Atypical Squamous Cells

Human PapillomaVirus (HPV) diagnostic tests are commonly performed among PAP positive women, but their impact on the detection, severity and disease management of cervical intraepithalialneoplasia (CIN) remains poorly understood. A recent study suggests HPV tests may indeed improve timing and detection rates of Atypical Squamous Cells and CIN among PAP positive women.


Human PapillomaVirus (HPV) is a sexually transmitted tumor virus responsible for the vast majority of cervical cancers in women. HPV infections are also remarkably common and outrank all other sexually transmitted diseases in terms of prevalence.

Owing to its high prevalence and potentially detrimental effects of the lives of infected women, screening programs were implemented to enable early diagnosis. One such test that is now widely performed is the PAP test, in which samples of cervical cells are evaluated by a pathologist for the presence of abnormalities called Atypical Squamous Cells of Undetermined Significance (ASC-US). An HPV test is often, but not always, co-performed in part to increase confidence in the results of the PAP test. However, the impacts of this test on the detection rate, severity and disease management of cervical intraepithelial neoplasia (CIN) among PAP-positive women remains unknown.

A recent retrospective observational study performed in New Mexico and published in JAMA Oncology investigated this question1. Between 2008 and 2012, medical records of457,317 women aged 21-64 years old were assessed for PAP and HPV test results and followed over a minimum of one year for the detection of CINs at different stages (1-3+, referred to as CIN1 to CIN3+) as well as the health care resources utilized to diagnose/test CIN.

The results show that a total of 20,677 (4.5%) women tested PAP positive (i.e., ASC-US was detected), among which 16,648 (80.5%) received an HPV test as well and 43.1% of them were indeed HPV-positive.Among all PAP-positive women, 84.1% had no abnormal histology during follow-up, consistent with the idea that most HPV infected do not develop CIN. However, 9.9% had CIN1, 3.6% had CIN2 and 2.4% were diagnosed with CIN3 or a more advanced disease stage.

When comparing women who received an HPV test with those who did not, the authors found that CIN2 and CIN3+ were detected three times faster among HPV-tested women (e.g, CIN3+ median time of detection: 103 vs. 393 days). Moreover, the CIN2 detection rate was significantly higher among HPV-tested (6.87%) compared to non-tested (0.05%) women. Finally, biopsy rates were also more frequent during follow-up among HPV-tested than non-tested women, but this difference gradually attenuated over time of follow-up, suggesting HPV-tested women underwent biopsies when the disease was at a more advanced stage.

Although the results clearly support the use of HPV co-testing with PAP, the study has two major limitations. First, as an observational nonrandomized study, it is not possible to distinguish whether the results are influenced by confounding factors such as physicians adapting their treatment strategy for women who tested positive to both tests or the fact that women who underwent HPV tests had a poorer initial prognosis for unknown reasons.Moreover, the authors do not corroborate their data with survival rates, raising questions about the clinical relevance of their findings. Thus, other studies appear necessary to confirm these findings using a double-blind randomized controlled trial study design.

Written by Samuel Rochette, M.Sc



  1. Cuzick J, Myers O, Lee JH, et al. Outcomes in Women With Cytology Showing Atypical Squamous Cells of Undetermined Significance With vs Without Human Papillomavirus Testing. JAMA oncology. Jun 22 2017.
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