3. Epidemiology – Cervical Carcinoma

Cervical cancer is the fourth most common gynecological malignancy worldwide. A total of 528,000 women were newly diagnosed with cervical carcinoma in 2012, and 266,000 women died of the disease. In Germany, this tumor entity has become a less frequent tumor type in recent decades, partly due to early detection. Partly thanks to early detection, cervical carcinoma has become a less frequent type of tumor in Germany over the last few decades. This has led to a reduction in the incidence of invasive cervical carcinoma during the last 30 years — from being the most frequent type of carcinoma among women (in 1971) to the thirteenth most frequent, at 1.9% of the total incidence of all malignancies among women (in 2016) in Germany [3]. This decline in cervical carcinoma is explained, among other factors, by the introduction in 1971 of early detection examinations using a cytological smear, which have made it possible to detect precursors and early stages of cancer in a timely way and treat them successfully [4]. The development and introduction of human papillomavirus (HPV) vaccines does not explain the observed decline in the incidence, as these vaccines were only included in the recommendations of the Standing Committee on Vaccines (STIKO) in 2007 (GBA decision 2008). However, it is expected that the implementation of HPV vaccination will further reduce the incidence and mortality rates in the future. Since June 2018, the STIKO has also recommended vaccination for boys aged 9–14. This is expected to further reduce the incidence and mortality of cervical cancer provided that sufficient vaccination coverage is achieved, including through herd immunity [5].

IIn Australia, a vaccination program using the quadrivalent vaccine (HPV types 6, 11, 16, and 18) was introduced between 2007 and 2009 for girls aged 12–13. Between 2006 and 2009, a reduction in the incidence of HSIL lesions from 0.85% to 0.22% in females under 18 years of age was observed (P = 0.03). No reduction was seen in other groups of patients. The reduction in HSIL lesions was therefore only found in patients who received vaccination [6]. In a cluster-randomized trial of HPV-associated invasive carcinoma, including a total of 9,529 initially 14–17-year-old girls who received the bivalent or quadrivalent HPV vaccine and 17,838 initially 14–19-year-old females without HPV vaccination, eight cervical carcinomas were diagnosed in the unvaccinated women after 7 years and no cervical carcinomas were seen in the vaccinated women. However, the data were not available to the guideline group in the form of a full publication, which is expected in 2021 [7].

A meta-analysis of 20 studies from nine countries including 16,600 women vaccinated against HPV showed a 64% reduction in the incidence of infection with HPV 16 and 18 in women aged 13–19 years (RR 0.36; 95% CI, 0.25 to 0.53) [8].

The incidence of more advanced tumor stages (≥ FIGO stage IIB) and the numbers of deaths have declined since 1980, but have been stagnating over the last 10 years. Overall, approximately one in 340 women currently dies of cervical carcinoma in Germany; 30 years ago, the figure was more than twice that [3].

Data from the Robert Koch Institute and GEKID for 2019 report a total of 4380 new patients with cervical carcinoma in 2016, and 1562 deaths from the disease. The incidence in comparison with 2002 (n = 6500 to 4380) has thus clearly declined, and the number of deaths (n = 1700 to 1562) due to cervical carcinoma has fallen slightly [3] [9]. The relative 5-year survival rate for patients with cervical carcinoma was 67% in 2016, while the 10-year survival rate was 63%.

The age distribution shows a peak between 40 and 59 years of age. The mean age at first diagnosis of cervical carcinoma, currently 55, has declined by 15 years during the last 25 years [3]. The mean age at which the disease develops is 34 for preinvasive precursor stages — a mean of 20 years younger [3]. TThe 5-year prevalence was 17,400 women in 2014, slightly lower than the 2016 rate of 17,500. In 2013–2014, 44% of cervical carcinomas were in stage UICC stage I at first diagnosis, 13% in stage II, 23% in stage II, and 20% in stage IV [3].

UICC stages according to TNM classification: UICC 0 = Tis N0 M0; UICC I = T1 N0 M0; UICC II = T2 N0 M0; UICC III = T3 N0 M0 or T1-3 N1 M0; UICC IV = T4 N0 M0 or T4 N1 M0 or any T any N M1.

Source: Bavarian Cancer Registry, 2013.

Squamous cell or nonsquamous cell carcinoma, as well as adenocarcinoma and adenosquamous carcinoma, are the most frequent histological types. Squamous cell carcinoma is present in approximately 80% of cases. The proportion of adenocarcinomas has increased during the last 25 years from 10% to approximately 20% [14] [15] [16]. Other tumor entities such as mixed forms (adenosquamous), neuroendocrine (large cell or small cell) or clear cell or serous papillary carcinomas are rare.

Reasons for the increase in adenocarcinomas may include improved histopathological classification of cervical carcinoma and the increasing role played by cofactors in carcinogenesis; adenocarcinoma in situ (AIS) is diagnosed in an endocervical location during screening more rarely than preinvasive squamous cell lesions (cervical intraepithelial neoplasia, CIN) [17] [18] [19] [20] [21][22][22][23][24][25] [24]. Research is still continuing to determine whether HPV vaccination is leading to a shift in the histological subtypes. Reference may be made here to the relevant Level 3 guideline on “Prevention of Cervical Carcinoma” (AWMF registry no. 015/27OL) and to the Level 3 guideline on “Vaccine Prevention of HPV-Associated Neoplasia” (AWMF registry no. 082/002).

The etiology and pathogenesis of cervical carcinoma have not yet been conclusively explained. The carcinogenetic process is multifactorial, with varying importance and interactions among the influencing factors. Different groups of risk factors for the development of invasive cervical carcinoma have been distinguished:

Major risk factors

• Infection with human papillomavirus (mainly HPV type 16+18; see section 3.4.1)
• Precancerous lesions/dysplasia — low-grade squamous intraepithelial lesion (LSIL); high-grade squamous intraepithelial lesion (HSIL), and adenocarcinoma in situ (AIS)

Nongenetic risk factors / cofactors
[26] [27] [28] [29] [30]

• Smoking (> 15 cigarettes per day)
• Patients with immunosuppression (HIV, medications)
• Early start of sexual activity (< 14 years of age)
• Frequently changing sexual partners (more than four in 10 years)
• Other infections (e.g., genital herpes, chlamydiae, gonococci)
• Low socioeconomic status
• Poor sexual hygiene
• Long-term use of oral contraceptives, > 5 years (for possible confounding factors, see section 3.4.2) 
• Large number of births

Genetic risk factors / co-factors

• Additional factors such as genetic variations (somatic) may influence the development of tumors. The extent to which these are of clinical relevance is as yet unclear. They have an odds ratio with just under a twofold increase [31][32]. By comparison, the OR for HPV high-risk positivity is 150, while with HPV 16 positivity it is as high as over 400 [33]. Nicotine abuse, with an OR of 2.17, also represents a higher risk [34]. Research is currently focusing on single nucleotide polymorphisms (SNPs) in the following genes, with no claim to completeness in the listing:
• HPV persistence: IRF 3, OAS3, SULF1, DUT, GTF2H4, FOXP3
• Progression to invasive cervical carcinoma: FANCA, IFNG, EVER1/EVER2, FAS 
• Specific to cervical carcinoma: TP 53, CCND1
• Genes with a general disposition toward tumor development: ATM