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Vaginal intraepithelial neoplasia (VaIN) is a rare condition, comprising 0.4% of all intraepithelial neoplasia of the lower female genital tract. VaIN has a well-known association with human papillomavirus (HPV) and cervical intraepithelial neoplasia (CIN), seen in up to 43% of women.[1, 2] When associated with CIN, the vaginal lesions are likely to be in continuation with the cervical abnormality, in part because the congenital transformation zone extends on to the vagina in 5% of women. The typically upper vaginal location of VaIN[1, 4-6] makes accessibility and detection difficult. Given its asymptomatic nature[4, 5, 7] it is typically detected cytologically,[5, 8] in particular after hysterectomy. Due to the complexities in diagnosis and management, and the risk of progression to cancer,[4, 7, 9] women with high-grade VaIN (grade 2 or 3) are usually referred to specialised tertiary cancer centres for further management.
Evidence for the best management of high-grade VaIN is lacking. Current practices include immediate surgical treatment with excision or ablation of all suspicious and/or symptomatic areas[5, 10] or medical management (chemo-ablation). However, repeated surgical treatments can result in significant surgical and psychosexual morbidity. Conservative surveillance (with vaginoscopy and cytology) for selected populations is also described in the literature[2, 4, 7] but the efficacy and safety of these approaches is not well known. Deficiencies exist in the majority of the studies: (1) clear definitions for ‘remission’ and ‘recurrence’ are lacking; (2) the majority of case series are smaller; (3) those of comparable size date back 10 years[4, 7, 9]; (4) previous papers report a mixed series of low-grade and high-grade VaIN; and in particular, (5) the role of abnormal cytology as a preclinical indicator of disease recurrence has not previously been established among women post-treatment.
The objective of this study is to establish if we, as clinicians, can be selective of which women we manage surgically and which can be managed with surveillance only. We present here the largest and only specific series of high-grade VaIN described in the literature.
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Women from northern England with a diagnosis of VaIN have historically been referred to the Northern Gynaecological Oncology Centre (NGOC) based at Gateshead. All such women from January 1995 until June 2011, attending for review at a specific NGOC vaginal precancer clinic, were included. Women were prospectively registered on the NGOC departmental database, from which data were accessed in conjunction with the medical notes. This study of clinical service provision was registered with the Safecare & Audit Department. Women known to have active vaginal cancer at referral and those without histological confirmation of VaIN were excluded.
Women's charts and records were reviewed and data were collected regarding demographics, risk factors, management strategy (primary treatment or conservative management), types of treatment (ablative or excisional), remission rate, recurrence rate and progression to cancer. In those women with abnormal cytology but normal vaginoscopy following treatment, recurrence rate of high-grade VaIN was noted. When more than one grade of VaIN was present on histology, women were assigned the highest grade of VaIN. At initial consultation, all women had a vaginoscopic examination by an accredited British Society of Cervical Cytology & Pathology colposcopist, using 3% aqueous acetic acid followed by application of Lugol's iodine.
Primary treatment was predefined as treatment before or immediate treatment after referral to the NGOC. Some of these women underwent repeated treatments. Conservative management was predefined as surveillance with cytology and vaginoscopy in the absence of initial treatment. In general, women were chosen for conservative management, irrespective of referral cytology, if they met the following criteria: no history of genital tract cancer; no evidence of immunosuppression; presence of a unifocal lesion measuring less than 2 cm in diameter; and no vaginoscopic abnormalities suspicious of invasion.
Recurrence was defined as histological evidence of VaIN after treatment; and remission was defined as the absence of recurrence within the first 12 months. Progression was defined as the histological evidence of invasion. Low-grade cytology was predefined as borderline nuclear abnormalities or mild dyskaryosis and high-grade cytology as moderate or severe dyskaryosis or borderline nuclear abnormalities with suspicion of high-grade change. Women who developed abnormal cytology but demonstrated no vaginoscopic abnormality were observed until a vaginoscopic lesion became apparent for biopsy. In the analysis of these, the authors considered each episode when normal vaginoscopy was accompanied by abnormal cytology to be a ‘case’. Therefore, each woman could have more than one episode of normal vaginoscopy accompanied by abnormal cytology during her follow-up. The follow-up policy was 3-monthly or 6-monthly surveillance with vaginoscopy and cytology. This became annual review in the presence of normal cytology. When vaginoscopic and cytological findings were both normal over a period of 2 years, women were discharged to primary care if vault or vaginal annual cytological follow-up could be agreed with their general practitioners.
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One hundred women with high-grade VaIN were identified. The median age of women at diagnosis was 50 years (range 22–83 years). Table 1 shows the indications for referral to the NGOC and clinical risk factors for all women seen. Multifocality of disease was demonstrated in 73% of women and cytological evidence of HPV was reported in 44%.
Table 1. Clinical risk factors for all women with high-grade VAIN
|Clinical risk factors/presentation||All women, n = 100|
| Age ||Median 50 years (range 22–83)|
| Main referral indication || |
|Histological high grade VaIN on referral||24|
| Non-vaginal lower genital tract precancer ||56|
| Non-vaginal lower genital tract cancer ||10|
| Smoking history ||44|
| Immunosuppression ||4|
| Previous hysterectomy ||48|
|For cervical cancer||7|
Forty-eight women had a previous hysterectomy, seven of which were for cervical cancer, 37 for CIN and the remaining four for benign gynaecological conditions. These latter four were referred with abnormal cytology, two of which were following diagnosis of VaIN at the vaginal cuff edges on the hysterectomy specimen. The median interval between hysterectomy to development of high-grade VaIN among all women was 2 years (range 0–46 years). Of these 48 post-hysterectomy women, 19 were diagnosed with high-grade VaIN within 1 year of hysterectomy (40%). Seventeen of these 19 had hysterectomy for CIN or cervical cancer and it is unclear whether the development of VaIN in these women was a result of de novo disease or whether this represented continuation or incomplete excision of cervical lesions. High-grade VaIN was located in the upper third of the vagina in 96% of all women who underwent previous hysterectomy. The lesion was described as located in the ‘dog ears’, that is the lateral corner recesses of the vaginal vault, in 27% of women. In contrast, among those women who had not had a hysterectomy, CIN was present in only 24 (46%).
Of the 100 women referred, 69 underwent primary treatment and 31 were managed conservatively with vaginoscopic and cytological surveillance. The histological outcomes are shown in Figure 1. The rate of progression to cancer was three out of 100 (3%) with all three cancers detected among the primary treatment group at a median of 59 months (range 8–249 months) after diagnosis of high-grade disease. All three women had persistent HG VaIN despite multiple surgical excisions. All three women are alive and well at 76–116 months following diagnosis and treatment of invasive disease and their histories are given as follows.
Figure 1. Histological outcomes of women with high-grade VaIN. *Median recurrence 29 months (15E214 months), repeated treatment performed in seven patients, no cancer. **Repeated treatment performed in seven patients, including three who later developed cancer.
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Patient 1, aged 64 years at referral, had previously had a hysterectomy for stage 1a1 squamous cell cancer of cervix but developed high-grade VaIN within 12 months of the hysterectomy. She had primary vaginal excisional treatment for the VaIN but due to residual disease underwent five further surgical procedures and a trial of Imiquimod. Despite this she developed moderately differentiated vaginal squamous cell cancer (stage IV with rectal involvement) at 59 months from VaIN diagnosis, and was treated with radiotherapy and concurrent chemotherapy. Patient 2, aged 37 years at referral, had previously undergone hysterectomy for CIN but developed high-grade VaIN within 12 months of the hysterectomy. She had primary excisional treatment but underwent 15 further surgical procedures and a trial of 5-fluorouracil before developing stage II vaginal cancer at 249 months from diagnosis of high-grade VaIN and was treated with radiotherapy. Patient 3, aged 68 years at referral, had undergone hysterectomy for CIN 19 years previously. She had primary ablative then excisional treatment but developed early stromal invasion at 8 months from diagnosis of high-grade VaIN. Despite three further excisional treatments and a trial of 5-fluorouracil she developed stage IV vaginal cancer (with bladder involvement) 8 years after diagnosis of early stromal invasion and was treated with radiotherapy. In none of these three women was total vaginectomy performed. Instead directed partial abdominal and vaginal vaginectomies were performed.
Of the 69 women managed with primary treatment, 22 had evidence of residual disease or recurrence within 12 months (32%). The remaining 47 women (68%) were in remission. Of those 47 in remission, seven developed a subsequent recurrence after a median follow-up of 29 months (range 15–214 months). Although the median number of surgical treatments received by each woman was one (range 1–16), a total of 18 women required repeated treatment with a median of two treatments (range 2–16). Table 2 shows the modes of treatment for primary and repeated treatments, and the remission rate among those undergoing primary excision was 33/46 (72%). It is worth noting that 22 women underwent primary ablative treatment. All these were asymptomatic on referral and 18 of the 22 had vaginsocopic evidence of multifocal disease. Excisional treatment was favoured for the majority of women undergoing repeated treatments. This was because of concern regarding increased risk of invasion with recurrent VaIN.
Table 2. Methods of treatment for high grade VaIN
|Method of treatment||Primary treatment, n = 69||Repeated treatment n = 18a||Treatment following conservative management, n = 5|
Of the 31 women managed conservatively, five required surgical treatment at a median of 16 months (range 9– 24 months) from first review, after which one woman had a recurrence. However, none progressed to cancer after a median period of 35 months (range 2–230 months) from diagnosis resulting in a total follow-up of 121 woman-years.
As demonstrated in Figure 2, the authors analysed histological outcomes of women who had previously been treated but developed subsequent abnormal cytology in the presence of normal vaginoscopy. Forty-three such ‘cases’ occurred in 31 women post-treatment. These were analysed in two groups. The first group comprised 24 cases (56%) where low-grade cytology was accompanied with normal vaginoscopy. Seven (29%) of these 24 cases developed subsequent high-grade VaIN after a median of 12 months (range 2–110 months) and none progressed to cancer. The remaining 17 cases remained recurrence-free after a median follow-up of 27 months (range 5–76 months).
Figure 2. Outcomes of abnormal cytology with normal colposcopy. LG, low grade; HG, high grade; VaIN, vaginal intraepithelial neoplasia.
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The second group comprised 19 cases (44%) where high-grade cytology was accompanied with normal vaginoscopy. Fifteen (79%) developed recurrence of high-grade VaIN at a median of 7 months (range 2–21 months). Kaplan–Meier analysis of cumulative hazard function demonstrates a statistically significant difference (P < 0.001) in high-grade VaIN recurrence rate between those with low-grade and high-grade cytology post-treatment (Figure 3). Hazard for recurrence of high-grade VaIN with high-grade cytology, compared with low-grade cytology, was 5.6 (95% confidence interval 2.0–15.5, P = 0.001).
Figure 3. Kaplan–Meier analysis of cumulative hazard function to develop high-grade VaIN among cases with abnormal cytology but normal vaginoscopy post-treatment. Log rank test P < 0.001.
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The median number of clinic appointments was seven (range 1–70 visits). Fifty-eight women were discharged, including 13 who migrated or self-discharged, at a median length of follow-up of 35 months (range 1–231 months) from diagnosis.