To determine the role of conservative management in high-grade vaginal intraepithelial neoplasia (HG VaIN).
To determine the role of conservative management in high-grade vaginal intraepithelial neoplasia (HG VaIN).
Retrospective observational study.
Northern Gynaecological Oncology Centre, Gateshead, UK.
A total of 100 women with histologically-proven HG VaIN.
Review of patient records from 1995 to 2011.
Rates of progression to cancer, treatment remission, and disease recurrence, particularly post-treatment when vaginoscopy is normal but cytology is abnormal.
Of 100 women referred, 69 underwent initial treatment of whom 47 (68%) went into remission: of these, seven developed a recurrence after a median follow-up of 29 months (range 15–214 months). Of the 31 women managed conservatively with cytological and vaginoscopic surveillance, no cancers developed after a median follow-up of 35 months (range 2–230 months). Rate of overall progression to cancer was 3% and all were detected among the initial treatment group after a median of 59 months (range 8–249 months). Post-treatment, when normal vaginoscopy was accompanied by abnormal cytology, two categories existed. Of 24 cases with low-grade cytological abnormality, recurrence of HG VaIN occurred in seven (29%) after a median follow-up of 12 months (range 2–110 months). Of 19 cases with HG cytological abnormality, 15 (79%) developed recurrence at a median follow-up of 7 months (range 2–21 months), giving a hazard ratio 5.6 (95% confidence interval 2.0–15.5, P = 0.001).
It is possible to select women with HG VaIN for conservative surveillance with excellent results. The majority of women undergoing initial treatment will enter remission. Post-treatment, if cytological abnormality develops in the presence of normal vaginoscopy, the majority of women will develop histological HG VaIN recurrence.
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.
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.
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%.
|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|
|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.
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.
|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).
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).
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.
Our results support the view that, with appropriate selection of women, conservative surveillance with vaginoscopy and cytology is safe and equally efficient in the management of a significant proportion of women with high-grade VaIN. Among the cohort of women managed conservatively no cancers developed.
This study also adds valuable information regarding the role of cytological surveillance after treatment. We have demonstrated that in the presence of low-grade cytology, there is a 29% rate of high-grade VaIN recurrence and so there is potential for a conservative approach to these women's disease, especially as none progressed to cancer. However, those with high-grade cytology should be monitored more frequently as there is a 79% rate of high-grade recurrence within the first 2 years after treatment.
This study describes the largest cohort of women with histologically proven high-grade VaIN. We used predefined outcome measures to standardise assessment of response to treatment. This study benefits from presenting the outcomes of a single institution, wherein the management policies have remained relatively unchanged. Our study benefits from long-term follow-up data and therefore the authors have included a flowchart demonstrating a management plan for this uncommon premalignant condition as given in Figure 4.
Furthermore, this study is the first of its kind to examine the utility of cytological surveillance in the absence of vaginoscopic abnormalities in predicting the recurrence of high-grade VaIN.
Given the retrospective nature of this study, we would recommend prospective study of our selection criteria to support our findings. It is our understanding that clinical risk assessment based on overall history, in particular presence of risk factors (such as history of previous lower genital cancer and immunosuppression) and clinical assessment of lesion (multifocality, large lesion ≥ 2 cm, and suspicious findings on vaginoscopy) played a role in such decision-making on the management approach. We believe that expertise can be developed with experience and adequate caseload to select women with high-grade VaIN who will benefit from a surveillance-only strategy.
Ablative treatment has not been well-represented in this study. Given the importance of histological diagnosis we have preferred to opt for excisional rather than ablative surgical management.
The age at diagnosis[2, 10-12] and patient risk factors[1, 3, 4, 13] presented here are comparable with what is described in the literature. The low overall progression to cancer of 3% is also in keeping with other studies, reporting rates as high as 12%.[2, 5, 8] It is natural to expect rates of invasion to increase with duration of follow-up and women with risk factors for invasive disease should be ‘flagged’, or highlighted, at initial referral.[5, 14] It is worth noting that the three women who developed invasive disease in our study demonstrated persistent residual high-grade VaIN following each treatment.
In keeping with the ‘field carcinogenesis’ theory previously described by Marcus and others,[15-17] post-hysterectomy for CIN almost all women had disease located in the upper third of the vagina, as previously described in the literature.[10, 11, 13, 14] Therefore, preoperative evaluation of the vaginal mucosa before definitive surgery for cervical dysplasia or cancer is vital, particularly the vaginal vault recesses, which can be common sites of recurrence. Our study underlines the importance of post-hysterectomy vaginoscopic and cytological follow-up of these vault recesses and is in keeping with published literature reporting that between 0.9 and 6.8% of women undergoing hysterectomy for CIN develop VaIN.[4, 11, 13, 18-20] Conversely, the risk of VaIN after hysterectomy for benign conditions is 1.3% at 10 years[5, 21] and no agreed cytological follow-up has been established or is recommended in this setting.
There may well be an association between HPV subtype, remission rate and grade of VaIN. Our study describes a 68% remission rate of high-grade VaIN, in particular after a single excisional treatment (72%). This is similar to other studies reporting rates of 35–67%.[5, 11] The heterogeneity of HPV subtypes seen in vaginal epithelium may possibly explain these high remission rates,[6, 22] in that although around 90% of VaIN is associated with HPV, only half of these are associated with the high-risk HPV-16.[23, 24] The likelihood that biopsy alone accounts for such a high remission is unlikely because the majority of cases of VaIN are multifocal. Frega et al. showed that positivity to HPV-16/18 was significantly higher in women with recurrent VaIN than those who remained in remission.
In future, it may be possible that HPV-16/18 testing after treatment could help triage women into two groups: those who are HPV-16/18-positive who could be surveyed every 3 months; and those with non-16/18 subtypes requiring less frequent surveillance. Inclusion of HPV testing in addition to cytological surveillance may aid prediction of high-grade recurrence before cytological or vaginoscopic abnormality.
Future studies should also include prospective cohort studies to not only aid prediction of the course of the disease, in particular recurrence and progression, but also response to treatment. Such studies may provide objective estimates of probability of recurrence and invasion as a supplement to clinical assessment.
In summary, this study demonstrates the safety and efficacy of conservative management in appropriately selected cases of high-grade VaIN and highlights the importance of cytological and vaginoscopic follow-up. We believe that employing the management strategy suggested can further improve monitoring of this rare condition and aid in selection of women for conservative management.
All authors declare there are no conflicts of interest.
RN and PC devised the study, supervised the data collection and contributed to the discussions. NR and PC collected the data. NR, AP and AF performed the analyses. All authors contributed to the discussions and approved the final manuscript.
This audit of clinical service provision was prospectively registered with the Safecare & Audit Department and ethics approval was not necessary.
The authors would like to thank Mr Daniel Spelman for collecting the computerised data and Dr Ioannis Biliatis for proof-reading. There are no conflicts of interest.