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Non-melanoma skin cancer, which includes cutaneous squamous cell carcinoma (cSCC), is the most common cancer. In the US, there are more than a million cases of cSCC diagnosed annually. Although most early stage cSCC are successfully treated with excision, cSCC results in significant morbidity, and approximately 4% of cSCC patients develop metastases and 2% die. Immune checkpoint inhibitors and other immunotherapies are becoming increasingly important in treating multiple cancer types, including cSCC, but only a fraction of patients respond. Yet, there is a paucity of clinically relevant cSCC murine models that can be used to study neoantigen-specific T cell responses. Outbred SKH-1 mice are highly susceptible to solar UV light-induced cSCC. However, an outbred strain limits the ability to evaluate MHC-restricted, antigen-specific T cell responses and perform studies with genetically engineered mice. To address this need, solar UV light was used to induce tumors in inbred FVB/N, BALB/c, and C57BL/6 mice. Solar UV light reliably induced tumors in FVB/N and BALB/c mice. In contrast, C57BL/6 mice were relatively resistant to tumor formation. Most tumors were histologically diagnosed as actinic keratosis, cSCC in situ, or invasive cSCC. Histologically confirmed solar UV-induced invasive cSCC tumors were used to create clonal cSCC cell lines on the BALB/c background. The cSCC cell lines recapitulate the high mutational burden, mutational profile, and driver mutations observed in human disease. These cSCC cell lines constitutively express MHC class I, and thus, can be targeted for destruction by CD8 T cells. T cells constrain the cSCC cell lines, as cSCC tumors grew faster in athymic mice, which lack mature T cells, compared to wild-type mice. In vivo depletion of CD8 and CD4 T cells demonstrated a major role for CD8 T cells and a supportive role for CD4 T cells in controlling cSCC growth. Vaccination with irradiated cSCC cells completely protected mice from tumor challeng

Squamous cell carcinomas arise from stratified squamous epithelia. Here, a comparative analysis based on recent studies defining the genetic alterations and composition of the stroma of oral and cutaneous squamous cell carcinomas (OSCC and CSCC, respectively) was performed. Both carcinomas share some but not all histological and genetic features. This review was focused on how mutations in tumor suppressor genes and protooncogenes cooperate to determine the differentiation, aggressiveness, and metastatic potential of OSCC and CSCC. In fact, driver mutations in tumor suppressor genes are more frequently observed in OSCC than CSCC. These include mutations in TP53 (encoding pP53 protein), CDKN2A (encoding cyclin dependent kinase inhibitor 2A), FAT1 (encoding FAT atypical cadherin 1), and KMT2D (encoding lysine methyltransferase 2D), with the exception of NOTCH (encoding Notch receptor 1), whose mutation frequency is lower in OSCC compared to CSCC. Finally, we describe the differential composition of the tumor microenvironment and how this influences the aggressiveness of each tumor type. Although both OSCC and CSCC tumors are highly infiltrated by immune cells, high levels of tumor-infiltrating lymphocytes (TILs) have been more frequently reported as predictors of better outcomes in OSCC than CSCC. In conclusion, OSCC and CSCC partially share genetic alterations and possess different causal factors triggering their development. The tumor microenvironment plays a key role determining the outcome of the disease., Instituto de Salud Carlos III, Ministerio de economía y competitividad (España), Depto. de Medicina, Fac. de Medicina, TRUE, pub, Descuento UCM

This doctoral thesis examines the interplay between the host immune response, a viral aetiology and head and neck cancer and its impact on the tumour microenvironment (TME), with a focus cutaneous squamous cell carcinoma (CSCC) and nasopharyngeal carcinoma (NPC). The first aim centres on examining the impact of compromised or competent host immune system on the TME in CSCC due to the disparate survival outcomes observed in immunocompromised patients compared to immunocompetent patients with CSCC. I hypothesise that differences exist between the TME of CSCC arising from the subgroups. By comprehensively profiling a large cohort of CSCC, I identified sub-populations of B cells define subgroups of CSCC, their lack of abundance in CSCC arising in immunocompromised patients and their association with improved survival. Interestingly, no genomic profiling revealed no intrinsic tumour differences between CSCC from immunocompetent and immunocompromised patients. Having characterised the impact of a compromised host immune system on the TME, I examined the influence of a viral aetiology, specifically of Epstein-Barr virus (EBV) on the TME of NPC, with a particular focus on CD103 expression, a marker of tissue-resident memory T cells (TRMs). Drawing parallels from human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC), where TRMs are linked to improved survival, I hypothesise a similar association in NPC. I showed NPC have abundant CD103 expression and that NPC tumours with high CD103 expression have transcriptomic features consist with high TRM expression. Despite these similarities however, CD103 expression was not prognostic for survival, in contrast to HPV+OPSCC, highlighting the need for better characterisation of sub-populations of TRMs in NPC. My third aim focuses on understanding the interplay between EBV and tumour survival mechanisms in NPC. Leveraging EBV's known exploitation of pro-survival pathways in lymphocytes for viral persistence, I

Cutaneous squamous cell carcinoma (cSCC) ranks among the most widespread malignancies with metastatic potential. Investigating the molecular mechanism of tumorigenesis will enhance our understanding of cSCC. Aberrant expression of non-coding RNAs has been extensively reported in human cancers. Here, we summarize our work exploring the role of a microRNA (miRNA) (Paper I) and a long non-coding RNA (lncRNA) (Paper II and III) in cSCC. Additionally, we discuss the role of cSCC-derived extracellular vesicles (EVs) in tumor formation (Paper IV). In Paper I, we explored the function of miR-130a in cSCC. We reported that miR-130a expression was downregulated in cSCC under the regulation of the MAPK pathway. We demonstrated a tumor suppressor role of miR-130a in cSCC: ectopic overexpression of miR-130a suppressed malignant behaviors of human cSCC cells and inhibited primary tumor growth in cSCC xenograft models. Mechanistically, we revealed a link between MAPK and BMP/SMAD signaling pathways, which was mediated by the direct target of miR-130a, ACVR1. In Paper II, we investigated the role of lncRNA PVT1 in cSCC. Elevated PVT1 expression in cSCC, under MYC regulation, suggested it may contribute to keratinocyte transformation. Subsequently, we revealed that PVT1 exerted an oncogenic role in cSCC through regulating CDKN1A/p21 expression and preventing cellular senescence. We identified exon 2 as a crucial element for maintaining PVT1's oncogenic role. In Paper III, we further investigated the underlying mechanism for the oncogenic role of PVT1 in cSCC. Our data revealed that PVT1 is mainly distributed in the nuclei of cSCC cells and the exon 2 is essential for nuclear localization of PVT1. Furthermore, we identified several subunits of the transcription-export (TREX) complex as interacting partners of PVT1 and demonstrated that PVT1 modulated the function of the TREX complex in nuclear export of poly (A)+ RNAs. In Paper IV, we found that cSCC cells secreted more EVs than pri

Cutaneous squamous cell carcinoma (cSCC) ranks among the most widespread malignancies with metastatic potential. Investigating the molecular mechanism of tumorigenesis will enhance our understanding of cSCC. Aberrant expression of non-coding RNAs has been extensively reported in human cancers. Here, we summarize our work exploring the role of a microRNA (miRNA) (Paper I) and a long non-coding RNA (lncRNA) (Paper II and III) in cSCC. Additionally, we discuss the role of cSCC-derived extracellular vesicles (EVs) in tumor formation (Paper IV). In Paper I, we explored the function of miR-130a in cSCC. We reported that miR-130a expression was downregulated in cSCC under the regulation of the MAPK pathway. We demonstrated a tumor suppressor role of miR-130a in cSCC: ectopic overexpression of miR-130a suppressed malignant behaviors of human cSCC cells and inhibited primary tumor growth in cSCC xenograft models. Mechanistically, we revealed a link between MAPK and BMP/SMAD signaling pathways, which was mediated by the direct target of miR-130a, ACVR1. In Paper II, we investigated the role of lncRNA PVT1 in cSCC. Elevated PVT1 expression in cSCC, under MYC regulation, suggested it may contribute to keratinocyte transformation. Subsequently, we revealed that PVT1 exerted an oncogenic role in cSCC through regulating CDKN1A/p21 expression and preventing cellular senescence. We identified exon 2 as a crucial element for maintaining PVT1's oncogenic role. In Paper III, we further investigated the underlying mechanism for the oncogenic role of PVT1 in cSCC. Our data revealed that PVT1 is mainly distributed in the nuclei of cSCC cells and the exon 2 is essential for nuclear localization of PVT1. Furthermore, we identified several subunits of the transcription-export (TREX) complex as interacting partners of PVT1 and demonstrated that PVT1 modulated the function of the TREX complex in nuclear export of poly (A)+ RNAs. In Paper IV, we found that cSCC cells secreted more EVs than pri

Background: Prevention campaigns for skin cancers have focused primarily on melanoma, and over time there has been increasing awareness of the need to select the population to be screened to maximize program effectiveness. Objectives: The objective of the study was to report the results of a free dermatological initiative, as part of an awareness campaign dedicated to keratinocyte cancers, targeting individuals pre-selected through a short questionnaire. Methods: One day of dermatological consultations was held at 15 dermato-oncology referral centers during May 22-June 30, 2021. For selection, individuals answered a telephone interview consisting of 7 yes/no questions on risk factors. Demographics, clinical characteristics of suspicious tumors, and histopathologic diagnosis of excised lesions were collected. Suspicion rate, detection rate, and positive predictive values (PPVs) for any skin cancer, basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma were calculated. Results: A total of 320 individuals (56.9% males; 43.1% females) with a median age of 69.6 (range 21-91) years qualified for the screening initiative. Overall, skin cancers and precancerous lesions were diagnosed in 65.9% of the patients. Suspicion rate was 28.7% for any skin cancer (92/320), 22.8% for BCC (73/320), 4.7% for cSCC (15/320), and 1.2% for melanoma (4/320). Detection rate was 23.4% for any skin cancer (PPV 93.7%), 18.1% for BCC (PPV 95.1%), 4.4% for cSCC (PPV 93.3%), and 0.9% for melanoma (PPV 75%). Conclusions: Selection of individuals at high risk is a cost-effective approach for early detection campaigns for keratinocyte cancers.

Cutaneous squamous cell carcinoma (cSCC) ranks among the most widespread malignancies with metastatic potential. Investigating the molecular mechanism of tumorigenesis will enhance our understanding of cSCC. Aberrant expression of non-coding RNAs has been extensively reported in human cancers. Here, we summarize our work exploring the role of a microRNA (miRNA) (Paper I) and a long non-coding RNA (lncRNA) (Paper II and III) in cSCC. Additionally, we discuss the role of cSCC-derived extracellular vesicles (EVs) in tumor formation (Paper IV). In Paper I, we explored the function of miR-130a in cSCC. We reported that miR-130a expression was downregulated in cSCC under the regulation of the MAPK pathway. We demonstrated a tumor suppressor role of miR-130a in cSCC: ectopic overexpression of miR-130a suppressed malignant behaviors of human cSCC cells and inhibited primary tumor growth in cSCC xenograft models. Mechanistically, we revealed a link between MAPK and BMP/SMAD signaling pathways, which was mediated by the direct target of miR-130a, ACVR1. In Paper II, we investigated the role of lncRNA PVT1 in cSCC. Elevated PVT1 expression in cSCC, under MYC regulation, suggested it may contribute to keratinocyte transformation. Subsequently, we revealed that PVT1 exerted an oncogenic role in cSCC through regulating CDKN1A/p21 expression and preventing cellular senescence. We identified exon 2 as a crucial element for maintaining PVT1's oncogenic role. In Paper III, we further investigated the underlying mechanism for the oncogenic role of PVT1 in cSCC. Our data revealed that PVT1 is mainly distributed in the nuclei of cSCC cells and the exon 2 is essential for nuclear localization of PVT1. Furthermore, we identified several subunits of the transcription-export (TREX) complex as interacting partners of PVT1 and demonstrated that PVT1 modulated the function of the TREX complex in nuclear export of poly (A)+ RNAs. In Paper IV, we found that cSCC cells secreted more EVs than pri

Cutaneous squamous cell carcinoma (cSCC) ranks among the most widespread malignancies with metastatic potential. Investigating the molecular mechanism of tumorigenesis will enhance our understanding of cSCC. Aberrant expression of non-coding RNAs has been extensively reported in human cancers. Here, we summarize our work exploring the role of a microRNA (miRNA) (Paper I) and a long non-coding RNA (lncRNA) (Paper II and III) in cSCC. Additionally, we discuss the role of cSCC-derived extracellular vesicles (EVs) in tumor formation (Paper IV). In Paper I, we explored the function of miR-130a in cSCC. We reported that miR-130a expression was downregulated in cSCC under the regulation of the MAPK pathway. We demonstrated a tumor suppressor role of miR-130a in cSCC: ectopic overexpression of miR-130a suppressed malignant behaviors of human cSCC cells and inhibited primary tumor growth in cSCC xenograft models. Mechanistically, we revealed a link between MAPK and BMP/SMAD signaling pathways, which was mediated by the direct target of miR-130a, ACVR1. In Paper II, we investigated the role of lncRNA PVT1 in cSCC. Elevated PVT1 expression in cSCC, under MYC regulation, suggested it may contribute to keratinocyte transformation. Subsequently, we revealed that PVT1 exerted an oncogenic role in cSCC through regulating CDKN1A/p21 expression and preventing cellular senescence. We identified exon 2 as a crucial element for maintaining PVT1's oncogenic role. In Paper III, we further investigated the underlying mechanism for the oncogenic role of PVT1 in cSCC. Our data revealed that PVT1 is mainly distributed in the nuclei of cSCC cells and the exon 2 is essential for nuclear localization of PVT1. Furthermore, we identified several subunits of the transcription-export (TREX) complex as interacting partners of PVT1 and demonstrated that PVT1 modulated the function of the TREX complex in nuclear export of poly (A)+ RNAs. In Paper IV, we found that cSCC cells secreted more EVs than pri

N6-methyladenosine (m6A) is the most abundant internal modification on RNA. It is a dynamical and reversible process, which is regulated by m6A methyltransferase and m6A demethylase. The m6A modified RNA can be specifically recognized by the m6A reader, leading to RNA splicing, maturation, degradation or translation. The abnormality of m6A RNA modification is closely related to a variety of biological processes, especially the occurrence and development of tumors. Recent studies have shown that m6A RNA modification is involved in the pathogenesis of skin cancers. However, the precise molecular mechanisms of m6A-mediated cutaneous tumorigenesis have not been fully elucidated. Therefore, this review will summarize the biological characteristics of m6A modification, its regulatory role and mechanism in skin cancers, and the recent research progress of m6A-related molecular drugs, aiming to provide new ideas for clinical diagnosis and targeted therapy of cutaneous cancers.

In order to update recommendations on treatment, supportive care, education, and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC), a multidisciplinary panel of experts from the European Association of Dermato-Oncology (EADO), the European Dermatology Forum (EDF), the European Society for Radiotherapy and Oncology (ESTRO), the European Union of Medical Specialists (UEMS), the European Academy of Dermatology and Venereology (EADV), and the European Organisation of Research and Treatment of Cancer (EORTC) was formed. Recommendations wereḥ based on an evidence-based literature review, guidelines, and expert consensus. Treatment recommendations are presented for common primary cSCC (low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or inoperable), and distant metastatic cSCC. For common primary cSCC, the first-line treatment is surgical excision with postoperative margin assessment or micrographically controlled surgery. Achieving clear surgical margins is the most important treatment consideration for patients with cSCCs amenable to surgery. Regarding adjuvant radiotherapy for patients with high-risk localised cSCC with clear surgical margins, current evidence has not shown significant benefit for those with at least one high-risk factor. Radiotherapy should be considered as the primary treatment for non-surgical candidates/tumours. For cSCC with cytologically or histologically confirmed regional nodal metastasis, lymph node dissection is recommended. For patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or radiotherapy, anti-PD-1 agents are the first-line systemic treatment, with cemiplimab being the first approved systemic agent for advanced cSCC by the Food and Drugs Administration/European Medicines Agency. Second-line systemic treatments for advanced cSCC, include epidermal growth factor receptor inhibitors (cetuximab) combined with chemotherapy or radiotherapy. Mu, SCOPUS: ar.j, info:eu-repo/semantics/published

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer, which predominantly occurs on the head and neck. Early detection and treatment of primary tumours is crucial to limit progression and local invasion of deep tissues. While high-risk markers of poor prognosis have been identified, factors predicting regional control or survival remain uncertain. Therefore, diagnosis and management of cSCC should be performed individually, considering patient's clinicopathological profile and the best available treatment options. Surgical excision, radiotherapy, and/or systemic treatments can be selected depending on patient's status and tumour stage. Considering that a more comprehensive assessment will be provided by a multidisciplinary team, we aimed to generate a practical document that may assist oncologists and dermatologists on the prognosis, diagnosis, management, and follow-up of patients with advanced cSCC. Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer, the incidence of which has risen over the last years. Although cSCC rarely metastasizes, early detection and treatment of primary tumours are critical to limit progression and local invasion. Several prognostic factors related to patients' clinicopathologic profile and tumour features have been identified as high-risk markers and included in the stratification scales, but their association with regional control or survival is uncertain. Therefore, decision-making on the diagnosis and management of cSCC should be made based on each individual patient's characteristics. Recent advances in non-invasive imaging techniques and molecular testing have enhanced clinical diagnostic accuracy. Surgical excision is the mainstay of local treatment, whereas radiotherapy (RT) is recommended for patients with inoperable disease or in specific circumstances. Novel systemic treatments including immunotherapies and targeted therapies have changed the therapeutic lands

N6-methyladenosine (m6A) is the most abundant internal modification on RNA. It is a dynamical and reversible process, which is regulated by m6A methyltransferase and m6A demethylase. The m6A modified RNA can be specifically recognized by the m6A reader, leading to RNA splicing, maturation, degradation or translation. The abnormality of m6A RNA modification is closely related to a variety of biological processes, especially the occurrence and development of tumors. Recent studies have shown that m6A RNA modification is involved in the pathogenesis of skin cancers. However, the precise molecular mechanisms of m6A-mediated cutaneous tumorigenesis have not been fully elucidated. Therefore, this review will summarize the biological characteristics of m6A modification, its regulatory role and mechanism in skin cancers, and the recent research progress of m6A-related molecular drugs, aiming to provide new ideas for clinical diagnosis and targeted therapy of cutaneous cancers.

BackgroundThe recent addition of immunotherapy as a treatment modality to surgery and radiation has vastly improved disease control for patients with keratinocyte-derived carcinomas (KCs) that are incurable with local therapies alone. With the advent of immune checkpoint inhibitors (ICPis) in non-melanoma skin cancers comes diagnostic and therapeutic challenges when considering treatment strategies for patients presenting with clinical perineural invasion (cPNI) of locally advanced KC of the head and neck.ObjectivesWe report four cases that convey the diagnostic and therapeutic complexity of managing patients with neuropathic symptoms from cutaneous neurotropic carcinomas of the head and neck. We also discuss an updated review regarding immunotherapies and perineural invasion within KC management.ConclusionPatients presenting with symptoms suspicious for cPNI warrant an expanded diagnostic evaluation to correlate neurological findings with neurotropic spread of disease. While nerve biopsies can be precarious in sensitive areas, a history of skin cancer and clinical presentation suggestive of neurotropism may be enough to pursue timely management in the form of surgery, radiation, and/or systemic therapy given each patient's individual priorities, comorbidities, and prognosis. When adding ICPi as a treatment modality for patients with disease not amenable to local therapies, the potential for immune-related adverse events must be considered. A multi-disciplinary review and approach to the management of patients with KC and cPNI is essential for obtaining optimal patient outcomes.

Optogenetic systems and tetracycline-induced expression systems have been used in biological research. In gene circuits, light and tetracycline are often used to control the activation or inhibition of gene expression. In our study, we used a blue light induction system and tetracycline induction system to construct an “OR” logic gate, which can specifically induce the expression of p53 protein or E-cadherin in the case of blue light or tetracycline, thus inhibiting the growth of cutaneous squamous cell carcinoma cells. Cutaneous squamous cell carcinoma is a kind of skin surface tumour. The activation of two tumour suppressor genes has a synergistic inhibitory effect on cutaneous squamous cell carcinoma, and blue light and tetracycline also provide a flexible means for gene regulation. © 2022 The Authors. Clinical and Translational Discovery published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

Introduction: Cutaneous squamous cell carcinoma (cSCC) is a frequent skin cancer with a high risk of recurrence characterized by tumor infiltration and, in advanced cases, a poor prognosis. ECT (electrochemotherapy) is an alternative treatment option for locally advanced or recurrent cSCC that is unsuitable for surgical resection. In this study, we aimed to evaluate the data in the InspECT (International Network for Sharing Practice on ECT) registry of the referral centers and to clarify the indications for the use of ECT as a treatment modality for cSCC. Materials and methods: Patients with primary, recurrent or locally advanced cSCC from 18 European centers were included. They underwent at least one ECT session with bleomycin between February 2008 and November 2020, which was performed following the European Standard Operating Procedures. Results: The analysis included 162 patients (mean age of 80 years; median, 1 lesion/patient). Side effects were mainly local and mild (hyperpigmentation, 11%; ulceration, 11%; suppuration, 4%). The response to treatment per patient was 62% complete and 21% partial. In the multivariate model, intravenous drug administration and small tumor size showed a significant association with a positive outcome (objective response). One-year local progression-free survival was significantly better (p<0.001) in patients with primary tumors (80% (95% C.I. 70%-90%) than in patients with locally advanced disease (49% (95% C.I. 30%-68%). Conclusion: In the present study, ECT showed antitumor activity and a favorable safety profile in patients with complex cSCC for whom there was no widely accepted standard of care. Better results were obtained in primary and small tumors (<3 cm) using intravenous bleomycin administration.

Introduction: Cutaneous squamous cell carcinoma (cSCC) is a frequent skin cancer with a high risk of recurrence characterized by tumor infiltration and, in advanced cases, a poor prognosis. ECT (electrochemotherapy) is an alternative treatment option for locally advanced or recurrent cSCC that is unsuitable for surgical resection. In this study, we aimed to evaluate the data in the InspECT (International Network for Sharing Practice on ECT) registry of the referral centers and to clarify the indications for the use of ECT as a treatment modality for cSCC. Materials and methods: Patients with primary, recurrent or locally advanced cSCC from 18 European centers were included. They underwent at least one ECT session with bleomycin between February 2008 and November 2020, which was performed following the European Standard Operating Procedures. Results: The analysis included 162 patients (mean age of 80 years; median, 1 lesion/patient). Side effects were mainly local and mild (hyperpigmentation, 11%; ulceration, 11%; suppuration, 4%). The response to treatment per patient was 62% complete and 21% partial. In the multivariate model, intravenous drug administration and small tumor size showed a significant association with a positive outcome (objective response). One-year local progression-free survival was significantly better (p<0.001) in patients with primary tumors (80% (95% C.I. 70%-90%) than in patients with locally advanced disease (49% (95% C.I. 30%-68%). Conclusion: In the present study, ECT showed antitumor activity and a favorable safety profile in patients with complex cSCC for whom there was no widely accepted standard of care. Better results were obtained in primary and small tumors (<3 cm) using intravenous bleomycin administration.

[Background]: Acantholytic cutaneous squamous cell carcinomas (aCSCCs) have been classically considered as a high-risk variant of CSCC. However, more recent studies show that aCSCC does not confer more aggressiveness. This study aims to establish whether the prognosis of the aCSCC is worse than that of the non-acantholytic (naCSCC) or not. [Methods]: Retrospective case-control study with 50 aCSCCs and 50 naCSCCs. For each aCSCC, an naCSCC with similar high-risk features to the aCSCC but with no acantholysis was selected. Prognosis between both groups was compared. [Results]: The mean age was 86 years (SD 9.61). Sixty-one patients were men. Thirty-nine CSCCs were located in high-risk head and neck areas. Twenty CSCCs exhibited a poor degree of differentiation, and 36 showed an infiltrative growth pattern. The tumor diameter was 18.71 mm (interquartile range, IQR 35), and the tumor thickness was 6.72 mm (IQR 15.50). Twelve CSCCs exhibited perineural infiltration, and eight CSCCs exhibited invasion beyond the subcutaneous fat. Positive margins after excision of the tumor in 22 aCSCCs vs eight naCSCCs (P < 0.02). Nineteen poor-prognosis events were observed (local recurrence, lymph node metastasis, and death from CSCC). However, no differences were observed between both groups when comparing poor-prognosis events. [Conclusion]: The proportion of unfavorable events is similar in aCSCC and naCSCC. The acantholytic histopathological subtype is not associated with a poorer prognosis than the non-acantholytic CSCC in our cohort.

Surgery remains the first-line therapeutic option for most patients with cutaneous squamous cell carcinoma (cSCC). However, in the current therapeutic landscape, surgery must attempt to the complete tumor resection (R0 resection) with the lowest risk of surgical complications. This double aim is usually accomplished through standard excision with clinical margins in patients with low-risk tumors or by some of the micrographically controlled surgery procedures for patients with tumors at high-risk of local recurrence and metastasis. Surgery is also a first-line treatment for nodal metastases of cSCC as well as an option to consider in patients who develop recurrences while receiving immunotherapy, or as a palliation procedure in patients with advanced tumors. Neoadjuvant immunotherapy, that is the use of a medical treatment before surgery, is under investigation in patients with cSCC. The decision-making process and guidelines recommendations regarding cSCC surgery are reviewed in this manuscript.

Surgery remains the first-line therapeutic option for most patients with cutaneous squamous cell carcinoma (cSCC). However, in the current therapeutic landscape, surgery must attempt to the complete tumor resection (R0 resection) with the lowest risk of surgical complications. This double aim is usually accomplished through standard excision with clinical margins in patients with low-risk tumors or by some of the micrographically controlled surgery procedures for patients with tumors at high-risk of local recurrence and metastasis. Surgery is also a first-line treatment for nodal metastases of cSCC as well as an option to consider in patients who develop recurrences while receiving immunotherapy, or as a palliation procedure in patients with advanced tumors. Neoadjuvant immunotherapy, that is the use of a medical treatment before surgery, is under investigation in patients with cSCC. The decision-making process and guidelines recommendations regarding cSCC surgery are reviewed in this manuscript.

ObjectiveWe analyzed the incidence of facial nerve sacrifice during parotidectomy for metastatic cutaneous squamous cell carcinoma (CSCC).Study designWe retrospectively reviewed the charts of patients with cutaneous squamous cell carcinoma.SettingWe used our CSCC institutional database, which includes patients treated at the University of California-Davis from 2001 to 2018.MethodsWe evaluated patients who presented with biopsy-proven head and neck CSCC who underwent parotidectomy as a part of surgical treatment. We assessed the frequency of facial nerve sacrifice required in patients with normal preoperative facial nerve function with metastatic disease to the parotid. We evaluated the association between sacrifice and high-risk tumor variables using multivariate analysis.ResultsWe identified 53 patients with parotid metastasis and normal preoperative facial nerve function. Thirteen percent of patients required sacrifice of the main trunk of the facial nerve and 27% required sacrifice of a branch of the facial nerve. All patients who underwent facial nerve sacrifice had extracapsular spread (ECS). Perineural invasion (PNI) in the primary tumor (odds ratio [OR], 9.11; P = .041) and location of metastasis within the parotid body (OR, 6.6; P = .044) were independently associated with facial nerve sacrifice.ConclusionPatients with regionally metastatic CSCC to the parotid gland frequently require sacrifice of all or a component of the facial nerve despite normal preoperative function. The likelihood of nerve sacrifice is highest for tumors with PNI and metastatic disease within the body of the parotid.

Surgery remains the first-line therapeutic option for most patients with cutaneous squamous cell carcinoma (cSCC). However, in the current therapeutic landscape, surgery must attempt to the complete tumor resection (R0 resection) with the lowest risk of surgical complications. This double aim is usually accomplished through standard excision with clinical margins in patients with low-risk tumors or by some of the micrographically controlled surgery procedures for patients with tumors at high-risk of local recurrence and metastasis. Surgery is also a first-line treatment for nodal metastases of cSCC as well as an option to consider in patients who develop recurrences while receiving immunotherapy, or as a palliation procedure in patients with advanced tumors. Neoadjuvant immunotherapy, that is the use of a medical treatment before surgery, is under investigation in patients with cSCC. The decision-making process and guidelines recommendations regarding cSCC surgery are reviewed in this manuscript.

[Introduction]: The Brigham and Women's Hospital and the Tübingen cutaneous squamous cell carcinoma (SCC) stratification systems propose different criteria from the American Joint Committee on Cancer, eighth edition. Our group identified prognostic subgroups within T3 stage according to the American Joint Committee on Cancer eighth edition's classification, the most common classification for high-risk cutaneous SCCs., [Objective]: To compare the performance and prognostic accuracy of these staging systems in a subset of high-risk cutaneous SCCs., [Methods]: Homogeneity, monotonicity, and McNemar tests for pairwise comparisons were assessed. Distinctiveness and relative risk of poor outcome were calculated by stage. Prognostic accuracy was compared with respect to quality (Akaike and Bayesian information criteria), concordance (Harrell C-index and Gönen and Heller concordance probability estimate), and predictive accuracy (sensitivity, specificity, negative predictive value, positive predictive value, and global accuracy)., [Results]: The Brigham and Women's Hospital and Salamanca systems were more distinctive, homogeneous, and monotonic than the Tübingen system. The Tübingen system was the most specific, whereas the Salamanca and Brigham and Women's Hospital systems were more sensitive. Negative predictive value was high in all 3 systems, but positive predictive value and accuracy were low overall., [Conclusions]: Alternative staging systems may partially overcome the heterogeneity and low prognostic accuracy of the American Joint Committee on Cancer, eighth edition and enable high-risk cutaneous SCCs to be stratified more reliably, but their prognostic accuracy is still low. Considering the accumulation of risk factors may improve high-risk cutaneous SCC risk stratification.

Background: Cutaneous squamous cell carcinoma (cSCC) has an overall favourable outcome, except for patients with an advanced stage disease. The programmed death protein-1 (PD-1) inhibitor cemiplimab has been approved for use in advanced cSCC. We report clinical outcomes from the named patient programme-compassionate use of cemiplimab for patients with advanced cSCC in Italy. Methods: This is a retrospective, observational, multicentre study. We analysed medical records of patients with advanced cSCC treated with cemiplimab between May 2019 and February 2020 in 17 referral Italian centres. We assessed the safety profile according to the Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v 5.0), the clinical activity in terms of response rate, clinical benefit and duration of response and baseline clinical-pathologic characteristics associated with response. Results: 131 patients were included, with a median age of 79 years. Of them, 9.2% had a concurrent chronic lymphoproliferative disease and 8.5% a concomitant autoimmune disease. Some 42.7% of the total patients had at least one treatment-related adverse events (AEs); out of above, 9.2% had grade 3–4 adverse events, and there were two fatal adverse events. The overall response rate (ORR) was 58%, and the disease control rate (DCR) was 71.7%. Cutaneous squamous cell carcinomas (cSCCs) arising on the head and neck area (p = 0.007) and haemoglobin values in normal range (p = 0.034) were significantly associated with a better response, while cSCCs on the genitalia (p = 0.041), treatment with any systemic antibiotic within 1 month of cemiplimab initiation (p = 0.012), performance status ≥1 (p = 0.012), chronic corticosteroids therapy (p = 0.038), previous radiation therapy to lymph nodes (p = 0.052) and previous chemotherapy (p = 0.0020) were significantly associated with a worse response. Conclusions: Our real-world study showed safety and effectiveness results comparable to those obtained in clinical t

The continuous improvement of life expectancy of patients with chronic lymphocytic leukemia (CLL) has resulted in increased risk of second primary malignancy that potentially may affect survival and quality of life of CLL patients. We performed a systematic review to assess the risk and the clinical-pathological features and prognosis of cutaneous squamous cell carcinoma (cSCC) in patients with CLL. We searched PubMed, Embase, and Cochrane Central Register of Control Trials databases for articles published from database inception to December 31, 2019. English-language studies reporting original data on patients with a specific diagnosis of CLL and cSCC were included. Data were extracted using a standardized extraction form, and any discordance was resolved by consensus. Descriptive data were generated by pooling patients from eligible studies. Of the 4588 non-duplicate records identified, 55 articles met our inclusion criteria. These studies reported that CLL patients have a 3.2% prevalence of cSCC, with an 11.5% cSCC-related lethality and an overall risk of metastasis of 5.7% (7.3% for regional lymph node involvement and 3.8% for distant metastasis). The quality of evidence was limited by the high heterogeneity in the design, populations, and objectives of the included studies. This systematic review suggests that cSCC in CLL patients tends to behave less aggressively compared with the solid organ transplant recipients but has a higher morbidity and mortality than in the general population. Future prospective studies are needed to increase the quality of evidence and to determine the best treatment modalities and screening intervals for these patients.

[Background]: Although the eighth edition of the American Joint Committee on Cancer staging system (AJCC8) provides improved prognosis stratification of cutaneous squamous cell carcinoma (CSCC) over AJCC7, T3 has a variable prognosis., [Objective]: To define prognostic subgroups in T3-AJCC8 CSCC., [Methods]: Retrospective cohort study of 196 primary T3-AJCC8 CSCCs. We conducted multidimensional scaling analysis using the 6 risk factors that define T3 CSCCs. The prognoses of the groups obtained were analyzed by means of competing risk analysis., [Results]: Group 1 was characterized by a tumor thickness greater than 6 mm (without invasion beyond the subcutaneous fat), alone or in combination with a tumor width of at least 4 cm. Group 2 was characterized by the presence of either invasion beyond the subcutaneous fat or by the involvement of nerves (≥0.1 mm, or deeper than the dermis). Group 3 was characterized by the combination of both T3b risk factors, or of 3 or more risk factors. Group 3 (tentatively named T3c) patients had the worst prognosis for disease-specific poor outcome events and major events, Group 2 (T3b) had intermediate risk, and Group 1 (T3a) had the best prognosis (disease-specific poor outcome events: hazard ratio [HR], 1.94; P = .00009; major events: HR, 2.55; P = .00001; disease-specific death: HR, 10.25; P = .0009)., [Limitations]: Retrospective study., [Conclusions]: There is statistically significant evidence that T3-AJCC8 may be classified into distinct prognostic subgroups.

Advances in virology and skin cancer over recent decades have produced achievements that have been recognized not only in the field of dermatology, but also in other areas of medicine. They have modified the therapeutic and preventive solutions that can be offered to some patients and represent a significant step forward in our knowledge of the biology of skin cancer. In this paper, we review the viral agents responsible for different types of skin cancer, especially for solid skin tumors. We focus on human papillomavirus and squamous cell cancers, Merkel cell polyomavirus and Merkel cell carcinoma, and human herpesvirus 8 and Kaposi’s sarcoma.

Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans, and is now responsible for as many deaths as melanoma. Immunotherapy has changed the therapeutic landscape of advanced CSCC after the FDA approval of anti-PD1 molecules for the treatment of locally advanced and metastatic CSCC. However, roughly 50% of patients will not respond to this systemic treatment and even those who do respond can develop resistance over time. The etiologies of primary and secondary resistance to immunotherapy involve changes in the neoplastic cells and the tumor microenvironment. Indirect modulation of immune system activation with new therapies, such as vaccines, oncolytic viruses, and new immunotherapeutic agents, and direct modulation of tumor immunogenicity using other systemic treatments or radiotherapy are now under evaluation in combined regimens. The identification of predictors of response is an important area of research. In this review, we focus on the features associated with the response to immunotherapy, and the evaluation of combination treatments and new molecules, a more thorough knowledge of which is likely to improve the survival of patients with advanced CSCC.

Background: Cutaneous squamous skin cell carcinoma (SCC) is the second most frequent type of non-melanoma skin cancer and is the second leading cause of death by skin cancer in Caucasian populations. However, at present it is difficult to predict patients with poor SCC prognosis. Objective: To identify proteins with expression levels that could predict SCC infiltration in SCC arising from actinic keratosis (SCC-AK). Methods: A total of 20 biopsies from 20 different patients were studied; 10 were SCC-AK samples and 10 were taken from normal skin. Early infiltrated SCC-AK samples were selected based on histological examination, and to determine the expression of proteins, fresh skin samples were processed by two-dimensional electrophoresis. Results: The expression levels of three proteins, namely alpha hemoglobin and heat shock proteins 27 and 70 (Hsp27 and Hsp70, respectively) were significantly increased in SCC-AK samples with respect to normal control skin. However, only the expression level of Hsp70 protein positively correlated with the level of SCC-AK dermis infiltration. Immunohistological examination suggested that increased expression of Hsp70 proteins seemed to mainly occur in the cytoplasm of keratinocytes. The increased cytoplasmic Hsp70 expression in SCC-AK was confirmed by Western blot experiments. Conclusion: Cytoplasmic expression of Hsp70 could be a potential biomarker of early infiltration of SCC arising from AK., Depto. de Medicina, Depto. de Salud Pública y Materno - Infantil, Fac. de Medicina, TRUE, pub

A 90-year-old man presented for evaluation of an incompletely excised squamous cell carcinoma above the right brow, with pathology demonstrating tumor extending to resection margins with perineural invasion. A cord of tumor was noted to extend past the orbital rim and towards the posterior orbit. Mohs excision versus coordinated resection and reconstruction with colleagues in the head and neck surgery and craniofacial plastic surgery departments were considered. Multidisciplinary consensus was to proceed with radical resection in the operating room followed by adjuvant radiation therapy. One year later, the patient presented to our Mohs unit with a 3cm eroded multinodular plaque. Following an in-depth discussion regarding the options of further surgery versus systemic treatment, the patient and his family opted to pursue consultation with a medical oncology consultant to discuss restaging and potential systemic therapy. A PET scan with concurrent CT revealed a hypermetabolic right temporal scalp mass without evidence of bony invasion or extension into the nodal basin. Immunotherapy with cemiplimab was started at a dose of 350mg IV every three weeks. After 7 cycles, the patient demonstrated complete clinical resolution with a repeat PET scan showing interval near resolution of abnormal metabolic activity.

Objectives: The aim of this study was to estimate the total annual direct costs incurred by the National Health Service for the management and treatment of CSCC and advanced CSCC patients in Italy. Methods: An incidence-based cost of illness (COI) model was developed to estimate direct costs associated with the treatment and management of CSCC patients in Italy. The identified treatment pathway was validated with a team of clinical experts and was distinguished between resectable CSCC and locally advanced CSCC or metastatic CSCC. Treatments costs were obtained through the analysis of the National Hospital Discharge Database (HDD) for the years 2015-2018; monitoring and terminal care costs were obtained from national tariffs of outpatient care service and from the literature respectively. Results: Associating the estimated costs for each phase of the treatment pathway with the proportion of patients present in each phase, the COI model estimated an annual economic burden of about € 25.9 million for the management and treatment of patients with CSCC in Italy, € 2.7 million of which were associated to patients with advanced CSCC. The average cost per patient with advanced CSCC was higher compared to that of patient with resectable CSCC (€ 4,490 vs € 2,236 respectively). Conclusions: Our analysis showed that advanced CSCC patients are associated with a higher average cost than patients with resectable CSCC.

A 90-year-old man presented for evaluation of an incompletely excised squamous cell carcinoma above the right brow, with pathology demonstrating tumor extending to resection margins with perineural invasion. A cord of tumor was noted to extend past the orbital rim and towards the posterior orbit. Mohs excision versus coordinated resection and reconstruction with colleagues in the head and neck surgery and craniofacial plastic surgery departments were considered. Multidisciplinary consensus was to proceed with radical resection in the operating room followed by adjuvant radiation therapy. One year later, the patient presented to our Mohs unit with a 3cm eroded multinodular plaque. Following an in-depth discussion regarding the options of further surgery versus systemic treatment, the patient and his family opted to pursue consultation with a medical oncology consultant to discuss restaging and potential systemic therapy. A PET scan with concurrent CT revealed a hypermetabolic right temporal scalp mass without evidence of bony invasion or extension into the nodal basin. Immunotherapy with cemiplimab was started at a dose of 350mg IV every three weeks. After 7 cycles, the patient demonstrated complete clinical resolution with a repeat PET scan showing interval near resolution of abnormal metabolic activity.

Objectives: The aim of this study was to estimate the total annual direct costs incurred by the National Health Service for the management and treatment of CSCC and advanced CSCC patients in Italy. Methods: An incidence-based cost of illness (COI) model was developed to estimate direct costs associated with the treatment and management of CSCC patients in Italy. The identified treatment pathway was validated with a team of clinical experts and was distinguished between resectable CSCC and locally advanced CSCC or metastatic CSCC. Treatments costs were obtained through the analysis of the National Hospital Discharge Database (HDD) for the years 2015-2018; monitoring and terminal care costs were obtained from national tariffs of outpatient care service and from the literature respectively. Results: Associating the estimated costs for each phase of the treatment pathway with the proportion of patients present in each phase, the COI model estimated an annual economic burden of about € 25.9 million for the management and treatment of patients with CSCC in Italy, € 2.7 million of which were associated to patients with advanced CSCC. The average cost per patient with advanced CSCC was higher compared to that of patient with resectable CSCC (€ 4,490 vs € 2,236 respectively). Conclusions: Our analysis showed that advanced CSCC patients are associated with a higher average cost than patients with resectable CSCC.

Antecedentes y objetivos La pandemia del coronavirus SARS-CoV-2 ha provocado un confinamiento indefinido. Una posible consecuencia de esta situación es un retraso en los procedimientos asistenciales de las enfermedades oncológicas. El objetivo de este estudio es estimar el hipotético impacto en la supervivencia que tendría el aumento del tamaño tanto para los carcinomas de células escamosas (CCE) como de los melanomas. Material y método Estudio observacional retrospectivo de cohorte multicéntrico. Se desarrolló un modelo de crecimiento exponencial para cada tumor basado en el tiempo de evolución que refiere el paciente. Resultados Se incluyeron un total de 200 pacientes con CCE localizados en la cabeza y el cuello y 1.000 pacientes con melanoma cutáneo. Se calculó una curva de crecimiento exponencial para cada tumor y se estimó el tamaño del tumor tras 1, 2 y 3 meses tras el diagnóstico. En la muestra, los CCE mayores de 4 cm o > 6 mm de grosor (definidos como T3) pasaron de 83 (41,5%) en el grupo de estudio real a una estimación del 58,5, 70,5 y 72% tras 1, 2 y 3 meses de retraso quirúrgico estimado, respectivamente. Se estimó una disminución de la supervivencia específica de enfermedad (SEE) de un 6,2, 8,2 y 5,2% a los 2, 5 y 10 años, respectivamente, tras 3 meses de retraso. Para los melanomas ultragruesos (> 6 mm de Breslow) pasaron del 6,9% en el grupo de estudio al 21,9, 30,2 y 30,2% tras 1, 2 y 3 meses de demora. La SEE a los 5 y 10 años del grupo de estudio descendió un 14,4% en ambos tiempos. Conclusiones En ausencia de un adecuado diagnóstico y tratamiento de los pacientes con CCE y melanoma en la actual situación de confinamiento en España, podemos llegar a asistir a un considerable aumento de los casos de CCE y melanomas gruesos y de gran tamaño. Se deben fomentar los esfuerzos para promocionar la autoexploración y facilitar el acceso a los dermatólogos para no aumentar la demora de estos pacientes., Background and objectives Spain is in a situation of indefinite lockdown due to the ongoing coronavirus disease 2019 (COVID-19) pandemic. One of the consequences of this lockdown is delays in medical and surgical procedures for common diseases. The aim of this study was to model the impact on survival of tumor growth caused by such delays in patients with squamous cell carcinoma (SCC) and melanoma. Material and methods Multicenter, retrospective, observational cohort study. We constructed an exponential growth model for both SCC and melanoma to estimate tumor growth between patient-reported onset and surgical excision at different time points. Results Data from 200 patients with SCC of the head and neck and 1000 patients with cutaneous melanoma were included. An exponential growth curve was calculated for each tumor type and we estimated tumor size after 1, 2, and 3 months of potential surgical delay. The proportion of patients with T3 SCC (diameter >4cm or thickness >6 mm) increased from 41.5% (83 patients) in the initial study group to an estimated 58.5%, 70.5%, and 72% after 1, 2, and 3 months of delay. Disease-specific survival at 2, 5, and 10 years in patients whose surgery was delayed by 3 months decreased by 6.2%, 8.2%, and 5.2%, respectively. The proportion of patients with ultrathick melanoma (>6 mm) increased from 6.9% in the initial study group to 21.9%, 30.2%, and 30.2% at 1, 2, and 3 months. Five- and 10-year disease-specific survival both decreased by 14.4% in patients treated after a potential delay of 3 months. Conclusions In the absence of adequate diagnosis and treatment of SCC and melanoma in the current lockdown situation in Spain, we can expect to see to a considerable increase in large and thick SCCs and melanomas. Efforts must be taken to encourage self-examination and facilitate access to dermatologists in order to prevent further delays.

Antecedentes y objetivos La pandemia del coronavirus SARS-CoV-2 ha provocado un confinamiento indefinido. Una posible consecuencia de esta situación es un retraso en los procedimientos asistenciales de las enfermedades oncológicas. El objetivo de este estudio es estimar el hipotético impacto en la supervivencia que tendría el aumento del tamaño tanto para los carcinomas de células escamosas (CCE) como de los melanomas. Material y método Estudio observacional retrospectivo de cohorte multicéntrico. Se desarrolló un modelo de crecimiento exponencial para cada tumor basado en el tiempo de evolución que refiere el paciente. Resultados Se incluyeron un total de 200 pacientes con CCE localizados en la cabeza y el cuello y 1.000 pacientes con melanoma cutáneo. Se calculó una curva de crecimiento exponencial para cada tumor y se estimó el tamaño del tumor tras 1, 2 y 3 meses tras el diagnóstico. En la muestra, los CCE mayores de 4 cm o > 6 mm de grosor (definidos como T3) pasaron de 83 (41,5%) en el grupo de estudio real a una estimación del 58,5, 70,5 y 72% tras 1, 2 y 3 meses de retraso quirúrgico estimado, respectivamente. Se estimó una disminución de la supervivencia específica de enfermedad (SEE) de un 6,2, 8,2 y 5,2% a los 2, 5 y 10 años, respectivamente, tras 3 meses de retraso. Para los melanomas ultragruesos (> 6 mm de Breslow) pasaron del 6,9% en el grupo de estudio al 21,9, 30,2 y 30,2% tras 1, 2 y 3 meses de demora. La SEE a los 5 y 10 años del grupo de estudio descendió un 14,4% en ambos tiempos. Conclusiones En ausencia de un adecuado diagnóstico y tratamiento de los pacientes con CCE y melanoma en la actual situación de confinamiento en España, podemos llegar a asistir a un considerable aumento de los casos de CCE y melanomas gruesos y de gran tamaño. Se deben fomentar los esfuerzos para promocionar la autoexploración y facilitar el acceso a los dermatólogos para no aumentar la demora de estos pacientes., Background and objectives Spain is in a situation of indefinite lockdown due to the ongoing coronavirus disease 2019 (COVID-19) pandemic. One of the consequences of this lockdown is delays in medical and surgical procedures for common diseases. The aim of this study was to model the impact on survival of tumor growth caused by such delays in patients with squamous cell carcinoma (SCC) and melanoma. Material and methods Multicenter, retrospective, observational cohort study. We constructed an exponential growth model for both SCC and melanoma to estimate tumor growth between patient-reported onset and surgical excision at different time points. Results Data from 200 patients with SCC of the head and neck and 1000 patients with cutaneous melanoma were included. An exponential growth curve was calculated for each tumor type and we estimated tumor size after 1, 2, and 3 months of potential surgical delay. The proportion of patients with T3 SCC (diameter >4cm or thickness >6 mm) increased from 41.5% (83 patients) in the initial study group to an estimated 58.5%, 70.5%, and 72% after 1, 2, and 3 months of delay. Disease-specific survival at 2, 5, and 10 years in patients whose surgery was delayed by 3 months decreased by 6.2%, 8.2%, and 5.2%, respectively. The proportion of patients with ultrathick melanoma (>6 mm) increased from 6.9% in the initial study group to 21.9%, 30.2%, and 30.2% at 1, 2, and 3 months. Five- and 10-year disease-specific survival both decreased by 14.4% in patients treated after a potential delay of 3 months. Conclusions In the absence of adequate diagnosis and treatment of SCC and melanoma in the current lockdown situation in Spain, we can expect to see to a considerable increase in large and thick SCCs and melanomas. Efforts must be taken to encourage self-examination and facilitate access to dermatologists in order to prevent further delays.

In order to update recommendations on treatment, supportive care, education and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC), a multidisciplinary panel of experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organization of Research and Treatment of Cancer was formed. Recommendations were based on evidence-based literature review, guidelines and expert consensus. Treatment recommendations are presented for common primary cSCC (low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or inoperable) and distant metastatic cSCC. For common primary cSCC (the most frequent cSCC type), first-line treatment is surgical excision with postoperative margin assessment or microscopically controlled sugery. Safety margins containing clinical normal-appearing tissue around the tumour during surgical excision and negative margins as reported in the pathology report are necessary to minimise the risk of local recurrence and metastasis. In case of positive margins, a re-excision shall be done, for operable cases. Lymph node dissection is recommended for cSCC with cytologically or histologically confirmed regional nodal involvement. Radiotherapy should be considered as curative treatment for inoperable cSCC, or for non-surgical candidates. Anti-PD-1 antibodies are the first-line systemic treatment for patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or radiation, with cemiplimab being the first approved systemic agent for advanced cSCC by the Food and Drug Administration/European Medicines Agency. Second-line systemic treatments for advanced cSCC include epidermal growth factor receptor inhibitors (cetuximab) combined with chemotherapy or radiation therapy. Multidisciplinary board decisions are mandatory for all patients with advanced disease who require more than surgery. Patients should be engaged with informed decisions on manage

In order to update recommendations on treatment, supportive care, education and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC), a multidisciplinary panel of experts from the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organization of Research and Treatment of Cancer was formed. Recommendations were based on evidence-based literature review, guidelines and expert consensus. Treatment recommendations are presented for common primary cSCC (low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or inoperable) and distant metastatic cSCC. For common primary cSCC (the most frequent cSCC type), first-line treatment is surgical excision with postoperative margin assessment or microscopically controlled sugery. Safety margins containing clinical normal-appearing tissue around the tumour during surgical excision and negative margins as reported in the pathology report are necessary to minimise the risk of local recurrence and metastasis. In case of positive margins, a re-excision shall be done, for operable cases. Lymph node dissection is recommended for cSCC with cytologically or histologically confirmed regional nodal involvement. Radiotherapy should be considered as curative treatment for inoperable cSCC, or for non-surgical candidates. Anti-PD-1 antibodies are the first-line systemic treatment for patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or radiation, with cemiplimab being the first approved systemic agent for advanced cSCC by the Food and Drug Administration/European Medicines Agency. Second-line systemic treatments for advanced cSCC include epidermal growth factor receptor inhibitors (cetuximab) combined with chemotherapy or radiation therapy. Multidisciplinary board decisions are mandatory for all patients with advanced disease who require more than surgery. Patients should be engaged with informed decisions on manage, SCOPUS: ar.j, info:eu-repo/semantics/published

Objectives: The aim of this study was to estimate the total annual direct costs incurred by the National Health Service for the management and treatment of CSCC and advanced CSCC patients in Italy. Methods: An incidence-based cost of illness (COI) model was developed to estimate direct costs associated with the treatment and management of CSCC patients in Italy. The identified treatment pathway was validated with a team of clinical experts and was distinguished between resectable CSCC and locally advanced CSCC or metastatic CSCC. Treatments costs were obtained through the analysis of the National Hospital Discharge Database (HDD) for the years 2015-2018; monitoring and terminal care costs were obtained from national tariffs of outpatient care service and from the literature respectively. Results: Associating the estimated costs for each phase of the treatment pathway with the proportion of patients present in each phase, the COI model estimated an annual economic burden of about € 25.9 million for the management and treatment of patients with CSCC in Italy, € 2.7 million of which were associated to patients with advanced CSCC. The average cost per patient with advanced CSCC was higher compared to that of patient with resectable CSCC (€ 4,490 vs € 2,236 respectively). Conclusions: Our analysis showed that advanced CSCC patients are associated with a higher average cost than patients with resectable CSCC.

Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and it can be locally invasive and metastatic to distant sites. MicroRNAs (miRNAs or miRs) are endogenous, small, non-coding RNAs of 19–25 nucleotides in length, that are involved in regulating gene expression at a post-transcriptional level. MicroRNAs have been implicated in diverse biological functions and diseases. In cancer, miRNAs can proceed either as oncogenic miRNAs (onco-miRs) or as tumor suppressor miRNAs (oncosuppressor-miRs), depending on the pathway in which they are involved. Dysregulation of miRNA expression has been shown in most of the tumors evaluated. MiRNA dysregulation is known to be involved in the development of cutaneous squamous cell carcinoma (CSCC). In this review, we focus on the recent evidence about the role of miRNAs in the development of CSCC and in the prognosis of this form of skin cancer.

Cutaneous squamous cell carcinoma (cSCC) is a serious complication after organ transplantation and patients benefit from an early risk assessment. We hypothesized that functional differences in circulating T cells may represent risk factors for post-transplant cSCC development. Here, we analysed genome-wide DNA methylation of circulating T cells of kidney transplant recipients before the clinical onset of cSCC, to identify differences associated with post-transplant cSCC development. This analysis identified higher DNA methylation of SERPINB9, which is an intracellular inhibitor of granzyme B, a protein that induces apoptosis in target cells. High DNA methylation of SERPINB9 in circulating T cells was confirmed in a second patient cohort during recurrent cSCC, indicating that high SERPINB9 methylation represents a persistent risk f

[Background]: The new eighth edition of the American Joint Committee on Cancer staging system (AJCC-8) incorporates changes regarding cutaneous squamous cell carcinoma (CSCC)., [Objectives]: We aimed to compare the AJCC-8 staging system with the previous seventh edition of the AJCC staging system (AJCC-7) and the Brigham and Women's Hospital (BWH) alternative staging system to identify their usefulness and the utility of their risk factors in defining prognostic groups in CSCC., [Methods]: A series of 186 CSCCs of the head and neck were retrospectively collected. All 3 staging systems were compared from the standpoint of their ability to predict poor prognosis. Binary logistic regression models were built to determine which risk factors were most relevant., [Results]: Poor prognosis was mainly associated with stage T2 of the AJCC-7, with stages T2b/T3 of the BWH system, and with stage T3 of the AJCC-8. The AJCC-8 and the BWH staging systems displayed overlap with each another in predicting poor prognosis, and both were superior to the AJCC-7. The new risk factors incorporated into the AJCC-8 and the poor degree of differentiation were independently associated with poor outcome.

Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and it can be locally invasive and metastatic to distant sites. MicroRNAs (miRNAs or miRs) are endogenous, small, non-coding RNAs of 19–25 nucleotides in length, that are involved in regulating gene expression at a post-transcriptional level. MicroRNAs have been implicated in diverse biological functions and diseases. In cancer, miRNAs can proceed either as oncogenic miRNAs (onco-miRs) or as tumor suppressor miRNAs (oncosuppressor-miRs), depending on the pathway in which they are involved. Dysregulation of miRNA expression has been shown in most of the tumors evaluated. MiRNA dysregulation is known to be involved in the development of cutaneous squamous cell carcinoma (CSCC). In this review, we focus on the recent evidence about the role of miRNAs in the development of CSCC and in the prognosis of this form of skin cancer.

The role of telomere biology and telomerase activation in skin cancers has been investigated in melanoma and basal cell carcinoma but limited evidence is available for cutaneous squamous cell carcinoma (cSCC). We will review the current knowledge on the role of telomere and telomerase pathway in cSCC pathogenesis. At the somatic level, both long and short telomere lengths have been described in cSCC. This telomere dichotomy is probably related to two different mechanisms of tumour initiation which determines two tumour subtypes. Telomere shortening is observed during the invasive progression from in situ forms of cSCC, such as Bowen’s disease (BD) and actinic keratosis (AK), to invasive cSCC. At the germline level, controversial results have been reported on the association between constitutive telomere length and risk of cSCC. Approximately 75–85% of cSCC tumours are characterized by a high level of telomerase activity. Telomerase activation has been also reported in AKs and BD and in sun-damaged skin, thus supporting the hypothesis that UV modulates telomerase activity in the skin. Activating TERT promoter mutations have been identified in 32–70% of cSCCs, with the majority showing the UV-signature. No significant correlation was observed between TERT promoter mutations and cSCC clinico-pathological features. However, TERT promoter mutations have been recently suggested to be independent predictors of an adverse outcome. The attention on telomere biology and telomerase activity in cSCC is increasing for the potential implications in the development of effective tools for prognostic assessment and of therapeutic strategies in patients with cutaneous cSCC.

Metastatic squamous cell carcinoma (SCC) to the skin can be distinguished histologically from primary cutaneous squamous cell carcinoma as, unlike the latter, it is typically separated from the normal overlying squamous epithelium. Rare cases have been reported of cutaneous metastases of SCC that demonstrate continuity with the overlying benign squamous epithelium, termed "epidermotropic cutaneous metastases of SCC." We report the first case of epidermotropic cutaneous metastases of SCC originating from primary esophageal SCC with a review of the literature on this rare histological phenomenon.

Metastatic squamous cell carcinoma (SCC) to the skin can be distinguished histologically from primary cutaneous squamous cell carcinoma as, unlike the latter, it is typically separated from the normal overlying squamous epithelium. Rare cases have been reported of cutaneous metastases of SCC that demonstrate continuity with the overlying benign squamous epithelium, termed "epidermotropic cutaneous metastases of SCC." We report the first case of epidermotropic cutaneous metastases of SCC originating from primary esophageal SCC with a review of the literature on this rare histological phenomenon.

Throughout gestation, the blood vessel network of the placenta is formed sequentially by processes known as vasculogenesis and angiogenesis, which together meet the needs of the growing fetus. Normal placental angiogenesis is critical to support adequate fetal growth and assure the health of the offspring. Proper angiogenesis requires precise regulation of expression of agents that modulate this process; otherwise, pathologies of pregnancy such as preeclampsia may occur. The placenta is composed of different layers of tissue, including the lamellar (LZ), junctional, and glandular zones, each with a vascular morphology attuned to its function. We hypothesized that higher expression of pro-angiogenic factors is associated with increased morphological metrics in the LZ, the major vascularized zone. Thus, we aimed to characterize the major changes in morphology and vascular development in the placenta throughout pregnancy in cats, alongside a compressive analysis of the expression of major angiogenic factors and their receptors in the placenta, with an emphasis on the identification and interaction of different isoforms of the VEGF family. Microscopic analysis of tissue specimens from different stages of pregnancy revealed increased thickness of the LZ, especially during early to mid-gestation, at which time the tissue is composed of abundant materno-fetal interdigitations that appears rich in capillaries. VEGF proteins were detected in placental tissue in both fetal and maternal cells of the placenta, suggesting stimulatory interactions between different cell types to promote growth and angiogenesis. Gene expression analysis of placenta revealed upregulation of the pro-angiogenic factor VEGF-A in mid-pregnancy, followed by a steady decline toward term, consistent with morphologic changes in the LZ. In contrast, another pro-angiogenic factor, PlGF, showed a marked increase toward term; Flt-1, which acts as a receptor or reservoir for PLGF and VEGF A, was also upregulate

Previous studies have established that 7,12-dimethylbenz(a)anthracene (DMBA) can initiate skin tumourigenesis in conventional furred mouse models by acting on hair follicle stem cells. However, further cancer progression depends on repeated applications of tumour promoter agents. This study evaluated the timeline involved in skin tumourigenesis and progression in immunocompetent hairless SKH1-hr mice with dysfunctional hair follicles using only DMBA with no additional tumour promoter agents. The results showed that topical application of 30 µg (117 nmol) of DMBA over the back and flank regions of the mouse once a week and 15 µg (58.5 nmol) twice a week produced skin tumours after 7–8 weeks. However, by week 14 a heavy benign tumour load required the mice to be euthanized. Lowering the DMBA dose to 15 µg (58.5 nmol) once a week produced tumours more slowly and allowed the mice to be studied for a longer period to week 23. This low-dose DMBA regimen yielded a high percentage of malignant tumours (58.8%) after 23 weekly applications. Additionally DMBA-treated skin showed an increase in mean epidermal thickness in comparison to untreated and acetone-treated skin. Despite the aberrant hair follicles in SKH1-hr mice, this chemically driven skin cancer model in hairless mice can serve as a suitable alternative to the ultraviolet-induced skin cancer models and can be reliably replicated as demonstrated by both the pilot and main experiments.

[Background]: Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and can be both locally invasive and metastatic at distant sites. While research efforts have been made to predict poor outcome of CSCC, there is a lack of knowledge regarding molecular markers. Podoplanin has been associated with poor outcome in several types of cancer including CSCC, but this is controversial and only a few studies have evaluated the prognostic implications of podoplanin in the development of this tumor. [Methods]: We evaluated podoplanin expression in a series of 94 CSCCs, and searched for associations between podoplanin expression and histopathological characteristics and with events of poor clinical evolution of the disease. [Results]: Podoplanin expression was observed in 48.9% of the cases and the expression was considered moderate to intense in 19 of the cases. Moderate/intense podoplanin was associated with infiltrative growth pattern, desmoplasia, lymphovascular invasion, higher risk of nodal progression (NP) and short disease-free survival, specifically with a short latency to NP. [Conclusions]: This article provides evidence supporting the implication of podoplanin expression as a marker of bad prognosis of CSCC.

Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in Caucasian populations, accounting for 20% of all cutaneous malignancies. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on cSCC diagnosis and management, based on a critical review of the literature, existing guidelines and the expert's experience. The diagnosis of cSCC is primarily based on clinical features. A biopsy or excision and histologic confirmation should be performed in all clinically suspicious lesions in order to facilitate the prognostic classification and correct management of cSCC. The first line treatment of cutaneous SCC is complete surgical excision with histopathological control of excision margins. The EDF-EADO-EORTC consensus group recommends a standardised minimal margin of 5 mm even for low-risk tumours. For tumours, with histological thickness of >6 mm or in tumours with high risk pathological features, e.g. high histological grade, subcutaneous invasion, perineural invasion, recurrent tumours and/or tumours at high risk locations an extended margin of 10 mm is recommended. As lymph node involvement by cSCC increases the risk of recurrence and mortality, a lymph node ultrasound is highly recommended, particularly in tumours with high-risk characteristics. In the case of clinical suspicion or positive findings upon imaging, a histologic confirmation should be sought either by fine needle aspiration or by open lymph node biopsy. In large infiltrating tumours with signs of involvement of underlying structures, additional imaging tests, such as CT or MRI imaging may be required to accurately assess the extent of the tumour and the presence of metastatic spread. Current staging systems for cSCC are not optimal, as they have been developed for head and neck tumours

Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers in Caucasian populations, accounting for 20% of all cutaneous malignancies. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on cSCC diagnosis and management, based on a critical review of the literature, existing guidelines and the expert's experience. The diagnosis of cSCC is primarily based on clinical features. A biopsy or excision and histologic confirmation should be performed in all clinically suspicious lesions in order to facilitate the prognostic classification and correct management of cSCC. The first line treatment of cutaneous SCC is complete surgical excision with histopathological control of excision margins. The EDF-EADO-EORTC consensus group recommends a standardised minimal margin of 5 mm even for low-risk tumours. For tumours, with histological thickness of >6 mm or in tumours with high risk pathological features, e.g. high histological grade, subcutaneous invasion, perineural invasion, recurrent tumours and/or tumours at high risk locations an extended margin of 10 mm is recommended. As lymph node involvement by cSCC increases the risk of recurrence and mortality, a lymph node ultrasound is highly recommended, particularly in tumours with high-risk characteristics. In the case of clinical suspicion or positive findings upon imaging, a histologic confirmation should be sought either by fine needle aspiration or by open lymph node biopsy. In large infiltrating tumours with signs of involvement of underlying structures, additional imaging tests, such as CT or MRI imaging may be required to accurately assess the extent of the tumour and the presence of metastatic spread. Current staging systems for cSCC are not optimal, as they have been developed for head and neck tumours, SCOPUS: ar.j, info:eu-repo/semantics/published