Accurate screening for risk-stratified HPV and cervical cancer control

    Cervical cancer is the second most common malignancy in Chinese women. The World Health Organization estimates that there are more than 470,000 new cases of cervical cancer worldwide each year, and the number of new cases of cervical cancer in China accounts for approximately 28% of the world’s total incidence each year.  Since human papillomavirus (HPV) can be found in almost all samples of cervical cancer cases, it confirms HPV as the causative virus of cervical cancer and makes cervical cancer the only cancer with a clear etiology among all human cancer lesions. HPV infection is a very common infection, with up to 75% of women likely to be infected with HPV during their lifetime, and not infrequently (4-15%) among sexually active young women under 30 years of age (18-28 years), with a lifetime accumulation rate of up to 40%, but the infection is usually “transient” or called “transient HPV carrier status” The average duration of infection is 8 months, and most are cleared and do not progress to precancerous lesions. In contrast, cervical precancerous lesions (cervical intraepithelial neoplasia CIN) can occur in women over 30 years of age in an average of 8-24 months of persistent HPV infection and can develop into invasive cancer in an average of 8-12 years. Therefore, persistent infection with high-risk HPV is responsible for the development of cervical precancer and cervical cancer.  High-risk HPV testing combined with cytology: a more accurate screening tool for cervical cancer.  The American Cancer Society (ACS), the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP) believe that the best strategy for cervical cancer screening should maximize the benefits of screening and minimize the potential harms of screening. For HPV testing, the most important test metrics are sensitivity and negative predictive value to determine who can return to routine population management without further treatment. Thus, the goal of HPV screening is to identify those who are truly at high risk, not to detect those who are simply infected with HPV.  The new cervical cancer screening guidelines issued by the U.S. Preventive Services Task Force (USPSTF) in 2012 and the new 2012 cervical cancer screening guidelines jointly issued by the ACS, ASCP, and ASCP prioritize the recommendation of combined cytology and high-risk HPV testing every 5 years for women aged 30-65 years. If the high-risk HPV test is negative, no further screening is required for 5 years; if the cytology test is negative and the high-risk HPV test is positive, the combined test needs to be repeated annually.  HPV16/18 typing: helps to better manage risk stratification in people at high risk of cervical cancer.  In fact, the use of HPV testing for screening raises new clinical questions, such as whether a cytology-negative, HPV-positive condition can be considered “new ASCUS”? How should follow-up be managed clinically? The European Organization for Research on Reproductive Tract Infections and Neoplasms (EUROGIN), in its 2008 strategy for cervical cancer prevention and treatment, envisages triage of cytology-negative, HPV-positive people through HPV16/18 genotyping, p16 or other biomarkers for early detection of high-risk groups.  ATHENA, the largest clinical study of cervical cancer screening in the United States (47,208 women enrolled over 5 years), found that 1/3 of cytologically missed high-grade cervical intraepithelial neoplasia were HPV16 and/or HPV18 positive. Women who were cytology negative but HPV16 positive had a 13.6% risk of developing lesions above CIN2, or an average of 1 in 8 cytologically missed lesions of CIN2 and higher. Women who were cytology negative but HPV18 positive had a 7% risk of developing lesions above CIN2. The risk of CIN2 and higher grade lesions in those with positive cytology ASC-US, high risk HPV clusters, is comparable to that of those with positive HPV 16 and/or 18 but negative cytology and should undergo immediate colposcopy. Therefore, combining HPV16/18 genotyping in screening allows for better stratification of risk management.  The new 2013 ASCCP guidelines also specifically propose HPV16/18 genotyping in cytology-negative, HPV-positive women over 30 years of age (see below) to identify in a timely manner those at high risk for CIN with normal cytology results and those with atypical squamous cells of undetermined significance (AS-CUS) who require closer follow-up.  How to manage women over 30 years of age who are cytology negative and HPV positiveundefined. HPV DNA testing: effective triage of ASCUS and LSIL ASCUS is the biggest confusion encountered by clinicians and cytology technicians and subjects. In the United States, ASCUS and LSIL have a prevalence of 1.6-7.7%, of which 15%-30% are CIN 2/CIN 3. ASCUS and LSIL are a problem that cannot be ignored, and for It is necessary to triage ASCUS and LSIL.  There are three common methods to detect ASCUS and LSIL triage: 1. Direct colposcopy combined with biopsy. This method not only aggravates the cost but also traumatizes the body and is not suitable for widespread dissemination; 2. Repeat cytology follow-up, where the subject needs multiple biopsies at months 12, 18, and 24, but for most patients who may be normal, repeat cytology can be time-consuming and add to the financial and emotional burden; 3. HPV DNA testing is recognized as the most effective method of detection. HPV positive patients have 3.8 times higher chance of CIN1 and 12.7 times higher chance of CIN2 and CIN3 than negative patients. HPV positive can predict the occurrence of different levels of CIN, early detection of severe squamous intraepithelial lesions (HSIL), reduce patient anxiety, and reduce the cost of repeat testing.  HPV DNA testing: guidance for CIN management, treatment and postoperative follow-up As the main cause of cervical cancer and its precancerous lesion CIN, the persistence of HPV infection is positively correlated with the degree of cervical lesions. Management varies among CIN 1, CIN 2 and CIN 3 patients. There is still confusion and controversy regarding the clinical opinion that patients with CIN 1 are basically considered to be left untreated.The reversal, persistence and progression of CIN 1 are 60%, 30% and 10%, respectively. Because of the slow progression, the chance of progression to invasive cancer is very small (<1%), which is likely to lead to overtreatment and is unnecessary in terms of health economics. Admittedly, CIN1 does have a potential risk of developing HSIL and cervical cancer, and HPV DNA testing can help identify patients at high risk. In contrast, CIN2 is a transitional state from CIN1 to CIN3, and HPV positivity versus HPV negativity can make a significant difference in the regression of CIN2 and is an important reference for clinical decision making.  In addition, HPV DNA testing plays an important role in the treatment and postoperative follow-up of CIN patients. Although reasonable and successful treatment rates of 90-95% can be achieved for CIN, there is still a 10% recurrence rate after treatment. These CIN patients are 4-5 times more likely to develop cervical cancer in the next 8 years than the general population, with the greatest risk coming from inappropriate treatment (residual) or multifocal disease recurrence. However, "clean" margins are not a good predictor, and patients with "clean" margins can also have residual disease and recurrence, so they need to be followed up and tested for HPV. The first review after CIN treatment is routinely required at 4-6 months, followed by follow-up and testing at 6-12 months.  According to the 2012 ASCCP/ACS/ASCP report: For the evaluation of HPV testing methods, CIN2 and CIN3 should be used as study adjudication endpoints. the sensitivity of HPV testing for CIN2+ and CIN3+ should be ≥ 90% and it is recommended not to use HPV testing without clinical validation for cervical cancer screening. If HC2 ( Hybrid Capture ) started a revolution in HPV testing and in improving women's health and preventing cervical cancer, the new method, cobas 4800 HPV DNA test, is driving a new advance in cervical cancer screening technology, providing simultaneous HPV 16 and 18 typing results and results for 12 other high-risk HPV subtypes in aggregate, with With clinically validated determination criteria (cut-off values) and a fully automated testing platform, it offers unique advantages in large sample screening, and clinical performance and reproducibility that meet current requirements for HPV testing. The test has been approved by US FDA, EU CE and China SFDA, and will have a broad application prospect in the field of cervical cancer screening and treatment.