VaIN is a precancerous condition of the lower genital tract and accounts for 0.4% of all lower genital tract precancerous lesions. The incidence of VaIN was 0.2-2/100,000 , and as the HPV infection rate increased, cervical fluid-based cytology improved, and HPV detection and colposcopy increased, the incidence of VaIN increased. VAIN is classified into low-grade VAIN (VAIN 1) and high-grade VAIN (including VAIN 2 and VAIN 3) based on the depth of the involved epithelium. The Hospital of Obstetrics and Gynecology affiliated with Fudan University reported that the detection rate of VaIN via colposcopy over the course of 2 years reached 2.58%. Because of its rarity, to date, there is no standardized guidance for VaIN. In our study, during a 10-year period, 657 patients with a histopathological diagnosis of VaIN were retrospectively included. Among 657 patients, 26.5% were diagnosed with VaIN 2/3. A total of 73.5% were diagnosed with VaIN 1.
The pathogenesis of VaIN is unclear, and some researchers believe that VaIN is the result of the progression of CIN. VaIN usually coexists with CIN rather than in isolation. In the Dodge study, 65% of cases of VaIN coexisted with CIN, but there are also many literature reports in which the proportion of independent VaIN is also large. The study of Sui et al reported that the proportion of VaIN patients with combined CIN ranges from 29.58–33.83%. Similarly in our study, among 576 patients without a history of hysterectomy, 72.6% were diagnosed with only VaIN, and 27.4% were diagnosed with VaIN concomitant with cervical or vulvar lesions. The proportion of patients with VaIN 2/3 among patients with concomitant cervical lesions was similar to that among patients with only VaIN (p= 0.5169).
Similar to CIN, there are three different grades of VaIN. VaIN 1 is also known as a low-grade squamous intraepithelial lesion (LSIL), whereas VaIN 2 and VaIN 3 are both high-grade squamous intraepithelial lesions (HSILs). Studies have shown that the proportion of patients with VaIN 2/3 is higher among patients who have undergone hysterectomy than in patients who have not undergone hysterectomy. Our results are consistent with those of previous studies (hysterectomy group 39.5% vs. no hysterectomy group 24.7%). Sui et al. retrospectively analyzed 529 patients with VaIN, and 17.8% of the patients had a history of hysterectomy; 83.9% of these patients were diagnosed with VaIN 1, and 16.1% were diagnosed with VaIN 2/3. In our study, 657 patients with VaIN were included, and 12.3% had a history of hysterectomy, including 60.5% of patients with VaIN 1 and 39.5% of patients with VaIN 2/3. The proportion of posthysterectomy patients in a previous study was higher than that in our study, while the proportion of patients with VaIN 2/3 in our study was higher than that in a previous study. In our institution, the proportion of patients with VaIN 2/3, regardless of whether hysterectomy had been performed, was higher than the proportions reported elsewhere, which is a cause for concern.
VaIN can be relatively more challenging after hysterectomy, especially when medical and conservative options have failed. The incidence of VaIN was higher in patients who had undergone hysterectomy due to cervical factors. In our study, 81 of the 657 patients underwent total hysterectomy. Among these patients, 66.7% underwent this operation due to cervical factors indicating cervical cancer (48.1%) or precancer (51.9%). A total of 33.3% underwent hysterectomy for noncervical lesions. In the study by Zhang, among the 99 patients with stage I cervical cancer or CIN III combined with VaIN undergoing hysterectomy, 12 patients (including 11 patients within 3 years after surgery) were followed up for 1-5 years and exhibited residual VaIN. Among the 12 patients with residual VaIN, 11 did not receive vaginal wall biopsy under colposcopy before surgery; among these patients, 4 with residual VaIN progressed, 2 patients developed vaginal cancer, and the residual recurrence rate was 2%. In addition, patients undergoing hysterectomy due to noncervical factors are not routinely followed up, but the latest literature reports that the incidence of postoperative vaginal cancer in patients undergoing total hysterectomy with prevalent CIN is significantly increased and that the increased risk lasts for more than 10 years. Patients with VAIN after hysterectomy attend multiple hospital visits, which is burdensome and increases healthcare service costs. Therefore, the entire vagina should be routinely inspected by colposcopy prior to hysterectomy to ensure that VaIN is identified. If it is diagnosed during the definitive management of CIN at the time of hysterectomy and is confined to the upper vagina, it could be surgically treated at the same time.
There is no clear consensus on the effectiveness of different tests for VaIN. In our study, the sensitivity of cytology for VaIN after hysterectomy was higher than the sensitivity of cytology for VaIN without hysterectomy for both VaIN 2/3 and VaIN 1. In patients without hysterectomy, the sensitivity of cytology was higher for concomitant VaIN than for only VaIN.
HPV testing is still controversial in the context of the diagnosis of VaIN. Some literature reports show that the HPV positive rate is low. Lamos et al. reported that the HPV positive rate was 66.7% among 9 cases of VaIN 1 and 66.7% among 58 cases of VaIN 2/3 . Wee et al. found that the HPV positive rate among 21 VaIN patients was 66.9%. Some of the literature has reported higher HPV positive rates. So et al. found that the detection rates of HPV in VaIN 1, VaIN 2 and VaIN 3 patients were 74.3%, 85.7% and 100%, respectively. In the study of Sui et al., the HPV positive rate among VaIN patients was 87.82%, among which the HPV positive rates of VaIN 1 alone, VaIN 2/3 alone, VaIN 1 after hysterectomy, and VaIN 2/3 after hysterectomy were 84.46%, 88.71%, 85.03%, and 91.36%, respectively. In our study, in patients who did not undergo hysterectomy, the sensitivity of hrHPV for VaIN 2/3 and VaIN 1 was 89.3% and 86.8%, respectively. The sensitivity of hrHPV for VaIN 2/3 and VaIN 1 after hysterectomy was 93.3% and 62.5%, respectively. In our study, hrHPV sampling of VaIN 1 in patients after hysterectomy was low, possibly due to incomplete sampling in women after hysterectomy.
Cytology and hrHPV cotesting increased the sensitivity of hrHPV for VaIN 2/3 and VaIN 1 in patients who did not undergo hysterectomy (96.5% and 94.9%, respectively). The sensitivity of cytology and hrHPV cotesting for VaIN 2/3 and VaIN 1 after hysterectomy was 97% and 93.8%, respectively. This finding is consistent with that of a British study, which showed that in more than half the patients, regardless of the VaIN grade, a combination of cytology and colposcopy was used for follow-up .
Previous studies have shown that HPV 16 is the main virus type associated with the development of VaIN . Interestingly, HPV types differ between low-grade and high-grade vaginal dysplasia. In L. Alemany's research, the largest VaIN 2/3 dataset published until 2014, they described the HPV DNA prevalence and type distribution in a large series of 189 VaIN 2/3 patients from 31 countries. They found that the HPV prevalence in VaIN 2/3 lesions was 96%. The most common HPV type was HPV16, which was detected in 59% of VaIN 2/3 lesions among the HPV DNA-positive cases. Among VaIN 2/3 patients, the prevalence of HPV16 was followed by that of HPV18 (6%), HPV52 (6%), and HPV73 (5%). Other HPV types accounted for less than 5% each. In our study, in patients without hysterectomy, HPV16 was detected in 22.10% of VaIN 2/3 lesions among the HPV DNA-positive cases, and the other 12 types were detected in 43.6% of VaIN 2/3 lesions. In patients who underwent hysterectomy, HPV16 was detected in 60.00% of VaIN 2/3 lesions among the HPV DNA-positive cases, and the other 12 types were detected in 13.3% of VaIN 2/3 lesions. In patients without hysterectomy, HPV16 was detected in 9.5% of VaIN 1 lesions among the HPV DNA-positive cases, and the other 12 types were detected in 62.6% of VaIN 1 lesions. In patients who underwent hysterectomy, HPV16 was detected in 2.1% of VaIN 1 lesions among the HPV DNA-positive cases, and the other 12 types were detected in 54.2% of VaIN 1 lesions. In our study, HPV16 account for a large proportion among patients with VaIN 2/3, especially among patients who underwent hysterectomy, but for VAIN 1, the 12 other types of high-risk HPV infections are more closely related compared with HPV16. This finding suggests that in clinical practice, we should also pay more attention to patients who are positive for the 12 types of high-risk HPV, and inspection of the entire vagina by colposcopy is recommended.