Invasive Cervical Cancers After an HPV-Negative Test: Insights From HPV Testing Histories

Human papillomavirus (HPV) testing is the primary method for cervical screening, and a negative HPV test is associated with a very low subsequent risk of invasive cancer. Nevertheless, some cervical cancers are diagnosed following an HPV-negative test. Using Swedish registry data, we identified women diagnosed with invasive cervical cancer between 2019 and 2024 and reconstructed HPV testing histories from the National Cervical Screening Registry. The HPV test closest to diagnosis, performed before or within 30 days after diagnosis, was defined as the index test. Of 3000 women diagnosed with invasive cervical cancer, 243 (8.1%) had an HPV-negative index test. These women were older and more frequently diagnosed at advanced stages than women with an HPV-positive index test. After adjustment for age, calendar year, and histology, an HPV-negative index test remained associated with advanced-stage disease (adjusted OR 2.91, 95% CI: 2.13-4.00). Among women with an HPV-negative index test, 128 of 243 (52.7%) had no prior HPV testing recorded, 83 of 243 (34.2%) had consistently HPV-negative histories, and 32 of 243 (13.2%) had prior HPV positivity. Cytology records were available for 229 to 243 (94.2%), and 33 to 243 (13.6%) had a previous high-grade histopathological diagnosis. Among women with an HPV-negative index test, recurrent HPV positivity following an intervening negative test was observed in only one woman. Cervical cancers diagnosed after an HPV-negative test reflect heterogeneous HPV testing histories. Most women either had no prior HPV testing recorded or had consistently HPV-negative results, while HPV positivity was observed in a smaller subgroup.