Finds HPV-negative HSIL discord in cytology
- High-grade squamous intraepithelial lesion on a Pap test can still signal serious cervical precancer even when the reflex high-risk human papillomavirus test is negative. - In one 2023 prospective series, 8 of 84 high-grade squamous intraepithelial lesion cases were HPV-negative, and 7 biopsied patients still had high-grade disease. - U.S. guidelines still send HPV-negative high-grade cytology to colposcopy or treatment because risk remains elevated. (acog.org)
A Pap test looks at cells under a microscope, while a human papillomavirus test looks for viral genetic material. Those two checks usually agree, but not always. (pathologyoutlines.com) (gocm.bmj.com) High-grade squamous intraepithelial lesion, or HSIL, is the Pap category for cells that look strongly precancerous. Under the Bethesda system, those cells are typically small, dark, crowded, and have a high nucleus-to-cytoplasm ratio. (pathologyoutlines.com) (bethesda.soc.wisc.edu) Most HSIL cases are tied to high-risk HPV, which is why HPV testing is now central to screening. But published studies show a small group of patients have HSIL cytology even though the HPV test reported negative. (pathologyoutlines.com) (pubmed.ncbi.nlm.nih.gov) In a 2023 prospective study from Virginia Mason Medical Center, 84 women with HSIL had Roche Cobas high-risk HPV testing, and 8 tested negative. Biopsies were available for 7 of those 8, and all 7 still had at least HSIL, including 1 invasive squamous cell carcinoma and 1 endocervical adenocarcinoma in situ. (pubmed.ncbi.nlm.nih.gov) A larger routine-practice study of 951 HSIL cytology cases cotested with Aptima messenger RNA HPV found 95.2% were HPV-positive. But 15 of 36 HPV-negative HSIL cases with follow-up still had cervical intraepithelial neoplasia grade 2 or worse, a 41.7% rate. (pubmed.ncbi.nlm.nih.gov) Older Kaiser Permanente Northern California data point the same way. Among women ages 30 to 64 with HSIL cytology, the 5-year risk of cervical intraepithelial neoplasia grade 3 or worse was 49% if HPV-positive and 30% if HPV-negative, while cancer risk was 6.6% versus 6.8%. (pmc.ncbi.nlm.nih.gov) That is why U.S. management guidelines do not treat HPV-negative HSIL like a reassuring result. The American Society for Colposcopy and Cervical Pathology and the American College of Obstetricians and Gynecologists say HSIL cytology generally warrants colposcopy or, in some nonpregnant patients 25 or older, expedited treatment. (pmc.ncbi.nlm.nih.gov) (acog.org) Researchers have proposed several reasons for the mismatch. The HPV level can be too low for the assay, the lesion can involve a genotype outside the test panel, the sample can be limited, or the original cytology can need expert review. (pubmed.ncbi.nlm.nih.gov 1) (pubmed.ncbi.nlm.nih.gov 2) (pubmed.ncbi.nlm.nih.gov 3) One genotype study found HPV in 20 of 21 biopsy samples from women whose earlier high-risk HPV tests had been negative despite biopsy-confirmed HSIL or worse. Ten had non-16/18 high-risk types, six had non-high-risk types, and only one sample stayed negative across all three methods. (pubmed.ncbi.nlm.nih.gov) The practical takeaway is narrow but important: a negative HPV result does not erase a high-grade Pap. When the cells look like HSIL, clinicians and cytopathologists still have to work up the lesion as potentially serious disease. (acog.org) (pubmed.ncbi.nlm.nih.gov)
