Currently, the HPV vaccine is gradually being used in the developing countries, but it has not fully covered all the regions. The effect of the HPV vaccination will reveal after several decades. In addition, the cervical cancer screening is still an essential method to prevent and treat cervical cancer for older women. Therefore, it’s significant to adopt the cervical cancer screening method to diagnose and prevent the cervical cancer.
ASC-US is an ambiguous term and an exclusionary diagnosis that suggests a risk of disease rather than a definitive diagnosis of abnormal lesions. For women with ASC-US, if the diagnosis is not clear or not timely, the optimal treatment will be delayed; on the other hand, the excessive diagnosis and treatment will not only bring physical and psychological burden to the women, but also can cause adverse pregnancy outcomes[14, 15]. In addition, it will increase the family and society economic burden and will not allocate medical resources reasonably.
This retrospective cross-sectional single-center study in China, lasting for 7 years, collected clinical data of 250,000 women who underwent HPV and TCT test at Qilu Hospital of Shandong University. The frequency of ASC-US was 2.80% (n=7001) in cervical screenings of this center, which was suggested the center strictly controlled the frequency of occurrence of ASC-US and reduced the phenomenon of ascus as the “Garbage Dump”, according previous research. Some studies have reported that the prevalence of CIN2+ among women with ASC-US is between 5% -39%[16-18]. The detection rate of HSIL+ in hr-HPV-positive/ASC-US women in this study was 35.65%, which was higher than some studies. The possible reasons are as follows: (1) The target population of this study was hr-HPV-positive/ASC-US women, while the target population of other studies were ASC-US women (including hr-HPV positive and negative women). The reported prevalence of hr-HPV among women with ASC-US in most studies was 23% to 74%. (2) This study was a retrospective study with the possibility of incomplete data collection.
In this cross-sectional study, the rates of HSIL+ ranged from 8.51% of HPV 56 to 63.09% of HPV16 in ASC-US women with single hr-HPV infection. The HSIL+ detection rates in women with HPV multiple infections was more than 39.77%. Previous research reported HPV-positive/ ASC-US women would have similar the 2-year cumulative risk of HSIL+ and be clinically equivalent with women with LSIL Pap results. We look forward to relevant longitudinal researches on relationship between HPV genotypes and risk of cervical lesions.
Systematic review[20, 21] and a large randomized trial consistently showed that, compared with repeat cytology, the accuracy of HC2 to detect underlying HSIL+ was higher in triage of women with ASC-US cytology. Previous studies suggested that the test may optimized by using a cutoff higher than this 1.0 pg/mL[22, 23]. The rates of HSIL+ in higher viral road of women with ASC-US cytology were higher (Cochran-Armitage Trend test χ2=35.03, P<0.0001) in this study.
The highest detection rate of HSIL+ (40.52%) was in the age group of women aged ≤30 years, and the lowest detection rate of HSIL+ (21.65%) was in the 51-60-year-old group in this study. A large longitudinal cohort study lasting 7 years within the Guanacaste population showed older women had a similar or slightly decreased risk of HSIL+ and especially CIN 3 compared with younger women. In addition, a systematic review included in 103 studies (including more than 12,400,000 women) found that HSIL prevalence in Asia peaked at a relatively younger age (25 to 40 years). The results in these studies are in coincidence with our findings. When calculating the cervical cancer detection rate, this study showed that the value of the cervical cancer detection rate increased with age, and older women had higher cervical cancer detection rates than younger women. The reasons are as follows:
(1) Due to hormone levels, the use of intrauterine device, more sexual behavior and inflammation in younger women, the cells of those with benign morphological changes mixed with cells of true precancerous lesions, and it may interfere doctors’ diagnosis.
(2) HPV prevalence rate among younger women are higher, and the rate of HPV prevalence is highly age-related and decreases with age. According to previous study, the HPV prevalence rate could be as high as 70% for women of aged <25 years.
(3) The previous research found that CIN1 and a subset CIN2 lesions are clinical manifestations of the result of productive hr-HPV infectio, which can regularly regress within 1–2 years spontaneously and have a low risk to progress to invasive carcinom.
(4) Older women could clear newly HPV infections (including HPV16 infections) as quickly as younger women. So, the lowest detection rate of HSIL+ was in the group aged 51-60 years old.
(5) Lower estrogen levels, thinning of the epithelium, decreasing lactobacilli and some genital tract infections combined diabetes etc., create favorable conditions for HPV infection in older women, especially for >60 years old women.
(6) Another subset of CIN2 lesions and CIN3 lesions are clinical manifestations of the result of transforming hr-HPV infection, which is characterized by a dysregulated expression of E6 and E7 viral oncogenes. It would take the long time of 20 - 30 years for the progression to invasive carcinoma from precancerous lesion in most patients.
(7) What’s more, persistent hr-HPV infection is a risk factor for cervical cancer and the risk of persistence increases with the increasing age of the woman. Therefore, older ASC-US women have a higher cervical cancer detection rate.
However, this study showed there was no statistically significant increase in the rate detection of HSIL in the group of > 60 years by 36.49% (29.55% vs 21.65%), compared with the 51-60 years group, which may be related to the relatively limited sample we studied.
A 2013 Cochrane Meta-analysis studied triage ASC-US by repeat cytology versus HPV testing and found that similar pooled CIN2+ and CIN3+ specificities that likely will translate to similar overtreatment rates. So, one way to solve the problem of overtreatment is to consider alternatives new method to triage women with ASC-US. Molecular markers may help identify cells with abnormal cell morphology. P16 or dual p16 and Ki-67 immunostaining on cytological preparations provides a promising method to triage HPV-positive women[30, 31]. Biomarkers based on DNA methylation includes methylation markers representing various combinations of genes, such as SRY-box 1 (SOX1), PAX1, NK6 homeobox 1 (NKX6-1), junctional adhesion molecule 3 (JAM3), EPB41L3, TERT, C13ORF18, and CADM1/MAL.
What’s more, this study found that women infected with HPV52 and HPV58 were also more common, except HPV16 and HPV18, in China. Therefore, it seems a wise choice to get a vaccine containing multiple hr-HPV types. Currently, there are two-valent HPV vaccines (HPV 16/18), four-valent HPV vaccines (HPV 6/11/16/18), and nine-valent HPV vaccines (HPV 6/11/16/18/31/33/45/52/58). Therefore, women should choose nine-valent HPV vaccines in China, if conditions permit.
Combined with knowledge about the biology of CIN and results of this study, here are a few suggestions to triage women with ASC-US cytology. Firstly, we should ensure the quality of TCT test and strictly control the occurrence frequency of ASC-US. It has been suggested that good management requires that the frequency of ASC be maintained at <5% of all cervical screenings , and ASC:SIL ratio be maintained at <1.5. Secondly, ASC-US women with obvious inflammation should accept anti-inflammatory treatment, and repeat cytology test 4-6 months after inflammation disappearing, especially young women. If the cytological results of women ≥ASC-US, then they are recommended to refer to colposcopy. In addition, we should strictly follow up on young women who have been diagnosed as HSIL by histological examination, rather than implementing excessive treatment. Finally, it is more and more important for us to find a new triage test.