HPV primary screening: unanswered questions

Dear Editor, I read with interest H.C. Kitchener’s recent editorial ‘HPV primary cervical screening: time for a change. ’ Although this editorial acknowledges the UK Cervical Screening Programme as ‘an exemplar,’ one which has reduced cervical cancer deaths between 1988 and 2014 by almost twothirds, discordant data which should raise questions about the ability of primary HPV screening at extended intervals to effectively sustain the accomplishments of cytology-based screening are not acknowledged. Although Dr Kitchener restates Walboomers’ often-cited assertion that HPV genomic material is present ‘in virtually 100% of cervical cancers,’ no acknowledgement is given to other more recent qualifying reports, for example, that 254 out of 682 (37%) international cervical adenocarcinoma tissues did not contain detectible carcinogenic HPV DNA or that over 10% of US tumour registry cervical cancer tissues did not contain HPV genotypes detectible by currently available HPV screening tests. These last observations are more consistent with studies of over 900 cervical cancer samples which document that around 10% of cervical cancers will yield negative HPV screening test results. Even more troubling, given the extended screening intervals being promoted now for primary HPV screening, are reports of even higher rates of baseline negative HPV test results (23–42%) in patients diagnosed with cervical cancer over extended follow-up periods. One cited study, (co-authored by Kitchener), reported that only 11 of 19 cervical cancers diagnosed 2.5–8 years after the onset of four European trials had baseline positive HPV test results. Therefore, 8 of 19 (42%) presumably tested HPV-negative. Unfortunately, this worrisome observation is largely obscured by a large table 2 dataset and minimal discussion on the following page of the article. Kitchener’s editorial further discusses this study, stating that ‘(cervical) cancer rates were similar until 2.5 years of follow-up but thereafter HPV-based screening provided 60–70% greater protection against cervical cancer compared with cytology alone. ’ Omitted, however, is the troubling observation that in the UK ARTISTIC trial, the only one of the four trials utilising quality-optimised liquid-based cytology, all 5 cervical cancers diagnosed 2.5–8 years after the onset of the trial actually occurred in the HPV experimental arm! No cancers were diagnosed during the same period in the cytology arm. The authors could easily have stated that in the UK ARTISTIC trial uniquely, ‘protection’ during the period 2.5–8 years after start of the trial was complete only in the cytology arm (zero cervical cancers), while during this same period five cervical cancers were diagnosed in the (less protective) HPV experimental arm. As noted in a recent Obstetrics and Gynecology commentary, protection against invasive cervical cancer is the most relevant endpoint in efforts to optimise cervical screening. CIN3 and CIN3+ endpoints can be significantly misleading in this regard, as most CIN3 cases will not develop into invasive cervical cancers over extended follow-up. It will be unfortunate if HPV primary screening at extended screening intervals, with widely anticipated cost savings, proves unable to sustain the levels of protection against cervical cancer previously achieved by the exemplar cytology-based UK Cervical Screening Programme.