Baseline HPV Status Predicts Development of High-Grade Cervical Intraepithelial Neoplasia

By Will Boggs MD

December 16, 2018

NEW YORK (Reuters Health) - The presence of human papillomavirus (HPV) subtypes HPV-16 and HPV-18 in women negative for intraepithelial lesions or malignancy is associated with an increased risk of developing high-grade cervical intraepithelial neoplasia (CIN), according to new research from Sweden.

"These findings, along with others, strongly indicate that testing for HPV should be incorporated into cervical-cancer screening programs," Dr. Karen Belkic from Karolinska University Hospital and Institute, in Stockholm, told Reuters Health by email. "Physicians should not rely solely upon normal cervical cytology findings in judging their patients' risk of developing high-grade CIN. Testing for HPV and especially HPV-16 or HPV-18 is essential."

Persistent HPV infection, especially with subtypes HPV-16 and HPV-18, plays an important causal role in the development of cervical cancer. Both European guidelines and American Cancer Society recommendations include HPV as part of primary screening starting at age 30 years.

Using data from a Swedish screening program, Dr. Belkic and colleagues examined the impact of baseline HPV status on the future risk of CIN grade 2 or worse (CIN2+) among women whose baseline cervical cytology was negative for intraepithelial lesions or malignancy (NILM).

During follow-up, 96 women developed CIN2+, and these were matched by age, index-cytology date and earlier screening history with 480 control women who had no cytological or histopathological diagnosis indicating CIN2+.

The findings of any HPV, HPV-16/18, and only other HPV types occurred significantly more often among the cases than among the controls, the researchers report in Cancer, online December 10.

Cases with CIN2+ had 6.78-fold greater odds of testing positive for any HPV and 8.93-fold greater odds of testing positive for HPV-16/18, compared with controls.

Similarly, cases with CIN3+ had 9.10-fold greater odds of testing positive for any HPV and 19.2-fold greater odds of testing positive for HPV-16/18.

The odds for having CIN2+ or CIN3+ were significantly increased for HPV and for HPV-16/18 both for women younger than 30 years and for those who were older.

Among the 15 women younger than 30 years who developed CIN2+ and had a positive result for HPV-16/18 at baseline, the number of detected cases rose sharply three years after the baseline NILM result and increased steadily until the eighth year of follow-up.

On the other hand, all five of these younger women with other HPV subtypes only were detected by the sixth year of follow-up.

For women aged 30 years and older, the number of cases rose steadily both for those with HPV-16/18 and for those with other HPV subtypes only until about 6.5 years after the baseline result.

"Women younger than age 30 with a positive HPV-16 or HPV-18 finding need to be closely followed, whereas other HPV types are much less likely to be associated with increased risk in these younger women," Dr. Belkic said. "Among women age 30 or above, any HPV positive finding should be closely followed."

"Further studies are needed with systematically repeated HPV measures," she said. "Thereby, transiently positive HPV findings with a negligible risk of subsequent high-grade CIN could be more conclusively identified. This would be especially important for avoiding the potential deleterious effects of over-screening and (excess work-up and treatment), especially for younger women."

Dr. Ming Guo from MD Anderson Cancer Center, in Houston, Texas, who recently found cytology and HPV co-testing to be valuable for stratifying CIN3 risk, told Reuters Health by email, "HPV testing with HPV-16/18 genotyping is critical for risk profiling and triage."

He was surprised that "non-HPV16/18 high-risk HPV types were not significantly associated with CIN2+ in women 30 years and younger."

"For women with Pap cytology and HPV co-testing, women's age may be considered for clinical triage, especially for women 30 years and older," said Dr. Guo, who was not involved in the new study.


Cancer 2018.