Evolution of Concepts on Cervical Precancerous Lesions and Methods for Predicting Cervical Carcinoma Risk: A Literature Review

Introduction. This review presents a systematic analysis of the evolution of views on the treatment of precancerous lesions of the cervix and methods for predicting the risk of developing cervical carcinoma.

Materials and methods. The historical path has been traced from the early morphological classifications based on the principle of gradation through the formation of the concept of dysplasia and cervical intraepithelial neoplasia (CIN) to the approval of the Bethesda system focused on clinical manifestations and patient management tactics.

Results. Special emphasis is placed on the problems of morphological diagnostics: the low reproducibility of diagnoses, the high level of spontaneous regression call into question traditional fundamental concepts. The proven link with persistent HPV infection and the development of cancer formed the basis of a new biological model. The review describes the key pathways of viral transformation, including the degradation of p53 and pRb proteins under the action of oncoproteins E6 and E7. Objective risk stratification based on molecular tests has become the solution to the problem of subjectivity. We have evaluated in detail the role of immunohistochemistry (p16, p16/Ki-67), HPV genotyping and DNA methylation markers (FAM 19A4, miR124-2) in modern screening diagnostic schemes.

Discussion. The prospects of studying regulatory RNAs (miRNA, circRNA), the use of artificial intelligence and the formation of unified platforms for the prevention of the entire group of HPV-dependent diseases are discussed. It is concluded that the evolution of ideas from descriptive phenomenology to a highly accurate one, with an assessment of the risk of malignancy, forms the scientific basis for achieving the goal of global elimination of cervical cancer. 

1. Vu M, Yu J, Awolude OA, Chuang L. Cervical cancer worldwide. Current Problems in Cancer. 2018;42(5):457– 465. DOI: https://doi.org/10.1016/j.currproblcancer.2018.06.003.

2. Broders AC. Squamous-cell epithelioma of the lip: A study of five hundred and thirty-seven cases. Journal of the American Medical Association. 1920;74(10):656–664. DOI: https://doi.org/10.1001/jama.1920.02620100016007.

3. Stein JJ. The study of cancer. The American Journal of Surgery. 1935;30(3):515–521. DOI: https://doi.org/10.1016/s0002-9610(35)91092-3.

4. Wright JR Jr. Albert C. Broders, tumor grading, and the origin of the long road to personalized cancer care. Cancer Medicine. 2020;9(13):4490–4494. DOI: https://doi.org/10.1002/cam4.3112.

5. Reagan JW, Hamonic MJ. Dysplasia of the uterine cervix. Annals of the New York Academy of Sciences. 1956;63(6):1236–1244. DOI: https://doi.org/10.1111/j.1749-6632.1956.tb32133.x.

6. Koss LG, Durfee GR. Unusual patterns of squamous epithelium of the uterine cervix: Cytologic and pathologic study of koilocytotic atypia. Annals of the New York Academy of Sciences. 1956;63(6):1245–1261. DOI: https://doi.org/10.1111/j.1749-6632.1956.tb32134.x.

7. Rous P, Beard JW. The progression to carcinoma of virus-induced rabbit papillomas (Shope). The Journal of Experimental Medicine. 1935;62(4):523–548. DOI: https://doi.org/10.1084/JEM.62.4.523.

8. Richart RM. Natural history of cervical intraepithelial neoplasia. Clinical Obstetrics and Gynecology. 1967;10:748. DOI: https://doi.org/10.1097/00003081-196712000-00002.

9. Carter B, Cuyler K, Thomas WL, Creadick R, Alter R. The methods of management of carcinoma in situ of the cervix. American Journal of Obstetrics and Gynecology. 1952;64(4):833–849. DOI: https://doi.org/10.1016/s0002-9378(16)38799-3.

10. Chao S, McCaffrey RM, Todd WD, Moore JG. Conization in evaluation and management of cervical neoplasia. American Journal of Obstetrics and Gynecology. 1969;103(4):574–584. DOI: https://doi.org/10.1016/s0002-9378(15)31860-3.

11. The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses. National Cancer Institute Workshop. Journal of the American Medical Association. 1989;262(7):931–934. PMID: https://pubmed.gov/2754794.

12. Kurman RJ, Malkasian GD Jr, Sedlis A, Solomon D. From Papanicolaou to Bethesda: The rationale for a new cervical cytologic classification. Obstetrics and Gynecology. 1991;77(5):779–782. PMID: https://pubmed.gov/1849626.

13. Ismail SM, Colclough AB, Dinnen JS, Eakins D, Evans DM, Gradwell E, et al. Reporting cervical intraepithelial neoplasia (CIN): Intra- and interpathologist variation and factors associated with disagreement. Histopathology. 1990;16(4):371–376. DOI: https://doi.org/10.1111/j.1365-2559.1990.tb01141.x.

14. Creagh T, Bridger JE, Kupek E, Fish DE, Martin-Bates E, Wilkins MJ. Pathologist variation in reporting cervical borderline epithelial abnormalities and cervical intraepithelial neoplasia. Journal of Clinical Pathology. 1995;48(1):59–60. DOI: https://doi.org/10.1136/jcp.48.1.59.

15. Dalla Palma P, Giorgi Rossi P, Collina G, Buccoliero AM, Ghiringhello B, Gilioli E, et al. The reproducibility of CIN Diagnoses among different pathologists: Data from histology reviews from a multicenter randomized study. American Journal of Clinical Pathology. 2009;132(1):125–132. DOI: https://doi.org/10.1309/AJCPBRK7D1YIUWFP.

16. Loopik DL, Bentley HA, Eijgenraam MN, IntHout J, Bekkers RLM, Bentley JR. The natural history of cervical intraepithelial neoplasia grades 1, 2, and 3: A systematic review and meta-analysis. Journal of Lower Genital Tract Disease. 2021;25(3):221–231. DOI: https://doi.org/10.1097/LGT.0000000000000604.

17. Kumar V, Bauer C, Stewart JH 4th. TIME is ticking for cervical cancer. Biology (Basel). 2023;12(7):941. DOI: https://doi.org/10.3390/biology12070941.

18. Buitrago-Pérez A, Garaulet G, Vázquez-Carballo A, Paramio JM, García-Escudero R. Molecular signature of HPV-induced carcinogenesis: pRb, p53 and gene expression profiling. Current Genomics. 2009;10(1):26– 34. DOI: https://doi.org/10.2174/138920209787581235.

19. Narisawa-Saito M, Kiyono T. Basic mechanisms of high-risk human papillomavirus-induced carcinogenesis: Roles of E6 and E7 proteins. Cancer Science. 2007;98(10):1505–1511. DOI: https://doi.org/10.1111/j.1349–7006.2007.00546.x.

20. Jabbar SF, Abrams L, Glick A, Lambert PF. Persistence of high-grade cervical dysplasia and cervical cancer requires the continuous expression of the human papillomavirus type 16 E7 oncogene. Cancer Research. 2009;69(10):4407–4414. DOI: https://doi.org/10.1158/0008-5472.CAN-09-0023.

21. Narisawa-Saito M, Inagawa Y, Yoshimatsu Y, Haga K, Tanaka K, Egawa N, et al. A critical role of MYC for transformation of human cells by HPV16 E6E7 and oncogenic HRAS. Carcinogenesis. 2012;33(4):910–917. DOI: https://doi.org/10.1093/carcin/bgs104.

22. Pinion SB, Kennedy JH, Miller RW, MacLean AB. Oncogene expression in cervical intraepithelial neoplasia and invasive cancer of cervix. The Lancet. 1991;337(8757):1579. DOI: https://doi.org/10.1016/0140-6736(91)92518-7.

23. Saslow D, Solomon D, Lawson HW, Killackey M, Kulasingam SL, Cain J, et al. American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer. CA: A Cancer Journal for Clinicians. 2012;62(3):147–172. DOI: https://doi.org/10.3322/caac.21139.

24. Wentzensen N, Schwartz L, Zuna RE, Smith K, Mathews C, Gold MA, et al. Performance of p16/Ki-67 immunostaining to detect cervical cancer precursors in a colposcopy referral population. Clinical Cancer Research. 2012;18(15):4154–4162. DOI: https://doi.org/10.1158/1078-0432.CCR-12-0270.

25. Pirtea L, Secosan C, Margan M, Moleriu L, Balint O, Grigoras D, et al. p16/Ki-67 dual staining has a better accuracy than human papillomavirus (HPV) testing in women with abnormal cytology under 30 years old. Bosnian Journal of Basic Medical Sciences. 2019;19(4):336–341. DOI: https://doi.org/10.17305/bjbms.2018.3560.

26. White C, Bakhiet S, Bates M, Keegan H, Pilkington L, Ruttle C, et al. Triage of LSIL/ASC-US with p16/Ki-67 dual staining and human papillomavirus testing: A 2-year prospective study. Cytopathology. 2016;27(4):269– 276. DOI: https://doi.org/10.1111/cyt.12317.

27. Luttmer R, Dijkstra MG, Snijders PJ, Berkhof J, van Kemenade FJ, Rozendaal L, et al. p16/Ki-67 dual-stained cytology for detecting cervical (pre)cancer in a HPV-positive gynecologic outpatient population. Modern Pathology. 2016;29(8):870–878. DOI: https://doi.org/10.1038/modpathol.2016.80.

28. Yu L, Fei L, Liu X, Pi X, Wang L, Chen S. Application of p16/Ki-67 dual-staining cytology in cervical cancers. Journal of Cancer. 2019;10(12):2654–2660. DOI: https://doi.org/10.7150/jca.32743.

29. Mao C, Balasubramanian A, Yu M, Kiviat N, Ridder R, Reichert A, et al. Evaluation of a new p16 (INK4A) ELISA test and a high-risk HPV DNA test for cervical cancer screening: Results from proof-of-concept study. International Journal of Cancer. 2007;120(11):2435–2438. DOI: https://doi.org/10.1002/ijc.22612.

30. Song F, Yan P, Huang X, Wang C, Du H, Qu X et al. Roles of extended human papillomavirus genotyping and multiple infections in early detection of cervical precancer and cancer and HPV vaccination. BMC Cancer. 2022;22(1):42. DOI: https://doi.org/10.1186/s12885-021-09126-3.

31. Schiffman M, Doorbar J, Wentzensen N, de Sanjosé S, Fakhry C, Monk BJ, et al. Carcinogenic human papillomavirus infection. Nature Reviews Disease Primers. 2016;2:16086. DOI: https://doi.org/10.1038/nrdp.2016.86.

32. Ito K, Kimura R, Konishi H, Ozawa N, Yaegashi N, Ohashi Y, et al. A comparison of liquid-based and conventional cytology using data for cervical cancer screening from the Japan Cancer Society. Japanese Journal of Clinical Oncology. 2020;50(2):138–144. DOI: https://doi.org/10.1093/jjco/hyz161.

33. Nedjai B, Reuter C, Ahmad A, Banwait R, Warman R, Carton J, et al. Molecular progression to cervical precancer, epigenetic switch or sequential model? International Journal of Cancer. 2018;143(7):1720–1730. DOI: https://doi.org/10.1002/ijc.31549.

34. Kaliff M, Lillsunde Larsson G, Helenius G, Karlsson MG, Bergengren L. Full genotyping and FAM19A4/ miR124-2 methylation analysis in high-risk human papillomavirus-positive samples from women over 30 years participating in cervical cancer screening in Örebro, Sweden. PLoS One. 2022;17(9):e0274825. DOI: https://doi.org/10.1371/journal.pone.0274825.

35. Salta S, Lobo J, Magalhães B, Henrique R, Jerónimo C. DNA methylation as a triage marker for colposcopy referral in HPV-based cervical cancer screening: A systematic review and meta-analysis. Clinical Epigenetics. 2023;15(1):125. DOI: https://doi.org/10.1186/s13148-023-01537-2.

36. Schreiberhuber L, Barrett JE, Wang J, Redl E, Herzog C, Vavourakis CD, et al. Cervical cancer screening using DNA methylation triage in a real-world population. Nature Medicine. 2024;30(8):2251–2257. DOI: https://doi.org/10.1038/s41591-024-03014-6.

37. Dick S, Vink FJ, Heideman DAM, Lissenberg-Witte BI, Meijer CJLM, Berkhof J. Risk-stratification of HPVpositive women with low-grade cytology by FAM19A4/miR124-2 methylation and HPV genotyping. British Journal of Cancer. 2022;126(2):259–264. DOI: https://doi.org/10.1038/s41416-021-01614-4.

38. Peronace C, Cione E, Abrego-Guandique DM, Fazio M, Panduri G, Caroleo MC, et al. FAM19A4 and hsa-miR124-2 Double methylation as screening for ASC-H- and CIN1 HPV-positive women. Pathogens. 2024;13(4):312. DOI: https://doi.org/10.3390/pathogens13040312.

39. Xia W, Wang J, Yang X, Sha Y, Hou F, Li J, et al. DNA methylation triage of human papillomavirus-positive atypical squamous cells of undetermined significance in cervical cancer screening. Journal of Obstetrics and Gynaecology. 2026;46(1):2623828. DOI: https://doi.org/10.1080/01443615.2026.2623828.

40. Cheng X, Chai R, Zhang T, Chen Y, Fan F, Ye Y, et al. A novel methylation-detection panel for HPV associated high-grade squamous intraepithelial lesion and cervical cancer screening. Scientific Reports. 2024;14(1):25556. DOI: https://doi.org/10.1038/s41598-024-75047-3.

41. McCormack M, Eminowicz G, Gallardo D, Diez P, Farrelly L, Kent C, et al. INTERLACE investigators. Induction chemotherapy followed by standard chemoradiotherapy versus standard chemoradiotherapy alone in patients with locally advanced cervical cancer (GCIG INTERLACE): An international, multicentre, randomised phase 3 trial. The Lancet. 2024;404(10462):1525–1535. DOI: https://doi.org/10.1016/S0140-6736(24)01438-7.

42. Donà MG, Giuliani E, Laquintana V, Covello R, Pellini R, Moretto S, et al. FAM19A4 and miR124-2 methylation status in human papillomavirus-driven and human papillomavirus-negative oropharyngeal squamous cell carcinomas. Infectious Agents and Cancer. 2025;20(1):71. DOI: https://doi.org/10.1186/s13027-025-00697-5.

43. Kniazeva M, Zabegina L, Shalaev A, Smirnova O, Lavrinovich O, Berlev I, Malek A. NOVAprep-miR-Cervix: New method for evaluation of cervical dysplasia severity based on analysis of six miRNAs. International Journal of Molecular Sciences. 2023;24(11):9114. DOI: https://doi.org/10.3390/ijms24119114.

44. Suvanasuthi R, Therasakvichya S, Kanchanapiboon P, Promptmas C, Chimnaronk S. Analysis of precancerous lesion-related microRNAs for early diagnosis of cervical cancer in the Thai population. Scientific Reports. 2025;15(1):142. DOI: https://doi.org/10.1038/s41598-024-84080-1.

45. Liu SS, Chan KKL, Chu DKH, Wei TN, Lau LSK, Ngu SF et al. Oncogenic microRNA signature for early diagnosis of cervical intraepithelial neoplasia and cancer. Molecular Oncology. 2018;12(12):2009–2022. DOI: https://doi.org/10.1002/1878-0261.12383.

46. Faizullin LZ, Karnaukhov VN, Bairamova GR, Chernova VF, Mzarelua GM, Chausov AA, et al. Expression of mir-29b in cervical epithelium in cervical intraepithelial neoplasias. Obstetrics and Gynecology. 2016;(2):87–90. (In Russ.). DOI: https://doi.org/10.18565/aig.2016.2.87-90.

47. Liu M, Wang W, Chen H, Lu Y, Yuan D, Deng Y, et al. miR-9, miR-21, miR-27b, and miR-34a expression in HPV16/58/52-infected cervical cancer. BioMed Research International. 2020;2020:2474235. DOI: https://doi.org/10.1155/2020/2474235.

48. Yu F, Liu J, Dong W, Xie J, Zhao X. The diagnostic value of miR-145 and miR-205 in patients with cervical cancer. American Journal of Translational Research. 2021;13(3):1825–1832. PMID: https://pubmed.gov/33841707.

49. Li Y, Zhang Z, Xiao Z, Lin Y, Luo T, Zhou Q, et al. Chemotherapy-mediated miR-29b expression inhibits the invasion and angiogenesis of cervical cancer. Oncotarget. 2017;8(9):14655–14665. DOI: https://doi.org/10.18632/oncotarget.14738.

50. Liu D, Liu C, Wang X, Ingvarsson S, Chen H. MicroRNA-451 suppresses tumor cell growth by down-regulating IL6R gene expression. Cancer Epidemiology. 2014;38(1):85–92. DOI: https://doi.org/10.1016/j.canep.2013.12.005.

51. Szekerczés T, Galamb Á, Varga N, Benczik M, Kocsis A, Schlachter K, et al. Increased miR-20b level in high grade cervical intraepithelial neoplasia. Pathology Oncology Research. 2020;26(4):2633–2640. DOI: https:// doi.org/10.1007/s12253-020-00852-w.

52. Zhang T, Xue X, Peng H. Therapeutic dlivery of miR-29b enhances radiosensitivity in cervical cancer. Molecular Therapy. 2019;27(6):1183–1194. DOI: https://doi.org/10.1016/j.ymthe.2019.03.020.

53. Han MS, Lee JM, Kim SN, Kim JH, Kim HS. Human papillomavirus 16 oncoproteins downregulate the expression of miR-148a-3p, miR-190a-5p, and miR-199b-5p in cervical cancer. BioMed Research International. 2018;2018:1942867. DOI: https://doi.org/10.1155/2018/1942867.

54. Dong H, Song J. miR-142-3p reduces the viability of human cervical cancer cells by negatively regulating the cytoplasmic localization of HMGB1. Experimental and Therapeutic Medicine. 2021;21(3):212. DOI: https://doi.org/10.3892/etm.2021.9644.

55. Calfa S, de Freitas AJA, Causin RL, Hirai W, Possati-Resende JC, Dos Reis R, et al. Exploring shared microRNA profiles in liquid-based cytology and plasma as biomarkers of high-grade intraepithelial lesions. Scientific Reports. 2025;16(1):828. DOI: https://doi.org/10.1038/s41598-025-30514-3.

56. Heydarnia E, Dorostgou Z, Hedayati N, Mousavi V, Yahyazadeh S, Alimohammadi M, et al. Circular RNAs and cervical cancer: Fiends or foes? A landscape on circRNA-mediated regulation of key signaling pathways involved in the onset and progression of HPV-related cervical neoplasms. Cell Communication and Signaling. 2024;22(1):107. DOI: https://doi.org/10.1186/s12964-024-01494-0.

57. Lou S, Yang W, Zhao Q, Ouyang Y, Cao L, Lin C. Identification of circRNA-mediated competing endogenous RNA network involved in the development of cervical cancer. Molecular and Cellular Probes. 2024;78:101984. DOI: https://doi.org/10.1016/j.mcp.2024.101984.

58. Du J, Tan T, Yu Y, Wang H. The mechanism of ECT1/E6E7 cervical intraepithelial neoplasia cells regulated by Acinetobacter lwoffii through circ-LDHA/HMGB1. BMC Microbiology. 2025;25(1):326. DOI: https://doi.org/10.1186/s12866-025-04043-y.

59. Xu Y, Li C, Cheng L, Wang S, Wu Y, Li S, et al. Prognostic and diagnostic value of circRNA expression in cervical cancer: A meta analysis. Frontiers in Oncology. 2025;14:1488040. DOI: https://doi.org/10.3389/fonc.2024.1488040.

60. Chauhan P, Pramodh S, Hussain A, Elsori D, Lakhanpal S, Kumar R, et al. Understanding the role of miRNAs in cervical cancer pathogenesis and therapeutic responses. Frontiers in Cell and Developmental Biology. 2024;12:1397945. DOI: https://doi.org/10.3389/fcell.2024.1397945.

61. Shukla V, Mallya S, Adiga D, Sriharikrishnaa S, Chakrabarty S, Kabekkodu SP. Bioinformatic analysis of miR-200b/429 and hub gene network in cervical cancer. Biochemical Genetics. 2023;61(5):1898–1916. DOI: https://doi.org/10.1007/s10528-023-10356-2.

62. Ling J, Sun Q, Tian Q, Shi H, Yang H, Ren J. Human papillomavirus 16 E6/E7 contributes to immune escape and progression of cervical cancer by regulating miR-142-5p/PD-L1 axis. Archives of Biochemistry and Biophysics. 2022;731:109449. DOI: https://doi.org/10.1016/j.abb.2022.109449.

63. Feng S, Lu Y, Sun L, Hao S, Liu Z, Yang F, et al. MiR-95-3p acts as a prognostic marker and promotes cervical cancer progression by targeting VCAM1. Annals of Translational Medicine. 2022;10(21):1171. DOI: https://doi.org/10.21037/atm-22-5184.

64. Naumova LA, Starodumova VA. Modern concepts in cervical carcinogenesis. Bulletin of Siberian Medicine. 2023;22(2):145–155. (In Russ.). DOI: https://doi.org/10.20538/1682-0363-2023-2-145-155.

65. Roy S, Roy A, Clarke MA, Gradissimo A, Burk RD, Wentzensen N, et al. Dynamic risk prediction for cervical precancer screening with continuous and binary longitudinal biomarkers. The Annals of Applied Statistics. 2024;18(1):246–265. DOI: https://doi.org/10.1214/23-aoas1788.

66. Williams J, Kostiuk M, Biron VL. Molecular detection methods in HPV-related cancers. Frontiers in Oncology. 2022;12:864820. DOI: https://doi.org/10.3389/fonc.2022.864820.

67. Mathivanan SK, Francis D, Srinivasan S, Khatavkar V, P K, Shah MA. Enhancing cervical cancer detection and robust classification through a fusion of deep learning models. Scientific Reports. 2024;14(1):10812. DOI: https://doi.org/10.1038/s41598-024-61063-w.

68. Mascarenhas M, Martins M, Barroso L, Spindler L, Fathallah N, Manzione T, et al. Automated detection and classification of cervical and anal squamous cancer precursors using deep learning and multidevice colposcopy. Scientific Reports. 2025;15(1):33068. DOI: https://doi.org/10.1038/s41598-025-14514-x.

69. Zeng K, Zheng W, Mo X, Liu F, Li M, Liu Z, et al. Dysregulated microRNAs involved in the progression of cervical neoplasm. Archives of Gynecology and Obstetrics. 2015;292(4):905–913. DOI: https://doi.org/10.1007/s00404-015-3702-5.

70. Wilting SM, Snijders PJ, Verlaat W, Jaspers A, van de Wiel MA, van Wieringen WN, et al. Altered microRNA expression associated with chromosomal changes contributes to cervical carcinogenesis. Oncogene. 2013;32(1):106–116. DOI: https://doi.org/10.1038/onc.2012.20.

71. Wan G, Xie W, Liu Z, Xu W, Lao Y, Huang N, et al. Hypoxia-induced MIR155 is a potent autophagy inducer by targeting multiple players in the MTOR pathway. Autophagy. 2014;10(1):70–79. DOI: https://doi.org/10.4161/auto.26534.

72. Wang Y, Chen A, Zheng C, Zhao L. miR-92a promotes cervical cancer cell proliferation, invasion, and migration by directly targeting PIK3R1. Journal of Clinical Laboratory Analysis. 2021;35(8):e23903. DOI: https://doi.org/10.1002/jcla.23893.

73. Arkhangelskaya PA, Bakhidze EV, Berlev IV, Samsonov RB, Ivanov MK, Malek AV. MicroRNA, HPV and cervical carcinogenesis: Molecular aspects and prospects of clinical application. Siberian Journal of Oncology. 2016;15(4):88–97. (In Russ.). DOI: https://doi.org/10.21294/1814-4861-2016-15-4-88-97.

74. Zhang SQ, Zhang J, Yu Y, Yu MM, Wei J, Tang YH. APOBEC3B expression has prognostic significance in cervical cancer. International Journal of Clinical and Experimental Pathology. 2023;16(3):48–56. PMID: https://pubmed.gov/37033395.

75. Shmakova NA, Chistyakova GN, Kononova IN, Remizova II, Grishkina AA. High-grade cervical intraepithelial neoplasia and cervical cancer: Relevance of the problem, search for prospects (literature review). Problems of Reproduction. 2021;27(1):33–38. (In Russ.). DOI: https://doi.org/10.17116/repro20212701133.