Cytological screening, HPV test or both?

Primary screening for cervical cancer has changed worldwide in recent years. New recommendations are also being developed in Switzerland. The most important prerequisite for success remains participation in the screening program.

All early cancer detection is based on knowledge of the carcinogenesis of the carcinoma being detected and is designed to detect precancerous lesions before symptoms occur. Cellular changes, carcinoma development and metastasis often take several years before clinical symptoms appear.
Screening for cervical cancer is based on this very knowledge to detect cervical dysplasia at early stages, treat it and prevent progression and carcinoma development.

Situation in Switzerland

Screening for cervical cancer has been established in Switzerland since the 1970s, but the effectiveness of screening has never been tested in randomized trials. The reduction in mortality rates now achieved and continuing in many countries reflects the success that can ultimately be achieved by early treatment of dysplastic precursors.

The incidence of cervical cancer in Switzerland (4.0 new cases per 100,000 women per year) is among the lowest in the world. To further reduce the incidence rate requires a large effort compared to countries with a high incidence.

In Switzerland, a broad but not systematically organized screening by gynecologists and general practitioners has become established, based on recommendations of medical societies and covered by the benefits catalog of the Health Insurance Act. It is not done in any way as part of a program with quality assurance. We still base screening on the cytological smear of the cervix (PAP), which with its relatively low sensitivity requires regular repetition. The 2012 recommendations of the Swiss Society of Gynecology and Obstetrics, which are currently still valid, stipulate a screening interval with cytology sampling of two years.

Since the 1990s, we have known that virtually all cervical cancers are associated with human papillomavirus (HPV) (Fig. 1) . Various HPV tests have been developed that were initially intended to increase the sensitivity of the Pap smear, but are now increasingly replacing it. If a screening test is chosen, it must be ensured that it combines high sensitivity (detection of the correctly ill) with acceptable specificity (low rate of false positive results). It is undisputed that HPV testing alone has a much higher sensitivity than PAP smears alone. This was clearly demonstrated in a meta-analysis of four randomized trials [1]. In addition, a negative HPV test provides a higher negative predictive value than cytology, which allows the time intervals between tests to be extended. However, the higher sensitivity of the HPV test comes at the expense of specificity. It has the disadvantage that it cannot distinguish between HPV-infected women and those who are clinically ill, which is why it is not advisable to use it in women under 30 years of age. We know that mainly women under 30 years of age are infected, but show a very high spontaneous remission rate without ever having shown dysplastic changes. HPV testing alone in women of all ages would assign more women to colposcopic examinations.

In some countries (Netherlands, Australia, Belgium, USA, Turkey, etc.) a switch from cytological smear to primary HPV testing has already been made, while other countries continue to prefer cervical cytology. The different approaches to screening have led to much debate about the “optimal” strategy, in terms of patient safety on the one hand, but also cost-effectiveness. Many questions were asked and addressed differently by the respective programs. Examples are:

Starting age for the HPV test
Length of the screening interval
Different procedures depending on
Screening result
Smear collection either as a self-test or at the specialist’s office
Triage for unclear findings
Procedure in case of HPV positivity and inconspicuous cytology
Which HPV test should be used
and meets the criteria for primary HPV screening?

Co-testing (cytology and HPV testing at the same time) was introduced by the US in 2012 in women aged 30-65 years. Evaluation has shown that the sensitivity of this test combination is only slightly higher than HPV screening alone.

In less industrialized countries with low financial and human resources for preventive/health care, the mortality of cervical cancer is significantly increased. This is where primary HPV screening has become established. In many places, “mobile” screening units visit rural areas that are difficult to access for health care, and HPV smears are usually performed by “self-sampling.” The evaluation of the test then takes place immediately on site. A “high risk” HPV detection leads to vaginal examination and immediate treatment of the cervix (“see and treat”).

CH: Cytological screening, HPV test or both?

In Switzerland, the current studies and findings are discussed in order to be able to make up-to-date recommendations for a program for the early detection of cervical carcinoma. Basically, it should be said that participation in a screening program remains the most important requirement, regardless of which screening method is chosen.

The Swiss Society of Gynecology and Obstetrics expert letter on this topic from 2012 has already been updated and is available for final approval by the Quality Assurance Commission. Anticipated changes to the recommendations published in 2012 could be in the sense of an extension of the recommended screening interval. Primary HPV screening for women younger than 30 years is unlikely to be recommended; for women 30 years and older, either HPV testing or cervical cytology may be performed; co-testing is unlikely to be recommended.

Prevention

Screening programs cannot be discussed without considering prevention. 70% of cervical cancers are caused by HPV types 16 and 18, and the approved vaccines ^Cervarix® and ^Gardasil® are available against these two types in Switzerland.

The Federal Commission on Immunization (EKIF) recommends vaccination of all girls 11 to 14 years of age – as well as a booster shot for 15- to 19-year-old girls. Vaccination is now also paid for in cantonal vaccination programs for women up to 26. Since 2015, there has also been a vaccination recommendation for male adolescents, and since July 2016, the costs have been covered by health insurance companies as part of the cantonal vaccination programs. Unfortunately, compliance to vaccination is not high (55%) and is lowest in the cantons where most cervical cancers occur. Studies in countries with high vaccination rates (e.g. Australia, Scotland) have shown that already dysplastic precursors occur much less frequently. However, even if vaccination rates can be increased, participation in screening remains necessary (with adjusted screening conditions).

Take-Home Messages

The incidence of cervical carcinoma is very low in Switzerland.
Primary screening for cervical cancer has changed worldwide in recent years, and the costs and benefits of the method used continue to be evaluated.
Screening programs depend on prevention programs and compliance in the population.
A negative HPV test has a higher negative predictive value than cytology, which allows the time intervals between tests to be extended.
In Switzerland, new recommendations on the national screening program will be made in the coming weeks and months.

Literature:

Murphy J, et al: HPV testing in primary cervical screening: a systematic review and meta-analysis. J Obstet Gynecol Can 2012; 34: 443-452.
Tjalma WA, et al: Differences in human papillomavirus type distribution in high-grade cervical intraepithelial neoplasia and invasive cervical cancer in Europe. Int J Cancer 2013; 132(4): 854-867.