**2. Materials and Methods**

All women affected by EMPD of the vulva and attending the Preventive Gynecologic Unit of the European Institute of Oncology, Milan, Italy, from October 1997 to May 2020, were retrieved from hospital file archives and enrolled in a retrospective analysis.

The local Institutional Review Board approved the study protocol (IEO protocol number UID 2408, date of approval: 22 June 2020) and written informed consent for the use of data for scientific purposes was obtained from all subjects prior to treatment.

Patients were included if the following criteria were met: (a) age at diagnosis of 18 years or older; (b) histologic confirmation of vulvar EMPD; (c) available data regarding follow-up. Patients were excluded in the case of different histology of vulvar neoplasia.

The data regarding clinical and pathological characteristics of the patients were recorded in a dedicated database.

The histological characteristics of first diagnosis, vulvar recurrence and cervical and/or vaginal localization were retrieved from surgical and pathological reports. All histological diagnoses were conducted by dedicated gynecological pathologists working at the Pathology Division of our Institute. Vulvar EMPD was classified according to the classification of Wilkinson and Brown as either primary, if Paget cells were of cutaneous origin, or secondary, in the case of vulvar skin involvement derived from an internal noncutaneous malignancy. The primary vulvar EMPD was further classified as exclusively intraepithelial (Type 1a), associated with stromal invasion (Type 1b) and as a manifestation of a primary vulvar adenocarcinoma (Type 1c). Secondary vulvar EMPD could be associated with anal or rectal adenocarcinoma (Type 2a), urothelial carcinoma (Type 2b) and distant tumors, including hepatocellular and breast carcinomas (Type 2c) [7].

Follow-up was routinely scheduled at the dedicated Vulvar Pathology Clinic of our Institute.

Apart from primary HPV screening, a pap smear was routinely performed once a year, also in women older than 65 years. In the case of abnormal cytology, women underwent colposcopy with cervical and/or vaginal guided biopsies. When atypical glandular cells were detected, endocervical curettage, endometrial biopsy and transvaginal ultrasound were always performed to rule out the origin of abnormal cells from endocervix, endometrium, ovary or Fallopian tube. If not available, HPV testing was conducted to exclude HPV-related disease.

A dedicated database was prospectively filled at each follow-up visit.

Therapeutic approaches, including surgery and alternative treatments such as topical therapy with imiquimod, photodynamic therapy and radiotherapy, as well as the type and timing of any persistence or recurrence, invasive disease and cervico-vaginal (CV) localization of EMPD were registered.

To improve the accuracy of the survival data, telephone interviews and consultation of civil registries were allowed in the case of patients lost to follow-up.
