Risk for invasive cutaneous squamous cell carcinoma (cSCC) was increased in patients with Olsen grade III actinic keratosis (AK) lesions, according to results of a study published in JAMA Dermatology.

This study was a secondary analysis of data from a single-blinded, multicenter randomized clinical trial conducted at 4 hospitals in the Netherlands from 2014 to 2017. Patients (N=624) with 5 or more AK lesions in the head and neck region were randomly assigned in a 1:1:1:1 ratio to receive 5% fluorouracil cream (n=155), 5% imiquimod cream (n=156), 0.015% ingenol mebutate gel (n=157), or methylaminolevulinate cream with photodynamic therapy (n=156). In this analysis, long-term risk for invasive cSCC was evaluated from 2019 to 2020.

The study population comprised 89.4% men, median age 73 (range, 48-94) years, 56.6% had a history of nonmelanoma skin cancer, patients had a median of 16 (range, 5-48) lesions, and 88.1% had at least 1 Olsen grade II lesion.

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At a median follow-up of 46 (interquartile range [IQR], 39-51) months, 227 patients needed additional treatment for their AK lesions. Fewer patients who received fluorouracil required additional treatment (23.3%) compared with imiquimod (34.5%; P =.04), methylaminolevulinate (42.7%; P <.001), or ingenol mebutate (53.1%; P <.001).

Histologically confirmed invasive cSCC was found in the target area in 26 patients. These patients had been randomly assigneded to receive fluorouracil (n=4), imiquimod (n=10), methylaminolevulinate (n=6), and ingenol mebutate (n=6). The investigators found that cSCC occurred in preexisting grade II lesions (n=14), grade III lesions (n=4), a non-preexisting AK lesion (n=3), and undetermined (n=5). Overall, the 4-year risk for cSCC was 3.7% (95% CI, 2.4%-5.7%).

Stratified by treatment group, cSCC risk was lowest for the fluorouracil group (2.2%; 95% CI, 0.7%-6.6%) followed by ingenol mebutate (3.0%; 95% CI, 1.1%-7.9%), methylaminolevulinate (3.6%; 95% CI, 1.5%-8.6%), and imiquimod (5.8%; 95% CI, 2.9%-11.3%) cohorts. Stratified by receipt of additional treatment, risk was highest for patients who received additional treatment for a grade III lesion (33.5%; 95% CI, 18.2%-56.3%).

Invasive cSCC was associated with Olsen grade III lesions (hazard ratio [HR], 6.72; 95% CI, 2.94-15.34; P <.001) and receiving additional treatment (HR, 3.67; 95% CI, 1.52-8.81; P =.004).

This analysis was likely underpowered to evaluate long-term risk for invasive cSCC, the researchers noted.

The study authors concluded that long-term risk for invasive cSCC was highest among patients who required additional treatment for Olsen grade III AK lesions. They suggested that these patients should be followed-up with and evaluated for cSCC.

Disclosure: An author declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Ahmady S, Jansen MHE, Nelemans PJ, et al. Risk of Invasive Cutaneous Squamous Cell Carcinoma After Different Treatments for Actinic Keratosis: A Secondary Analysis of a Randomized Clinical Trial. JAMA Dermatol. 2022;158(6):634-640. doi:10.1001/jamadermatol.2022.1034