Validation of four cutaneous squamous cell carcinoma staging systems using nationwide data.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer worldwide with relatively low metastatic potential (2-5%). Developments in therapeutic options have highlighted the need to better identify high-risk patients who could benefit from closer surveillance, adjuvant therapies and baseline/follow-up imaging, while at the same time safely omitting low-risk patients from further follow-up. Controversy remains regarding the predictive performance of current cSCC staging systems and which methodology to adopt. OBJECTIVES: To validate the performance of four cSCC staging systems [American Joint Committee on Cancer 8th edition (AJCC8), Brigham and Women's Hospital (BWH), Tübingen and Salamanca T3 refinement] in predicting metastasis using a nationwide cohort. METHODS: A nested case-control study using data from the National Disease Registration Service, England, 2013-2015 was conducted. Metastatic cSCC cases were identified using an algorithm to identify all potential cases for manual review. These were 1 : 1 matched on follow-up time to nonmetastatic controls randomly selected from 2013. Staging systems were analysed for distinctiveness, homogeneity, monotonicity, specificity, positive predictive value (PPV), negative predictive value (NPV) and c-index. RESULTS: We included 887 metastatic cSCC cases and 887 nonmetastatic cSCC controls. The BWH system showed the highest specificity [92.8%, 95% confidence interval (CI) 90.8-94.3%, PPV (13.2%, 95% CI 10.6-16.2) and c-index (0.84, 95% CI 0.82-0.86). The AJCC8 showed superior NPV (99.2%, 95% CI 99.2-99.3), homogeneity and monotonicity compared with the BWH and Tübingen diameter and thickness classifications (P < 0.001). Salamanca refinement did not show any improvement in AJCC8 T3 cSCC staging. CONCLUSIONS: We validated four cSCC staging systems using the largest nationwide dataset of metastatic cSCC so far. Although the BWH system showed the highest overall discriminative ability, PPV was low for all staging systems, which shows the need for further improvement and refining of current cSCC staging systems.

Cumulative incidence and disease-specific survival of metastatic cutaneous squamous cell carcinoma: A nationwide cancer registry study.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) represents the most serious form of keratinocyte cancers because of its metastatic potential. Studies on nationwide incidence and disease-specific survival rates of metastatic cSCC (mcSCC) are lacking. OBJECTIVE: To investigate the cumulative incidence and disease-specific survival of patients with mcSCC in the Dutch population and assess patient-based risk factors. METHODS: We conducted a nationwide cancer registry study including all patients with the first cSCC in 2007 or 2008, using data from the Netherlands Cancer Registry, the nationwide network and registry of histopathology and cytopathology, and Statistics Netherlands. Cumulative incidence and Kaplan-Meier curves were calculated, and time-dependent Cox proportional hazards regression analyses were used. RESULTS: Of the 11,137 patients, metastases developed in 1.9% (n = 217). The median time to metastasis was 1.5 years (interquartile range 0.6-3.8 years). The risk factors were age (adjusted hazard ratio [aHR] 1.03, 95% CI 1.02-1.05), male sex (aHR 1.7, 95% CI 1.3-2.3), and immunosuppression (aHR [organ transplant recipient] 5.0, 95% CI 2.5-10.0; aHR [hematologic malignancy] 2.7, 95% CI 1.6-4.6). The 5-year disease-specific survival for patients with mcSCC was 79.1%. LIMITATIONS: Only histopathologically confirmed mcSCCs were included. CONCLUSION: About 2% of cSCCs metastasize, with higher risk for men, increasing age, and immunocompromised patients. Disease-specific survival for patients with mcSCC is high.

Risk factors for metastatic cutaneous squamous cell carcinoma: Refinement and replication based on 2 nationwide nested case-control studies.

BACKGROUND: Risk factors for cutaneous squamous cell carcinoma (cSCC) metastasis have been investigated only in relatively small data sets. OBJECTIVE: To analyze and replicate risk factors for metastatic cSCC. METHODS: From English and Dutch nationwide cancer registry cohorts, metastatic cases were selected and 1:1 matched to controls. The variables were extracted from pathology reports from the National Disease Registration Service in England. In the Netherlands, histopathologic slides from the Dutch Pathology Registry were revised by a dermatopathologist. Model building was performed in the English data set using backward conditional logistic regression, whereas replication was performed using the Dutch data set. RESULTS: In addition to diameter and thickness, the following variables were significant risk factors for metastatic cSCC in the English data set (n = 1774): poor differentiation (odds ratio [OR], 4.56; 95% CI, 2.99-6.94), invasion in (OR, 1.69; 95% CI, 1.05-2.71)/beyond (OR, 4.43; 95% CI, 1.98-9.90) subcutaneous fat, male sex (OR, 2.59; 95% CI, 1.70-3.96), perineural/lymphovascular invasion (OR, 2.12; 95% CI, 1.21-3.71), and facial localization (OR, 1.57; 95% CI, 1.02-2.41). Diameter and thickness showed significant nonlinear relationships with metastasis. Similar ORs were observed in the Dutch data set (n = 434 cSCCs). LIMITATIONS: Retrospective use of pathology reports in the English data set. CONCLUSION: cSCC staging systems can be improved by including differentiation, clinical characteristics such as sex and tumor location, and nonlinear relationships for diameter and thickness.

Longitudinal Assessment of the Prevalence of Actinic Keratosis and Extensive Risk Factor Evaluation: An Update from the Rotterdam Study.

Population-based studies available to analyze the prevalence, risk factors, and longitudinal outlook of actinic keratoses (AKs) are limited. These features mentioned earlier were assessed using Rotterdam study participants aged ≥40 years who underwent a full-body skin examination by a dermatology-trained physician. ORs with 95% confidence intervals were calculated for the associations between risk factors and the presence of AK. Among 8,239 eligible participants, the prevalence of one or more AKs was 21.1% (95% confidence interval = 20.2-22.0) and was higher in men. Male sex, age, lighter hair and eye color, baldness, genetic risk score, and digital photoaging measures (digitally assessed pigmented spots, telangiectasias, and global facial wrinkling) had a positive association with AK. Cigarette smokers had reduced odds of having AK, with current smokers having the lowest risk. Among patients with two AK assessments, there was no difference in the presence of AK during follow-up between treated and untreated participants. In conclusion, genetic risk score and digital photoaging measures showed associations with increased lesion count. At the individual level, patients were most likely to decrease in AK severity group over time, possibly regardless of whether or not participants were treated.

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

Background: 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. Methods: 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. Findings: 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/). Interpretation: 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. Funding: PPP Allowance made available by Health-Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships.

Assessment of the Diagnostic Accuracy of Baseline Clinical Examination and Ultrasonographic Imaging for the Detection of Lymph Node Metastasis in Patients With High-risk Cutaneous Squamous Cell Carcinoma of the Head and Neck.

IMPORTANCE: Patients with cutaneous squamous cell carcinoma (SCC) of the head and neck may develop lymph node metastasis; therefore, additional workup of the regional lymph nodes in these patients should be considered. However, there is uncertainty regarding the value of baseline ultrasonographic imaging in addition to clinical examination for the detection of metastasis. OBJECTIVE: To assess the diagnostic accuracy of clinical examination and baseline ultrasonography for the detection of metastasis among patients with high-risk cutaneous SCC of the head and neck and to assess the accuracy of ultrasonography when baseline clinical examination produces negative results. DESIGN, SETTING, AND PARTICIPANTS: This diagnostic study was conducted among a retrospective cohort of 233 patients with 246 high-risk cutaneous SCC tumors of the head and neck. The study included all patients with high-risk cutaneous SCC of the head and neck who received clinical examination and baseline ultrasonographic imaging of their lymph nodes at the Erasmus Medical Center Cancer Institute, a tertiary referral hospital for patients with skin cancer in Rotterdam, the Netherlands, between January 1, 2015, and December 31, 2017. Data were analyzed from October 13, 2020, to September 29, 2021. MAIN OUTCOMES AND MEASURES: Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. Fine-needle aspiration cytologic biopsy and 6 months of follow-up per patient were used as the reference standards. RESULTS: Among 233 patients (176 men [75.5%]; median age, 79.1 years [IQR, 71.5-83.7 years]; data on race and ethnicity were not collected) with 246 high-risk cutaneous SCC tumors of the head and neck, 20 metastases were cytologically confirmed at baseline, and 2 metastases were detected during 6 months of follow-up, yielding a 9% metastasis rate. The sensitivity of clinical examination was 50% (95% CI, 28%-72%), and the specificity was 96% (95% CI, 93%-98%). The PPV and NPV were 55% (95% CI, 36%-72%) and 95% (95% CI, 93%-97%), respectively. In the total cohort, ultrasonography had a sensitivity of 91% (95% CI, 71%-99%) and a specificity of 78% (95% CI, 72%-83%), with a PPV of 29% (95% CI, 23%-35%) and an NPV of 99% (95% CI, 96%-100%). In the group of patients with negative results at baseline clinical examination, 9 of 11 metastases were detected by ultrasonography, with 82% sensitivity (95% CI, 48%-98%); specificity was 79% (95% CI, 73%-84%), PPV was 17% (95% CI, 12%-23%), and NPV was 99% (95% CI, 96%-100%). CONCLUSIONS AND RELEVANCE: In this diagnostic study, among a cohort of patients with high-risk cutaneous SCC of the head and neck, baseline ultrasonography was more sensitive than clinical examination alone for the detection of lymph node metastasis. In the setting of a negative result at baseline clinical examination, ultrasonography had high sensitivity for detecting nodal metastases, but this sensitivity should be evaluated against the high rate of false-positive findings.

Incidence of Multiple vs First Cutaneous Squamous Cell Carcinoma on a Nationwide Scale and Estimation of Future Incidences of Cutaneous Squamous Cell Carcinoma.

Importance: Until now, most studies on cutaneous squamous cell carcinoma (cSCC) incidence rates concerned only the first cSCC per patient. Given the increase in incidence rates and the frequent occurrence of subsequent cSCCs per patient, population-based data on the incidence rates of both first and multiple cSCCs are needed. Objectives: To calculate annual age-standardized incidence rates for histopathologically confirmed first and multiple cSCCs per patient and to estimate future cSCC incidence rates up to 2027. Design, Setting, and Participants: A nationwide population-based epidemiologic cohort study used cancer registry data on 145 618 patients with a first histopathologically confirmed cSCC diagnosed between January 1, 1989, and December 31, 2017, from the Netherlands Cancer Registry and all patients with multiple cSCCs diagnosed in 2017. Main Outcomes and Measures: Age-standardized incidence rates for cSCC-standardized to the European Standard Population 2013 and United States Standard Population 2000-were calculated per sex, age group, body site, and disease stage. A regression model with positive slope was fitted to estimate cSCC incidence rates up to 2027. Results: A total of 145 618 patients in the Dutch population (84 572 male patients [58.1%]; mean [SD] age, 74.5 [11.5] years) received a diagnosis of a first cSCC between 1989 and 2017. Based on incident data, European Standardized Rates (ESRs) increased substantially, with the highest increase found among female patients from 2002 to 2017, at 8.2% (95% CI, 7.6%-8.8%) per year. The ESRs for first cSCC per patient in 2017 were 107.6 per 100 000 person-years (PY) for male patients, an increase from 40.0 per 100 000 PY in 1989, and 68.7 per 100 000 PY for female patients, an increase from 13.9 per 100 000 PY in 1989, which corresponds with a US Standardized Rate of 71.4 per 100 000 PY in 2017 for men and 46.4 per 100 000 PY in 2017 for women. Considering multiple cSCCs per patient, ESRs increased by 58.4% for men (from 107.6 per 100 000 PY to 170.4 per 100 000 PY) and 34.8% for women (from 68.7 per 100 000 PY to 92.6 per 100 000 PY). Estimation of ESRs for the next decade show a further increase of 23.0% for male patients (ESR up to 132.4 per 100 000 PY [95% prediction interval, 125.8-139.0 per 100 000 PY]) and 29.4% for female patients (ESR up to 88.9 per 100 000 PY [95% prediction interval, 84.3-93.5 per 100 000 PY]). Conclusions and Relevance: This nationwide epidemiologic cohort study suggests that incidence rates of cSCC keep increasing, especially among female patients, and that the occurrence of multiple cSCCs per patient significantly adds to the current and future burden on dermatologic health care. Revision of skin cancer policies are needed to halt this increasing trend.

Assessment of Cutaneous Squamous Cell Carcinoma (cSCC) In situ Incidence and the Risk of Developing Invasive cSCC in Patients With Prior cSCC In situ vs the General Population in the Netherlands, 1989-2017.

Importance: The incidence rates of keratinocyte cancer are increasing globally; however, the incidence rates of cutaneous squamous cell carcinoma (cSCC) in situ and the risk of developing subsequent invasive cSCC remain unknown. Objective: To estimate annual population-based age-standardized incidence rates of histopathologically confirmed cSCC in situ stratified by sex, age, and body site and to assess the risk of developing invasive cSCC among patients with cSCC in situ compared with the general population. Design, Setting, and Participants: This nationwide epidemiological population-based cohort study used cancer registry data to identify all patients with a first incident of histopathologically confirmed cSCC in situ between January 1, 1989, and December 31, 2017. In addition, all patients with cSCC in situ who subsequently had a first incident of invasive cSCC were identified up to June 11, 2019. Data were analyzed between March 18 and November 12, 2019. Main Outcomes and Measures: Age-standardized incidence rates per year for cSCC in situ, standardized to the 2013 edition of the European Standard Population, were calculated by sex, age, and body site. Cumulative risks, standardized incidence ratios, and absolute excess risks were calculated to assess the risk of invasive cSCC in patients with cSCC in situ compared with the general population. Results: In this population-based cohort study of 88 754 patients with a first incident of cSCC in situ between January 1, 1989, and December 31, 2017, 58.8% were women; the median age was 75 years (interquartile range [IQR], 67-82 years) for women and 73 years (IQR, 65-80 years) for men. Increasing incidence rates were observed, with the highest incidence rates in 2017 among women in general (71.7 cases per 100 000 person-years) and among men 80 years and older (540.9 cases per 100 000 person-years). The most common body site among women was the face (15.9 cases per 100 000 person-years) and among men was the scalp and/or neck (12.3 cases per 100 000 person-years). After 5 years of follow-up, among patients with cSCC in situ, the cumulative risk of developing an invasive cSCC at any anatomic location was 11.7% (95% CI, 11.6%-11.9%) in men and 6.9% (95% CI, 6.8%-7.0%) in women (P < .001). The standardized incidence ratio was highest in the first year of follow-up among both men (16.6; 95% CI, 15.7-17.5) and women (15.1; 95% CI, 14.2-16.1). Conclusions and Relevance: This study reports the first nationwide incidence rates of cSCC in situ to date. The increasing incidence rates of cSCC in situ and the high risk of developing invasive cSCC among patients with cSCC in situ may increase the health care burden associated with precursors of keratinocyte cancer and highlight the need to include cutaneous skin cancer precursor lesions when exploring policies to address skin cancer care.