Background: Actinic keratosis (AK) is a common premalignant skin disorder associated with chronic ultraviolet exposure and a recognized risk of progression to cutaneous squamous cell carcinoma. Tirbanibulin 1% ointment is an effective short-course field therapy for AK, but its efficacy in hyperkeratotic lesions (Olsen grade II–III) may be limited by reduced drug penetration through a thickened stratum corneum. Keratolytic pretreatment may represent a plausible strategy to improve topical drug delivery in these more challenging lesions. Methods: This retrospective chart review included consecutive adults with Olsen grade II–III AK treated in routine clinical practice with either a bland emollient lead-in followed by tirbanibulin (Group A) or salicylic acid 30% ointment pre-treatment (Decapan, Sanitpharma; Milan, Italy) followed by tirbanibulin (Group B). No study-driven procedures or additional visits were implemented. The 14-day bland emollient lead-in used in Group A was part of the routine clinical management applied during the relevant treatment period and was not introduced or retrospectively constructed for the purposes of the present comparative analysis. Outcomes were extracted from de-identified medical records and photographic documentation obtained as part of standard care. For the purposes of analysis, post-treatment evaluations were grouped into predefined windows of 3–6 weeks (T1), 10–14 weeks (T2), and 22–30 weeks (T3), corresponding approximately to 1, 3, and 6 months after treatment initiation. The primary efficacy endpoints were the Actinic Keratosis Area and Severity Index (AKASI) and Total Lesion Count (TLC). Secondary endpoints included quality of life assessed by the Dermatology Life Quality Index (DLQI). Results: Both treatment regimens were associated with clinically meaningful improvements in AK severity. At T3, mean AKASI was significantly lower in Group B than in Group A (0.86 ± 0.38 vs. 1.35 ± 0.27; p < 0.001), corresponding to reductions from baseline of 60.6% and 36.9%, respectively. Similarly, mean TLC at T3 was significantly lower in Group B than in Group A (4.80 ± 1.5 vs. 6.35 ± 1.6; p < 0.001), corresponding to reductions from baseline of 46.7% and 27.0%, respectively. Quality-of-life outcomes also favored the sequential approach, with lower DLQI scores at T3 in Group B compared with Group A (2.9 ± 1.6 vs. 3.8 ± 1.9; p = 0.006). Both treatments were generally well tolerated. Although the incidence of local skin reactions (LSRs) was similar between groups, Group B showed lower retrospectively documented composite LSR scores and lower patient-reported discomfort (p < 0.001) and lower patient-reported discomfort (p < 0.001). Conclusions: Sequential keratolytic pretreatment followed by tirbanibulin was associated with greater reductions in disease burden and with lower severity of treatment-related local reactions in this retrospective cohort (Olsen grade II–III). This retrospective study suggests that keratolytic pretreatment may represent a useful adjunctive strategy in hyperkeratotic AK treated with tirbanibulin. Prospective randomized studies are warranted to confirm these findings and to define standardized treatment protocols.

This report describes a case of 62-year-old monozygotic twin sisters showing markedly different patterns of cutaneous aging despite identical genetics. One twin, affected by long-standing non-segmental vitiligo, exhibited features of hypertrophic photoaging, including pronounced wrinkling and dermal thickening, while the unaffected twin showed an atrophic phenotype with smoother, thinner skin. Imaging findings supported these differences. The case highlights the complex interplay between ultraviolet exposure, genetic factors such as MC1R, and non-genetic influences, suggesting that melanocytic loss and environmental factors contribute significantly to divergent skin aging outcomes.