Squamous precursor lesions of the vulva: current classification and diagnostic challenges

Abstract

Growing evidence has established two major types of vulvar intraepithelial neoplasia (VIN), which correspond to two distinct oncogenic pathways to vulvar squamous cell carcinoma (VSCC). While the incidence of VSCC has remained relatively stable over the last three decades, the incidence of VIN has increased. VIN of usual type (uVIN) is human papillomavirus (HPV)-driven, affects younger women and is a multicentric disease. In contrast, VIN of differentiated type (dVIN) occurs in post-menopausal women and develops independent of HPV infection. dVIN often arises in a background of lichen sclerosus and chronic inflammatory dermatoses. Although isolated dVIN is significantly less common than uVIN, dVIN bears a greater risk for malignant transformation to VSCC and progresses over a shorter time interval. On histological examination, uVIN displays conspicuous architectural and cytological abnormalities, while the morphological features that characterise dVIN are much more subtle and raise a wide differential diagnosis. On the molecular level, dVIN is characterised by a higher number of somatic mutations, particularly in TP53. Here we review the classification, epidemiology, clinical features, histomorphology, ancillary markers and molecular genetics of both types of VIN, and discuss the morphological challenges faced by pathologists in interpreting these lesions.

Keywords: Diagnosis; pathology; precursor; squamous carcinoma in situ; squamous dysplasia; squamous intraepithelial lesion; vulva; vulvar intraepithelial neoplasia.

Fig. 1

Pathways of oncogenesis in vulvar squamous cell carcinoma. Modified from Nascimento et al.

Fig. 2

Vulvar intraepithelial neoplasia, usual type (uVIN). (A) Warty type; (B) basaloid type; (C) expansion of the rete ridges; (D) loss of nuclear organisation, hyperchromasia and mid-level mitoses; (E) VIN extending into hair follicle; (F) condyloma acuminatum or low-grade intraepithelial lesion with abundant koilocytes.

Fig. 3

Vulvar intraepithelial neoplasia, differentiated type (dVIN). (A) Partial thickness dysplasia with retention of keratohyaline granules; (B) basal atypia, nuclei with prominent nucleoli and intercellular bridges; (C) hypereosinophilia and premature keratinisation; (D) irregular branching and anastomoses of rete ridges; (E) pseudoinvasion, regular spacing of nests with rounded contours (arrows); (F) paradoxical maturation suggestive of early invasion.

Fig. 4

Vulvar intraepithelial neoplasia (VIN), immunohistochemical features. p16 with (A) diffuse strong block-like staining in VIN 3; (B) patchy staining in condyloma acuminatum; (C) negative in dVIN. p53 shows (D) weak patchy staining in normal skin, (E) increased basal staining in squamous cell hyperplasia, and (F) increased basal and parabasal staining in dVIN. Ki-67 shows (G) full thickness staining in VIN 3, and (H) increased basal and parabasal staining in dVIN. (I) normal skin shows no Ki-67 staining in the basal layer (arrows).

Fig. 5

Differential diagnosis for vulvar intraepithelial neoplasia (VIN). (A) Lichen sclerosus; (B) hypertrophic lichen sclerosus with (C) increased p53 staining; (D) squamous hyperplasia due to candida; (E) spongiotic dermatitis with rare eosinophils; (F) pseudoepitheliomatous hyperplasia due to extramammary Paget’s disease; (G) squamous hyperplasia due to melanoma in situ; (H) basaloid variant of dVIN mimicking uVIN.