Published online Nov 15, 2026. doi: 10.4251/wjgo.122992
Revised: June 15, 2026
Accepted: July 15, 2026
Published online: November 15, 2026
Processing time: 180 Days and 15.1 Hours
Direct gastric invasion in esophageal squamous cell carcinoma (ESCC) is uncommon, and its clinical significance remains poorly characterized.
To investigate the clinicopathological characteristics and prognostic impact of direct gastric invasion in ESCC.
A retrospective analysis was conducted using a prospectively established single-center ESCC cohort including 398 patients enrolled between 2011 and 2020. Direct gastric invasion was defined as continuous tumor extension across the gastroesophageal junction on endoscopy. Treatment allocation was determined by a multidisciplinary team based on disease stage and patient condition. Survival outcomes were assessed using Kaplan-Meier analysis and Cox proportional hazards regression models.
Among the 398 patients with ESCC, 23 (5.8%) had direct gastric invasion, which was associated with advanced-stage disease, a high rate of lymph node metastasis (95%), and poor survival. The median overall survival was 10.6 months. Patients who underwent chemoradiotherapy (CRT) followed by surgery had the longest survival (12.6 months), compared with CRT alone (8.6 months) or best supportive care (1.7 months). In patients with lower-third ESCC, gastric invasion was associated with significantly worse survival. Multivariable Cox regression analysis identified gastric invasion as an independent predictor of poor survival (hazard ratio = 2.2, P = 0.01).
Direct gastric invasion in ESCC is associated with poor prognosis. Although CRT followed by surgery was associated with improved survival in this cohort, the observed differences across treatment modalities should be interpreted cautiously owing to potential selection bias.
Core Tip: Direct gastric invasion is a rare but clinically important manifestation of esophageal squamous cell carcinoma (ESCC). In our cohort, patients with direct gastric invasion of ESCC typically presented with advanced-stage disease and experienced significantly poorer survival than those without gastric invasion. Although patients treated with chemoradiotherapy followed by surgery demonstrated longer survival, this finding should be interpreted cautiously because of the small sample size and potential treatment selection bias. Overall, our results suggest that direct gastric invasion may serve as a marker of poor prognosis and warrants further investigation in larger prospective studies.
- Citation: Wang YK, Shen CS, Yu FJ, Chen YH, Chen WC, Lee JY, Wu MT, Wu IC. Direct gastric invasion is associated with poor prognosis in esophageal squamous cell carcinoma involving the lower-third esophagus. World J Gastrointest Oncol 2026; 18(11): 122992
- URL: https://www.wjgnet.com/1948-5204/full/v18/i11/122992.htm
- DOI: https://dx.doi.org/10.4251/wjgo.122992
Esophageal cancer remains a major global health burden and is the sixth leading cause of cancer-related mortality worldwide[1]. Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype in Asia and is frequently diagnosed at advanced stages, contributing to its poor prognosis[1-3]. ESCC is characterized by rapid progression, direct invasion of adjacent organs, and a high frequency of lymph node metastasis at a very early stage, all of which are important factors that cause poor prognosis[4,5].
Nearly half of ESCC cases occur in the middle third of the esophagus (49%), while the lower third is the second most common location (40%)[6]. Although the esophagus is anatomically contiguous with the stomach, gastric involvement in ESCC is relatively uncommon. Previous studies have reported an incidence of 1%-8% and have shown that gastric involvement is associated with poorer outcomes[7-9]. Based on the limited available data, the reported mean survival time for patients with ESCC with gastric involvement ranges from 5.6 months to 12.5 months, with a 1-year survival rate of approximately 26%-40%[7,8,10].
According to the current American Joint Committee on Cancer (AJCC) staging system, T4 disease is defined as tumor invasion into adjacent structures; however, the stomach is not included among these structures. Therefore, whether gastric invasion represents a distinct prognostic entity or simply reflects more advanced local disease extension remains unclear. Direct gastric invasion may represent a particularly aggressive pattern of local tumor extension, and while the biological mechanisms remain poorly understood, alterations in tumor-stromal interactions, extracellular matrix remodeling, epithelial–mesenchymal transition, and tumor microenvironmental factors have all been implicated in the invasive behavior of ESCC[2].
Previous studies have described several patterns of gastric involvement in ESCC, including direct invasion, intramural metastasis, intraepithelial spread, and lymphatic extension. In a case series of 32 patients with ESCC and gastric involvement, direct invasion of the gastric wall by the primary tumor was the most common pattern, accounting for 37.5% of cases[8]. Although this is the most frequently observed representation, its clinical significance remains unclear because it has been insufficiently investigated. Owing to its rarity, evidence regarding optimal treatment strategies for ESCC with direct gastric invasion remains extremely limited.
Previous studies have primarily focused on the clinicopathological characteristics, patterns of gastric involvement, and survival outcomes of ESCC with gastric invasion, whereas detailed comparisons of different treatment modalities have been performed rarely. Most available reports consist of small case series or retrospective studies with heterogeneous treatment approaches, making it difficult to draw meaningful conclusions regarding treatment efficacy. Consequently, whether multimodality treatment, including chemoradiotherapy (CRT) followed by surgery, provides additional survival benefits in this patient population remains unclear[7-10].
In this study, we investigated the clinicopathological characteristics and survival outcomes of patients with ESCC and direct gastric invasion in a prospectively established cohort. To reduce heterogeneity related to tumor location, we restricted our analysis to patients with tumors involving the lower third of the esophagus, in whom direct gastric invasion is more likely to occur. Furthermore, to evaluate differences in outcomes across treatment modalities, we focused on patients receiving standard treatments, including CRT alone and CRT followed by surgery.
A prospective, incident-driven cohort of patients with pathologically confirmed ESCC has been established at Kaohsiung Medical University Hospital (KMUH) since October 2011[11]. In the present study, we conducted a retrospective analysis using data derived from this cohort, in which all patients had undergone esophagogastroduodenoscopy. By December 2020, a total of 398 patients with newly diagnosed ESCC had been enrolled. For the primary analysis, we included patients with tumors involving the lower third of the esophagus to reduce anatomical heterogeneity (Figure 1). Direct gastric invasion was defined by endoscopic findings of continuous tumor extension from the esophagus across the gastroesophageal junction into the stomach, reflecting routine endoscopic assessment in clinical practice. Patients were excluded if they met any of the following criteria: (1) Presence of gastric metastasis, as metastatic lesions could be distinguished clearly from the primary esophageal tumor; (2) Regional lymph node metastasis with secondary gastric involvement; or (3) Concurrent malignancies. This study was approved by the Institutional Review Board of KMUH, No. KMUHIRB-E(II)-20220189.
Demographic data were collected using a standardized questionnaire, and clinicopathological information was extracted from medical records. Variables included age, sex, history of substance use, tumor length, histological differentiation, clinical stage, Eastern Cooperative Oncology Group (ECOG) performance status, nutritional status as assessed by serum albumin level, and treatment modality. Cigarette smoking was defined as smoking at least 10 cigarettes per week for a minimum of 1 year; alcohol consumption was defined as intake of any alcoholic beverage at least once per week for a minimum of 1 year; and betel nut chewing was defined as consumption of at least one areca nut per day for a minimum of 1 year. Tumor length was defined as the maximum tumor extent measured on computed tomography (CT). Clinical stage was determined according to the seventh or eighth edition of the AJCC staging system, depending on the year of diagnosis.
Treatment strategies for patients with ESCC were determined by a multidisciplinary team at KMUH, including gastroenterologists, medical oncologists, thoracic surgeons, radiation oncologists, radiologists, pathologists, and specialist nurses. Eligible patients with locally advanced disease underwent CRT followed by surgery. Patients with unresectable tumors received CRT, chemotherapy alone, radiotherapy alone, or best supportive care, depending on clinical stage and performance status.
Chemotherapy regimens and radiotherapy protocols were based on National Comprehensive Cancer Network guidelines[12-14]. In accordance with Taiwan’s National Health Insurance reimbursement policy, most patients received a cisplatin plus 5-fluorouracil regimen. Cisplatin (75 mg/m2) was administered on day 1 with standard hydration and antiemetic support, followed by continuous intravenous infusion of 5-fluorouracil (1000 mg/m2/day) on days 1-4, with treatment cycles being repeated every 4 weeks. Radiotherapy was delivered concurrently with chemotherapy in patients receiving CRT, 5 days per week at 2 Gy per fraction for a total dose of 50 Gy. Surgery was performed 6-8 weeks after completion of CRT in patients who were considered medically fit for surgical intervention.
Patients were followed up at our institution every 2 weeks to 3 months during and after treatment. Follow-up evaluations included physical examination, serum biochemical testing, chest CT, and esophagogastroduodenoscopy performed at regular outpatient visits every 3 months during the first 2 years. Overall survival was defined as the interval between the date of ESCC diagnosis and death from any cause. Patients who were alive at the last follow-up were censored, and survival data were collected through May 2021.
Categorical and continuous variables were compared using the χ2 test and the Mann-Whitney U test, as appropriate. Survival outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards regression models were used to estimate hazard ratio (HR) and 95% confidence interval (CI) for prognostic factors. All statistical tests were two-sided, and a P value < 0.05 was considered statistically significant. Statistical analyses were performed using STATA version 15 (StataCorp LLC, College Station, TX, United States).
A total of 23 patients (5.8%, 23/398) had direct gastric invasion from the primary tumor. Among patients with tumors involving the lower third of the esophagus, the incidence of gastric invasion was 9.2% (23/250). The mean patient age was 58.7 years, and the majority of patients were male (96%). Most patients had relatively preserved nutritional status (mean serum albumin level was 3.9 g/dL) and good performance status, with 83% having an ECOG score of 0 or 1. Approximately 90% of patients had a history of cigarette smoking and alcohol consumption. The median tumor length was 9.0 (interquartile range: 7.0-11.7) cm. Poorly differentiated histology was observed in 35% of patients, and most primary tumors (78%) were confined to the lower third of the esophagus. At initial diagnosis, 91% of patients had advanced-stage disease (stage III or IV), including 65% with T3 tumors, 95% with regional lymph node metastasis, and 26% with distant metastasis. Among the 23 patients with gastric invasion, 15 received CRT, 5 underwent CRT followed by surgery, and 3 received best supportive care (Table 1).
| Variable | n (%) |
| Age in years (mean ± SD) | 58.7 ± 9.3 |
| Sex | |
| Male | 22 (95.7) |
| Female | 1 (4.3) |
| Smoking | 20 (87.0) |
| Alcohol consumption | 22 (95.7) |
| Betel nut chewing | 14 (60.9) |
| T category | |
| T2 | 1 (4.3) |
| T3 | 15 (65.2) |
| T4a | 2 (8.7) |
| T4b | 5 (21.7) |
| N category | |
| N0 | 1 (4.3) |
| N1 | 8 (34.8) |
| N2 | 4 (17.4) |
| N3 | 10 (43.5) |
| M category | |
| M0 | 17 (73.9) |
| M1 | 6 (26.1) |
| Clinical stage | |
| II | 2 (8.7) |
| III | 10 (43.5) |
| IV | 11 (47.8) |
| Histological differentiation | |
| Grade 2, moderately differentiated | 15 (65.2) |
| Grade 3, poorly differentiated | 8 (34.8) |
| Tumor location | |
| Upper to lower third of the esophagus | 1 (4.3) |
| Middle to lower third of the esophagus | 4 (17.4) |
| Lower third of the esophagus | 18 (78.3) |
| Tumor length in cm (median, IQR) | 9.0 (7.0-11.7) |
| Serum albumin in g/dL (mean ± SD) | 3.9 ± 0.5 |
| ECOG performance status | |
| 0 | 2 (8.7) |
| 1 | 17 (73.9) |
| 2 | 4 (17.4) |
| Treatment | |
| CRT | 15 (65.2) |
| CRT followed by surgery | 5 (21.7) |
| Best supportive care | 3 (13.0) |
The median follow-up duration was 7.4 months. The mean and median overall survival times were 8.9 months and 10.6 months, respectively. In univariable Cox regression analysis, ECOG performance status and treatment modality were significantly associated with overall survival in patients with ESCC and gastric invasion. Better performance status and receipt of CRT or CRT followed by surgery were associated with more favorable survival outcomes. After adjustment for age, sex, clinical stage, and treatment modality, poor performance status, the presence of distant metastasis, and receipt of best supportive care remained associated with worse survival outcomes. Compared with best supportive care, both CRT followed by surgery and CRT alone were associated with longer survival (Table 2).
| Univariable | Multivariable1 | Multivariable2 | ||||
| Variable | HR (95%CI) | P value | HR (95%CI) | P value | HR (95%CI) | P value |
| Age in years | ||||||
| < 58.1 | 1 | 1 | 1 | |||
| ≥ 58.1 | 1.13 (0.4-2.9) | 0.76 | 1.3 (0.4-4.4) | 0.68 | 0.65 (0.2-2.2) | 0.48 |
| Sex | ||||||
| Female | 1 | 1 | 1 | |||
| Male | 0.68 (0.1-5.4) | 0.71 | 0.1 (0.00-1.8) | 0.12 | 0.2 (0.01-3.7) | 0.26 |
| Clinical stage | ||||||
| II | 1 | 1 | - | |||
| III | 1.4 (0.2-11.1) | 0.78 | 2.2 (0.2-24.6) | 0.53 | - | |
| IV | 1.4 (0.2-11.2) | 0.77 | 1.4 (0.2-12.4) | 0.78 | - | |
| ECOG performance status | ||||||
| 0-1 | 1 | 1 | 1 | |||
| 2 | 18.8 (3.3-107.4) | < 0.01 | 16.6 (2.7-103.4) | < 0.01 | 27.2 (3.1-237.2) | < 0.01 |
| T category | ||||||
| T2 | 1 | - | 1 | |||
| T3-T4 | 1.2 (0.1-8.9) | 0.89 | - | 0.9 (0.1-12.6) | 0.94 | |
| N category | ||||||
| N0-N1 | 1 | - | 1 | |||
| N2-N3 | 0.4 (0.1-1.2) | 0.11 | - | 0.5 (0.1-2.2) | 0.39 | |
| M category | ||||||
| M0 | 1 | - | 1 | |||
| M1 | 2.1 (0.8-5.8) | 0.16 | - | 2.9 (0.6-13.5) | 0.17 | |
| Treatment modality | ||||||
| Best supportive care | 1 | 1 | 1 | |||
| CRT | 0.3 (0.1-1.7) | 0.18 | 0.3 (0.04-1.6) | 0.15 | 0.11 (0.01-1.05) | 0.06 |
| CRT followed by surgery | 0.1 (0.02-0.7) | 0.02 | 0.03 (0.00-0.5) | 0.02 | 0.03 (0.002-0.6) | 0.02 |
When patients were stratified by treatment modality, overall survival differed significantly among the treatment groups (log-rank test, P = 0.02), with the longest survival observed in patients who underwent CRT followed by surgery (Figure 2). The median overall survival times were 12.6 months, 8.6 months, and 1.7 months for patients who received CRT followed by surgery, CRT alone, and best supportive care, respectively.
To compare overall survival between patients with ESCC with and without direct gastric invasion under comparable treatment conditions, we analyzed 176 patients with tumors involving the lower third of the esophagus who received CRT or CRT followed by surgery. Patients who received best supportive care, chemotherapy alone, radiotherapy alone, endoscopic submucosal dissection, or surgery alone were excluded (Figure 1). Among these 176 patients, baseline characteristics, including demographic features, clinical stage, renal function, nutritional status, performance status, and treatment modality, were comparable between patients with and without gastric invasion (Table 3). Kaplan-Meier analysis demonstrated that patients with direct gastric invasion had significantly worse overall survival than those without gastric invasion (log-rank test, P = 0.001; Figure 3A). The 2-year overall survival rate was 9.7% in patients with gastric invasion, compared with 44.1% in those without gastric invasion. The median overall survival was 12.2 months in patients with gastric invasion and 18.4 months in those without gastric invasion.
| Variable | With gastric invasion (n = 20) | Without gastric invasion (n = 156) | P value |
| Age in years (mean ± SD) | 58.2 ± 8.7 | 57.3 ± 8.3 | 0.65 |
| < 57.3 | 10 (50.0) | 75 (48.1) | 0.87 |
| ≥ 57.2 | 10 (50.0) | 81 (51.9) | |
| Sex | 0.58 | ||
| Male | 19 (95.0) | 150 (96.2) | |
| Female | 1 (5.0) | 6 (3.8) | |
| T category | 0.31 | ||
| T2 | 1 (5.0) | 23 (14.7) | |
| T3 | 13 (65) | 94 (60.3) | |
| T4a | 2 (10.0) | 5 (3.2) | |
| T4b | 4 (20.0) | 34 (21.8) | |
| N category | |||
| N0 | 1 (5.0) | 16 (10.3) | 0.11 |
| N1 | 8 (40.0) | 50 (32.1) | |
| N2 | 4 (20.0) | 64 (41.0) | |
| N3 | 7 (35.0) | 26 (16.7) | |
| M category | |||
| M0 | 15 (75.0) | 137 (87.8) | 0.16 |
| M1 | 5 (25.0) | 19 (12.2) | |
| Clinical stage | 0.27 | ||
| I | 0 (0.0) | 1 (0.6) | |
| II | 2 (10.0) | 16 (10.3) | |
| III | 9 (45.0) | 99 (63.5) | |
| IV | 9 (45.0) | 40 (25.6) | |
| Histological grade | 0.41 | ||
| Grade 1, well differentiated | 0 (0.0) | 9 (5.8) | |
| Grade 2, moderately differentiated | 14 (70.0) | 105 (67.3) | |
| Grade 3, poorly differentiated | 6 (30.0) | 31 (19.9) | |
| Missing | 0 (0.0) | 11 (7.1) | |
| Tumor location | 0.001 | ||
| Upper to lower third of the esophagus | 0 (0.0) | 18 (11.5) | |
| Middle to lower third of the esophagus | 3 (15.0) | 74 (47.4) | |
| Lower third of the esophagus | 17 (85.0) | 64 (41.0) | |
| Tumor length, cm (median, IQR) | 7.1 (6.3-10.8) | 7.1 (5.0-10.0) | 0.41 |
| Baseline renal function | > 0.99 | ||
| eGFR < 60 mL/minutes | 3 (15.0) | 28 (17.9) | |
| eGFR ≥ 60 mL/minutes | 17 (85.0) | 128 (82.1) | |
| Serum albumin, g/dL (mean ± SD) | 3.9 ± 0.5 | 4.0 ± 0.5 | 0.69 |
| ECOG performance status | 0.08 | ||
| 0 | 2 (10.0) | 24 (15.4) | |
| 1 | 15 (75.0) | 127 (81.4) | |
| 2 | 3 (15.0) | 5 (3.2) | |
| Treatment modality | 0.24 | ||
| CRT | 15 (75.0) | 96 (61.5) | |
| CRT followed by surgery | 5 (25.0) | 60 (38.5) |
A global comparison among the four groups demonstrated significant differences in overall survival (log-rank test, P < 0.001; Figure 3B). Pairwise comparisons within both the CRT and CRT-followed-by-surgery groups also showed significantly worse survival among patients with gastric invasion (both P < 0.01). In the CRT-followed-by-surgery group, patients without gastric invasion had longer median overall survival compared with those with gastric invasion (42.0 months vs 17.4 months). In the CRT group, the median overall survival was 12.1 months in patients without gastric invasion and 7.4 months in those with gastric invasion.
In Cox regression analysis, direct gastric invasion was associated with worse overall survival in the univariable model (HR = 2.5, 95%CI: 1.4-4.4). After adjustment for age, sex, clinical stage, ECOG performance status, and treatment modality, gastric invasion remained independently associated with poorer survival (HR = 2.2, 95%CI: 1.2-3.9). Among patients with ESCC involving the lower third of the esophagus, those who underwent CRT followed by surgery had longer survival compared with those who received CRT alone (Table 4).
| Univariable | Multivariable1 | Multivariable2 | ||||
| Variable | HR (95%CI) | P value | HR (95%CI) | P value | HR (95%CI) | P value |
| Gastric invasion | ||||||
| No | 1 | 1 | 1 | |||
| Yes | 2.5 (1.4-4.4) | 0.001 | 2.2 (1.2-3.9) | 0.01 | 1.9 (1.0-3.7) | 0.04 |
| Age in years | ||||||
| < 57.3 | 1 | 1 | 1 | |||
| ≥ 57.3 | 1.1 (0.8-1.6) | 0.53 | 0.8 (0.5-1.2) | 0.25 | 0.8 (0.5-1.2) | 0.21 |
| Sex | ||||||
| Female | 1 | 1 | 1 | |||
| Male | 1.1 (0.4-2.9) | 0.92 | 0.6 (0.2-1.6) | 0.32 | 0.7 (0.2-1.8) | 0.41 |
| Clinical stage | ||||||
| I-II | 1 | 1 | - | |||
| III | 1.1 (0.5-2.2) | 0.82 | 1.2 (0.6-2.5) | 0.58 | - | |
| IV | 2.2 (1.1-4.7) | 0.03 | 1.7 (0.8-3.7) | 0.15 | - | |
| Treatment | ||||||
| CRT | 1 | 1 | 1 | |||
| CRT followed by surgery | 0.3 (0.2-0.5) | < 0.001 | 0.3 (0.2-0.5) | 0.01 | 0.3 (0.2-0.5) | < 0.001 |
| ECOG performance status | ||||||
| 0 | 1 | 1 | 1 | |||
| 1 | 1.0 (0.6-1.9) | 0.89 | 1.0 (0.5-2.0) | 0.95 | 0.9 (0.4-1.8) | 0.71 |
| 2 | 2.3 (0.9-6.2) | 0.09 | 1.8 (0.6-5.1) | 0.27 | 1.6 (0.5-4.6) | 0.43 |
| T category | ||||||
| T2 | 1 | - | 1 | |||
| T3 | 0.8 (0.5-1.5) | 0.60 | - | 1.2 (0.6-2.6) | 0.62 | |
| T4 | 1.7 (0.9-3.2) | 0.08 | - | 1.5 (0.7-3.0) | 0.27 | |
| N category | ||||||
| N0 | 1 | - | 1 | |||
| N1 | 1.4 (0.7-2.8) | 0.35 | - | 1.3 (0.6-2.8) | 0.55 | |
| N2 | 1.1 (0.5-2.3) | 0.77 | - | 1.0 (0.4-2.1) | 0.95 | |
| N3 | 1.4 (0.6-3.1) | 0.41 | - | 1.0 (0.4-2.3) | > 0.99 | |
| M category | ||||||
| M0 | 1 | - | 1 | |||
| M1 | 3.0 (1.8-4.9) | < 0.001 | - | 1.7 (0.9-2.9) | 0.06 | |
A total of 65 patients with ESCC involving the lower third of the esophagus underwent surgery following CRT. The types of surgical procedures performed following CRT are summarized in Table 5. Pathological examination of surgical specimens from these 65 patients revealed no residual squamous cell carcinoma in the gastric portion of the resected specimens.
| Type of surgery | With gastric invasion (n = 5) | Without gastric invasion (n = 60) |
| Esophagectomy with proximal gastrectomy | 2 (40.0) | 32 (53.3) |
| Video-assisted thoracoscopic esophagectomy with proximal gastrectomy | 1 (20.0) | 19 (31.7) |
| Robot-assisted esophagectomy with proximal gastrectomy | 2 (40.0) | 9 (15.0) |
ESCC with direct gastric invasion is an uncommon condition, and its clinical significance has not been well investigated. Previous studies have primarily focused on gastric metastasis as the most commonly reported form of gastric involvement in ESCC[7-10]. Other patterns of gastric involvement include lymph node metastasis, intraepithelial spread, and direct invasion[8]. The reported incidence of gastric involvement in ESCC ranges from 1% to 8%[7-9]. Kuwano et al[8] reported that 12 of 402 patients (3%) who underwent esophageal resection had direct invasion of the gastric wall, representing the most common pattern of gastric involvement in their cohort. In the present study, 23 patients of 398 patients (5.8%) were identified as having direct gastric invasion. The relatively higher incidence observed in our cohort may be attributable to the use of endoscopic assessment, which may detect gastric invasion more sensitively than surgical findings alone, as not all patients underwent surgery.
In our cohort, tumors in 23 patients with ESCC and direct gastric invasion were predominantly located in the lower third of the esophagus. The median tumor length was 9.0 (range: 7.0-11.7) cm. Previous studies have similarly reported that ESCC tumors with gastric involvement are generally located in the lower third of the esophagus and exhibit variable tumor lengths ranging from 3 cm to > 10 cm[7-9]. Consistent with our findings, two previous studies demonstrated that histological differentiation (well, moderately, or poorly differentiated) was not significantly associated with gastric involvement[7,9]. In our study, the most common T stage at initial diagnosis among patients with direct gastric invasion was T3 (65%). Similarly, Ebihara et al[9] reported that 62% of patients with ESCC and gastric intramural metastasis were diagnosed at the T3 stage. These findings suggest that ESCC with gastric involvement tends to present at an advanced stage. Furthermore, lymph node metastasis was observed in 95% of patients with direct gastric invasion in our cohort. Previous studies have reported lymph node involvement in 75%-100% of patients with ESCC and gastric involvement at diagnosis[7-9].
Poor survival among patients with ESCC and gastric involvement has been reported in previous studies, with mean survival times ranging from 1 month to 13 months[7-10]. Kuwano et al[8] reported that, among 12 patients with ESCC and direct gastric invasion, the mean and median survival times were 14.3 months and 9.5 months, respectively; however, a wide range of survival durations (2-78 months) was observed in that study. In our study, the mean and median overall survival times among the 23 patients with direct gastric invasion were 8.9 months and 10.6 months, respectively. Notably, ECOG performance status and treatment modality were significantly associated with survival outcomes. Patients who underwent CRT followed by surgery had longer survival compared with those who received CRT alone or best supportive care (Table 2).
To minimize the potential influence of treatment modality, we analyzed a subgroup of 176 patients with ESCC involving the lower third of the esophagus who received CRT alone or CRT followed by surgery. Patients without gastric invasion served as the reference group to evaluate the association between direct gastric invasion and survival outcomes. After stratification by treatment modality, direct gastric invasion remained associated with worse survival in both CRT and CRT-followed-by-surgery groups (Figure 3B).
Owing to the rarity of this condition, the optimal treatment strategy for ESCC with direct gastric invasion has not been well established. Previous studies have demonstrated various treatment approaches, including surgery, chemotherapy, radiotherapy, and CRT but have lacked comprehensive statistical analyses[7-10]. In our cohort, the majority of patients received CRT (61%), whereas 26% underwent CRT followed by surgery. Patients who underwent CRT followed by surgery had longer survival compared with those who received CRT alone or best supportive care (Table 2 and Figure 2). Baseline demographic and clinical characteristics were generally comparable across treatment groups (Table 6); however, treatment selection appeared to be influenced by clinical factors, particularly disease stage and performance status. Notably, CRT followed by surgery was performed only in patients with good performance status and no evidence of distant metastasis. Direct gastric invasion does not appear to preclude surgical intervention in appropriately selected patients; furthermore, no residual squamous cell carcinoma was identified in the gastric portion of resected specimens. Although this finding may suggest a favorable local response to treatment, its clinical significance remains uncertain given the small sample size and the retrospective nature of the study.
| Variable | CRT (n = 15) | CRT followed by surgery | Supportive care (n = 3) | P value |
| Age in years (mean ± SD) | 58.5 ± 9.9 | 57.2 ± 4.3 | 62.2 ± 14.1 | 0.65 |
| < 58.1 | 7 (46.7) | 3 (60.0) | 1 (33.3) | > 0.99 |
| ≥ 58.1 | 8 (53.3) | 2 (40.0) | 2 (66.7) | |
| Sex | 0.35 | |||
| Male | 15 (100.0) | 4 (80.0) | 3 (100.0) | |
| Female | 0 (0.0) | 1 (20.0) | 0 (0.0) | |
| T category | 0.70 | |||
| T2 | 1 (6.7) | 0 (0.0) | 0 (0.0) | |
| T3 | 8 (53.3) | 5 (100.0) | 2 (66.7) | |
| T4a | 2 (13.3) | 0 (0.0) | 0 (0.0) | |
| T4b | 4 (26.7) | 0 (0.0) | 1 (33.3) | |
| N category | 0.07 | |||
| N0 | 1 (6.7) | 0 (0.0) | 0 (0.0) | |
| N1 | 7 (46.7) | 1 (20.0) | 0 (0.0) | |
| N2 | 1 (6.7) | 3 (60.0) | 0 (0.0) | |
| N3 | 6 (40.0) | 2 (20.0) | 3 (100.0) | |
| M category | 0.38 | |||
| M0 | 10 (66.7) | 5 (100.0) | 2 (66.7) | |
| M1 | 5 (33.3) | 0 (0.0) | 1 (33.3) | |
| Clinical stage | 0.49 | |||
| II | 2 (13.3) | 0 (0.0) | 0 (0.0) | |
| III | 5 (33.3) | 4 (80.0) | 1 (33.3) | |
| IV | 8 (53.3) | 1 (20.0) | 2 (66.7) | |
| Histological grade | 0.32 | |||
| Grade 2, moderately differentiated | 10 (66.7) | 4 (80.0) | 1 (33.3) | |
| Grade 3, poorly differentiated | 5 (33.3) | 1 (20.0) | 2 (66.7) | |
| Tumor location | 0.14 | |||
| Upper to lower or middle to lower third of the esophagus | 3 (20.0) | 0 (0.0) | 2 (66.7) | |
| Lower third of the esophagus | 12 (80.0) | 5 (100.0) | 1 (33.3) | |
| Tumor length, cm (median, IQR) | 9.0 (7.0–11.7) | 7.0 (6.6–10.1) | 13.0 (7.7–19) | 0.22 |
| Serum albumin, g/dL (mean ± SD) | 3.9 ± 0.4 | 3.8 ± 0.8 | 3.62 | 0.68 |
| ECOG performance status | 0.13 | |||
| 0 | 0 (0.0) | 2 (40.0) | 0 (0.0) | |
| 1 | 12 (80.0) | 4 (60.0) | 2 (66.7) | |
| 2 | 3 (20.0) | 0 (0.0) | 1 (33.3) |
This study has several limitations. First, this was a single-center retrospective analysis, and inherent selection bias cannot be excluded. In particular, treatment allocation was determined through multidisciplinary clinical decision-making rather than random assignment. Although patients who underwent CRT followed by surgery demonstrated longer survival in our cohort, this finding should be interpreted cautiously because treatment selection was influenced by clinical characteristics. Patients selected for surgery generally had good performance status and no evidence of distant metastasis, which may have contributed to the observed survival differences. Second, direct gastric invasion was defined based on endoscopic findings of continuous tumor extension across the gastroesophageal junction. Although patients with obvious gastric metastases or secondary gastric involvement from regional lymph node metastases were excluded, misclassification between direct invasion and other forms of gastric involvement, such as intramural metastasis, intraepithelial spread, or lymphatic extension, cannot be completely ruled out. Third, clinical staging was based on both the seventh and eighth editions of the AJCC staging system according to the year of diagnosis, which may have introduced some degree of staging heterogeneity. Fourth, as direct gastric invasion is an uncommon manifestation of ESCC, the number of affected patients was limited, reducing the statistical power of subgroup analyses and precluding comprehensive comparisons of less frequently used treatment modalities. Finally, detailed analyses of surgical techniques and reconstruction methods were not feasible because of the limited number of surgical cases.
Future multicenter studies with larger cohorts are needed to validate the prognostic significance of direct gastric invasion and to determine the optimal treatment strategy for this uncommon subgroup of patients with ESCC. In addition, molecular profiling and characterization of the tumor microenvironment may provide further insight into the biological mechanisms underlying direct gastric invasion and help identify potential prognostic and predictive biomarkers.
Direct gastric invasion in ESCC is associated with a poor prognosis. Although patients who underwent CRT followed by surgery demonstrated longer survival in our cohort, this observation should be interpreted cautiously because of the small sample size and potential treatment selection bias. Larger prospective studies are needed to clarify the biological significance and clinical implications of direct gastric invasion in ESCC.
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