Before OR After: Is There a Connection Between the Use of Adjunctive Nonmelanoma Skin Cancer Treatments and Subsequent Invasive Tumors?

Basal cell carcinomas (BCCs) account for 80% of nonmelanoma skin cancers (NMSC) in the United States.¹ Although surgical excision remains the treatment gold standard, less invasive modalities are increasingly being employed. ² Imiquimod, fluorouracil cream, and photodynamic therapy (PDT) are 3 such treatments that are widely used. Recently, reports emerged implicating each of these modalities in causing more aggressive recurrent subtypes of BCCs.^2-4 Yet an alternative plausible explanation relates to the concept that the BCCs were “lying beneath.”⁵ Here we review the mechanism and indications for PDT, imiquimod, and topical fluorouracil, discuss the recent literature implicating these agents in causing aggressive BCCs, and elaborate on the concept that the BCCs were “lying beneath.”

PDT consists of application of a photosensitizing agent followed by its photoactivation by light. This process generates singlet oxygen within biologic tissues, which induces cellular destruction. ⁶ There are 2 different photosensitizers: 5-aminolevulinic acid (ALA) and methyl aminolevulinate (MAL). ALA is approved by the U.S. Federal Drug Administration (FDA), Canada, Korea, and several Latin American countries for minimally to moderately thick actinic keratoses (AKs) of the face or scalp. MAL is approved for the treatment of AKs and BCCs in over 30 countries and is a recognized treatment option for Bowen’s disease in 22 European countries.

The application of either photosensitizer leads to conversion by the neoplastic tissue to photoactive porphyrins, which upon exposure to a light source causes direct cytotoxicity. A 417 nm blue light is used for ALA and a 635 nm red light is used for MAL.⁷ PDT does have the ability to cause selective tumor destruction— in addition to confining drug application to the area of the tumor, there is inherent difference in the permeability barrier and accumulation of porphyrins in the neoplastic cells and normal skin.⁶ PDT has been shown to be efficacious in the treatment of AKs, Bowen’s disease, superficial BCC, and nodular BCC.⁷ Sustained clearance at 12 months ranges from 50.7%⁸ to 72.8%.⁹ However, Fiechter et al² retrospectively identified 12 patients with 16 post-PDT recurrent BCCs and compared the histologic features pre-PDT and post-PDT. The authors found that 62.5% of recurrent BCCs transitioned from a non-aggressive to aggressive subtype. From this data, they concluded that PDT may favor selection of more aggressive tumor cells.

Imiquimod 5%, an imidazoquinolone, is an immunostimulating agent that binds to toll-like receptor (TLR)-7 and TLR-8, activating nuclear factor-κB and inducing proinflammatory cytokines resulting in a T helper type 1 (TH1) immune response.¹⁰ Imiquimod is FDA-approved for the treatment of AKs, external genital warts, and non-head or neck superficial BCCs.⁹ Sustained clearance at 12 months ranges from 83.4%⁹ to 92%.¹¹ Skaria reviewed his patients treated with Mohs surgery since 2012 and identified 8 who had previously been treated with imiquimod therapy.⁴ Although only 5 had been biopsied before imiquimod, he noted that 7 out of 8 of the patients had increase in the “aggressivity in their tumor”. Similar to Fiechter et al,² this author raised concerns that imiquimod may select more aggressive tumor cells.

Fluorouracil is a structural analog of thymine and irreversibly inhibits the enzyme thymidylate synthase, arresting protein synthesis and ultimately leading to cell death. Although fluorouracil does not specifically target tumor cells, the effects are more pronounced in rapidly proliferating cells.¹⁰ There are 4 strengths of topical fluorouracil: Efudex® (5% and 2%