Primary Care Corner with Geoffrey Modest MD: Cervical Cancer Screening Less Frequently?

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By Dr. Geoffrey Modest

A recent review of cervical HPV screenings in the Netherlands found that those with negative screening could potentially be screened less frequently than every 5 years (see doi.org/10.1136/bmj.i4924).

Details:

  • 43,339 women aged 29-61 with a negative HPV and/or cytology were randomly assigned to HPV and cytology co-testing (intervention group) or cytology testing alone (control group); with 3 screens: at baseline, 5 years and 10 years; and with followup at 14 years. Those in the cytology only group also got HPV testing but this was blinded to all.
  • Mean age 43
  • Their triage approach (different from US recommendations):
    • For intervention group (cytology plus HPV):
      • Normal HPV and cytology: repeat in 5 years
      • At least moderate dyskaryosis on cytology: colposcopy
      • HPV positive, and neg or borderline/mild dyskaryosis (eg ASCUS or LGSIL) on cytology: repeat HPV/cytology at 6 and 18 months. refer to colposcopy if continued HPV positive or cytology worse
    • For control group (cytology only)
      • Normal cytology: cont routine screen
      • At least moderate dyskaryosis on cytology: colposcopy
      • Borderline/mild dyskaryosis (eg ASCUS or LGSIL) on cytology: repeat cytology at 6 and 18 months. refer to colposcopy if cytology same or worse

Results:

  • Co-testing group: 20,490 of 21,623 women had double negative HPV/cytology, 764 had pos HPV/neg cytology, 369 pos cytology/neg HPV
  • Cytology only group: 20,533 of 21,716 had negative cytology, 814 had pos HPV/neg cytology (the HPV results were blinded), 369 pos cytology/neg HPV
  • During 14 years of followup:
    • Co-testing: 149 CIN2, 152 CIN3 (including 5 adenoca in situ), 8 squamous cell and 6 adeno carcinomas
    • Cytology only: 126 CIN2, 169 CIN3 (including 5 adenoca in situ), 17 squamous cell and 10 adeno carcinomas
  • Breakdown of the 14 year followup according to cytology and HPV status (again, HPV results were blinded for the control group)
    • Cancer:
      • Cytology neg/HPV neg: 7 in intervention, 12 control; 3.3 vs 5.7/100,000 women, incidence ratio 0.58 (0.23-1.48), nonsignficant
      • Cytology neg/HPV pos: 4 in intervention, 15 control; 55.4 vs 190.9/100,000 women, incidence ratio 0.29 (0.10-0.87)
      • Cytology pos/HPV neg: 3 in intervention, 0 control; 79.7 vs 13.4/100,000 women, incidence ratio 5.97 (0.30-119.22), nonsignficant [but they had to use 0.5 instead of 0 for the cancer count, in order to do the math]
    • CIN3+ (the combination of cervical cancer and precancer):
      • Cytology neg/HPV neg: 74 in intervention, 86 control; 35.0 vs 40.7/100,000 women, incidence ratio 0.86 (0.63-1.17), nonsignficant
      • Cytology neg/HPV pos: 82 in intervention, 94 control; 1135.1 vs 1196.1/100,000 women, incidence ratio 0.95 (0.71-1.28), nonsignificant
      • Cytology pos/HPV neg: 10 in intervention, 16 control; 265.7 vs 427.1/100,000 women, incidence ratio 0.62 (0.28-1.37), nonsignficant
    • The cumulative incidence of cervical cancer 14 years after the initial negative cytology/negative HPV screen in the co-testing group (0.09%) was the same as in the cytology negative patients in the cytology-only group after 9 years
    • The cumulative incidence of CIN3+ was 0.56% 14 years after the initial negative/negative screen in the co-testing group, but 0.69% in the cytology negative patients in the cytology-only group after 9 years
    • Combining both groups, the incidence of CIN3+ was 72.1% lower (60.5-80.4%) in women >40 years old vs younger; no statistically significant difference in cervical cancer

Commentary:

  • Several studies have supported using only HPV screening without cytology (primary HPV screening) for detection of cervical dysplasia/cancer (g., see doi.org/10.1136/bmj.e670 from BMJ or Ronco G. Lancet 2014; 383 (9916): 524); the latter study found that there was 60-70% better protection with primary HPV screening over cytology screening. And primary HPV screening might avoid over-referral to colposcopy and biopsies. And decrease the number of screens done/longer intervals between screenings. Several countries now do primary HPV screening including Australia, Italy, Netherlands, New Zealand, Sweden and the UK. The current study looked not just at cervical cancer, which may take years to manifest itself, but also to high-grade precancerous lesions (CIN3+) to try to ascertain if the longer screening interval could miss women with evolving cancers (which it didn’t: those with combined screening had the same incidence at 14 years as the cytology only group at 14 years).
  • So, this study suggests several things:
    • It confirms the superiority of HPV/cytology screening over cytology alone
    • The very low incidence of CIN3+ in the overall combined groups (including the blinded HPV testing of the cytology-only group) who had negative HPV testing (independent of cytology) was quite low: 84 events in 20,859 patients (e.g., as compared to those who were HPV positive but cytology negative, with CIN3+ in 82 of 764 patients), affirming that HPV testing is superior to cytology testing
    • The study also confirmed the utility of testing more than just the highest risk HPV 16/18 types, since there were 30 of 501 patients with CIN3+ who were HPV positive/cytology negative and HPV 16/18 negative
    • And the big conclusion was the very low risk of CIN3+ and cervical cancer itself in patients who were >40yo and had dually negative initial HPV/cytology
    • Putting this all together, in 2017 the Netherlands will implement the strategy of every 10-year screening for HPV negative women at least 40 years old
  • So, there really seems to be increasing data suggesting that primary HPV is a superior screening test (adding cytology seems to add more false positives than providing real clinical benefit), though i would imagine there need to be more studies in different populations to see what the optimal screening interval should be.
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