Abstract
BACKGROUND
A significant association between increased age and an increased risk of metachronous gastric cancer (MGC) following curative endoscopic submucosal dissection (ESD) has previously been reported.
AIM
To determine risk factors for the metachronous occurrence of early gastric cancer (EGC) in elderly individuals.
METHODS
This retrospective cohort study comprised 653 elderly patients (aged ≥ 65 years) who underwent curative ESD for EGC between January 2014 and June 2020 at Nanjing Drum Tower Hospital. Comprehensive analyses were conducted to compare lifestyle habits, comorbidities, and Helicobacter pylori (H. pylori) infections as potential indicators.
RESULTS
During a median follow-up of 38 months, 46 patients (7.0%, 20.46/1000 person-years) developed MGC in the elderly cohort. The cumulative incidences of MGC at 2, 3, and 5 years were 3.3%, 5.3%, and 11.5%, respectively. In multivariate Cox regression analyses, the independent risk factors for MGC included metabolic dysfunction-associated steatotic liver disease (MASLD) [hazard ratio (HR) = 2.44, 95% confidence interval (CI): 1.15-5.17], persistent H. pylori infection (HR = 10.38, 95%CI: 3.36-32.07), severe mucosal atrophy (HR = 2.71, 95%CI: 1.45-5.08), and pathological differentiation of EGC (well/moderately differentiated vs poorly differentiated: HR = 10.18, 95%CI: 1.30-79.65). Based on these risk factors, a risk stratification system was developed to categorize individuals into low (0-1 point), intermediate (2-3 points), and high (4-8 points) risk categories for MGC, with cumulative incidence rates of 12.3%, 21.6%, and 45%, respectively.
CONCLUSION
Among elderly individuals, MASLD, persistent H. pylori infection, severe mucosal atrophy, and well/moderately differentiated EGC were associated with an increased risk of MGC. Elderly patients are recommended to adopt healthy lifestyle practices, and undergo regular endoscopic screening and H. pylori testing after curative ESD for EGC.
Keywords: Comorbidities, Early gastric cancer, Metachronous gastric cancer, The elderly, Risk factors
Core Tip: This study retrospectively examined the risk factors for the metachronous occurrence of early gastric cancer (EGC) in elderly individuals. The study findings indicated that metabolic dysfunction-associated steatotic liver disease, persistent Helicobacter pylori infection, severe mucosal atrophy, and well/moderately differentiated EGC were associated with a higher risk of metachronous gastric cancer.
INTRODUCTION
Stomach cancer ranks fifth in both incidence and mortality rates worldwide, with the highest rates observed in both men and women in Eastern Asia[1]. In 2022, approximately 0.97 million new cases of gastric cancer (GC) were diagnosed, 33.7% of which occurred in China[2]. A Markov model predicted that between 2021 and 2035, there will be 10.0 million new cases of GC and 5.6 million GC-related deaths. The model indicated that a significant proportion of these cases, ranging from 7.6% to 35.5%, and the related deaths, ranging from 6.9% to 44.5%, could be avoided through various prevention strategies[3]. Early GC (EGC), limited to the mucosa or submucosa regardless of lymph node metastasis, is known to have a favorable prognosis[4,5]. Recently, endoscopic resection (ER) has gained popularity as a standard, minimally invasive treatment for EGC. Metachronous GC (MGC) refers to a secondary carcinoma appearing in an area different from the primary lesion at least one year after curative ER[6]. The cumulative incidences of MGC at 5, 7, and 10 years were 9.5%, 13.1%, and 22.7%, respectively[7].
Population aging significantly contributes to the increasing burden of cancer[8]. The peak incidence and mortality of cancer occurs in individuals aged 60-79 years. Males experience higher years lived with disability owing to neoplasms, cardiovascular diseases, and diabetes, while females show higher rates related to musculoskeletal, mental, and neurological disorders starting in older age groups (≥ 60 years)[9]. The prevalence and incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) are rising worldwide; its overall prevalence is estimated to be 32.4% [95% confidence interval (CI): 29.9-34.9], while the overall incidence is approximately 4612.8 cases (95%CI: 3931.5-5294.2) per 100000 person-years[10], posing significant health and economic burdens on societies[11]. Some studies have reported an inverted U curve concerning the age-prevalence of MASLD, indicating a decrease in prevalence in individuals aged ≥ 65 years; nevertheless, MASLD gradually progresses to cancer over time[12,13]. MASLD was associated with an almost 1.8-fold increased risk of stomach cancer [pooled random-effects hazard ratio (HR) = 1.81, 95%CI: 1.19-2.75][14]. These findings suggest that MASLD increases the risk of developing MGC after ER.
Several studies have identified various risk factors for MGC, including age > 65 years, smoking, male sex, lower body mass index, Helicobacter pylori (H. pylori) infection, differentiated types, serum pepsinogen levels, and severe atrophic gastritis (AG)[7,15-22]. However, the correlation between comorbidities and the risk of MGC remains unclear.
Therefore, this study aimed to investigate the risk factors of MGC after curative endoscopic submucosal dissection (ESD), focusing on MASLD and other comorbidities in elderly patients.
MATERIALS AND METHODS
Study design and patient selection
This retrospective cohort study included 848 elderly patients aged ≥ 65 years who underwent curative ESD for EGC at the Affiliated Drum Tower Hospital of Nanjing University Medical School between January 2014 and June 2020. We excluded patients who did not meet the criteria for curative resection, those with an indefinite H. pylori infection status, those with a history of GC or gastrectomy, those who were scheduled for surgery within one year, those who had incomplete information, or those who had follow-up periods of < 12 months. In total, 653 eligible patients were included in the analysis.
Verbal informed consent was obtained from each patient; the requirement for written informed consent was waived owing to the study’s retrospective design. The study protocol was approved by the Human Ethics Review Committee of the Nanjing Drum Tower Hospital, No. 2024-395-01.
Independent variables
Demographic and clinical characteristics, including age, sex, lifestyle habits, comorbidities, and H. pylori infection status, were collected from the patients’ medical records. Diagnoses of MASLD, hypertension, diabetes, cardiovascular disease, and cerebrovascular disease were confirmed and validated based on international classification of diseases, tenth revision, clinical modification codes. A diagnosis of MASLD, excluding other causes of chronic liver disease, was based on ultrasonography or computed tomography performed by experienced radiologists during the preoperative examinations. Curative resection of EGC was performed according to Japanese gastric cancer treatment guidelines[23]. Two experienced gastrointestinal endoscopists and pathologists evaluated the endoscopic and histopathological features based on the World Health Organization classification of GC[24].
H. pylori infection and mucosal atrophy
The presence of H. pylori infection was determined using ¹³C-urea breath and fast urease tests, and a histological examination. Based on their H. pylori infection status, patients were categorized into the following three groups: (1) A negative group, consisting of patients without active H. pylori infection at the time of ESD and prior to ESD; (2) An eradicated group, indicating successful eradication of H. pylori; and (3) A persistent group, comprising patients who did not attempt or failed to eradicate H. pylori. Mucosal atrophy was classified into two grades according to the Kimura-Takemoto classification, namely, mild/moderate (C0-C3) and severe (O1-O3)[25,26].
Outcome measurement
MGC was defined as a secondary carcinoma detected in areas other than the primary carcinoma > 12 months following the index ESD[6]. Confirmation of MGC relied on a histological examination of biopsy, ER, or gastrectomy specimens. Follow-up esophagogastroduodenoscopy was conducted periodically after the index ESD, every 3 months for the first 12 months, and annually thereafter, as part of the MGC surveillance protocols. The follow-up period was defined as the time interval from the index ESD to either histological confirmation of MGC or the last follow-up visit.
Statistical analysis
Univariate and multivariate Cox proportional hazard regression analyses were performed to identify the independent risk factors for MGC. Covariates with clinical or statistical significance (P < 0.1) in the univariate analysis were included in the multivariate analysis. The cumulative probabilities of developing MGC were calculated using the Kaplan-Meier method and assessed using a log-rank test. Continuous variables were compared using t- or Mann-Whitney U tests, and were reported as mean ± SD for parametrically distributed data, or as median interquartile range (IQR) for nonparametrically distributed data. Categorical data were compared using Pearson’s χ2 or Fisher’s exact tests. All statistical tests were two-sided, with P < 0.05 considered statistically significant. Statistical product and service solutions version 26.0 (IBM Corp., Armonk, NY, United States) and R version 4.0.5 (R Foundation for Statistical Computing, Vienna, Austria) software programs were used for analysis.
RESULTS
The socio-demographic profile of the elderly patients
In accordance with the inclusion and exclusion criteria, 653 patients aged ≥ 65 years were eligible for the retrospective analysis (Figure 1). In our study, 46 patients (7.0%, 20.46/1000 person-years) developed MGC during a median follow-up period of 38 months (IQR: 25-55). The cumulative incidences of MGC in the elderly patients at 2, 3, and 5 years were 3.3%, 5.3%, and 11.5%, respectively. The HRs for the cumulative incidence of MGC based on age at initial ESD are shown in Supplementary Figure 1, according to the EGC database at our hospital. The baseline and clinicopathological characteristics of the included study patients were compared based on the presence or absence of MGC (Table 1). The median age at the time of the index ESD was 70 years (IQR: 67-74 years; males, 71.2%). The incidence of MASLD was 9.6% (n = 63) at the time of the index ESD. The status of H. pylori infection (P < 0.001), baseline mucosal atrophy (P = 0.031), differentiation (P = 0.047), and median follow-up time (P < 0.001) differed significantly between the MGC and non-MGC groups.
Figure 1.
Flow diagram of the enrolled study patients. ESD: Endoscopic submucosal dissection; MGC: Metachronous gastric cancer; H. pylori: Helicobacter pylori.
Table 1.
A comparison between baseline and clinicopathological characteristics of elderly patients in different groups, n (%)
|
Characteristics
|
Number (n = 653)
|
Non-MGC (n = 607)
|
MGC (n = 46)
|
P value
|
| Age, years (IQR) | 70 (67-74) | 70 (67-74) | 69 (67-73) | 0.186 |
| Sex | 0.354 | |||
| Male | 465 (71.2) | 429 (70.7) | 36 (78.3) | |
| Female | 188 (28.8) | 178 (29.3) | 10 (21.7) | |
| Tobacco abuse | 225 (34.5) | 205 (33.8) | 20 (43.5) | 0.240 |
| Alcohol abuse | 180 (27.6) | 166 (27.3) | 14 (30.4) | 0.779 |
| Family history of cancer | 101 (15.5) | 92 (15.2) | 9 (19.6) | 0.558 |
| MASLD | 63 (9.7) | 53 (8.73) | 10 (21.7) | 0.008 |
| Hypertension | 202 (30.9) | 185 (30.5) | 17 (37.0) | 0.453 |
| Diabetes | 68 (10.4) | 62 (10.2) | 6 (13.0) | 0.614 |
| Cardiovascular disease | 55 (8.4) | 52 (8.6) | 3 (6.5) | 0.837 |
| Cerebrovascular disease | 43 (6.6) | 37 (6.1) | 6 (13.0) | 0.111 |
| H. pylori infection | < 0.001 | |||
| Negative | 99 (15.2) | 95 (15.7) | 4 (8.70) | |
| Eradicated | 508 (77.8) | 481 (79.2) | 27 (58.7) | |
| Persistent | 46 (7.0) | 31 (5.1) | 15 (32.6) | |
| Baseline atrophy | 0.031 | |||
| Mild/moderate (C0-C3) | 479 (73.4) | 452 (74.5) | 27 (58.7) | |
| Severe (O1-O3) | 174 (26.6) | 155 (25.5) | 19 (41.3) | |
| Location | 0.593 | |||
| Cardia | 323 (49.5) | 298 (49.1) | 25 (54.3) | |
| Non-cardia | 330 (50.5) | 309 (50.9) | 21 (45.7) | |
| Macroscopic shape | 0.034 | |||
| Elavated (I, IIa) | 220 (33.7) | 206 (33.9) | 14 (30.4) | |
| Flated (IIb) | 180 (27.6) | 160 (26.4) | 20 (43.5) | |
| Depressed (IIc, III) | 253 (38.7) | 241 (39.7) | 12 (26.1) | |
| Tumor size, cm | 0.614 | |||
| < 2 | 371 (56.8) | 347 (57.2) | 24 (52.2) | |
| ≥ 2 | 282 (43.2) | 260 (42.8) | 22 (47.8) | |
| Depth of invasion | 1 | |||
| Mucosa | 488 (74.7) | 454 (74.8) | 34 (73.9) | |
| Submucosa | 165 (25.3) | 153 (25.2) | 12 (26.1) | |
| Differentiation | 0.047 | |||
| WD/MD | 581 (89.0) | 536 (88.3) | 45 (97.8) | |
| PD | 72 (11.0) | 71 (11.7) | 1 (2.2) | |
| Ulceration | 46 (7.0) | 41 (6.8) | 5 (10.9) | 0.452 |
| Initial multifocality | 121 (18.5) | 107 (17.6) | 14 (30.4) | 0.050 |
| Median follow-up time, months | 38 (25-55) | 38 (26-56) | 29 (19-45) | 0.001 |
C: Closed; MASLD: Metabolic dysfunction-associated steatotic liver disease; MD: Moderately differentiated; O: Open; PD: Poorly differentiated; WD: Well-differentiated; H. pylori: Helicobacter pylori; MGC: Metachronous gastric cancer.
Risk factors associated with MGC
Demographic and clinical characteristics including age, sex, lifestyle habits, and comorbidities, H. pylori infection, and endoscopic and histological features were analyzed using univariate Cox regression analyses (Table 2). The results indicated that MASLD (P < 0.001), cerebrovascular disease (P = 0.034), persistent H. pylori infection (P < 0.001), severe mucosal atrophy (P = 0.002), and well/moderately differentiated (WD/MD) tumors (P = 0.039) increased the likelihood of developing MGC. Multivariate Cox regression analysis identified MASLD (HR = 2.44, 95%CI: 1.15-5.17), persistent H. pylori infection (HR = 10.38, 95%CI: 3.36-32.07), severe mucosal atrophy (HR = 2.71, 95%CI: 1.45-5.08), and WD/MD differentiation (HR = 10.18, 95%CI: 1.30-79.65) as independent risk factors for MGC. No notable differences were observed in the initial multiplicity (HR = 1.79, 95%CI: 0.90-3.56, P = 0.096) in the multivariate Cox regression analysis. The cumulative incidences of MGC after curative ESD among the different subgroups of MASLD, H. pylori infection, baseline mucosal atrophy, and differentiation are illustrated in Figure 2, all showing statistical significance.
Table 2.
Univariate and multivariate Cox analyses of risk factors for metachronous gastric carcinoma development
| Characteristics |
Univariate analysis
|
Multivariate analysis
|
Risk
|
||
|
HR (95%CI)
|
P value
|
HR (95%CI)
|
P value
|
Points1
|
|
| Age, years | 0.95 (0.89-1.02) | 0.142 | |||
| Sex | 0.342 | ||||
| Male | Reference | ||||
| Female | 0.71 (0.35-1.44) | ||||
| Tobacco abuse | 1.47 (0.82-2.64) | 0.191 | |||
| Alcohol abuse | 1.17 (0.62-2.19) | 0.628 | |||
| Family history of cancer | 1.47 (0.71-3.04) | 0.298 | |||
| MASLD | 3.35 (1.65-6.79) | < 0.001 | 2.44 (1.15-5.17) | 0.020 | 1 |
| Hypertension | 1.47 (0.81-2.68) | 0.206 | |||
| Diabetes | 1.44 (0.61-3.41) | 0.404 | |||
| Cardiovascular disease | 0.74 (0.23-2.38) | 0.609 | |||
| Cerebrovascular disease | 2.46 (1.04-5.82) | 0.034 | 1.79 (0.72-4.42) | 0.207 | |
| H. pylori infection | < 0.001 | ||||
| Negative | Reference | Reference | |||
| Eradicated | 1.46 (0.51-4.17) | 1.17 (0.41-3.38) | 0.769 | ||
| Persistent | 11.8 (3.89-35.8) | 10.38 (3.36-32.07) | < 0.001 | 3 | |
| Baseline atrophy | 0.002 | ||||
| Mild/moderate (C0-C3) | Reference | Reference | |||
| Severe (O1-O3) | 2.47 (1.37-4.46) | 2.71 (1.45-5.08) | 0.002 | 1 | |
| Location | 0.977 | ||||
| Cardia | Reference | ||||
| Non-cardia | 0.99 (0.55-1.78) | ||||
| Macroscopic shape | 0.015 | ||||
| Elavated (I, IIa) | Reference | ||||
| Flated (IIb) | 2.17 (1.09-4.32) | 2.22 (1.07-4.59) | 0.031 | ||
| Depressed (IIc, III) | 0.87 (0.40-1.89) | 0.77 (0.34-1.75) | 0.537 | ||
| Tumor size, cm | 0.727 | ||||
| < 2 | Reference | ||||
| ≥ 2 | 1.11 (0.62-1.98) | ||||
| Depth of invasion | 0.789 | ||||
| Mucosa | Reference | ||||
| Submucosa | 0.91 (0.47-1.77) | ||||
| Differentiation | 0.039 | 0.027 | |||
| WD/MD | 6.21 (0.86-45.0) | 10.18 (1.30-79.65) | 3 | ||
| PD | Reference | Reference | |||
| Ulceration | 1.32 (0.52-3.34) | 0.562 | |||
| Initial multifocality | 2.17 (1.15-4.07) | 0.014 | 1.79 (0.90-3.56) | 0.096 | |
The coefficient of each variable was divided by 0.387 (the lowest log hazard ratio value), corresponding to metabolic dysfunction-associated steatotic liver disease, and rounded to the nearest integer.
C: Closed; MASLD: Metabolic dysfunction-associated steatotic liver disease; MD: Moderately differentiated; O: Open; PD: Poorly differentiated; WD: Well-differentiated; H. pylori: Helicobacter pylori; HR: Hazard ratio; CI: Confidence interval.
Figure 2.
Cumulative incidences of metachronous gastric cancer after curative endoscopic submucosal dissection between different risk factors. A: The presence or absence of metabolic dysfunction-associated steatotic liver disease; B: Different Helicobacter pylori infection status; C: Degrees of mucosal atrophy; D: Differentiation of the lesions. MASLD: Metabolic dysfunction-associated steatotic liver disease; MGC: Metachronous gastric cancer; PD: Poorly differentiated; WD: Well differentiated; MD: Moderately differentiated.
Subgroup analyses based on MASLD and severe AG
In the MASLD group, 10 patients (15.9%, 53.76/1000 person-years) developed MGC compared with 36 patients (6.1%, 17.45/1000 person-years) in the non-MASLD group (Figure 2). The cumulative incidences of MGC in the MASLD group at 2, 3, and 5 years were 8.8%, 16.9%, and 31.8%, respectively, whereas those in the non-MASLD group were 2.7%, 4.2%, and 9.7%, respectively. We performed subgroup analyses to evaluate the influence of MASLD on MGC development (Figure 3). MASLD was associated with a high incidence of MGC, which was consistent across various lifestyle factors, other comorbidities, and the negative and eradicated status of H. pylori infection subgroups (all P values < 0.05).
Figure 3.
A subgroup analyses forest plot of the risk factors for metabolic dysfunction-associated steatotic liver disease associated with metachronous gastric cancer. MASLD: Metabolic dysfunction-associated steatotic liver disease; PD: Poorly differentiated; WD: Well differentiated; MD: Moderately differentiated; HR: Hazard ratio; CI: Confidence interval; H. pylori: Helicobacter pylori.
Severe AG was also associated with high incidence of MGC (Supplementary Figure 2). In the subgroup analyses based on sex, male sex was associated with a higher risk of MGC (P = 0.006) in the severe AG group. Factors such as alcohol consumption or smoking history (P = 0.005), absence of MASLD (P = 0.007), hypertension (P = 0.001), and diabetes (P = 0.002) showed a close association between severe AG and MGC. No interactions were found between severe AG and the aforementioned variables in the subgroup analyses (all P values for interactions, > 0.05). Additional subgroup analyses based on the differentiation between WD/MD and persistent H. pylori infection are shown in Supplementary Table 1 and Supplementary Figure 3.
Risk stratification for MGC
After assigning weighted scores to the b regression coefficient (log HR) values, the variables MASLD, persistent H. pylori infection, severe mucosal atrophy, and differentiation of WD/MD tumors were assigned 1, 3, 1, and 3 points, respectively (Table 2). This risk stratification subsequently categorized patients into low (0-1 point), intermediate (2-3 points), and high (4-8 points) groups for MGC, with cumulative incidence rates of 12.3%, 21.6%, and 45%, respectively (Table 3). The risk stratification system highlighted significant differences in the cumulative incidence rates of MGC among the risk groups (Figure 4).
Table 3.
Risk stratification based on the independent risk factors for metachronous gastric carcinoma in elderly patients
|
Risk stratification
|
Total points
|
Total patients (n = 653)
|
MGC (n = 46)
|
Rate of MGC (%)
|
Cumulative hazard
|
95%CI
|
| Low | 0-1 | 526 | 27 | 5.1 | 12.3 | 6.4-18.2 |
| Intermediate | 2-3 | 88 | 11 | 12.5 | 21.6 | 8.9-34.3 |
| High | 4-8 | 39 | 8 | 20.5 | 45 | 16.1-73.8 |
MGC: Metachronous gastric carcinoma; CI: Confidence interval.
Figure 4.
Cumulative incidence of metachronous gastric cancer according to the risk stratification based on the risk factors. MGC: Metachronous gastric cancer.
DISCUSSION
The development and utilization of endoscopic technology has drawn increased attention to the incidence of MGC following ER. Previous studies have indicated that older age (mean difference, 1.08 years; 95%CI: 0.21-1.96) is an independent risk factor for the increased incidence of MGC[27,28]. However, specific factors that contribute to the development of MGC in elderly individuals remain unclear. In this study, 46 patients (7.0%, 20.46/1000 person-years) developed MGC, with cumulative incidences of 3.3%, 5.3%, and 11.5% at 2, 3, and 5 years, respectively. Our findings indicated that MASLD, persistent H. pylori infection, and severe mucosal atrophy were independent risk factors for MGC in patients aged > 65 years.
Earlier studies have associated factors such as male sex [odds ratio (OR) = 1.43, 95%CI: 1.22-1.66], synchronous lesions (OR = 1.72, 95%CI: 1.30-2.28), severe gastric mucosal atrophy (OR = 2.77, 95%CI: 1.22-6.29), lower pepsinogen I/II ratio (mean difference -0.54, 95%CI: -0.86 to -0.22), current smoking (HR: 1.5, 95%CI: 1.03-2.16), and well-differentiated tumors (risk ratio = 4.02, 95%CI: 1.96-8.26) with a significantly increased risk of MGC post-ER[16,27,29]. Recent retrospective cohort studies and prospective randomized controlled trials have indicated that H. pylori infection is a significant risk factor for MGC development[15,20,30,31]. Elderly individuals with severe endoscopic atrophy in our study were at a substantially higher risk of developing MGC.
The subgroup analysis conducted in our study suggests a possible connection between MASLD and MGC in the elderly. Prior studies have indicated that MASLD is associated with an increased risk of developing GC (incidence rate ratio = 2.3, 95%CI: 1.3-4.1)[14,32]. MASLD has also been linked to a higher risk of metachronous colorectal neoplasia in both men (adjusted HR = 1.17, 95%CI: 1.06-1.29) and women (adjusted HR = 1.63, 95%CI: 1.27-2.07)[33]. Furthermore, bariatric surgery in patients with MASLD and severe obesity has shown significant risk reductions for GC (lower crude HR = 0.30, 95%CI: 0.02-1.70 and adjusted HR = 0.46, 95%CI: 0.03-2.44)[34]. Our findings showed a strong association between MASLD and a higher incidence of MGC in the elderly, consistent across various subgroups, including sex, smoking and drinking status, H. pylori eradication, family history of tumors, diabetes, hypertension, histological differentiation, and mild/moderate mucosal atrophy. However, future studies are needed to further investigate this association.
This study provides valuable insights into the development of MGC in elderly patients after ESD. The risk-scoring system had several advantages, particularly in assessing the effects of H. pylori infection status, gastric mucosal atrophy, and MASLD on MGC development. The link between MASLD and MGC has rarely been reported in previous studies. Additionally, we incorporated potential risk factors to establish a risk stratification for elderly patients with EGC post-ESD. This stratification can aid in determining the appropriate frequency of endoscopic surveillance for the different risk groups. For high-risk patients (total, 4-8 points), annual endoscopic surveillance is recommended for an extended period. Following the initial yearly surveillance, moderate-risk patients (total, 2-3 points) should be evaluated every other year. For low-risk patients (total, 0-1 points), the surveillance intervals can be extended appropriately. Consultation with healthcare professionals provides personalized medical advice and recommendations.
This study had several limitations. This was a retrospective, single-center study with a relatively small population size. We only gathered clinical characteristics and did not include laboratory tests for genetic and epigenetic markers and microsatellite instability. There was a time lag between the occurrence of MGC and availability of clinical follow-up records. The postoperative follow-up period was relatively short, limiting our ability to draw more accurate conclusions. In conclusion, this study underscores the need for further large-scale cohort studies and prospective randomized controlled trials to thoroughly evaluate risk factors associated with MGC.
CONCLUSION
Our findings suggest that MASLD, persistent H. pylori infection, and severe mucosal atrophy are associated with the development of MGC in elderly patients. These results provide valuable insights into management and surveillance strategies for this population. However, further studies are needed to confirm and expand upon these findings.
Footnotes
Institutional review board statement: All procedures performed in studies involving human participants were approved by the Human Ethics Review Committees of Nanjing Drum Tower Hospital (No. 2024-395-01). This research was retrospective and the data on patients were anonymous, and the requirement for informed consent was waived by the Ethics Committee.
Informed consent statement: All data were anonymous, and patient images were not reported. Verbal informed consent for publication was obtained from each patient or their guardian. Verbal informed consent was obtained after a series of telephone interviews with the patients.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade A, Grade A, Grade C, Grade C
Novelty: Grade A, Grade B, Grade B, Grade B
Creativity or Innovation: Grade A, Grade B, Grade B, Grade B
Scientific Significance: Grade A, Grade A, Grade B, Grade B
P-Reviewer: Agidew MM; Arumugam VA; Jean Simon D S-Editor: Fan M L-Editor: A P-Editor: Zhang L
Contributor Information
Ying Xiang, Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, Jiangsu Province, China.
Ying Yuan, Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China.
Zhen-Yu Wang, Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China.
Yan-Mei Zhu, Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, Jiangsu Province, China.
Wen-Ying Li, Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, Jiangsu Province, China.
Qian-Ge Ye, Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Jiangsu University, Nanjing 210008, Jiangsu Province, China.
Ya-Nan Wang, Department of Gastroenterology, Hospital Clinical College of Nanjing Medical University, Nanjing 210008, Jiangsu Province, China.
Qi Sun, Department of Pathology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China.
Xi-Wei Ding, Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China.
Faraz Longi, Feinberg School of Medicine, Northwestern University, Chicago, IL 60601, United States.
De-Hua Tang, Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China.
Gui-Fang Xu, Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing 210008, Jiangsu Province, China; Department of Gastroenterology, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China; Department of Gastroenterology, Hospital Clinical College of Nanjing Medical University, Nanjing 210008, Jiangsu Province, China. xuguifang@njglyy.com.
Data sharing statement
All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.
References
- 1.Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–263. doi: 10.3322/caac.21834. [DOI] [PubMed] [Google Scholar]
- 2.Zhang X, Yang L, Liu S, Cao LL, Wang N, Li HC, Ji JF. [Interpretation on the report of global cancer statistics 2022] Zhonghua Zhong Liu Za Zhi. 2024;46:710–721. doi: 10.3760/cma.j.cn112152-20240416-00152. [DOI] [PubMed] [Google Scholar]
- 3.Wang Z, Han W, Xue F, Zhao Y, Wu P, Chen Y, Yang C, Gu W, Jiang J. Nationwide gastric cancer prevention in China, 2021-2035: a decision analysis on effect, affordability and cost-effectiveness optimisation. Gut. 2022;71:2391–2400. doi: 10.1136/gutjnl-2021-325948. [DOI] [PubMed] [Google Scholar]
- 4.Park IS, Lee YC, Kim WH, Noh SH, Lee KS, Kim H. Clinicopathologic characteristics of early gastric cancer in Korea. Yonsei Med J. 2000;41:607–614. doi: 10.3349/ymj.2000.41.5.607. [DOI] [PubMed] [Google Scholar]
- 5.Nakamura K, Ueyama T, Yao T, Xuan ZX, Ambe K, Adachi Y, Yakeishi Y, Matsukuma A, Enjoji M. Pathology and prognosis of gastric carcinoma. Findings in 10,000 patients who underwent primary gastrectomy. Cancer. 1992;70:1030–1037. doi: 10.1002/1097-0142(19920901)70:5<1030::aid-cncr2820700504>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
- 6.Maehata Y, Nakamura S, Fujisawa K, Esaki M, Moriyama T, Asano K, Fuyuno Y, Yamaguchi K, Egashira I, Kim H, Kanda M, Hirahashi M, Matsumoto T. Long-term effect of Helicobacter pylori eradication on the development of metachronous gastric cancer after endoscopic resection of early gastric cancer. Gastrointest Endosc. 2012;75:39–46. doi: 10.1016/j.gie.2011.08.030. [DOI] [PubMed] [Google Scholar]
- 7.Abe S, Oda I, Suzuki H, Nonaka S, Yoshinaga S, Nakajima T, Sekiguchi M, Mori G, Taniguchi H, Sekine S, Katai H, Saito Y. Long-term surveillance and treatment outcomes of metachronous gastric cancer occurring after curative endoscopic submucosal dissection. Endoscopy. 2015;47:1113–1118. doi: 10.1055/s-0034-1392484. [DOI] [PubMed] [Google Scholar]
- 8.Xia C, Dong X, Li H, Cao M, Sun D, He S, Yang F, Yan X, Zhang S, Li N, Chen W. Cancer statistics in China and United States, 2022: profiles, trends, and determinants. Chin Med J (Engl) 2022;135:584–590. doi: 10.1097/CM9.0000000000002108. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1789–1858. doi: 10.1016/S0140-6736(18)32279-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Le MH, Le DM, Baez TC, Wu Y, Ito T, Lee EY, Lee K, Stave CD, Henry L, Barnett SD, Cheung R, Nguyen MH. Global incidence of non-alcoholic fatty liver disease: A systematic review and meta-analysis of 63 studies and 1,201,807 persons. J Hepatol. 2023;79:287–295. doi: 10.1016/j.jhep.2023.03.040. [DOI] [PubMed] [Google Scholar]
- 11.Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018;67:123–133. doi: 10.1002/hep.29466. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Alqahtani SA, Schattenberg JM. NAFLD in the Elderly. Clin Interv Aging. 2021;16:1633–1649. doi: 10.2147/CIA.S295524. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Eguchi Y, Hyogo H, Ono M, Mizuta T, Ono N, Fujimoto K, Chayama K, Saibara T JSG-NAFLD. Prevalence and associated metabolic factors of nonalcoholic fatty liver disease in the general population from 2009 to 2010 in Japan: a multicenter large retrospective study. J Gastroenterol. 2012;47:586–595. doi: 10.1007/s00535-012-0533-z. [DOI] [PubMed] [Google Scholar]
- 14.Mantovani A, Petracca G, Beatrice G, Csermely A, Tilg H, Byrne CD, Targher G. Non-alcoholic fatty liver disease and increased risk of incident extrahepatic cancers: a meta-analysis of observational cohort studies. Gut. 2022;71:778–788. doi: 10.1136/gutjnl-2021-324191. [DOI] [PubMed] [Google Scholar]
- 15.Okada K, Suzuki S, Naito S, Yamada Y, Haruki S, Kubota M, Nakajima Y, Shimizu T, Ando K, Uchida Y, Hirasawa T, Fujisaki J, Tsuchida T. Incidence of metachronous gastric cancer in patients whose primary gastric neoplasms were discovered after Helicobacter pylori eradication. Gastrointest Endosc. 2019;89:1152–1159.e1. doi: 10.1016/j.gie.2019.02.026. [DOI] [PubMed] [Google Scholar]
- 16.Ishioka M, Yoshio T, Miyamoto Y, Namikawa K, Tokai Y, Yoshimizu S, Horiuchi Y, Ishiyama A, Hirasawa T, Tsuchida T, Fujisaki J. Incidence of metachronous cancer after endoscopic submucosal dissection: a comparison between undifferentiated-type and differentiated-type early gastric cancer. Gastrointest Endosc. 2021;93:557–564.e1. doi: 10.1016/j.gie.2020.06.067. [DOI] [PubMed] [Google Scholar]
- 17.Chung CS, Woo HS, Chung JW, Jeong SH, Kwon KA, Kim YJ, Kim KO, Park DK. Risk Factors for Metachronous Recurrence after Endoscopic Submucosal Dissection of Early Gastric Cancer. J Korean Med Sci. 2017;32:421–426. doi: 10.3346/jkms.2017.32.3.421. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Ami R, Hatta W, Iijima K, Koike T, Ohkata H, Kondo Y, Ara N, Asanuma K, Asano N, Imatani A, Shimosegawa T. Factors Associated With Metachronous Gastric Cancer Development After Endoscopic Submucosal Dissection for Early Gastric Cancer. J Clin Gastroenterol. 2017;51:494–499. doi: 10.1097/MCG.0000000000000620. [DOI] [PubMed] [Google Scholar]
- 19.Liou JM, Malfertheiner P, Lee YC, Sheu BS, Sugano K, Cheng HC, Yeoh KG, Hsu PI, Goh KL, Mahachai V, Gotoda T, Chang WL, Chen MJ, Chiang TH, Chen CC, Wu CY, Leow AH, Wu JY, Wu DC, Hong TC, Lu H, Yamaoka Y, Megraud F, Chan FKL, Sung JJ, Lin JT, Graham DY, Wu MS, El-Omar EM Asian Pacific Alliance on Helicobacter and Microbiota (APAHAM) Screening and eradication of Helicobacter pylori for gastric cancer prevention: the Taipei global consensus. Gut. 2020;69:2093–2112. doi: 10.1136/gutjnl-2020-322368. [DOI] [PubMed] [Google Scholar]
- 20.Kwon Y, Jeon S, Nam S, Shin I. Helicobacter pylori infection and serum level of pepsinogen are associated with the risk of metachronous gastric neoplasm after endoscopic resection. Aliment Pharmacol Ther. 2017;46:758–767. doi: 10.1111/apt.14263. [DOI] [PubMed] [Google Scholar]
- 21.Kim JL, Kim SG, Kim J, Park JY, Yang HJ, Kim HJ, Chung H. Clinical Outcomes of Metachronous Gastric Cancer after Endoscopic Resection for Early Gastric Cancer. Gut Liver. 2020;14:190–198. doi: 10.5009/gnl18575. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Rei A, Ortigão R, Pais M, Afonso LP, Pimentel-Nunes P, Dinis-Ribeiro M, Libânio D. Metachronous lesions after gastric endoscopic submucosal dissection: first assessment of the FAMISH prediction score. Endoscopy. 2023;55:909–917. doi: 10.1055/a-2089-6849. [DOI] [PubMed] [Google Scholar]
- 23.Japanese Gastric Cancer Association. Japanese Gastric Cancer Treatment Guidelines 2021 (6th edition) Gastric Cancer. 2023;26:1–25. doi: 10.1007/s10120-022-01331-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. [Anonymous]. WHO Classification of Tumours Editorial Board. WHO classification of tumours. Digestive system tumours[M]. 5th ed. Lyon: IARC Press, 2019. [Google Scholar]
- 25.Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, Taniyama K, Sasaki N, Schlemper RJ. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345:784–789. doi: 10.1056/NEJMoa001999. [DOI] [PubMed] [Google Scholar]
- 26.Kaji K, Hashiba A, Uotani C, Yamaguchi Y, Ueno T, Ohno K, Takabatake I, Wakabayashi T, Doyama H, Ninomiya I, Kiriyama M, Ohyama S, Yoneshima M, Koyama N, Takeda Y, Yasuda K. Grading of Atrophic Gastritis is Useful for Risk Stratification in Endoscopic Screening for Gastric Cancer. Am J Gastroenterol. 2019;114:71–79. doi: 10.1038/s41395-018-0259-5. [DOI] [PubMed] [Google Scholar]
- 27.Ortigão R, Figueirôa G, Frazzoni L, Pimentel-Nunes P, Hassan C, Dinis-Ribeiro M, Fuccio L, Libânio D. Risk factors for gastric metachronous lesions after endoscopic or surgical resection: a systematic review and meta-analysis. Endoscopy. 2022;54:892–901. doi: 10.1055/a-1724-7378. [DOI] [PubMed] [Google Scholar]
- 28.Kwon YH, Heo J, Lee HS, Cho CM, Jeon SW. Failure of Helicobacter pylori eradication and age are independent risk factors for recurrent neoplasia after endoscopic resection of early gastric cancer in 283 patients. Aliment Pharmacol Ther. 2014;39:609–618. doi: 10.1111/apt.12633. [DOI] [PubMed] [Google Scholar]
- 29.Bae SE, Jung HY, Kang J, Park YS, Baek S, Jung JH, Choi JY, Kim MY, Ahn JY, Choi KS, Kim DH, Lee JH, Choi KD, Song HJ, Lee GH, Kim JH. Effect of Helicobacter pylori eradication on metachronous recurrence after endoscopic resection of gastric neoplasm. Am J Gastroenterol. 2014;109:60–67. doi: 10.1038/ajg.2013.404. [DOI] [PubMed] [Google Scholar]
- 30.Choi IJ, Kook MC, Kim YI, Cho SJ, Lee JY, Kim CG, Park B, Nam BH. Helicobacter pylori Therapy for the Prevention of Metachronous Gastric Cancer. N Engl J Med. 2018;378:1085–1095. doi: 10.1056/NEJMoa1708423. [DOI] [PubMed] [Google Scholar]
- 31.Fukase K, Kato M, Kikuchi S, Inoue K, Uemura N, Okamoto S, Terao S, Amagai K, Hayashi S, Asaka M Japan Gast Study Group. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet. 2008;372:392–397. doi: 10.1016/S0140-6736(08)61159-9. [DOI] [PubMed] [Google Scholar]
- 32.Allen AM, Hicks SB, Mara KC, Larson JJ, Therneau TM. The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity - A longitudinal cohort study. J Hepatol. 2019;71:1229–1236. doi: 10.1016/j.jhep.2019.08.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Kim NH, Jung YS, Park JH, Park DI, Sohn CI. Impact of nonalcoholic fatty liver disease on the risk of metachronous colorectal neoplasia after polypectomy. Korean J Intern Med. 2021;36:557–567. doi: 10.3904/kjim.2019.360. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Rustgi VK, Li Y, Gupta K, Minacapelli CD, Bhurwal A, Catalano C, Elsaid MI. Bariatric Surgery Reduces Cancer Risk in Adults With Nonalcoholic Fatty Liver Disease and Severe Obesity. Gastroenterology. 2021;161:171–184.e10. doi: 10.1053/j.gastro.2021.03.021. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.