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THE CERVIX: Premalignant Lesions of the Cervix: Epidemiology and Role of HPV
NATURAL HISTORY AND MALIGNANT POTENTIAL OF CERVICAL NEOPLASIA
Cervical cancer was once a leading cause of cancer death in the United States. Now, invasive cervical cancers are relatively uncommon. This change is probably mostly due to effective identification and eradication of cancer precursor lesions(CIN). Laboratory surveys from the College of American Pathologists (CAP) indicate that more than 1 million women each year are diagnosed with low-grade intraepithelial lesions, and 500,000 will be found to have CIN-2 or CIN-3 level lesions.
Persistent human papillomavirus (HPV) infection is requisite to the development of cervical neoplasia. Oncogenic HPV types have a molecular advantage in establishing a persistent infection that disrupts the apoptotic machinery of the cervical epithelial cell. This leads to disorganized, unchecked proliferation of cells and loss of normal maturation as they progress upwards through the epithelial cell layers. HPV persistence is demonstrated before the appearance and even after the regression of cervical cytological abnormalities (Castle, Schiffman). Multiple studies (Ho, Kulaga, Peyton, Giuliano) have shown that the mean duration of an HPV infection is between 4 and 10 months and is longer when the infecting HPV type is oncogenic versus non-oncogenic. Parity (Molano) and cytological abnormalities (Dalstein) correlate with a greater persistence of HPV and therefore an increased risk of cervical dysplasia.
The natural history and potential outcomes of cervical intraepithelial neoplasia (CIN) can be estimated from previous studies (Table 1) (Ostor).
Degree of
Dysplasia |
|
Regression
(%) |
|
Persistence
(%) |
|
Progression
to CIN 3
(%) |
|
Progression to
Invasive Cancer
(%) |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
| CIN I |
|
60 |
|
30 |
|
10 |
|
1 |
|
|
|
|
|
|
|
|
|
| CIN II |
|
40 |
|
40 |
|
15 |
|
5 |
|
|
|
|
|
|
|
|
|
| CIN III |
|
33 |
|
55 |
|
N/A |
|
> 12 |
Factors that may determine the biologic behavior of cervical dysplasia remain elusive. Age greater than 35 years old, smoking, co-infection with HIV or Chlamydia have all been proposed as promoters of the malignant progression of cervical dysplasia to cancer, but none have been definitely proven. Future research should provide insight into molecular surrogates of dysplasia (e.g. HPV diagnostics, gene methylation patterns, proliferation markers) that could help predict outcomes and the safety of expectant management or need for closer follow-up and treatment.
References: General
- Castle PE, Wacholder S, Sherman ME, Lorincz AT, Glass AG, Scott DR, Rush BB, Demuth F, Schiffman M. Absolute risk of a subsequent abnormal pap among oncogenic human papillomavirus DNA-positive, cytologically negative women. Cancer 2002;95(10):2145-51
- Schiffman M, Wheeler CM, Castle PE; Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study Group. Human papillomavirus DNA remains detectable longer than related cervical cytologic abnormalities. J Infect Dis. 2002; 186(8): 1169-72.
- Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998; 338(7): 423-8
- Schlecht NF, Kulaga S, Robitaille J, Ferreira S, Santos M, Miyamura RA, Duarte-Franco E, Rohan TE, Ferenczy A, Villa LL, Franco EL. Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia. JAMA 2001;286(24):3106-14
- J Giuliano AR, Harris R, Sedjo RL, Baldwin S, Roe D, Papenfuss MR, Abrahamsen M, Inserra P, Olvera S, Hatch K. Incidence, prevalence, and clearance of type-specific human papillomavirus infections: The Young Women's Health Study. Infect Dis 2002;186(4):462-9
- Peyton CL, Gravitt PE, Hunt WC, Hundley RS, Zhao M, Apple RJ, Wheeler CM. Determinants of genital human papillomavirus detection in a US population. J Infect Dis 2001;183(11):1554-64
- Molano M, Van den Brule A, Plummer M, Weiderpass E, Posso H, Arslan A, Meijer CJ, Munoz N, Franceschi S; HPV Study Group. Determinants of clearance of human papillomavirus infections in Colombian women with normal cytology: a population-based, 5-year follow-up study. Am J Epidemiol. 2003;158(5):486-94
- Dalstein V, Riethmuller D, Pretet JL, Le Bail Carval K, Sautiere JL, Carbillet JP, Kantelip B, Schaal JP, Mougin C. Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions: a longitudinal French cohort study. Int J Cancer. 2003;106(3):396-403
References: Natural History of Cervical Dysplasia
- Ostor AG.Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol. 1993; 12(2): 186-92.
- Montz FJ, Monk BJ, Fowler JM, Nguyen L. Natural history of the minimally abnormal Papanicolaou smear. Obstet Gynecol. 1992; 80: 385-8
- Narod SA, Thompson DW, Jain M, Wall C, Green LM, Miller AB. Dysplasia and the natural history of cervical cancer: early results of the Toronto Cohort Study. Eur J Cancer. 1991; 27(11): 1411-6.
- Chang AR.Carcinoma in situ of the cervix and its malignant potential. A lesson from New Zealand. Cytopathology. 1990; 1(6): 321-8.
- Luthra UK, Prabhakar AK, Seth P, Agarwal SS, Murthy NS, Bhatnagar P, Das DK, Sharma BK. Natural history of precancerous and early cancerous lesions of the uterine cervix. Acta Cytol. 1987; 31(3): 226-34
- Bamford PN, Beilby JO, Steele SJ, Vlies R.The natural history of cervical intraepithelial neoplasia as determined by cytology and colposcopic biopsy. Acta Cytol. 1983; 27(5): 482-4
- Remmink AJ, Walboomers JM, Helmerhorst TJ, Voorhorst FJ, Rozendaal L, Risse EK, Meijer CJ, Kenemans P. The presence of persistent high-risk HPV genotypes in dysplastic cervical lesions is associated with progressive disease: natural history up to 36 months. Int J Cancer 1995;61(3):306-11
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