Keywords Endoscopy Upper GI Tract - Precancerous conditions & cancerous lesions (displasia
and cancer) stomach - Endoscopy Upper GI Tract - Endoscopic resection (ESD, EMRc,
...) - Endoscopy Upper GI Tract
Introduction
Undifferentiated early gastric cancer (UD-EGC) represents a distinct malignant entity
of stomach, not significantly associated with Helicobacter pylori infection, consisting of two pathological subtypes: poorly differentiated adenocarcinoma
and signet-ring cell carcinoma [1 ] Therapeutic approach and management are challenging for clinicians and endoscopists,
as UD-EGC is characterized by more aggressive behavior even in early stages, compared
with differentiated adenocarcinomas. Current data support that increased diameter,
superficial ulceration, deep invasion, and lymphovascular invasion are associated
with high recurrence and lymph node metastases rates, thus radical resection is required
[1 ]
[2 ]
[3 ]
[4 ]
[5 ].
Endoscopic submucosal dissection (ESD) has been established as a treatment mainstay
for EGC. ESD is indicated to treat EGC for, among other things, histological subtype,
with UD-EGC considered an expanded indication according to the European Society of
Gastrointestinal Endoscopy (ESGE). More specifically, ESGE recommends considering
endoscopic management only if the UD-EGC is < 20 mm in diameter, without ulceration,
and it can be curative only for mucosal cancer if no lymphovascular invasion is present
[6 ]. The Japanese Gastroenterological Endoscopy Society suggests that ESD is absolutely
indicated for non-ulcerated UD-EGC ≤ 20 because the risk of lymph node metastasis
in the absence of ulceration and lymphovascular invasion is 2.8% [95% confidence interval
(CI): 1.0%-6.0%] [7 ].However, when the cumulative size of undifferentiated components exceeds 20 mm on
histology, resection is not considered curative [7 ]. Although lesion size is used as a factor to guide the decision to proceed or not
with ESD, these recommendations are based on low-moderate quality of data.
This multicenter study aimed to answer this question by evaluating recurrence rates
for UD-EGC after ESD, with respect to established and potential risk factors to guide
patient selection for endoscopic management.
Patients and methods
Study design
Seventeen centers around the globe participated in this retrospective multicenter
study by providing their records from 2008 to 2022. The study was structured based
on the Strengthening the Reporting of Observational studies in Epidemiology (STROBE)
guidelines (Supplementary Table 1) [8 ]. A predefined protocol, which conformed to the ethical guidelines of the last revision
of Declaration of Helsinki and complied with Good Clinical Practice Guidelines [9 ]
[10 ], was centrally approved by the Scientific Committee of the main coordinating center,
and was the reference for all involved centers. Patient anonymity was ensured and
the data received were de-identified.
Patients
Adult patients (≥ 18 years old), ineligible or unwilling to undergo surgery, who underwent
ESD for UD-EGC, with complete en-block excision, defined as clear margins in the pathology
specimen, were enrolled in this study. Exclusion criteria included patients who underwent
surgery after UD-EGC diagnosis, those with metastatic disease, synchronous or previous
malignancy, incomplete resection (positive vertical or lateral margins in histology),
indefinite or missing data and absent follow up.
Data collection
Cases fulfilling the eligibility criteria were recruited. The eligibility of the included
cases was evaluated by AP. The following variables were retrieved: 1) demographics
(age at diagnosis, sex, race); 2) endoscopic features of the lesion (location, size,
superficial morphology, and electronic chromoendoscopy findings of demarcation line,
corkscrew vessels, absent microsurface pattern in magnification); 3) duration of ESD;
4) complications (intraprocedural bleeding, perforation); 5) histologic findings (size
of specimen, UD-EGC subtype, and submucosal, lymphovascular, perineural or vascular
invasion); 6) presence of H. Pylori infection, defined as positive gastric histology, rapid-urease, C13 urea breath or
stool antigen test; 7) duration and frequency of follow up; and 8) need for adjuvant
chemotherapy after ESD recurrence-metastasis.
An Excel file (Microsoft Excel for Mac 2019, Microsoft Corporation, Redmond, Washington,
United States) with predetermined available variable values was created and shared
with the involved centers. All data were stored on a secure server.
Outcomes
The primary endpoint of the current study was the recurrence rate for UD-EGC after
initial treatment with ESD. Secondary outcomes included assessment of potential risk
factors associated with recurrence, determination of the time of recurrence, and assessment
of ESD-related adverse events.
Statistical analysis
Data analysis was performed using the Statistical Package for Social Science Software
for Windows (IBM SPSS Statistics, Version 28.0. Armonk, New York, United States: IBM
Corp). Continuous variables are presented as mean (± standard deviation) and categorical
variables are shown as percentages. Recurrence after ESD over time was calculated
according to the Kaplan-Meier method. The log-rank test was be performed for analysis.
Univariable models were used to investigate individual associations between independent
variables and recurrence, while in the multivariable Cox regression, all variables
were inserted to assess their relationship with recurrence over time. Hazard ratios
(HRs) and their 95% CIs were derived from each variable coefficient in the final model.
P ≤ 0.05 (two tailed) was considered statistically significant.
Results
After applying the inclusion/exclusion criteria, 71 patients were eligible to our
analysis (Supplementary Fig. 1). [Table 1 ] summarizes the main characteristics of our sample. The female to male ratio was
2:1 and the mean age was 65.8 ± 11.8 years. The majority of patients were White (40;
56.3%), followed by Asians (17; 23.9%), and Hispanics (12; 16.9%), whereas only two
Africans were included.
Fig. 1 Kaplan-Meier curve presenting the time of recurrence of UD-EGC with regard to lymphovascular
invasion.
Table 1 Main characteristics of the UD-EGC cohort.
Variable
N (or mean ± SD)
%
UD-EGC, undifferentiated early gastric cancer; ESD, endoscopic submucosal dissection.
Gender
Female
44
62
Male
27
38
Age
65.8 (±11.8)
Race
White
40
56.3
Asian
17
23.9
Hispanic
12
16.9
African
2
2.8
Tumor size (endoscopy, mm)
33.5 (±18.8)
Tumor size (histology, mm)
39.6 (±22.0)
Tumor location
Cardia
7
9.9
Fundus
8
11.3
Corpus
26
36.6
Antrum
15
21.1
Incisura
15
21.1
Surface (white light)
Ulcerated
3
4.3
Scar deformity
6
8.6
Erythema
8
11.4
Discoloration
10
14.3
Nodularity
19
27.1
Depression
24
34.3
Chromoendoscopy
Demarcation line (yes)
42
59.2
Corkscrew vessels (yes)
23
32.4
Absent microsurface pattern (yes)
36
50.7
H.pylori infection
Previous
19
26.8
Active
5
7
Indicative biopsy before ESD (yes)
52
73.2
Histological subtype
Poorly differentiated
25
35.2
Signet-ring cell
46
64.8
Submucosal Invasion (yes)
16
22.5
Lymphovascular invasion (yes)
7
9.9
Perineural invasion (yes)
3
4.8
Vascular invasion (yes)
4
5.6
Depth of invasion
Mucosa
55
77.4
sm1
7
9.9
> sm1
9
12.7
ESD duration (mins)
113.1 (±74.9)
Complications
Intraprocedural bleeding
9
12.7
Perforation
5
7
Follow-up intervals (months)
5.6 (±3.7)
Follow-up duration (months)
29.3 (±15.3)
The most frequent site of UD-EGC in this cohort was the gastric corpus 36.6% (26/71),
followed by the antrum and incisura, each 42.2%. Eight lesions were resected from
fundus and seven from the cardia. The mean size of the tumors, as assessed by the
endoscopists, was 33.5 ± 18.8 mm, with 70.4% > 20 mm. Considering mucosal features
under white light, 34.3% had a depression, whereas about one-fourth had a nodular
surface. The main chromoendoscopic descriptions included a demarcation line between
the lesion and the surrounding mucosa in 59.2%, corkscrew vessels in 32.4%, and absent
microsurface pattern after using magnification in 50.7%. Interestingly, in 73.2% of
cases, the endoscopists had a histology result from UD-EGC before the procedure.
The mean ESD duration was 113.2 ± 74.9 minutes and in 19.7% of procedures a complication
was recorded: 12.7% (9/71) intraprocedural bleeding and 7.0% (5/71) perforation. Complications
were associated with male sex (P = 0.024) and the lesion location (cardia or fundus, P = 0.024). The mean size of the resected specimens, measured by the pathologists,
was 39.6 ± 22.0 mm. The vast majority of patients (65.7%) had a negative work-up for
H. pylori infection, 26.8% had a history of eradication, and five patients had an active infection.
Regarding UD-EGC subtypes, the ratio of signet-ring cell type to poorly differentiated
cancer was almost 2:1. Sixteen tumors (22.5%) invaded the submucosa, and the level
of invasion was at least sm1 in nine of them (12.7%). Vascular, lymphovascular, and
perineural invasions were detected in 5.6%, 9.9%, and 4.8%, respectively.
After resection, 10 patients (14.9%) received adjuvant chemotherapy, based on their
preference and fitness for surgery, after adopting an individualized approach. The
mean follow-up duration was 29.3 ± 15.3 months (median: 20 months) and patients were
followed up every 5.6 ± 3.7 months. Local recurrence was recorded in four cases (5.6%),
8.8 ± 6.5 months post-ESD, with no lymph node or distal metastasis been reported.
Three of the recurrencies were detected at the site of the previous resection and
one was a metachronous UD-EGC. Lesion size (42 ± 17.9 mm) was not associated with
recurrence (P = 0.32), even when a diameter of 20mm was considered as a cut-off size (P = 0.97). Similarly, chi-square test investigating the association between depth of
invasion and recurrence did not reveal any statistical significance (P = 0.14), although two of the lesions invaded the submucosa. In contrast, lymphovascular
and perineural invasion were independently associated with recurrence (P = 0.006 and P < 0.001, respectively) and co-existed in two of the four recurrent lesions, whereas
vascular invasion did not reach significance (P = 0.084) ([Table 2 ]). Based on the presence of lymphovascular and perineural invasion, a Kaplan-Meier
curve revealed a significantly earlier recurrence with regard to both variables. Patients
with lymphovascular invasion developed recurrence < 20 months after resection (P = 0.012) ([Fig. 1 ]), as did those with perineural invasion (P < 0.001) ([Fig. 2 ]). Multivariable Cox regression did not reveal any statistically significant association
between included variables and recurrence.
Fig. 2 Kaplan-Meier curve presenting the time of recurrence of UD-EGC with regard to perineural
invasion.
Table 2 Associations between potential risk factors and UD-EGC recurrence.
Univariate analysis
Multivariate analysis
Variable
Cases of recurrence
Chi-square value
P value
Hazard ratio
P value
UD-EGC, undifferentiated early gastric cancer.
Size (mm)
28.8
0.319
1.04
0.26
Size (> 20 mm)
3
0.001
0.971
0.07
0.28
Subtype (poorly differentiated)
3
2.9
0.086
0.34
0.40
Submucosal invasion
2
2.8
0.92
2.49
0.64
Lymphovascular invasion
2
7.7
0.006
4.88
0.44
Vascular invasion
1
2.9
0.084
3.89
0.43
Perineural invasion
2
19.3
< 0.001
24.6
0.06
Discussion
This multicenter study, not limited to a specific subpopulation or region, is the
first that indicates that the size of UD-EGC is not associated with recurrence after
ESD, thus supporting the approach that endoscopic assessment of UD-EGC cannot predict
the outcomes of endoscopic resection, and further management should be based on histology.
More specifically, the mean size of the resected tumors was 33.5 ± 18.8 mm, greater
than the threshold of 20 mm suggested by ESGE. Nevertheless, the recurrence rate in
our cohort was 5.6%, similar to other studies, and it was not associated with lesion
diameter [11 ]. In contrast, pathological confirmation of lymphovascular or perineural invasion
was strongly associated with recurrence.
To date, multiple variables have been assessed to provide a reliable predictor of
UD-EGC recurrence after endoscopic treatment. Among them, size and lymphovascular
invasion have been the most commonly recorded [6 ]. The impact of size on recurrence was not significant in our study (P = 0.32), although lymphovascular (P = 0.006) and perineural invasion were significant (P < 0.001). Perineural invasion has not been investigated as a predictive factor for
recurrence in ESD studies for UD-EGC. Nevertheless, it is known to represent an independent
risk factor for recurrence, even after surgical resection (P = 0.011) and is associated with worse survival (HR = 1.69, 95%CI:1.38–2.06) [12 ]
[13 ]
[14 ]. The use of nonsteroidal anti-inflammatory drugs also has been incriminated in EGC
recurrence, albeit in an isolated and mixed cohort of EGC [15 ]. Yang et al [16 ] developed a predictive model based on retrospective data, including tumor site in
the stomach, thus suggesting that the more proximal the tumor is the higher possibility
of non-curative ESD (odds ratio [OR] 1.45; 95% CI: 1.03–2.04). They included this
variable, and the size of the resected tumor (diameter of 10–20 mm [OR = 2.40; 95%
CI: 1.54–3.73], and 20 mm [OR 14.00; 95% CI 6.81–28.77]) into a model to predict curative
ESD with an area under the curve (AUC): 0.720 (95% CI 0.673–0.766). Nevertheless,
this model was targeted to endoscopic prediction of curative resection, with regard
to the current definition of cure, and does not predict recurrence [6 ]. In our study, most recurrencies were diagnosed in patients with a primary lesion
located in the incisura, although that did not reach significance compared to other
sites (P = 0.33).
As previously mentioned, the gold standard modality for treating UD-EGC is surgery.
Most studies have assessed the efficacy of ESD in the spectrum of expanded indications
with regard to UD-EGC [17 ]
[18 ]
[19 ]. Huh et al [18 ] meta-analyzed five Korean studies comparing ESD with surgery and found a higher
rate of recurrence after ESD, although cases with incomplete primary resection were
included (44.4% had complete resection beyond the existing criteria), thus impacting
the result. Our study excluded cases with remnant malignant lesion or unclear margins,
as that was an independent risk factor for recurrence. Li et al [11 ], in a retrospective study, compared ESD with surgery for UD-EGC in lesions > 20
mm. Both choices provided similar survival rates, although ESD was associated with
increased recurrence compared to surgery [HR = 5.2 (95% CI: 1.0–25.8, P = 0.045)], thus warranting long-term follow-up. Similarly, a recent meta-analysis
compared surgery with curative ESD, defined as en bloc, R0 resection, ≤ 20 mm, intramucosal cancer, and absence of lymphovascular invasion,
and both approaches provided comparable overall survival, although ESD was associated
with shorter disease-free survival and increased recurrence [19 ].
All of the recurrencies in present study were recorded during the first 18 months
after resection. However, the duration of follow-up varied among cases, thereby hindering
a clear estimation of the long-term outcomes in our cohort. A larger cohort of 198
patients showed that the mean time of recurrence was 4.5 years (range: 3.1–5.4) after
ESD, although it included cases of metachronous cancer [15 ]. To date, there is no standardized follow-up interval for these patients, and the
approach varies among centers. Endoscopy every 3 to 6 months for the first year, followed
by biannual reassessment for 2 to 3 years and then annual follow up, is a general
pattern [15 ]
[20 ]. Based on our results, this practice seems efficient for diagnosing early recurrence,
although given the potential for late metachronous lesions, extension of biannual
follow up to 5 years post-ESD seems reasonable. Nevertheless, the necessity for long-term
and frequent endoscopies and the increased worry about recurrence should be taken
into account before selecting ESD, as it could impact patient quality of life (QoL)
and the health care system. On the other hand, those treated with surgery seem to
experience more impaired QoL, due to fatigue, nausea/vomiting, loss of appetite, diarrhea,
pain, reflux, eating restrictions, anxiety, taste impairment, and poor body image
[21 ].
This study has some limitations. First, the retrospective single-arm design limits
the ability to generalize the results. However, prospective and comparative studies
in this field are difficult to organize, especially in western countries, where the
guidelines for UD-EGC management suggest ESD as a potential choice in lesions < 20
mm. Because the centers that were included comply with these recommendations, our
sample size was also limited, which may have affected the resulted association of
some variables with the recurrence, at least considering the multivariate regression
analysis. The absence of a predefined protocol to describe the lesions resulted in
variability in endoscopic reports, mainly histology descriptions. Further pathological
findings, for example, blurring muscularis mucosae or cumulative size of undifferentiated
foci inside the entire lesion or inside a mixed-type gastric cancer, could also have
been assessed as predictors of recurrence if the data were adequate. Finally, the
follow-up approach was not uniform between centers, with regard to duration and the
intervals, thus providing limited value for the long-term therapeutic results of ESD.
Conclusions
To conclude, ESD for UD-EGC, even “non-curative” based on the current recommendations,
seems to have a role in the management algorithm, at least as a diagnostic tool for
whole-lesion biopsy in marginal cases. In this study, lymphovascular and perineural
invasion, but not lesion size, were associated with recurrence, thus implying a potential
benefit even for patients with larger lesions. This observation, however, needs further
evaluation in larger studies with longer follow-up, assessing more variables.
