Diagnostic Modalities and Nodal Staging in High-Risk Cutaneous Squamous Cell Carcinoma

Importance: Early detection of nodal metastases in high-risk cutaneous squamous cell carcinoma (cSCC) is crucial, yet the optimal baseline staging approach remains uncertain. Objective: To compare the diagnostic performance of physical examination, ultrasonography, and contrast-enhanced computed tomography (CT) in detecting nodal metastases at baseline staging of high-risk cSCC, both overall and stratified by patients' immune status. Design, Setting, and Participants: This was a prospective, multicenter, paired diagnostic study conducted from January 2022 to April 2025 across 13 tertiary dermato-oncology centers in Spain. The study included patients with histologically confirmed high-risk cSCC (stage T2b/T3 or T2a with additional high-risk features). Data were analyzed from July to September 2025. Main Outcomes and Measures: Sensitivity, specificity, predictive values, and area under the receiver operating characteristic curve (AUROC) of each diagnostic modality, benchmarked against histology or short-term clinical follow-up as reference standard. Results: The analysis included 155 patients (median [IQR] age, 80.3 [74.4-85.5] years; 34 [21.9%] female and 121 [78.1%] male; 64 [41.3%] immunosuppressed), of whom 12 patients (7.7%; 95% CI, 4.3%-13.4%) developed nodal metastases within 3 months after surgery. Ultrasonography results showed the highest overall sensitivity (63.6%; 95% CI, 30.8%-89.1%), followed by CT (54.5%; 95% CI, 23.4%-83.3%) and physical examination (8.3%; 95% CI, 0.2%-38.5%). Specificities were 95.6% (95% CI, 90.6%-98.4%), 95.0% (95% CI, 90.0%-98.0%), and 99.3% (95% CI, 96.2%-100%), respectively. Ultrasonography and CT demonstrated almost perfect agreement (κ = 0.87; 95% CI, 0.72-1.00), whereas concordance with physical examination was poor. Subgroup analysis by immune status revealed marked disparities in diagnostic performance. In patients with immunocompetence, both ultrasonography and CT achieved 100% sensitivity (95% CI, 54.1%-100% and 47.8%-100%, respectively) and excellent AUROC (0.98; 95% CI, 0.96-1.00 for both). In contrast, sensitivity declined markedly among patients who were immunosuppressed (20.0% [95% CI, 0.5%-71.6%] for ultrasonography and 16.7% [95% CI, 0.4%-64.1%] for CT; AUROCs, 0.57 ([95% CI, 0.37-0.77] and 0.55 [95% CI, 0.38-0.72], respectively), with metastases often emerging abruptly during follow-up despite negative baseline staging. Conclusions and Relevance: This diagnostic study found that ultrasonography and CT significantly outperformed physical examination for detecting baseline nodal metastases in high-risk cSCC and can be used interchangeably depending on clinical context and resource availability. However, their poor performance in patients with immunosuppression reveals a need for tailored recommendations in future clinical practice guidelines and emphasizes the importance of close clinical follow-up in this subgroup.