Triage of HPV positive women in cervical cancer screening

Abstract

Despite HPV vaccines, screening will remain central for decades to control cervical cancer. Recently, HPV testing alone or with cytology was introduced as an alternative to cytology screening. However, most HPV infections are harmless and additional tests are required to identify women with progressing infections or precancer. With three options for primary screening, and without clear strategies for triage of screen-positive women, there is great confusion about the best approach. Also, increasing HPV vaccination coverage will lead to lower disease prevalence, and force new screening approaches. Currently recommended triage strategies for primary HPV screening include HPV genotyping for HPV16 and HPV18 and cytology. Other alternatives that are currently evaluated include p16/Ki-67 dual stain cytology, host methylation, and viral methylation testing. Clinical management of women with cervical cancer screening results is moving to use risk thresholds rather than individual test results. Specific risk thresholds have been defined for return to primary screening, repeat testing, referral to colposcopy, and immediate treatment. Choice of test algorithms is based on comparison of absolute risk estimates from triage tests with established clinical thresholds. Importantly, triage tests need to be evaluated together with the primary screening test and the downstream clinical management. An optimal integrated screening and triage strategy should reassure the vast majority of women that they are at very low risk of cervical cancer, send the women at highest risk to colposcopy at the right time, when disease can be colposcopically detected, and minimize the intermediate risk group that requires continued surveillance.

Keywords: Cervical cancer screening; Cytology; HPV; Methylation; Triage; p16/Ki-67.

Figure 1

Risk-based management in cervical cancer screening. The absolute risk of precancer from 0 to 1 is shown on the y-axis. Clinically relevant risk strata are shown, ranging from minimal to high risk of precancer. On the population level, the risk of precancer is very low. A positive primary screening test (e.g. HPV testing) increases the risk of precancer, but not high enough to refer women to colposcopy. A triage test is applied in women with a positive screening result and should distinguish women who need colposcopy referral from women who need continued surveillance or who can be released to primary screening. At colposcopy, women with precancer are identified who need treatment. An idealized example is shown. The risk thresholds may vary between health systems and populations. Different primary screening and triage tests may group women in different risk strata.

Figure 2

Two examples of algorithms for primary HPV screening A: In the United States, primary HPV screening using the cobas assay (Roche) was approved by the FDA. Women negative for HPV will go back to routine screening with 3-year intervals. Women with HPV16/18-positive results are referred to colposcopy immediately. Among women positive for other carcinogenic types, cytology is performed and women with ASC-US or higher are referred to colposcopy, while women with normal cytology are re-tested after 12 months B: In the Netherlands, a primary HPV screening approach has been proposed and approved for implementation. All HPV-positive women are triaged with cytology. If cytology is positive, women are referred to colposcopy. Women with negative cytology will have repeat cytology after 6 months and are referred to colposcopy when cytology is positive, otherwise they are released back to routine screening. For women with a previous negative HPV screening test, the screening interval is 5 years if <45 years and 10 years for women aged >= 45. For women 45 years or older with a positive HPV test but with double negative cytology triage, the next invitation will be sent after 5 years instead of after 10 years.