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Can we stop looking? Immunohistochemistry and the diagnosis of Hirschsprung disease.

The enteric nervous system (ENS) is essential for normal motility and many other physiologic properties of the gastrointestinal tract.1 It is composed of intrinsic neurons, the cell bodies and most processes of which are located inside the bowel wall, and extrinsic nerve fibers that project into the gut from autonomic and sensory ganglia. Although extrinsic innervation modulates the activity of intrinsic neurons, the latter are necessary and sufficient for the complex reflexes pathways that ensure peristaltic activity. Intrinsic neurons of the ENS are located in the ganglia of two interconnected myenteric and submucosal nerve plexuses. Nerves in both plexuses are a mixture of intrinsic and extrinsic fibers and specialized enteric glial cells. Enteric nerves are ultrastructurally distinct from the central and nonenteric peripheral nervous systems. They project to many sites in all layers of the bowel wall, including the muscularis propria, muscularis mucosa, and lamina propria. Congenital intestinal aganglionosis, or Hirschsprung disease, is a malformation of the ENS, in which the obligate diagnostic feature is absence of intrinsic ganglion cells from the distal rectum and a variable length of contiguous bowel.2 It affects an estimated 1:5,000 liveborns and enters into the clinical differential diagnosis for infants, children, and adults with severe and/or chronic constipation. Dysmotility is due to constriction of the aganglionic segment, which requires intrinsic innervation to relax. In addition to absent intrinsic ganglion cells, other malformations of the ENS are usually present in the aganglionic rectum of the patient with Hirschsprung disease. Perhaps the most striking and diagnostically useful finding is the presence of hypertrophic nerve fibers in the myenteric and submucosal plexuses. The diameters of normal submucosal nerves are less than 40 μm. In contrast, 90% of suction rectal biopsies from patients with Hirschsprung disease contain nerves with diameters of 40 μm or greater.3 These hypertrophic nerves represent extrinsic fibers, primarily from pelvic autonomic ganglia. They are ultrastructurally and immunohistochemically similar to extrinsic nerves that exist normally in the mesentery and serosa, and which adopt an “enteric” phenotype when they merge with the intrinsic innervation. In aganglionic bowel, small branches from hypertrophic nerves distribute to the muscularis propria and mucosa4 but do not express synaptic proteins or other antigens that characterize the normal intrinsic innervation of these targets.5-7