Risk of progression to high-grade intraepithelial neoplasia and gastric cancer: A multi-center prospective study in Anhui Province, China

Abstract

BACKGROUND

Gastric cancer is one of the most common cancers worldwide, especially in East Asia.

AIM

To explore the clinical outcomes and progression-related factors of low-grade intraepithelial neoplasia (LGIN) in the gastric mucosa and provide valuable guidance for improving treatment efficacy.

METHODS

A total of 357 patients diagnosed with LGIN based on initial pathological examination in Anhui Provincial Hospital or three other medical consortium units between January 2022 and June 2024 were included. Among them, 296 patients were followed up with endoscopic and biopsy pathology. Logistic regression was utilized to analyze the relevant risk factors for LGIN progression in the gastric mucosa.

RESULTS

The distribution sites of LGIN among the 357 patients were as follows: Gastric antrum (54.6%), gastric cardia (24.1%), gastric angulus (8.7%), gastric body (4.8%), gastric fundus (4.8%), and multiple sites (3.1%). Additionally, of the 357 patients with LGIN, 112 (31.4%) developed ulceration and 59 (16.5%) experienced gastric polyps. Furthermore, 231 of the 357 (64.71%) patients with LGIN tested positive for Helicobacter pylori (H. pylori) infection. The H. pylori infection rates of the patients with LGIN with accompanying atrophy, intestinal metaplasia, and gastric ulcer were 51.95%, 59.31%, and 28.57%, respectively. Multivariate logistic regression analysis showed that age ≥ 60 years [odds ratio (OR) = 3.063, 95% confidence interval (CI): 1.351-6.945, P = 0.007], H. pylori infection (OR = 3.560, 95%CI: 1.158-10.949, P = 0.027), multiple locations (OR = 10.136, 95%CI: 2.045-50.237, P = 0.005), lesion size ≥ 2 cm (OR = 3.921, 95%CI: 1.664-9.237, P = 0.002), and gastric ulcer (OR = 2.730, 95%CI: 1.197-6.223, P = 0.017) were predictive factors for LGIN progression.

CONCLUSION

LGIN progression is closely related to age, H. pylori positivity, multiple locations, lesion size ≥ 2 cm, and gastric ulcer. Thus, actively identifying these risk factors in patients with LGIN may have certain clinical significance in preventing further tumor progression.

Key Words: Low-grade intraepithelial neoplasia; Gastric cancer; Progression; Risk factor; Prospective study

Core Tip: Excessive endoscopic follow-up may increase the examination-related risks and treatment costs for patients at a low-risk stage. Therefore, identifying risk factors is necessary and provides practical clinical value in predicting and evaluating the likelihood of low-grade intraepithelial neoplasia (LGIN) progression. Here, we conducted a multi-center prospective study to investigate the risk factors associated with LGIN progression and to predict the prognosis of patients with LGIN for effectively identifying high-risk groups that may progress to gastric cancer.

INTRODUCTION

Gastric cancer is one of the most common cancers worldwide, especially in East Asia[1]. Early diagnosis of this cancer is essential to improve patient survival rate. Gastric cancer development is a complex process[2]. Gastric intraepithelial neoplasia (GIN) is classified into low-grade intraepithelial neoplasia (LGIN) and high-grade intraepithelial neoplasia (HGIN). Based on the new 2019 World Health Organization (WHO) classification of tumors, LGIN is one of the precancerous lesions of gastric cancer, demonstrating a close association with gastric cancer[3].

Drug therapy and endoscopic treatment are recommended by WHO/Vienna for GIN[4]. The European guidelines[5] suggest that detected gastric LGINs should be resected, and the resected samples should undergo a more accurate pathological examination. Endoscopic resection is recommended regardless of the adenoma size or concurrent dysplasia[6,7]. Furthermore, experts[6] recommend that LGIN lesions present even after a 1-year follow-up should be treated with endoscopic resection. Thus, the treatment principles are varied, highlighting the lack of a currently available universal strategy to evaluate and manage LGIN worldwide.

In China, endoscopic treatment might not be necessary for certain patients with LGIN. Conversely, disregarding the risk of LGIN may result in its missed diagnosis or misdiagnosis[8]. Moreover, excessive endoscopic follow-up may increase the examination-related risks and treatment costs for patients at a low-risk stage. Therefore, identifying risk factors is necessary and provides practical clinical value in predicting and evaluating the likelihood of LGIN progression. Here, we conducted a multi-center prospective study to investigate the risk factors associated with LGIN progression and to predict the prognosis of patients with LGIN for effectively identifying high-risk groups that may progress to gastric cancer. Our study outcomes may aid in strengthening the monitoring and active treatment of patients with LGIN, ultimately contributing to reducing gastric cancer incidence and avoiding excessive examination and wastage of medical resources.

MATERIALS AND METHODS

Demographic characteristics

This prospective review initially enrolled 442 patients > 18 years of age who underwent gastroscopy in the endoscopy centers of Anhui Provincial Hospital or three other medical consortium units (Fuyang People’s Hospital, Bozhou People’s Hospital, and Taihe County People’s Hospital) between January 2022 and June 2024 and were diagnosed with LGIN on pathological examination (Figure 1). The diagnostic criteria for LGIN were based on the WHO pathological diagnostic criteria for digestive system tumors[3]. A total of 85 patients were excluded because the endoscopic treatment and surgical procedure that they underwent did not allow the observation of the natural course of LGIN. Consequently, 357 patients were finally included in this study, from which 61 were lost to follow-up for at least 1 year of the study follow-up period.

Figure 1 Patient selection flow chart. LGIN: Low-grade intraepithelial neoplasia.

Data collection

The observation indicators encompassed fundamental clinical and pathological data, including age, gender, outpatient or hospital identification number, duration of the disease, history of gastric surgery, endoscopic findings related to lesions (such as their location and size), postoperative histopathological diagnoses, and subsequent disease progression. The primary endpoint of the observation was the pathological examination results indicating either the regression or progression of LGIN. Furthermore, the risk factors evaluated for long-term progression included the temporal course, age, gender, lesion location, presence of multiple lesions, lesion size, and lesion morphology. This study received approval from the Ethics Committee of Anhui Provincial Hospital (No. 2024-KY-372).

Statistical analysis

All data were analyzed and processed using statistical product and service solutions 22.0 software. Continuous variables were expressed as mean ± SD and compared using the t test. Count data were presented as percentages and compared by performing the χ² test. Progressive factor analysis was performed using multivariate logistic regression analysis. A P value of < 0.05 indicated statistically significant differences.

RESULTS

Demographic characteristics

We initially selected data from 442 patients from the four institutions described above. However, 85 patients were excluded because they had undergone endoscopic treatment and surgery. Ultimately, 357 patients (mean age: 54.66 ± 14.48 years) were included in this study. Additionally, 61 patients were lost to follow-up for at least 1 year of the study follow-up period. A flowchart of the patient screening process in this study is illustrated in Figure 1.

Clinical and pathological characteristics of the patients with LGIN

The 357 patients with LGIN selected in this study showed varying lesion shapes during endoscopy. The distribution sites of LGIN were as follows: Gastric antrum (54.6%), gastric cardia (24.1%), gastric angulus (8.7%), gastric body (4.8%), gastric fundus (4.8%), and multiple sites (3.1%). Moreover, of the 357 patients with LGIN, 112 (31.4%) had ulceration and 59 (16.5%) had gastric polyps. Furthermore, most patients [291 (81.5%)] had a lesion size < 2 cm, with protuberant lesions being the most common form of LGIN [165 (46.2%)]. Table 1 provides the complete details of the clinical and pathological characteristics of the study patients.

Table 1 Clinical and pathological characteristics of low-grade intraepithelial neoplasia patients, n (%).

Characteristic	Overall patients (n = 357)	Patients follow up (n = 296)
Age, mean ± SD	54.66 ± 14.48	54.34 ± 14.40
Gender
Male	198 (55.5)	163 (55.1)
Female	159 (44.5)	133 (44.9)
Lesion location
Antrum	195 (54.6)	161 (54.4)
Angulus	31 (8.7)	25 (8.4)
Body	17 (4.8)	14 (4.7)
Fundus	17 (4.8)	14 (4.7)
Cardia	86 (24.1)	72 (24.3)
Multiple location	11 (3.1)	10 (3.4)
Lesion size
< 2 cm	291 (81.5)	241 (81.4)
≥ 2 cm	66 (18.5)	55 (18.6)
Congestion
Yes	250 (70.0)	207 (69.9)
No	107 (30.0)	89 (30.1)
Form
Protuberant	165 (46.2)	135 (45.6)
Flat	139 (38.9)	118 (39.9)
Central depression	53 (14.8)	43 (14.5)
Comorbidities
Ulceration	112 (31.4)	90 (30.4)
Gastric polyps	59 (16.5)	52 (17.6)
None	186 (52.1)	154 (52.0)
Prognosis
Progress		33 (11.1)
Retrogress		200 (67.6)
Unchanged		63 (31.3)

Relationship of Helicobacter pylori infection with atrophy, intestinal metaplasia, and gastric ulcer in patients with LGIN

Of the 357 patients with LGIN, 231 (64.71%) tested positive for Helicobacter pylori (H. pylori) infection. The H. pylori infection rates of patients with LGIN combined with atrophy, intestinal metaplasia, and gastric ulcer were 51.95%, 59.31%, and 28.57%, respectively. Further information on these associations is presented in Table 2.

Table 2 Relationship between Helicobacter pylori infection and intestinal metaplasia, atrophy, and gastric ulcer in low-grade intraepithelial neoplasia patients.

	H. pylori infection		P value
	Positive (n = 231)	Negative (n = 126)
Atrophy
Yes	120	64	0.740
No	111	62
Intestinal metaplasia
Yes	137	77	0.835
No	94	49
Ulceration
Yes	66	46	0.122
No	165	80

H. pylori: Helicobacter pylori.

Follow-up and outcome of the patients with LGIN

Given that 61 patients were lost to follow-up for at least 1 year of the study follow-up period, follow-up data was obtained from the remaining 296. The patients included 163 men and 133 women, with an average age of 54.34 ± 14.40 years. The average follow-up time was 2.53 ± 0.84 years. Gastric ulcer was the primary comorbidity in 90 (30.4%) patients. Furthermore, disease progression occurred in 33 of the 296 patients, leading to an LGIN development rate of 11.1%. Among them, LGIN reversal accounted for 67.6%, maintenance for 29.3%, and progression for 14.0% (see Table 1). Of the 33 patients who experienced LGIN progression, 21 had advanced to HGIN and 12 to gastric cancer, with an average progression time of 18.13 months.

Univariate logistic regression analysis

The differences between patients with LGIN progression and non-progression were assessed by performing univariate logistic regression analysis. The results showed that age ≥ 60 years, multiple locations, lesion size ≥ 2 cm, concurrent gastric ulcer, and H. pylori infection were risk factors for LGIN progression (all P < 0.05), whereas the other evaluated risk factors did not exhibit any such association (see Table 3).

Table 3 Univariate logistic regression analysis of risk factors on low-grade intraepithelial neoplasia progression.

Characteristic	Progress	Non-progress	OR (95%CI)	P value
Age
≥ 60	21	92	3.114 (1.356-7.153)	0.007
< 60	12	171	Ref.
Gender
Male	13	150	1.795 (0.785-4.105)	0.166
Female	20	113	Ref.
Multiple location
Yes	5	5	10.838 (2.023-58.076)	0.005
No	28	258	Ref.
Lesion size
≥ 2 cm	15	40	4.189 (1.751-10.018)	0.001
< 2 cm	18	223	Ref.
Congestion
Yes	10	79	1.208 (0.474-3.078)	0.157
No	23	187	Ref.
Form
Protuberant	11	107	0.757 (0.413-1.387)	0.367
Flat	18	117	0.966 (0.587-2.236)	0.438
Central depression	4	39	Ref.
Ulceration
Yes	16	74	2.685 (1.161-6.207)	0.021
No	17	189	Ref.
Atrophy
Yes	18	125	1.107 (0.482-2.542)	0.811
No	15	1381	Ref.
Intestinal metaplasia
Yes	159	104	0.815 (0.346-1.922)	0.640
No	20	13	Ref.
H. pylori infection
Yes	29	163	4.448 (1.159-13.027)	0.006
No	4	100	Ref.

H. pylori: Helicobacter pylori; OR: Odds ratio; CI: Confidence interval.

Multivariate logistic regression analysis

The factors influencing LGIN progression were explored by conducting a multivariate logistic regression analysis of the statistically significant risk factors detected in the univariate logistic regression analysis. Our findings demonstrated that age ≥ 60 years [odds ratio (OR) = 3.063, 95% confidence interval (CI): 1.351-6.945, P = 0.007], H. pylori infection (OR = 3.560, 95%CI: 1.158-10.949, P = 0.027), multiple locations (OR = 10.136, 95%CI: 2.045-50.237, P = 0.005), lesion size ≥ 2 cm (OR = 3.921, 95%CI: 1.664-9.237, P = 0.002), and gastric ulcer (OR = 2.730, 95%CI: 1.197-6.223, P = 0.017) were predictive factors for LGIN progression. Table 4 provides complete information on the multivariate logistic regression analysis.

Table 4 Multivariate logistic regression analysis of risk factors on low-grade intraepithelial neoplasia progression.

Characteristic	Progress	Non-progress	OR (95%CI)	P value
Age
≥ 60	21	92	3.063 (1.351-6.945)	0.007
< 60	12	171	Ref.
Multiple location
Yes	5	5	10.136 (2.045-50.237)	0.005
No	28	258	Ref.
Lesion size
≥ 2 cm	15	40	3.921 (1.664-9.237)	0.002
< 2 cm	18	223	Ref.
Ulceration
Yes	16	74	2.730 (1.197-6.223)	0.017
No	17	189	Ref.
H. pylori infection
Yes	29	163	3.560 (1.158-10.949)	0.027
No	4	100	Ref.

H. pylori: Helicobacter pylori; OR: Odds ratio; CI: Confidence interval.

DISCUSSION

Various domestic and international guidelines recommend endoscopic submucosal dissection therapy for all pathologically diagnosed HGIN cases without exception. However, the principle of LGIN treatment remains controversial. Although LGIN is a known precancerous lesion that has a low likelihood of progressing to cancer, its progression rate to HGIN has been reported to be 0%-23%. Moreover, the annual progression rate from LGIN to gastric cancer is approximately 0.6%[9]. A previous study showed that 12 of 98 (12.2%) patients with LGIN progressed during a 33-month median follow-up period[10]. Another single-center follow-up study found that progression occurred in 42 of 449 patients, resulting in a cancer development rate of 9.4%. The investigation also revealed that foci > 10 mm, ulcerative lesions, and H. pylori positivity were factors significantly affecting LGIN outcomes (P < 0.05)[11]. LGIN progression has been shown to be slow, with the average time for progression to cancer ranging from 10 months to 4 years[12,13]. Although the treatment strategies for LGIN are inconsistent, long-term follow-up is recommended by most guidelines. However, follow-up examinations can exacerbate the financial burden on patients and increase medical risks. Therefore, exploring the risk factors of LGIN progression is extremely crucial. In this study, we identified the LGIN population with a low cancer risk (not needing regular checkups), moderate cancer risk (requiring regular checkups), and high cancer risk (necessitating short-term treatment).

Our study found a significant association between LGIN progression and age, consistent with the results from previous studies[14,15]. Furthermore, onset at multiple sites was demonstrated to be an independent risk factor for LGIN progression, which was contradictory to the prevalent conclusions about single lesions in gastric cancer. In earlier studies, the similar factors were shown to be independent risk factors for postoperative pathological progression in patients with gastric LGIN[14]. Similarly, Liu et al[15] indicated that age, H. pylori infection, a history of antibiotic misuse, and spicy and high-fat diets (all P < 0.05) were independent risk factors of gastric LGIN in asymptomatic patients undergoing physical examination. However, prior studies have also reported contrasting results, such as no correlation between age and LGIN progression[16,17]. Another research suggested that male sex was an independent risk factor for the prolongation or progression of LGIN, which was in line with the higher incidence of gastric cancer in men[18]. A previous study[19] also confirmed that the gastric mucosa undergoes structural changes as LGIN lesions progress, with central depression or nodular surface being associated with the progression of LGIN lesions. In this study, the multivariate logistic regression analysis results indicated a correlation between the prolongation or progression of LGIN and ulceration. However, no significant association was observed between the prolongation or progression of LGIN and lesion morphology (flat, protuberant, or central depression).

Extensive data indicate that the diagnosis of LGIN via gastroscopic biopsy produces results that differ from those obtained through larger biopsy specimens. For instance, previous research has identified a pathological discrepancy of 20.1% between endoscopic forceps biopsy and surgical resection[20]. Notable risk factors include a lesion surface diameter exceeding 1 cm, surface erythema, and a nodular surface. Investigations conducted by Ryu et al[21] have established a significant association between central depression, nodular surface characteristics, and surface redness with early gastric cancer (EGC) and low-grade dysplastic lesions. Consequently, the observed decline in LGIN cases may be attributed to diagnostic inconsistencies. Lesion size is recognized as a common characteristic of malignant tumors, aligning with the findings of our study[22]. An increase in lesion size correlates with an elevated risk of LGIN progression. The Operative Link on Gastritis Assessment (OLGA) and Operative Link on Gastritis Intestinal Metaplasia (OLGIM) staging systems are currently utilized to evaluate the accuracy of gastric mucosal atrophy and intestinal metaplasia. According to these systems, patients classified as OLGA/OLGIM stages III and IV are deemed at high risk for gastric cancer[23]. The OLGIM staging system demonstrates a higher rate of interdisciplinary diagnostic agreement compared to the OLGA system, albeit with lower sensitivity[24]. A prior case-control study indicated that OLGA and OLGIM stages II, III, and IV were more prevalent among patients with EGC compared to control subjects. Furthermore, multivariable analysis identified a family history of gastric cancer, previous H. pylori infection, and OLGA stages II and III-IV, as well as OLGIM stages II and III-IV, as independent risk factors for EGC (ORs: 4.04, 1.87, 2.52, 6.79, 4.11, and 10.78, respectively)[25]. In the current study, we found that intestinal metaplasia did not serve as an independent risk factor for the progression of LGIN, which may be attributable to the methodology employed in assessing intestinal metaplasia.

The development of gastric cancer is a stepwise process[2], with LGIN representing a stage in this transformation process. However, the current multi-center prospective study aimed to review patients with LGIN who were followed up in the endoscopy centers at one of four institutions in Anhui Province between January 2022 and June 2024. The follow-up time of this study was at least 1 year. A previous study reported that 12 of 98 (12.2%) patients with LGIN progressed during the 33-month median follow-up period[10], which was similar to our study finding (11.1%).

Endoscopic resection techniques, specifically endoscopic mucosal resection and endoscopic submucosal dissection, are widely recognized as the standard therapeutic approach for EGC[26,27]. Moreover, recent advancements in endoscopic methodologies have resulted in a 5-year overall survival rate of > 90% in patients with EGC who meet the absolute or expanded criteria for endoscopic intervention[28,29]. This treatment strategy has not only gained notable traction in Asian nations but has also started to attract the interest of endoscopists in Western countries[30]. The successful endoscopic management of EGC necessitates a standardized treatment protocol, encompassing thorough preoperative evaluation and careful interpretation of postoperative pathology. This procedure is particularly critical in determining the requirement for additional surgical intervention following a non-curative resection of the malignancy. Among the various risk factors, H. pylori infection is associated with inflammatory cell infiltration in the mucosal layer and increased intercrop distance[31]. Furthermore, implementing H. pylori eradication therapy can potentially reverse these morphological changes in the short term[32,33]. Nevertheless, regular follow-up and gastroscopy biopsy combined with magnifying staining endoscopy should be strengthened to assist in discrimination.

Our study has several limitations that should be considered. First, the relatively small sample size (296 patients with sufficient follow-up data) and the study focus on a single geographic region may have limited the generalizability of our findings. Second, the short follow-up duration may not have fully captured the long-term progression dynamics of LGIN. Thus, a long-term perspective of LGIN progression should be provided by performing longitudinal follow-up studies. Finally, some unexplored variables, such as dietary factors, genetic predisposition, or a family history of gastric cancer, could have also influenced LGIN progression. Therefore, future studies exploring these uninvestigated factors in larger and more diverse populations should be conducted to validate our results.

CONCLUSION

The present study found that age, H. pylori positivity, multiple locations, lesion size ≥ 2 cm, and gastric ulcer are closely related to LGIN progression based on the preliminary analysis of potential factors linked to the prognosis of patients with LGIN who had a clear diagnosis and regular follow-up. Our findings indicate that clinical physicians should comprehensively evaluate the clinical characteristics of patients with LGIN, especially those with the risk factors mentioned above. In conclusion, LGIN progression is closely associated with age, H. pylori positivity, multiple locations, lesion size ≥ 2 cm, and gastric ulcer. Furthermore, actively identifying such relevant risk factors in patients with LGIN is essential, providing certain clinical significance in preventing further tumor progression.