Single-Visit Cervical Screening Strategy Picks Up Suspect Lesions

Pam Harrison

November 19, 2018

A low-cost, single-visit cervical cancer screening strategy during which women are screened using a modified Pap test and visual inspection, and referred for immediate biopsy if the Pap test is positive, captures more cervical abnormalities than standard Pap testing alone and minimizes loss to follow-up, a prospective study indicates.

"Compliance is a serious limiting factor affecting the effectiveness of cervical screening not only in developing countries, but also in low-income communities within more developed countries," senior author Wen Jie Zhang, MD, PhD, Shihezi University School of Medicine, China, and colleagues observe. Their findings were published online November 5 in Obstetrics & Gynecology.

"Simple modification of a conventional Pap test allows both cervical cytology and visual inspection with acetic acid [vinegar] tests to be performed in a single day," they add.

"[And we found that] single-visit cervical screening with both a modified Pap test and visual inspection...could be an efficient low-cost strategy for low-resource settings," the authors conclude, pointing out that their approach cost approximately $6 per test in their healthcare system.

Commenting on the study during an Obstetrics & Gynecology podcast, John Fischer, MD, professor and chair of Obstetrics, Gynecology, and Women's Health at the University of Minnesota, Minneapolis, said the study was very well thought out. Researchers took into consideration that providers would not be able to visually examine the cervix had they had done a regular Pap smear because a regular Pap brush disrupts the squamous epithelium of the cervix, making it difficult to visualize immediately after, hence the modification.

Nancy Chescheir, MD, editor-in-chief of Obstetrics & Gynecology, commenting during the same podcast, also applauded the researchers for their work.

"I think the really interesting thing is that they did all these modifications — the modified Pap test, the visual inspection with acetic acid, then Lugol's [iodine], and then they did a regular Pap test so they had the gold standard to look at too, so this was a very complicated strategy and I give them a lot of credit for what they did."

Chescheir cautioned that the same modifications have to be validated in other low-resource settings because some training was involved in the current strategy and the study design required a pathologist to be on-site to read the smears quickly. "It's not a slam dunk that this strategy can be replicated in other settings," she noted.

"But if it could be, that would be terrific for countries, or areas of a country, that are really struggling with the same problem," she concluded.

Modification of the Pap Smear Test for Underserved Women

The Pap test and visual inspection with acetic acid are relatively low-cost screening methods, both of which have played important roles in alleviating the burden of cervical cancer, the researchers explain. But these two screening procedures typically require separate visits.

"This feasibility study tests a screening strategy of slight modification of the Pap test with rapid interpretation, allowing for more accurate visual inspection with acetic acid and the option of biopsy for confirmatory histology on the same day," they explain.

Two low-income Uyghur communities in China's far western Kashi Prefecture, almost 3000 miles from Beijing, were selected for both the pilot and validation parts of the study because they represented an underserved population with low rates of cervical screening. Inclusion criteria included not being screened in the past 5 years.

A total of 4049 women between 30 and 59 years of age were screened for the presence of cervical abnormalities from November 2011 to August 2014.

Because visual inspection of the cervix using vinegar is less sensitive if done after a conventional Pap test, at least on the same day, "we modified the Pap test using a long cotton swab to collect mucus fluid-cells surrounding the transformation zone and endocervix with several rotations, which contained cervical cells for Pap testing," the authors explain.

They then proceeded to prepare Pap slides by rolling the cotton swabs across the glass, which was fixed in alcohol and ready for interpretation by an on-site cytopathologist within about 20 minutes.

Once the Pap test had been collected, women were visually inspected with the help of acetic acid. If the area under scrutiny turned white after applying 5% acetic acid, positivity was established. In instances where the visual inspection was negative, 5% Lugol's iodine was applied and women were again visually inspected after that application.  

Finally, they performed a normal Pap test as a sampling quality comparison.

Both the modified Pap test interpretation, visual inspection with acetic acid, and visual inspection with Lugol's iodine could be completed in 1.5 hours or less.

Women who tested positive on visual inspection were immediately referred to onsite-directed biopsy under colposcopy.

Women negative for visual inspection were asked to wait in the screening facility until their Pap test results were completed. Patients with atypical squamous cells of undetermined significance or worse findings were also referred to same-day colposcopy, although some (20%) had to be referred for colposcopy in the following days if test results came back late in the day.

If a cervical abnormality was identified by colposcopically, a biopsy was taken at that location; otherwise, random four-quadrant biopsies were taken. The pathology specimens were placed in 10% formalin and sent by courier to the researchers' department (1689 km away from the sites). Histologic diagnoses were made by pathologists and reports were returned in approximately 5 days.

"We have adopted routine courier services to transport formalin-fixed biopsies, Pap slides, or both to pathology laboratories for diagnosis, allowing for quality treatment of high-grade CINs in remote communities," the researchers explain.

Single-Visit Screening: Same Day Service Had Best Results

The primary outcome of this single-visit strategy was the diagnosis of cervical intraepithelial neoplasia (CIN) grades 1, 2, and 3, as well as frank cervical cancer.

Overall, combined screening in this study reached a sensitivity of 96.0% in detecting CIN 2 or worse disease, which was superior, in fact, to Pap testing alone at 76% (P < .001) or visual inspection with either acetic acid or Lugol's iodine at 48% and 59.3%, respectively (P < .001), "and similar to that of HPV testing," they point out.

They were also able to achieve a negative predictive value of 98.2% on detecting the same lesions using the same approach.

Their approach identified an extremely high prevalence of CIN grade 1 (2741 per 100,000 women), CIN 2 or 3 (1457/100,000), and cervical cancer (395/100,000) among these under-screened, at-risk women.

The $6 cost of combined screening in China's secondary healthcare facilities "is very cost-effective in any setting," they note, and represents "only 10% of the cost of HPV testing."

All patients diagnosed with cervical cancer in this single-visit program received treatment, while 92% of those with CIN grades 2 or 3 were also treated.

"We observed more patients willing to undergo screening and a recommended biopsy in the validation study as we gained experience," the authors acknowledge.

They also observed that most patients lost to follow-up had Pap test results that were not available by the end of the day and therefore had to return for biopsy.

Thus, the authors recommend that any similar screen-and-diagnosis program undertaken elsewhere be carried out in the morning or early afternoon so as not to miss opportunities to refer patients for biopsy on the same day.

"No single screening strategy is globally suitable for all low-income settings," the investigators caution.

"Choosing an affordable yet effective strategy to control cervical cancer requires novel approaches to achieve 'good health at low cost' in low-income settings," they advise.

Striking Global Disparities in Cervical Cancer Deaths

During the Obstetrics & Gynecology podcast, Fischer points out that the global disparities in the incidence of cervical cancer are striking.

For example, in 2012 an estimated 528,000 new cases of cervical cancer were diagnosed globally, while in the same year, 266,000 women died of the disease, "the vast majority of these being in the developing world where they do not have access to things like HPV screening," he observed.

In contrast, "the incidence and mortality of cervical cancer have declined sharply in developed countries," the authors note in their article.

Despite widespread implementation of effective screening strategies, including visual inspection with acetic acid, Pap testing, and human papillomavirus (HPV) testing, "the past three decades have witnessed a 20% increase in cervical cancer cases worldwide and 23% of the total deaths are women aged 15 to 49 years in developing countries," they stress.  

After 60 years of adopting Pap testing, "the severe global disparity in the distribution of cases and deaths resulting from cervical cancer suggests a sad failure to effectively control this cancer in resource-limited countries."

But there is hope, they stress.

As a result of high prices of HPV vaccines, "we have proposed a subsidized 'semi-mandatory HPV vaccination' strategy particularly designed for those low-income women at high risk which, if adopted with this [study] strategy, would further alleviate the burden of cervical cancer in developing countries."

The authors have reported no relevant financial relationships. Chescheir and Fischer have reported no relevant financial relationships.

Obstetrics & Gynecology. Published online November 5, 2018. Full text

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