Cervical cancer screening by co-testing in women 35 years and older: an analysis of the 1st round of screening in Germany

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In this study, we investigated the added value of co-testing in organized cervical screening for the German screening population. Methods: A total of 1956 women were referred to our large dysplasia consultation institution due to abnormal screening results in the first round of screening between 2020 and 2022. The endpoint of this retrospective study was the posttest probability of a CIN 2+/CIN 3+ lesion on the cervix uteri. In addition, the influence of HPV subtypes on the endpoints was investigated. Results: CIN 2+ or CIN 3+ lesions were diagnosed in 21.6% and 13.0%, respectively, of the patients. The risk of severe dysplasia increases with the grade of cytological abnormality and is dependent on the HPV subtype. The risk for detecting invasive cervical cancer (16 patients in total) was significantly greater for women with HPV16 infection than for women with HPV infection of other high-risk types (odds ratio 11.18; 95% confidence interval 3.01, 40.81). CIN 2+ lesions were diagnosed in 10.1% of patients with normal cytology. Conclusions: CIN 2+ lesions could be detected in more than every 5th woman with an abnormal screening result. Normal Pap smear results with HPV evidence must be confirmed by colposcopy. Risk stratification based on the underlying HPV subtype appears to be particularly useful if HPV 16 is detected. Trial registration: German Clinical trials register (ID: DRKS00027014, Registration date: 03.12.2021) cervical dysplasia colposcopy HPV HSIL Pap smear Figures Figure 1 Figure 2 BACKGROUND In Germany, nationwide cervical cancer screening using the Papanicolaou test (PAP test) was introduced in 1971. This opportunistic cancer screening program led to a drastic reduction in the incidence of cervical cancer. However, the incidence of invasive cancer of the cervix uteri has not further decreased and has stagnated over the last two decades [ 1 ]. For this reason, a new, organized cancer screening program has been launched: since January 1, 2020, women aged > 20 years are entitled to gynecological cancer screening once a year. It should be noted that women between the ages of 20 and 34 are entitled to an annual smear test using the PAP test. For women over the age of 35, a test for the presence of human papillomavirus (HPV) is carried out in addition to the PAP test. However, this "co-test" is only offered every 3 years. In the case of a conspicuous screening result, the PAP test will be repeated or further assessed by means of biopsy under colposcopic vision according to the defined clarification algorithm [ 2 ]. As a result of the new program, colposcopic examination has now become a central component of early cervical cancer screening in Germany. The clarification procedure that has now been defined stipulates that colposcopy is indicated by an assumed posttest probability (PAP test and HPV test) of severe cervical intraepithelial neoplasia (CIN 3) or adenocarcinoma in situ (AIS) of 10% [ 3 ]. The background for this approach is the data from studies that have investigated the cumulative risk for the presence of precancerous lesions according to cytological and virological findings [ 4 – 10 ]. Moreover, these data are no longer up-to-date and may not adequately reflect the current population that has been vaccinated against the HP virus. Moreover, no data on the success of the German program have been available since the introduction of the new screening concept. In this retrospective study, we evaluated the posttest probability of a CIN2+/CIN3 + lesion on the cervix uteri according to initial cytological (PAP test) and virological (HPV test) findings in women aged 35 years and older. The aim of this study was to create a database for the German screening population after the introduction of the systematic screening program. To achieve this goal, we analyzed the data from all women referred to our institution for the treatment of cervical dysplasia in the first round of screening (complete 3-year period). METHODS This retrospective trial was carried out at a center for cervical cancer prevention in Germany in a population of women referred to this institution for colposcopy. The outpatient consultation has a supraregional catchment area, and up to 2,000 women present themselves with a genital precancerous lesion every year. The center has been certified by the German Cancer Society since 2013. We included women over the age of 35 with abnormal screening results according to the new guidelines for organized cervical cancer screening (shown in Fig. 1). We excluded women under the age of 35. Furthermore, women who were pregnant or had a history of cervical cancer disease, previous cervical treatments (in particular conization) in the past 3 years, or a known cervical precancerous lesion were excluded. Approval for this study was obtained from the institutional review board. The trial was registered in the German clinical trials register. Two gynecologists performed the examinations. Both are experts in cervical cancer screening and have broad practical experience in colposcopy. The examination was carried out with a video colposcope (Vidan® 2 full-HD Video Colposcope, Schmitz und Söhne, Wickede an der Ruhr, Germany) using a × 30 magnification. The colposcopic examination procedure was the same for each patient. First, detailed inspection of the external anogenital area was performed. After the introduction of a self-retaining speculum, the vagina and especially the cervix uteri were assessed in the native state. After the application of 5% acetic acid solution, the cervix uteri and adjacent vagina were then assessed for suspicious changes at 7-15x magnification. Lugol's solution was not applied as a standard procedure. Biopsies were performed the area of maximum changes (maximum 3 biopsies). In addition, endocervical curettage was performed if an endocervical lesion was suspected and, where possible, if the transformation zone was not fully visible. If the squamocolumnar junction was completely visible (transformation zone type 1 or 2) and if normal colposcopic findings were present, no biopsy was taken. Similarly, if the squamocolumnar junction was not completely visible (transformation zone type 3) and concomitant cervical canal stenosis and unremarkable ectocervix were present, no biopsy was taken. We defined cervical stenosis as the inability to insert a 4.5 mm curette into the cervical canal. The examination results were documented according to the 2011 terminology of the International Federation for Cervical Pathology and Colposcopy [ 11 ]. First and secondary endpoints The primary outcome parameter of this retrospective study was the posttest probability of a CIN3 + lesion on the cervix uteri depending on the initial cytological (PAP test) and virological (HPV test) findings in women aged 35 years and older. The secondary outcome parameter was the posttest probability of a CIN2 + lesion on the cervix uteri depending on the initial cytological (PAP test) and virological (HPV test) findings in women aged 35 years and older. In addition, the influence of HPV subtype on the primary and secondary outcome parameters was investigated. For HPV types, differentiation between types 16, 18, and 12 of other HPV types in the high-risk group was performed as a total result (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) using polymerase chain reaction (PCR) technology with the Cobas system (Roche Diagnostics GmbH, Mannheim, Germany). Data collection and statistical analysis Patient data from colposcopic examinations were entered into a study database. All relevant information from the digital patient records was collected. These were abnormal co-test results, which led to the patient's presentation at the consultation, as well as complete documentation of the clarification colposcopy. All histological results were included in the evaluation for the presence of precancerous lesions (biopsy as part of the clarification colposcopy and histological processing of the specimen removed in the case of a performed conization or hysterectomy). The database was created using the Excel program (Microsoft Corporation, Redmond, Washington, USA). The statistical analysis was performed using Microsoft Excel and SAS 9.4 (SAS Institute, North Carolina, USA). Mean, standard deviation, median, and extrema were used to describe the metric data. For categorical data, absolute and relative frequencies were determined. To examine the association between two categorical variables, the chi-square test was performed. RESULTS Between January 2020 and December 2022, a total of 1956 women were referred to the dysplasia consultation for further clarification due to abnormal co-test results. Table 1 shows the essential patient data, including the underlying cytological smear results and the current HPV status, and provides an overview of the colposcopic examination results. TABLE 1. Patient characteristics (n=1956) Variable n % HPV status positive / negative HPV 16 HPV 18 Other high Risk types than 16/18 1891 / 65 462 114 1394 96.7 / 3.3 23.6 5.8 71.3 Referring cytology NILM ASC-US AGC endocervical NOS ASC-H AGC endocervical favor neoplastic LSIL HSIL (corresponding to CIN 2) HSIL (corresponding to CIN 3) AIS HSIL with features suspicious for invasion Squamous cell carcinoma 632 382 188 70 47 371 175 69 19 2 1 32.3 19.5 9.6 3.6 2.4 19.0 8.9 3.5 1.0 0.1 0.1 General assessment Adequate/Inadequate Cervical stenosis Type of transformation zone Type 1 Type 2 Type 3 Colposcopic findings Normal colposcopic finding Minor change Major change Non specific Suspicious for invasion Miscellaneous findings 1941 / 15 304 676 141 1124 506 914 240 40 7 244 99.2 / 0.8 15.5 34.6 7.2 57.5 25.9 46.7 12.3 1.5 0.4 12.5 Biopsy / no biopsy 1593 / 363 81.4 / 18.6 The median patient age was 45.0 years (35.0–85.0 years). In 1891 patients (96.7%), infection with the high-risk HPV type was detected. In 75 patients (3.8%), a combined infection with HPV types 16, 18 or other high-risk HPV types was present. A total of 99.2% of all the examinations showed adequate examination conditions. In 15 patients (0.8%), the examination was inadequate: 9 patients had postoperative scarring, 4 patients had heavy bleeding at the time of examination, and 2 patients had a body mass index greater than 45; moreover, the cervix uteri could not be observed. One or more biopsies were performed for 1593 patients (81.4%). Figure 2 provides an overview of the histological results. The results from conizations (n = 240) and hysterectomies (n = 6), which were performed relating to the clarification colposcopy, were also considered. In 45.0% (n = 880) and 18.6% (n = 363) of the patients, the histological results were unremarkable, or no samples were taken from the cervix uteri. CIN1 was detected in 14.9% (n = 291) of all patients. This included two patients with VAIN 1. CIN 2 + or CIN 3 + was diagnosed in 21.6% and 13.0%, respectively, of the examined patients; CIN 2, 8.6% (n = 168); CIN 3 or AIS, 11.9% (n = 233); and CIN 3+, 0.3% (n = 5), respectively; and invasive cervical cancer, 0.8% (n = 16) of the examined patients. In 3 patients, histological evaluation revealed concomitant portions of CIN 3 and AIS. The cervical cancers detected were squamous cell cancer of the cervix in 12 patients and adenocarcinoma of the cervix in the remaining 4 patients. Two of the 16 diagnosed cancers were detected via colposcopy-guided biopsy, and 14 were detected after conization. Fifteen of the diagnosed cancers were localized cervical cancer (≤ FIGO stage IIA), and one was diagnosed with advanced cervical cancer according to FIGO stage IIIC1. The posttest probabilities of CIN 2 + or CIN 3 + patients according to the results of the co-test are shown in Table 2 . All histologic reports available at the time of evaluation were considered. In one patient with a PAP smear result AIS the corresponding histological result was high-grade squamous intraepithelial lesion (HSIL) corresponding to CIN 2. In 15 patients with a PAP smear result AIS HSIL corresponding to CIN 3 was found, and in 3 patients invasive cervical cancer was diagnosed. Table 2 Posttest probability of a CIN2+/CIN3 + lesion on the cervix uteri Co-testing result CIN 2+ CIN 3+ NILM, HPV positive 10.1 4.6 ASC-US, HPV positive 14.9 7.3 AGC endocervical NOS, HPV positive 23.4 14.9 LSIL 18.1 10.8 ASC-H 24.3 12.9 AGC endocervical favor neoplastic 31.9 21.3 HSIL (corresponding to CIN 2) 45.7 27.4 HSIL (corresponding to CIN 3) 81.2 72.5 AIS 100 94.7 HSIL with features suspicious for invasion 50.0 50.0 Squamous cell carcinoma 100 100 Data are presented as % In 8 patients with a PAP smear result HSIL (corresponding to CIN 3) and in 1 patient with a PAP smear result HSIL ( with features suspicious for invasion ) , diagnostic conization was recommended after unremarkable clarification colposcopy, but histopathological data could not be collected in the context of this study. Table 3 a shows the posttest probability of cervical precancerous lesions according to HPV subtype. The proportion of CIN 3 + patients was greater in the presence of HPV 16 (25.6%) than in the presence of HPV 18 (14.9%) or other high-risk HPV types (8.4%). The odds ratio for the detection of cervical cancer was 2.18 for patients with HPV16 infection compared to those with HPV18 infection (95% confidence interval: [0.28;17.28]). The odds ratio for the detection of cervical cancer was 11.18 for patients with HPV16 infection compared to patients with HPV infection of other high-risk HPV types (95% confidence interval: [3.01;40.81]). Table 3 A. Posttest probability of a cervical precancer depending on the virological (HPV test) findings (n = 1816) HPV-Subtype Histological results 16 (n = 403) 18 (n = 87) high risk other types than 16/18 (n = 1326) n %* n %* n %* No Biopsy/ NILM 207 51.4 51 58.6 906 68.3 CIN 1 (inc. VAIN 1) 55 13.6 11 12.6 207 15.6 CIN 2 38 9.4 12 13.8 102 7.7 CIN3/ AIS 93 23.1 12 13.8 108 8.2 Cervical cancer 10 2.5 1 1.1 3 0.2 * The percentages refer to the share of the category of the row variable within the column (Column total per row variable = 100%). The chi-square test comparing the distribution of histological results findings of the three groups of HPV subtypes provided a p value of p < 0.001. Table 3 B. Posttest probability of a cervical precancer in case of unremarkable cytology (NILM) depending on the virological (HPV test) findings (n = 612) HPV-Subtype Histological results 16 (n = 91) 18 (n = 23) high risk other types than 16/18 (n = 498) n %* n %* n %* No Biopsy/ NILM 70 76.9 17 73.9 414 83.1 CIN 1 9 9.9 2 8.7 40 8.0 CIN 2 5 5.5 3 13.0 25 5.0 CIN3/ AIS 7 7.7 1 4.3 19 3.8 * The percentages refer to the share of the category of the row variable within the column (Column total per row variable = 100%). The chi-square test comparing the distribution of histological results findings of the three groups of HPV subtypes provided a p value of p = 0.401. Additionally, in the case of unremarkable cytology (NILM), the proportion of CIN 3 was greater in the presence of HPV 16 (7.7%) than in the presence of other high-risk HPV types (3.8%) (Table 3 b). DisCUSSION The present study presents meaningful data on the risk of cervical precancerous lesions in the German screening population after the introduction of an organized, combined cervical cancer screening program in 2020. Due to the introduction of a new screening concept with a defined clarification concept, we observed a significantly increased rate of colposcopy-guided cervical biopsies. This leads to several abnormal first screening cases. Based on the data of this study, the posttest probability of the presence of a CIN3 + lesion on the cervix uteri could be determined based on the co-test results for women aged 35 years and older. Severe precancerous lesions of the cervix uteri (CIN 3/AIS) were identified in 12.2% of all women for whom clarification colposcopy was indicated due to an abnormal co-test result. Furthermore, cervical cancer was present in 0.8% of all patients. If CIN 2 lesions are included in the evaluation, it can be stated that in more than every 5th patient (21.6%), higher-grade dysplasia (HSIL) is diagnosed at the cervix uteri. The risk for the diagnosis of cervical precancerous lesions increases with the degree of cytological abnormalities. Thus, the risk for the presence of CIN 3 + increases from 7.3–10.8% in the presence of low (ASCUS and LSIL, respectively) to 27.4% in the presence of moderate (HSIL corresponding to CIN 2) or to 72.5% in the presence of severe (HSIL corresponding to CIN 3) squamous epithelial lesions. Cytologic abnormalities in the cylindrical epithelium of the uterine cervix require special attention in this context since graduation of glandular changes is less possible than graduation of squamous lesions. The risk factors for the presence of CIN 2 + or CIN 3 + in Pap smears indicating low glandular abnormalities (AGC endocervical NOS) were 23.4% and 14.9%, respectively. The risk factors for the presence of CIN 2 + or CIN 3 + in Pap smears indicating high glandular abnormalities (AGC endocervical favors neoplastic) were 31.9% and 21.3%, respectively. In the presence of a cytological smear indicating AIS, HSIL was present in 84.2% of the patients, and invasive cervical cancer was present in 15.8% of the patients. From a cytological point of view, clear morphological transitions are much more difficult to identify in glandular changes. The assignment of glandular changes therefore varies due to the subjective examination method used. This circumstance should be considered in every clarification colposcopy. Accordingly, the performance of endocervical curettage should always be considered, especially if the transformation zone is not visible. The risk for detecting cervical precancer remains dependent on the underlying HPV subtype. The data from our study showed that the proportion of CIN 3 + patients detected via histologic evaluation was significantly greater in the presence of infection with high-risk HPV type 16 than in the presence of infection with other high-risk HPV types. The risk for detecting invasive cervical cancer was significantly greater in women with HPV16 infection than in women with HPV18 infection (OR 2.18) or women with HPV infection of other high-risk types (OR 11.18). These results are in line with the observations of other studies [ 12 – 16 ] and underline the importance of HPV genotyping in the context of co-testing. Even with unremarkable cytology, the proportion of CIN 3 + detections in the histologic evaluation was highest in the presence of HPV16. This finding allows the conclusion that risk stratification depending on the HPV subtype is useful in individual cases. The association between the persistence of HPV infection and the development of cervical cancer remains well established [ 17 , 18 ]. Since the current screening concept in Germany is novel and nationwide HPV testing has only been conducted since 2020, the duration of HPV infection is usually unknown. Therefore, it cannot be excluded that HPV infection has persisted for a longer period and that affected women are thus at increased risk of developing cancer. In this context, the data of our study suggest that even in the case of inconspicuous cytological smear results and simultaneous detection of high-risk HPV infection, the presence of HSIL cannot be excluded; therefore, clarifying colposcopy is indicated; thus, for women with inconspicuous cytology but HPV detection, CIN 2 + was detected in 10.1%, and CIN 3 + was detected in 4.6% of our study group. Nonetheless, our study has several limitations due to its retrospective and single-center nature. Importantly, in 18.6% of patients, no biopsy was performed due to a normal appearance of the transformation zone or, as in most cases, due to cervical stenosis. Because many women (mainly postmenopausal women) present with cervical stenosis, diagnosis is difficult, and up to date recommendations for these circumstances are lacking. Moreover, no conclusions can be drawn about the effect of HPV vaccination because these data were not collected. Our work collected data from women who presented to the dysplasia consultation for the first time. We did not include follow-up controls in the data analysis, so no conclusions about the progression or regression of precancerous lesions could be drawn. Additionally, it is not possible to make statements about the intervals at which further controls should be performed in the case of inconspicuous histology after clarification colposcopy. Furthermore, this study did not include patients in whom cancers other than cervical cancer such as endometrial cancer, were detected during screening. It should also be noted that the detection probability rates given here refer to the first round of screening. As time progresses, precancerous lesions in the cervix uteri will be detected and treated earlier under the new screening concept so that the number of abnormalities during screening is expected to decrease. In addition, a greater number of vaccinated women will lead to a further reduction of HPV-related precancerous lesions, as already observed in other countries with successful vaccination programs [ 19 , 20 ]. The strengths of our study are, on the one hand, the supraregional catchment area of the consultation. The study population included a representative cross-section of the population. Compared to the data of the public cancer screening program, which has yet to be evaluated and does not document privately insured patients or those insured through other funding sources (e.g., asylum, medical care, etc.), the present study collects data from all population groups. Overall, the present study contributes essential knowledge to the context of the new cancer screening program and provides a database for the German screening population. The data of this study further emphasize the necessity of performing a clarifying colposcopy in the case of a conspicuous co-test result for women aged 35 years and older. Our results can correctly classify the risk of developing cervical precancerous lesions and may help colposcopic physicians make decisions about individual case constellations. Furthermore, this study provides a basis for future work examining the impact of this new screening method in terms of reducing the prevalence of severe precancerous lesions and cervical cancer in subsequent rounds of screening. CONCLUSIONS The new screening program led to the detection of a high portion of severe cervical precancerous lesions. Risk stratification based on the underlying HPV subtype appears to be particularly useful if HPV 16 is detected. Abbreviations AGC endocervical favor neoplastic Atypical glandular endocervical cells favor neoplastic AGC endocervical NOS Atypical glandular endocervical cells not otherwise specified AIS Adenocarcinoma in situ ASC-H Atypical squamous cells of undetermined significance cannot be excluded ASC-US Atypical squamous cells of undetermined significance CIN Cervical intraepithelial lesion HPV Human papillomavirus HSIL High-grade squamous intraepithelial lesion LSIL Low-grade squamous intraepithelial lesion NILM Negative for intraepithelial lesion or malignancy OR Odds ratio PAP Papanicolaou VAIN Vaginal squamous intraepithelial lesion Declarations ETHICS APPROVAL This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Ruhr University Bochum (Date 22 October 2021/No 21-7274). CONSENT TO PARTICIPATE Not applicable CONSENT FOR PUBLICATION Not applicable AVAILABILITY OF DATA AND MATERIALS The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. COMPETING INTERESTS The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. The authors declare that they have no competing interests: FUNDING Not applicable AUTHOR CONTRIBUTIONS All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Raffaella Carassiti, Matthias Jentschke and Ziad Hilal. The first draft of the manuscript was written by Ziad Hilal and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Rc: Protocol/Project development, Data Collection and Management, Data analysis, Manuscript writing MJ: Protocol development, Data analysis, Manuscript writing PS: Protocol development, Manuscript writing Zh: Protocol/Project development, Data Collection and Management, Data analysis, Manuscript writing ACKNOWLEDGEMENTS Not applicable References Robert-Koch-Institut. (2019) Krebs in Deutschland für 2015/2016. https://www.krebsdaten.de/Krebs/DE/Content/Publikationen/Krebs_in_Deutschland/kid_2019/krebs_in_deutschland_2019.pdf?__blob=publicationFile . Accessed 22 March 2023. Gemeinsamer B. (2018) Richtlinie für organisierte Krebsfrüherkennungsprogramme und Krebsfrüherkennungs-Richtlinie: Programm zur Früherkennung von Zervixkarzinomen. https://www.g-ba.de/downloads/40-268-5486/2018-11-22_oKFE-RL_Zervixkarzinom_TrG.pdf . Accessed 22 March 2023. Leitlinienprogramm O. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4589563","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":322148172,"identity":"e98b2220-6606-4cc5-bc33-00adf74a80c3","order_by":0,"name":"Raffaella Carassiti","email":"","orcid":"","institution":"GYNDOMED, Frauenärztliches Versorgungszentrum","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Raffaella","middleName":"","lastName":"Carassiti","suffix":""},{"id":322148173,"identity":"c105d86d-3648-4e9e-a806-95fb74e5cea1","order_by":1,"name":"Matthias Jentschke","email":"","orcid":"","institution":"Medizinische Hochschule Hannover","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Matthias","middleName":"","lastName":"Jentschke","suffix":""},{"id":322148174,"identity":"4e291b3d-fc1c-41c2-a6a3-c16ac93e0bfa","order_by":2,"name":"Philipp Soergel","email":"","orcid":"","institution":"Universitätsfrauenklinik der Ruhr-Universität Bochum, Johannes Wesling Klinikum Minden","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Philipp","middleName":"","lastName":"Soergel","suffix":""},{"id":322148175,"identity":"db563b95-f294-4fce-af01-e09d97564e9b","order_by":3,"name":"Ziad Hilal","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIie3PrQoCQRDA8ZGBuTJoXVnhXmHlQAS/nkWuLiKYxGAQ1iJYfQ3LZQ+D5eyCxdNssJgM7l2WO22G/beB/TE7AC7XP4YAElQbqt4qn7n6JRFAnADsLKFvFkkAS4TOCZQSf4npeTwWPtXv8e2h+w0CTK+nAlJZUNDZKNE0chSqOArtxygIdNEpCC3JSlSM1C0RR2gJkywihN4zIwNTTzIyLyeMnG8ZGsEZ2ZcTgTzpWBIa1oE6RgcmLLnFXx+2Z351e2svaV6m0WxQ8xbprYh8CH977nK5XK4PvQHZkTbXhczREwAAAABJRU5ErkJggg==","orcid":"","institution":"GYNDOMED, Frauenärztliches Versorgungszentrum","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Ziad","middleName":"","lastName":"Hilal","suffix":""}],"badges":[],"createdAt":"2024-06-16 11:53:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4589563/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4589563/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12905-025-03836-7","type":"published","date":"2025-10-21T16:16:34+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60529386,"identity":"f82cd3c0-5d2d-4124-a07a-31f3d5c4f202","added_by":"auto","created_at":"2024-07-17 19:59:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":26009,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4589563/v1/0f4d955e6249ed433ebc2d0f.png"},{"id":60529387,"identity":"a1a1a8a6-324b-45ea-b997-650957f4b24f","added_by":"auto","created_at":"2024-07-17 19:59:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":291193,"visible":true,"origin":"","legend":"\u003cp\u003eLegend not included with this version\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4589563/v1/8d9fcdf7b3197ff3ecd08a59.png"},{"id":94490701,"identity":"7b852442-b3a2-45e4-99fc-09744c79a90d","added_by":"auto","created_at":"2025-10-27 17:13:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":821022,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4589563/v1/5c87b456-ffcd-48ef-a7f9-8b4193d2c038.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cervical cancer screening by co-testing in women 35 years and older: an analysis of the 1st round of screening in Germany","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eIn Germany, nationwide cervical cancer screening using the Papanicolaou test (PAP test) was introduced in 1971. This opportunistic cancer screening program led to a drastic reduction in the incidence of cervical cancer. However, the incidence of invasive cancer of the cervix uteri has not further decreased and has stagnated over the last two decades [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. For this reason, a new, organized cancer screening program has been launched: since January 1, 2020, women aged\u0026thinsp;\u0026gt;\u0026thinsp;20 years are entitled to gynecological cancer screening once a year. It should be noted that women between the ages of 20 and 34 are entitled to an annual smear test using the PAP test. For women over the age of 35, a test for the presence of human papillomavirus (HPV) is carried out in addition to the PAP test. However, this \"co-test\" is only offered every 3 years. In the case of a conspicuous screening result, the PAP test will be repeated or further assessed by means of biopsy under colposcopic vision according to the defined clarification algorithm [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. As a result of the new program, colposcopic examination has now become a central component of early cervical cancer screening in Germany.\u003c/p\u003e \u003cp\u003eThe clarification procedure that has now been defined stipulates that colposcopy is indicated by an assumed posttest probability (PAP test and HPV test) of severe cervical intraepithelial neoplasia (CIN 3) or adenocarcinoma in situ (AIS) of 10% [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The background for this approach is the data from studies that have investigated the cumulative risk for the presence of precancerous lesions according to cytological and virological findings [\u003cspan additionalcitationids=\"CR5 CR6 CR7 CR8 CR9\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Moreover, these data are no longer up-to-date and may not adequately reflect the current population that has been vaccinated against the HP virus. Moreover, no data on the success of the German program have been available since the introduction of the new screening concept.\u003c/p\u003e \u003cp\u003eIn this retrospective study, we evaluated the posttest probability of a CIN2+/CIN3\u0026thinsp;+\u0026thinsp;lesion on the cervix uteri according to initial cytological (PAP test) and virological (HPV test) findings in women aged 35 years and older. The aim of this study was to create a database for the German screening population after the introduction of the systematic screening program. To achieve this goal, we analyzed the data from all women referred to our institution for the treatment of cervical dysplasia in the first round of screening (complete 3-year period).\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eThis retrospective trial was carried out at a center for cervical cancer prevention in Germany in a population of women referred to this institution for colposcopy. The outpatient consultation has a supraregional catchment area, and up to 2,000 women present themselves with a genital precancerous lesion every year. The center has been certified by the German Cancer Society since 2013.\u003c/p\u003e \u003cp\u003e We included women over the age of 35 with abnormal screening results according to the new guidelines for organized cervical cancer screening (shown in Fig.\u0026nbsp;1). We excluded women under the age of 35. Furthermore, women who were pregnant or had a history of cervical cancer disease, previous cervical treatments (in particular conization) in the past 3 years, or a known cervical precancerous lesion were excluded.\u003c/p\u003e \u003cp\u003e Approval for this study was obtained from the institutional review board. The trial was registered in the German clinical trials register.\u003c/p\u003e \u003cp\u003eTwo gynecologists performed the examinations. Both are experts in cervical cancer screening and have broad practical experience in colposcopy.\u003c/p\u003e \u003cp\u003eThe examination was carried out with a video colposcope (Vidan\u0026reg; 2 full-HD Video Colposcope, Schmitz und S\u0026ouml;hne, Wickede an der Ruhr, Germany) using a \u0026times; 30 magnification.\u003c/p\u003e \u003cp\u003eThe colposcopic examination procedure was the same for each patient. First, detailed inspection of the external anogenital area was performed. After the introduction of a self-retaining speculum, the vagina and especially the cervix uteri were assessed in the native state. After the application of 5% acetic acid solution, the cervix uteri and adjacent vagina were then assessed for suspicious changes at 7-15x magnification. Lugol's solution was not applied as a standard procedure.\u003c/p\u003e \u003cp\u003eBiopsies were performed the area of maximum changes (maximum 3 biopsies). In addition, endocervical curettage was performed if an endocervical lesion was suspected and, where possible, if the transformation zone was not fully visible. If the squamocolumnar junction was completely visible (transformation zone type 1 or 2) and if normal colposcopic findings were present, no biopsy was taken. Similarly, if the squamocolumnar junction was not completely visible (transformation zone type 3) and concomitant cervical canal stenosis and unremarkable ectocervix were present, no biopsy was taken. We defined cervical stenosis as the inability to insert a 4.5 mm curette into the cervical canal.\u003c/p\u003e \u003cp\u003eThe examination results were documented according to the 2011 terminology of the International Federation for Cervical Pathology and Colposcopy [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFirst and secondary endpoints\u003c/p\u003e \u003cp\u003eThe primary outcome parameter of this retrospective study was the posttest probability of a CIN3\u0026thinsp;+\u0026thinsp;lesion on the cervix uteri depending on the initial cytological (PAP test) and virological (HPV test) findings in women aged 35 years and older. The secondary outcome parameter was the posttest probability of a CIN2\u0026thinsp;+\u0026thinsp;lesion on the cervix uteri depending on the initial cytological (PAP test) and virological (HPV test) findings in women aged 35 years and older.\u003c/p\u003e \u003cp\u003eIn addition, the influence of HPV subtype on the primary and secondary outcome parameters was investigated. For HPV types, differentiation between types 16, 18, and 12 of other HPV types in the high-risk group was performed as a total result (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) using polymerase chain reaction (PCR) technology with the Cobas system (Roche Diagnostics GmbH, Mannheim, Germany).\u003c/p\u003e \u003cp\u003eData collection and statistical analysis\u003c/p\u003e \u003cp\u003ePatient data from colposcopic examinations were entered into a study database. All relevant information from the digital patient records was collected. These were abnormal co-test results, which led to the patient's presentation at the consultation, as well as complete documentation of the clarification colposcopy. All histological results were included in the evaluation for the presence of precancerous lesions (biopsy as part of the clarification colposcopy and histological processing of the specimen removed in the case of a performed conization or hysterectomy).\u003c/p\u003e \u003cp\u003eThe database was created using the Excel program (Microsoft Corporation, Redmond, Washington, USA). The statistical analysis was performed using Microsoft Excel and SAS 9.4 (SAS Institute, North Carolina, USA). Mean, standard deviation, median, and extrema were used to describe the metric data. For categorical data, absolute and relative frequencies were determined. To examine the association between two categorical variables, the chi-square test was performed.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eBetween January 2020 and December 2022, a total of 1956 women were referred to the dysplasia consultation for further clarification due to abnormal co-test results. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the essential patient data, including the underlying cytological smear results and the current HPV status, and provides an overview of the colposcopic examination results.\u003c/p\u003e \u003cp\u003e\u003cstrong\u003eTABLE 1.\u003c/strong\u003e Patient characteristics (n=1956)\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.707602339181285%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.146198830409357%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003en\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.146198830409357%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e%\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.707602339181285%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003eHPV status\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003epositive / negative\u003c/p\u003e\n \u003cp\u003eHPV 16\u003c/p\u003e\n \u003cp\u003eHPV 18\u003c/p\u003e\n \u003cp\u003eOther high Risk types than 16/18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.146198830409357%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1891 / 65\u003c/p\u003e\n \u003cp\u003e462\u003c/p\u003e\n \u003cp\u003e114\u003c/p\u003e\n \u003cp\u003e1394\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.146198830409357%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e96.7 / 3.3\u003c/p\u003e\n \u003cp\u003e23.6\u003c/p\u003e\n \u003cp\u003e5.8\u003c/p\u003e\n \u003cp\u003e71.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.707602339181285%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eReferring cytology\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eNILM\u003c/p\u003e\n \u003cp\u003eASC-US\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eAGC endocervical NOS\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eASC-H\u003c/p\u003e\n \u003cp\u003eAGC endocervical favor neoplastic\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003cp\u003eLSIL\u003c/p\u003e\n \u003cp\u003eHSIL (corresponding to CIN 2)\u003c/p\u003e\n \u003cp\u003eHSIL (corresponding to CIN 3)\u003c/p\u003e\n \u003cp\u003eAIS\u003c/p\u003e\n \u003cp\u003eHSIL with features suspicious for invasion\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.146198830409357%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e632\u003c/p\u003e\n \u003cp\u003e382\u003c/p\u003e\n \u003cp\u003e188\u003c/p\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003cp\u003e47\u003c/p\u003e\n \u003cp\u003e371\u003c/p\u003e\n \u003cp\u003e175\u003c/p\u003e\n \u003cp\u003e69\u003c/p\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.146198830409357%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e32.3\u003c/p\u003e\n \u003cp\u003e19.5\u003c/p\u003e\n \u003cp\u003e9.6\u003c/p\u003e\n \u003cp\u003e3.6\u003c/p\u003e\n \u003cp\u003e2.4\u003c/p\u003e\n \u003cp\u003e19.0\u003c/p\u003e\n \u003cp\u003e8.9\u003c/p\u003e\n \u003cp\u003e3.5\u003c/p\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003cp\u003e0.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.707602339181285%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eGeneral assessment\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eAdequate/Inadequate\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eCervical stenosis\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eType of transformation zone\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eType 1\u003c/p\u003e\n \u003cp\u003eType 2\u003c/p\u003e\n \u003cp\u003eType 3\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cem\u003eColposcopic findings\u003c/em\u003e\u003c/p\u003e\n \u003cp\u003eNormal colposcopic finding\u003c/p\u003e\n \u003cp\u003eMinor change \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003cp\u003eMajor change\u003c/p\u003e\n \u003cp\u003eNon specific\u003c/p\u003e\n \u003cp\u003eSuspicious for invasion\u003c/p\u003e\n \u003cp\u003eMiscellaneous findings\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.146198830409357%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1941 / 15\u003c/p\u003e\n \u003cp\u003e304\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e676\u003c/p\u003e\n \u003cp\u003e141\u003c/p\u003e\n \u003cp\u003e1124\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e506\u003c/p\u003e\n \u003cp\u003e914\u003c/p\u003e\n \u003cp\u003e240\u003c/p\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003cp\u003e244\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.146198830409357%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e99.2 / 0.8\u003c/p\u003e\n \u003cp\u003e15.5\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e34.6\u003c/p\u003e\n \u003cp\u003e7.2\u003c/p\u003e\n \u003cp\u003e57.5\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e25.9\u003c/p\u003e\n \u003cp\u003e46.7\u003c/p\u003e\n \u003cp\u003e12.3\u003c/p\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003cp\u003e0.4\u003c/p\u003e\n \u003cp\u003e12.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.707602339181285%\" valign=\"top\"\u003e\n \u003cp\u003eBiopsy / no biopsy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.146198830409357%\" valign=\"top\"\u003e\n \u003cp\u003e1593 / 363\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.146198830409357%\" valign=\"top\"\u003e\n \u003cp\u003e81.4 / 18.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e \u003cp\u003eThe median patient age was 45.0 years (35.0\u0026ndash;85.0 years). In 1891 patients (96.7%), infection with the high-risk HPV type was detected. In 75 patients (3.8%), a combined infection with HPV types 16, 18 or other high-risk HPV types was present. A total of 99.2% of all the examinations showed adequate examination conditions. In 15 patients (0.8%), the examination was inadequate: 9 patients had postoperative scarring, 4 patients had heavy bleeding at the time of examination, and 2 patients had a body mass index greater than 45; moreover, the cervix uteri could not be observed. One or more biopsies were performed for 1593 patients (81.4%).\u003c/p\u003e \u003cp\u003eFigure\u0026nbsp;2 provides an overview of the histological results. The results from conizations (n\u0026thinsp;=\u0026thinsp;240) and hysterectomies (n\u0026thinsp;=\u0026thinsp;6), which were performed relating to the clarification colposcopy, were also considered.\u003c/p\u003e \u003cp\u003eIn 45.0% (n\u0026thinsp;=\u0026thinsp;880) and 18.6% (n\u0026thinsp;=\u0026thinsp;363) of the patients, the histological results were unremarkable, or no samples were taken from the cervix uteri. CIN1 was detected in 14.9% (n\u0026thinsp;=\u0026thinsp;291) of all patients. This included two patients with VAIN 1. CIN 2\u0026thinsp;+\u0026thinsp;or CIN 3\u0026thinsp;+\u0026thinsp;was diagnosed in 21.6% and 13.0%, respectively, of the examined patients; CIN 2, 8.6% (n\u0026thinsp;=\u0026thinsp;168); CIN 3 or AIS, 11.9% (n\u0026thinsp;=\u0026thinsp;233); and CIN 3+, 0.3% (n\u0026thinsp;=\u0026thinsp;5), respectively; and invasive cervical cancer, 0.8% (n\u0026thinsp;=\u0026thinsp;16) of the examined patients.\u003c/p\u003e \u003cp\u003eIn 3 patients, histological evaluation revealed concomitant portions of CIN 3 and AIS. The cervical cancers detected were squamous cell cancer of the cervix in 12 patients and adenocarcinoma of the cervix in the remaining 4 patients. Two of the 16 diagnosed cancers were detected via colposcopy-guided biopsy, and 14 were detected after conization. Fifteen of the diagnosed cancers were localized cervical cancer (\u0026le;\u0026thinsp;FIGO stage IIA), and one was diagnosed with advanced cervical cancer according to FIGO stage IIIC1.\u003c/p\u003e \u003cp\u003eThe posttest probabilities of CIN 2\u0026thinsp;+\u0026thinsp;or CIN 3\u0026thinsp;+\u0026thinsp;patients according to the results of the co-test are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. All histologic reports available at the time of evaluation were considered. In one patient with a PAP smear result \u003cem\u003eAIS\u003c/em\u003e the corresponding histological result was high-grade squamous intraepithelial lesion (HSIL) corresponding to CIN 2. In 15 patients with a PAP smear result \u003cem\u003eAIS\u003c/em\u003e HSIL corresponding to CIN 3 was found, and in 3 patients invasive cervical cancer was diagnosed.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePosttest probability of a CIN2+/CIN3\u0026thinsp;+\u0026thinsp;lesion on the cervix uteri\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCo-testing result\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCIN 2+\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCIN 3+\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNILM, HPV positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eASC-US, HPV positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAGC endocervical NOS, HPV positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLSIL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eASC-H\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAGC endocervical favor neoplastic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHSIL (corresponding to CIN 2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHSIL (corresponding to CIN 3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAIS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e94.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHSIL with features suspicious for invasion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSquamous cell carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eData are presented as %\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn 8 patients with a PAP smear result HSIL (corresponding to CIN 3) and in 1 patient with a PAP smear result \u003cem\u003eHSIL (\u003c/em\u003ewith features suspicious for invasion\u003cem\u003e)\u003c/em\u003e, diagnostic conization was recommended after unremarkable clarification colposcopy, but histopathological data could not be collected in the context of this study.\u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e3\u003c/span\u003ea shows the posttest probability of cervical precancerous lesions according to HPV subtype. The proportion of CIN 3\u0026thinsp;+\u0026thinsp;patients was greater in the presence of HPV 16 (25.6%) than in the presence of HPV 18 (14.9%) or other high-risk HPV types (8.4%). The odds ratio for the detection of cervical cancer was 2.18 for patients with HPV16 infection compared to those with HPV18 infection (95% confidence interval: [0.28;17.28]). The odds ratio for the detection of cervical cancer was 11.18 for patients with HPV16 infection compared to patients with HPV infection of other high-risk HPV types (95% confidence interval: [3.01;40.81]).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eA.\u003c/b\u003e Posttest probability of a cervical precancer depending on the virological (HPV test) findings (n\u0026thinsp;=\u0026thinsp;1816)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eHPV-Subtype\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistological results\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;403)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e18\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;87)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003ehigh risk\u003c/p\u003e \u003cp\u003eother types than 16/18\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;1326)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e%*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e%*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo Biopsy/ NILM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e207\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e58.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e906\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e68.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCIN 1 (inc. VAIN 1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e12.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e207\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e15.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCIN 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCIN3/ AIS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCervical cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e* The percentages refer to the share of the category of the row variable within the column (Column total per row variable\u0026thinsp;=\u0026thinsp;100%). The chi-square test comparing the distribution of histological results findings of the three groups of HPV subtypes provided a p value of \u003cem\u003ep\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.001.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eB.\u003c/b\u003e Posttest probability of a cervical precancer in case of unremarkable cytology (NILM) depending on the virological (HPV test) findings (n\u0026thinsp;=\u0026thinsp;612)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"6\" nameend=\"c7\" namest=\"c2\"\u003e \u003cp\u003eHPV-Subtype\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistological results\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;91)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e18\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003ehigh risk\u003c/p\u003e \u003cp\u003eother types than 16/18\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;498)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e%*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e%*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e%*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo Biopsy/ NILM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e76.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e73.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e414\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e83.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCIN 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e8.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCIN 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e13.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCIN3/ AIS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"7\" nameend=\"c7\" namest=\"c1\"\u003e \u003cp\u003e* The percentages refer to the share of the category of the row variable within the column (Column total per row variable\u0026thinsp;=\u0026thinsp;100%). The chi-square test comparing the distribution of histological results findings of the three groups of HPV subtypes provided a p value of \u003cem\u003ep\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.401.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAdditionally, in the case of unremarkable cytology (NILM), the proportion of CIN 3 was greater in the presence of HPV 16 (7.7%) than in the presence of other high-risk HPV types (3.8%) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e3\u003c/span\u003eb).\u003c/p\u003e"},{"header":"DisCUSSION","content":"\u003cp\u003eThe present study presents meaningful data on the risk of cervical precancerous lesions in the German screening population after the introduction of an organized, combined cervical cancer screening program in 2020. Due to the introduction of a new screening concept with a defined clarification concept, we observed a significantly increased rate of colposcopy-guided cervical biopsies. This leads to several abnormal first screening cases.\u003c/p\u003e \u003cp\u003eBased on the data of this study, the posttest probability of the presence of a CIN3\u0026thinsp;+\u0026thinsp;lesion on the cervix uteri could be determined based on the co-test results for women aged 35 years and older. Severe precancerous lesions of the cervix uteri (CIN 3/AIS) were identified in 12.2% of all women for whom clarification colposcopy was indicated due to an abnormal co-test result. Furthermore, cervical cancer was present in 0.8% of all patients. If CIN 2 lesions are included in the evaluation, it can be stated that in more than every 5th patient (21.6%), higher-grade dysplasia (HSIL) is diagnosed at the cervix uteri.\u003c/p\u003e \u003cp\u003eThe risk for the diagnosis of cervical precancerous lesions increases with the degree of cytological abnormalities. Thus, the risk for the presence of CIN 3\u0026thinsp;+\u0026thinsp;increases from 7.3\u0026ndash;10.8% in the presence of low (ASCUS and LSIL, respectively) to 27.4% in the presence of moderate (HSIL corresponding to CIN 2) or to 72.5% in the presence of severe (HSIL corresponding to CIN 3) squamous epithelial lesions. Cytologic abnormalities in the cylindrical epithelium of the uterine cervix require special attention in this context since graduation of glandular changes is less possible than graduation of squamous lesions. The risk factors for the presence of CIN 2\u0026thinsp;+\u0026thinsp;or CIN 3\u0026thinsp;+\u0026thinsp;in Pap smears indicating low glandular abnormalities (AGC endocervical NOS) were 23.4% and 14.9%, respectively. The risk factors for the presence of CIN 2\u0026thinsp;+\u0026thinsp;or CIN 3\u0026thinsp;+\u0026thinsp;in Pap smears indicating high glandular abnormalities (AGC endocervical favors neoplastic) were 31.9% and 21.3%, respectively. In the presence of a cytological smear indicating AIS, HSIL was present in 84.2% of the patients, and invasive cervical cancer was present in 15.8% of the patients. From a cytological point of view, clear morphological transitions are much more difficult to identify in glandular changes. The assignment of glandular changes therefore varies due to the subjective examination method used. This circumstance should be considered in every clarification colposcopy. Accordingly, the performance of endocervical curettage should always be considered, especially if the transformation zone is not visible.\u003c/p\u003e \u003cp\u003eThe risk for detecting cervical precancer remains dependent on the underlying HPV subtype. The data from our study showed that the proportion of CIN 3\u0026thinsp;+\u0026thinsp;patients detected via histologic evaluation was significantly greater in the presence of infection with high-risk HPV type 16 than in the presence of infection with other high-risk HPV types. The risk for detecting invasive cervical cancer was significantly greater in women with HPV16 infection than in women with HPV18 infection (OR 2.18) or women with HPV infection of other high-risk types (OR 11.18). These results are in line with the observations of other studies [\u003cspan additionalcitationids=\"CR13 CR14 CR15\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] and underline the importance of HPV genotyping in the context of co-testing. Even with unremarkable cytology, the proportion of CIN 3\u0026thinsp;+\u0026thinsp;detections in the histologic evaluation was highest in the presence of HPV16. This finding allows the conclusion that risk stratification depending on the HPV subtype is useful in individual cases.\u003c/p\u003e \u003cp\u003eThe association between the persistence of HPV infection and the development of cervical cancer remains well established [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Since the current screening concept in Germany is novel and nationwide HPV testing has only been conducted since 2020, the duration of HPV infection is usually unknown. Therefore, it cannot be excluded that HPV infection has persisted for a longer period and that affected women are thus at increased risk of developing cancer. In this context, the data of our study suggest that even in the case of inconspicuous cytological smear results and simultaneous detection of high-risk HPV infection, the presence of HSIL cannot be excluded; therefore, clarifying colposcopy is indicated; thus, for women with inconspicuous cytology but HPV detection, CIN 2\u0026thinsp;+\u0026thinsp;was detected in 10.1%, and CIN 3\u0026thinsp;+\u0026thinsp;was detected in 4.6% of our study group.\u003c/p\u003e \u003cp\u003eNonetheless, our study has several limitations due to its retrospective and single-center nature. Importantly, in 18.6% of patients, no biopsy was performed due to a normal appearance of the transformation zone or, as in most cases, due to cervical stenosis. Because many women (mainly postmenopausal women) present with cervical stenosis, diagnosis is difficult, and up to date recommendations for these circumstances are lacking.\u003c/p\u003e \u003cp\u003eMoreover, no conclusions can be drawn about the effect of HPV vaccination because these data were not collected. Our work collected data from women who presented to the dysplasia consultation for the first time. We did not include follow-up controls in the data analysis, so no conclusions about the progression or regression of precancerous lesions could be drawn. Additionally, it is not possible to make statements about the intervals at which further controls should be performed in the case of inconspicuous histology after clarification colposcopy. Furthermore, this study did not include patients in whom cancers other than cervical cancer such as endometrial cancer, were detected during screening. It should also be noted that the detection probability rates given here refer to the first round of screening. As time progresses, precancerous lesions in the cervix uteri will be detected and treated earlier under the new screening concept so that the number of abnormalities during screening is expected to decrease. In addition, a greater number of vaccinated women will lead to a further reduction of HPV-related precancerous lesions, as already observed in other countries with successful vaccination programs [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe strengths of our study are, on the one hand, the supraregional catchment area of the consultation. The study population included a representative cross-section of the population. Compared to the data of the public cancer screening program, which has yet to be evaluated and does not document privately insured patients or those insured through other funding sources (e.g., asylum, medical care, etc.), the present study collects data from all population groups.\u003c/p\u003e \u003cp\u003eOverall, the present study contributes essential knowledge to the context of the new cancer screening program and provides a database for the German screening population. The data of this study further emphasize the necessity of performing a clarifying colposcopy in the case of a conspicuous co-test result for women aged 35 years and older. Our results can correctly classify the risk of developing cervical precancerous lesions and may help colposcopic physicians make decisions about individual case constellations. Furthermore, this study provides a basis for future work examining the impact of this new screening method in terms of reducing the prevalence of severe precancerous lesions and cervical cancer in subsequent rounds of screening.\u003c/p\u003e"},{"header":"CONCLUSIONS","content":"\u003cp\u003eThe new screening program led to the detection of a high portion of severe cervical precancerous lesions. Risk stratification based on the underlying HPV subtype appears to be particularly useful if HPV 16 is detected.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAGC endocervical favor neoplastic\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Atypical glandular endocervical cells favor neoplastic\u003c/p\u003e\n\u003cp\u003eAGC endocervical NOS \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Atypical glandular endocervical cells not otherwise specified\u003c/p\u003e\n\u003cp\u003eAIS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Adenocarcinoma in situ\u003c/p\u003e\n\u003cp\u003eASC-H\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Atypical squamous cells of undetermined significance cannot be excluded\u003c/p\u003e\n\u003cp\u003eASC-US \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Atypical squamous cells of undetermined significance\u003c/p\u003e\n\u003cp\u003eCIN \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Cervical intraepithelial lesion\u003c/p\u003e\n\u003cp\u003eHPV\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Human papillomavirus\u003c/p\u003e\n\u003cp\u003eHSIL\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;High-grade squamous intraepithelial lesion\u003c/p\u003e\n\u003cp\u003eLSIL\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Low-grade squamous intraepithelial lesion\u003c/p\u003e\n\u003cp\u003eNILM\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Negative for intraepithelial lesion or malignancy\u003c/p\u003e\n\u003cp\u003eOR\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Odds ratio\u003c/p\u003e\n\u003cp\u003ePAP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Papanicolaou\u003c/p\u003e\n\u003cp\u003eVAIN \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Vaginal squamous intraepithelial lesion\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eETHICS APPROVAL\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Ruhr University Bochum (Date 22 October 2021/No 21-7274).\u003c/p\u003e\n\u003cp\u003eCONSENT TO PARTICIPATE\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003eCONSENT FOR PUBLICATION\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003eAVAILABILITY OF DATA AND MATERIALS\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eCOMPETING INTERESTS\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests:\u003c/p\u003e\n\u003cp\u003eFUNDING\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003eAUTHOR CONTRIBUTIONS\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by\u0026nbsp;\u003c/em\u003eRaffaella Carassiti, Matthias Jentschke\u003cem\u003eand Ziad Hilal. The first draft of the manuscript was written by Ziad Hilal and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eRc: Protocol/Project development, Data Collection and Management, Data analysis, Manuscript writing\u003c/p\u003e\n\u003cp\u003eMJ: Protocol development, Data analysis, Manuscript writing\u003c/p\u003e\n\u003cp\u003ePS: Protocol development, Manuscript writing\u003c/p\u003e\n\u003cp\u003eZh: Protocol/Project development, Data Collection and Management, Data analysis, Manuscript writing\u003c/p\u003e\n\u003cp\u003eACKNOWLEDGEMENTS\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRobert-Koch-Institut. (2019) Krebs in Deutschland f\u0026uuml;r 2015/2016. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.krebsdaten.de/Krebs/DE/Content/Publikationen/Krebs_in_Deutschland/kid_2019/krebs_in_deutschland_2019.pdf?__blob=publicationFile\u003c/span\u003e\u003cspan address=\"https://www.krebsdaten.de/Krebs/DE/Content/Publikationen/Krebs_in_Deutschland/kid_2019/krebs_in_deutschland_2019.pdf?__blob=publicationFile\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 22 March 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGemeinsamer B. (2018) Richtlinie f\u0026uuml;r organisierte Krebsfr\u0026uuml;herkennungsprogramme und Krebsfr\u0026uuml;herkennungs-Richtlinie: Programm zur Fr\u0026uuml;herkennung von Zervixkarzinomen. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.g-ba.de/downloads/40-268-5486/2018-11-22_oKFE-RL_Zervixkarzinom_TrG.pdf\u003c/span\u003e\u003cspan address=\"https://www.g-ba.de/downloads/40-268-5486/2018-11-22_oKFE-RL_Zervixkarzinom_TrG.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 22 March 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLeitlinienprogramm O. (2020) S3-Leitlinie Pr\u0026auml;vention des Zervixkarzinoms. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://register.awmf.org/assets/guidelines/015-027OLl_Praevention_Zervixkarzinom_2020-03-verlaengert.pdf\u003c/span\u003e\u003cspan address=\"https://register.awmf.org/assets/guidelines/015-027OLl_Praevention_Zervixkarzinom_2020-03-verlaengert.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed 14 March 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuyten A, Buttmann-Schweiger N, Luyten K, et al. Early detection of CIN3 and cervical cancer during long-term follow-up using HPV/Pap smear co-testing and risk-adapted follow-up in a locally organised screening programme. Int J Cancer. 2014;135:1408\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuyten A, Petry KU. Relevance of HPV Screening for Triaging Equivocal Cytology Findings in the Pap II-p, Pap III and Pap IIID Groups - Results of Two Long-Term Studies. Gebfra. 2015;75:1058\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKatki HA, Schiffman M, Castle PE, et al. Five-year risks of CIN 3\u0026thinsp;+\u0026thinsp;and cervical cancer among women who test Pap-negative but are HPV-positive. J Low Genit Tract Dis. 2013;17:56\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKatki HA, Schiffman M, Castle PE, et al. Five-year risks of CIN 3\u0026thinsp;+\u0026thinsp;and cervical cancer among women with HPV testing of ASC-US Pap results. J Low Genit Tract Dis. 2013;17:36\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArbyn M, Haelens A, Desomer A, et al. Cervical cancer screening program and Human Papillomavirus (HPV) testing, part II: Update on HPV primary screening, in KCE Reports. Belgian Health Care Knowledge Centre (KCE): Brussel; 2015.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWright TC, Behrens CM, Ranger-Moore J, et al. Triaging HPV-positive women with p16/Ki-67 dual-stained cytology: Results from a sub-study nested into the ATHENA trial. Gynecol Oncol. 2017;144:51\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKinney WK, Manos MM, Hurley LB, Ransley JE. Where's the high-grade cervical neoplasia? The importance of minimally abnormal Papanicolaou diagnoses. Obstet Gynecol. 1998;91:973\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBornstein J, Bentley J, B\u0026ouml;sze P, et al. 2011 colposcopic terminology of the International Federation for Cervical Pathology and Colposcopy. Obstet Gynecol. 2012;120:166\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKhan MJ, Castle PE, Lorincz AT, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005;97:1072\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKj\u0026aelig;r SK, Frederiksen K, Munk C, Iftner T. Long-term Absolute Risk of Cervical Intraepithelial Neoplasia Grade 3 or Worse Following Human Papillomavirus Infection: Role of Persistence. J Natl Cancer Inst. 2010;102:1478\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStoler MH, Wright TC, Sharma A, Apple R, Gutekunst K, Wright TL. High-risk human papillomavirus testing in women with ASC-US cytology: results from the ATHENA HPV study. Am J Clin Pathol. 2011;135:468\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWright TC, Stoler MH, Sharma A, Zhang G, Behrens CM, Wright TL. Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV\u0026thinsp;+\u0026thinsp;cytology-negative results. Am J Clin Pathol. 2011;136:578\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWright TC, Stoler MH, Behrens CM, Sharma A, Zhang G, Wright TL. Primary cervical cancer screening with human papillomavirus: end of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol. 2015;136:189\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet. 2007;370:890\u0026ndash;907.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoscicki AB, Schiffman M, Burchell A, et al. Updating the natural history of human papillomavirus and anogenital cancers. Vaccine. 2012;30:24\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHammad A, Donovan A, Wand H, et al. Genital warts in young Austra- lians five years into national human papillomavirus vac- cination programme: national surveillance data. BMJ. 2013;346:f2032.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePalmer T, Wallace L, Pollock KG, et al. Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12\u0026ndash;13 in Scotland: retrospective population study. BMJ. 2019;365:l1161.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"cervical dysplasia, colposcopy, HPV, HSIL, Pap smear","lastPublishedDoi":"10.21203/rs.3.rs-4589563/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4589563/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cu\u003eBackground:\u003c/u\u003eSince 2020, co-testing for women over the age of 35 has been a new strategy for cervical cancer screening in Germany. In this study, we investigated the added value of co-testing in organized cervical screening for the German screening population.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eMethods:\u003c/u\u003e A total of 1956 women were referred to our large dysplasia consultation institution due to abnormal screening results in the first round of screening between 2020 and 2022. The endpoint of this retrospective study was the posttest probability of a CIN 2+/CIN 3+ lesion on the cervix uteri. In addition, the influence of HPV subtypes on the endpoints was investigated.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eResults:\u003c/u\u003eCIN 2+ or CIN 3+ lesions were diagnosed in 21.6% and 13.0%, respectively, of the patients. The risk of severe dysplasia increases with the grade of cytological abnormality and is dependent on the HPV subtype. The risk for detecting invasive cervical cancer (16 patients in total) was significantly greater for women with HPV16 infection than for women with HPV infection of other high-risk types (odds ratio 11.18; 95% confidence interval 3.01, 40.81). CIN 2+ lesions were diagnosed in 10.1% of patients with normal cytology.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eConclusions:\u003c/u\u003e CIN 2+ lesions could be detected in more than every 5th woman with an abnormal screening result. Normal Pap smear results with HPV evidence must be confirmed by colposcopy. Risk stratification based on the underlying HPV subtype appears to be particularly useful if HPV 16 is detected.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eTrial registration:\u003c/u\u003e German Clinical trials register (ID: DRKS00027014, Registration date: 03.12.2021)\u003c/p\u003e","manuscriptTitle":"Cervical cancer screening by co-testing in women 35 years and older: an analysis of the 1st round of screening in Germany","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-17 19:59:25","doi":"10.21203/rs.3.rs-4589563/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-07-08T07:49:26+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-05T11:26:44+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-04T22:10:08+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-04T20:45:06+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-07-04T07:57:46+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"7053107610593469262258621357527612277","date":"2024-07-02T03:53:37+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-26T20:44:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"29801303764270508067804815522899076735","date":"2024-06-26T08:11:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"266098994404267029327608749883762307158","date":"2024-06-26T07:54:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"118143085087457009885935120638789710113","date":"2024-06-25T09:47:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"227777059780602386048077813872582709289","date":"2024-06-24T13:20:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"75704742853212136420328516929622903261","date":"2024-06-19T15:21:47+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-06-19T13:59:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-19T03:55:57+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-18T23:30:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Women's Health","date":"2024-06-16T11:47:40+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-womens-health","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmwh","sideBox":"Learn more about [BMC Women's Health](http://bmcwomenshealth.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmwh/default.aspx","title":"BMC Women's Health","twitterHandle":"","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bcdad594-9171-4efb-9be1-4b45f8e9c430","owner":[],"postedDate":"July 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-27T16:39:54+00:00","versionOfRecord":{"articleIdentity":"rs-4589563","link":"https://doi.org/10.1186/s12905-025-03836-7","journal":{"identity":"bmc-womens-health","isVorOnly":false,"title":"BMC Women's Health"},"publishedOn":"2025-10-21 16:16:34","publishedOnDateReadable":"October 21st, 2025"},"versionCreatedAt":"2024-07-17 19:59:25","video":"","vorDoi":"10.1186/s12905-025-03836-7","vorDoiUrl":"https://doi.org/10.1186/s12905-025-03836-7","workflowStages":[]},"version":"v1","identity":"rs-4589563","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4589563","identity":"rs-4589563","version":["v1"]},"buildId":"omnImTCwR2MFx8CMYfrG7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}