Exploring Cervical Adenocarcinoma: Epidemiology, Diagnostic and Therapeutic Challenges, and Pathogenetic Mechanisms

Academic Background

Cervical cancer poses a significant threat to women’s health globally, particularly in developing countries. The main histological types of cervical cancer include squamous cell carcinoma (SCC) and cervical adenocarcinoma (CA). Although the incidence of CA is relatively low, its aggressive nature, high recurrence rate, poor prognosis, and low early detection rate present significant challenges for clinical management. In recent years, while the overall incidence of cervical cancer has declined, the incidence of CA has risen, especially in high-income countries. Additionally, there are notable differences in the pathogenesis, tumor heterogeneity, and tumor immune microenvironment (TME) between CA and SCC, but current understanding of these differences remains limited.

To address these challenges, researchers Shuhui Li, Congrong Liu, and Liang Weng have authored a review paper summarizing the epidemiological characteristics, diagnostic and therapeutic challenges of CA, and the latest advances in its pathogenesis. The paper particularly highlights the significant heterogeneity in TME characteristics between CA and SCC and summarizes the commonly used preclinical models in CA research, along with their advantages and disadvantages.

Source of the Paper

The paper was co-authored by Shuhui Li from the Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center; Congrong Liu and Liang Weng from the Department of Pathology, Third Hospital, Peking University Health Science Center. It was published in 2025 in the journal Cancer Medicine under the title Exploring Cervical Adenocarcinoma: Epidemiological Insights, Diagnostic and Therapeutic Challenges, and Pathogenetic Mechanisms. The paper is an open-access review article.

Main Content of the Paper

1. Epidemiology of Cervical Adenocarcinoma

According to the latest global cancer statistics, there were approximately 604,127 new cases of cervical cancer and 341,831 deaths worldwide in 2020. The incidence of cervical cancer varies significantly across regions, with higher rates of SCC in developing countries and a rising incidence of CA in some high-income countries. Asia accounts for 58% of global cervical cancer cases, followed by Africa (20%), Europe (10%), and Latin America (10%). China and India account for 18% and 21% of global cervical cancer cases, respectively, and 17% and 23% of deaths.

Although the incidence of CA is lower than that of SCC, it exhibits higher malignancy, lower survival rates, and a greater risk of distant metastasis. HPV (human papillomavirus) infection is the primary cause of CA, with approximately 75% of CA cases associated with high-risk HPV types such as HPV16, 18, and 45. However, about 15% of CA cases show no detectable HPV infection, suggesting a more complex pathogenesis.

2. Diagnostic and Therapeutic Challenges of CA

The diagnosis of CA primarily relies on cervical cytology and HPV testing, but these methods have low detection rates for CA, leading to potential oversight or misdiagnosis. In 2020, the World Health Organization (WHO) updated the histological classification of CA, dividing it into HPV-associated and HPV-independent types. HPV-independent CA includes gastric, mesonephric, and clear cell types, which differ significantly from HPV-associated CA in terms of pathogenesis and clinical management.

In terms of treatment, CA has higher rates of recurrence and metastasis, and current therapeutic approaches have limitations in controlling these processes. Early-stage CA patients may achieve better outcomes through surgical interventions such as radical hysterectomy, but the efficacy of treatment for advanced-stage CA is poor. For example, the 5-year survival rate for stage I CA is typically 70%-90%, while for stages II and III, it drops significantly to 30%-60%. The success rate of treatment for recurrent disease is generally low.

3. Tumor Immune Microenvironment (TME) in CA

TME plays a crucial role in the pathogenesis of CA. Comprising blood vessels, immune cells, stromal cells, signaling molecules, and the extracellular matrix, TME enables tumor cells to promote their growth and spread by enhancing angiogenesis and suppressing the host’s immune response. The application of omics technologies, such as single-cell RNA sequencing (scRNA-seq), allows researchers to precisely identify cell subpopulations and genomic mutations within the TME, revealing the mechanisms of tumor growth, evolution, and molecular pathways.

Studies have shown significant differences in TME characteristics between CA and SCC. For instance, CA tumor cells exhibit higher malignancy, and their immune microenvironment is more immunosuppressive. Additionally, CA’s TME is enriched with regulatory T cells (Tregs) and tumor-promoting neutrophils, which may explain its insensitivity to immunotherapy.

4. Preclinical Research Models for CA

To better understand the pathogenesis of CA, researchers have developed various preclinical models, including cell lines, animal models, and organoids. While cell lines are easy to maintain and cost-effective, they lack tumor heterogeneity and cell-TME interactions. Animal models and organoids more closely mimic the actual tumor environment, providing better simulations of tumor development and treatment responses.

However, the number of cell lines available for CA research is limited, and the success rate of organoid models is low (50% for SCC and 25% for CA). Additionally, patient-derived xenograft (PDX) models, which retain the TME and cellular characteristics of primary tumors, are costly and have a success rate of only 62.2%. Therefore, developing more preclinical models suitable for CA research is a key focus for future studies.

Significance and Value of the Paper

This review systematically summarizes the epidemiological characteristics, diagnostic and therapeutic challenges, and the latest advances in the pathogenesis of CA, particularly highlighting the significant heterogeneity in TME characteristics between CA and SCC. The paper also emphasizes the importance of developing more preclinical models for CA research and proposes future research directions, including exploring potential treatment strategies and reliable biomarkers for CA.

Through this review, the researchers aim to provide new insights and directions for subsequent research, clinical diagnosis, and treatment strategies for CA. The publication of this paper not only enriches the academic understanding of CA but also offers valuable reference information for clinicians, contributing to improved prognosis and quality of life for CA patients.

Key Highlights

1. TME Heterogeneity Between CA and SCC: The paper delves into the differences in TME characteristics between CA and SCC, revealing the more immunosuppressive microenvironment of CA.
2. Pathogenesis of HPV-Independent CA: The paper highlights the unique pathogenesis of HPV-independent CA, offering new perspectives for its diagnosis and treatment.
3. Development of Preclinical Models: The paper summarizes the commonly used preclinical models in CA research and identifies their limitations, providing direction for future model development.
4. Potential of Immunotherapy: Although CA is insensitive to immunotherapy, the paper suggests the possibility of improving patient outcomes by exploring new biomarkers and combination therapies.

This review not only provides important theoretical support for basic research on CA but also offers valuable guidance for clinical practice, making it a significant contribution to both scientific and applied fields.