March 2003

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Diagnosis: Extramammary Paget's Disease

Histology:

Histology reveals a prominent epidermal infiltrate composed of epithelioid cells with abundant pale cytoplasm and pleomorphic large nuclei as seen on H&E (Fig. 2). The differential diagnosis at this point includes melanoma in situ versus extramammary Paget's disease. CAM 5.2 stain is markedly positive, showing the epithelial nature of the infiltrate (Fig. 3). Melan-A stain highlights the resident melanocytes (Fig. 4), which are normal in number and do not correspond to the epithelioid cells seen on H&E. Cytokeratin 20 is positive (Fig. 5). Colloidal iron (Fig. 6) and Mucicarmine stains highlight the cytoplasmic mucin in the cellular infiltrate.

Discussion:

Extramammary Paget's disease is an intraepithelial adenocarcinoma that is clinically and Histologically (on H&E) similar to Paget's disease of the breast. However, whereas mammary Paget's disease represents epidermal extension of underlying ductal adenocarcinoma of the breast, extramammary Paget's disease most often arises as a primary cutaneous adenocarcinoma. Approximately 25% of tumors are associated with an underlying cutaneous adnexal carcinoma such as apocrine gland carcinoma, eccrine gland carcinoma, sebaceous carcinoma of the eyelid, cancer of Moll's gland of the eyelid and carcinoma of the ceruminous gland. Other reported associations include internal carcinomas of the prostate, bladder, rectum, cervix, urethra, vagina and vulva and may represent direct extension or metastasis to the epidermis due to the proximity of the lesions.

Extramammary Paget's disease (EMPD) is most often seen in areas that are rich in apocrine glands such as on the genitalia, perineum, axillae, eyelid and external auditory canal. It is uncommon. EMPD is seen in adults, usually after the fifth decade of life and is more common in women than men. Clinical findings are nonspecific and a high index of suspicion is needed for diagnosis. Patients usually present with the complaint of pruritus in apocrine gland-rich skin. Lesions range in appearance from eczematous or lichenified scaly erythematous plaques to macerated, crusted or excoriated erythematous to gray white patches or plaques that persist despite appropriate treatment. Differential diagnosis includes fungal, viral or bacterial infection, Hailey-Hailey disease, pemphigus, neurodermatitis, psoriasis, seborrheic dermatitis, lichen sclerosis et atrophicus, lichen simplex chronicus, lichen planus, necrolytic migratory Erythema, histiocytosis, mycosis fungoides, Bowen's disease, malignant melanoma and periorificial tuberculosis.

Diagnosis is a histologic one and features an intraepithelial infiltrate of epithelioid cells with abundant pale-staining cytoplasm and large nuclei; mitoses are frequently present. A mixed inflammatory infiltrate may be seen in the dermis. Immunohistochemical stains are used to differentiate these lesions from malignant melanoma and squamous cell carcinoma-in-situ. Positive staining with low molecular weight keratin (CAM 5.2), cytokeratin 7, cytokeratin 20 and carcinoembryonic antigen may help to confirm the diagnosis. The cells of extramammary Paget's disease contain sialomucin (diastase-resistant) in the cytoplasm that may be visualized with colloidal iron, mucicarmine, Alcian blue pH 2.5, PAS and aldehyde-fuschin pH 1.7.

Treatment of extramammary Paget's disease centers on surgical excision. Recurrences are common and treatment is challenging due to the multifocal nature of the tumor and the tendency to extend beyond the visible margins of disease. Excision with margin control or Moh's micrographic surgery are good options. Radiation may be an option if a patient is unable to undergo surgical treatment. Other reported treatments include topical chemotherapy, desiccation and curettage, cryosurgery, photodynamic therapy, CO2 laser and imiquimod.

Workup of the patient should include a detailed review of systems and physical examination, including a full skin examination, palpation of all lymph nodes. Laboratory testing with special attention to the region adjacent to the site of the extramammary Paget's lesion should be performed (such as colorectal examination, cystoscopy, pelvic examination with Papanicoulaou test, breast examination and colposcopy as appropriate). Due to the high rate of recurrence of these tumors, patients should be closely followed after treatment.

References:

Connolly, SM. Mammary and Extramammary Paget's Disease. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, Fitzpatrick TB, eds. Fitzpatrick's Dermatology in General Medicine. New York: McGraw-Hill, 1999; 919-924.

Lloyd J. Flanagan AM. Mammary and extramammary Paget's disease. Journal of Clinical Pathology. 53(10):742-9, 2000 Oct.

Shieh S. Dee AS. Cheney RT. Frawley NP. Zeitouni NC. Oseroff AR. Photodynamic therapy for the treatment of extramammary Paget's disease. British Journal of Dermatology. 146(6):1000-5, 2002 Jun.

Zampogna JC. Flowers FP. Roth WI. Hassenein AM. Treatment of primary cutaneous extramammary Paget's disease with topical imiquimod monotherapy: two case reports. Journal of the American Academy of Dermatology. 47(4 Suppl):S229-35, 2002 Oct.

Zollo JD. Zeitouni NC. The Roswell Park Cancer Institute experience with extramammary Paget's disease. British Journal of Dermatology. 142(1):59-65, 2000 Jan.

My thanks to Dr. Natalie Semchyshyn, Dr. M. Hurt and Dr. D. Santa Cruz for their assistance in the preparation of this case.