Enhancing Diagnosis in Squamous Cell Carcinoma: Non-Invasive Imaging and Multimodal Approach.

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with diverse clinical presentations. This study aims to correlate findings from dermoscopy, ultrasonography, ex vivo confocal microscopy, and histology to improve diagnostic accuracy and guide better clinical management of cSCC. Methods: This cross-sectional study, conducted between July 2022 and December 2024, included 26 patients with 35 clinically suspicious cSCC tumors, analyzed through clinical, dermoscopic, high-frequency ultrasound (HFUS), ex vivo confocal fluorescence microscopy (FCM), and histopathology. Tumors were evaluated for various clinical, imaging, and histopathological criteria, such as tumor thickness, vascularization, differentiation degree, and invasion level, with FCM applied to 24 tumors for advanced microscopic analysis. Results: The study analyzed 35 cases of histopathologically confirmed cSCC, finding that invasive SCC was associated with greater tumor thickness, increased vascularization, and ulceration on both ultrasound and dermatoscopy, while in situ SCC showed homogeneous echogenicity and specific dermoscopic patterns like dotted vessels and white halos. Strong correlations were identified between ultrasound and histopathological measurements of tumor thickness and invasion depth, and confocal microscopy revealed that features like plump bright cells and nest-like structures were linked to invasive and poorly differentiated tumors. Conclusions: This study uniquely integrates advanced imaging techniques-dermatoscopy, skin ultrasound, and ex vivo confocal microscopy-with histopathological analysis to provide new insights into tumor grade, vascularity, and invasion depth in cSCC, enhancing non-invasive diagnosis.