Introduction
Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection are highly
effective techniques for resection of colorectal lesions. However, they have several
limitations [1]. In particular, EMR of lesions or laterally spreading lesions involving the appendiceal
orifice is technically demanding ([Fig. 1]) due to difficult access to the appendiceal lumen and a high risk of perforating
the thin cecal wall. Therefore, surgical intervention is often necessary [2]
[3]. To allow definitive diagnosis and treatment, an endoscopic full-thickness resection
(EFTR) device (Ovesco Endoscopy, Tübingen, Germany) had been developed. It enables
the endoscopist to perform EFTR with immediate defect closure [4]. The system is suitable for resection in difficult anatomical places with high risk
of perforation, such as in para-diverticular or para-appendicular disease [2]
[5]. In addition, the prompt closure provided by the EFTR device had been described
as minimizing the risk of peritoneal irritation during resection by shortening the
contact time between bowel lumen and peritoneal cavity [6]. To date, the largest published study dealing with colonic EFTR included 181 patients
and reported R0 resection rates of 77.7 % and 72.4 % for difficult-to-resect colorectal
lesions and early cancers, respectively [1].
Fig. 1 Adenoma affecting the appendiceal orifice.
As EFTR affecting the appendiceal orifice is associated with subtotal appendectomy,
it remains unclear whether the risk of developing appendicitis is increased (see Fig. 1 s in the online-only supplementary material). The aim of this retrospective study was
to further evaluate the risks associated with EFTR at this challenging location.
Methods
All procedures were performed in an inpatient setting with patients under propofol
sedation with or without midazolam, and with CO2 inflation. Lesion diameter and extension into the appendix were estimated during
an initial endoscopy. After marking lateral lesion margins, the endoscope was equipped
with the EFTR device and advanced to the lesion. The colonic EFTR device was mounted
onto a standard colonoscope (diameter 11.5 – 13.2 mm). The device consists of a transparent
cap with a pre-assembled over-the-scope (OTS) clip device. The tip of the cap harbors
a polypectomy snare, which runs along the outside of the scope covered by a sleeve
to prevent entrapment of tissue between the snare and scope. The specimen was pulled
into the cap by grasping forceps. The OTS clip was deployed by turning the hand wheel
on the endoscope handle, and the so created pseudopolyp, with the targeted tissue
above the clip, was removed using the preloaded snare. Thereafter, the resected specimen
was captured within the cap and withdrawn [7] ([Fig. 2], [Video 1]). For lesions > 2 cm, which are too big to be resected via the EFTR method alone,
a hybrid technique consisting of EFTR and EMR (hybrid EMR-EFTR) was used. For the
present study, all cases of colonic EFTR performed at three participating endoscopy
centers (Ludwigsburg, Neumarkt, Ulm) between 2014 and 2019 were retrospectively reviewed.
Fig. 2 Area of adenoma near the appendiceal orifice resected by endoscopic full-thickness
resection including subtotal appendectomy.
Video 1 Full-thickness resection of a lesion affecting the appendiceal orifice.
The rate of development of post-interventional appendicitis leading to possible indication
for surgical appendectomy was defined as the primary end point. Post-interventional
appendicitis was defined as inflammatory response of the residual appendix with characteristic
clinical signs, symptoms, and laboratory results. Abdominal sonography was possible
but not mandatory for diagnosis.
Resection state and histopathology of resected specimens were also analyzed. Resection
state was defined using the R classification [8]. R0 histology was defined as “no residual tumor,” R1 as “microscopically detected
residual tumor,” and Rx as “evaluation regarding residual tumorous tissue not possible.”
Descriptive statistical analysis was performed on the data using SPSS Statistics version
25 (IBM Corp., Armonk, New York, USA).
Results
Resection of lesions at the appendix was performed in 56 patients by expert endoscopists.
Six of the 56 patients were excluded from the analysis owing to prior appendectomy.
Of the 50 remaining patients, EFTR was technically successful in 48 (96 %) ([Table 1]). In two cases, deployment of the OTS clip was not possible due to a highly angulated
colonoscope; a standard resection (EMR) was successfully performed in these cases.
Follow-up was terminated after a mean of 4 months.
Table 1
Patient and treatment characteristics.
|
Patients[*], n
|
50
|
|
Sex, n (%)
|
|
|
16 (32)
|
|
|
34 (68)
|
|
Age, mean (range), years
|
65.8 (46 – 83)
|
|
Endoscopic accessibility of lesion site, n (%)
|
50 (100)
|
|
Technically successful intervention, n (%)
|
48 (96)
|
|
Lesion size, mean (SD), mm
|
18.3 (10.6)
|
|
Prophylactic antibiotics, mean, days
|
4
|
|
R status, n (%)
|
|
|
32 (64)
|
|
|
15 (30)
|
|
|
3 (6)
|
|
Histopathology, n (%)
|
|
|
22 (44)
|
|
|
13 (26)
|
|
|
2 (4)
|
|
|
4 (8)
|
|
|
3 (6)
|
|
|
1 (2)
|
|
|
5 (10)
|
|
Adverse events, n (%)
|
|
|
7 (14)
|
|
|
1 (2)
|
|
Treatment of adverse events, n (% of adverse events)
|
|
|
4 (50)
|
|
|
4 (50)
|
SD, standard deviation; LGIEN, low grade intraepithelial neoplasia; HGIEN, high grade
intraepithelial neoplasia.
* Patients with prior appendectomy were excluded.
All patients were sedated with propofol (± midazolam) and received antibiotics peri-interventionally
for a mean of 4 days. R0 resection was achieved in 32 patients (64 %), Rx in 15 (30 %),
and R1 in 3 (6 %). In 7 of the 15 cases with an Rx result, the lesions were resected
using the hybrid EMR-EFTR technique. Histology results are presented in [Table 1] and [Fig. 3]. In five cases, histology showed no adenomatous tissue in the resected specimen,
although indication for resection was given macroscopically.
Fig. 3 Histopathologic specimen showing a sessile serrated adenoma (on the left of the image);
the appendix in submucosal tissue after subtotal appendectomy can also be seen (right
of center).
Post-interventional appendicitis occurred in seven patients (14 %), four of whom were
managed conservatively with intravenous hydration, antibiotics (3 – 5 days) and analgesics
([Table 2]). Three patients with appendicitis underwent surgical appendectomy. A bimodal distribution
of the onset of appendicitis was observed: four appendicitis cases occurred during
the first 10 days of post-interventional monitoring; another three occurred after
a latency period of < 1 month after the procedure. Patients with uncomplicated appendicitis
received conservative treatment. Patients with increased risk for perforation underwent
primary surgery. Therapeutic decisions were made by visceral surgeons and gastroenterologists.
Table 2
Characteristics of all seven cases with appendicitis.
|
1
|
2
|
3
|
4
|
5
|
6
|
7
|
|
Age, years
|
75
|
58
|
51
|
77
|
72
|
71
|
52
|
|
Lesion diameter, mm
|
30
|
7
|
13
|
10
|
25
|
8
|
10
|
|
Resection method used
|
EFTR + EMR
|
EFTR
|
EFTR
|
EFTR
|
EFTR + EMR
|
EFTR
|
EFTR
|
|
Lesion pathology
|
SSA
|
SSA
|
SSA
|
–
|
TVA, HG
|
–
|
TVA, LG
|
|
R status
|
Rx
|
R0
|
R0
|
–
|
Rx
|
–
|
R0
|
|
Time of onset
|
With latency
|
With latency
|
Early
|
Early
|
Early
|
With latency
|
Early
|
|
Management
|
Conservative
|
Surgery
|
Conservative
|
Conservative
|
Conservative
|
Surgery
|
Surgery
|
EFTR, endoscopic full-thickness resection; EMR, endoscopic mucosal resection; SSA,
sessile serrated adenoma; –, no adenoma; TVA, tubulovillous adenoma; HG, high grade;
LG, low grade.
Three out of the four patients (75 %) with appendicitis during the first 10 days after
the procedure were treated by antibiotic administration, and the other patient underwent
surgery ([Table 2]). In contrast, two out of the three patients (67 %) with appendicitis within < 1
month needed surgical therapy.
In one case of sessile serrated adenoma, post-interventional perforation of the cecum
occurred and was treated surgically ([Table 1]). No other post-procedural complications (bleeding, severe pain, unexpected hospitalization)
were reported.
In conclusion, 92 % of cases with lesions involving the appendiceal orifice were treated
using an EFTR technique alone instead of surgery.
Discussion
EFTR is an emerging technique for the resection of epithelial and subepithelial lesions
throughout the gastrointestinal tract. The resection of lesions at the appendix is
often considered a controversial issue due to a high risk of perforation or R1/Rx
resection. Conventionally, patients are referred for surgical resection. In this retrospective
multicenter study on EFTR of lesions involving the appendiceal orifice, 50 cases were
analyzed.
The target lesion could be reached in all cases, although advancing the endoscope
equipped with the sturdy EFTR device can be problematic. Nevertheless, a technical
resection success rate of 96 % was achieved. However, the R0 resection rate was only
64 %, which is lower than that reported by other authors [9]. The comparably high rate of Rx or R1 histology might be explained by the difficulty
in assessing the depth of infiltration into the appendiceal lumen. We therefore conclude
that visualization of adenoma margins should be mandatory when using this technique.
Rx histology in 7 of the 15 cases might have been due to the use of the hybrid EMR-EFTR
technique, as the combination of EFTR and piecemeal EMR of bigger lesions may impede
histological assessment of the R status. Precise follow-up examinations to evaluate
residual and/or recurrent polypoid tissue are therefore mandatory. If residual or
recurrent lesions are detected, repeat EFTR, conventional techniques or surgery might
be necessary. In previous studies, R0 resection of recurrent or residual lesions with
the EFTR system was possible in 77.7 % [1].
Complications were managed surgically in four patients (8 %); therefore, EFTR presented
as an alternative to primary surgery in 92 % of cases. However, Rx or R1 procedures
may require follow-up surgical therapy. This effect was not monitored in our study
and could therefore lead to a bias regarding recurrent lesions, as follow-up was terminated
after a mean of 4 months. Extended follow-up is crucial for future evaluation. Furthermore,
the retrospective design of the study and lack of a control group impairs study validity.
As tumor size is a major limitation of conventional EFTR, the hybrid EMR-EFTR technique
seems to be an effective approach for larger lesions [10]. However, two patients treated with hybrid EMR-EFTR developed post-procedural appendicitis.
As the case number is too small to derive significant data, evaluation of the outcome
of different techniques seems warranted.
In addition, histology must be reviewed carefully. In patients diagnosed with carcinoma
who undergo an Rx procedure, it must be ensured that no residual neoplastic tissue,
which may have been moved during clipping with the EFTR device, is located on the
serosal side of the colon [11].
Although all patients received prophylactic antibiotic treatment for a mean of 4 days,
seven patients developed secondary appendicitis. Four of these patients (57 %) were
treated conservatively with antibiotics and were discharged after inpatient monitoring.
A bimodal distribution of appendicitis onset was observed. Data may indicate that
early onset and detection of appendicitis was associated with milder disease progression
resulting in conservative treatment options. No specific patient risk factors for
appendicitis were determined in this study population.
Endoscopists as well as visceral surgeons should be aware of the complications of
EFTR, and patients should be informed about the risk of appendicitis and potential
need for surgery prior to undergoing the procedure.
In summary, EFTR of lesions near or affecting the appendiceal orifice was associated
with an acceptable complication rate. The risk of developing acute appendicitis was
14 %; however, more than half (57 %) of these cases could be treated conservatively
owing to prompt detection. Further studies to determine risk factors for development
of post-procedural appendicitis are mandatory.
