Title: Characteristics of primary signet ring cell carcinoma of colon and rectum: a case control
study
Version: 1 Date: 05 Jan 2022
Reviewer's report:
In the current study, the authors utilized clinical data of 11,515 colorectal cancers (CRCs) and
analyzed 18 primary signet ring cell carcinoma of the colon and rectum (PSRCCR) found in the
cohort. Their data provide important information regarding this rare entity, but methods for data
analyses may not be optimal.
Major comments:
1. The authors identified 18 PSRCCR among 11,515 CRCs registered in their pathological
databank, but the criteria for pathological diagnosis of PSRCCR are not clearly mentioned,
perhaps due to the retrospective nature of the current study. To ensure the legitimacy of the
original pathological diagnosis, pathological review should be performed at least for the tumors
with available H&E slides.
2. They utilized 72 non-PSRCCR CRC as controls. Because the comparisons between PSRCCR
and non-PSRCCR CRCs are essential part of the current study, how they selected these 72
tumors out of all the non-PSRCCR CRCs must be clearly mentioned. To justify their analyses,
bioinformatical rationale for the selection of control cases should be explained.
3. The authors aimed to find clues for diagnosis of PSRCCR. Because CRCs are usually
diagnosed by colonoscopy, I would recommend analyzing endoscopic findings at least for
available cases.
4. The authors mentioned that in PSRCCR cases, infiltrative/ulcerative configuration as well as
long segmental wall thickening detected by CT scan could lead to possible misdiagnosis as non-
malignant disease such as Crohn’s disease. Importantly, they showed that endoscopic biopsy
failed to identify malignant cells in more than one third of PSRCCRs. Because these findings
provide relevant information for gastroenterologists, detailed analyses of colonoscopic, CT,
and histological findings are recommended. In addition, please clarify the definition of tumor
configuration (exophytic, ulcerative, or infiltrative) as well as “long segment colonic stenosis”.
Minor comments:
1. Please do not use non-standard abbreviation such as “CFS”. I suppose it stands for
colonoscopy but not sure.
2. Because PSRCCR patients were younger than non-PSRCC CRC patients, I wonder if they
contain any patients with hereditary cancer syndromes such as Lynch syndrome and hereditary
diffuse gastric cancer. Information on personal and familial cancer occurrence and microsatellite
instability testing may be useful if available.
3. I think it is difficult to evaluate the efficacy of bevacizumab and cetuximab against PSRCCR
in such a small number of cases, especially without information on major confounding factors
such as RAS/BRAF mutations and chemotherapeutic regimen.
4. Features associated with PSRCCR such as poor outcome, high CEA, and low albumin may
be all attributed to advanced stage at diagnosis rather than biological nature of PSRCCR itself.
I prefer to see those data stratified by tumor stages (especially stage III vs stage IV).
Title: Characteristics of primary signet ring cell carcinoma of colon and rectum: a case control
study
Version: 1 Date: 05 Jan 2022
Reviewer's report:
In the current study, the authors utilized clinical data of 11,515 colorectal cancers (CRCs) and
analyzed 18 primary signet ring cell carcinoma of the colon and rectum (PSRCCR) found in the
cohort. Their data provide important information regarding this rare entity, but methods for data
analyses may not be optimal.
Major comments:
1. The authors identified 18 PSRCCR among 11,515 CRCs registered in their pathological
databank, but the criteria for pathological diagnosis of PSRCCR are not clearly mentioned,
perhaps due to the retrospective nature of the current study. To ensure the legitimacy of the
original pathological diagnosis, pathological review should be performed at least for the tumors
with available H&E slides.
2. They utilized 72 non-PSRCCR CRC as controls. Because the comparisons between PSRCCR
and non-PSRCCR CRCs are essential part of the current study, how they selected these 72
tumors out of all the non-PSRCCR CRCs must be clearly mentioned. To justify their analyses,
bioinformatical rationale for the selection of control cases should be explained.
3. The authors aimed to find clues for diagnosis of PSRCCR. Because CRCs are usually
diagnosed by colonoscopy, I would recommend analyzing endoscopic findings at least for
available cases.
4. The authors mentioned that in PSRCCR cases, infiltrative/ulcerative configuration as well as
long segmental wall thickening detected by CT scan could lead to possible misdiagnosis as non-
malignant disease such as Crohn’s disease. Importantly, they showed that endoscopic biopsy
failed to identify malignant cells in more than one third of PSRCCRs. Because these findings
provide relevant information for gastroenterologists, detailed analyses of colonoscopic, CT,
and histological findings are recommended. In addition, please clarify the definition of tumor
configuration (exophytic, ulcerative, or infiltrative) as well as “long segment colonic stenosis”.
Minor comments:
1. Please do not use non-standard abbreviation such as “CFS”. I suppose it stands for
colonoscopy but not sure.
2. Because PSRCCR patients were younger than non-PSRCC CRC patients, I wonder if they
contain any patients with hereditary cancer syndromes such as Lynch syndrome and hereditary
diffuse gastric cancer. Information on personal and familial cancer occurrence and microsatellite
instability testing may be useful if available.
3. I think it is difficult to evaluate the efficacy of bevacizumab and cetuximab against PSRCCR
in such a small number of cases, especially without information on major confounding factors
such as RAS/BRAF mutations and chemotherapeutic regimen.
4. Features associated with PSRCCR such as poor outcome, high CEA, and low albumin may
be all attributed to advanced stage at diagnosis rather than biological nature of PSRCCR itself.
I prefer to see those data stratified by tumor stages (especially stage III vs stage IV).
Please review this paper.
user
Title: Characteristics of primary signet ring cell carcinoma of colon and rectum: a case control
study
Version: 1 Date: 05 Jan 2022
Reviewer's report:
In the current study, the authors utilized clinical data of 11,515 colorectal cancers (CRCs) and
analyzed 18 primary signet ring cell carcinoma of the colon and rectum (PSRCCR) found in the
cohort. Their data provide important information regarding this rare entity, but methods for data
analyses may not be optimal.
Major comments:
1. The authors identified 18 PSRCCR among 11,515 CRCs registered in their pathological
databank, but the criteria for pathological diagnosis of PSRCCR are not clearly mentioned,
perhaps due to the retrospective nature of the current study. To ensure the legitimacy of the
original pathological diagnosis, pathological review should be performed at least for the tumors
with available H&E slides.
2. They utilized 72 non-PSRCCR CRC as controls. Because the comparisons between PSRCCR
and non-PSRCCR CRCs are essential part of the current study, how they selected these 72
tumors out of all the non-PSRCCR CRCs must be clearly mentioned. To justify their analyses,
bioinformatical rationale for the selection of control cases should be explained.
3. The authors aimed to find clues for diagnosis of PSRCCR. Because CRCs are usually
diagnosed by colonoscopy, I would recommend analyzing endoscopic findings at least for
available cases.
4. The authors mentioned that in PSRCCR cases, infiltrative/ulcerative configuration as well as
long segmental wall thickening detected by CT scan could lead to possible misdiagnosis as non-
malignant disease such as Crohn’s disease. Importantly, they showed that endoscopic biopsy
failed to identify malignant cells in more than one third of PSRCCRs. Because these findings
provide relevant information for gastroenterologists, detailed analyses of colonoscopic, CT,
and histological findings are recommended. In addition, please clarify the definition of tumor
configuration (exophytic, ulcerative, or infiltrative) as well as “long segment colonic stenosis”.
Minor comments:
1. Please do not use non-standard abbreviation such as “CFS”. I suppose it stands for
colonoscopy but not sure.
2. Because PSRCCR patients were younger than non-PSRCC CRC patients, I wonder if they
contain any patients with hereditary cancer syndromes such as Lynch syndrome and hereditary
diffuse gastric cancer. Information on personal and familial cancer occurrence and microsatellite
instability testing may be useful if available.
3. I think it is difficult to evaluate the efficacy of bevacizumab and cetuximab against PSRCCR
in such a small number of cases, especially without information on major confounding factors
such as RAS/BRAF mutations and chemotherapeutic regimen.
4. Features associated with PSRCCR such as poor outcome, high CEA, and low albumin may
be all attributed to advanced stage at diagnosis rather than biological nature of PSRCCR itself.
I prefer to see those data stratified by tumor stages (especially stage III vs stage IV).
assistant