AKs are dysplastic proliferations of keratinocytes with the potential to progress to cSCC [2]. To standardize clinical evaluation, Olsen et al. proposed a grading system based on lesion thickness: grade 1 AKs are slightly palpable, grade 2 are moderately thick, and grade 3 are thick and hyperkeratotic lesions [3]. This clinical classification is widely employed in randomized clinical trials (RCTs) to define eligibility criteria. Most studies enroll patients with Olsen grade 1 or 2 lesions, excluding hyperkeratotic lesions (Olsen grade 3). As a result, this grading scheme plays a significant role in shaping the indications for which AK therapies ultimately receive regulatory approval.

Histologically, AKs are classified according to the vertical extent of keratinocyte atypia within the epidermis, ranging from involvement of the lower third (grade I) to full-thickness atypia (grade III), the latter overlapping with cSCC in situ [5].

However, recent evidence has shown that the Olsen clinical classification does not accurately match the histological classification of the same lesions [6]. These findings underscore the importance of treating all AKs, regardless of their clinical grade, as histopathological severity cannot be reliably inferred from clinical presentation alone [6].

Despite this, currently approved AK therapies are not indicated for hyperkeratotic lesions (Olsen grade 3), as the thickened keratin layer may hinder adequate drug penetration. Another concern is the historical association between Olsen grade 3 lesions and histologically more aggressive, pre-invasive forms of AK. These assumptions should be re-evaluated in light of the previously discussed evidence [6].

A wide range of therapeutic options are available for the treatment of AKs, with different clearance rates, scheduling applications, and tolerability profiles. AK treatments include “lesion-directed” approaches for isolated AKs, and “field-directed” therapies aimed at addressing subclinical lesions within the photodamaged area [1]. The concept of field cancerization, namely an area of photodamaged skin with subclinical dysplasia, has gained importance, as the visible number of AKs poorly reflects the underlying burden of dysplastic keratinocytes. This underscores the need for field-directed treatment in patients with multiple lesions in the context of photodamaged skin [7, 8].

Isolated lesions are commonly treated with cryotherapy or carbon dioxide laser, whereas field-directed therapies include topical agents such as 5-FU 4% cream, imiquimod (IMI) cream, diclofenac 3% gel, 5-FU/salicylic acid (5-FU/SA), tirbanibulin 1% ointment, or PDT [9]. Treatment selection depends on multiple factors, including the number, size, clinical grade, and location of the lesions, as well as patient adherence and comorbidities.

In clinical practice, combination strategies are often employed, particularly in the management of hyperkeratotic (Olsen grade 3) AKs, to enhance therapeutic outcomes [1]. Since hyperkeratosis may impair topical drug penetration, pretreatment strategies such as lesion debulking, ablative procedures (e.g., laser ablation), or keratolytic agents (e.g., urea or salicylic acid) are commonly recommended [1].

Since its approval in 1962, 5-FU has been a cornerstone of topical AK therapy, used in both lesion-directed and field-directed treatment approaches. 5-FU is a pyrimidine analogue that irreversibly inhibits thymidylate synthase, thereby disrupting DNA synthesis and inducing apoptosis in the highly proliferative AK keratinocytes [4]. Furthermore, it triggers the release of cellular antigens, thus amplifying the immune response and inflammation. This inflammatory reaction promotes necrosis and contributes to AK clearance [9, 10].

Topical 5-FU is available in various formulations, with concentrations ranging from 0.5% to 5%. The 5-FU 4% cream (Tolak®/Tolerak®; Pierre Fabre) is approved for the treatment of non-hyperkeratotic, non-hypertrophic AKs (Olsen grade I and II) on the face, ears, and scalp in adults [4]. Compared to 5-FU 5% cream, the newer formulation of 5-FU 4% cream has been proven to improve patient compliance and clinical outcome. The application of 5-FU 4% cream once daily reached comparable rates of CC (54.4% vs. 57.9%) and PC of AK lesions (80.5% vs. 80.2%) compared to the traditional 5-FU 5% cream treatment applied twice a day [4].

Both RCTs and real-world studies confirm the high efficacy of 5-FU 4% cream in non-hyperkeratotic AKs, often outperforming other topical agents in sustained long-term clearance [11, 12]. Nevertheless, its effectiveness in treating hyperkeratotic AKs has not been previously investigated in real-life studies. In our cohort, 5-FU 4% cream demonstrated meaningful clinical efficacy, with CC achieved in 54.5% and PC in 24.2% of treated lesions.

Notably, in our study, response rates varied significantly by anatomical site, with facial lesions showing better outcomes (74% of CC) compared to scalp lesions (29% of CC) (p < 0.001). These findings suggest that anatomical factors—such as skin thickness, follicular density, or local immune microenvironment—may influence therapeutic outcomes.

To the best of our knowledge, few studies have explored field-directed therapies specifically for the treatment of hyperkeratotic AKs. A retrospective study on 51 hyperkeratotic AKs in the context of field cancerization reported a complete response rate of 54.9% and a partial response rate of 25.5% following treatment with tirbanibulin 1% ointment for 5 consecutive days [13]. These results are consistent with our findings.

A prospective study by Zhu et al. on Olsen grade 3 AKs treated with four sessions of ALA-PDT reported high initial and sustained complete response rates (87.9% and 89.7% at 3 and 12 months, respectively), albeit previous pretreating each lesion with curettage [14]. Furthermore, a phase II RCT comparing once-daily topical 5-FU/SA to cryosurgery for hyperkeratotic AKs reported superior histological clearance (62.1% vs. 41.9%) and lower 6-month recurrence rates (39.4% vs. 84.8%) in the 5-FU/SA arm [15]. These data may suggest that combining keratolytic agents or employing pretreatment techniques, such as curettage, enhances drug penetration and, finally, efficacy. This approach was not incorporated into our protocol, as we aimed to directly evaluate the efficacy of 5-FU 4% cream without the potential confounding effects of pretreatment or curettage. Nonetheless, we observed a clinically meaningful CC and PC rate of 54.5% and 24.2%, respectively.

All patients in our study developed at least one LSR, with erythema and stinging being the most frequently recorded. The LSR profile observed in our cohort aligns with findings from clinical trials and real-world studies, which consistently identify erythema and stinging as the most frequent reactions, occurring in more than 85–95% of patients. The predominantly mild-to-moderate severity and absence of treatment discontinuation in our patients are consistent with the established safety and tolerability profile of 5-FU 4% cream [4, 16].

In our study, the onset of LSRs, particularly erythema, correlated positively with AK clearance. This is in line with the known pharmacodynamic mechanism of 5-FU, which exerts its antineoplastic effects partly through cytotoxicity-induced inflammation [9, 10].

It is also consistent with previous real-life studies highlighting that inflammatory reactions often precede optimal field clearance, although such effects must be balanced with patient comfort and compliance. Heppt et al. correlated the severity of LSRs during treatment with 5% 5-FU for AKs with higher lesion clearance rates. In particular, erythema was associated with greater efficacy, suggesting it may serve as an early predictor of treatment response [16].

Moreover, Stockfleth et al. demonstrated that the severity of LSRs correlated with the number of AKs, with patients presenting more than 10 AKs experiencing more intense LSRs [17]. However, daily emollient applications during the 4-week treatment course did not impact the safety and efficacy profile of 5-FU 4% cream [18].

Our study has limitations. The absence of a control group prevents direct comparison with other treatment modalities, The small sample size limits statistical power, and the 12-week follow-up does not allow assessment of long-term efficacy or recurrence. Lastly, the lack of histopathological confirmation of lesion clearance represents a methodological limitation, as clinical and dermoscopic evaluations may overestimate the treatment success rate. Future studies should address these limitations through larger randomized controlled trials with extended follow-up and histopathologic validation to comprehensively assess the durability of 5-FU 4% cream in hyperkeratotic AKs.