Title: Endoscopic mucosal resection: still a reliable therapeutic option for gastrointestinal
neuroendocrine tumors
Version: 3 Date: 28 Jan 2021
Reviewer:  Davide Ravizza
Reviewer's report:
The study shows the long term results obtained in 36 patients with NETs of the stomach,
duodenum and rectum treated with EMR.
Two relevant aspects need to be clarified. The first is to adequately stage the lesions to be
considered to entry in the study. The second concerns the resected specimens histopathological
evaluation (see the comment).
I agree with the authors that the strength of their study is the long term follow up of patients
after endoscopic resection. However, I think that the results firstly indicate that EMR is not an
effective procedure to treat NETs of the stomach, duodenum and rectum because of the high
rate of tumor margin involvement of the resected specimens. Secondly, that this involvement is
not relevant for the prognosis of these patients. This latter result is very interesting and might
be topic for a different study.
INTRODUCTION
“… Gastrointestinal neuroendocrine tumors (NETs), called carcinoid tumors, feature a
wide spectrum of malignant potential and originate from enterochromaffin-like (ECL) cells.
Gastrointestinal NETs involve 7 to 8% of all neuroendocrine tumors and are classified into
three main types. The first type accounts for 75% of patients and is associated with chronic
atrophic gastritis (1, 2), while the second accounts for 6% of cases and is linked with multiple
endocrine neoplasm (MEN) disease (including Zollinger-Ellison syndrome) and the third is the
most invasive type with a high chance of metastasis (3, 4). …”
Only gastric NETs are classified into three types.
“… The EMR technique is a relatively simple technique requiring unsophisticated skills and
inexpensive tools. This technique is used for well-differentiated gastric or duodenal lesions
smaller than 20 mm in diameter and well-differentiated tumors confined to the mucosal layer
without invasion to the lymph nodes or blood vessels. …”
Any endoscopic resection technique can be considered for the treatment of NETs in the absence
of:
- involvement beyond the submucosa;
- lymph nodal and/or distant spread.
Tumor size # 1 cm is a potential predictor of lymph nodal metastases and should be the lesion
characteristic considered first when their management is planned
It is quite difficult that a NET greater than mm 10 in size does not invade the submucosa as cited
by the Authors into the DISCUSSION.
EMR can be successfully used for NETs without a deep invasion of the submucosa as cited by
the Authors into the DISCUSSION.
“… Besides, ESD enables the en bloc removal of the lesion, which permits a more accurate
pathological evaluation. …”
EMR allows the en bloc resection of a neuroendocrine lesion, especially if a “modified EMR”
is used (i.e. using a band ligation method).
“… This study was designed to address the debate on the safety and long-term follow-up of
EMR for localized NETs in the rectum and upper gastrointestinal (GI) tract. …”
In RESULTS there is not any data about the safety of EMR (i.e. perforation or bleeding, which
are frequently observed during duodenal NETs treatment).
PATIENTS AND METHODS
“… Patients with advanced tumors unfit for endoscopic removal (larger than 2 cm in size,
higher than T1 stage on endoscopic ultrasound [EUS], and/or poorly differentiated lesions) were
excluded …”
The TNM classification of malignant tumours (Bierley J, Gospodarowicz MK, Wittekind C,
International Union against Cancer. TNM classification of malignant tumours. 8th ed. Oxford,
UK; Hoboken, NJ: Wiley-Blackwell; 2017) classifies:
STOMACH AND DUODENUM
T1  Tumour invades lamina propria or submucosa and 1 cm or less in greatest dimension
T2  Tumour invades muscularis propria or is more than 1 cm in greatest dimension
Stage I  T1 N0 M0
Accordingly, gastric and duodenal NETs greater than cm 1 should be considered as T2 and then
excluded from the study.
EUS is unable to detect distant spread (i.e. liver metastases) and can not be considered the only
technique to stage a neoplasm. CT scan or MRI should also be used for this pourpose
“… In the beginning, EUS was conducted using a radial array echoendoscope for all patients
with gastroduodenal and rectal lesions for precise staging prior to resection. …”
The term “precise staging” should be changed with local staging.
“… Then, cases with lesions limited to the mucosa or submucosa (T1) and less than 2 cm in
diameter were considered for EMR. …”
See the above comment about T1 lesions (TNM classification of malignant tumours. 8th ed.).
“… After resecting the lesion, patients were followed with endoscopy or proctoscopy
(considering the tumor size, grade, and location) according to the recommended guidelines. …”
What kind of instrumentation was used during endoscopic procedure, endoscopic follow up and
for proctoscopy?
“… All pathologic reports were reviewed and appropriate information including the size of the
lesion, grading, and margin clearance (R0) status was recorded. …”
Did any specimens show a lymphovascular invasion ?
This is a relevant pathological finding in terms of indication for further treatments, follow up
and prognosis.
RESULTS
“… Six patients underwent surgical resection due to having tumors with a high grade (G3),
unsuitable location (ileum), or advanced stage (>T1). …”
See the above comment about T1 lesions (TNM classification of malignant tumours. 8th ed.).
“… Based on the pathology report, 22 tumors (61.1%) were smaller than 1 cm in diameter while
14 (38.9%) were between 1-2 cm. …”
According to MATHERIALS AND METHOD, gastric and duodenal NETs greater than cm 1
should not be considered because they are T2, Stage II.
“… Twenty-two (61.1%) patients had a margin of specimen involved with the tumor. …”
I think it is necessary to specify what kind of resection margin involvement was observed:
vertical or horizontal. This difference is relevant in terms of indication for further treatments,
follow up and prognosis.
Why any further treatment was not suggested in patients with resection margin involvement?
This is particularly relevant for duodenal NETs whose prognosis may be worrisome.
How many patients were treated using the band ligation EMR?
How many of these patients had a resection margin involvement?
What was the size of the lesions treated with EMR?
What was the size of the lesions treated with band ligation EMR?
“… No recurrence was observed during the mean follow-up time of 63.5 ± 19.8 months (range:
39-103 months). …”
How many endoscopic investigations were carried out per patient during follow up?
At the end of follow did the patients receive CT or MRI to assess the presence of local or distant
metastases?
DISCUSSION
“… In this study, we performed EMR as the only available technique for resection of GI NETs
smaller than 2 cm in diameter and below T1 on EUS. …”
See the above comment about T1 lesions (TNM classification of malignant tumours. 8th ed.).
“.. In our study, we implemented the simple EMR technique with a submucosal saline injection
for most individuals, which is why we could only achieve a 40% complete resection rate. ..”
In MATERIALS AND METHODS is stated that “… EMR was performed with either snare
polypectomy after submucosal saline injection or via the band ligation method …”. If “simple
EMR” was implemented in all the patients, why this implementation is considered the reason
of the low complete resection rate observed?
“… Twenty-two (61.1%) patients had a margin of specimen involved with the tumor. …”
How do the authors explain a so high number of specimens with margins involvement?
“… Out of the tumors with positive margins, 69.6% were smaller than 1 cm and 30.4% were
between 1-2 cm. …”
How do the authors explain that the margins involvement was mostly observed after the resection
of smaller lesions?
“… In conclusion, EMR might be considered as a safe and effective procedure for
gastrointestinal NETs smaller than 20 mm and limited to the mucosa or submucosa, particularly
where and when equipment, instruments, or adequate expertise for ESD are not readily
accessible. …”
I do not think that any conclusion about EMR safety can be drawn from the data presented in
the study.
It is difficult to consider EMR an effective procedure to treat gastrointestinal NETs if in 61% of
the treated patients the technique is unable to obtain clear margins.
Title: Endoscopic mucosal resection: still a reliable therapeutic option for gastrointestinal
neuroendocrine tumors
Version: 3 Date: 28 Jan 2021
Reviewer:  Davide Ravizza
Reviewer's report:
The study shows the long term results obtained in 36 patients with NETs of the stomach,
duodenum and rectum treated with EMR.
Two relevant aspects need to be clarified. The first is to adequately stage the lesions to be
considered to entry in the study. The second concerns the resected specimens histopathological
evaluation (see the comment).
I agree with the authors that the strength of their study is the long term follow up of patients
after endoscopic resection. However, I think that the results firstly indicate that EMR is not an
effective procedure to treat NETs of the stomach, duodenum and rectum because of the high
rate of tumor margin involvement of the resected specimens. Secondly, that this involvement is
not relevant for the prognosis of these patients. This latter result is very interesting and might
be topic for a different study.
INTRODUCTION
“… Gastrointestinal neuroendocrine tumors (NETs), called carcinoid tumors, feature a
wide spectrum of malignant potential and originate from enterochromaffin-like (ECL) cells.
Gastrointestinal NETs involve 7 to 8% of all neuroendocrine tumors and are classified into
three main types. The first type accounts for 75% of patients and is associated with chronic
atrophic gastritis (1, 2), while the second accounts for 6% of cases and is linked with multiple
endocrine neoplasm (MEN) disease (including Zollinger-Ellison syndrome) and the third is the
most invasive type with a high chance of metastasis (3, 4). …”
Only gastric NETs are classified into three types.
“… The EMR technique is a relatively simple technique requiring unsophisticated skills and
inexpensive tools. This technique is used for well-differentiated gastric or duodenal lesions
smaller than 20 mm in diameter and well-differentiated tumors confined to the mucosal layer
without invasion to the lymph nodes or blood vessels. …”
Any endoscopic resection technique can be considered for the treatment of NETs in the absence
of:
- involvement beyond the submucosa;
- lymph nodal and/or distant spread.
Tumor size # 1 cm is a potential predictor of lymph nodal metastases and should be the lesion
characteristic considered first when their management is planned
It is quite difficult that a NET greater than mm 10 in size does not invade the submucosa as cited
by the Authors into the DISCUSSION.
EMR can be successfully used for NETs without a deep invasion of the submucosa as cited by
the Authors into the DISCUSSION.
“… Besides, ESD enables the en bloc removal of the lesion, which permits a more accurate
pathological evaluation. …”
EMR allows the en bloc resection of a neuroendocrine lesion, especially if a “modified EMR”
is used (i.e. using a band ligation method).
“… This study was designed to address the debate on the safety and long-term follow-up of
EMR for localized NETs in the rectum and upper gastrointestinal (GI) tract. …”
In RESULTS there is not any data about the safety of EMR (i.e. perforation or bleeding, which
are frequently observed during duodenal NETs treatment).
PATIENTS AND METHODS
“… Patients with advanced tumors unfit for endoscopic removal (larger than 2 cm in size,
higher than T1 stage on endoscopic ultrasound [EUS], and/or poorly differentiated lesions) were
excluded …”
The TNM classification of malignant tumours (Bierley J, Gospodarowicz MK, Wittekind C,
International Union against Cancer. TNM classification of malignant tumours. 8th ed. Oxford,
UK; Hoboken, NJ: Wiley-Blackwell; 2017) classifies:
STOMACH AND DUODENUM
T1  Tumour invades lamina propria or submucosa and 1 cm or less in greatest dimension
T2  Tumour invades muscularis propria or is more than 1 cm in greatest dimension
Stage I  T1 N0 M0
Accordingly, gastric and duodenal NETs greater than cm 1 should be considered as T2 and then
excluded from the study.
EUS is unable to detect distant spread (i.e. liver metastases) and can not be considered the only
technique to stage a neoplasm. CT scan or MRI should also be used for this pourpose
“… In the beginning, EUS was conducted using a radial array echoendoscope for all patients
with gastroduodenal and rectal lesions for precise staging prior to resection. …”
The term “precise staging” should be changed with local staging.
“… Then, cases with lesions limited to the mucosa or submucosa (T1) and less than 2 cm in
diameter were considered for EMR. …”
See the above comment about T1 lesions (TNM classification of malignant tumours. 8th ed.).
“… After resecting the lesion, patients were followed with endoscopy or proctoscopy
(considering the tumor size, grade, and location) according to the recommended guidelines. …”
What kind of instrumentation was used during endoscopic procedure, endoscopic follow up and
for proctoscopy?
“… All pathologic reports were reviewed and appropriate information including the size of the
lesion, grading, and margin clearance (R0) status was recorded. …”
Did any specimens show a lymphovascular invasion ?
This is a relevant pathological finding in terms of indication for further treatments, follow up
and prognosis.
RESULTS
“… Six patients underwent surgical resection due to having tumors with a high grade (G3),
unsuitable location (ileum), or advanced stage (>T1). …”
See the above comment about T1 lesions (TNM classification of malignant tumours. 8th ed.).
“… Based on the pathology report, 22 tumors (61.1%) were smaller than 1 cm in diameter while
14 (38.9%) were between 1-2 cm. …”
According to MATHERIALS AND METHOD, gastric and duodenal NETs greater than cm 1
should not be considered because they are T2, Stage II.
“… Twenty-two (61.1%) patients had a margin of specimen involved with the tumor. …”
I think it is necessary to specify what kind of resection margin involvement was observed:
vertical or horizontal. This difference is relevant in terms of indication for further treatments,
follow up and prognosis.
Why any further treatment was not suggested in patients with resection margin involvement?
This is particularly relevant for duodenal NETs whose prognosis may be worrisome.
How many patients were treated using the band ligation EMR?
How many of these patients had a resection margin involvement?
What was the size of the lesions treated with EMR?
What was the size of the lesions treated with band ligation EMR?
“… No recurrence was observed during the mean follow-up time of 63.5 ± 19.8 months (range:
39-103 months). …”
How many endoscopic investigations were carried out per patient during follow up?
At the end of follow did the patients receive CT or MRI to assess the presence of local or distant
metastases?
DISCUSSION
“… In this study, we performed EMR as the only available technique for resection of GI NETs
smaller than 2 cm in diameter and below T1 on EUS. …”
See the above comment about T1 lesions (TNM classification of malignant tumours. 8th ed.).
“.. In our study, we implemented the simple EMR technique with a submucosal saline injection
for most individuals, which is why we could only achieve a 40% complete resection rate. ..”
In MATERIALS AND METHODS is stated that “… EMR was performed with either snare
polypectomy after submucosal saline injection or via the band ligation method …”. If “simple
EMR” was implemented in all the patients, why this implementation is considered the reason
of the low complete resection rate observed?
“… Twenty-two (61.1%) patients had a margin of specimen involved with the tumor. …”
How do the authors explain a so high number of specimens with margins involvement?
“… Out of the tumors with positive margins, 69.6% were smaller than 1 cm and 30.4% were
between 1-2 cm. …”
How do the authors explain that the margins involvement was mostly observed after the resection
of smaller lesions?
“… In conclusion, EMR might be considered as a safe and effective procedure for
gastrointestinal NETs smaller than 20 mm and limited to the mucosa or submucosa, particularly
where and when equipment, instruments, or adequate expertise for ESD are not readily
accessible. …”
I do not think that any conclusion about EMR safety can be drawn from the data presented in
the study.
It is difficult to consider EMR an effective procedure to treat gastrointestinal NETs if in 61% of
the treated patients the technique is unable to obtain clear margins.
Please review this paper.
user
Title: Endoscopic mucosal resection: still a reliable therapeutic option for gastrointestinal
neuroendocrine tumors
Version: 3 Date: 28 Jan 2021
Reviewer:  Davide Ravizza
Reviewer's report:
The study shows the long term results obtained in 36 patients with NETs of the stomach,
duodenum and rectum treated with EMR.
Two relevant aspects need to be clarified. The first is to adequately stage the lesions to be
considered to entry in the study. The second concerns the resected specimens histopathological
evaluation (see the comment).
I agree with the authors that the strength of their study is the long term follow up of patients
after endoscopic resection. However, I think that the results firstly indicate that EMR is not an
effective procedure to treat NETs of the stomach, duodenum and rectum because of the high
rate of tumor margin involvement of the resected specimens. Secondly, that this involvement is
not relevant for the prognosis of these patients. This latter result is very interesting and might
be topic for a different study.
INTRODUCTION
“… Gastrointestinal neuroendocrine tumors (NETs), called carcinoid tumors, feature a
wide spectrum of malignant potential and originate from enterochromaffin-like (ECL) cells.
Gastrointestinal NETs involve 7 to 8% of all neuroendocrine tumors and are classified into
three main types. The first type accounts for 75% of patients and is associated with chronic
atrophic gastritis (1, 2), while the second accounts for 6% of cases and is linked with multiple
endocrine neoplasm (MEN) disease (including Zollinger-Ellison syndrome) and the third is the
most invasive type with a high chance of metastasis (3, 4). …”
Only gastric NETs are classified into three types.
“… The EMR technique is a relatively simple technique requiring unsophisticated skills and
inexpensive tools. This technique is used for well-differentiated gastric or duodenal lesions
smaller than 20 mm in diameter and well-differentiated tumors confined to the mucosal layer
without invasion to the lymph nodes or blood vessels. …”
Any endoscopic resection technique can be considered for the treatment of NETs in the absence
of:
- involvement beyond the submucosa;
- lymph nodal and/or distant spread.
Tumor size # 1 cm is a potential predictor of lymph nodal metastases and should be the lesion
characteristic considered first when their management is planned
It is quite difficult that a NET greater than mm 10 in size does not invade the submucosa as cited
by the Authors into the DISCUSSION.
EMR can be successfully used for NETs without a deep invasion of the submucosa as cited by
the Authors into the DISCUSSION.
“… Besides, ESD enables the en bloc removal of the lesion, which permits a more accurate
pathological evaluation. …”
EMR allows the en bloc resection of a neuroendocrine lesion, especially if a “modified EMR”
is used (i.e. using a band ligation method).
“… This study was designed to address the debate on the safety and long-term follow-up of
EMR for localized NETs in the rectum and upper gastrointestinal (GI) tract. …”
In RESULTS there is not any data about the safety of EMR (i.e. perforation or bleeding, which
are frequently observed during duodenal NETs treatment).
PATIENTS AND METHODS
“… Patients with advanced tumors unfit for endoscopic removal (larger than 2 cm in size,
higher than T1 stage on endoscopic ultrasound [EUS], and/or poorly differentiated lesions) were
excluded …”
The TNM classification of malignant tumours (Bierley J, Gospodarowicz MK, Wittekind C,
International Union against Cancer. TNM classification of malignant tumours. 8th ed. Oxford,
UK; Hoboken, NJ: Wiley-Blackwell; 2017) classifies:
STOMACH AND DUODENUM
T1  Tumour invades lamina propria or submucosa and 1 cm or less in greatest dimension
T2  Tumour invades muscularis propria or is more than 1 cm in greatest dimension
Stage I  T1 N0 M0
Accordingly, gastric and duodenal NETs greater than cm 1 should be considered as T2 and then
excluded from the study.
EUS is unable to detect distant spread (i.e. liver metastases) and can not be considered the only
technique to stage a neoplasm. CT scan or MRI should also be used for this pourpose
“… In the beginning, EUS was conducted using a radial array echoendoscope for all patients
with gastroduodenal and rectal lesions for precise staging prior to resection. …”
The term “precise staging” should be changed with local staging.
“… Then, cases with lesions limited to the mucosa or submucosa (T1) and less than 2 cm in
diameter were considered for EMR. …”
See the above comment about T1 lesions (TNM classification of malignant tumours. 8th ed.).
“… After resecting the lesion, patients were followed with endoscopy or proctoscopy
(considering the tumor size, grade, and location) according to the recommended guidelines. …”
What kind of instrumentation was used during endoscopic procedure, endoscopic follow up and
for proctoscopy?
“… All pathologic reports were reviewed and appropriate information including the size of the
lesion, grading, and margin clearance (R0) status was recorded. …”
Did any specimens show a lymphovascular invasion ?
This is a relevant pathological finding in terms of indication for further treatments, follow up
and prognosis.
RESULTS
“… Six patients underwent surgical resection due to having tumors with a high grade (G3),
unsuitable location (ileum), or advanced stage (>T1). …”
See the above comment about T1 lesions (TNM classification of malignant tumours. 8th ed.).
“… Based on the pathology report, 22 tumors (61.1%) were smaller than 1 cm in diameter while
14 (38.9%) were between 1-2 cm. …”
According to MATHERIALS AND METHOD, gastric and duodenal NETs greater than cm 1
should not be considered because they are T2, Stage II.
“… Twenty-two (61.1%) patients had a margin of specimen involved with the tumor. …”
I think it is necessary to specify what kind of resection margin involvement was observed:
vertical or horizontal. This difference is relevant in terms of indication for further treatments,
follow up and prognosis.
Why any further treatment was not suggested in patients with resection margin involvement?
This is particularly relevant for duodenal NETs whose prognosis may be worrisome.
How many patients were treated using the band ligation EMR?
How many of these patients had a resection margin involvement?
What was the size of the lesions treated with EMR?
What was the size of the lesions treated with band ligation EMR?
“… No recurrence was observed during the mean follow-up time of 63.5 ± 19.8 months (range:
39-103 months). …”
How many endoscopic investigations were carried out per patient during follow up?
At the end of follow did the patients receive CT or MRI to assess the presence of local or distant
metastases?
DISCUSSION
“… In this study, we performed EMR as the only available technique for resection of GI NETs
smaller than 2 cm in diameter and below T1 on EUS. …”
See the above comment about T1 lesions (TNM classification of malignant tumours. 8th ed.).
“.. In our study, we implemented the simple EMR technique with a submucosal saline injection
for most individuals, which is why we could only achieve a 40% complete resection rate. ..”
In MATERIALS AND METHODS is stated that “… EMR was performed with either snare
polypectomy after submucosal saline injection or via the band ligation method …”. If “simple
EMR” was implemented in all the patients, why this implementation is considered the reason
of the low complete resection rate observed?
“… Twenty-two (61.1%) patients had a margin of specimen involved with the tumor. …”
How do the authors explain a so high number of specimens with margins involvement?
“… Out of the tumors with positive margins, 69.6% were smaller than 1 cm and 30.4% were
between 1-2 cm. …”
How do the authors explain that the margins involvement was mostly observed after the resection
of smaller lesions?
“… In conclusion, EMR might be considered as a safe and effective procedure for
gastrointestinal NETs smaller than 20 mm and limited to the mucosa or submucosa, particularly
where and when equipment, instruments, or adequate expertise for ESD are not readily
accessible. …”
I do not think that any conclusion about EMR safety can be drawn from the data presented in
the study.
It is difficult to consider EMR an effective procedure to treat gastrointestinal NETs if in 61% of
the treated patients the technique is unable to obtain clear margins.
assistant