4. Prevention and early detection – Cervical Carcinoma

Recommendations on primary prevention of cervical carcinoma by vaccination against the high-risk genotypes of human papillomavirus (HR-HPV), HPV 16 and 18, are given in Germany in the Level 3 guideline on “Vaccine Prevention of HPV-Associated Neoplasia” (AMWF register no. 082/002), by the Paul Ehrlich Association for Chemotherapy (HPV Management Forum Working Group), the German STI Association, the German Dermatological Association, and in the recommendations of the Standing Vaccination Committee of the Robert Koch Institute (STIKO).

Infection of the cervical epithelium with high-risk types of human papillomavirus (HPV) is the main cause of the development of cervical carcinoma. More than 95% of cervical carcinomas are HPV-positive, with HPV type 16 being found in 50–60% and HPV type 18 in 10–20% of the carcinomas [38] [39]. In German studies, approximately 60% of all high-grade cervical intraepithelial neoplasias (CIN 2/3) have been found to be associated with HPV types 16 and 18. The risk of infection with HPV increases with the number of sexual partners. Consistent use of condoms reduces the risk of transmission, but does not provide absolute protection against infection [40]. HPV is a common sexually transmitted infection. The risk of infection with HPV increases with the number of sexual partners. Consistent condom use reduces the risk of transmission but is not absolute protection [41]. Cofactors that influence the risk of HPV-positive women developing invasive carcinoma include prolonged use of oral contraceptives, smoking, high parity, immunosuppression, HIV infection, and other genital infections such as chlamydia or herpes [42]. HPV infection is common, but not all patients develop manifest dysplasia or carcinoma, as the rate of spontaneous recovery is high.

TThe bivalent and nonavalent HPV vaccines that are currently approved contain noninfectious virus-like particles (VLPs) without any viral DNA and are directed against HPV 16/18 and in the nonavalent vaccines against HPV 6/11/31/33/45/52/58 in addition. These VLPs can stimulate the humoral and in some cases also the cellular immune system [43]. Many studies have confirmed that the vaccines are remarkably effective for prophylaxis in young women with no exposure to HPV, women aged 25–45, and also in HPV-naïve men and in children against vaccine type–specific anogenital diseases [44]. The safety profile of these vaccines is very good — after two decades of their use. In several countries with high rates of vaccination coverage, a significant decline in genital warts (> 90%) and a reduction in the numbers of cases of intraepithelial neoplasia among young women have been recorded.

On the basis of theoretical vaccine efficacy, the nonavalent HPV vaccine introduced in 2016 will provide marked improvements of 90% against invasive cervical carcinomas, 75–85% against CIN 2/3, and 50–60% against CIN 1 [45] Studies have also confirmed very high effectiveness relative to the end points of vaccine type–specific intraepithelial neoplasia of the cervix, vulva, and vagina [46]. The current vaccination rate is 44.6% according to the RKI in 2018 and 57.9% after at least one vaccination dose. There is increasing evidence from national registry analyses — from Australia, for example — that a single vaccination provides adequate immunity.

The STIKO recommends general vaccination of all girls and boys aged 9–14. Vaccination with two vaccination doses at an interval of 6 months should be completed if possible before the first sexual intercourse [47]. A third vaccination dose is required above the age of 14. Repeat vaccination should be given by age 17. Since 2018, HPV vaccination is now also recommended by the STIKO for all boys aged 9–14. The background to this is the significant reduction in the disease burden of HPV-associated tumors in both sexes that can be expected with the current vaccination rates among girls as a result of the additional vaccination of boys [48].

Recommendations for secondary prevention of cervical carcinoma are dealt with in the Level 3 guideline on “Prevention of Cervical Cancer,” register no. 015-027OL, under the auspices of the German Association for Gynecology and Obstetrics (DGGG) [49].

Primary screening and diagnosis are regulated in the guideline published by the Federal Joint Committee (G-BA) on November 22, 2018 on organized cancer screening programs and the program for the early detection of cervical carcinoma.

Recent findings from meta-analyses of randomized and controlled studies and cohort studies using testing for high-risk genital human papillomavirus (HPV) in comparison with cytology led to discussions concerning the further development of cervical cancer screening. The aims were to improve the sensitivity of the examination and to increase the participation rate. Following intensive discussions among the various groups of interested parties, the G-BA defined the design of the future screening program at a meeting held on September 15, 2018 and set it out in the a guideline [51] [52]. The guideline is largely based on the recommendations of the Level 3 guideline on prevention of cervical carcinoma [49], [51]. Organized screening in Germany started on January 1, 2020:

• For the first time, women are entitled to cervical cancer screening services starting from age 20: eligible women (Section 5) qualify to receive an invitation, information and explanations, cytology-based or combined primary screening with a clinical examination, reporting of findings and counseling (Section 6), and further diagnosis (Section 7).

• Women aged 20–34 are eligible for annual cytology-based cervical cancer screening in accordance with Section 6, paragraph 3. If a negative HPV test is obtained, women aged 30–34 with Pap group II-p or II-g cytology results are eligible for repeat participation in primary screening.

• In the future, women aged 35 and over are to be offered a combination examination consisting of an HPV test and a cytological examination every 3 years instead of the annual cytological examination.

• Eligible women will be invited to participate when they reach the age of initial eligibility. Further invitations are to be issued in each case at the ages of 25, 30, 35, 40, 45, 50, 55, 60, and 65.

• No upper age limit has been set. However, women should be informed about the conditions in which stopping screening will only involve a low residual risk of cervical cancer.

• During a transitional phase of at least 6 years, data will be collected as part of the monitoring process to determine whether further changes in the screening strategy are needed.