Background
Extramammary Paget disease (EMPD) is morphologically and histologically identical to mammary Paget disease (PD) of the nipple, the primary difference being the anatomic location. EMPD most commonly targets the vulva in women and the perianal region in men, but it can affect other apocrine-rich cutaneous sites as well. EMPD may arise as a primary intraepithelial adenocarcinoma (primary EMPD), or it may develop as an extension of an underlying visceral malignancy or adnexal adenocarcinoma (secondary EMPD). EMPD is not a common disorder, but it must be considered in the differential diagnosis of patients with chronic genital or perianal dermatitis.
PD of the nipple was first described by Sir James Paget in 1874. EMPD was first recognized and reported as a distinct clinical entity by Radcliffe Crocker in 1889, who described a patient with erythematous patches on his penis and scrotum.
Please see the following for more information on these associated conditions:
Pathophysiology and Etiology
The precise pathogenesis of extramammary Paget disease (EMPD) is unclear. EMPD may be primary or secondary in its etiology. Primary EMPD is thought to arise as a primary intraepithelial adenocarcinoma in most cases, while secondary EMPD represents extension of an underlying adnexal adenocarcinoma or visceral malignancy. The majority of cases of EMPD are primary.
In both forms of EMPD, the epidermis becomes infiltrated with neoplastic cells showing glandular differentiation. Tumor cells may originate from apocrine gland ducts or from keratinocytic stem cells. The proliferative neoplastic cells are Paget cells, which have abundant pale cytoplasm and large pleomorphic nuclei. The cells may be arranged singly or in small groups in early lesions, and usually spread into the contiguous epithelium of eccrine ducts and hair follicles. While the greatest concentration of tumor cells is in the lower part of the epidermis, the entire thickness of the epidermis may also be involved. Rarely, Paget cells may invade the dermis. [1]
The cause of primary EMPD is unknown, but is thought to arise as a primary intraepidermal neoplasm from the apocrine gland ducts or pluripotent keratinocyte stem cells. Toker cells have also been suggested as potential precursors. Toker cells are epithelial clear cells found in the areolar and nipple areas of the breast, vulvar region, and in other areas of the skin bearing apocrine glands. [2] The cells are thought to be a constant feature of the interface between the epidermis and the epithelium in these areas. [3] It has more recently been suggested that Toker cells may be benign precursors of Paget cells. [4, 5]
A minority of EMPD cases (range, 7-40%; but most often reported as 25%) are secondary to an underlying internal malignancy, with epidermal invasion of malignant adenocarcinoma cells. [3, 6] Urothelial and anorectal carcinomas are the most common underlying visceral malignancies. [1] The anatomic location of EMPD plays a role in predicting the risk of underlying carcinoma. For instance, genital disease is associated with carcinoma in about 4-7% of patients. [7] Perianal disease is associated with underlying colorectal carcinoma in 25-35% of cases. [7] The anatomic location of EMPD also may be indicative of the specific type of underlying malignancy. For example, EMPD found in the penoscrotal region is more likely to be associated with an underlying genitourinary malignancy, while perianal EMPD may be indicative of urogenital or gastrointestinal malignancy. [7]
Rare cases of EMPD associated with tumors arising in distant organs without direct epithelial connection to the affected epidermis have been reported. Roy et al reported EMPD in a retrorectal dermoid cyst. [8] No clear evidence supports a causal link between these distant tumors and cutaneous EMPD.
Epidemiology
Extramammary Paget disease (EMPD) is a relatively rare condition; there are only several hundred cases in the world literature. It most commonly appears in individuals aged 50-80 years, with a peak incidence at age 65 years. Women are overall more commonly affected by EMPD than men. The female-to-male ratio was 4.5:1 in one series of 55 patients and 3:1 in another series of 197 patients. [7] Of note, a nearly 1:1 male-to-female ratio of EMPD has been reported in Asian patients, although the reason for this has not yet been elucidated. [9, 10] EMPD is more frequently seen in Whites and is rarely seen in the Black population. [11] Familial occurrence has been reported in a few rare cases. [12, 13, 14] No genes have currently been implicated.
Prognosis
The prognosis for extramammary Paget disease (EMPD) is generally favorable, but it depends on early diagnosis with definitive surgical treatment. The course of EMPD may extend over a period of 10-15 years without evidence of cancer or metastases. [15] In a minority of patients, tumor cells infiltrate the dermis, adnexa, or lymph nodes. Both mortality and morbidity are increased in these patients because of the extensive surgical treatment or chemotherapy required.
Full recovery is possible in patients with purely epidermal disease and negative margins after micrographic surgery. However, the recurrence rate of EMPD is 30% even with margin control. Prognosis is also dependent on whether the EMPD is primary or secondary to an underlying malignancy. One study analyzing 196 reported cases of EMPD showed a mortality of 18% for patients without associated carcinoma and 46% for those with underlying carcinoma over the studied 20-year period. These mortalities were due to either metastatic EMPD or a metastatic associated internal malignancy. [7]
Perianal disease, dermal invasion, and two or more lymph node metastases are poor prognostic indicators. Other characteristics associated with worse survival include increased serum carcinoembryonic antigen (CEA) levels, tumor thickness over 4 mm, distant metastasis, and the presence of nodules in the primary lesion. Some patients develop recurrences more than 15 years after initial treatment, making long-term clinical follow-up ideal. [1]
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Classic histology of extramammary Paget disease (EMPD). Clusters of large cells with pale, vacuolated cytoplasm scattered throughout the epidermis.
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High power image of extramammary Paget disease (EMPD). Clusters of large cells with pale, vacuolated cytoplasm scattered throughout the epidermis.
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Classic appearance of extramammary Paget disease (EMPD). Courtesy of Kenneth E Greer, MD.
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Classic "strawberries and cream" appearance of extramammary Paget disease (EMPD). Courtesy of Kenneth E Greer, MD.
