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Introduction: Skin cancer is the most common type of cancer and is classified in melanoma and non-melanoma cancers, which include basal cell, squamous cell, and Merkel cell carcinoma. Specific microRNAs are dysregulated in each skin cancer type. MicroRNAs act as oncogene or tumor suppressor gene regulators and are actively released from tumor cells in the circulation. Cell-free microRNAs serve many, and possibly yet unexplored, functional roles, but their presence and abundance in the blood has been investigated as disease biomarker. Indeed, specific microRNAs can be isolated and quantified in the blood, usually in serum or plasma fractions, where they are uncommonly stable. MicroRNA levels reflect underlying conditions and have been associated with skin cancer presence, stage, evolution, or therapy efficacy. Areas covered: In this review, we summarize the state of the art on circulating microRNAs detectable in skin cancer patients including all the studies that performed microRNA identification and quantification in the circulation using appropriate sample size and statistics and providing detailed methodology, with a specific focus on diagnostic and prognostic biomarkers. Expert Opinion: Circulating microRNAs display a relevant biomarker potential. We expect the development of methodological guidelines and standardized protocols for circulating miRNA quantification in clinical settings.

Background The neutrophil-to-lymphocyte ratio (NLR) is a known prognostic biomarker for survival and is predictive of sentinel lymph node (SLN) positivity in some cancers. However, its usefulness as a prognostic biomarker for cutaneous squamous cell carcinoma (cSCC) has not been fully investigated. Objective Our objective was to investigate the relationship between the NLR and the disease-specific survival and SLN positivity in patients with cSCC. Methods In this single-center retrospective case series, we analyzed patients with cSCC who underwent blood tests prior to the initiation of treatment at our oncology hospital. The relationship between the patients’ clinical characteristics (including the NLR) and the disease-specific survival and SLN positivity was evaluated using univariate and multivariate analyses. Results An elevated NLR was an independent prognostic factor for poor disease-specific survival and a predictive factor for SLN positivity. Limitations Limitations include the small number of participants and selection bias due to the large proportion of high-risk cases in our patient population. Conclusion NLR is a useful biomarker in cSCC because it is simple to measure and can predict prognosis.

Cutaneous squamous cell carcinoma (CSCC) is the most frequent post-transplant tumour entity resulting from immunosuppression treatment that is needed to prevent organ rejection. Solid organ transplant (SOT) recipients are at higher risk for CSCC and vulnerable for aggressive disease or a fatal course. Here, we report on a case of post-kidney transplant metastatic CSCC, demonstrating efficacy of cemiplimab in achieving complete remission after previous disease progression under cetuximab treatment. Unfortunately, the patient developed severe pneumonia, which was only later diagnosed as cemiplimab-associated pneumonitis. Due to a rapidly evolving septic condition, intensive care treatment was required and resulted in a fatal outcome. The patient's transplant remained intact, yet first-line treatment of advanced CSCC, such as with cemiplimab, should be weighed critically in SOT recipients, as transplant rejection may occur. However, the present case underlines the feasibility of cemiplimab as a second-line treatment option in this patient collective.

It is well known that organ transplant recipients are prone to develop non-melanoma skin cancers, particularly cutaneous squamous cell carcinoma (cSCC). This is explained by the long-term use of immunosuppressants and thus the decrease of the immunosurveillance that protects from developing malignant tumours. Solid organ transplant recipients (SOTRs) are 65-250 times more likely to develop cSCC compared to the general population (Am J Transplant 2017; 17: 2509). Moreover, in these patients cSCCs follow a more aggressive course. Close follow-up and regular skin check-ups by a dermatologist are, therefore, crucial in the management of these patients. When detected early, cSCC can be easily and effectively treated by a simple excision. However, when advanced, outcomes are poor. Immune checkpoints inhibitors (ICIs) have been recently added to our arsenal and represent a breakthrough, having proved to be effective in achieving long-term responses. We, hereby, present two cases of difficult-to-treat cSCCs in renal transplanted patients.

Cutaneous squamous cell carcinoma (cSCC) is the most common tumour entity that grows secondarily into the orbital area, while basal cell carcinoma (BCC) is the most common periocular and eyelid tumour. Diagnostic delays are common and may increase post-treatment complications. The therapy is challenging and must be discussed at an interdisciplinary tumour board. We discuss four cases of cSCC with orbital invasion treated with immune-checkpoint inhibitors with variable responses.

Limited data exist on the use of immune checkpoint inhibitors (ICI) for the treatment of metastatic cutaneous squamous cell carcinoma (CSCC) in solid organ transplant recipients (SOTR). We report a case of a SOTR who developed metastatic disease following multiple surgeries, three cycles of adjuvant radiotherapy, and minimization of immunosuppression. He was subsequently treated with pembrolizumab and achieved a complete response. However, the patient developed ICI-induced allograft rejection requiring therapy discontinuation. The allograft was salvaged following IVIg and steroids. The patient developed recurrent disease which failed rechallenge with pembrolizumab but achieved a partial response following cemiplimab administration. This case illustrates the potential to treat metastatic CSCC in a SOTR with anti-programmed death-1 therapy and preserve graft function despite allograft rejection.

INTRODUCTION: The optimal definitive radiotherapy (RT) scheme in cutaneous squamous cell carcinoma (cSCC) remains controversial, especially in elderly patients. METHODS: Data of elderly patients with cSCC lesion(s) treated with weekly hypofractionated RT (8 Gy per week per 7-8 weeks) were analyzed. RESULTS: Eighteen patients (median age 89 years) with 23 cSCC lesions have been identified including nine males (50%) and nine females (50%). The most common tumor localization was the head and neck region (n = 21; 91.3%), and the majority of lesions (n = 15; 65.2%) was stage ≥ III. At diagnosis, pain and bleeding were ascribed in 13 (56.5%) and eight (34.8%) cSCC, respectively. Compliance with weekly hypofractionated RT was excellent. The overall response rate at 12 weeks after treatment was 95.7%. Bleeding and pain relief were achieved in all cases. Severe toxicity was not recorded. The 1-year overall survival was 66.0%. The 1-year progression-free survival was 58.7%. CONCLUSIONS: Weekly hypofractionated RT provides a safe, efficient, and cost-effective treatment in elderly cSCC patients with minimal side effects.

BACKGROUND: Most cutaneous squamous cell carcinomas (CSCCs) can be treated with surgical excision or radiation; however, approximately 1% of patients develop advanced disease. In 2018, the FDA appr...

Background The eighth edition of the American Joint Committee on Cancer Staging Manual includes a staging system for head and neck cutaneous squamous cell carcinoma for the first time. The pN categories for head and neck cutaneous squamous cell carcinoma and mucosal squamous cell carcinoma are identical, despite the vastly different biological behavior of these diseases. This study aimed to survey head and neck cancer specialists’ views regarding the clinical utility of the American Joint Committee on Cancer Staging Manual for head and neck cutaneous squamous cell carcinoma and to identify avenues for improvement. Design An electronic survey of 19 questions relating to the prognostic utility of the staging system was designed based on the findings of a literature review. The survey was distributed internationally to specialists managing head and neck cutaneous squamous cell carcinoma. Results Literature review identified 9 articles describing primary research relevant to the performance of the American Joint Committee on Cancer Staging Manual for head and neck cutaneous squamous cell carcinoma, which recognized a lack of homogeneity, monotonicity, and distinctiveness in the pN staging system. One hundred and five survey responses were received: 71% indicated that mucosal and head and neck cutaneous squamous cell carcinoma require different nodal staging categories; 63% indicated that immunosuppression should be included in the staging system; 70% thought that soft tissue metastases portend a worse prognosis compared with extranodal extension; 38% almost never saw pN3a tumors; and 40% felt that the N stage is a poor predictor of survival. Conclusion The views of head and neck cancer specialists across disciplines and countries align with evidence suggesting that head and neck cutaneous squamous cell carcinoma merits a staging system distinct from mucosal squamous cell carcinoma, that immunosuppression should be considered in prognostication, and that the use of extranodal extension should be modified.

[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., Funding sources: Dr Cañueto is partially supported by the grants PI18/000587 (Instituto de Salud Carlos III, cofinanciación Fondo Europeo de Desarrollo Regional [FEDER]) and GRS 1835/A/18 (Gerencia Regional de Salud de Castilla y León), and by the Programa de Intensificación de la Actividad Investigadora de la Gerencia Regional de Salud de Castilla y León (INT/M/10/19), Spain.

PD-1 inhibitors are immunotherapeutic agents used in the treatment of advanced cutaneous squamous cell carcinoma (cSCC). This study aimed to determine the pooled objective response and disease control rates of patients with advanced cSCC treated with PD-1 inhibitors. Pubmed, Cochrane Library and EMBASE databases were searched up to 1 January 2021 to include eligible articles. Objective response rate (ORR) and disease control rate (DCR) were pooled and analysed. Subgroup analysis of the odds ratio (OR) for ORR for patients by PD-L1 tumour proportion score (TPS) was performed. Seven articles including a total of 453 patients were identified and included. Pooled estimate of ORR was 44% (95% CI: 39-49%, I2 = 23.7%) and of DCR was 66% (95% CI: 57-74%, I2 = 68.2%). Pooled odds ratio of ORR for patients by PD-L1 TPS was 2.81 (95% CI: 1.22-6.51, I2 = 0.0%). These results were derived from single-arm studies, some of which were retrospective. No head-to-head trials comparing PD-1 inhibitors have been reported. We present aggregate estimates of ORR and DCR for patients with advanced cSCC treated with PD-1 inhibitors, as well as subgroup analysis for ORR for patients by PD-L1 TPS.

Epithelial to mesenchymal transition (EMT) is an important mechanism of invasion in cutaneous squamous cell carcinomas (cSCCs) and has been found to be enhanced in tumors originated from actinic keratosis with transformation limited to the basal epithelial layer -differentiated pathway-, compared to cases with invasion subsequent to complete epidermal transformation -classical pathway-. Several microRNAs and proteins can contribute to EMT modulation in cSCCs. MicroRNA21 and microRNA31 are involved in posttranscriptional regulation of protein expression and could play a relevant role in EMT and cSCC progression. Throughout the EMT process upregulation of matrix metalloproteinases (MMPs) enhances invasiveness and MMP-1 and MMP-3 contribute to local invasion, angiogenesis and metastasis in cSCCs. Additionally, cSCC development is associated with PTEN loss and NF-kappa B, NOTCH-1 and p63 activation. The aim of this work is to identify differences in the expression of those molecules between both pathways of cSCCs development. Eight tissue microarrays from 80 consecutive cSCCs were analyzed using LNA-based miRNA in situ hybridization for miRNA21 and miRNA31 evaluation, and immunohistochemistry for MMP-1, MMP-3, PTEN, NOTCH-1, NF-kappa B, p63 and CD31. Significantly higher expression of miRNA31 (p < 0.0001) and MMP-1 (p = 0.0072) and angiogenesis (p = 0.0199) were found in the differentiated pathway, whereas PTEN loss (p = 0.0430) was more marked in the classical pathway. No significant differences were found for the other markers. Our findings support a contribution of miRNA31 and MMP-1 in the differentiated pathway, associated to EMT and increased microvascularization. The greater PTEN loss in the classical pathway indicate that its relevance in cSCC is not EMT-related.

Mutations found in skin are acquired in specific patterns, clustering around mutation-prone genomic locations. The most mutation-prone genomic areas, mutation hotspots, first induce the growth of small cell clones in healthy skin. Mutations accumulate over time, and clones with driver mutations may give rise to skin cancer. Early mutation accumulation is a crucial first step in photocarcinogenesis. Therefore, a sufficient understanding of the process may help predict disease onset and identify avenues for skin cancer prevention. Early epidermal mutation profiles are typically established using high-depth targeted next-generation sequencing. However, there is currently a lack of tools for designing custom panels to capture mutation-enriched genomic regions efficiently. To address this issue, we created a computational algorithm that implements a pseudo-exhaustive approach to identify the best genomic areas to target. We benchmarked the current algorithm in three independent mutation datasets of human epidermal samples. Compared to the sequencing panel designs originally used in these publications, the mutation capture efficacy (number of mutations/base pairs sequenced) of our designed panel improved 9.6–12.1-fold. Mutation burden in the chronically sun-exposed and intermittently sun-exposed normal epidermis was measured within genomic regions identified by hotSPOT based on cutaneous squamous cell carcinoma (cSCC) mutation patterns. We found a significant increase in mutation capture efficacy and mutation burden in cSCC hotspots in chronically sun-exposed vs. intermittently sun-exposed epidermis (p < 0.0001). Our results show that our hotSPOT web application provides a publicly available resource for researchers to design custom panels, enabling efficient detection of somatic mutations in clinically normal tissues and other similar targeted sequencing studies. Moreover, hotSPOT also enables the comparison of mutation burden between normal tissues and cancer.

Chondroitin sulfate (CS) proteoglycan 4 (CSPG4) is a cell surface proteoglycan that is currently under investigation as a marker of cancer malignancy, and as a potential target of anticancer drug treatment. CSPG4 acts as a driver of tumourigenesis by regulating turnover of the extracellular matrix (ECM) to promote tumour cell invasion, migration as well as inflammation and angiogenesis. While CSPG4 has been widely studied in certain malignancies, such as melanoma, evidence is emerging from global gene expression studies, which suggests a role for CSPG4 in squamous cell carcinoma (SCC). While relatively treatable, lack of widely agreed upon diagnostic markers for SCCs is problematic, especially for clinicians managing certain patients, including those who are aged or infirm, as well as those with underlying conditions such as epidermolysis bullosa (EB), for which a delayed diagnosis is likely lethal. In this review, we have discussed the structure of CSPG4, and quantitatively analysed CSPG4 expression in the tissues and pathologies where it has been identified. The aim of this review has been to collate the information available from functional studies and recent transcriptome analysis to determine the usefulness of CSPG4 expression as a diagnostic marker and therapeutic target in management of malignant SCC.

There exist relatively sparse and conflicting data on high-level microsatellite instability (MSI-H) and deficient mismatch repair (dMMR) in cutaneous malignancies. We aimed to determine the expression profiles of MMR proteins (MSH2, MSH6, MLH1, and PMS2) in different progression stages of cutaneous squamous cell carcinoma (cSCC, 102 patients in total) by immunohistochemistry, and search for MSI-H in patients with low-level MMR or dMMR using multiplex-PCR. Low-level MMR protein expression was observed in five patients: One patient with primary cSCC &lt, 2 mm thickness and low-level MLH1, three patients with primary cSCC &gt, 6 mm (including one with low-level MSH2, as well as MSH6 expression, and two with low-level PMS2), and one patient with a cSCC metastasis showing low-level MSH2 as well as MSH6. Intergroup protein expression analysis revealed that MLH1 and MSH2 expression in actinic keratosis was significantly decreased when compared to Bowen’s disease, cSCC &lt, 2 mm, cSCC &gt, 6 mm, and cSCC metastasis. In cases with low-level MMR, we performed MSI-H tests revealing three cases with MSI-H and one with low-level MSI-L. We found low-level MMR expression in a small subset of patients with invasive or metastatic cSCC. Hence, loss of MMR expression may be associated with tumour progression in a small subgroup of patients with non-melanoma skin cancer.

Background Current staging systems for cutaneous squamous cell carcinoma (cSCC) incorporate histologic grade. There are no universally agreed on criteria to define differentiation for cSCC. Objective To determine the interrater and intrarater reliability among dermatopathologists and Mohs surgeons in grading histological differentiation for cSCC. Methods and materials One hundred thirty-one archived slides were selected. Three dermatopathologists and 3 Mohs surgeons graded the tumors in a blinded manner (Round 1). In an attempt to improve concordance, all 6 participants were then asked to regrade the tumors based on a devised quantitative grading scale (Round 2). Results For Round 1, overall κ was 0.56 corresponding to a weak agreement. κ for well, moderate, and poorly differentiated tumors was 0.68, 0.39, and 0.59, respectively, corresponding to moderate, minimal, and weak concordance. For Round 2 of the study, overall κ was 0.60, with κ = 0.75, 0.46, and 0.61 for well, moderate, and poorly differentiated tumors, respectively. Overall intrarater reliability was 0.70 (κ = 0.70, 0.77, 0.68, 0.71, 0.56, and 0.75), corresponding to a moderate concordance. Conclusion Overall concordance for cSCC histologic grading is weak to moderate among the experimental group. Substantial differences in concordance exist among histological degrees of differentiation, with lowest agreement in moderately differentiated tumors.

[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, Instituto de Salud Carlos III, Grant/Award Number: PI18/000587

Cutaneous squamous cell carcinomas (cSCC) have upstage rates of approximately 10.3% to 11.1%. Data are currently limited on the rate of upstaging for metastatic cSCC.The aim of this study was to determine the rates of upstaging, between diagnosis and surgery, and differences in management for metastatic and non-metastatic high-risk cSCC.This was a retrospective, case-control, single institution, multi-center study. Univariate analysis was used.Sixty-eight subjects (34 metastatic34 non-metastatic) with 69 tumors were included. The overall rate of upstaging was 46.4%. The most common reasons for upstage were undocumented tumor size and under-diagnosis of poor differentiation. There were no differences in rates of upstaging. Preoperative imaging was performed in 43.6% of wide local excisions (WLE) versus 3.3% of Mohs micrographic surgery (MMS; p.001). The median days from surgery to sentinel lymph node biopsy (SLNB), or nodal dissection was shorter for WLE versus MMS (0 vs 221 days, p.001).Improved clinical documentation, including documenting tumor size, and the identification of pathologic risk factors, including poor differentiation and depth of invasion, are needed for proper staging. Preoperative imaging and discussion of SLNB may be beneficial for high-risk T2b and T3 tumors.

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.

Objective To propose a first-aid management protocol for myiasis in neglected cutaneous squamous cell carcinoma (SCC) in the ED based on a recent literature review. Data sources PubMed. Study selection Inclusion criteria were all series and case reports of primary/secondary cutaneous SCC with myiasis of the head and neck, including orbital SCC cases, published after 2005. Data extraction A total of 14 articles including 15 patients were included. Data synthesis Demographics, socioeconomic situation, site of the lesion, larvae species with bacterial suprainfection, and first-aid treatment options were discussed. Two representative cases are described. Conclusions Large, ulcerated, necrotic, myiasis-burdened SCC lesions in the head and neck area present a challenge for treatment, and to date, no consensus regarding first-aid management exists. The authors' proposed four-pillar first-aid management scheme may be a valid option to rapidly improve wound condition through disinfection, pain relief, and malodor and discharge eradication as a bridge to surgery.

Introduction Non-melanoma skin cancer (NMSC) is becoming ever more prevalent among older adults. However, older adults with NMSC are often underrepresented in clinical trials and guidelines on effective management is still unclear. The International Society of Geriatric Oncology (SIOG) created a multi-disciplinary task force to explore the potential in developing practical guidelines for the treatment of older patients with basal cell carcinoma (BCC) and skin (cutaneous) squamous cell carcinoma (cSCC). Materials and Methods A systematic literature search to identify relevant and up-to-date literature on treatment of NMSC in older adults was conducted on various databases including MEDLINE, Embase, CINAHL, Cochrane, and PubMed. The resulting papers were discussed by an expert panel, leading to a consensus recommendation. Results A total of 154 articles were identified for the expert panel to utilise in generating consensus recommendations. A major focus on geriatric assessment and management options including surgery, radiotherapy, systemic therapy, clinical monitoring, and medical/medicophysical therapy were reviewed for recommendations. Discussion Patient age should not be the sole deciding factor in the management of patients with NMSC. Assessment from a multidisciplinary team (MDT) is crucial, and the decision-making process should consider the patient's lifestyle, needs, and expectations. A comprehensive geriatric assessment should also be considered. Patients should feel empowered to advocate for themselves and have their views considered a part of the MDT discussion.

Cutaneous squamous cell carcinoma (SCC) is an increasingly prevalent and potentially fatal disease with considerable implications if not recognized early and treated promptly. Several disease features contribute to a higher risk profile and adverse outcomes in affected patients. Given the clinical observation that elderly males from rural communities often present with large SCCs of the scalp, we sought to investigate and describe features of disease and sociodemographic factors from a cohort of patients with scalp SCCs. Histology reports of scalp primary SCCs were retrospectively assessed. Disease and demographic features were recorded. Descriptive statistics were generated, and statistical analyses (Fisher’s exact, Mann–Whitney U and Spearman’s rank test) were utilized to examine relationships between high-risk disease features and sociodemographic features. Ninety-three occurrences of scalp SCC in 61 patients were assessed. The average age at presentation was 78.81 years. Males were predominantly affected at a 14:1 ratio. Half of all tumours were greater than 2 cm (47/93 (50.54%)). The geographical distance from treatment was significantly associated with larger tumours at presentation. (rs = .34 P = 0.002). Recurrence and metastasis rates were determined amongst 188 patients with a primary scalp SCC, and low rates were observed (2.66% and 2.13%, respectively). Elderly males are inordinately affected by scalp SCC compared to females. Those living further from care exhibited larger tumours at presentation. Data from this study characterize features of SCC of the scalp and provide evidence to suggest that rural isolation may act as a mediator of high-risk presentation and larger tumour size.

Standard of care for high‐risk cutaneous squamous cell carcinoma (cSCC) is surgical excision of the primary lesion with clear margins when possible, and additional resection of positive margins when feasible. Even with negative margins, certain high‐risk factors warrant consideration of adjuvant therapy. However, which patients might benefit from adjuvant therapy is unclear, and supporting evidence is conflicting and limited to mostly small retrospective cohorts. Here, we review literature from the last decade regarding adjuvant radiation therapy and systemic therapy in high‐risk cSCC, including recent and current trials and the role of immune checkpoint inhibitors. We demonstrate evidence gaps in adjuvant therapy for high‐risk cSCC and the need for prognostic tools, such as gene expression profiling, to guide patient selection. More large‐cohort clinical studies are needed for collecting high‐quality, evidence‐based data for determining which patients with high‐risk cSCC may benefit from adjuvant therapy and which therapy is most appropriate for patient management.

Weibiao Xiong,1,* Lan’e Wu,1,* Runke Tang,2 Qingqing Zhang,1 Qian Guo,1 Shuhua Song3 1Xiong Wei-Biao Workroom, Jiangxi Province Hospital of Integrated Chinese and Western Medicine, Nanchang, Jiangxi, 330003, People’s Republic of China; 2Department of Rehabilitation, Jiangxi Province Hospital of Integrated Chinese and Western Medicine, Nanchang, Jiangxi, 330003, People’s Republic of China; 3Department of Dermatology, Jiangxi Province Hospital of Integrated Chinese and Western Medicine, Nanchang, Jiangxi, 330003, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lan’e WuXiong Wei-Biao Workroom, Jiangxi Province Hospital of Integrated Chinese and Western Medicine, No. 90, Bayi Road, Nanchang, Jiangxi, 330003, People’s Republic of ChinaTel +86-0791-86292774Email wulane502@163.comBackground: Grape seed proanthocyanidins (GSPs) have been shown to inhibit the progression of many cancers, including cutaneous squamous cell carcinoma (CSCC). Circular RNA (circRNA) is a key regulator for cancer progression. However, it is unclear whether GSPs can mediate the progression of CSCC by regulating circRNA.Methods: Quantitative real-time PCR was conducted to determine the expression of hsa_circ_0070934, microRNA (miR)-136-5p and prenylated Rab acceptor family 2 (PRAF2). MTT assay and colony formation assay were used to assess cell proliferation. Cell cycle process and apoptosis were detected by flow cytometry, and cell migration and invasion were measured by transwell assay. Western blot analysis was utilized to examine protein expression. In addition, dual-luciferase reporter assay and RIP assay were used to evaluate the interaction between miR-136-5p and hsa_circ_0070934 or PRAF2. Subcutaneous xenograft models were constructed to explore the function of GSPs on CSCC tumor growth in vivo.Results: GSPs could reduce hsa_circ_0070934 expression and inhibit CSCC cell proliferation, cell cycle process, migration, invasion, while promote apoptosis. Overexpressed hsa_circ_0070934 could reverse the suppressive effect of GSPs on CSCC cell progression. MiR-136-5p could be sponged by hsa_circ_0070934, and its overexpression also abolished the positively regulation of hsa_circ_0070934 on the progression of GSPs-induced CSCC cells. PRAF2 was a target of miR-136-5p, and its expression could be decreased by GSPs and increased by hsa_circ_0070934. The inhibitory effect of miR-136-5p on CSCC cell progression could be reversed by PRAF2 overexpression. Additionally, GSPs also could inhibit CSCC tumor growth in vivo.Conclusion: Our data showed that GSPs regulated the hsa_circ_0070934/miR-136-5p/PRAF2 axis to restrain CSCC progression.Keywords: cutaneous squamous cell carcinoma, GSPs, hsa_circ_0070934, miR-136-5p, PRAF2

Xeroderma Pigmentosum (XP) is a rare genetic disorder with a poor prognosis due to high photosensitivity in affected patients. Herein, we describe the first case of the use of cemiplimab in a patient with XP, a 19-year-old girl presented with locally advanced squamous cell carcinoma of the right periorbital and nasal region. This treatment has been undertaken after a cycle of proton beam radiotherapy. Besides, it is reported a description of the few cases in the literature describing the effectiveness of immunotherapy on skin cancers in XP-patients. This case is in line with those reported, underlining how anti-PD1 monoclonal antibodies may be a promising treatment in this genodermatosis.

Background Human papillomavirus (HPV) infection is known to promote the development of mucosal squamous cell carcinoma (mSCC), including pathologically high-grade lesions, but its role in cutaneous squamous cell carcinoma (cuSCC) remains unclear, particularly in lesions that are considered high risk. Objective We aimed to determine whether enhanced HPV transcriptional activity can be detected in high-risk cuSCC samples compared with low-grade SCC samples or normal skin. Methods We performed RNA sequencing of cuSCC across 23 risk-stratified skin lesions. A subset of samples was tested for the presence of HPV DNA. High-quality, non-human reads from each sample group were used for viral analysis using Microbiome Coverage Profiler. Results None of the samples analysed had detectable expression of HPV RNA, while 64% of samples tested positive for HPV DNA. All samples were found to have expression of human endogenous retrovirus, and multiple samples showed expression of other viruses. Conclusions Viral and prophage gene expression can be monitored in cuSCC or normal skin biopsies, yet no sample in our study showed evidence of active HPV gene expression despite evidence of HPV genome presence. This suggests HPV transcription does not play a role in differentiating high-risk cuSCCs from low-risk cuSCCs or normal skin.

Background Regional metastasis of head and neck cutaneous squamous cell carcinoma (HNcSCC) can be seen in either parotid and/or cervical lymph nodes. The aim of this study was to assess whether there was a difference in prognosis between parotid and cervical nodal metastases. Methods Patients with regional metastasis from HNcSCC were identified from an institutional database. Disease-specific (DSS) and overall survival (OS) were calculated using the Kaplan-Meier method and Cox proportional hazards models. Results Five hundred and thirty-five patients were identified with median follow-up of 26.4 months (3-255 months). Two hundred and thirty-five patients had parotid metastasis, 96 patients had neck metastasis, and 204 patients had both. On multivariable analysis, any regional metastasis to the neck when compared to parotid alone conferred worse DSS (HR 1.8, p = 0.007) and OS (HR 1.3, p = 0.024). Conclusion Regional metastasis of HNcSCC to the neck confers worse outcomes compared to metastasis to the parotid alone.

Squamous cell carcinoma of the skin, or cutaneous squamous cell carcinoma (CSCC), is the second most frequent type of skin cancer, and its incidence continues to rise all over the world. Usually has a benign clinical behavior, but it can be presented as locally invasive and metastatic aggressive tumor with 2% mortality rate. Nowadays, new risk factors for have appeared, that form pharmacologically-induced CSCC after immunosuppressant drugs used for organ transplantation, or BRAF inhibitors used for melanoma. In recent years we have got a new information about the role of mutational burden, signaling pathways involved in CSCC development and new possibilities and molecules for targeted therapy. Better understanding of the immune system functioning and benefits of immunotherapy with immune checkpoint inhibitors (PD-1) for CSCC that has changed the therapeutic approach. According to recent clinical trials data, new treatment options with PD-1 inhibitors achieved a response rate of 50% for locally advanced CSCC and 47% for metastatic CSCC, including 16.1% complete remissions. This review focuses on the molecular profile, targeted therapies and immunotherapy for locally advanced and metastatic CSCC.

Cutaneous squamous cell carcinoma (cSCC), a malignant skin tumor, begins in the epidermis and the keratinocytes of the skin appendages. However, the cause remains unclear. MicroRNA-200c (miR-200c), a key modulator of epithelial-to-mesenchymal transition (EMT), has been reported to act as an anticancer gene in a variety of cancers. However, its role and partial mechanism in cSCC remain undetermined. The results of this study showed depleted levels of miR-200c in cSCC tissues. Its suppressive effects on cell proliferation, and motility, as well as its apoptosis-promoting effect, were observed in the A-431 cells. Additionally, immunofluorescence and qRT-PCR assays revealed that FYN acted as a direct target of miR-200c, and FYN knockdown exerted had similar impact as that of miR-200c overexpression, including increased cellular apoptosis and decreased cellular growth. These results emphasized the onco-suppressive nature of miR-200c, which was evident based on its interaction with FYN in cSCC. This finding could have potential benefits in developing cSCC therapy.

To investigate factors that affect and also decrease the duration for recurrences and secondary tumors in cSCC. A retrospective study was conducted for all patients who were treated for a cSCC of the head and neck between 2009 and 2016. Anamnestic as well as epidemiological and histological data were noted and correlated with the occurrence of recurrences and secondary cancers. The duration between surgery and these events was used to determine if histological factors accelerate their occurrence. The highest risk for recurrences was seen in patients with previous skin cancers (RR 3.23). Histological ulceration (p = 0.003) and grading (p = 0.031) of the tumor were found as significant factors accelerating the time to relapse. Surrounding chronic precancerotic lesions (p < 0.001) and poor tumor grading (p = 0.035) were found as significant factors accelerating the time until a secondary cSCC was observed. Known risk factors increase not only the risk for a cSCC but also for recurrences. Specific histologic findings can help to adjust follow-up intervals to identify recurrences and secondary tumors at an early stage as these were shown to decrease the duration for a further event.

[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., Dr Cañueto is partially supported by grant PI18/000587 (Instituto de Salud Carlos III, cofinanced by FEDER funds).

Background Perineural invasion (PNI) is a known risk factor for recurrence, metastasis, and death in cutaneous squamous cell carcinoma (cSCC). Current staging systems include PNI, but none define its extent or severity. Objective To identify histopathologic features of cSCC with PNI that may be associated with adverse outcomes. Materials and methods This is a retrospective cohort study that included 45 patients with cSCC and PNI treated with surgical excision. Histopathologic slides were analyzed for 5 features of PNI: largest affected nerve diameter, number of nerves affected, depth of nerve involvement, intra- versus extratumoral PNI, and focal versus circumferential PNI. Results The median largest affected nerve diameter was 0.13 mm, and the median number of nerve structures involved was 4. After a median follow-up time of 24 months, 6 patients developed adverse outcomes, including 2 local recurrences, 4 metastases, and 2 tumor-related deaths. Univariate logistic regression analysis revealed that nerve diameter and number of affected nerves were significantly associated with adverse outcome. A composite PNI score, calculated from 5 histopathologic features, was the strongest predictor of adverse outcome (p = .020). Conclusion Histopathologic features of PNI can be quantified with a composite PNI score that is significantly associated with adverse outcomes in cSCC.

Introduction Clinical indications of immune checkpoint inhibitors have expanded to a variety of malignancies. Nearly 50% of patients with advanced cutaneous squamous cell carcinoma, respond to the programmed-death 1 inhibitor cemiplimab. To date, insulin-dependent diabetes mellitus has been documented with the use of several immune checkpoint inhibitors but not cemiplimab. Case report We report herein the first case of a patient with cutaneous squamous cell carcinoma who developed diabetic ketoacidosis and insulin-dependent diabetes mellitus following only two cycles of cemiplimab. A score of 6 on the Naranjo nomogram makes the causality relationship between cemiplimab use and the insulin-dependent diabetes mellitus probable. Management and outcome The patient's developed diabetic ketoacidosis was managed with intravenous fluids and intravenous insulin, with a prompt resolution. Cemiplimab was discontinued, and the patient was discharged on long-acting and short-acting insulin therapy, with a follow-up with endocrinology. Discussion/conclusions The mechanism by which cemiplimab caused insulin-dependent diabetes mellitus is most likely due to lack of endogenous insulin production in the setting of immune-mediated loss of pancreatic beta-cells. Patients may benefit from fasting blood glucose monitoring and early immune checkpoint inhibitor discontinuation where elevated serum glucose is detected.

Cutaneous squamous cell carcinoma (SCC) causes approximately 1,000,000 cases and 9000 deaths each year in the United States. While individual tumor sequencing studies have discovered driver mutations in SCC, there has yet to be a review and subsequent analysis synthesizing current studies. To conduct a comprehensive synthesis and analysis of SCC sequencing studies with individual patient-level data, a comprehensive literature search was performed. Statistical analyses were performed to identify trends. Studies meeting inclusion criteria included a total of 279 patients (189 localized SCCs, 90 metastatic SCCs). Several mutations were correlated with demographic characteristics (TP53, MLL4, BRCA2, COL4A1). TP53, TERT, SPEN, MLL3, and NOTCH2 mutations were significantly more likely to be found in metastatic versus localized SCCs even after the Bonferroni correction for multiple comparisons. Silent mutations were found more in localized SCCs than metastatic SCCs, and nonsense mutations were found more in metastatic SCCs than localized SCCs (p = 0.0003 and p = 0.04, respectively). Additional mutations were identified that have not yet been explored in SCC including AHNAK2, LRP1B, TRIO, MDN1, COL4A2, SVIL, VPS13C, DST, DMD, and DYSF. Overall, novel mutations were identified and differences between mutation patterns in localized and metastatic SCCs were found. These findings may have clinical applications.

Background and objectives We performed a critical analysis of the 8th edition American Joint Committee on Cancer (AJCC) staging for head and neck cutaneous squamous cell carcinoma (HNcSCC) with nodal metastases and compared the performance to the N1S3 and ITEM systems. Methods Multicenter study of 990 patients with metastatic HNcSCC treated with curative intent. The end points of interest were disease-specific (DSS) and overall survival (OS). Model fit was evaluated using Harrell's Concordance Index (C-index), proportion of variation explained (PVE), Akaike information criterion, and Bayesian information criterion. Results N1S3 and ITEM demonstrated good distribution into risk categories in contrast to the AJCC system, which classified the majority (90.6%) of patients as N2-3 and Stage IV due to the high rate of extranodal extension. The N2c and N3a categories appeared redundant. There was considerable discordance between systems in risk allocation on an individual patient basis. N1S3 was the best performed (DSS: C-index 0.62, PVE 10.9%; OS: C-index 0.59, PVE 4.5%), albeit with relatively poor predictive value. Conclusions The AJCC N category and tumor node metastasis stage have poor patient distribution and predictive performance in HNcSCC. The AJCC stage, N1S3, and ITEM score all provide limited prognostic information based on objective measures highlighting the need to develop a staging system specific to HNcSCC.

Objective To evaluate high-frequency ultrasound (HFUS) features for diagnosing cutaneous squamous cell carcinoma (cSCC) as a spectrum of progressively advanced malignancies, including precursor actinic keratosis (AK), Bowen's disease (BD), and invasive squamous cell carcinoma (iSCC). Method In this retrospective study, 160 skin lesions diagnosed histopathologically (54 AK, 54 BD, and 52 iSCC) in 160 patients were included. The HFUS features of AK, BD, and iSCC were analyzed. The obtained data were evaluated using univariate and forward multivariate logistic regression analyses. Results The most significant HFUS features in AK were regular surface (odds ratio [OR], 8.42) and irregular basal border (OR, 6.36). The most significant HFUS features in BD were crumpled surface (OR, 19.62) and layer involvement confined to the epidermis (OR, 3.96). The most significant HFUS features in iSCC were concave surface (OR, 27.06), stratum corneum (SC) detachment (OR, 14.41), irregular basal border (OR, 4.01), and convex surface (OR, 3.73). The characteristics of surface features, basal border, and layer involvement could be valuable HFUS clues in the discrimination of AK, BD, and iSCC. Conclusion High-frequency ultrasound is valuable for the differentiation of AK, BD, and iSCC, which may allow dynamic and noninvasive monitoring in the spectrum of cSCC.

Patients with chronic lymphocytic leukemia (CLL), a B-cell malignancy characterized by impaired humoral and cellular immunity, are at increased risk of developing cutaneous squamous cell carcinoma (cSCC). Human papilloma virus (HPV) is the most common sexually transmitted infection worldwide and it has been associated with various malignancies, including cSCC. Impaired cell-mediated immunity is considered a primary risk factor in HPV-induced cSCC. We examined cSCC lesions from CLL patients with consensus review and HPV genetic analysis to further characterize the relationship between HPV and prevalence of cutaneous malignancy in this population. Eleven patients with CLL contributed 35 cSCCs. Treatment with chemotherapy shortened the latency time to first cSCC. HPV was detected in 54% of the lesions. Among the HPV-positive cSCC lesions, 84% of the lesions contained alpha-genus HPV, 42% contained beta-genus HPV, and 26% of the lesions contained both genera. There was a significant association between HPV-containing lesions and peritumoral lymphocytic inflammation, suggesting this as a future area for further characterization. The majority of the lesions, including those with alpha-genus HPV, occurred in sun-exposed areas, such as the scalp and face. These findings may lead to practice-changing recommendations for skin cancer, including the use of vaccinations to reduce HPV-associated skin cancer.

To review and elucidate the complex, multimodal management of periocular cutaneous squamous cell carcinoma (SCC) with perineural invasion (PNI), and offer practical, evidence-based patient care recommendations.Three exemplary cases of high-risk periocular cutaneous SCC with PNI were selected from a single surgeon's experience. The clinical courses, management, and clinical outcomes, with follow-up intervals of 19, 19, and 24 months after presentation, were reviewed. The English-language literature on PNI, with attention to the management of cutaneous SCC of the head and neck (SCCHN), was reviewed.PNI of cutaneous SCCHN portends aggressive tumor behavior and a worsened prognosis. Treatment is multimodal, with varied combinations of surgical excision, radiotherapy (RT), and systemic chemotherapy. Retrospective reports from multiple institutions involve heterogenous patient populations, treatment strategies, and confounding variables that preclude formulation of a standardized treatment paradigm. Newer, comparative studies of advanced RT techniques (e.g., hyper-fractionation), novel systemic chemotherapeutic agents (e.g., cetuximab, cemiplimab), and varied integrative regimens are providing additional insights. Prompt initiation of adjuvant therapies (within 6-8 weeks of surgery), and careful evaluation of lymphatic basins can increase oncologic control. Utilizing deep-tissue fixation of advancement flaps and eyelid stabilization can enhance functional and aesthetic results.Management of cutaneous SCC with PNI remains complex and in most cases requires combined-modality therapy directed by a multidisciplinary tumor board. With novel therapies and new treatment patterns, optimal combinations and intensities of individual modalities require further elucidation. The oculofacial plastic surgeon plays a pivotal role - in diagnosis, coordination of interdisciplinary management, thoughtful surgical reconstruction, and postoperative surveillance.

Purpose This study aimed to evaluate imaging findings of cutaneous angiosarcoma (cAS) of the scalp compared with those of cutaneous squamous cell carcinoma (cSCC). Methods This study included 15 patients with primary cAS and 10 with primary cSCC of the scalp. Seven patients with cAS and eight with cSCC underwent magnetic resonance imaging, and 11 patients with cAS and eight with cSCC underwent 18F-fluorodeoxyglucose–positron emission tomography/computed tomography imaging. Imaging findings for both pathologies were retrospectively reviewed and compared. Results All 15 cAS cases were elevated lesions with an obtuse angle, invading the subcutaneous fat tissue. Multiple lesions were observed in only five cAS cases (33%) and no cSCC cases. Maximum diameter-to-height ratio was significantly higher in cAS than in cSCC (3.3 ± 1.0 versus 2.3 ± 0.6; p Conclusions Cases of cAS of the scalp always exhibited flat elevated lesions with invasion of the subcutaneous fat tissue. Compared with cSCC, intratumoral hypointensity and mixed hyper- and hypointensity on T2-weighted images were more frequent in cAS. These findings will help with the differential diagnosis of cAS.

O carcinoma de células escamosas (CCE) é um neoplasma cutâneo maligno originário dos queratinócitos. Sua casuística é muito comum na clínica de animais de companhia e o médico veterinário deve ter amplo conhecimento a respeito de como esta enfermidade se comporta e evolui para evitar o comprometimento da vida de seus pacientes. O presente estudo teve como objetivo realizar uma revisão bibliográfica sobre o carcinoma de células escamosas cutâneo na espécie canina. Foram levados em consideração dados relevantes a respeito da etiopatogenia do CCE (radiação ultravioleta, infecção por herpesvírus, perda de moléculas de adesão celular e imunossupressão), da epidemiologia, dos sinais clínicos, da macroscopia, das características microscópicas dos subtipos tumorais (bem-diferenciado, diferenciado e indiferenciado), da graduação histopatológica (grau I, II e III), do diagnóstico, do prognóstico, do tratamento e da prevenção.

Learning objectives After studying this article, the participant should be able to: 1. List important prognostic features that affect cutaneous squamous cell carcinoma risk. 2. Summarize the changes to the AJCC Cancer Staging Manual, Eighth Edition, staging system for cutaneous squamous cell carcinoma. 3. Evaluate the draining nodal basin with appropriate imaging modalities. 4. Recommend adjuvant radiation therapy in the correct clinical setting for high-risk tumors. 5. Recognize the currently available treatments for advanced cutaneous squamous cell carcinoma. Summary This continuing medical education article reviews the features, management, and prognosis of cutaneous squamous cell carcinoma with an emphasis on high-risk squamous cell carcinoma and data from the past 3 years. This review will discuss the primary tumor management, high-risk features of a squamous cell carcinoma, changes to the American Joint Committee on Cancer staging system, and the utility of sentinel lymph node biopsy, and critically review the evidence regarding adjuvant therapy.

BACKGROUND Limited literature exists regarding whether intraoperative analysis of frozen debulk specimens during Mohs micrographic surgery (MMS) improves identification of high-risk features (HRF) of cutaneous squamous cell carcinoma (CSCC). OBJECTIVE Primary: identification of new HRF on debulk specimens. Secondary: CSCC upstaged after considering debulk data. MATERIALS AND METHODS A single-center, retrospective cohort study of patients with biopsy-proven CSCC treated by MMS with intraoperative frozen debulk analysis. Restricted (poor differentiation, new perineural invasion ≥0.1 mm, and Breslow depth >6 mm) and nonrestricted (any worsened tumor differentiation, any new perineural invasion, and Breslow depth >2 mm) analyses were performed. RESULTS In restricted analysis, 3.94% of cases had 1 new HRF on debulk analysis. In nonrestricted analysis, 32.9% of cases had ≥1 new HRF; 7.6% increased by 2 HRF. Approximately 2.0% of cases were upstaged by American Joint Committee on Cancer system, eighth edition criteria, 1.4% by Brigham and Women's Hospital. Tumor size ≥2 cm, male sex, and moderate differentiation on biopsy were significantly associated with new HRF identified on debulk analysis. CONCLUSION Intraoperative frozen debulk analysis can reveal HRF of CSCC not seen on biopsy or MMS stages, particularly among tumors ≥2 cm. American Joint Committee on Cancer system, eighth edition T2 tumors were most likely to be upstaged. Identification of new HRF on debulk analysis can improve CSCC staging and may impact patient treatment and follow-up.