Extramammary Paget's disease (EMPD) is an uncommon clinical condition. However, cases of EMPD increasingly have been reported in recent years because of advancements in diagnostic technique and increased awareness of the disease. There are 3 patterns of EMPD: (1) cutaneous in situ epithelial with no associated underlying cancer; (2) epithelial with an associated underlying adnexal cancer; and (3) disease associated with underlying organ involvement (ie, genitourinary, gastrointestinal, or another distant site). Treatment of EMPD is problematic because the disease is associated with a high rate of recurrence. Preliminary results with topical imiquimod monotherapy demonstrate that this treatment may serve as a potential nonsurgical cure for the disease. We report a case of a patient who failed to respond to surgery or imiquimod monotherapy but who responded to imiquimod combination therapy with 5-fluorouracil (5-FU) and retinoic acid.
Case Report
A 68-year-old Chinese man presented with a pruritic rash in the scrotal area of 7 years' duration (Figure 1). Results of a skin biopsy revealed diffuse clusters of malignant pagetoid intraepidermal epithelial proliferation that stained positive with colloidal iron, mucicarmine, and periodic acid-Schiff with diastase (Figure 2). The results were diagnostic for EMPD. Results of detailed clinical and laboratory examinations showed no evidence of malignancy in other sites.
The patient underwent a large surgical excision with skin flap repair. One year later, he complained of an itchy rash within the surgical scar. Results of a repeat biopsy confirmed EMPD. The patient refused further surgery. As an alternative treatment, imiquimod 5% cream was applied nightly (Monday through Friday) for 6 weeks; because of moderate irritation, the application was decreased to every other day for the next 4 weeks. In general, the patient tolerated the treatment well and only reported erythema, burning, and some tenderness in the affected area. At the end of the 10-week treatment, histologic evaluation results revealed residual epidermal EMPD. The patient was then treated with imiquimod, 5-FU, and retinoic acid combination chemotherapy. The protocol involved applying 5-FU 5% cream every morning, retinoic acid 0.1% gel every afternoon, and imiquimod every evening. After 12 days, the patient complained of severe burning and pain in the affected area, and results of an examination showed severe erosive erythema (Figure 3). At that point, topical chemotherapy was discontinued. Zinc oxide 2% and polysporin ointment were applied alternatively 4 times daily for 2 weeks.
In the third week after the topical chemotherapy, results of multiple punch biopsies on several sites revealed no residual malignancy. The patient remained asymptomatic, and the results of a repeat biopsy revealed no residual microscopic malignancy at the 2-year follow-up visit.
Comment EMPD is a multifocal epidermal malignancy that possibly is related to the proliferation of pleuripotential epithelial stem cells. EMPD follows an unpredictable clinical course, ranging from indolent skin disease to aggressive malignancy. In general, EMPD appears in individuals aged 50 to 80 years, particularly in those who are white. Typical anatomic sites involve the vulvar, perianal, perineal, scrotal, and penile regions. Less common sites include the thighs, buttocks, axilla, eyelids, and external ear canal. The lesions of EMPD present as well-defined erythematous plaques that usually are accompanied by pruritus. The main differential diagnoses of EMPD include psoriasis, contact dermatitis, fungal infection, lichen sclerosis, atopic dermatitis, Bowen's disease, melanoma, histiocytosis, pagetoid basal cell carcinoma, and mycosis fungoides. The nonspecific presentation of EMPD often leads to a misdiagnosis, and an average of one year may pass before a biopsy is performed and a definitive diagnosis is made. Microscopically, the margins of EMPD are multicentric and vague, with skip areas that frequently extend beyond the clinically detectable lesion, which results in the high rate of recurrence of EMPD. In addition, there is a lack of clinical experience with cutaneous EMPD because the disease has a relatively rare occurrence. Case reports constitute the majority of literature on EMPD. The successful management of EMPD is compromised by the multifocal nature of the disease; recurrence of lesions after conventional surgical management is high, ranging from 44% to 75%. Even with Mohs micrographic surgery, the lesions have a reported recurrence rate of 27%.1-2 Imiquimod is an immodulator that stimulates the production of a wide range of cytokines, including interleukins 1, 6, 8, and 12; interferon; and tumor necrosis factor. Imiquimod activates B-cell responses by increasing the expression of class II major histocompatibility complex markers, which increase immunoglobulin production. Imiquimod also may enhance Langerhans cell migration from the skin to the lymph nodes, thus improving antigen presentation.3 An in vitro study has demonstrated that imiquimod inhibits tumor-associated angiogenesis and diminishes tumor burden in transplantable murine carcinoma.4 Results of a biopsy specimen from one melanoma patient also showed apoptosis after treatment with topical imiquimod cream and systemic dacarbazine.5 We identified 5 cases (in 4 reports) in which the effect of topical imiquimod monotherapy applied to the perianal/genital area of patients with EMPD was evaluated.6-9 All 5 cases showed a clinical and histologic cure, with minimal functional disturbance. In the study with the longest follow-up period, the patient remained disease free at the 14-month follow-up visit.7 In the study with the most frequent dosing interval, the medication was applied once daily.9 Treatment duration ranged from 6 to 16 weeks (Table).6-9