Combined Cervical Cancer Screening and the Incidence of Adenocarcinoma

An Analysis of Data from the German Cancer Registries

Background: Despite the declining incidence and mortality of cervical cancer following the introduction of the opportunistic cytological screening, a diagnostic gap persisted, particularly for adenocarcinoma, due to the lower sensitivity of conventional cytology for glandular versus squamous lesions, resulting in a stagnating or modest increase in adenocarcinoma incidence. Since 2020, combined screening with HPV testing and cytology has been recommended in Germany for women aged 35 years and older.

Methods: The present analysis is based on nationwide data from the German Cancer Registry. Women who received the diagnosis of a cervical adenocarcinoma in situ (ACIS) or invasive adenocarcinoma in the years 2016–2022 were included in the analysis. Trends in age-specific and standardized incidence in three age groups (under age 35, age 35–64, and age 65 and above) were analyzed with joinpoint regression.

Results: Data on 4128 women with ACIS and 6244 with invasive adenocarcinoma were evaluated. In women aged 35–64, the introduction of combined screening led to a marked increase in ACIS diagnoses (average annual increase, 17.3%; 95% confidence interval [14.9; 19.6]. The rise was particularly large in 2020, with an annual percentage change (APC) of 27.5%, [17.4; 38.5]. Over the same period, there was a decline in invasive adenocarcinomas from 2021 onward (APC −10.8%, [−22.7; 2.8]). The incidence of ACIS also rose among women aged 65 and above, while that of adenocarcinoma fell slightly.

Conclusion: Combined screening for cervical cancer improved the early detection of preinvasive glandular lesions. There is also evidence for a reduction of invasive disease in the screened population. For the full potential of screening to be achieved, there is a need for quality-assured organized programs and additional biomarkers for HPV-negative adenocarcinoma.

Cite this as: Schwab R, Emrich K, Heimes AS, Schwarzer K, Schmidt M, Hasenburg A, Justenhoven C, on behalf of the German Cancer Registries: Combined cervical cancer screening and the incidence of adenocarcinoma: An analysis of data from the German Cancer Registries. Dtsch Arztebl Int 2026; 123: 213–8. DOI: 10.3238/arztebl.m2026.0001

With approximately 570 000 new cases and 311 000 deaths in 2018, cervical cancer is worldwide one of the most common cancers in women (1). In 2020, the age-standardized incidence in Germany was 9.5 per 100 000 women, with 4640 new cases recorded (2).

Cervical cancer (mixed cohorts consisting of glandular and predominantly squamous histologic subtypes) is caused by persistent infection with high-risk human papilloma viruses (hrHPV) in up to 99% of cases (3, 4). Recognition of the causal role of persistent hrHPV infection in the carcinogenesis of cervical cancer has produced a paradigm shift in prevention and early detection over time.

The introduction of cytology-based early detection (Pap smear) in Germany in the 1970s led to a decline in the incidence of cervical cancer by over 70% (5). This reduction is mainly driven by a decrease in squamous cell carcinoma of the cervix (approximately 70 to 80% of all cervical cancers). In contrast, the incidence of cervical adenocarcinoma (approximately 16 to 25% of cases) has been stable or even increased in many Western countries over recent decades, especially in younger women (6, 7, 8, 9). The cause is believed to be a diagnostic gap due to the lower sensitivity of conventional cytology in detecting preinvasive glandular lesions (6, 10).

In Germany, cytology-based, opportunistic screening was replaced in 2020 by an organized screening program. This screening approach aims to increase participation and improve quality assurance through invitations, structured algorithms, and systematic documentation (11). Before the introduction of the organized program, the latest annual participation rate was less than 50% and approximately 70 to 75% over a three-year period (12). Given the high survival rates when diagnosed early, there is a real need to increase participation in the screening program – especially for high-risk groups – and to avoid over- and under-screening by optimizing screening intervals (13).

International recommendations now favor primary HPV-based screening, where the screening intervals are extended to between three and five years, because the sensitivity of the HPV test for detecting cervical intraepithelial neoplasia grade 2 or higher-grade lesions is above that of cytology (13, 14). Long-term data from the Kaiser Permanente Northern California (KPNC) co-testing cohort showed that HPV-based screening detected significantly more adenocarcinomas in situ (ACIS, 80% versus 40%) and invasive adenocarcinomas (78% versus 15%) than cytology alone (14). It was also shown that a negative HPV test and a negative co-test result were associated with an extremely low risk of cervical cancer (3 to 4 cases per 100 000 women per year) over a period of five years (14).

Since 2020, the German early detection program has offered combined screening (HPV test and cytology, so-called “co-testing”) every three years to women from the age of 35, while younger women up to the age of 34 are still recommended to undergo annual Pap screening (9, 11). Combined screening involves taking cell samples from the cervix and examining them for possible alterations (cytology) and for high-risk HPV types (11). For women from the age of 35, approximately 2.3 million examinations were documented in 2021 and around 1.3 million in 2022 as part of the co-testing program; due to the three-year screening interval, it has not yet been possible to calculate any robust participation rate (15). The benefit of continuing screening for women over the age of 65 has not yet been fully assessed; it is recommended to make a decision on an individual basis, taking previous findings and vaccination status into consideration (11, 16, 17). At the same time, HPV vaccination is becoming increasingly important, both for the primary prevention of cervical cancer and for planning future individual screening intervals (18).

The primary aim of the present analysis was to assess the effect of the combined cervical cancer screening program (HPV testing and cytology), introduced in 2020, on the detection rates of ACIS and invasive adenocarcinoma in women from the age of 35. The focus was on the potential to improve the early diagnosis of preinvasive and invasive glandular lesions through the combined screening approach. The persistent and even increasing incidence of adenocarcinoma, despite successful cytology-based screening, highlights the urgent need to focus research and healthcare facilities on this subgroup.

Data sources and statistical methods

The analyses are based on data from all German cancer registries, compiled by the Center for Cancer Registry Data of the Robert Koch Institute (as of December 2024). This center in Berlin produces completeness estimates for Germany’s cancer registries. In 2020, the calculated completeness ranged from 80% to 100% across all registries, with 13 of the 16 registries exceeding 95% (2). Women diagnosed with an ACIS or invasive adenocarcinoma in the years 2016 to 2022 were included in the analysis.

Median age, case numbers, and age-specific and age-standardized incidence rates were calculated per 100 000 women (19) for ACIS and adenocarcinoma. The rates are standardized according to the old European standard population and were calculated for three age groups:

• ≤34 years
• 35–64 years
• ≥65 years.

The trends in age-standardized and age-specific rates were analyzed using joinpoint regression. Annual percentage change (APC) and average annual percentage change (AAPC) were estimated on the log scale and then transformed back (R, function segmented) (20, 21). Confidence intervals were reported instead of p-values due to the chosen estimation method: if the overall interval is above or below zero, the APC or AAPC is considered significant and indicates a rise or fall, respectively. This study is an exploratory descriptive investigation. All statistical analyses were performed with SAS 9.4 and R (RStudio) (22, 23).

Ethics

Ethics approval was not necessary because only retrospective, anonymized data were used.

Results

A total of 4128 women with ACIS (median age 40 years) and 6244 with invasive adenocarcinoma (median age 53 years), diagnosed between 2016 and 2022, were included in the analysis. Figure 1 presents the annual case numbers in the three age groups for ACIS and invasive adenocarcinoma. An increase in ACIS diagnoses was observed in the 35 to 64 age group during the study period, starting at the end of 2019 (Figure 1). Completeness of the cancer registry data ranged from 80% to 100%, with a median of over 95% (2). The highest number of cases was seen within the 35 to 64 age group, for both ACIS and invasive adenocarcinoma (Figure 1). In the 35-and-under age group, the proportion of invasive adenocarcinoma among abnormal lesions (ACIS and invasive adenocarcinoma) was 38.4%. The corresponding proportions were 56.3% in the 35 to 64 age group and 91.3% in the 65 and over age group (averaged for 2016 to 2022).

Figure 1

Case numbers of patients with ACIS and invasive adenocarcinoma of the cervix between 2016 and 2022.

The age-standardized rates of all patients with ACIS increased during the observation period (Figure 2). In women between the ages of 35 and 64, the ACIS case numbers rose over the entire period 2016 to 2022 by approximately 260 to 700 cases per year (Figure 1). There was an annual increase in ACIS rates (APC) of 27.5% [17.4%; 38.5%] in the same age group from the end of 2019 (i.e., from the beginning of 2020) until the end of 2022. The average annual rise in the 35 to 64 age group (AAPC) was 17.3% [14.9%; 19.6%] for the entire period from 2016 to 2022 (Figure 3a).

Figure 2

Trends in ACIS and invasive adenocarcinoma from 2016 to 2022, stratified by age group. Age-standardized incidence rates (European standard, per 100 000 women) and joinpoint analyses for patients with ACIS or invasive adenocarcinoma in the years 2016–2022. The trend is significant. The x-axis indicates the diagnosis years (for example, 2019 includes women diagnosed between January 1, 2019, and December 31, 2019). ACIS and invasive adenocarcinoma are color-coded. The y-axis represents age-standardized incidence rates. AAPC, average annual percentage change; ACIS, adenocarcinoma in situ; APC, annual percentage change

Figure 3a

Trends in ACIS for the period 2016–2022 in the various age groups (<35 years; 35–64 years; =65 years). The x-axis indicates the completed diagnosis years (for example, 2019 includes women diagnosed between January 1, 2019, and December 31, 2019). The y-axis represents age-specific incidence rates per 100 000 women. The different years are color-coded. AAPC, average annual percentage change; ACIS, adenocarcinoma in situ; APC, annual percentage change

No clear trend was evident over the entire observation period for invasive adenocarcinoma (Figure 3b) among 35- to 64-year-olds. However, a decline of an annual percentage of −10.8% [−22.7; 2.8] was noticed during the last observation interval (end of 2021 to end of 2022) (Table). The case numbers fell in this period from approximately 580 to 525 cases (Figure 1).

Figure 3b

Trends in invasive adenocarcinoma for the period 2016–2022 in the various age groups (<35 years; 35–64 years; =65 years). The x-axis indicates the completed diagnosis years (for example, 2019 includes women diagnosed between January 1, 2019, and December 31, 2019). The y-axis represents age-specific incidence rates per 100 000 women. The different years are color-coded. AAPC, average annual percentage change

Table

Trends in APCs and AAPCs with confidence intervals for age-specific incidence rates of ACIS and invasive adenocarcinoma in three age groups and for age-standardized incidence rates (all age groups)

A rise in ACIS incidence was observed among women aged 65 and older, especially during 2016 to 2018 (APC: 30.3% [0.6; 68.7]). This rise extends, albeit to a lesser extent, over the entire period (Figure 3a; AAPC: 12.9 % [5.5; 20.3]; Table). A slight decline in the incidence of invasive adenocarcinoma was evident in the same age group for the entire period (AAPC: −1.5% [−2.5; −0.7]; Figure 3b, Table).

In the age group of women under 35 (cytological screening), a mild, less pronounced decline in ACIS cases became noticeable from 2017 onwards (Table, Figure 3a). There was a decline in the incidence of adenocarcinoma over the entire study period (AAPC: −10.5% [−16.7; −4.4]) (Figure 3b).

Discussion

The present analysis was conducted using nationwide cancer registry data. It demonstrates that the combined cervical cancer screening program (HPV and cytology) implemented in Germany in 2020 was associated with a rise in ACIS detection (17.9% annual increase from the end of 2019 to the end of 2022). At the same time, a decline in the incidence of invasive adenocarcinoma from the end of 2020 was also identified. The findings suggest a possible preventive effect resulting from the combined screening program and HPV vaccination.

Results of the different age groups

The highest number of cases with abnormal findings was evident in the 35 to 64 age group – the main target group of the combined screening program (11). A significant increase in ACIS diagnoses characterized this age group. Between 2016 and 2022, the average annual increase in rates was 17.3%, with a marked rise from the end of 2019. These observations are linked to the combined screening program. They suggest that the pre-existing diagnostic gap in the early detection of preinvasive glandular lesions may have been reduced. At the same time, a decline in the incidence of invasive adenocarcinoma was observed from late 2021 into 2022 (APC: −10.8%), although it was not significant. Further longitudinal data and prospective studies are required to assess the clinical and statistical relevance of these trends.

These findings could indicate a preventive effect of combined screening for glandular lesions, given that the incidence of invasive adenocarcinoma declined during the observation period due to early detection and subsequent treatment. The present data from the nationwide cancer registries are consistent with international data from the KPNC trial, which confirmed the superiority of HPV screening over cytology in the detection of ACIS (sensitivity of 80% versus 40%) and invasive adenocarcinoma (detection rate of 78% versus 15%) (14). The ATHENA trial reported that HPV 16 and HPV 18 were responsible for over 80% of cervical adenocarcinomas, with HPV 18 causing about 50% of ACIS and adenocarcinomas (24). The present analysis also emphasizes the effectiveness of co-testing for glandular lesions. A Finnish study also stressed the importance of a structured screening program, as only 11% of endocervical neoplasms were symptomatic (25).

The superiority of HPV screenings resulted in many countries (for example, the Netherlands and the United Kingdom) implementing a primary HPV-based, organized screening program with longer intervals (13, 17). However, approximately 15 to 20% of adenocarcinomas are HPV-negative (26). In order to also detect these rare, yet clinically significant subtypes early, the development and integration of additional biomarkers into the screening program are required (27).

Colposcopy as an additional measure to purely cytology-based screening also presented significant limitations: a British study reported a sensitivity of only 9.8% for endocervical lesions, a false-negative rate of 33.7% and a sensitivity of 25% for invasive adenocarcinoma (28).

There was a significant rise in ACIS cases in women aged 65 and over during the period from 2016 to 2022 (AAPC: 12.9%), with the strongest increase occurring up to 2018 (APC for 2016 to 2018: 30.3%). A slight decline was noticed from 2019 onwards, which had a high variation, however, so that a clear trend cannot be confirmed. There was also a slight rise in incidence for adenocarcinoma until 2020 (APC: 2.2%), followed by a decline. The incidence of adenocarcinoma declined mildly over the entire period (AAPC: −1.5%). The age group of 65 and older demonstrated the highest proportion of invasive findings, based on the total number of abnormal results (ACIS and adenocarcinoma), indicating that this age group is at high risk for developing adenocarcinoma..

These results demonstrate that combined screening can also contribute towards early detection of (pre)invasive glandular lesions in the older age group, even though long-term effects cannot be conclusively assessed. The long-term implementation of combined screening for women aged 65 and older could contribute towards lowering the risk of developing invasive adenocarcinoma in this age group.

In the age group of women younger than 35, there was a mild decline of ACIS diagnoses from the end of 2017 and a decline of invasive adenocarcinoma from the end of 2018. Given that the screening program has remained unchanged since 1971 for this age group, the observed trends appear to be associated with the introduction of HPV vaccination. This hypothesis is supported by the findings of Grieger et al., who demonstrated a decline in the incidence of invasive cervical cancer in cohorts eligible for vaccination (29). It is noteworthy that the temporal proximity of the trend reversals in ACIS and invasive adenocarcinomas could suggest that progression of ACIS to invasive carcinoma develops more rapidly in younger age groups than previously assumed (30). The findings also indicate the potential effectiveness of HPV vaccination with respect to glandular lesions. This is an important aspect, since HPV-based screening shows limited effectiveness in this young cohort as demonstrated by its high false-positive rates (6, 10).

The observed trends must be interpreted in light of the COVID-19 pandemic: from 2020 to 2022, age-related interference disrupted the otherwise regular screening examinations in Germany which may have led to temporary fluctuations in screening uptake (15). These changes could have affected the course of some trends, especially the number of cases in 2020 and 2021.

Long-term impact of combined screening

A crucial concern in the present analysis is the assessment of the long-term impact of combined screening on the incidence of invasive adenocarcinoma. The findings indicate the promising detection of preinvasive and invasive glandular cervical lesions. However, long-term observations are required for robust conclusions to be drawn on mortality reduction and lasting effectiveness of combined screening.

Among the 35 to 64-year-olds, the detected reduction in incidence in the final observation year of 2022 (APCC: −10.8%) contrasts with the absence of a significant overall trend from 2016 to 2022. This could indicate that the preventive effects of screening on adenocarcinoma incidence in this age group only become manifest with some delay. The data suggest that combined screening could help prevent invasive disease by allowing early diagnosis of preinvasive lesions. They also indicate that a decline in adenocarcinomas and their detection at earlier stages only become apparent over the longer term.

Earlier trials have not provided sufficient data on the long-term impact of combined screening on glandular lesions in women aged 65 and above: a fact which highlights the relevance of the present analysis (16). The current findings suggest that at least one HPV-based combination screening should be performed in this age group. The targeted inclusion of this age group in the combined screening process could help prevent or contribute towards early detection of invasive adenocarcinoma in older age groups. Further studies are required to identify the optimal screening frequency and to assess whether a single negative HPV test, as recommended by European guidelines, can end the need for screening at the age of 65 (16).

Given its descriptive study design, no causal conclusions can be drawn from the present analysis, thus emphasizing the urgent need for further prospective randomized trials to confirm this association.

Cancer registry data allow trend analyses in the overall population and across age groups. However, they do not provide any information to date on the proportion of screened women, thus limiting the interpretability regarding the efficacy of screening for preinvasive and invasive glandular lesions. Different degrees of registry completeness may also affect these trends. Nevertheless, cancer registries are a crucial component of the quality assessment of screening programs. Apart from detecting interval cancer by mammography screening, they also contribute toward the evaluation of organized cancer screening programs by comparing screening data (31, 32).

Methodologically, however, the present analysis also has its particular strengths: it comprehensively captures the detection rates of ACIS and invasive adenocarcinoma over a period of seven years and allows for an initial estimate of short- and long-term developments after the introduction of combined screening in Germany.

In summary, therefore, the present analysis of nationwide cancer registry data provides strong evidence that combined screening for cervical cancer can optimize early detection of preinvasive glandular lesions and lead to a reduction of invasive disease in the screening population.

eBox

Participants of the German Cancer Registries (DKR)

Conflict of interest statement

ASH has received professional fees for lectures and consulting activities from Pfizer Pharma, Roche Pharma, Streamedup!, AstraZeneca, Lilly, Daiichi Sankyo, Novartis Pharma, and med update.

MS states having received personal fees from AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, Eurobio, Exact Sciences, Gilead, Lilly, Menarini-Stemline, Molecular Health, MSD, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, and Roche. His institution has received research funds from AstraZeneca, BioNTech, Eisai, Genentech, the German Breast Group, Novartis, Palleos, Pantarhei Bioscience, Pfizer, Pierre Fabre, and Roche. MS is also listed as an inventor on patents EP 2390370 B1 and EP 2951317 B1.

AH has received lecture fees from AstraZeneca, Abbvie, GSK, Lilly Germany, MedConcept, Medico Seminare, Medudy, Med update, Pfizer, MSD, and Streamedup!. She has received consulting fees from AstraZeneca, MSD, GSK, and Pfizer.

RS has received lecture and consulting fees from Roche Pharma, AstraZeneca, MSD Sharp & Dohme, Sanofi, and Streamedup!.

The other authors declare that no conflict of interest exists.

Manuscript received on August 18, 2025, revised version accepted on January 7, 2026 Translated from the original German by Dr. Grahame Larkin

Corresponding author:
PD Dr. med. Roxana Schwab

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