Advances in the application of photodynamic diagnosis in Skin Tumors

• Core Value and Unique Advantages of PDD • High Sensitivity and Specificity: PDD can detect target molecules at extremely low concentrations. It demonstrates a diagnostic specificity of 95.77% and sensitivity of 92.74% for cutaneous squamous cell carcinoma (cSCC), enabling precise differentiation between tumor and normal tissue. • Real-Time Visualization: It provides intuitive fluorescence images, allowing for real-time display of tumor borders and identification of multifocal and subclinical lesions difficult to detect with the naked eye. This is particularly applicable to conditions like Bowen's disease and actinic keratosis. • Theranostic Integration: PDD shares the same photosensitizer (e.g., 5-ALA) with photodynamic therapy (PDT), enabling a combined diagnostic-therapeutic strategy. • Non-Invasiveness and Repeatability: It eliminates the need for surgical biopsy, significantly reducing patient trauma and discomfort. This makes it suitable for pediatric and elderly patients, as well as areas with high cosmetic concerns, and allows for repeated use in follow-up monitoring. • Importance of PDD in the Preoperative, Intraoperative, and Postoperative Management of Skin Tumors, Supported by Literature Data and Research • Preoperative Planning: PDD clearly delineates tumor margins and identifies subclinical lesions. For cutaneous squamous cell carcinoma (cSCC), preoperative PDD guidance can achieve a histologically negative surgical margin rate as high as 98.6% (compared to only 69.2% in the control group). For extramammary Paget disease (EMPD), combining PDD with reflectance confocal microscopy (RCM) significantly improves the accuracy of margin assessment. • Intraoperative Guidance: PDD provides real-time guidance for determining excision boundaries during Mohs micrographic surgery. For basal cell carcinoma (BCC), the fluorescence border outlined by PDD shows a 70% concordance rate with the final histologic margin, aiding in reducing the number of surgical stages and preserving healthy tissue. • Postoperative Evaluation and Follow-up: It enables non-invasive assessment of treatment response (e.g., post-PDT), monitoring for residual disease, or detecting early recurrence. For instance, in Bowen's disease, areas where fluorescence completely disappears show a strong correlation with pathological complete remission. • Current Limitations • False-Positive Interference: Inflammatory cells, due to their high metabolic activity, can also accumulate the photosensitizer, leading to nonspecific fluorescence. • Limited Depth of Penetration: Conventional photosensitizers are water-soluble at physiological pH, exhibiting poor permeability and targeting ability. Furthermore, the commonly used blue excitation light has a penetration depth of only a few hundred micrometers, limiting diagnostic efficacy for nodular, infiltrative, and other deep-seated tumors. • Interference from Nonspecific Fluorescence: Autofluorescence from tumor tissue itself can hinder diagnosis. On the other hand, inflammatory cell infiltrates in some non-neoplastic tissues may also accumulate protoporphyrin IX (PpIX) due to heightened cellular metabolism, producing nonspecific fluorescence. • Stability and Toxicity of Fluorescent Markers: Some fluorescent markers are susceptible to photobleaching and degradation under unsuitable conditions (e.g., excessive light, temperature variations), leading to diminished fluorescence signals and compromised sensitivity and accuracy. Additionally, certain markers may possess inherent toxicity. • Influence of Tumor Cell Characteristics on PpIX Accumulation: One study indicates that cells with high PpIX accumulation are often in a dormant state, where metabolic suppression may reduce PpIX consumption. • Future Prospects and Innovative Directions • Development of Novel Fluorescent Markers: Third-generation photosensitizers (e.g., utilizing nanocarrier delivery systems) leverage the enhanced permeability and retention (EPR) effect to improve targeting specificity and tissue penetration depth. Developing probes with organelle-targeting functions (e.g., mitochondria-targeting) enables real-time monitoring at the microscopic level. • Integration of Multimodal Imaging Technologies: Combining PDD with other imaging modalities such as optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) allows for the simultaneous acquisition of metabolic-functional, cellular-morphological, and three-dimensional structural information, facilitating multidimensional precision diagnosis. • Integration of Artificial Intelligence with Fluorescence Detection Technology: Applying AI algorithms to analyze fluorescence images enables real-time automated identification and localization of tumor nodules, improves the sensitivity and accuracy of detecting micro-metastases, and assists in constructing predictive models for personalized treatment strategies. Photodynamic Diagnosis (PDD) is a non-invasive imaging technique. It relies on a photosensitizer that, when activated by a specific light source, causes metabolically active tissues like tumors to emit visible red fluorescence. PDD offers high sensitivity, high specificity, and real-time visualization. This article reviews advances in the use of PDD for common cutaneous tumors, including Keratinocyte Carcinoma and extramammary Paget disease (EMPD). In managing skin tumors, PDD can be used during preoperative, intraoperative, and postoperative stages. This helps optimize diagnosis and treatment. Preoperatively, PDD clearly delineates tumor margins and identifies subclinical lesions. It aids in planning surgical or photodynamic therapy—especially for multifocal or ill-defined lesions, such as Bowen’s disease and actinic keratosis. Intraoperatively, PDD guides surgeons in determining excision boundaries in real-time. This increases the rate of negative margins (for example, up to 98.6% in cutaneous squamous cell carcinoma surgery) while reducing the number of surgical stages and tissue damage. Postoperatively, PDD can evaluate treatment response, monitor for residual disease, or detect early recurrence. This enables non-invasive, repeatable follow-up. Limitations of PDD include false positives due to inflammation, interference from nonspecific fluorescence, limited depth of fluorescence penetration, and variability in tumor tissue. Looking forward, new technologies such as nanotechnology, artificial intelligence, and multimodal imaging may broaden the use of fluorescence detection in dermatology.