Depression and anxiety in women with malignant ovarian germ cell (MOGCT) and sex cord stromal tumors (SCST): an analysis of the AGO-CORSETT database.

INTRODUCTION: The intention of this study was to evaluate the level of anxiety and depression of malignant ovarian germ cell (MOGCT) and sex cord stromal tumors (SCST) survivors and to identify possible alterable cofactors. METHODS: CORSETT was an observational, multicenter, mixed retrospective/prospective cohort study of the AGO Studygroup. Women who had been diagnosed with MOGCTs and SCSTs between 2001 and 2011 were asked to complete the Hospital Anxiety and Depression Scale (HADS) to evaluate distress. Predictors of distress (type of surgery, chemotherapy, time since diagnosis, recurrence, second tumor, pain) were investigated using multivariate linear regression analysis. RESULTS: 150 MOGCT and SCST patients with confirmed histological diagnosis completed the questionnaire median seven years after diagnosis. They had a HADS total score ≥ 13 indicating severe mental distress in 34% of cases. Patients after fertility-conserving surgery had lower probability of severe mental distress than those without fertility-conserving treatment (ß = - 3.1, p = 0.04). Pain was associated with the level of distress in uni- and multivariate analysis (coef 0.1, p < 0.01, coef. Beta 0.5). DISCUSSION: Severe mental distress was frequent in patients with MOGCT and SCST and the level of pain was associated with the level of distress. Fertility conserving therapy, however, was associated with less mental distress. Screening and treatment of pain and depression is required to improve mental well-being in survivors of MOGCT and SCST.

Prognostic gene expression signature for high-grade serous ovarian cancer.

BACKGROUND: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC. PATIENTS AND METHODS: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies. RESULTS: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02-2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to -), 5.4 (4.6-7.0), 3.8 (3.3-4.6), 3.2 (2.9-3.7) and 2.3 (2.1-2.6) years. CONCLUSION: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.

Iatrogenic endometriosis harbors somatic cancer-driver mutations.

STUDY QUESTION: Does incisional endometriosis (IE) harbor somatic cancer-driver mutations? SUMMARY ANSWER: We found that approximately one-quarter of IE cases harbor somatic-cancer mutations, which commonly affect components of the MAPK/RAS or PI3K-Akt-mTor signaling pathways. WHAT IS KNOWN ALREADY: Despite the classification of endometriosis as a benign gynecological disease, it shares key features with cancers such as resistance to apoptosis and stimulation of angiogenesis and is well-established as the precursor of clear cell and endometrioid ovarian carcinomas. Our group has recently shown that deep infiltrating endometriosis (DE), a form of endometriosis that rarely undergoes malignant transformation, harbors recurrent somatic mutations. STUDY DESIGN, SIZE, DURATION: In a retrospective study comparing iatrogenically induced and endogenously occurring forms of endometriosis unlikely to progress to cancer, we examined endometriosis specimens from 40 women with IE and 36 women with DE. Specimens were collected between 2004 and 2017 from five hospital sites in either Canada, Germany or the Netherlands. IE and DE cohorts were age-matched and all women presented with histologically typical endometriosis without known history of malignancy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Archival tissue specimens containing endometriotic lesions were macrodissected and/or laser-capture microdissected to enrich endometriotic stroma and epithelium and a hypersensitive cancer hotspot sequencing panel was used to assess for presence of somatic mutations. Mutations were subsequently validated using droplet digital PCR. PTEN and ARID1A immunohistochemistry (IHC) were performed as surrogates for somatic events resulting in functional loss of respective proteins. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, we detected somatic cancer-driver events in 11 of 40 (27.5%) IE cases and 13 of 36 (36.1%) DE cases, including hotspot mutations in KRAS, ERBB2, PIK3CA and CTNNB1. Heterogeneous PTEN loss occurred at similar rates in IE and DE (7/40 vs 5/36, respectively), whereas ARID1A loss only occurred in a single case of DE. While rates of detectable somatic cancer-driver events between IE and DE are not statistically significant (P > 0.05), KRAS activating mutations were more prevalent in DE. LIMITATIONS, REASONS FOR CAUTION: Detection of somatic cancer-driver events were limited to hotspots analyzed in our panel-based sequencing assay and loss of protein expression by IHC from archival tissue. Whole genome or exome sequencing, or epigenetic analysis may uncover additional somatic alterations. Moreover, because of the descriptive nature of this study, the functional roles of identified mutations within the context of endometriosis remain unclear and causality cannot be established. WIDER IMPLICATIONS OF THE FINDINGS: The alterations we report may be important in driving the growth and survival of endometriosis in ectopic regions of the body. Given the frequency of mutation in surgically displaced endometrium (IE), examination of similar somatic events in eutopic endometrium, as well as clinically annotated cases of other forms of endometriosis, in particular endometriomas that are most commonly linked to malignancy, is warranted. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by a Canadian Cancer Society Impact Grant [701603, PI Huntsman], Canadian Institutes of Health Research Transitional Open Operating Grant [MOP-142273, PI Yong], the Canadian Institutes of Health Research Foundation Grant [FDN-154290, PI Huntsman], the Canadian Institutes of Health Research Project Grant [PJT-156084, PIs Yong and Anglesio], and the Janet D. Cottrelle Foundation through the BC Cancer Foundation [PI Huntsman]. D.G. Huntsman is a co-founder and shareholder of Contextual Genomics Inc., a for profit company that provides clinical reporting to assist in cancer patient treatment. R. Aguirre-Hernandez, J. Khattra and L.M. Prentice have a patent MOLECULAR QUALITY ASSURANCE METHODS FOR USE IN SEQUENCING pending and are current (or former) employees of Contextual Genomics Inc. The remaining authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Unexpected malignant uterine pathology: Incidence, characteristics and outcome in a large single-center series of hysterectomies for presumed benign uterine disease.

OBJECTIVE: Hysterectomy is a frequently used therapeutic option for benign gynecological conditions. The purpose of this study was to investigate the incidence and characteristics of unforeseen malignant pathologies of the uterine corpus in a large population-based, single center cohort. METHODS: Patients who underwent hysterectomy for presumed benign conditions between 2003 and 2016 were identified. In cases of unexpected malignancies of the uterine corpus (UUM), available tissue samples were collected and a specialized gynecopathological review was performed. RESULTS: A total of 10,756 patients underwent hysterectomy for benign indications. After chart and gynecopathological review, 45/10,756 (0.42%) cases of unexpected uterine malignancies were confirmed. 33/45 (73.3%) were endometrial carcinomas (UEC) and 12/45 (26.7%) were uterine sarcomas (UUS). 27/33 (81.8%) UEC were FIGO IA, 5/33 (15.2%) FIGO IB and 1/33 (3%) FIGO stage II disease. Endometrioid and serous histotype were present in 31/33 (93.9%) and in 2/33 (6.1%) cases, respectively. 8/12 (66.7%) USS were early stage (FIGO IA or IB); only 3/12 (25.0%) were diagnosed at an advanced stage (≥FIGO II). Fatal outcome was observed in 1 patient diagnosed with UEC and 3 patients diagnosed with UUS. CONCLUSION: Our study shows that diagnosis of UUM is rare (0.42%). The majority of UUM tend to be early stage, making preoperative diagnosis difficult. In case of UEC, patient outcome is generally favorable. Nevertheless, the appropriate surgical approach for hysterectomy for a benign indication should be chosen carefully, taking all preoperative findings into account. Patients should always be informed about the residual risk of UUM.

Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series.

Background: We have previously developed and confirmed a pragmatic molecular classifier for endometrial cancers; ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer). Inspired by the Cancer Genome Atlas, ProMisE identifies four prognostically distinct molecular subtypes and can be applied to diagnostic specimens (biopsy/curettings) enabling earlier informed decision-making. We have strictly adhered to the Institute of Medicine (IOM) guidelines for the development of genomic biomarkers, and herein present the final validation step of a locked-down classifier before clinical application. Patients and methods: We assessed a retrospective cohort of women from the Tübingen University Women's Hospital treated for endometrial carcinoma between 2003 and 2013. Primary outcomes of overall, disease-specific, and progression-free survival were evaluated for clinical, pathological, and molecular features. Results: Complete clinical and molecular data were evaluable from 452 women. Patient age ranged from 29 to 93 (median 65) years, and 87.8% cases were endometrioid histotype. Grade distribution included 282 (62.4%) G1, 75 (16.6%) G2, and 95 (21.0%) G3 tumors. 276 (61.1%) patients had stage IA disease, with the remaining stage IB [89 (19.7%)], stage II [26 (5.8%)], and stage III/IV [61 (13.5%)]. ProMisE molecular classification yielded 127 (28.1%) MMR-D, 42 (9.3%) POLE, 55 (12.2%) p53abn, and 228 (50.4%) p53wt. ProMisE was a prognostic marker for progression-free (P = 0.001) and disease-specific (P = 0.03) survival even after adjusting for known risk factors. Concordance between diagnostic and surgical specimens was highly favorable; accuracy 0.91, κ 0.88. Discussion: We have developed, confirmed, and now validated a pragmatic molecular classification tool (ProMisE) that provides consistent categorization of tumors and identifies four distinct prognostic molecular subtypes. ProMisE can be applied to diagnostic samples and thus could be used to inform surgical procedure(s) and/or need for adjuvant therapy. Based on the IOM guidelines this classifier is now ready for clinical evaluation through prospective clinical trials.

Better resource utilisation and quality of care for ovarian cancer patients using internet-based pathology review.

BACKGROUND: The current literature indicates that a considerable number of patients in ovarian carcinoma clinical trials have histopathological diagnoses in conflict with inclusion criteria. It has been suggested that specialised pathology review prior to randomisation should become the standard procedure in study protocols. We hypothesised that our new, internet-based high-throughput infrastructure would be capable of providing specialised pathology review within 10 working days (w.d.). METHODS: Patients scheduled for the AGO OVAR17 ovarian carcinoma chemotherapy trial were registered for expert pathologic case review using a new internet-based central pathology review platform prior to randomisation. All original slides were requested from local pathologists. Slides were scanned and uploaded to a secured internet server. A network of experienced gynaecological pathologists was connected to the server through a custom-designed software platform. If deemed necessary by the expert pathologists, immunohistochemistry was available through a collaborating pathology lab. RESULTS: A total of 880 patients with an original diagnosis of ovarian epithelial carcinoma were registered for expert pathology review from October 2011 to July 2013. For case review, five gynaecopathologists from Austria, Switzerland and Germany were available online. Median number of w.d. required to complete the whole process from patient registration to transmission of final review diagnoses was 4 (range 2-31) (w.d.), and in 848 out of 880 (97.5%) cases, it amounted to ⩽10 w.d. In 2.5% (n=22) of cases, a major diagnostic discrepancy of potential clinical relevance was found leading to exclusion from the chemotherapy trial. CONCLUSIONS: Our results show that the use of a new internet-based infrastructure makes timely specialised case review, prior to patient randomisation feasible within ⩽10 w.d. Our new approach helped to protect against overtreatment with chemotherapy of patients with ovarian borderline tumours and inadequate treatment of patients with ovarian metastases, as a result of their inappropriate entry into a clinical trial designed for patients with primary ovarian carcinoma.

Surgical staging and prognosis in serous borderline ovarian tumours (BOT): a subanalysis of the AGO ROBOT study.

BACKGROUND: Incomplete surgical staging is a negative prognostic factor for patients with borderline ovarian tumours (BOT). However, little is known about the prognostic impact of each individual staging procedure. METHODS: Clinical parameters of 950 patients with BOT (confirmed by central reference pathology) treated between 1998 and 2008 at 24 German AGO centres were analysed. In 559 patients with serous BOT and adequate ovarian surgery, further recommended staging procedures (omentectomy, peritoneal biopsies, cytology) were evaluated applying Cox regression models with respect to progression-free survival (PFS). RESULTS: For patients with one missing staging procedure, the hazard ratio (HR) for recurrence was 1.25 (95%-CI 0.66-2.39; P=0.497). This risk increased with each additional procedure skipped reaching statistical significance in case of two (HR 1.95; 95%-CI 1.06-3.58; P=0.031) and three missing steps (HR 2.37; 95%-CI 1.22-4.64; P=0.011). The most crucial procedure was omentectomy which retained a statistically significant impact on PFS in multiple analysis (HR 1.91; 95%-CI 1.15-3.19; P=0.013) adjusting for previously established prognostic factors as FIGO stage, tumour residuals, and fertility preservation. CONCLUSION: Individual surgical staging procedures contribute to the prognosis for patients with serous BOT. In this analysis, recurrence risk increased with each skipped surgical step. This should be considered when re-staging procedures following incomplete primary surgery are discussed.

[Specialized histopathological second opinion of advanced ovarian cancer. Experiences with collectives from prospective randomized phase III studies]. / Spezialisierte histopathologische Zweitbegutachtung fortgeschrittener Ovarialkarzinome. Erfahrungen an Kollektiven aus prospektiv randomisierten Phase-III-Studien.

BACKGROUND: Retrospective studies have shown that a significant number of ovarian borderline tumors, ovarian metastases, and nonepithelial tumors were erroneously diagnosed as ovarian carcinomas. This may lead to unnecessary morbidity, suboptimal therapeutic modalities, and unintended bias in clinical trials. The aim of this study was to investigate the frequency and clinical significance of such diagnostic discrepancies. MATERIAL AND METHODS: Original histological slides from patients with ovarian carcinomas included in phase III chemotherapy trials of the Working Group on Gynecological Oncology (AGO) were reviewed by at least two specialized pathologists. Diagnostic discrepancies were classified as being either clinically relevant (major) or clinically not relevant (minor). RESULTS: A total of 454 out of 533 patients from the AGO OVAR11 (ICON7) trial gave consent to the second opinion on the pathology results. All of the 104 institutes of pathology responsible for the original diagnoses contributed to the study. The first diagnosis and the second opinion pathology review were identical in 295 out of 454 (65%) cases. In 128 cases (28.2%) a minor discrepancy was found and 31 cases (6.8%) were shown to have a major discrepancy. CONCLUSION: The assumption of a significant number or erroneous diagnoses in chemotherapy trials of ovarian carcinomas was confirmed. A pathology review seems therefore desirable and may help to reduce unnecessary morbidity and optimize therapeutic strategies. Moreover, improvement of quality in therapy trials may become possible. In another study a new concept allowing a rapid pathology review before randomization of patients has now been successfully tested and it may well have potential to form the basis for modern networking consultation pathology.

Sphingosine-kinase-1 expression is associated with improved overall survival in high-grade serous ovarian cancer.

PURPOSE: Sphingosine-kinase-1 (SPHK1) is a key enzyme of sphingolipid metabolism which is involved in ovarian cancer pathogenesis, progression and mechanisms of drug resistance. It is overexpressed in a variety of cancer subtypes. We investigated SPHK1 expression as a prognostic factor in epithelial ovarian cancer patients. METHODS: Expression analysis of SPHK1 was performed on formalin-fixed paraffin-embedded tissue from 1005 ovarian cancer patients with different histological subtypes using immunohistochemistry. Staining intensity of positive tumor cells was assessed semi-quantitatively, and results were correlated with clinicopathological characteristics and survival. RESULTS: In our ovarian cancer collective, high levels of SPHK1 expression correlated significantly with complete surgical tumor resection (p = 0.002) and lower FIGO stage (p = 0.04). Progression-free and overall survival were further significantly longer in patients with high-grade serous ovarian cancer and overexpression of SPHK1 (p = 0.002 and p = 0.006, respectively). CONCLUSION: Our data identify high levels of SPHK1 expression as a potential favorable prognostic marker in ovarian cancer patients.

Brachytherapy quality assurance in the PORTEC-4a trial for molecular-integrated risk profile guided adjuvant treatment of endometrial cancer.

OBJECTIVE: The PORTEC-4a trial investigates molecular-integrated risk profile guided adjuvant treatment for endometrial cancer. The quality assurance programme included a dummy run for vaginal brachytherapy prior to site activation, and annual quality assurance to verify protocol adherence. Aims of this study were to evaluate vaginal brachytherapy quality and protocol adherence. METHODS: For the dummy run, institutes were invited to create a brachytherapy plan on a provided CT-scan with the applicator in situ. For annual quality assurance, institutes provided data of one randomly selected brachytherapy case. A brachytherapy panel reviewed and scored the brachytherapy plans according to a checklist. RESULTS: At the dummy run, 15 out of 21 (71.4%) institutes needed adjustments of delineation or planning. After adjustments, the mean dose at the vaginal apex (protocol: 100%; 7 Gy) decreased from 100.7% to 99.9% and range and standard deviation (SD) narrowed from 83.6-135.1 to 96.4-101.4 and 8.8 to 1.1, respectively. At annual quality assurance, 22 out of 27 (81.5%) cases had no or minor and 5 out of 27 (18.5%) major deviations. Most deviations were related to delineation, mean dose at the vaginal apex (98.0%, 74.7-114.2, SD 7.6) or reference volume length. CONCLUSIONS: Most feedback during the brachytherapy quality assurance procedure of the PORTEC-4a trial was related to delineation, dose at the vaginal apex and the reference volume length. Annual quality assurance is essential to promote protocol compliance, ensuring high quality vaginal brachytherapy in all participating institutes.

Prognostic impact of additional extended surgical procedures in advanced-stage primary ovarian cancer.

BACKGROUND: Treatment of advanced-stage ovarian carcinoma includes radical cytoreductive surgery, which aims at removing all visible tumor tissue followed by platinum and paclitaxel chemotherapy. Complete tumor resection may require extended surgical procedures. This paper reports on the prognostic impact of extensive surgery and surgical morbidity in patients with advanced-stage ovarian carcinoma. METHODS: Patients with ovarian carcinoma [Fédération Internationale de Gynécologie et d'Obstétrique (FIGO) stage IIIB-IV] undergoing primary surgery in our tertiary gynecologic oncology unit between 1997 and 2007 were eligible for this study. The impact of established prognostic factors and the interaction with extent of surgical procedures on survival were assessed. RESULTS: A total of 267 patients aged between 29 and 88 years (median 64 years) were eligible for this study. Overall survival time was improved in patients who underwent complete tumor resection [hazard ratio (HR) 3.61 (1.91-6.61), P < 0.001]. No significant survival difference was observed between completely operated patients in whom extended or standard surgical procedures were applied [HR 1.37 (0.70-2.69), P = 0.358], and severe surgical complications were found to be equally distributed between the two patient groups. CONCLUSIONS: Our results may encourage the application of extended surgical procedures in patients who would otherwise be rendered incompletely debulked after primary cytoreduction. We could demonstrate an impact of complete tumor resection on patient prognosis and this was not traded off for extensive additional surgical morbidity.

[Central pathology review. Inclusion criterion for clinical studies of ovarian carcinomas?]. / Histopathologische Zweitbegutachtung. Einschlusskriterium für klinische Studien bei Ovarialkarzinomen?

Currently histopathological review is not standard practice in clinical studies of ovarian carcinomas. Published retrospective analyses as well as own unpublished observations have indicated that a certain percentage of study patients may have ovarian lesions other than ovarian carcinomas which may be in conflict with study inclusion criteria. In this context, the distinction of ovarian carcinomas from borderline tumors, ovarian metastases, and sex cord tumors has been shown to be a potential pitfall. In cases of incorrect diagnoses, non-beneficial morbidity at unnecessary high cost may occur, in other instances, more adequate therapeutic modalities might be withheld from a patient. At present, the concept of a central histopathology review for patients with ovarian carcinomas is being studied prospectively in a translational research project of the AGO-Ovar termed "HIstologische STandardisierte Zweitbegutachtung in einem Studienkollektiv fortgeschrittener Ovarialkarzinome, OVAR 11t-HISTO" (Histological standardized review in a study collective of advanced ovarian cancer; http://www.mh-hannover.de/institute/pathologie/dgp:Studien).

Clinical Characteristics, Surgical Management and Adjuvant Therapy of Patients with Uterine Carcinosarcoma: A Retrospective Case Series.

Purpose: To review a single-center experience over a 27-year period of managing uterine carcinosarcoma (UCS), focusing on surgical practice, adjuvant therapy and clinical outcome. Material and Methods: This was a retrospective study of women with histologically proven UCS treated at the Department of Obstetrics and Gynecology, University of Tübingen, Germany, between 1983 and 2010. Inpatient and outpatient records were reviewed; follow-up and survival data were ascertained. Results: The study population comprised 18 patients with UCS. Primary surgical treatment consisted of total abdominal hysterectomy in 12 patients (67 %) and laparoscopic total hysterectomy in 4 patients (22 %). Bilateral salpingo-oophorectomy was performed in 94 % of patients (17/18). Lymph nodes were evaluated in 15 patients (83 %). Positive pelvic lymph nodes were present in 2 patients (11 %). A total of 17 patients (94 %) received adjuvant therapy. Disease recurred in 7 (39 %) patients of our study group, with no recurrence noted in the 4 patients who underwent laparoscopic surgical staging. Median disease-free survival (DFS) was 48.7 months (95 % CI: 0.0-157.3) and median overall survival (OS) was 49.9 months (95 % CI: 0.0-108.2). The 5-year survival rate was 40 %. Conclusion: UCS is a rare and aggressive uterine neoplasm with high recurrence rates and metastatic potential. Surgical staging consisting of total hysterectomy with bilateral salpingo-oophorectomy and systematic lymphadenectomy is the most important treatment for patients with UCS. Adjuvant radiation therapy appears to decrease pelvic recurrence, but there is a high incidence of distant recurrence, indicating the need for additional systemic treatment.

Re-operation outcome in patients referred to a gynecologic oncology center with presumed ovarian cancer FIGO I-IIIA after sub-standard initial surgery.

BACKGROUND: Surgery is the mainstay of treatment for early ovarian cancer both as therapeutic and comprehensive staging. Only the latter allows appropriate tailoring of systemic treatment. However, the compliance with guidelines for comprehensive staging has been reported to be only moderate and, therefore, re-staging procedures are commonly indicated to avoid undertreatment. The purpose of our study was to evaluate re-operation in a tertiary gynecologic oncology unit after primary operation for presumably ovarian cancer FIGO I-IIIA in general gynecology departments. MATERIAL AND METHODS: Forty consecutive patients after primary surgery in the outside institutions for presumed early ovarian cancer with assumed tumor spread limited to the pelvis (FIGO I-IIIA) admitted to our department between 1999 and 2007 were included. In 35 cases re-staging surgery in our unit was indicated. The intra- and post-operative results were compared with initial diagnosis and sites of undetected disease were evaluated. Reasons for re-staging and referral pattern were studied. RESULTS: 40 patients were enrolled of whom 53% came by self-referral. Only 18% were referred by the primary surgeon and the remaining patients were referred by their home gynecologist. Only 5 patients (13%) were classified as having had a comprehensive staging by surgical records and pathology reports and 35 patients underwent comprehensive re-staging laparotomy after which 20 patients (50%) experienced an upstaging including 13 patients with final diagnosis of FIGO stage IIIC. Most frequent sites of primarily undetected tumor were peritoneum (pelvic 34%, diaphragm 13%, paracolic 8%), lymph nodes (para aortic 32%, pelvic 11%), intestines 24%, and residual omental tissue 18%. The indication for post-operative chemotherapy was modified in 53% of patients. CONCLUSION: Comprehensive staging of presumed early ovarian cancer has been described as major problem especially outside gynecologic oncology units. Re-staging results in our department confirmed this deficiency by showing a considerable proportion of upstaging associated with alterations of recommendations for systemic treatment. However, series like this may even underestimate the problem, because incomplete staging is unfortunately accompanied by non-systematic referral practices not reflecting staging quality.

[Transitional cell carcinoma of the ovary. Morphological and clinical features]. / Das transitionalzellige Ovarialkarzinom. Morphologische und klinische Besonderheiten.

Transitional cell carcinoma of the ovary (TCC-O) is a less common type of malignant surface epithelial-stromal tumor of the ovary, still with uncertain incidence. Histologically, TCC-O resembles urothelial carcinoma of the urinary system, and by definition does not contain a Brenner tumor component. TCC-O may not be a bona fide urothelial neoplasm, however, but rather a lesion of the Müllerian type derived from the ovarian surface epithelium. This notion is supported by the existence of mixed tumors consisting of TCC-O and other histological types of ovarian carcinoma, as well as the observation that TCC-O has a Müllerian type but not a urothelial-like immunohistochemical profile. Besides metastatic urothelial carcinoma of the urinary tract, the other types of ovarian carcinoma, as well as sex cord-stromal tumors such as adult granulosa cell tumors, have to be considered in the differential diagnosis of TCC-O. A recent analysis of a large series of advanced ovarian carcinomas treated by radical surgery and postoperative chemotherapy confirms studies that had suggested that TCC-O has a better prognosis (with current treatment) than that of the other histological types of ovarian carcinoma. Further studies applying standardized histopathological criteria are needed to clarify the true incidence and behavior of TCC-O. In addition, it is important to study the biological and molecular background of this apparently less aggressive phenotype.

Independent prognostic significance of cell cycle regulator proteins p16(INK4a) and pRb in advanced-stage ovarian carcinoma including optimally debulked patients: a translational research subprotocol of a randomised study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group.

The purpose of the study is to test the hypothesis that expression of cell cycle regulatory proteins p16(INK4a) and pRb is significantly associated with prognosis in ovarian carcinomas. We performed immunohistochemical analysis of p16(INK4a) and pRb expression and correlated with survival in a series of 300 patients with FIGO stage IIb-IV ovarian carcinoma which were enrolled in a randomized prospective trial evaluating two different platinum and paxlitaxel chemotherapy combinations after radical surgery. p16(INK4a) negative tumours (17/300; 6%) had a significantly worse prognosis (univariate analysis, P<0.001; multivariate analysis: odds ratio 2.41, P=0.009). Among p16(INK4a)-positive tumours (283 out of 300; 94%), survival was better for patients with intermediate expression as compared to low or high expression levels (P=0.001). High expression levels of pRb were associated with an incremental deterioration of prognosis (univariate analysis, P=0.004; multivariate analysis: odds ratio 2.98, P=0.002). This observation held also true in the subgroup of optimally debulked patients (n=82), in whom the most important established prognostic factor, postoperative residual tumour cannot be applied. In conclusion p16(INK4a) and pRb are independent prognostic factors in advanced-stage ovarian carcinomas after radical surgery and postoperative chemotherapy. High pRb expression is a significant prognosticator in optimally debulked patients and may hold potential for subgroup stratification in postoperative treatment.