Colon nontumor
Congenital anomalies
Hirschsprung disease



Topic Completed: 1 May 2013

Revised: 8 October 2019

Copyright: (c) 2003-2018, PathologyOutlines.com, Inc.

PubMed Search: Hirschsprung disease[title]

Hanni Gulwani, M.B.B.S.
Page views in 2018: 11,664
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Cite this page: Gulwani H. Hirschsprung disease. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/colonhirschsprung.html. Accessed October 19th, 2019.
Definition / general
  • Caused by lack of parasympathetic ganglion cells in submucosal and myenteric plexus of part of colon, causing functional obstruction and colonic dilation proximal to affected segment (eMedicine)
Terminology
  • Also called congenital aganglionic megacolon
  • Classic: aganglionic portion begins in distal colorectum and extends a considerable distance proximally
  • Ultrashort segment: less than 2 cm affected in rectum and sigmoid; more common in boys; difficult to document because this portion of rectum typically lacks ganglion cells even in normals
  • Short segment: aganglionic portion involves rectum and rectosigmoid for only a few centimeters (Ann Saudi Med 2006;26:200)
  • Long segment: 10% of cases; involves 40 cm or more of colon, may extend into small bowel; patients have obstruction without megacolon; more common in girls; may lack hypertrophied nerve trunks, but do have increase in acetylcholinesterase+ nerve abnormalities
  • Zonal colonic aganglionosis: involvement of short segment of bowel; ganglion cells are present above and below this segment
  • Total colonic aganglionosis (TCA): uncommon; clinical, histologic, and genetic differences; more difficult to diagnose and manage (Arch Pathol Lab Med 2010;134:1467)
Epidemiology
  • Most sources: 1 in 5000 live births, some as low as 1 in 30,000
  • General agreement on male predominance (3 to 4.5:1)
  • Approximately 10% associated with Down syndrome
  • Up to 15% have other conditions
  • About 5% have neurologic abnormalities that may be serious
  • Associated with intestinal atresia and malrotation, anorectal malformations and other abnormalities of the GI tract
  • Also associated with tumors and other syndromes
  • 5% have a sibling with disease; familial cases have also been reported
  • Patients usually present in the immediate perinatal period; 80% present before their first birthday but up to 10% of cases are diagnosed in adulthood
Sites
  • Classic form: starts just proximal to pectinate line and extends proximally for a variable distance
  • Short segment form: aganglionic segment may be as short as 3 cm
  • Long segment form: aganglionic segment involves at least the entire rectum and sigmoid
  • Total colonic aganglionosis: entire large bowel lacks ganglia and variable length of small intestine is affected
  • Zonal colonic aganglionosis: ganglia are found distal to aganglionic segment
    • Some investigators believe zonal colonic aganglionosis is not true Hirschsprung disease but due to in utero injury
  • Approximately 90% of cases are classic or short segment type
Pathophysiology
  • Absence of parasympathetic ganglia causes a loss of intrinsic inhibitory innervation that leads to continuous contraction of the involved segment, as well as an inability of the affected segment to relax in response to a peristaltic wave
  • As the disease progresses, the bowel proximal to the aganglionic segment undergoes muscular hypertrophy and dilation
  • Normally, neural crest cells migrate into bowel, forming intestinal neural plexus; in Hirschsprung, usually are heterogeneous defects in genes regulating migration and survival of neuroblasts (endothelin 3 and its receptor, OMIM 600155), glial cell derived growth factor (neurogenesis) and receptor tyrosine kinase activity (RET, Ann Med 2006;38:11, Am J Pathol 2006;168:1262, OMIM 142623)
  • Altered distribution of Interstitial cells of Cajal may contribute to motility dysfunction (Arch Pathol Lab Med 2003;127:1192, Arch Pathol Lab Med 2002;126:928)
  • Altered cytoskeletal proteins (Arch Pathol Lab Med 2002;126:692)
  • Notch-1 / Jagged-2 also downregulated (Int J Colorectal Dis 2012;27:37)
  • May have features of distal peripheral nerve instead of ganglia (Hum Pathol 2005;36:1055)
  • Syndromic disease may be due to dysplastic enteric nervous system (Neuropathology 2006;26:8)
Etiology
  • The proximate cause is failure of migration of parasympathetic ganglia from the neural crest; however, several genetic abnormalities have been described
  • It is probably best regarded as a genetic disorder having a complex and poorly understood inheritance pattern involving at least 8 genes
  • The RET protooncogene appears to play a prominent role in many cases and dozens of RET mutations have been described (Histol Histopathol 2013;28:1117)
  • Increased MHC class II antigens have been found in the aganglionic segment and some investigators believe that in some cases, the disease may have an immune mediated component
Clinical features
  • Most common presentation is delayed passage of meconium associated with abdominal distension and anal tightness in the first 1 - 2 days of life
  • Children may have failure to thrive
  • Down syndrome patients more commonly have associated enterocolitis
  • Older patients may present with chronic constipation, abdominal distension, vomiting
  • 80% male; usually sporadic (1 per 5,000 live births); occurs in 4% of siblings of affected patients
  • 10% have Down syndrome; another 5% have other serious neurologic impairment
  • Always affects rectum, usually also sigmoid, not other segments; anus and rectum usually small and devoid of stool
  • Symptoms: failure to pass meconium, obstructive constipation; may have occasional passage of stool or diarrhea if short segment of rectum affected
  • Complications: proximal innervated colon may become massively distended (15 cm in diameter) with muscular wall hypertrophy and rupture / perforation, usually near cecum or appendix; also acute intestinal obstruction, enterocolitis with fluid and electrolyte imbalance
  • Mortality: currently 5 - 10%
Diagnosis
  • Mucosal rectal biopsy with serial sections to detect ganglion cells (more irregular in submucosal plexus but process is less invasive than classic method of full thickness rectal biopsy; further identify in frozen section stained with acetylcholinesterase (see below); other diagnostic tests are contrast enema and anorectal manometry (J Pediatr Gastroenterol Nutr 2006;42:496)
  • Variability in cholinergic innervation may contribute to false negatives and false positives (Pediatr Dev Pathol 2008;11:274)
  • Classic method: biopsy muscular wall of rectum and examine for ganglion cells in myenteric plexus; should biopsy 2+ cm above anal valve in infants, 3+ cm in older children; if squamous epithelium present, must biopsy higher
  • Frozen sections: to document absence of ganglion cells and determine level of bowel transaction at surgery; also for acetylcholinesterase staining
Case reports
Treatment
  • Surgical: excision of aganglionic segment with a pull through procedure to achieve continence; successful in most cases
  • Frozen section may be obtained during the procedure to determine where ganglionic segment begins but the accuracy of this technique is inferior to usual frozen section
    • Use of Giemsa, Diff-Quik, or toluidine blue stains in addition to routine H&E has been advocated to improve diagnostic accuracy at frozen section
  • Most patients are successfully treated
  • Treatment failures may have abnormal ganglion cells anastomosed to anorectum or subsequently develop aganglionosis
Clinical images

Images hosted on other servers:

Slide tray

Gross description
  • Normal anus but small rectum and anal canal without stool, dilated proximal bowel
Gross images

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Dilated bowel

Microscopic (histologic) description
  • There is a complete absence of ganglia in both Meissner submucosal plexus and Auerbach myenteric plexus
  • Ganglia in newborns are smaller than in older children and nucleoli and Nissl substance may be lacking, a situation even more pronounced in premature infants
  • Ganglia near the junction of the ganglionic and aganglionic segment may be decreased in number or be small with abnormal staining patterns
  • Associated nerve hypertrophy is a helpful clue but is not diagnostic
  • No / reduced myenteric and muscular interstitial cells of Cajal in rectosigmoid colon
  • Thickening and hypertrophy of nonmyelinated nerve fibers and muscularis mucosa
  • Stercoral ulcers (sharply demarcated shallow ulcers with mucosal inflammation due to pressure of feces on obstructed colon)
  • Fibromuscular dysplasia of arteries between normal and diseased colon
  • Hypoganglionosis: arises between normal and aganglionic bowel; reduced number of ganglion cells (such as 10% of normal)
Microscopic (histologic) images

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Lack of ganglion cells

Increased acetylcholine positive nerve fibers

Hyperplastic nerves but no ganglion cells


Reduced interstitial cells of Cajal

Suction rectal biopsy specimen

Frozen sections

Segment of ileum and colon

Ganglion cells


Various images

Normal colon - calretinin+

Calretinin expression

Transitional zone - calretinin+

Normal ganglion cells: sympathetic ganglion cells

Positive stains
  • Several techniques have been advocated to improve diagnostic accuracy and improve speed of diagnosis but there is controversy in the literature about their utility
  • Acetylcholinesterase positive fibers in lamina propria and muscularis mucosa
  • Neuron specific enolase to identify ganglia
  • RET oncoprotein in ganglion cells (Am J Clin Pathol 2006;126:49)
  • Acetylcholinesterase (increase in staining in lamina propria and muscularis mucosa reflects increase in nerve fibers, Pediatr Surg Int 2005;21:255)
Negative stains
Electron microscopy description
  • Altered cytoskeletal proteins in affected colon
Differential diagnosis
  • Chronic idiopathic pseudo-obstruction
  • Enteric hypoganglionosis syndromes
  • Hyperplasia of myenteric plexus: may occur secondary to inflammation in idiopathic inflammatory bowel disease or neurofibromatosis
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