Invasive vulvar extramammary Paget's disease in the United States

Highlights

• Invasive vulvar EMPD is rare but demonstrates excellent cancer specific survival in localized cases.

• Rate of secondary malignancies in invasive EMPD was higher compared to matched controls (SIR 3.9; 95% CI 3.3–4.7).

• Patients with invasive vulvar EMPD had substantial risk of secondary malignancy; specifically, breast, GI, and GU tract.

Abstract

Objective

To assess the incidence, treatment, and outcomes in patients with invasive vulvar extramammary Paget's disease (EMPD) in a national cohort of patients.

Methods

Patients from the Surveillance, Epidemiology and End Results (SEER) database with diagnoses of vulvar EMPD from 1992 to 2016 were included. Demographic, treatment, and outcome data were analyzed.

Results

A total of 1268 cases of invasive EMPD were identified. Of those, 69.6% had localized disease, 12.0% regional disease, 1.3% distant disease, and 17.1% were unstaged. The annual incidence of invasive vulvar EMPD was 0.36 per 100,000 person years: rates have increased >2-fold since 1992 (1992: 0.19 per 100,000 person years to 0.50 per 100,000 person years in 2016). Most patients underwent primary surgery (n = 1034; 81.5%). Five-year cancer specific survival (CSS) was 95.5% and was associated with stage. Compared to patients with localized disease, patients with distant metastases had dramatically worse CSS (HR: 85.8 (31.8–248) p < 0.0001). Synchronous cancers (diagnosed within one calendar year of EMPD diagnosis year) were observed in 35 cases (2.8%), and 195 patients (15.4%) developed a secondary malignancy (diagnosed >one year from year of EMPD diagnosis year). The most common synchronous breast, gastrointestinal tract, melanoma and the most common secondary cancers were breast, gastrointestinal tract and genitourinary tract.

Conclusions

The incidence of invasive vulvar EMPD has increased over time. CSS is excellent for localized disease, but those with metastatic disease are in need of novel therapies. Approximately 15% will develop a secondary malignancy, indicating that patients with invasive vulvar EMPD should undergo site specific preventative health screens during recurrence surveillance.

Introduction

Extramammary Paget's disease (EMPD) is a rare neoplasm arising from apocrine glands of the epidermis. Vulvar EMPD is the most common subtype. Despite its first description in the late 1800s, its pathogenesis and incidence remain poorly understood [1]. Most patients with vulvar EMPD have benign, intraepithelial disease, but invasive disease can occur as either primary invasive EMPD or in association with an adjacent adenocarcinoma. While reported rates of invasive EMPD vary widely (8–43%) [[2], [3], [4]], these cases represent only 1–6% of vulvar cancers in the United States [5,6]. Both invasive and non-invasive EMPD are rare, and there are no national guidelines to inform management. Standard treatment for intraepithelial and invasive EMPD is surgical excision, but topical therapy, laser ablation, systemic therapy, and radiation have been described. Because most outcome studies are small, retrospective series that include both invasive and non-invasive disease, it is unclear whether different treatment strategies are needed for patients with invasive vulvar EMPD [7].

The association between invasive EMPD and synchronous or subsequent malignancies is similarly poorly described. Reported rates of malignancies associated with or following vulvar EMPD vary from 11 to 54% [[8], [9], [10]],: however few patients with invasive disease are included in most series so the true rates for invasive cases is not evident [7]. The literature on management, prognosis, and development of second primary malignancies in patients with invasive EMPD is mostly limited to small, single institution case series or reviews.

Given limited existing data, survival following EMPD has not been adequately described. Cancer specific survival is excellent in patients with intraepithelial EMPD, but it is rarely reported for patients with invasive EMPD. There are no large clinical trials to inform prognosis of EMPD, but lower cancer specific survival is hypothesized for those with invasive disease [11].

Given the rarity of invasive EMPD, we utilized a national population-based tumor registry to better define the incidence, clinical management, association with underlying malignancy, and survival characteristics of invasive vulvar EMPD in a large cohort of patients.