Risk Of Cervical Intraepithelial Neoplasia Research Articles

Screening for cervical cancer: new alternatives and research.

Evidence for the clinical utility of human papillomavirus (HPV) DNA testing has increased over the years and has now become very convincing. Some specific uses of HPV detection are a) triage of women with cytological determinations of atypical squamous cells of undetermined significance (ASC-US) and related management strategies, b) as a marker for test of cure post-treatment, and c) most importantly, as an adjunct to cytology in routine cervical disease screening programs. There are many studies that support each of these applications and include 8 studies on ASC-US triage, 10 on test of cure and 13 on adjunctive or stand-alone HPV screening. The most notable investigation of ASC-US triage was ALTS, a randomized controlled trial of 3,488 women. With respect to routine HPV screening the combined studies included 77,000 women, providing as a histological endpoint more than 1,000 cases of high-grade cervical intraepithelial neoplasia (CIN) or cancer. Testing methods were either the Hybrid Capture 2 (HC2) test or the polymerase chain reaction (PCR) test. HPV testing of women with ASC-US cytology had on average a higher sensitivity (90%) and specificity (70%) than repeating the cytological test (sensitivity 75%, specificity 60%) and was also more sensitive than colposcopy for follow-up. As an adjunct to the Papanicolaou (Pap) cytology test in routine screening, HPV DNA testing was a more sensitive indicator for prevalent high-grade CIN than either conventional or liquid cytology. A combination of HPV DNA and Papanicolaou testing had almost 100% sensitivity and negative predictive value. The specificity of the combined tests was slightly lower than the specificity of the Papanicolaou test. One "double-negative" HPV DNA and Papanicolaou test indicated a higher prognostic assurance against risk of future CIN 3 than three subsequent negative conventional Papanicolaou tests and may safely allow three-year or longer screening intervals for such low-risk women. It appears that HPV DNA testing is on the way to becoming a common testing strategy in cervical cancer prevention programs. Research continues into approaches for improving the performance and cost-effectiveness of HPV detection methods. Hybrid Capture 3 will offer improved HPV typing capabilities and the Rapid Capture machine allows for robot-assisted HPV DNA testing, permitting greater test throughput. PCR test improvements are expected to contribute to the growth of flexible accurate and cost-effective HPV DNA tests. It is likely that improved diagnostic technology along with HPV genotyping and quantitation may provide more value in future. A particularly promising approach is to combine HPV DNA testing with expression levels of other markers such as proliferative or cell cycle regulatory proteins to subdivide HPV-positive women into those who are at greater risk of cancer and those who can be safely followed by screening at longer intervals. This paper is available too at: http://www.insp.mx/salud/index.html.

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Viral load as a predictor of the risk of cervical intraepithelial neoplasia.

HPV infections are believed to be a necessary cause of cervical cancer. Viral burden, as a surrogate indicator for persistence, may help predict risk of subsequent SIL. We used results of HPV test and cytology data repeated every 4-6 months in 2,081 women participating in a longitudinal study of the natural history of HPV infection and cervical neoplasia in São Paulo, Brazil. Using the MY09/11 PCR protocol, 473 women were positive for HPV DNA during the first 2 visits. We retested all positive specimens by a quantitative, low-stringency PCR method to measure viral burden in cervical cells. Mean viral loads and 95% CIs were calculated using log-transformed data. RRs and 95% CIs of incident SIL were calculated by proportional hazards models, adjusting for age and HPV oncogenicity. The risk of incident lesions increased with viral load at enrollment. The mean number of viral copies/cell at enrollment was 2.6 for women with no incident lesions and increased (trend p = 0.003) to 15.1 for women developing 3 or more SIL events over 6 years of follow-up. Compared to those with <1 copy per cell in specimens tested during the first 2 visits, RRs for incident SIL increased from 1.9 (95% CI 0.8-4.2) for those with 1-10 copies/cell to 4.5 (95% CI 1.9-10.7) for those with >1,000 copies/cell. The equivalent RR of HSIL for >1,000 copies/cell was 2.6 (95% CI 0.5-13.2). Viral burden appears to have an independent effect on SIL incidence. Measurement of viral load, as a surrogate for HPV persistence, may identify women at risk of developing cervical cancer precursors.

Autofluorescence spectroscopy for the diagnosis of cervical intraepithelial neoplasia

Objective To assess the feasibility of autofluorescence spectroscopy in the diagnosis of cervical intraepithelial neoplasia (CIN) using broadband light excitation. Design Feasibility study. Setting Colposcopy clinic of an university hospital. Population Sixty-eight patients at risk for CIN. Methods After excitation with a broadband light between 375 and 440 nm, spectral distribution of native tissue fluorescence (autofluorescence) was acquired from 685 cervical sites for the localisation and differentiation of CIN, and compared with colposcopically directed biopsy and human papillomavirus (HPV) DNA testing. Main outcome measure Detection of CIN. Results The evaluation of spectral measurements revealed significantly lower autofluorescence values for CIN 3 lesions compared with normal tissue ( P < 0.001), and compared with CIN 1 or CIN 2 ( P < 0.002). High grade CIN lesions (CIN 2/3) presented with a significant reduced autofluorescence compared with CIN 1 ( P < 0.002). Patients with a positive HPV DNA testing showed a significantly lower autofluorescence than patients tested negative for HPV DNA ( P < 0.05). Severe inflammation such as chronic cervicitis may lead to false positive results. Conclusions Autofluorescence spectroscopy represents an interesting approach for the detection of cervical neoplasia. Using an excitation wavelength band between 375 and 440 nm, significant differences between normal and precancerous lesions of the cervix can be seen.

Burning wood in the kitchen increases the risk of cervical neoplasia in HPV-infected women in Honduras.

There is suggestive evidence that the use of wood for cooking increases the risk of invasive cervical cancer. We investigated this association in women with cervical neoplasia in Honduras. Women aged 20-64 years with cervical intraepithelial neoplasia (CIN) grade I (n = 44), CIN II (n = 36) or CIN III (n = 45) were recruited from screening programs in Tegucigalpa City and each was matched by age and clinic to 2 controls (241 total) without cervical abnormalities. The clinics selected women of low socioeconomic status. Cervical scrapes were tested for the presence of human papillomavirus (HPV) DNA using a general primer set directed against the L1 open reading frame, and HPV genotyping was performed. Odds ratios (ORs) were computed through conditional logistic regression; p-values were from tests for linear trend of risk with increasing exposure. HPV DNA was detected in 48% of women with CIN I, 67% with CIN II and 89% with CIN III. The ORs were 1.5, 2.5 and 38.3 respectively. At univariate analysis, age at first intercourse was consistently lower among cases than controls. Risk was reduced by 50% or more in all 3 CIN classes when initiation of sexual activity at age 20 years or older was compared with initiation before age 16 years (p = 0.013 for CIN I). No effect was observed for smoking, oral contraceptives or previous cytologic screening. Effects for number of sexual partners, parity, age at first pregnancy and education were in the expected directions but never persisted after adjustment for HPV. Chronic exposure to wood smoke significantly increased the risk of CIN III (p = 0.022). However, women who said "No" when asked if they ever used wood in the kitchen had a higher risk than those with low or intermediate exposure. This was taken as evidence that the initial screening question had either been misunderstood or that answers were biased. Restricting the analysis to women who reported exposure yielded positive associations in all CIN classes with for CIN III ORs of 2.3 for 25-34 and 9.5 for 35+ years compared with women who had 1-14 years of exposure (p = 0.017). A multivariate analysis of the complete dataset (n = 366) allowed for separate ORs for HPV in each CIN class. Inclusion of age at first intercourse significantly improved this model (p = 0.021). Adding exposure to wood smoke further improved the model only if an interaction between woodsmoke and HPV was allowed for. If, as the data suggest, it was assumed that wood smoke had its effect among HPV-positives only, there was a significant linear dose-response relationship between exposure to woodsmoke and risk of CIN (p = 0.026). This association was independent of other risk factors including education, parity and number of sexual partners. ORs in the final model were 0.37 for age at first intercourse 20 years or higher and 5.69 for more than 35 years of exposure to wood burning in the kitchen. The present study suggests that the use of wood for cooking is a risk factor for cervical neoplasia that deserves further study, given its high prevalence in developing countries.

Natural history of cervical human papillomavirus infection in young women: a longitudinal cohort study

Laboratory and epidemiological research suggests an association between human papillomavirus (HPV) and cervical intraepithelial neoplasia (CIN). We studied the natural history of incident cervical HPV infection and its relation to the development of CIN. We recruited 2011 women aged 15-19 years who had recently become sexually active. We took a cervical smear every 6 months and stored samples for virological analysis. We immediately referred all women with any cytological abnormality for colposcopic assessment, but postponed treatment until there was histological evidence of progression to high-grade CIN. In 1075 women who were cytologically normal and HPV negative at recruitment, the cumulative risk at 3 years of any HPV infection was 44% (95% CI 40-48): HPV 16 was the most common type. The cumulative risk at 3 years of detecting an HPV type not present in the first positive sample was 26% (20-32). 246 women had an abnormal smear during follow-up, of whom 28 progressed to high-grade CIN. The risk of high-grade CIN was greatest in women who tested positive for HPV 16 (risk ratio 8.5 [3.7-19.2]); this risk was maximum 6-12 months after first detection of HPV 16. All HPV types under consideration were associated with cytologically abnormal smears. Although abnormality was significantly less likely to be associated with low-viral-load samples, the cumulative risk at 3 years of a high-viral-load sample after a low-viral-load sample was 45% (95% CI 35-56). Five women who progressed to high-grade CIN consistently tested negative for HPV. Our findings suggest that attempts to exploit the association between cervical neoplasia and HPV infection to improve effectiveness of cervical screening programmes might be undermined by the limited inferences that can be drawn from the characterisation of a woman's HPV status at a single point in time, and the short lead time gained by its detection.

Does Histological Incomplete Excision of Cervical Intraepithelial Neoplasia Following Large Loop Excision of Transformation Zone Increase Recurrence Rates? A Six Year Cytological Follow Up

Objective To determine the risk of recurrent cervical intraepithelial neoplasia (CIN) in women with complete or incomplete excision of cervical intraepithelial neoplasia treated by large loop excision of transformation zone (LLETZ). Design A retrospective study Setting One consultant-led colposcopy clinic at Leicester Royal Infirmary Population Three hundred and ninety-four women referred consecutively to the colposcopy clinic between 1991 and 1992. Main outcome measures The histological recurrence rate of CIN, length of cytological follow up following treatment related to degree of completeness of excision at initial treatment. Results Three hundred and twenty-two women had complete cytological or histological follow up. The mean length of follow up was 73 months with a mean number of six smears. Women with incomplete excision of CIN had a significantly higher risk of recurrent CIN (relative risk 8.23) occurring in a significantly shorter time compared with women with complete excision. Conclusions This study demonstrates that large loop excision of transformation zone is successful in over 95% of cases. Cytological surveillance is satisfactory for follow up of women who have complete excision of CIN. Women with incomplete excision of CIN at initial LLETZ remain at significant risk of developing further CIN and long term colposcopic and cytological follow up is necessary.

Genital Human Papillomavirus Types in Immunocompetent and Immunodepressed Women in Northeast Italy: Prevalence and Cytomorphological Correlations

We evaluated the prevalence of genital human papillomavirus (HPV) types in correlation with cytomorphological findings in patients at different risk for cervical intraepithelial neoplasia living in northeast Italy. Exfoliated cervicovaginal cells from 943 women, who were divided into three groups, were analyzed by polymerase chain reaction. Overall, HPV prevalence rates were 7%, 38%, and 52%, respectively. The single most frequent type was HPV 16 (18%), followed by types 6, 31, 53, 58, 61, and novel/unidentified (5-7%); other types had a frequency <5%. Infection with multiple types was present in 12%. In HIV-infected women, HPV infection was correlated with lower CD4 level and higher viral load; HGSILs were correlated only with a lower CD4 count, and no correlations were found for LGSILs. HGSILs were associated with high-risk types, mainly HPV 16 (40%). LGSILs, instead, were associated with a broad spectrum of low-risk and high-risk types.

Genital Human Papillomavirus Types in Immunocompetent and Immunodepressed Women in Northeast Italy

Objective We evaluated the prevalence of genital human papillomavirus (HPV) types in correlation with cytomorphological findings in patients at different risk for cervical intraepithelial neoplasia living in northeast Italy. Methods Exfoliated cervicovaginal cells from 943 women, who were divided into three groups, were analyzed by polymerase chain reaction. Results Overall, HPV prevalence rates were 7%, 38%, and 52%, respectively. The single most frequent type was HPV 16 (18%), followed by types 6, 31, 53, 58, 61, and novel/unidentified (5–7%); other types had a frequency <5%. Infection with multiple types was present in 12%. In HIV-infected women, HPV infection was correlated with lower CD4 level and higher viral load; HGSILs were correlated only with a lower CD4 count, and no correlations were found for LGSILs. Conclusions HGSILs were associated with high-risk types, mainly HPV 16 (40%). LGSILs, instead, were associated with a broad spectrum of low-risk and high-risk types.

Does histological incomplete excision of cervical intraepithelial neoplasia following large loop excision of transformation zone increase recurrence rates? A six year cytological follow up.

To determine the risk of recurrent cervical intraepithelial neoplasia (CIN) in women with complete or incomplete excision of cervical intraepithelial neoplasia treated by large loop excision of transformation zone (LLETZ). A retrospective study One consultant-led colposcopy clinic at Leicester Royal Infirmary Three hundred and ninety-four women referred consecutively to the colposcopy clinic between 1991 and 1992. The histological recurrence rate of CIN, length of cytological follow up following treatment related to degree of completeness of excision at initial treatment. Three hundred and twenty-two women had complete cytological or histological follow up. The mean length of follow up was 73 months with a mean number of six smears. Women with incomplete excision of CIN had a significantly higher risk of recurrent CIN (relative risk 8.23) occurring in a significantly shorter time compared with women with complete excision. This study demonstrates that large loop excision of transformation zone is successful in over 95% of cases. Cytological surveillance is satisfactory for follow up of women who have complete excision of CIN. Women with incomplete excision of CIN at initial LLETZ remain at significant risk of developing further CIN and long term colposcopic and cytological follow up is necessary.

Effect of Total Plasma Homocysteine on Cervical Dysplasia Risk

We investigated whether total plasma homocysteine (tHcy) is associated with risk for cervical intraepithelial neoplasia (CIN). tHcy was evaluated, along with numerous risk factors for CIN and biochemical indexes of nutrients, in a previously reported study population of 294 subjects with CIN and 170 female controls without CIN. tHcy was significantly higher in cases than in controls (9.1 vs. 8.3 μmol/l, p = 0.002). Human papillomavirus type 16 infection [odds ratio (OR) = 6.7], oral contraceptive use (OR = 6.0), parity (OR = 2.2), and cigarette smoking (OR = 1.9) were significantly associated with CIN after adjustment for each other and for age, number of sexual partners, and plasma tHcy, folate, iron, and zinc. Human papillomavirus type 16 positivity increased risk for CIN more when tHcy was >9.12 μmol/l (OR = 4.7) than when it was ≤9.12 μmol/l (OR = 3.0). Cigarette use increased risk for CIN when tHcy was >9.12 μmol/l (OR = 3.9), but not when tHcy was ≤9.12 μmol/l (OR = 1.5). Parity increased risk for CIN more when tHcy was >9.12 μmol/l (OR = 4.0) than when tHcy was ≤9.12 μmol/l (OR = 2.0). These results suggest that elevated plasma tHcy is a risk factor for cervical dysplasia and that it enhances the effects of other risk factors. It is unknown whether tHcy is serving as a marker of folate deficiency or is acting through other mechanisms.

Cervical neoplasia and repeated positivity of human papillomavirus infection in human immunodeficiency virus-seropositive and -seronegative women.

Increased risk for cervical intraepithelial neoplasia (CIN) in human immunodeficiency virus (HIV)-infected women may be explained by repeated positivity of human papillomavirus (HPV) infection facilitated by HIV infection and related immunosuppression. As part of a longitudinal study with semiannual examinations, 268 women in Baltimore, Maryland (of whom 184 were HIV+), provided 1,426 cervicovaginal lavage specimens tested for HPV DNA by a polymerase chain reaction-based assay between 1992 and 1998. HPV positivity and time to HPV clearance according to HIV serostatus and CD4+ cell count were compared using models for correlated binary data and survival analysis. Of the 187 participants who had at least one positive measurement, the probability of subsequent HPV positivity among HIV- women and HIV+ women with CD4+ > or =200 and <200 cells/microl was 47.5%, 78.7%, and 92.9% (p < 0.001). Within-women HPV results were correlated (i.e., clustered) in each group (p < 0.01). Compared with HIV-participants, the relative incidence of HPV clearance was 0.29 and 0.10 among HIV+ women with CD4+ > or =200 and <200 cells/microl (p < 0.001). At the end of follow-up, 11 women had biopsy-confirmed CIN. The association of HIV and CIN (p = 0.014) was fully explained by repeated HPV positivity induced by HIV infection (p = 0.648). Reversal of immunosuppression following potent antiretroviral therapy must be expected to have a dramatic impact on HIV-related CIN.

The false negative rate of cervical smears in high risk HIV seropositive and seronegative women.

We undertook a prospective study of cytology and concurrent colposcopically directed biopsies of both Human Immunodeficiencey Virus seronegative (HIV-) and seropositive (HIV +) women at high risk for cervical intraepithelial neoplasia (CIN) to determine the accuracy of Pap smears in this population. Women were recruited from a sexually transmitted disease clinic and a women's prison in eastern Massachusetts. All were interviewed, blood was tested for HIV with CD4 counts done in 101 of the 102 HIV + women, and all received a pelvic exam that included a conventional Pap smear, a Thinprep test, and colposcopy with directed biopsies and endocervical curettage. A total of 184 women volunteered. 82 were HIV- and 102 were HIV+. The prevalence of CIN in HIV+ women was 37%, more than twice the 17% prevalence of CIN in HIV-women (P = 0.002). When Atypical Squamous Cells of Undetermined Significance (ASCUS) findings were included with "negative" cytology, the conventional Pap smear false negative rates for HIV- and HIV+ women were 21% and 37%, respectively. When ASCUS was included with "positive" cytology, the false negative rates dropped to 14.3% for HIV- women and 10.5% for HIV+ women. We conclude that ASCUS diagnoses comprised the majority of false negatives in HIV+ women.

HLA and susceptibility to cervical neoplasia

The association between cervical neoplasia and certain HLA phenotypes observed in different studies has not been consistent. By serological typing, the association between HLA antigens, cervical carcinoma and cervical intraepithelial neoplasia (CIN) was studied in a group of 172 and 116 patients, respectively. We demonstrated an increased frequency of B63 in patients with HPV types other than HPV 16 or 18, and B55 in patients that were negative for all HPV types. The association between cervical carcinoma and DQ3, described in various populations, was not observed in the present study. However, we confirmed other previously observed associations between cervical cancer and class II antigens, i.e., a positive correlation with DR15 irrespective of the HPV status, with DR3 in patients harboring HPV types other than HPV 16 or 18, and with DR11 among HPV 16 positive patients. In contrast, a negative correlation between DR13 and HPV positive cervical cancer was observed which suggests protection of this antigen against HPV-associated cervical cancer. A slight increase of DR15 and DQ4 antigens was observed in CIN patients, suggesting that these specific HLA antigens may be important in determining the risk of CIN.

Sexual behaviour and papillomavirus exposure in cervical intraepithelial neoplasia: a population-based case-control study.

Sexual history is an established risk determinant for cervical neoplasia. It is not clear if human papillomavirus (HPV) exposure entirely explains the sexual behaviour-related risk or if other sexually transmitted agents may act as cofactors for HPV in carcinogenesis. The aim of this study was to elucidate whether HPV exposure or HPV persistence explains the sexual history-related risk of high-grade cervical intraepithelial neoplasia (CIN) using a population-based case-control study of most of the 254 women referred to colposcopy in the Vasterbotten county in Sweden because of an abnormal cervical smear during October 1993 to December 1995 and 320 age-matched women from the general population. The women were interviewed for sexual history and tested for presence of serum antibodies to HPV-16, -18 and -33 as well as for presence of HPV DNA in cervical brush samples. HPV-16, -18 and -33 seropositivity was specific for the corresponding type of HPV DNA, dependent on the lifetime sexual history and associated with a two- to threefold increased risk of CIN 3. There was no sexual history-related risk of CIN among HPV-seropositive women and adjustment for HPV DNA presence explained the sexual history-related risk of CIN. In conclusion, HPV exposure appeared to explain the sexual history-related risk of high-grade CIN.

Lower genital tract intraepithelial neoplasia in HIV-infected women: guidelines for evaluation and management.

Human immunodeficiency virus (HIV) and human papillomavirus (HPV) are both sexually transmitted viruses with many risk factors in common. Studies have found that HIV-seropositive women are at least five times as likely to be infected with HPV as seronegative controls. In immunocompromised HIV-seropositive women, the risk of cervical intraepithelial neoplasia (CIN) is almost as high as in women with squamous intraepithelial lesions on their Pap smear. Some studies have shown the false-negative rate of cervical cytology in HIV-seropositive women to be very high, although others have shown it to be comparable with the rate in seronegative controls. However, given the prevalence of CIN in this population, even a "normal" false-negative rate may result in many missed CIN lesions. Among HIV-seropositive women and especially among those who are immunocompromised, CIN is more likely to progress and recur after treatment. Recurrence rates may reach 87 percent 36 months after treatment in markedly immunosuppressed women. Cryotherapy is especially ineffective in these patients. Vulvar condyloma and vulvar intraepithelial neoplasia (VIN) are much more prevalent in HIV-seropositive women and especially in those who are markedly immunosuppressed or who have been immunosuppressed for a prolonged period of time. It is recommended that all HIV-seropositive women undergo periodic evaluation at intervals no less than every 6 months. Immunocompromised women should be followed with cytology and colposcopy of the cervix and vulva, although those with normal immune systems may be followed with cytology alone. Because the rates of recurrence and progression are so high after treatment of these women, they should be followed with colposcopy and cytology every 6 months. New approaches to treatment need to be explored in this population. Obstetricians & Gynecologists, Family Physicians. After completion of this article, the reader will understand the association between the immune suppression of HIV and HPV-related diseases, be familiar with the treatment options for the HIV-seropositive woman with cervical intraepithelial neoplasia (CIN), understand the natural history of CIN in the patient with HIV-seropositivity, and become aware of the appropriate surveillance of the HIV-seropositive woman treated for CIN.

Viral characteristics of human papillomavirus infection and antioxidant levels as risk factors for cervical dysplasia

Genital human papillomavirus (HPV) infection is the major causal factor of cervical intraepithelial neoplasia (CIN). The potential role of nutrition as an additional, independent risk factor for CIN has not been appropriately addressed in the context of HPV. This case-control study evaluated the etiologic role of HPV in terms of viral type and load and examined the association between CIN and plasma levels of micronutrients adjusting for HPV. Cases (n = 378) with histo-pathologically confirmed CIN and controls (n = 366) with no history of abnormal Pap smears were recruited from colposcopy and gynecology clinics, respectively. Risk of CIN was significantly increased among women who were infected with multiple HPV types (odds ratio [OR] = 21.06), a high viral load (OR = 13.08) and HPV 16 (OR = 62.49). After adjusting for HPV positivity and demographic factors, there was an inverse correlation between plasma alpha-tocopherol and risk of CIN (OR = 0.15). Plasma ascorbic acid was protective at a high level of > or = 0.803 mg/dl (OR = 0.46). CIN was not associated with plasma retinol and beta-carotene levels. The effect of genital HPV infection on CIN development is highly influenced by oncogenic viral type and high viral load. Vitamins C and E may play an independent protective role in development of CIN that needs to be confirmed in prospective studies.

Genomic Variation of Human Papillomavirus Type 16 and Risk for High-Grade Cervical Intraepithelial Neoplasia

Background Epidemiologic studies have demonstrated strong and consistent associations between the detection of human papillomavirus (HPV) type 16 DNA and the risk of cervical intraepithelial neoplasia (CIN) and cervical cancer. However, HPV16 is also the most common type of HPV in the normal population, and only a minority of women with HPV16 infection develop cervical cancer. Studies of genomic heterogeneity in HPV16 have demonstrated the presence of multiple variant forms in all human populations examined to date. It is conceivable that the natural variants of HPV16 in a given population may not have the same biologic behavior. Purpose This study was designed to determine the association between natural variants of HPV16 and the risk of biopsy-confirmed CIN 2 or 3, the most important precancerous lesions of the uterine cervix. Methods Prospective studies were conducted among 1) women attending a university and 2) women presenting to a sexually transmitted disease clinic. Subjects were eligible for inclusion in this investigation if the initial cytologic findings did not reveal CIN 2-3 and HPV16 DNA was detected by means of a polymerase chain reaction (PCR)-based method in one or more cervical or vulvovaginal samples. Eligible subjects were followed every 4 months with cervical Pap smears and colposcopic examinations. Women were referred for biopsy if cytology or colposcopy suggested CIN 2-3. Two groups of HPV16 variants, prototype-like and nonprototype-like, were determined by means of single-strand conformation polymorphism (SSCP) analysis of PCR products from the noncoding region of the viral genome. Representative SSCP patterns from HPV16 variants were further characterized by direct DNA sequencing of the PCR products. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated by Cox regression analysis. Results Prototype-like variants accounted for 79% of the HPV16 detected in university students and 86% of the virus detected in patients presenting to the sexually transmitted disease clinic. CIN 2-3 was confirmed by biopsy in nine of 57 HPV16-positive women attending the university and in 10 of 66 HPV16-positive women presenting to the sexually transmitted disease clinic. Among university students, those with HPV16 nonprototype-like variants were 6.5 (95% CI = 1.6-27.2) times more likely to develop CIN 2-3 than those with prototype-like variants. A similar association was observed among women presenting to the sexually transmitted disease clinic (RR = 4.5; 95% CI = 0.9-23.8). Conclusions This study suggests that the risk of developing CIN 2-3 is not the same with all variants of HPV16 and that nonprototype-like variants confer a greater risk compared with prototype-like variants. The important genomic differences underlying this increased risk of CIN 2-3 remain to be determined.

Evaluation of atypical and low-grade cervical cytology in private practice

Objective: To evaluate the adequacy of cytology alone for diagnosis of grade of cervical intraepithelial neoplasia (CIN) and to study performance of cytology, human papillomavirus (HPV) testing, and colposcopy in the evaluation of cytologic findings suggesting low-grade squamous intraepithelial lesions (SIL), or atypical squamous (ASCUS) or atypical glandular (AGCUS) cells of undetermined significance. Methods: Standard gynecologic and cytologic evaluation and colposcopic inspection as an additional screening approach were performed on women with no prior hysterectomies screened in a private practice between January 1, 1993, and August 1, 1995. Among these 7651 women, 367 had ASCUS, AGCUS, or SIL cytology or clinically or colposcopically visible cervical lesions. Sensitivity, specificity, and relative risk of CIN in the 367 women were compared by colposcopic, cytologic, histologic and virologic diagnoses. Results: The sensitivity of all non-negative Papanicolaou smears for CIN 2–3 and cancer was 92%, combined cytologic categories of high- and low-grade SIL were 59%, and high-grade SIL alone was 22%. Colposcopy was performed in all 367 patients, and positive findings led to biopsies in 48%. Colposcopy of patients with ASCUS increased detection of CIN 2–3 by 32% and CIN 1 by 48%. Cervical cytology was false negative in 8% of patients with CIN 2–3 and in 14% of those with CIN 1. These cases of CIN were detected by screening colposcopic inspection. High-risk HPV DNA was positive in 41% of women with CIN 2–3, and in 25% of those with CIN 1. The positive predictive value of ASCUS cytology increased from 5% to 42% for CIN 2–3 and from 30% to 85% for all grades of CIN in patients carrying high-risk HPV DNA. Virologic studies did not add to an increase in the sensitivity for CIN 2–3 among women in the low- and high-grade SIL cytology groups. Conclusion: Because of the limited sensitivity of the high-grade SIL cytologic category for CIN 2–3, we recommend that all women with ASCUS, AGCUS, low- or high-grade SIL cytology be recalled for colposcopy, with biopsy only when indicated by colposcopic findings.

Can the number of cigarettes smoked predict high-grade cervical intraepithelial neoplasia among women with mildly abnormal cervical smears?

OBJECTIVE: We investigated whether the number of cigarettes smoked by women who had mildly abnormal cytologic study results could identify those at risk for high-grade dysplasia. STUDY DESIGN: This was a prospective study of all women who were referred for colposcopy with a mildly abnormal cervical smear over a 4-year period. A detailed questionnaire was completed that evaluated sociodemographic characteristics including smoking history. Colposcopy then determined the degree of disease. RESULTS: One hundred seventy-three women were referred with a mildly abnormal cervical smear. There was a significant relationship between the numbers of cigarettes smoked and the risk of high grade disease ( P = .007). Once the number of cigarettes smoked daily exceeded 20, the risk of high grade cervical intraepithelial neoplasia was increased fivefold (odds ratio 5.85 [95% confidence interval 1.92 to 17.80]). CONCLUSION: Cigarette smoking is associated with a dose-dependent increased risk of cervical intraepithelial neoplasia grade 2 or 3 among women who have mildly abnormal cervical smears. (Am J Obstet Gynecol 1998; 179: 399-402.)