Closing clinical gaps in cervical cancer

The last few decades may very well be considered the decades of innovation for improvement in women’s sexual health. Since the Pap’s efficacy in detecting cervical cancer was proved in 1941,1 little innovation has occurred until recently to advance cervical health and better manage cervical cancer risk.1 Labs have played a major role in recent advancements to bridge clinical gaps in cervical health. 

Once the leading cause of cancer death among women, cervical cancer is the most preventable of all gynecologic cancers. In the past 40 years, the number of cases and deaths from cervical cancer have decreased significantly as more women regularly had Pap tests and with the introduction of human papillomavirus (HPV) testing and the development of HPV vaccines.

HPV primary screening/extended genotyping

The link between HPV and cervical cancer was discovered in the 1980s. However, as not all the 100 types of HPV cause cervical cancer, it became important to distinguish which do.2 In the 1990s, high-risk HPV genotypes were identified as the main risk factor for developing cervical cancer. HPV testing was first recommended for triage of ASC-US lesions by the American Society of Colposcopy and Cervical Pathology (ASCCP) in 2001.3

So far, 14 genotypes of HPV are linked to cancer, with HPV 16 and 18 causing 70 percent of cervical cancer and cervical cancer lesions. Today, several PCR tests exist that can identify different HPV genotypes. 

United States Preventive Services Task Force guidelines support different methods of screening. The most common are a primary screening HPV test or co-testing – Pap cytology testing and an HPV test. ASCCP management guidelines state that positive results from HPV primary screening for 12 high-risk HPV genotypes (exclusive of HPV 16 and 18, which are recommended for direct colposcopy) without a history of abnormal results should be followed by another screening in one year as most of the time the infection goes away on its own.

Dual-stain cytology

However, that left a gap in the screening continuum. Healthcare providers and their patients who were sent home with high-risk genotypes other than HPV 16 and HPV 18 didn’t know for sure what would happen over the course of the year until their next exam.  It is especially important to identify when an HPV infection is transforming as early as possible because only about 4 in 10 women come back for later testing,4 and a transforming HPV infection, a precursor of pre-cancer, could still occur.

To bridge this gap, a new cytology-based, dual-stain technology was introduced in 2020. P16 is a biomarker that occurs in normal cells and signifies cell cycle arrest. Ki-67 is also a biomarker that occurs in normal cells and signifies cell cycle division. Dual-stain technology can detect the tumor-suppressor protein p16 and cell proliferation marker Ki-67 in women with positive HPV results. A cell is considered positive if both stains are present in the same cell. The same sample used for HPV primary screening or Pap cytology can also be used for dual-stain cytology, and the technology is approved for use with one specific HPV screening test. 

The information from the dual-stain test immediately gives healthcare providers and patients the information they need to move forward. Finding cancer as early as possible is critical for treatment. When detected at an early stage, the five-year survival rate for women with invasive cervical cancer is 92 percent.5

The IMPACT clinical trial has shown that dual-stain as a triage detected cervical disease earlier than Pap cytology in seven out of ten women who were already identified as HPV positive.6,7 This allows providers to treat disease earlier, a critical factor in improving cancer patient outcomes. The IMPACT dual-stain clinical trial had representation from diverse patent segments, including 21% Black, 24% Hispanic-Latino and 0.3% American Indian or Alaskan Native participants. 

Testing in diverse populations is important as HPV disproportionately impacts Hispanic and Black women.8  Black women are less likely to be diagnosed with cervical cancer, yet they have the highest death rates compared to all other racial and ethnic groups due to profound survival disparities, which may be attributed to a lack of access to timely, high-quality care.9

Other more recent studies demonstrating the efficacy of dual-stain also included diverse populations. The KPNC population includes a diverse population from California, including 24% Hispanic, 18% Asian/Pacific Islander and 8% Black.10 The STRIDES study population includes a diverse population from Mississippi, with 60% being Black women.11


Access to HPV screening through self-collection is likely one of the last hurdles to better detect pre-cancer before it develops into cancer. It offers women an alternative to clinician collection and opens access for women who have never been tested and have no access to healthcare.

Affordable point-of-care and self-testing products are listed as an action item by the Women’s Health Innovation Opportunity Map 2023, 50 High-Return Opportunities to Advance Global Women’s Health R&D from the Innovation Equity Forum sponsored by the Bill & Melinda Gates Foundation and the US National Institutes of Health.12

The concept is for women, with healthcare professional directions, to use a swab or collection device to collect a sample from their vagina that is then sent to a lab for analysis and tested for HPV in the same manner as samples collected from providers. Collecting a sample away from the traditional doctor’s office creates more flexibility for screening to reach different populations.

The following populations may benefit from self-collection:

      Women who live in rural or medically underserved areas to travel to screening.

      Women who live in a culture that requires a certain level of privacy that prevents providers from directly taking a sample.

      Women who have undergone physical trauma.

      People with a cervix whose providers believe the test to be appropriate for them.

While no self-collection test has yet been approved by the Food and Drug Administration, they are expected to be part of a future menu of HPV testing, similar to how the tests are currently used in other countries. 

Self-collection, dual-stain cytology, and extended genotyping could be technologies that enable providers to make patient care decisions and make sure no women are left behind in cervical cancer screening and early detection. 


1.     Vilos G. The history of the papanicolaou smear and the Odyssey of George and Andromache Papanicolaou. Obstet Gynecol. 1998;91(3):479-483. doi:10.1016/s0029-7844(97)00695-9.

2.     HPV (human papillomavirus). U.S. Food and Drug Administration. Published November 1, 2023. Accessed January 26, 2024.

3.     Saraiya M, Steben M, Watson M, Markowitz L. Evolution of cervical cancer screening and prevention in United States and Canada: implications for public health practitioners and clinicians. Prev Med. 2013;57(5):426-33. doi:10.1016/j.ypmed.2013.01.020.

4.     Rebolj M, Lynge E. Incomplete follow-up of positive HPV tests: overview of randomised controlled trials on primary cervical screening. Br J Cancer. 2010;27;103(3):310-4. doi:10.1038/sj.bjc.6605771.

5.     Cervical cancer - statistics. Published June 25, 2012. Accessed January 26, 2024.

6.     CINtec® PLUS Cytology. Package insert. Roche Diagnostics; 2020.

7.     Safaeian M, Wright TC Jr, Stoler MH, et al. The Improving Primary Screening and Colposcopy Triage trial: human papillomavirus, cervical cytology, and histopathologic results from the baseline and 1-year follow-up phase. Am J Obstet Gynecol. 2021;225(3):278.e1-278.e16. doi:10.1016/j.ajog.2021.03.047.

8.     Hispanic or Latino people and cancer. Published July 19, 2023. Accessed January 26, 2024.

9.     Cohen CM, Wentzensen N, Castle PE, et al. Racial and ethnic disparities in cervical cancer incidence, survival, and mortality by histologic subtype. J Clin Oncol. 2023;41(5):1059-1068. doi:10.1200/jco.22.01424.

10.  Enduring Guidelines Dual Stain Summary for Public Comment. Accessed January 29, 2024. 

11.  Risley C, Stewart MW, Geisinger KR, et al. STRIDES - Studying risk to improve Disparities in cervical cancer in Mississippi – design and baseline results of a statewide cohort study. Prev Med. 2021;153(106740):106740. doi:10.1016/j.ypmed.2021.106740.

12.  Map OM 2023. Women’s health innovation women’s health innovation. Accessed January 29, 2024.

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