A new generation of studies of human papillomavirus DNA testing in cervical cancer screening.

JNCI Vol. 101, Issue 23 | December 2, 2009 “All zoogles are boogles. You saw a boogle. Is it a zoogle?” Question in an SAT examination (Nassim Nicholas Taleb in “The Black Swan”) “Not necessarily” is the resounding answer to this thought experiment, in analogy to the central argument in the debate on the clinical utility of human papillomavirus (HPV) testing in cervical cancer screening. Virtually all cervical cancers are caused by infections with oncogenic HPV types ( 1 ). However, does a positive HPV DNA test result indicate that cervical cancer or precancerous lesion is present or imminent for a woman attending routine screening? Although most cervical HPV infections, even those with oncogenic types, will be inconsequential, it is also true that a provider will be more likely to fi nd cervical cancers or their precursors if screening is with HPV DNA testing rather than with Papanicolaou cytology ( 2 , 3 ). This extra sensitivity exacts a penalty on the specifi city of HPV DNA testing, which (by design) detects the presence of viral DNA in cervical cells irrespective of whether or not the molecular changes are in the context of an infection that has already produced morphological abnormalities recognizable by cytology. In other words, HPV DNA testing brings the focus of screening “upstream” in the natural history of cervical neoplasia relative to the decades-old paradigm of Papanicolaou cytology. Returning to the above thought experiment, all cervical cancers arise from cervical intraepithelial neoplasia (CIN), whose grade correlates with the extent of Papanicolaou abnormality. Although it is easier to fi nd a “zoogle” with the HPV DNA “boogle” identifi er than with the Papanicolaou “boogle” identifi er, the latter will have fewer false positives than the former. Recognition of the above-described test properties has not been the main rationale for how the scientifi c community has designed studies to collect evidence on the value of HPV DNA testing in cervical cancer screening and for how professional guidelines emerged in consequence. Although less specifi c than Papanicolaou cytology, the HPV DNA test was fi rst evaluated and approved to be used conditionally as a triage tool based on the Papanicolaou cytology result exclusively to identify women who need to undergo colposcopy because of an equivocal Papanicolaou diagnosis ( 4 , 5 ). Later, mounting evidence that HPV DNA testing could increase the sensitivity of screening when used in parallel with Papanicolaou cytology led to co-testing as an accepted practice that permitted screening intervals in the United States to be safely extended from annual to triennial ( 6 ). The impetus for Papanicolaou and HPV co-testing prompted the initiation of European randomized controlled trials (RCTs) comparing the co-testing strategy with traditional cytology-only screening. The results from these trials have confi rmed that 1) more cervical precancerous lesions are detected by co-testing than by cytology ( 7 – 9 ) and 2) the extra detection is benefi cial because the excisional treatment given at the time of the discovery lowers the rate of such lesions in subsequent screening rounds, thus proving that many of them would likely persist or progress if left untreated ( 8 – 10 ). Affiliation of author: Division of Cancer Epidemiology, Departments of Oncology and Epidemiology & Biostatistics, McGill University, Montreal, QC, Canada.