A Comparative Analysis of Usual- and Gastric-Type Cervical Adenocarcinoma in a Japanese Population Reveals Distinct Clinicopathological and Molecular Features with Prognostic and Therapeutic Insights

Abstract

Gastric-type cervical adenocarcinoma (GCA) is a rare and aggressive subtype of cervical adenocarcinoma. Despite its clinical significance, its molecular carcinogenesis and therapeutic targets remain poorly understood. This study aimed to compare the clinicopathological, immunohistochemical, and molecular profiles of GCA and usual-type cervical adenocarcinoma (UCA), exploring prognostic and therapeutic biomarkers in a Japanese population. A total of 110 cervical adenocarcinoma cases, including 16 GCA and 94 UCA cases, were retrospectively analyzed for clinicopathological features, and a panel of immunohistochemical markers was assessed. Sanger sequences were performed for the KRAS, PIK3CA, and BRAF genes, and survival and clinicopathological correlations were assessed using Kaplan-Meier and Cox regression analyses. GCA was significantly associated with more aggressive features than UCA, including lymph node involvement, advanced FIGO stages, increasing recurrence rate, and poor survival status. High ARID1B expression was observed in a subset of GCA cases and correlated with worse progression-free and overall survival. Additionally, PD-L1 expression was more frequent in GCA than UCA and was associated with unfavorable prognostic factors. Conversely, UCA cases showed strong p16 expression, supporting their HPV-driven pathogenesis. Molecular profiling revealed KRAS and PIK3CA mutations in both subtypes, while BRAF mutations were identified exclusively in GCA. These findings reveal distinct clinical and molecular profiles for both tumor types and underscore ARID1B and PD-L1 as predictive prognostic and therapeutic biomarkers in GCA, implicating the use of subtype-specific treatment strategies.

Keywords: ARID1B; gastric-type cervical adenocarcinoma; immune checkpoint inhibitor (ICI) therapy; prognostic biomarker; usual-type cervical adenocarcinoma.

Figure 1

Representative H&E-stained sections of UCA and GCA. (A) UCA displaying well-formed glandular structures lined by atypical columnar epithelial cells with pseudostratified, hyperchromatic nuclei and frequent mitoses. (B) GCA is characterized by irregular, dilated glands with pale to eosinophilic cytoplasm, distinct cell borders, and variably atypical nuclei, often with clear or foamy appearance.

Figure 2

Kaplan–Meier curves for the patients with GCA and UCA. (A) Progression-free survival (PFS) showing significantly poorer outcomes in the GCA group compared to UCA (log-rank test, p = 0.014). (B) Overall survival (OS) indicating a worse prognosis in GCA than UCA (log-rank test, p = 0.032), with a steady decline observed in the GCA cohort.

Figure 3

Prognostic significance of p16 expression in UCA. (A,B) Representative immunohistochemical staining of p16 showing positive (A) and negative (B) expressions. Kaplan–Meier curves indicating that p16-positive cases had significantly better progression-free survival (C) (log-rank test, p = 0.048) and overall survival (D) (log-rank test, p = 0.005) compared to p16-negative cases.

Figure 4

Immunohistochemical expression of ARID1B and its association with clinical outcomes in GCA. Representative high (A) and low (B) ARID1B nuclear staining patterns. (C) High ARID1B expression was associated with significantly worse progression-free survival (log-rank test, p = 0.031). (D) Similarly, overall survival was poor in patients with high ARID1B expression (log-rank test, p = 0.045).

Figure 5

PD-L1 expression in GCA and its potential clinical significance. Representative positive (A) and negative (B) PD-L1 expression patterns. Kaplan–Meier curves demonstrate that positive or high PD-L1 expression correlates with significantly poorer (C) progression-free survival (log-rank test, p = 0.025) and (D) overall survival (log-rank test, p = 0.007).