High-risk cSCC Research Articles

Clinical Versus Histologic Margins for Cutaneous Squamous Cell Carcinoma: Comparing Outcomes for High-Risk Tumors Treated With Mohs Micrographic Surgery.

High-risk cutaneous squamous cell carcinoma (cSCC) is associated with poor clinical outcomes. Traditionally, preoperative clinical tumor size ≥2 cm, based on Brigham and Women's Hospital (BWH) staging criteria, is high risk. To compare outcomes of cSCC treated with Mohs micrographic surgery (MMS) with a preoperative size ≥2 cm (clinically ≥2 cm) versus cSCC with preoperative size <2 cm and postoperative defect size ≥2 cm (histologically ≥2 cm). Prospective data were collected from January 1, 2014, to December 31, 2020, on MMS cases for cSCC with a preoperative and/or postoperative size ≥2 cm. Clinical outcomes were followed until March 15, 2023. Data were analyzed using multivariate regression. Three hundred thirty cases of MMS for cSCC were included. Cutaneous squamous cell carcinoma clinically ≥2 cm occurred more frequently in elderly patients; cSCC histologically ≥2 cm were more commonly located in the H region, required wider surgical margins, and more MMS stages to achieve clearance. There were no significant differences in rates of recurrence and metastasis between the groups. These data suggest that postoperative (histologic) MMS defect size may allow for better risk stratification of high-risk cSCC and improved staging of cSCC.

Plasma circulating tumor DNA in patients with cutaneous squamous cell carcinoma: Initial experience.

e15034 Background: Circulating tumor DNA (ctDNA) has emerged as a potential noninvasive biomarker to assess tumor burden throughout cancer treatment and to aid in clinical decision-making. However, data on the use of ctDNA in cutaneous squamous cell carcinoma (cSCC) is currently lacking. In this study, we report our first experience with ctDNA in patients with cSCC. Methods: In this IRB-approved study at a tertiary care center, an initial cohort of patients with intermediate to high-risk cSCC had tissue and plasma sent for ctDNA analysis using Natera®’s proprietary bioinformatics pipeline. This cohort included 21 patients treated from 2023 to the present. Initial tissue samples were obtained through biopsy (i.e., excisional, punch, or shave), Mohs surgery, or surgical resection. Some patients had additional plasma sample(s) drawn later during or after the treatment course. Patients either received a “positive,” “positive below analytical range,” or “negative” result or had ‘insufficient sample’ to receive a result based on Natera®’s analysis. All patients were treated curatively with surgical resection with or without adjuvant radiation as per the standard of care. The assessment of gross disease was determined based on whether the patient had disease present on imaging or physical exam at the time of the plasma draw. A comparison of ctDNA results and the presence of gross disease was done using Fisher’s exact test. Results: Of the samples submitted for Natera® ctDNA analysis, 18/21 had sufficient tissue for analysis of tumor DNA. All 3 tumors with insufficient tissue were from biopsies (6/9 sufficient), while 12/12 of those from Mohs or surgical resection had sufficient tissue. The average tumor volume in these patients with insufficient samples for tumor analysis was relatively low (0.35 cm3) compared to those that resulted (17-30 cm3). 7/9 (78%) patients with gross disease had a positive ctDNA result, which was significantly greater than those with no gross disease (1/9 patients, 11%) (p = 0.004). Three patients in our cohort with an initially positive ctDNA result had multiple plasma draws, with all having a later draw demonstrating a negative ctDNA result after having surgery and/or radiation. Conclusions: Circulating tumor DNA is a reliable marker for patients with cSCC with a high tumor burden and is feasible in those with adequate tissue. However, in patients where it is only possible to obtain a small volume of tumor tissue and/or low tumor burden, ctDNA may be a less reliable biomarker. [Table: see text]

Patient-initiated follow-up for high-risk cutaneous squamous cell carcinoma: how we do it and 2 years ofoutcome data.

For patients with high-risk cutaneous squamous cell carcinomas (cSCCs), current guidance suggests we should 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 confirm that recurrence and metastasis are rarer events, and that perhaps these intense follow-up schedules do not really lead to improved health outcomes. To question whether current follow-up practices are truly needed by introducing an option of patient-initiated follow-up (PIFU). We enrolled 476 patients with cSCC (January 2020-January 2023) who fulfilled the definition of high-risk cSCC based on guidelines in use at the time. Of the total, 59 did not fulful the inclusion criteria and were excluded; 250 (52.5%) did not recontact us during the 2-year period, with no clinical record of complications or recurrences; and 167 (35.1%) utilized the PIFU pathway, of which 119 patients required only one face-to-face appointment. Seven patients (1.5%) developed metastatic disease, 11 (2.3%) developed recurrence and 68 (14.3%) developed cSCC at another site. All lesions were identified by the patient via PIFU. We saved 1250 follow-up appointments from those who did not contact us (n = 250), financially equating to £181 462.50. Our data imply 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 healthcare resources. Our findings support a call for revision of existing skin cancer health policies to cope with and subsequently improve our practices for 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.

A pilot study of p53 immunohistochemistry in atypical squamous lesions, using a vulvar scoring system.

Histopathologic overlap between cutaneous squamous cell carcinoma (cSCC) and its indolent mimics likely leads to the overdiagnosis of cSCC. To perform a pilot study of the p53 immunohistochemical scoring system developed on vulvar squamous lesions in cSCC. The consistency and reliability of p53 immunostaining using a scoring system developed on vulvar cases, as compared with TP53 genomic sequencing, was studied in an initial cohort of 28 cutaneous cases. p53 labeling was further assessed in an additional 63 cases of atypical squamous lesions, including 20 atypical squamous lesions classified by the authors as benign, 22 cases diagnosed as cSCC without high-risk features, and 21 cases of high-risk cSCC (cSCC-HR). The concordance of p53 labeling and TP53 sequencing was 82.1%. Four positive patterns of p53 mutation were identified: basal, parabasal/diffuse, null, and cytoplasmic. p53 positivity in atypical, benign squamous lesions (10%) was significantly lower than that of low-risk cSCC (63.6%, p = 0.0004) or cSCC-HR (90.5%, p < 0.0001). p53 positivity in low-risk cSCC versus cSCC-HR was not statistically significant (p = 0.07). p53 Labeling may be a helpful biomarker to support the diagnosis of cSCC and distinguish cSCC from atypical but benign mimics.

CUTANEOUS SQUAMOUS CELL CARCINOMA AT NATIONAL HOSPITAL OF DERMATOLOGY AND VENEREOLOGY: A FOLLOW-UP RETROSPECTIVE STUDY

Objectives: This study assessed the postoperative follow-up attendance of patients with cutaneous squamous cell carcinoma (cSCC) who underwent management at the National Hospital of Dermatology and Venereology, following the protocol based on the American Academy of Dermatology (AAD) guidelines of care for the management of cutaneous squamous cell carcinoma in 2018 and the classification of low and high-risk cSCC according to the National Comprehensive Cancer Network (NCCN). Materials and Methods: A retrospective study involving 60 cSCC patients was conducted. The monitoring included recurrent cancerous lesions, new cancerous lesions (cSCC, BCC, melanoma, and other types), detection of metastatic lesions (lymph node and distant metastases), late complication monitoring (bad scarring), and mortality monitoring. Results: Depending on their stage and risk factors, cSCC patients underwent tumor removal by wide local excision (61.7%) or Mohs surgery (38.3%). Regional lymph node screening for metastasis included clinical examination, ultrasound, cytology, or sentinel lymph node biopsy (SLNB). Distant metastases in cSCC were infrequent, accounting for 1.7%, mainly presenting as lymph node metastases (6.7%). Patients were re-examined at least 5 years after treatment, revealing 4 of 56 patients with lymph node metastasis, 1 with bone metastasis, and 4 in the high-risk group who succumbed in the subsequent period. Conclusion: The management of cSCC, following the AAD guidelines and risk classification by NCCN, is effective, with treatment modifications as needed and strict monitoring being imperative. Received 19 June 2023Revised 18 September 2023Accepted 25 November 2023

Use of the 40-Gene Expression Profile (40-GEP) Test in Medicare-Eligible Patients Diagnosed with Cutaneous Squamous Cell Carcinoma (cSCC) to Guide Adjuvant Radiation Therapy (ART) Decisions Leads to a Significant Reduction in Healthcare Costs

Objective: Adjuvant radiation therapy (ART) is often recommended for high-risk cSCC patients but carries significant costs and risks. This study aims to determine if utilizing the 40-GEP test to guide ART can reduce healthcare costs in cSCC management. Methods: Medical claims data with new diagnoses of cSCC for the 12 months ending June 2022 in the Medicare (≥65 years) population (source: IQVIA claims database) were obtained and normalized to the general population for missingness. CPT codes associated with radiation therapy within one-year post diagnosis were used to establish adjuvant RT use (defined as ‘ART’). Average weighted direct costs for four major ART modalities were calculated from published studies and (IQVIA). Sensitivity analysis was used to assess the financial impact of ART treatment using varying distributions of 40-GEP Class results. Results: Normalized medical claims data identified 22,917 Medicare-eligible cSCC patients who received ART within the United States. The weighted average direct cost for ART, which includes the four most used CPT code-defined modalities (IGRT, IMRT, IMPT, and XRT), was $60,693 per patient, amounting to an annual projected ART cost of $1.4 billion. Using the distribution of 40-GEP results from published studies, utilization of a 40-GEP test result to avoid ART in these patients could save up to $972 million in Medicare-eligible population. Sensitivity analysis shows, depending upon the distribution of the 40-GEP results, that for every 10% of Class 2A test results omitting ART, an extra $38-66 million in annual savings is expected Limitations: Potential limitations include a need for more comprehensive patient information and the cost of ART-related complications. Conclusion: Utilizing the 40-GEP test results to guide ART decision-making would result in material savings to Medicare.

Prognostic Outcomes of Cutaneous Squamous Cell Carcinoma in Solid Organ Transplant Recipients: A Retrospective Comparative Cohort Study.

Cutaneous squamous cell carcinoma (cSCC) is the second most common cutaneous neoplasm, and its incidence is on the rise. While most cSCCs have an excellent prognosis, certain risk factors, especially immunosuppression, have been associated with higher rates of local recurrence (LR), metastasis, and poor prognosis. This study aims to assess the risk factors for LR and metastasis development in cSCC among solid organ transplant recipients (SOTRs) and compare these rates with those in immunocompetent patients. A retrospective observational study included cSCC cases from the University Hospital Reina Sofía in Córdoba, Spain, between 2002 and 2019. Demographic, clinical, and histopathological data were collected. Local recurrence and metastasis rates were analyzed, along with progression-free survival. Univariate analyses were performed to identify prognostic factors in SOTRs. Among 849 cSCC cases, we found higher rates of local recurrence and metastasis in tumors developed by SOTRs compared to those in immunocompetent individuals. However, no significant differences in local recurrence, metastasis, or progression-free survival were observed between the two groups. Risk factors for adverse outcomes in SOTRs included tumor size > 2 cm, depth > 4 mm, and a higher Clark level. A total of 34.4% of SOTRs developed a second primary cSCC during the follow-up. In our study, cSCCs in SOTRs did not exhibit statistically significant differences in the rates of adverse outcomes compared to immunocompetent patients. The prognosis of cSCCs in SOTRs may be more related to other tumor-dependent risk factors than to the immunosuppression status itself. Future studies are needed to refine risk stratification and follow-up protocols to ensure the optimal management of high-risk cSCC cases, particularly among immunosuppressed patients.

Risk-Stratification using the 40-Gene Expression Profile (40-GEP) Test Identifies Patients with Node Negative Cutaneous Squamous Cell Carcinoma (cSCC) at Higher Risk of Metastasis Who May Benefit from Adjuvant Radiation Therapy (ART)

ART is a standard treatment used to reduce the risk of metastasis and recurrence in moderate‒to‒high-risk cSCC patients. Indications for ART have been largely based on pathologic risk factors and informed by staging systems, and while radiation oncologists generally designate a >10% risk threshold for usage of ART, there is no consensus on which groups of tumors may benefit from ART. The 40-GEP test has been independently validated to predict a cSCC patient's risk for regional/distant metastasis in patients with one or more high-risk clinicopathologic factors and reports three biologic risk groups: Class 1 (low, ∼7%), Class 2A (moderate, 20-25%), and Class 2B (high risk, >50%) for metastasis. This study aims to evaluate whether a biomarker informed risk stratification approach using a 40-GEP result could refine the ability to select patients with node negative cSCC at higher risk of metastasis who are most likely to benefit from ART. In this retrospective study, all patients had primary cSCC tissue with verified clinicopathologic information of tumors with one or more high-risk factors, met clinical testing criteria, were comprehensively staged, and had outcomes data (n = 954). Patients with node positive disease, or those with nodal failure within 3 months of diagnosis were excluded (n = 19). From the n = 935, an intermediate risk population wherein ART is often considered was defined as Brigham and Women's Hospital (BWH) ≥T2a (n = 489). Kaplan-Meier survival analysis and log-rank test were used to assess metastasis free survival (MFS). Univariate Cox regression compared metastasis rates between 40-GEP results. The 3-year MFS rate for this eligible for ART cohort was 82.4% The 40-GEP demonstrated statistically significant risk stratification with MFS rates of 92.4%, 76.1% and 59.4% for Class 1, Class 2A and Class 2B, respectively (p<0.0001). Cox regression was significant for Class 2A and 2B compared to Class 1, with a 3.2-fold and 6.4-fold increase in metastasis, respectively (p<0.0001). 64% (59/92) of all metastases received a Class 2A result, and 44% (14/32) of Class 2B patients metastasized. 46% (223/489) of the cohort received a Class 1 result. Of patients staged BWH T1 (n = 446), those with a Class 2A and 2B had an 88.7% and 66.7% MFS rate, respectively. Within this eligible for ART population, patients with Class 2A or 2B 40-GEP results have inferior rates of MFS, while Class 1 patients have <10% risk of metastasis. Nearly half of this population received a 40-GEP Class 1 result and could be considered for treatment de-intensification trials. Conversely, patients with low-risk BWH T1 stage, who are traditionally not considered for ART, that received a Class 2A or 2B (>10% risk of metastasis) could be considered for adjuvant therapy.

Tumour budding in cutaneous squamous cell carcinoma: A novel prognosis risk factor.

Most cutaneous squamous cell carcinomas (cSCC) have a good prognosis, there is a small group where metastasis and death occur and the evaluation of this risk is still cause for controversy. Tumour budding is a pattern of histological invasion that is an emerging risk factor in other solid tumours. To examine the association between tumour budding and other known high-risk predictors in cSCC. In addition, the impact of tumour budding on overall survival (OS) and disease-specific survival (DSS) was analysed. Retrospective study. It included patients with a diagnosis of non-genital cSCC by excisional biopsy at a university hospital, between 2010 and 2020. A pathologist re-analysed their histological slides and evaluated budding. Univariate and multivariate analyses were made to study the associations. 156 cSCC biopsies were found, and positive tumour budding was found in 13.5%. This correlated with worse DSS and OS. On univariate analysis, budding was correlated with the diameter, thickness of the tumour, histological grade, level of invasion, perineural and lymphovascular invasion, previous radiotherapy, recurrent tumours and lymph node metastasis (LNM). Multivariate analysis: tumour budding was associated with poorly differentiated tumours, prior radiotherapy and LNM. An association was found between tumour budding and most known risk factors in cSCC. We found findings that indicate that the presence of tumour budding is associated with a worse prognosis in terms of LNM, OS and DSS. This supports the results of previous work which has suggested that budding could be related to high-risk cSCC.

Personalised decision making to predict absolute metastatic risk in cutaneous squamous cell carcinoma: development and validation of a clinico-pathological model

Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer, affecting more than 2 million people worldwide yearly and metastasising in 2-5% of patients. However, current clinical staging systems do not provide estimates of absolute metastatic risk, hence missing the opportunity for more personalised treatment advice. We aimed to develop a clinico-pathological model that predicts the probability of metastasis in patients with cSCC. Nationwide cohorts from (1) all patients with a first primary cSCC in The Netherlands in 2007-2008 and (2) all patients with a cSCC in 2013-2015 in England were used to derive nested case-control cohorts. Pathology records of primary cSCCs that originated a loco-regional or distant metastasis were identified, and these cSCCs were matched to primary cSCCs of controls without metastasis (1:1 ratio). The model was developed on the Dutch cohort (n=390) using a weighted Cox regression model with backward selection and validated on the English cohort (n=696). Model performance was assessed using weighted versions of the C-index, calibration metrics, and decision curve analysis; and compared to the Brigham and Women's Hospital (BWH) and the American Joint Committee on Cancer (AJCC) staging systems. Members of the multidisciplinary Skin Cancer Outcomes (SCOUT) consortium were surveyed to interpret metastatic risk cutoffs in a clinical context. Eight out of eleven clinico-pathological variables were selected. The model showed good discriminative ability, with an optimism-corrected C-index of 0.80 (95% Confidence interval (CI) 0.75-0.85) in the development cohort and a C-index of 0.84 (95% CI 0.81-0.87) in the validation cohort. Model predictions were well-calibrated: the calibration slope was 0.96 (95% CI 0.76-1.16) in the validation cohort. Decision curve analysis showed improved net benefit compared to current staging systems, particularly for thresholds relevant for decisions on follow-up and adjuvant treatment. The model is available as an online web-based calculator (https://emc-dermatology.shinyapps.io/cscc-abs-met-risk/). This validated model assigns personalised metastatic risk predictions to patients with cSCC, using routinely reported histological and patient-specific risk factors. The model can empower clinicians and healthcare systems in identifying patients with high-risk cSCC and offering personalised care/treatment and follow-up. Use of the model for clinical decision-making in different patient populations must be further investigated. PPP Allowance made available by Health-Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships.

Artificial intelligence-empowered cellular morphometric risk score improves prognostic stratification of cutaneous squamous cell carcinoma.

Risk stratification of cutaneous squamous cell carcinoma (cSCC) is essential for managing patients. To determine if artificial intelligence and machine learning might help to stratify patients with cSCC by risk using more than solely clinical and histopathological factors. We retrieved a retrospective cohort of 104 patients whose cSCCs had been excised with clear margins. Clinical and histopathological risk factors were evaluated. Haematoxylin and eosin-stained slides were scanned and analysed by an algorithm based on the stacked predictive sparse decomposition technique. Cellular morphometric biomarkers (CMBs) were identified via machine learning and used to derive a cellular morphometric risk score (CMRS) that classified cSCCs into clusters of differential prognoses. Concordance analysis, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were calculated and compared with results obtained with the Brigham and Women's Hospital (BWH) staging system. The performance of the combination of the BWH staging system and the CMBs was also analysed. There were no differences among the CMRS groups in terms of clinical and histopathological risk factors and T-stage assignment, but there were significant differences in prognosis. Combining the CMRS with BWH staging systems increased distinctiveness and improved prognostic performance. C-indices were 0.91 local recurrence and 0.91 for nodal metastasis when combining the two approaches. The NPV was 94.41% and 96.00%, the PPV was 36.36% and 41.67%, and accuracy reached 86.75% and 89.16%, respectively, with the combined approach. CMRS is helpful for cSCC risk stratification beyond classic clinical and histopathological risk features. Combining the information from the CMRS and the BWH staging system offers outstanding prognostic performance for patients with high-risk cSCC.

CD271 activation prevents low to high-risk progression of cutaneous squamous cell carcinoma and improves therapy outcomes

BackgroundCutaneous squamous cell carcinoma (cSCC) is the second most prevalent form of skin cancer, showing a rapid increasing incidence worldwide. Although most cSCC can be cured by surgery, a sizeable number of cases are diagnosed at advanced stages, with local invasion and distant metastatic lesions. In the skin, neurotrophins (NTs) and their receptors (CD271 and Trk) form a complex network regulating epidermal homeostasis. Recently, several works suggested a significant implication of NT receptors in cancer. However, CD271 functions in epithelial tumors are controversial and its precise role in cSCC is still to be defined.MethodsSpheroids from cSCC patients with low-risk (In situ or Well-Differentiated cSCC) or high-risk tumors (Moderately/Poorly Differentiated cSCC), were established to explore histological features, proliferation, invasion abilities, and molecular pathways modulated in response to CD271 overexpression or activation in vitro. The effect of CD271 activities on the response to therapeutics was also investigated. The impact on the metastatic process and inflammation was explored in vivo and in vitro, by using zebrafish xenograft and 2D/3D models.ResultsOur data proved that CD271 is upregulated in Well-Differentiated tumors as compared to the more aggressive Moderately/Poorly Differentiated cSCC, both in vivo and in vitro. We demonstrated that CD271 activities reduce proliferation and malignancy marker expression in patient-derived cSCC spheroids at each tumor grade, by increasing neoplastic cell differentiation. CD271 overexpression significantly increases cSCC spheroid mass density, while it reduces their weight and diameter, and promotes a major fold-enrichment in differentiation and keratinization genes. Moreover, both CD271 overexpression and activation decrease cSCC cell invasiveness in vitro. A significant inhibition of the metastatic process by CD271 was observed in a newly established zebrafish cSCC model. We found that the recruitment of leucocytes by CD271-overexpressing cells directly correlates with tumor killing and this finding was further highlighted by monocyte infiltration in a THP-1-SCC13 3D model. Finally, CD271 activity synergizes with Trk receptor inhibition, by reducing spheroid viability, and significantly improves the outcome of photodynamic therapy (PTD) or chemotherapy in spheroids and zebrafish.ConclusionOur study provides evidence that CD271 could prevent the switch between low to high-risk cSCC tumors. Because CD271 contributes to maintaining active differentiative paths and favors the response to therapies, it might be a promising target for future pharmaceutical development.

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.

DS15 Metastatic cutaneous squamous cell carcinoma: how best to develop a skin cancer service for future populations

Abstract The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing in the White population. Despite a favourable prognosis in the majority, it remains a cause of morbidity and mortality, especially in immunosuppressed and elderly individuals. Large cSCCs can be challenging for surgical clearance, recurrence and metastatic disease, despite guidelines for the management and staging of cSCC. We sought to identify high-risk features of those who develop metastatic disease. Our centre typically manages 300 cSCCs annually, but only cSCCs discussed at our two multidisciplinary team (MDT) meetings (head and neck and skin cancer) at our level 4 hospital over a 3-year period (2019–2021) were included in a retrospective observational study. A total of 124 patients with high-risk cSCC (due to patient or tumour factors) were included. Male sex predominated. Sixteen cases had metastatic disease. Median age at diagnosis was 80 years in the total MDT group and 86.5 years in the metastasis group. Of 16 patients with metastases, eight had complete primary excisions. Five cases had incomplete primary excision (peripheral or deep margins involved), and three cases had a narrow margin of &amp;lt; 1 mm. Primary tumour size was similar in both the MDT and metastasis groups (median size 17 vs. 20 mm). Head and neck sites predominated in both (88%). In the metastatic group, one had chronic lymphocytic leukaemia, but no other patients with immunosuppression were identified, and the majority (81%) suffered with multimorbidity (≥ 2 chronic illnesses). Nine patients with metastatic cSCC received radiotherapy, two systemic chemotherapies, five neck dissections and one immunotherapy. Most patients presenting with metastatic cSCC at our centre were &amp;gt; 85 years old, a group sometimes known as ‘the oldest old’, and many had multimorbidity. This, coupled with tumour location, poses challenges for healthcare professionals in managing the initial cSCC aggressively and implementing a reasonable follow-up and surveillance schedule. In comparing both groups, advanced age was the predominant difference, with twice as many aged &amp;gt; 85 years in the metastasis group vs. the MDT group. Immunosenescence is a process of immune dysfunction that occurs with age and includes remodelling of lymphoid organs, leading to changes in the immune function of the elderly and relates to the development of malignant tumours. It is estimated that 5 million people in the UK will be in this age group by 2050 (www.ageuk.org.uk/globalassets/age-uk/documents/reports-and-publications/reports-and-briefings/health–wellbeing/rb_feb13_understanding_the_oldest_old_improving_later_life.pdf). There is a need to continue to consider this dynamic group (those aged &amp;gt; 85 years) and those with multimorbidity when strategies for the projected management of cSCC are being considered.

DS07 (P22) Clinicopathologic characteristics of metastatic cutaneous squamous cell carcinoma: a cohort study

Abstract Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte tumour with excellent prognosis following early-stage surgical treatment. Nevertheless, cSCC possesses an inherent potential for locoregional and distant metastasis in ∼4% of cases, contributing to disease-specific mortality. Recent guidance on cSCC management risk stratifies patients based on clinicopathological factors to identify those patients most at risk of metastasis. A retrospective cohort study identified 3455 cSCCs arising in 2522 patients, via review of histopathological diagnoses of cSCC at a tertiary hospital in Dublin, Ireland, between the years of 2009 and 2019. The aim of the study was to describe adequately a large cohort of patients with metastatic cSCC and investigate factors associated with metastasis. Metastatic disease was identified by histopathological and/or radiological confirmation in 116 patients, with complete data available in 105 cases. Twenty-two (21%) were female. Mean age at primary tumour diagnosis was 74.8 years, and mean time to first metastasis was 0.8 years. Twenty-six (25%) patients were immunosuppressed, the commonest reason for which was haematological malignancy. Median (SD) size of the primary tumour was 36 (21.65) mm, and median depth was 10 (7.43) mm. Eighty-six (82%) tumours were located on the head and neck. Seventeen (16%) of the tumours were recurrent, 58 (55%) were &amp;gt; 20 mm, 38 (36%) demonstrated extension beyond subcutaneous fat, 22 (21%) demonstrated lymphovascular invasion, 24 (23%) demonstrated perineural invasion of nerves &amp;gt; 0.1 mm in diameter, and 41 (39%) tumours were poorly differentiated. Twenty-six patients developed distant metastatic disease in addition to nodal metastasis. In most patients in our cohort, AJCC 8th Edition histopathological high-risk cSCC features were absent, apart from size &amp;gt; 20 mm. Conversely, most patients exhibited at least one clinical high-risk cSCC feature as per the British Association of Dermatologists guidelines for the management of cutaneous squamous cell carcinoma, including advanced age and tumour location (Keohane SG, Botting J, Budny PG et al. British Association of Dermatologists guidelines for the management of people with cutaneous squamous cell carcinoma 2020. Br J Dermatol 2021; 184:401–14). All patients were discussed at a specialist skin multidisciplinary team meeting, with significant variability noted in preoperative imaging, depending on the primary treating specialty. This cohort illustrates the importance of risk stratification of cSCC on clinicopathological features. This facilitates management decisions and ongoing patient surveillance with a view to preventing disease-specific morbidity and mortality.

DS16 Clinicopathological features of metastatic squamous cell carcinoma treated with Mohs micrographic surgery: a case series

Abstract Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte tumour with inherent metastatic potential. Approximately 4% of cSCCs metastasize locoregionally and/or distally. Mohs micrographic surgery (MMS) is efficacious, with cure rates in selected cases of 95–99%. Diagnoses of cSCC treated at St James’s Hospital between the years 2010 and 2019 were identified via histopathology reports. Clinicopathological and treatment data in cases with metastatic disease were collected. Nodal metastasis was defined as biopsy-confirmed cSCC in locoregional lymph nodes and/or supporting radiological evidence. During the timeframe, 3455 cSCCs occurred in 2522 patients. Metastatic disease was identified in 116 patients, with complete data available in 105 cases. Six patients had undergone MMS to the primary tumour. Mean age at time of surgery was 75.6 years (range 65–85); five patients were male. Tumours were located on the cheek (n = 2), ear (n = 2), lower eyelid and nasal tip. Mean time to first metastasis was 6.67 months (range 2–16). Two patients were immunosuppressed at time of metastasis. All patients demonstrated high-risk cSCC features, with four patients demonstrating very-high-risk features as defined by the British Association of Dermatologists. One patient received adjuvant radiotherapy prior to detectable metastasis. All patients were discussed at either skin or head and neck multidisciplinary team (MDT) meetings. No patient received preoperative imaging. This series highlights the importance of risk stratification in cSCC management, irrespective of treatment modality. Consideration should be given to patient age and relative immune status, with dedicated locoregional imaging being guided by MDT discussion.

P22 Clinicopathologic characteristics of metastatic cutaneous squamous cell carcinoma: a cohort study

Abstract Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte tumour with excellent prognosis following early-stage surgical treatment. Nevertheless, cSCC possesses an inherent potential for locoregional and distant metastasis in approximately 4% of cases, contributing to disease-specific mortality. Recent guidance on cSCC management risk stratifies patients based on clinicopathological factors to identify those patients most at risk of metastasis. A retrospective cohort study identified 3455 cSCCs arising in 2522 patients, via review of histopathological diagnoses of cSCC at a tertiary hospital in Dublin, Ireland, between the years of 2009 and 2019. The aim of the study was to describe adequately a large cohort of patients with metastatic cSCC and investigate factors associated with metastasis. Metastatic disease was identified by histopathological and/or radiological confirmation in 116 patients, with complete data available in 105 cases. Twenty-two (21%) were female. Mean age at primary tumour diagnosis was 74.8 years and mean time to first metastasis was 0.8 years. Twenty-six (25%) patients were immunosuppressed, the commonest reason for which was haematological malignancy. Median (SD) size of the primary tumour was 36 (21.65) mm and median depth was 10 (7.43) mm. Eighty-six (82%) tumours were located on the head and neck. Seventeen (16%) of the tumours were recurrent, 58 (55%) were &amp;gt; 20 mm, 38 (36%) demonstrated extension beyond subcutaneous fat, 22 (21%) demonstrated lymphovascular invasion, 24 (23%) demonstrated perineural invasion of nerves &amp;gt; 0.1 mm in diameter and 41 (39%) tumours were poorly differentiated. Twenty-six patients developed distant metastatic disease in addition to nodal metastasis. In most patients in our cohort, AJCC 8th Edition histopathological high-risk cSCC features were absent, apart from size &amp;gt; 20 mm. Conversely, most patients exhibited at least one clinical high-risk cSCC feature as per the British Association of Dermatologists’ guidelines for the management of cutaneous squamous cell carcinoma, including advanced age and tumour location (Keohane SG, Botting J, Budny PG et al. British Association of Dermatologists guidelines for the management of people with cutaneous squamous cell carcinoma 2020. Br J Dermatol 2021; 184:401–14). All patients were discussed at a specialist skin multidisciplinary team meeting, with significant variability noted in preoperative imaging, depending on the primary treating specialty. This cohort illustrates the importance of risk stratification of cSCC on clinicopathological features. This facilitates management decisions and ongoing patient surveillance with a view to preventing disease-specific morbidity and mortality.

The efficacy of dermoscopy in defining the surgical margins of cutaneous squamous cell carcinoma: a retrospective study.

To investigate the diagnostic value of dermoscopy in defining the tumor margin of cutaneous squamous cell carcinoma (cSCC) for the appropriate surgical margin. A total of 90 cSCC patients were enrolled in the study. All patients were recruited into two groups: those who preserved intact macroscopic features of neoplasms without or after incisional biopsy and those with uncertain residual tumors after excisional biopsy. A dermoscopy-defined surgical margin of 8mm outward was used according to the tumor boundaries observed with the naked eye and dermoscopy. All excised tumor specimens were divided into serial sections according to the four "3, 6, 9, 12" directions at every 4-mm interval from the dermoscopy-detected tumor margin. Pathological examination was performed at 0mm, 4mm, and 8mm margins to confirm tumor remnants. Retrospective analysis of dermatoscopic results showed inconsistent clinical and dermatoscopic borders in 43 of 90 cases (47.8%). The ability of dermoscopy to detect tumor borders showed no statistical difference between the two groups (p > 0.05). In the unbiopsy or incisional biopsy group, 66.6% of the tumors were resected with a 4-mm margin and 98.3% with an 8-mm margin, with significant differences (p = 0.047). For patients with inconspicuous clinical evidence of residual tumor after excisional biopsy, the tumor clearance rate was 53.3% at 0mm, 93.3% at 4mm, and 100.0% at 8mm. Statistically significant differences were noted between 0mm and 4mm (p = 0.017), as well as between 0mm and 8mm (p = 0.043) but did not differ between 4mm and 8mm (p>0.05). Dermoscopy defined the tumor margin of cSCC better than visual inspection alone. Direct dermoscopic-guided surgery with at least 8-mm expansion was recommended for high-risk cSCC. Dermoscopy also assisted in identifying surgical margins at the healing biopsy site, making 8mm still the recommended expansion range.

A Prospective, Multi-Center Clinical Utility Study Demonstrates That the 40-Gene Expression Profile (40-GEP) Test Impacts Clinical Management for Medicare-Eligible Patients with High-Risk Cutaneous Squamous Cell Carcinoma (cSCC)

The incidence and mortality rates of cutaneous squamous cell carcinoma (cSCC) in the Medicare population are rapidly increasing. The current national guidelines are broad and the available staging systems for stratification are inadequate to accurately guide patient management. A prognostic 40-gene expression profile (40-GEP) test has demonstrated both analytical and clinical validity for assessment of metastatic risk of high-risk cSCC patients independent of traditional clinicopathologic factors. Real-world data have shown that clinicians can identify appropriate patients for 40-GEP testing and use this personalized, molecular risk stratification tool to guide risk-aligned clinical planning and patient management. The data herein focuses on 59 Medicare-eligible patients (≥65 years of age) enrolled within a multicenter, prospective Clinical Utility and Health Outcomes Study (UTILISE) conducted to demonstrate patterns of 40-GEP test utilization, distribution of results across clinicopathologic variables, and impact on clinician recommendations for clinical management of high-risk cSCC patients. Of patients under study, more than 80% of clinicians reported that the 40-GEP had a positive impact toward managing their high-risk SCC patient, 42% stated, a 40-GEP test result was the single most influential factor in determining management plans and 24% made changes to their treatment plan in after receiving the 40-GEP result­‑ a clinical actionability rate comparable to those of currently covered molecular tests for cancer patients. This analysis demonstrates the positive impact the 40-GEP is having on clinicians’ assessment of risk for their high-risk cSCC patients, which, in line with guidelines, is driving risk-aligned changes in treatment plans.