A 60-year-old menopausal female presented with vulvar itching for one year. She had noticed a whitish lesion on the vulva that slowly increased in size over the year. She had been unsuccessfully treated with oral fluconazole and topical clotrimazole-mometasone combinations and the plaque had gradually spread to involve the clitoris and peri-urethral area. She was neither diabetic nor hypertensive and had no other systemic complaints. Examination revealed a well-defined non-tender whitish plaque situated on her left labia minora and clitoris (Figure 1). A swab from the plaque did not grow any organism. Routine blood chemistry including a VDRL and HIV ELIZA were within normal limits. A punch biopsy from the lesion was taken and histopathology findings were as seen in (Figures 2 and 3).
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| Figure 1 | Figure 2 |
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| Figure 3 | Figure 4 |
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The epidermis appeared hyperplastic and was infiltrated with large, pale-staining cells that were arranged in groups towards the basal layer and tended to lie singly higher up. The cells had abundant vacuolated cytoplasm and large vesicular nuclei, characteristic of Paget cells. As the cells were restricted within the epidermis, a final diagnosis of intra-epithelial Paget disease was made.
Our patient presented with an itchy plaque on the vulva, gradually increasing in size over one year. We considered a differential diagnosis of Paget disease, vulvar intra-epithelial neoplasia (VIN), and candidiasis. With the histological findings confirming the diagnosis of Paget disease of the vulva, a thorough search for an underlying malignancy was done. A cystoscopy, and a CT scan of the abdomen ruled out a genito-urinary and a lower gastro-intestinal tumor. The patient was counseled for a surgical excision of the tumor as recommended for the treatment of extramammary Paget disease. However, the patient refused surgery and topical 5 percent imiquimod cream on three nights of the week was recommended. A month later, although there was a marked reduction in the size of the lesion, she returned with extensive eczematization on the vulva and thighs (Figure 4). This resolved with topical fluticasone propionate cream (0.05%) applications, and she was advised to continue the imiquimod use. Clinical evaluation at the end of three months showed complete resolution of the lesion (Figure 5). A repeat biopsy from an area adjacent to the previous biopsy site showed a normal epidermis completely devoid of Paget cells (Figure 6). Repeat cystoscopy and stool for occult blood was negative. The patient has been asked to continue the imiquimod twice weekly and maintain regular, 3-month follow-up visits.
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| Figure 5 | Figure 6 |
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Paget disease of the vulva is a form of extra mammary Paget disease (EMPD) seen in women, most frequently in their 5th decade of life. It affects the vulva, peri-anal region, and occasionally the axilla [1]. It often begins de novo but may be associated with an underlying urinary or gastro-intestinal adenocarcinoma. The patients may present with well-defined areas of erythema with overlying scale, crust, and erosions, described as “red lesion with white coating (cake icing).” [2] Symptoms may include itching, irritation, burning, or bleeding. The histopathology is diagnostic with characteristic large, clear cells devoid of intercellular bridges, the Paget cells. These are seen lying in the epidermis singly or in clumps and often in the outer root sheaths of hair follicles, in eccrine and apocrine sweat ducts, and in sebaceous glands [3].
Wide local excision with a 1 to 2 cm margin is currently the recommended treatment [4]. However, a high recurrence rate of 20 percent to 60 percent has been reported. Parker et al. reported, on frozen sections, a recurrence of 33 percent in patients with tumor-free margins [5]. Even with Mohs micrographic surgery, Hendi et al. have reported recurrence rates of 16 percent in patients with primary disease and up to 50 percent in those with recurrent disease [6]. Nonsurgical treatment is used only as a palliative measure in those refusing surgery or unfit for surgery.
Zampogna et al. were the first to report the use of imquimiod in the treatment of EMPD [7]. They used it successfully for treating scrotal and crural EMPD. Imiquimod was first used for vulvar EMPD by Wang et al. in 2003 [8]. Since then there have been several reports of its use for Paget disease of the vulva [9-16].
Imiquimod is an imidazoquinolone amine that has traditionally been classified as an immune response modifier. It has been used for the treatment of genital warts, actinic keratoses, and superficial basal cell epitheliomas. The exact mechanism of action of imiquimod is unknown but it causes a strong up-regulation of Th1 cytokines at the site of application. Acting via the toll-like receptor 7, it induces mRNAs encoding for interferon-alfa, tumor necrosis factor-alpha, and interleukins 1, 6, and 8. These serve as chemo-attractants for mononuclear cells consisting predominantly of T-helper lymphocytes and natural killer cells [9]. The latter may be responsible for the anti-tumor response.
It is important to note that the best dose schedule of imiquimod is yet to be defined and that patients may respond differently to topical application. The treatment may cause eczematization and patients must be forewarned about this side effect. The use of topical corticosteroids to reduce the associated eczematization does not appear to blunt the local anti-tumor response and thus can be used in conjunction with imiquimod. Sendagorta et al. propose daily application of imiquimod for 3 weeks followed by alternate day application for another 3 weeks for primary Paget disease of the vulva; there was no sign of recurrence at 20, 22, and 26 months in the 3 cases presented [9].
Wide surgical excision in our patient would have had a disastrous cosmetic result with probable loss of function of the area. Because this is the recommended treatment modality, it was offered to the patient, but she refused. Imiquimod provided a good alternative to surgery, avoiding removal of important structures like the clitoris and peri-urethral area. Thus, imiquimod should be seriously considered as an alternative or an adjuvant to surgery in lesions extending over large areas where wide excision would be anatomically disfiguring and psychologically disabling for the patient. To the best of our knowledge, this is the first case report from India of the successful use of imiquimod in Paget disease of the vulva.
© 2010 Dermatology Online Journal