Characteristics of Metachronous Gastric Neoplasms After Curative ESD

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Characteristics of Metachronous Gastric Neoplasms After Curative Endoscopic Submucosal Dissection for Early Gastric Neoplasms

Introduction
Endoscopic submucosal dissection (ESD) is the standard treatment for early gastric cancer (EGC) and dysplasia without lymph node metastasis. While ESD preserves gastric function and improves quality of life, metachronous gastric neoplasms (MGN)—new lesions occurring ≥12 months post-ESD and ≥1 cm from the initial site—pose a significant clinical challenge. Prior studies report MGN rates of 2.7%–15.6% after ESD, higher than the 0.1%–3.0% rate following surgery. This study analyzes the incidence, risk factors, clinicopathological characteristics, and long-term outcomes of MGN to refine surveillance strategies and improve patient management.

Methods
A retrospective cohort of 1,361 patients who underwent ESD for EGC or dysplasia at a single center from November 2006 to September 2019 was analyzed. After exclusions (non-curative resections, surgeries, insufficient follow-up, etc.), 814 patients were included. Follow-up included endoscopic surveillance at 3, 6, and 12 months post-ESD, then annually or biannually. MGN was diagnosed based on histological confirmation of new lesions ≥1 cm from the original site.

Key variables analyzed:

  • Patient demographics: Age, sex, smoking/alcohol history, family history of gastric cancer.
  • Lesion characteristics: Size, location (long/short axis), gross morphology (elevated, flat, depressed), histology (differentiated/undifferentiated carcinoma, dysplasia).
  • Pathological factors: Depth of invasion, lymphovascular involvement, resection margins.
  • H. pylori status: Assessed via histology, rapid urease test, or 13C-urea breath test; eradication success confirmed post-treatment.

Statistical analyses included Cox proportional hazards models for risk factors, Kaplan-Meier survival curves for cumulative incidence, and χ²/Fisher’s exact tests for categorical variables.

Results

Patient and Lesion Characteristics
Among 814 patients (median age 60 years, 76.4% male), 4.5% (37/814) developed MGN over a median follow-up of 40.5 months. Initial lesions were predominantly elevated (77.3%), located in the lower third of the stomach (44.7%), and classified as dysplasia (61.3%) or differentiated carcinoma (34.2%). Most lesions (95.3%) were confined to the mucosa.

Cumulative Incidence of MGN
The cumulative incidence of MGN increased over time: 3.5% at 3 years, 5.1% at 5 years, 6.9% at 7 years, and plateauing at 11.3% by 99 months post-ESD (Figure 2).

Clinicopathological Features of MGN
MGN lesions (median size 1.5 cm) showed no correlation with initial lesions in gross morphology, location (long/short axis), or histology (Table 1). Notably:

  • 64.9% of MGN lesions were elevated.
  • 37.8% occurred in the lower third, 32.4% in the middle third.
  • Histologically, 37.8% were differentiated carcinoma, 29.7% high-grade dysplasia.

Risk Factors for MGN
Univariate analysis identified severe gastric atrophy (83.8% vs. 62.7%, P = 0.003) and initial multiplicity (21.6% vs. 6.6%, P = 0.001) as significant predictors. Multivariate Cox regression confirmed initial multiplicity as the sole independent risk factor (HR 4.3, 95% CI 2.0–9.4, P < 0.001). H. pylori eradication status did not significantly impact MGN risk.

Treatment and Outcomes
Of 37 MGN patients:

  • 73% (27/37) underwent endoscopic resection (26 ESD, 1 EMR), with 96% en bloc resection and 82% curative resection rates.
  • Non-curative resections (5/27): Due to positive margins (2), piecemeal resection (1), or lymphovascular invasion (2).
  • Two patients required surgery for advanced lesions; both had poor outcomes (one died of lymph node metastasis).
  • Disease-specific survival was significantly lower in MGN patients (94.6% vs. 99.6%, P = 0.006), though overall survival did not differ (94.6% vs. 97.3%, P = 0.893) (Figure 4).

Discussion

Key Findings
This study highlights the persistent risk of MGN over time, emphasizing the need for long-term surveillance. The cumulative incidence plateauing at 99 months suggests a minimum 8-year follow-up. The absence of correlation between initial and MGN lesions supports the “field cancerization” theory, where chronic gastritis and atrophy create a milieu for independent tumor development.

Initial multiplicity—a strong risk factor—underscores the importance of meticulous initial endoscopic evaluation. The 11.3% MGN rate aligns with prior reports (e.g., 15.6% in Japanese cohorts), likely reflecting differences in H. pylori prevalence, surveillance protocols, or genetic susceptibility.

Clinical Implications

  • Surveillance: Annual/biannual endoscopy for ≥8 years post-ESD, particularly for patients with multiple initial lesions.
  • Treatment: Endoscopic resection remains effective for early MGN, achieving high curative rates (82%).
  • Prognosis: Despite lower disease-specific survival in MGN patients, overall survival remains comparable, highlighting the value of early detection.

Limitations
Single-center design, retrospective data, and reliance on indirect follow-up (telephone/email) for some patients may introduce bias. The study’s observational nature precludes causal conclusions about H. pylori eradication’s role.

Future Directions
Prospective multicenter studies should validate these findings, explore molecular markers of field cancerization, and refine risk stratification. Investigating H. pylori eradication timing and its impact on MGN risk is warranted.

Conclusion
Metachronous gastric neoplasms after curative ESD require vigilant, long-term endoscopic surveillance. Patients with multiple initial lesions face elevated risks, necessitating tailored follow-up. Endoscopic resection achieves favorable outcomes for early MGN, reinforcing the importance of timely detection.

doi.org/10.1097/CM9.0000000000001762

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