Best Practice & Research Clinical Gastroenterology xxx (xxxx) xxx

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Best Practice & Research Clinical Gastroenterology

journal homepage: www.elsevier.com/locate/bpg

Curative criteria for endoscopic treatment of gastric cancer

João A. Cunha Neves a, Pedro G. Delgado-Guillena b, Patrícia Queirós a, Diogo Libânio c, d, 1,
Enrique Rodríguez de Santiago e, *, 1
a
Department of Gastroenterology, Centro Hospitalar Universitário Do Algarve, Portimão, Portugal
b
Department of Gastroenterology, Hospital de Mérida, Badajoz, Spain
c
Department of Gastroenterology, Porto Comprehensive Cancer Center Raquel Seruca, and RISE@CI-IPO (Health Research Network), Porto, Portugal
d
MEDCIDS (Department of Community Medicine, Health Information, and Decision), Faculty of Medicine, University of Porto, Porto, Portugal
e
Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria
(IRYCIS), and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain

A R T I C L E I N F O A B S T R A C T

Handling Editor: Dr. Manon Spaander Endoscopic treatment, particularly endoscopic submucosal dissection, has become the primary treatment for
early gastric cancer. A comprehensive optical assessment, including white light endoscopy, image-enhanced
Keywords: endoscopy, and magnification, are the cornerstones for clinical staging and determining the resectability of le­
Endoscopic mucosal resection sions. This paper discusses factors that influence the indication for endoscopic resection and the likelihood of
Endoscopic submucosal dissection
achieving a curative resection. Our review stresses the critical need for interpreting the histopathological report
Early neoplasms
in accordance with clinical guidelines and the imperative of tailoring decisions based on the patients’ and le­
Gastric cancer
Gastrointestinal endoscopy sions’ characteristics and preferences. Moreover, we offer guidance on managing complex scenarios, such as
those involving non-curative resection. Finally, we identify future research avenues, including the role of arti­
ficial intelligence in estimating the depth of invasion and the urgent need to refine predictive scores for lymph
node metastasis and metachronous lesions.

1. Introduction
Gastric cancer (GC) poses a significant global healthcare challenge,
ranking as the fifth most prevalent cancer and the fourth leading cause
of cancer-related deaths worldwide [1]. While there has been a decrease
in both incidence and mortality rates in recent years [2], the overall
5-year survival rate for GC patients remains at 31%, and over 50% of
patients in unscreened populations are still diagnosed at advanced
stages [3]. Moreover, a recent study projected a rise in new GC diagnoses
and a 7% increase in age-standardized incidence rates is expected be­
tween 2015 and 2050 in the United States of America [4]. This growing
disease burden emphasizes the prompt need to shift towards primary
prevention and early detection.
Early gastric cancer (EGC) is defined as a malignant tumor that is
circumscribed to the mucosa or submucosa, regardless of lymph node
metastasis (LNM) [5]. The presence of LNM is associated with decreased
long-term survival, being considered one of the most relevant prognostic
factors [6]. While gastrectomy with lymphadenectomy has traditionally
been the standard treatment for GC, the landscape of EGC therapy has
undergone a significant transformation in recent years. Innovations in
endoscopic resection techniques, such as endoscopic mucosal resection
(EMR) and endoscopic submucosal dissection (ESD) have expanded the
treatment options for EGC, offering patients less invasive approaches. In
particular, ESD demonstrates comparable long-term outcomes with
lower adverse events and costs compared to surgery and is currently
considered the first-line treatment option for selected cases of EGC
bearing minimal risk of LNM [7,8].
Nevertheless, the rate of non-curative (NC) endoscopic resections
requiring subsequent surgical therapy may reach 20%, emphasizing the
need to enhance clinical staging and refine patient selection [9–11]. In
fact, a thorough evaluation of the criteria for determining the eligibility
of EGC for endoscopic resection plays a pivotal role in optimizing the
outcomes of patients.
This review aims to provide a comprehensive overview of the tech­
nical aspects that guide the decision-making process when considering
curative endoscopic therapy for EGC.

* Corresponding author. Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Carretera de Colmenar Viejo, km 9.1; 28034, Madrid,
Spain.
E-mail address: enrodesan@gmail.com (E. Rodríguez de Santiago).
1
Joint senior authors.

https://doi.org/10.1016/j.bpg.2024.101884
Received 30 December 2023; Accepted 23 January 2024
Available online 3 February 2024
1521-6918/© 2024 Published by Elsevier Ltd.

Please cite this article as: João A. Cunha Neves et al., Best Practice & Research Clinical Gastroenterology, https://doi.org/10.1016/j.bpg.2024.101884
J.A. Cunha Neves et al.
2. Indication for endoscopic treatment
2.1. Optical diagnosis
2.1.1. The gastric carcinogenesis model: from histology to endoscopy
The histological sequence of gastric carcinogenesis (inflammation →
glandular atrophy [GA] →intestinal metaplasia [IM] → dysplasia →
adenocarcinoma) must be kept in mind during a gastroscopy as many of
these changes can be identified endoscopically [12,13]. Advancements
in endoscopic imaging, such as Image-Enhanced Endoscopy (IEE) and
Magnifying Endoscopy allow endoscopists to characterize the gastric
mucosa more effectively, ranging from normality to a high-risk stomach
where the likelihood of visible lesions with dysplasia/adenocarcinoma is
significantly elevated (Fig. 1). From an endoscopic perspective, akin to
histology, a high-risk stomach is identified by the presence of endo­
scopic signs of GA or IM.
GA can be identified using White-Light Endoscopy (WLE), being
characterized by a pale colour, increased visibility of submucosal ves­
sels, and the recognition of the proximal transition of the pyloric and
fundic border, referred to as the atrophic border in the Kimura-
Takemoto classification.
IM can present different endoscopic characteristics depending on the
method of observation. Using WLE, IM appears as slightly flat elevated
with whitish patches [12,14–16]. Another observed sign with WLE is the
“map-like” redness, also known as mottled reddish depression, espe­
cially present in the post Helicobacter pylori (Hp) eradicated status [16,
17].
In the simplified Narrow Band Imaging (NBI) classification, IM is
described as a regular tubulo-villous pattern [18]. Other endoscopic
signs, such as the whitish-bluish crest and the white opaque substance,
have also been documented using NBI and similar technologies,
although the white opaque substance is not specific for IM since it can
also be present in adenomatous lesions [15,19]. When using magnifying
endoscopy, two important signs are the presence of Light Blue Crest and
the Marginal Turbid Band [20,21].
2.1.2. Detection of a visible lesion
Once a high-risk stomach is identified during endoscopy, it is crucial
for endoscopists to be aware of the increased risk of cancer. Detecting a
visible lesion involves recognizing an endoscopic abnormality that
needs characterization to determine its actual neoplastic condition.
Therefore, in the cancer diagnosis process, two key steps stand out:
detection and characterization.
WLE remains the primary and traditional method for detection of
gastric lesions, although there is increasing evidence that IEE is an
important asset in lesion detection [22,23].
Gastric cancer can be overlooked in around 10% of cases during a
gastroscopy due to the subtle appearance of EGC [24–26]. Thus, any
Fig. 1. Gastric cancer carcinogenesis: from histology to endoscopy.
2
Best Practice & Research Clinical Gastroenterology xxx (xxxx) xxx
irregularities or slight changes in colour tone (reddish/whitish or faded
pale areas) or variations in concavity or convexity should raise suspicion
[16]. Upon detection of a suspected lesion, further characterization of
the mucosal pattern is required.
2.1.3. Characterization of a visible lesion
Certain characteristics of the identified lesion may be described
through WLE, including its macroscopic morphology and topography
(location and its relation to the atrophic border). Some of these features
are associated with specific types of adenocarcinomas. Differentiated
(intestinal) adenocarcinoma is usually situated inside the atrophic
border, surrounded by GA and IM. In contrast, undifferentiated (diffuse)
adenocarcinoma is often located outside the atrophic border and sur­
rounded by non-metaplastic changes. WLE complemented by IEE (dye-
based and virtual chromoendoscopy), allow a finer characterization of
the lesion, as illustrated in Fig. 2 [13,16]. Despite these features that aid
in identifying the histological type, both magnifying endoscopy and
biopsies are essential in this task.
However, by relying on conventional WLE, we can estimate the
depth of invasion. The features associated with deep submucosal inva­
sion are a size of ≥30 mm, an irregular surface, marked redness, mar­
ginal elevation, hypertrophy, or fusion of concentrated folds,
submucosal tumour-like raised margins, and the non-extension sign
[13].
The presence of optical ulceration, which carries different clinical
implications than histologically confirmed ulceration, is a key feature to
assess resectability. The assessment of ulceration can be performed using
WLE and IEE. An active ulcer is characterized by a mucosal defect
accompanied by a deep white coat, and it should be distinguished from a
shallow erosion. Conversely, an ulcer in the process of healing and
scarring exhibits converging folds, necessitating differentiation from
concentrated folds associated with deep submucosal invasion [27].
The characterization and qualitative assessment of the lesion can be
refined using IEE and magnifying endoscopy. These allow the endo­
scopist to precisely identify the horizontal margins (demarcation line)
and explore the distribution of the microvascular (MV) and microsurface
(MS) patterns through the Vessel plus Surface (VS) classification [28]. A
regular distribution of MV and MS patterns excludes the presence of
cancer, whereas an irregular pattern or the absence of them raises sus­
picion of neoplasia. This method has shown its effectiveness for differ­
entiated neoplasms and has been included in the MESDA-G approach in
accordance with Japanese guidelines [13,29]. Magnifying NBI endos­
copy also unveils distinctive features that differentiate between differ­
entiated and undifferentiated adenocarcinoma. These features serve as
crucial clues for directing targeted biopsies, thus increasing the diag­
nostic yield. Notably, differentiated adenocarcinoma typically presents
with an irregular "fine-network" pattern, encircled by metaplastic
glands. Conversely, undifferentiated adenocarcinoma commonly
J.A. Cunha Neves et al. Best Practice & Research Clinical Gastroenterology xxx (xxxx) xxx

Fig. 2. Detected lesions and its characterization by using HD-WLE with IEE. A(1–3): Morphology: 0-IIb lesion. Size: 20 mm. Topography: Located in the antrum-
corpus transition (anterior wall), inside the atrophic border. Submucosal invasion: No signs. MV/MS pattern: Regular tubular. Histology: Intestinal metaplasia. B
(1–3): Morphology: 0-IIa lesion. Size: 12 mm. Topography: Located in the incisura, inside the atrophic border. Submucosal invasion: No signs. MV/MS pattern:
Irregular. Histology: Low-grade dysplasia. C (1–3): Morphology: 0-Is lesion. Size: 25 mm. Topography: Located in the incisura, inside the atrophic border. Sub­
mucosal invasion: No signs. MV/MS pattern: Irregular. Histology: high-grade dysplasia. D (1–2): Morphology: 0-IIb-IIc lesion. Size: 30 mm. Topography: Located in
the lesser curvature of the corpus, inside the atrophic border. Submucosal invasion: No signs. MV/MS pattern: Irregular and absent in some areas. Histology:
Intraepithelial well-differentiated adenocarcinoma. Pictures were captured using HD-WLE (A-1, B-1, C-1 and D-1), IEE with virtual chromoendoscopy mode SFI (A-2,
B-2, C-2 and D-2) and VIST (A-3, B-3 and C-3) by SonoScape (Medical Corp, Shenzhen, China). In addition, IEE with Indigo carmine was used in Picture D. HD: High-
definition; IEE: Image-Enhanced Endoscopy; MS: microsurface; MV: microvascular; SFI: Spectral Focused Imaging; VIST: Versatile Intelligent Staining Technology;
WLE: White-Light Endoscopy. Yellow arrowheads indicate borders of the lesion. (For interpretation of the references to colour in this figure legend, the reader is
referred to the Web version of this article.)

exhibits an irregular "corkscrew" pattern, devoid of a microsurface
pattern and surrounded by non-metaplastic glands. Nevertheless,
magnifying endoscopy in the stomach has not shown an improved ac­
curacy in the estimation of invasion depth compared to WLE, and lacks a
validated classification system.
2.2. The role of complementary tests
Endoscopic ultrasound (EUS) proves valuable in the locoregional
staging of gastric neoplasms. However, EUS has the potential to both
underestimate and overestimate the extent of gastric wall invasion and
leading to false positives and negatives in nodal staging [7,27,30]. Its
precision in discerning the degree of submucosal invasion in superficial
neoplasms is only moderate, as indicated by a Cochrane methodology
meta-analysis (T1a vs. T1b, sensitivity: 87% [95% confidence interval
(CI): 81%–92%], specificity: 75% [95% CI: 62%–84%]) [31]. Conse­
quently, scientific societies guidelines do not advocate for its routine
use, although it may be considered in borderline lesions with risk factors
for submucosal invasion [7,27,30]. The utilization of high-frequency
miniprobes, which are used in some Eastern countries, does not seem
to improve the diagnostic yield [32].
The use of abdominal CT or PET-CT scans is not recommended for
determining the endoscopic curability of EGC [7]. The incidence of
visible distant metastases in imaging tests for EGC is extremely low, and
the identification of perigastric adenopathy through imaging may not
necessarily indicate pathological involvement, potentially leading to
misguided decisions regarding endoscopic resection. In a retrospective
study involving 210 early lesions, the detection of EGC that was not
curable by ESD showed 79% sensitivity (95% CI 67%–87%) and 91%
specificity (95% CI 85%–95%). The authors suggested that PET/CT scan
might be useful in this context, but the lack of prospective and
cost-effectiveness data hinders the endorsement of this approach [33].
We should also acknowledge that lesions being considered for endo­
scopic resection generally pose a low risk of LNM (<10%–20%). In this
context, suboptimal specificity for LNM/deep invasion implies a low
positive predictive value. Consequently, the use of EUS/CT/PET can

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J.A. Cunha Neves et al.
potentially result in overstaging and overtreatment.
2.3. Pre-treatment biopsy
For early-stage lesions under consideration for endoscopic treatment,
the recommended biopsy protocol involves just 1–2 biopsies to confirm
their neoplastic nature and determine the histological type [30,34].
Additionally, a histological diagnosis based on a biopsy reflects only a
limited area of the entire lesion, resulting in histological discrepancies
between the biopsied sample and the resected lesion in around one-third
of cases [35]. Some initial non-neoplastic biopsies have led to the dis­
covery of cancer in the resected lesion, while 24% of cases initially
diagnosed as low-grade dysplasia on biopsy were subsequently identi­
fied as high-grade dysplasia, and 53% of high-grade dysplasia cases were
upstaged to adenocarcinomas. Moreover, 8% of initially differentiated
adenocarcinomas ultimately proved to be undifferentiated adenocarci­
nomas [36]. Nevertheless, histological assessment is essential to confirm
the neoplastic nature and assess differentiation of a gastric lesion, and
thus 1–2 targeted biopsies are recommended prior to endoscopic
resection.
3. Guidelines recommendations for endoscopic resection
Endoscopic resection is recommended as the standard treatment for
EGC when the presumed risk of LNM is <1% [7,27,37].
The Japanese guidelines define as absolute indications for endo­
scopic resection: 1) dysplastic lesions regardless of size; 2) non-ulcerated
differentiated intramucosal (cT1a) lesions of any size or ≤30 mm if ul­
cerated and 3) undifferentiated cT1a lesions with ≤20 mm without ul­
cerative findings [7,27,37]. Similarly, the European guidelines consider
the first two criteria as absolute indications for endoscopic resection
(Table 1) [7].
Both guidelines also define expanded indications for endoscopic
resection, i.e. lesions presumed to have a 1%–3% risk of LNM [7,27,37].
European recommendations include in this group undifferentiated cT1a
lesions with ≤20 mm and without ulcerative findings, whereas Japanese
guidelines include in this category eCura-C1 recurring cT1a lesions
(Table 1) [7,27,37].
In parallel with the Japanese recommendations, the American
guidelines have recently defined stricter absolute indications for endo­
scopic resection, including in this group only non-ulcerated differenti­
ated cT1a lesions with ≤20 mm. Furthermore, the authors define the
following as expanded indications: 1) non-ulcerated differentiated le­
sions >20 mm, presence of submucosal invasion <500 μm, or ulcerated
lesions with ≤30 mm; 2) Poorly and undifferentiated lesions ≤20 mm
without ulceration; and 3) en-bloc resected lesions at risk for
Table 1
Clinical staging: absolute and expanded indications for endoscopic resection according to European, Japanese, and American guidelines.
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Best Practice & Research Clinical Gastroenterology xxx (xxxx) xxx
submucosally invasive cancer (Table 1) [38].
4. Treatment
4.1. EMR vs. ESD
Endoscopic therapy, either by EMR or ESD, provide patients with a
less invasive alternative to surgery, while maintaining high rates of
curability, with 5-year overall survival (OS) and disease-specific survival
(DSS) rates of 89%–95% and above 99%, respectively [39–41].
EMR is a suitable technique for lesions confined to the mucosa.
However, due to the snare’s size and lesion morphology (e.g. Paris 0-IIc
non-lifting lesions), en bloc resection of larger lesions is limited.
Incomplete or piecemeal resection is associated with local recurrence
and hinders adequate histopathological evaluation and staging, thus
hampering subsequent management [42,43]. European guidelines sug­
gest that EMR is a viable option for 0-IIa lesions ≤10 mm with a low
likelihood of malignancy [7]. In contrast, American and Japanese
guidelines specify that EMR may be employed for the resection of
non-ulcerated differentiated lesions ≤20 mm [27,37,38].
Currently, ESD is recommended as the first option for the endoscopic
treatment of EGC [7,27]. ESD is associated with higher rates of curative
resection and lower recurrence (<5%), being significantly superior to
EMR in achieving en bloc and complete resection (over 95% and 90%,
respectively) for lesions of any size [7,10,27,37,44].
Four meta-analyses have compared the safety and efficacy outcomes
of EMR and ESD (Table 2). Both techniques have low rates of adverse
events, with similar risk of post-procedural bleeding (≈5%). However,
ESD is associated with higher, albeit still low, perforation rates, longer
procedural time and longer learning curve [10,39,44–48].
Although ESD is considered safer than surgery, adverse events may
also occur. The most frequent adverse event after ESD is post-procedural
bleeding (4.4%–5.1%) [10,49]. To reduce the rate of delayed bleeding,
proton-pump inhibitor administration after ESD and coagulation of
visible vessels in post-ESD scars are recommended [27,50–52].
The endoscopic approach to resectable gastric lesions presents a low
rate of adverse events and allows for the preservation of the stomach’s
structure and functions. However, the spared mucosa poses a risk for
metachronous lesions.
4.2. ESD vs. surgery
Partial or total gastrectomy with D2 lymphadenectomy is considered
the gold-standard surgical curative treatment for GC [37]. In contrast to
ESD, gastrectomy ensures superior en bloc, complete and curative
resection rates, therefore minimizing the risk of local recurrence or
J.A. Cunha Neves et al. Best Practice & Research Clinical Gastroenterology xxx (xxxx) xxx

Table 2
EMR vs. ESD – safety and efficacy outcomes.
Author, year Procedure duration (minutes) Perforation rate Local recurrence En bloc resection Complete resection

Lian J, 2012 [46] WMD: 59.4 [16.8–102.0] *0.9% vs. 4.3%

Facciorusso A, 2014 [47]
Zhao Y, 2018 [48]
Tao M, 2019 [45]
SMD: 1.73 [0.52–2.95]
MD: 49.86 [-71.62 to − 28.10]
SMD: 1.12 [0.13–2.10]
+
*6.4% vs. 0.8%
+
*51.7% vs. 92.4%
+
*42.2% vs.+82.1%
OR 4.67 [2.77–7.87] OR 0.10 [0.06–0.18] OR 9.69 [7.74–12.13] OR 5.66 [2.92–10.96]
*0.9% vs.+4.3% *6.0% vs.+0.6% *51.7% vs.+92.4% *42.2% vs.+82.1%
OR 4.67 [2.77–7.87] OR 0.09 [0.05–0.17] OR 9.69 [7.74–12.13] OR 5.66 [2.92–10.96]
*1.2% vs.+3.2% *5.2% vs.+0.2% *55.7% vs.+93.4% *57.4% vs.+91.7%
OR 0.37 [0.24–0.57] OR 14.94 [7.26–30.74] OR 0.10 [0.09–0.13] OR 0.14 [0.12–0.17]
OR 2.55 [1.48–4.39] OR 0.18 [0.09–0.34] OR 9.00 [6.66–12.17] OR 8.43 [5.04–14.09]

*EMR: endoscopic mucosal resection; +ESD: endoscopic submucosal dissection; [] - 95% confidence intervals.
MD: mean difference; OR: odds ratio; SMD: standard mean difference; WMD: weighted mean difference.

metachronous lesions (ESD: 5.2%–6.0% vs. surgery: 0.4%–0.5%) [38, 5. Curative criteria based on the histopathological assessment
53]. On the other hand, gastrectomy is associated with higher proce­
dural time, length of stay, impairment of patients’ reported quality of To define the management after endoscopic resection, histopatho­
life, and risk of adverse events and mortality [8,38,42,53–56]. logical assessment of the specimen is required to classify the resection as
In terms of long-term outcomes, despite ESD having a higher recur­ curative or non-curative. The criteria for determining curability of EGC
rence risk and lower 5-year disease-free survival (DFS), studies have have been established based on the assessment risk of LNM. The inci­
shown comparable 5-year OS and DSS for both ESD and surgery (95% dence of LNM in EGC is documented to range from 0% to 20%,
and 99%, respectively) (Table 3) [8,53,55–57]. Overall, if a lesion is depending on several histological factors, and this risk is minimal when
endoscopically resectable and has a predictable high curability poten­ certain conditions are met [7,55,58,62]. Several studies have identified
tial, ESD is considered a superior option. lymphovascular invasion as the strongest risk factor associated with
However, the choice between endoscopic or surgical management LNM (OR: 6.7, 95% CI 5.0–8.9) [58,63–65]. Also, the depth of tumor
for GC is also largely influenced by tumor differentiation. Undifferen­ invasion across layers has been shown to linearly increase the LNM rate
tiated GCs carry a significantly higher risk of LNM, potentially hindering [66–68]. Overall, lymphovascular invasion, deep submucosal invasion
curative resections and contributing to higher recurrence rates [38,58, (>500 μm), size >30 mm, ulceration and undifferentiated histology
59]. Current recommendations for the management of undifferentiated have been consistently identified as independent risk factors for LNM
GC are divergent. On one hand, European and Japanese guidelines and are the core of current curative criteria [7,55,58,62,69–72].
recommend that non-ulcerated undifferentiated lesions with ≤20 mm
may be managed by ESD, while the American Society for Gastrointes­ 5.1. Guidelines recommendations
tinal Endoscopy recommends that undifferentiated lesions should un­
dergo surgical resection, independently of size [7,27,38]. Two European guidelines define curative resections in two groups
meta-analyses revealed that, in patients with non-ulcerated undiffer­ (Fig. 3A) [7]. Very-low risk resections (LNM <1%) include en bloc
entiated lesions with ≤20 mm, ESD achieved similar results to surgical resected differentiated mucosal lesions (pT1a) without lymphovascular
cohorts, in terms of 5-year DFS, OS and DSS (Table 3) [60,61]. Most invasion and with negative margins, of any size if non-ulcerated or ≤30
importantly in these cases, regardless of the chosen technique, the mm if ulcerated. No further radiological staging or treatment are
decision-making process should involve the patient and their physician, required in these lesions. Low risk resections (LNM <3%) encompass
considering both short- and long-term outcomes. non-ulcerated en bloc resected undifferentiated pT1a lesions ≤20 mm or
differentiated non-ulcerated lesions with ≤30 mm, shallow submucosal
invasion ≤500 μm (pT1b1), without lymphovascular invasion and with
negative margins. Although these lesions do not generally require sub­
sequent treatment, complete staging is recommended, and case-by-case
Table 3 multidisciplinary discussion should take place to decide whether further
ESD vs. Surgery – long-term survival comparison. surgical treatment is needed, since the LNM risk is low but not null.
Author, year OS DSS DFS Lesions that do not fulfill curative criteria may also be included in
Abdelfatah MM, *96% vs.+96% *99.4% *95.9% two groups (Fig. 3B). Local risk resections include lesions with very-low
2019 [55] vs.+99.2% vs.+98.5% risk criteria that are piecemeal resected or contain positive horizontal
OR: 0.96 OR: 0.7 OR: 1.86 margins, and also differentiated pT1b1 lesions ≤30 mm resected in
(0.74–1.25) (0.16–2.19) (0.57–6.0) piecemeal or with positive horizontal margin, provided that the vertical
Gu L, 2019 [8] *96.3% *99.7% *90.2%
vs.+96.3% vs.+99.1% vs.+97.2%
margins are negative and there is no submucosally invasive tumor at the
RR: 0.90 RR: 0.40 RR: 3.40 horizontal resection margin. Although the risk of LNM is very low, these
(0.68–1.19) (0.15–1.03) (2.39–4.84) lesions have an increased risk of local recurrence, though its manage­
Li H, 2020 [56] HR: 0.51 – – ment should be decided according to the patient’s preference. Guide­
(0.26–1.00)
lines advocate that, whenever possible, a close follow-up with
Liu Q, 2020 [53] HR: 0.92 HR: 0.73 HR: 4.58
(0.71–1.19) (0.36–1.49) (2.79–7.52) endoscopic reintervention should be favored over surgery, either by
Huh CW, 2021 [60] OR: 2.29 – – performing scar biopsies or ESD/scar ablation. Lastly, high risk re­
(0.98–5.36) sections are considered noncurative in case of any of the following: 1)
Xu X, 2022 [57] HR: 1.22 – HR: 3.29 lymphovascular invasion; 2) positive vertical margins (with carcinoma);
(0.66–2.25) (1.60–6.76)
Yang HJ, 2022 [61] *95.8% *95.8% *90.5%
3) deep submucosal invasion; 4) poorly differentiated histology with
vs.+96.9% vs.+96.9% vs.+96.7% >20 mm or ulceration or any degree of submucosal invasion, and 5)
RR: 1.18 RR: 2.49 RR: 2.49 >30 mm differentiated pT1b1 lesions or pT1a ulcerated lesions >30
(0.60–2.32) (0.47–37.93) (1.42–4.35) mm. These lesions have indication for additional complete staging and
* ESD: endoscopic submucosal dissection; +Surgery. further surgical resection is the standard treatment, although in case of
DFS: disease-free survival; DSS: disease-specific survival; HR: hazard ratio; OR: patients’ refusal or performance status precluding surgical intervention,
odds ratio; OS: overall survival; RR: risk ratio. surveillance may be an option, especially in eCura low or intermediate

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J.A. Cunha Neves et al. Best Practice & Research Clinical Gastroenterology xxx (xxxx) xxx

Fig. 3. Post-resection management according to the European ESD guidelines. HM0: negative horizontal margin; HMx: piecemeal resection; HM1: positive horizontal
margin; LV0: no lymphovascular invasion; pT1a: intramucosal adenocarcinoma; pT1b (SM1): adenocarcinoma with superficial submucosal invasion (≤500 μm); UL0:
non-ulcerated; UL1: ulcerated; VM0: negative vertical margin.

risk categories (see below). a) eCuraA – the effect of endoscopic resection is equal or superior to
Japanese guidelines define the curability of resected lesions ac­ surgery. These include all the very-low risk lesions comprised in the
cording to the eCura grading system, depending on the long-term effect European guidelines and also non-ulcerated en bloc primarily
of endoscopic resection compared to surgery (Fig. 4) [27,37,73]:

Fig. 4. Endoscopic curability criteria – Japanese guidelines. HM0: negative horizontal margin; HMx: piecemeal resection; HM1: positive horizontal margin; LV0: no
lymphovascular invasion; LV+: lymphovascular invasion; M: mucosal invasion; SM1: adenocarcinoma with superficial submucosal invasion (≤500 μm); UL0: non-
ulcerated; UL1: ulcerated; VM0: negative vertical margin; VM1: positive vertical margin.

6
J.A. Cunha Neves et al.
undifferentiated pT1a lesions ≤20 mm, without lymphovascular in­
vasion, negative vertical and horizontal margins.
b) eCuraB – the effect of endoscopic resection is anticipated to be su­
perior to surgery, but long-term data is scarce. These include en bloc
resected differentiated pT1b1 lesions without lymphovascular inva­
sion, <30 mm, negative vertical and horizontal margins.
c) eCuraC – non-curative resections. This category can be divided into 2
subgroups:
- eCuraC1: all differentiated eCuraA or eCuraB lesions that were
piecemeal resected or had positive horizontal margins.
- eCuraC2: all other non-curative resections, including primarily
differentiated lesions with a >20 mm undifferentiated segment and
lesions with an undifferentiated component in the submucosa.
5.2. Management after curative endoscopic resection
Since endoscopic resection techniques allow organ preservation,
local recurrence and metachronous lesions may arise, making surveil­
lance paramount in these patients. Recently, the cumulative incidence of
metachronous lesions after endoscopic resection was determined at
9.5% at 5 years and predicted to reach up to 14.9% at 10 years, as
opposed to 0.7% and 2.3% for surgery, respectively [74].
Currently, European guidelines recommend the first follow-up
endoscopy 3–6 months after a curative resection or a local-risk resec­
tion without local recurrence, followed by an annual endoscopic sur­
veillance [7]. On the other hand, Japanese guidelines recommend
annual endoscopic surveillance following eCuraA resections and annual
or biannual endoscopy combined with abdominal ultrasonography or
CT following eCuraB resections. Although an endoscopy interval shorter
than 12 months does not appear to raise the rate of metachronous lesions
suitable for endoscopic resection, a surveillance interval exceeding 12
months is significantly associated with the recurrence of adenocarci­
noma, larger lesions, and a higher likelihood of patients undergoing
surgical treatment [74,75].
Persistent Hp infection, older age, male sex, a family history of GC,
the presence of synchronous lesions, corpus IM, severe GA, and a lower
pepsinogen I/II ratio have been associated with a significant risk of
metachronous lesions and may help to customize surveillance [74]. In
particular, Hp eradication seems to be associated with reduced rates of
metachronous GC [76–81]. Current guidelines advocate determining the
presence and treating Hp positive patients who underwent an endo­
scopic resection of EGC [27,37,82].
More recently, Rei et al. developed the FAMISH score, based on six
clinical predictors [83]. In a cohort of patients monitored for 3 years
post-ESD for EGC, this monitoring tool allowed the identification of
patients with a low-to-intermediate risk for metachronous lesions [83].
This score has been further validated to the Eastern population and may
become a valuable asset to extend the surveillance intervals in selected
patients [84].
While the risk of metachronous lesions rises in older patients, it also
appears to increase up to 10 years after endoscopic resection, regardless
of age. Still, the precise duration of follow-up after endoscopic resection
of EGC remains undefined since a stable cumulative incidence of
metachronous lesions seems to occur 10 years after resection [85].
5.3. Approach to non-curative resections
Whenever a non-curative resection is achieved, accurate evaluation
of the risk for local recurrence and LNM is crucial for effective decision-
making and reduce the rate of futile surgeries. This assessment should
consider adverse prognostic factors and be weighed against surgical
risks, the patient’s physical condition, and their preferences. In certain
cases, the risk of recurrence might be outweighed by the surgical risks
and surveillance might be a viable option, with comparable DSS rates to
those achieved through surgery [86–89]. On the other hand, 75% of
subsequent gastrectomy specimens from non-curative resections neither
7
Best Practice & Research Clinical Gastroenterology xxx (xxxx) xxx
harbored residual parietal lesions nor LNM [90].
5.3.1. eCura
In order to identify non-curative resections that may require further
surgical therapy, Hatta et al. designed the eCura score system, stratifying
Eastern patients with non-curative resections based on the risk of LNM
[73]. This score system attributes points to five distinct risk factors for
LNM: three points – lymphatic invasion; one point each – tumors >30
mm, positive vertical margins, venous invasion, and submucosal inva­
sion >500 μm. According to the overall score, patients are divided into
three different categories, depending on the LNM risk: low risk (2.5%) –
zero to one point; intermediate risk (6.7%) – two to four points; high risk
(22.7%) – five to seven points. The score was then validated, demon­
strating that stratifying patients in these three different categories is
associated with a significant reduction of DSS at 5 years (99.6%, 96%
and 90.1%, respectively; p < 0.001). Moreover, this validation high­
lights that ESD without additional treatment might suffice in low-risk
patients, since they have a DSS comparable to patients who fulfill
curative endoscopic resection criteria [73].
5.3.2. W-eCura
The eCura score system, originally developed for the Eastern setting,
has been recently assessed and validated to the Western population [91].
Morais et al. demonstrated that the LNM risk was significantly different
among the eCura groups [low-risk - 0% (95% CI 0%–6.1%),
intermediate-risk - 9.2% (95% CI 3.5–19.0%), and high-risk - 53.1%
(95% CI 34.7%–70.9%), p < 0001], with an AUROC of 0.90 (95% CI
0.85–0.95). The authors also identified that piecemeal resection (OR =
5.29, 95% CI 1.33–21.03), lymphatic invasion (OR = 5.070, 95% CI
1.78–14.43) and depth of submucosal invasion (OR = 1.97, 95% CI
1.16–3.35) are significantly associated with a higher risk of residual
lesion (both parietal residual lesion and LNM). Moreover, the authors
proposed a modified version of the eCura score (W-eCura), establishing
the cut-off of submucosal invasion to ≥1 mm. This change in submucosal
depth invasion granted a 2% specificity increase for the detection of
LNM, without sensitivity loss, and an AUROC for LNM of 0.92 (95% CI
0.87–0.96), significantly higher compared with the original eCura (p =
0.012), although these findings should be validated in further studies
before implementation in clinical practice.
6. Conclusion
ESD has become a cornerstone in the management of EGC, necessi­
tating meticulous and standardized lesion assessment for determining
resectability (Fig. 5). The first step is clinical staging based on WLE, IEE
and magnification. These modalities serve to delineate the horizontal
margins of the lesions and estimate the depth of invasion. Optical signs
influencing endoscopic resection decisions include lesion size,
morphology, ulcer presence, and anatomical location. Other staging
modalities, such as EUS, CT scan, or PET, should not be routinely
employed but rather reserved for cases where deep submucosal invasion
is suspected, due to their limited incremental value. Additionally,
guidelines still advocate one or two targeted biopsies to verify the
diagnosis and assess the tumor type and differentiation grade.
Following resection, histopathological assessment and subsequent
treatment decisions should adhere to guideline recommendations. These
decisions consider factors such as tumor size and type, ulceration pres­
ence, lymphovascular invasion, and invasion depth, noting that Western
and Eastern guidelines may vary. Post-curative resection management
requires long-term monitoring, including annual endoscopies to detect
metachronous lesions, considering patient demographics, family his­
tory, and ongoing Hp infection. For non-curative resections, a person­
alized approach within a multidisciplinary team is essential. Here, the
eCura score may help evaluate the risk of LNM and the necessity for
surgery.
Looking forward, a critical unresolved issue is minimizing
J.A. Cunha Neves et al.
Fig. 5. Systematic approach to determine the curability of early gastric lesions.
CT: computed tomography; EMR: endoscopic mucosal resection; ESD: endo­
scopic submucosal dissection; EUS: endoscopic ultrasonography; LNM: lymph
node metastasis, PET: positron emission tomography.
unnecessary surgery. Artificial Intelligence is expected to aid in the
assessment of invasion depth and the development of predictive scores
for LNM and metachronous lesions. This advancement is poised to aid
endoscopists in making more informed decisions, enabling personalized
patient care.
7. Practice points
• Lesion evaluation to define treatment strategy should include
assessment with HD-WLE and virtual chromoendoscopy (very useful
for horizontal margin delineation).
• The following factors influence the indication for endoscopic resec­
tion and likelihood of curative resection and should be routinely
assessed:
a) size
8
Best Practice & Research Clinical Gastroenterology xxx (xxxx) xxx
b) morphology and ulceration (sessile, depressed, and ulcerated le­
sions are associated with higher risk of submucosal invasion)
c) location (lesions located in the upper third of the stomach are
associated with higher risk of submucosal invasion and non-
curative resection)
d) optical signs of deep submucosal invasion (convergence/club­
bing/abrupt cutting of gastric folds; non-extension sign;
submucosal-tumor like appearance; deep ulcer with markedly
elevated margins; friability or marked nodularity)
e) tumor differentiation - although upstaging after resection is
frequent (20–40%), 1–2 biopsy fragments should be taken to
assess differentiation.
• Other staging methods (EUS, CT and PET scans) are not routinely
recommended and should be reserved for cases with suspicion of
deep submucosal invasion.
• The interpretation of the histopathological report of the resected
specimen should be made according to guidelines. In cases of high-
risk resection/eCURAC2 resection, gastrectomy is generally recom­
mended although the decision should include patients’ preferences
and performance status. The eCura score should be used to stratify
the risk of LNM in these cases, being lymphatic invasion the most
important predictor for LNM.
• After a curative resection, patients should be included in long-term
endoscopic follow-up (annual endoscopy). Patient characteristics
such as male sex, corpus IM, family history of GC, synchronous le­
sions or persistent Hp can influence the risk of metachronous lesions.
8. Research agenda
• Artificial intelligence will probably have a role in the estimation of
invasion depth, helping endoscopists in treatment decisions.
• Refinement of scores for prediction of LNM and of metachronous
lesions is important for individualized treatment decisions.
Role of the funding source
The authors have no funding sources to declare.
CRediT authorship contribution statement
João A. Cunha Neves: Writing – original draft, Writing – review &
editing. Pedro G. Delgado-Guillena: Writing – original draft, Writing –
review & editing. Patrícia Queirós: Writing – original draft, Writing –
review & editing. Diogo Libânio: Conceptualization, Writing – original
draft, Writing – review & editing, Supervision. Enrique Rodríguez de
Santiago: Conceptualization, Supervision, Writing – original draft,
Writing – review & editing.
Declaration of competing interest
Enrique Rodríguez de Santiago declares: Olympus (educational ac­
tivities and advisory), Apollo Endosurgery (educational activities),
Norgine (congresses fee and education activities), Adacyte Ther­
apeuthics (advisory activities) and Casen Recordati (congresses fee).
Pedro G. Delgado-Guillena declares: Sonoscape (educational activities
and advisory), ST Endoscopy (educational activities and congresses fee)
and Casen Recordati (congresses fee). The remaining authors declare
that there is no conflict of interest.
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