Improving preoperative diagnosis in endometrial cancer using systematic morphological assessment and a small immunohistochemical panel.

Preoperative histopathological classification determines the primary surgical approach in endometrial carcinoma (EC) patients but has only moderate agreement between preoperative and postoperative diagnosis. The aim of the PIpelle Prospective ENDOmetrial carcinoma (PIPENDO) study is to determine whether histopathological assessment and a small panel of diagnostic biomarkers decreases discrepancies between preoperative and postoperative diagnosis in EC. Preoperative endometrial tissue of 378 included patients with EC was stained with 15 different antibodies. Clinically relevant discrepancies in grade or histological subtype between original preoperative and reviewed postoperative diagnosis were observed in 75 (20%) patients. Highest clinically relevant discrepancy was found in grade 2 ECs (20%), compared to 5% and 14% in respectively grade 1 and 3 endometrioid endometrial carcinomas (EECs). A practical two-biomarker panel with PR and p53 improved diagnostic accuracy (AUC = 0.92; 95%CI = 0.88-0.95) compared to solely morphological evaluation (AUC = 0.86). In preoperative high-grade EC, the diagnostic accuracy of histological subtype was improved by a three-immunohistochemical biomarker panel (PR, IMP3, and L1CAM) (AUC = 0.93; 95%CI = 0.88-0.98) compared to solely morphological evaluation (AUC = 0.81). In conclusion to improve correct preoperative diagnosis in EC, we recommend use of a panel of at least two easily accessible immunohistochemical biomarkers (PR and p53), only in grade 2 ECs. Overall, this will reduce clinically relevant discrepancies in tumor grade and subtype with postoperative diagnosis with 6% (from 20% to 14%). Addition of PR, IMP3, and L1CAM for histological subtyping in high-grade EECs resulted in a further decrease in discrepancies with 8% (from 20% to 12%).

The role of MMP-14 in ovarian cancer: a systematic review.

AIM: In order to evaluate the role of MMP-14 in ovarian cancer, a systematic review was conducted. METHODS: In March 2020, a search in Pubmed was performed with MMP-14 and ovarian cancer as search terms. After exclusion of the references not on MMP-14 or ovarian cancer or not in English, the studies found were classified into two categories: basic research and clinicopathological research. RESULTS: In total, 94 references were found of which 33 were excluded. Two additional articles were found in the reference lists of the included studies. Based on the full texts, another 4 were excluded. Eventually, 59 studies were included in the review, 32 on basic research and 19 on clinicopathological research. 8 studies fell in both categories. The basic research studies show that MMP-14 plays an important role in ovarian cancer in the processes of proliferation, invasion, angiogenesis and metastasis. In clinocopathological research, MMP-14 expression is found in most tumours with characteristics of poor prognosis but this immunohistochemical MMP-14 determination does not seem to be an independent predictor of prognosis. CONCLUSIONS: From this systematic review of the literature concerning MMP-14 in ovarian cancer it becomes clear that MMP-14 plays various important roles in the pathophysiology of ovarian cancer. The exact translation of these roles in the pathophysiology to the importance of MMP-14 in clinicopathological research in ovarian cancer and possible therapeutic role of anti-MMP-14 agents needs further elucidation.

Preoperative risk stratification in endometrial cancer (ENDORISK) by a Bayesian network model: A development and validation study.

BACKGROUND: Bayesian networks (BNs) are machine-learning-based computational models that visualize causal relationships and provide insight into the processes underlying disease progression, closely resembling clinical decision-making. Preoperative identification of patients at risk for lymph node metastasis (LNM) is challenging in endometrial cancer, and although several biomarkers are related to LNM, none of them are incorporated in clinical practice. The aim of this study was to develop and externally validate a preoperative BN to predict LNM and outcome in endometrial cancer patients. METHODS AND FINDINGS: Within the European Network for Individualized Treatment of Endometrial Cancer (ENITEC), we performed a retrospective multicenter cohort study including 763 patients, median age 65 years (interquartile range [IQR] 58-71), surgically treated for endometrial cancer between February 1995 and August 2013 at one of the 10 participating European hospitals. A BN was developed using score-based machine learning in addition to expert knowledge. Our main outcome measures were LNM and 5-year disease-specific survival (DSS). Preoperative clinical, histopathological, and molecular biomarkers were included in the network. External validation was performed using 2 prospective study cohorts: the Molecular Markers in Treatment in Endometrial Cancer (MoMaTEC) study cohort, including 446 Norwegian patients, median age 64 years (IQR 59-74), treated between May 2001 and 2010; and the PIpelle Prospective ENDOmetrial carcinoma (PIPENDO) study cohort, including 384 Dutch patients, median age 66 years (IQR 60-73), treated between September 2011 and December 2013. A BN called ENDORISK (preoperative risk stratification in endometrial cancer) was developed including the following predictors: preoperative tumor grade; immunohistochemical expression of estrogen receptor (ER), progesterone receptor (PR), p53, and L1 cell adhesion molecule (L1CAM); cancer antigen 125 serum level; thrombocyte count; imaging results on lymphadenopathy; and cervical cytology. In the MoMaTEC cohort, the area under the curve (AUC) was 0.82 (95% confidence interval [CI] 0.76-0.88) for LNM and 0.82 (95% CI 0.77-0.87) for 5-year DSS. In the PIPENDO cohort, the AUC for 5-year DSS was 0.84 (95% CI 0.78-0.90). The network was well-calibrated. In the MoMaTEC cohort, 249 patients (55.8%) were classified with <5% risk of LNM, with a false-negative rate of 1.6%. A limitation of the study is the use of imputation to correct for missing predictor variables in the development cohort and the retrospective study design. CONCLUSIONS: In this study, we illustrated how BNs can be used for individualizing clinical decision-making in oncology by incorporating easily accessible and multimodal biomarkers. The network shows the complex interactions underlying the carcinogenetic process of endometrial cancer by its graphical representation. A prospective feasibility study will be needed prior to implementation in the clinic.

Molecular profiling identifies synchronous endometrial and ovarian cancers as metastatic endometrial cancer with favorable clinical outcome.

Synchronous primary endometrial and ovarian cancers (SEOs) represent 10% of all endometrial and ovarian cancers and are assumed to develop as independent entities. We investigated the clonal relationship between endometrial and ovarian carcinomas in a large cohort classified as SEOs or metastatic disease (MD). The molecular profiles were compared to The Cancer Genome Atlas (TCGA) data to explore primary origin. Subsequently, the molecular profiles were correlated with clinical outcome. To this extent, a retrospective multicenter study was performed comparing patients with SEOs (n = 50), endometrial cancer with synchronous ovarian metastasis (n = 19) and ovarian cancer with synchronous endometrial metastasis (n = 20). Targeted next-generation sequencing was used, and a clonality index was calculated. Subsequently, cases were classified as POLE mutated, mismatch repair deficient (MMR-D), TP53-wild-type or TP53-mutated. In 92% of SEOs (46/50), the endometrial and concurrent ovarian carcinoma shared at least one somatic mutation, with a clonality index above 0.95, supporting a clonal origin. The SEO molecular profiles showed striking similarities with the TCGA endometrial carcinoma set. SEOs behaved distinctly different from metastatic disease, with a superior outcome compared to endometrial MD cases (p < 0.001) and ovarian MD cases (p < 0.001). Classification according to the TCGA identified four groups with different clinical outcomes. TP53 mutations and extra-utero-ovarian disease were independent predictors for poor clinical outcome. Concluding, SEOs were clonally related in an overwhelming majority of cases and showed a favorable prognosis. Their molecular profile implied a primary endometrial origin. TP53 mutation and extra-utero-ovarian disease were independent predictors for outcome, and may impact adjuvant systemic treatment planning.

Primary Ovarian Tumors With Lymphogenic and Hematogenic Metastasis Express High MMP-14, Which Colocalizes With Highly Sulfated Chondroitin Sulfate in the Stroma.

Lymphogenic and hematogenic metastases are uncommon in ovarian cancer, especially at presentation. We hypothesized that MMP-14 and MMP-2, CD44, and highly sulfated chondroitin sulfate (CS-E) may be overexpressed in tumors with these metastatic patterns. These molecules are all present in the ovarian tumor microenvironment, wherein they may interact. In an ovarian cancer cohort of 44 patients with metastases in lymph nodes, spleen, and/or liver, the presence of MMP-14, MMP-2, CD44, and CS-E in both the primary tumor and the metastases was determined with immunohistochemistry and related to clinical characteristics. Immunohistochemical expression was found for MMP-14 in all primary tumors as well as in all metastases and for MMP-2 expression in most of the samples. Most primary tumors with synchronous metastases were positive for CS-E, as well as most primary tumors with metachronous lymphogenic metastases. The expression of the MMPs and CS-E in the stroma seemed to colocalize. For CD44 immunohistochemical expression, this relationship was not found. Epithelial MMP-14 on the one hand and stromal CS-E on the other hand seem to be essential players in ovarian cancer with lymphogenic and hematogenic metastases. CD44 expression is not correlated with the other markers. More research on the interaction of these molecules and their role in the process of dissimination of disease is warranted.

Mutational analysis of cervical cytology improves diagnosis of endometrial cancer: A prospective multicentre cohort study.

Endometrial carcinoma (EC) is traditionally diagnosed by a histopathological assessment of an endometrial biopsy, leaving up to 30% of patients undiagnosed due to technical failure or an inadequate amount of tissue. The aim of the current study is to assess whether mutational analysis of cervical cytology or pipelle endometrial biopsies improves the diagnostic accuracy of traditional histopathological diagnosis of EC. This prospective multicentre cohort study included patients surgically treated for EC or a benign gynaecological condition (control group). A Pap brush sample, cervicovaginal self-sample, pipelle endometrial biopsy and surgical specimen of either the EC or normal endometrium were obtained. A targeted next-generation sequencing panel was used to analyse these samples for mutations in eight genes. Sensitivity, specificity and predictive values were calculated. Fifty-nine EC patients and 31 control patients were included. In these patients, traditional histopathological diagnosis by pipelle had a sensitivity of 79% and a specificity of 100%. For EC patients, 97% of surgical specimens contained at least one mutation. Mutational analysis of Pap brush samples, self-samples and pipelle endometrial biopsies yielded a sensitivity of 78, 67 and 96% with a specificity of 97, 97 and 94%, respectively. Combining one of these three methods with histopathological pipelle endometrial biopsy evaluations yielded a sensitivity of 96, 93 and 96%, respectively. Our study has shown that mutational analysis of either cervical cytology or pipelle endometrial biopsies improves diagnosis of EC. Prospective validation will support implementation in clinical practice.

Polymorphisms in MMP-14 and MMP-2 genes and ovarian cancer survival.

BACKGROUND: Functional polymorphisms in matrix metalloproteinases can increase or decrease the risk of cancer. This study focused on ovarian cancer and investigated how polymorphisms in the coding region of MMP-14 and the promoter region of MMP-2 are related to clinical characteristics including survival. METHODS: In 144 patients with ovarian tumours from a Caucasian population, polymorphisms of MMP-14 (+7096 and +6767) and MMP-2 (-735 and -1306) were analysed. These results were then correlated to the immunohistochemical expression of MMP-14 and MMP-2 and clinical characteristics. RESULTS: In these patients, the MMP-14 +7096 polymorphism showed only TT genotype, in sharp contrast to the described MAF (minimal allele frequency) C of 27%. The MMP-14 +6767 G>A polymorphism was found to have a hazard ratio of 2.09 (CI 1.00-4.35, p 0.046) for recurrence-free survival in advanced-stage patients. However, this significance disappeared after Bonferroni correction for multiple testing. No other correlations between MMP-14 and MMP-2 polymorphisms, immunohistochemistry and clinical characteristics were found, except between the MMP-2 -1306 polymorphism and differentiation grade, with a Spearman correlation coefficient of -0.19, p 0.064. CONCLUSIONS: In ovarian cancer, the MMP-14 +6767 G>A polymorphism in the coding region seems to improve recurrence-free survival with a hazard ratio of 2.09 (CI 1.00-4.35, p 0.046). However, as this significance disappeared after correction for multiple testing, there is a need for further research on the functional effect of this change in the MMP-14 gene with larger patient sample sizes.

Gene Promoter Methylation in Endometrial Carcinogenesis.

Up to 60% of untreated atypical hyperplastic endometrium will develop into endometrial carcinoma (EC), and for those who underwent a hysterectomy a coexisting EC is found in up to 50%. Gene promoter methylation might be related to the EC development. The aim of this study is to determine changes in gene promoter profiles in normal endometrium, atypical hyperplasia (AH) and EC in relation to K-Ras mutations. A retrospective study was conducted in patients diagnosed with endometrial hyperplasia with and without subsequent EC. Promoter methylation of APC, hMLh1, O6-MGMT, P14, P16, RASSF1, RUNX3 was analysed on pre-operative biopsies, and correlated to the final histological diagnosis, and related to the presence of K-Ras mutations. In the study cohort (n=98), differences in promoter methylation were observed for hMLH1, O6-MGMT, and P16. Promoter methylation of hMLH1 and O6-MGMT gradually increased from histologically normal endometrium to AH to EC; 27.3, 36.4% and 38.0% for hMLH1 and 8.3%, 18.2% and 31.4% for O6-MGMT, respectively. P16 promoter methylation was significantly different in AH (7.7%) compared to EC (38%). K-Ras mutations were observed in 12.1% of AH, and in 19.6% of EC cases. No association of K-Ras mutation with promoter methylation of any of the tested genes was found. In conclusion, hMLH1 and O6-MGMT promoter methylation are frequently present in AH, and thus considered to be early events in the carcinogenesis of EC, whereas P16 promoter methylation was mainly present in EC, and not in precursor lesions supporting a late event in the carcinogenesis.

Tissue microarray is suitable for scientific biomarkers studies in endometrial cancer.

The aim of this study was to define the concordance between tissue microarrays (TMAs) of different sizes and whole slide for 15 different antibodies in endometrial cancer and study the use of TMAs in preoperative endometrial samples. Cores of preoperative and hysterectomy specimens of 14 endometrial cancer and three atypical hyperplasia cases were collected in TMA blocks. Two 0.6-mm and two 2.0-mm cores were used from each sample. Different antibodies were tested in TMAs and compared with results of whole slides of hysterectomy. Tested antibodies were as follows: ER, PR, p53, Ki-67, MLH1, PMS2, MSH2, MSH6, ARID1A, stathmin, IMP3, L1CAM, PTEN, ß-catenin, and p16. Seventeen cases with four cores per paraffin block (both 0.6 and 2.0 mm in duplicate) and 15 different antibodies resulted in a total of 1020 cores for both preoperative and hysterectomy specimen. Overall, 2.0-mm cores were more assessable for evaluation than 0.6-mm cores (96.0 versus 79.5%, p < 0.01). For most antibodies, a substantial to good agreement between hysterectomy TMA and whole slide was present, with lowest agreement for p16 and stathmin and perfect agreement for mismatch repair proteins. Preoperative TMAs showed for most antibodies moderate to perfect agreement with hysterectomy TMAs. In conclusion, 2.0-mm cores are the preferred size for immunohistochemical studies in endometrial cancer. For all tested antibodies, TMAs are a good alternative for whole slide analysis in scientific studies with large patient cohorts, even in preoperative endometrial samples. However, caution is required for interpretation of TMA results of p16 and stathmin.

Molecular profiles of benign and (pre)malignant endometrial lesions.

Endometrial carcinomas are histologically classified as endometrioid, assumed to originate from hyperplastic endometrium, or non-endometrioid carcinomas, assumed to originate from atrophic endometrium. However, both on a histological and a molecular level there are indications that there are more carcinoma types and carcinogenetic pathways. This study aims to analyze endometrial carcinogenesis on a molecular level. The presence of known KRAS, PIK3CA, AKT1, CTNNB1, BRAF, EGFR and NRAS mutations was studied in proliferative, atrophic and hyperplastic endometrium, endometrioid and serous carcinomas, and the endometrium next to these carcinomas, using single molecule Molecular Inversion Probes. Mutations were found in 9 (15%) of the 62 non atypical, and in 6 (18%) of the 34 atypical hyperplasia cases. In comparison, mutations were found in 1 (3%) of the simple, and 8 (30%) of the 27 complex hyperplasia cases. In 12/22 (55%) endometrioid carcinomas, a mutation was found. The KRAS gene was most often mutated in carcinomas next to hyperplastic endometrium, whereas PIK3CA and CTNNB1 mutations were found in endometrioid carcinomas with adjacent atrophic endometrium. Complex hyperplasia rather than atypical hyperplasia appears to be the most important lesion in the carcinogenesis of endometrioid carcinomas, and KRAS, PIK3CA and CTNNB1 mutations appear to play an important role in this process. Carcinogenesis of endometrioid carcinomas next to hyperplasia seems to be different to that of those next to atrophia. The value of these findings in managing endometrial hyperplasia and carcinoma should be studied.

Completeness of pathology reports in stage II colorectal cancer.

INTRODUCTION: The completeness of the pathological examination of resected colon cancer specimens is important for further clinical management. We reviewed the pathological reports of 356 patients regarding the five factors (pT-stage, tumor differentiation grade, lymphovascular invasion, tumor perforation and lymph node metastasis status) that are used to identify high-risk stage II colon cancers, as well as their impact on overall survival (OS). METHODS: All patients with stage II colon cancer who were included in the first five years of the MATCH study (1 July 2007 to 1 July 2012) were selected (n = 356). The hazard ratios of relevant risk factors were calculated using Cox Proportional Hazards analyses. RESULTS: In as many as 69.1% of the pathology reports, the desired information on one or more risk factors was considered incomplete. In multivariable analysis, age (HR: 1.07, 95%CI 1.04-1.10, p < .001), moderately- (HR: 0.35, 95%CI 0.18-0.70, p = .003) and well (HR 0.11, 95%CI 0.01-0.89, p = .038) differentiated tumors were significantly associated with OS. CONCLUSIONS: Pathology reports should better describe the five high-risk factors, in order to enable proper patient selection for further treatment. Chemotherapy may be offered to stage II patients only in select instances, yet a definitive indication is still unavailable.

Reproducibility of measurement of myometrial invasion in endometrial carcinoma.

Myometrial invasion (MI) as a percentage (%MI), categorized into <50 or ≥50 %, is an important predictor of prognosis in endometrial carcinoma. Recent studies suggest that tumor-free distance (TFD) to serosa and the absolute depth of invasion (DOI) might be stronger predictors of prognosis. Although reproducibility is important in clinical practice for patient prognostication and treatment, reproducibility of these methods for the measurement of MI is largely unknown. One or two slides from 50 patients with FIGO stage I endometrioid endometrial carcinoma were viewed by seven gynecological pathologists, who were requested to measure %MI, TFD, and DOI. We categorized %MI as <50 % (including no MI) or ≥50 %, TFD as ≤1.75 or >1.75 mm (including no MI), ≤7 or >7 mm (including no MI), and ≤10 or >10 mm (including no MI) and DOI as <4 mm (including no MI) or ≥4 mm. Light's kappa for multi-rater agreement was calculated. The %MI, TFD, and DOI could be measured in 88, 83, and 79 % of cases, respectively. Kappa was 0.75 for %MI, 0.77, 0.73, and 0.69 respectively for TFD with cutoffs of 1.75, 7, and 10 mm, and 0.59 for DOI. Pathologists reach substantial agreement when measuring %MI and TFD and moderate agreement when measuring DOI. The %MI can be measured in more cases than TFD and DOI. This supports the use of %MI in daily clinical practice, but future studies should compare %MI and TFD more extensively, including inter-observer variability.

MMP-14 and CD44 in Epithelial-to-Mesenchymal Transition (EMT) in ovarian cancer.

BACKGROUND: To investigate the expression of MMP-14 and CD44 as well as epithelial-to-mesenchymal transition(EMT)-like changes in ovarian cancer and to determine correlations with clinical outcome. METHODS: In 97 patients with ovarian cancer, MMP-14 and CD44 expression as determined by immunohistochemistry was investigated in relation to EMT-like changes. To determine this, immunohistochemical staining of E-cadherin and vimentin was performed. RESULTS: Patients with expression of both MMP-14 and CD44 in their tumors had a poor prognosis despite complete debulking. Serous histology in advanced-stage tumors (FIGO IIB-IV) correlated with CD44 (rho .286, p < 0.01). Also, CD44 correlated with percentage vimentin expression (rho .217, p < 0.05). In logistic regression analysis with complete debulking as the outcome parameter, CD44 expression was found to be significant (OR 3,571 (95 % Confidence Interval 1,112-11,468) p = 0.032), though this was not the case for MMP-14 and EMT parameters. CONCLUSION: The subgroup of patients with double expression of MMP-14 and CD44 had a poor prognosis despite complete debulking. Serous subtype in advanced-stage patients and CD44 expression were found to be correlated with vimentin expression, and CD44 expression was found to be significantly correlated with complete debulking. However, a significant correlation between EMT and clinical parameters was not found.

Limited independent prognostic value of MMP-14 and MMP-2 expression in ovarian cancer.

BACKGROUND: In cancer, various MMPs play a role in progression and metastasis and their overexpression generally indicates a poor prognosis. MMP-14 is the main activator of MMP-2 and both molecules play a role in normal ovarian follicular development. Earlier reports indicated a prognostic value for both MMP-14 and MMP-2 in ovarian cancer. This study was designed to determine the prognostic value of MMP-14 and MMP-2 expression in ovarian cancer with data on long-term follow-up. METHODS: Tumor samples of 94 consecutive ovarian cancer patients from one regional laboratory were evaluated. Clinical and survival data were collected and related to known prognostic factors, as well as to the expression of MMP-14 and MMP-2 as determined by semi-quantitative immunohistochemistry. RESULTS: Epithelial MMP-14 expression correlated with stromal MMP-14 expression (rho = .47, p < .01) and epithelial MMP-2 expression was found to correlate with both MMP-14 epithelial and stromal expression (rho = -.28, p < .01 respectively rho = -.21, p < .05). In univariable analysis of 64 advanced-staged tumours, no MMP parameter was significant for progression-free or overall survival. In multivariable analysis for PFS, stromal MMP-14 expression and epithelial MMP-2 expression remained in the model. For overall survival, no MMP parameter showed significance. CONCLUSIONS: We confirmed the correlation between epithelial and stromal MMP-14 expression and between epithelial MMP-2 and both epithelial and stromal MMP-14 expression. In this study with long-term follow-up, the independent prognostic value of MMP-14 and MMP-2 expression in ovarian cancer is limited to a role in PFS for stromal MMP-14 expression and epithelial MMP-2 expression.

PIpelle Prospective ENDOmetrial carcinoma (PIPENDO) study, pre-operative recognition of high risk endometrial carcinoma: a multicentre prospective cohort study.

BACKGROUND: Endometrial carcinoma is the most common gynaecologic malignancy in industrialised countries and the incidence is still rising. Primary treatment is based on preoperative risk classification and consists in most cases of hysterectomy with bilateral salpingo-oophorectomy. In patients with serous and clear cell histology a complete surgical staging is mandatory. However, in routine clinical practice final histology regularly does not correspond with the preoperative histological diagnosis. This results in both over and under treatment. METHODS/DESIGN: The aim of this multicentre, prospective cohort study is to select a panel of prognostic biomarkers to improve preoperative diagnosis of endometrial carcinoma in order to identify those patients that need extended surgery and/or additional treatment. Additionally, we will determine whether incorporation of cervical cytology and comorbidity could improve this preoperative risk classification. All patients treated for endometrial carcinoma in the participating hospitals from September 2011 till December 2013 are included. Patient characteristics, as well as comorbidity are registered. Patients without preoperative histology, history of hysterectomy and/or endometrial carcinoma or no surgical treatment including hysterectomy are excluded. The preoperative histology and final pathology will be reviewed and compared by expert pathologists. Additional immunohistochemical analysis of IMP3, p53, ER, PR, MLH1, PTEN, beta-catenin, p16, Ki-67, stathmin, ARID1A and L1CAM will be performed. Preoperative histology will be compared with the final pathology results. Follow-up will be at least 24 months to determine risk factors for recurrence and outcome. DISCUSSION: This study is designed to improve surgical treatment of endometrial carcinoma patients. A total of 432 endometrial carcinoma patients were enrolled between 2011 and 2013. Follow-up will be completed in 2015. Preoperative histology will be evaluated systematically and background endometrium will be classified. This is the first study incorporating immunohistochemistry, cervical cytology and comorbidity to define the optimal panel of prognostic biomarkers that contribute in clinical decision making in the management of endometrial carcinoma. TRIAL REGISTRATION: Netherlands Trial Register number NTR3503.

Effect of undiagnosed deep adenomyosis after failed NovaSure endometrial ablation.

STUDY OBJECTIVE: To determine the prevalence of adenomyosis and deep adenomyosis after NovaSure (Hologic Inc., Newark, DE) endometrial ablation in hysterectomy specimens after NovaSure endometrial ablation failure. DESIGN: Prospective observational study (Canadian Task Force classification II-2). SETTING: The TweeSteden Hospital, a teaching hospital in the south of the Netherlands. PATIENTS: All women who underwent hysterectomy for menorrhagia and/or dysmenorrhea after failure of NovaSure endometrial ablation between November 2007 and January 2011. INTERVENTIONS: All patients who underwent hysterectomy between January 2005 and April 2009 for the same indication but did not undergo prior endometrial ablation from choice or the lack of availability of the endometrial ablation procedure. MEASUREMENTS AND MAIN RESULTS: Of 213 patients who underwent NovaSure therapy, 22 (10.3%) underwent a hysterectomy because NovaSure failed. Of these, 10 (45.5%) exhibited adenomyosis in their hysterectomy specimens. The control group patients had a similar adenomyosis prevalence (74/173, 42.8%). However, the NovaSure failure group had a significantly higher prevalence of deep adenomyosis (>2.5 mm endometrial penetration) (9/22, 40.9%) than the control group (37/173, 21.4%, p < .05). CONCLUSION: Deep adenomyosis after failed NovaSure endometrial ablation was present in a significant number of patients. It is not clear whether adenomyosis is induced by endometrial ablation or whether it causes endometrial ablation failure.

The lymph node ratio as a prognostic factor for gastric cancer.

To predict prognosis of gastric cancer, an adequate assessment of the stage of gastric cancer is important. The UICC/AJCC TNM classification is the most commonly used classification system. For adequate N staging at least 15 lymph nodes should be retrieved. In some countries, this amount of lymph nodes is not met, which can lead to understaging. Therefore, the lymph node ratio (LNR) is proposed as an alternative N staging modality. The purpose of this study was to compare the different staging modalities. Patients and methods. We included all patients who underwent surgery for gastric cancer, newly diagnosed between 2000 and 2009 and staged patient by UICC/AJCC TNM 5th/6th or 7th and by LNR. We conducted crude survival analysis, univariate and multivariate analyses according to the different staging systems. Results. The five-year overall survival rates ranged from 58% for N0 disease to 18% in case of more than 15 metastatic lymph nodes. The distribution of overall five-year survival according to LNR was 58% for LNR0 and 10% for LNR3. Univariate analysis showed that all the UICC/AJCC TNM classification systems as well as the LNR were strong prognostic factors for overall survival. The LNR correlated less with the number of nodes examined. Conclusion. LNR is a good prognostic tool for overall survival, it is an independent prognostic factor with a more homogenous spread of hazard ratios and five-year survival rates than UICC/AJCC systems. Furthermore, the LNR has a lower correlation with the number of nodes examined, making it less vulnerable for stage migration.

Preoperative identification of synchronous ovarian and endometrial cancers: the importance of appropriate workup.

OBJECTIVE: For treatment of patients with both endometrial and ovarian cancer, it is important to discriminate between 2 primary tumors and metastatic disease. Currently, criteria are based on postoperative findings. The aim of this study was to determine whether clinical parameters can discriminate between these groups preoperatively and whether a practical guideline could improve appropriate workup and treatment. METHODS: A total of 45 patients with a diagnosis of both endometrium and ovarian cancer between 1998 and 2009 and were included for analysis. Clinical and pathological data were obtained, and initial CA-125 was registered; patients had a diagnosis of 2 primary tumors or tumors with metastasis. All patients were reclassified according to workup and treatment. RESULTS: Patients with synchronous primary tumors were significantly younger, presented more often with abnormal uterine bleeding, and had a lower initial CA-125 than both metastatic groups (P < 0.05). With age and CA-125 included in a polytomic logistic regression model, 83.3% of diagnoses could be classified correctly. In 15 of 17 patients presented with adnexal mass, workup was incomplete owing to lack on information of the endometrial status. In patients presenting with abnormal uterine bleeding, 13 of 21 patients had an incomplete workup leading to staging laparotomy secondary to initial surgical treatment in 2 patients. CONCLUSIONS: Patients with synchronous endometrial and ovarian cancers are young, often present with abnormal uterine bleeding and have a low initial CA-125. Adequate workup with attention to both ovarian and endometrial status, especially in young patients with a wish to preserve fertility, is important to make the right decision for treatment.

Predicting the coexistence of an endometrial adenocarcinoma in the presence of atypical complex hyperplasia: immunohistochemical analysis of endometrial samples.

OBJECTIVE: This study aimed to determine whether immunohistochemical markers in complex atypical endometrial hyperplasia could predict the presence of a concurrent endometrial carcinoma. METHODS: Endometrial biopsies of 39 patients with complex atypical hyperplasia were selected retrospectively between 1999 and 2006. Only patients who underwent a hysterectomy were included. A coexisting endometrial carcinoma was present in 25 patients (64%). Immunohistochemical analysis was performed on formalin-fixed paraffin-embedded sections of the endometrial biopsies, using antibodies for MIB-1, ß-catenin, E-cadherin, p53, PTEN, CD44, HER2-neu, survivin, COX-2, tenascin, and bcl-2. To evaluate the potential utility of these markers, a prediction model was constructed. RESULTS: In the univariate analysis, expressions of both PTEN and HER2-neu were significantly different between the groups with and without a coexisting endometrial carcinoma (P < 0.05). Loss of PTEN staining was found in 13 (54%) and 1 (7%) of the patients with and without a coexistent carcinoma, respectively (odds ratio, 16.55; 95% confidence interval [CI], 1.87-146.65). HER2-neu expression was found in only 2 (8.6%) and 6 (43%) patients with and without a coexistent carcinoma, respectively, and was excluded from further analysis because of its low expression. A prediction model containing PTEN expression only showed an area under the curve of 73.4% (95% CI, 57.3%-89.6%). After adding MIB-1 and p53, discriminative power improved to 87.2% (95% CI, 75.1%-99.3%). CONCLUSIONS: This study showed that PTEN expression in complex endometrial hyperplasia is a promising factor for the prediction of the presence of a coexisting endometrial carcinoma, and prediction may even better when MIB-1 and p53 expressions are considered simultaneously.

Clinical value of morphometric and DNA flow cytometric variables as independent predictors of survival in epithelial ovarian carcinoma: a 5-year follow-up study.

The aim of this follow-up study is to validate the clinical significance of quantitative morphometric and DNA flow cytometric variables as independent prognostic factors of overall survival and progression-free survival in epithelial ovarian carcinoma. Tumor samples were collected from 135 patients with epithelial ovarian carcinoma at 3 hospitals in the Netherlands. Evaluated clinico-pathologic variables were age, histologic subtype, differentiation grade, clinical stage [International Federation of Gynecology and Obstetrics (FIGO)], presence of ascites, serum CA-125, and the completeness of debulking surgery. Morphometry and DNA flow cytometric techniques were assessed on each tumor sample to determine the mitotic activity index (MAI), volume percentage epithelium, mean nuclear area (MNA), standard deviation of MNA (SD MNA), nuclear perimeter (NP), and DNA ploidy. Univariate analysis showed that differentiation grade, FIGO stage, presence of ascites, preoperative CA-125 levels, DNA ploidy, and MAI, NP, and MNA were of significant prognostic value. After multivariate analysis (using forward Cox proportional hazard analysis), only differentiation grade and FIGO stage remained significant. From this study, we can conclude that morphometry and DNA flow cytometry are not independent prognosticators and therefore have no clinical value in predicting prognosis in ovarian carcinoma.