Cervical glandular neoplasias (CGN) present a challenge for cervical cancer prevention due to their complex histopathology and difficulties in detecting preinvasive stages with current screening practices. Reports of human papillomavirus (HPV) prevalence and type-distribution in CGN vary, providing uncertain evidence to support prophylactic vaccination and HPV screening. This study [108288/108290] assessed HPV prevalence and type-distribution in women diagnosed with cervical adenocarcinoma in situ (AIS, N = 49), adenosquamous carcinoma (ASC, N = 104), and various adenocarcinoma subtypes (ADC, N = 461) from 17 European countries, using centralised pathology review and sensitive HPV testing. The highest HPV-positivity rates were observed in AIS (93.9%), ASC (85.6%), and usual-type ADC (90.4%), with much lower rates in rarer ADC subtypes (clear-cell: 27.6%; serous: 30.4%; endometrioid: 12.9%; gastric-type: 0%). The most common HPV types were restricted to HPV16/18/45, accounting for 98.3% of all HPV-positive ADC. There were variations in HPV prevalence and ADC type-distribution by country. Age at diagnosis differed by ADC subtype, with usual-type diagnosed in younger women (median: 43 years) compared to rarer subtypes (medians between 57 and 66 years). Moreover, HPV-positive ADC cases were younger than HPV-negative ADC. The six years difference in median age for women with AIS compared to those with usual-type ADC suggests that cytological screening for AIS may be suboptimal. Since the great majority of CGN are HPV16/18/45-positive, the incorporation of prophylactic vaccination and HPV testing in cervical cancer screening are important prevention strategies. Our results suggest that special attention should be given to certain rarer ADC subtypes as most appear to be unrelated to HPV.

1st Department of Oncologic Gynaecology and Gynaecology Medical University of Lublin Poland

Center for Pharmacoepidemiology Clinical Epidemiology Unit Department of Medicine Karolinska Institute Solna Sweden

CERVIVA Research Consortium Funded by the Health Research Board Ireland Based at the Department of Pathology The Coombe Women and Infants University Hospital and Trinity College Dublin Ireland

Clinics Biostatistics Paris France

Comprehensive Cancer Center Department of Gynecology and Obstetrics Medical University of Vienna Vienna Austria

DDL Diagnostic Laboratory Rijswijk The Netherlands

Department of Anatomical Pathology General Hospital of Patras Achaia Greece

Department of Gynaecology and Oncologic Gynaecology Military Institute of Medicine Warsaw Poland

Department of Obstetrics and Gynaecology Hvidovre University Hospital Hvidovre Copenhagen Denmark

Department of Obstetrics and Gynecologic Oncology St Stephan Hospital Budapest Hungary

Department of Obstetrics and Gynecology Medical University of Graz Graz Austria

Department of Oncology University of Sheffield Medical School Sheffield England United Kingdom

Department of Pathology Belfast Health and Social Care Trust Belfast Northern Ireland United Kingdom

Department of Pathology Weill Medical College of Cornell University New York Presbyterian Hospital New York NY

Epidemiology Department GlaxoSmithKline Vaccines Wavre Belgium

Global Health Economics GSK Vaccines Wavre Belgium

Hospital Clinic August Pi i Sunyer Biomedical Research Institute University of Barcelona Barcelona Spain

IMS Health Stockholm Sweden

Institute of Cancer and Genetics HPV Research Group Cardiff University School of Medicine Cardiff Wales United Kingdom

Institute of Oncology of RAMS Siberian Branch Tomsk Russia

Laboratory of Microbiology DO Ott Research Institute of Obstetrics and Gynaecology St Petersburg Russia

Multidisciplinary Breast Clinic Gynecological Oncology Unit Department of Obstetrics and Gynecology Antwerp University Hospital University of Antwerp Antwerpen Belgium

Obstetrics and Gynaecology Department University Hospital Puerto De Hierro Majadahonda Madrid Spain

University Hospital Motol Prague Czech Republic

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