Invasive Cutaneous Squamous Cell Carcinoma Risk Increased in Actinic Keratosis

actinic keratosis
actinic keratosis
The risk for invasive cutaneous squamous cell carcinoma (cSCC) in patients with actinic keratosis (AK) lesions is assessed.

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.

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