By Rebecca B. Perkins, MD, MSc
Professor, Department of Obstetrics and Gynecology, Boston University School of Medicine/Boston Medical Center, Boston
SYNOPSIS: This study examined rates of cervical intraepithelial neoplasia grade 2 (CIN2) regression and progression among women ages 25-30 years and found that regression rates varied by human papillomavirus (HPV) genotype: 51% regression and 47% progression in HPV 16 infections compared to 83% regression and 16% progression for infections with other HPV types.
SOURCE: Kylebäck K, Ekeryd-Andalen A, Greppe C, et al. Active expectancy as alternative to treatment for cervical intraepithelial neoplasia grade 2 in women aged 25 to 30 years: ExCIN2 – a prospective clinical multicenter cohort study. Am J Obstet Gynecol 2022; Jun 29. doi: 10.1016/j.ajog.2022.06.051. [Online ahead of print].
Cervical histology results from colposcopic biopsy are graded either using the Bethesda system for cervical intraepithelial neoplasia (CIN) terminology, including CIN1, CIN2, and CIN3, or lower anogenital squamous terminology (LAST) terminology, which includes low-grade intraepithelial lesion (LSIL) or high-grade intraepithelial lesion (HSIL).1,2 CIN1 or LSIL corresponds to active human papillomavirus (HPV) infection and is considered consistent with low-grade cellular changes and not a cancer precursor. Observation is preferred to treatment for CIN1/LSIL, even when the diagnosis is confirmed on biopsy over several consecutive years.
In contrast, CIN2 and CIN3 or HSIL are considered high-grade or precancers, for which treatment typically is recommended. Compared with CIN3, however, CIN2 diagnoses are more heterogenous and less reproducible between pathologists. Studies indicate substantial rates of regression of CIN2 lesions.3 Because treatment has been associated with preterm delivery in some but not all studies, observation is an option for patients with CIN2 who desire future fertility.4-6
The 2019 American Society for Colposcopy and Cervical Pathology (ASCCP) Risk-Based Consensus Management Guidelines recommend that pathologists using LAST terminology indicate whether an HSIL histology diagnosis is more consistent with CIN2 or CIN3, since treatment always is recommended for nonpregnant patients with CIN3, but observation up to two years is acceptable for patients with CIN2 whose concerns about the effects of treatment on future childbearing outweigh their concerns about cancer.6 Current guidelines do not address other factors that may be associated with progression or regression of CIN2, such as HPV genotype.
The study by Kylebäck et al examines CIN2 regression rates among 127 women aged 25-30 years undergoing expectant management of CIN2 lesions.7 Women were followed at two, six, 12, 18, and 24 months, and those with HPV 16 infection were compared with those infected with other HPV types. They found that rates of regression and progression, as determined by colposcopy/biopsy, differed based on the presence or absence of HPV 16 infection.
Among those infected with HPV 16, 51% regressed and 47% progressed over the two-year period. In contrast, 83% regressed and 16% progressed among those with non-HPV 16 HPV infections (P < 0.0001). They also noted that most regression and progression occurred within 15 months. Of note, progression and regression rates of other specific genotypes, such as HPV 18, were not addressed in this study.
COMMENTARY
This study has implications for both pathologists and clinicians managing patients with cervical precancer. For pathologists, these data underscore the importance of distinguishing CIN2 from CIN3 on colposcopic biopsy diagnoses, even when LAST terminology is used.6 High rates of regression of CIN2, as noted by Kylebäck et al, have been documented previously in other studies.3,7 Failing to distinguish CIN2 from CIN3 deprives patients of the option of observation, since observing CIN3 is unsafe and observation of histologic HSIL for patients aged 25 years and older is not recommended in national guidelines unless the HSIL is qualified as CIN2.6
For clinicians, the Kylebäck et al study adds important prognostic information related to HPV genotype, which can be helpful when counseling patients who may qualify for observation of CIN2.7 Importantly, only patients with a fully visible squamocolumnar junction, in whom the entire lesion can be seen, and who do not have CIN2 or higher on endocervical sampling are candidates for observation.
Among observation candidates, patients with HPV 16 should be advised that they have a risk of approximately 50% that their lesions will progress. Most progressions will occur within the first year of observation. HPV 16 is the most oncogenic HPV type, which alone is responsible for more than half of cervical cancers.8 HPV 16 produces oncogenic proteins that powerfully suppress the p53 and pRb host tumor suppressor genes, leading to rapid clonal proliferation, and more rapid onset of precancerous lesions and cancer.8 The Kylebäck et al data indicate that CIN2 in the presence of an HPV 16 infection behaves differently, and more aggressively, than CIN2 in the presence of other HPV types.7 Given the high progression rate and over a short timeline, many patients may prefer immediate treatment to observation. In addition, treatment may be a safer option for patients with CIN2 and HPV 16 infections who might have difficulty following up with frequent colposcopies.
In contrast, patients with CIN2 who do not have HPV 16 infections can be counseled that the majority of lesions regress over time, most frequently in the first 15 months. In the future, national consensus guidelines may be revised to consider genotyping in the recommendations for observation of CIN2.9
REFERENCES
- Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda System: Terminology for reporting results of cervical cytology. JAMA 2002;287:2114-2119.
- Darragh TM, Colgan TJ, Cox JT, et al. The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: Background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. J Low Genit Tract Dis 2012;16:205-242.
- Silver MI, Gage JC, Schiffman M, et al. Clinical outcomes after conservative management of cervical intraepithelial neoplasia grade 2 (CIN2) in women ages 21-39 years. Cancer Prev Res (Phila) 2018;11:165-170.
- Werner CL, Lo JY, Heffernan T, et al. Loop electrosurgical excision procedure and risk of preterm birth. Obstet Gynecol 2010;115:605-608.
- Bruinsma FJ, Quinn MA. The risk of preterm birth following treatment for precancerous changes in the cervix: A systematic review and meta-analysis. BJOG 2011;118:1031-1041.
- Perkins RB, Guido RS, Castle PE, et al. 2019 ASCCP Risk-Based Management Consensus Guidelines for Abnormal Cervical Cancer Screening Tests and Cancer Precursors. J Low Genit Tract Dis 2020;24:102-131.
- Kylebäck K, Ekeryd-Andalen A, Greppe C, et al. Active expectancy as alternative to treatment for cervical intraepithelial neoplasia grade 2 in women aged 25 to 30 years: ExCIN2 – a prospective clinical multicenter cohort study. Am J Obstet Gynecol 2022; Jun 29. doi: 10.1016/j.ajog.2022.06.051. [Online ahead of print].
- Schiffman M, Doorbar J, Wentzensen N, et al. Carcinogenic human papillomavirus infection. Nat Rev Dis Primers 2016;2:16086.
- National Cancer Institute. Enduring Consensus Cervical Cancer Screening and Management Guidelines. https://dceg.cancer.gov/research/cancer-types/cervix/enduring-guidelines
