Wen ZL, Ren H, Niu PH, Fei H, Li ZF, Zhao DB. Clinicopathological features and prognosis of gastric adenocarcinoma with enteroblastic differentiation. World J Gastrointest Oncol 2026; 18(9): 121562 [DOI: 10.4251/wjgo.121562]
Corresponding Author of This Article
Dong-Bing Zhao, Chief Physician, Professor, Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China. dbzhao@cicams.ac.cn
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
research-article
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Ze-Lin Wen, Hu Ren, Peng-Hui Niu, He Fei, Ze-Feng Li, Dong-Bing Zhao, Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Author contributions: Wen ZL and Ren H contributed equally to this manuscript and are co-first authors. Wen ZL, Ren H, Niu PH, Fei H, Li ZF and Zhao DB designed the research study; Wen ZL, Ren H, Niu PH, and Fei H performed the research and collected the data; Wen ZL, Ren H, and Niu PH analyzed the data; Wen ZL drafted the manuscript; Li ZF and Zhao DB critically revised the manuscript for important intellectual content and supervised the study; and all authors have read and approved the final manuscript.
AI contribution statement: The design, writing, data analysis, result interpretation, and chart generation of this article did not use any AI tools.
Supported by Beijing Hope Run Special Fund of Cancer Foundation of China, No. LC2022L03.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (Approval No. 23/122-3864).
Informed consent statement: Patients were not required to give informed consent to the study because the analysis used anonymous data that were obtained after each patient agreed to treatment by written consent.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at dbzhao@cicams.ac.cn.
Corresponding author: Dong-Bing Zhao, Chief Physician, Professor, Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, China. dbzhao@cicams.ac.cn
Received: March 27, 2026 Revised: April 17, 2026 Accepted: May 25, 2026 Published online: September 15, 2026 Processing time: 166 Days and 17.3 Hours
Abstract
BACKGROUND
Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare histological subtype of gastric cancer with unique embryonic characteristics, and its clinicopathological features and prognostic significance remain unclear to date.
AIM
To compare the clinicopathological features and survival outcomes between GAED and conventional gastric adenocarcinoma.
METHODS
A retrospective analysis was conducted on 330 patients who underwent radical gastrectomy at a single center from 2015 to 2024, including 81 GAED patients and 249 patients with conventional gastric adenocarcinoma. The clinicopathological features of the two groups were compared, and Kaplan-Meier analysis and Cox proportional hazards model were used to evaluate overall survival and progression-free survival.
RESULTS
Compared with the conventional gastric adenocarcinoma group, GAED patients had higher proportions of smoking history (25.9% vs 12.9%, P = 0.008) and drinking history (18.5% vs 8.8%, P = 0.024); lesions were mostly located in the distal stomach (51.9% vs 26.5%), and the proportion of cross-site lesions was lower (19.7% vs 39.0%; P < 0.001 for inter-group difference in tumor location); the proportion of intestinal type in Lauren classification was higher (60.0% vs 37.1%, P = 0.001), the proportion of signet ring cell features was lower (9.9% vs 28.5%, P = 0.001), and there was a difference in the distribution of HER2 scores (P = 0.012); the operation time was shorter (median 190 minutes vs 215 minutes, P = 0.002), the rates of perineural invasion (17.3% vs 36.5%, P < 0.001) and vascular tumor thrombus (11.1% vs 53.4%, P < 0.001) were lower, but the metastasis or recurrence rate was higher (45.7% vs 30.9%, P = 0.022). Kaplan-Meier analysis showed that overall survival and progression-free survival of GAED patients were significantly worse than those of patients with conventional gastric adenocarcinoma; multivariate analysis confirmed that GAED was an independent prognostic factor for both survival outcomes.
CONCLUSION
Compared with conventional gastric adenocarcinoma, GAED has unique clinicopathological features and worse survival outcomes. As an independent adverse prognostic factor, GAED patients require closer monitoring and more individualized management.
Core Tip: Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare subtype of gastric cancer with distinct clinicopathological characteristics. In this retrospective study, GAED was associated with unique pathological features, a higher risk of recurrence or metastasis, and significantly poorer survival than conventional gastric adenocarcinoma. Notably, its adverse prognosis persisted despite lower rates of some traditional invasive pathological features. These findings suggest that GAED may represent a biologically distinct and clinically aggressive entity that requires closer follow-up and more individualized treatment strategies.
Citation: Wen ZL, Ren H, Niu PH, Fei H, Li ZF, Zhao DB. Clinicopathological features and prognosis of gastric adenocarcinoma with enteroblastic differentiation. World J Gastrointest Oncol 2026; 18(9): 121562
Gastric cancer is one of the most common malignant tumors worldwide and the leading cause of digestive system cancer-related deaths[1-3]. Although advances in early screening and surgical treatment have improved the prognosis of some patients, a large number of cases are still diagnosed at advanced stages, with poor overall prognosis[4,5]. Currently, classification systems such as the Lauren classification and the World Health Organization classification are widely used in clinical practice, but they still cannot fully reflect the biological heterogeneity of gastric cancer. Clinical behavior, treatment response and survival outcomes may vary among different histological subtypes.
Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare gastric cancer subtype with unique pathological features, characterized by enteric differentiation and expression of carcinoembryonic markers such as alpha-fetoprotein, glypican-3, and spalt-like transcription factor 4[6-10]. Immunohistochemical studies have shown that GAED has focal expression of carcinoembryonic proteins, often positive for CD10, CDX-2, and MUC6, and negative for MUC2 and MUC5AC, suggesting a mixed gastrointestinal differentiation phenotype[11]. Histologically, GAED mostly presents as solid, tubular or papillary structures. Previous studies have suggested that it is more aggressive and associated with worse survival[12-15], but available evidence is relatively limited, and most published studies are small case series or case reports. Therefore, the clinicopathological features and prognostic significance of GAED, especially its differences from conventional gastric adenocarcinoma, remain unclear.
This study compared the clinicopathological features and survival outcomes of GAED patients and conventional gastric adenocarcinoma patients in a single-center cohort, aiming to clarify the unique characteristics and prognostic value of GAED, and provide more evidence for its clinical identification and management.
MATERIALS AND METHODS
Study design and patient screening
This retrospective study included patients who underwent radical gastrectomy for gastric cancer at our center from January 2015 to December 2024. After histopathological confirmation of subtypes, they were divided into GAED group and conventional gastric adenocarcinoma group, and neoadjuvant chemotherapy status was not considered for enrollment. Patients with distant metastasis at diagnosis, incomplete follow-up or missing survival data were excluded: A total of 2 GAED patients and 11 conventional gastric adenocarcinoma patients were excluded due to incomplete clinical data, and another 2 conventional gastric adenocarcinoma patients with liver metastasis at diagnosis who underwent surgery only for persistent tumor bleeding did not meet the inclusion criteria and were excluded. Finally, 81 GAED patients and 249 randomly selected conventional gastric adenocarcinoma patients were included, and the control group was selected at a ratio of approximately 1:3.
Clinical and pathological data
Demographic and clinical information were collected, including gender, age, smoking and drinking history, tumor location and size, histological type (Lauren classification, Borrmann classification), differentiation degree, Helicobacter pylori infection status, surgery-related information (surgical procedure, approach, duration), as well as pathological results such as T/N/M stage, margin status, lymph node involvement, perineural invasion, lymphovascular invasion, vascular tumor thrombus, and length of hospital stay and survival outcomes were also recorded. Tumor location was divided into three categories: Proximal (cardia, fundus, gastric body), distal (gastric antrum, pylorus), and whole stomach; the degree of differentiation was determined according to World Health Organization criteria, and tumor staging followed the 8th edition of American Joint Committee on Cancer criteria. Overall survival (OS) was defined as the time from surgery to death or the last follow-up, in months. Patients were followed up every 6 months by telephone and outpatient/inpatient medical records, and the median follow-up time of the entire cohort was 43 months (range: 1-65 months).
Statistical analysis
Normality test was performed for continuous variables. Data conforming to normal distribution were expressed as mean ± SD, and t-test was used for inter-group comparison; data not conforming to normal distribution were expressed as median and interquartile range, and Mann-Whitney U test was used. Categorical variables were compared between groups using χ2 test or Fisher’s exact test. Kaplan-Meier method was used to draw survival curves, and log-rank test was used for inter-group comparison. Variables associated with OS (P < 0.05) or with clinical significance in univariate Cox regression were included in the multivariate Cox model, and the results were expressed as hazard ratio (HR) and 95% confidence interval (CI). A two-sided P < 0.05 was defined as statistically significant, and all analyses were performed using R software (version 4.3.1).
RESULTS
Baseline characteristics
A total of 330 patients were included in Table 1, including 81 in the GAED group and 249 in the conventional gastric adenocarcinoma group. Compared with the conventional group, the GAED group had higher proportions of smoking history and drinking history, higher proportion of distal tumors, lower proportion of cross-site lesions, higher proportion of intestinal type in Lauren classification, lower proportion of signet ring cell features, different distribution of HER2 scores, shorter operation time, lower rates of perineural invasion and vascular tumor thrombus, but higher metastasis/recurrence rate, and the above differences were statistically significant. There were no significant differences between the two groups in gender, age, Helicobacter pylori infection status, tumor size, surgical approach, blood transfusion status, number of metastatic lymph nodes, number of dissected lymph nodes, Borrmann classification, linitis plastica, degree of differentiation, T stage, N stage, pTNM stage, lymphovascular invasion, vascular invasion, postoperative complications, and postoperative hospital stay.
Table 1 Baseline characteristics of patients with gastric adenocarcinoma with enteroblastic differentiation and conventional gastric adenocarcinoma, n (%).
Kaplan-Meier survival analysis showed a significant difference in OS between the two groups: OS of GAED patients was shorter than that of patients with conventional gastric cancer (log-rank test P = 0.029), and progression-free survival (PFS) showed a similar trend (log-rank test P = 0.022), as shown in Figure 1.
Figure 1 Kaplan-Meier survival analysis of overall survival and progression-free survival between gastric adenocarcinoma with enteroblastic differentiation group and gastric cancer.
A: Overall survival; B: Progression-free survival. GC: Gastric cancer; GAED: Gastric adenocarcinoma with enteroblastic differentiation.
Kaplan-Meier curves stratified by pathological TNM stage showed no significant difference in survival outcomes between the two groups for patients with stage I and stage II (Figure 2); however, among patients with stage III, OS and PFS of the GAED group were significantly worse than those of the conventional gastric adenocarcinoma group, suggesting that the prognostic disadvantage of GAED is more obvious with the increase of stage.
Figure 2 Kaplan-Meier survival analysis of overall survival and progression-free survival between gastric adenocarcinoma with enteroblastic differentiation group and gastric cancer across different tumor-node-metastasis stages.
A and B: Tumor-node-metastasis (TNM) stage I; C and D: TNM stage II; E and F: TNM stage III. GC: Gastric cancer; GAED: Gastric adenocarcinoma with enteroblastic differentiation.
Analysis
Multivariate logistic regression analysis in Table 2 showed that compared with Helicobacter pylori-negative patients, positive patients had a lower risk of postoperative complications [odds ratio (OR) = 0.402, 95%CI: 0.208-0.779, P = 0.006]; compared with proximal tumors, distal tumors had a lower risk of postoperative complications (OR = 0.288, 95%CI: 0.128-0.647, P = 0.003), that is, negative Helicobacter pylori and proximal tumor location were independent factors associated with increased risk of postoperative complications.
Table 2 Univariate and multivariate complications logistic regression of gastric cancer with or without enteroblastic differentiation in China National Cancer Center.
Multivariate Cox regression analysis in Table 3 confirmed that GAED was still an independent prognostic factor for OS and PFS (OS: HR = 1.714, 95%CI: 1.207-2.435, P = 0.012; PFS: HR = 1.823, 95%CI 1.287-5.596, P = 0.005, Table 3). Supplementary Table 1 shows that negative Helicobacter pylori, larger tumor volume, and later pathological stage were independent predictors of worse OS, and better differentiation was associated with better OS (HR = 0.465, 95%CI: 0.305-0.709, P = 0.003). Except for Helicobacter pylori status, factors associated with PFS were consistent with those for OS (Supplementary Table 2): Larger tumor volume and later pathological stage were independently associated with worse PFS, and better differentiation was associated with better PFS (HR = 0.504, 95%CI: 0.332-0.766, P = 0.007). The remaining clinicopathological variables were not significantly associated with survival outcomes (all P > 0.05).
Table 3 Univariate and multivariate survival analysis between gastric adenocarcinoma with enteroblastic differentiation group and gastric cancer group in total patients.
Further univariate and multivariate Cox regression analysis was performed for GAED patients, and the results are shown in Supplementary Table 3: Histological subtype and TNM stage were independent factors associated with OS, later TNM stage was associated with worse OS (HR = 6.089, 95%CI: 1.637-22.646, P = 0.023), and better differentiation was associated with better OS (HR = 0.473, 95%CI: 0.255-0.876, P = 0.046). Supplementary Table 4 shows that vascular tumor thrombus was an independent factor associated with worse PFS in GAED patients (HR = 3.381, 95%CI: 1.279-8.940, P = 0.039).
Univariate and multivariate analyses showed differences in prognostic patterns among different pathological TNM stages (Table 4 and Supplementary Tables 5-10): Among patients with stage III, GAED was still an independent prognostic factor for OS (HR = 1.845, 95%CI: 1.219-2.997, P = 0.042) and PFS (HR = 1.640, 95%CI: 1.034-2.879, P = 0.048), while larger tumor volume was associated with worse OS, and better differentiation was associated with better OS; among patients with stage I, both OS and PFS were significantly associated with negative Helicobacter pylori and surgical approach; among patients with stage II, tumors distributed across gastric regions had significantly better OS and PFS than proximal tumors.
Table 4 Univariate and multivariate survival analysis between gastric adenocarcinoma with enteroblastic differentiation group and gastric cancer group in pTNM I-III patients.
This study compared the clinical features of GAED patients and conventional gastric adenocarcinoma patients. Although GAED is relatively rare, the results suggest that it has a worse prognosis and is an independent adverse prognostic factor. Most GAED patients have Lauren intestinal type, lesions located in the distal stomach, and the distribution of HER2 scores is different from that of conventional adenocarcinoma; despite lower incidence rates of perineural invasion and vascular tumor thrombus, the survival outcome is worse, and this difference is particularly obvious in patients with stage III, while there is no significant difference in survival between the two groups for patients with stage II.
In recent years, GAED has received extensive attention due to its unique morphological characteristics and embryonic marker expression, but available evidence is still limited, and most published studies are small case series or case reports[16-18]. This study adopted a retrospective design, but it directly compares GAED with conventional gastric adenocarcinoma in a relatively large clinical cohort, which provides a supplement to existing research.
The biological differences of GAED are worthy of attention: The proportion of Lauren classification and the distribution of HER2 scores of GAED in this cohort are significantly different from those of conventional gastric adenocarcinoma, suggesting that it not only has a different morphology from conventional gastric cancer, but also has differences in potential occurrence and development pathways. There are currently two hypotheses about its pathogenesis: One holds that GAED is a terminal phenotypic transition during tumor progression, especially in mucinous adenocarcinoma, where tumor cells acquire stem cell-like characteristics and gradually replace traditional glandular components[14,17,19,20]; the other holds that GAED arises primarily from transformed mucosa without clear adenocarcinoma transition components, suggesting that its tumorigenesis pathway is independent of the classic gastric cancer tumorigenesis pathway[21]. In this cohort, the incidence rates of perineural invasion and vascular tumor thrombus of GAED were lower, but this did not translate into a better prognosis; instead, the risk of metastasis/recurrence was higher and OS was worse, suggesting that traditional local invasive pathological indicators cannot fully reflect the invasiveness of GAED. A possible explanation is that GAED has a unique biological phenotype, and even if classic adverse pathological features are not obvious, there is a tendency for early systemic dissemination, treatment resistance or higher hematogenous metastasis; its embryonic differentiation phenotype also suggests that the tumor is in a more primitive and more aggressive state, which can lead to adverse survival independent of perineural invasion and vascular tumor thrombus, so the adverse outcome of GAED is more driven by underlying tumor biological characteristics rather than the incidence of traditional local invasive features[22]. Emerging molecular evidence suggests that TP53 alterations may be involved in the pathogenesis of GAED. Yatagai et al[23] proposed that hypermethylation of the TP53 promoter may lead to loss of p53 expression in some cases, and epigenetic abnormalities such as abnormal methylation of TET1 and reduced overall 5-hydroxymethylcytosine levels may also be involved in tumorigenesis, which are associated with the aggressive behavior of GAED; in addition, Yatagai et al[24] reported that reduced SMAD4 expression is associated with later stage, larger tumor size and lymph node metastasis of GAED, further supporting its association with adverse clinicopathological features. Both Kaplan-Meier analysis and multivariate model in this study confirmed that GAED patients have a significant survival disadvantage. Available evidence suggests that unique tumor microenvironment, altered signaling pathway activity, and immune-related mechanisms may jointly contribute to the aggressive clinicopathological behavior of GAED[25-28].
This study found that surgical approach is also associated with survival, and patients who underwent laparoscopic or minimally invasive surgery have better prognosis. This correlation may be partly due to case selection bias: Usually patients with smaller tumors and earlier stages are more suitable for minimally invasive surgery, and the lower intraoperative blood loss in this group is also consistent with this explanation, but it cannot be ruled out that the surgical strategy itself will affect the long-term outcome of high-risk tumors such as GAED, which needs to be verified by further studies.
Clinically, the results of this study support that GAED should not be regarded as an ordinary histological variant. It has independent prognostic significance, and its unique clinicopathological features and worse survival suggest that more careful management of such patients is required, and more active staging, closer follow-up, and individualized adjuvant therapy may benefit these patients[29-32].
There are several limitations in this study: First, it adopts a retrospective design. Although the collection span of GAED cases is 6 years, the sample size is still relatively small. Second, not all cases were routinely tested for immunohistochemical markers such as SALL4, alpha-fetoprotein, and glypican-3, which may lead to missed diagnosis of some GAED cases. Third, due to the lack of molecular data, it is impossible to further explore the genetic and epigenetic differences between GAED and traditional gastric adenocarcinoma. In addition, excluding patients with missing key data may introduce selection bias, but the number of excluded cases is small; standardized nutritional assessment data such as the 2002 edition of Nutritional Risk Screening were not routinely collected and cannot be included in the analysis. Finally, postoperative complications were only recorded as binary outcomes without detailed subclassification or Clavien-Dindo grading, which limits further evaluation of the type and severity of complications.
Despite the above limitations, after adjusting for clinicopathological confounding factors, multivariable Cox proportional hazards regression analysis still confirmed that GAED is an independent adverse prognostic factor. The results of this study highlight the clinical importance of identifying GAED as an independent gastric cancer subtype, and further multicenter studies including molecular feature analysis are needed to better clarify its biological characteristics and optimize patient management.
CONCLUSION
GAED is a special subtype of gastric adenocarcinoma with unique clinicopathological features and worse survival outcomes. It is an independent adverse prognostic factor after radical gastrectomy, so closer follow-up and more individualized management should be carried out for patients.
ACKNOWLEDGEMENTS
We acknowledge all the authors whose publications are referred in our article.
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