Extramammary Paget's Disease Resistant to Surgery and Imiquimod Monotherapy But Responsive to Imiquimod Combination Topical Chemotherapy With 5-Fluorouracil and Retinoic Acid: A Case Report

5-FU has selective toxicity in premalignant and malignant epithelial lesions. 5-FU is a chemotherapeutic drug that induces notable regression in advanced locally progressing EMPD.10,11 The mechanisms of action of 5-FU are based on the drug's steric similarity to uracil and its irreversible binding to thymidylate synthetase, which prevents the synthesis of thymidine from uridine. Consequently, RNA and DNA synthesis are inhibited, faulty RNA is produced, and cell toxicity ensues. Paget's cells have a high metabolic activity that requires abundant RNA. This high demand for RNA synthesis may be responsible for the sensitivity of Paget's cells to 5-FU. Six cases (in 6 reports) published in the English literature evaluated the effect of 5-FU monotherapy in the treatment of EMPD.11-16 Four reports showed clinical cure after treatment with 5-FU.12-14,16 In 2 of the reports, microscopic evidence of disease persisted after treatment12-13; in one report, no follow-up biopsy was performed14; in another report, no microscopic evidence of disease after treatment was identified.16 In the case report by Del Castillo et al,16 the patient applied topical 5-FU 5% intermittently (at the patient's discretion) to the affected axilla region for one year. The surgical removal of the lesion after one year of intermittent treatment showed no evidence of EMPD. In the case reports by Bewley et al11 and Eliezri et al,15 application of 5-FU 5% increased the disease margins. In summary, these reports demonstrate that topical 5-FU cannot be considered a safe and effective first-line choice of treatment due to its erosive feature and false impression of total clinical resolution. Retinoic acid has antiproliferative activity and induces apoptosis by its selective binding activity to the γ receptor in the nuclear receptor–independent pathway in neoplastic cells.17-18 We identified no published reports of topical retinoic acid for the treatment of EMPD. The most common use of retinoid antitumor agents is in the treatment of leukemia. In our case report, the tumor recurred after initial surgery and remained after 10 weeks of monotherapy with imiquimod. The reason imiquimod therapy failed in this case may relate to the presence of the tumor in the area of scar tissue; imiquimod by itself could not achieve adequate tissue penetration to induce the appropriate immune response. Consequently, we applied 5-FU cream in the morning to induce a selective toxicity in the Paget's cell, and retinoic acid gel in the afternoon to promote an antiproliferative apoptosis and to facilitate the penetration of imiquimod, which was applied in the evening. This combination therapy could potentiate a stronger stimulation of cytokines and interferon, which would then lead to the activation of T and B cells, natural killer cells, and a macrophage host response, all of which could be responsible for the destruction of the intraepithelial EMPD. In conclusion, we have demonstrated that a combination treatment of topical imiquimod, 5-FU, and retinoic acid may serve as an effective treatment option for patients who have failed imiquimod monotherapy. Acknowledgments—The authors would like to thank their colleagues John O'Dea, MD; Tony Chin, MD; Robert Uyeda, MD; and Simon Chan, MD, for reviewing and critiquing this manuscript. The authors also would like to thank Irma Marques for editing the manuscript.