Management and prognostic factors of epithelioid trophoblastic tumors: Results from the International Society for the Study of Trophoblastic Diseases database.

OBJECTIVE: Epithelioid Trophoblastic Tumor (ETT) is an extremely rare form of Gestational Trophoblastic Neoplasia (GTN). Knowledge on prognostic factors and optimal management is limited. We identified prognostic factors, optimal treatment, and outcome from the world's largest case series of patients with ETT. METHODS: Patients were selected from the international Placental Site Trophoblastic Tumor (PSTT) and ETT database. Fifty-four patients diagnosed with ETT or mixed PSTT/ETT between 2001 and 2016 were included. Cox regression analysis was used to identify prognostic factors for overall survival (OS). RESULTS: Forty-five patients with ETT and 9 patients with PSTT/ETT were included. Thirty-six patients had FIGO stage I and 18 had stages II-IV disease. Patients were treated with surgery (n = 23), chemotherapy (n = 6), or a combination of surgery and chemotherapy (n = 25). In total, 39 patients survived, including 22 patients with complete sustained hCG remission for at least 1 year. Patients treated with surgery as first line treatment had early-stage disease and all survived. Most patients treated with chemotherapy with or without surgery had FIGO stages II-IV disease (55%). They underwent multiple lines of chemotherapy. Eleven of them did not survive. Interval since antecedent pregnancy and FIGO stage were prognostic factors of OS (p = 0.012; p = 0.023 respectively). CONCLUSIONS: Advanced-stage disease and an interval of ≥48 months since the antecedent pregnancy are poor prognostic factors of ETT. Surgery seems adequate for early-stage disease with a shorter interval. Advanced-stage disease requires a combination of treatment modalities. Because of its rarity, ETT should be treated in a centre with experience in GTN.

Stop routine screening for associated malignancies in cutaneous noninvasive vulvar Paget disease?

BACKGROUND: Vulvar Paget disease (VPD) is extremely rare and thought to be associated with other malignancies. OBJECTIVES: To evaluate the risk of developing breast, intestinal and urological malignancies in patients with VPD compared with the general population, and in particular to focus on the risk of malignancy in patients with cutaneous noninvasive VPD. METHODS: Data on the oncological history of patients with any type of VPD between 2000 and 2015 were obtained from PALGA, a nationwide archive containing all pathology reports in the Netherlands. Follow-up data and a control group from the general population were obtained from the Netherlands Cancer Registry. After correction for age and calendar year at time of diagnosis, standardized incidence ratios (SIRs) for the first 3 years after VPD diagnosis were estimated with 95% confidence intervals (CIs). RESULTS: We identified 199 patients with a first diagnosis of VPD [164 noninvasive, 35 (micro)invasive] between 2000 and 2015. The SIR of developing an associated malignancy in the first 3 years after diagnosis was 4·67 (95% CI 2·66-7·64). This was due mainly to the high incidence of intestinal malignancies among patients with secondary VPD. Subgroup analysis for cutaneous noninvasive VPD did not reveal a significantly increased risk for associated malignancies: SIR 2·08 (95% CI 0·76-4·62). CONCLUSIONS: Of our patients with VPD, 76·9% were diagnosed with cutaneous noninvasive VPD, and this group has no increased risk for developing malignancies of the breast, intestine or urological tract. Our study suggests that routine screening for these malignancies in patients diagnosed with cutaneous noninvasive VPD may not be necessary.

Vulvar cancer: Two pathways with different localization and prognosis.

BACKGROUND: Two etiologic pathways for vulvar squamous cell carcinoma (SCC) are described: in a background of lichen sclerosus and/or differentiated vulvar intraepithelial neoplasia and related to high-risk human papillomavirus (HPV) infection with high grade squamous intraepithelial lesion (HSIL) as precursor. The aim was to compare the predilection site and survival of HPV-related to non HPV-related vulvar SCCs. METHODS: Data of patients treated for primary vulvar SCC at the Radboudumc between March 1988 and January 2015 were analyzed. All histological specimens were tested for HPV with the SPF10/DEIA/LiPA25 system assay and p16INK4a staining was performed using CINtec® histology kit. Vulvar SCCs were considered HPV-related in case of either >25% p16INK4a expression and HPV positivity or >25% p16INK4a expression and HSIL next to the tumor without HPV positivity. Tumor localization, disease specific survival (DSS), disease free survival (DFS) and overall survival (OS) of patients with HPV-related and non HPV-related vulvar SCC were compared. RESULTS: In total 318 patients were included: 55 (17%) had HPV-related (Group 1) and 263 (83%) had non HPV-related vulvar SCC (Group 2). Tumors in Group 1 were significantly more often located at the perineum compared to Group 2, 30% and 14%, respectively (p=0.001). The DSS, DFS and OS were significantly better in HPV-related than in non HPV-related vulvar SCC patients. CONCLUSION: HPV-related vulvar SCCs are more frequently located at the perineum and have a favorable prognosis compared to non HPV-related vulvar SCCs. Both localization and HPV-relation could explain this favorable prognosis. HPV-related vulvar SCC seems to be a separate entity.

Reactivation of Latent HPV Infections After Renal Transplantation.

Female renal transplant recipients (RTRs) have an increased risk for developing human papillomavirus (HPV)-related (pre)malignant lesions of the genital tract. This study aims to assess the genital prevalence of HPV before and after renal transplantation (RT). In female patients who were counseled for RT at the Radboud University Medical Center Nijmegen, the Netherlands, gynecological examination was performed at first visit, and 1 and 2 years later. HPV self-sampling and questionnaires on sexual behavior were performed every 3 months. In 65 patients who underwent RT, the high-risk human papillomavirus (hrHPV) prevalence as assessed with the highly sensitive SPF10 -LiPA25 test increased significantly from 19% before to 31% after RT (p = 0.045). Based upon the clinically validated Cobas 4800 HPV test, the hrHPV prevalence increased from 10% before to 14% after RT (p = 0.31). During follow-up, no changes in sexual behavior were reported. Thirty-three patients who did not undergo RT showed a hrHPV prevalence of 21% at study entry and of 27% after 12 months with the sensitive test, and a stable prevalence of 16% with the clinically validated test. The results of this study indicate that activation of latent HPV infections may contribute to the increased risk of HPV-related (pre)malignant lesions in female RTRs.

Can the FIGO 2000 scoring system for gestational trophoblastic neoplasia be simplified? A new retrospective analysis from a nationwide dataset.

BACKGROUND: Worldwide introduction of the International Fedaration of Gynaecology and Obstetrics (FIGO) 2000 scoring system has provided an effective means to stratify patients with gestational trophoblastic neoplasia to single- or multi-agent chemotherapy. However, the system is quite elaborate with an extensive set of risk factors. In this study, we re-evaluate all prognostic risk factors involved in the FIGO 2000 scoring system and examine if simplification is feasible. PATIENTS AND METHODS: Between January 2003 and December 2012, 813 patients diagnosed with gestational trophoblastic neoplasia were identified at the Trophoblastic Disease Centre in London and scored using the FIGO 2000. Multivariable analysis and stepwise logistic regression were carried out to evaluate whether the FIGO 2000 scoring system could be simplified. RESULTS: Of the eight FIGO risk factors only pre-treatment serum human chorionic gonadotropin (hCG) levels exceeding 10 000 IU/l (OR = 5.0; 95% CI 2.5-10.4) and 100 000 IU/l (OR = 14.3; 95% CI 4.7-44.1), interval exceeding 7 months since antecedent pregnancy (OR = 4.1; 95% CI 1.0-16.2), and tumor size of over 5 cm (OR = 2.2; 95% CI 1.3-3.6) were identified as independently predictive for single-agent resistance. In addition, increased risk was apparent for antecedent term pregnancy (OR = 3.4; 95% CI 0.9-12.7) and the presence of five or more metastases (OR = 3.5; 95% CI 0.4-30.4), but patient numbers in these categories were relatively small. Stepwise logistic regression identified a simplified risk scoring model comprising age, pretreatment serum hCG, number of metastases, antecedent pregnancy, and interval but omitting tumor size, previous failed chemotherapy, and site of metastases. With this model only 1 out 725 patients was classified different from the FIGO 2000 system. CONCLUSION: Our simplified alternative using only five of the FIGO prognostic factors appears to be an accurate system for discriminating patients requiring single as opposed to multi-agent chemotherapy. Further work is urgently needed to validate these findings.

The added value of hysterectomy in the management of gestational trophoblastic neoplasia.

BACKGROUND: Despite the undoubted effectiveness of chemotherapeutic treatment in gestational trophoblastic neoplasia (GTN), problems related to toxicity of chemotherapy and chemo-resistant disease have led to reconsideration of the use of hysterectomy. Aim of the present study was to evaluate indications for and outcome of hysterectomy in patients with GTN in a nation-wide cohort. METHODS: Between 1977 and 2012, we identified all patients diagnosed with GTN and treated with hysterectomy from the Dutch national databases. Demographics, clinical characteristics and follow-up were recorded retrospectively. RESULTS: One hundred and nine patients (16.5% of all registered patients with GTN) underwent hysterectomy as part of their management for GTN. The majority of patients was classified as low-risk disease (74.3%), post-molar GTN (73.5%) and disease confined to the uterus (65.1%). After hysterectomy, complete remission was achieved in 66.2% of patients with localized disease and in 15.8% of patients with metastatic disease. For patients with localized disease, treated with primary hysterectomy, treatment duration was significantly shorter (mean 3.2weeks and 8.0weeks respectively, p=0.01) with lower number of administered chemotherapy cycles (mean 1.5 and 5.8 respectively, p<0.01) than patients in a matched control group. CONCLUSION: In selected cases, a hysterectomy may be an effective means to either reduce or eliminate tumor bulk. Primary hysterectomy should mainly be considered in older patients with localized disease and no desire to preserve fertility, whereas patients with chemotherapy-resistant disease may benefit from additional hysterectomy, especially when disease is localized. For patients with widespread metastatic disease, the benefit of hysterectomy lies in the removal of chemotherapy-resistant tumor bulk with subsequent effect on survival.

High-risk human papillomavirus detection in self-sampling compared to physician-taken smear in a responder population of the Dutch cervical screening: Results of the VERA study.

In 2017 the cervical cancer screening program in The Netherlands will be revised. Cervical smears will primarily be tested for the presence of high-risk human papillomavirus (hrHPV) instead of cytology, and vaginal self-sampling will be offered to non-responders. This includes a potential risk that part of the women who would otherwise opt for a cervical smear will wait for self-sampling. However, self-sampling for hrHPV in a responder population has never been studied yet. The aim of this study was to investigate the applicability and accuracy of self-sampling in detecting hrHPV in a screening responder population. A total of 2049 women, aged 30-60years, participating in the screening program in The Netherlands were included from April 2013 to May 2015. After they had their cervical smear taken, women self-collected a cervicovaginal sample with a brush-based device, the Evalyn Brush. Both the cervical smear and self-sample specimen were tested with the COBAS 4800 HPV platform. The hrHPV prevalence was 8.0% (95% CI 6.9-9.2) among the physician-taken samples, and 10.0% (95% CI 8.7-11.3) among the self-samples. There was 96.8% (95% CI 96.0-97.5) concordance of hrHPV prevalence between self-samples and physician-taken samples. Women in our study evaluated self-sampling as convenient (97.1%), user-friendly (98.5%), and 62.8% preferred self-sampling over a physician-taken sampling for the next screening round. In conclusion, self-sampling showed high concordance with physician-taken sampling for hrHPV detection in a responder screening population and highly acceptable to women. Implementation of HPV-self-sampling for the responder population as a primary screening tool may be considered.

The effect of video information on anxiety levels in women attending colposcopy: a randomized controlled trial.

OBJECTIVE: The aim was to investigate whether additional information, in video form, reduces anxiety, depression and pain levels in women referred for colposcopy. MATERIAL AND METHODS: Between September 2012 and March 2015, 136 patients referred for colposcopy were randomized into two study arms. Group A received video information in addition to the regular information leaflet, and group B (control group) received only the regular information leaflet. The patients were requested to complete standardized online questionnaires. The first online questionnaire (T1) was pre-randomization, and was completed at home, 5 days prior to the appointment. The second online questionnaire (T2) was completed directly before the colposcopy appointment, and the last online questionnaire (T3) was completed directly following colposcopy at the out-patient clinic. The questionnaires included the Spielberger State-Trait Anxiety Inventory (STAI), the Hospital Anxiety and Depression Scale (HADS), and the Numeric Rating Scale (NRS) to assess pain. RESULTS: The STAI state anxiety score was high (44.6), but there was no significant difference in STAI, HADS and NRS between the two groups at the three measuring points. A post hoc analysis showed that women with a generally higher baseline anxiety trait had significantly lower HADS anxiety levels following video information. CONCLUSIONS: Additional information (video) before colposcopy did not significantly reduce anxiety, depression, and expected or experienced pain, as measured by the STAI, HADS and NRS in patients attending their first colposcopy appointment. However, most patients positively appreciated the video information, which may reduce the anxiety of extremely anxious patients.

The value of fine needle aspiration cytology diagnosis in ovarian masses in children and adolescents.

STUDY QUESTION: Is ovarian cytology a reliable predictor for a malignant ovarian mass? SUMMARY ANSWER: Cytology of an ovarian mass in children and adolescents cannot be used to exclude malignancy. WHAT IS KNOWN ALREADY: It is hard to predict malignancy in case of an ovarian mass in a child or adolescent. The most common reason to perform fine needle aspiration cytology (FNAC) is to exclude malignancy. Ovarian cytology has shown varying results in adults, but test performance in a younger population is unknown. STUDY DESIGN, SIZE, DURATION: This was a retrospective diagnostic test accuracy study. We used a nationwide registry, the PALGA database, to select girls aged 18 or younger with matching ovarian cytology and histology reports available between 1990 and 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Histology diagnoses were classified according to the WHO classification of ovarian pathology. Cytology diagnoses were classified as benign, borderline malignant or malignant. Cases with inconclusive cytology diagnoses were excluded from the analysis of diagnostic accuracy. Diagnostic accuracy was calculated using a 2 × 2 table. MAIN RESULTS AND THE ROLE OF CHANCE: Included were 552 girls under the age of 18 who had a cytology and a histology report of the same ovary available in the PALGA database. In 523 (94.7%) patients the mass was benign; 19 (3.4%) patients had a borderline malignancy and 9 (1.7%) patients had a malignant tumour. The histology diagnosis was unknown in one patient due to torsion of the ovary. Cytological diagnosis was inconclusive in 96 patients (17.4%). Cytology had a sensitivity of 32.0% and a specificity of 99.8%. Post-test probability of malignancy with positive cytology was 88.9%; the post-test probability of a malignancy with negative cytology was 3.8%, compared with a pre-test probability of 5.5%. LIMITATIONS, REASONS FOR CAUTION: This study was retrospective, using data gathered over 24 years. Cytology was retrieved during surgery or at the pathology department in 86.6% of the cases and pathologists were not blinded, which can be a cause for bias. WIDER IMPLICATIONS OF THE FINDINGS: Since the sensitivity is low, FNAC is not a recommended diagnostic tool in children. The post-test probability of a negative test compared with the incidence in our population resulted in a minimal difference not worth an invasive procedure. STUDY FUNDING/COMPETING INTERESTS: No study funding was received and no competing interests are present. TRIAL REGISTRATION NUMBER: NA.

Very high uptake of risk-reducing salpingo-oophorectomy in BRCA1/2 mutation carriers: A single-center experience.

OBJECTIVE: Risk-reducing salpingo-oophorectomy (RRSO) is the only effective surgical strategy to reduce the increased risk of epithelial ovarian cancer in BRCA1/2 mutation carriers. Given the long-term health consequences of premature surgical menopause, we need insight in uptake and timing of RRSO to guide us in improving healthcare. METHODS: A single-center retrospective cohort study of BRCA1/2 mutation carriers diagnosed and counseled at the multidisciplinary Family Cancer Clinic of the Radboud university medical center in Nijmegen, The Netherlands, between 1999 and 2014. Descriptive statistics were used to analyze uptake and timing of RRSO. RESULTS: Data of 580 BRCA1/2 were analyzed. The uptake of RRSO among mutation carriers who are currently above the upper limit of the recommended age for RRSO, is 98.5% and 97.5% for BRCA1 and BRCA2 mutation carriers, respectively. The vast majority undergoes RRSO ≤40 (BRCA1) or ≤45 (BRCA2) years of age, provided that mutation status is known by that age: 90.8% and 97.3% of BRCA1 and BRCA2 mutation carriers, respectively. CONCLUSIONS: The uptake of RRSO among BRCA1/2 mutation carriers who were counseled at our Family Cancer Clinic is extremely high. High uptake might be largely attributed to the directive and uniform way of counseling by professionals at our Family Cancer Clinic. Given the fact that RRSO is often undergone at premenopausal age in our population, future research should focus on minimizing long-term health consequences of premature surgical menopause either by optimization of hormone replacement therapy or by investigating alternative strategies to RRSO.

Trends in incidence for gestational trophoblastic disease over the last 20 years in a population-based study.

BACKGROUND: Gestational trophoblastic disease (GTD) represents a heterogeneous group of disorders. Wide variations in incidence rates are reported worldwide, probably explained by a lack of centralized databases and heterogeneity in case definition. The aim of the present study was to determine the trends in incidence of GTD in the last 20 years with the use of population-based data. PATIENTS AND METHODS: Data on patients with pathologically confirmed diagnosis of GTD between 1994 and 2013 were obtained from PALGA, a nationwide archive containing all pathology reports in the Netherlands. RESULTS: In the 20-year period 6343 cases were registered with GTD, representing an overall incidence rate of 1.67 per 1000 deliveries per year. An initial rise in incidence rate was seen over the first 10 years (0.075 per year, 95% CI 0.040-0.109), followed by a stabilization from 2004 to 2013 (increase per year 0.011, 95% CI -0.017-0.040). Although partial hydatidiform mole (HM) was more common in earlier years, complete and partial HM reached comparable incidence rates of 0.68 and 0.64 per 1000 deliveries respectively from 2009 onwards. In the last decade, unspecified HM diagnosis declined significantly from 0.14 per 1000 deliveries in 2003 to 0.03 per 1000 deliveries (per year -0.011, CI -0.016-0.06), suggesting improved diagnostic analyses. CONCLUSION: After an initial rise in GTD incidence in the Netherlands rates remained steady from 2004 onwards. As pathological confirmation is currently the norm and advanced pathological techniques are now widely available, true steady incidence rates may have been reached.

Evidence supporting see-and-treat management of cervical intraepithelial neoplasia: a systematic review and meta-analysis.

BACKGROUND: Studies of see-and-treat management of cervical intraepithelial neoplasia (CIN) vary in their inclusion criteria, resulting in a broad range of overtreatment rates. OBJECTIVES: To determine overtreatment rates in see-and-treat management of women referred for colposcopy because of suspected CIN, in order to define circumstances supporting see-and-treat management. SEARCH STRATEGY: MEDLINE, EMBASE, and the Cochrane Library were searched from inception up to 12 May 2014. SELECTION CRITERIA: Studies of see-and-treat management in women with a reported cervical smear result, colposcopic impression, and histology result were included. DATA COLLECTION AND ANALYSIS: Methodological quality was assessed with the Newcastle-Ottawa scale. We used the inverse variance method for pooling incidences, and a random-effects model was used to account for heterogeneity between studies. Overtreatment was defined as treatment in patients with no CIN or CIN1. MAIN RESULTS: Thirteen studies (n = 4611) were included. The overall overtreatment rate in women with a high-grade cervical smear and a high-grade colposcopic impression was 11.6% (95% CI 7.8-15.3%). The overtreatment rate in women with a high-grade cervical smear and low-grade colposcopic impression was 29.3% (95% CI 16.7-41.9%), and in the case of a low-grade smear and high-grade colposcopic impression it was 46.4% (95% CI 15.7-77.1%). In women with a low-grade smear and low-grade colposcopic impression, the overtreatment rate was 72.9% (95% CI 68.1-77.7%). AUTHOR'S CONCLUSIONS: The pooled overtreatment rate in women with a high-grade smear and high-grade colposcopic impression is at least comparable with the two-step procedure, which supports the use of see-and-treat management in this subgroup of women. TWEETABLE ABSTRACT: See-and-treat management is justified in the case of a high-grade smear and a high-grade colposcopic impression.

Cervicovaginal HPV infection in female renal transplant recipients: an observational, self-sampling based, cohort study.

Immunosuppressive treatment of organ transplant recipients is associated with an increase in the occurrence of human papillomavirus (HPV) related anogenital (pre)malignancies. This cohort study investigated the genotype-specific prevalence of HPV infections in a large cohort of female renal transplant recipients (RTRs). Participants self-collected a cervicovaginal sample for detection and genotyping of HPV. Besides, they completed a questionnaire regarding sociodemographic variables, medical data and sexual behavior. Anogenital screening was offered to all HPV-positive participants. A total number of 218 female RTRs was included. The prevalence of mucosal HPV infections was 27.1% and 17.4% for high risk HPV in particular. The studied cohort showed a broad range of HPV genotypes and multiple HPV genotypes were found in 27.1% of HPV-positive patients. Seven participants were identified with occult premalignant anogenital lesions. In conclusion, this study shows a high point-prevalence of HPV in female RTRs (age-matched West-European general population: 9-10%) with a shift in the distribution of genotypes as compared with the general population. Moreover, a substantial number of patients with occult premalignancies was identified. The introduction of self-sampling for HPV positivity can help in early detection of (pre)malignant anogenital lesions in this vulnerable population.

A preliminary study on a new model system to evaluate tumour-detection and tumour-purging protocols in ovarian cortex tissue intended for fertility preservation.

STUDY QUESTION: Is it possible to create a model system that mimics ovarian metastatic disease in order to devise new strategies to detect cancer cells and prevent cancer cell transmission via ovarian tissue autotransplantation in cancer survivors? SUMMARY ANSWER: Injection of bovine or human ovarian cortex fragments with cells from different cancer types led to the formation of proliferating tumour masses and newly formed small metastatic lesions. WHAT IS KNOWN ALREADY: Autotransplantation of ovarian tissue comes with the major concern of cancer cells possibly being present in the tissue. A model system to develop strategies aimed at enhancing the safety of ovarian tissue autotransplantation is currently lacking. STUDY DESIGN, SIZE, DURATION: The ability of injected human leukaemia, lymphoma, Ewing's sarcoma or breast cancer cells to proliferate and form tumour-like structures in bovine and human ovarian cortex tissue in vitro was assessed. The injected cells were from human cancer cell lines. After 4 days of culture, some tissue fragments were harvested for standard histological staining and immunohistochemical staining of tumour cell specific antigens and the Ki67 proliferation marker, while the remaining fragments were incubated for an additional 6 days (bovine tissue) or 3 days (human tissue) before analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Experiments were performed with ovarian tissue from women after prophylactic salpingo-oophorectomy. Bovine ovarian tissue was obtained at an abattoir. Glucose uptake during in vitro culture was monitored to quantify the viability of tissue. Tumour formation was assessed at Day 4 and Day 10 in bovine ovarian tissue and at Day 4 and Day 7 in human ovarian tissue, using histology and immunohistochemistry. MAIN RESULTS AND THE ROLE OF CHANCE: We found that bovine and human ovarian cortex tissue could be cultured for up to 10 and 7 days, respectively, without any loss of viability. Our preliminary results show that all cell lines tested were capable of forming proliferating tumours in ovarian cortex tissue in vitro. Lymphoma and breast cancer cells produced small metastases near the original lesions. LIMITATIONS, REASONS FOR CAUTION: The tumour model presented was based on the growth of human cancer cell lines in ovarian cortex tissue. It is unknown whether these cells behave differently from malignant cells derived from primary tumours. In addition, the human ovarian tissue was derived from women over 39 years of age, which is obviously considerably older than patients opting for ovarian tissue cryopreservation. WIDER IMPLICATIONS OF THE FINDINGS: Our model system will facilitate the development of procedures to detect cancer cells in, or purge cancer cells from, human ovarian tissue. STUDY FUNDING/COMPETING INTERESTS: Unconditional funding was received from the Radboud Institute for Health Sciences, KiKa Foundation and Merck Serono. There are no conflicts of interest to declare.

The opinion of gynecologists on the management of early-stage, high-grade endometrioid endometrial cancer.

PURPOSE OF INVESTIGATION: There is no consensus on the management of Stage I endometrioid endometrial cancer (EEC) with grade 3 histology. This study evaluates the opinion of gynecologists in The Netherlands on the management of Stage I, grade 3 EEC. MATERIALS AND METHODS: Members of the Dutch Gynecologic Oncology Working Group were requested to complete a digital questionnaire on the management of Stage I, grade 3 EEC. Actual treatment of patients with Stage I, grade 3 EEC was assessed by analysis of PALGA, the Dutch Pathology Registry. RESULTS: Most gynecologists prefer routine lymphadenectomy or complete staging (62.3%), while these were actually performed in 27.3% of the cases. Gynecologic oncologists are more likely to perform a lymphadenectomy than general gynecologists. There was a wide variation of clinical practice. CONCLUSION: The results of this study underline the need for additional research into management of Stage I, grade 3 EEC as well as the need for conclusive guidelines.

External validation of three prognostic models for overall survival in patients with advanced-stage epithelial ovarian cancer.

BACKGROUND: For various malignancies, prognostic models have shown to be superior to traditional staging systems in predicting overall survival. The purpose of this study was to validate and compare the performance of three prognostic models for overall survival in patients with advanced-stage epithelial ovarian cancer. METHODS: A multi-institutional epithelial ovarian cancer database was used to identify patients and to evaluate the predictive performance of two nomograms, a prognostic index and FIGO (International Federation of Obstetrics and Gynecology) stage. All patients were treated for advanced-stage epithelial ovarian cancer between January 1996 and January 2009 in 11 hospitals in the eastern part of The Netherlands. RESULTS: In total, 542 patients were found to be eligible. Overall performance did not differ between the three prognostic models and FIGO stage. The discriminative performance for Chi's model was moderately good (c indices 0.65 and 0.68) and for the models of Gerestein and Teramukai reasonable (c indices between 0.60 and 0.62). The c indices of FIGO stage ranged between 0.54 and 0.62. After recalibration, the three models showed almost perfect calibration, whereas calibration of FIGO stage was reasonable. CONCLUSION: The three prediction models showed general applicability and a reasonably well-predictive performance, especially in comparison to FIGO stage. To date, there are no studies available that analyse the impact of these prognostic models on decision-making and patient outcome. Therefore, the usefulness of these models in daily clinical practice remains to be investigated.

DNA methylation analysis in self-sampled brush material as a triage test in hrHPV-positive women.

BACKGROUND: Primary high-risk human papillomavirus (hrHPV) testing in cervical cancer screening shows relatively low specificity, which makes triage testing necessary. In this study, DNA methylation analysis was compared with cytology for triage testing in hrHPV-positive women. Moreover, feasibility of DNA methylation analysis directly on brush-based self-sampled specimens was assessed. METHODS: Non-responding women from population-based screening were invited to self-collect a cervico-vaginal specimen for hrHPV testing; hrHPV-positive women were referred to a physician for triage liquid-based cytology. DNA methylation analysis was performed on 128 hrHPV-positive physician-collected triage samples and 50 matched brush self-samples with QMSP for C13ORF18, EPB41L3, JAM3 and TERT. RESULTS: In physician-taken triage material, DNA methylation analysis of JAM3 showed the highest combined specificity (88%) and sensitivity (82%) for detection of CIN3+, whereas cytology showed a specificity of 48% and a sensitivity of 91%. Out of 39 women with abnormal cytology and normal histology (false-positive by cytology), 87% were negative for JAM3 and 90% for C13ORF18 methylation. Agreement between DNA methylation analysis performed directly on the matched self-sampled material and physician-taken samples was 88% for JAM3 (κ=0.75, P<0.001) and 90% for C13ORF18 (κ=0.77; P<0.001). CONCLUSIONS: DNA methylation analysis as a triage test in hrHPV-positive women is an attractive alternative to cytology. Furthermore, DNA methylation is feasible directly on brush-based self-samplers and showed good correlation with matched physician-taken samples. Direct molecular triage on self-collected specimens could optimise the screening program, especially for non-responders, as this would eliminate the need for an additional physician-taken scraping for triage testing.

Prospective follow-up of 2,065 young unscreened women to study human papillomavirus incidence and clearance.

Human papillomavirus (HPV) is a necessary factor in the development of cervical intraepithelial neoplasia and cervical cancer. However, HPV is also a very common sexually transmitted virus and many women clear their infection. To study HPV incidence and clearance, 2,065 women, aged 18-29 years, were followed for 12 months and were asked to provide a self-collected cervico-vaginal sample and fill-out a questionnaire every 3 months. For HPV DNA detection, the SPF10 -DEIA LiPA25 system was used. Incidence rates of any-type high-risk HPV and low-risk HPV were 17.0 per 1,000-person months, and 14.3 per 1,000-person months, respectively. HPV types 16, 52, 51 and 31 had the highest type-specific incidence rates. HPV incidence was increased in singles, and women having a new relationship. A higher number of lifetime sex partners, and a higher frequency of sexual contacts in the past 3 months was associated with an increased HPV incidence. The overall clearance of the newly detected type-specific high-risk HPV infections and low-risk HPV infections was 61.2% and 69.0%, respectively. Having a sexual relationship compared to being single, and a higher sexual age both positively influenced the clearance of any-type high-risk HPV. Among the women infected with HPV 16, the women who had a co-infection had a lower proportion of clearance of HPV 16. In conclusion, in this young Dutch study population, HPV incidence rates are not related to age and comparable to other western countries. Clearance was only independently related to factors associated with sexual behavior, either past or current.

Absolute depth of myometrial invasion in endometrial cancer is superior to the currently used cut-off value of 50%.

OBJECTIVE: In endometrial carcinoma, myometrial invasion is a well known predictor of recurrence, and important in the decision making for adjuvant treatment. According to the FIGO staging system, myometrial invasion is expressed as invasion of <50%> of the myometrium (50%MI). It has been suggested to use the absolute depth of invasion (DOI), or the tumor free distance to the serosa (TFD). The aim of this study was to compare DOI, 50%MI, and TFD. METHODS: All patients diagnosed with endometrioid endometrial carcinoma at the RUNMC, and the CWH from 1999 to 2009 were included. Histologic slides were reviewed for histologic type and grade, DOI, 50%MI, and TFD. After review, 335 patients were identified. DOI, 50%MI, and TFD were evaluated for their prediction of clinicopathologic characteristics. RESULTS: The prediction of recurrence was best performed by DOI when compared to TFD, with an area under the ROC curve of 0.726, and 0.638 respectively. The optimal cut-off value for DOI was 4mm. DOI independently correlated with recurrence of disease, and death of disease. TFD was associated with advanced age and large tumor diameter. DOI was the best predictor of progression-free and disease-specific survival next to 50%MI and TFD (HR 3.15, 95%CI 1.16-8.56) and (HR 10.35, 95%CI 1.23-86.93). CONCLUSIONS: DOI showed better predictive performance than TFD, and was more strongly correlated with clinicopathologic parameters than TFD and 50%MI. Possibly, DOI should substitute 50%MI as measure to express myometrial invasion in daily clinical practice. External validation is mandatory to confirm the proposed cut-off value of 4mm.

Cytology of the vulva: feasibility and preliminary results of a new brush.

OBJECTIVE: Taking a biopsy is a standard procedure to make the correct diagnosis in patients with suspicious premalignant vulvar lesions. The use of a less invasive diagnostic tool as triage instrument to determine whether biopsy is necessary may improve patient comfort especially in patients with chronic vulvar disorders that may warrant consecutive biopsies. This study was conducted to investigate whether vulvar brush cytology is feasible and may be used to detect (pre)malignant vulvar lesions. METHODS: A pilot study was performed with patients having clinically normal vulvar skin, lichen sclerosus (LS), usual or differentiated vulvar intraepithelial neoplasia or squamous cell carcinoma. A total of 65 smears were taken with the use of a vulvar brush and biopsies were performed for histopathological analysis. RESULTS: Out of 65 smears, 17 (26%) were discarded because of poor cellularity. A total of 28 of 29 (97%) smears with a histological proven (pre)malignancy had a smear classified as 'suspicious' or 'uncertain'. Cytology classified 11 smears as 'non-suspicious', of which 10 (91%) were indeed normal skin or LS. The accuracy, based on the presence of a lesion, for (pre)malignant lesions with the use of the brush showed a sensitivity of 97% and a negative predictive value of 88%. CONCLUSION: Vulvar brush cytology is feasible and may be a first step in the development of a triage instrument to determine whether subsequent biopsy of a clinically (pre)malignant lesion is necessary.