Recent progress and therapeutic strategies in the treatment of cervical neuroendocrine neoplasms (Review).

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors with neuroendocrine differentiation that can arise in virtually any organ, including the gastrointestinal tract, lungs, head and neck, thymus, thyroid, breasts, skin and genitourinary system. NENs often secrete peptide hormones or biogenic amines, such as serotonin and gastrin, leading to endocrine imbalances ( 1 , 2 ). In the uterine cervix, NENs account for 0.9-1.5% of all cervical malignancies ( 1 ). Small-cell neuroendocrine carcinoma (SCNEC) is the most common subtype, followed by large-cell NEC (LCNEC), and their etiology is typically linked to human papillomavirus (HPV) infection, particularly HPV16 and HPV18 ( 3 , 4 ). The 2014 World Health Organization (WHO) classification divided NECs of the cervix (NECCs) into low-grade (carcinoid and atypical carcinoid) and high-grade (small cell carcinoma and LCNEC) groups ( 5 , 6 ). With the growing recognition of notable differences in etiology, pathogenesis, clinical behavior, pathological features, molecular alterations, treatment responses and prognoses, the 2020 WHO classification further distinguished well-differentiated neuroendocrine tumors (NETs) from poorly differentiated NECs ( 7 ). Clinically, patients with NECC often present with abnormal vaginal bleeding or post-coital bleeding, sometimes accompanied by abdominal pain or dysuria, whereas overt carcinoid syndrome is rare ( 8 - 12 ). Gynecological examination may reveal visible lesions, and liquid-based cytology of cervical samples can aid screening ( 8 , 13 ). Compared with cervical squamous cell carcinoma (SCC) or adenocarcinoma (ADC), NECC is markedly more prone to lymphovascular space invasion, lymph node involvement, and both local and distant recurrence ( 14 ). However, in clinical practice, the diagnosis of NECC presents notable challenges, as these lesions often share morphological features with poorly differentiated ADC and SCC, rendering routine histopathological evaluation insufficient for accurate classification. Therefore, immunohistochemistry has become essential for differential diagnosis. Neuroendocrine differentiation is typically confirmed by detecting the expression of markers such as chromogranin A (CgA), synaptophysin (SYN), CD56 and neuron-specific enolase (NSE); among these, SYN and CD56 offer the highest sensitivity, whereas CgA is the most specific. More recently, insulinoma-associated protein 1 (INSM1) has emerged as a highly sensitive and specific adjunctive diagnostic marker. Given that nearly all cervical high-grade NECCs are associated with high-risk HPV infection, immunohistochemical staining for p16 also serves as a useful surrogate marker supporting diagnosis ( 15 ). Due to its rarity and the absence of prospective clinical trials, no disease-specific treatment guidelines currently exist; despite advances in genomic profiling, NECC remains an orphan disease in terms of therapeutic development because of its rarity. Clinical decisions are mainly derived from two sources: Surgical options follows the principles of cervical cancer treatment (for example, radical hysterectomy), whereas chemotherapy and chemoradiation regimens are borrowed from small-cell lung cancer (SCLC) ( 16 ). This hybrid approach often leads to inconsistent outcomes and high recurrence rates. Moreover, the lack of standardized diagnostic criteria contributes to misclassification. The uncertainty at both diagnostic and therapeutic levels represents an urgent clinical problem to be addressed; moreover, since >60% of patients with stage I-II NECC already exhibit early lymphovascular invasion or lymph node metastasis, this poses additional challenges for prognosis ( 17 ). Current treatment strategies include radical hysterectomy followed by adjuvant chemotherapy or concurrent chemoradiation for early-stage disease; definitive concurrent chemoradiation with or without neoadjuvant chemotherapy for locally advanced disease; and palliative chemotherapy for metastatic disease ( 1 ). Platinum combined with etoposide is the most commonly used regimen for advanced stages ( 18 ). For recurrent or progressive disease, chemotherapy agents such as topotecan and paclitaxel, as well as the anti-angiogenic targeted agent bevacizumab, are often employed ( 19 , 20 ). Notably, the rapid development of targeted therapies and immunotherapies has provided novel options for treatment. For example, immune checkpoint inhibitors (ICIs), such as the anti-programmed cell death protein 1 (PD-1) monoclonal antibody pembrolizumab, have shown activity against small-cell NECC (SCNECC) and may also benefit HPV-associated metastatic or recurrent non-SCNECC ( 21 , 22 ). Combining ICIs with radiotherapy and chemotherapy holds promise for improving clinical outcomes. Nevertheless, current evidence remains limited to case reports, and the lack of robust clinical trials and evidence-based guidelines poses notable challenges for gynecological oncologists. Furthermore, recent studies have identified potentially actionable molecular alterations in NECC, including delta-like 3 (DLL3) expression and activation of the PI3K/AKT/mTOR (PAM) pathway ( 23 , 24 ). Therefore, translating these molecular insights into targeted interventions has academic importance and clinical value. The present systematic review summarizes the pathogenesis, pathological features, treatment modalities and overall prognosis of NECC, explores future therapeutic prospects, and offers practical recommendations to aid clinicians in diagnosing and managing this aggressive disease. A deeper understanding of NECC biology is expected to reveal novel therapeutic targets for personalized treatment, ultimately leading to innovative and effective therapies.

The current understanding of the pathogenesis of NECC is limited and low-quality evidence hinders the development of clinical management. Radical surgery and combined or non-combined radiotherapy with cisplatin and etoposide are the main treatment methods for early stage disease, whereas chemotherapy with cisplatin and etoposide or topotecan, paclitaxel and bevacizumab is suitable for women with locally advanced or recurrent NECC. In the future, multi-omics integration may serve a central role in refining the biological classification and individualized treatment of NECC. With the increasing number of genomes in The Cancer Genome Atlas database, genetic testing provides broad prospects for personalized treatment of cervical NENs with targeted drugs. Further research is needed to investigate the molecular, biological and therapeutic associations between cervical NETs and extracervical NETs arising from other organs (for example, lungs, gastrointestinal tract and pancreas). In-depth exploration of the underlying molecular abnormalities and signal transduction, including genetic and epigenetic factors, is key to improving therapeutic efficacy. Current histopathological classification mainly relies on morphology, neuroendocrine marker expression, mitotic activity and Ki-67 index; however, these parameters are insufficient to fully capture the molecular heterogeneity of NECC. Genomic studies have demonstrated that high-grade NECC harbors recurrent alterations in several cancer-related genes and pathways, including PIK3CA, TP53, Myc, PTEN, RB1, KRAS, ARID1A, and components of the PAM and Notch signaling pathways ( 57 , 60 , 79 , 102 , 109 , 154 , 155 ). Eskander et al ( 53 ) reported a unique genomic landscape of high-grade NECC and highlighted frequent alterations in PIK3CA, Myc, TP53 and PTEN, suggesting that genomic profiling may help identify therapeutically actionable subgroups. Similarly, Wang et al ( 156 ) performed whole-exome sequencing of cervical and endometrial SCNECs and identified shared mutational features, supporting the value of comparative genomic analysis in defining NEC across gynecological sites. Beyond DNA-level alterations, transcriptomic, epigenomic, proteomic and immune microenvironmental profiling may further improve the precision of NECC stratification. For example, expression of neuroendocrine lineage regulators such as ASCL1, NEUROD1, DLL3 and Notch pathway-related molecules may help distinguish biologically distinct NECC subsets ( 75 , 85 , 88 , 157 ). In addition, immune biomarkers, including PD-L1 expression, TILs, MSI/MMR status, tumor mutational burden and DNA damage repair-related markers such as PARP1, may contribute to predicting sensitivity to ICIs or DNA damage response-targeted therapy. Previous studies have reported heterogeneous PD-L1 expression, largely preserved MMR status and frequent PARP1 expression in NECC, indicating that single biomarkers may be insufficient for treatment selection ( 113 , 158 ). Therefore, a multi-dimensional model integrating histology, HPV status, somatic mutations, transcriptional programs, epigenetic changes, immune contexture and druggable surface antigens may provide a more reliable framework for precision diagnosis and risk stratification. For clinical translation, future studies should incorporate next-generation sequencing, RNA sequencing, methylation profiling, multiplex immunohistochemistry, spatial transcriptomics and single-cell sequencing into prospective NECC cohorts. Such approaches may help clarify tumor origin, distinguish well-differentiated NETs from poorly differentiated NECs, identify mechanisms of treatment resistance and guide rational combination strategies. Given the rarity of NECC, international multi-center collaboration and shared molecular databases are essential for validating molecular subtypes and establishing biomarker-driven clinical trials. Notably, antibody-drug conjugates (ADCs) represent another promising direction for the treatment of recurrent or metastatic NECC. ADCs combine the target specificity of monoclonal antibodies with the cytotoxic potency of chemotherapy payloads, allowing selective delivery of highly active agents to tumor cells expressing specific surface antigens ( 159 ). This strategy may be particularly attractive for NECC because conventional chemotherapy has limited durability, while several potentially targetable antigens, including DLL3, HER2, TROP-2, tissue factor and SSTRs have been explored in neuroendocrine or cervical malignancies ( 41 , 89 , 104 , 160 - 162 ). DLL3 is one of the most biologically relevant targets in high-grade NEC. Other ADC targets may also be relevant to NECC. The future development of ADCs in NECC should be biomarker-driven rather than empiric. Routine assessment of DLL3, HER2, TROP-2 and tissue factor by immunohistochemistry or molecular assays may help identify patients suitable for ADC-based therapy. Moreover, ADCs may be combined with ICIs, PARPi, anti-angiogenic agents or radiotherapy to enhance antitumor activity, especially in tumors with DNA damage repair deficiency, high antigen expression or immune-active microenvironments. However, because direct clinical evidence in NECC remains limited, prospective basket trials, rare tumor registries and translational studies using patient-derived organoids or xenograft models are urgently needed. Overall, ADCs provide a rational and potentially effective precision treatment strategy for NECC, but their success will depend on accurate target selection, toxicity management and collaborative clinical trial design. Various clinical trials are currently underway to expand the existing options for monotherapy and combination therapies. In a phase II clinical trial ( NCT05910177 ) on neoadjuvant therapy for cervical NEN, the application of camrelizumab in combination with etoposide and cisplatin was investigated ( 163 ). In addition, the safety and tolerability of AK104 as a new chemotherapy drug for advanced/recurrent high-grade NECC are currently being studied (phase II- NCT05063916 ) ( 164 ). Camrelizumab (an anti-PD-1 antibody) has antitumor activity in NEN, and its efficacy combined with cisplatin/paclitaxel/bevacizumab in the treatment of recurrent or advanced NECC is currently being evaluated (phase II- NCT04635956 ) ( 165 ). In an ongoing phase II clinical trial, the role of XmAb20717 in advanced rare cancers, such as NEC, was evaluated to explore its prognostic biomarkers ( NCT05337735 ) ( 166 ). Upregulation of SSTR2A has been detected in NECC ( 167 ), which is an important target for nuclear medicine molecular imaging diagnosis and peptide receptor-mediated radionuclide therapy ( 168 ). The efficacy of 177 Lu-DOTA-TATE in treating patients with SSTR-positive NET (phase II- NCT01876771 ) ( 169 ), and the combination of 177 Lu and nivolumab for the treatment of grade 3 well-differentiated NETs or poorly differentiated NEC is currently being studied (phase II- NCT04525638 ) ( 170 ). MSI-H/dMMR tumors express a large number of new antigens due to high mutation, forming a microenvironment of immune-cell infiltration and upregulated expression of immune checkpoint proteins in tumor cells ( 153 ). The application of pembrolizumab and nivolumab in MSI-H/dMMR tumors has shown the potential of ICIs and marks the progress of precision medicine ( 171 ). Surufatinib is a potent small molecule tyrosine kinase inhibitor that selectively targets VEGF receptors 1, 2 and 3, fibroblast growth factor receptor 1 and colony stimulating factor 1 receptor, and NENs are highly vascularized tumors ( 172 ). Surufatinib may therefore have potential in treating NENs. In a dose escalation/expansion study, the 4-month and 11-month PFS rates in an extrapancreatic NET cohort treated with surufatinib were 93.8% (95% CI: 63.2, 99.1) and 51.1% (95% CI: 12.8, 80.3), respectively, supporting the antitumor efficacy of surufatinib for extrapancreatic NETs ( 173 ). Serplulimab is a novel anti-PD-1 antibody; serplulimab and surufatinib combined with standard chemotherapy (platinum/etoposide) are being studied to determine whether they can improve the efficacy in patients with NEN (phase II: NCT05747729 ) ( 174 ). Furthermore, new drugs are being tested in advanced or metastatic extra-pulmonary NECs. NP-101 has antioxidant and anti-angiogenic effects; combined with immunotherapy drugs, such as nivolumab and ipilimumab, it may enhance efficacy in advanced neuroendocrine cancer ( NCT05262556 ) ( 175 ). Histone deacetylase (HDAC) serves an important role in tumor development by modifying the structure of chromosomes and regulating gene expression, and the anticancer effect of HDAC inhibitors is notable ( 176 ). Among them, chidamide is being studied as a single treatment drug or in combination with cyclooxygenase (COX)-1/COX-2 inhibitors and ICIs for a variety of solid malignant tumors, which can slow tumor progression by altering the tumor immune microenvironment ( 177 , 178 ). In addition, the efficacy and safety of chidamide combined with etoposide and cisplatin/carboplatin in the treatment of advanced extrapulmonary NEC are being studied ( NCT05076786 ) ( 179 ). The results of these clinical trials are awaited, and by evaluating various combinations of treatments for better tumor control, it is hoped that in the near future, effective management models can be developed to improve patient with NECs prognosis and quality of life ( Table V ). The metastatic potential, morphological characteristics and manifestations of endocrine paraneoplastic syndrome, such as carcinoid syndrome and syndrome of inappropriate antidiuretic hormone secretion, in cervical NENs provide evidence for early diagnosis ( 180 ). Our latest understanding of the histological, pathological and genetic factors of these tumors may help to provide better diagnostic markers and treatment options, thereby improving prognosis. Various clinical trials are being extensively conducted with the aim of expanding the selection of single and combination therapies for NENs. Although ICIs may be beneficial, there is a lack of effective strategies to predict response, manage immune-related adverse events or select suitable patients for these therapies. Improvements in molecular analysis and further mechanistic research are required to determine which patients will benefit from immunotherapy, targeted monotherapy or combination therapy, and to customize personalized treatment plans according to different situations, which will markedly improve the treatment effectiveness of patients. Further research is needed to evaluate the potential of MSI status in guiding immunotherapy across tumor types. This represents a notable advancement in precision medicine. Targeted therapies, such as somatostatin analogs, PAM inhibitors and anti-angiogenic drugs, have been used in extra-cervical NEN therapy ( 181 , 182 ). However, to the best of our knowledge, there are currently no data available on their application in cervical NENs, which urgently requires strong cooperation between gynecological oncologists and relevant researchers to ensure progress in the treatment of these invasive diseases.