title: 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 postsurgical dysmotility. We 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 and/or 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 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-positive [Hu+] ganglion cells) was observed. A conservative diagnostic threshold for IND-SH (control mean ± 3× 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 of 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, sex, 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.
authors.affiliation: 1 Department of Laboratories, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Swaminathan
authors.affiliation: 1 Department of Laboratories, Seattle Children's Research Institute, Seattle, WA 98101, USA.
authors.forename: Assaf P
authors.initials: AP
authors.lastname: Oron
authors.affiliation: 3 Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Sumantra
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: 4 Children's Health, University of Texas Southwestern, Dallas, TX 75390, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Piper
authors.affiliation: 5 Cook Children's Medical Center, Fort Worth, TX 76104, USA.
authors.forename: Sandy
authors.initials: S
authors.lastname: Cope-Yokoyama
authors.affiliation: 3 Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Aravinda
authors.initials: A
authors.lastname: Chakravarti
authors.affiliation: 1 Department of Laboratories, Seattle Children's Research Institute, Seattle, WA 98101, USA.|2 Department of Pathology, University of Washington, Seattle, WA 98101, USA.
authors.forename: Raj P
authors.initials: RP
authors.lastname: Kapur
mesh_terms: D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D002452:Cell Count; D003082:Colectomy; D003106:Colon / Q000294:innervation* / Q000473:pathology / Q000601:surgery; D051959:ELAV Proteins / Q000032:analysis; D017615:Enteric Nervous System / Q000473:pathology*; D005260:Female; D006627:Hirschsprung Disease / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D007231:Infant, Newborn; D007410:Intestinal Diseases / Q000235:genetics / Q000473:pathology*; D008297:Male; D009422:Nervous System Diseases / Q000235:genetics / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D016612:Paraffin Embedding; D011237:Predictive Value of Tests; D015203:Reproducibility of Results
chemical_list: D015415:Biomarkers; D051959:ELAV Proteins
keywords: Hirschsprung; hyperganglionosis; neuronal dysplasia; observer bias; transition zone