**3. Results**

After applying the inclusion and exclusion criteria, 94 women affected by vulvar EMPD and treated at the European Institute of Oncology, from October 1997 to May 2020, were selected for our retrospective analysis.

The mean age of patients at the time of first diagnosis was 63.3 years (range: 31–88) and the median follow-up time was 7 years + 10 months (range: 2 months–30 years + 7 months).

The main clinical and pathological characteristics of the enrolled women at first diagnosis and during follow-up are shown in Table 1.

Most of the patients (81%) were affected by intraepithelial EMPD (Type 1a) at first diagnosis. Invasive EMPD occurred in only 36% of cases, including 17 patients diagnosed at first occurrence and 17 during follow-up. The histology of the invasive EMPD patients is listed in Table 1.

Persistence or recurrence was very common, taking place in 86% of cases and, thus, often requiring multiple surgical instances (median: 2; range: 0–11). The histology of persistence/recurrence of EMPD is detailed in Table 1. Alternative treatments were applied, especially in the case of relapse, including local therapy with imiquimod (63%), photodynamic therapy (5%) and radiotherapy (12%). *Diagnostics* **2023**, *13*, 464 5 of 12

> After excluding one patient with an unknown death date, the 5 year overall survival was 90.5% (95% CI: 81.8–95.1%), as shown in Figure 1.

(95% CI: 4.8–27.8%) at 15 years, respectively (Figure 2).

sidering death as a competing event (N = 93).

**Figure 1.** Overall survival of women affected by vulvar EMPD (N = 93). **Figure 1.** Overall survival of women affected by vulvar EMPD (N = 93).

Overall, nine women developed CV localization of EMPD, with a cumulative inci‐ dence of 2.5% (95% CI: 0.5–8.0%) at 5 years, 6.5% (95% CI: 1.9–15.1%) at 10 years and 14.0%

**Figure 2.** Cumulative incidence function of cervico‐vaginal (CV) localization of vulvar EMPD, con‐


**Table 1.** Clinical and pathological characteristics of women affected by vulvar EMPD at first diagnosis and during follow-up (N = 94).


*Diagnostics* **2023**, *13*, 464 5 of 12

Overall, nine women developed CV localization of EMPD, with a cumulative incidence of 2.5% (95% CI: 0.5–8.0%) at 5 years, 6.5% (95% CI: 1.9–15.1%) at 10 years and 14.0% (95% CI: 4.8–27.8%) at 15 years, respectively (Figure 2). dence of 2.5% (95% CI: 0.5–8.0%) at 5 years, 6.5% (95% CI: 1.9–15.1%) at 10 years and 14.0% (95% CI: 4.8–27.8%) at 15 years, respectively (Figure 2).

**Figure 2.** Cumulative incidence function of cervico‐vaginal (CV) localization of vulvar EMPD, con‐ sidering death as a competing event (N = 93). **Figure 2.** Cumulative incidence function of cervico-vaginal (CV) localization of vulvar EMPD, considering death as a competing event (N = 93).

The main characteristics of women who developed CV involvement from vulvar EMPD are reported in Table 2, including histology at diagnosis and at vulvar recurrence and the timing and type of CV localization. The majority of women (6/9) showed an intraepithelial vulvar EMPD (Type 1a) at first diagnosis, but three of them developed an invasive disease (Type 1b) at recurrence. The CV localizations occurred after a median time of 133 months (range: 16–334) from the first diagnosis of vulvar EMPD. All cases except one were firstly detected by abnormal pap smear and histologically confirmed by cervical and vaginal colposcopic-guided biopsies.




Most patients (5/9) developed invasive EMPD of the cervix and/or vagina. In the case of invasive or unusual disease, magnetic resonance imaging (MRI) of the lower abdomen and total body positron emission tomography (PET) were performed to rule out pelvic node or distant metastases. Interestingly, one woman with vulvar EMPD Type 1a at the onset developed invasive cervico-vaginal involvement with node metastasis after 251 months from the initial diagnosis. CV intraepithelial EMPD occurred in only two patients, among which one later developed invasive EMPD of the urethra. Two CV localizations manifested with other associated diseases: invasive urothelial carcinoma and invasive mucinous intestinal-type adenocarcinoma with node metastasis.

Most of the women underwent hysterectomy with partial or total colpectomy based on the site of extravulvar EMPD localization. The patient with node metastases was treated with chemotherapy in association with anti-HER2 (human epidermal growth factor 2) targeted monoclonal antibodies. Instead, the patient diagnosed with cervical invasive mucinous intestinal-type adenocarcinoma refused any treatment because of comorbidities and died nine months after the diagnosis. Radiotherapy was offered to the woman who developed an unresectable and advanced form of invasive EMPD of the urethra.
