Invasive cervical cancers after an HPV-negative test: insights from HPV testing histories in Sweden

HPV testing is the primary method for cervical cancer screening, and a negative HPV test is associated with a low subsequent risk of invasive cervical cancer. Nevertheless, some cervical cancers are diagnosed following a negative HPV test. Researchers from Karolinska Institute (Stockholm, Sweden) 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. Among 3000 women diagnosed with 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 (aOR 2.91; 95% CI 2.13-4.00). Among women with an HPV-negative test, 128 of 243 (52.7%) had no prior HPV testing recorded, while 83 (34.2%) had consistently HPV-negative history, and 32 (13.2%) had prior HPV-positivity. Cytology records were available for 229 of 243 patients (94.2%) and 33 of 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. The authors conclude that cervical cancer diagnosed after an HPV-negative test reflect heterogeneous HPV testing histories (graphical abstract).