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Simple Summary: In patients with locally advanced cervical cancer, the availability of imaging techniques for accurately defining the residual tumor would be clinically relevant for selecting patients who could be offered a more tailored surgery. The novelty of this prospective study is the development of multiparametric predictive models of histopathological response using a unique data set with three imaging modalities (transvaginal ultrasound, magnetic resonance (MRI) and 18F-FDG-PET/CT) evaluated at three time points ("baseline", two ("early") and five ("final") weeks after treatment). In a cohort of 88 patients, the predictive models retrieved integrating morphometric, vascular, perfusion and metabolic parameters, demonstrated that two imaging approaches (MRI and PET/CT at "final" evaluation or PET/CT at "baseline" and "final" evaluation) are sufficient to identify possible residual disease after chemotherapy. These findings could be useful in selecting patients with residual disease, helping clinicians to tailor the radicality of the surgical approach. Purpose: This study aimed to develop predictive models for pathological residual disease after neoadjuvant chemoradiation (CRT) in locally advanced cervical cancer (LACC) by integrating parameters derived from transvaginal ultrasound, MRI and PET/CT imaging at different time points and time intervals. Methods: Patients with histologically proven LACC, stage IB2–IVA, were prospectively enrolled. For each patient, the three examinations were performed before, 2 and 5 weeks after treatment ("baseline", "early" and "final", respectively). Multivariable logistic regression models to predict complete vs. partial pathological response (pR) were developed and a cost analysis was performed. Results: Between October 2010 and June 2014, 88 patients were included. Complete or partial pR was found in 45.5% and 54.5% of patients, respectively. The two most clinically useful models in pR prediction were (1) using percentage variation of SUVmax retrieved at PET/CT "baseline" and "final" examination, and (2) including high DWI signal intensity (SI) plus, ADC, and SUVmax collected at "final" evaluation (area under the curve (95% Confidence Interval): 0.80 (0.71–0.90) and 0.81 (0.72–0.90), respectively). Conclusion: The percentage variation in SUVmax in the time interval before and after completing neoadjuvant CRT, as well as DWI SI plus ADC and SUVmax obtained after completing neoadjuvant CRT, could be used to predict residual cervical cancer in LACC patients. From a cost point of view, the use of MRI and PET/CT is preferable. [ABSTRACT FROM AUTHOR]

Simple Summary: Lynch syndrome (LS) is a genetic condition predisposing to a variety of tumors, including endometrial (EC) and ovarian cancers (OC), with cancer lifetime risk depending on the specific LS-mutation involved. Universal Screening is the standard for LS detection. Prophylactic surgery is a risk-reducing option that may be considered, and the age at hysterectomy and recommendation for bilateral oophorectomy depend on the mutated variant and offspring desire. Besides surgery, chemoprevention via contraceptives combination or progestin-alone is a viable option, and vaccination with tumor-specific antigens has shown promising results in mouse models. LS patients requiring adjuvant radiotherapy or systemic treatment for EC or OC are managed according to international standard of care. However, when conservative treatment for EC is considered, worse oncologic and obstetric outcomes are reported for patients with mismatch repair deficiency or LS. Moreover, LS-related tumors are characterized by a highly immunogenic tumor-environment that can be targeted by specific immune checkpoint inhibitors. This review provides a comprehensive update on recent evidence regarding gynecologic tumors associated with Lynch Syndrome (LS). Endometrial cancer (EC) and ovarian cancer (OC) are the first and second most common gynecologic malignancies in developed countries, respectively, and LS is estimated to be the hereditary cause in 3% of both EC and OC. Despite the increasing evidence on LS-related tumors, few studies have analyzed the outcomes of LS-related EC and OC stratified by mutational variant. This review aims to provide a comprehensive overview of the literature and comparison between updated international guidelines, to help outline a shared pathway for the diagnosis, prevention, and management of LS. Through the widespread adoption of the immunohistochemistry-based Universal Screening, LS diagnosis and identification of mutational variants could be standardized and recognized by international guidelines as a feasible, reproducible, and cost-effective method. Furthermore, the development of a better understanding of LS and its mutational variants will support our ability to better tailor EC and OC management in terms of prophylactic surgery and systemic treatment in the light of the promising results shown by immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of the present review is to analyze the novel and most relevant prognostic factors in primary and recurrent cervical cancer. Based on our findings, tumour budding and cell nest size grading system, depth of stromal invasion, lympho-vascular space invasion, perineural invasion, tumor free distance and tumor infiltrating lymphocytes appeared the most relevant factors which may be included in the pathology report to help future studies to further elucidate cervical cancer prognosis. Background: Several pathological parameters, including tumor size, depth of stromal invasion, lympho-vascular space invasion and lymph node status, have been proposed as prognostic predictors in cervical cancer. However, given the high mortality and recurrence rate of cervical cancer, novel parameters that are able to provide additional prognostic information are needed in order to allow a better prognostic stratification of cervical cancer patients. Methods: A search was conducted on PubMed to identify relevant literature data regarding prognostic factors in cervical cancer. The key words "cervical cancer", "prognostic factors", "pathology", and "outcome" were used. Results: The novel pathological grading system based on tumor budding and cell nest size appeared the most relevant prognostic factor in primary neoplasms. Moreover, other potentially useful prognostic factors were tumor size, depth of stromal invasion, lympho-vascular space invasion, perineural invasion, tumor-free distance and tumor-infiltrating lymphocytes. Prognostic factors related to advanced-stage cervical cancer, including lymph-nodes status, endometrial and cervical involvement as well as distant metastases, were also taken into consideration. Conclusions: According to our findings, tumor budding and cell nest size grading system, depth of stromal invasion, lympho-vascular space invasion, perineural invasion, tumor-free distance and tumor-infiltrating lymphocytes appeared the most relevant factors included in the pathology report. [ABSTRACT FROM AUTHOR]

Simple Summary: The rate of positive parametrial lymph nodes in a series of apparent early-stage cervical cancer patients undergoing bilateral sentinel lymph node mapping was 3.1%. After ultrastaging of parametrial tissue, no occult micrometastasis was detected. Occult parametrial involvement in apparent early-stage cervical cancer might be overlooked with standard pathologic assessment. The primary endpoint of the present study was to assess the rate of positive parametrial lymph nodes and of microscopic continuous or discontinuous parametrial involvement. This is a retrospective, single-center, observational study including patients with FIGO 2018 stage IA1–IIA1 and IIIC1p in whom bilateral sentinel lymph node (SLN) detection and ultrastaging of SLN were performed according to institutional protocol, with surgery as primary treatment performed between May 2017 and February 2021, as well as type B2/C1/C2 (Querleu–Morrow) radical hysterectomy and usual histology (squamous cell, adenocarcinoma and adenosquamous carcinoma). Thirty-one patients were included in the study period. Six (18.7%) patients had metastatic lymph nodes, of whom four had only SLN metastasis (two cases of ITC, one case of micrometastasis and one case of macrometastasis). We found a macroscopic deposit of cancer cells in the parametrial lymph node of one patient (3.1%). There was a positive statistical correlation between the incidence of parametrial lymph node involvement and the metastatic pelvic lymph nodes (p = 0.038). When performed per patient, the sensitivity, negative predictive value and accuracy of parametrial lymph node involvement in predicting pelvic lymph node metastasis were 16.7%, 83.3% and 83.9%, respectively. Ultrastaging of parametrial tissue did not identify any occult continuous or discontinuous parametrial metastasis. In conclusion, the incidence of lymph node parametrial involvement in a retrospective series of early-stage cervical cancer was 3.1% of all included patients. Lymph node involvement of the parametrium was associated with lymph node metastasis. The sensitivity of parametrial lymph node involvement to predict pelvic lymph node metastasis was low. The lack of parametrial involvement revealed by parametrial ultrastaging could be related to the number of patients with tumors with a pathologic diameter < 2 cm (54.8%). Further prospective studies are needed to analyze the role of parametrial ultrastaging in early-stage cervical cancer and to assess whether it can be considered the "sentinel" of the sentinel lymph node. [ABSTRACT FROM AUTHOR]

Simple Summary: Ovarian hormones are involved in ovarian cancer pathogenesis. However, few reports have investigated the hormone receptor pattern according to BRCA mutational status. The aim of this single-center, observational, retrospective study was to explore the relationship between hormone receptor status and BRCA1/2 mutation in a cohort of 207 high-grade serous ovarian carcinoma (HGSOC) patients. Interesting differences emerged between BRCA-mutated and BRCA wild-type women, in terms of pattern of receptor expression and its association to the outcome. On the whole, our findings, though needing further validation, extend our understanding of the complex interplay between BRCA1/2 protein and hormone signaling, suggesting new pathways to be exploited in order to develop future personalized therapy. Several studies have explored the prognostic role of hormone receptor status in high-grade serous ovarian cancer (HGSOC) patients. However, few reports have investigated their expression according to BRCA mutational status. The aim of this single-center, observational, retrospective study was to explore the hormone receptor pattern and its potential prognostic role in a cohort of 207 HGSOC women stratified for BRCA mutational status. To this end, ERα, ERβ1, ERβ2, ERβ5, PR, and AR expression were assessed by immunohistochemistry in 135 BRCA-wild type (BRCA-wt) and 72 BRCA1/2 mutation carriers (BRCA-mut). No significant difference emerged in hormone receptor expression between the two sub-samples, except for a significantly lower ERα expression observed in pre-menopausal BRCA1/2-mut as compared to BRCA-wt patients (p = 0.02). None of the examined hormone receptors has revealed a significant prognostic role in the whole sample, apart from the ratio ERα/ERβ5 nuclear, for which higher values disclosed a positive role on the outcome in BRCA-wt subgroup (HR 0.77; CI 0.61–0.96; p = 0.019). Conversely, it negatively affected overall survival in the presence of BRCA1/2-mut (HR 1.41; CI 1.06–1.87; p = 0.020). Finally, higher PR levels were associated with platinum sensitivity in the whole sample (p = 0.019). Our data, though needing further validation, suggest a potential role of oestrogen-mediated pathways in BRCA1/2-associated HGSOC tumorigenesis, thus revealing a possible therapeutic potential for targeting this interaction. [ABSTRACT FROM AUTHOR]

Simple Summary: L1CAM overexpression (≥10%) and the microcystic, elongated, and fragmented (MELF) pattern of invasion have previously been assessed as prognostic factors in endometrial carcinoma. We aimed to assess the relationship between L1CAM expression, MELF glands, and lymph node involvement in endometrial carcinoma, as all these factors are related to epithelial-to-mesenchymal transition. We evaluated L1CAM expression in 58 cases of uterine-confined, low-grade endometrioid carcinomas. We found that most cases (65.5%) expressed L1CAM in a limited manner to MELF glands. Cases with L1CAM expression in ≥10% of the MELF component showed a significantly higher tendency to lymph node spread (p < 0.001), even when adjusted for lymphovascular space invasion, depth of myometrial invasion and p53/mismatch repair status. On this account, L1CAM expression in the MELF component may stratify the prognosis and management in patients with uterine-confined, low-grade carcinomas. In endometrial carcinoma, both L1CAM overexpression and microcystic, elongated and fragmented (MELF) patterns of invasion have been related to epithelial-to-mesenchymal transition and metastatic spread. We aimed to assess the association between L1CAM expression, the MELF pattern, and lymph node status in endometrial carcinoma. Consecutive cases of endometrial carcinoma with MELF pattern were immunohistochemically assessed for L1CAM. Inclusion criteria were endometrioid-type, low-grade, stage T1, and known lymph node status. Uni- and multivariate logistic regression were used to assess the association of L1CAM expression with lymph node status. Fifty-eight cases were included. Most cases showed deep myometrial invasion (n = 42, 72.4%) and substantial lymphovascular space invasion (n = 34, 58.6%). All cases were p53-wild-type; 17 (29.3%) were mismatch repair-deficient. Twenty cases (34.5%) had positive nodes. No cases showed L1CAM positivity in ≥10% of the whole tumor. MELF glands expressed L1CAM at least focally in 38 cases (65.5%). L1CAM positivity in ≥10% of the MELF component was found in 24 cases (41.4%) and was the only significant predictor of lymph node involvement in both univariate (p < 0.001) and multivariate analysis (p < 0.001). In conclusion, L1CAM might be involved in the development of the MELF pattern. In uterine-confined, low-grade endometrioid carcinomas, L1CAM overexpression in MELF glands may predict lymph node involvement. [ABSTRACT FROM AUTHOR]

Simple Summary: A more in-depth molecular characterization of uterine leiomyosarcomas (uLMS), a rare disease characterized with dismal prognosis, could provide data suitable for the identification of potential target-based drugs. We aimed to define frequencies of gene alterations in uLMS, especially regarding the somatic mutations of BRCA and HRR gene alterations, and identify the impact of these molecular alterations on clinical outcomes. This retrospective analysis of the mutational profile of uLMS showed that the most frequent alterations involved the TP53 gene, and that patients with TP53 alterations experienced a worse prognosis compared to patients with wild-type TP53 genes. Conversely, patient clinical outcomes were similar within patients with BRCA- and HRR-related genes versus non-HRR-related genes. However, although the frequency of patients with BRCA- and HRR-related alterations and mutations was relatively small, this setting could deserve an investigation into drug actionability, and potentially benefit from PARP inhibitors. Uterine leiomyosarcomas (uLMS) is a very rare disease, and patients experience a dismal prognosis even when treated with chemotherapy. Therefore, a more in-depth molecular characterization of this disease could provide suitable data for the identification of potential target-based drugs. This retrospective, single institutional study aimed to define the frequencies of gene alterations in uLMS, especially regarding the somatic mutations of BRCA and Homologous Recombination Repair (HRR) genes, and the impact of molecular alterations on clinical outcomes. The 16-genes Next-Generation Sequencing (NGS) panel, Homologous Recombination Solution TM (HRS, Sophia Genetics, Saint Sulpice, Switzerland), was used for the molecular evaluation of samples. The majority of patients (66/105, 63%) carried at least one sequence alteration, with a prevalence of TP53 involvement followed by RAD51B, BRCA1/2, and FANCL. Patients with TP53 gene alterations experienced a significantly worse prognosis for progression free survival (PFS) and overall survival (OS) versus wild-type patients. Given the number of patients with the BRCA1/2 mutation (N = 12), we included them in the HRR patient group; there was no difference in clinical outcomes with HRR versus non-HRR. The Cox's multivariate analysis showed that stage and TP53 gene alterations resulted in a significantly worse OS. The integration of gene networking data, such as tumor mutation burdens and cancer driver gene identification, could show a clearer discrimination of gene distribution patterns, and lead to the implementation of therapeutic targets. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite rapid progress in the research on epithelial ovarian cancer (EOC), it is usually diagnosed during the advanced stage with only 30% of patients surviving longer than 5 years. This is the first study in which the whole CXCR4-CXCL12-CXCR7 axis was systematically evaluated in tumor and stromal cells, through rigorous statistical methods in a prospective clinical trial. CXCL12 expression in cancer cells is associated with worse progression-free survival in stage III EOC patients, and deserves further attention as a potential prognostic and therapeutic target. This study investigated the prognostic role of the CXCR4-CXCL12-CXCR7 axis in advanced epithelial ovarian cancer (EOC) patients receiving first-line treatment within the MITO16A/MaNGO-OV2 phase-IV trial. CXCR4-CXCL12-CXCR7 expression was evaluated in the epithelial and stromal component of 308 EOC IHC-stained tumor samples. The statistical analysis focused on biomarkers' expression, their association with other variables and prognostic value. Zero-inflated tests, shrinkage, bootstrap procedures, and multivariable models were applied. The majority of EOC (75.0%) expressed CXCR4 and CXCR7, 56.5% expressed the entire CXCR4-CXCL12-CXCR7 axis, while only 4.6% were negative for CXCL12 and its cognate receptors, in regard to the epithelial component. Stromal CXCL12 and CXCR7, expressed in 11.2% and 65.5%, respectively, were associated with the FIGO stage. High CXCL12 in epithelial cancer cells was associated with shorter progression-free and overall survival. However, after adjusting for overfitting due to best cut-off multiplicity testing, the significance was lost. This is a wide-ranging, prospective study in which CXCR4-CXCL12-CXCR7 were systematically evaluated in epithelial and stromal components, in selected stage III-IV EOC. Although CXCL12 was not prognostic, epithelial expression identified high-risk FIGO stage III patients for PFS. These data suggest that it might be worth studying the CXCL12 axis as a therapeutic target to improve treatment efficacy in EOC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated the immunohistochemical expression of 14 biological markers as potential prognostic/therapeutic factors in vulvar squamous cell carcinoma, comparing 53 node-negative (Group A) and 48 node-positive (Group B) patients. Our results show a significantly higher p16 expression (surrogate of HPV-related tumors) in the vulvar samples of non-metastatic patients. In Group B, PD-L1 positivity and high EGFR expression were found in the vast majority of vulvar and/or nodal specimens. VEGF showed strong/moderate-diffuse expression in almost 14% of all vulvar samples. A mutated p53 and over-expressed PD-L1 showed a significant association with nodal metastasis. Our results support a potential role of immune checkpoint inhibitors and anti-VEGF and anti-EGFR drugs, especially in patients with worse prognosis (metastatic, HPV-independent). A panel including EGFR, VEGF, PDL1, p16, and p53 might be performed routinely in primary tumor and repeated in case of lymph node metastases to identify changes in marker expression. Introduction: The study's aim was to investigate the immunohistochemical (IHC) expression of biological markers as potential prognostic/therapeutic factors in vulvar squamous cell carcinoma (VSCC). Methodology: A series of 101 patients surgically treated at our center from 2016 to 2020 were retrospectively enrolled: 53 node-negative (Group A) and 48 node-positive (Group B). A total of 146 samples, 101 from primary tumor (T) and 45 from nodal metastases (N), were investigated. The IHC panel included: p16, p53, MLH1, MSH2, MSH6, PMS2, PD-L1, CD3, HER2/neu, ER, PR, EGFR, VEGF, and CD31. The reactions were evaluated on qualitative and semi-quantitative scales. Generalized Linear Model (GLM) and cluster analysis were performed in R statistical environment. A distance plot compared the IHC panel of T with the correspondent N. Results: In Group A: p16-positive expression (surrogate of HPV-dependent pathway) was significantly higher (20.8% vs. 6.2%, p = 0.04). In Group B: PD-L1 positivity and high EGFR expression were found, respectively, in 77.1% and 97.9% patients (T and/or N). Overall, p16-negative tumors showed a higher PD-L1 expression (60.9% vs. 50.0%). In both groups: tumoral immune infiltration (CD3 expression) was mainly moderate/intense (80% vs. 95%); VEGF showed strong/moderate-diffuse expression in 13.9% of T samples; CD31, related to tumoral microvessel density (MVD), showed no difference between groups; a mutated p53 and over-expressed PD-L1 showed significant association with nodal metastasis, with Odds Ratios (OR) of 4.26 (CI 95% = 1.14–15.87, p = 0.03) and 2.68 (CI 95% = 1.0–7.19, p < 0.05), respectively; since all mismatch repair proteins (MMR) showed a retained expression and ER, PR, and HER2/neu were negative, they were excluded from further analysis. The cluster analysis identified three and four sub-groups of molecular profiles, respectively, in Group A and B, with no difference in prognosis. The molecular signature of each N and corresponding T diverged significantly in 18/41 (43.9%) cases. Conclusions: Our results support a potential role of immune checkpoint inhibitors and anti-VEGF and anti-EGFR drugs especially in patients with worse prognosis (metastatic, HPV-independent). A panel including EGFR, VEGF, PDL1, p16, and p53 might be performed routinely in primary tumor and repeated in case of lymph node metastases to identify changes in marker expression. [ABSTRACT FROM AUTHOR]

Simple Summary: The possibility to identify, with appropriate biomarkers, patients that might mostly benefit from any given treatment is the basis of personalized oncology. Cancer biomarkers should be properly identified and validated on a large number of patients possibly enrolled in dedicated clinical trials. Here, we report the first molecular results of the MITO16A-ManGo-OV2 phase IV trial that was specifically designed to identify prognostic biomarkers of survival in epithelial ovarian cancer patients treated in first line with carboplatin-paclitaxel plus Bevacizumab (NCT01706120), a treatment for which validated predictive or prognostic biomarkers are still lacking. With this work we propose not only novel possible biomarkers for Bevacizumab-treated patients but also a way through which they can be properly collected, analyzed and statistically evaluated in the frame of large multicenter clinical trials. Background. Epithelial ovarian cancer (EOC) is a rare, highly lethal disease. In a subset of high grade EOC patients, maintenance therapy with the antiangiogenic drug Bevacizumab (BEV) is a valuable option. To date, no validated predictive or prognostic biomarkers exist for selecting EOC patients that might benefit from BEV treatment. Methods. Immunohistochemistry and RT-qPCR evaluated the expression of seven angiogenesis-related proteins and of a twelve microRNAs angio-signature in EOC patients, treated in first line with chemotherapy plus BEV (MITO16A/ManGO OV-2 phase IV trial). Centralized statistical analyses assessed the associations between each biomarker, clinical prognostic factors and survival outcomes. Results. High miR-484 expression was associated with longer progression-free and overall survival. Notably, the combined expression of miR-484 and its target VEGFB identified a subset of patients that might mostly benefit from BEV treatment. No other significant correlations were found between the other analyzed biomarkers and patients' survival. The application of a shrinkage procedure to adjust for over-fitting hazard ratio estimates reduced the association significance. Conclusions. The analysis of angiogenesis related biomarkers in EOC patients homogenously treated with BEV in first line provides novel insight in their prognostic value and suggests that some of them might merit to be tested as predictive markers of drug activity in dedicated randomized trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Endometrial cancer (EC) reportedly have a better prognosis in patients with coexistent adenomyosis. It is possible to hypothesize that this difference may be attributable to different clinical profiles. On this account, we aimed to define the clinical profile of endometrial cancer (EC) patients with and without adenomyosis through a systematic review and meta-analysis. We included 8 studies with 5681 patients and found that EC women with adenomyosis were less likely to be nulliparous than EC women without adenomyosis, while no significant differences were found with regard to age, BMI, and premenopausal status. A better endometrial cancer (EC) prognosis in patients with coexistent adenomyosis has been reported. Unfortunately, it is still unclear if this better prognosis is related to a more favorable clinical profile of adenomyosis patients. We aimed to evaluate differences in the clinical profiles of EC patients with and without adenomyosis. A systematic review and meta-analysis was performed by searching seven electronics databases for all studies that allowed extraction of data about clinical characteristics in EC patients with and without adenomyosis. Clinical characteristics assessed were: age, Body Mass Index (BMI), premenopausal status, and nulliparity. Mean difference in mean ± standard deviation (SD) or odds ratio (OR) for clinical characteristics between EC patients with and without adenomyosis were calculated for each included study and as a pooled estimate, and graphically reported on forest plots with a 95% confidence interval (CI). The Z test was used for assessing the overall effect by considering a p value < 0.05 as significant. Overall, eight studies with 5681 patients were included in the qualitative analysis, and seven studies with 4366 patients in the quantitative analysis. Pooled mean difference in mean ± SD between EC women with and without adenomyosis was −1.19 (95% CI: −3.18 to 0.80; p = 0.24) for age, and 0.23 (95% CI: −0.62 to 1.07; p = 0.60) for BMI. When compared to EC women without adenomyosis, EC women with adenomyosis showed a pooled OR of 1.53 (95% CI: 0.92 to 2.54; p = 0.10) for premenopausal status, and of 0.60 (95% CI: 0.41 to 0.87; p = 0.007) for nulliparity. In conclusion, there are not significant differences in clinical characteristics between EC patients with and without adenomyosis, with the exception for nulliparity. Clinical features seem to not underlie the better EC prognosis of patients with adenomyosis compared to patients without adenomyosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Histopathological classification of endometrial carcinoma has evidenced two main groups with different biological behavior: low-grade (G1–G2) and high-grade (G3) endometrial tumors. Moreover, the Cancer Genome Atlas (TCGA) documented four molecular categories with distinct clinical, pathologic, and molecular features: POLE/ultramutated (7% of cases) microsatellite instability (MSI)/hypermutated (28%), copy-number low/endometrioid (39%), and copy-number high/serous-like (26%). The aim of the present paper is to review all endometrial carcinoma histotypes in light of the morphological and molecular prognostic TCGA groups. Endometrial carcinoma represents the most common gynecological cancer in Europe and the USA. Histopathological classification based on tumor morphology and tumor grade has played a crucial role in the management of endometrial carcinoma, allowing a prognostic stratification into distinct risk categories, and guiding surgical and adjuvant therapy. In 2013, The Cancer Genome Atlas (TCGA) Research Network reported a large scale molecular analysis of 373 endometrial carcinomas which demonstrated four categories with distinct clinical, pathologic, and molecular features: POLE/ultramutated (7% of cases) microsatellite instability (MSI)/hypermutated (28%), copy-number low/endometrioid (39%), and copy-number high/serous-like (26%). In the present article, we report a detailed histological and molecular review of all endometrial carcinoma histotypes in light of the current ESGO/ESTRO/ESP guidelines. In particular, we focus on the distribution and prognostic value of the TCGA groups in each histotype. [ABSTRACT FROM AUTHOR]

Background. Gynecological neuroendocrine neoplasms (NENs) are extremely rare, accounting for 1.2–2.4% of the NENs. The aim of this study was to test cervical NENs for novel markers of potential utility for differential diagnosis and target therapy. Methods. All cases of our center (n = 16) were retrieved and tested by immunohistochemistry (IHC) for 12 markers including markers of neuroendocrine differentiation (chromogranin A, synaptophysin, CD56), transcription factors (CDX2 and TTF1), proteins p40, p63, p16INK4a, and p53, somatostatin receptors subtypes (SST2-SST5) and the proliferation marker Ki67 (MIB1). Results. All cases were poorly differentiated neuroendocrine carcinomas (NECs), 10 small cell types (small cell–neuroendocrine carcinomas, SCNECs) and 6 large cell types (large cell–neuroendocrine carcinomas, LCNECs); in 3 cases a predominant associated adenocarcinoma component was observed. Neuroendocrine cancer cells expressed at least 2 of the 3 tested neuroendocrine markers; p16 was intensely expressed in 14 (87.5%) cases; SST5 in 11 (56.25%, score 2–3, in 9 cases); SST2 in 8 (50%, score 2–3 in 8), CDX2 in 8 (50%), TTF1 in 5 (31.25%), and p53 in 1 case (0.06%). P63 and p40 expressions were negative, with the exception of one case that showed moderate expression for p63. Conclusions. P40 is a more useful marker for the differential diagnosis compared to squamous cell carcinoma. Neither CDX2 nor TTF1 expression may help the differential diagnosis versus potential cervical metastasis. P16 expression may suggest a cervical origin of NEC; however, it must be always integrated by clinical and instrumental data. The expression of SST2 and SST5 could support a role for SSAs (Somatostatin Analogues) in the diagnosis and therapy of patients with cervical NECs. [ABSTRACT FROM AUTHOR]

Estrogen activity towards cancer-related pathways can impact therapeutic intervention. Recent omics data suggest possible crosstalk between estrogens/gender and MDM4, a key regulator of p53. Since MDM4 can either promote cell transformation or enhance DNA damage-sensitivity, we analysed in vivo impact of estrogens on both MDM4 activities. In Mdm4 transgenic mouse, Mdm4 accelerates the formation of fibrosarcoma and increases tumor sensitivity to cisplatin as well, thus confirming in vivo Mdm4 dual mode of action. Noteworthy, Mdm4 enhances chemo- and radio-sensitivity in male but not in female animals, whereas its tumor-promoting activity is not affected by mouse gender. Combination therapy of transgenic females with cisplatin and fulvestrant, a selective estrogen receptor degrader, was able to recover tumor cisplatin-sensitivity, demonstrating the relevance of estrogens in the observed sexual dimorphism. Molecularly, estrogen receptor-α alters intracellular localization of MDM4 by increasing its nuclear fraction correlated to decreased cell death, in a p53-independent manner. Importantly, MDM4 nuclear localization and intra-tumor estrogen availability correlate with decreased platinum-sensitivity and apoptosis and predicts poor disease-free survival in high-grade serous ovarian carcinoma. These data demonstrate estrogen ability to modulate chemo-sensitivity of MDM4-expressing tumors and to impinge on intracellular trafficking. They support potential usefulness of combination therapy involving anti-estrogenic drugs. [ABSTRACT FROM AUTHOR]