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10.5009/gnl240006
gnl-18-5-807
Original Article
Alimentary Tract
Clinicopathological Characteristics and Lymph Node Metastasis Rates in Early Gastric Lymphoepithelioma-Like Carcinoma: Implications for Endoscopic Resection
https://orcid.org/0000-0003-3950-4516
Kim Tae-Se 1
https://orcid.org/0000-0003-1690-4947
An Ji Yeong 2
https://orcid.org/0000-0003-3394-5177
Choi Min Gew 2
https://orcid.org/0000-0002-0131-1527
Lee Jun Ho 2
https://orcid.org/0000-0002-9553-3234
Sohn Tae Sung 2
https://orcid.org/0000-0003-3928-0743
Bae Jae Moon 2
https://orcid.org/0000-0001-7471-1305
Min Yang Won 1
https://orcid.org/0000-0003-4271-7205
Lee Hyuk 1
https://orcid.org/0000-0002-5272-1841
Lee Jun Haeng 1
https://orcid.org/0000-0003-0495-5296
Rhee Poong-Lyul 1
https://orcid.org/0000-0002-0226-1330
Kim Jae J. 1
https://orcid.org/0000-0002-1162-9205
Kim Kyoung-Mee 3
https://orcid.org/0000-0001-8048-361X
Min Byung-Hoon 1
1 Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea;
2 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea;
3 Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Corresponding Author Byung-Hoon Min, ORCID https://orcid.org/0000-0001-8048-361X, E-mail bhmin@skku.edu
Tae-Se Kim and Ji Yeong An contributed equally to this work as first authors.

16 9 2024
26 7 2024
26 7 2024
18 5 807813
4 1 2024
22 3 2024
8 4 2024
Copyright © Gut and Liver.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background/Aims

Lymphoepithelioma-like carcinoma (LELC) is a rare subtype of gastric cancer. We aimed to identify the clinicopathological features and rate of lymph node metastasis (LNM) to investigate the feasibility of endoscopic submucosal dissection for early gastric LELC confined to the mucosa or submucosa.

Methods

We compared the clinicopathological characteristics of 116 early gastric LELC patients and 5,753 early gastric well- or moderately differentiated (WD or MD) tubular adenocarcinoma patients treated by gastrectomy.

Results

Compared to WD or MD early gastric cancer (EGC) patients, early LELC patients were younger and had a higher prevalence of proximally located tumors. Despite more frequent deep submucosal invasion (86.2% vs 29.8%), lymphatic invasion was less frequent (6.0% vs 16.2%) in early LELC patients than in WD or MD EGC patients. Among tumors with deep submucosal invasion, the tumor size was smaller, lymphatic invasion was less frequent (6.0% vs 40.2%) and the rate of LNM was lower (10.0% vs 19.4%) in patients with LELC than in those with WD or MD EGC. The overall rate of LNM in early LELC patients was 8.6% (10/116). The risk of LNM in patients with mucosal, shallow submucosal invasive, or deep submucosal invasive LELC was 0% (0/6), 0% (0/10), and 10% (10/100), respectively.

Conclusions

Early LELC is a distinct subtype of EGC with more frequent deep submucosal invasion but less lymphatic invasion and LNM than WD or MD EGCs. Endoscopic submucosal dissection may be considered curative for patients with early LELC confined to the mucosa or shallow submucosa, given its negligible rate of LNM.

Early gastric cancer
Endoscopic resection
Lymphoepithelioma-like carcinoma
Lymph node metastasis
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pmcINTRODUCTION

Lymphoepithelioma-like carcinoma (LELC) is a rare variant of gastric cancer characterized by poorly developed tubular structures with prominent lymphoid infiltration in the tumor stroma.1 LELC constitutes 1% to 4% of all gastric cancer cases and more than 80% of LELC cases are associated with Epstein-Barr virus (EBV) infection.2,3 Previous studies have reported that LELC in general has distinctive clinicopathological features and better survival than conventional gastric cancers.4,5 However, only a few studies have specifically evaluated the clinicopathological features of early LELC confined to mucosa or submucosa.6-8 Due to its rarity, the clinicopathological characteristics and prognosis of early LELC remain unclear. Accordingly, appropriate treatment strategy for early LELC is yet to be established.

In the present study, we aimed to identify the clinicopathological characteristics of early LELC compared to those of well- or moderately differentiated (WD or MD) early gastric cancer (EGC) and explore the feasibility of endoscopic submucosal dissection (ESD) for the treatment of early LELC.

MATERIALS AND METHODS

1. Patients

From October 1994 to December 2018, 13,913 patients with EGC underwent radical gastrectomy with lymph node (LN) dissection at Samsung Medical Center. Among these patients, the following patients were excluded from the study population: 616 patients with multiple lesions, 7,110 patients with poorly cohesive carcinoma or poorly differentiated tubular adenocarcinoma, 195 patients with papillary adenocarcinoma, 46 patients with mucinous adenocarcinoma, four patients with hepatoid adenocarcinoma, and five patients with other unspecified pathology reports. Additionally, 32 patients with cancers arising from the remnant stomach and 36 patients with missing values were excluded. Finally, a total of 5,869 patients with single EGC lesion (116 patients with early LELC and 5,753 patients with WD or MD EGC) were analyzed (Fig. 1). LELC was defined as a tumor with poorly developed tubular structures associated with prominent lymphoid infiltration of the stroma.1 Clinicopathological data including demographic features, tumor characteristics, and LN metastasis status were obtained by retrospective review of medical records using the intranet resources of Samsung Medical Center. The study protocol was approved by the Institutional Review Board of Samsung Medical Center (approval number: 2023-10-049-001). This study was conducted in accordance with the guidelines of the Declaration of Helsinki. The requirement for informed consent was waived.

2. Surgical procedures and follow-up strategy

Distal, proximal, or total gastrectomy was performed according to the location and macroscopic tumor type by experienced surgeons. The extent of LN dissection was more than D1+beta, based on the recommendations of the Korean and Japanese guidelines.9,10 Follow-up endoscopy and abdominal computed tomography were performed every three to 6 months for the first 3 years and then annually until 5 years after surgery.

3. Histopathological evaluation

Specimens were fixed in 10% formalin and then serially sectioned at 5-mm intervals, embedded in paraffin blocks, and stained with hematoxylin and eosin. Tumors were classified histologically using the World Health Organization classification guidelines.1 The degree of submucosal invasion was classified: as either shallow submucosal invasion (SM1, invasion depth less than one-third of the submucosal layer or <500 µm from the muscularis mucosa layer when the exact number was provided) or deep submucosal invasion (SM2 or SM3, invasion depth greater than one-third of the submucosal layer or ≥500 µm from the muscularis mucosa layer when the exact number was provided). A tumor was considered positive for lymphovascular invasion when tumor emboli were found within a space clearly lined by endothelial cells. LNs were cut into two pieces, and the cut surfaces were examined to determine the metastasis status of the node based on hematoxylin and eosin staining.11 The N category was determined according to the Cancer Staging Manual of the American Joint Committee on Cancer (8th edition).12

4. EBV-encoded ribonucleic acid in situ hybridization

EBV status was confirmed with EBV-encoded RNA in situ hybridization. Three-micrometer-thick sections were cut from each tissue block and mounted on Superfrost-plus slides (Thermo Scientific, Waltham, MA, USA). The entire procedure was performed with a fully automatic system (BOND-MAX) for in situ hybridization with an EBV-encoded RNA probe (Leica, Newcastle, UK) according to the manufacturer’s instructions. Only sections that showed a strong signal within almost all tumor cell nuclei were considered as positive.13

5. Definitions of variables

Tumor location was categorized as lower third (pylorus and antrum), middle third (angle, low body, and mid-body), or upper third (high body, fundus, and cardia). The Paris classification was used to categorize the macroscopic type of early LELC: type I (protruded) and type IIa (superficial elevated) were categorized as the elevated type, type IIb (flat) as the flat type, and type IIc (superficial depressed) and type III (excavated) as the depressed type.14 Overall survival time was calculated from the date of surgery to the date of all-cause death or the cutoff date (October 4, 2023). Survival status was checked in the National Health Insurance System database by the cutoff date.

6. Statistical analysis

Clinicopathological characteristics were compared between two groups of interest using the Student t-test or Mann-Whitney test for continuous variables and the chi-square test or Fisher exact test for categorical variables. Statistical significance was set at p<0.05. All analyses were performed using SPSS version 28.0 (IBM SPSS Statistics for Windows, version 28.0; Armonk, NY, USA).

RESULTS

1. Clinicopathological characteristics of early gastric LELC versus WD or MD adenocarcinoma

The study population included 116 early LELC patients and 5,753 WD or MD EGC patients. Table 1 summarizes and compares the clinicopathological characteristics of early LELC patients with WD or MD EGC patients. Patients with early LELC were younger and more frequently located in the proximal stomach than those with WD or MD EGC. Compared to patients with WD or MD EGC, patients with early LELC had more frequent deep submucosal invasion (SM2 or SM3; 86.2% vs 29.8%) but less frequent lymphatic invasion (6.0% vs 16.2%).

Among 116 early LELC patients, 113 patients were evaluated for EBV status (Supplementary Table 1). EBV positivity was found in 94.6% (107/113) of the patients. There was no significant difference in the rate of lymphatic invasion or LNM between those positive and negative for EBV among early LELC patients.

Table 2 compares the clinicopathological characteristics of early LELC patients and WD or MD EGC patients with deep submucosal invasion. Patients with early LELC were younger and more frequently located in the proximal stomach than those with WD or MD EGC. Patients with early LELC had smaller tumors, less frequent lymphatic invasion (6.0% vs 40.2%) and less frequent lymph node metastases (LNM; 10.0% vs 19.4%) than patients with WD or MD EGC.

2. LNM of early gastric LELC

Table 3 summarizes the clinicopathological characteristics of early gastric LELC patients according to LNM status. Overall rate of LNM in early LELC patients was 8.6% (10/116). Risk of LNM in patients with mucosal, shallow submucosal invasive, or deep submucosal invasive LELC was 0% (0/6), 0% (0/10), and 10% (10/100), respectively. Lymphatic invasion was more frequent in patients with positive LNM than negative LNM (20.0% vs 4.7%, p =0.111), but this difference was not statistically significant.

Rates of LNM in early LELC patients according to the status of lymphovascular invasion, depth of invasion, and tumor size are summarized in Fig. 2. No LNM was found in patients with mucosal or shallow submucosal invasive LELC. Detailed clinicopathological characteristics and outcomes of early LELC patients with LNM are described in Table 4. All patients had deep submucosal invasion and half of the patients had N1 disease while the other half had N2 disease. Nine patients (seven patients in our hospital and two in other hospitals) underwent adjuvant chemotherapy and one patient underwent careful observation without chemotherapy due to old age. Five-year overall survival among these patients was 90% (9/10). No gastric cancer-specific death occurred during the follow-up period among these patients.

DISCUSSION

Gastric LELC is a rare but important subtype of gastric cancer with a favorable prognosis having a reported incidence of around 4%.15 Due to its rarity, clinicopathological features of early gastric LELC and its LNM rate are not well described and the feasibility of ESD for this entity remains uncertain. Furthermore, previous studies were limited by the heterogeneity of their control group including aggressive papillary adenocarcinoma as well as WD or MD EGC. In this study, we compared 116 early gastric LELC patients with 5,753 WD or MD EGC patients. We found that early LELC patients were younger, more frequently had proximally located tumors, and showed less frequent lymphatic invasion despite more frequent deep submucosal invasion than WD or MD EGC patients. We also found that there was no LNM among patients with mucosal or shallow submucosal invasive early LELCs.

It is widely accepted that tumors with submucosal invasion are more likely to have lymphatic invasion as well as LNM than those confined to the mucosal layer.16 It is also assumed that when a certain type of tumor has a high rate of submucosal invasion, it will have an aggressive clinicopathological behavior. However, early LELC seems to be an exception to this assumption. In the present study, a significantly greater portion of LELC patients had deep submucosal invasion than WD or MD EGC patients (86.2% vs 29.8%). However, lymphatic invasion was significantly less frequent among patients with early LELC than WD or MD EGC (6.0% vs 16.2%). Moreover, LNM was significantly less frequent in deep submucosal invasive LELC than WD or MD EGC (10.0% vs 19.4%, p=0.025). Likewise, previously studies consistently showed that patients with LELC tumors have less LNM and a better prognosis than non-LELC patients.4,17,18 The possible mechanism behind this lower risk of LNM in LELC patients may be due to the protective effect of the host inflammatory immune responses represented by dense lymphocytic infiltration surrounding the tumor.5 Gullo et al.19 found that patients with LELC harbored cytotoxic T-cell enriched profile at the invasive front of tumors, based on their quantitative digital analysis of tumor microenvironment. Further research is needed to clarify the biological mechanisms behind the less aggressive behavior of LELC despite the high frequency of deep submucosal invasion.

The current Japanese gastric cancer treatment guidelines divide gastric cancers into two categories: differentiated-type and undifferentiated-type.20 Because LELC is not mentioned in either category, there are no established indications or curability criteria of ESD for early LELC. As the main components comprising the indication or curability criteria for ESD are tumor size, lymphatic invasion and depth of invasion, we examined the LNM status of early LELC patients according to these components (Fig. 2). We found that none of the mucosal or shallow submucosal invasive LELCs had LNM (0/16), regardless of the status of lymphatic invasion or the size of the tumor. Consistently, Shin et al.7 and Lim et al.6 reported no LNM in early LELCs confined to the SM1 layer (0/2 and 0/14, respectively). Given the negligible rate of LNM among early LELCs confined to the mucosa or shallow submucosa, we argue that ESD may be considered curative when the review of ESD pathology reveals tumor invasion depth of SM1 or less. Previous studies on the outcomes of ESD for early LELC showed favorable results. Shin et al.7 reported no recurrences in 10 patients treated with ESD during a mean follow-up of 37.2 months. In a single-center retrospective study by Lim et al.,21 which included 40 ESD cases for LELC, the complete resection rate was 85.0% (34/40). In this study,21 no LNM was found in 17 patients referred for additional surgery after ESD and no extra-gastric recurrence was found during a mean follow-up of 49.7 months after ESD in 23 patients without additional surgical treatment.

LNM was present in 10% of early LELC patients with deep submucosal invasion (Table 2). When we examined the clinicopathological features and outcomes of those with LNM (Table 4), we found that 50% of patients (5/10) had N2 disease. However, long-term outcomes after surgery were excellent. In fact, nine of 10 patients with LNM survived longer than 5 years. Considering the significant rate of LNM (10%) and the excellent outcomes after surgery, we think that surgery should be generally recommended for LELC patients with clinical evidence of deep submucosal invasion.

This study has following limitations. First, it was performed at a single tertiary referral center and had a retrospective design. Second, we did not evaluate the underlying biological mechanism behind the favorable behavior of early LELC despite frequent submucosal invasion. Third, although our study had a relatively larger sample size than those of previous studies,7,17 it remains insufficient to make definitive conclusions. Fourth, our study did not include patients who underwent endoscopic resection for EGC, who might harbor a lower risk of submucosal invasion or lymphovascular invasion compared to patients who underwent surgery. This could have caused selection bias. Further studies with actual ESD outcomes are required to establish the role of ESD for the treatment of early gastric LELC. Fifth, the sample size of EBV-negative LELC patients was limited. Therefore, the association of EBV positivity and the rate of LNM could not be properly evaluated in this study.

In conclusion, we observed that early LELC is a distinct subtype of EGC that presents with more frequent deep submucosal invasion but less lymphatic invasion and LNM than WD or MD EGCs. Further large-scale studies are warranted to confirm the low rate of LNM and the feasibility of ESD for patients with early LELC confined to mucosa or shallow submucosa.

SUPPLEMENTARY MATERIALS

Supplementary materials can be accessed at https://doi.org/10.5009/gnl24006.

Fig. 1 Flowchart for study population. LN, lymph node; EGC, early gastric cancer; LELC, lymphoepithelioma-like carcinoma; WD, well differentiated; MD, moderately differentiated.

Fig. 2 Rate of lymph node metastasis according to lymphovascular invasion, depth of invasion, and tumor size.

Table 1 Clinicopathological Characteristics of eLELC and WD or MD Adenocarcinoma in the Total Study Population

Characteristic	eLELC
(n=116)	WD or MD EGC
(n=5,753)	p-value	
Age, yr			<0.001	
Mean±SD	56.7±10.2	60.5±10.1		
Median (range)	56 (29–82)	61 (25–88)		
Sex			0.051	
Male	96 (82.8)	4,302 (74.8)		
Female	20 (17.2)	1,451 (25.2)		
Location of tumor			<0.001	
Lower third	15 (12.9)	2,982 (51.8)		
Middle third	59 (50.9)	2,224 (38.7)		
Upper third	42 (36.2)	547 (9.5)		
Tumor shape (pathology)			0.149	
I	9 (7.8)	272 (4.7)		
IIa	21 (18.1)	890 (15.5)		
IIb	20 (17.2)	1,560 (27.1)		
IIc	63 (54.3)	2,939 (51.1)		
III	3 (2.6)	84 (1.5)		
AGC-like	0	8 (0.1)		
Tumor size (pathology), cm			0.383	
Mean±SD	2.6±1.4	2.8±1.8		
Median (range)	2.4 (0.5–9.0)	2.4 (0.1–16.0)		
Tumor depth			<0.001	
Mucosa	6 (5.2)	3,302 (57.4)		
SM1	10 (8.6)	736 (12.8)		
SM2 and SM3	100 (86.2)	1,715 (29.8)		
Lymphatic invasion (yes)	7 (6.0)	931 (16.2)	0.003	
Venous invasion (yes)	2 (1.7)	117 (2.0)	1.000	
Perineural invasion (yes)	4 (3.4)	81 (1.4)	0.087	
Lymph node metastases			0.720	
No	106 (91.4)	5,328 (92.6)		
Yes	10 (8.6)	425 (7.4)		
Data are presented as number (%) unless indicated otherwise.

eLELC, early gastric lymphoepithelioma-like carcinoma; WD, well differentiated; MD, moderately differentiated; EGC, early gastric cancer; AGC, advanced gastric cancer; SM1, submucosal invasion depth <500 µm from muscularis mucosa layer; SM2 or SM3, submucosal invasion depth ≥500 µm from muscularis mucosa layer.

Table 2 Clinicopathological Characteristics of eLELC and WD or MD Adenocarcinoma in Patients with Deep Submucosal Invasion

Characteristic	eLELC (n=100)	WD or MD EGC (n=1,715)	p-value	
Age, yr			<0.001	
Mean±SD	57.4±10.5	62.0±9.8		
Median (range)	57 (29–82)	63 (28–88)		
Sex			0.184	
Male	82 (82.0)	1,299 (75.7)		
Female	18 (18.0)	416 (24.3)		
Location of tumor			<0.001	
Lower third	13 (13.0)	906 (52.8)		
Middle third	47 (47.0)	603 (35.2)		
Upper third	40 (40.0)	206 (12.0)		
Tumor shape (pathology)			0.606	
I	9 (9.0)	108 (6.3)		
IIa	18 (18.0)	353 (20.6)		
IIb	16 (16.0)	345 (20.1)		
IIc	55 (55.0)	882 (51.4)		
III	2 (2.0)	22 (1.3)		
AGC-like	0	5 (0.3)		
Tumor size (pathology), cm			0.001	
Mean±SD	2.7±1.4	3.3±1.8		
Median (range)	2.4 (0.6–9.0)	2.8 (0.4–13.0)		
Lymphatic invasion (yes)	6 (6.0)	690 (40.2)	<0.001	
Venous invasion (yes)	2 (2.0)	99 (5.8)	0.120	
Perineural invasion (yes)	4 (4.0)	74 (4.3)	1.000	
Lymph node metastases			0.025	
No	90 (90.0)	1,382 (80.6)		
Yes	10 (10.0)	333 (19.4)		
Data are presented as number (%) unless indicated otherwise.

eLELC, early gastric lymphoepithelioma-like carcinoma; WD, well differentiated; MD, moderately differentiated; EGC, early gastric cancer; AGC, advanced gastric cancer.

Table 3 Clinicopathological Characteristics of Early Gastric Lymphoepithelioma-Like Carcinoma According to LNM Status

Characteristic	LNM positive
(n=10)	LNM negative
(n=106)	p-value	
Age, yr			0.794	
Mean±SD	55.9±12.8	56.8±9.9		
Median (range)	54 (39–82)	56.5 (29–80)		
Sex			0.682	
Male	8 (80.0)	88 (83.0)		
Female	2 (20.0)	18 (17.0)		
Location of tumor			0.657	
Lower third	2 (20.0)	13 (12.3)		
Middle third	4 (40.0)	55 (51.9)		
Upper third	4 (40.0)	38 (35.8)		
Tumor shape (pathology)			0.170	
Elevated	3 (30.0)	63 (59.4)		
Flat	3 (30.0)	17 (16.0)		
Depressed	4 (40.0)	26 (24.5)		
Tumor size (pathology), cm			0.701	
Mean±SD	2.6±1.2	2.6±1.4		
Median (range)	2.3 (1.2–5.0)	2.4 (0.5–9.0)		
Tumor depth			0.767	
Mucosa	0	6 (5.7)		
SM1	0	10 (9.4)		
SM2 and SM3	10 (100.0)	90 (84.9)		
Lymphatic invasion (yes)	2 (20.0)	5 (4.7)	0.111	
Venous invasion (yes)	0	2 (1.9)	1.000	
Perineural invasion (yes)	1 (10.0)	3 (2.8)	0.306	
Data are presented as number (%) unless indicated otherwise.

LNM, lymph node metastasis; SM1, submucosal invasion depth <500 µm from muscularis mucosa layer; SM2 or SM3, submucosal invasion depth ≥500 µm from muscularis mucosa layer.

Table 4 Clinicopathological Characteristics and Outcomes of Early Gastric Lymphoepithelioma-Like Carcinoma Patients with LNM

No.	Age, yr	Sex	Reconstruction	Location	Shape	Size, cm	Depth	LI	VI	PNI	No. of LNM	Location of LNM	Further treatment	OS, yr	Death	
1	57	M	BII	HB AW	I	5.0	Deep SM	N	N	N	1 (N1)	GC	Adjuvant LF/RT	17.3	Yes	
2	82	F	BI	Antrum GC	IIc	2.0	Deep SM	N	N	N	4 (N2)	GC	Old age → FU only	8.8	Yes	
3	55	M	TG	HB LC	IIa	1.2	Deep SM	N	N	N	3 (N2)	LC	Adjuvant LF/RT	21.8	No	
4	39	M	BI	Antrum GC	IIc	2.5	Deep SM	N	N	N	2 (N1)	LC	Adjuvant TS-1 #8	15.2	No	
5	45	M	BI	LB GC	IIb	2.0	Deep SM	P	N	N	3 (N2)	GC	Outside hospital	14.0	No	
6	45	M	TG	Cardia PW	IIb	4.2	Deep SM	N	N	N	1 (N1)	LC	Adjuvant LF/RT	12.8	No	
7	50	M	TG	MB GC	IIb	1.7	Deep SM	N	N	P	4 (N2)	LC, CHA	Outside hospital	12.5	No	
8	53	M	BII	LB GC	IIa	2.1	Deep SM	N	N	N	1 (N1)	GC	Adjuvant LF/RT	10.9	No	
9	67	M	TG	Cardia AW	I	3.2	Deep SM	P	N	N	5 (N2)	Left PC, LC, left GA	Adjuvant S-1/Oxaliplatin (study)	4.0	Yes	
10	66	F	RY	MB GC	IIc	2.4	Deep SM	N	N	N	1 (N1)	GC	Adjuvant LF	6.7	No	
LNM, lymph node metastases; LI, lymphatic invasion; VI, venous invasion; PNI, perineural invasion; OS, overall survival; BI/II, Billroth I/II; TG, total gastrectomy; RY, Roux-en-Y; HB, high body; AW, anterior wall; GC, greater curvature; LC, lesser curvature; LB, low body; PW, posterior wall; MB, mid-body; SM, submucosa; N, negative; P, positive; CHA, common hepatic artery; PC, pericardial; GA, gastric artery; LF, leucovorin + 5-fluorouracil; RT, radiotherapy; FU, follow-up.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Study concept and design: T.S.K., B.H.M. Data analysis and interpretation: T.S.K., B.H.M. Data acquisition: T.S.K., J.Y.A., M.G.C., J.H.L., T.S.S., J.M.B., Y.W.M., H.L., J.H.L., P.L.R., J.J.K., K.M.K., B.H.M. Drafting of the manuscript: T.S.K., J.Y.A., B.H.M. Critical revision of the manuscript for important intellectual content: T.S.K., J.Y.A., M.G.C., J.H.L., T.S.S., J.M.B., Y.W.M., H.L., J.H.L., P.L.R., J.J.K., K.M.K., B.H.M. Approval of final manuscript: all authors.
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