Title: Immunohistochemical Staining for IMP3 in Patients with Duodenal Papilla Tumors:
Assessment of the Potential for Diagnosing Endoscopic Resectability and Predicting Prognosis
Version: 2 Date: 20 Feb 2021
Reviewer's report:
This single centre study retrospectively evaluates 25 resected papillary tumours and their
corresponding biopsies for immunohistochemical expression of Insulin-like growth factor 2
mRNA protein 3 (IMP3) and correlated the percentage of IMP3 positive cells with presence
sphincter of Oddi involvement by invasive carcinoma and prognosis. It is concluded that IMP3
immunostaining of resected and biopsy specimens from papillary tumours objectively enables
the diagnosis of sphincter of Oddi involvement and effectively predicts the prognosis.
This is an interesting study evaluating IMP3 immunohistochemistry in papillary tumours and
its role for determining endoscopic resectability and prognosis with the aim of being relevant
for clinical practice.
Comments:
Major:
1. The ultimate goal behind the study is predicting resectability of papillary adenocarcinomas by
doing IMP3 immunohistochemistry on diagnostic biopsies to distinguish stage T1 carcinomas
with sphincter of Oddi invasion from those without to select patients for endoscopic resection.
Was direct case by case correlation of staining between biopsies and their corresponding
resections performed?  The results provided appear to show that the median number of IMP3
positive cells in biopsy specimens was higher in cases of T1 papillary carcinoma (10%) without
sphincter of Oddi invasion than in pT1 cases with sphincter of Oddi invasion (5%) whereas the
reverse was the case in resected cases (5% versus 50%) raising concern about the validity of
results in biopsies. The very broad range of staining results (ranging e.g. from 0-80% in benign
adenomas alone) and the very small numbers of cases of papillary carcinomas of stage Tis/
T1 without sphincter of Oddi invasion (5 patients) and T1 with sphincter of Oddi invasion (3
patients) raise further significant concern regarding reliable results to support the conclusion of
IMP3 objectively enabling sphincter of Oddi involvement.
2. Has IMP3 immunohistochemistry been correlated with clinicopathological data including
adjuvant treatments to assess its role as an independent prognostic marker?
3. How was the percentage of IMP3 assessed? How many blocks and fields were assessed and
how were the counts performed? How was consensus achieved?
4. Description of pathological staging in the method section may be better included in the result
section. The discussion would benefit from removing repetition of results and including critical
discussion of any similar studies using IMP3 immunohistochemistry.
Additional comments:
In the method section, how exactly were the study patients identified as having sufficient
pathological examination? How many patients in total underwent resection for papillary tumours
during the specified years and how many patients were then excluded and on which grounds?
The discussion might also benefit from including the impact of heterogeneity of histological
tumour types (mixture of intestinal and pancreatobiliary types).
Some statements and terminology used in the manuscript might benefit from revision to give
the manuscript more clarity and accuracy (e.g. replacing T-factor level with T-stage, specifying
resectable tumours as endoscopically resectable, being more accurate of the types of tumours in
which IMP3 has been assessed as prognostically relevant)
The study provides evidence that IMP3 expression in ampullary tumours is increasing with
advancing stages of the tumour. Would it be a consideration to present the results as an
observation that IMP3 also indicates aggressiveness in ampullary carcinomas like it is in many
other tumours?
Title: Immunohistochemical Staining for IMP3 in Patients with Duodenal Papilla Tumors:
Assessment of the Potential for Diagnosing Endoscopic Resectability and Predicting Prognosis
Version: 2 Date: 20 Feb 2021
Reviewer's report:
This single centre study retrospectively evaluates 25 resected papillary tumours and their
corresponding biopsies for immunohistochemical expression of Insulin-like growth factor 2
mRNA protein 3 (IMP3) and correlated the percentage of IMP3 positive cells with presence
sphincter of Oddi involvement by invasive carcinoma and prognosis. It is concluded that IMP3
immunostaining of resected and biopsy specimens from papillary tumours objectively enables
the diagnosis of sphincter of Oddi involvement and effectively predicts the prognosis.
This is an interesting study evaluating IMP3 immunohistochemistry in papillary tumours and
its role for determining endoscopic resectability and prognosis with the aim of being relevant
for clinical practice.
Comments:
Major:
1. The ultimate goal behind the study is predicting resectability of papillary adenocarcinomas by
doing IMP3 immunohistochemistry on diagnostic biopsies to distinguish stage T1 carcinomas
with sphincter of Oddi invasion from those without to select patients for endoscopic resection.
Was direct case by case correlation of staining between biopsies and their corresponding
resections performed?  The results provided appear to show that the median number of IMP3
positive cells in biopsy specimens was higher in cases of T1 papillary carcinoma (10%) without
sphincter of Oddi invasion than in pT1 cases with sphincter of Oddi invasion (5%) whereas the
reverse was the case in resected cases (5% versus 50%) raising concern about the validity of
results in biopsies. The very broad range of staining results (ranging e.g. from 0-80% in benign
adenomas alone) and the very small numbers of cases of papillary carcinomas of stage Tis/
T1 without sphincter of Oddi invasion (5 patients) and T1 with sphincter of Oddi invasion (3
patients) raise further significant concern regarding reliable results to support the conclusion of
IMP3 objectively enabling sphincter of Oddi involvement.
2. Has IMP3 immunohistochemistry been correlated with clinicopathological data including
adjuvant treatments to assess its role as an independent prognostic marker?
3. How was the percentage of IMP3 assessed? How many blocks and fields were assessed and
how were the counts performed? How was consensus achieved?
4. Description of pathological staging in the method section may be better included in the result
section. The discussion would benefit from removing repetition of results and including critical
discussion of any similar studies using IMP3 immunohistochemistry.
Additional comments:
In the method section, how exactly were the study patients identified as having sufficient
pathological examination? How many patients in total underwent resection for papillary tumours
during the specified years and how many patients were then excluded and on which grounds?
The discussion might also benefit from including the impact of heterogeneity of histological
tumour types (mixture of intestinal and pancreatobiliary types).
Some statements and terminology used in the manuscript might benefit from revision to give
the manuscript more clarity and accuracy (e.g. replacing T-factor level with T-stage, specifying
resectable tumours as endoscopically resectable, being more accurate of the types of tumours in
which IMP3 has been assessed as prognostically relevant)
The study provides evidence that IMP3 expression in ampullary tumours is increasing with
advancing stages of the tumour. Would it be a consideration to present the results as an
observation that IMP3 also indicates aggressiveness in ampullary carcinomas like it is in many
other tumours?
Please review this paper.
user
Title: Immunohistochemical Staining for IMP3 in Patients with Duodenal Papilla Tumors:
Assessment of the Potential for Diagnosing Endoscopic Resectability and Predicting Prognosis
Version: 2 Date: 20 Feb 2021
Reviewer's report:
This single centre study retrospectively evaluates 25 resected papillary tumours and their
corresponding biopsies for immunohistochemical expression of Insulin-like growth factor 2
mRNA protein 3 (IMP3) and correlated the percentage of IMP3 positive cells with presence
sphincter of Oddi involvement by invasive carcinoma and prognosis. It is concluded that IMP3
immunostaining of resected and biopsy specimens from papillary tumours objectively enables
the diagnosis of sphincter of Oddi involvement and effectively predicts the prognosis.
This is an interesting study evaluating IMP3 immunohistochemistry in papillary tumours and
its role for determining endoscopic resectability and prognosis with the aim of being relevant
for clinical practice.
Comments:
Major:
1. The ultimate goal behind the study is predicting resectability of papillary adenocarcinomas by
doing IMP3 immunohistochemistry on diagnostic biopsies to distinguish stage T1 carcinomas
with sphincter of Oddi invasion from those without to select patients for endoscopic resection.
Was direct case by case correlation of staining between biopsies and their corresponding
resections performed?  The results provided appear to show that the median number of IMP3
positive cells in biopsy specimens was higher in cases of T1 papillary carcinoma (10%) without
sphincter of Oddi invasion than in pT1 cases with sphincter of Oddi invasion (5%) whereas the
reverse was the case in resected cases (5% versus 50%) raising concern about the validity of
results in biopsies. The very broad range of staining results (ranging e.g. from 0-80% in benign
adenomas alone) and the very small numbers of cases of papillary carcinomas of stage Tis/
T1 without sphincter of Oddi invasion (5 patients) and T1 with sphincter of Oddi invasion (3
patients) raise further significant concern regarding reliable results to support the conclusion of
IMP3 objectively enabling sphincter of Oddi involvement.
2. Has IMP3 immunohistochemistry been correlated with clinicopathological data including
adjuvant treatments to assess its role as an independent prognostic marker?
3. How was the percentage of IMP3 assessed? How many blocks and fields were assessed and
how were the counts performed? How was consensus achieved?
4. Description of pathological staging in the method section may be better included in the result
section. The discussion would benefit from removing repetition of results and including critical
discussion of any similar studies using IMP3 immunohistochemistry.
Additional comments:
In the method section, how exactly were the study patients identified as having sufficient
pathological examination? How many patients in total underwent resection for papillary tumours
during the specified years and how many patients were then excluded and on which grounds?
The discussion might also benefit from including the impact of heterogeneity of histological
tumour types (mixture of intestinal and pancreatobiliary types).
Some statements and terminology used in the manuscript might benefit from revision to give
the manuscript more clarity and accuracy (e.g. replacing T-factor level with T-stage, specifying
resectable tumours as endoscopically resectable, being more accurate of the types of tumours in
which IMP3 has been assessed as prognostically relevant)
The study provides evidence that IMP3 expression in ampullary tumours is increasing with
advancing stages of the tumour. Would it be a consideration to present the results as an
observation that IMP3 also indicates aggressiveness in ampullary carcinomas like it is in many
other tumours?
assistant