4.Discussion
In the present study, the HR-HPV detection rate was 88.5% (883/998) in all cases of VaIN. Specifically, the detection rate was 95.4% in cases of VaIN2+.The most common hr-HPV genotypes found in VaIN were HPV16, HPV52, HPV58, HPV53. The median age of patients with VaIN2+ was 11.5 years older than VaIN1. The proportion of postmenopausal women in the population with VaIN2+ disease was higher than that in the population with VaIN1 disease. Patients with VaIN2+ tended to have more pregnancies and deliveries than those with VaIN1. Additionally, they were more likely to have a history of CIN. VaIN grade was significantly positive correlated with cervical lesions, but correlation was weak (r=0.387). HPV 16 was present in 54.5% cases of VaIN2+ making it the most prevalent HPV type in VaIN2+, followed by HPV58 (17.0%), HPV52 (14.8%), HPV51 (11.4%), and HPV18 (10.2%).. The sensitivity of hr-HPV testing for VaIN2+ and CIN2+ were significantly higher than that of cytology testing. However, for VaIN of vaginal stumps, they had no difference. Furthermore, the sensitivity of cervical cytology and hr-HPV testing for detecting VaIN2+ was not significantly different from their sensitivity for detecting CIN2+.
In previous studies, the HPV detection rate in patients with VaIN2/3 ranged from 50% to 100%, and from 25% to 89% in vaginal cancer.11-13 The different results may be attributed to variations in study sample sizes, HPV detection methods, and sample site selections (cervix or vaginal wall). HPV 16 was the dominated HPV type in VaIN especially in VaIN2+ in all former studies.13-17 In a global multicenter study17 that performed HPV DNA detection and typing in 597 vaginal precancerous and cancerous lesions, HPV 16 accounted for 59% of VaIN2+, which is very close to the result of this study.. Aside from HPV 16, the following HPV genotypes were not consistent in different studies, which may due to the regional differences in HPV type prevalence. HPV18, 33, 45, 31 were the following common HPV types in VaIN2+ in Europe and North America13, while HPV 58, 52, 39, 33 were the following common in Taiwan, China14. The result of this study show the HPV prevalent in VaIN2+ is similar to HPV prevalent in CIN2+ in our previous study18, but HPV 58 exceeded HPV 52 to become the second most common HPV type in VaIN 2+ in present study, however, the difference was not great. HPV vaccination provides an excellent opportunity to prevent VaIN2+. Denmark, a country with high HPV vaccination coverage, found that the incidence rate of high-grade VaIN decreased by nearly 16% per year among women younger than 30 years old after the introduction of HPV vaccine.19 As China is a country with poor HPV vaccine coverage20, the results of HPV prevalent presents near baseline distribution and inspire the use of HPV vaccines that cover HPV 16, 58, 52, 51, and 18 to provide excellent protection against VaIN2+.
Research has shown that a history of high-grade cervical lesions and cervical cancer increases the risk of developing noncervical HPV-related anogenital premalignancies and carcinomas for at least 20 years21, 22, even after total hysterectomy23-25. Consistent with these findings, the present study revealed that patients with VaIN2+ were more likely to have a history of high-grade cervical lesions or cervical cancer than those with VaIN1. Moreover, postmenopausal women, those with gravidity and parity more than three times, and those with hr-HPV infection are all at increased risk of developing VaIN2+. These results underscore the importance of screening high-risk populations for VaIN2+. Currently, both cytology and HPV testing are performed on the cervix except for vaginal stumps. It is important to evaluate the sensitivity of cervical cancer screening for detecting VaIN2+ and how it compares to CIN2+. Previous studies have shown that the sensitivity of cytology for detecting CIN2+ ranged from 47% to 72.9%, while the sensitivity of HPV testing ranged from 89.9% to 95%.26, 27 Meanwhile, the sensitivity of cytology for detecting VaIN2+ ranged from 61.5% to 83.8%, the sensitivity of HPV testing ranged from 82.5% to 97.3%, and cotesting had a sensitivity ranging from 95.2% to 100%.28, 29 Although these findings suggest that cervical cancer screening has a higher sensitivity for detecting VaIN2+ compared to CIN2+, direct comparison between studies is not possible due to differences in HPV testing methods and cytologic quality, as well as the object of study. This study has a unique advantage in that it directly compares the sensitivity of cervical cancer screening (cytology or HPV test) for VaIN2+ and CIN2+ within the same study. The results indicate that the sensitivity of cervical cytology and hr-HPV testing are equivalent for detecting both VaIN2+ and CIN2+, with cotesting having the highest detection rate. However, for patients who have undergone hysterectomy, the sensitivity of cytology for VaIN2+ was comparable to that of HPV testing, but the small sample size may have biased the results. Vaginal cytology testing has a reported sensitivity of 83% for predicting vaginal HSIL30, while vaginal hr-HPV testing has a sensitivity of 100%31, but a direct comparison between these tests is not appropriate. Thus, future well-designed controlled studies are necessary to further investigate these findings.
Most of the vaginal lesions occur in the upper one-third of the vagina. A colposcopy is a necessary procedure for diagnosing VaIN. Acetic acid should be applied to the entire vaginal mucosa, including the fornix, for 1-2 minutes, followed by the application of Lugol’s iodine to confirm the presence or absence of abnormal epithelium throughout the vaginal mucosa and fornix. In this study, 32.3% of VaIN2+ cases were not accompanied by CIN. Therefore, when cervical cancer screening is abnormal and there are no abnormal images on the cervix, attention should be paid to the vaginal wall. According to the 2019 American Society of Colposcopy and Cervical Pathology (ASCCP) guidelines32, for non-pregnant patients ≥25 years old with HSIL cytology, expedited treatment (treatment without colposcopic biopsy) for cervix is preferred. However, this type of management of abnormal cervical cancer screening may lead to a missed diagnosis of VaIN. Therefore, when choosing expedited treatment, colposcopic examination should also be performed not only on the cervix but also on the vaginal wall, and it is important to take a biopsy where a lesion is identified on the vagina.
The limitations of this study are as follows: firstly, this is a single hospital-based retrospective analysis, and selection bias may exist. Secondly, three types of HPV testing were used in this study, which may have resulted in heterogeneity of the results. Thirdly, since all the patients included in this study were diagnosed because of abnormal cervical cancer screening, VaIN without abnormal TCT or positive hr-HPV results were not taken into account, so the sensitivity of cervical cancer screening may be over-estimated.