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Objective Neuroendocrine cervical carcinoma (NECC) is a rare but highly aggressive tumor. The clinical management of NECC follows neuroendocrine neoplasms and cervical cancer in general. However, the diagnosis and prognosis of NECC remain dismal. The aim of this study was to identify a specific protein signature for the diagnosis of NECC. Methods Protein and gene expression data for NECC and other cervical cancers were retrieved or downloaded from self-collected samples or public resources. Eleven machine-learning algorithms were packaged into 66 combinations, of which we selected the optimal algorithm, including randomForest, SVM-RFE, and LASSO, to select key NECC specific dysregulated proteins (kNsDEPs). The diagnostic effect of kNsDEPs was validated by a set of predictive models and immunohistochemical staining method. The dysregulation patterns of kNsDEPs were further investigated in other neuroendocrine carcinomas. Results Our results showed that NECC displays distinctive biological characteristics, such as HPV18 infection, and exhibits unique molecular features, particularly an enrichment in cytoskeleton-related functions. Furthermore, secretagogin (SCGN), adenylyl cyclase-associated protein 2 (CAP2), and calcyclin-binding protein (CACYBP) were identified as kNsDEPs. These kNsDEPs play a central role in cytoskeleton protein binding and showcase robust diagnostic ability and specificity for NECC. Moreover, the concurrent upregulation of SCGN and CACYBP, along with the downregulation of CAP2, represents a unique feature of NECC, distinguishing it from other neuroendocrine carcinomas. Conclusions This study uncovers the significance of kNsDEPs and elucidates their regulated networks in the context of NECC. It highlights the pivotal role of kNsDEPs in NECC diagnosis, thus offering promising prospects for the development of diagnostic biomarkers for NECC.

Primary signet‐ring cell carcinoma and poorly differentiated adenocarcinoma with poorly cohesive morphology in the cervix are rare conditions, and their clinicopathological features remain poorly described. This study defines primary cervical poorly differentiated adenocarcinomas meeting the diagnostic criteria for poorly cohesive carcinoma as outlined in the 2019 WHO Classification of Digestive System Tumors as ‘HPV‐associated cervical poorly cohesive carcinomas’ (HPV‐associated CPCC) and describe their clinicopathological and molecular features. Sixteen HPV‐associated CPCC cases were analyzed and classified into three histological subtypes: signet‐ring cell carcinoma (n = 4), not otherwise specified (n = 6), and mixed types (n = 6). All patients were Chinese (median age: 46 years; range: 30–66). Vaginal bleeding was the primary presenting symptom (100.0%). High‐risk human papillomavirus (HPV) was identified in all tumors, with HPV‐18 as the predominant genotype (n = 13), HPV‐16 in two cases, and a single case exhibiting concurrent infection with HPV‐16, ‐18, and ‐58. Overall, 56.3% presented with advanced‐stage disease (International Federation of Gynecology and Obstetrics [FIGO] IIIB–IVB), frequently involving regional lymph nodes (56.3%) and distant sites (18.8%). Histopathological examination revealed diffuse stromal infiltration (100%), lymphovascular invasion (75.0%), necrosis (75.0%), and desmoplasia. Immunohistochemically, all cases showed p16 block positivity. Variable expression of antibody‐drug conjugate targets was observed, with HER2‐low expression (33.3%), and positive staining for Trop‐2 (85.7%), nectin‐4 (42.9%), and tissue factor (92.3%). During follow‐up, disease‐specific mortality was 50.0%. The 3‐year overall survival rate was 56.3%, which was significantly lower in advanced‐stage disease (45.0%) than in early‐stage disease (75.0%). Whole‐exome sequencing revealed low tumor mutational burden (median 1.28 Muts/Mb), recurrent mutations in AK1, ARHGAP39, KRT24, MICAL3, SLC6A9 (27.3%), KRAS, and KMT2C (18.2%), alongside MUC2 copy gain (63.6%) and bidirectional Y_(R)NA alterations (gain 54.5%/loss 45.5%). Collectively, HPV‐associated CPCC represents a distinct and aggressive subtype characterized by distinctive histopathological features, a predominant association with HPV18, frequent presentation at advanced stages, and marked molecular and biomarker heterogeneity.

At the first interim analysis of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study, the addition of pembrolizumab to chemoradiotherapy provided a statistically significant and clinically meaningful improvement in progression-free survival in patients with locally advanced cervical cancer. We report the overall survival results from the second interim analysis of this study. Eligible patients with newly diagnosed, high-risk (FIGO 2014 stage IB2–IIB with node-positive disease or stage III–IVA regardless of nodal status), locally advanced, histologically confirmed, squamous cell carcinoma, adenocarcinoma, or adenosquamous cervical cancer were randomly assigned 1:1 to receive five cycles of pembrolizumab (200 mg) or placebo every 3 weeks with concurrent chemoradiotherapy, followed by 15 cycles of pembrolizumab (400 mg) or placebo every 6 weeks. Pembrolizumab or placebo and cisplatin were administered intravenously. Patients were stratified at randomisation by planned external beam radiotherapy type (intensity-modulated radiotherapy [IMRT] or volumetric-modulated arc therapy [VMAT] vs non-IMRT or non-VMAT), cervical cancer stage at screening (FIGO 2014 stage IB2–IIB node positive vs III–IVA), and planned total radiotherapy (external beam radiotherapy plus brachytherapy) dose (<70 Gy vs ≥70 Gy [equivalent dose of 2 Gy]). Primary endpoints were progression-free survival per RECIST 1.1 by investigator or by histopathological confirmation of suspected disease progression and overall survival defined as the time from randomisation to death due to any cause. Safety was a secondary endpoint. Between June 9, 2020, and Dec 15, 2022, 1060 patients at 176 sites in 30 countries across Asia, Australia, Europe, North America, and South America were randomly assigned to treatment, with 529 patients in the pembrolizumab–chemoradiotherapy group and 531 patients in the placebo–chemoradiotherapy group. At the protocol-specified second interim analysis (data cutoff Jan 8, 2024), median follow-up was 29·9 months (IQR 23·3–34·3). Median overall survival was not reached in either group; 36-month overall survival was 82·6% (95% CI 78·4–86·1) in the pembrolizumab–chemoradiotherapy group and 74·8% (70·1–78·8) in the placebo–chemoradiotherapy group. The hazard ratio for death was 0·67 (95% CI 0·50–0·90; p=0·0040), meeting the protocol-specified primary objective. 413 (78%) of 528 patients in the pembrolizumab–chemoradiotherapy group and 371 (70%) of 530 in the placebo–chemoradiotherapy group had a grade 3 or higher adverse event, with anaemia, white blood cell count decreased, and neutrophil count decreased being the most common adverse events. Potentially immune-mediated adverse events occurred in 206 (39%) of 528 patients in the pembrolizumab–chemoradiotherapy group and 90 (17%) of 530 patients in the placebo–chemoradiotherapy group. This study is registered with ClinicalTrials.gov, NCT04221945. Pembrolizumab plus chemoradiotherapy significantly improved overall survival in patients with locally advanced cervical cancer These data, together with results from the first interim analysis, support this immuno-chemoradiotherapy strategy as a new standard of care for this population. Merck Sharp & Dohme, a subsidiary of Merck & Co.

To explore and analyze the correlation between LncRNA TDRG1 expression degree and the prognosis of cervical carcinoma tissues. The cervical cancer tissues and para-carcinoma tissues of 106 patients with cervical carcinoma surgically removed in our hospital were chosen as specimens. LncRNA TDRG1 expression in cervical carcinoma tissues and para-carcinoma tissues was inspected by real-time fluorescence quantitative PCR, and the correlation between LncRNA TDRG1 and the clinicopathological parameters and disease prognosis was analyzed. The relative expression of LncRNA TDRG1 in cervical carcinoma tissues was critically gone up ( P  < 0.05) compared to para-carcinoma tissues. The relative expression of LncRNA TDRG1 in cervical carcinoma was correlated with FIGO staging, lymph node metastasis, infiltrating depth of cervical basal, and the differentiation of cancer cells ( P  < 0.05). According to the results of the Kaplan–Meier curve and Log-rank test, the overall survival conditions of subjects with low-lncRNA TDRG1 were superior to that of those with high-lncRNA TDRG1 expression ( P  < 0.05). The expression of LncRNA TDRG1 in cervical carcinoma tissues and the clinicopathological features in predicting the overall survival (OS) in sufferers with cervical carcinoma were investigated by the Cox regression model. LncRNA TDRG1 expression in cervical carcinoma tissues is tightly associated with the progression and prognosis of cervical carcinoma, which may be a latent biological indicator for clinical diagnosis and prognosis of cervical carcinoma.

Background Immune exclusion contributes to heterogeneous benefit from immunotherapy in cervical squamous carcinoma, but the malignant epithelial state most closely associated with this phenotype and its tissue- and morphology-level correlates remain unclear. We investigated whether a lesion-grade-associated malignant epithelial state was linked to immune-excluded tissue architecture and could be translated across transcriptomic and pathology modalities. Methods We integrated single-cell RNA-seq discovery (GSE208653), spatial transcriptomic evaluation (GSE208654), bulk RNA-seq translation in primary squamous TCGA-CESC tumors, external whole-tumor evaluation in CGCI-HTMCP-CC, and whole-slide H&E analysis of 259 slides from 250 TCGA patients. External immune-focused datasets, a local neoadjuvant immunotherapy-treated cervical squamous carcinoma cohort, and a representative pilot whole-section multiplex immunofluorescence were used as supportive layers. Results A basal-squamous stress keratinization (BSK) program was the malignant epithelial state most consistently associated with the cross-sectional normal–HSIL–squamous carcinoma spectrum. Across four spatial sections, BSK showed a section-consistent core-boundary-shell organization comprising a BSK-rich tumor core, a stromal-myeloid boundary, and a more peripheral lymphoid shell. In primary squamous TCGA-CESC tumors, this biology was translated most clearly into an epithelial-exclusion bulk state associated with fibro-myeloid niche enrichment and weaker engagement of inflamed/dysfunctional CD8 T-cell programs. Patient-level out-of-fold morphology scores from matched TCGA H&E slides correlated positively with epithelial exclusion, supporting a detectable histologic correlate within the matched pathology arm. In a local 18-patient neoadjuvant immunotherapy-treated cohort, H&E-derived morphology scores were associated with postoperative pathological response grade, providing exploratory clinical-pathology support rather than predictive validation. The exclusion-centered ordering was directionally preserved in CGCI-HTMCP-CC and aligned with stromal/EMT/TGFβ, angiogenesis, and more moderate gMDSC-related programs. Conclusions BSK marks an exclusion-associated cervical squamous carcinoma state that is spatially organized, measurable in bulk transcriptomes, and partially reflected in routine histology. These findings provide a human-data-derived translational framework for future immune-access stratification and prospective biomarker testing but do not establish BSK as a causal driver or validated predictor of immunotherapy response.

Squamous cervical carcinoma (SCC) requires particular attention in diagnostic and clinical management. New diagnostic tools, such as (positron emission tomography–magnetic resonance imaging) PET–MRI, consent to ameliorate clinical staging accuracy. The availability of new technologies in radiation therapy permits to deliver higher dose lowering toxicities. In this clinical scenario, new surgical concepts could aid in general management. Lastly, new targeted therapies and immunotherapy will have more room in this setting. The aim of this narrative review is to focus both on clinical management and new therapies in the precision radiotherapy era.

Background Cervical cancer is the tenth diagnosed cancer in the world. Early-stage and locally recurrent disease may be cured with radical surgery or chemo-radiotherapy. However, if disease persists or recurs, options are limited and the prognosis is poor. In addition to chemotherapy, bevacizumab, an antiangiogenic agent, has recently demonstrated its efficacy in this setting. Cabozantinib is an oral small molecule tyrosine kinase inhibitor that exhibits potent inhibitory activity against several receptor tyrosine kinases that are known to influence tumor growth, metastasis, and angiogenesis. The main targets of Cabozantinib are VEGFR2, MET and AXL. It is currently approved for the treatment of metastatic renal cell carcinoma, hepatocellular carcinoma and medullary thyroid carcinoma. Given its angiogenic properties associated with growth factor receptors inhibition, Cabozantinib represents a potential active treatment in cervical carcinoma. In this context, we propose to assess the efficacy and safety of cabozantinib monotherapy in advanced/metastatic cervical carcinoma (CC) after failure to platinum-based regimen treatment. Methods This study is a single-arm two-stage multicenter phase II aiming to simultaneously assess efficacy and safety of Cabozantinib among advanced/metastatic cervical carcinoma (CC) after failure to platinum-based regimen treatment. The main criterion will be based on both safety and clinical efficacy by conducting a Bryant-and-Day design. Safety endpoint is the proportion of patients with clinical gastro-intestinal (GI) perforation/fistula, GI-vaginal fistula and genito-urinary (GU) fistula events grade ≥ 2 (NCI CTCAE V.5.0) occurring up to one month after the end of treatment. Efficacy endpoint is the proportion of patients with disease control rate 3 months after Cabozantinib initiation. A patients’ self-reported quality of life evaluation is also planned, as well as the investigation of nutritional outcomes. Cabozantinib will be administered at the daily dose of 60 mg given orally, without interruption until disease progression or discontinuation for any cause. Discussion Cabozantinib is a promising drug for patients with advanced/metastatic cervical cancer where few therapeutics options are available after failure to platinum-based regimen metastatic CC. It appears challenging to assess the interest of Cabozantinib in this indication, taking into account the potential toxicity of the drug. Trial registration NCT04205799 , registered “2019 12 19”. Protocol version Version 3.1 dated from 2020 08 31.

Neuroendocrine cervical carcinoma (NECC) is a rare and highly aggressive gynecological tumor, with poor prognosis and limited standardized treatment options. Inflammation plays a significant role in tumor progression, and systemic inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) have shown prognostic value in other malignancies. However, their role in NECC remains unclear. This single-center retrospective study included 25 NECC patients treated at our hospital between 2014 and 2024. Patients were divided into three groups based on treatment regimens: paclitaxel plus cisplatin combined with radiotherapy, etoposide plus cisplatin combined with radiotherapy, and radiotherapy alone. Baseline characteristics, inflammatory markers, and clinical outcomes were analyzed. Kaplan-Meier survival analysis and Log-rank tests were used to compare survival differences. The median survival time was significantly longer in the etoposide plus cisplatin plus radiotherapy group (1,000 days) compared to the paclitaxel plus cisplatin plus radiotherapy group (776 days) and the radiotherapy-alone group (347 days, P = 0.037). The radiotherapy-alone group had significantly higher neutrophil counts (median = 5.46 × 10 /L, P = 0.006), platelet counts (median = 282.5 × 10 /L, P = 0.017), NLR (median = 4.68, P < 0.05), and PLR (median = 231.93, P < 0.05), while LMR (median = 1.89, P < 0.05) was lower. For postoperative patients, the median survival time was 1,453 days for the surgery plus etoposide plus cisplatin plus radiotherapy group, compared to 987 days for the surgery plus paclitaxel plus cisplatin plus radiotherapy group (P = 0.048). Combined chemotherapy with etoposide plus cisplatin and radiotherapy significantly improves survival outcomes in NECC patients compared to radiotherapy alone. This regimen may be particularly beneficial for postoperative patients and those with high-risk factors such as lymphovascular space invasion. Further studies are needed to validate these findings and establish standardized treatment protocols for NECC.

Objective Small cell carcinoma of the cervix (SCCC) is rare but extremely aggressive and resistant to current therapies. We herein evaluate the efficacy of bevacizumab, apatinib, and anlotinib in recurrent/metastatic SCCC patients in a real-world setting. Methods Recurrent/metastatic SCCC patients were recruited between January 2013 and July 2020. Baseline characteristics were extracted from medical records, and patients were divided into an anti-angiogenic group and non-anti-angiogenic group. The efficacy of treatments was determined using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Kaplan–Meier analysis was performed for survival analysis. Results Sixteen patients received anti-angiogenic drugs after tumor recurrence/metastasis; of them, 10 cases received them as first-line treatment, 5 cases as second-line treatment, and 1 case as fourth-line treatment. Another 23 patients received traditional therapies, including surgery, chemotherapy, and radiotherapy. The use of anti-angiogenic drugs in first-line treatment significantly prolonged progression-free survival (PFS) compared to the controls, with a median PFS of 8 months (2-20 months) and 3 months (1-10 months), respectively (P = .025). This trend was also notable in patients who started anti-angiogenic treatment after the second-line recurrence/metastasis. However, there was no benefits for overall survival (OS) in either the 10 first-line cases or all 16 cases (P = .499 and .31, respectively). Both bevacizumab and small molecule drugs (apatinib and anlotinib) presented similar efficacy in SCCC patients. Conclusions At present, this is the largest cohort study that provides real-world data, showing that anti-angiogenic regimens could significantly prolong PFS in recurrent/metastatic SCCC. Aside from bevacizumab, the novel oral small molecule drugs provide more choices with similar efficacy. These findings warrant further validation in well-designed future studies.

Cervical cancer being one of the primary causes of high mortality rates among women is an area of concern, especially with ineffective treatment strategies. Extensive studies are carried out to understand various aspects of cervical cancer initiation, development and progression; however, invasive cervical squamous cell carcinoma has poor outcomes. Moreover, the advanced stages of cervical cancer may involve lymphatic circulation with a high risk of tumor recurrence at distant metastatic sites. Dysregulation of the cervical microbiome by human papillomavirus (HPV) together with immune response modulation and the occurrence of novel mutations that trigger genomic instability causes malignant transformation at the cervix. In this review, we focus on the major risk factors as well as the functionally altered signaling pathways promoting the transformation of cervical intraepithelial neoplasia into invasive squamous cell carcinoma. We further elucidate genetic and epigenetic variations to highlight the complexity of causal factors of cervical cancer as well as the metastatic potential due to the changes in immune response, epigenetic regulation, DNA repair capacity, and cell cycle progression. Our bioinformatics analysis on metastatic and non-metastatic cervical cancer datasets identified various significantly and differentially expressed genes as well as the downregulation of potential tumor suppressor microRNA miR-28-5p. Thus, a comprehensive understanding of the genomic landscape in invasive and metastatic cervical cancer will help in stratifying the patient groups and designing potential therapeutic strategies.