Intestinal Neuronal Dysplasia-Like Submucosal Ganglion Cell Hyperplasia at the Proximal Margins of Hirschsprung Disease Resections

Abstract

Intestinal neuronal dysplasia type B (IND) denotes an increased proportion of hyperplastic submucosal ganglia, as resolved histochemically in 15 µm-thick frozen sections. IND has been reported proximal to the aganglionic segment in patients with Hirschsprung disease (HSCR) and is putatively associated with a higher rate of post-surgical dysmotility. We have developed and validated histological criteria to diagnose IND-like submucosal ganglion cell hyperplasia (IND-SH) in paraffin sections, and used the approach to study the incidence and clinical/genetic associations of IND-SH at the proximal margins of HSCR pull-through resection specimens. Full-circumference paraffin sections from the proximal margins of 64 HSCR colonic pull-through specimens and 24 autopsy controls were immunostained for the neuron-specific Hu antigen and nucleated ganglion cells in each submucosal ganglion were counted. In controls, an age-related decline in the relative abundance of “giant” ganglia (≥7 nucleated Hu+ ganglion cells) was observed. A conservative diagnostic threshold for IND-SH (control mean + 3 times the standard deviation) was derived from 15 controls less than 25 weeks of age. No control exceeded this threshold, whereas in the same age range, IND-SH was observed at the proximal margins in 15% (7/46) of HSCR resections, up to 15 cm proximal to the aganglionic segment. No significant correlation was observed between IND-SH and length of or distance from the aganglionic segment, gender, trisomy 21, RET or SEMA3C/D polymorphisms, or clinical outcome, but analysis of more patients with better long-term follow-up will be required to clarify the significance of this histological phenotype.

Pediatric enteric neuropathies: diagnosis and current management

“…In the latter scenario, it has been proposed to cause persistent obstructive symptoms after pullthrough surgery [12] but whether this is true is debated. [13] IND remains a controversial entity, with some suggesting that its histologic features are secondary to chronic obstruction rather than a primary cause of constipation. Regardless, treatment is similar to that of chronic constipation, with some severe cases requiring surgery, including sphincterotomy, diverting colostomy, or colectomy.…”

Intestinal neuronal dysplasia type B: A still little known diagnosis for organic causes of intestinal chronic constipation

“…The most recent study on this subject was from Gálvez et al [62] (2004) who identified histopathological changes suggestive of INDB in some adult rats in a model of chronic colonic obstruction. An association between INDB and HD has also been reported [8,35,6365] . In such cases, the segments proximal to the aganglionic obstructed segment present histological characteristics of INDB [6,54] .…”

“…IND proximal to a segment of aganglionosis is not uncommon and has been suggested to be a possible cause of persistent bowel problems after surgery for HD. This association may occur in 6% to 44% of HD patients [5,28,34,35] .…”

Intestinal Neuronal Dysplasia Type B: An Updated Review of a Problematic Diagnosis

“…One formalin-fixed, paraffin-embedded approach to assess IND B-like submucosal ganglion cell hyperplasia was published by Swaminathan and colleagues 24 in 2014. Ganglion cell bodies were immunolabeled with an antibody specific for the Hu C/D antigen, which specifically and robustly localizes to the cell bodies of all enteric neurons.…”

“…This may be one reason for the age-related decline in submucosal ganglion size during infancy and early childhood. 24,25 In the context of these dynamic changes in ganglionic morphology, section thickness will also affect ganglion cell counts, and therefore must be standardized.…”