High‐Grade Squamous Intraepithelial Lesions

High‐Grade Squamous Intraepithelial Lesions

Fabrizio Bogliatto and Fiona M. Lewis

It is now well recognised that there are two pathways to the development of vulval cancer: HPV‐associated pre‐invasive lesions or HPV‐independent changes developing on a background of a chronic inflammatory dermatosis, most commonly lichen sclerosus [1]. The most common precursors of vulval cancer are the oncogenic HPV‐driven intraepithelial lesions. There have been several changes in terminology (see below), but the most recent classification of the International Society for the Study of Vulvovaginal Disease using the LAST (Lower Anogenital Squamous Terminology) project uses the terms low‐grade (LSIL) and high‐grade (HSIL) squamous intraepithelial lesions. There are inconsistencies with this, as the low‐grade lesions are simple condylomata without any significant neoplastic risk, yet these are still included. These are discussed in Chapter 16 and the differentiated type of vulval intraepithelial neoplasia in Chapter 41. For clarity, we will use the term HSIL in this discussion, which replaces the usual or undifferentiated type vulval intraepithelial neoplasia that was in the previous classification.


In 1986, a modified nomenclature for the uniform classification of ‘vulval intraepithelial neoplasia’ (VIN), to be intended as a single diagnostic category, was proposed [2].

This classification graded vulval atypia in a manner similar to that commonly used for intraepithelial neoplasia of the cervix and included all the pre‐cancerous lesions of the vulva, squamous and non‐squamous. VIN was thus classified as follows:

  1. Squamous (including HPV change)

    • VIN 1 (showing mild atypia)
    • VIN 2 (moderate atypia)
    • VIN 3 (severe atypia, Carcinoma in situ)

  2. Non‐squamous

    • Paget’s disease
    • Melanoma in situ

This simplification permits a clear identification of the lesions at risk for invasive cancer, but includes different clinical entities in the same categories which are markedly different in biology and oncological potential. The grading of VIN 1, 2, and 3 was not helpful as it showed considerable inter and intra‐observer variation, particularly with VIN1, where there are frequently similar features to those seen with inflammatory dermatoses, particularly lichen planus [3].

The recognition of two pathways to vulval cancer, one HPV related and the other non‐HPV related but linked to chronic inflammatory dermatoses, has led to the definition of two different types of precursor squamous lesions, related and unrelated to HPV, respectively.

The recent VIN terminology has therefore been modified including the LAST [4] but keeping in mind that not all vulvar intraepithelial lesions are caused by HPV.

This terminology for vulval intraepithelial lesions [5] is shown in Table 40.1.

According to this terminology, VIN graded as VIN1, VIN2, and VIN3, using the same criteria used to grade cervical intraepithelial neoplasia, is abandoned [6]. There are still some challenges with this classification, and it is important to remember that LSILs do not have malignant potential [7].


The incidence of HSIL is estimated at 5/100 000 women per year [8], but with the use of the HPV vaccine this is likely to fall. In those who are HPV naïve, there is a 94.9% reduction in vulval intraepithelial lesions and a 75.6% effect in those who have been previously exposed [9]. Interestingly, the incidence of pre‐invasive disease has increased over time, but the rate of invasive squamous cell carcinoma (SCC) has remained stable [10]. In a large study of over 13 000 women, the rate of HSIL increased by 411% between the years 1973 and 2000, whereas invasive vulval cancer increased only by 20% [11]. HSIL most commonly affects those between the ages of 30 and 40.

Table 40.1 2015 Terminology for squamous epithelial lesions.

Classification Abbreviation Previous terminology
Low‐grade squamous intraepithelial lesions LSIL Flat condyloma or HPV effect
High‐grade squamous intraepithelial lesions HSIL VIN usual or undifferentiated type
Differentiated type VIN dVIN Differentiated VIN

Molecular genetics

The molecular genetics of vulval precursor lesions and invasive malignancy is an emerging field. Gains in chromosome 3q are a common feature in vulval SCC [12], and gains in 3q26 were found in 50% of HSIL cases [13].


The identification of two histological subtypes of VIN, one high‐risk HPV related and the other independent of HPV infection but usually found in a background of a dermatosis such as lichen sclerosus, has permitted a better understanding of the pathophysiology of squamous precursor lesions.

Most HSIL is related to infections with the oncogenic HPV types 16, 18, and 33. HPV16 accounts for over 70% of cases. It is thought that the oncogenic process is mediated via the E6 and E7 proteins, which interfere with tumour suppressor genes and hence proliferation of the HPV infected cells. It is well known that the persistence of HPV infection can result in neoplastic changes of the anogenital tract. In these cases, the infection reduces the immune response and an immunosuppressed state of the epidermis has been observed, showing a reduction of immature myeloid dendritic cells and CD8+ T‐cells. This permits the HPV effect neoplastic progression. Cell cycle and DNA damage is much more strongly linked to high‐risk oncogenic HPV types [14].

Histological features

HSIL is characterised by a proliferation of atypical, hyperchromatic squamous cells with enlarged nuclei and frequent mitoses [15]. These features are best appreciated in the basal and parabasal regions, but varying degrees of atypia will extend upwards through the epidermis (Figure 40.1a). As the cells mature, the cytoplasm is more eosinophilic, and there may be features of koilocytosis with enlarged nuclei surrounded by a clear halo. The individual cells may vary from basaloid to large keratinocytes. The basaloid cells have scant cytoplasm, mildly to moderately enlarged nuclei with hyperchromatic smudged chromatin, and fail to undergo maturation beyond the normal parabasal area. Atypical keratinocytes have a variable amount of eosinophilic cytoplasm and large nuclei with prominent nucleoli, and, regardless of the amount of cytoplasm, there is an increased nuclear–cytoplasmic ratio compared with normal keratinocytes. There is often a mixture of the abnormal basaloid and keratinocyte cells, with the basaloid cells being present in the lower epidermal layers and the keratinocytes with koilocytosis in the upper layers. The degree of atypia should help to distinguish HSIL from low‐grade warts.

Photo depicts (a) high-grade squamous intraepithelial lesions (HSIL) histological features showing full-thickness atypia in the epidermis, (b) p16 positive staining.

Figure 40.1 (a) High‐grade squamous intraepithelial lesions (HSIL) histological features showing full‐thickness atypia in the epidermis, (b) p16 positive staining.

Generally, the epithelium is acanthotic with elongation and broadening of the rete pegs. The surface is usually parakeratotic, but may be hyperkeratotic or both, with atypical hyperchromatic enlarged nuclei in the parakeratotic cells or granular cell layer. Architectural disruption of the epidermis is often described as showing a ‘wind‐blown’ pattern. Apoptotic bodies are common with dyskeratotic features, dense cytoplasm, and pyknotic nuclei. The adjacent stroma usually has a chronic inflammatory cell infiltrate, but in the absence of ulceration, eosinophils are usually absent.

Two types of HSIL are recognised – warty and basaloid – but there is frequently a mixed picture, and in practice, it is not that useful as it does not alter prognosis or management [16, 17]. Mucinous and Pagetoid variants are reported but are rare [15]. In warty HSIL, the epidermis is acanthotic with deep and wide rete ridges. There are increased numbers of koilocytes and dyskeratotic cells in this type.

In the basaloid type, only basaloid cells are seen. The epidermis is flatter, and there may be marked melanin pigmentation that frequently spills over into the adjacent non‐neoplastic stroma. Mitotic figures are present above the parabasal layer and may extend throughout the full thickness of the epithelium.

Not uncommonly, HSIL extends into pilosebaceous units, and occasionally into sweat gland ducts. Extension into adnexal structures and tangential sectioning of acanthotic epithelium may mimic invasion, but, unlike invasive tumours, the nests retain a lobular configuration and lack the streaming pattern of invasion.

Paradoxical maturation to large atypical keratinocytes among the basaloid cells is a ‘pre‐invasive’ change that warrants a more careful search for early invasion if not seen in the initial planes of completely sectioned specimens or by submitting additional sections in incompletely sectioned large specimens. The presence of intraepithelial eosinophils in incisional and excisional specimens is again indicative of some degree of invasion [18].

Special stains

Multiple biomarkers have been investigated

Only gold members can continue reading. Log In or Register to continue

Stay updated, free articles. Join our Telegram channel

Nov 10, 2022 | Posted by in GYNECOLOGY | Comments Off on High‐Grade Squamous Intraepithelial Lesions

Full access? Get Clinical Tree

Get Clinical Tree app for offline access