Photodynamic Diagnosis for Actinic Keratosis Remains Technically Promising, but Protocols Vary Widely
Actinic keratosis is usually recognized at the bedside as a rough, hyperkeratotic papule, yet the biologic story extends beyond the visible lesion. The field cancerization concept matters here: clinically normal-appearing skin around an obvious keratosis may already harbor subclinical change, and imaging methods that can map those hidden areas have real appeal in daily dermatology practice. Photodynamic diagnosis offers that possibility by exploiting the fluorescence generated after topical photosensitizer uptake, creating a contrast signal that may help clinicians define lesion burden and judge treatment effect more precisely.
Across the literature synthesized in this systematic review, enthusiasm for the technique is tempered by a striking lack of procedural uniformity. Thirty-seven studies met inclusion criteria, and the descriptive nature of the synthesis reflects how difficult it is to compare one protocol with another when the core variables shift so much from study to study. A clinician trying to interpret the evidence is immediately confronted by a practical problem: the same diagnostic concept has been built on different photosensitizers, different incubation windows, different light sources, and different imaging hardware.
Photosensitizers, Incubation Windows, and Excitation Wavelengths Do Not Follow a Single Standard
The two agents most often used were methyl aminolevulinate and aminolevulinic acid, appearing in 54% and 51% of studies, respectively. Even this basic starting point was not settled, and several studies used protocols that diverged substantially in how the photosensitizer was applied and allowed to accumulate in tissue. Incubation times ranged from 20 to 1080 minutes, while 70% of studies followed a 3-hour protocol. That range is more than a technical footnote; fluorescence intensity depends on how much protoporphyrin IX accumulates in dysplastic epithelium, so the timing of drug exposure can shape lesion conspicuity and the apparent performance of the diagnostic method.
The excitation step was more consistent, though still not fully standardized. Most studies, 89%, used light in the 400-410 nm range, a wavelength window that aligns with the absorption characteristics of the fluorophore used in conventional photodynamic workflows. In practice, that ultraviolet-blue range makes biological sense because it supports excitation of the photosensitizer and the resulting fluorescence signal, but the review makes clear that wavelength consistency alone does not solve the broader reproducibility problem. If the drug, incubation, and device setup all vary at the same time, then apparent differences in diagnostic yield can be difficult to attribute to any single variable.
Clinical-grade systems dominated the excitation and imaging workflow in 54% of studies. These platforms likely offer the best internal standardization because they are designed for controlled illumination, image capture, and procedural reproducibility. Still, nearly half of the studies used different approaches, and the field has not settled on a single operational benchmark for routine use.
Imaging Hardware and Quantification Methods Limit Cross-Study Comparison
Hardware differences were substantial. Integrated clinical systems were used in 54% of studies, while 30% relied on independent cameras. This split speaks directly to a core tension in dermatologic imaging: the tools that are easiest to deploy are not always the most standardized, yet the systems that are most standardized can be expensive and less accessible outside specialized centers. Low-cost alternatives may broaden access, but they also raise questions about calibration, sensitivity, and the reproducibility of fluorescence capture under real-world conditions.
Quantitative analysis was reported in 62% of studies, and 54% used specialized software. Those numbers suggest that many investigators attempted to move beyond simple visual assessment, but even there the methods were not aligned. Fluorescence quantification can be clinically useful when it captures relative signal intensity across lesions or treatment zones, especially in a disease driven by both visible and occult abnormal epithelium. But quantification only becomes meaningful when the acquisition conditions are consistent enough that changes in signal reflect biology rather than device noise, operator technique, or ambient setup.
One particularly thin area was procedural reporting. Patient positioning was described in only 8% of studies. In a technique that depends on optical geometry, that omission is not trivial. Camera angle, distance from the skin surface, and lesion orientation can all influence the quality of fluorescence imaging. When those details are absent, replication becomes harder and interpretation becomes less secure. The review therefore exposes a familiar problem in procedural dermatology research: a technology can look sophisticated while the practical steps needed to reproduce it remain underdescribed.
Standardization Will Matter More Than Additional Small Protocol Tweaks
The central finding is not that photodynamic diagnosis lacks value. It is that the evidence base is built on heterogeneous methods that resist clean comparison. For actinic keratosis, where clinicians are trying to identify both overt lesions and the surrounding subclinical field, any imaging method that sharpens lesion mapping could improve selection of treatment sites and assessment of response. Yet those downstream benefits depend on whether the signal is generated in a consistent way across centers and across patient encounters.
The review also makes a broader point about adoption. Clinical-grade systems can support reproducibility, but they are not the only possible route forward. Lower-cost options may be essential if the method is ever to move beyond tertiary centers and into routine outpatient dermatology, especially in settings where access to dedicated imaging platforms is limited. The tradeoff is obvious: accessibility increases when the equipment burden falls, but validation becomes more difficult when platforms diverge.
A standardized protocol would need to settle several unresolved steps at once: photosensitizer choice, incubation duration, excitation wavelength, camera system, image analysis method, and even patient positioning. Without those anchors, future studies will continue to generate fragmented evidence that is hard to pool and hard to translate into consistent bedside practice.
This review leaves the field with a clear technical agenda. Before photodynamic diagnosis of actinic keratosis can be judged against routine clinical assessment on firmer ground, investigators will need shared procedural definitions, consistent imaging workflows, and reporting standards detailed enough to make the method reproducible outside a single center.