Background: Squamous intraepithelial lesions observed in Papanicolaou (Pap) test gynecologic cytology arise as a result of infection of the cervicovaginal tract by human papillomavirus (HPV). The viral cytopathic effect of HPV manifests as koilocytosis, also known as low-grade squamous intraepithelial lesion (LSIL) in The Bethesda System (TBS). Integration of HPV genetic material into the genome of squamous cells can, in some women, result in progressive accumulation of mutations and abnormalities of growth and maturation leading to high-grade squamous intraepithelial lesion (HSIL) and possibly invasive squamous cell carcinoma. Due to morphologic overlap between reactive processes and these changes related to HPV, TBS includes equivocal categories that may be applied to Pap tests with uncertain morphology: atypical squamous cells of undetermined significance (ASC-US) and atypical squamous cells cannot exclude HSIL (ASC-H). Quality assurance (QA) measures in gynecologic cytology laboratories aim to maximize the sensitivity for LSIL and HSIL lesions while simultaneously keeping the use of ASC-US at reasonable levels. Summary: TBS provides a comprehensive nomenclature for squamous abnormalities encountered in screening, but subjectivity in interpretation remains. QA practices attempt to identify problematic patterns of misinterpretation for correction. Key Message: This review aimed to provide practical recommendations for cytology practitioners seeking to alter their interpretive thresholds for ASC-US, LSIL, and HSIL in response to feedback from QA procedures indicating deviation from desired norms.

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