Vulvar intraepithelial neoplasia associated with HPV infection: clinical, diagnostic, therapeutic and prophylactic aspects: A review

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Vulva diseases are one of the urgent problems of modern medicine. Infectious processes, dermatoses, manifestations of hormonal and systemic diseases, intraepithelial neoplasia, as well as cancer characterize a wide range of pathology of the vulva [1].
In recent years, there has been a trend towards an increase in HPV-associated vulvar diseases worldwide, which is most likely due to an increase in the incidence of HPV infection in general [2]. From 1992 to 2005, the incidence of intraepithelial neoplasia of the vulva (VIN) almost doubled — from 1.2 per 100 thousand to 2.1 per 100 thousand, while the incidence of invasive vulvar cancer remained stable [3]. Intraepithelial neoplasia of the vulva (VIN) is characterized by atypia of epithelial cells, proliferation of atypical basal cells in the epithelium of the vulva. The term VIN was introduced in the early 1980s to generalize the concepts of dysplastic lesions and vulvar carcinoma. Until the 80s, such names as Keirat's erythroplasia, Bowen's disease and hyperplastic dystrophy with atypia could be found in the literature [4]. In 2004, the International Society for the Study of Vulvovaginal Disease (ISSVD) introduced a new classification of VIN based on morphological and pathogenetic criteria.
 Ordinary type VIN (uVIN)
 Differentiated type VIN (dVIN)
 Unclassified VIN type (VIN NOS)
In 2015, ISSVD adopted the modern VIN classification: Squamous intraepithelial lesion associated with HPV infection (uVIN1/LSIL, uVIN 2,3/HSIL), or:
- Squamous intraepithelial vulvar lesion of low severity —LSIL, which includes uVIN1, flat condyloma and HPV-carrier;
Squamous intraepithelial vulvar lesion of high severity - HSIL (VIN2 and VIN3) or uVIN
– Differentiated (dVIN) - not associated with HPV infection [5, 6].
High-grade squamous intraepithelial lesion associated with HPV infection (uVIN) is most often found in women of reproductive age (25-45 years) and often in combination with other HPV-associated diseases of the anogenital region. Numerous studies in the field of studying the etiology of uVIN have shown that HPV infection is detected in more than 80% of cases, and in the vast majority of cases HPV types 16, 33 and 18 are detected [7]. It is widely known that HPV infection is the most significant etiological factor in the development of cervical cancer. Human papilloma viruses are a large family with a systematic classification of five genera (α, β, γ, μ and v), 48 species and 206 types. The ability of specific HPV types to cause cancer varies, based on this, the International Agency for Research on Cancer (IARC) has compiled its own classification of HPV: 12 HPV carcinogenic types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) IARC Groups 1, 2A – probably carcinogenic (type 68), possibly carcinogenic types (26, 30, 34, 53, 66, 67, 69, 70, 73, 82, 85, 97; IARC group 2B) and other low-risk types (HPV 6, 11, 42, 44; IARC Group 3) [8].
In most cases, the immune system copes with the infection on its own for one year, however, in some cases, the persistence of papillomavirus infection (PVI) occurs. It is known that the long-term persistence of high-risk HPV (HPV BP) causes malignant degeneration of uVIN.
The state of the immune system plays a dominant role in the persistence of HPV infection [9]. Thus, studies by Meeuwis KA, et al clearly demonstrate that the risk of uVIN malignancy in patients with immunosuppressive diseases is 50 times higher compared to the general population [10].
As is known, HPV oncoproteins E6 and E7 are embedded in the chromosome of infected cells, stimulate their proliferation and cause a violation of their differentiation and maturation. And as in response to the expression of cancer protein E7, cell proliferation is stimulated, contributing to an increase in the expression levels of p16, Ki-67. [11, 12]. HPV cancer protein E6 can lead to dysfunction of the tumor suppressor gene p53, while E7 can inactivate the retinoblastoma tumor suppressor gene (pRb), which leads to overexpression of p16ink4a and p14arf and hyperproliferation of infected cells. Most uVIN lesions are positive on immunohistochemical analysis for p16ink4a and p14arf. [13].
A number of studies have shown that about 1/3 of cases of vulvar carcinoma develop against the background of uVIN, and are associated with human papillomavirus (HPV) [14, 15].
Unlike uVIN, dVIN, as a rule, develops against the background of chronic inflammatory diseases of the vulva, sclerosing lichen, occurs in postmenopausal women and is more likely to progress to squamous cell carcinoma of the vulva in a shorter period [16].
The role of HPV in the development of uVIN is widely discussed and is now generally accepted.
With a differentiated type of intraepithelial neoplasia of the vulva
(dVIN) revealed its association with TP53 mutations. For example, a recent study of targeted sequencing showed the presence of a number of mutations, such as NOTCH1 and HRAS in dVIN. It was found that NOTCH1 was present in 20% of dVIN cases, and HRAS was present in 10% of dVIN. In cases of HPV-negative vulvar cancer, NOTCH1 mutations occurred in 33.3% of cases, and HRAS mutations occurred in 27.8%, which suggests the role of NOTCH1 and HRAS in the development of vulvar cancer. It was also found that patients with squamous cell vulvar cancer have several additional mutations, such as CDKN2A, PIK3CA and PPP2R1A, which are not present in dVIN [17].
Risk factors for the development of uVIN are: postmenopausal age, vulvar dermatoses, a history of CIN, early menopause, diabetes, obesity; chronic inflammatory processes of the vulva. Also, risk factors for the development of uVIN include: immunodeficiency conditions and diseases. It is believed that smoking is one of the most significant risk factors and, together with HPV infection, contributes to the development of vulvar dysplasia [18].
In 18-52% of cases, uVIN is combined with dysplasia of the anogenital region, the cervix [19, 20], which involves a comprehensive examination (cervix, vagina, anal area) such patients.
The most common complaints include itching in the vulva, pain, foreign body sensation, discomfort [21, 22], however, in 20% of cases, uVIN is asymptomatic.
The clinical picture of uVIN is very diverse. On examination, lesions are usually multifocal, differ in localization on the vulva, number, size, shape, color and thickness of lesions, often localized on the labia minora, raised. The contours of the affected areas are sometimes clearly outlined, but may also be irregular in the form of white or erythematous spots or papules (may merge, forming plaques). In 10% of cases, uVIN can be represented by foci of hyperpigmentation [23].
The diagnosis of uVIN includes visual examination, vulvoscopy, HPV detection by PCR, cytological examination of smears from the vulva, targeted biopsy from suspicious areas (Punch biopsy, radio wave, etc.) with histological examination of the material [24, 25]. It should be noted that cytological examination is a less sensitive method of diagnosing uVIN than in diseases of the cervix and vagina [26, 27], which, according to researchers, is due to the lack of material intake due to a thickened keratin layer. According to Vesna Kesic, conducting a cytological examination for the diagnosis of uVIN is uninformative [1].
Vulvoscopy is a diagnostically significant method for examining the vulva, and in the presence of lesions allows you to identify their localization and exact boundaries. Features of vulva tissues (skin thickness, vascular pattern) determine the manifestation of its various lesions. Thus, the thickness of the skin varies in different areas of the vulva, and areas of pigmentation can mask vascular pattern and punctuation, the mosaic may be less pronounced in the diagnosis of VIN, compared with similar changes in the cervix [28]. Pronounced changes in the epithelium of the vulva (rough punctuation and mosaics) are less common and are detected on the inside of the labia minora, where the epithelium does not contain a keratin layer.
Thus, areas of the aceto-white epithelium (ABE) are the most frequent vulvoscopic manifestations of vulvar pathology. However, compared to the cervical epithelium, acetic acid solution has a less noticeable effect when applied to the vulva due to keratinized skin. In this connection, the use of 5% acetic acid solution for the test should be long enough (2-3 minutes) to determine mild or pronounced changes in the epithelium of the vulva. It should be noted that vulvoscopy is not specific - it has high sensitivity (97%), but low specificity (40%) for the verification of intraepithelial lesions of high severity [29].
Characteristic signs of uVIN (HSIL) during vulvoscopy are papules and plaques with a smooth or warty surface, hyperpigmentation, multiple areas of ABE protruding above the surface. In some cases, vascular atypia is visualized, which is characterized by horizontal vascular growth and rough uneven punctuation and/or mosaics.
Vulvoscopy allows you to establish the boundaries of the lesion, to identify foci that are not determined by the naked eye.

About the authors

Anna N. Mheryan

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Author for correspondence.
Email: docanna@mail.ru
ORCID iD: 0000-0003-0574-1230

Cand. Sci. (Med.), Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Russian Federation, Moscow

Niso M. Nazarova

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Email: grab2@yandex.ru
ORCID iD: 0000-0001-9499-7654

D. Sci. (Med.), Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Russian Federation, Moscow

Vera N. Prilepskaya

Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Email: vprilepskaya@mail.ru
ORCID iD: 0000-0003-3993-7629

D. Sci. (Med.), Prof., Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology

Russian Federation, Moscow

References

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