Keywords
appendix - histopathology - Hirschsprung
New Insights and the Importance for the Pediatric Surgeon
Aganglionosis of the appendix has long been considered to be an important finding
and diagnostic for total colonic Hirschsprung disease, but the reliability of this
pathological finding has seldom been discussed. We present a case in which the finding
of an aganglionic appendix misled the surgeons in terms of diagnosis and had severe
implications with regards to the management of the child. We identified other case
reports in the pediatric surgical and pathologic literature reporting similar findings
to ours. We have reviewed the literature in this article and would encourage all pediatric
surgeons to be familiar with the current histopathological guidelines with regards
to making the diagnosis of Hirschsprung disease.
Case History
A newborn male infant (born at term) presented with abdominal distension and failure
to pass meconium in the first 24 hours of life. Hirschsprung disease (HD) was suspected;
however, the contrast enema failed to demonstrate a transition zone and was read as
normal by radiology. The child was treated with rectal irrigations but remained persistently
distended. All laboratory values were normal. Because of this, the infant underwent
a diagnostic laparoscopy. No anatomic obstruction was noted. The appendix was then
sent for histopathologic examination and found to be aganglionic, and the case was
therefore determined to be total colonic HD. Based on this finding, the surgeons felt
they had confirmed HD and a total colonic type, and thus did not perform a rectal
biopsy. An ileostomy was fashioned.
The child thrived after the ileostomy and did not have any episodes of Hirschsprung-associated
enterocolitis (HAEC). No further evaluation was done. The child was then referred
to our institution for ongoing care and for undergoing the pull-through procedure.
The referral center was advised that further surgical intervention should be delayed
until the child was potty-trained for urine and the ileostomy output had thickened.
At the visit for the planned ileoanal pull-through, a contrast enema revealed no obstruction,
and a colon that was a little narrowed but consistent with the fact that it was defunctionalized
for the preceding 2 years. A rectal biopsy was sent to reconfirm the diagnosis as
a matter of routine ([Fig. 1]). To our surprise, the rectal biopsy revealed normal ganglion cells and no evidence
of hypertrophic nerves. The decision was made then to proceed with closure of the
ileostomy. The ileum was flushed in the operating room and no obstruction was noted,
and the colon was also flushed and shown to have no anatomic obstruction. The child
had normal stools postoperatively and 2 years later remained asymptomatic, with normal
stooling and growth.
Fig. 1 H&E stain (×100). Representative example of a normal suction rectal biopsy with several
groups of ganglion cells seen in the submucosa.
Discussion
Aganglionosis of the appendix has long been considered to be an important finding
in a patient in whom total colonic aganglionosis (TCA) is suspected, but its reliability
for diagnosis has seldom been discussed.[1] Our literature review has revealed several cases where surgeons have been misled
by the histopathology.[1]
[2]
A similar case to ours was reported by Shih et al[1] in 1998, where the diagnosis of total colonic HD was made, on the basis of the appendix
histopathology, in a premature infant (30 weeks' gestation) with a birth weight of
1,140 g. The infant was reported to have had an “easy passage of meconium” and to
have “tolerated initial feeding,” but developed pneumoperitoneum on day 6 of life.
At the time of laparotomy, the infant was found to have an ileal perforation, 15 cm
proximal to the ileocecal valve. Another finding that the surgeon felt supported the
diagnosis of total colonic HD was a small-caliber colon distal to the perforation.
The appendix was resected and found to be aganglionic, which was felt to support the
presumed diagnosis of total colonic HD. No colonic biopsies were taken and an ileostomy
was formed. At the time of definitive surgery, as with our presented case, the distal
colon was found on repeat rectal biopsies to be ganglionic in its entirety.
In 1986, Anderson and Chandra reported a case of a newborn infant, who was managed
as total colonic HD, after the appendix was found to be aganglionic.[2] At the time of definitive surgery, further biopsies were taken, with the descending
and transverse colon being aganglionic; however, the ascending colon was found to
be ganglionic, suggesting that the child had long-segment HD. Following this case,
the group attempted to clarify the histopathologic findings of the appendix in children
with HD, by studying the appendix of 36 children with a known diagnosis of HD. The
number of ganglion cells (per ×10 power field) was compared with a control group of
children without HD. No ganglion cells were seen in the appendix of children with
total colonic HD. Children with rectosigmoid HD were found, however, to have on average
3.0 ganglion cells per high-power field (hpf) (range 0.5–5.1) in the appendix and
those with longer-segment disease had 2.2 cells/hpf (range 1.4–5.9). Their report
supported the presumption that children with total colonic HD have an aganglionic
appendix.
There is little published work, looking at ganglion histopathology of the normal appendix.
Over 40 years ago, Kamoshita and Landing recognized that it is often difficult to
find myenteric plexus nerve cells in sections of the appendix, in which the muscle
is thin and the size of the nerve population is proportionally small.[3] [Figs. 2] and [3] are both representative examples of a normal appendix and demonstrate that ganglion
cells may be seen in the myenteric plexus or in the submucosa alone. Another paper
concluded that the myenteric plexus in the human appendix consists of several distinct
networks, and appears to be unique in comparison with the other parts of the intestine.[4] Therefore the histopathology of the appendix cannot be assumed to be representative
of the small bowel and colon. Further attempts have been made to clarify the histopathologic
findings of the appendix; however, appendiceal specimens available for research purposes
tend to be those resected due to acute appendicitis in which the inflammatory process
itself can alter the histopathology.[5]
Fig. 2 H&E stain (×100). Appendix of a 5-week-old infant—normal appendix removed during
Ladd procedure. Ganglion cells in the myenteric plexus shown by the arrow. The muscularis
propria is indicated by the solid line. IML, inner muscular layer; OML, outer muscular
layer.
Fig. 3 H&E stain (×100). Appendix—ganglion cells along the outer submucosa shown at the
arrow. The muscularis propria is indicated by the solid line. IML, inner muscular
layer; OML, outer muscular layer.
In 2000, Xiong et al[6] published a study, looking at the status of the enteric nervous system in normal
and inflamed appendices. They looked at 10 appendices in those with histologically
proven appendicitis, 10 in those with clinically suspected but histologically normal
appendices, and 10 from patients undergoing elective abdominal surgery. This study
group identified an increased number of nerve fibers, Schwann cells and enlarged ganglia
widely distributed in the muscularis externa and submucosa in all 10 patients with
acute appendicitis, and in 4/10 of those with clinically suspected appendicitis. The
number and size of ganglia in the muscularis externa and in the submucosa of appendices
with acute appendicitis were significantly larger when compared with the control appendices.
In 2008, Singh et al[5] looked at the eosinophils, mast cells, nerves, and ganglion cells (in the mucosa,
submucosa, and muscularis propria) in a total of 329 appendices. In this study they
were able to examine the histopathologic features of the appendix in patients with
acute appendicitis (group A), clinically acute but histologically normal appendix
(group B), elective appendectomy (group C), and normal controls from medicolegal autopsies
(group D). They found a significantly higher number of mast cells and eosinophils
in the mucosa, submucosa, and muscularis propria in groups A and B compared with C
and D. The number of nerves and ganglion cells was significantly higher in group A
when compared with B, C, and D. This may suggest that the mast cells and eosinophils
cause pain in those with clinically apparent, but “histopathologically normal” appendicitis.
Interestingly, however, the changes seen in the number of ganglion cells in those
with histopathologically proven appendicitis (group A) make the use of the appendix
(in children with appendicitis) undergoing appendicectomy, for assessment of ganglion
cells in the appendix, problematic as this study suggests that inflammation may change
the histopathologic findings. Miller et al[7] have studied the distribution of enteric nerve cells and interstitial cells of Cajal
(ICC) in the normal human appendix and in type 1 diabetics (a group known to have
gastrointestinal motility disorders), and concluded that the appendix, a readily available
source of human tissue, may be useful in the study of human motility disorders. In
a subsequent review article, however, Knowles and De Giorgio acknowledge the ongoing
concerns about the reliability of the appendix histopathology being useful “in the
heterogeneous” repertoire of systemic diseases affecting the gut, and suggest that
the any histopathologic changes observed in idiopathic gastrointestinal motility disorders
will be subtle and probably not identifiable in the appendix,[8] although this has not been formally tested.
Previous studies have established that the appendix is a site at which aganglionosis
may be diagnosed. Appendiceal aganglionosis does not, however, equate with TCA in
all patients[9]
[10] as demonstrated in [Figs. 4] and [5]. [Fig. 4] is the histology from a child with confirmed TCA, and ganglion cells are seen in
the submucosa of the appendix specimen, whereas [Fig. 5] is a representative example of a child with TCA and aganglionosis of the appendix.
Fig. 4 H&E stain (×100). Appendix of a 4-day-old infant with total colonic Hirschsprung
disease (HD). Despite absence of ganglion cells in the entire colon, there were ganglion
cells in the submucosa of the appendix as shown by the arrows. The muscularis propria
is indicated by the solid line. IML, inner muscular layer; OML, outer muscular layer.
Fig. 5 H&E stain (×100). Appendix of a 3-day-old infant with total colonic Hirschsprung
disease (HD). No ganglion cells in the appendix. The normal location of the myenteric
plexus is designated by arrows. The muscularis propria is indicated by the solid line.
IML, inner muscular layer; OML, outer muscular layer.
To standardize the histopathologic methodology and reporting of specimens in gastrointestinal
neuromuscular pathology, an international working group published explicit histopathologic
guidelines for diagnosis in certain gastrointestinal diseases, including HD.[11] The guidelines stipulate that the appendix should not be used for the diagnosis
of total colonic HD, and that serial colonic biopsies should be examined before TCA
is histopathologically reported. Our case report is intended to reaffirm these guidelines,
although we support the notion that further research is required in the field.
