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Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and prevention

Jason D Wright, MD
Section Editor
Barbara Goff, MD
Deputy Editor
Sandy J Falk, MD, FACOG


Cervical intraepithelial neoplasia (CIN) is a premalignant condition of the uterine cervix [1]. The ectocervix (surface of the cervix that is visualized on vaginal speculum examination) is covered in squamous epithelium, and the endocervix, including the cervical canal, is covered with glandular epithelium. CIN refers to squamous abnormalities. Glandular cervical neoplasia includes adenocarcinoma in situ and adenocarcinoma. (See "Cervical cytology: Evaluation of atypical and malignant glandular cells" and "Cervical adenocarcinoma in situ" and "Invasive cervical adenocarcinoma".)

Screening for cervical cancer includes cervical cytology and testing for oncogenic subtypes of human papillomavirus (HPV). Follow-up of abnormalities in screening tests with colposcopy and cervical biopsy may result in a diagnosis of CIN or cervical cancer [2].

CIN may be low-grade or high-grade. Women with low-grade CIN have minimal potential for developing cervical malignancy, while those with high-grade lesions are at high risk of progression to malignancy.

The definition, incidence, and pathogenesis of CIN are reviewed here. The management of CIN and the epidemiology and virology of HPV infection are discussed separately. (See "Cervical intraepithelial neoplasia: Management of low-grade and high-grade lesions" and "Human papillomavirus infections: Epidemiology and disease associations" and "Virology of human papillomavirus infections and the link to cancer".)


Historically, premalignant squamous changes of the cervix were described as mild, moderate, or severe cervical dysplasia. In 1988, a new terminology system was introduced, the Bethesda system, which was then revised in 1991 and 2001. In this system, different terminology was used for cytologic (on Pap test) and histologic (on biopsy) findings [3-5]. Cytologic findings were described with the term "squamous intraepithelial lesion (SIL)" and histologic changes were described with the term "cervical intraepithelial neoplasia (CIN)." The term CIN has three degrees of severity (figure 1 and picture 1):

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Literature review current through: Dec 2017. | This topic last updated: Apr 18, 2017.
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  1. Montz FJ. Management of high-grade cervical intraepithelial neoplasia and low-grade squamous intraepithelial lesion and potential complications. Clin Obstet Gynecol 2000; 43:394.
  2. Massad LS, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis 2013; 17:S1.
  3. Solomon D, Davey D, Kurman R, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002; 287:2114.
  4. Luff RD. The Bethesda System for reporting cervical/vaginal cytologic diagnoses. Report of the 1991 Bethesda workshop. Am J Clin Pathol 1992; 98:152.
  5. The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses. National Cancer Institute Workshop. JAMA 1989; 262:931.
  6. Waxman AG, Chelmow D, Darragh TM, et al. Revised terminology for cervical histopathology and its implications for management of high-grade squamous intraepithelial lesions of the cervix. Obstet Gynecol 2012; 120:1465.
  7. Darragh TM, Colgan TJ, Thomas Cox J, 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. Int J Gynecol Pathol 2013; 32:76.
  8. Insinga RP, Glass AG, Rush BB. Diagnoses and outcomes in cervical cancer screening: a population-based study. Am J Obstet Gynecol 2004; 191:105.
  9. Schiffman MH, Bauer HM, Hoover RN, et al. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst 1993; 85:958.
  10. Kaufman RH, Adam E, Icenogle J, et al. Relevance of human papillomavirus screening in management of cervical intraepithelial neoplasia. Am J Obstet Gynecol 1997; 176:87.
  11. Khan MJ, Partridge EE, Wang SS, Schiffman M. Socioeconomic status and the risk of cervical intraepithelial neoplasia grade 3 among oncogenic human papillomavirus DNA-positive women with equivocal or mildly abnormal cytology. Cancer 2005; 104:61.
  12. Moscicki AB, Hills N, Shiboski S, et al. Risks for incident human papillomavirus infection and low-grade squamous intraepithelial lesion development in young females. JAMA 2001; 285:2995.
  13. Beutner KR, Tyring S. Human papillomavirus and human disease. Am J Med 1997; 102:9.
  14. Josefsson AM, Magnusson PK, Ylitalo N, et al. Viral load of human papilloma virus 16 as a determinant for development of cervical carcinoma in situ: a nested case-control study. Lancet 2000; 355:2189.
  15. Ylitalo N, Sørensen P, Josefsson AM, et al. Consistent high viral load of human papillomavirus 16 and risk of cervical carcinoma in situ: a nested case-control study. Lancet 2000; 355:2194.
  16. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999; 189:12.
  17. Castellsagué X, Díaz M, de Sanjosé S, et al. Worldwide human papillomavirus etiology of cervical adenocarcinoma and its cofactors: implications for screening and prevention. J Natl Cancer Inst 2006; 98:303.
  18. Alani RM, Münger K. Human papillomaviruses and associated malignancies. J Clin Oncol 1998; 16:330.
  19. Ylitalo N, Josefsson A, Melbye M, et al. A prospective study showing long-term infection with human papillomavirus 16 before the development of cervical carcinoma in situ. Cancer Res 2000; 60:6027.
  20. Böhmer G, van den Brule AJ, Brummer O, et al. No confirmed case of human papillomavirus DNA-negative cervical intraepithelial neoplasia grade 3 or invasive primary cancer of the uterine cervix among 511 patients. Am J Obstet Gynecol 2003; 189:118.
  21. Wright TC Jr, Denny L, Kuhn L, et al. HPV DNA testing of self-collected vaginal samples compared with cytologic screening to detect cervical cancer. JAMA 2000; 283:81.
  22. Manos MM, Kinney WK, Hurley LB, et al. Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results. JAMA 1999; 281:1605.
  23. Chichareon S, Herrero R, Muñoz N, et al. Risk factors for cervical cancer in Thailand: a case-control study. J Natl Cancer Inst 1998; 90:50.
  24. Zielinski GD, Snijders PJ, Rozendaal L, et al. HPV presence precedes abnormal cytology in women developing cervical cancer and signals false negative smears. Br J Cancer 2001; 85:398.
  25. de Villiers EM, Fauquet C, Broker TR, et al. Classification of papillomaviruses. Virology 2004; 324:17.
  26. Woodman CB, Collins SI, Young LS. The natural history of cervical HPV infection: unresolved issues. Nat Rev Cancer 2007; 7:11.
  27. Plummer M, Schiffman M, Castle PE, et al. A 2-year prospective study of human papillomavirus persistence among women with a cytological diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion. J Infect Dis 2007; 195:1582.
  28. Muñoz N, Bosch FX, de Sanjosé S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003; 348:518.
  29. Clifford GM, Smith JS, Plummer M, et al. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer 2003; 88:63.
  30. Mao C, Hughes JP, Kiviat N, et al. Clinical findings among young women with genital human papillomavirus infection. Am J Obstet Gynecol 2003; 188:677.
  31. Bosch X, Harper D. Prevention strategies of cervical cancer in the HPV vaccine era. Gynecol Oncol 2006; 103:21.
  32. Centers for Disease Control and Prevention. STD Prevention. Genital HPV infection, May 2001.
  33. Castle PE, Solomon D, Schiffman M, Wheeler CM. Human papillomavirus type 16 infections and 2-year absolute risk of cervical precancer in women with equivocal or mild cytologic abnormalities. J Natl Cancer Inst 2005; 97:1066.
  34. Ries LAG, Melbert D, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2004. National Cancer Institute; Bethesda, MD 2007.
  35. Li N, Franceschi S, Howell-Jones R, et al. Human papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: Variation by geographical region, histological type and year of publication. Int J Cancer 2011; 128:927.
  36. Kjaer SK, van den Brule AJ, Paull G, et al. Type specific persistence of high risk human papillomavirus (HPV) as indicator of high grade cervical squamous intraepithelial lesions in young women: population based prospective follow up study. BMJ 2002; 325:572.
  37. Wright TC, Cox JT. Human papillomaviruses — natural history of infections. In: Clinical uses of human papillomavirus (HPV) DNA testing, American Society for Colposcopy and Cervical Pathology, 2004.
  38. Rodríguez AC, Schiffman M, Herrero R, et al. Rapid clearance of human papillomavirus and implications for clinical focus on persistent infections. J Natl Cancer Inst 2008; 100:513.
  39. Schlecht NF, Kulaga S, Robitaille J, et al. Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia. JAMA 2001; 286:3106.
  40. Moberg M, Gustavsson I, Gyllensten U. Type-specific associations of human papillomavirus load with risk of developing cervical carcinoma in situ. Int J Cancer 2004; 112:854.
  41. Wallin KL, Wiklund F, Angström T, et al. Type-specific persistence of human papillomavirus DNA before the development of invasive cervical cancer. N Engl J Med 1999; 341:1633.
  42. Bory JP, Cucherousset J, Lorenzato M, et al. Recurrent human papillomavirus infection detected with the hybrid capture II assay selects women with normal cervical smears at risk for developing high grade cervical lesions: a longitudinal study of 3,091 women. Int J Cancer 2002; 102:519.
  43. Koshiol J, Lindsay L, Pimenta JM, et al. Persistent human papillomavirus infection and cervical neoplasia: a systematic review and meta-analysis. Am J Epidemiol 2008; 168:123.
  44. Nobbenhuis MA, Helmerhorst TJ, van den Brule AJ, et al. Cytological regression and clearance of high-risk human papillomavirus in women with an abnormal cervical smear. Lancet 2001; 358:1782.
  45. Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst 2005; 97:1072.
  46. Ho GY, Bierman R, Beardsley L, et al. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998; 338:423.
  47. Moore EE, Danielewski JA, Garland SM, et al. Clearance of human papillomavirus in women treated for cervical dysplasia. Obstet Gynecol 2011; 117:101.
  48. Woodman CB, Collins S, Winter H, et al. Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study. Lancet 2001; 357:1831.
  49. Dunne EF, Unger ER, Sternberg M, et al. Prevalence of HPV infection among females in the United States. JAMA 2007; 297:813.
  50. Cuzick J, Clavel C, Petry KU, et al. Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 2006; 119:1095.
  51. Moscicki AB, Ma Y, Wibbelsman C, et al. Rate of and risks for regression of cervical intraepithelial neoplasia 2 in adolescents and young women. Obstet Gynecol 2010; 116:1373.
  52. Shepherd J, Weston R, Peersman G, Napuli IZ. Interventions for encouraging sexual lifestyles and behaviours intended to prevent cervical cancer. Cochrane Database Syst Rev 2000; :CD001035.
  53. Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep 2015; 64:1.
  54. Herfs M, Yamamoto Y, Laury A, et al. A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer. Proc Natl Acad Sci U S A 2012; 109:10516.
  55. Nucci MR, Crum CP. Redefining early cervical neoplasia: recent progress. Adv Anat Pathol 2007; 14:1.
  56. Association of Reproductive Health Professionals. Clinical Proceedings. Human Papillomavirus (HPV) and cervical cancer, Association of Reproductive Health Specialists, Washington, DC March 2001.
  57. Carter JJ, Koutsky LA, Hughes JP, et al. Comparison of human papillomavirus types 16, 18, and 6 capsid antibody responses following incident infection. J Infect Dis 2000; 181:1911.
  58. Bontkes HJ, de Gruijl TD, Walboomers JM, et al. Immune responses against human papillomavirus (HPV) type 16 virus-like particles in a cohort study of women with cervical intraepithelial neoplasia. II. Systemic but not local IgA responses correlate with clearance of HPV-16. J Gen Virol 1999; 80 ( Pt 2):409.
  59. Arany I, Tyring SK. Activation of local cell-mediated immunity in interferon-responsive patients with human papillomavirus-associated lesions. J Interferon Cytokine Res 1996; 16:453.
  60. Pett M, Coleman N. Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis? J Pathol 2007; 212:356.
  61. Snijders PJ, Steenbergen RD, Heideman DA, Meijer CJ. HPV-mediated cervical carcinogenesis: concepts and clinical implications. J Pathol 2006; 208:152.
  62. de Villiers EM. Relationship between steroid hormone contraceptives and HPV, cervical intraepithelial neoplasia and cervical carcinoma. Int J Cancer 2003; 103:705.
  63. Münger K, Phelps WC, Bubb V, et al. The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol 1989; 63:4417.
  64. D'Anna R, Le Buanec H, Alessandri G, et al. Selective activation of cervical microvascular endothelial cells by human papillomavirus 16-e7 oncoprotein. J Natl Cancer Inst 2001; 93:1843.
  65. Klaes R, Woerner SM, Ridder R, et al. Detection of high-risk cervical intraepithelial neoplasia and cervical cancer by amplification of transcripts derived from integrated papillomavirus oncogenes. Cancer Res 1999; 59:6132.
  66. Wright TC Jr, Ellerbrock TV, Chiasson MA, et al. Cervical intraepithelial neoplasia in women infected with human immunodeficiency virus: prevalence, risk factors, and validity of Papanicolaou smears. New York Cervical Disease Study. Obstet Gynecol 1994; 84:591.
  67. Duerr A, Kieke B, Warren D, et al. Human papillomavirus-associated cervical cytologic abnormalities among women with or at risk of infection with human immunodeficiency virus. Am J Obstet Gynecol 2001; 184:584.
  68. Ellerbrock TV, Chiasson MA, Bush TJ, et al. Incidence of cervical squamous intraepithelial lesions in HIV-infected women. JAMA 2000; 283:1031.
  69. Ahdieh L, Muñoz A, Vlahov D, et al. Cervical neoplasia and repeated positivity of human papillomavirus infection in human immunodeficiency virus-seropositive and -seronegative women. Am J Epidemiol 2000; 151:1148.
  70. Vernon SD, Holmes KK, Reeves WC. Human papillomavirus infection and associated disease in persons infected with human immunodeficiency virus. Clin Infect Dis 1995; 21 Suppl 1:S121.
  71. Jamieson DJ, Duerr A, Burk R, et al. Characterization of genital human papillomavirus infection in women who have or who are at risk of having HIV infection. Am J Obstet Gynecol 2002; 186:21.
  72. Maiman M, Fruchter RG, Clark M, et al. Cervical cancer as an AIDS-defining illness. Obstet Gynecol 1997; 89:76.
  73. Williams AB, Darragh TM, Vranizan K, et al. Anal and cervical human papillomavirus infection and risk of anal and cervical epithelial abnormalities in human immunodeficiency virus-infected women. Obstet Gynecol 1994; 83:205.
  74. Sillman F, Stanek A, Sedlis A, et al. The relationship between human papillomavirus and lower genital intraepithelial neoplasia in immunosuppressed women. Am J Obstet Gynecol 1984; 150:300.
  75. Ognenovski VM, Marder W, Somers EC, et al. Increased incidence of cervical intraepithelial neoplasia in women with systemic lupus erythematosus treated with intravenous cyclophosphamide. J Rheumatol 2004; 31:1763.
  76. Malouf MA, Hopkins PM, Singleton L, et al. Sexual health issues after lung transplantation: importance of cervical screening. J Heart Lung Transplant 2004; 23:894.
  77. Ozsaran AA, Ateş T, Dikmen Y, et al. Evaluation of the risk of cervical intraepithelial neoplasia and human papilloma virus infection in renal transplant patients receiving immunosuppressive therapy. Eur J Gynaecol Oncol 1999; 20:127.
  78. Tam LS, Chan AY, Chan PK, et al. Increased prevalence of squamous intraepithelial lesions in systemic lupus erythematosus: association with human papillomavirus infection. Arthritis Rheum 2004; 50:3619.
  79. Castellsagué X, Muñoz N. Chapter 3: Cofactors in human papillomavirus carcinogenesis--role of parity, oral contraceptives, and tobacco smoking. J Natl Cancer Inst Monogr 2003; :20.
  80. Castle PE, Wacholder S, Lorincz AT, et al. A prospective study of high-grade cervical neoplasia risk among human papillomavirus-infected women. J Natl Cancer Inst 2002; 94:1406.
  81. Plummer M, Herrero R, Franceschi S, et al. Smoking and cervical cancer: pooled analysis of the IARC multi-centric case--control study. Cancer Causes Control 2003; 14:805.
  82. Deacon JM, Evans CD, Yule R, et al. Sexual behaviour and smoking as determinants of cervical HPV infection and of CIN3 among those infected: a case-control study nested within the Manchester cohort. Br J Cancer 2000; 83:1565.
  83. Olsen AO, Dillner J, Skrondal A, Magnus P. Combined effect of smoking and human papillomavirus type 16 infection in cervical carcinogenesis. Epidemiology 1998; 9:346.
  84. Winkelstein W Jr. Smoking and cervical cancer--current status: a review. Am J Epidemiol 1990; 131:945.
  85. Luhn P, Walker J, Schiffman M, et al. The role of co-factors in the progression from human papillomavirus infection to cervical cancer. Gynecol Oncol 2013; 128:265.
  86. Trevathan E, Layde P, Webster LA, et al. Cigarette smoking and dysplasia and carcinoma in situ of the uterine cervix. JAMA 1983; 250:499.
  87. Sasson IM, Haley NJ, Hoffmann D, et al. Cigarette smoking and neoplasia of the uterine cervix: smoke constituents in cervical mucus. N Engl J Med 1985; 312:315.
  88. Prokopczyk B, Cox JE, Hoffmann D, Waggoner SE. Identification of tobacco-specific carcinogen in the cervical mucus of smokers and nonsmokers. J Natl Cancer Inst 1997; 89:868.
  89. Giuliano AR, Sedjo RL, Roe DJ, et al. Clearance of oncogenic human papillomavirus (HPV) infection: effect of smoking (United States). Cancer Causes Control 2002; 13:839.
  90. Barton SE, Maddox PH, Jenkins D, et al. Effect of cigarette smoking on cervical epithelial immunity: a mechanism for neoplastic change? Lancet 1988; 2:652.
  91. Anttila T, Saikku P, Koskela P, et al. Serotypes of Chlamydia trachomatis and risk for development of cervical squamous cell carcinoma. JAMA 2001; 285:47.
  92. Smith JS, Bosetti C, Muñoz N, et al. Chlamydia trachomatis and invasive cervical cancer: a pooled analysis of the IARC multicentric case-control study. Int J Cancer 2004; 111:431.
  93. Madeleine MM, Anttila T, Schwartz SM, et al. Risk of cervical cancer associated with Chlamydia trachomatis antibodies by histology, HPV type and HPV cofactors. Int J Cancer 2007; 120:650.
  94. Herrington CS. Human papillomaviruses and cervical neoplasia. II. Interaction of HPV with other factors. J Clin Pathol 1995; 48:1.
  95. Smith JS, Herrero R, Bosetti C, et al. Herpes simplex virus-2 as a human papillomavirus cofactor in the etiology of invasive cervical cancer. J Natl Cancer Inst 2002; 94:1604.
  96. Hara Y, Kimoto T, Okuno Y, Minekawa Y. Effect of herpes simplex virus on the DNA of human papillomavirus 18. J Med Virol 1997; 53:4.
  97. Jha PK, Beral V, Peto J, et al. Antibodies to human papillomavirus and to other genital infectious agents and invasive cervical cancer risk. Lancet 1993; 341:1116.
  98. Zhong G, Fan T, Liu L. Chlamydia inhibits interferon gamma-inducible major histocompatibility complex class II expression by degradation of upstream stimulatory factor 1. J Exp Med 1999; 189:1931.
  99. Silins I, Ryd W, Strand A, et al. Chlamydia trachomatis infection and persistence of human papillomavirus. Int J Cancer 2005; 116:110.
  100. International Collaboration of Epidemiological Studies of Cervical Cancer, Appleby P, Beral V, et al. Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet 2007; 370:1609.
  101. Shields TS, Falk RT, Herrero R, et al. A case-control study of endogenous hormones and cervical cancer. Br J Cancer 2004; 90:146.
  102. García-Closas R, Castellsagué X, Bosch X, González CA. The role of diet and nutrition in cervical carcinogenesis: a review of recent evidence. Int J Cancer 2005; 117:629.
  103. Zelmanowicz Ade M, Schiffman M, Herrero R, et al. Family history as a co-factor for adenocarcinoma and squamous cell carcinoma of the uterine cervix: results from two studies conducted in Costa Rica and the United States. Int J Cancer 2005; 116:599.
  104. Hemminki K, Li X, Mutanen P. Familial risks in invasive and in situ cervical cancer by histological type. Eur J Cancer Prev 2001; 10:83.
  105. Mahmud SM, Robinson K, Richardson H, et al. HLA polymorphisms and cervical human Papillomavirus infection in a cohort of Montreal University students. J Infect Dis 2007; 196:82.
  106. Muñoz N, Franceschi S, Bosetti C, et al. Role of parity and human papillomavirus in cervical cancer: the IARC multicentric case-control study. Lancet 2002; 359:1093.
  107. D'Souza G, Palefsky JM, Zhong Y, et al. Marijuana use is not associated with cervical human papillomavirus natural history or cervical neoplasia in HIV-seropositive or HIV-seronegative women. Cancer Epidemiol Biomarkers Prev 2010; 19:869.