Abnormalities of C-Kit–Positive Cellular Network in Isolated
By Udo Rolle, Akihiro Yoneda, Valeria Solari, Laszlo Nemeth, and Prem Puri
Dublin, Ireland and Szeged, Hungary
Background/Purpose: C-Kit–positive interstitial cells of Cajal
(ICCs) have a key role in the normal motility function and
development of the bowel. They are pacemaker cells, which
facilitate active propagation of electrical events and neuro-
transmission in the bowel wall. ICCs are present in the bowel
as myenteric ICCs (ICC
) and muscular ICCs (ICC
aim of this study was to examine the distribution of c-Kit–
positive ICCs and their relationship to the autonomic intrinsic
innervation in bowel specimens from patients with isolated
Methods: Full-thickness large bowel specimens were ob-
tained from 6 patients with hypoganglionosis and from 4
patients during bladder augmentation (controls). Frozen sec-
tions and whole-mount preparations were stained using c-Kit
immunohistochemistry, nicotinamide adenine dinucleotide
phosphate (NADPH)-diaphorase, and acetylcholinesterase
(AChE) histochemistry and evaluated using normal bright-
ﬁeld and confocal laser scanning microscopy.
Results: NADPH-diaphorase and AChE histochemistry ﬁnd-
ings showed characteristic histologic features of hypogangli-
onosis, eg, sparse and small myenteric ganglia and low or
absent AChE activity in the lamina propria. Myenteric plexus
in the normal bowel was surrounded by a dense network of
s, whereas in hypoganglionosis sparse
s were found. C-Kit–positive ICC
s were re
duced markedly in the longitudinal and circular muscle layer
and at the innermost part of the circular muscle in hypogan-
Conclusion: Deﬁcient expression of c-Kit–positive myenteric
and muscular ICCs in the hypoganglionic colon may contrib-
ute to the motility dysfunction in the affected bowel.
J Pediatr Surg 37:709-714. Copyright 2002, Elsevier Science
(USA). All rights reserved.
INDEX WORDS: Interstitial cells of Cajal, hypoganglionosis,
YPOGANGLIONOSIS as an isolated condition is
rare. Its clinical presentation resembles Hirsch-
sprung’s disease (HD).
Suction rectal biopsy results in
these patents show absence of submucosal ganglion cells
with no or extremely low acetylcholinesterase (AChE)
activity in lamina propria or muscularis mucosae. Full-
thickness biopsy usually is required for the reliable
diagnosis of hypoganglionosis. Characteristic histologic
features of hypoganglionosis include sparse and small
myenteric ganglia, absence or low AChE activity in the
lamina propria, and hypertrophy of muscularis mucosae
and circular muscle.
The normal motility of the gastrointestinal tract de-
pends on the enteric nervous system (ENS), the muscle
layers, and the interstitial cells of Cajal (ICC). ICCs are
pacemaker cells, which generate slow waves and facili-
tate active propagation of electrical events and mediate
neurotransmission in the bowel wall.
ICCs can be rec-
ognized either by their unique ultrastructure on electron
microscopy or with the immunohistochemical demon-
stration of their surface receptor tyrosine kinase Kit
(c-Kit). Recent studies have found that the c-Kit receptor
is essential for the development of the ICCs. Mesenchy-
mal ICCs precursors that carry the c-Kit receptor require
the kit ligand (KL), which can be provided by neuronal
cells or smooth muscle cells. According to the inﬂuence
of the KL from either neuronal or smooth muscle cells,
the ICCs develop as either myenteric ICC
s are associated with neurons and envelop
the myenteric plexus. In the normal bowel, ICC
found in the layers of the smooth muscle and the sub-
mucosal surface of the circular muscle bundle.
The aim of this study was to examine the distribution
of myenteric and muscular ICCs and their relationship to
the enteric nervous system in bowel specimen from
patients with isolated hypoganglionosis.
MATERIALS AND METHODS
Full-thickness large bowel biopsy specimens were obtained from 6
patients (age range, 6 months to 8 years) with isolated hypogangliono-
From the Children’s Research Centre, Our Lady’s Hospital for Sick
Children, Dublin, Ireland, and the Department of Pediatric Surgery,
University of Szeged, Szeged, Hungary.
The work of Udo Rolle was supported by a grant of the Deutsche
Forschungsgemeinschaft (DFG, No. RO 229/1-1).
Address reprint requests to Mr Prem Puri, Director of Research,
Children’s Research Centre, Our Lady’s Hospital for Sick Children,
Crumlin, Dublin 12, Ireland.
Copyright 2002, Elsevier Science (USA). All rights reserved.
709Journal of Pediatric Surgery, Vol 37, No 5 (May), 2002: pp 709-714