Introduction: Brenner tumors are uncommon epithelial-stromal neoplasms that usually arise in the ovary and comprise a small proportion of ovarian tumors. Extraovarian Brenner tumors are exceedingly rare, and cervical involvement is exceptional. Because of their unusual location and histologic resemblance to other cervical epithelial lesions, accurate diagnosis can be challenging on limited biopsy material. Case Description: A 43-year-old woman presented with prolonged menstrual bleeding and a clinically suspicious cervical mass. An initial cervical punch biopsy demonstrated benign inflammatory and metaplastic changes. Due to persistent symptoms, a repeat biopsy was performed. Histopathologic examination revealed well-defined nests and cords of urothelial-like epithelial cells with focal cystic change embedded in a dense fibrous stroma. The tumor cells showed elongated nuclei with dense chromatin, inconspicuous nucleoli, and clear cytoplasm with distinct cell borders. Occasional mitotic figures were present without significant cytologic atypia. Immunohistochemical studies demonstrated tumor cell positivity for GATA-3, CK7, p63, and p16, with estrogen receptor positivity in the surrounding stroma, supporting the diagnosis of a borderline extra-ovarian Brenner tumor of the cervix. Discussion: Cervical Brenner tumors are extremely rare and may closely mimic squamous cell carcinoma, transitional cell carcinoma, or benign squamous metaplasia, particularly in small biopsy specimens. Recognition of the characteristic nested urothelial-like architecture, together with a focused immunohistochemical panel, is essential for accurate classification and to prevent misdiagnosis and unnecessary aggressive management. Conclusion This case highlights a rare borderline extra-ovarian Brenner tumor arising in the cervix and emphasizes the importance of correlating histomorphologic features with immunohistochemistry in establishing the correct diagnosis of unusual cervical neoplasms.
Brenner Tumor ; Immunohistochemistry ; Urothelium ; Uterine Cervical Neoplasms

Objective To explore the expression levels of CD33⁺ myeloid-derived suppressor cell (MDSC)-mediated T lymphocyte function and related inflammatory factors secreted by T lymphocyte subsets in patients with cervical cancer, and to analyze their correlation with the treatment efficacy of ¹²⁵I particle implantation combined with arterial chemoembolization, as well as predictive value for treatment outcomes and interaction effects. Methods From January 1st, 2021 to January 1st, 2024, our hospital admitted 152 patients with advanced cervical cancer, who were confirmed by pathological examination. All patients received uterine artery chemoembolization combined with ¹²⁵I particle implantation. The predictive value of CD33⁺MDSC levels for clinical treatment response in cervical cancer was assessed using receiver operating characteristic (ROC) curve analysis. Multivariate logistic regression analysis was performed to evaluate both multiplicative and additive interactions between CD33⁺MDSC and T lymphocytes in predicting clinical treatment failure of cervical cancer. Kaplan Meier method was used to analyze the survival differences between cervical cancer patients with high and low CD33⁺MDSC expression levels. Results Compared with the effective group, patients in the ineffective group had decreased expression levels of CD3⁺ T lymphocyte, CD4⁺ T lymphocyte, interleukin 2 (IL-2) and interferon γ (IFN-γ), while showing increased expression levels of CD33⁺MDSC, CD8⁺ T lymphocyte, IL-4 and IL-6, along with increased tumor necrosis factor α (TNF-α) levels, larger maximum tumor diameters, and a higher incidence of lymph node metastasis. The expression levels of CD33⁺MDSCs demonstrated good predictive performance for treatment efficacy in cervical cancer patients. The high CD33⁺MDSC expression group had a significantly shorter overall survival (OS) than the low CD33⁺MDSC expression group (6.0±1.0 months vs. 12.0±1.2 months; t=33.280). The interaction analysis revealed that CD33⁺MDSCs and CD8⁺ T lymphocytes were highly expressed, while CD3⁺ and CD4⁺ T lymphocytes were lowly expressed, which was associated with an increased risk of clinical treatment failure in cervical cancer patients. Conclusion CD33⁺MDSCs can inhibit CD3⁺ and CD4⁺ T lymphocytes. It can upregulate the expression of CD8⁺ T lymphocytes, form an immunosuppressive microenvironment, and reduce the treatment response rate of ¹²⁵I particle implantation combined with arterial chemoembolization. CD33⁺MDSCs may serve as an independent biomarker for predicting the therapeutic efficacy and poor prognosis.
Humans ; Female ; Uterine Cervical Neoplasms/immunology* ; Middle Aged ; Chemoembolization, Therapeutic/methods* ; Sialic Acid Binding Ig-like Lectin 3/immunology* ; Adult ; T-Lymphocytes/immunology* ; Aged ; Treatment Outcome

OBJECTIVES: To analyze the global disease burden of cervical cancer and the association between screening coverage and the quality of disease management. METHODS: The data of global burden of cervical cancer 2021 and the data of cervical cancer screening 2019 were obtained from IHME Global Burden of Disease (GBD) and the WHO global health observatory, respectively. The age-standardized disease burden index was calculated, the quality of care index (QCI) was determined with principal component analysis, and the correlation between QCI and cervical cancer screening coverage was examined with linear regression analysis by regions and populations. RESULTS: The burden of cervical cancer and the quality of management exhibited significant variability across countries with differing levels of social development. The indicators of cervical cancer burden in China were close to the average level of countries with higher socio-demographic index (SDI). The global QCI was 22.22 (10.50, 35.43), and that of China was 26.30. The global screening coverage rate for cervical cancer was 42% (12%, 86%) and that in China was 31%. After adjusting for the social development level of countries, the coverage level of cervical cancer screening was associated with QCI (β=0.27, P<0.01), with no difference between low and high SDI countries (P>0.05). The association was significantly stronger among 25-30 years old women (β=1.48, P<0.05). CONCLUSIONS There are discrepancies in both the disease burden of cervical cancer and the quality of disease management among countries with different socioeconomic levels, and there is still considerable room for improvement in China. Expanding coverage of cervical cancer screening may be an effective strategy to enhance the management quality of cervical cancer, particularly among younger women where the screening benefits are most pronounced.
Humans ; Uterine Cervical Neoplasms/prevention & control* ; Female ; Early Detection of Cancer ; Global Burden of Disease ; China/epidemiology* ; Mass Screening ; Quality of Health Care ; Disease Management ; Adult ; Middle Aged

BACKGROUND: Hyperthermia (HT), while a cancer treatment approach, isn't always effective alone. Therefore, identifying hyperthermia enhancers is crucial. We demonstrated that Mito-TEMPO ([2-[(1-Hydroxy-2,2,6,6-tetramethylpiperidin-4-yl) amino]-2-oxoethyl]-triphenylphosphanium, MT) acts as a potent thermosensitizer, promoting cell death in human cervical cancer (HeLa) cells. METHODS: Cells were pretreated with 0.4 mM MT for 5 minutes, followed by exposure to hyperthermia (42 °C for 60 minutes). The impacts of MT/HT on cell viability, proliferation, apoptosis, endoplasmic reticulum (ER) stress, apoptosis-related proteins and autophagy, autophagy-related proteins expression were measured. The relationships between autophagy and apoptosis were further investigated using the specific autophagy inhibitor chloroquine (CQ) and the autophagy inducer rapamycin (Rapa). RESULTS: The combined treatment reduced the mitochondrial membrane potential (MMP) and increased ROS production. It also upregulated the pro-apoptotic protein Bax and downregulated anti-apoptotic proteins such as Bcl-2 and MCL-1. As a result, Caspase-3 was activated. Additionally, the combined treatment upregulated the expression of p-PERK/PERK, ATF-4, CHOP proteins. Moreover, the combined treatment also increased the expression of LC3 II and p62, decreased expression of LAMP 1 and Cathepsin D and increased lysosomal pH, indicating coordinated changes in autophagy regulation. Notably, intensification of apoptosis induced by the combined treatment was observed with CQ, whereas attenuation was seen with Rapa. CONCLUSIONS MT effectively enhanced HT-induced apoptosis in HeLa cells. Elevated ER stress and interruption of autophagy flux are the possible underlying molecular mechanisms for this phenomenon. These findings suggested MT can act as a potential thermosensitizer, highlighting its versatility in cancer treatment strategies.
Humans ; Apoptosis/drug effects* ; Autophagy/drug effects* ; HeLa Cells ; Uterine Cervical Neoplasms/therapy* ; Female ; Hyperthermia, Induced ; Spin Labels ; Endoplasmic Reticulum Stress/drug effects* ; Cyclic N-Oxides/pharmacology* ; Cell Survival/drug effects*

Atypical placental site nodules (APSN) are a rare form of trophoblastic disease in pregnancy. There is limited research on APSN, and treatment methods are controversial, with unclear prognosis. This study collected clinical and prognostic data of 5 patients diagnosed with APSN at Xiangya Hospital of Central South University from June 2008 to June 2023, aiming to provide a better understanding of the prognosis of APSN patients and offer scientific evidence for clinical treatment. The average age of the 5 APSN patients was 32.60 years, and all patients underwent dilation and curettage or hysteroscopic surgery or hysteroscopic surgery without hysterectomy. Except for one patient who was lost to follow-up after 30 days, the remaining 4 patients were followed up for 1.36 to 4.61 years. During the follow-up, gynecological ultrasound did not show abnormalities, and serum human chorionic gonadotropin (HCG) tests were negative, with no evidence of malignancy. A search of both English and Chinese databases yielded 8 articles reporting the diagnosis, treatment, and follow-up outcomes of APSN, with 37 cases cumulatively followed up. Among them, 2 (5.41%) cases developed epithelial trophoblastic tumors or placental site trophoblastic tumors during follow-up, but there is insufficient evidence to determine whether these tumors directly originated from APSN or were secondary to APSN. Currently, there is no direct evidence suggesting that APSN has the potential for malignant transformation. Patients with APSN who have completed their childbearing may consider preserving their uterus, but close follow-up is needed to further evaluate the prognosis.
Humans ; Female ; Pregnancy ; Adult ; Trophoblastic Tumor, Placental Site/pathology* ; Uterine Neoplasms/diagnosis* ; Prognosis ; Dilatation and Curettage ; Chorionic Gonadotropin/blood*

OBJECTIVES: Hysterectomy remains the only definitively effective treatment for diffuse uterine leiomyomatosis (DUL). However, no standardized management strategy exists for DUL patients wishing to preserve fertility. This study summarizes and analyzes 5 cases of individualized treatment in DUL patients desiring fertility preservation, aiming to provide a clinical reference for personalized management of similar patients. METHODS: We retrospectively analyzed the clinical data of 5 DUL patients with fertility intentions admitted to the Department of Obstetrics and Gynecology at Third Xiangya Hospital of Central South University. To preserve fertility, individualized treatment plans were selected based on clinical manifestations and fibroid distribution. One patient received high-intensity focused ultrasound (HIFU); one underwent hysteroscopic myomectomy (HM) combined with laparoscopic myomectomy (LRM); one underwent HIFU combined with HM and LRM; one received drug therapy combined with staged HM; and one underwent HIFU combined with staged HM and drug therapy. Treatment outcomes and pregnancy results were analyzed. RESULTS: After treatment, all 5 patients showed marked improvement in menstrual volume or dysmenorrhea symptoms and significant reduction in uterine volume; mild intrauterine adhesions occurred in 3 cases. All 5 patients achieved successful pregnancy. One patient with chronic hypertension developed severe preeclampsia at 34 weeks and underwent cesarean section, while the remaining 4 delivered at term by cesarean section. Three cases of placenta accreta and 2 cases of postpartum hemorrhage occurred. During long-term follow-up, one patient underwent hysterectomy 2 years postpartum due to increased menstrual volume, while the other 4 remained stable. CONCLUSIONS Individualized treatment tailored to DUL patients' conditions can preserve fertility, support successful pregnancy, and achieve favorable pregnancy outcomes.
Humans ; Female ; Pregnancy ; Leiomyomatosis/therapy* ; Uterine Neoplasms/therapy* ; Adult ; Retrospective Studies ; Fertility Preservation/methods* ; Hysterectomy ; Uterine Myomectomy/methods* ; High-Intensity Focused Ultrasound Ablation ; Pregnancy Outcome

OBJECTIVES: To investigate the regulatory effects of Aurora-A in regulating proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of cervical cancer cells and the role of actin-related protein 2/3 complex subunit 4 (ARPC4) in mediating its effects. METHODS: The plasmids pCDH-NC, pCDH-Aurora-A, and shRNA-ARPC4 were used for inducing Aurora-A overexpression or ARPC4 knockdown in HeLa cells. The cells were divided into vector group, Aurora-A overexpression group, Aurora-A overexpression+ARPC4 knockdown group, and Aurora-A overexpression+NF‑κBp65 inhibitor group and transfected with the corresponding plasmids. The proliferation, colony-forming ability, migration and invasion of the treated Hela cells was evaluated using EdU immunofluorescence assay, crystal violet staining, scratch assay, Transwell assay, and Matrigel assay. Western blotting was performed to detect the changes in cellular expressions of EMT-related proteins and expression levels of NF-κBp65 and ARPC4. RESULTS: The expression of ARPC4 was significantly decreased in HeLa cells with Aurora-A knockdown and increased in Aurora-A-overexpressing cells. Aurora-A overexpression obviously promoted proliferation, migration, and invasion abilities of HeLa cells, and these effects was significantly antagonized by ARPC4 knockdown. In Aurora-A-overexpressing cells, the phosphorylation level of NF-κBp65 and the expression level of ARPC4 were increased significantly, and application of the NF‑κBp65 inhibitor obviously lowered the expression level of ARPC4. CONCLUSIONS Aurora-A overexpression upregulates the expression of ARPC4 by activating the NF-κBp65 signaling pathway, thereby promoting migration, invasion and EMT of HeLa cells.
Humans ; Uterine Cervical Neoplasms/metabolism* ; Female ; HeLa Cells ; Epithelial-Mesenchymal Transition ; Signal Transduction ; Cell Movement ; Neoplasm Invasiveness ; Cell Proliferation ; Aurora Kinase A/metabolism* ; Transcription Factor RelA/metabolism* ; Neoplasm Metastasis

OBJECTIVES: To study the effect of CDC20 knockdown on proliferation, migration and invasion of cervical cancer cells and its underlying mechanism. METHODS: CDC20 expression in cervical cancer tissues was analyzed using the TCGA database, and the protein expressions of CDC20 and β-Catenin in clinical specimens of cervical cancer and adjacent tissues were detected using immunohistochemistry. A dual target sgRNA2&7 sequence for CDC20 gene was designed for CDC20 gene knockdown in cervical cancer C33A cells using CRISPR/Cas9 technology, and CDC20 mRNA and protein expression levels in the transfected cells were detected using qRT-PCR and Western blotting. The changes in proliferation, cell cycle, apoptosis, migration and invasiveness of the transfected cells were evaluated using colony-forming assay, fluorescence activated cell sorting (FACS) and Transwell assay. In the animal experiment, naïve C33A cells and the cells with CDC20 knockdown were injected subcutaneously into the left and right axillae of nude mice (n=5) to observe tumor growth. The expressions of CDC20 and β-Catenin proteins in transfected cells and the xenograft were analyzed using Western blotting, and their interaction was confirmed by co-immunoprecipitation (CoIP) and immunofluorescence co-localization assays. RESULTS: Cervical cancer tissues expressed significantly higher CDC20 and β‑Catenin levels than the adjacent tissues. C33A cells with CDC20 knockdown showed reduced proliferation, increased apoptosis, and lowered migration and invasion abilities. CDC20 knockdown significantly suppressed the growth of C33A cell xenograft in nude mice, and the tumor-bearing mice did not exhibit obvious body mass changes. CDC20 and β-Catenin levels were both significantly lowered in C33A cells with CDC20 knockdown. Co-immunoprecipitation and co-localization assays confirmed the interaction between CDC20 and β‑Catenin. CONCLUSIONS CDC20 is highly expressed in cervical cancer tissues, and CDC20 knockdown can suppress proliferation, invasion, and metastasis while enhancing apoptosis of C33A cells, which is closely related with the regulation of the Wnt/β-Catenin signaling pathway.
Humans ; Uterine Cervical Neoplasms/metabolism* ; Female ; Cdc20 Proteins/genetics* ; Cell Proliferation ; Animals ; Cell Movement ; Neoplasm Invasiveness ; Apoptosis ; Mice, Nude ; beta Catenin/metabolism* ; CRISPR-Cas Systems ; Mice ; Cell Line, Tumor ; Gene Knockout Techniques ; Neoplasm Metastasis

OBJECTIVES: To explore the therapeutic mechanism of Guizhi Fuling (GZFL) Pellets against cervical cancer. METHODS: Publicly available databases were used to identify the targets of GZFL Pellets and cervical cancer to construct the protein-protein interaction (PPI) network, followed by GO biological process and KEGG pathway enrichment analysis of the hub genes. The "Traditional Chinese Medicine-Active Ingredients-Targets-Pathways" network for GZFL Pellets in cervical cancer treatment was generated using Cytoscape v10.0.0, and molecular docking of the drug and potential targets was performed to predict the specific targets of active components in Guizhi Fuling Pellets. The inhibitory effects of hederagenin, an active ingredient in GZFL Pellets, was tested in cultured cervical cancer cells and in nude mice bearing cervical cancer xenografts. RESULTS: GZFL Pellets contain 338 active components targeting 247 action sites. A total of 10127 cervical cancer-related targets were obtained, and among them 195 were identified as potential therapeutic targets of GZFL Pellets for cervical cancer treatment, including the key targets of GABRA1, PTK2, JAK2, HTR3A, GSR, and IL-17. Molecular docking study showed low binding energies of the active components such as hederagenin, campesterol, and stigmasterol for protein-molecule interaction. GO enrichment analysis suggested that GZFL Pellets inhibited cervical cancer primarily by regulating responses to steroid hormones, oxidative stress, and lipopolysaccharides. Among the active components of GZFL Pellets, hederagenin was found to inhibit cervical cancer cells in vitro and significantly reduced STAT3 phosphorylation level in the cancer cells. In nude mice bearing cervical cancer xenografts, hederagenin effectively inhibited tumor growth rate without causing obvious adverse effects. CONCLUSIONS GZFL Pellets inhibit cervical cancer cell growth through its multiple active components that target different pathways. Among these components, hederagenin inhibits tumor cell growth possibly by directly binding to JAK2 protein to inhibit STAT3 phosphorylation.
Female ; Animals ; Uterine Cervical Neoplasms/pathology* ; Mice, Nude ; Humans ; Mice ; Oleanolic Acid/therapeutic use* ; Drugs, Chinese Herbal/therapeutic use* ; Molecular Docking Simulation ; Xenograft Model Antitumor Assays ; Cell Line, Tumor ; STAT3 Transcription Factor/metabolism* ; Protein Interaction Maps ; Janus Kinase 2/metabolism*

BACKGROUND: Cervical squamous cell carcinoma (CESC), the most common subtype of cervical cancer, is primarily caused by the high-risk human papillomavirus (HPV) infection and genetic susceptibility. Single-cell RNA sequencing (scRNA-seq) has been widely used in CESC research to uncover the diversity of cell types and states within tumor tissues, enabling a detailed study of the tumor microenvironment (TME). This technology allows precise mapping of HPV infection in cervical tissues, providing valuable insights into the initiation and progression of HPV-mediated malignant transformation. METHODS: We performed the scRNA-seq to characterize gene expression in tumor tissues and paired adjacent para-cancerous tissues from four patients with early-stage CESC using the 10× Genomics platform. The HPV infection and its subtypes were identified using the scRNA data and viral sequence mapping, and trajectory analyses were performed using HPV+ or HPV- cells. Interactions between different types of keratinized cells and their interactions with other cell types were identified, and pathways and specificity markers were screened for proliferating keratinized cells. The Cancer Genome Atlas (TCGA) dataset was used to verify the prognostic correlation between tumor-specific PI3+S100A7+ keratinocyte infiltration and CESC, and the localization relationship between PI3+S100A7+ keratinocytes and macrophages was verified by immunofluorescence staining. RESULTS: Various types of keratinocytes and fibroblasts were the two cell types with the most significant differences in percentage between the tumor tissue samples and paired adjacent non-cancerous tissue samples in the early stages of CESC. We found that PI3+S100A7+ keratinocytes were associated with early HPV-positive CESC, and PI3+S100A7+ keratinocytes were more abundant in tumors than in adjacent normal tissues in the TCGA-CESC dataset. Analysis of clinical information revealed that the infiltration of PI3+S100A7+ keratinocytes was notably higher in tumors with poor prognosis than in those with good prognosis. Additionally, multiplex immunofluorescence analysis showed a specific increase in PI3+S100A7+ expression within tumor tissues, with PI3+S100A7+ keratinocytes and CD163+ macrophages being spatially very close to each other. In the analysis of cell-cell interactions, macrophages exhibited strong crosstalk with PI3+S100A7+ proliferating keratinocytes in HPV-positive CESC tumors, mediated by tumor necrosis factor (TNF), CCL2, CXCL8, and IL10, highlighting the dynamic and tumor-specific enhancement of macrophage-keratinocyte interactions, which are associated with poor prognosis and immune modulation. Using CIBERSORTx, we discovered that patients with high infiltration of both PI3+S100A7+ proliferating keratinocytes and macrophages had the shortest overall survival. In the analysis of cell-cell interactions, PI3+S100A7+ proliferating keratinocytes and macrophages were found to be involved in highly active pathways that promote differentiation and structure formation, including cytokine receptor interactions, the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, and TNF signaling pathway regulation. Further subtyping of fibroblast populations identified four subtypes. The C1 group, characterized by its predominance in tumor tissues, is a subtype enriched with cancer-associated fibroblasts (CAFs), whereas the C3 group is primarily enriched in adjacent non-cancerous tissues and consists of undifferentiated cells. Moreover, the distinct molecular and cellular differences between HPV16- and HPV66-associated tumors were demonstrated, emphasizing the unique tumor-promoting mechanisms and microenvironmental influences driven by each HPV subtype. CONCLUSIONS We discovered a heterogeneous population of keratinocytes between tumor and adjacent non-cancerous tissues caused by HPV infection and identified macrophages and specific CAFs that play a crucial role during the early stage in promoting the inflammatory response and remodeling the cancer-promoting TME. Our findings provide new insights into the transcriptional landscape of early-stage CESC to understand the mechanism of HPV-mediated malignant transformation in cervical cancer.
Humans ; Female ; Papillomavirus Infections/genetics* ; Uterine Cervical Neoplasms/genetics* ; Carcinoma, Squamous Cell/pathology* ; Keratinocytes/metabolism* ; Single-Cell Analysis/methods* ; Tumor Microenvironment/genetics*