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High grade endometrioid endometrial cancer (HGEEC) is a heterogeneous group of tumors with unclear prognostic features. The aim of the present study is to evaluate the independent risk factors for recurrence and mortality and to describe the recurrence patterns of HGEEC. Ninety-six consecutive cases of HGEEC treated with primary surgery in a single Tertiary Center were retrospectively reviewed. Clinicopathological and treatment details were recorded, and all patients were closely followed up. Disease-free, overall and cancer-specific survival rates were 83.8%, 77.8% and 83.6%, respectively. Cervical stromal involvement was independently related to recurrence (HR = 25.67; 95%CI 2.95–223.30; p = 0.003) and cancer-related death (HR = 15.39; 95%CI 1.29–183.43; p = 0.031) after adjusting for other pathological and treatment variables. Recurrence rate was 16%, with 60% of these cases having lung metastases and only one case with single vaginal vault recurrence. 81.81% of the recurrences presented with symptoms and not a single recurrence was diagnosed in routine follow-up clinical examination. In conclusion, the recurrence pattern may suggest that patient-initiated follow-up (PIFU) could be considered a potential alternative to clinical-based follow-up for HGEEC survivors, especially for patients without cervical involvement and after two years from treatment. Additional caution is needed in patients with cervical stromal involvement.

Purpose: Using RNA sequencing, we recently developed the 52-gene–based Oxford classifier of carcinoma of the ovary (Oxford Classic, OxC) for molecular stratification of serous ovarian cancers (SOCs) based on the molecular profiles of their cell of origin in the fallopian tube epithelium. Here, we developed a 52-gene NanoString panel for the OxC to test the robustness of the classifier. Experimental Design: We measured the expression of the 52 genes in an independent cohort of prospectively collected SOC samples (n = 150) from a homogenous cohort who were treated with maximal debulking surgery and chemotherapy. We performed data mining of published expression profiles of SOCs and validated the classifier results on tissue arrays comprising 137 SOCs. Results: We found evidence of profound nongenetic heterogeneity in SOCs. Approximately 20% of SOCs were classified as epithelial-to-mesenchymal transition–high (EMT-high) tumors, which were associated with poor survival. This was independent of established prognostic factors, such as tumor stage, tumor grade, and residual disease after surgery (HR, 3.3; P = 0.02). Mining expression data of 593 patients revealed a significant association between the EMT scores of tumors and the estimated fraction of alternatively activated macrophages (M2; P < 0.0001), suggesting a mechanistic link between immunosuppression and poor prognosis in EMT-high tumors. Conclusions: The OxC-defined EMT-high SOCs carry particularly poor prognosis independent of established clinical parameters. These tumors are associated with high frequency of immunosuppressive macrophages, suggesting a potential therapeutic target to improve clinical outcome.

High-grade endometrial cancers (ECs) are an aggressive subset of ECs accounting for 70-80% of EC-related deaths. Currently, staging surgery, together with chemotherapy or radiotherapy, is the primary treatment strategy for these cancers. The widespread use of next-generation sequencing has led to a refined understanding of EC's genomics with important information for diagnosis and therapy for individual patients (precision medicine). However, advances in the genomics assessment of high-grade tumors have been slower due to their lower incidence than low-grade EC. This article will briefly introduce the current state of knowledge of the genomics of G3 endometrioid EC, serous uterine cancer, clear cell uterine carcinoma and uterine carcinosarcoma and discuss its implications for diagnosis and targeted therapy.

The inter-differentiation between cell states promotes cancer cell survival under stress and fosters non-genetic heterogeneity (NGH). NGH is, therefore, a surrogate of tumor resilience but its quantification is confounded by genetic heterogeneity. Here we show that NGH in serous ovarian cancer (SOC) can be accurately measured when informed by the molecular signatures of the normal fallopian tube epithelium (FTE) cells, the cells of origin of SOC. Surveying the transcriptomes of ∼6,000 FTE cells, predominantly from non-ovarian cancer patients, identified 6 FTE subtypes. We used subtype signatures to deconvolute SOC expression data and found substantial intra-tumor NGH. Importantly, NGH-based stratification of ∼1,700 tumors robustly correlated with survival. Our findings lay the foundation for accurate prognostic and therapeutic stratification of SOC. Using single-cell RNA sequencing, Hu et al. identify six subtypes of fallopian tube epithelium (FTE) cells in normal human fallopian tube tissues. The FTE cellular subtypes reveal intra-tumoral heterogeneity in serous ovarian cancer (SOC) and define SOC subtypes that correlate with patient prognosis.