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 cervical cancer samples, 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. It is not uncommon among sexually active young women (4-15%) and has a lifetime accumulation probability 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 can be cleared without developing 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) agree 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.
In the new cervical cancer screening guidelines released by the U.S. Preventive Services Task Force (USPSTF) in 2012 and the new 2012 cervical cancer screening guidelines jointly released by ACS, ASCP, and ASCP, combined cytology and high-risk HPV testing is recommended as a priority 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 brings some new confusion and questions to the clinic, for example, can a negative cytology but positive HPV status be considered as “new ASCUS”? What is the clinical management of follow-up? The European Organization for Research on Reproductive Tract Infections and Neoplasms (EUROGIN), in its 2008 strategy for cervical cancer prevention and treatment, envisages the early detection of high-risk groups through HPV16/18 genotyping, p16 or other biomarkers, and triage of cytology-negative, HPV-positive populations.
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 the risk in 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 positive
HPV DNA testing: effective triage of ASCUS vs. LSIL
ASCUS is the biggest confusion for clinicians and cytology technicians as well as test subjects. In the United States, ASCUS and LSIL have an incidence 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 triage of ASCUS and LSIL is essential. It is necessary to perform triage for ASCUS and LSIL.
There are three commonly used methods to detect ASCUS and LSIL triage.
1. direct colposcopy combined with biopsy. This method is not only costly but also traumatic and not suitable for widespread use;
2, Repeat cytology follow-up, the subject needs multiple biopsies at the 12th, 18th and 24th month, but for most patients who may be normal, repeat cytology will take a lot of time and increase the financial and emotional burden;
3, HPV DNA testing is recognized as the most effective test. 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 persistent infection rate of HPV is positively correlated with the degree of cervical lesion. 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 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 inadequate treatment (residual) or multifocal disease recurrence. However, “clean” margins are not a good predictor, and patients with “clean” margins may 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 the study adjudication endpoints. the sensitivity of HPV testing for CIN2+ and CIN3+ should be ≥ 90% and it is recommended not to use HPV testing that is not clinically validated for cervical cancer screening.
If HC2 ( Hybrid Capture ) started a revolution in HPV testing and improving women’s health and preventing cervical cancer, the new method, cobas 4800 HPV DNA test, is driving new advances 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 clinically validated adjudication criteria (cut-off values) and a fully With a clinically validated determination criteria (cut-off value) and fully automated testing platform, the test has unique advantages in large sample screening, and clinical performance and reproducibility meet the 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.