List of Abbreviations
VIN | Vulval Intraepithelial Neoplasia |
|---|---|
LSIL | Low-grade squamous intraepithelial lesion |
HSIL | High-grade squamous intraepithelial lesion |
dVIN | Differentiated vulvar intraepithelial neoplasia |
uVIN | Usual type VIN (usual vulvar intraepithelial neoplasia) |
NOS | Not otherwise specified |
HIV | Human immunodeficiency virus |
HPV | Human papillomavirus |
WHO | World Health Organization |
HR HPV | High-risk human papillomavirus |
IHC | Immunohistochemical examination |
LP | Lichen planus |
ICD-10 | International Statistical Classification of Diseases and Related Health Problems (10th revision) |
VLS | Vulvar lichen sclerosus |
DEVIL | Differentiated exophytic vulvar intraepithelial lesion |
VSCC | Vulvar Squamous Cell Carcinoma |
VAAD | Vulvar Acanthosis with Altered Differentiation |
VaIN | Vaginal Intraepithelial Neoplasia |
AIN | Anal Intraepithelial Neoplasia |
Terms and Definitions
See Section 1.1.
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Vulvar intraepithelial neoplasia (VIN) is a group of vulvar disorders characterized by the proliferation of atypical basal cells and dysplastic changes in the stratified squamous epithelium of the vulva [1,2].
Vulvar LSIL – Low-grade squamous intraepithelial lesions of the vulva – include flat condylomas of the vulva or other manifestations of HPV infection [1,2].
Vulvar HSIL – High-grade squamous intraepithelial lesions of the vulva – include VIN II (moderate vulvar intraepithelial neoplasia), VIN III (severe vulvar intraepithelial neoplasia and carcinoma in situ) [1,2].
dVIN – differentiated vulvar intraepithelial neoplasia [2,3,4].
DEVIL – differentiated exophytic vulvar intraepithelial lesion [2,5,6,7].
VAAD – vulvar acanthosis with altered differentiation [2,5,6,7].
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
There are 2 histological subtypes of VIN with different etiopathogenetic pathways, prognosis, and treatment:
The first – LSIL and HSIL (formerly uVIN) – are associated with HPV infection. They occur more frequently in women aged 30 to 50 years, with a mean age of 35 years [8].
The second – dVIN – is not associated with HPV and develops on the background of chronic inflammatory dermatoses of the vulva, most commonly vulvar lichen sclerosus (VLS). It is more frequently seen in older women and has a higher malignant potential [8,9,10].
Vulvar LSIL is associated with HPV type 6 or 11 infection in 90% of cases, which includes anogenital warts (condyloma acuminatum) [1,11].
Vulvar HSIL is associated with high-risk HPV types – 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 66, 68 (HPV 16 in > 70% of cases). The prevalence of HPV in VIN is 86.7%, with HPV 16 being the most common type (77.2%), followed by HPV type 33 (10.6%), HPV type 18 (2.6%), and HPV type 31 (1.2%) [11].
The oncogenesis of vulvar HSIL is comparable to that of high-grade squamous intraepithelial lesions (HSIL) of the cervix, vagina, and anal canal [8,9,10].
dVIN and HPV-independent vulvar squamous cell carcinoma mainly arise in the area of VLS. Mechanisms of development include chronic inflammation, ischemic and oxidative stress, and p53 mutations [11,41]. An imbalance in commensal microbes against the background of disrupted vulvar and vaginal microbiome also serves as a trigger for inflammation and the development of neoplasia. dVIN is a precursor to HPV-independent invasive squamous cell carcinoma of the vulva [12,13].
1.3 Epidemiology of the Disease or Condition
The frequency of vulvar HSIL is significantly higher than that of dVIN (90–95% vs. 5–10%, respectively), whereas the probability of progression to vulvar squamous cell carcinoma (VSCC) is higher in women with dVIN (10% and 50%, respectively). Furthermore, vulvar HSIL is more common in young women, whereas dVIN is more common in postmenopausal women [9,10,14,15].
Over the past 20 years, the incidence of HSIL has increased by approximately 40%, with this growth being largely driven by HPV-independent lesions.
The incidence of vulvar HSIL ranges from 2.5 to 8.8 per 100,000 women and can transform into HPV-associated VSCC. Progression of HSIL to VSCC is observed in 3–5% of treated patients and in 10% of untreated patients [11]. Women with HSIL more frequently develop anal squamous cell carcinoma and its precursors due to shared etiological factors, primarily HPV infection [16].
1.4 Features of Coding the Disease or Condition
In ICD-10, VIN is coded under N90 – Other noninflammatory disorders of vulva and perineum:
N90.0 - Mild vulvar dysplasia – Vulvar intraepithelial neoplasia, grade I
N90.1 - Moderate vulvar dysplasia – Vulvar intraepithelial neoplasia, grade II
N90.2 - Severe vulvar dysplasia, not elsewhere classified – Severe vulvar dysplasia NOS (Not Otherwise Specified)
Excluded: vulvar intraepithelial neoplasia III (VIN III) with or without mention of severe dysplasia (D07.1))
N90.3 - Dysplasia of vulva, unspecified
N84.3 - Polyp of vulva to be
N90.4 - Leukoplakia of vulva
N90.6 - Hypertrophy of vulva
N90.7 - Cyst of vulva
N90.8 - Other specified noninflammatory disorders of vulva and perineum
1.5 Classification of the disease or condition
According to the 2020 WHO Classification of Tumours, vulvar intraepithelial lesions (VIN) are categorized into [2]:
1. HPV-associated vulvar squamous intraepithelial lesions
Low-grade vulvar squamous intraepithelial lesion (LSIL)
High-grade vulvar squamous intraepithelial lesion (HSIL) (formerly Usual-type VIN)
2. HPV-independent VIN
Differentiated vulvar intraepithelial neoplasia (dVIN)
Differentiated exophytic vulvar intraepithelial lesion (DEVIL)
Vulvar acanthosis with altered differentiation (VAAD)
1.6 Clinical presentation of the disease or condition
See Item 2.1.
2. Diagnostics, medical indications and contraindications for diagnostic methods
Diagnosis of VIN requires a visual examination of the vulva with vulvoscopy, targeted vulvar biopsy followed by pathomorphological examination of the biopsy (surgical) specimen (with immunohistochemical (IHC) staining if necessary) [1,11].
Differential diagnosis [18] of VIN is performed with the following conditions:
- Lichen simplex chronicus
- Vulvar lichen sclerosus (VLS)
- Lichen planus (LP)
- Psoriasis
- Contact dermatitis
- Vulvar squamous cell carcinoma (VSCC)
- Extramammary Paget's disease in situ
- Melanoma in situ, etc.
2.1 Complaints and Anamnesis
There is no single pathognomonic clinical picture for VIN. In 60% of cases, women present with vulvar complaints of [11]:
Itching and burning
Irritation
Fissures, erosions, and ulcers on the vulva
Pain due to erosions and/or fissures
Contact bleeding
Dyspareunia
Palpable nodules
In 40–50% of cases, VIN is asymptomatic and is diagnosed during a gynecological examination.
It is recommended that all patients undergo history taking to identify risk factors for VIN development [8,9,10].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comment: risk factors for VIN development include smoking (including passive smoking), immunocompromising conditions (hepatitis B, C, HIV), immunosuppressive therapy, and prolonged use of combined oral contraceptives (COCs [11] according to the Anatomical Therapeutic Chemical (ATC) classification: progestogens and estrogens (fixed combinations)) [8,9,10].
2.2 Physical Examination
It is recommended that all patients with VIN undergo a visual inspection of the external genitalia, perineum, perianal, and anal region, speculum examination of the vagina and cervix, and bimanual pelvic examination to detect intraepithelial lesions [9,10,11,17].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: clinical manifestations of VIN vary by:
- Number of lesions (can be single or multiple)
- Shape (as raised papules with sharp borders and a keratotic, rough surface)
- Surface
- Thickness
- Size
- Color (ranging from white to red, gray, blue, or brown)
- Location (HSIL is more often multifocal, involving the labia minora and the vaginal introitus)
dVIN more frequently arises on the background of LSC, presenting as single hyperkeratotic, erosive/ulcerative gray-white or red lesions, most commonly on hairless areas: around the clitoris, on the labia minora, in the vaginal vestibule, and in case of their atrophy, also on the labia majora [9,10,11,17].
In vulvar HSIL, multifocal lesions are visualized as white, erythematous, or pigmented, wart-like, moist, or ulcerated plaques [9,10,11,17].
Vulvar HSIL may be accompanied by multifocal/concomitant epithelial lesions of the cervix, vagina, perianal, and anal regions.
2.3 Laboratory Diagnostics
It is recommended that all patients with suspected VIN undergo a pathomorphological (biopsy/surgical) examination of vulvar tissue for final diagnosis verification and determination of further management tactics [1,11,17,18].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comment: HPV-associated VIN is characterized by a basaloid cell morphotype. Vulvar LSIL is characterized by abnormal maturation and dysplasia of epithelial cells in the lower third of the epithelial layer. Vulvar HSIL is characterized by abnormal maturation and dysplasia of epithelial cells extending above the lower third of the epithelium. Dysplastic changes involve the entire thickness of the epithelium and are characterized by marked cellular polymorphism, disruption of the nuclear-cytoplasmic ratio with nuclear hyperchromasia. Koilocytic changes in the upper epithelial layers are characteristic [20]. HPV-associated VIN precursors are invasive HPV-associated VSCC [2]. Cytological examination of the vulva is not as informative as in CIN and VAIN [18], but it can be used to detect pathological epithelial changes [42,43].
It is recommended to use immunohistochemical methods in the pathomorphological examination of vulvar biopsy (surgical) material for the differential diagnosis of VIN—performing immunohistochemical (IHC) testing with the determination of p16 and p53 expression, since the morphological features characteristic of HPV-associated and non-HPV-associated VIN are similar. Positive expression of p16 (an HPV marker) indicates a high probability of HSIL, while p53 expression is a positive marker for dVIN [2,9,10,11,17,19].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: for HPV-independent VIN (dVIN), cellular atypia is not a defining feature. Morphological diagnosis of dVIN presents certain difficulties due to mild atypia, a high degree of differentiation of dysplastic cells, as well as the lack of precise diagnostic criteria and similarity to differentiated vulvar intraepithelial neoplasia (dVIN) [8]. It is characterized by epithelial hyperplasia with hyper- and parakeratosis, elongation of epithelial cells, as well as anastomosing epidermal ridges, basal nuclear atypia of cells with an increase in their size and the presence of nucleoli, absence of the granular layer, presence of cells with abundant eosinophilic cytoplasm, and mitotic figures [2]. Koilocytic changes are absent [21,22]. In some cases, atypia may be absent, and then the basis for the diagnosis will be the presence of other morphological and immunohistochemical features. HSIL-like VIN is characterized by uVIN morphology, however, this lesion is HPV-independent and has a corresponding immunophenotypic profile. During IHC examination in HPV-independent VIN (dVIN), p16 expression is absent and 2 variants of p53 expression are possible: aberrant (p53-mutant VIN) or "wild" type [2,17].
HPV-independent p53-mutant VIN includes dVIN and HSIL-like VIN. Most commonly, dVIN is a precursor to invasive well-differentiated VSCC.
HPV-independent VIN with a "wild-type" p53 expression pattern includes VAAD (vulvar acanthosis with altered differentiation) and DEVIL (differentiated exophytic vulvar intraepithelial lesion).
VAAD was originally described in 2004 and has characteristic morphological features: marked acanthosis with diverse wart-like architecture, hyperkeratosis - plaque-like parakeratosis layers, hypogranulosis (loss of the granular layer), and pale cytoplasm of superficial epithelial cells [2]. It is important to consider that VAAD can coexist with dVIN and serve as a precursor to verrucous squamous cell carcinoma of the vulva [6,7].
DEVIL has an atypical verrucous structure with the following morphological criteria: exophytic growths with marked acanthosis or wart-like architecture, absence of HPV-related morphological features (e.g., koilocytopathic atypia or atypia in all epithelial layers, nuclear hyperchromasia, high nuclear-cytoplasmic ratio, and pleomorphism), and absence of basal atypia characteristic of dVIN. DEVIL can be a precursor to verrucous carcinoma of the vulva [23].
Despite the absence of a mutation in the TP53 gene, VAAD and DEVIL may harbor mutations in the PIK3CA and ARID2 genes.
Among HPV-unrelated lesions with a "wild-type" p53 expression pattern, verrucous lichen simplex chronicus is also distinguished, which is morphologically characterized by hypergranulosis, hyperkeratosis, and the absence of eosinophilic changes in the cytoplasm of epithelial cells. Currently, it is recommended to use the term "HPV-unrelated VIN (verrucous/acanthotic) characterized by a "wild-type" p53 expression pattern" [24].
2.4 Instrumental Diagnostics
It is recommended that all patients with suspected VIN undergo magnified vulvoscopy to identify pathological areas of the vulva, as well as to select site(s) for biopsy according to indications [9,10,11,18].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comment: evaluation of vulvar tissues is performed using a colposcope, which allows:
— More precisely determining the extent and margins of the lesion
— Identifying the biopsy site(s) in the area(s) of the most clinically severe lesion
Indications for vulvoscopy are: [1,19]
Persistent vulvar pruritus and pain without visible lesions
Persistence of vulvovaginitis symptoms after appropriate treatment
If vulvar lesions are not clearly visible or lack distinct margins
When VIN is suspected, 3–5% acetic acid is applied for 3–5 minutes [1]. Characteristic vulvoscopic signs of VIN include:
— Raised, sharply demarcated acetabular epithelium – a sign corresponding to HSIL
— Lack of reaction to acetic acid is characteristic of dVIN
Vulvoscopy should be accompanied by colposcopy of the vagina and cervix, as intraepithelial lesions frequently coexist [19].
It is recommended that all patients with suspected VIN undergo targeted (multifocal if necessary) vulvar biopsy under colposcopic guidance, followed by pathomorphological examination of the vulvar biopsy (surgical) material in order to verify the diagnosis [9,10,11,18,19].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comment: biopsy should be performed in postmenopausal women with visible condylomata acuminata and in women of any age with suspected condylomata if local therapy fails. Vulvar biopsy may be required in human immunodeficiency virus (HIV)-seropositive women and immunosuppressed patients after organ transplantation [1]. When performing a biopsy with suspected VIN, the following conditions must be met [8,25]:
— Performing the biopsy with a scalpel, punch biopsy instrument, or conchotome
— In the case of an ulcer or fissure, the biopsy is performed in the area of undamaged epithelium
— The width of the biopsy specimen is not < 4 mm
— Depth of the biopsy specimen: 5 mm for skin areas with hair follicles; 3 mm for mucous membranes and hairless skin.
2.5 Other Procedures
It is recommended to perform a cervical cytological examination in all patients with VIN to rule out CIN and cervical cancer [45].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
It is recommended to perform a molecular biological test of the cervical canal discharge (cervical epithelial scraping) for human papillomavirus (Papilloma virus) for the entire group of high-risk HPV types 13–14 (excluding low carcinogenic risk types) in women with suspected VIN [26] to rule out CIN and VaIN, since these diseases are associated with HPV [1,9,26,27].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
The goals of treatment for HSIL and dVIN are:
— Prevention of progression to vulvar squamous cell carcinoma
— Preservation of normal vulvar anatomy
— Relief/management of vulvar symptoms
— Maintenance of quality of life, including sexual function
In vulvar LSIL, expectant management is recommended (spontaneous regression is possible) with clinical monitoring every 6 months for 18–24 months (for early detection of progression) [9,10,11,19].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: in the absence of spontaneous regression and the presence of symptoms in the patient, medical and/or surgical treatments may be used.
It is recommended due to the occurrence of dVIN in the area of lichen sclerosus (LS), to treat the latter with topical corticosteroids (according to the ATC "Corticosteroids") to reduce the risk of developing VSCC [1,28].
GPP BLOE 3Grade of Recommendation B (Level of Evidence – 3).
3.1 Medical treatment
It is recommended to use #imiquimod 5% cream applications in patients over 18 years of age with VIN [11,17,29].
Level CLevel 3Level of recommendation evidence C (reliability level of evidence – 3).
Comment: #Imiquimod is an immune response modifier. Topical treatment with #imiquimod effectively stimulates cell-mediated immunity against various types of HPV. Regimen: application of #imiquimod 5% cream 3 times weekly for 12–20 weeks, on average 16 weeks, with clinical evaluation of efficacy every 4–6 weeks [1,9,10,17,29,30]. Treatment is limited by the occurrence of side effects. Lesions persisting after #imiquimod treatment are surgically removed.
3.2 Surgical Treatment
It is recommended to perform surgical removal (A16.20.096) of all visible lesions to relieve symptoms and prevent the development of VSCC [1,9,10,11,19].
GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).
Comment: surgical treatment methods for HSIL include:
— Surgical excision (ranging from local excision of the lesion with a scalpel or electrosurgical loop to vulvectomy)
— Surgical ablation with a CO2 laser (according to the Federal Service Nomenclature - Laser surgery for neoplasms of the female genital organs).
Wide excision of pathological areas is performed with a margin of 5–10 mm from the edge of the lesion and a depth of 2 mm in hairless areas and 4 mm in hair-bearing areas [1,19]. If occult invasion is suspected, wide excision of the affected area is recommended for effective morphological assessment. If morphological signs of VIN are present at the margins of the removed lesion and there are no clinical signs of the lesion after surgical excision of HSIL, subsequent follow-up of patients is necessary.
It is recommended in dVIN to perform an excisional removal of the pathological focus (A16.20.096.001) with negative surgical margins followed by continuous monitoring (every 6 months for the first two years and annual monitoring thereafter) due to the risk of rapid progression from dVIN to invasive squamous cell carcinoma of the vulva [9,10,11,17,19,45].
GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).
Comment: after surgical treatment of vulvar HSIL, the time to progression to VSCC in 15% of women averages 71.5 months [30].
3.3 Laser ablation
Laser ablation of HSIL is recommended (in the Federal Service Nomenclature "Laser surgery for neoplasms of the female genital organs") to a depth of 1 mm to 2 mm for the mucous membrane epithelium, and at least 3 mm for hair-bearing skin areas [9,17].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comment: in HSIL, CO2 laser ablation of the lesion is carried out to a depth of no more than 2 mm to avoid skin tightening and hypertrophic scar formation. In hair-bearing areas of the vulva, it is recommended to remove hair follicles using laser exposure, as VIN cells may be located in them and spread into the subcutaneous tissue by ≥ 3 mm [1]. In the case of extensive VIN lesions in hair-bearing areas of the vulva, other treatment methods are recommended. The risk of VIN recurrence during laser vaporization is higher than during excision [9,10,19,30].
3.4 Photodynamic therapy (PDT)
Photodynamic therapy (PDT) is recommended (in the Federal Service Nomenclature "Photodynamic therapy for neoplasms of the female genital organs") with local or systemic administration of a photosensitizer (according to the ATC "Sensitizers used in photodynamic / radiation therapy") in combination with laser radiation of the appropriate wavelength in patients with VIN (A22.20.001) [11,19].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comment: the laser interacts with protoporphyrin IX, resulting in the formation of free radicals that exert a local cytotoxic effect. Oxidation reactions lead to cell apoptosis. PDT can be performed on an outpatient basis. The efficacy of the method is comparable to laser ablation.
4. Medical Rehabilitation and Sanatorium-Resort Treatment
Specific rehabilitation has not been developed. It is recommended for all patients to undergo an examination (consultation) by a physical therapy physician to determine a rehabilitation program [17,44].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
5. Prevention and Dispensary Observation
It is recommended to prevent HPV-associated diseases of the cervix, vagina, and vulva according to WHO principles [31].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Immunization with quadrivalent recombinant human papillomavirus vaccine (types 6, 11, 16, 18), which is effective against HPV genotypes 6, 11, 16, and 18, reduces the risk of VIN and is recommended for girls aged 11–12 years with re-vaccination up to 26 years if they were not vaccinated at 9–10 years of age [1,17].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
It is recommended to treat lichen sclerosus (LS), which can serve as a background for the development of dVIN, with topical corticosteroid preparations (according to the ATC "Corticosteroids"), which may reduce the risk of developing VSCC [1,9,17].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comments: approximately 10% of HSIL cases and 50% of dVIN cases progress to vulvar squamous cell carcinoma within 10 years [8]. Risk factors for VSCC progression include VIN type, age, and LS [17].
It is recommended to conduct systematic examination of the lower genital tract [17], since women with vulvar HSIL are at risk for disease recurrence and vulvar cancer throughout their lives [1], and risk factors for recurrence include age, presence of CIN or VaIN, and immunosuppression [9,17].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
Comment: recommended minimum follow-up intervals after treatment are 6 months for the first two years and annual follow-up thereafter [45]. Regardless of the treatment methods for VIN, the recurrence rate after treatment ranges from 5% to 9%. A higher recurrence rate is also observed in multiple vulvar lesions [1].
It is recommended to screen for anal squamous cell carcinoma in patients with HPV-associated VIN and VSCC [8,45].
GCR CLOE 5Grade of Recommendation C (Level of Evidence – 5).
Comment: 4%–25% of women with VIN are at risk of developing CIN, VaIN, AIN.
It is recommended to inform patients about the symptoms of VIN (pain, ulcers, etc.), the appearance of which should prompt the woman to seek earlier consultation with an obstetrician-gynecologist [1,8,9].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
It is recommended to provide all patients after VIN treatment with follow-up care (including regular appointments (examinations, consultations) with an obstetrician-gynecologist with careful clinical evaluation and biopsy of any suspicious vulvar area) every 6 months for 2 years after initial treatment, and then—if treatment is effective and there are no new lesions—annually for 5 years [1,8,17].
Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).
6. Organization of Medical Care
Excisional and ablative treatments are preferably performed on an outpatient basis or in a day hospital setting.
Indications for hospitalization: vulvectomy.
Criteria for patient discharge: clinical recovery.
7. Additional Information
Not applicable.
Criteria for Evaluating the Quality of Medical Care
№ | Quality criteria | Performance assessment (yes/no) |
|---|---|---|
1. | Inspection of the vulva, vagina, and cervix using a speculum, and bimanual vaginal examination were performed to detect intraepithelial lesions of the vulva, vagina, and cervix | Yes/no |
2. | Vulvoscopy performed in patients with suspected VIN | Yes/no |
3. | Vulvar biopsy performed in patients with suspected VIN | Yes/no |
4. | Pathological examination of biopsy (surgical) material performed for definitive diagnosis verification and determination of further management tactics (if necessary, immunohistochemical (IHC) assay for p16 and p53 markers) | Yes/no |
References
Show references
1. Committee Opinion No.675: Management of Vulvar Intraepithelial Neoplasia. Obstet Gynecol. 2016 Oct;128(4):e178-e182. doi: 10.1097/AOG.0000000000001713. Erratum in: Obstet Gynecol. 2017 Jan;129(1):209. doi: 10.1097/AOG.0000000000001839. PMID: 27661656.
2. WHO Classification of Tumours Editorial Board. Female genital tumours. 5th ed. Lyon; 2020. https://tumourclassification.iarc.who.int/chapters/34.
3. Pils S., Gensthaler L., Alemany L., Horvat R., de Sanjose S., Joura E.A.. HPV prevalence in vulvar cancer in Austria. Wiener klinischeWochenschrift. 2017; 129: 805-809. doi: 10.1007/s00508-017-1255-2.
4. Wakeham K., Kavanagh K., Cuschieri K., Millan D., Pollock K.G., Bell S., et al. HPV status and favourable outcome in vulvar squamous cancer. IntJ Cancer. 2017; 140(5): 1134-1146. doi: 10.1002/ijc.30523.
5. Roy S.F., Wong J., Le Page C., Tran-Thanh D., Barkati M., Pina A., Trinh V.Q., Rahimi K.. DEVIL, VAAD and vLSC constitute a spectrum of HPV-independent, p53-independent intra-epithelial neoplasia of the vulva. Histopathology. 2021 Dec;79(6):975-988. doi: 10.1111/his.14451. Epub 2021 Sep 20. PMID: 34265101.
6. Day T., Marzol A., Pagano R., Jaaback K., Scurry J.. Clinicopathologic diagnosis of vulvar intraepithelial neoplasia and vulvar aberrant maturation. J Lower Genit Tract Dis. 2020; 24(4): 317-329.doi: 10.1097/LGT.0000000000000569.
7. Nascimento A.F., Granter S.R, Cviko A., Yuan L., Hecht J.L.,Crum C.P. Vulvar acanthosis with altered differentiation: A precursor to verrucous carcinoma? Am J Surg Pathol. 2004; 28(5): 638-643.doi: 10.1097/00000478-200405000-00012.
8. Preti M., Joura E., Vieira-Baptista P., Van Beurden M., Bevilacqua F., Bleeker M.C.G., Bornstein J., Carcopino X., Chargari C., Cruickshank M.E., Erzeneoglu B.E., Gallio N., Heller D., Kesic V., Reich O., Stockdale C.K., Temiz B.E., Woelber L., Planchamp F., Zodzika J., Querleu D., Gultekin M.. The European Society of Gynaecological Oncology (ESGO), the International Society for the Study of Vulvovaginal Disease (ISSVD), the European College for the Study of Vulval Disease (ECSVD) and the European Federation for Colposcopy (EFC) Consensus Statements on Pre-invasive Vulvar Lesions. J Low Genit Tract Dis. 2022 Jul 1;26(3):229-244. doi: 0.1097/LGT.0000000000000683. Epub 2022 Jun 21. PMID: 35763611; PMCID: PMC9232287.
9. Van der Meijden W.I., Boffa M.J., Ter Harmsel B., Kirtschig G., Lewis F., Moyal-Barracco M., Tiplica G.S., Sherrard J. 2021 European guideline for the management of vulval conditions. J Eur Acad Dermatol Venereol. 2022 Jul;36(7):952-972. doi: 10.1111/jdv.18102. Epub 2022 Apr 12. PMID: 35411963.
10. Oonk M.H.M., Planchamp F., Baldwin P., Mahner S., Mirza M.R., Fischerová D., Creutzberg C.L., Guillot E., Garganese G., Lax S., Redondo A., Sturdza A., Taylor A., Ulrikh E., Vandecaveye V., van der Zee A., Wölber L., Zach D., Zannoni G.F., Zapardiel I.. European Society of Gynaecological Oncology Guidelines for the Management of Patients with Vulvar Cancer - Update 2023. Int J Gynecol Cancer. 2023 Jul 3;33(7):1023-1043. doi: 10.1136/ijgc-2023-004486. PMID: 37369376; PMCID: PMC10359596.
11. M. Lebreton, I. Carton, S. Brousse, V. Lavoué, G. Body, J. Levêque, K. Nyangoh-Timoh,Vulvar intraepithelial neoplasia: Classification, epidemiology, diagnosis, and management,Journal of Gynecology Obstetrics and Human Reproduction,Volume 49, Issue 9,2020, https://doi.org/10.1016/j.jogoh.2020.101801.
12. Pagan L., Ederveen R.A.M., Huisman B.W. Schoones J.W., Zwittink R.D., Schuren F.H.J., Rissmann R., Piek J.M.J., van Poelgeest M.I.E.. The Human Vulvar Microbiome: A Systematic Review. Microorganisms. 2021 Dec 12;9(12):2568. doi: 10.3390/microorganisms9122568. PMID: 34946169; PMCID: PMC8705571.
13. Rustetska N., Szczepaniak M., Goryca K., Bakuła-Zalewska E., Figat M., Kowalik A., Góźdź S., Kowalewska M. The intratumour microbiota and neutrophilic inflammation in squamous cell vulvar carcinoma microenvironment. J Transl Med. 2023 Apr 28;21(1):285. doi: 10.1186/s12967-023-04113-7.
14. Hoang L.N., Park K.J., Soslow R.A., Murali R. Squamous precursor lesions of the vulva: Current classification and diagnostic challenges. Pathology. 2016; 48(4): 291-302. doi: 10.1016/j.pathol.2016.02.015.
15. Cohen P.A., Anderson L., Eva L., Scurry J. Clinical and molecular classification of vulvar squamous pre-cancers. IntJ Gynecol Cancer. 2019; 29(4): 821-828. doi: 10.1136/ijgc-2018-000135.
16. Brzeziński M., Stukan M. Anal Cancer and Anal Intraepithelial Neoplasia Risk among Patients Treated for HPV-Related Gynecological Diseases - A Systematic Review. J. Clin. Med. 2023, 12, 4216. https://doi.org/10.3390/jcm12134216.
17. Henderson I., Lewis F., Williams A., Yap J., Krishna A. The diagnosis and management of vulval intraepithelial neoplasia. TheObstetrician & Gynaecologist 2024;26:18–26. https://doi.org/10.1111/tog.12906.
18. Kesi´c V., Vieira-Baptista P., Stockdale C.K. Early Diagnostics of Vulvar Intraepithelial Neoplasia. Cancers 2022, 14, 1822. https:// doi.org/10.3390/cancers14071822.
19. Preventive Oncology for the Gynecologist Sumita Mehta, Anshuja Singla Springer Nature Singapore Pte Ltd. 2019 https://doi.org/10.1007/978-981-13-3438-2.
20. Cohen P.A., Anderson L., Eva L., Scurry J. Clinical and molecular classification of vulvar squamous pre-cancers. IntJ Gynecol Cancer. 2019; 29(4): 821-828. doi: 10.1136/ijgc-2018-000135.
21. Hoang L.N., Park K.J., Soslow R.A., Murali R. Squamous precursor lesions of the vulva: Current classification and diagnostic challenges. Pathology. 2016; 48(4): 291-302. doi: 10.1016/j.pathol.2016.02.015.
22. Jin C., Liang S. Differentiated vulvar intraepithelial neoplasia: A brief review of clinicopathologic features. Arch PatholLab Med. 2019; 143(6): 768-771. doi: 10.5858/arpa.2018-0019-RS.
23. Watkins J.C., Howitt B.E, Horowitz N.S., Ritterhouse L.L., Dong F., MacConaill L.E., et al. Differentiated exophytic vulvar intraepithelial lesions are genetically distinct from keratinizing squamous cell carcinomas and contain mutations in PIK3CA. Mod Pathol. 2017; 30(3): 448-458. doi: 10.1038/modpathol.2016.187.
24. Parra-Herran C., Nucci M.R., Singh N., Rakislova N., Howitt B.E., Hoang L., Gilks C.B., Bosse T., Watkins J.C. HPV-independent, p53-wild-type vulvar intraepithelial neoplasia: a review of nomenclature and the journey to characterize verruciform and acanthotic precursor lesions of the vulva. Mod Pathol. 2022 Oct;35(10):1317-1326. doi: 10.1038/s41379-022-01079-7.
25. Heller D.S., Day T., Allbritton J.I. et al.. Diagnostic criteria for differentiated vulvar intraepithelial neoplasia and vulvar aberrant maturation. J Low Genit Tract Dis 2021;25:57–70.
26. Clinical Guidelines. Cervical intraepithelial neoplasia, erosion and ectropion of the cervix, 2024.
27. Zhang L., Hemminki O., Chen T., Zheng G., Försti A., Sundquist K., Sundquist J., Hemminki K. Familial Clustering, Second Primary Cancers and Causes of Death in Penile, Vulvar and Vaginal Cancers. Sci Rep. 2019 Aug 14;9(1):11804. doi: 10.1038/s41598-019-48399-4. PMID: 31413311; PMCID: PMC6694134.
28. Lee A., Bradford J., Fischer G.. Long-term management of adult vulvar lichen sclerosus: a prospective cohort study of 507 women. JAMA Dermatol 2015;151:1061–7.
29. Inayama Y., Yamanishi Y., Nakatani E., Aratake J., Sasagasako N., Yamada K., Gou R., Kawamura A., Yamanishi M., Kosaka K. Imiquimod for vaginal intraepithelial neoplasia 2-3: A systematic review and meta-analysis. Gynecol Oncol. 2021 Jan;160(1):140-147. doi: 10.1016/j.ygyno.2020.09.031. Epub 2020 Oct 1. PMID: 33010966.
30. Lawrie T.A., Nordin A., Chakrabarti M., Bryant A., Kaushik S., Pepas L. Medical and surgical interventions for the treatment of usual-type vulval intraepithelial neoplasia. Cochrane Database of Systematic Reviews 2016, Issue 1. Art. No.: CD011837. DOI: 10.1002/14651858.CD011837.pub2.
31. Comprehensive Cervical Cancer Control: A Guide to Essential Practice. 2nd ed. Geneva: World Health Organization; 2014.
32. Kew F. M., Cruickshank D. J. Routine follow-up after treatment for a gynecological cancer: a survey of practice //International Journal of Gynecologic Cancer. – 2006. – Vol. 16. – No. 1. – P. 380-384.
33. Minkina G.N. et al. Post-treatment monitoring of cervical intraepithelial neoplasias //Journal of Obstetrics and Women's Diseases. – 2011. – Vol. 60. – No. 1.
34. Meijer C. et al. Validation of high-risk HPV tests for primary cervical screening //Journal of Clinical Virology. – 2009. – Vol. 46. – P. S1-S4.
35. Poljak M. et al. Commercially available molecular tests for human papillomaviruses: a global overview. Clin Microbiol Infect. 2020.
36. Human papillomavirus vaccines: WHO position paper, no. 43. 2014.
37. Baranov A.A. et al. Vaccine prophylaxis of diseases caused by human papillomavirus: evidence-based medicine perspectives. Clinical guidelines review //Current Pediatrics. – 2017. – Vol. 16. – No. 2.
38. National Advisory Committee on Immunization (NACI) et al. Updated Recommendations on Human Papillomavirus (HPV) Vaccines: 9-valent HPV vaccine 2-dose immunization schedule and the use of HPV vaccines in immunocompromised population. 2017. Ottawa //ON: Pub.
39. ACOG. Committee Opinion No.704: Human Papillomavirus Vaccination., vol. 129, no.6. 2017.
40. Global Advisory Committee on Vaccine Safety, 4–5 December 2019. WHO. Weekly epidemiological record No 4, 2020.
41. Parra-Herran C., Nucci M.R., Singh N., Rakislova N., Howitt B.E., Hoang L., Gilks C.B., Bosse T., Watkins J.C. HPV-independent, p53-wild-type vulvar intraepithelial neoplasia: a review of nomenclature and the journey to characterize verruciform and acanthotic precursor lesions of the vulva. Mod Pathol. 2022 Oct;35(10):1317-1326. doi: 10.1038/s41379-022-01079-7. Epub 2022 Apr 18. PMID: 35437330.
42. Abu-Rustum N.R. et al. Vulvar Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology //Journal of the National Comprehensive Cancer Network. – 2024.
43. Dennerstein G. (2009). Vulvar Cytology. Journal of Lower Genital Tract Disease, 13(3), 192.
44. Strugatsky V.M., Malanova T.B., Arslanyan K.N. Physiotherapy in the practice of an obstetrician-gynecologist (clinical aspects and prescriptions). - 2nd ed. – Moscow: MEDpress-inform, 2008.
45. Morrison J., Baldwin P., Buckley L., et al. British Gynaecological Cancer Society (BGCS) vulval cancer guidelines: recommendations for practice. Eur J Obstet Gynecol Reprod Biol. 2020;252:502e525.
Appendix A1. Working Group Composition
1. Leyla V. Adamyan – Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Deputy Director of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of the Russian Federation, Honored Worker of Science of Russia, Head of the Department of Reproductive Medicine and Surgery at the A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Ministry of Health of Russia, Chief Specialist of the Ministry of Health of Russia in Obstetrics and Gynecology, member of the Society for Reproductive Medicine and Surgery, Russian Association of Gynecological Endoscopists, Russian Association for Endometriosis, Russian Society of Obstetricians and Gynecologists.
2. Inna A. Apolikhina – Doctor of Medical Sciences, Professor, Head of the Department of Aesthetic Gynecology and Rehabilitation at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of Russia, Professor at the Department of Obstetrics, Gynecology, Perinatology and Reproductology of the Institute of Professional Education at the I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia, Professor at the Department of Obstetrics and Gynecology of the Professional Education Department at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of Russia.
3. Alexandra V. Asaturova – Doctor of Medical Sciences, Head of the 1st Department of Pathology at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of the Russian Federation.
4. Natalia V. Artymuk - Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology named after Professor G.A. Ushakov at Kemerovo State Medical University of the Ministry of Health of Russia, Chief freelance specialist of the Ministry of Health of Russia in Obstetrics and Gynecology in the Siberian Federal District, member of the Russian Society of Obstetricians and Gynecologists.
5. Tatyana E. Belokrinitskaya – Doctor of Medical Sciences, Professor, Head of the Department of Obstetrics and Gynecology of the Faculty of Additional Professional Education at Chita State Medical Academy of the Ministry of Health of Russia, Honored Doctor of the Russian Federation, Chief freelance specialist of the Ministry of Health of Russia in Obstetrics and Gynecology in the Far Eastern Federal District (Chita), member of the Russian Society of Obstetricians and Gynecologists, President of the Trans-Baikal Society of Obstetricians and Gynecologists.
6. Gyuldana R. Bayramova – Doctor of Medical Sciences, Honored Doctor of the RF, Head of Department – Obstetrician-Gynecologist of the Scientific and Policlinic Department at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of Russia, Professor at the Department of Obstetrics and Gynecology of the Professional Education Department at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of Russia, member of the Russian Society of Obstetricians and Gynecologists.
7. Elena A. Gorbunova – Obstetrician-Gynecologist of the highest qualification category, Physiotherapist, Researcher at the Department of Aesthetic Gynecology and Rehabilitation at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of Russia.
8. Elmira R. Dovletkhanova – Candidate of Medical Sciences, Senior Researcher at the Scientific and Policlinic Department at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of Russia.
9. Lyubov I. Korolenkova – Doctor of Medical Sciences, Professor, Senior Researcher at the National Medical Research Center for Oncology named after N.N. Blokhin of the Ministry of Health of the RF (Moscow).
10. Galina N. Minkina - Doctor of Medical Sciences, Professor, Professor at the Department of Obstetrics, Gynecology and Reproductive Medicine of the N.A. Semashko Research and Educational Institute of Clinical Medicine at the Russian University of Medicine; member of the Association for Cervical Pathology and Colposcopy, member of the Russian Society of Obstetricians and Gynecologists (Moscow).
11. Vera N. Prilepskaya – Doctor of Medical Sciences, Professor, Head of the Scientific and Policlinic Department at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of Russia.
12. Narine M. Tonoyan – Candidate of Medical Sciences, Obstetrician-Gynecologist at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of the Russian Federation (Moscow).
13. Elena V. Uvarova – Corresponding Member of the RAS, Doctor of Medical Sciences, Professor, Honored Worker of Science of the RF, Head of the 2nd Gynecological Department at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Ministry of Health of the Russian Federation, Professor at the Department of Obstetrics, Gynecology and Reproductology of the Institute of Professional Education at the I.M. Sechenov First Moscow State Medical University (Sechenov University) of the Ministry of Health of the Russian Federation, Chief freelance Pediatric and Adolescent Gynecologist of the Ministry of Health of the Russian Federation, President of the Association of Pediatric and Adolescent Gynecologists of Russia, member of the Russian Society of Obstetricians and Gynecologists.
14. Maria I. Yarmolinskaya – Professor of the RAS, Doctor of Medical Sciences, Professor, Head of the Department of Gynecology and Reproductive Endocrinology at the D.O. Ott Research Institute of Obstetrics and Gynecology, Professor at the Department of Obstetrics and Gynecology at the I.I. Mechnikov North-Western State Medical University of the Ministry of Health of Russia, member of the Russian Society of Obstetricians and Gynecologists.
Conflict of interest: none.
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience for these clinical guidelines:
Obstetricians-gynecologists,
Dermatovenerologists,
Family medicine physicians,
Students, residents, PhD candidates, and faculty of medical universities.
Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Table 2. Levels of Evidence (LoE) grading scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitation interventions)
LoE | Definitions |
|---|---|
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Table 3. Scale for assessing grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or satisfactory methodological quality, and their conclusions regarding the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or satisfactory methodological quality and/or their conclusions regarding the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of evidence of proper quality (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality and their conclusions regarding the outcomes of interest are inconsistent) |
Procedure for updating clinical guidelines.
The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.
Appendix A3. Reference Materials
These clinical guidelines were developed taking into account the following regulatory legal documents:
Order of the Ministry of Health of the Russian Federation dated October 20, 2020, No. 1130n "On approval of the Procedure for the provision of medical care in the profile of 'obstetrics and gynecology'".
"Procedure for the provision of medical care in the profile 'Dermatovenerology'", approved by Order of the Ministry of Health of the Russian Federation dated November 15, 2012, No. 924n, as amended and supplemented on February 21, 2020.
Differential diagnosis (clinical) of HSIL and dVIN [11,17]
HSIL | dVIN | |
|---|---|---|
Age, years | 30-50 (mean 40) | 60-80 (mean 70) |
Frequency of occurrence, % | 95 | 5 |
Lesions | Multiple | Single |
Risk factors | History of squamous lesion of the lower anogenital tract | LSC |
Smoking | Chronic inflammation | |
Immunosuppression | Less than 1.5% HPV+ | |
HR HPV | ||
Promiscuity (sexual relations with multiple partners) | ||
Symptoms | Periodic pruritus | Pruritus |
Irritation | Pain | |
Pain | Dryness | |
Psychosexual issues | Dyspareunia | |
Asymptomatic (30%) | Bleeding | |
Clinical presentation | Diverse, includes: | Shiny, slightly elevated, broad red plaque on the vestibular mucosa of the vagina |
| White, depigmented, broad thickened plaque at the mucosal border | |
| Maculopapular plaque with minor warty structure on the skin | |
| Poorly demarcated plaque with erythema or whitening | |
| ||
| ||
| ||
Risk of invasion, % | 5 | 35 |
Time from biopsy to invasion, months | 41 | 23 |
Recurrence | Frequent | Less frequent than in HSIL (15-50 %) |
Most common histological type in recurrences | VSCC | Warty/basaloid carcinoma |
Appendix B. Physician Action Algorithms
Treatment algorithm for women with VIN [11,17].
Appendix C. Patient Information
Cancer and precancerous lesions of the vulva are rare and difficult to diagnose. Therefore, understanding the developmental mechanisms and identifying pathological conditions of the vulva is of great importance. Timely identification of pathological processes helps prevent the development of serious oncological diseases and ensures appropriate treatment is prescribed in due time.
The development of vulvar squamous intraepithelial lesions may be associated with human papillomavirus. Early onset of sexual activity and frequent changes of sexual partners increase the risk of human papillomavirus infection.
It is important to note that precancerous lesions and vulvar cancer are generally asymptomatic. Therefore, regular preventive examinations by an obstetrician-gynecologist are extremely important.
It is necessary to observe personal and intimate hygiene rules, avoid frequent changes of sexual partners, and casual sexual relations.
Gentle intimate hygiene is recommended for women with VIN.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
No.