Genome-integrated Human Papilloma Viruses Testing: A Complement to Colposcopy-guided Biopsy for Cervical Cancer Screening

Abstract

Objective

Our research aims to evaluate the diagnostic accuracy of colposcopy-guided biopsy (CGB) in detecting high-grade cervical lesions and explore how human papilloma virus (HPV) integration status and other factors affect its performance.

Methods

A retrospective cohort analysis involving 550 patients was conducted to evaluate whether the HPV integration plays a role in identifying high-grade cervical lesions and cervical cancer. Logistic regression models and area under the curve (AUC) calculations were employed.

Results

Our findings revealed that 53.5% of CGB/surgery pairs demonstrated congruent diagnoses, whereas 17.1% showed underestimation and 29.5% overestimation. Furthermore, multivariate logistic regression analysis identified several key predictors for cervical intraepithelial neoplasia (CIN)2+ and CIN3+ according to surgical pathology. Notably, a CGB confirming CIN2+ [odds ratio (OR)=6.0, 95% confidence interval (CI): 3.9–9.1, P<0.001], high-grade cytology (OR=2.6, 95% CI: 1.4–1.9, P=0.003), and HPV integration positivity (OR=2.2, 95% CI: 1.3–3.5, P<0.001) emerged as significant factors for CIN2+. Similarly, for CIN3+ identification, CGB confirming CIN2+ (OR=5.3, 95% CI: 3.4-8.3, P<0.001), high-grade cytology (OR=2.6, 95% CI: 1.5–4.7, P=0.001), and HPV integration positivity (OR=2.0, 95% CI: 1.3–3.1, P=0.003) were independent predictors.

Conclusion

Our study highlights the innovative role of HPV integration testing as a pivotal adjunct to CGB and cytology, offering a comprehensive approach that may enhance the diagnostic precision for high-grade cervical lesions, ultimately achieving more precise management strategies.

References

[1] Sung H, Ferlay J, Siegel RL, et al.. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin, 2021, 71(3): 209-249

[2] Bray F, Laversanne M, Sung H, et al.. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2024, 74(3): 229-263

[3] Rahangdale L, Mungo C, O’Connor S, et al.. Human papillomavirus vaccination and cervical cancer risk. BMJ, 2022, 379: e070115

[4] Zhang L, Tan W, Yang H, et al.. Detection of Host Cell Gene/ HPV DNA Methylation Markers: A Promising Triage Approach for Cervical Cancer. Front Oncol, 2022, 12: 831949

[5] Loopik DL, Koenjer LM, Siebers AG, et al.. Benefit and burden in the Dutch cytology-based vs high-risk human papillomavirus-based cervical cancer screening program. Am J Obstet Gynecol, 2021, 224(2): 200.e1-e9

[6] Eheman CR, Leadbetter S, Benard VB, et al.. National Breast and Cervical Cancer Early Detection Program data validation project. Cancer, 2014, 120(Suppl 16): 2597-2603 0 16)

[7] Stuebs FA, Schulmeyer CE, Mehlhorn G, et al.. Accuracy of colposcopy-directed biopsy in detecting early cervical neoplasia: a retrospective study. Arch Gynecol Obstet, 2019, 299(2): 525-532

[8] Jung Y, Lee AR, Lee SJ, et al.. Clinical factors that affect diagnostic discrepancy between colposcopically directed biopsies and loop electrosurgical excision procedure conization of the uterine cervix. Obstet Gynecol Sci, 2018, 61(4): 477-488

[9] Kabaca C, Koleli I, Sariibrahim B, et al.. Is cervical punch biopsy enough for the management of low-grade cervical intraepithelial neoplasia?. J Low Genit Tract Dis, 2014, 18(3): 240-245

[10] Witt BL, Factor RE, Jarboe EA, et al.. Negative loop electrosurgical cone biopsy finding following a biopsy diagnosis of high-grade squamous intraepithelial lesion: frequency and clinical significance. Arch Pathol Lab Med, 2012, 136(10): 1259-1261

[11] Duesing N, Schwarz J, Choschzick M, et al.. Assessment of cervical intraepithelial neoplasia (CIN) with colposcopic biopsy and efficacy of loop electrosurgical excision procedure (LEEP). Arch Gynecol Obstet, 2012, 286(6): 1549-1554

[12] Stoler MH, Vichnin MD, Ferenczy A, et al.. The accuracy of colposcopic biopsy: analyses from the placebo arm of the Gardasil clinical trials. Int J Cancer, 2011, 128(6): 1354-1362

[13] Kjellberg L, Tavelin B. ‘See and treat’ regime by LEEP conisation is a safe and time saving procedure among women with cytological high-grade squamous intraepithelial lesion. Acta Obstet Gynecol Scand, 2007, 86(9): 1140-1144

[14] Murta EF, Conti R, Rodovalho J, et al.. Outcome after treatment of high-grade squamous intraepithelial lesions: relation between colposcopically directed biopsy, conization and cervical loop excision. Eur J Gynaecol Oncol, 2004, 25(5): 587-590

[15] Chappatte OA, Byrne DL, Raju KS, et al.. Histological differences between colposcopic-directed biopsy and loop excision of the transformation zone (LETZ): a cause for concern. Gynecol Oncol, 1991, 43(1): 46-50

[16] Skehan M, Soutter WP, Lim K, et al.. Reliability of colposcopy and directed punch biopsy. Br J Obstet Gynaecol, 1990, 97(9): 811-816

[17] Athanasiou A, Veroniki AA, Efthimiou O, et al.. Comparative effectiveness and risk of preterm birth of local treatments for cervical intraepithelial neoplasia and stage IA1 cervical cancer: a systematic review and network meta-analysis. Lancet Oncol, 2022, 23(8): 1097-108

[18] Kyrgiou M, Athanasiou A, Kalliala IEJ, et al.. Obstetric outcomes after conservative treatment for cervical intraepithelial lesions and early invasive disease. Cochrane Database Syst Rev, 2017, 11(11): CD012847

[19] Bjorge T, Skare GB, Bjorge L, et al.. Adverse Pregnancy Outcomes After Treatment for Cervical Intraepithelial Neoplasia. Obstet Gynecol, 2016, 128(6): 1265-1273

[20] Kyrgiou M, Athanasiou A, Paraskevaidi M, et al.. Adverse obstetric outcomes after local treatment for cervical preinvasive and early invasive disease according to cone depth: systematic review and meta-analysis. BMJ, 2016, 354: i3633

[21] Kyrgiou M, Mitra A, Arbyn M, et al.. Fertility and early pregnancy outcomes after treatment for cervical intraepithelial neoplasia: systematic review and meta-analysis. BMJ, 2014, 349: g6192

[22] Miller ES, Grobman WA. The association between cervical excisional procedures, midtrimester cervical length, and preterm birth. Am J Obstet Gynecol, 2014, 211(3): 242.e1-e4

[23] Andia D, Mozo de Rosales F, Villasante A, et al.. Pregnancy outcome in patients treated with cervical conization for cervical intraepithelial neoplasia. Int J Gynaecol Obstet, 2011, 112(3): 225-228

[24] Arbyn M, Kyrgiou M, Simoens C, et al.. Perinatal mortality and other severe adverse pregnancy outcomes associated with treatment of cervical intraepithelial neoplasia: meta-analysis. BMJ, 2008, 337: a1284

[25] Kyrgiou M, Koliopoulos G, Martin-Hirsch P, et al.. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet, 2006, 367(9509): 489-498

[26] Sadler L, Saftlas A, Wang W, et al.. Treatment for cervical intraepithelial neoplasia and risk of preterm delivery. JAMA, 2004, 291(17): 2100-2106

[27] Litman EA, Cigna ST. Female Sexual Dysfunction in Women After Treatment of Cervical Dysplasia. Sex Med Rev, 2022, 10(3): 360-366

[28] Tanaka Y, Ueda Y, Kakuda M, et al.. Predictors for recurrent/ persistent high-grade intraepithelial lesions and cervical stenosis after therapeutic conization: a retrospective analysis of 522 cases. Int J Clin Oncol, 2017, 22(5): 921-926

[29] Spracklen CN, Harland KK, Stegmann BJ, et al.. Cervical surgery for cervical intraepithelial neoplasia and prolonged time to conception of a live birth: a case-control study. BJOG, 2013, 120(8): 960-965

[30] Treszezamsky AD, Molina Boero MF, Mehta I. Cervical conization complicated by sepsis with lung and liver abscesses. J Low Genit Tract Dis, 2010, 14(2): 130-133

[31] Tainio K, Athanasiou A, Tikkinen KAO, et al.. Clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: systematic review and meta-analysis. BMJ, 2018, 360: k499

[32] Leung SOA, Vitonis AF, Feldman S. Loop Electrosurgical Excision Procedure in Managing Persistent Low-Grade Abnormality or Human Papillomavirus Positivity. J Low Genit Tract Dis, 2021, 25(4): 281-286

[33] Zuchna C, Hager M, Tringler B, et al.. Diagnostic accuracy of guided cervical biopsies: a prospective multicenter study comparing the histopathology of simultaneous biopsy and cone specimen. Am J Obstet Gynecol, 2010, 203(4): 321.e1-e6

[34] Underwood M, Arbyn M, Parry-Smith W, et al.. Accuracy of colposcopy-directed punch biopsies: a systematic review and meta-analysis. BJOG, 2012, 119(11): 1293-1301

[35] McBride AA, Warburton A. The role of integration in oncogenic progression of HPV-associated cancers. PLoS Pathog, 2017, 13(4): e1006211

[36] Arias-Pulido H, Peyton CL, Joste NE, et al.. Human papillomavirus type 16 integration in cervical carcinoma in situ and in invasive cervical cancer. J Clin Microbiol, 2006, 44(5): 1755-1762

[37] Hu Z, Zhu D, Wang W, et al.. Genome-wide profiling of HPV integration in cervical cancer identifies clustered genomic hot spots and a potential microhomology-mediated integration mechanism. Nat Genet, 2015, 47(2): 158-163

[38] Hu T, Li K, He L, et al.. Testing for viral DNA integration among HPV-positive women to detect cervical precancer: An observational cohort study. BJOG, 2024, 131(3): 309-318

[39] Solomon D, Davey D, Kurman R, et al.. The 2001 Bethesda System: terminology for reporting results of cervical cytology. Jama, 2002, 287(16): 2114-2119

[40] Fokom-Domgue J, Combescure C, Fokom-Defo V, et al.. Performance of alternative strategies for primary cervical cancer screening in sub-Saharan Africa: systematic review and meta-analysis of diagnostic test accuracy studies. BMJ, 2015, 351: h3084

[41] Del Vecchio NJ, Beaber EF, Garcia MP, et al.. Provider- and Facility-Level Variation in Precancerous Cervical Biopsy Diagnoses. J Low Genit Tract Dis, 2023, 27(2): 113-119

[42] Stuebs FA, Dietl AK, Behrens A, et al.. Concordance Rate of Colposcopy in Detecting Cervical Intraepithelial Lesions. Diagnostics (Basel), 2022, 12(10): 2436

[43] Stoler MH, Ronnett BM, Joste NE, et al.. The Interpretive Variability of Cervical Biopsies and Its Relationship to HPV Status. Am J Surg Pathol, 2015, 39(6): 729-736

[44] Mustafa RA, Santesso N, Khatib R, et al.. Systematic reviews and meta-analyses of the accuracy of HPV tests, visual inspection with acetic acid, cytology, and colposcopy. Int J Gynaecol Obstet, 2016, 132(3): 259-265

[45] Cai B, Ronnett BM, Stoler M, et al.. Longitudinal evaluation of interobserver and intraobserver agreement of cervical intraepithelial neoplasia diagnosis among an experienced panel of gynecologic pathologists. Am J Surg Pathol, 2007, 31(12): 1854-1860

[46] Castle PE, Stoler MH, Solomon D, et al.. The relationship of community biopsy-diagnosed cervical intraepithelial neoplasia grade 2 to the quality control pathology-reviewed diagnoses: an ALTS report. Am J Clin Pathol, 2007, 127(5): 805-815

[47] Zhang X, Dou Y, Wang M, et al.. A retrospective analysis on 1901 women with high grade cervical intraepithelial neoplasia by colposcopic biopsy. Eur J Obstet Gynecol Reprod Biol, 2017, 217: 53-58

[48] Huang J, Qian Z, Gong Y, et al.. Comprehensive genomic variation profiling of cervical intraepithelial neoplasia and cervical cancer identifies potential targets for cervical cancer early warning. J Med Genet, 2019, 56(3): 186-194

[49] Pett M, Coleman N. Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis?. J Pathol, 2007, 212(4): 356-367