High-risk Cutaneous Squamous Cell Carcinoma Research Articles

Management Approaches for High-Risk Cutaneous Squamous Cell Carcinoma with Perineural Invasion: An Updated Review.

Cutaneous squamous cell carcinoma (cSCC) stands as the second most prevalent non-melanoma skin cancer worldwide, comprising approximately 20% of all cutaneous malignancies. Determining its precise incidence poses challenges; however, reports indicate a global increase in its prevalence. At the time of diagnosis, the majority of cSCCs are localized, resulting in favorable 5-year cure rates surpassing 90%. Nevertheless, a subset of patients (3-7%) encounters locally advanced or metastatic cSCC, leading to substantial morbidity and mortality. The risk of metastasis ranges from 0.1% to 9.9%, carrying an associated mortality risk of 2.8%. Factors influencing recurrence, metastasis, and disease-specific mortality underscore the significance of perineural invasion (PNI) as a key indicator. Patients with PNI may manifest clinical symptoms and/or radiologic signs of PNI, while the majority remain asymptomatic, and PNI is frequently identified upon histologic examination. Despite its lower frequency compared to other cancer types, PNI serves as a recognized adverse prognostic factor for cSCC. Surgery is the elective treatment for these patients, while the role of adjuvant radiotherapy (ART) is yet contentious and have not been conclusively assessed, particularly in clear surgical margin. Prospective comparative studies are required to comprehensively evaluate the benefit and the risks of ART for cSCC and PNI patients.

Patient-initiated follow-up for high-risk cutaneous squamous cell carcinoma. How we do it and two years of outcome data.

Why do we follow-up patients with high-risk cutaneous squamous-cell carcinomas (cSCC)? Current guidance suggests we offer post-treatment follow-up appointments at regular intervals for 24 months. Is this to improve prognosis, provide psychological support or find the next cancer? Recent data confirms recurrence and metastasis to be rarer events. We question whether these follow-up practices are truly 'needed' by introducing an option of patient-initiated follow-up (PIFU). We enrolled 476 cSCC patients (January 2020 - January 2023) who fulfilled the definition of high-risk cSCC based on guidelines in use at the time. 59 patients were excluded. 53% (n=250) did not re-contact us during the 2-year period, with no clinical record of complications or recurrences. 35% (n=167) utilised the PIFU pathway, of which 119 patients only required 1 face-to-face appointment. 7 patients (1.5%) developed metastatic disease, 11 patients developed recurrence, and 68 patients developed cSCC at another site. All lesions were identified by the patient via PIFU. We saved 1250 follow-up appointments from those that did not contact us (n=250); financially equating to £181,462.50. Our data implies that PIFU can be considered safe alternative practice for patients with cSCC. Patients independently identified the need for review without scheduled follow-up, making these appointments available to other patient cohorts. Although follow-up appointments may provide mental health support, they can be inconvenient and not the ideal use of our health resources. Our findings support a call for revision of existing skin cancer health policies, to cope with and subsequently improve our practices, to better patient care.

Sentinel lymph node biopsy versus observation in high-risk cutaneous squamous cell carcinoma in immunosuppressed and immunocompetent patients: An inverse probability of treatment weighting study.

The survival benefit of sentinel lymph node biopsy (SLNB) in immunocompetent and immunosuppressed patients with high-risk cutaneous squamous cell carcinoma (cSCC) has not been established. To determine whether SLNB improves disease-specific survival (DSS) in high-risk cSCC. Secondary objectives were to analyse disease-free survival, nodal recurrence-free survival and overall survival (OS). Multicentre, retrospective, observational cohort study comparing survival outcomes in immunosuppressed and immunocompetent patients treated with SLNB or watchful waiting. Inverse probability of treatment weighting was used to adjust for possible confounding effects. We studied 638 tumours in immunocompetent patients (SLNB n = 42, observation n = 596) and 173 tumours in immunosuppressed patients (SLNB n = 28, observation n = 145). Overall, SLNB was positive in 15.7% of tumours. SLNB was associated with a reduced risk of nodal recurrence (NR)(hazard ratio [HR], 0.05 [95% CI, 0.01-0.43]; p = 0.006), disease specific mortality (HR, 0.17 [95% CI, 0.04-0.72]; p = 0.016) and all-cause mortality (HR, 0.33 [95% CI, 0.15-0.71]; p = 0.004) only in immunocompetent patients. SLNB was associated with improvements in NR, DSS and OS in immunocompetent but not in immunosuppressed patients with high-risk cSCC.

[Translated article] Longitudinal Study of Different Progression Patterns in High-Risk Cutaneous Squamous Cell Carcinoma

Background and objectiveCutaneous squamous cell carcinoma (cSCC) is the second leading cause of skin cancer mortality in Europe. Few studies have analyzed the different pathways of this tumor progression in its natural history. The main objective of this study was to analyze the different metastatic and progression pathways and their temporal occurrence in the evolution of cSCC. Material and methodWe conducted a multicenter, retrospective, and observational study of consecutive high-risk sSCCs included in the SQUAMATA project. ResultsA total of 222 out of the 1346 patients included relapsed. The most frequent route of progression was the lymphatic one (62.6%). A total of 20.2% of the cases with lymphatic progression developed distant metastases. Only 1 case (3.1%) of distant metastasis followed local recurrence without previous lymphatic metastasis. The median time to disease-related mortality was longer in patients who developed systemic metastases than in those who died of locoregional progression. ConclusionsThe mortality of patients with cSCC is mostly due to the regional progression of their lymphatic metastases. The appearance of distant metastases is practically always (96.9%) associated with previous lymphatic metastatic progression. Therefore, in the future, new studies will be needed to assess the regional management of cSCC in both surgical and adjuvant therapies.

Use of Imaging in Cutaneous Squamous Cell Carcinoma to Detect High-Risk Tumor Features, Nodal Metastasis, and Distant Metastasis: A Systematic Review.

Imaging has been shown to impact management and disease outcomes in cutaneous squamous cell carcinoma, but the literature on optimal modalities is lacking. To perform a systematic review evaluating the performance of various imaging studies for the detection of perineural spread, bony invasion, nodal metastasis (NM), and distant metastasis in cutaneous squamous cell carcinoma. Four databases were searched for relevant terms. Articles were included if they presented primary data on 5 or more subjects with cutaneous squamous cell carcinoma who underwent imaging to detect perineural spread, bony involvement, NM, or distant metastasis. Thirty studies and 1,027 subjects were included in the pooled analysis. Magnetic resonance imaging had a 94.9% sensitivity in detecting perineural spread. Computed tomography (CT) demonstrated a sensitivity of 75.7% and specificity of 98.6% in detecting bony invasion. While ultrasound, positron emission tomography-computed tomography, and CT all performed reasonably well in detecting NM, CT demonstrated the highest sensitivity (96.4%) and specificity (100%). Imaging changed management in up to 33% of cases. Imaging is useful in high-risk cutaneous squamous cell carcinoma. Magnetic resonance imaging performs best in the detection of perineural spread, and CT is the most accurate modality to detect bony invasion and NM.

Management of High-Risk Cutaneous Squamous Cell Carcinomas Among Mohs Surgeons.

Management of High-Risk Cutaneous Squamous Cell Carcinomas Among Mohs Surgeons.

Prognostic Performance of Sentinel Lymph Node Biopsy for the Clinically Negative Neck in High-Risk Cutaneous Squamous Cell Carcinoma

Prognostic Performance of Sentinel Lymph Node Biopsy for the Clinically Negative Neck in High-Risk Cutaneous Squamous Cell Carcinoma

Integrating the 40-Gene Expression Profile (40-GEP) Test Improves Metastatic Risk-Stratification Within Clinically Relevant Subgroups of High-Risk Cutaneous Squamous Cell Carcinoma (cSCC) Patients.

The validated 40-gene expression profile (40-GEP) test independently stratifies risk of regional or distant metastasis for cutaneous squamous cell carcinoma (cSCC) tumors with high-risk clinicopathologic features. This study evaluated the stratification of risk by the 40-GEP test in a large cohort of tumors with one or more high-risk factors and in clinically relevant subgroups, including tumors within National Comprehensive Cancer Network (NCCN) high- and very-high-risk groups, lower-stage BWH T1 and T2a tumors, and patients > 65years old. This multicenter (n = 58) performance study of the 40-GEP included 897 patients. Kaplan-Meier analyses were performed to assess risk stratification profiles for 40-GEP Class 1 (low), Class 2A (higher) and Class 2B (highest) risk groups, while nested Cox regression models were used to compare risk prediction of clinicopathologic risk classification systems versus risk classification systems in combination with 40-GEP. Patients classified as 40-GEP Class 1, Class 2A, or Class 2B had significantly different metastatic risk profiles (p < 0.0001). Integrating 40-GEP results into models with individual clinicopathologic risk factors or risk classification systems (Brigham and Women's Hospital, American Joint Committee on Cancer Staging Manual, 8th Edition) and NCCN demonstrated significant improvement in accuracy for prediction of metastatic events (ANOVA for model deviance, p < 0.0001 for all models). The 40-GEP test demonstrates accurate, independent, clinically actionable stratification of metastatic risk and improves predictive accuracy when integrated into risk classification systems. The improved accuracy of risk assessment when including tumor biology via the 40-GEP test ensures more risk-aligned, personalized patient management decisions.

Postoperative permanent section evaluation of Mohs micrographic surgery debulk specimens does not result in upstaging of cutaneous squamous cell carcinoma compared to stage at the completion of surgery: A retrospective case series

BackgroundMohs micrographic surgery (MMS) is used for the treatment of high-risk cutaneous squamous cell carcinoma (cSCC). MMS examines the surgical margins in real time and does not commonly examine the central component of the tumor. ObjectiveTo determine if debulk specimens provide additional details relevant to tumor staging not gained from routine MMS. MethodsA retrospective chart review of debulk specimens taken during MMS for cSCC was conducted. Dermatopathology reports were analyzed and tumors were staged using Brigham and Women's Hospital (BWH) and American Joint Committee on Cancer’s 8th edition (AJCC8) staging systems. ResultsPermanent section evaluation of debulk specimens did not result in clinically meaningful information for staging that could not be gained from MMS layers or initial biopsy analysis. LimitationsA single institution, and the small sample size of 39 tumors. ConclusionsEvaluation of debulk specimens during MMS may not always be an effective use of time or healthcare resources.

Immunosuppression is associated with an increased risk of distant metastases in high-risk cutaneous squamous cell carcinoma: A retrospective cohort study

Immunosuppression is associated with an increased risk of distant metastases in high-risk cutaneous squamous cell carcinoma: A retrospective cohort study

Indications for adjuvant radiotherapy in high-risk cutaneous squamous cell carcinoma with clear margins: a Delphi consensus.

The aim of this study was to provide indications for adjuvant radiotherapy in high-risk cutaneous squamous cell carcinoma.

Use of sirolimus as an adjuvant therapy for kidney transplant recipients with high-risk cutaneous squamous cell carcinomas: a prospective non-randomized controlled study

RESUMO Introdução: Pesquisas anteriores demonstraram benefícios da conversão tardia para inibidores de mTOR contra carcinomas espinocelulares cutâneos (CECs) em receptores de transplante renal (RTR), apesar da baixa tolerabilidade. Este estudo investigou se a conversão gradual para monoterapia com sirolimo sem dose de ataque modificou o curso da doença com melhor tolerabilidade. Métodos: Esse estudo prospectivo exploratório incluiu RTR não sensibilizados com mais de 12 meses pós-transplante, uso contínuo de terapia imunossupressora baseado em inibidor de calcineurina (CNI) associado a micofenolato de sódio ou azatioprina, com lesões de CECs de mau prognóstico. Comparou-se densidades de incidência de CECs de alto risco durante 3 anos após conversão para monoterapia com sirolimo à um grupo não randomizado com CECs classificados conforme os mesmos critérios de gravidade do grupo sirolimo, mas inadequado/não disposto à conversão. Resultados: Foram incluídos 44 pacientes (83% homens, idade média 60 ± 9,7 anos, 62% com fototipo de pele II, tempo médio pós-transplante 9 ± 5,7 anos). 25 pacientes foram convertidos para SRL e 19 indivíduos mantidos em CNI. Foi observado tendência de diminuição da densidade de incidência de todos CECs no grupo SRL e de aumento no grupo CNI (1,49 a 1,00 lesões/paciente-ano; 1,74 a 2,08 lesões/paciente-ano; p = 0,141). A densidade de incidência de lesões moderadamente diferenciadas diminuiu significativamente no grupo SRL enquanto aumentou significativamente no grupo CNI (0,31 a 0,11 lesões/paciente-ano; 0,25 a 0,62 lesões/paciente-ano; p = 0,001). No grupo SRL não houve descontinuação do sirolimo, nenhum episódio de rejeição aguda e nenhuma formação de DSA de novo. Função renal permaneceu estável. Conclusões: Esse estudo sugere que a monoterapia com sirolimo pode ser útil como terapia adjuvante de CECs de alto risco em RTR. A estratégia de conversão usada foi bem tolerada e segura em relação aos principais desfechos do transplante a médio prazo.

44006 Clinicians’ use of the 40-gene expression profile (40-GEP) test for high-risk cutaneous squamous cell carcinoma (SCC) patients is consistent with intended use parameters

44006 Clinicians’ use of the 40-gene expression profile (40-GEP) test for high-risk cutaneous squamous cell carcinoma (SCC) patients is consistent with intended use parameters

Contrast tomography (CT) performed to detect nodal metastasis for high-risk cutaneous squamous cell carcinomas of the head and neck has a high negative predictive value but a poor positive predictive value

Contrast tomography (CT) performed to detect nodal metastasis for high-risk cutaneous squamous cell carcinomas of the head and neck has a high negative predictive value but a poor positive predictive value

Evaluation of prognostic prediction ability of the novel Japanese risk factor scoring system in a Japanese cohort of resectable cutaneous squamous cell carcinoma: A retrospective cross-sectional study.

Japanese patients with very high-risk cutaneous squamous cell carcinomas (cSCCs), based on the National Comprehensive Cancer Network guidelines, have been reported to display a higher cumulative incidence of relapse and disease-specific death (DSD) than those with high-risk cSCC. Therefore, prognosis prediction is crucial for Japanese patients with very high-risk cSCCs. Herein, we aimed to evaluate the prognostic prediction ability of our novel Japanese Risk Factor Scoring Systems (JARF scoring) in a Japanese cohort of cSSC patients. Data of 424 Japanese patients with resectable very high-risk cSCCs were analysed. We compared the prognostic ability of the following three staging systems: Brigham and Women's Hospital (BWH) tumour staging, number of NCCN very high-risk factors, and JARF scoring, including recurrent tumour, high-risk histological features, deep tumour invasion and lymphatic or vascular involvement as risk factors. The prognostic ability of these staging systems was evaluated according to the cumulative incidence of local recurrence (LR), regional lymph node metastasis (RLNM), DSD, and overall survival (OS). When BWH staging was used, high T stage led to significantly poor outcomes only in the cumulative incidence of RLNM (p = 0.01). The presence of very high-risk NCCN factors led to significantly poor outcomes in terms of RLNM (p = 0.03) and OS (p = 0.02). Meanwhile, a high number of risk factors in the JARF scoring system clearly led to poor outcomes in terms of LR (p = 0.01), RLNM (p < 0.01), DSD (p = 0.03), and OS (p < 0.01). The JARF scoring system may accurately predict the risk of recurrence and death in very high-risk cSCC patients in Japan.

010 Enhanced outcome prediction in cutaneous squamous cell carcinoma using deep-learning and computational histopathology (cSCCnet)

Abstract Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer and leads to a significant disease burden. Although metastases occur in &amp;lt; 5% of patients, effective treatments are limited and 5-year survival is poor, with mortality rates equivalent to those of melanoma in some regions of the world. Despite recent advances in understanding the molecular pathogenesis of cSCC, patient risk stratification is limited and based on clinicopathological staging, with few validated prognostic biomarkers available to guide management [de Jong E, Lammerts MUPA, Genders RE, Bowes Bavinck JN. Update of advanced cutaneous squamous cell carcinoma. J Eur Acad Dermatol Venereol 2022; 36(Suppl. 1):6–10]. In this study, we aimed to use artificial intelligence technology to develop a deep learning model using digitized whole-slide images of cSCC to quantify the risk of metastasis. Routine haematoxylin and eosin-stained slides of 256 primary cSCCs from immunocompetent patients at four collaborating centres were scanned. The area of interest encompassing tumour and peritumoral stroma was annotated, and 512 × 512 pixel tiles were generated from each slide. High-quality tiles (containing sufficient tumour content) were pooled together, with patient-level labels inherited by tiles. We trained multiple models using an 80:10:10 split for training, validation and testing, and the model achieving the highest tile- and slide-level validation accuracy was identified (ResNet50). The final model, namely, cSCCnet, achieved 88% sensitivity, 73% specificity, 64% positive predictive value and 92% negative predictive values on the independent test set. Blinded review of the top predictive tiles by three histopathologists suggested that the predictive features identified by cSCCnet were distinct from histopathological features commonly used by clinicians to estimate metastatic risk. We have demonstrated that it is possible to train a deep learning model using digital pathology to predict the risk of metastasis. cSCCnet surpassed the published performance of currently used staging systems, as well as commercially available gene panel testing (de Jong et al.; Wysong A, Newman JG, Covington KR et al. Validation of a 40-gene expression profile test to predict metastatic risk in localized high-risk cutaneous squamous cell carcinoma. J Am Acad Dermatol 2021; 84:361–9). The morphological features and patterns identified by cSCCnet are different from established histopathological high-risk criteria, indicating that this technology can enhance current practice. Although further validation in a prospective cohort is pending, this is an important step toward creating a risk stratification tool that can be incorporated into routine pathology workflows, significantly improving patient outcomes for this common cancer.

Integration of the 40-Gene Expression Profile (40-GEP) for Management and Treatment of High-risk Cutaneous Squamous Cell Carcinoma (cSCC): A Real-world Algorithm

Integration of the 40-Gene Expression Profile (40-GEP) for Management and Treatment of High-risk Cutaneous Squamous Cell Carcinoma (cSCC): A Real-world Algorithm

C-POST protocol update: A Phase 3, randomized, double-blind study of adjuvant cemiplimab versus placebo post surgery and radiation therapy in patients with high-risk cutaneous squamous cell carcinoma

C-POST protocol update: A Phase 3, randomized, double-blind study of adjuvant cemiplimab versus placebo post surgery and radiation therapy in patients with high-risk cutaneous squamous cell carcinoma

How Mohs surgeons utilize prognostic testing for high-risk cutaneous squamous cell carcinoma (SCC): a clinical impact study

How Mohs surgeons utilize prognostic testing for high-risk cutaneous squamous cell carcinoma (SCC): a clinical impact study

Performance and clinical decision-making using the prognostic 40-gene expression profile (40-GEP) test in 1,018 patients with high-risk cutaneous squamous cell carcinoma (SCC)

Performance and clinical decision-making using the prognostic 40-gene expression profile (40-GEP) test in 1,018 patients with high-risk cutaneous squamous cell carcinoma (SCC)