Frequency and Prognostic Significance of Intertumoural Heterogeneity in Multifocal Jejunoileal Neuroendocrine Tumours

Round 1

Reviewer 1 Report

This is a very interesting study evaluating the concept of intertumoral heterogeneity in patient with multifocal SI-NETs. Authors did a great job providing a sound analysis plan and analyzing their findings. I do not have any specific comments to make. For the future, it would be interesting to evaluate the genomic landscape of multifocal SI-NETs in that setting. 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

The article by Jesinghaus et al is exploring intertumoral heterogeneity in multifocal SI-NETs

and whether it affects the prognosis of the disease. The article is well written and easy to

read. It is an interesting finding that there is such a heterogeneity regarding important SINET

IHC markers in different PTs within patients. A question that is immediately raised is:

what is the situation in the metastases? Is this heterogeneity reflected in the metastases?

Since the primary tumours most often are surgically removed, the following treatment is

directed against the remaining metastases. Therefore, it would be of great interest to

explore if the situation is similar here.

The authors´ conclusion of the study is that an eventual heterogeneity between multiple

primary tumours does not affect the prognosis of the disease. Therefore, one should not

treat patients with multifocal PTs differently than ones with unifocal PTs. Most patients in

the study had a stage 4 disease. As the authors mention, tumour stage is a well-known

prognostic factor. However, there is very little discussion on the characteristics of the

metastases in the patients. Were any of the metastases examined pathologically? It would

improve the interpretation of whether the PT heterogeneity is of any importance if an

analysis of the metastases could be presented. Please comment.

Regarding survival analysis and Figure 3:

The authors perform a survival analysis between patients with unifocal and multifocal

primaries. However, very few patients seem to have died during follow-up, i.e. there were

very few “true” events (= deaths). In fact, the readers are not told all the figures: How many

in the “unifocal group” died? Only disease-specific deaths are presented in the “multifocal

group”. Were there patients that died from other reasons? Furthermore, the small cohorts

are another weakness for the interpretation of the data. The authors should comment on

this as limitations of the study.

Censored patients are left-out Figure 3. The authors should consider adding censored

patients in the graph. Also, a table with patients at risk would improve the understanding.

Minor comment:

Line 304: the authors present an explanation model for why primary tumours often are not

visible on SSTR imaging. However, the most reasonable explanation is that due to their small

size (compared to mets) the radionuclide uptake is not high enough to detect them.

Minor adjustments:

Line 120: please specify which serotonin antibody was used.

Line 228: Sentence beginning with “In a first general analysis ..” is hard to read and

understand. What were the observations? Please rewrite.

Line 297: It seems like a “to” is missing in the sentence. ..the pathologist who has to consider

that..

Author Response

Please see the attachment.

Author Response File: Author Response.pdf