HPV negative cervical cancers and primary HPV screening

More than 25 years ago it was established that a HPV (Human Papilloma Virus) infection was the causal factor for cervical cancer. Based on this discovery HPV vaccines were developed and primary HPV screening proposed. The impact of 10 years prophylactic HPV vaccination with the bivalent and quadrivalent vaccines has been tremendous. There is a reduction of HPV infections 16/18, 31, 33 and 45 of respectively 89%, 94%, 79% and 83%. High grade lesions have been reduced by 85% and warts by 90%. Within 20 to 30 years a reduction in cervical cancer incidence, by 70-80%, is to be expected. The 9 valent HPV vaccine, which was introduced last year and is reimbursed for girls between 12 - 19 years, is expected to increase the figures by 14 to 18%. Recently, doubt has been created regarding primary HPV screening. Since 2017, the annual screening report in Belgium suggests that 15% of the cervical cancers were HPV negative. Previous published data in Belgium (period 2001 - 2008) showed that the number of HPV negative tumors is less than half of the suggested figure (7%). Frequent reasons for false negative HPV tumors are the used HPV testing methods and the misclassification of endometrial cancers or metastasis as cervical cancers. Other explanations are the loss of HPV expression and the existence of cervical cancers independent of HPV. The incidence of HPV negative tumors doesn't give any information about the performance of primary HPV screening. Data from randomized controlled trials are very clear: if a woman has a normal cytology and no HPV infection or normal cytology and a HPV infection, then her chance of developing a CIN3 + lesion after 5 years is, respectively, 0,2% and 6%. In Belgium, primary HPV screening with dual-stain cytology triage would considerably reduce the incidence (36%) and mortality (40%) of cervical cancer. There is necessity to improve the screening as we are entering an era of vaccinated women who will get screened. Standardized high quality HPV testing is the key stone for improvement. HPV screening preferable with triage markers is superior to cytology, despite the fact that there are HPV negative cancers. The fact that there are HPV negative cancers should not undermine all idea's regarding primary HPV screening.