
==== Front
Chin Med J (Engl)
Chin Med J (Engl)
CM9
Chinese Medical Journal
0366-6999
2542-5641
Lippincott Williams & Wilkins Hagerstown, MD

38602084
CMJ-2023-2126
10.1097/CM9.0000000000003080
00009
3
Original Article
Role of submucosal injection in radiofrequency ablation of gastric low-grade dysplasia: Effects on symptoms and outcomes
Niu Xiaotong 1 2
Wang Nanjun 2
Wang Yan 2 3
Feng Jia 4
Li Longsong 2
Han Ke 1 2
Chai Ningli 2
Linghu Enqiang 2
Pan Xiangxiang
1 Medical School of Chinese PLA General Hospital, Beijing 100853, China
2 Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, Beijing 100853, China
3 Nankai University School of Medicine, Nankai University, Tianjin 300071, China
4 Department of Gastroenterology, Bethune International Peace Hospital, ShijiaZhuang, Hebei 050082, China
Correspondence to: Enqiang Linghu, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing 100853, China E-Mail: linghuenqiang@vip.sina.com;
Ningli Chai, Department of Gastroenterology and Hepatology, The First Medical Center, Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing 100853, China E-Mail: chainingli@vip.163.com
10 4 2024
05 9 2024
137 17 20992110
08 10 2023
Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

Abstract

Background:

To date, there is still a lack of standardized management strategies for gastric low-grade dysplasia (LGD), which is a direct neoplastic precancerous lesion and requires specifically superficial destruction. Radiofrequency ablation (RFA) is expected to be an effective method for gastric LGD, but post-RFA pain may affect patients’ satisfaction and compliance. The current study aimed to evaluate the value of a submucosal injection prior to RFA (SI-RFA) for postoperative pain and treatment outcomes.

Methods:

Between October 2014 and July 2021, gastric LGDs without risk factors (size >2 cm, unclear boundary, and abnormal microsurface and microvascularity) undergoing regular RFA and SI-RFA were retrospectively analyzed. Postoperative pain scores, wound healing, and clinical efficacy were compared. Propensity score matching, stratified analysis, and multivariable logistic regression were performed to control the confounding variables.

Results:

One hundred and ninety-seven gastric LGDs in 151 patients received regular RFA. Forty-nine gastric LGDs in 36 patients received SI-RFA. Thirty-six pairs of patients were selected for the assessment of postoperative pain by propensity score matching. Compared to regular RFA, SI-RFA significantly decreased the degree and duration of postoperative pain (OR, 0.32; 95% CI, 0.13–0.84; P = 0.020), improved wound healing rate (80.0% [36/45] vs. 58.9% [89/151], P = 0.012), increased the complete ablation rate (91.8% [45/49] vs. 86.3% [170/197], χ2 = 1.094, P = 0.295), but correlated with higher rates of local recurrence and progression (25.6% [10/39] vs. 13.2% [18/136], χ2 = 3.471, P = 0.062; 8.3% [3/36] vs. 0.9% [1/116], P = 0.042). The multivariable logistic regression model confirmed that submucosal injection was associated with local recurrence (OR, 2.93; 95% CI, 1.13–7.58; P = 0.027).

Conclusions:

Submucosal injections prior to RFA may reduce postoperative pain and scar formation while ensuring complete ablation of gastric LGD. However, local recurrence and progression should be considered seriously.

Keywords:

Gastric low-grade dysplasia
Radiofrequency ablation
Submucosal injection
Postoperative pain
Treatment outcome
OPEN-ACCESSTRUE
SDCT
==== Body
pmcIntroduction

Gastric dysplasia (GD), a direct neoplastic precancerous lesion, is histologically classified into low-grade dysplasia (LGD) and high-grade dysplasia (HGD) based on the degree of cellular and architectural atypia.[1] There is a consensus that gastric HGD is highly indicative of invasive carcinoma and requires endoscopic resection (ER),[2,3] whereas agreement has not been reached on the therapeutic strategies for LGD due to uncertainty regarding its clinical prognosis and the discrepancy between pretreatment histology and post-ER results.[45678] Follow-up strategies may place patients at risk of missing the best opportunity for treatment, and repeated endoscopic examination with biopsies can impose a physical, psychological, and financial burden on the patients. Hence, the management of epithelial precancerous conditions and lesions in the stomach (MAPS II) guideline by the European Society of Gastrointestinal Endoscopy (ESGE) suggests that endoscopically visible lesions with any neoplastic change should be considered for treatment.[9] ER, which allows for accurate histological diagnosis, is recommended by many researchers for gastric LGDs, especially for those with the following risk factors: a size ≥1 cm, depressed morphology, surface erythema, nodularity, or erosion.[8,10,11] But ER still carries a risk of adverse events and requires hospital admission.[12] Thus, for gastric LGDs without risk factors, a safer, more convenient, and effective treatment that can be delivered in the outpatient setting is needed and of realistic clinical value.

Radiofrequency ablation (RFA) has been recommended as an efficient therapy in treating LGD,[131415] providing controlled ablation depth, safety, and no necessity for hospital admissions. However, the thermal effects of RFA can sometimes be extended into the submucosa and muscularis propria layers,[161718] increasing the risk of adverse events, such as bleeding and perforation. Moreover, patients experience varying degrees of gastric pain after RFA,[19202122] which may be partly due to the deep-tissue injury. Exploring a method ensuring superficial precise-depth ablation with the preserving of deeper layers will help prevent adverse events and alleviate postoperative discomfort, thus enhancing patients’ satisfaction and compliance with additional treatment or surveillance.

Submucosal injection is a competent method to improve the safety and outcomes of ER.[23] The injection lifts up the lesion, separating it from the deeper muscular layer, thereby reducing thermal injury to deep tissues. Argon plasma coagulation (APC) combined with submucosal injection has been reported to be useful for the treatment of gastric LGD,[24] but pieces of evidence are lacking on the application of submucosal injection prior to RFA (SI-RFA). In this retrospective study, the use of SI-RFA in gastric LGD management was elucidated by comparing postoperative pain, wound healing, and clinical efficacy to regular RFA outcomes in outpatients.

Methods

Study design

This was a retrospective cohort study of patients who underwent RFA for gastric LGD at the Chinese PLA General Hospital between October 2014 and July 2021, following the Declaration of Helsinki.

The study proposal was reviewed and approved by the Ethics Committee of the Chinese PLA General Hospital (No. S2018-213-02). The Ethics Committee waived the requirement for written informed consent. Two study groups were defined based on whether the submucosal injection was performed prior to RFA. The data were extracted by two experienced endoscopists in consensus after reviewing the patient medical records, gastroscopic images, and pathology reports from the medical digital engineering database system (Medcare, Qingdao, Shandong Province, China).

Inclusion criteria

Patients were consecutively included in the study if they underwent an endoscopic therapy for gastric LGD diagnosed by the index endoscopic forceps biopsy (EFB) between October 2014 and July 2021. The diagnostic criteria of gastric LGD referred to the World Health Organization (WHO) classification of the digestive system tumors,[25] that is, minimal architectural disarray and only mild-to-moderate cytological atypia, corresponding to mild and moderate gastric atypical hyperplasia and low-grade intraepithelial neoplasia. The histological images were first independently assessed by a gastroenterological pathologist with 3–5 years of experience and then confirmed by an expert pathologist with 5–10 years of experience. The lesion type was identified by the consensus between the two pathologists. In case of disagreement, a third pathologist with more than 10 years of experience conducted further evaluation and, following discussion, they collectively reached a final decision.

Exclusion criteria

Patients were excluded based on the following situations: (1) they received interventions other than RFA (e.g., ER and APC); (2) the patients had a medical history of gastrointestinal tract carcinoma, gastrectomy, chemical therapy, or radiotherapy on the abdomen; (3) the patients previously had HGD on the lesion site or had received endoscopic therapy within six months; (4) post-RFA biopsy samples from the lesion site were suggestive of HGD or gastric cancer (GC) within 12 months; and (5) the patients did not complete any surveillance gastroscopy (SG) at our hospital.

RFA procedure

All endoscopic procedures were performed by three skilled endoscopists in the outpatient department. A therapeutic endoscope (GIF-Q260J; Olympus Medical Corp, Tokyo, Japan) and the Barrx Radiofrequency Ablation System (Covidien GI Solutions, Sunnyvale, CA, USA) were used for RFA. An accessory equipment of the Barrx System (Covidien TTS-1100; 60RFA Conduit 909300, Medtronic, Minnesota, USA) and a high-frequency generator (ICC-200; Erbe Elektromedizin GmbH, Tübingen, Germany) were used to ablate the lesion. A disposable injector (NM-200L-0425; Olympus Medical Corp, Tokyo, Japan) was used to inject normal saline (NS) submucosally. Hemostatic forceps (FD-410 LR; Olympus Medical Corp, Tokyo, Japan) and the EZ hemostasis clip (HX-610-135; Olympus Medical Corp, Tokyo, Japan) were used to control hemorrhage and prevent perforation.

A comprehensive examination of the upper gastrointestinal tract was carried out before RFA using white-light high-resolution endoscopy and magnifying endoscopy (ME) with narrow-band imaging (NBI) to better characterize the mucosa and delineate the target area. The lesion images of the close view and the long view were captured. For lesions with risk factors (size of >2 cm, unclear boundary, and abnormal microsurface and microvascularity),[15] EFB was performed to confirm the diagnosis before treatment. Lesions without risk factors were treated with RFA.

Regular RFA

The procedure has been reported previously.[20] A through-the-scope catheter was attached to the endoscope and then advanced to the stomach for a focal RFA. The electrode was apposed to the lesion by manipulating the endoscope to achieve adequate contact, and the lesion was then ablated with a power output of 48 W or 57 W and an energy density of 12 J/cm2 or 15 J/cm2. After the ablation, the surface of the lesion was covered with white coagulated necrotic tissue that was eventually removed before the subsequent ablation. Three sequential applications were done to ensure complete lesion destruction.

SI-RFA

Before ablation, NS was injected into the submucosa of the lesion area until the mucosal layer and the muscle layer were sufficiently separated. When the lesion was elevated by the NS cushion, RFA was performed according to the regular RFA.

Postoperative pain scoring

Pain perceived after the treatment was assessed using the Wong–Baker FACES® Pain Rating Scale (WBFPS). The WBFPS is a visual analog scale representing six faces with increasing degrees of pain from left to right, scored from 0 (no pain) to 10 (worst pain imaginable) at intervals of 2. Patients were asked to point out which face most accurately represented their daily pain and to record the corresponding pain score on a form from postoperative days 0–13. The form was given to the endoscopist at the patient’s first SG.

Post-RFA management

Each patient fasted for 4–6 h after RFA and then started with a liquid or semiliquid diet and gradually transitioned to a normal diet. A proton pump inhibitor (esomeprazole at a dosage of 20 mg/day) and a mucosal protectant (teprenone at a dosage of 150 mg/day) were administered for 4 weeks following RFA.

SG was performed at 1–3 months, 6 months, and 12 months after the RFA to evaluate wound healing and clinical efficacy, and it was scheduled annually thereafter. During the SG, the original ablation site was thoroughly examined using a combination of white light high-resolution endoscopy with NBI. Biopsy sampling was performed in the original ablation site and other suspected areas, and the samples were histologically examined to confirm or exclude the presence of dysplasia. Patients diagnosed with residual or recurrent LGD received a second RFA, or endoscopic follow-up after the 3-month medical treatment. Patients diagnosed with HGD or early gastric cancer (EGC) underwent endoscopic submucosal dissection (ESD). The original ablation site was determined by viewing digital image recordings taken during the RFA and observing the postoperative scar as appropriate.

Definitions

The disease duration was defined as the interval between the first pathological diagnosis of LGD at any part of the stomach and the RFA. The lesion duration was defined as the interval between the initial pathological diagnosis of the lesion as LGD and the RFA for it. The presence of current Helicobacter pylori (H. pylori) infection was determined according to the [13C]-urea breath test before RFA or postoperative histological evaluation.

The number of lesions was classified as singular, synchronous multiple, and metachronous multiple. Lesions in a different part of the stomach were defined as synchronous if they were detected within 12 months after the RFA, and those were defined as metachronous if diagnosed more than 12 months.[26] The gross morphology of the lesions was determined based on the Paris classification.[27] The surface configuration referred to the color, erosion, ulcer, and spontaneous bleeding of the lesions.[6,28] The lesion size was estimated using endoscopic forceps. The ablation area was estimated using an electrode sheet for RFA.

The gastric mucosa was evaluated for the presence of active inflammation, atrophy, and intestinal metaplasia, based on the updated Sydney system.[29] Endoscopic evaluation of gastric atrophy was determined following the Kimura and Takemoto[30] classification (close types C-0–C-3 and open types O-1–O-3).

The starting date of the follow-up was defined as the date of the RFA, and the end of the follow-up was the last date of the follow-up endoscopy. The clinical efficacy was judged according to the pathological results of the biopsy from the post-RFA site. If the pathological results were all negative within 6 months after the procedure, the lesion was considered completely ablated. If LGD at the post-RFA site was pathologically diagnosed within 6 months, it was defined as residue. If LGD at the post-RFA site was pathologically diagnosed more than 6 months after the procedure, it was defined as local recurrence. If HGD or GC at the post-RFA site was pathologically diagnosed within 12 months, it was regarded as previous EFB-underestimation. If HGD or GC at the post-RFA site was pathologically diagnosed more than 12 months after the procedure, it was defined as progression.[2,6]

Referring to Sakita’s[31] endoscopic staging system of the peptic ulcer, the healing process of the wound was categorized into five stages: active (A), healing (H), red scarring (S1), white scarring (S2), and complete healing (C). Complete healing was defined as the complete repair of the mucosal defect without scarring, the endoscopic appearance of which was the same as that of the surrounding mucosa, or only erythema and other inflammatory manifestations were seen.

Statistical analysis

The primary outcomes were the postoperative pain score and the complete ablation of gastric LGD. The secondary outcomes were wound healing, local recurrence, and progression of the cancerous lesion. Since this was the first retrospective study comparing the clinical outcomes between SI-RFA and regular RFA, the required sample size could not be calculated in advance. If a patient was treated more than once at different times, it was counted as different patients. Normally distributed continuous variables were compared using the independent sample t-test. Non-normally distributed continuous variables and ranked ordinal variables were compared by the Mann–Whitney U-test. Categorical variables were compared by the chi-squared test or Fisher’s exact test.

The logistic regression model calculated the propensity score of the case based on the ablation area and the presence of acute inflammation. Then, patients from the two groups were paired using the nearest-neighbor propensity score in a 1:1 ratio with a caliper of 0.2. In the matched cohorts, the trend of postoperative pain scores over time was compared by a generalized estimation equation. The factors associated with postoperative pain on the day of the RFA were estimated using ordinal multinomial logistic regression.

We used the Cochran–Mantel–Haenszel test to control for stratification factors (lesion location, gross morphology, lesion size, and disease duration), and then analyzed the adjusted association between submucosal injection and clinical outcomes (residual rate, local recurrence rate, and progression rate). Further, univariable and multivariable regression analyses were performing to identify the factors affecting clinical efficacy. Covariates that were statistically significant with a P-value of <0.2 from the univariable analysis and those considered clinically significant were selected as candidates to incorporate into the multivariable regression model. A P-value of <0.05 was considered statistically significant. Statistical analyses were performed using the SPSS software version 26.0 (SPSS Inc., Chicago, IL, USA).

Results

Basic characteristics

The flowchart of the patient inclusion in the study is presented in Figure 1. A total of 246 gastric LGDs (median size, 6 mm; interquartile range [IQR], 5–10 mm) from 187 patients (mean age with standard deviation, 57.6 ± 9.9 years; 37.4% [70/187] women) were ultimately assessed. Of these conditions, 197 gastric LGDs in 151 patients received regular RFA. Forty-nine gastric LGDs in 36 patients underwent SI-RFA [Figure 1]. Besides the median ablation area, no significant differences in patient or lesion characteristics were found between the two groups [Table 1].

Figure 1 Flowchart of the present study. APC: Argon plasma coagulation; ER: Endoscopic resection; GC: Gastric cancer; HGD: High-grade dysplasia; LGD: Low-grade dysplasia; RFA: Radiofrequency ablation; SI-RFA: Submucosal injection prior to RFA.

Table 1 Basic characteristics of patients with gastric low-grade dysplasia and lesion characteristics of gastric low-grade dysplasia.

Items	Regular RFA	SI-RFA	Statistics	P-value	
Patient characteristics	n = 151	n = 36			
Age (years)	57.7 ± 10.3	56.9 ± 8.4	0.435*	0.664	
Male	91 (60.3)	26 (72.2)	1.775†	0.183	
Disease duration (days)	90.0 (30.0–236.0)	64.0 (45.0–356.0)	–1.019‡	0.308	
Current H. pylori infection	40 (26.5)	4 (11.1)	3.821†	0.051	
Number of lesions				0.220§	
Singular	70 (46.4)	19 (52.8)			
Synchronous multiple	50 (33.1)	7 (19.4)			
Metachronous multiple	16 (10.6)	3 (8.3)			
Synchronous and metachronous multiple	15 (9.9)	7 (19.4)			
Number of lesions ablated this time			3.091†	0.213	
1	107 (70.9)	26 (72.2)			
2	40 (26.5)	7 (19.4)			
3	4 (2.6)	3 (8.3)			
Lesion characteristics	n = 197	n = 49			
Median lesion duration (days)	47.0 (23.0–137.0)	58.0 (45.0–98.0)	–1.442‡	0.149	
Median lesion length (cm)	0.6 (0.5–1.0)	0.6 (0.5–0.8)	–1.099‡	0.272	
Location				0.223§	
Gastric fundus—cardia area	1 (0.5)	2 (4.1)			
Gastric body	15 (7.6)	3 (6.1)			
Gastric angle	52 (26.4)	10 (20.4)			
Antrum of stomach—pylorus area	129 (65.5)	34 (69.4)			
Paris classification				0.424§	
0-I	4 (2.0)	1 (2.0)			
0-IIa	20 (10.2)	7 (14.3)			
0-IIb	83 (42.1)	14 (28.6)			
0-IIc	30 (15.2)	8 (16.3)			
0-IIa + IIc	60 (30.5)	19 (38.8)			
Surface configuration					
Erythema	181 (91.9)	48 (98.0)		0.207§	
Erosion	106 (53.8)	28 (57.1)	0.176†	0.675	
Ulcer/ulcer scar	2 (1.0)	0 (0)		1.000§	
Spontaneous bleeding	3 (1.5)	0 (0)		1.000§	
Gastric mucosa					
Acute gastric inflammation	135 (68.5)	31 (63.3)	0.495†	0.482	
Atrophy			–0.499‡	0.618	
No	60 (30.5)	13 (26.5)			
C-1	49 (24.9)	15 (30.6)			
C-2	75 (38.1)	14 (28.6)			
C-3	12 (6.1)	7 (14.3)			
O-1	1 (0.5)	0 (0)			
Intestinal metaplasia	192 (97.5)	46 (93.9)		0.199§	
Previous treatment at the lesion site				0.409§	
None	193 (98.0)	47 (95.9)			
RFA	3 (1.5)	2 (4.1)			
APC	1 (0.5)	0 (0)			
Number of lesions			0.179†	0.673	
Singular	70 (35.5)	19 (38.8)			
Multiple	127 (64.5)	30 (61.2)			
Procedural characteristics					
Per patient median ablation area (cm2)	4.0 (2.0–7.5)	1.4 (1.0–3.0)	–3.770‡	<0.001	
Per lesion median ablation area (cm2)	3.0 (1.9–5.3)	1.0 (0.5–2.0)	–5.498‡	<0.001	
Per lesion median ablation time (min)	6.0 (2.0–9.0)	5.0 (3.0–7.0)	–1.261‡	0.207	
Values are presented with n, n (%), mean ± standard deviation, or median with interquartile range. *t values; †χ2 values; ‡Z-value; §Fisher’s exact test. APC: Argon plasma coagulation; H. pylori: Helicobacter pylori; RFA: Radiofrequency ablation; SI-RFA: Submucosal injection prior to RFA.

Postoperative pain

After propensity score matching, 36 pairs of patients who received regular RFA and SI-RFA were selected for the analysis. These patients did not differ in any of the basic characteristics [Table 2]. On the day of the ablation procedure, patients who received SI-RFA suffered less pain than those who had undergone regular RFA (Z = –2.115, P = 0.034) [Table 3]. On postoperative days 0–13, SI-RFA was associated with a decrease in pain intensity and duration (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.13–0.84; P = 0.020) [Figure 2]. On the first postoperative day, the pain-free rate in the SI-RFA group was 61.1% (22/36), which was only 36.1% ([13/36], χ2 = 2.083; P = 0.037) in the regular RFA group and did not reach 61.1% until the 8th postoperative day. Further, none of the patients in the SI-RFA group experienced severe pain since the first postoperative day, while one patient ([1/36], 2.8%) in the regular RFA group reported severe pain persisting on the 7th postoperative day [Figure 2]. Univariable and multivariable regression analyses further confirmed that submucosal injection corresponded to a lower likelihood of postoperative pain (OR, 0.32; 95% CI, 0.12–0.82; P = 0.017) [Table 4].

Table 2 Basic characteristics of patients with gastric LGDs treated by regular RFA and SI-RFA in matched cohorts.

Items	Regular RFA (n = 36)	SI-RFA (n = 36)	Statistics	P-value	
Age (years)	56.1 ± 10.6	56.9 ± 8.4	0.396*	0.693	
Male	20 (55.6)	26 (72.2)	2.167†	0.220	
Disease duration (days)	50.0 (31.3–136)	64.0 (45.0–356.0)	–1.712‡	0.087	
Current H. pylori infection	11 (30.6)	4 (11.1)	4.126†	0.079	
Acute gastric inflammation	21 (58.3)	20 (55.6)	0.057†	0.812	
Atrophy			–1.631‡	0.103	
No	16 (44.4)	10 (27.8)			
C-1	11 (30.6)	12 (33.3)			
C-2	8 (22.2)	11 (30.6)			
C-3	1 (2.8)	3 (8.3)			
O-1	0 (0)	0 (0)			
Number of lesions				0.132§	
Singular	19 (52.8)	19 (52.8)			
Synchronous multiple	11 (30.6)	7 (19.4)			
Metachronous multiple	5 (13.9)	3 (8.3)			
Synchronous and metachronous multiple	1 (2.8)	7 (19.4)			
Number of lesions ablated this time				0.211§	
1	31 (86.1)	26 (72.2)			
2	5 (13.9)	7 (19.4)			
3	0 (0)	3 (8.3)			
Per patient median ablation area (cm2)	2.0 (0.5–4.5)	1.4 (1.0–3.0)	–0.695‡	0.487	
Values are presented with n, n (%), mean ± standard deviation, or median with interquartile range. *t values; †χ2 values; ‡Z-value; §Fisher’s exact test. LGD: Low-grade dysplasia; H. pylori: Helicobacter pylori; RFA: Radiofrequency ablation; SI-RFA: Submucosal injection prior to RFA.

Table 3 Postoperative pain score on the day of RFA.

Items	Regular RFA (n = 36)	SI-RFA (n = 36)	Z-value	P-value	
Postoperative pain scores		–2.115	0.034	
0	12 (33.3)	21 (58.3)			
2	9 (25.0)	7 (19.4)			
4	10 (27.8)	5 (13.9)			
6	3 (8.3)	2 (5.6)			
8	2 (5.6)	1 (2.8)			
Values are presented with n (%). RFA: Radiofrequency ablation; SI-RFA: Submucosal injection prior to RFA.

Figure 2 Daily pain score on postoperative days 0–13 in the regular RFA group and the SI-RFA group. The trends of postoperative pain score over time were compared by the generalized estimation equation. SI-RFA predicted a significantly decreased OR for postoperative pain in comparison with regular RFA (OR, 0.32; 95% CI, 0.13–0.84; χ2 = 5.422; P = 0.020). *P <0.05. CI: Confidence interval; OR: Odds ratio; RFA: Radiofrequency ablation; SI-RFA: Submucosal injection prior to RFA.

Table 4 Univariable and multivariable regression analyses of factors associated with postoperative pain on the day of RFA.

Variable	Univariable analysis	Multivariable analysis	
OR (95% CI)	Statistics	P-value	OR (95% CI)	Statistics	P-value	
Submucosal injection (yes vs. no)	0.39 (0.16–0.93)	–0.951	0.034	0.32 (0.12–0.82)	–1.129	0.017	
Gender (female vs. male)	0.53 (0.22–1.33)	–0.627	0.177				
Age (years)	1.04 (0.99–1.09)	0.038	0.111				
Disease duration (days)	1.001 (1.000–1.002)	0.001	0.139				
Current H. pylori infection (yes vs. no)	1.57 (0.56–4.42)	0.450	0.394				
Acute gastric inflammation (yes vs. no)	3.15 (1.27–7.83)	1.148	0.014	3.08 (1.19–8.02)	1.126	0.021	
Atrophy (yes vs. no)	1.45 (0.59–3.56)	0.373	0.415				
Number of lesions ablated this time (multiple vs. single)	0.69 (0.24–2.02)	–0.370	0.499				
Per patient median ablation area (cm2)	1.22 (1.07–1.39)	0.201	0.002	1.21 (1.06–1.38)	0.188	0.005	
CI: Confidence interval; H. pylori: Helicobacter pylori; OR: Odds ratio; RFA: Radiofrequency ablation.

Wound healing

Lesions ablated using SI-RFA achieved better wound healing in the first month (Z = –2.512, P = 0.012) with more complete healing (80.0% [36/45] vs. 58.9% [89/151]) and less scar formation (39.7% [60/151] vs. 20.0% [9/45]) [Table 5].

Table 5 Treatment outcomes of gastric LGDs treated by regular RFA and SI-RFA.

Items	Regular RFA	SI-RFA	Statistics	P-value	
Median follow-up period (months)	18.0 (6.0–35.0)	30.0 (10.0–47.5)	–1.619‡	0.106	
Wound healing in the first month after RFA			–2.512‡	0.012	
Active stage (A)	1/151 (0.7)	0/45 (0)			
Healing stage (H)	1/151 (0.7)	0/45 (0)			
Red scarring stage (S1)	38/151 (25.1)	6/45 (13.3)			
White scarring stage (S2)	22/151 (14.6)	3/45 (6.7)			
Complete healing stage (C)	89/151 (58.9)	36/45 (80.0)			
Clinical efficacy per lesion					
Complete ablation	170/197 (86.3)	45/49 (91.8)	1.094§	0.295	
Residue	27/197 (13.7)	4/49 (8.2)	1.094§	0.295	
Local recurrence*	18/136 (13.2)	10/39 (25.6)	3.471§	0.062	
Progression†	1/116 (0.9)	3/36 (8.3)		0.042‖	
Median recurrent period (months)	26.0 (12.5–44.5)	25.0 (8.0–34.0)	–0.768‡	0.442	
Values are presented with n/N (%), or median with interquartile range. *One hundred and thirty-six lesions in the regular RFA group and 39 lesions in the SI-RFA group were followed for more than 6 months. †One hundred and sixteen lesions in the regular RFA group and 36 lesions in the SI-RFA group were followed for more than one year. ‡Z-value; §χ2 values; ‖Fisher’s exact test. LGD: Low-grade dysplasia; RFA: Radiofrequency ablation; SI-RFA: Submucosal injection prior to RFA.

Treatment outcomes

Bleeding or perforation was not reported in either group. Compared with the RFA group, the SI-RFA group achieved a higher complete ablation rate (91.8% [45/49] vs. 86.3% [170/197]) and a lower residual rate (8.2% [4/49] vs. 13.7% [27/197]), but a higher local recurrence rate (25.6% [10/39] vs. 13.2% [18/136]) was noticed; however, all of the differences were not statistically significant (P = 0.295; 0.295; 0.062; respectively). But a significantly higher rate of progression was observed in the SI-RFA group (8.3% [3/36] vs. 0.9% [1/116], P = 0.042) [Table 5]. The additional treatment and prognosis of residual, recurrent, and progressive lesions are detailed in Supplementary File, http://links.lww.com/CM9/B959. The pathological features, clinical characteristics, and follow-up of patients who progressed to HGD or GC are presented in Supplementary Table 1, http://links.lww.com/CM9/B959.

In stratification analysis, after adjusting for confounding variables, submucosal injection was not associated with residue. After adjusting for lesion length, the submucosal injection was associated with local recurrence (OR, 2.54; 95% CI, 1.03–6.24; P = 0.043). The submucosal injection was not associated with local recurrence for lesions with a disease duration of <1 year (OR, 1.47; 95% CI, 0.48–4.46; P = 0.543); but for lesions with a disease duration of ≥1 year, the submucosal injection was a risk factor for the local recurrence (OR, 8.33; 95% CI, 1.10–63.35; P = 0.008). Likewise, the submucosal injection was associated with a higher likelihood of progression after stratifying by lesion location, gross morphology, and lesion length, with a combined OR value of 11.66 (95% CI, 1.07–127.45; P = 0.044), 16.38 (95% CI, 1.38–192.73; P = 0.033), and 19.17 (95% CI, 1.45–252.69; P = 0.029), respectively [Table 6].

Table 6 Stratification analysis of the association between submucosal injection and clinical outcomes.

Items	Regular RFA	SI-RFA	The test of Homogeneity of the odds ratio	The test for interaction	
χ2-value	P-value	OR (95% CI)	χ2-value	P-value	
Residual rate	
Lesion location			3.363	0.067	0.61 (0.20–1.80)	0.454	0.500	
Non-gastric angle	9.0 (13/145)	10.3 (4/39)						
Gastric angle	26.9 (14/52)	0 (0/10)	
Gross morphology			0.014	0.906	0.57 (0.19–1.71)	0.595	0.440	
Non-elevated	14.2 (16/113)	9.1 (2/22)						
Elevated	13.1 (11/84)	7.4 (2/27)	
Lesion size			1.309	0.253	0.58 (0.19–1.76)	0.518	0.472	
Length <1 cm	12.0 (17/142)	9.8 (4/41)						
Length ≥1 cm	18.2 (10/55)	0 (0/8)	
Disease duration			1.970	0.160	0.61 (0.21–1.80)	0.458	0.499	
Disease duration <1 y	13.6 (23/169)	12.1 (4/33)						
Disease duration ≥1 y	14.3 (4/28)	0 (0/16)	
Local recurrence rate	
Lesion location			0.017	0.897	2.34 (0.97–5.66)	2.787	0.095	
Non-gastric angle	11.1 (11/99)	23.3 (7/30)						
Gastric angle	18.9 (7/37)	33.3 (3/9)	
Gross morphology			0.046	0.830	2.31 (0.94–5.66)	2.575	0.109	
Non-elevated	13.4 (11/82)	28.6 (4/14)						
Elevated	13.0 (7/54)	24.0 (6/25)	
Lesion size			0.003	0.957	2.54 (1.03–6.24)	3.265	0.043	
Length <1 cm	9.8 (10/102)	21.9 (7/32)						
Length ≥1 cm	23.5 (8/34)	42.9 (3/7)	
Disease duration			4.655	0.031				
Disease duration <1 y	15.9 (18/113)	21.7 (5/23)			1.47 (0.48–4.46)		0.543	
Disease duration ≥1 y	0 (0/23)	31.3 (5/16)	8.33 (1.10–63.35)		0.008	
Progression rate	
Lesion location			1.185	0.276	11.66 (1.07–127.45)	3.540	0.044	
Non-gastric angle	0 (0/88)	7.1 (2/28)						
Gastric angle	3.6 (1/28)	12.5 (1/8)	
Gross morphology			0.213	0.644	16.38 (1.38–192.73)	4.571	0.033	
Non-elevated	1.6 (1/64)	15.4 (2/13)						
Elevated	0 (0/52)	4.3 (1/23)	
Lesion size			0.237	0.626	19.17 (1.45–252.69)	4.775	0.029	
Length <1 cm	0 (0/89)	3.3 (1/30)						
Length ≥1 cm	3.7 (1/27)	33.3 (2/6)	
Disease duration			0.706	0.401	11.16 (0.88–142.46)	2.280	0.131	
Disease duration <1 y	1.1 (1/93)	4.5 (1/22)						
Disease duration ≥1 y	0 (0/21)	14.3 (2/14)	
Values are presented with % (n/N). CI: Confidence interval; OR: Odds ratio. When the P-value of the test of Homogeneity of the Odds Ratio was <0.05, it was considered that there was heterogeneity among different layers, and the odds ratio should be reported by layers rather than integrated by the test for interaction.When the P-value of the test for interaction was <0.05, submucosal injection was considered to be significantly correlated with clinical outcomes.

Factors associated with residue and local recurrence

From both univariable and multivariable logistic regression analyses, only the gastric angle predicted a significantly increased OR for residue (OR, 2.73; 95% CI, 1.25–5.96; P = 0.012) [Table 7]. In the univariable analysis, the submucosal injection, lesion duration of ≥6 months, lesion size of ≥1 cm, and atrophy were considered to be associated with local recurrence with a P value of <0.2 and were included in multivariable analyses. Ultimately, only submucosal injection and atrophy proved to be the variables that correlated significantly to local recurrence (OR, 2.93; 95% CI, 1.13–7.58; P = 0.027; OR, 9.79; 95% CI, 1.25–76.75; P = 0.030; respectively) [Table 8].

Table 7 Univariable and multivariable regression analyses of factors associated with residual lesions.

Variable	Univariable analysis	Multivariable analysis	
OR (95% CI)	Statistics	P-value	OR (95% CI)	Statistics	P-value	
Submucosal injection (yes vs. no)	0.56 (0.19–1.68)	1.094	0.295	0.57 (0.19–1.76)	−0.555	0.330	
Gender (female vs. male)	1.51 (0.70–3.22)	1.124	0.289				
Age (≥60 years vs. <60 years)	0.85 (0.40–1.80)	0.186	0.666				
Disease duration (≥1 year vs. <1 year)	0.65 (0.22–1.96)	0.600	0.439				
Lesion duration (≥6 months vs. <6 months)	0.69 (0.23–2.09)	0.436	0.509				
Current H. pylori infection (yes vs. no)	0.94 (0.39–2.30)	0.020	0.889				
Location (gastric angle vs. non-gastric angle)	2.87 (1.32–6.23)	7.495	0.006	2.73 (1.25–5.96)	1.003	0.012	
Lesion length (≥1 cm vs. <1 cm)	1.46 (0.65–3.29)	0.823	0.364				
Gross morphology 1 (elevated vs. non-elevated)	0.86 (0.40–1.85)	0.145	0.703				
Gross morphology 2 (depressed vs. non-depressed)	1.20 (0.57–2.56)	0.233	0.629				
Erythema (yes vs. no)	0.65 (0.18–2.41)	0.422	0.457				
Erosion (yes vs. no)	0.76 (0.36–1.61)	0.529	0.467				
Acute gastric inflammation (yes vs. no)	0.63 (0.29–1.35)	1.433	0.231	0.66 (0.30–1.44)	−0.423	0.292	
Atrophy (yes vs. no)	1.25 (0.53–2.93)	0.254	0.614				
Number of lesions (multiple vs. single)	1.04 (0.47–2.27)	0.007	0.931				
CI: Confidence interval; H. pylori: Helicobacter pylori; OR: Odds ratio.

Table 8 Univariable and multivariable regression analyses of factors associated with local recurrence.

Variable	Univariable analysis	Multivariable analysis	
OR (95% CI)	Statistics	P-values	OR (95% CI)	Statistics	P-value	
Submucosal injection (yes vs. no)	2.26 (0.94–5.40)	3.471	0.062	2.93 (1.13–7.58)	1.076	0.027	
Gender (female vs. male)	0.84 (0.36–1.99)	0.157	0.692				
Age (≥60 years vs. <60 years)	0.99 (0.44–2.23)	0.000	0.987				
Disease duration (≥1 year vs. <1 year)	0.72 (0.26–2.05)	0.377	0.539				
Lesion duration (≥6 months vs. <6 months)	2.00 (0.76–5.29)	2.009	0.165	2.24 (0.78–6.42)	0.805	0.134	
Current H. pylori infection (yes vs. no)	1.27 (0.53–3.03)	0.284	0.594				
Location (gastric angle vs. non-gastric angle)	1.71 (0.73–4.05)	1.529	0.216				
Lesion length (≥1 cm vs. <1 cm)	2.52 (1.07–5.95)	4.672	0.031	2.40 (0.96–5.99)	0.876	0.060	
Gross morphology 1 (elevated vs. non-elevated)	1.06 (0.47–2.39)	0.022	0.881				
Gross morphology 2 (depressed vs. non-depressed)	1.59 (0.70–3.60)	1.262	0.261				
Erythema (yes vs. no)	3.03 (0.38–23.97)	1.213	0.472				
Erosion (yes vs. no)	0.79 (0.35–1.78)	0.318	0.573				
Acute gastric inflammation (yes vs. no)	0.71 (0.30–1.71)	0.590	0.442				
Atrophy (yes vs. no)	9.75 (1.28–74.10)	7.031	0.008	9.79 (1.25–76.75)	2.281	0.030	
Intestinal metaplasia (yes vs. no)	0.80 (0.09–7.42)	0.581	1.000				
Number of lesions (multiple vs. single)	1.62 (0.61–4.26)	0.961	0.327				
Residue (yes vs. no)	1.14 (0.31–4.26)	0.038	0.738				
CI: Confidence interval; H. pylori: Helicobacter pylori; OR: Odds ratio.

Discussion

To the best of our knowledge, this was the first comparative study between the outcomes of SI-RFA and regular RFA on gastric LGD management. As the main result, the SI-RFA reduced postoperative pain and scar formation while ensuring complete ablation of superficial lesions. However, the submucosal injection was associated with higher rates of local recurrence and progression.

The gastric HGD is highly predictive of invasive carcinoma and therefore, requires ER,[123] whereas the gastric LGD has a relatively benign course and requires superficial destruction. RFA is an efficient therapeutic procedure in treating LGD, which transfers a thermal effect to the lesion through a high-frequency alternating current, causing coagulative necrosis of the lesion.[32] Our previous studies[20] demonstrated the safety and efficacy of the ablation regimen for the treatment of gastric LGD. In the previous analysis, 92.8% (193/208) of the patients achieved curative ablation at 6 months after the procedure without any serious adverse events. However, 53.8% (136/253) of the patients experienced postoperative abdominal pain at varying degrees.

Post-RFA pain may be partly due to the injury of the submucosa and muscularis propria, where the nerves and blood vessels are mainly distributed. Further, a deep-tissue injury may promote the formation of deep ulcers and aggravate the inflammatory response, increasing postoperative pain.[33,34] The submucosal fluid cushion provides an insulating effect and prevents the conduction of thermal energy, protecting the muscularis propria from additional injuries, thereby alleviating postoperative pain. This study found that the incidence, severity, and duration of postoperative pain in the SI-RFA group were significantly lower than those in the regular RFA group, suggesting the protective role of submucosal injection during ablation, which was further supported by multivariable analysis. Additionally, acute inflammation of the gastric mucosa was also a risk factor for postoperative pain, suggesting that preoperative administration of proton inhibitors to relieve gastric inflammation may aid in alleviating postoperative pain. The area of ablation was another risk factor for post-RFA pain, similar to the previously reported result that post-ER pain was associated with the size of the postoperative ulcer.[33] Lesion location in the lower third of the stomach and longer procedural time[35,36] were also correlated to the development of pain after ESD. But, in this study, some patients were treated with RFA for multiple lesions simultaneously, posing difficulty in defining the lesion location and procedural time on a patient basis. The effect of these two variables on post-RFA pain was not analyzed, warranting future studies.

The depth of injury also affects the healing speed and the quality of the postoperative wound.[37,38] Superficial injury of the gastric mucosa is usually re-epithelialized by the migration of gastric epithelial cells in close proximity to the wound area. This restitution occurs rapidly without submucosal fibrosis. The repair process of the deep erosions or ulcers is much slower than the restitution of the superficial lesions, involving fibrous tissue proliferation accompanied by scar formation. Severe fibrosis poses a technical challenge and a high risk of adverse events to additional ER of a residual or recurrent tumor at the same location.[39] This study showed better wound healing and a lower scar rate in the SI-RFA group, suggesting that submucosal injection is conducive to preventing submucosal fibrosis, thereby minimizing the negative impact on future ER.

Only a few studies reported the long-term outcomes of gastric LGD treated by RFA. In 2015, Leung et al[20] stated a complete eradication rate of 100% in four cases of gastric LGD treated by RFA with a 12-month follow-up. In this study, 87.4% (215/246) of gastric LGDs were completely ablated at 6 months after RFA, slightly lower than our previous report (92.8%, 193/208), and this variation might have been due to the different inclusion and exclusion criteria. The gastric angle was the only independent risk factor for residue. Although a significantly statistical difference was not reached, stratified analysis showed that the SI-RFA group had a lower residual rate than the regular RFA group at the gastric angle (0 vs. 26.9%, P = 0.099). This outcome may have been due to the large physiological radian at the gastric angle, posing difficulty in completely fitting the electrode sheet to the lesion. The lift-up effect of submucosal injection adjusts the height difference between the lesion and surrounding mucosa, leading to a better fit of the electrode and the lesion, thus facilitating complete ablation.

After the RFA, the local recurrence rate of gastric LGD was 16% (28/175). The submucosal injection was a risk factor for the local recurrence, especially when the disease duration was longer than 1 year. Non-performing the histopathologic evaluation of the resected specimens is a drawback of RFA. Several studies[67840] showed that 12.1–33.9% of the gastric LGDs diagnosed by EFB may have been underestimated and undergo postoperative pathological upgrading to HGD or EGC. The frequency of upgraded diagnosis increased with the number of risk factors (lesion size of ≥1 cm, depressed lesion, surface erythema, nodularity, and erosion).[7] In this study, 85.7% (24/28) of the recurrent lesions had more than two risk factors, suggesting that some malignancies may have been underestimated as LGDs and received RFA, despite meticulous preoperative endoscopic evaluation and exclusion of cases with possible higher grade diagnosis. The superficial ablation depth of RFA, especially SI-RFA, may have led to incomplete ablation of malignant lesions with deep invasive potential, contributing to the development of local recurrence. Further, based on the multivariable analysis, no correlation was found between the residue and the local recurrence. Despite the complete ablation of mucosal lesions, a recurrence was still possible, which suggests that the recurrence may be related to deeper lesions. And a lesion size ≥1 cm, a recognized independent predictor of upgraded diagnosis of LGD,[7,8,40] was associated with a higher likelihood of recurrence in the univariate analysis. However, it was not significant in the multivariable analysis (P = 0.060). Hence, preoperative evaluation is of great significance for appropriately managing gastric LGD diagnosed by EFB. For lesions with a high risk of upgraded diagnosis, ER is strongly recommended.

A comprehensive multivariable analysis was not possible because of the low number of cases with progression (n = 4, 2.6%). Nevertheless, the stratified analysis suggested that submucosal injection was associated with progression. Similar to the local recurrence, the progression after RFA for gastric LGD may also be partially attributable to the underestimation of pathological grade preoperatively. In one lesion associated with three risk factors of higher-stage diagnosis (depressed lesion, surface erythema, and erosive lesion), recurrence occurred at 8 months and progressed to HGD at 13 months after SI-RFA, for which the presence of HGD before surgery could not be excluded. However, the other three lesions all underwent a long course of evolution before progression to HGD (26 months, 64 months) or ECG (38 months). Male sex, multi-site, hyperemia, ulcer, and morphological characteristics were independent risk factors for the prolongation or progression of gastric LGD,[11] which were also partially present in this study. For recurrent lesions after RFA, the risk factors for the progression should be identified, and the development of appropriate follow-up strategies and timely intervention are necessary.

As the first report on SI-RFA, our research has certain significance and innovation. We focused on both the postoperative symptoms and the treatment outcomes, while predicting its impact on subsequent ER by wound healing. While ensuring the treatment effect, minimizing the postoperative discomfort of patients is conducive to improving the compliance of patients with additional treatment and surveillance, which is particularly important for gastric LGD, a disease prone to recurrence. Our findings help to guide current clinical practice in exploring an appropriate treatment for gastric LGD on an outpatient department basis.

However, this study also had some limitations. First, the required sample size could not be calculated in advance due to the lack of previous studies. Nevertheless, the results of this study could assist in designing future prospective studies. Second, it was conducted as a retrospective, single-center study, and inevitably sample selection bias may have been present. However, we performed propensity-score matching, multivariable logistic regression analysis, and stratification analysis to minimize the selection bias. Third, pain scores were self-reported and recorded by patients, affecting the reliability and objectivity of the data. Fourth, the knowledge of LGD and the proficiency of the operators may have led to the imbalance of the data in the pre- and post-study phases. Fifth, although the lesions were re-evaluated before RFA, insufficient identification of high-risk lesions might have existed, especially in the early stages of the study, which may have resulted in higher recurrence and progression rates than the actual rates. The practical feasibility of SI-RFA in the future depends on the establishment of a risk-assessment system for gastric LGD, which requires more valid data from large prospective, comparative studies.

In conclusion, this study demonstrated that the SI-RFA was a reasonable intervention for gastric LGDs without risk factors of upgraded diagnosis, especially for lesions located at the gastric angle. Thorough endoscopic evaluation before treatment is necessary to identify high-risk lesions. After treatment, a follow-up endoscopy is recommended for the detection of recurrence and progression. Future prospective work is an essential next step to substantiate our results, standardize the patient selection criteria for SI-RFA, and establish effective surveillance strategies after RFA.

Funding

The research work was supported by the National Natural Science Foundation of China (No. 82070682) and the Chinese PLA General Hospital Young Independent Innovation Science Fund (No. 22QNFC028).

Conflicts of interest

None.

Supplementary Material

SUPPLEMENTARY MATERIAL

Xiaotong Niu and Nanjun Wang contributed equally to this work.

How to cite this article: Niu XT, Wang NJ, Wang Y, Feng J, Li LS, Han K, Chai NL, Linghu EQ. Role of submucosal injection in radiofrequency ablation of gastric low-grade dysplasia: Effects on symptoms and outcomes. Chin Med J 2024;137:2099–2110. doi: 10.1097/CM9.0000000000003080
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