Capsule endoscopy in Lynch Syndrome for small intestinal tumour screening:
the CELSIUS study

Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer (HNPCC), is
an autosomal dominantly inherited disorder characterized by a very high risk of
early-onset colorectal and endometrial cancer and an increased risk of other
cancers, including cancers of the stomach, ovary, urinary tract, hepatobiliary
tract, pancreas and small bowel [1]. LS is caused by germline mutations in one
of the mismatch repair (MMR) genes, mostly hMLH1, hMSH2 and hMSH6. Recently,
several studies, including one from the Netherlands, have evaluated the
life-time risk of small bowel cancer (SBC) in LS patients [2-6]. From these
studies the life-time risk of SBC is estimated around 4 %. This is similar to
the life-time risk of colorectal cancer in the general population, for which
screening is generally advised [7]. The risk of SBC increases with age, with an
estimated prevalence of 1:500 at the age of 40, rising to an estimated
prevalence of around 1:70 at the age of 60. Compared with the general
population, LS patients with SBC generally present 10-20 years earlier as most
patients with sporadic SBC are in their sixth or seventh decade of life [8].
The localisation of SBC in LS is almost equal in the duodenum and jejunum, with
localisation in the ileum generally occurring at a lower frequency [8].Until
now, screening for small bowel neoplasia in Lynch syndrome patients is
generally not recommended [9,10]. However, the development of two new
techniques to visualize the small intestine has raised the question whether
screening might be useful and advisable. Small bowel capsule endoscopy (CE) has
been developed as a safe, patient-friendly, minimally invasive modality for
visualization of the small bowel [11]. In addition, double-balloon enteroscopy
(DBE) has been developed, a technique which allows endotherapeutic
interventions [12]. The diagnostic yields of both techniques are markedly
higher than the conventional methods, such as push-enteroscopy and
enteroclysis. To date, no study has been performed on screening for small bowel
neoplasia in Lynch syndrome patients by means of these techniques.
This study will provide data on the prevalence and incidence of small bowel
lesions in Lynch syndrome. Together, the results will indicate whether
screening for small bowel neoplasia in patients with Lynch syndrome is useful.

References
1. Hendriks YM, De Jong AE, Morreau H, et al. Diagnostic approach and
management of Lynch syndrome (hereditary nonpolyposis colorectal carcinoma): a
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risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC)
syndrome. Int J Cancer 1995;64:430-33.
3. Vasen HF, Wijnen JT, Menko FH, et al. Cancer risk in families with
hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis.
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bowel carcinoma in hereditary nonpolyposis colorectal carcinoma. International
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small bowel indicated for Lynch syndrome families? Gut 2007;56:1198-1201.
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nonpolyposis colorectal cancer families. J Clin Oncol 2001;19:4074-80.
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individuals with an inherited predisposition to Lynch syndrome: a systematic
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10. Vasen HF, Möslein G, Alonso A, et al. Guidelines for the clinical
management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet
2007;44:353-62.
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12. Yamamoto H, Sekine Y, Sato Y, et al. Total enteroscopy with a nonsurgical
steerable double-balloon method. Gastrointest Endosc 2001;53:216-20.
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spontaneous capsule passage after retention? A nationwide study to evaluate the
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Primary objective
The primary aim of the study is to determine the prevalence and incidence of
small bowel neoplasia in Lynch syndrome patients using small bowel CE and DBE.
Secondary objectives
The secondary aim is to identify risk factors for small bowel pathology useful
in clinical practice to identify patients that might benefit from screening and
to determine the additional interventional risk associated with the endoscopic
procedures.

This is a national multi-centre study evaluating the yield of small bowel
screening using capsule endoscopy and double balloon enteroscopy in Lynch
syndrome subjects. The intervention consists of performing a capsule endoscopy
procedure at baseline and at 2-year follow-up. In patients with polyps or
malignant appearing abnormalities on capsule endoscopy, double balloon
enteroscopy will be performed with subsequent endoscopic or surgical removal of
neoplastic lesions. In patients with unexpected findings at capsule endoscopy,
the findings will be weighed in relation to the clinical context by the
attending physician.

Capsule endoscopy.
All participating centres have local experience with or easy access to capsule
endoscopy facilities. Bowel preparation for capsule endoscopy will consist of 2
L of polyethylene glycol electrolyte solution (Moviprep®), allowing adequate
inspection of the small bowel. Patients will be allowed to drink fluids after 3
h and to consume a light meal after 5 h after ingestion of the capsule.
Capsules will be used from Given Imaging (Yoqneam, Israel), with a recording
time of 8 hours, using Rapid 5.0 ® software.
All capsule endoscopy procedures will be evaluated by an experienced local
endoscopist. In addition, capsule endoscopy procedures will be processed on a
DVD disk and subsequently assesses centrally by the principal investigator.
Findings of capsule endoscopy will be recorded. Only if capsule endoscopy
reveals polyps or malignant appearing lesions, a double balloon enteroscopy
will be performed.
Double balloon enteroscopy.
All participating centres have local experience with or easy access to double
balloon enteroscopy facilities. Bowel preparation for DBE will consist of 2 L
of polyethylene glycol electrolyte solution (Moviprep®), allowing adequate
inspection of the small bowel. Patients will start fasting from midnight before
the procedure. DBE can be carried out through the oral (antegrade) or the anal
(retrograde) route. The choice of route will be determined by the capsule
endoscopy findings: if abnormalities at CE are seen within the first two-thirds
of the CE procedure, the antegrade approach will be chosen [13]. In all other
cases, the retrograde approach will be chosen. At the farthest point of
introduction, a tattoo mark will be left behind. If no abnormalities are
encountered with one approach, the alternative approach will be chosen in a
second procedure. If the target lesion(s) are reached, biopsy samples will be
taken for routine histology and, if possible also for snap frozen storage. If
considered amenable, lesions will be removed. If lesions are considered too
large to allow endoscopic resection, a tattoo mark will be placed to facilitate
surgical identification and resection. All mucosal lesions will be recorded
with regard to location (duodenum, jejunum, ileum).
Expected complications.
Previous studies indicate that the risk of complications with capsule endoscopy
is extremely low. The clinically most relevant risk of capsule endoscopy is
that of capsule retention, which is reported to occur in up to 2.5 % of
procedures [14]. The most important risk factor for capsule retention is
Crohn's disease. Patients with suspected capsule retention will be evaluated
with an abdominal X-ray. The risk of complications associated with DBE is low,
especially for diagnostic DBE procedures. In a recent multicenter survey,
reporting on 2362 DBE procedures, the complication rate of diagnostic DBE was
0.8 % and that of therapeutic DBE procedures 4.3 % [15].