3.

The aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcription factor associated with adaptive responses to cellular stress. Its role in cutaneous squamous cell carcinoma (cSCC) remains poorly understood. The aim of this study was to investigate the role of ARNT in cSCC. Immunohistochemistry revealed downregulation of ARNT in cSCC, precancerous lesions (actinic keratosis), and cells. Knockdown of ARNT in A431 and SCL-1 cells significantly enhanced cell growth and metastasis. Microarray analysis and Ingenuity Pathway Analysis confirmed that loss of ARNT in A431 cells was highly correlated with cell growth and movement and upregulated CXCL3 expression. Cellular and xenograft experiments further confirmed that ARNT regulates cSCC proliferation and invasiveness in a CXCL3-dependent manner. ARNT may regulate CXCL3 expression through ROS-STAT3 pathway. In conclusion, this study demonstrates that ARNT plays a critical role in the development of cSCC and significantly affects the proliferation and metastatic ability of cSCC cells. It has the potential to serve as an ideal treatment target for cSCC.

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

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.

Cutaneous squamous cell carcinomas of the nose in a child treated with external radiation therapy: a case report.

Cutaneous squamous cell carcinomas are very rare in children. The recommended treatment for localized cancers is surgery with sufficient margins which can sometimes be mutilating especially for facial localizations. We report a rare case of facial skin carcinoma in a 13-year-old girl measuring 3 cm in diameter infiltrating the tip of the nose. The treatment was an exclusive external radiation therapy with a dose of 70 Gy in 35 fractions in standard fractionation. The technique used was intensity-modulated conformational radiotherapy. It was proposed as an alternative to surgery which could be mutilating. A complete tumour response was obtained with a good aesthetic result and without major toxicity.

Skin cancer in solid organ transplant recipients: still an open problem.

In the last two decades, the optimization of organ preservation and surgical techniques, and the personalized immunosuppression have reduced the rate of acute rejections and early post-transplant complications. However, long-term graft survival rates have not improved over time, and evidence suggest a role of chronic calcineurin inhibitor toxicity in this failure. Solid organ transplant recipients may develop chronic dysfunction/damage and several comorbidities, including post-transplant malignancies. Skin cancers, mostly non-melanoma skin cancers (squamous cell carcinoma and basal cell carcinoma), are the most common malignancies in Caucasian solid organ transplant recipients. Several factors, together with immunosuppression, may contribute to the susceptibility for skin cancers which, although often treatable, could be associated with a much higher mortality rate than in the general population. The rapid identification and treatment (including reduction of immunosuppression and early surgical treatments) have an important role to avoid an aggressive behavior of these malignancies. Organ transplant recipients with a history of skin cancer should be followed closely for developing new and metastatic lesions. Additionally, patient education on the daily use of sun-protective measures and the recognition of the early signs (self-diagnosis) of coetaneous malignancies are useful preventive measures. Finally, clinicians should make themselves aware of the problem and build, in every clinical follow-up center, collaborative network involving transplant clinicians, dermatologists and surgeons who should work together to easily identify and rapidly treat these complications. In this review, we discuss the current literature regarding the epidemiology, risk factors, diagnosis, preventive strategies and treatments of skin cancer in organ transplantation.

Cemiplimab in cutaneous squamous cell carcinomas (SCC): an overview and a clinical case.

INTRODUCTION: Cemiplimab, a monoclonal antibody directed against the PD-1 receptor of immune cells, has recent indication for the treatment of patients with locally advanced or metastatic cutaneous squamous cell carcinoma (cSCC). CASE DESCRIPTION: We present the clinical case of an elderly woman affected by locally advanced squamous carcinoma of the left cheek, in excellent response after only one course of therapy with cemiplimab, with good tolerability. CONCLUSIONS: Immunotherapy is a new therapeutic option in cSCC.

TEAD1 Silencing Regulates Cell Proliferation and Resistance to 5-Fluorouracil in Cutaneous Squamous Cell Carcinoma.

Purpose: Cutaneous squamous cell carcinoma (cSCC) is a skin malignant tumor account for approximately one-third of all nonmelanoma skin cancers. Studies have shown that TEA domain transcription factor 1 (TEAD1) is discovered to be involved in the pathogenesis of some human cancers, but to our knowledge its role in cSCC has not been reported. Patients and Methods: Samples from 16 cSCC patients and 27 healthy individuals were obtained for immunohistochemical staining of TEAD1. The expressions of TEAD1 in SCL-1, HSC-1 cells compared with the primary neonatal human epithelial keratinocytes were detected by Western blot and RT-qPCR. Proliferation and cell cycle of TEAD1 knockdown in cSCC cell lines were examined by MTT and flow cytometry analysis. Annexin V/PI and JC-1 staining were used to determine the cell apoptosis. Results: The expression of TEAD1 decreased significantly in cSCC compared to its expression in normal skin tissues and cell lines. Down-regulation of TEAD1 in cSCC cell lines promoted cell growth via regulation of the G2/M progression. Additionally, silence of TEAD1 also protected cells against 5-Fluorouracil-induced apoptosis and decreased the expression of apoptosis-related protein (p53). Conclusion: Our results suggested that TEAD1 expression is down-regulated and functioned as a tumor suppressor in cSCC and that it may serve as a biomarker or therapeutic target of cSCC.

Characterization of the Expression of Angiogenic Factors in Cutaneous Squamous Cell Carcinoma of Domestic Cats.

Cutaneous squamous cell carcinoma (CSCC) is a common malignant skin cancer with a significant impact on health, and it is important to determine the degree of reliance of CSCC on angiogenesis for growth and metastasis. Major regulators of angiogenesis are the vascular endothelial growth factor (VEGF) family and their associated receptors. Alternative pre-mRNA splicing produces multiple isoforms of VEGF-A and PLGF with distinct biological properties. Several studies highlight the function of VEGF-A in CSCC, but there are no studies of the different isoforms of VEGF-A and PLGF for this neoplasm. We characterized the expression of three isoforms of VEGF-A, two isoforms of PLGF, and their receptors in cat CSCC biopsies compared to normal haired skin (NHS). Although our results revealed no significant changes in transcript levels of panVEGF-A or their isoforms, the mRNA levels of PLGF I and the receptors Flt-1 and KDR were downregulated in CSCC compared to NHS. Differences were observed in ligand:receptor mRNA expression ratio, with the expression of VEGF-A relative to its receptor KDR higher in CSCC, which is consistent with our hypothesis and prior human SCC studies. Immunolocalization in tissue showed increased expression of all measured factors and receptors in tumor cells compared to NHS and surrounding vasculature. We conclude that the factors measured may play a pivotal role in CSCC growth, although further studies are needed to clarify the role of angiogenic factors in feline CSCC.

Eruptive Non-melanoma Skin Cancers/Squamous Atypia Following Skin Surgery. Report of Two New Cases, Concise Review of the Literature With Special Emphasis on Treatment Options.

Introduction: Eruptive cutaneous squamous cell carcinomas (ESCC), eruptive squamous atypia (ESA) and eruptive keratoacanthomas (EKA) are different terms used to describe the occurrence of multiple cutaneous squamous neoplasms after skin surgery, laser treatment, traumas, such as tattoos, and local or systemic medical treatments. ESCC have been reported to arise at the sites of skin surgery, including the area affected by the primary tumor and split thickness skin graft (STSG) donor and recipient sites. Objectives: The aim of this study is to report 2 additional cases of ESCC after skin surgery and make a critical revision of the literature, analyzing the clinical, histological features and outcomes of ESCC after cutaneous surgery. Methods: Up to August 2021, according to our systematic review of the literature, we have collected 19 published articles and a total of 34 patients, including our 2 cases. Results: The results of this review highlight five red flags that clinicians should consider: (i) lower and upper limbs represent the cutaneous site with the highest risk, representing 83,78% of the cases in the literature; (ii) the median time to onset of ESCC is approximately 6 weeks; (iii) primary cutaneous squamous cell carcinomas were completely excised with free margins on histologic examination in the totality of the cases of the literature, and therefore ESCC should not be considered recurrences; (iv) any surgical technique involves a risk to promote ESCC; (v) treatment of ESCC includes medical treatment, surgery or combined surgical and medical treatment. Conclusions: This review highlights 5 red flags which could support clinicians in the diagnosis and management of ESCC after skin surgery.

Epigenetic regulatory mechanisms of histone acetylation in the treatment of cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the second most common malignancy; as such, novel systemic therapies are important for the treatment of locally advanced or metastatic disease. Histone deacetylase (HDAC) inhibitors have been increasingly studied in recent years as epigenome-targeted therapy for cSCC. HDACs inhibitors reduce tumorigenesis by blocking HDAC activity and creating a more relaxed chromatin structure, thus inducing gene expression by inhibiting deacetylation of transcription factors. In vitro experiments and in vivo mice studies have shown that HDAC inhibition halts cSCC pathogenesis. Ginsenoside 20(R)-Rg3 has been successfully employed to inhibit HDAC3 and thereby inhibit cSCC epithelial mesenchymal transition. Similarly, vorinostat has been found to blunt growth of human xenograft epidermoid cSCCs in highly immunosuppressed mice. Additionally, trichostatin A induces irreversible growth arrest in SCC cells, and MS-275 significantly reduces cSCC tumor burden in mice. These recent studies indicate that HDAC inhibitors represent a promising emerging therapy for cSCC.

Downregulation of ARMC8 promotes tumorigenesis through activating Wnt/ß-catenin pathway and EMT in cutaneous squamous cell carcinomas.

BACKGROUND: Aberrant expression of Armadillo repeat containing 8 (ARMC8) plays crucial roles in tumor growth and metastasis of various cancers. The specific role of ARMC8 in cutaneous squamous cell carcinoma (cSCC) is yet to be elucidated. OBJECTIVE: The present study aimed to investigate the molecular mechanisms of ARMC8 and epithelial-mesenchymal transition (EMT) in cSCC development and provide translational insights for future therapeutics. METHODS: cSCC tumor specimens were used to determine the ARMC8 by immunohistochemistry. Three cSCC cell lines including HSC-1, HSC-5 and A431 as well as BALB/C mouse tumor model was utilized to study the potential mechanisms in tumorigenesis. RESULTS: Our data identified ARMC8 as a direct downstream target of miR-664. We found that ARMC8 was remarkably low expression in cSCC patient specimens and cSCC cell lines. Knockdown of ARMC8 promotes tumorigenic behaviors such as increased cell proliferation, migration and invasion capacities in vitro and enhanced tumorigenicity in xenograft mouse model. Whereas ARMC8 over-expression inhibits tumorigenesis in cSCC. Together, it revealed ARMC8 functions as a tumor suppressor via restraining Wnt/ß-catenin pathway and epithelial-mesenchymal transition in cSCC. CONCLUSION: Our data verifies that aberrant expression of ARMC8 plays a vital role in carcinogenesis of cSCC. And overexpression of ARMC8 will facilitate future development of cSCC therapeutic interventions.

MicroRNA-664 functions as an oncogene in cutaneous squamous cell carcinomas (cSCC) via suppressing interferon regulatory factor 2.

BACKGROUND: Aberrant expression of microRNA-664 was involved in tumor growth and metastasis of various cancers. The specific role of miR-664 in cutaneous squamous cell carcinoma (cSCC) is yet to be elucidated. OBJECTIVE: The present study aimed to investigate the molecular mechanisms underpinning of cSCC development and provide translational insights for future therapeutics. METHODS: Human cSCC specimens were used to determine the miR-664 by in situhybridization and IRF2 by immunohistochemistry. To study the potential mechanisms in tumorigenesis, three cSCC cell lines including HSC-5, HSC-1 and A431 as well as BALB/C mouse tumor model was utilized. RESULTS: We found that miR-664 was remarkably high in cSCC patient specimens and cSCC cell lines. Overexpression of miR-664 promotes tumorigenic behaviors such as increased cell proliferation, migration and invasion capacities in vitro and enhanced tumorigenicity in xenograft mouse model. Our data further identified IRF2 as a direct downstream target of miR-664. Knockdown of IRF2 reverses pro-tumorigenesis phenotype of miR-664; whereas IRF2 over-expression inhibits miR-664 tumorigenesis in cSCC. Together, it revealed miR-664 functions as an oncogene in cSCC via suppression of IRF2. CONCLUSION: Our data demonstrates that aberrant expression of miR-664 plays a critical role in carcinogenesis of cSCC. The discovery of novel targets such as miR-664 and IRF2 will facilitate future development of therapeutic interventions.

Incidence rate of cutaneous squamous cell carcinoma is rapidly increasing in Akita Prefecture: Urgent alert for super-aged society.

Incidence rates of cutaneous squamous cell carcinoma (SCC) are increasing in many countries. To estimate detailed trends of SCC incidence rates in the population of Akita Prefecture as the forerunner of super-aged societies, we conducted a retrospective analysis of patients diagnosed with SCC between 2007 and 2016 in Akita University Hospital. The crude SCC incidence rate increased rapidly between 2007 and 2016 from 2.5 to 10.0/100 000 people. Remarkably, the age-specific incidence rate of people aged 80 years or over increased between 2007 and 2016 from 14.7 to 51.6/100 000 people, suggesting that SCC incidence rates increase possibly due to not only the increased number of aged people but also because of unidentified cancer-prone environments. When the findings of the present study are generalized to other regions entering the era of super-aging, it is clear that we need to prepare for the economic disease burden together with careful monitoring to confirm future trends for SCC.

The Role of Human Papillomaviruses and Polyomaviruses in BRAF-Inhibitor Induced Cutaneous Squamous Cell Carcinoma and Benign Squamoproliferative Lesions.

Background: Human papillomavirus (HPV) has long been proposed as a cofactor in the pathogenesis of cutaneous squamous cell carcinoma (cSCC). More recently, the striking clinico-pathological features of cSCCs that complicate treatment of metastatic melanoma with inhibitors targeting BRAF mutations (BRAFi) has prompted speculation concerning a pathogenic role for oncogenic viruses. Here, we investigate HPV and human polyomaviruses (HPyV) and correlate with clinical, histologic, and genetic features in BRAFi-associated cSCC. Materials and Methods: Patients receiving BRAFi treatment were recruited at Barts Health NHS Trust. HPV DNA was detected in microdissected frozen samples using reverse line probe technology and degenerate and nested PCR. HPV immunohistochemistry was performed in a subset of samples. Quantitative PCR was performed to determine the presence and viral load of HPyVs with affinity for the skin (HPyV6, HPyV7, HPyV9, MCPyV, and TSPyV). These data were correlated with previous genetic mutational analysis of H, K and NRAS, NOTCH1/2, TP53, CDKN2A, CARD11, CREBBP, TGFBR1/2. Chromosomal aberrations were profiled using single nucleotide polymorphism (SNP) arrays. Results: Forty-five skin lesions from seven patients treated with single agent vemurafenib in 2012-2013 were analyzed: 12 cSCC, 19 viral warts (VW), 2 actinic keratosis (AK), 5 verrucous keratosis/other squamoproliferative (VK/SP) lesions, one melanocytic lesion and 6 normal skin samples. Significant histologic features of viral infection were seen in 10/12 (83%) cSCC. HPV DNA was detected in 18/19 (95%) VW/SP, 9/12 (75%) cSCC, 4/5 (80%) SP, and 3/6 (50%) normal skin samples and in 1/12 cases assessed by immunohistochemistry. HPyV was co-detected in 22/30 (73%) of samples, usually at low viral load, with MCPyV and HPyV7 the most common. SNP arrays confirmed low levels of chromosomal abnormality and there was no significant correlation between HPV or HPyV detection and individual gene mutations or overall mutational burden. Conclusion: Despite supportive clinicopathologic evidence, the role for HPV and HPyV infection in the pathogenesis of BRAFi-induced squamoproliferative lesions remains uncertain. Synergistic oncogenic mechanisms are plausible although speculative. Nonetheless, with the prospect of a significant increase in the adjuvant use of these drugs, further research is justified and may provide insight into the pathogenesis of other BRAFi-associated malignancies.

Induction of Tyrosine Phosphorylation of UV-Activated EGFR by the Beta-Human Papillomavirus Type 8 E6 Leads to Papillomatosis.

Epidemiological evidence is accumulating that beta-human papillomaviruses (HPV) synergize with UV-light in the development of precancerous actinic keratosis, and cutaneous squamous cell carcinomas (cSCC), one of the most common cancers in the Caucasian population. We previously demonstrated the tumorigenic activity of beta-HPV type 8 (HPV8) in the skin of transgenic mice and its cooperation with UV-light. Analysis of underlying mechanisms now showed that in keratinocytes expressing the HPV8E6 protein a transient increase of tyrosine phosphorylated epidermal growth factor receptor (EGFR) in response to UV-irradiation occurred, while EGFR tyrosine phosphorylation, i.e., receptor tyrosine kinase (RTK)-activity was hardly affected in empty vector control cells. FACS and immunofluorescences revealed that the EGFR was internalized into early endosomes in response to UV-exposure in both, HPV8E6 positive and in control cells, yet with a higher rate in the presence of HPV8E6. Moreover, only in HPV8E6 expressing keratinocytes the EGFR was further sorted into CD63+ intraluminal vesicles, indicative for trafficking to late endosomes. The latter requires the ubiquitination of the EGFR, and in correlation, we could show that only in HPV8E6 positive keratinocytes the EGFR was ubiquitinated upon UV-exposure. HPV8E6 and tyrosine phosphorylated EGFR directly interacted which was enhanced by UV-irradiation. The treatment of K14-HPV8E6 transgenic mice with Canertinib, an inhibitor of the RTK-activity of the EGFR, suppressed skin papilloma growth in response to UV-irradiation. This confirms the crucial role of the RTK-activity of the EGFR in HPV8E6 and UV-mediated papillomatosis in transgenic mice. Taken together, our results demonstrate that HPV8E6 alters the signaling of the UV-activated EGFR and this is a critical step in papilloma formation in response to UV-light in transgenic mice. Our results provide a molecular basis how a beta-HPV type may support early steps of skin tumor formation in cooperation with UV-light.