Risk of cervical intra-epithelial neoplasia and invasive cancer of the cervix in DES daughters.

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.

The increased detection of cervical intraepithelial neoplasia when using a second biopsy at colposcopy.

OBJECTIVE: It has been suggested that colposcopy can miss a significant percentage of high-grade cervical intraepithelial neoplasia (CIN2+). Improved disease ascertainment was evaluated by taking multiple lesion-directed biopsies. METHODS: In a cross-sectional multicenter study in the Netherlands and Spain, 610 women referred to colposcopy following abnormal cervical cytology results were included. Multiple directed biopsies were collected from lesions and ranked according to impression. A non-directed biopsy of normal-appearing tissue was added if fewer than four biopsies were collected. We evaluated the additional CIN2+ yield for one and two directed biopsies. Colposcopic images were reviewed for quality control. RESULTS: In women with at least two lesion-directed biopsies the yield for CIN2+ increased from 51.7% (95%CI; 45.7-57.7) for one directed biopsy to 60.4% (95%CI; 54.4-66.2, p<0.001) for two biopsies. The highest CIN2+ yield was observed in women who were HPV16-positive, had high-grade squamous intraepithelial lesion (HSIL) cytology, and high-grade colposcopy impression. The yield increased from 83.1% (95%CI; 71.5-90.5) with one directed biopsy to 93.2% (95%CI; 83.8-97.3) with two directed biopsies. Only 4.5% additional CIN2+ were detected in biopsies not targeting abnormal areas on the cervix. CONCLUSIONS: A second lesion-directed biopsy is associated with a significant increase in CIN2+ detection. Performing a second lesion-directed biopsy and using a low threshold for abnormality of any acetowhitening should become the standard clinical practice of colposcopy.

Vaginal and (uncommon) cervical cancers in the Netherlands, 1989-2003.

BACKGROUND: The clinical and prognostic evaluation of cervical and vaginal tumors other than squamous cell and adenocarcinomas is hampered by the low incidence, and clinical and epidemiological studies on these uncommon tumors are scarce. Having close affinity with the pathology laboratories, the Netherlands Cancer Registry offers a great opportunity to study frequency, stage, treatment, and survival of uncommon tumors in the cervix and vagina and separately, the clear cell adenocarcinoma of the vagina and cervix. METHODS: All invasive cervical tumors (n = 10,570) and all in situ and invasive vaginal tumors (n = 778) diagnosed in the Netherlands during 1989-2003 were selected from the Netherlands Cancer Registry. Age, stage at diagnosis, and treatment were described for each histological subgroup to find differences between common and uncommon tumors, including 5-year relative survival rates. RESULTS: Twenty-five patients (3%) with cervical cancer subsequently developed a vaginal tumor (during 1989-2003), and 19 of these patients underwent hysterectomy for their cervical cancer. A significantly worse prognosis was found for patients with small cell neuroendocrine cervical tumors and for patients with vaginal melanomas. Patients with clear cell adenocarcinoma of the vagina and cervix were found across all age categories. CONCLUSIONS: The less common histological types of cervical and vaginal cancers were clearly different from squamous cell carcinomas, especially with respect to age at diagnosis and survival rates. Spreading population-based knowledge of effects of treatment of these uncommon tumors should help clinical decision making and therefore improve prognosis.

[A falsely reassuring cervical smear in adenocarcinoma of the external os]. / Een onterecht geruststellend cervixuitstrijkje bij een adenocarcinoom van de baarmoedermond.

3 women with only mild changes in cervical smears were later found to be suffering from cervical adenocarcinoma. The first patient was 53 years old. Her smears repeatedly showed Pap 3 with moderately atypical glandular cells. After 3 colposcopic examinations with biopsies and 2 loop electrosurgical excision procedures of the cervix which showed no histological signs of malignancy, diagnostic conization revealed an adenocarcinoma of the endocervix. She underwent a radical hysterectomy and chemoradiation because of positive pelvic nodes. The second patient was 30 years old and had persistent vaginal discharge and an enlarged cervix, but no cytological abnormalities. Colposcopy was unsatisfactory and the tissue obtained by loop electrosurgical excision was normal. Adenocarcinoma was diagnosed after conization. She was treated with radical hysterectomy and radiotherapy but died after one year. The third patient, aged 26, had a long history of slightly abnormal Pap smears and vulvar condylomata, and was referred with vaginal discharge. A severe abnormal smear with glandular atypia was followed by colposcopical biopsies and conization, which revealed an endocervical adenocarcinoma. She underwent radical hysterectomy. Adenocarcinoma is a rare type of cervical cancer: III cases out of 584 patients with cervical cancer in 2003 in the Netherlands. This neoplasm is more difficult to detect than cervical squamous cell carcinoma. Cervical cytology is not an effective tool for screening and diagnosis. Due to the localization, multifocality and diversity in its presentation, the assessment of cytology has a high false-negative percentage. Screening may be enhanced by combining cytology with testing for high-risk HPV types, notably type 18. If cervical cytology shows persistent atypical glandular cells with no conclusive histological result, then due to the endocervical localisation of the lesions adenocarcinoma can only be excluded by conization.

[Vaccines against human papillomavirus (HPV); between registration and implementation]. / Vaccins tegen Humaan papillomavirus (HPV); tussen registratie en implementatie.

--Each year, 600-700 women in the Netherlands are diagnosed with cervical cancer. Over the last 10 years, an average of 250 women have died annually due to cervical cancer. --Gardasil, the first vaccine for Human papillomavirus (HPV), was recently approved in Europe for the prevention of cervical cancer. --The availability of a vaccine for HPV prompts the question whether it should be included in the Dutch National Immunisation Programme. --At the end of 2006, the Medicines Evaluation Board, the Health Council of the Netherlands and the Centre for Infectious Disease Control of the National Institute for Public Health and the Environment organised a workshop for experts in the field to answer that question. --The HPV vaccine provides protection against HPV-16 and HPV-18, which cause approximately 70% of cervical cancers. --Because the efficacy of vaccination is only evident after many years, preserving good participation in the screening programme is essential. --The current screening could be improved by introducing an HPV test combined with self-sampling for women who do not participate in screening. --Vaccination is unarguably an important development. However, there are still several unanswered questions regarding vaccination and its actual protection, duration of protection, long-term safety and cost-effectiveness. --April 1st, 2008, the Health Council of the Netherlands had recommended including HPV vaccination in the National Immunisation Programme.

[New version of the pathology practice guideline for cervical cytology: sharpened criteria for adequacy; expanded use of new techniques]. / Nieuwe versie van de pathologiepraktijkrichtlijn voor cervixcytologisch onderzoek: criteria voor adequaatheid aangescherpt; gebruik van nieuwe technieken verruimd.

The Dutch Pathology Association (NVVP) has modified the practice guideline for cervical cytology. The changes were made in consultation with the Dutch College ofGeneral Practitioners (NHG) and the Dutch Society for Obstetrics and Gynaecology (NVOG). The four most important changes are: (a) breastfeeding is no longer a contraindication for smear taking; (b) the rejection of smears, under certain conditions, if the cervix has not been visualised; the representativeness of a smear depends in part on the degree to which the requesting physician has verified that the smear was taken from the cervix; if the smear lacks endocervical cells, it must be considered inadequate if the requestor has not seen the cervix or designates the portio as abnormal; (c) the use of thin-layer cytology is accepted; (d) addition of the test for high-risk Human papilloma virus (hrHPV-test) may reduce the number of secondary repeat smears.

[The 1996 revision of the Dutch cervical cancer screening programme: increased coverage, fewer repeat smears and less opportunistic screening]. / Herziening bevolkingsonderzoek op baarmoederhalskanker 1996: hogere dekkingsgraad, minder herhalingsuitstrijkjes en minder opportunistische screening.

OBJECTIVE: Comparison of the indicators of effectiveness and efficiency of the Dutch national cervical cancerscreening programme in 2003 and 1994, the last year before implementation of important changes in the medical and organisational guidelines. DESIGN: Descriptive. METHOD: Data on all Pap smears made in 1994 and 2003 were retrieved from the Pathologic Anatomical National Automated Archive (PALGA), together with the matching cytological and histological follow-up until April 2004. In order to calculate the 5-year coverage, the number of women that had had a smear taken was placed in the numerator and divided by the number of women that had been invited for the screening programme during those 5 years. RESULTS: The 5-year coverage in the age range 30-64 years increased from 69 in 1994 to 77% in 2003. The percentage of smears resulting in a recommendation for a repeat smear decreased from 10 to 2. The percentage of timely compliance with recommendations for a repeat smear increased from 47 to 86, while that of smears with an immediate referral recommendation remained the same (about go). There was a sharp decrease in screening outside of the target-age range and screening with too short an interval. As a consequence, despite the higher coverage, the total number of smears decreased. CONCLUSION: The changes in the Dutch cervical cancerscreening programme in 1996 with regard to participation, the number of and compliance with recommendations for repeat smears, and screening activity outside of the target group were accompanied by significant improvements in agreement with the goals of the revision. The potential consequences for the effectiveness of the screening programme (reduction of cervical cancer mortality) will become apparent in the years to come.

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.

Gene expression profiling in human endometrial cancer tissue samples: utility and diagnostic value.

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.

Prognostic factors in adenocarcinoma of the uterine cervix.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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, age < 35 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. CONCLUSIONS: 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.

[Follow up after an abnormal pap smear: time interval acceptable, nature of follow up leaves room for improvement]. / Vervolgonderzoek na een afwijkend uitstrijkje: tijdsinterval acceptabel, aard van het vervolgonderzoek vaak niet.

OBJECTIVE: To investigate whether the interval between an abnormal Pap smear and follow-up is too long and whether the guidelines for histological follow-up after an abnormal Pap smear are being followed. DESIGN: Descriptive. METHOD: Data on all Pap smears of a minimum Pap class 3a (moderate dysplasia) from the national cervical-cancer screening programme in the Rotterdam area of the Netherlands were acquired from the Pathological Anatomical National Automated Archive (PALGA). The test results from each woman were arranged chronologically and the nature of the follow-up cervical examinations (cytological and histological) was recorded. The observation period was 360 days. The average interval in days between Pap smear and follow-up as well as the nature of the follow-up were analysed. RESULTS: In total, data on 156 women were analysed. In 93% of women follow-up was done during our observation period. The average interval was 60 days. In 80% of the women follow-up took place within 3 months and in 90% within 6 months. In 32% of women in the follow-up group the Pap smear was repeated at their first follow-up visit and in the remaining cases, a histological examination was performed according to the guidelines. In 7% of cases no cytological or histological follow-up at all took place within the year. CONCLUSION: The average interval between an abnormal Pap smear and follow-up is acceptable because of the slow natural course of cervical carcinoma. Attention should be focused on the incorrect repetition of the cytological test and on the fact that in a number of cases no follow-up at all is done within 1 year.

[Diagnostic image (142). A woman with persistent dyspareunia and vaginal discharge. Vaginal adenosis]. / Diagnose in beeld (142). Een vrouw met persisterende dyspareunie en fluor. Vaginale adenose.

In a 30-year-old woman with persistent dyspareunia and vaginal discharge additional investigations revealed a vaginal adenosis.

[A repeat advice no longer applies for cervical smears without endocervical cells in population studies for cervical cancer]. / Geen herhalingsadvies meer bij een cervixuitstrijk zonder endocervicale cellen in het bevolkingsonderzoek op baarmoederhalskanker.

Recent Dutch and non-Dutch studies have shown that the absence of endocervical cells (ecc-) in an adequate cervical smear does not present an increased risk for the presence or occurrence of cervical cancer or premalignant abnormalities in a later phase. Based on these findings, the Coordination Committee Cervical Cancer Screening of the Dutch Health Insurance Council had advised dropping the repeat advice for non-abnormal ecc- smears by January 1st 2002. The National Health Insurance Council has agreed to this advice. The following measures have been taken: (a) no repeat advice for ecc- smears; in the case of negative findings the woman waits until the next five-yearly invitation from the screening programme; (b) whether the portio cervicis was seen has to be stated on the national request form; (c) the reporting of an ecc- in the cytology report and periodical feedback to general practitioners remains unchanged; (d) in the case of a non-abnormal ecc- smear with an uninspected portio or doubts as to whether the transformation zone was adequately scraped, either the smear will have to be repeated or the patient will have to be referred to the gynaecologist.

[Vulvovaginal complaints, dyspareunia and oral mucosa abnormalities: erosive lichen planus]. / Vulvovaginale klachten, dyspareunie en orale mucosa-afwijkingen: erosieve lichen planus.

Three women, aged 46, 48 and 73 years respectively, suffered from erosive genital lichen planus. Vulvar irritation, dyspareunia and vaginal discharge are the prominent signs of this disease. Lichen planus is an inflammatory dermatosis, which can involve skin and oral and genital mucosa. Diagnosis and treatment are difficult. Prolonged local application of a corticosteroid cream, e.g. clobetasol, is usually warranted. Narrowing of the vagina and painful mucosal lesions often prevent sexual intercourse. The combination of oral and genital complaints can help in the diagnosis of lichen planus. Strict follow-up is necessary because of the possible malignant degeneration of the disease.

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.

Clinical significance of endocervical curettage as part of colposcopic evaluation. A review.

This paper addresses the role of endocervical curettage (ECC) as an adjunct of colposcopic evaluation of patients with abnormal cervical cytology. In a meta-analysis of literature data the contribution of ECC to the diagnostic accuracy of colposcopic examination and in the predictive value with regard to the final histologic diagnosis is discussed. The clinical impact of the application of ECC appears to be limited. Figures suggest a reduction in underdiagnosis of (micro)carcinoma in patients with satisfactory colposcopy and an increase of predictive value in diagnosis of invasive disease in unsatisfactory colposcopy.