By Molly A. Brewer, DVM, MD, MS

Professor and Chair, Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Connecticut Health Center, Farmington CT

Dr. Brewer reports she receives grant/research support from the National Cancer Institute.

SYNOPSIS: A recent study found that genotyping for human papillomavirus 16/18 is a reasonable approach to help calculate the risk of progression to CIN3 or worse.

SOURCE: Chatzistamatiou K, Moysiadis T, Moschaki V, et al. Comparison of cytology, HPV DNA testing and HPV 16/18 genotyping alone or combined targeting to the more balanced methodology for cervical cancer screening. Gynecol Oncol 2016;142:120-127.

First described by Georgios Papanikolaou in 1928 as a means to detect both uterine cancer and cervical cancer, the Pap smear was the standard of care until the liquid-based Pap smear (ThinPrep) was found to be more accurate.1 Most institutions changed to this technology in 2003-2005. There have been multiple studies addressing how to best manage early detection for cervical cancer. The Pap smear is responsible for significantly reducing the incidence of invasive cervical cancer in the United States. However, widespread use has resulted in an enormous cost to society because of the false-positive rate of Pap smears as well as the false-negative rate. The role of human papillomavirus (HPV) in the etiology of cervical cancer was introduced in the 1960s by the German virologist Harold zur Hausen, who discovered HPV 11 and subsequently HPV 16 and 18. He discovered that these viral subtypes were strongly linked to cervical cancer and could be detected in 70% of cervical cancers. In 1999, further research revealed that 99.7% of cervical cancers are linked to HPV infections. HPV was not accepted as causative in cervical cancer until almost 2007.2

In this recent study from Greece, the authors evaluated multiple approaches to cervical cancer screening.3 Women 25-55 years of age recruited for the HERMES (HEllenic Real life Multicentric cErvical Screening) study were screened in terms of cytology and high-risk (hr) HPV testing with HPV 16/18 genotyping. Women positive for cytology and/or hrHPV+ were referred for colposcopy, biopsy, and treatment. Ten screening algorithms based on different combinations of cytology, HPV testing, and HPV 16/18 genotyping were investigated for diagnostic accuracy. They balanced efficacy by calculating sensitivity, or the ability to detect all cases of CIN2 or greater vs. the rate of unnecessary colposcopies and the number of false positives. HPV testing alone had a sensitivity of 100% for CIN2 or greater but resulted in the largest number of colposcopies and a three-fold increase in false-positive rates compared to cytology alone. HPV testing with HPV 16/18 genotyping, referring HPV 16/18+ women directly to colposcopy, and hrHPV+ (non 16/18) women to reflex cytology (ASCUS threshold), as a triage method to colposcopy, reflects the best equilibrium between screening effectiveness and harm. HPV genotyping with reflex cytology for those patients who were hrHPV+ but 16/18-, and referral for colposcopy for those who were 16/18+, resulted in more colposcopies than the HPV with cytology triage but had a sensitivity of 83% compared to the HPV with cytology triage, which had a sensitivity of 53%. Each of the approaches either had excellent sensitivity but a high cost in terms of many more colposcopies or had poorer sensitivity but lower cost in terms of fewer colposcopies. The authors’ approach was to balance risk of disease against harm caused by unnecessary testing.

Ultimately, the authors recommended that patients be hrHPV tested and, if positive, have genotyping done for HPV 16/18. Those who were HPV 16/18+ would be referred to colposcopy and those who were hrHPV+ but 16/18- would have cytology only performed. This approach was more cost effective and identified 83% of the women with CIN2 or greater.4 HPV 16/18+ is responsible for 70% of cervical cancers and has a cumulative incidence of progressing to CIN3 over three years of 25-30%, while hrHPV+16/18- only has a cumulative incidence of progressing to CIN3 over three years of 5.4%, making this a reasonable approach.5

COMMENTARY

How can practitioners decide the best approach to screening for cervical neoplasia given the complicated algorithms and the confusing nature of so much seemingly contradictory data? We all have seen young women with high-grade dysplasia ( CIN2) who were followed every six months with repeat colposcopy and cytology for years and had multiple excisional procedures that probably were never going to progress to cancer. However, some women will progress to cancer a year or less after being diagnosed with high-grade cervical dysplasia if they are not treated. Genotyping for HPV 16/18 is a reasonable approach to help calculate the risk of progression to CIN3 or worse. Based on these data, as well as the results from the ATHENA trial, I now genotype any patient with an hrHPV type for HPV 16/18. If she is hrHPV+ 16/18- and cytology is negative, she can have repeat evaluation in 12 months with cytology and HPV subtyping. Those patients who are HPV 16/18+ with negative cytology should have repeat colposcopy (± biopsy) and cytology in six months. Those who are cytology + (ASCUS or greater) need colposcopy and biopsy. Hopefully with a more thoughtful approach, we can do a better job of determining which women really need close screening and which women have a low risk of progression to cancer and, thus, can avoid the cost and morbidity associated with unnecessary treatment.

REFERENCES

  1. Negri G, Menia E, Egarter-Vigl E, et al. ThinPrep versus conventional Papanicolaou smear in the cytologic follow-up of women with equivocal cervical smears. Cancer 2003;99:342-345.
  2. Schiffman M, Castle PE, Jeronimo J, et al. Human papillomavirus and cervical cancer. Lancet 2007;370:890-907.
  3. Chatzistamatiou K, Moysiadis T, Moschaki V, et al. Comparison of cytology, HPV DNA testing and HPV 16/18 genotyping alone or combined targeting to the more balanced methodology for cervical cancer screening. Gynecol Oncol 2016;142:120-127.
  4. Skroumpelos A, Agorastos T, Chatzistamatiou K, et al. Budget impact analysis of high-risk Hpv Dna (Hrhpv) test with 16/18 genotyping as a primary screening method for cervical cancer in Greece. Value Health 2015;18:A349.
  5. Wright TC, Stoler MH, Behrens CM, et al. Primary cervical cancer screening with human papillomavirus: End of study results from the ATHENA study using HPV as the first-line screening test. Gynecol Oncol 2015;136:189-197.