Vaginal intraepithelial neoplasia

Authors
Christine H Holschneider, MD
Jonathan S Berek, MD, MMS
Section Editor
Barbara Goff, MD
Deputy Editor
Sandy J Falk, MD, FACOG
Disclosures: Christine H Holschneider, MD Nothing to disclose. Jonathan S Berek, MD,
MMS Grant/Research/Clinical Trial Support: Tesaro [Cancer Rx (Naraparib)]. Barbara Goff, MD Nothing to
disclose. Sandy J Falk, MD, FACOG Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed
by vetting through a multi-level review process, and through requirements for references to be provided to support the
content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.
Conflict of interest policy

All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jun 2015. | This topic last updated: Jan 09, 2014.
INTRODUCTION The diagnosis of vaginal intraepithelial neoplasia (VaIN) has increased steadily
over the past several decades as a result of heightened awareness, expanded cytologic screening,
and the liberal use of colposcopy. The relative rarity of VaIN, which is far less common than cervical
intraepithelial neoplasia (CIN) or vulvar intraepithelial neoplasia (VIN), is an impediment to a
thorough understanding of the disease process and its natural course. As a result, much of this
information is an extrapolation of our knowledge of the pathophysiology of cervical and vulvar
intraepithelial neoplasia.
Diagnosis and management of women with VaIN is reviewed here. VIN and CIN are discussed
separately. (See "Vulvar intraepithelial neoplasia" and "Cervical intraepithelial neoplasia:
Management of low-grade and high-grade lesions" and "Cervical intraepithelial neoplasia:
Treatment and follow-up".)
CLASSIFICATION Vaginal intraepithelial neoplasia is defined by the presence of squamous cell
atypia without invasion. The disease is classified according to the depth of epithelial involvement:
VaIN 1 and 2 involve the lower one-third and two-thirds of the epithelium, respectively, and VaIN 3
involves more than two-thirds of the epithelium (picture 1). Carcinoma in situ, which encompasses
the full thickness of the epithelium, is included under VaIN 3. In 2012, as part of the lower
anogenital squamous terminology (LAST) standardization project for human papilloma virus (HPV)associated lesions, the College of American Pathologists and the American Society for Colposcopy
and Cervical Pathology have proposed a revised terminology by which VaIN is reported using a
two-tiered nomenclature: LSIL for low-grade disease (VaIN 1) and HSIL for high-grade disease [1].
Intraepithelial vaginal dysplasia of glandular origin, or atypical vaginal adenosis, is a separate entity.
This lesion has a well-established association with in utero diethylstilbestrol (DES) exposure and
may be a precursor to DES-associated clear-cell adenocarcinoma [2]. In addition, cases have been
reported of atypical adenosis and vaginal adenocarcinomas in non-DES-exposed women [3].

EPIDEMIOLOGY The true incidence of VaIN is unknown, but is estimated at 0.2 to 0.3 cases per
100,000 women in the United States [4]. The average patient is between 43 and 60 years of age [57]. Based on data from the United States (US) Centers for Disease Control and Prevention's
National Program of Cancer Registries and the National Cancer Institute's Surveillance,
Epidemiology and End Results Program, the incidence of vaginal carcinoma in situ in the US is
estimated at 0.1 cases per 100,000 women. Vaginal carcinoma in situ incidence peaks at age 70 to
79 years, slightly younger than the peak incidence age for vaginal carcinoma [8].
Risk factors Although multiple risk factors have been implicated in the genesis of lower genital
tract neoplasias, infection with human papillomavirus (HPV) is a common association
(see 'Etiology' below) [5]. As an example, in a case-control study of 19 patients, low level of
education, low family income, and history of vaginal condyloma were all risk factors for developing
VaIN, but are also dependent variables predicting exposure to HPV [9]. Genetic and acquired
immunosuppression, including human immunodeficiency virus (HIV) infection, are risk factors for
developing both VaIN and HPV infection, as with CIN [10-12]. (See "Vulvar and vaginal
intraepithelial neoplasia in HIV-infected women", section on 'Incidence' and "Cervical cancer
screening tests: Techniques for cervical cytology and human papillomavirus testing", section on
'HPV testing'.)
VaIN is consistently associated with prior or concurrent neoplasia elsewhere in the lower genital
tract. In most studies, 50 to 90 percent of patients with VaIN had or currently have either
intraepithelial neoplasia or carcinoma of the cervix or vulva [6,13-15]. In addition, approximately 1 to
7 percent of patients undergoing hysterectomy for CIN develop VaIN a few months to several years
after surgery [16-19]. As an example, one study found VaIN in 5 percent of 793 patients followed for
10 years after surgery for CIN 3 [20]. There is evidence that some high grade vulvar and vaginal
intraepithelial neoplasia is a monoclonal lesion derived from high grade or malignant cervical
disease [21].
Women who undergo hysterectomy for benign conditions other than CIN are at lower risk for
developing VaIN than women with CIN or cancer. In one report, the average time to diagnosis of
VaIN after hysterectomy in women with benign disease was 11 years, compared with one year
among women with CIN [22]. Another large cohort study found a mean time to diagnosis of VaIN for
women who had undergone hysterectomy of 14 years if the hysterectomy was for benign
indications and 10 years if the hysterectomy was for dysplasia or carcinoma [15]. Subsequent occult
vaginal invasion appears to be more common in patients with CIN treated with hysterectomy than in
those whose cervix was retained [22]. This may be the result of lower rates of follow-up cytology
and more difficult examination of the vaginal apex in hysterectomized women. It may also be a
result of selection bias, as only women with no cervical dysplasia are likely to have their cervix
retained. (See "Cervical cancer screening tests: Techniques for cervical cytology and human
papillomavirus testing".)
Some data suggest an increased risk for VaIN 2/3 in high risk HP-positive women who smoke
compared to high risk HPV-positive non-smokers [23]. The data regarding the role of previous
radiation treatment in the development of secondary neoplasia of the vagina are conflicting [24,25].
ETIOLOGY Two etiologies have been proposed to explain the strong association between VaIN
and neoplasia elsewhere in the lower genital tract. One possibility is that women who develop VaIN
shortly after surgery for CIN may simply have vaginal extension of cervical disease that was not

detected and treated. However, VaIN is frequently multifocal, can occur several years after a
hysterectomy for neoplasia, is independent of the amount of vaginal cuff excised, and is often
observed de novo in the absence of cervical disease [26]. Thus, it is unlikely that the condition is the
result of extension from the cervix in every case.
A second theory is that lower genital tract neoplasias share common etiologic factors, since
approximately one-half of VaIN lesions are associated with concomitant cervical or vulvar neoplasia
[13,15]. This field effect is based upon the principle that tissues of common embryological origin are
susceptible to neoplasia from exposure to similar carcinogenic stimuli. In particular, exposure to
HPV appears to induce neoplasms in all three locations of the lower female genital tract (cervix,
vagina, vulva) [27].
HPV infection HPV-associated lesions are often multifocal (originating within several discrete
foci at one anatomic site) and multicentric (involving several distinct anatomic sites of the lower
genital tract). Although the relationship between HPV infection and intraepithelial neoplasia of the
cervix is well known, there are less data available regarding vaginal neoplasia [28]. A review of 232
published VaIN cases reported a high prevalence of HPV in these lesions as detected by either
polymerase chain reaction or hybrid capture assays for HPV DNA detection: 92.6 percent in
VaIN 2/3, and 98.5 percent in VaIN 1 [29].
Several viral subtypes are associated with VaIN (table 1), with HPV 16 and 18 being the most
prevalent HPV types [30]. The prevalence of oncogenic HPV subtypes in the vagina is similar in
women who have and have not undergone hysterectomy [31]. Thus, presence of the cervix does
not appear to be necessary for oncogenic HPV to infect the genital tract. (See "Cervical cancer
screening tests: Techniques for cervical cytology and human papillomavirus testing", section on
'HPV testing'.)
The disparity between the relatively high incidence of CIN and rarity of VaIN in women who test
positive for HPV may be due to increased susceptibility of the metaplastic transformation zone of
the cervix to oncogenic stimuli. In contrast, the mature, stable, squamous epithelium of the vagina
may be less vulnerable to the same stimuli [32]. Women who have been exposed to DES in utero
often have squamous metaplasia of the vagina, instead of normal columnar epithelium; this
observation may explain the increased incidence of VaIN noted in some studies of these women
[33,34].
DIAGNOSIS Vaginal intraepithelial neoplasia is usually asymptomatic, although patients can
present with postcoital spotting or vaginal discharge. It should be excluded in all women with an
abnormal Pap smear who are posthysterectomy or who do not have identifiable cervical lesions that
could account for the abnormality.
The examination should include digital palpation to assess for thickening or irregularity of the
vaginal wall and a thorough colposcopic assessment of the entire vagina. In the postmenopausal
patient, a few weeks of topical estrogen treatment will often accentuate visualization and improve
detection of VaIN. After the insertion of a speculum and the application of acetic acid, lesions will
appear as raised or flat white, granular epithelium with sharply demarcated borders and may
contain areas of vascular punctation. A biopsy should be taken from any suspicious areas.
The majority of lesions are located in the upper one-third of the vagina [35]. Lesions located in posthysterectomy vaginal recesses can be difficult to visualize; skin hooks may be used to gently evert

these areas. The presence of a markedly irregular surface or severe vascular abnormalities with
unusual branching suggests an invasive process, which warrants an excisional biopsy. Schiller's or
Lugol's iodine solution can be used to detect lesions and confirm boundaries prior to excision.
Biopsy technique A speculum is placed in the vagina and the planned biopsy site is prepared
with iodine (or an alternative preparation solution, if the patient is allergic to iodine). When biopsy is
attempted, it is helpful to partially close the speculum to allow the vagina to fold in on itself. Keeping
the vagina taut makes performing a biopsy difficult. Local anesthetic is injected (eg, 1
percent lidocaine without epinephrine).
For sessile lesions, the biopsy is taken using a cervical biopsy forceps (eg, Kevorkian). Some raised
or pedunculated lesions can be grasped with a forceps and biopsied using a fine scissor (eg,
Metzenbaum). Hemostasis is usually obtained with application of Monsel's solution or use of silver
nitrate. If bleeding persists, a suture may be necessary.
NATURAL HISTORY The natural course of VaIN has not been fully characterized. Although
there have been no prospective studies, several retrospective investigations of various treatment
modalities of VaIN have reported that 2 to 5 percent of cases of VaIN progress to invasive vaginal
carcinoma [13-15,36-39]. One of the largest retrospective series had only 127 women; there were
no cases of progression to invasive disease with a median follow-up of 34 months [40]. The rate of
persistent or recurrent VaIN did not differ significantly with treatment or by grade: overall (11
percent); without treatment (VaIN 1: 15 percent; VaIN 2,3: 7 percent); with treatment (VaIN 1: 13
percent; VaIN 2,3: 5 percent).
Another study, as an example, found that 9 of 32 patients undergoing vaginectomy for VaIN 3 had
foci of invasive carcinoma upon histologic examination [36]. In another series, 18 of 23 patients with
VaIN followed expectantly for at least three years had complete regression of their lesions, three
patients had persistent disease, and two (one with VaIN 3 and another with a lower grade lesion)
progressed to invasive carcinoma resulting in an estimated lifetime risk of malignant transformation
of VaIN to invasive vaginal carcinoma of 9 to 10 percent [13].
TREATMENT A broad range of treatment options are available for therapy of VaIN: excision,
ablation, topical therapy, and radiation of lesions. We manage women with VaIN 1 with close
surveillance, rather than treatment. VaIN 1 lesions often regress spontaneously, do not have an
established malignant potential, are multifocal, and tend to recur frequently after treatment.
Treatment options for VaIN 2/3 are reviewed in this section
Surgical therapy Surgical excision is the mainstay of VaIN treatment (table 2). This approach
permits histologic diagnosis, a significant advantage over other treatments since invasive foci have
been detected in up to 28 percent of specimens [22]. Surgical approaches include local excision,
partial vaginectomy, and, rarely, total vaginectomy for extensive and persistent disease.
(See "Vaginectomy".) Most excisions are performed transvaginally, although at times an open or
minimally invasive abdominal approach is necessary. A partial vaginectomy is often required when
VaIN is buried in the post-hysterectomy vaginal vault recesses, as these lesions are frequently
inaccessible to other forms of treatment. Presurgical administration of topical therapy may reduce
lesion size, allow loosening of epithelial-stromal adherence, and enable VaIN to be stripped from
the underlying tissue during local excision [14]. Partial vaginectomy is required when VaIN is buried

in posthysterectomy suture recesses, as these lesions are frequently inaccessible to other forms of
treatment.
Complications of surgical therapy range from shortening or stenosis of the vagina due to wide local
excisions, to significant postoperative morbidity following abdominal procedures. The risk of
complications is significantly increased in previously irradiated patients [6]. Electrosurgical loop
excision, laser vaginectomy, and ultrasonic surgical aspiration are modifications of the cold-knife
approach that may promote rapid healing and reduce the frequency of complications [41-44].
A literature review of surgical treatment of VaIN reported an 18 percent incidence (range 0 to 50
percent) of recurrent disease during follow-up periods of three months to 18 years (table 2)
[6,14,16,22,36,37,42]. Recurrences of VaIN have also been described in vaginal tissue grafts
performed to repair the vagina after vaginectomy [45].
Ablation The CO2 laser is one commonly used technique for local tissue ablation. Although
approximately one-third of patients will require more than one treatment, the procedure is generally
well tolerated, heals satisfactorily, and results in minimal sexual dysfunction (table 3) [46-53]. Pain
and bleeding are the most frequent complications, requiring intervention in 20 percent of patients in
one series [54].
A randomized controlled trial of carbon dioxide laser versus ultrasonic surgical aspiration involving
110 patients demonstrated no difference in recurrence of dysplasia during a one-year follow-up
period (26 versus 24 percent); there was less postoperative pain and less vulvar scarring with the
ultrasonic surgical aspiration [55].
Ablative therapy should not be performed if the entire area of abnormal epithelium cannot be
visualized or if there is any suspicion of invasion during thorough colposcopy.
Topical therapy While partial or total vaginectomy appears to be the safest method of treating
multifocal high-grade VaIN, a variety of alternate less radical modalities have been used and
studied. 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.
There are no guidelines clearly defining the ideal treatment for multifocal high-grade VaIN. Topical
therapy appears to be an appropriate first-line therapy in women with early lesions and multifocal
disease or those who are poor surgical candidates. As with ablation, it is a prerequisite for topical
treatment that invasion be excluded by thorough colposcopic examination and biopsy.
Imiquimod There are several small case series on the use of topical application of 5
percent imiquimod cream for the treatment of vaginal intraepithelial neoplasia with promising results
[56-59]. In these reports variable imiquimod treatment regimens lead to complete response in a
considerable percentage of patients with a reported 22 to 29 percent persistence or recurrence rate.
In addition, patients who experienced partial response required less extensive excision. In one
reported regimen, 5 percent imiquimod cream is applied to the vaginal lesions three times a week
for eight weeks [57]. The most common adverse events are local burning and soreness, which are
generally not severe enough for patients to discontinue treatment. Based on the available data,
imiquimod may be a reasonably effective and well-tolerated topical therapy option in the treatment
of VaIN. However, larger studies with standardized treatment protocols and longer follow-up are
needed to make safe conclusions regarding the effectiveness, recurrence rates, and durability
(recurrence free interval) of this treatment.

5-fluorouracil (5-FU) Failure rates are comparable to other techniques (table 4) [50,52,60-64].
Complications of topical 5-FU include vaginal irritation or burning and ulcerations [61,65].
External zinc oxide cream or petroleum jelly can be used as a barrier to help protect against
ulceration in adjacent areas. Topical estrogen also may reduce patient discomfort. Columnar
metaplasia of the vaginal mucosa can occur after topical 5-FU; the clinical significance of this
finding is not known [66].
Several dosing protocols have been suggested, ranging from twice daily application for fourteen
days to once weekly for 10 weeks.
Vaccines directed against HPV are another investigational approach. (See "Recommendations for
the use of human papillomavirus vaccines".)
Radiation therapy Intracavitary radiation therapy, while an effective form of treatment, is rarely
used because simple resection of the cuff or ablative therapy is usually successful and it is
associated with higher rates of morbidity than other therapies. Radiation therapy is reserved for
patients who have failed previous treatments, are poor surgical candidates, or who have extensive,
multifocal disease. The optimum dose is unclear. In one study of 14 patients who received high
dose rate brachytherapy for VaIN 3, disease regressed, progressed to invasive cancer, or persisted
in 12, one, and one patients, respectively, during a median follow-up of 46 months [67]. In another
series with median follow-up of 77 months, regression occurred in 17 of 22 patients who received
medium dose rate brachytherapy for VaIN 3 [68]. Low dose rate brachytherapy has also been used.
Vaginal complications caused by intracavitary radiation include atrophy, stenosis, and shortening.
These anatomic distortions can interfere with sexual function and are an impediment to thorough
colposcopic follow-up. Bowel and bladder changes and the induction of menopause also can occur.
Poor wound healing of irradiated tissue is a concern for patients who subsequently require surgical
intervention [18].
Selection of treatment modality The goals of therapy of VaIN are prevention of disease
progression, while minimizing potential treatment sequelae and improving quality of life. Previous
treatment failures, the presence of multifocal disease, the patient's general health and comorbidities
as well as her desire to preserve sexual function are factors to consider in selecting a therapeutic
course. Prerequisites for ablative therapy are that the lesion is fully visualized and invasive disease
is excluded by biopsy. Thus, if there is uncertainty whether invasive disease has been reliably
excluded, excisional therapy is required.
Complications most commonly associated with medical therapies for VaIN include pain, irritation,
and superficial ulcerations. Surgical therapies may induce pain, scarring, and sexual dysfunction.
No randomized controlled trials comparing treatment modalities for VaIN have been performed.
However, a recent review of 21 available studies on therapeutic modalities found cure rates for VaIN
were similar for excision, laser ablation, and CUSA (69 to 87.5 percent) [69].
Posttreatment surveillance Posttreatment follow-up with cytological smears every six months
for one to two years and annually thereafter is reasonable. Given the high prevalence of HPV in
VaIN, there may be a role for HPV-testing in the posttreatment follow-up of patients with VaIN
similar to that observed post CIN treatment. In a study of 44 women with VaIN, posttreatment HPV
testing had a sensitivity of 90 percent and specificity of 78 percent [70].

Management of these lesions requires long term follow-up. A study of multicentric dysplasias
including CIN with VaIN and/or VIN reported a particularly high rate of residual lesions (55 percent)
and recurrence (44 percent) in these patients [71].
Prevention Immunization with HPV vaccination could potentially prevent approximately 70
percent of VaIN [72,73].
Smoking cessation and complete or proper treatment of CIN, VIN, and adenocarcinoma in situ are
other interventions recommended to decrease the likelihood of VaIN [74].
SUMMARY AND RECOMMENDATIONS
Vaginal intraepithelial neoplasia (VaIN) is defined by the presence of squamous cell atypia
without invasion. The disease is classified according to the depth of epithelial involvement:
VaIN 1 and 2 involve the lower one-third and two-thirds of the epithelium, respectively, and
VaIN 3 involves more than two-thirds of the epithelium (picture 1). Carcinoma in situ, which
encompasses the full thickness of the epithelium, is included under VaIN 3.
(See 'Classification' above.)
The true incidence of VaIN is unknown, but is estimated at 0.2 to 0.3 cases per 100,000
women in the United States. The average patient is between 43 and 60 years of age.
(See 'Epidemiology' above.)
VaIN is usually asymptomatic, although patients can present with postcoital spotting or
vaginal discharge. It should be excluded in all women with an abnormal Pap smear who are
posthysterectomy or who do not have identifiable cervical lesions that could account for the
abnormality. (See 'Diagnosis' above.)
VaIN is a histologic diagnosis, typically made based upon colposcopically directed biopsy of
the vagina. (See 'Diagnosis' above.)
Once high-grade VaIN is diagnosed, invasive disease must be excluded by colposcopy and
biopsy, especially before undertaking nonexcisional therapy that does not permit further
histologic confirmation of disease. (See "Colposcopy".)
Surgical excision, laser ablation, topical therapy, and intracavitary radiation successfully
eliminate the lesion in approximately 70 to 80 percent of women; there is a 20 to 30 percent
recurrence rate. (See 'Treatment' above.)
The choice of therapy depends upon the patient's general health, surgical risks, desire for
vaginal sexual function, presence of multifocal disease, and the certainty with which invasive
disease has been excluded. (See 'Treatment' above.)
Following therapy, gynecologic examination and vaginal cytology should be performed every
six months for one to two years and annually thereafter to evaluate for persistent or
progressive disease. Thereafter, patients can be followed at annual intervals. HPV testing may
be useful as part of posttreatment surveillance. (See'Posttreatment surveillance' above.)
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