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Imiquimod

Imiquimod (Aldara™) is a prescription medication used to treat certain diseases of the skin, including skin cancer (malignant melanoma and actinic keratosis) as well as genital warts. It works by helping the immune system to respond to disease. Most other treatments rely on cutting, burning, or freezing warts, while Aldara is a patient-applied cream that doesn't affect healthy skin.

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Successful treatment of Extramammary Paget's Disease with imiquimod - Case Reports
From Journal of Drugs in Dermatology, 1/1/03 by Zheng Qian

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

(1.) Connolly SM. Mammary and extramammary Paget's disease. In: Dermatology in General Medicine (Freedberg,IM, Eisen,AZ, Wolff,K et al, eds.), 5th ed. McGraw-Hill, 1999:919-24.

(2.) Jones RE, Jr., Austin C, Ackerman AB. Extramammary Paget's disease: A critical reexamination. Am J Dermatopathol 1979; 1:101-32.

(3.) Parker LP, Parker JR, Bodurka-Bevers D et al. Paget's disease of the vulva: pathology, pattern of involvement, and prognosis. Gynecol Oncol 2000; 77:183-9.

(4.) Goldblum JR, Hart WR. Perianal Paget's disease: a histologic and immunohistochemical study of 11 cases with and without associated rectal adenocarcinoma. Am J Surg Pathol 1998; 22:170-9.

(5.) Goldblum JR, Hart WR. Vulvar Paget's disease: a clinicopathologic and immunohistochemical study of 19 cases. Am J Surg Pathol 1997; 21:1178-87.

(6.) Coldiron BM, Goldsmith BA, Robinson JK. Surgical treatment of extramammary Paget's disease. A report of six cases and a reexamination of Mohs micrographic surgery compared with conventional surgical excision. Cancer 1991; 67:933-8.

(7.) Zollo JD, Zeitouni NC. The Roswell Park Cancer Institute experience with extramammary Paget's disease. Br J Dermatol 2000; 142:59-65.

(8.) Shieh S, Dee AS, Cheney RT et al. Photodynamic therapy for the treatment of extramammary Paget's disease. Br J Dermatol 2002; 146:1000-5.

(9.) Henta T, Itoh Y, Kobayashi M et al. Photodynamic therapy for inoperable vulval Paget's disease using delta-aminolaevulinic acid: successful management of a large skin lesion. Br J Dermatol 1999; 141:347-9.

(10.) Runfola MA, Weber TK, Rodriguez-Bigas MA et al. Photodynamic therapy for residual neoplasms of the perianal skin. Dis Colon Rectum 2000; 43:499-502.

(11.) Burrows NP, Jones DH, Hudson PM et al. Treatment of extramammary Paget's disease by radiotherapy. Br J Dermatol 1995; 132:970-2.

(12.) Besa P, Rich TA, Delclos L et al. Extramammary Paget's disease of the perineal skin: role of radiotherapy. Int J Radiat Oncol Biol Phys 1992; 24:73-8.

(13.) Choi JB, Yoon ES, Yoon DK et al. Failure of carbon dioxide laser treatment in three patients with penoscrotal extramammary Paget's disease. BJU Int 2001; 88:297-8.

(14.) Becker-Wegerich PM, Fritsch C, Schulte KW et al. Carbon dioxide laser treatment of extramammary Paget's disease guided by photodynamic diagnosis. Br J Dermatol 1998; 138:169-72.

(15.) Bewley AP, Bracka A, Staughton RC et al. Extramammary Paget's disease of the scrotum: treatment with topical 5-fluorouracil and plastic surgery. Br J Dermatol 1994; 131:445-6.

(16.) Voigt H, Bassermann R, Nathrath W. Cytoreductive combination chemotherapy for regionally advanced unresectable extramammary Paget carcinoma. Cancer 1992; 70:704-8.

(17.) Watring WG, Roberts JA, Lagasse LD et al. Treatment of recurrent Paget's disease of the vulva with topical bleomycin. Cancer 1978; 41:10-1.

(18.) Reiter MJ, Testerman TL, Miller RL et al. Cytokine induction in mice by the immunomodulator imiquimod. J Leukoc Biol 1994; 55:234-40.

(19.) Savage P, Horton V, Moore J et al. A phase I clinical trial of imiquimod, an oral interferon inducer, administered daily. Br J Cancer 1996; 74:1482-6.

(20.) Wagner TL, Ahonen CL, Couture AM et al. Modulation of TH1 and TH2 cytokine production with the immune response modifiers, R-848 and imiquimod. Cell Immunol 1999; 191: 10-9.

(21.) Eedy DJ. Imiquimod: a potential role in dermatology? Br.J.Dermatol. 2002; 147: 1-6.

(22.) Stockfleth E, Meyer T, Benninghoff B et al. Successful treatment of actinic keratosis with imiquimod cream 5%: a report of six cases. Br J Dermatol 2001; 144:1050-3.

(23.) Mackenzie-Wood A, Kossard S, de Launcy J et al. Imiquimod 5% cream in the treatment of Bowen's disease. J Am Acad Dermatol 2001; 44:462-70.

(24.) Chen TM, Rosen T, Orengo I. Treatment of a large superficial basal cell carcinoma with 5% imiquimod: a case report and review of the literature. Dermatol Surg 2002; 28:344-6.

(25.) Marks R, Gebauer K, Shumack S et al. Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: results of a multicenter 6-week dose-response trial. J Am Acad Dermatol 2001; 44:807-13.

(26.) Beutner KR, Geisse JK, Helman D et al. Therapeutic response of basal cell carcinoma to the immune response modifier imiquimod 5% cream. J Am Acad Dermatol 1999; 41:1002-7.

(27.) Todd RW, Etherington IJ, Luesley DM. The effects of 5% imiquimod cream on high-grade vulval intraepithelial neoplasia. Gynecol Oncol 2002; 85:67-70.

(28.) Ahmed I, Berth-Jones J. Imiquimod: a novel treatment for lentigo maligna. Br.J.Dermatol. 2000; 143: 843-5.

(29.) Zampogna JC, Flowers FP, Roth WI et al. Treatment of primary limited cutaneous extramammary Paget's disease with topical imiquimod monotherapy: two case reports. J Am Acad Dermatol 2002; 47:S229-S235.

(30.) Spencer, J and Berman, B. Successful treatment of recurrent extramammary Paget's disease. Chicago. 3rd Combined Annual Meeting of American Society of Dermatologic Surgery and American College of Mohs Micrographic Surgery and Cutaneous Oncology. Oct 30, 2002:190.

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

COPYRIGHT 2003 Journal of Drugs in Dermatology
COPYRIGHT 2003 Gale Group

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