PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of jclinpathJournal of Clinical PathologyVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
 
J Clin Pathol. 1998 February; 51(2): 96–103.
PMCID: PMC500501

Aetiology, pathogenesis, and pathology of cervical neoplasia.

Abstract

Early epidemiological studies of cervical neoplasia suggested a causal relation with sexual activity and human papillomaviruses (HPVs) have emerged as prime suspects as venerally transmitted carcinogens. HPVs fall into two broad camps: low risk types, associated with cervical condylomas and CIN 1; and high risk types (mostly 16 and 18), found in 50-80% of CIN 2 and CIN 3 lesions, and 90% of cancers. This association with cancer is very strong, with odds ratios of > 15 (often much higher) in case-control studies that are methodologically sound. An infrequently detected third group of intermediate risk type HPVs is associated with all grades of CIN and occasionally with cancers. HPVs have also been detected in a wide range of asymptomatic controls, indicating that other events are required for development of neoplasia such as viral persistence and/or altered expression of viral genes, often following integration of the viral genome. This leaves the two major viral oncogenes, E6 and E7, directly coupled to viral enhancers and promoters, allowing their continued expression after integration. High risk HPV E7 proteins bind and inactivate the Rb protein, whereas E6 proteins bind p53 and direct its rapid degradation. A range of putative cofactors has been implicated in progression: HLA type, immunosuppression, sex steroid hormones, and smoking; most of these cofactors appear to influence progression to CIN 3. The natural history includes progression to CIN 3 in 10% of CIN 1 and 20% of CIN 2 cases, whereas at least 12% of CIN 3 cases progress to invasive carcinoma. Cervical glandular intraepithelial neoplasia (CGIN) often coexists with squamous CIN, and the premalignant potential of high grade CGIN is not in doubt, but the natural history of low grade CGIN remains uncertain. A high proportion of CGIN lesions and adenocarcinomas are HPV positive, and HPV18 has been implicated more in glandular than in squamous lesions. A strong clinical case for the application of HPV typing of cells recovered from cervical scrapes can be made; however, a rigorous cost-benefit analysis of introducing HPV typing into the cervical screening programme is required. Prophylactic and therapeutic HPV vaccines are under development. This article reviews the aetiology, pathogenesis, and pathology of cervical neoplasia, emphasising the role of HPVs.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.7M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Muñoz N, Bosch X, Kaldor JM. Does human papillomavirus cause cervical cancer? The state of the epidemiological evidence. Br J Cancer. 1988 Jan;57(1):1–5. [PubMed]
  • Vonka V, Kanka J, Roth Z. Herpes simplex type 2 virus and cervical neoplasia. Adv Cancer Res. 1987;48:149–191. [PubMed]
  • Arends MJ, Wyllie AH, Bird CC. Papillomaviruses and human cancer. Hum Pathol. 1990 Jul;21(7):686–698. [PubMed]
  • Schiffman MH, Bauer HM, Hoover RN, Glass AG, Cadell DM, Rush BB, Scott DR, Sherman ME, Kurman RJ, Wacholder S, et al. Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst. 1993 Jun 16;85(12):958–964. [PubMed]
  • Cuzick J, Terry G, Ho L, Hollingworth T, Anderson M. Type-specific human papillomavirus DNA in abnormal smears as a predictor of high-grade cervical intraepithelial neoplasia. Br J Cancer. 1994 Jan;69(1):167–171. [PubMed]
  • Stanley M. Genital papillomaviruses, polymerase chain reaction and cervical cancer. Genitourin Med. 1990 Dec;66(6):415–417. [PMC free article] [PubMed]
  • Lorincz AT, Reid R, Jenson AB, Greenberg MD, Lancaster W, Kurman RJ. Human papillomavirus infection of the cervix: relative risk associations of 15 common anogenital types. Obstet Gynecol. 1992 Mar;79(3):328–337. [PubMed]
  • Kurman RJ, Schiffman MH, Lancaster WD, Reid R, Jenson AB, Temple GF, Lorincz AT. Analysis of individual human papillomavirus types in cervical neoplasia: a possible role for type 18 in rapid progression. Am J Obstet Gynecol. 1988 Aug;159(2):293–296. [PubMed]
  • Schwarz E, Freese UK, Gissmann L, Mayer W, Roggenbuck B, Stremlau A, zur Hausen H. Structure and transcription of human papillomavirus sequences in cervical carcinoma cells. Nature. 1985 Mar 7;314(6006):111–114. [PubMed]
  • Choo KB, Pan CC, Han SH. Integration of human papillomavirus type 16 into cellular DNA of cervical carcinoma: preferential deletion of the E2 gene and invariable retention of the long control region and the E6/E7 open reading frames. Virology. 1987 Nov;161(1):259–261. [PubMed]
  • Shirasawa H, Tomita Y, Sekiya S, Takamizawa H, Simizu B. Integration and transcription of human papillomavirus type 16 and 18 sequences in cell lines derived from cervical carcinomas. J Gen Virol. 1987 Feb;68(Pt 2):583–591. [PubMed]
  • Smotkin D, Wettstein FO. The major human papillomavirus protein in cervical cancers is a cytoplasmic phosphoprotein. J Virol. 1987 May;61(5):1686–1689. [PMC free article] [PubMed]
  • Woodworth CD, Bowden PE, Doniger J, Pirisi L, Barnes W, Lancaster WD, DiPaolo JA. Characterization of normal human exocervical epithelial cells immortalized in vitro by papillomavirus types 16 and 18 DNA. Cancer Res. 1988 Aug 15;48(16):4620–4628. [PubMed]
  • Woodworth CD, Doniger J, DiPaolo JA. Immortalization of human foreskin keratinocytes by various human papillomavirus DNAs corresponds to their association with cervical carcinoma. J Virol. 1989 Jan;63(1):159–164. [PMC free article] [PubMed]
  • zur Hausen H. Molecular pathogenesis of cancer of the cervix and its causation by specific human papillomavirus types. Curr Top Microbiol Immunol. 1994;186:131–156. [PubMed]
  • Storey A, Pim D, Murray A, Osborn K, Banks L, Crawford L. Comparison of the in vitro transforming activities of human papillomavirus types. EMBO J. 1988 Jun;7(6):1815–1820. [PubMed]
  • Dürst M, Gallahan D, Jay G, Rhim JS. Glucocorticoid-enhanced neoplastic transformation of human keratinocytes by human papillomavirus type 16 and an activated ras oncogene. Virology. 1989 Dec;173(2):767–771. [PubMed]
  • Arends MJ, McGregor AH, Wyllie AH. Apoptosis is inversely related to necrosis and determines net growth in tumors bearing constitutively expressed myc, ras, and HPV oncogenes. Am J Pathol. 1994 May;144(5):1045–1057. [PubMed]
  • Phelps WC, Yee CL, Münger K, Howley PM. The human papillomavirus type 16 E7 gene encodes transactivation and transformation functions similar to those of adenovirus E1A. Cell. 1988 May 20;53(4):539–547. [PubMed]
  • Münger K, Werness BA, Dyson N, Phelps WC, Harlow E, Howley PM. Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. EMBO J. 1989 Dec 20;8(13):4099–4105. [PubMed]
  • Münger K, Yee CL, Phelps WC, Pietenpol JA, Moses HL, Howley PM. Biochemical and biological differences between E7 oncoproteins of the high- and low-risk human papillomavirus types are determined by amino-terminal sequences. J Virol. 1991 Jul;65(7):3943–3948. [PMC free article] [PubMed]
  • Werness BA, Levine AJ, Howley PM. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science. 1990 Apr 6;248(4951):76–79. [PubMed]
  • Scheffner M, Münger K, Byrne JC, Howley PM. The state of the p53 and retinoblastoma genes in human cervical carcinoma cell lines. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5523–5527. [PubMed]
  • Lane S, Wells M. Human papillomaviruses, p53, and cervical neoplasia. J Pathol. 1994 Apr;172(4):299–300. [PubMed]
  • Jeffers MD, Richmond J, Farquharson M, McNicol AM. p53 immunoreactivity in cervical intraepithelial neoplasia and non-neoplastic cervical squamous epithelium. J Clin Pathol. 1994 Dec;47(12):1073–1076. [PMC free article] [PubMed]
  • Busby-Earle RM, Steel CM, Williams AR, Cohen B, Bird CC. p53 mutations in cervical carcinogenesis--low frequency and lack of correlation with human papillomavirus status. Br J Cancer. 1994 Apr;69(4):732–737. [PubMed]
  • White AE, Livanos EM, Tlsty TD. Differential disruption of genomic integrity and cell cycle regulation in normal human fibroblasts by the HPV oncoproteins. Genes Dev. 1994 Mar 15;8(6):666–677. [PubMed]
  • Arends MJ, Wyllie AH, Bird CC. Human papillomavirus type 18 is associated with less apoptosis in fibroblast tumours than human papillomavirus type 16. Br J Cancer. 1995 Sep;72(3):646–649. [PubMed]
  • Herrington CS, Evans MF, Hallam NF, Charnock FM, Gray W, McGee JD. Human papillomavirus status in the prediction of high-grade cervical intraepithelial neoplasia in patients with persistent low-grade cervical cytological abnormalities. Br J Cancer. 1995 Jan;71(1):206–209. [PubMed]
  • Cox JT. HPV DNA testing: clinical boon or boondoggle? Lancet. 1995 Sep 16;346(8977):717–719. [PubMed]
  • Londesborough P, Ho L, Terry G, Cuzick J, Wheeler C, Singer A. Human papillomavirus genotype as a predictor of persistence and development of high-grade lesions in women with minor cervical abnormalities. Int J Cancer. 1996 Oct 21;69(5):364–368. [PubMed]
  • Arends MJ, Benton EC, McLaren KM, Stark LA, Hunter JA, Bird CC. Renal allograft recipients with high susceptibility to cutaneous malignancy have an increased prevalence of human papillomavirus DNA in skin tumours and a greater risk of anogenital malignancy. Br J Cancer. 1997;75(5):722–728. [PubMed]
  • Luesley D, Blomfield P, Dunn J, Shafi M, Chenoy R, Buxton J. Cigarette smoking and histological outcome in women with mildly dyskaryotic cervical smears. Br J Obstet Gynaecol. 1994 Jan;101(1):49–52. [PubMed]
  • Sasson IM, Haley NJ, Hoffmann D, Wynder EL, Hellberg D, Nilsson S. Cigarette smoking and neoplasia of the uterine cervix: smoke constituents in cervical mucus. N Engl J Med. 1985 Jan 31;312(5):315–316. [PubMed]
  • Ali S, Astley SB, Sheldon TA, Peel KR, Wells M. Detection and measurement of DNA adducts in the cervix of smokers and non-smokers. Int J Gynecol Cancer. 1994 May;4(3):188–193. [PubMed]
  • Warwick AP, Redman CW, Jones PW, Fryer AA, Gilford J, Alldersea J, Strange RC. Progression of cervical intraepithelial neoplasia to cervical cancer: interactions of cytochrome P450 CYP2D6 EM and glutathione s-transferase GSTM1 null genotypes and cigarette smoking. Br J Cancer. 1994 Oct;70(4):704–708. [PubMed]
  • Hughes DE, Rebello G, al-Nafussi A. Integrin expression in squamous neoplasia of the cervix. J Pathol. 1994 Jun;173(2):97–104. [PubMed]
  • Vessey CJ, Wilding J, Folarin N, Hirano S, Takeichi M, Soutter P, Stamp GW, Pignatelli M. Altered expression and function of E-cadherin in cervical intraepithelial neoplasia and invasive squamous cell carcinoma. J Pathol. 1995 Jun;176(2):151–159. [PubMed]
  • Anderson MC, Brown CL, Buckley CH, Fox H, Jenkins D, Lowe DG, Manners BT, Melcher DH, Robertson AJ, Wells M. Current views on cervical intraepithelial neoplasia. J Clin Pathol. 1991 Dec;44(12):969–978. [PMC free article] [PubMed]
  • Ostör AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol. 1993 Apr;12(2):186–192. [PubMed]
  • McIndoe WA, McLean MR, Jones RW, Mullins PR. The invasive potential of carcinoma in situ of the cervix. Obstet Gynecol. 1984 Oct;64(4):451–458. [PubMed]
  • al-Nafussi AI, Hughes DE. Histological features of CIN3 and their value in predicting invasive microinvasive squamous carcinoma. J Clin Pathol. 1994 Sep;47(9):799–804. [PMC free article] [PubMed]
  • Shepherd JH. Revised FIGO staging for gynaecological cancer. Br J Obstet Gynaecol. 1989 Aug;96(8):889–892. [PubMed]
  • Östör AG, Rome RM. Micro-invasive squamous cell carcinoma of the cervix: a clinico-pathologic study of 200 cases with long-term follow-up. Int J Gynecol Cancer. 1994 Jul;4(4):257–264. [PubMed]
  • Burghardt E, Ostör A, Fox H. The new FIGO definition of cervical cancer stage IA: a critique. Gynecol Oncol. 1997 Apr;65(1):1–5. [PubMed]
  • Ostör AG, Pagano R, Davoren RA, Fortune DW, Chanen W, Rome R. Adenocarcinoma in situ of the cervix. Int J Gynecol Pathol. 1984;3(2):179–190. [PubMed]
  • Casper GR, Ostör AG, Quinn MA. A clinicopathologic study of glandular dysplasia of the cervix. Gynecol Oncol. 1997 Jan;64(1):166–170. [PubMed]
  • Duggan MA, Benoit JL, McGregor SE, Inoue M, Nation JG, Stuart GC. Adenocarcinoma in situ of the endocervix: human papillomavirus determination by dot blot hybridization and polymerase chain reaction amplification. Int J Gynecol Pathol. 1994 Apr;13(2):143–149. [PubMed]
  • Ursin G, Peters RK, Henderson BE, d'Ablaing G, 3rd, Monroe KR, Pike MC. Oral contraceptive use and adenocarcinoma of cervix. Lancet. 1994 Nov 19;344(8934):1390–1394. [PubMed]
  • Kaspar HG, Dinh TV, Doherty MG, Hannigan EV, Kumar D. Clinical implications of tumor volume measurement in stage I adenocarcinoma of the cervix. Obstet Gynecol. 1993 Feb;81(2):296–300. [PubMed]

Articles from Journal of Clinical Pathology are provided here courtesy of BMJ Group