Imiquimod

Abstract:

Extramammary Paget's Disease (EMPD) is an uncommon neoplasm found in the genital, anorectal, or axillary area. Surgical excision is considered the standard treatment, although possible loss of tissue function and disease recurrence are seen. Other treatment modalities such as radiotherapy, topical chemotherapy, and photodynamic therapy are associated with varying degrees of effectiveness, but the search for an effective, safe treatment with minimal side effects proves to be challenging. We report a case where complete clinical and histological resolution of non-invasive EMPD of the penis was achieved with minimal adverse effects after six weeks of imiquimod (Aldara) application. As an immune system modifier that stimulates cytokine and interferon production, imiquimod may be a useful alternative or adjuvant in the treatment of EMPD.

Case Report

A 73 year-old white male was first diagnosed with intraepithelial extramammary Paget's disease (EMPD) of the scrotum in March of 1995. Extensive work-up at that time excluded any gastrointestinal or urological malignancies. The patient underwent Mohs micrographic surgery (MMS) and then aminolevulinic acid-photodynamic therapy (ALA-PDT) for the scrotal lesion; upon recurrence adjacent to the MMS site 16 months later, ALA-PDT was repeated in February of 1997; recurrence after ALA-PDT was treated with another Mohs procedure in October of 1998. This lesion has been free of disease to date. The patient also developed three other EMPD lesions on the ventral penile shaft in June of 1995, which were initially treated with ALA-PDT. One of the lesions recurred in December of 1998, and was subsequently retreated with ALA-PDT in December 1998, July 1999, and November 2000 (Fig. 1). Despite multiple treatments of ALA-PDT, repeat biopsies in May of 2001 at three different locations within the lesion showed persistent intraepithelial EMPD (Fig. 2). There was no evidence of invasive disease.

[FIGURES 1-2 OMITTED]

The patient was started on imiquimod in May of 2001 three times a week for a duration of six weeks. During the treatment, there was mild to moderate erythema, but no crusting, itching, or any discomfort. Six weeks after the last imiquimod application, repeat biopsies from three separate locations within the diseased area showed complete histological resolution (Fig. 3). The patient was seen in clinic every 2-3 months after imiquimod treatment, and photos were taken at each visit. These areas remain clinically free of disease 14 months after the treatment, without any erythema or pruritus (Fig. 4).

[FIGURES 3-4 OMITTED]

Discussion

Extramammary Paget's Disease (EMPD) is a rare cutaneous carcinoma usually affecting middle-aged to elderly white females. Clinically, EMPD appears as well-demarcated, erythematous patches or slightly raised plaques in the genital, anorectal, or axillary areas, often accompanied by pruritus. The differential diagnoses include contact dermatitis, psoriasis, tined cruris, erythrasma, lichen simplex chronicus, squamous cell carcinoma (SCC), superficial basal cell carcinoma (BCC), and mycosis fungoides (1).

Although often considered to derive from apocrine or eccrine glands, the histological origin of EMPD remains controversial. EMPD can also be associated with adenocarcinomas arising from the anogenital, the urinary tract, or from remote internal organs (1-3). In a series involving 19 patients with vulvar Paget's disease and 11 patients with perianal Paget's disease, Goldblum and Hart demonstrated that EMPD can be divided into two types based on clinico-histological features (4;5). In type I EMPD, which comprises roughly 3/4 of vulvar and 1/4 of perianal cases, the Paget's cells appear to be of epidermal origin and spread widely through the epidermis and adnexa, and may invade longitudinally into the dermis with time. In type II EMPD, which comprises 1/4 of vulvar and 3/4 of perianal cases, the Paget's cells appear to originate from an internal malignancy and spread secondarily to epidermis (3-5). They are associated with different immunological profiles. Type I is usually CK7+/GCDFP15+, while type II tends to be CK7+/GCDFP15-.

The management of EMPD can be challenging and occasionally frustrating. Several factors contribute to the disease recurrence and treatment failures. EMPD is clinically ill-defined and multicentric in nature. Long standing lesions may develop invasive disease foci if left untreated, while unrecognized type II EMPD may be inappropriately treated. Because of the high mortality associated with invasive EMPD, the initial approach should be to determine whether or not the disease is invasive, and whether the patient has any local or distant carcinomas. Invasive EMPD or type II EMPD should be managed with surgical resection and possible lymph node dissection.

In extensive type II cases, simple and radical vulvectomy or scrotectomy can be used. However, recurrence rates after surgery range from 15% to 61% (6,7); and may involve tissue loss with associated morbidity. To address these problems, several non-surgical approaches have been used with varying degrees of success, including photodynamic therapy (PDT) (7,10), radiotherapy (11,12), CO2 laser vaporization (13:14) and topical chemotherapy (15-17).

Imiquimod (Aldara) is an immunomodulator that stimulates the production of a range of cytokines including IL-1, IL-6, IL-8, and IL-12, and especially interferon IFN-a and TNF1 (8-20). It is currently FDA-approved for the treatment of genital warts, but has been used off-label to successfully treat other viral diseases such as molluscum contagiosum and common warts (21), several cutaneous premalignant and malignancies conditions such as actinic keratosis (22), Bowen's disease (23), basal cell carcinoma (24-26), vulvar intraepithelial neoplasia27, and lentigo meligna (28). Recently Zampogna et al published 2 cases of scrotal EMPD successfully treated with imiquimod for 7.5 to 16 weeks, where the patients remained clinically disease free for 12 and 4 months respectively (29); another case of recurrent scrotal EMPD was treated successfully with 8 weeks of imiquimod (30).

We report a case of non-invasive EMPD of the penis that persisted after multiple topical ALA-PDT treatments, but achieved complete clinical and histological resolution with the use of imiquimod. For non-invasive EMPD, imiquimod may provide an exciting alternative or adjuvant treatment modality. Rather than simply destroying the diseased tissue, imiquimod stimulates the host immune system to achieve its therapeutic effects (19;20). The stimulated cytokines and interferons in turn lead to activation of B and T lymphocytes, stimulation of NK cells, and macrophages, which may be responsible for the destruction of intraepithelial EMPD. The mechanism of recruitment, migration and proliferation of the immunogenic cells after imiquimod application is not yet known, but it raises the possibility that the stimulated cytokines and interferons may stimulate the immunogenic cells surrounding the application site, and possibly extend its therapeutic effects beyond the irregular histological border of the diseased tissue.

Imiquimod is generally well tolerated, without any major side effects or tissue damage. In this case, the patient has been disease free for 16 months. Given the high recurrence rate of EMPD, further follow up is needed to evaluate the long-term response. Nonetheless, given the preservation of tissue function and minimal adverse effects, even with comparable recurrence rate to other treatments, repeat treatments with imiquimod may be justified. If the findings reported here are reproducible in larger number of patients, imiquimod may prove to be a useful topical treatment for type I EMPD. In addition, it could be a useful adjunct therapy before or after surgical resection, or in combination with other non-surgical approaches for patients who are not surgical candidates.

Reference

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ADDRESS FOR CORRESPONDENCE:

Nathalie C. Zeitoun MD

Department of Dermatology, Roswell Park Cancer Institute

Elm and Carlton Streets,

Buffalo, NY 14263

Phone: 716-845-4033

Fax: 716-845-2364

E-mail: Nathalie.zeitouni@roswellpark.org

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