*3.3. Colposcopy*

Colposcopy with endocervical curettage and guided ectocervical and/or vaginal biopsies was performed in all patients diagnosed with atypical glandular cells on pap smear in order to assess the nature of the atypical cells, the extent of the disease and make the best therapeutic decision.

The colposcopic findings were heterogeneous in our CV localizations of EMPD and could sometimes be misdiagnosed as high-grade intraepithelial squamous lesions. After acetic acid wash, major abnormal colposcopic findings were revealed in all patients. However, some cases showed dense acetowhite epithelium with a sharp border, whereas other cases appeared as micropapillary lesions with ridge sign or large papillae with irregular surface and fragile vessels. Coarse punctuation was common in almost all cases of CV EMPD. The location of lesions could be inside or outside the transformation zone of the cervix and in the vaginal fornices or walls. Most of the lesions were multifocal and with a wide extension (Figure 4). *Diagnostics* **2023**, *13*, 464 8 of 12 cases appeared as micropapillary lesions with ridge sign or large papillae with irregular surface and fragile vessels. Coarse punctuation was common in almost all cases of CV EMPD. The location of lesions could be inside or outside the transformation zone of the cervix and in the vaginal fornices or walls. Most of the lesions were multifocal and with a wide extension (Figure 4).

**Figure 4.** Heterogeneous colposcopic findings in women diagnosed with CV involvement from vulvar EMPD: (**a**,**b**) Dense acetowhite epithelium with sharp borders and coarse punctuation: inside the transformation zone of the cervix and in the left vaginal fornix (**a**); in the middle third of the left vaginal wall (**b**). (**c**,**d**) Micropapillary lesions with ridge sign and coarse punctuation: outside the transformation zone of the cervix (**c**); in the upper third of the left vaginal wall (**d**). (**e**,**f**) Large papillae with an irregular surface and fragile vessels: in the left vaginal wall (**e**); in the right and left vaginal walls with a wide extension (**f**).

#### *3.4. Histopathological Diagnosis* vaginal walls with a wide extension (**f**).

As in vulvar EMPD, the diagnostic clue in CV localization is the presence of Paget cells in the epithelium or stroma. Paget cells are large cells with abundant pale cytoplasm, large vesicular nuclei and prominent nucleoli, arranged as single cells or cell clusters throughout the epithelium and/or in the stroma (Figure 5). The diagnosis is not so difficult in cases with a long history of vulvar EMPD, but it could represent a challenge in some instances. Among the differential diagnoses, it is mandatory to consider intraepithelial or invasive squamous cells carcinoma and malignant melanoma in the first instance and to take into account the involvement by an internal regional cancer (colon or urinary bladder, mainly). A diagnostic immunohistochemical panel is recommended for excluding EMPD mimics [3], comprising cytokeratin (CK)7, CK20, p63, SOX10 and carcinoembryonic antigen (CEA). EMPD is typical CK7-positive, CK20-positive or negative, p63-negative, SOX10-negative and CEA-positive unlike squamous cell carcinoma which is p63-positive and malignant melanoma which is SOX10-positive. To rule out the possibility of spread from an internal tumor, CDX-2 (negative in EMPD and positive in colon cancer) and uroplakin-III (negative in EMPD and positive in urothelial carcinoma) are helpful. *3.4. Histopathological Diagnosis* As in vulvar EMPD, the diagnostic clue in CV localization is the presence of Paget cells in the epithelium or stroma. Paget cells are large cells with abundant pale cytoplasm, large vesicular nuclei and prominent nucleoli, arranged as single cells or cell clusters throughout the epithelium and/or in the stroma (Figure 5). The diagnosis is not so difficult in cases with a long history of vulvar EMPD, but it could represent a challenge in some instances. Among the differential diagnoses, it is mandatory to consider intraepithelial or invasive squamous cells carcinoma and malignant melanoma in the first instance and to take into account the involvement by an internal regional cancer (colon or urinary blad‐ der, mainly). A diagnostic immunohistochemical panel is recommended for excluding EMPD mimics [3], comprising cytokeratin (CK)7, CK20, p63, SOX10 and carcinoembry‐ onic antigen (CEA). EMPD is typical CK7‐positive, CK20‐positive or negative, p63‐nega‐ tive, SOX10‐negative and CEA‐positive unlike squamous cell carcinoma which is p63‐ positive and malignant melanoma which is SOX10‐positive. To rule out the possibility of spread from an internal tumor, CDX‐2 (negative in EMPD and positive in colon cancer) and uroplakin‐III (negative in EMPD and positive in urothelial carcinoma) are helpful.

*Diagnostics* **2023**, *13*, 464 9 of 12

**Figure 4.** Heterogeneous colposcopic findings in women diagnosed with CV involvement from vul‐ var EMPD: (**a**,**b**) Dense acetowhite epithelium with sharp borders and coarse punctuation: inside the transformation zone of the cervix and in the left vaginal fornix (**a**); in the middle third of the left vaginal wall (**b**). (**c**,**d**) Micropapillary lesions with ridge sign and coarse punctuation: outside the transformation zone of the cervix (**c**); in the upper third of the left vaginal wall (**d**). (**e**,**f**) Large pa‐ pillae with an irregular surface and fragile vessels: in the left vaginal wall (**e**); in the right and left

**Figure 5.** Cervical EMPD: (**a**) intraepithelial and (**b**) invasive. Note the (arrow) Paget cells, with clear cytoplasm and prominent nucleoli, arranged as single cells or little clusters in the ectocervical epi‐ thelium (**a**) and as gland‐like structures in the cervical stroma (**b**). **Figure 5.** Cervical EMPD: (**a**) intraepithelial and (**b**) invasive. Note the (arrow) Paget cells, with clear cytoplasm and prominent nucleoli, arranged as single cells or little clusters in the ectocervical epithelium (**a**) and as gland-like structures in the cervical stroma (**b**).
