Introduction
Endoscopic resection (ER) is accepted as an effective, minimally invasive treatment
for early superficial esophageal squamous cell cancer (SESCC) [1]
[2]
[3]
[4]. Although extensive ER has become more common as endoscopic techniques by piecemeal
endoscopic mucosal resection (EMR) have developed, piecemeal resection is a significant
risk factor for local recurrence after ER [5]
[6]. Endoscopic submucosal dissection (ESD) has advanced for en bloc resection regardless
of tumor size or tumor location [7]. Furthermore, ESD for SESCC yields favorable long-term outcomes [8]
[9].
However, when resecting large lesions, the frequency of esophageal strictures after
ESD has increased [10]
[11]. Esophageal strictures following ER are associated with wide mucosal defects greater
than three-quarters of the luminal circumference [12]. When the mucosal defect exceeds three-quarters of the luminal circumference, stricture
occurrence is prevalent in 68 – 100 % cases [10]
[11]
[12]
[13]. Although oral prednisolone or locoregional steroid injections have shown promising
results for the prevention of esophageal strictures following ESD [14]
[15]
[16], some patients may still develop dysphagia and require repeated endoscopic balloon
dilation even after steroid therapy [17].
Markings for ESD are generally made 5 mm away from the borders of the lesion [18]. However, iodine staining enables clear visualization of the SESCC margins [19], so we applied markings with energy devices just on the border and commenced the
incision just outside the applied marks so as to minimize luminal defects for large
SESCC cases involving over three-quarters of the luminal circumference. This retrospective
study aims to clarify the clinical feasibility of ESD with minimum lateral margin
of SESCC.
Methods
Patients
A total of 268 patients with 289 esophageal lesions consecutively underwent ESD of
SESCC at our institution between 2005 and 2013. Endoscopic resection was indicated
for histologically proven squamous cell carcinoma on biopsy and was not performed
in patients with apparent massive submucosal invasion or nodal metastasis. The depth
of invasion was estimated by white-light endoscopy, and magnified narrow-band imaging
and chromoendoscopy with iodine staining. Endoscopic ultrasonography was also performed
to determine the depth of invasion as necessary. Mizuta et al. [10] reported that a lesion more than half of the luminal circumference was closely associated
with an ESD-induced mucosal defect involving over three-quarters of the luminal circumference
and was considered to be an independent risk factor for esophageal stricture. Thus,
amongst those patients, we investigated those who had a lesion more than half of the
luminal circumference and met endoscopic clearance for SESCC and who were followed
up without any additional treatment. In this study, endoscopic clearance was defined
as en bloc resection of SESCC histologically confined to the mucosa without lymphovascular
invasion and with a free deep margin, regardless of the lateral margin. In reference
to the Guidelines for Diagnosis and Treatment of Carcinoma of the Esophagus edited
by the Japan Esophageal Society, those lesions confined to the epithelium (EP) and
lamina propria mucosae (LPM) have almost no risk of metastasis; lesions limited to
the muscularis mucosae (MM) without lymphovascular invasion also have a very low risk
of metastasis [20]. At our institution during the study period, a SESCC involving the whole circumference
was mainly treated with chemoradiotherapy rather than ESD.
ESD procedure
The ESD procedure was performed by expert endoscopists skilled in ESD or trainees
with support from expert endoscopists. Trainees were defined as those who had limited
experience in performing esophageal ESD procedures (30 cases or less), and expert
endoscopists had experienced performing more than 30 esophageal ESD procedures [21].
A dual knife (KD-650; Olympus, Tokyo) was used to make markings close to the margins
of the lesion. The dual knife and an insulation-tipped (IT) knife nano (KD-612; Olympus)
were used for mucosal incision and submucosal dissection. Intraoperative bleeding
was treated using a hemostatic forceps (Coagrasper, FD-411 QR; Olympus). ESD was performed
with the patient under deep sedation using a combination of midazolam or propofol
with pentazocine. The ESD strategy for esophageal lesions with minimum lateral margins
comprised these three steps: 1) chromoendoscopy with iodine staining to clearly visualize
the margin of SESCC; 2) circumferential marking close to the margins of the lesion,
and 3) mucosal incision close to the marking, or on the marking in some cases ([Fig. 1]). This strategy was applied to lesions more than half of the circumference that
were closely associated with a mucosal defect involving over three-quarters of the
luminal circumference.
Fig. 1 Endoscopic submucosal dissection (ESD) strategy for esophageal lesions with minimum
lateral margins. a Chromoendoscopy with iodine staining clearly visualized a superficial esophageal
squamous cell carcinoma (SESCC). b Markings close to the margins. c Mucosal incision close to the marking. d Minimize the luminal circumference for large SESCC to avoid stenosis from excessive
resection.
Stricture prevention
In this study, until 2010, prophylactic endoscopic balloon dilation (EBD) was performed
to avoid esophageal stricture following widespread endoscopic resection [22]. Oral prednisolone and/or locoregional triamcinolone injection were introduced in
2011 based on the discretion of the endoscopist.
Histology
After fixing in 10 % formalin and serial sectioning at 2-mm intervals, the resected
specimens were assessed using histological mapping. Expert pathologists were engaged
to assess the macroscopic appearance, tumor size, depth of invasion, lymphatic and
vascular involvement, and lateral and vertical margins, with reference to the Japanese
Classification of Esophageal Carcinoma [23]
[24]. Lymphovascular involvement was first determined using hematoxylin and eosin (HE)-stained
sections; when the diagnosis of lymphovascular involvement was inconclusive using
HE-stained sections, immunohistochemistry was also performed with the monoclonal antibody
D2-40 and/or Victoria blue or Elastica van Gieson staining.
Follow-up after endoscopic clearance
All patients who achieved endoscopic clearance generally underwent esophagogastroduodenoscopy
(EGD) surveillance on an annual or biannual basis. In addition, a computed tomography
(CT) scan was performed every 6 months or 1 year to identify lymph node and distant
metastases in patients with muscularis mucosa invasion. A local recurrence was defined
as an iodine-unstained area detected adjacent to an ESD scar and cancer cells were
verified histologically in a biopsy specimen. Metachronous esophageal squamous cell
cancer (ESCC) was defined as ESCC other than local recurrence detected in surveillance
EGD.
Assessment
This study evaluated short- and long-term outcomes in cases with a lesion more than
half of the circumference undergoing endoscopic clearance.
In this study, we investigated alcohol consumption, smoking habits, and grade of Lugol-voiding
lesion (LVL) as patient background. LVL was graded according to the number of LVLs
per endoscopic view (A, no lesions; B, 1 – 9 lesions; C, ≥ 10 lesions) [25].
Technical results, adverse events, and histopathological results were assessed to
determine short-term outcomes. Long-term outcomes included local recurrence, lymph
node metastasis, distant metastases, 3-year cumulative incidence of metachronous ESCC,
3-year overall survival (OS), and 3-year disease-free survival (DFS) after endoscopic
clearance.
Statistical analysis
All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical
University, Saitama, Japan), which is a graphical user interface for R (The R Foundation
for Statistical Computing, Vienna, Austria) [26]. Continuous variables were compared using the Mann-Whitney U test and categorical variables were compared using the χ2 test or Fisher’s exact test as appropriate. OS and DFS survival rates were calculated
by Kaplan-Meier analysis. OS was measured from the date of ESD to the date of death
or the date of the latest confirmation of survival. DFS was measured from the date
of ESD to the date of death from ESSC.
Results
Amongst 268 consecutive patients with 289 SESCCs, 94 patients with 94 initial SESCCs
had lesions more than half of the circumference. Of those, 24 patients with 24 SESCCs
were excluded as 13 patients had pathological submucosal invasion, seven patients
had mucosal cancer with lymphovascular invasion, and four patients underwent additional
chemoradiotherapy for muscularis mucosae lesions. The remaining 70 patients with 70
SESCCs had achieved endoscopic clearance for initial SESCC and were followed up without
any additional treatment ([Fig. 2]).
Fig. 2 In total, 94 patients with 94 superficial esophageal squamous cell carcinoma (SESCCs)
had lesions more than half of the circumference. Of those, we investigated 70 patients
who met endoscopic clearance for initial SESCC and who were followed up without any
additional treatment.
The male/female ratio was 6.8:1 (61 men/9 women), and median age was 69 years (range,
50 – 86 years); 78.6 % of patients had a current or previous habit of alcohol consumption
and 68.6 % of patients were smokers; 88.6 % of patients had multiple dysplastic lesions.
More than half of the lesions (57.1 %) were located in the middle esophagus. The median
tumor size was 35 mm (range, 20 – 85). With regard to depth of invasion, 4.3 % were
EP, 77.1 % were LPM, and 18.6 % of lesions had invaded to the depth of the MM ([Table 1]). All lesions had achieved en bloc resection. Complete curative resection with a
negative lateral margin was achieved in 61.4 % (43/70) of patients and with a positive
lateral margin in 38.6 % (27/70) of patients. The median procedure time was 120 minutes
(range, 50 – 570). The stricture rate was 35.7 % (25/70). Twelve cases were orally
administered prednisolone and five patients underwent locoregional triamcinolone injection;
57.1 % (40/70) of patients had a mucosal defect involving over three-quarters of the
luminal circumference. Of those, stenosis was seen in 16 of 25 cases (64 %) in the
group who underwent preemptive EBD and in 5 of 15 cases (33 %) in the group who underwent
steroid treatment ([Table 2]). In terms of lateral margin, tumor size was significantly larger in the positive
lateral margin group than in the negative lateral margin group. However, there was
no statistically significant difference between the two groups in the rate of cases
with a circumferential mucosal defect greater than three-quarters of the circumference
([Table 3]).
Table 1
Patients (n = 70) and tumor characteristics.
|
Age, median (range), years
|
69 (50 – 86)
|
|
Sex
|
|
|
61
|
|
|
9
|
|
Alcohol consumption status
|
|
|
15
|
|
|
55
|
|
Cigarette smoking status
|
|
|
22
|
|
|
48
|
|
Location
|
|
|
6
|
|
|
40
|
|
|
24
|
|
Tumor depth
|
|
|
3
|
|
|
54
|
|
|
13
|
|
LVL grade
|
|
|
8
|
|
|
33
|
|
|
29
|
|
Tumor size, median (range), mm
|
35 (20 – 85)
|
EP, epithelium; LPM, lamina propria mucosae; MM, muscularis mucosae; LVL, Lugol-voiding
lesion.
Table 2
Short-term outcomes for patients in this study (n = 70).
|
En bloc resection, %
|
100
|
|
Lateral margin
|
|
|
43
|
|
|
27
|
|
Procedure time, median (range), min
|
120 (50 – 570)
|
|
Endoscopist
|
|
|
55
|
|
|
15
|
|
Mucosal defect greater than 3/4 of luminal circumference, %
|
57.1 (40/70)
|
|
Resection size, median (range), mm
|
45 (22 – 110)
|
|
Steroid treatment
|
|
|
53
|
|
|
12
|
|
|
5
|
|
Stricture, %
|
35.7 (25/70)
|
|
Perforation, %
|
2.9 (2/70)
|
Table 3
Comparison of cases with a negative lateral margin vs positive or indeterminate lateral
margin.
|
Negative lateral margin
|
Positive or indeterminate lateral margin
|
P value
|
|
Rate of cases with a mucosal defect greater than 3/4 of the luminal circumference,
%
|
51.2 (21/41)
|
65.5 (19/29)
|
0.3
|
|
Tumor size, median (range), mm
|
35 (20 – 55)
|
50 (20 – 85)
|
< 0.01
|
During a median follow-up period of 3.8 years, there was no local or nodal recurrence
in the 70 patients. The cumulative incidence of metachronous ESCC at 3 years was 11.8 %
([Fig. 3]). LVL grade was associated with progressive increases in the 3-year cumulative incidence
of metachronous ESCCs (0.0 %, 6.6 %, and 23.4 %, respectively) ( [Fig. 4]). The 3-year OS rate was 98.5 % ([Fig. 5]) and the 3-year DFS rate was 100 %, respectively.
Fig. 3 Cumulative incidence of metachronous esophageal squamous cell carcinoma (ESSC) in
all patients.
Fig. 4 Cumulative incidence of metachronous esophageal squamous cell carcinoma (ESSC) according
to Lugol-voiding lesion (LVL) grade. LVL was graded according to the number of LVLs
per endoscopic view (A, no lesions; B, 1 – 9 lesions; C, ≥ 10 lesions).
Fig. 5 Kaplan-Meier curve of the overall survival rate after endoscopic submucosal dissection
(ESD).
Discussion
Chromoendoscopy with iodine staining has been reported to be useful in identifying
the margins of SESCC [19]
[27]. It allows us to make markings close to the margins of the lesion so as to avoid
excessive resection. The strength of this study was that no patient developed local
recurrence or nodal metastasis in ESD with minimum lateral margins, and this suggested
the SESCCs that achieved endoscopic clearance could be clinically and oncologically
followed as R0 resections.
Esophageal stricture following ESD has been associated with wide mucosal defects greater
than three-quarters of the luminal circumference [12]. Mizuta et al. reported that many cases of lesions greater than half of the circumference
were the result of a mucosal defect involving over three-quarters of the luminal circumference
[10]. Because the minimum lateral margin strategy is a method of reducing the risk of
mucosal defects involving over three-quarters of the luminal circumference, we included
patients who had a lesion involving more than half of the luminal circumference. This
study demonstrated that mucosal defects involving over three-quarters of the luminal
circumference were seen in only 57.1 % of cases that had a lesion greater than half
of the circumference. The proportion of cases with a mucosal defect involving over
three-quarters of the luminal circumference was lower than that in standard esophageal
ESD [10].
Locoregional steroid injection and oral prednisolone could reduce the stenosis rate
of lesions with wide mucosal defects greater than three-quarters of the luminal circumference
to 10.0 – 62.5 % and 5.3 – 50 %, respectively [14]
[15]
[16]
[28]. Steroid treatments were demonstrated to have a significant effect in preventing
stricture. However, locoregional steroid injection can cause delayed perforation,
and oral prednisolone can cause systemic adverse effects, including diabetes, peptic
ulceration, osteoporosis, and increased susceptibility to infection [29]
[30]. Furthermore, some patients with wide mucosal defects greater than three-quarters
of the luminal circumference failed to avoid esophageal stricture even with steroid
treatment, particularly in those with mucosal defects involving the whole circumference
[31]. Therefore, it is important to reduce lesions with a mucosal defect involving over
three-quarters of the luminal circumference as much as possible using the minimum
lateral margin strategy. We believe our strategy could reduce the risk of extensive
ESD and thus minimize preventive steroid administration, which was generally unnecessary
for lesions which did not have the risk factor of post-ESD stricture.
En bloc curative resection is considered to be the ideal for both EMR and ESD treatment
because it provides an accurate histological assessment and reduces the risk of local
recurrence [9]. Ishihara et al. evaluated factors associated with local recurrence following endoscopic
resection of SESCC and concluded that multiple piecemeal resection (more than five
pieces) was a significant risk factor for local recurrence and that there were few
recurrences if en bloc resection could be achieved [6]. In terms of lateral margin, a positive lateral margin tended to occur in large
lesions. Although the positive lateral margin rate was 38.6 % in this study, there
was no local recurrence in those who achieved endoscopic clearance. Nagami et al.
also reported that the rate of en bloc resection with tumor-free margins was 90.4 %
and no local recurrence was encountered regardless of tumor margins in ESD [32]. The results of previous reports support the concept of endoscopic clearance but
did not support piecemeal resection.
Similar conclusions have been reported in our institution for large colorectal tumors
[33]. Electrocautery devices might damage the squamous epithelium on the lateral margin
of the lesion, and therefore the pathologists might be unable to evaluate whether
or not the margins of the lesion were neoplastic. Since squamous cell carcinoma has
a clear boundary with iodine staining, the potential for neoplastic tissue to remain
within the lumen is believed to be very low. Furthermore, Matsuda et al. reported
squamous cell carcinoma invading under the epithelium in only 0.67 % of surgically
excised specimens [34]. There were very few cases of squamous cell carcinomas invading under the epithelium
and this result also supported our strategy of minimum lateral margins for SESCC.
The cumulative recurrence rate was consistent with previous reports, which showed
that multiple dysplastic lesions in the esophagus increase the risk of multiple ESCCs
[25]. Surveillance endoscopy should be performed focusing on the early detection of metachronous
SESCC rather than local recurrence after endoscopic clearance.
This study had some limitations. First, this was a single center, retrospective study.
Second, it is difficult to conclude that the endoscopic clearance strategy reported
in this study directly resulted in the prevention of stricture formation. Prophylactic
steroid treatment was introduced in 2011 to avoid post-ESD esophageal stricture and
it became the current standard of care for wide mucosal defects that were greater
than three-quarters of the luminal circumference. The steroid treatment could contribute
to stricture prevention in our study. Further prospective study is warranted to investigate
the efficacy of ESD with minimum lateral margins.
In conclusion, ESD for SESCCs with minimum lateral margins using our institutions’
strategy was oncologically acceptable and this approach could reduce the known risk
factor of post-ESD stricture.
