Objective
The purpose of this study was to review a large cohort of patients with vaginal intraepithelial neoplasia (VAIN) and to analyze the epidemiology and outcomes with various treatment modalities.
Study Design
A retrospective chart review was performed that encompassed patients who were treated for VAIN at a single center from 1990-2007. Demographics, disease characteristics, referring cytology, and histologic information were recorded. Primary outcome was recurrence or progression to carcinoma. Statistical analyses were performed with statistical software.
Results
One hundred sixty-three women were included in the study: median age, 50 years (range, 21–84 years); white, 87%; current or previous smokers, 35%. At the time of diagnosis, 23% of the women had VAIN1; 37% of the women had VAIN2, and 35% of the women had VAIN3. Referral Papanicolaou smear results of high-grade squamous intraepithelial lesion or atypical glandular cells revealed VAIN2 or VAIN3 in 89% of cases ( P = .0019) vs 53% of cases with low-grade squamous intraepithelial lesion. The median follow-up period was 18 months (range, 1–194 months). VAIN1 was observed in 70% of cases; 71% of patients who were treated for VAIN1 had recurrence or progression. VAIN2 was treated in 77% of patients; 53% of those who were treated had recurrence or progression. VAIN3 was treated in 94% of cases; 31% of them had recurrence or progression. Risk of recurrence was not correlated to VAIN type ( P = .3). Six carcinomas were discovered in patients with VAIN2 and VAIN3. Median time to progression was 17 months for VAIN1, 11 months for VAIN2, and 11 months for VAIN3 ( P = .036).
Conclusion
Despite the subtype, VAIN often recurs but does so more quickly with higher grade dysplasia.
Although the true prevalence is unknown, the incidence of vaginal intraepithelial neoplasia (VAIN) has increased steadily over recent years because of increased use of screening methods such as cytology and colposcopy. VAIN was first reported by Hummer in 1933 and is estimated to occur in 0.2-0.3 per 100,000 women in the United States. VAIN is defined as squamous cell atypia without stromal invasion and is classified by the involved depth of epithelium. Accordingly, VAIN1 involves only the lower one-third of the epithelium; VAIN2 encompasses the lower and middle thirds, and VAIN3 involves the lower, middle, and at least part of the upper third of the epithelium ( Figure 1 ). Human papillomavirus (HPV) plays a critical role in the development of anogenital neoplasia. Historically, research has focused on cervical neoplasia; however, over recent years HPV has been linked closely with high-grade vaginal (92.6%) and vulvar neoplasia (80.4%) as well. In a systematic review by Smith et al, HPV types 16 and/or 18 were identified in 60% of high-grade VAIN (VAIN 2/3) and 41% of low-grade VAIN (VAIN1). Further risk factors for VAIN mirror those of dysplasia and carcinoma of the cervix and include multiple sexual partners, early age at sexual debut, low socioeconomic status, tobacco abuse, and immunosuppression, all of which increase the likelihood of HPV infection. High-grade VAIN is a direct precursor to carcinoma of the vagina.
Despite the similarity in pathogenesis, the incidence of VAIN is much lower than that of cervical intraepithelial neoplasia. Sillman et al reported a 100-fold difference in incidence at their institution over a 10-year period. This striking difference is explained by the lack of a vulnerable squamocolumnar junction in the vagina. Additionally, it is speculated that HPV infection of the vagina occurs as frequently as in the cervix but that a lytic cell reaction in the vagina enables the regression of lesions in contrast to the characteristic latent infection in the cervix, which causes persistent dysplasia.
Given the disease rarity, the epidemiologic patterns, natural history, and treatment outcomes with VAIN are not well understood. Our study objective was to review a contemporary cohort of patients with VAIN and to evaluate risk factors, grade and histologic distribution, primary treatment, and outcomes.
Materials and Methods
All patients had histologically confirmed VAIN and underwent treatment by gynecologic oncologists at The University of Oklahoma from 1990-2007. Institutional review board approval was granted before the initiation of data collection. Slides were not reviewed for this study, but gynecologic pathologists at The University of Oklahoma Health Sciences Center analyzed all cases at the time of diagnosis. Exclusion criteria included the presence of synchronous tumors and incomplete documentation. Patients were followed from the time of the initial diagnosis until death, loss to follow up, or completion of study. Race, age at diagnosis, hysterectomy, medical history, and tobacco abuse were recorded. Disease characteristics including grade, referral Papanicolaou smear, and treatment modalities such as surgery type or medical treatment were recorded; when combination treatments were utilized, this was noted. All vaginal biopsies and procedures that were performed during the study period were documented. Treatments administered were observation, surgical therapy with vaginectomy or local excision, ablative procedures (laser, rollerball, or cryotherapy), and chemotherapy; 5-fluorouracil was the only chemotherapy used. Regimens were not uniform but were based on physician preference. Primary outcome measures were the recurrence of VAIN and progression to carcinoma. Diagnosis of recurrence required histologic confirmation. Recurrence was defined as the return of vaginal dysplasia on biopsy after a preceding normal biopsy. Death from disease was defined as any treatment or tumor complications that were associated with cancer and death that was attributed to cancer.
Descriptive statistics were used to characterize the clinical and demographic attributes of the study sample. χ 2 and Fisher exact tests were used, as appropriate, to evaluate associations. Multiple regression analysis was used to examine disease recurrence and progression with a variety of factors. Statistical analyses were performed with SAS statistical software (version 9.2; SAS Institutes, Cary, NC).
Results
One hundred sixty-three patients met the study criteria. Table 1 describes the patient demographics. Median age was 50 years (range, 21–84 years), and 35% of the patients were either current or previous cigarette smokers. Race distribution was 87% white, 7% African American, 2.5% Native American, 2.5% Hispanic, and 1% other. At the time of diagnosis, 38 of the women (23%) had VAIN1; 61 of the women (37%) had VAIN2, and 57 of the women (35%) had VAIN3. Two patients initially had benign biopsy results but later experienced VAIN1 (1 patient) or vaginal carcinoma (1 patient). Sixteen percent of the women had previous cancer of the lower genital tract (excluding vagina). Of these patients, all had a history of cervix cancer, except 2 patients who had vulvar cancer. Fifty-seven percent of the total group had previous nonvaginal lower genital tract dysplasia. Eighty-one of these women had cervical dysplasia; 6 women had vulvar dysplasia, and 7 women had multifocal dysplasia. Two additional patients had a history of both lower genital tract dysplasia and carcinoma of the cervix or vulva. Fifteen patients previously had radiation, and 120 patients had a previous hysterectomy. Indication for hysterectomy was available from the medical record for 108 patients; most procedures were performed for benign disease. Surgical indications were dysplasia (28%), menorrhagia (27%), cancer (18%), endometriosis (14%), and pelvic pain (12%).
| Patient characteristic | Subjects (n = 161) |
|---|---|
| Age, y a | 51 (21–84) |
| Race, n (%) | |
| White | 135 (83.9) |
| African American | 11 (6.8) |
| Unknown/other | 6 (3.7) |
| Native American | 4 (2.5) |
| Hispanic | 4 (2.5) |
| Asian | 1 (0.6) |
| History of lower genital tract neoplasia, n (%) | |
| Dysplasia | 68 (42) |
| Carcinoma | 24 (15) |
| Both dysplasia and carcinoma | 2 (1.2) |
| No previous neoplasia | 67 (42) |
| Hysterectomy, n (%) | 129 (80) |
| Indication for hysterectomy, % | |
| Cervical dysplasia | 28 |
| Cancer of the cervix | 18 |
| Benign indication | 26 |
Referral Papanicolaou smear was available for 159 patients. The distribution of abnormal cytologic conditions included atypical squamous cells of uncertain significance with the presence of high-risk HPV in 2.5%, atypical squamous cells but cannot rule out high-grade lesion (ASC-H) in 1.3%, persistent atypical squamous cells in 10.7%, low-grade squamous epithelial lesion in 35%, and high-grade intraepithelial lesion in 45.3%. Nine patients (5.7%) were referred because of the detection of a visible vaginal lesion. Histologic examination of these 9 lesions demonstrated VAIN1 (11%), VAIN2 (22%), and VAIN3 (67%). HPV status was available for 72 patients (45%). Of these, 85% of the women were high-risk HPV positive. Table 2 shows cytologic and initial histologic diagnoses according to HPV status. Patients who were referred for abnormal cytology harbored varying grades of VAIN ( Table 3 ). In those with a Papanicolaou smear that indicated atypical squamous cells (or ASC-H), 39% of the women had VAIN1; 39% of the women had VAIN2, and 21% of the women had VAIN3. Patients with an index Papanicolaou smear of low-grade squamous epithelial lesion had the following histologic conditions: 38% VAIN1, 40% VAIN2, 13% VAIN3, and 8% benign. High-grade squamous epithelial lesion or atypical glandular cell cytology resulted in 6% VAIN1, 36% VAIN2, 53% VAIN3, and 2% benign histology on biopsy ( P = .0019).
| Human papillomavirus status when known | Referring cytologic condition, n (%) | Initial histologic condition, n (%) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Atypical squamous cells of undetermined significance | Atypical squamous cells a | Low-grade squamous intraepithelial lesion | High-grade squamous intraepithelial lesion | Atypical glandular cells | Not known | Vaginal intraepithelial neoplasia | Not known | |||
| 1 | 2 | 3 | ||||||||
| Positive (n = 61) | 13 (21) | 2 (3) | 24 (39) | 20 (33) | 0 | 3 (5) | 16 (26) | 25 (41) | 14 (23) | 6 (10) |
| Negative (n = 11) | 1 (9) | 0 | 3 (27) | 7 (64) | 0 | 0 | 2 (18) | 7 (64) | 3 (27) | 0 |
a Cannot rule out high-grade squamous intraepithelial lesion.
| Variable | Normal, n (%) | Vaginal intraepithelial neoplasia, n (%) | Biopsy not done or missing, n (%) | ||
|---|---|---|---|---|---|
| 1 | 2 | 3 | |||
| Atypical squamous cells of undetermined significance (n = 21) | 0 | 9 (43) | 7 (33) | 5 (24) | 0 |
| Atypical squamous cells (n = 2) a | 0 | 0 | 2 (100) | 0 | 0 |
| Low-grade squamous intraepithelial lesion (n = 55) | 1 (2) | 21 (38) | 22 (40) | 7 (13) | 4 (7) |
| High-grade squamous intraepithelial lesion (n = 70) | 1 (1) | 5 (7) | 26 (37) | 37 (53) | 1 (1) |
| Visible lesion (n = 9) | 0 | 1 (11) | 2 (22) | 6 (67) | 0 |
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