Villoglandular Pattern in HPV-associated Endocervical Adenocarcinoma is Associated With Excellent Prognosis: A Reappraisal of 31 Cases Using IECC and Silva Pattern Classification.

Villoglandular adenocarcinoma of the cervix is a rare histologic entity that typically develops in young women, characterized by an association with oral contraceptives and excellent prognosis, though this point is controversial. These tumors have not been studied in the context of the International Endocervical Adenocarcinoma Criteria and Classification (IECC) or Silva Pattern Classification. We analyzed 31 cases that met strict diagnostic criteria, including being completely excised with negative margins. These were categorized according to IECC and Silva Pattern Classification and the association with various pathologic parameters analyzed. Most patients were young with a mean age of 41.1 (range 25-79). There were 14 (45.2%) pattern A, 11 (35.5%) pattern B, and 6 (19.3%) pattern C cases. Only 1 of 22 patients (4.5%) presented with lymph node metastasis at the time of diagnosis (pattern C, stage IB1) and 3 (9.7%) had lymphovascular invasion (2 pattern C, 1 pattern B). Overall survival was 100%, while recurrence-free survival was 96.2% for the entire cohort with only 1 case (3.2%) recurring 25 mo after surgery (IB2, pattern B). Kaplan Meier analysis (log rank test) revealed no significant correlation for recurrence-free survival at 5 and 10 yr associated with depth of invasion, tumor size, Silva pattern, FIGO stage, lymphovascular invasion, or lymph node metastasis. Cox univariate analysis demonstrated no independent prognostic factors predicting recurrence-free survival. These results indicate that completely excised villoglandular adenocarcinoma generally has an excellent prognosis and when Silva Pattern Classification is applied, those tumors that potentially have a higher chance for adverse outcomes can be identified.

Vulvar Adenocarcinoma of Intestinal Type: A Case Report of an Uncommon Entity.

Vulvar cancer is rare and accounts for only 5% of all gynecologic cancers. Squamous cell carcinoma is the most common and makes up 90% of the cases. Vulvar adenocarcinoma usually arises in Bartholin and other vulvar glands. Primary vulvar intestinal-type adenocarcinoma is an extremely rare disease with an unclear prognosis and treatment. Its origin is still unknown, the most accepted theory suggests cloacal remnants as the source of origin. Only a few cases have been reported in the literature. We present a case of a 66-yr-old female who presented with vulvar pruritus and local discomfort, showing a 2 cm tumor located in the left labium minor in the region of vulvar fourchette. Wide vulvar excision and bilateral lymph nodes dissection were performed. Other concomitant lesions and distant extension of tumor were ruled out by positron emission tomography. Pathologic study revealed a colonic-type adenocarcinoma with typical villoglandular architecture with an irregular glandular structure composed of atypical columnar epithelium. The lesion had direct contact with epidermal surface and mainly was external without involving the dermis. Immunohistochemical analysis revealed positive staining for cytokeratin 20 and CDX2. p16 showed an abnormal diffuse and strong immunoexpression. The presence of a low-risk human papillomavirus was detected by polymerase chain reaction, therefore, the expression of p16 cannot be explained in this case by the presence of human papillomavirus. Additional studies are needed in additional cases to clarify the role of human papillomavirus in this kind of tumor.

Genomic Validation of Endometrial Cancer Patient-Derived Xenograft Models as a Preclinical Tool.

Endometrial cancer (EC) is the second most frequent gynecological cancer worldwide. Although improvements in EC classification have enabled an accurate establishment of disease prognosis, women with a high-risk or recurrent EC face a dramatic situation due to limited further treatment options. Therefore, new strategies that closely mimic the disease are required to maximize drug development success. Patient-derived xenografts (PDXs) are widely recognized as a physiologically relevant preclinical model. Hence, we propose to molecularly and histologically validate EC PDX models. To reveal the molecular landscape of PDXs generated from 13 EC patients, we performed histological characterization and whole-exome sequencing analysis of tumor samples. We assessed the similarity between PDXs and their corresponding patient's tumor and, additionally, to an extended cohort of EC patients obtained from The Cancer Genome Atlas (TCGA). Finally, we performed functional enrichment analysis to reveal differences in molecular pathway activation in PDX models. We demonstrated that the PDX models had a well-defined and differentiated molecular profile that matched the genomic profile described by the TCGA for each EC subtype. Thus, we validated EC PDX's potential to reliably recapitulate the majority of histologic and molecular EC features. This work highlights the importance of a thorough characterization of preclinical models for the improvement of the success rate of drug-screening assays for personalized medicine.

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.

Poor outcome in hypoxic endometrial carcinoma is related to vascular density.

BACKGROUND: Identification of endometrial carcinoma (EC) patients at high risk of recurrence is lacking. In this study, the prognostic role of hypoxia and angiogenesis was investigated in EC patients. METHODS: Tumour slides from EC patients were stained by immunofluorescence for carbonic anhydrase IX (CAIX) as hypoxic marker and CD34 for assessment of microvessel density (MVD). CAIX expression was determined in epithelial tumour cells, with a cut-off of 1%. MVD was assessed according to the Weidner method. Correlations with disease-specific survival (DSS), disease-free survival (DFS) and distant disease-free survival (DDFS) were calculated using Kaplan-Meier curves and Cox regression analysis. RESULTS: Sixty-three (16.4%) of 385 ECs showed positive CAIX expression with high vascular density. These ECs had a reduced DSS compared to tumours with either hypoxia or high vascular density (log-rank p = 0.002). Multivariable analysis showed that hypoxic tumours with high vascular density had a reduced DSS (hazard ratio [HR] 3.71, p = 0.002), DDFS (HR 2.68, p = 0.009) and a trend for reduced DFS (HR 1.87, p = 0.054). CONCLUSIONS: This study has shown that adverse outcome in hypoxic ECs is seen in the presence of high vascular density, suggesting an important role of angiogenesis in the metastatic process of hypoxic EC. Differential adjuvant treatment might be indicated for these patients.

Therapeutic potential of the new TRIB3-mediated cell autophagy anticancer drug ABTL0812 in endometrial cancer.

OBJECTIVES: The PI3K/AKT/mTOR pathway is frequently overactivated in endometrial cancer (EC). We assessed the efficacy of ABTL0812, a novel first-in-class molecule presenting a unique mechanism of action inhibiting this pathway. METHODS: We investigated the effects of ABTL0812 on proliferation, cell death and modulation of intracellular signaling pathways in a wide panel of endometrioid and non-endometrioid cell lines, an inducible PTEN knock-out murine model, and two patient-derived xenograft murine models of EC. Then, TRIB3 expression was evaluated as potential ABTL0812 pharmacodynamic biomarker in a Phase 1b/2a clinical trial. RESULTS: ABTL0812 induced an upregulation of TRIB3 expression, resulting in the PI3K/AKT/mTOR axis inhibition and autophagy cell death induction on EC cells but not in healthy endometrial cells. ABTL0812 treatment also impaired PTEN knock-out cells to progress from hyperplasia to cancer. The therapeutic effects of ABTL0812 were demonstrated in vivo. ABTL0812 increased TRIB3 mRNA levels in whole blood samples of eight EC patients, demonstrating that TRIB3 mRNA could be used as a pharmacodynamic biomarker to monitor the ABTL0812 treatment. CONCLUSIONS: ABTL0812 may represent a novel and highly effective therapeutic agent by inducing TRIB3 expression and autophagy in EC patients, including those with poorer prognosis.

[Twin gestation with complete hydatidiform mole and a coexisting live fetus: A case report and review of the literature]. / Embarazo gemelar con mola hidatiforme completa y feto vivo asociado: reporte de un caso y revisión bibliográfica.

Twin pregnancies with complete hydatidiform mole and coexisting live fetus are very rare, with only about 300 reported cases. This type of pregnancy is considered a high obstetric risk due to the possibility of severe maternal-fetal complications. Although the clinical and ultrasound findings can be highly suggestive of this type of pregnancy, the definitive diagnosis is usually reached by histopathological examination. The differential diagnosis usually includes partial hydatidiform mole and hydropic pregnancies, which can present similar findings in specimens from the first trimester of pregnancy and thus it is important to interpret correctly the differentiating features. The use of immunohistochemistry for p57 can prove very useful, although some cases show an aberrant expression. We present a case of a twin pregnancy with complete hydatidiform mole associated with a live fetus, with magnetic resonance imaging and ultrasound for radiopathological correlation. We discuss the differential diagnosis and the utility of p57 immunohistochemistry.

Clear Cell Carcinoma (CCC) of the Cervix Is a Human Papillomavirus (HPV)-independent Tumor Associated With Poor Outcome: A Comprehensive Analysis of 58 Cases.

Cervical clear cell carcinoma (CCC) is a rare human papillomavirus-independent adenocarcinoma. While recent studies have focused on gastric-type endocervical adenocarcinoma (GTA), little is known about CCC. A total of 58 (CCCs) were collected from 14 international institutions and retrospectively analyzed using univariable and multivariable methods and compared with 36 gastric-type adenocarcinomas and 173 human papillomavirus-associated (HPVA) endocervical adenocarcinoma (ECA) regarding overall survival (OS) and recurrence-free survival (RFS). Most cases were FIGO stage I (72.4%), with Silva C pattern of invasion (77.6%), and the majority were treated with radical surgery (84.5%) and adjuvant therapy (55.2%). Lymphovascular invasion was present in 31%, while lymph node metastasis was seen in 24.1%; 10.3% were associated with abdominopelvic metastases at the time of diagnosis; 32.8% had recurrences, and 19% died of disease. We did not find statistically significant differences in OS and RFS between CCC and GTA at 5 and 10 years (P=0.313 and 0.508, respectively), but there were significant differences in both OS and RFS between CCC and HPVA ECA (P=0.003 and 0.032, respectively). Also, OS and RFS in stage I clear cell and GTA were similar (P=0.632 and 0.692, respectively). Multivariate analysis showed that OS is influenced by the presence of recurrence (P=0.009), while RFS is influenced by the FIGO stage (P=0.025). Cervical CCC has poorer outcomes than HPVA ECA and similar outcomes to human papillomavirus-independent GTA. Oncologic treatment significantly influences RFS in univariate analysis but is not an independent prognostic factor in multivariate analysis suggesting that alternative therapies should be investigated.

The cutoff for estrogen and progesterone receptor expression in endometrial cancer revisited: a European Network for Individualized Treatment of Endometrial Cancer collaboration study.

There is no consensus on the cutoff for positivity of estrogen receptor (ER) and progesterone receptor (PR) in endometrial cancer (EC). Therefore, we determined the cutoff value for ER and PR expression with the strongest prognostic impact on the outcome. Immunohistochemical expression of ER and PR was scored as a percentage of positive EC cell nuclei. Cutoff values were related to disease-specific survival (DSS) and disease-free survival (DFS) using sensitivity, specificity, and multivariable regression analysis. The results were validated in an independent cohort. The study cohort (n = 527) included 82% of grade 1-2 and 18% of grade 3 EC. Specificity for DSS and DFS was highest for the cutoff values of 1-30%. Sensitivity was highest for the cutoff values of 80-90%. ER and PR expression were independent markers for DSS at cutoff values of 10% and 80%. Consequently, three subgroups with distinct clinical outcomes were identified: 0-10% of ER/PR expression with, unfavorable outcome (5-year DSS = 75.9-83.3%); 20-80% of ER/PR expression with, intermediate outcome (5-year DSS = 93.0-93.9%); and 90-100% of ER/PR expression with, favorable outcome (5-year DSS = 97.8-100%). The association between ER/PR subgroups and outcomes was confirmed in the validation cohort (n = 265). We propose classification of ER and PR expression based on a high-risk (0-10%), intermediate-risk (20-80%), and low-risk (90-100%) group.

Metabolomic and Lipidomic Profiling Identifies The Role of the RNA Editing Pathway in Endometrial Carcinogenesis.

Endometrial cancer (EC) remains the most common malignancy of the genital tract among women in developed countries. Although much research has been performed at genomic, transcriptomic and proteomic level, there is still a significant gap in the metabolomic studies of EC. In order to gain insights into altered metabolic pathways in the onset and progression of EC carcinogenesis, we used high resolution mass spectrometry to characterize the metabolomic and lipidomic profile of 39 human EC and 17 healthy endometrial tissue samples. Several pathways including lipids, Kynurenine pathway, endocannabinoids signaling pathway and the RNA editing pathway were found to be dysregulated in EC. The dysregulation of the RNA editing pathway was further investigated in an independent set of 183 human EC tissues and matched controls, using orthogonal approaches. We found that ADAR2 is overexpressed in EC and that the increase in expression positively correlates with the aggressiveness of the tumor. Furthermore, silencing of ADAR2 in three EC cell lines resulted in a decreased proliferation rate, increased apoptosis, and reduced migration capabilities in vitro. Taken together, our results suggest that ADAR2 functions as an oncogene in endometrial carcinogenesis and could be a potential target for improving EC treatment strategies.