Response to the Possibility of the Application of Topical Photodynamic Therapy Leading to Development of More Histologically Aggressive Subtypes of Basal Cell Carcinomas

The incidence of non-melanoma skin cancers (NMSCs) has been dramatically increasing, with basal cell carcinomas (BCCs) accounting for about 80% of the tumors.¹ In the last decade, huge efforts have been made to develop ‘surgery-sparing’ procedures, with the ultimate goal of obtaining tumor remission with minimal scarring and of avoiding repeated interventions.² Chemoprevention with photodynamic therapy (PDT), along with the field treatment with imiquimod or topical 5-fluorouracil (5-FU), have emerged as such alternatives. PDT involves topical application of a photosensitizer, 20% 5-aminolevulinic acid (5-ALA; DUSA Levulan Kerastick) followed by exposure to blue light 417 nm wavelength. 5-ALA is a precursor of the photosensitizer protoporphyrin IX (PpIX), with PpIX having a maximal absorption at the blue light wavelength of 417 nm in the visible light spectrum. In the presence of molecular oxygen, singlet oxygen is generated and a phototoxic reaction is produced, leading to selective cellular destruction.³

Tumor keratinocytes have a higher 5-ALA absorption rate, particularly for the lipophillic form, relative to normal healthy keratinocytes. This is due to various mechanisms including differences in the activities of the heme biosynthesis enzyme cascade, iron availability, properties of the stratum corneum, and in cell membrane permeability, expressing various transmembrane transporters to actively uptake the molecule.^{4-6, 7} Higher concentration of porphyrins are produced in rapidly proliferating cells, such as tumor cells, after 5-ALA administration.⁵ Moreover, the microtubule and spindle apparatus essential for cellular mitoses are also sensitive to destruction by ALA-PDT.⁸ With the combination of various cellular mechanism, ALA-PDT generates cellular necrosis and apoptosis. On the tissue level, ALA-PDT appears to target both the tumor, as well as its vascular supply. The benefit of topical ALA-PDT is to selectively target cancerous cells, while preserving the normal surrounding structures.

Numerous studies have proven the efficacy of ALA-PDT for the treatment of the superficial cutaneous premalignant and malignant conditions such as actinic keratoses (AKs), Bowen’s disease, and superficial BCCs.⁹ However, a recent article has noted the recurrence of BCCs with a histologically more aggressive behavior after treatment with PDT.² Some of the criticism and issues with the paper by Fiechter, et al, 2012 center on the fact that the authors present a retrospective analysis of specific referrals of recurrences and not a randomized study or even a prospective study of one entire patient population. Most importantly, the reported study compares ‘aggressive histologic recurrences’, noted as more severe histopathologic subtypes of BCC, with the rate of same after simple surgery, which they note to be 20%.² It would be interesting to instead see comparison with the rate of recurrence and the histological type of the tumors that have recurred following field treatment with imiquimod or 5-FU. In a further article by one of the author’s of Fiechter et al 2012 manuscript, Skaria comments that imiquimod may also select more aggressive tumor cells.¹⁰ However, there are no studies that examine the rate and histological subtypes of the tumors that recur after treatment with ALA-PDT versus treatment with imiquimod or 5-FU.

Some of the explanations for the observations reported by Fiechter et al 2012, could be that the more aggressive subtypes may be hidden deep within a tumor beyond reach of the ALA-PDT and that these areas were not apparent on the initial biopsy. It could also be possible that genetic mutations within tumors progress after treatment at a more rapid rate than usual, and these mutations may also confer some degree of resistance to ALA-PDT, thus resulting in more histologically aggressive tumors reported in the follow up biopsies. But, in this retrospective study there is no evidence that supports the authors’ hypothesis that ALA-PDT in fact increases the rate of mutations in tumors. Furthermore, if the authors’ hypothesis were correct, then performing ALA-PDT multiple times on patients who are at extreme risk of recurrence of NMSCs should increase the aggressiveness of tumors in these patients. This would include patients with Gorlin’s syndrome, as well as the solid organ transplant recipients. However, ALA-PDT has been repeatedly shown by many investigators to decrease the incidence of cancers in these patients, and those tumors that did develop in these patients were not of highly aggressive types.^{11, 12}

In conclusion, we would like to point out that most of the manuscripts reported in the literature show that PDT is a safe and effective method for treating AKs and superficial BCCs, with good clearance of the AKs and superficial NMSCs, and that ALA-PDT should continue to be used for treatment of AKs and superficial NMSCs.