•EMPD demonstrates high rates of recurrence with standard excision.

•Mohs surgery has proven effective in the treatment of EMPD, and the implementation of CK7 immunostaining shows promise in further reducing the recurrence rate.

22.1Introduction

Extramammary Paget disease (EMPD) is a rare, intraepithelial adenocarcinoma that affects anatomic regions with abundant apocrine sweat glands. The disease exists most commonly in a primary form, originating in the epidermis or cutaneous adnexa. Less often, EMPD occurs in a secondary form, associated with an underlying internal malignancy, usually of the lower gastrointestinal or urinary tract. Secondary EMPD is also reported to occur in association with underlying adnexal adenocarcinoma, though it is impossible in many cases to determine if epidermal disease leads to subsequent deeper, dermal adnexal involvement or epidermal disease results from epidermotropic spread of underlying adnexal adenocarcinoma. Adnexal adenocarcinoma can also develop as a separate neoplastic process, difficult to distinguish from EMPD. It is likely that EMPD represents the clinical manifestation of a variety of neoplastic processes.

When limited to the epidermis, primary EMPD is not life-threatening, but invasive disease can occur and may portend a poor prognosis, depending on depth of invasion, the degree of dermal adnexal involvement, as well as the presence of lymphovascular invasion. Patients with primary EMPD have a better prognosis than those with secondary EMPD due to the association of the latter with internal malignancy, so it is important to perform a full evaluation to exclude coexistent malignancy. Not only do patients with secondary EMPD have a significantly higher mortality rate up to 50% that is related to underlying internal malignancy; the presence of secondary EMPD signifies a worse prognosis compared to patients without EMPD who have the same coexistent malignancy.

Recent advances in immunohistochemistry have improved our understanding of the potential etiology of EMPD and allowed for more accurate diagnosis. Immunohistochemistry has been explored as a tool to

aid in differentiating primary from secondary EMPD. The addition of CK7 staining to Mohs surgery has led to improved surgical margin control for a disease notorious for indistinct clinical margins, high rates of recurrence, and significant morbidity.

Surgical excision remains the mainstay of treatment for EMPD, and Mohs micrographic surgery is considered the treatment of choice in many cases, allowing for precise margin control with reduced recurrence rates. Alternative treatment regimens continue to be explored, including topical treatment with 5-fluoroura- cil and imiquimod, photodynamic therapy, laser vaporization, chemotherapy, and radiation therapy.

Summary: History of EMPD and Epidemiology

•EMPD is a disease of apocrine gland-bearing areas.

•EMPD most commonly affects Caucasian women ages 64–75.

•Primary and secondary EMPD are important to distinguish.

•Between 4% and 42% of patients with EMPD have or develop coexistent malignancy, though the association is not always clear. The affected age group is at higher baseline risk for malignancy, and causality is difficult to establish.

•Lower gastrointestinal and genitourinary malignancies are the most common associated underlying internal cancers.

•EMPD originating in deeper adnexal structures is sometimes present and may lead to epidermal disease by upward spread, though invasive disease originating in the epidermis secondarily affecting adnexa may be impossible to distinguish. In many cases, therefore, reportedly associated underlying adnexal adenocarcinoma may be a misnomer.

22.2History of EMPD and Epidemiology

22.2.1 History of EMPD

Paget published the first series of cases of mammary Paget disease in 1874, describing 15 women with an intraepithelial adenocarcinoma associated with

underlying breast cancer [1]. Fifteen years later, Crocker described an intraepithelial adenocarcinoma of the penis and scrotum with histopathologic features indistinguishable from Paget disease [2]. As case reports have accumulated in the medical literature, EMPD is now known to occur in areas rich in apocrine glands, including the vulvar, perianal, penoscrotal, and axillary areas, with rare involvement of the auditory canal, umbilicus, extramammary chest, thighs, tongue, eyelids, and cheek. Since Crocker’s initial report over 100 years ago, the natural history of EMPD is better understood, but much about the etiology and pathogenic mechanism of the neoplasm remains a mystery.

22.2.2 Epidemiology

EMPD is rare, with an incidence estimated to be 0.11 per 100,000 person years [3]. Of all cases of Paget disease (both mammary and extramammary), EMPD accounts for 7–14% [3]. One of the largest registries including patients with mammary and extramammary Paget disease documents EMPD patients having invasive disease 21% of the time, compared to 44% of patients with invasive mammary Paget disease [3].

The age of onset of EMPD is typically 64–75 years, with no significant difference for patients with in situ versus invasive disease. Caucasian women and Asian men are affected at disproportionately high rates. Reasons for this discrepancy are unclear. In Caucasian patients, women predominate with a ratio ranging from 1.4:1 to 3.2:1, whereas in Asian patients, men predominate 2.2:1 to 14:1 [4]. EMPD with internal malignancy is less common in Asian patients when compared to Caucasian patients [4]. It has been speculated that this is due to the lower overall prevalence in the Asian population of cancers associated with secondary EMPD, including rectal cancer and urinary tract adenocarcinoma.

22.2.3 Associated Malignancies

Of patients with EMPD, 5–42% are reported to have an additional malignancy documented either before or after development of EMPD. These range from extragenital skin cancer to distant internal malignancies. The wide range of published percentages of second

malignancy as well as the spectrum of different cancers has led to significant controversy regarding the true association between internal malignancies and EMPD. The baseline risk of cancer in the aged population typically affected by EMPD may account for many of the reported second malignancies. Nevertheless, the rate of internal malignancy is higher in patients with EMPD with a standardized incidence ratio of 1.7 [3]. The presence of EMPD should prompt a search for internal malignancy, especially of the lower gastrointestinal or genitourinary tract.

Of those patients with EMPD and a second malignancy, slightly more than half present with a second malignancy prior to their diagnosis of EMPD with a median time from diagnosis of primary malignancy until the diagnosis of EMPD ranging from 2.8 to 10.9 years. For patients diagnosed with EMPD prior to the diagnosis of a second malignancy, the median time to diagnosis of the second malignancy is 2.9–3.8 years [3]. The wide range noted in these patients further calls into question the likelihood of any true association of EMPD and a second malignancy in many cases.

In cases of EMPD with coexistent internal cancer, the location of EMPD is often correlated with site of the underlying internal malignancy. Perianal EMPD is associated with lower gastrointestinal malignancy, and penoscrotal EMPD is associated with urinary tract malignancy.

Distant internal malignancies reported in association with EMPD include breast carcinoma, ovarian carcinoma, bile duct carcinoma, hepatocellular carcinoma, renal cell carcinoma, lung carcinoma, stomach carcinoma, and pancreatic carcinoma [5, 6]. Whether a true association exists between distant primary neoplasms and EMPD or the tumors are coincidental remains to be proven. However, it is possible that there is a common yet undefined subcellular mechanism that leads to an increased incidence of diverse and distant synchronous or metachronous malignancy, a so-called oncogenic stimulus.

Though recent authors consider secondary EMPD to be a disease only related to underlying internal malignancy, some also classify EMPD related to local, deeper adnexal adenocarcinoma as secondary EMPD. Many EMPD cases labeled as secondary to underlying adnexal adenocarcinoma may actually be primary EMPD with deeper spread and subsequent adnexal involvement. It may be impossible to distinguish the initial site of malignancy as epidermal with