Chromoendoscopy in Lynch syndrome patients

Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer (HNPCC), is
an autosomally dominantly inherited disorder that accounts for 1-2 % of
colorectal cancer cases [1-4]. LS is caused by germline genomic alterations in
one of the mismatch repair (MMR) genes hMLH1, hMSH2, hMSH6 and hPMS2 [1].
Genetic alterations in the hMLH1 and hMSH2 genes account for the large majority
of LS cases. The lifetime incidence of colorectal cancer is 20-75 % in these
mutation carriers [5, 6]. Individuals with LS-associated colorectal cancer
differ from those with sporadic disease in several ways: the tumours are
diagnosed at an earlier age; the majority of tumours is located in the proximal
colon; there is an increased risk of developing synchronous or metachronous
colorectal cancers and the prognosis relatively favourable compared to sporadic
cases [1]. It is generally accepted that LS associated colorectal cancers
develop along the adenoma-carcinoma sequence as in sporadic cases [1]. There is
evidence suggesting that the adenoma-carcinoma sequence is accelerated in LS
patients as compared to the general population [1].
Colonoscopic screening and subsequent removal of polyps at a 3-year interval in
asymptomatic at-risk members of LS families has shown to reduce the incidence
of colorectal cancer and improve overall survival [7]. However, within such an
interval in surveillance programs, interval cancers have been observed [8, 9].
It is therefore currently recommended that MMR gene mutation carriers should be
kept under surveillance by regular colonoscopy every 1-2 years beginning at the
age of 20-25 or 5-10 years younger than the earliest affected family member
[10, 11].
LS adenomas are predominantly located in the proximal colon [12] and frequently
carry villous architecture and high-grade dysplasia, markers that are
associated with an increased risk of developing colorectal cancer [13-16]. Even
in LS adenomas smaller than 5-7 mm in size, high-grade dysplasia can be
encountered [12, 16]. Therefore, the identification of high-risk precursor
lesions in LS is considered of paramount importance.
It is known that conventional colonoscopy has a certain miss rate for
colorectal neoplasms, especially small adenomas [17]. A few years ago, the
technique of chromoendoscopy was introduced. Chromoendoscopy, in which one of
various dyes are sprayed onto the colonic mucosa via a spray catheter passed
through the working channel of the endoscope, offers detailed evaluation of the
mucosal surface [18]. Indigo carmine is a contrast stain that is not absorbed
and does not react with the surface mucosa. In 2 large randomised controlled
trials chromoendoscopy significantly increased the detection of small adenomas
in the proximal colon as compared to conventional colonoscopy [19, 20].
Recently, 2 trials in LS patients revealed that chromoscopic endoscopy improved
the detection of adenomas, particularly flat lesions, compared to conventional
colonoscopy [21, 22]. Together, these data suggest that chromoendoscopy may
improve detection rates of significant neoplastic colonic lesions in LS
patients. However, the true value of chromoendoscopy in the management of LS
patients remains to be demonstrated.
The aim of this study is to determine whether chromoendoscopy, including
polypectomy of all detected lesions, reduces the development of colorectal
neoplasia and the need for colectomy in LS patients at follow-up endoscopy.
The results of the study will indicate the value of chromoendoscopy in the
management of LS patients and whether the technique should be implemented in
current surveillance procedures.

References
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The aim of this study is to determine whether chromoendoscopy, including
polypectomy of all detected lesions, reduces the development of colorectal
neoplasia in Lynch syndrome patients at follow-up endoscopy.

This is a national multi-center randomised trial.

Patients will be randomised between conventional colonoscopy and
chromoendoscopy at baseline, followed by chromoendoscopy in all patients at two
year follow-up.

Participation will result in minimal burden for this patient group.
Chromoendoscopy requires slightly longer endoscopy procedure times (minutes).
All neoplastic lesions encountered will be removed if technically possible,
associated with known low risks of complications. Otherwise, the study will not
be associated with additional endoscopic procedures, visits, additional blood
sampling, additional physical examinations or other tests.