Objective To investigate the natural course of low-grade squamous intraepithelial lesions (LSILs) that cannot be histologically confirmed by colposcopy-directed biopsy. Methods In a multicenter, prospective, cohort study of Japanese women with LSILs, we analyzed the follow-up data from 64 women who had a negative biopsy result at the initial colposcopy (biopsy-negative LSIL) in comparison with those from 479 women who had a histologic diagnosis of cervical intraepithelial neoplasia grade 1 (LSIL/CIN1). Patients were monitored by cytology and colposcopy every 4 months for a mean follow-up period of 39.0 months, with cytologic regression defined as two consecutive negative smears and normal colposcopy. Results In women with biopsy-negative LSILs, there were no cases of CIN3 or worse (CIN3+) diagnosed within 2 years; the difference in the 2-year risk of CIN3+ between the two groups was marginally significant (0 vs. 5.5%; P = 0.07). The cumulative probability of cytologic regression within 12 months was much higher in the biopsynegative LSIL group (71.2 vs. 48.6%; P = 0.0001). The percentage of women positive for high-risk human papillomaviruses (hrHPVs) was significantly lower in the biopsynegative LSIL group than in the LSIL/CIN1 group (62.1 vs. 78.4%; P = 0.01); however, the 12-month regression rate of biopsy-negative LSIL was similar between hrHPV-positive and -negative women (67.3 vs. 74.4%, P = 0.73). Conclusion In women with biopsy-negative LSILs, the risk of CIN3+ diagnosed within 2 years was low; furthermore, approximately 70% underwent cytologic regression within 12 months, regardless of HPV testing results. Biopsy-negativeLSILsmay represent regressing lesions rather than lesions missed by colposcopy.
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