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Introduction. Recent studies have shown that CADM1/MAL-methylation testing detects high-grade CIN lesions with a high short-term progression risk for cervical cancer. Women treated for CIN2/3 are at risk of post-treatment disease, representing either persistent (incompletely treated) or incident (early onset) lesions. Here, we evaluated CADM1/MAL-methylation analysis as potential tool for detecting recurrent high-grade CIN lesions (rCIN2/3). Methods and materials. A multicenter prospective clinical cohort study was conducted among 364 women treated for CIN2/3. Cervical scrapes were taken prior to treatment, and six and 12 months post-treatment and tested for cytology, hrHPV (plus genotype) and CADM1/MAL-methylation. When at six months either of these tests was positive, a colposcopy-directed biopsy was obtained. At 12 months, all women underwent an exit-colposcopy with biopsy. In case of rCIN2/3, re-treatment was done. Results. We found 28 rCIN2 (7.7%) and 14 rCIN3 (3.8%), resulting in a total recurrence rate of 11.5%. All 14 women with rCIN3 and 15/28 (54%) with rCIN2 showed hrHPV type-persistence. Of these, 9/14 ( 64%) rCIN3 and 8/15 (53%) rCIN2 were CADM1/MAL-methylation positive. All incident rCIN2, characterized by hrHPV genotype-switch, were CADM1/MAL-methylation negative. All three carcinomas found after re-treatment were CADM1/MAL-methylation positive. CADM1/MAL-methylation positivity at both baseline and follow-up significantly increased the risk of >= rCIN3 (from 0.7% to 18.4%), and >= rCIN2 (from 82% to 36.8%), compared to a consistently CADM1/MAL-methylation negative result (p-value

Objective Referral for colposcopy because of abnormal Pap test results is likely to be distressing, but the extent and duration of these effects are unknown. We aimed to fill this gap. Methods We conducted a prospective observational study at two departments of Obstetrics and Gynecology (an academic and a non-academic setting). Women referred for colposcopy completed questionnaires before colposcopy, and at 1, 3, and 6months afterwards. A reference group of 706 screen participants, aged 29–60years old, was included and completed questionnaires once. Main outcome measures were generic health-related quality of life (HRQoL), assessed through the EQ-5D and the SF-12 physical and mental scores (PCS-12 and MCS-12); anxiety as assessed by STAI-6, and screen-specific anxiety as assessed by the psychological consequences questionnaire (PCQ). Results 154 women responded to the questionnaire, of whom 132 were included in the analyses. Histological results were CIN 1 in 17/115 women (15%) and CIN 2+ in 62 (54%). In 36 women (31%) there was no histologically confirmed neoplasia. Before colposcopy physical HRQoL scores were similar or slightly better than in the reference group, while mental HRQoL (MSC-12) and (screen-specific) anxiety were worse (p Conclusions Referral for gynecological evaluation because of abnormal PAP-test results was distressing. Anxiety – and not the physical burden of management – seemed to be the most bothersome to women. For all CIN-grades, distress disappeared over six months following colposcopy, suggesting a reassuring effect of gynecological management.

Objective To review and characterise by clinical evaluation, immunohistochemistry and HPV typing a group of adenocarcinomas initially diagnosed with primary localisation in the cervix. Furthermore, to assess the prevalence and prognostic significance of HPV genotypes in a large series of HPV positive cervical adenocarcinomas (AC). Methods One hundred and seventy-one cases of adenocarcinomas (AC) with a primary localisation in the cervix and diagnosed between 1989 and 2008 in the region of Rotterdam, the Netherlands were retrieved. Slides and blocks were reviewed and immunohistochemically stained for CEA and vimentin. HPV testing for high-risk HPV (hrHPV) by PCR (GP5+/6+) and genotyping by reversed line blot were performed. Results In 113 of 171 patients HPV evaluation was possible. 101 were HPV-positive (89%) and 11 were HPV-negative (11%). The 5-year disease free survival was 80% in the HPV-positive group versus 74% in the HPV-negative group (ns). The distribution of HPV types was type 18 in 55 patients (54%), type 16 in 37 (37%), type 45 in 7 (7%), types 53 and 39 were found in 2 respective patients. 5-year overall-survival in patients with HPV-18 was not significantly worse than in patients with HPV-16 (81 versus 87%). Patients with HPV-45 had a worse 5-year survival, 57%. Conclusions AC is hrHPV related in most cases (89%) and HPV-18 is the most frequent type (54%). With the exception of HPV-45, HPV-positivity or type in endocervical AC has no significant influence on survival.

Objective Women exposed to diethylstilbestrol in utero (DES) have an increased risk of clear cell adenocarcinoma (CCA) of the vagina and cervix, while their risk of non-CCA invasive cervical cancer is still unclear. Methods We studied the risk of pre-cancerous (CIN) lesions and non-CCA invasive cervical cancer in a prospective cohort of 12,182 women with self-reported DES exposure followed from 2000 till 2008. We took screening behavior carefully into account. Incidence was obtained through linkage with the Netherlands Nationwide Pathology database (PALGA). General population data were also derived from PALGA. Results The incidence of CIN1 was increased (Standardized Incidence Ratio (SIR)=2.8, 95% Confidence Interval (CI)=2.3 to 3.4), but no increased risk was observed for CIN2+ (CIN2, CIN3 or invasive cancer) compared to the screened general population (SIR=1.1, 95% CI=0.95 to1.4). Women with DES-related malformations had increased risks of both CIN1 and CIN2+ (SIR=4.1, 95%CI=3.0 to 5.3 and SIR=1.5, 95%CI=1.1 to 2.0, respectively). For CIN2+, this risk increase was largely restricted to women with malformations who were more intensively screened. Conclusions An increased risk of CIN1 among DES daughters was observed, especially in women with DES-related malformations, probably mainly due to screening. The risk of CIN2+ (including cancer) was not increased. However, among DES daughters with DES-related malformations a true small risk increase for non-CCA cervical cancer cannot be excluded.

Objective. Recently we reported on the efficacy of imiquimod for treating vulvar intraepithelial neoplasia (VIN) in a placebo-controlled, double-blinded randomized clinical trial (RCT). Four weeks after treatment, a complete response was observed in 35% of patients and a partial response in 46%. All complete responders remained disease-free at 12 months follow-up. In the current investigations, we assessed long-term follow-up at least 5 years after the initial RCT. Methods. Twenty-four of 26 imiquimod-treated patients who had participated in the initial RCT were seen for follow-up. Primary endpoint was durability of clinical response to imiquimod assessed by naked eye vulvar examination and histology. Long-term clinical response was correlated to lesion size before start of the initial RCT. Secondary endpoints were mental health, global quality of life, body image and sexual function in relation with long-term clinical response. Results. Median follow-up period was 7.2 years (range 5.6-8.3 years). VIN recurred in one of nine complete responders. Of the initial partial responders, two became disease-free after additional imiquimod treatment. In the other partial responders, VIN recurred at least once after the initial RCT. In long-term complete responders, lesion size at study entry was smaller and these patients had a significantly better global quality of life at follow-up than patients with residual disease and/or recurrence after imiquimod treatment. Conclusions. In case of a complete response, imiquimod is effective in the long-term. Furthermore, patients with a long-term complete response had a significantly better global quality of life than patients who recurred after imiquimod treatment. (C) 2010 Elsevier Inc. All rights reserved.

Objective. Recently, gene expression profiling techniques have been used on several human cancers to classify tumor subgroups with a specific biological behavior, which were previously undetected by the conventional histopathologic staging systems. In the current study, the clinical usefulness and prognostic value of gene expression profiling in human endometrial carcinomas were studied. Methods. A macro cDNA array, containing cDNAs of 588 genes selected from different areas of cancer research, was used to generate gene expression profiles of tumor tissue samples. The gene expression profiles of 12 endometrial cancers, 3 benign (e.g. noncancer) endometrial tissue samples and 3 myometrial tissue samples, taken from human surgical specimen, were compared. Results. The efficacy to generate a gene expression profile of these tissue samples was 77%. The RNA samples could be randomly taken from the tissue samples and were highly reproducible. Cluster analysis of gene expression profiles of the different samples showed that the benign endometrial and the myometrial samples clustered separately from the tumor samples, indicating that the gene expression profiles were tissue specific and not patient specific. Cluster analysis of the tumor samples revealed two distinct tumor clusters. Ranking of the tumors in the two clusters showed high similarity with the histopathologic classification [International Federation of Gynecology and Obstetrics (FIGO) grading]. Conclusion. Classification of endometrial tumors on basis of their gene expression profiles showed similarity with the FIGO grading system.

Referral for colposcopy because of abnormal Pap test results is likely to be distressing, but the extent and duration of these effects are unknown. We aimed to fill this gap.We conducted a prospective observational study at two departments of Obstetrics and Gynecology (an academic and a non-academic setting). Women referred for colposcopy completed questionnaires before colposcopy, and at 1, 3, and 6 months afterwards. A reference group of 706 screen participants, aged 29-60 years old, was included and completed questionnaires once. Main outcome measures were generic health-related quality of life (HRQoL), assessed through the EQ-5D and the SF-12 physical and mental scores (PCS-12 and MCS-12); anxiety as assessed by STAI-6, and screen-specific anxiety as assessed by the psychological consequences questionnaire (PCQ).154 women responded to the questionnaire, of whom 132 were included in the analyses. Histological results were CIN 1 in 17/115 women (15%) and CIN 2+ in 62 (54%). In 36 women (31%) there was no histologically confirmed neoplasia. Before colposcopy physical HRQoL scores were similar or slightly better than in the reference group, while mental HRQoL (MSC-12) and (screen-specific) anxiety were worse (p0.001). Irrespective of CIN-grades, anxiety washed out during follow-up (p0.001), with changes being clinically relevant.Referral for gynecological evaluation because of abnormal PAP-test results was distressing. Anxiety--and not the physical burden of management--seemed to be the most bothersome to women. For all CIN-grades, distress disappeared over six months following colposcopy, suggesting a reassuring effect of gynecological management.

The purpose of this work was to study intraobserver and interobserver variation in the interpretation of colposcopic images of cervical intraepithelial neoplasia (CIN). Twenty-three experienced colposcopists were asked to assess colposcopic images presented on slides and to select the biopsy site. Eleven cases were independently interpreted twice with an interval of 2-3 months by all observers. No information about the cytological classification was available. In each case the "majority assessment" was considered as the standard, being "no CIN" in 2 cases, CIN I in 4 cases, CIN II in 3 cases, and CIN III in 2 cases. Intraobserver concordance was 66.7%, the kappa value was 0.54. Interobserver agreement was found to be 52.4 and 51.0% in the first and second sessions, respectively, while the mean kappa values were 0.41 and 0.33, respectively. In selecting the site for biopsy, 77.4% of all observers agreed while the same site was selected in 85.3% of cases by the individual colposcopist in the two sessions. Overall, CIN I and II interpretations revealed lower levels of agreement than no CIN or CIN III interpretations. It is concluded that observer variability in interpreting colposcopic images and selecting the site for biopsy is in the same range as observer variation in other subjective diagnostic tests such as cytology and histopathology. This variation should be taken into account in the colposcopical management of patients with abnormal cytology.

To determine the behaviour of adenocarcinomas of the uterine cervix during the last 10 years in the southwest region of the Netherlands, and to determine prognostic factors.Three hundred and five cases of primary cervical adenocarcinomas (ACs) diagnosed between 1989 and 1999 in the region of Rotterdam, The Netherlands, were retrieved. Clinical and pathological data were reviewed and analysed.Mean age at presentation was 52 years. The mean follow-up time for surviving patients was 61 months. The overall survival was 60% at 5 years. The 5-year survival rates for stages I and II were, respectively, 79% and 37%. The 5-year survival rates for stages III and IV were less than 9%. Using univariate analysis stage, grade, age35 years and histological type were significant prognostic factors. In the group of patients who underwent surgery (n = 200), stages I-IIA, lymph node metastases, lymph-vascular-space-invasion (LVSI) and depth of stromal invasion were significant for survival. For patients with stages I and II-A disease, survival was significantly better where the primary treatment was surgical as opposed to primary radiotherapy (P = 0.002). Using multivariate analysis, only stage, grade and lymph node metastases remained significant independent predictors for survival.This report about cervical adenocarcinoma in the southwest region of The Netherlands shows similar results for survival to previous reports. Longest survival was for patients with early stage disease, younger patients and after primary surgery. We found FIGO stage, grade and lymph node metastases of significant prognostic value for survival in cervical adenocarcinoma.

Detection of HPV-DNA in squamous vulvar carcinoma, its prognostic significance, and investigation of the presence of lichen sclerosus near HPV-DNA-positive vulvar carcinomas were the objectives of this study. In 60 samples of squamous vulvar cancer, we looked for HPV-DNA by means of PCR. The same samples were examined for the presence of lichen sclerosus. The possible prognostic significance of the presence of HPV-DNA and lichen sclerosus was studied. Nineteen (32%) of the samples were HPV-DNA positive using PCR. Patients with an HPV-positive tumor had a better prognosis than those with an HPV-negative tumor (P = 0.03). Lichen sclerosus was found in 19 tumor samples, of which 7 had detectable HPV-DNA. Only a minority of vulvar cancers contain HPV-DNA. In contrast to previous statements, near some of these HPV-positive cancers, lichen sclerosus can be found.

Sixty-four patients with FIGO stages IB and IIA squamous cell carcinoma of the uterine cervix were studied to assess the prognostic potential of the presence of HPV DNA and HPV genotypes in the tumor, as detected by a general primer-mediated polymerase chain reaction followed by a type-specific PCR on paraffin-embedded tissue sections of the primary tumor. The prevalence of various HPV types in 32 patients with positive lymph nodes was compared to the prevalence found in 32 age-matched controls with negative lymph nodes. In both patient groups HPV DNA was found in all cases. The prevalence rates of HPV types 16, 18, and X in the positive and negative lymph node group were 78% versus 72%, 13% versus 9%, and 3% versus 16%, respectively. These differences were not statistically significant. HPV genotypes 6, 11, and 31 were not found. Differences in recurrence rate and 5-year survival rate between the patient groups with different tumor-containing HPV genotypes were not statistically significant. Nor was there any statistically significant relationship between HPV type and other well-know prognosticators. In conclusion, in our study a 100% HPV DNA prevalence was found in squamous cell cervical carcinomas. Neither the presence of HPV DNA nor the HPV genotype appeared to be related to either the presence of lymph node metastases at the time of initial treatment or to 5-year survival.

Endocervical curettage as routine part of colposcopic examination in patients with abnormal cervical cytology is recommended by many experts. Endocervical curettage (ECC) by Vabra aspiration has never been reported in literature. The results of Vabra ECC in 103 patients are analyzed and compared to the results of a second endocervical specimen, obtained by conventional curettage, cone biopsy, or hysterectomy. An accordance of over 98% is demonstrated and the difference is discussed. In 88% and 71% adequate Vabra ECC specimens were available for cytological and histological examination, respectively. In any patient at least one result was present. Both cytological and histological specimens are of reliable quality. No cases of invasive (adeno)carcinoma were missed. In addition, the results are compared to literature data concerning Vabra aspiration for endometrial disease and ECC by other techniques. Vabra ECC is considered an efficient, safe, and well-tolerated diagnostic outpatient method and recommended as a standard part of colposcopic evaluation.

Predictive values of endocervical curettage (ECC) in the investigation of patients with abnormal Pap-smears were calculated with regard to a second histological diagnosis and with regard to results of conservative treatment of CIN. By using the combined follow up data of all 290 patients with colposcopically directed biopsies and ECC, the predictive value of a positive ECC for invasive cancer in patients with satisfactory colposcopy was 2%, and for unsatisfactory colposcopy 15%. Predictive value of a negative ECC was 100% in patients with satisfactory colposcopy, and 98% for unsatisfactory colposcopy. It is concluded that ECC should be used routinely in the investigation of patients with abnormal Pap smears. However, a positive ECC is not considered an absolute contraindication to conservative treatment, provided that colposcopy is satisfactory, that there is no suspicion of invasive cancer, and that a strict follow-up scheme can be maintained during the first year.

A randomized study was performed to compare efficacy and side effects of laser and cryotherapy: 51 patients were treated with laser vaporization and 50 patients with cryotherapy. Success rates for laser and cryotherapy were not significantly different. Success rates were significantly related to lesion size. Grade of CIN, positive endocervical curettage, parity, and age at treatment were not found to be related. Vaginal discharge, both in duration and amount, was significantly less in patients treated with laser vaporization, compared with cryotherapy, but pain and bleeding occurred more often in patients treated with laser vaporization. A brief review of possible sources of bias in comparative studies on laser and cryotherapy is given, indicating the preference for a randomized study. It is concluded that widespread introduction of laser facilities in smaller centers is not justified, because the success rates are not better than those of cryotherapy, and because the advantages of less discharge are outweighed by the high cost.