Sen Li

A Retrospective Study on the Clinicopathological Characteristics and Prognostic Analysis of Gynecologic Neuroendocrine Carcinoma

ABSTRACT Background Gynecologic neuroendocrine carcinomas (NECs) are rare, highly aggressive malignancies with early metastatic potential and limited evidence to guide optimal management across different primary sites. Aims To characterize the clinicopathological features, treatment patterns, survival outcomes, and prognostic factors of gynecologic NECs (cervix, endometrium, and ovary) treated at a single tertiary center over a 10‐year period. Materials and Methods This observational, single‐center retrospective cohort study included patients diagnosed with gynecologic NEC at Women's Hospital, Zhejiang University School of Medicine, between January 2013 and August 2023. Clinicopathological data, treatment modalities, recurrence, and follow‐up outcomes were collected. Progression‐free survival (PFS) and overall survival (OS) were estimated using Kaplan–Meier methods. Prognostic factors were assessed using log‐rank tests and multivariable Cox proportional hazards models. Results A total of 52 patients were identified, of whom 78.8% had cervical NEC. Primary surgery was performed in 90.4% of patients; adjuvant chemotherapy and radiotherapy were administered in 65.4% and 51.9%, respectively. Among cervical NEC cases with HPV testing, 69.7% were HPV16/18‐positive. Immunohistochemical (IHC) showed high positivity for synaptophysin (95.3%) and chromogranin A (72.7%); Ki‐67 exceeded 50% in 89.1% of evaluated cases. Median PFS for cervical NEC was 29 months; stage I cervical NEC showed a 5‐year PFS of 51.6% and 5‐year OS of 68.4%. Poorer prognosis was associated with FIGO stage ≥ IB3, mixed neuroendocrine‐non‐neuroendocrine neoplasm (MiNEN) with squamous cell carcinoma, tumor size > 4 cm, and lymph node metastasis. On multivariable analysis of cervical NEC, MiNEN with squamous cell carcinoma remained an independent predictor of reduced PFS (HR = 6.97, 95% CI: 1.60–30.31; p  = 0.010). Discussion Despite multimodal treatment, gynecologic NECs showed poor outcomes. The identification of MiNEN with squamous cell carcinoma as an independent adverse factor for PFS suggests histologic composition may meaningfully affect prognosis and warrants validation in larger, multicenter cohorts. Conclusion Cervical NEC was the predominant subtype, most patients underwent surgery with adjuvant therapy, and survival was strongly stage‐dependent. MiNEN with squamous cell carcinoma independently predicted worse PFS, highlighting a potential high‐risk subgroup and reinforcing the need for multicenter prospective studies and more effective, potentially targeted treatment approaches for gynecologic NECs.

Single-Cell RNA Sequencing Reveals the Tissue Architecture in Human High-Grade Serous Ovarian Cancer

Abstract Purpose: The heterogeneity of high-grade serous ovarian cancer (HGSOC) is not well studied, which severely hinders clinical treatment of HGSOC. Thus, it is necessary to characterize the heterogeneity of HGSOC within its tumor microenvironment (TME). Experimental Design: The tumors of 7 treatment-naïve patients with HGSOC at early or late stages and five age-matched nonmalignant ovarian samples were analyzed by deep single-cell RNA sequencing (scRNA-seq). Results: A total of 59,324 single cells obtained from HGSOC and nonmalignant ovarian tissues were sequenced by scRNA-seq. Among those cells, tumor cells were characterized by a set of epithelial-to-mesenchymal transition (EMT)-associated gene signatures, in which a combination of NOTCH1, SNAI2, TGFBR1, and WNT11 was further selected as a genetic panel to predict the poor outcomes of patients with HGSOC. Matrix cancer-associated fibroblasts (mCAF) expressing α-SMA, vimentin, COL3A, COL10A, and MMP11 were the dominant CAFs in HGSOC tumors and could induce EMT properties of ovarian cancer cells in the coculture system. Specific immune cell subsets such as C7-APOBEC3A M1 macrophages, CD8+ TRM, and TEX cells were preferentially enriched in early-stage tumors. In addition, an immune coinhibitory receptor TIGIT was highly expressed on CD8+ TEX cells and TIGIT blockade could significantly reduce ovarian cancer tumor growth in mouse models. Conclusions: Our transcriptomic results analyzed by scRNA-seq delineate an ecosystemic landscape of HGSOC at early or late stages with a focus on its heterogeneity with TME. The major applications of our findings are a four–EMT gene model for prediction of HGSOC patient outcomes, mCAFs’ capability of enhancing ovarian cancer cell invasion and potential therapeutic value of anti-TIGIT treatment.