BACKGROUND: Timely detection of endometrial carcinoma in Lynch syndrome patients ensures prompt treatment and appropriate cancer screening for the patient and impacted family members. While cervical cytology is utilized primarily in cervical cancer screening, endometrial glandular abnormalities can be identified as part of routine cervical cancer screening or during work-up for abnormal uterine bleeding.
METHODS: We retrospectively evaluated cervical cytology samples from Lynch syndrome patients with endometrial carcinoma to determine how often atypical/malignant glandular cells were identified on prior/concurrent cytology.
RESULTS: We identified 14 Lynch syndrome patients with cervical cytology available within a year of endometrial carcinoma diagnosis. The average patient age was 55 years (36-73). Cervical cytology preceded diagnostic biopsy in 57% and was concurrent in 43%. A glandular abnormality was identified on original diagnosis in 43% and ranged from atypical glandular cells (AGC), not otherwise specified to adenocarcinoma consistent with endometrial primary. In 4 cases, abnormal cervical cytology triggered the subsequent biopsy. Evaluation of 8 cases with accessible cytology slides revealed 2 previously unrecognized glandular abnormalities, leading to an abnormal rate of 63% among cases reviewed retrospectively and a final glandular abnormality detection rate of 57% based on either original or review diagnosis.
CONCLUSIONS: In summary, abnormal glandular cells were commonly identified in endometrial cancer patients with Lynch syndrome and led to endometrial cancer work-up and diagnosis in a subset. These results suggest that cervical cytology may have utility in endometrial cancer screening in this population and indicate that awareness of the patient\'s familial cancer risk is important for maximizing sensitivity of this test. They also caution against primary human papillomavirus screening in the Lynch syndrome population, as this may result in missed opportunities for early endometrial carcinoma detection among these high-risk individuals.

Endometrial carcinomas (EC) of no special molecular profile (NSMP) represent the largest molecular category of EC, comprising a mixture of tumors with different histology and molecular profiles. These facts likely point to different tumor biology, clinical outcomes, and targeted therapy responses within this molecular category. The PIK3CA is currently the only targetable kinase oncoprotein directly implicated in EC carcinogenesis. Investigating a unique single-institution cohort, we attempted to stratify NSMP ECs based on the presence of the PIK3CA pathogenic mutation. Those cases were further analyzed for other well-established-associated oncogenic driver gene mutations. Histological and clinical variables were also correlated in each case. Altogether, 175 ECs were prospectively tested by a limited custom NGS panel containing ARID1A, BCOR, BRCA1, BRCA2, CTNNB1, KRAS, MLH1, MSH2, MSH6, NRAS, PIK3CA, PMS2, POLD1, POLE, PTEN,and TP53 genes. We identified 24 PIK3CA mutated cases in the group of 80 NSMP ECs, with another co-occurring mutation in at least one oncogenic driver gene (CTNNB1, PTEN, ARID1A, KRAS, BCOR, PMS2) in 19 cases. In conclusion, a limited NGS panel can effectively test EC tissue for specific pathogenetically relevant oncogene mutations. The NSMP EC category contains 30% of the PIK3CA mutated cases. Of those, 21% contain the PIK3CA mutation as a sole EC-associated oncogene mutation, while 79% harbor at least one more mutated gene. These findings may inform future healthcare planning and improve the effectiveness of EC patient selection for the PIK3CA-targeted therapy.

OBJECTIVE: Mesonephric-like adenocarcinoma (MLA) of the endometrium or ovary is a rare but distinct endometrial carcinoma which has a combination of characteristic morphological, immunohistochemical (IHC) and molecular features. SOX17 has been recently identified as a highly sensitive and specific marker for endometrial and ovarian carcinomas. In this study, we aimed to investigate SOX17 expression in MLA together with other IHCs to differentiate MLAs from other endometrial carcinomas.
METHODS: Seventeen previously diagnosed endometrial/ovarian MLAs were collected, and multiple IHCs were performed. Additionally, we performed SOX17, PAX8 and ER on tissue microarrays (TMAs) composed of 652 endometrial carcinomas from 2012 to 2015 when MLA diagnostic criteria were not established.
RESULTS: All 17 MLAs showed diffuse strong positive PAX8, negative ER and variable TTF1/GATA3 staining. Notably, all MLAs showed negative (n = 10) or focal weak/moderate (n = 7) staining for SOX17, which is more diffuse and stronger than PAX8 in other endometrial carcinoma subtypes. This finding prompted us to screen TMAs with 652 endometrial carcinomas diagnosed before MLA by an approach of combined SOX17 and PAX8 IHCs, and 14 cases with positive PAX8 but negative/focal weak SOX17 were identified. We further studied the 14 cases by examining morphology and performing additional IHCs (TTF1, GATA3, ER and CD10) and would classify seven (50%) of them as MLAs based on morphological features and positive CD10, TTF1 and/or GATA3 staining.
CONCLUSIONS: Our results suggest that a combination of SOX17 and PAX8 IHCs would aid in diagnosing MLA if the results show strong positive PAX8, but negative SOX17.

BACKGROUND: Regulatory T (Treg) cells reportedly play crucial roles in tumor angiogenesis as well as antitumor immunity. In order to explore their therapeutic potential, we investigated the precise prognostic impact of Treg markers in endometrial carcinoma.
METHODS: We performed multiplexed immunofluorescence and quantitative image analyses of CD25, FOXP3, CTLA4, and CD45RA in tumor specimens from 176 consecutive patients treated at our institution for primary endometrial carcinomas. Bioinformatics analyses were further conducted to corroborate the findings.
RESULTS: High CD25+, FOXP3+, and CD25+FOXP3+CD45RA- stromal cell counts correlated with better overall survival (OS) (p = 0.00019, 0.028 and 0.0012) and MSI-high (p = 0.015, 0.016 and 0.047). High CD45RA+ stromal cell count was associated with superficial myometrial invasion (p = 0.0038). Bioinformatics survival analysis by Kaplan-Meier plotter showed that high CD25, FOXP3, CTLA4, and CD45RA mRNA expressions correlated with better OS (p = 0.046, 0.00042, 0.000044, and 0.0022). Univariate and multivariate analyses with various clinicopathologic prognostic factors indicated that high CD25+ or CD25+FOXP3+CD45RA- stromal cell count was significant and independent for favorable OS (p = 0.0053 and 0.0015). We subsequently analyzed the correlations between the multiplexed immunofluorescence results and treatment-free interval (TFI) after primary chemotherapy in recurrent cases, finding no significant associations. Further analysis revealed that high ratio of CD25+ : CD8+ cell count or CD25+FOXP3+CD45RA- : CD8+ cell count correlated with longer TFI (p = 0.021 and 0.021).
CONCLUSIONS: The current observations suggest that the balance between CD25+ or CD25+FOXP3+CD45RA- cells and CD8+ cells, corresponding to promoting or inhibiting effect on tumor angiogenesis, affect tumor chemosensitivity leading to prognostic significance. CD25+FOXP3+CD45RA- effector Treg tumor infiltration may serve as a useful prognostic biomarker and a potential target for immunotherapeutic manipulation of tumor chemosensitivity by novel management for advanced/recurrent endometrial carcinomas.

The case report details the adaptive radiotherapy management of a 75-year-old female diagnosed with high-grade endometrial carcinoma. The patient, who was known to be hypertensive with no other comorbidities and no family history of cancer, presented with a complaint of bleeding per vagina for six months. Following extensive investigations, she underwent a laparoscopic radical hysterectomy. Postoperative histopathology confirmed endometrial adenocarcinoma International Federation of Gynecology and Obstetrics (FIGO) stage IA, grade III. The adjuvant treatment plan included adjuvant chemoradiotherapy to the postoperative tumor bed and draining lymph nodes. On planning computed tomography (CT), the patient\'s lymphocele responded remarkably to radiation therapy, an unusual outcome that underscores the potential efficacy of adaptive radiotherapy in complex cases.

Background Post-menopausal bleeding (PMB) is a very common complaint seen in current practice. Endometrial carcinoma (EC) commonly presents with PMB. Endometrial biopsy is the tool for definitive diagnosis, but it is invasive. Transvaginal sonography (TVS) is a non-invasive tool that can help us in the initial evaluation of such patients. Methods A prospective observational study was conducted on 76 women with PMB. TVS and histopathological study, along with basic evaluation and investigations, were performed on all participants, followed by necessary treatment and follow-up. Data collected were studied and statistically analyzed. Results A maximum of 27.63% (n=21) of patients had endometrial atrophy causing their PMB. Proliferative endometrium was observed in 21.06% (n=16) of cases, 13.15% (n=10) of women had secretory endometrium, 23.68% (n=18) had simple endometrial hyperplasia, 3.94% (n=3) had complex endometrial hyperplasia without atypia, and another 3.94% (n=3) had complex endometrial hyperplasia with atypia. Further classifying, women with benign hyperplasia included 27.63% (n=21) and those with atypical hyperplasia included 3.94% (n=3). Out of the 5.26% (n=4) patients diagnosed with EC on histopathology, TVS identified carcinoma in 75% (n=3) cases. This indicates that the sensitivity and specificity of TVS in detecting EC are 75% and 100%, respectively. The positive predictive value (PPV) is 100%, the negative predictive value (NPV) is 98.63%, and the accuracy is 98.68%. Conclusion If the cut-off for endometrial thickness is set at 4 mm, then TVS proves to be an effective and reliable tool for screening and diagnosing EC. It can thus serve as a safe threshold to screen patients with PMB using TVS.

A characteristic feature of uterine pathologies is a specific change in cell metabolism, which predominantly manifests as a shift in the need for nutrients, thereby directing cells to engage in different angiogenic marker activities. Angiogenesis is one of the main signals supporting the survival and development of cells and tissues not only under physiological conditions. Therefore, it is necessary that we understand pathological hyperactivation in all uterine diseases, from endometriosis through ovarian endometrioid adenocarcinoma to malignant transformed cells of the uterine epithelium and body. This work presents the gene expression results of selected angiogenesis targets (VEGF-A, TGF-β1, ANG1/2, and HIF-1α), cell migration, and cell-cell interaction determined in vitro. Our results suggest that angiogenesis varies in the tested pathological conditions (ectopic endometriosis-12Z; ovarian endometrioid adenocarcinoma-A2780; tumors-SK-UT-1 and RL-95-2) compared to physiological angiogenesis (HME1). The differential expression of angiogenic factors may contribute (or is a contributing factor) to the observed differences to acknowledge an inherent variability in angiogenesis among cell lines. Determining the genomic phenomena responsible for processes associated with inadequate angiogenesis in the pelvic region could help us to develop individual treatment strategies and explain resistance to treatment.

The synchronous occurrence of primary endometrioid endometrial adenocarcinoma and primary squamous cell carcinoma of the cervix is exceedingly rare. Ovarian and endometrial cancers represent the most frequently observed forms of synchronous gynaecological malignancies. In contrast, in less than 1 % of cases, endometrial cancer coexists with primary cervical cancer. Considering the unique characteristics of each primary malignancy, the management of synchronous tumours of the female genital tract poses significant challenges and requires a multidisciplinary, tailored approach to treatment. This report concerns the case of a 63-year-old woman who underwent radical hysterectomy, bilateral salpingo-oophorectomy and bilateral pelvic lymph node dissection following a histological diagnosis of a poorly differentiated squamous cell carcinoma on cervical biopsy. Histological assessment of the surgical specimen also confirmed a primary grade I endometrioid endometrial adenocarcinoma confined to the endometrium and grade 3 squamous cell cancer of the cervix. The patient was successfully treated with adjuvant vaginal brachytherapy after primary surgery. Synchronous endometrial adenocarcinoma and squamous cell carcinoma of the cervix is rare and associated with a poor prognosis. Fewer than ten cases could be found in the medical literature. This report raises awareness and adds to the study of an unusual synchronous cancer of the female genital tract and contributes evidence to advance the development of standardized treatment protocols.

BACKGROUND: Endometrial cancer is a kind of well-known tumors of female genitourinary system. Cervical stromal invasion is an adverse factor for poor prognosis of endometrial cancer. There is still controversy regarding the use of magnetic resonance imaging (MRI) in the diagnosis of cervical stromal invasion of endometrial cancer. The diagnosis of cervical stromal invasion varies significantly between different observers and institutions. We present a limited case series of the particular pattern of endometrial cancer, which infiltrates the cervical stroma and is often overlooked.
METHODS: We present three cases of endometrial carcinoma with cervical stromal invasion with cancer-free uterine cavity. One patient, a reproductive-aged woman, exhibited irregular menstruation and was diagnosed with endometrial polyps by hysteroscopy and segmental curettage. A MRI scan revealed polypoid nodules within the internal cervical orifice. The other two cases were postmenopausal women who presented with abnormal vaginal bleeding. Hysteroscopy and segmental curettage suggested atypical hyperplasia of the endometrium. MRI scans did not detect any malignant signs in the endometrium. In one case, a non-thickened endometrium was observed, while in another, hyperplasia of the endometrium was seen. Notably, none of these patients had malignant tumors identified in the uterine cavity via MRI scans. However, postoperative pathological results following hysterectomy consistently indicated cervical stromal invasion.
CONCLUSIONS: Cervical stromal invasion is easily missed if no cancer is found in the uterine body on MRI. Immunohistochemistry of endoscopic curettage specimens should be conducted to avoid underestimation of the disease.

OBJECTIVE: Radiomics offers little explainability. This study aims to develop a radiomics model (Rad-Score) using diffusion-weighted imaging (DWI) to predict high-risk patients for nodal metastasis or recurrence in endometrial cancer (EC) and corroborate with choline metabolism.
METHODS: From August 2015 to July 2018, 356 EC patients were enrolled. Rad-Score was developed using LASSO regression in a training cohort (n = 287) and validated in an independent test cohort (n = 69). MR spectroscopy (MRS) was also used in 230 patients. Nuclear MRS measured choline metabolites in 70 tissue samples. The performance was compared against European Society for Medical Oncology (ESMO) risk groups. A P < .05 denoted statistical significance.
RESULTS: Rad-Score achieved 71.1% accuracy in the training and 71.0% in the testing cohorts. Incorporating clinical parameters of age, tumor type, size, and grade, Rad-Signature reached accuracies of 73.2% in training and 75.4% in testing cohorts, closely matching the performance to the post-operatively based ESMO\'s 70.7% and 78.3%. Rad-Score was significantly associated with increased total choline levels on MRS (P = .034) and tissue levels (P = .019).
CONCLUSIONS: Development of a preoperative radiomics risk score, comparable to ESMO clinical standard and associated with altered choline metabolism, shows translational relevance for radiomics in high-risk EC patients.
BACKGROUND: This study was registered in ClinicalTrials.gov on 2015-08-01 with Identifier NCT02528864.