Review for 10.1186/s12876-025-03746-w (2025)

Title: Choledocholithiasis as a risk factor for cholangiocarcinoma: a nationwide retrospective
cohort study
Version: 2 Date: 13 Jan 2025
Reviewer's report:
The authors have performed a retrospective cohort study of cholangiocarcinoma risk in
individuals diagnosed with choledocholithiasis to assess whether choledocholithiasis is an
independent risk factor for cholangiocarcinoma. This was done in a large administrative
database in South Korea (the NHIS). I have received this manuscript for review after an
initial review by two other reviewers and after the authors have responded to the original
reviewers' comments. They separately assessed incidence of cholangiocarcinoma in the first 2
years after choledocholithiasis diagnosis and after the first 2 years. The authors have responded
to the main concerns expressed by the original reviewers and appropriately contextualized
the associations measured as being inadequate to demonstrate causality. I have the following
additional comments:
In the introduction, the authors state that prior studies demonstrating an association between
choledocholithiasis and cholangiocarcinoma require further validation because of their case-
control design. However, both cohort and case control studies are at risk of bias introduced
by investigators; a well-designed case control study with appropriate control selection is not
inherently less valid than a cohort design. I suggest altering the language or being more specific
if the source case-control studies had significant flaws in control selection or other key design
features.
In the results section, the outcomes of cholangiocarcinoma should be reported as "diagnosed"
not "developed";  for example, in line 179, I suggest the following wording: "In almost half of
the patients diagnosed with ECA, almost half received this diagnosis within the first 2 years
after choledocholithiasis diagnosis." It is not known from the administrative dataset when in
each patient's history they developed the cancer, only when it was diagnosed.
There are frequently short delays in the capture of diagnoses in administrative databases that do
not reflect clinically meaningful sequence of events. For example, a  patient is diagnosed with
one condition and within a few weeks the second condition is discovered in further work up,
but they were both truly present at the time of the first diagnosis. I suggest adding a period in
which the diagnoses are considered contemporaneous (something like 90 days) to distinguish
between cholangiocarcinoma that is diagnosed as part of the same "illness episode" as the
choledocholithiasis and cholangiocarcinoma that is diagnosed separately in the future.
The possibility that choledocholithiasis is a presenting symptom of existing cholangiocarcinoma
is supported by the stronger association between choledocholithiasis and extrahepatic
cholangiocarcinoma with a steeper slope in the earliest period of the cumulative incidence
curve. This is addressed by the authors in the discussion, but a brief exclusion period (described
above) could also address this methodologically. (The authors performed a sensitivity analysis
in which they excluded all cholangiocarcinoma that develops within the first 2 years of
choledocholithiasis diagnosis in their analyses.)