Human papillomavirus DNA testing for the detection of cervical intraepithelial neoplasia grade 3 and cancer: 5-year follow-up of a randomised controlled implementation trial.

BACKGROUND: Tests for the DNA of high-risk types of human papillomavirus (HPV) have a higher sensitivity for cervical intraepithelial neoplasia grade 3 or worse (CIN3+) than does cytological testing, but the necessity of such testing in cervical screening has been debated. Our aim was to determine whether the effectiveness of cervical screening improves when HPV DNA testing is implemented. METHODS: Women aged 29-56 years who were participating in the regular cervical screening programme in the Netherlands were randomly assigned to combined cytological and HPV DNA testing or to conventional cytological testing only. After 5 years, combined cytological and HPV DNA testing were done in both groups. The primary outcome measure was the number of CIN3+ lesions detected. Analyses were done by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN20781131. FINDINGS: 8575 women in the intervention group and 8580 in the control group were recruited, followed up for sufficient time (> or =6.5 years), and met eligibility criteria for our analyses. More CIN3+ lesions were detected at baseline in the intervention group than in the control group (68/8575 vs 40/8580, 70% increase, 95% CI 15-151; p=0.007). The number of CIN3+ lesions detected in the subsequent round was lower in the intervention group than in the control group (24/8413 vs 54/8456, 55% decrease, 95% CI 28-72; p=0.001). The number of CIN3+ lesions over the two rounds did not differ between groups. INTERPRETATION: The implementation of HPV DNA testing in cervical screening leads to earlier detection of CIN3+ lesions. Earlier detection of such lesions could permit an extension of the screening interval.

Proliferation accurately identifies the high-risk patients among small, low-grade, lymph node-negative invasive breast cancers.

BACKGROUND: The proliferation factor mitotic activity index (MAI) is the strongest prognosticator in lymph node-negative invasive breast cancer patients under age 71. The question remains, whether this also holds for 'favourable prognosis' subgroups. PATIENTS AND METHODS: The study was a multicentre prospective analysis of the MAI for recurrence-free survival and overall cancer-related survival of grade, MAI, and other prognosticators in 853 long-term follow-up, T1-3N0M0 breast cancer patients under 71 years. RESULTS: In all tumours together (N = 853), in grade 3 (n = 269), in tumours <1 cm all grades (n = 84), 1-2 cm, grades 1 + 2 (n = 300), and 2-3 cm, grades 1 + 2 (n = 124), the MAI is prognostically superior. Other features [grade, estrogen receptor (ER), diameter, and age] did not enhance its prognostic value except in grades 1 + 2 tumours 2-3 cm diameter with MAI <10, where ER has an additional prognostic value. CONCLUSIONS: In women <71 years with T1-3N0M0 small or low-grade invasive breast cancer usually not receiving systemic treatment, MAI > or =10 accurately identifies those at high risk. These high-risk patients should be considered for adjuvant systemic therapy.

[Flat penile lesions in the sexual transmission of human papillomavirus]. / Vlakke penisafwijkingen in de seksuele overdracht van Humaan papillomavirus.

--Infection with high-risk genital Human papillomavirus (hrHPV) is necessary for the development of cervical cancer and its early stages. --Although it is widely accepted that infection with hrHPV is sexually transmitted, insight into the clinical manifestations of hrHPV infection in men is limited. --Flat penile lesions may be the hrHPV reservoir in men. --Their limited visibility with the naked eye explains why flat penile lesions may escape the attention of both the carrier and the clinician. The lesions can be visualized by the application of an acetic acid solution. They should be distinguished from papillary abnormalities occurring close to the frenulum and the pearl-shaped penile papulae around the coronary sulcus that do not accompany HPV. --Only flat penile lesions are associated with high numbers of HPV copies and therefore contribute to the sexual viral spread. --The use of condoms protects against sexual transmission of HPV.

Insulin, androgen, and gonadotropin concentrations, body mass index, and waist to hip ratio in the first years after menarche in girls with regular menstrual cycles, irregular menstrual cycles, or oligomenorrhea.

Data on changes in hormone concentrations during the first years after menarche are scarce. We studied the relation between gynecological age (age minus age at menarche), hormone concentrations, and body measurements from the lst to the 6th yr after menarche in 229 observations of girls with regular menstrual cycles, 157 observations of girls with irregular menstrual cycles, and 104 observations of girls with oligomenorrhea. Body Mass Index, waist circumference, hip circumference, LH, androstenedione, testosterone, and dehydro-epiandrosterone sulphate increased significantly (linear regression, P < 0.05) by gynecological age in all menstrual cycle pattern groups. For PRL and estradiol a significant increase with gynecological age was only documented in the regular menstrual cycle group and for waist to hip ratio only in the irregular menstrual cycle group. No significant correlation could be documented between gynecological age and overnight fasting insulin concentrations or glucose to insulin ratio. We found no significant correlation between insulin concentrations or glucose to insulin ratio and androgen concentrations. Significant positive correlations were found between LH and androgens. LH and androgen levels increase during the first years after menarche, and reference values should be adjusted for gynecological age. In these years, no significant correlation between hyperinsulinemia and hyperandrogenemia could be documented.

Regional differences in breast cancer survival are correlated with differences in differentiation and rate of proliferation.

Patients with invasive ductal breast cancer and with 5 to 12 years of follow-up, identified from two pathology laboratories serving hospitals in two distinct but fairly close regions, were studied for differences in length of survival. In the years when the cases were diagnosed, population screening was not performed, adjuvant systemic therapy was not administered, and surgical treatment and irradiation protocols were similar in the hospitals served by the two laboratories. There was a significant difference in length of survival between the two regional groups (N1 = 160, N2 = 111; P = .006). Survival rate at 10 years in the two regions was 48% and 69%. Distribution of age, tumor size, and lymph node status (as negative or positive as well as number of positive nodes) were similar, but quantitative and qualitative microscopic features differed. Patients from the region in which the prognosis was less favorable had the higher median values for the mitotic activity index (14 v 4; P less than .0001) and for nuclear area (59.2 v 38.2; P less than .0001). Nuclear and histologic grade distributions were also different between the regions. Logistic regression analysis confirmed that the regional survival differences are correlated with the microscopic features, even after adjustment for age, tumor size, and lymph node status. Comparison of breast cancers from the periods 1970 to 1974 and 1988 to 1989 in one of the two regions revealed that the clinical and microscopic proliferation features were similar over time. These results, apart from indicating regional variation in breast cancer survival rate correlated to differences in the microscopic characteristics of the disease between regions, provide additional support to previous reports that qualitative and, especially, quantitative microscopic differentiation and proliferation features have significant bearing on the prognosis of breast cancer patients.

PCR based high risk HPV testing is superior to neural network based screening for predicting incident CIN III in women with normal cytology and borderline changes.

BACKGROUND/AIMS: To improve the accuracy of conventional cytology in cervical cancer screening, high risk human papillomavirus (HPV) testing and neural network based screening have been developed. This study assessed the power of both techniques to detect women at risk of developing incident CIN III; that is, CIN III detected during the follow up of women with normal cytology and borderline nuclear changes. METHODS: A cohort of 2250 women, 34-54 years of age, who attended population based cervical cancer screening from 1988 to 1991 and had normal smears or borderline nuclear changes was followed. All smears were tested for high risk HPV and the smears were rescreened using neural network based screening. The value of neural network based screening for predicting incident CIN III during a mean follow up period of 6.4 years was compared with that of high risk HPV testing. In addition, morphological markers presumed to be related to HPV were correlated with HPV status. RESULTS: Thirteen (0.6%) women had incident CIN III. Both high risk HPV positivity and abnormal cytology were associated with an increased risk for incident CIN III (odds ratio, 240 and 22, respectively) and high risk HPV positivity was associated with abnormal cytology. The sensitivity of high risk HPV testing for predicting incident CIN III was much higher than that of neural network based screening (92% and 46%, respectively). None of the morphological markers assessed, including koilocytosis, was correlated with high risk HPV status. CONCLUSION: High risk HPV testing is superior to neural network based screening in identifying women at risk of developing CIN III. For women with normal cytology and borderline changes and a negative high risk HPV test, the screening interval can be considerably prolonged.

Human papillomavirus in false negative archival cervical smears: implications for screening for cervical cancer.

AIM: To assess the value of detecting human papillomavirus (HPV) DNA in false negative archival cervical smears in population based screening programmes for cervical cancer. METHODS: Cytomorphologically classified false negative archival Pap smears (n = 27) taken from 18 women up to six years before cervical cancer was diagnosed were blindly mixed with 89 smears from hospital patients with a variety of gynaecological complaints and tested for HPV by the polymerase chain reaction (PCR). Corresponding cervical cancer biopsy specimens were also available for HPV analysis. Neither the examining cytopathologist nor the molecular biologist was aware of the study design. RESULTS: HPV DNA was detected in the smears of 16 patients with cervical cancer missed previously by cytology. HPV 16 and 18 were found predominantly in those smears taken up to six years before the diagnosis of cervical cancer. The smears of the two remaining patients were reclassified as inadequate for cytology or contained no suitable DNA for PCR. In 15 patients the same HPV type could be found in the smears and the cervical cancer biopsy specimens. CONCLUSIONS: The results indicate that high risk HPV types can be detected in archival smears classified as false negative on cytology and that cytological screening errors may be reduced if combined with PCR testing for HPV.

Primary screening for high risk HPV by home obtained cervicovaginal lavage is an alternative screening tool for unscreened women.

BACKGROUND/AIMS: Self sampling is considered an adjuvant tool to facilitate the participation of women in cervical cancer screening programmes. This study aimed to evaluate whether cervicovaginal lavage could be an alternative for the cervical smear in cytology and human papillomavirus (HPV) testing and to assess the acceptance of the self sampling device by women. METHODS: Fifty six women with abnormal cervical cytology (very mild dyskaryosis or worse) and 15 women with normal cervical cytology obtained a self collected cervicovaginal lavage at home and filled in a questionnaire on the use of the device. At the colposcopy clinic the gynaecologist performed the same procedure followed by a cervical smear for cytology and HPV DNA testing. RESULTS: The self sampling device was acceptable to 88% of the women. The concordance between the cytology results in the smear and the lavage by the doctor and the patient was 54% and 41%, respectively (kappa = 0.28 and 0.14). The concordance between high risk HPV detection in the smear and the lavage by the doctor and the patient was 93% and 78%, respectively (kappa = 0.82 and 0.53). Ninety one per cent of the women with high grade cervical intraepithelial neoplasia (CIN) had a high risk HPV positive test in the smear, compared with 91% and 81% in the lavages taken by the doctor and the patient, respectively. CONCLUSIONS: HPV DNA testing by home obtained samples is useful as a screening tool for cervical cancer, whereas cervical cytology by self sampling is not. Although the sensitivity for high grade CIN by high risk HPV testing in the lavage by the patient is not significantly lower than that in the cervical smear, self sampling for HPV DNA is a feasible alternative method in women who decline to participate in population based cervical cancer screening programmes. However, participation in the screening programme remains the best option.

Reliable high risk HPV DNA testing by polymerase chain reaction: an intermethod and intramethod comparison.

BACKGROUND: The development of a reproducible, sensitive, and standardised human papillomavirus (HPV) polymerase chain reaction (PCR) test is required to implement HPV testing in cervical cancer screening programmes and for triaging women with mild to moderate dysplasia. AIMS: To determine the intermethod agreement between different GP5+/6+ and MY09/11 PCR based protocols for the detection and typing of high risk (HR) HPV DNA in cervical smears and to assess the intramethod reproducibility of the GP5+/6+ PCR enzyme immunoassay (EIA) for HR-HPV detection. METHODS: For the intermethod comparison, crude aliquots of 20 well characterised cervical smears comprising five HPV negative samples, and six and nine samples containing single and multiple HPV infections, respectively, were coded and sent from reference laboratory (A) to three other laboratories. One of these (laboratory B) used the GP5+/6+ PCR-EIA and was provided with standard protocols. Another laboratory (C) used GP5+/6+ PCR combined with sequence analysis and type specific PCR, whereas two laboratories (D and E) used MY09/11 PCR followed by restriction fragment length polymorphism (RFLP) analysis for the detection and typing of HR-HPV. The intramethod agreement of GP5+/6+ PCR-EIA was analysed in a subsequent study with four other laboratories (F to I) on crude aliquots of 50 well characterised cervical smears, consisting of 32 HR-HPV positive and 18 HPV negative samples. Standardised protocols, primers, and probes were also provided by the reference laboratory for HR-HPV detection. RESULTS: In the intermethod comparison, pairwise agreement of the different laboratories with reference laboratory A for the detection of HR-HPV varied between 75% and 100% (kappa values: 0.5 to 1). Typing data revealed a broader range in pairwise agreement rates between 32% and 100%. The highest agreement was found between laboratories A and B using standardised protocols and validated reagents. In the intramethod evaluation, pairwise comparison of the laboratories F to I with reference laboratory A revealed excellent agreement rates from 92% to 100% (kappa values: 0.88 to 1.0) with an overall sensitivity of 97.5% (195/200) and specificity of 99.5% (199/200). CONCLUSIONS: The detection of HR-HPV as a group is highly reproducible with GP5+/6+ PCR-EIA provided that standardised protocols and validated reagents are used.

Pregnancy rates after timed intercourse or intrauterine insemination after human menopausal gonadotropin stimulation of normal ovulatory cycles: a controlled study.

Forty-eight patients with male (n = 16) or idiopathic (n = 32) infertility were stimulated with human menopausal gonadotropin. Intrauterine insemination (IUI) or natural intercourse were performed after either human chorionic gonadotropin (hCG)-induced or spontaneous, urinary luteinizing hormone (LH) surge-monitored ovulation. A total of 148 cycles were analyzed. In 40 cycles treated with hCG-induced ovulation and IUI, 3 (7.5%) patients conceived, whereas 37 women accomplished natural intercourse after hCG-induced ovulation and 2 (5.5%) became pregnant. When inseminated after a spontaneous LH surge, 3 (8.8%) of 34 patients achieved a pregnancy; no conception occurred in 37 spontaneously ovulatory cycles combined with timed intercourse. Pregnancy rates did not substantially differ between the treatment modalities or between mono-ovulatory and polyovulatory cycles. The cycle characteristics between spontaneous ovulatory and hCG-induced cycles significantly did differ.

Intrauterine insemination does and clomiphene citrate does not improve fecundity in couples with infertility due to male or idiopathic factors: a prospective, randomized, controlled study.

In the present prospective study we compared, in terms of pregnancy rates, the differences between intrauterine insemination (IUI) of in vitro capacitated husband's semen and timed natural intercourse in spontaneous or clomiphene citrate (CC) stimulated cycles. A rapid urinary luteinizing hormone peak detection test was used for timing of ovulation. Forty patients suffering from longstanding infertility of male (n = 17), cervical (n = 2), and idiopathic (n = 21) origin were randomly assigned into four distinct treatment modalities during 4 consecutive cycles. A total of 132 cycles were analyzed. In 35 cycles treated with CC plus IUI, five conceptions were achieved, whereas three pregnancies occurred in 32 inseminated spontaneous cycles. Only 1 patient conceived after timed intercourse in 31 CC stimulated cycles, and no pregnancy resulted from 34 spontaneous cycles combined with timed intercourse. There was a statistically significant higher conception rate in cycles in which IUI was performed, whereas the use of CC does not seem to improve the pregnancy rate. Analysis of results for other modifying factors did not substantially affect the relative risk (odds ratio) of pregnancy.

Polycystic ovaries in adolescents and the relationship with menstrual cycle patterns, luteinizing hormone, androgens, and insulin.

STUDY OBJECTIVE: To evaluate the possible role of inappropriate LH secretion, hyperandrogenism, and hyperinsulinemia in the development of polycystic ovaries (PCO) and the polycystic ovary syndrome. DESIGN: Observational. SETTING: General population samples. PARTICIPANTS: 58 adolescents with regular menstrual cycles, 50 with irregular menstrual cycles, and 29 with oligomenorrhea (age 16.7+/-0.9 years). INTERVENTIONS: Transabdominal pelvic ultrasonography and vena puncture. MAIN OUTCOME MEASURES: PCO; LH, androstenedione, and testosterone levels; overnight fasting insulin concentrations; and oligomenorrhea. RESULTS: The prevalence of PCO increased significantly with the irregularity of the menstrual cycle pattern, as illustrated by the study, finding PCO in 9% of the girls with regular menstrual cycles, 28% of those with irregular menstrual cycles, and 45% of oligomenorrheic girls. The LH and androgen concentrations were significantly higher in girls with PCO; the insulin levels and the glucose-insulin ratio did not differ when the girls with PCO were compared with girls with normal ovaries. Oligomenorrheic girls with PCO had the highest androgen and LH concentrations; their insulin concentrations and glucose-insulin ratio were in the same range as girls with regular menstrual cycles and normal ovaries; and both their hip and waist girths were wider, although their waist-hip ratio was normal. CONCLUSIONS: PCO in adolescents is associated with irregular menstrual cycles, oligomenorrhea, and/or high androgen and LH levels; but no relationship was found with the insulin level or glucose-insulin ratio. Thus, it is doubtful that hyperinsulinemia is an important factor in the development of PCO or polycystic ovary syndrome.

HPV testing and monitoring of women after treatment of CIN 3: review of the literature and meta-analysis.

According to the current guidelines in most western countries, women treated for cervical intraepithelial neoplasia grade 3 (CIN 3) are followed for at least 2 years after treatment by cytology.High-risk human papillomavirus (hrHPV) infections are necessary for the development and maintenance of CIN 3. HrHPV testing could be used to improve monitoring of women treated for CIN 3. This has prompted numerous studies for the implementation of hrHPV testing in monitoring of women treated for CIN 3. Included in this review are 20 studies, published between 1996 and 2003, comparing hrHPV testing with either resection margins or cervical cytology to predict recurrent/residual disease, and 11 of them could be used in a meta-analysis. In the meta-analysis of the 11 studies, the negative predictive value (NPV) for recurrent/residual disease of hrHPV testing was 98% (95% CI 97-99%), that of resection margins 91% (95% CI 87-94%), and that of cervical cytology 93% (95% CI 90-95%). When hrHPV testing was performed in conjunction with cytology, the sensitivity was 96% (95% CI 89-99%), specificity was 81% (95% CI 77-84%), the associated positive predictive value (PPV) was 46% (95% CI 38-54%), and the NPV was 99% (95% CI 98-100%). Combined hrHPV and cytology testing yielded the best test characteristics. We propose to include hrHPV testing in conjunction with cytology for monitoring women treated for CIN 3. Some follow-up visits for women testing negative for both hrHPV and cytology can be skipped. In western countries, this could mean that for women double negative at 6 months, retesting at 12 months should be skipped while keeping the 24-month follow-up visit.

Human papillomavirus DNA and genotypes: prognostic factors for progression of cervical intraepithelial neoplasia.

A retrospective study of 227 patients presenting with abnormal cervical cytology was conducted to investigate the relationship between human papillomavirus (HPV) and progression of untreated cervical intraepithelial neoplasia (CIN) lesions. All patients had colposcopically directed biopsies for histologic diagnosis. The patients were followed cytologically and colposcopically for a mean of 19 months (range 6-42 months). Progression of a cervical lesion was defined as progression to a higher CIN grade confirmed histologically by directed biopsy. HPV DNA detection was done on material remaining from the cervical swabs by the general primer polymerase chain reaction (PCR) and type-specific PCR method, which made the detection of HPV types 6, 11, 16, 18, 31, 33 and not yet sequenced DNA types (X) possible. The presence of HPV DNA increased with the severity of the lesion (P < 0.001). In CIN III, a 100% HPV DNA prevalence was found, with HPV type 16 being the most prevalent type in 75%. Progression was significantly related to the presence of HPV DNA, in particular HPV type 16. The percentage of progressive disease was 21% in the case of HPV DNA positive lesions (n = 130) and 29% in the presence of HPV type 16, whereas HPV DNA negative lesions (n = 97) showed no progression. The detection of HPV DNA and HPV genotype can be used to identify patients with high-risk cervical lesions, since the presence of HPV DNA and genotype 16 in particular are closely related to CIN progression.

Reliability of urinary LH testing for planning of endometrial biopsies.

A rapid urinary luteinizing hormone (LH) test was used to plan a late luteal phase endometrial biopsy from 20 women undergoing an infertility evaluation. Histologic dating was correlated with the day of urinary LH surge detection, the day of the basal body temperature (BBT) nadir, and the onset of the next menstrual period (NMP). From 17 interpretable specimens, histologic dating correlated well with the day of the biopsy as determined following a positive LH test detection (P = 0.079). No correlation was found following the BBT shift (P = 0.65), and it was significantly correlated with the NMP (P = 0.016). Moreover, the urinary LH test showed to be the best method to predict the onset of the NMP. These findings confirm urinary LH testing as a valuable adjunct in the investigation of luteal phase disorders.

A case of pre-eclampsia arising in the fourth pregnancy.

A case of severe pre-eclampsia, with histologically proven eclamptogenic glomerulopathy, appearing in the 32nd wk of the 4th pregnancy is presented. During 'conservative' management with bed-rest and sodium restriction, further deterioration of circulation took place. The results are described of treatment with a combination of a peripheral-acting antihypertensive drug and volume expansion, whereby the fetus could remain in utero until sufficient maturation of the respiratory system could be proven.

Is maternal whole blood viscosity a factor in fetal growth?

Many authors have correlated changes in maternal hemodynamics during pregnancy with fetal growth. Sufficient plasma volume expansion in pregnancy seems mandatory for an optimal reproductive result. A correlation between rheological characteristics (low-shear whole blood viscosity and yield shear stress) and birthweight centiles was found in 26 third-trimester pregnancies. The level of statistical significance (P less than 0.05) was reached in nulliparous pregnancies but not in parous pregnancies. Measurements of whole blood viscosity at low shear rate and yield shear stress seem to provide information on the efficacy of placental perfusion. There have been reports in the literature to support the assumption of the prevalence of low-shear circumstances in the intervillous space. The hypothesis is put forward that, during pregnancy, the changes in maternal hemodynamics influence fetal growth by their impact on the flow through the placenta.

Maternal characteristics and expected birth weight.

Fetal growth charts currently used aggregate birth weights of infants with various natural histories from 1931 until 1967. In order to modernize these charts, avoiding deviation from the natural history of fetal development, we report data from infants born after spontaneous onset of labour in 'normal' pregnancy from a gestational age of 267 to 295 days between 1972 and 1982 (n = 14,113). The relationship between birth weight and gestational age in days was studied by multiple regression analysis, containing dummy variables for parity and gender. The estimated proportion of the variance in the model, attributed to these characteristics, was 15%. This could be improved to 22% by supplementing the model with maternal characteristics such as age, height, mid-pregnancy weight and ethnic origin. According to this extended model, in the Dutch section of the population 511 (4.6%) babies had a birth weight below the 5th percentile, whereas 412 (3.7%) babies would be labeled as such according to the conventional birth weight tables. Moreover, 93 babies would be wrongly considered too small, corresponding with a sensitivity of 62.4%, and 192 babies would be wrongly considered normal, corresponding with a specificity of 99.3%. Integration of the four currently used tables into one, and adjustment for easily available maternal characteristics, could substantially improve classification methods.

Assessment of tobacco-exposure during pregnancy; behavioural and biochemical changes.

Smoking-behavior during pregnancy and the reliability of an interview were prospectively investigated. The tobacco-exposure was assessed a) by an intake interview b) by a smoking diary and c) by maternal thiocyanate and carboxy-hemoglobin concentrations. Of the 115 nulliparous women, 66 smoked (57.4%). Seventeen women (25.8%) quit and 39 women (59.1%) reduced smoking. Directly after intake, in the first week of the diary, significantly more cigarettes were smoked than stated during the intake interview. According to the diaries, the number of cigarettes increased during the first half of pregnancy. In the 24th week significantly more cigarettes were smoked than in the first week after intake. Also a significant increase of thiocyanate between the measurements at intake and in the 24th of amenorrhea was found. The maternal carboxy-hemoglobin levels did not significantly change during pregnancy. Investigators should be aware of changes in smoking behavior during pregnancy and the potential bias of self reported smoking behavior at the beginning of pregnancy. The tobacco-exposure should be assessed (anamnestic or biochemical) several times during pregnancy, anyway it should include the second half of pregnancy.

[Human papillomavirus and screening for cervical cancer: state of art and prospects]. / Humaan papillomavirus en screening op baarmoederhalskanker: stand van zaken en mogelijkheden.

More than 99% of all cervical cancers contain high risk HPV. Only a persistent infection with high risk HPV of the cervical epithelium results in cervical cancer. Because the risk of cervical cancer is identical for all different HPV types, tests which detect all 14 high risk HPV types at one time are sufficient for clinical management. Testing for hr-HPV is mandatory for women with mild dyskaryosis and for the follow-up of women treated for CIN lesions. Based on efficiency to detect CIN3 and cervical cancer and preliminary cost benefit analysis, the combination of a high risk HPV test in conjunction with a cervical smear appears to be the best way of cervical cancer screening. A definite point of view on using high risk HPV testing for primary screening for cervical cancer will be obtained after the completion of a randomized trial of 44,000 women, in which the efficiency to detect CIN3 and cervical cancer by high risk HPV testing in conjunction with a cytomorphological smear is compared with screening by classical cytology.