Vulva & vagina
Squamous carcinoma & precursor lesions
Vaginal intraepithelial neoplasia (VAIN)
Authors: Shazia Khan, M.D., Natalia Buza, M.D.
Editorial Board Member: Stephanie L. Skala, M.D.
Deputy Editor-in-Chief: Gulisa Turashvili, M.D., Ph.D.
Last author update: 19 November 2024
Last staff update: 19 November 2024
Copyright: 2002-2024, PathologyOutlines.com, Inc.
PubMed Search: Vaginal intraepithelial neoplasia (VAIN)
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Prognostic factors | Case reports | Treatment | Gross description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Khan S, Buza N. Vaginal intraepithelial neoplasia (VAIN). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/vaginavain.html. Accessed December 26th, 2024.
Definition / general
- Vaginal intraepithelial neoplasia (VAIN) is defined as squamous cell dysplasia including maturation abnormalities and cytopathic changes, which do not extend beyond the basement membrane
- VAIN lesions are divided into a 2 tier system, low grade (VAIN 1) and high grade (VAIN 2 - 3) (Arch Pathol Lab Med 2012;136:1266)
Essential features
- Squamous dysplasia, which does not extend beyond the basement membrane
- Most commonly associated with human papillomavirus (HPV) but may also be associated with tobacco use, postmenopause and history of cervical intraepithelial neoplasia (CIN) (Chin Med J (Engl) 2012;125:1219)
- This disease is rare, representing < 1% of all intraepithelial neoplasias of the female genital tract (PLoS One 2016;11:e0167386)
Terminology
- Related terminology includes low grade squamous intraepithelial lesion (LSIL) (VAIN 1 / mild squamous dysplasia) and high grade squamous intraepithelial lesion (HSIL) (VAIN 2 / moderate squamous dysplasia and VAIN 3 / severe squamous dysplasia)
ICD coding
Epidemiology
- True incidence of VAIN is unknown but is estimated to be 0.1 cases per 100,000 women in the U.S. (J Womens Health (Larchmt) 2009;18:1731)
- Current reported values may underestimate the incidence
- Risk factors include advanced age, HPV infection, concomitant cervical intraepithelial neoplasia, cervical cancer and hysterectomy (J Obstet Gynaecol Res 2021;47:1624)
- Mean age is ~50 - 60 years although can occur over a wide age range (22 - 80 years) (Acta Obstet Gynecol Scand 1999;78:648, J Obstet Gynaecol Res 2010;36:94)
- Recurrence rate is high and malignant potential is well established
Sites
- More common in upper third of the vagina and fornices (J Obstet Gynaecol Res 2010;36:94)
Pathophysiology
- Exact pathophysiological mechanisms are still under investigation
- HPV E6 and E7 protein expression induce high grade changes of squamous epithelium (Nat Rev Dis Primers 2016;2:16086)
Etiology
- HPV has been implicated in pathogenesis of VAIN
- HPV associated lesions are often multifocal and multicentric and foci of squamous intraepithelial neoplasia in the cervix are commonly found (Eur J Gynaecol Oncol 2017;38:10)
- Prevalence of HPV in VAIN 2 - 3 and VAIN 1 is 92.6% and 98.5%, respectively, higher than in vulvar lesions (Obstet Gynecol 2009;113:917)
- VAIN 1 / LSIL may be associated with either low risk or high risk HPV types, while VAIN 2 - 3 / HSIL is associated with high risk HPV
- HPV 16 is the most common HPV type in vaginal (55.4%) cancers and VAIN 2 - 3 (65.8%) (Obstet Gynecol 2009;113:917, Int J Cancer 2019;145:78)
- On the basis of their association with premalignant and malignant lesions, 13 HPV types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 68) have been defined as high risk (HR) (J Pathol 2014;234:431)
- History of prior pelvic radiation (7.4%), associated neoplasia of the lower genital tract (67.6%) and history of prior hysterectomy (54.4%) (J Obstet Gynaecol Res 2010;36:94)
- Arises from native squamous epithelium, not metaplastic epithelium as in cervix
Clinical features
- Lesions may be raised, flat, white, gray or have irregular pigmentation
- VAIN is usually asymptomatic but may present with postcoital spotting or vaginal discharge
- Most common presentation is abnormal cytology (J Obstet Gynaecol Res 2010;36:94)
- Colposcopy directed biopsy has a sensitivity of > 80% (Arch Gynecol Obstet 2020;301:769)
- Must be excluded in all women with an abnormal Pap smear who had a hysterectomy or who do not have identifiable cervical lesions that could account for the abnormality
Diagnosis
- VAIN is a histologic diagnosis, typically based on colposcopic assessment and directed biopsy of the vagina (J Obstet Gynaecol Res 2010;36:94)
- Lugol iodine solution can be used to detect lesions and confirm boundaries prior to excision
Prognostic factors
- HSIL / VAIN 2 - 3 is a precursor to invasive squamous cell carcinoma of the vagina
- HPV serotypes 16 and 18 are associated more with VAIN 2 - 3 (HSIL)
- HPV serotypes 6 and 11 are associated more with VAIN 1 (LSIL)
- Reference: Obstet Gynecol 2009;113:917
Case reports
- 32 year old woman with concurrent nonavalent HPV vaccination and immune stimulation with imiquimod to treat recalcitrant HPV associated high grade vaginal intraepithelial neoplasia (Gynecol Oncol Rep 2024;52:101350)
- 39 year old woman with vaginal intraepithelial neoplasia 3, without simultaneous cervical intraepithelial neoplasm (J Med Cases 2020;11:246)
- 53 year old woman with recurrent vaginal intraepithelial neoplasia successfully treated with topical imiquimod (Mol Clin Oncol 2020;13:19)
- 54 year old woman with inherited chromosomally integrated human herpesvirus type 6A and vaginal neoplasia induced by an unusual papillomavirus subtype (Gynecol Obstet Invest 2017;82:307)
- 10 cases of vaginal intraepithelial neoplasia after radiation therapy for gynecologic malignancies (Gynecol Oncol 2011;120:108)
- Case series of 657 women with intraepithelial neoplasia (Eur J Gynaecol Oncol 2022;43:42)
Treatment
- Surgical excision is the mainstay of VAIN treatment (J Low Genit Tract Dis 2012;16:306)
- Surgical approaches include local excision, partial vaginectomy; rarely total vaginectomy for extensive and persistent disease
- Partial or total vaginectomy appears to be the safest method of treating multifocal high grade VAIN
- Complications include shortening or stenosis of the vagina following wide local excision and significant postoperative morbidity following abdominal procedures
- CO2 laser therapy is also used for local tissue ablation, with pain and bleeding being the most frequent complications (J Reprod Med 1990;35:941)
- Ablative therapy should not be performed if the entire area of abnormal epithelium cannot be visualized or if there is any suspicion of invasion through colposcopy
- Medical therapy
- Topical application of therapeutic agents has the advantage of treating the entire vaginal mucosa with good coverage of multifocal disease and disease in folds and recesses of the vagina
- Imiquimod 5% cream is commonly used (Int J Gynaecol Obstet 2008;101:3, Int J Gynecol Cancer 2005;15:898, J Low Genit Tract Dis 2003;7:290, J Low Genit Tract Dis 2012;16:306)
- Complications of topical fluorouracil (5FU) include vaginal irritation or burning and ulcerations (Obstet Gynecol 1981;58:580)
- Radiation therapy includes high dose brachytherapy (Gynecol Oncol 1997;65:74)
- Conservative options in the form of laser ablation and topical agents are useful as first line treatment methods, especially in young women and for multifocal disease
- Radical options like brachytherapy and vaginectomy should be reserved for highly selected cases (J Low Genit Tract Dis 2012;16:306)
Gross description
- On colposcopy with application of 3 - 5% acetic acid, lesions appear as raised or flat white, granular epithelium with sharply demarcated borders with punctation and mosaic pattern more prevalent in VAIN 2 - 3 (J Obstet Gynaecol Res 2010;36:94)
Microscopic (histologic) description
- By definition, lesions must not extend beyond the basement membrane
- Basal cells may display large, dark nuclei with basophilic cytoplasm
- Affected cells may display koilocytic / viral cytopathic changes and eosinophilic cytoplasm as they approach the surface
- VAIN is classified in a similar manner to cervical dysplasia / cervical intraepithelial neoplasia
- VAIN 1: mild dysplasia
- VAIN 2: moderate dysplasia
- VAIN 3: severe dysplasia / carcinoma in situ
- VAIN is classified according to the depth of epithelial involvement
- VAIN 1 involves the lower one - third of epithelium
- VAIN 2 involves lower two - thirds of epithelium
- VAIN 3 involves more than two - thirds of epithelium
- Carcinoma in situ, which encompasses the full thickness of the epithelium, is included under VAIN 3
- Low grade VAIN corresponds to VAIN 1 and is analogous to LSIL
- High grade VAIN corresponds to VAIN 2 - 3 and is analogous to HSIL
- Reference: Am J Obstet Gynecol 2013;208:410.e1
Microscopic (histologic) images
Contributed by Shazia Khan, M.D. and Natalia Buza, M.D.
LSIL / VAIN 1
HSIL / VAIN 2
LSIL / VAIN1 (p16 immunostain)
LSIL / VAIN1 (Ki67 immunostain)
HSIL / VAIN 2 (p16 immunostain)
HSIL / VAIN 2 (p53 immunostain)
HSIL / VaIN2 (Ki67 immunostain)
Cytology description
- Cytological features are similar to cervical Pap smear
- Low grade: mild squamous dysplasia, including koilocytic atypia and nuclei that are enlarged at least 3 - 4 times that of the normal intermediate cell nucleus; HPV cytopathic changes including distinct perinuclear cytoplasmic halo and binucleation or multinucleation may be noted
- High grade: moderate to severe squamous dysplasia comprising high N:C ratio, immature cytoplasm and greater nuclear pleomorphism
- Reference: Am J Obstet Gynecol 2013;208:410.e1
Positive stains
- p16 strong diffuse block positivity involving basal keratinocytes and extending beyond the lower third of the epithelium is found in nearly all high grade lesions
- Low risk HPV E7 protein expression may produce focal or weak p16 staining in lower grade lesions
- p53 immunostaining pattern is wild type
- Ki67 proliferation index may be elevated in both low grade and high grade lesions
- Reference: J Obstet Gynaecol Res 2018;44:2077
Sample pathology report
- Vagina, 3 o’clock, biopsy:
- Low grade squamous intraepithelial lesion (VAIN 1)
Differential diagnosis
- Atrophy / transitional metaplasia (StatPearls: Genitourinary Syndrome of Menopause [Accessed 24 October 2024]):
- Squamous cell carcinoma:
- Evaluation of the basement membrane is necessary to rule out an invasive process
Additional references
Board review style question #1
Which HPV subtype is the most common driver of VAIN 2 - 3 / vaginal high grade squamous intraepithelial lesion (HSIL)?
- HPV 16
- HPV 18
- HPV 31
- HPV 33
- HPV 35
Board review style answer #1
A. HPV 16 is the most common high risk HPV subtype associated with VAIN 2 - 3 / HSIL. Answers B, C, D and E are incorrect because although they are all high risk HPV subtypes, they are less common.
Comment Here
Reference: Vaginal intraepithelial neoplasia (VAIN)
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Reference: Vaginal intraepithelial neoplasia (VAIN)
Board review style question #2
A raised vaginal lesion in a 52 year old woman was biopsied and showed the features in the image above. What is your diagnosis?
- High grade squamous intraepithelial lesion (HSIL) / VAIN 2
- HSIL / VAIN 3
- Low grade squamous intraepithelial lesion (LSIL) / VAIN 1
- Reactive changes, no dysplasia is identified
Board review style answer #2
C. Low grade squamous intraepithelial lesion (LSIL) / VAIN 1. The biopsy shows papillomatous architecture, increased cellularity, koilocytic change, increased mitotic activity, hyperkeratosis and parakeratosis, consistent with the diagnosis of LSIL / VAIN 1. Answers A and B are incorrect because the dysplastic changes do not extend beyond one - third of the epithelium. Answer D is incorrect because the combination of morphological changes (including increased mitotic figures and koilocytic changes) is beyond dysplastic changes.
Comment Here
Reference: Vaginal intraepithelial neoplasia (VAIN)
Comment Here
Reference: Vaginal intraepithelial neoplasia (VAIN)
