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Terra SA, Gonçalves AC, Lourenção PLTDA, Rodrigues MAM. Challenges in the diagnosis of intestinal neuronal dysplasia type B: A look beyond the number of ganglion cells. World J Gastroenterol 2021; 27:7649-7660. [PMID: 34908804 PMCID: PMC8641051 DOI: 10.3748/wjg.v27.i44.7649] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/26/2021] [Accepted: 11/11/2021] [Indexed: 02/06/2023] Open
Abstract
Intestinal neuronal dysplasia type B (IND-B) is a controversial condition among gastrointestinal neuromuscular disorders. Constipation is its most common clinical manifestation in patients. Despite intense scientific research, there are still knowledge gaps regarding the diagnostic criteria for IND-B in the histopathological analysis of rectal biopsies. The guidelines published in the past three decades have directed diagnostic criteria for quantifying the number of ganglion cells in the nervous plexus of the enteric nervous system. However, it is very complex to distinguish numerically what is pathological from what is normal, mainly because of the difficulty in determining a reliable control group composed of healthy children without intestinal symptoms. Thus, a series of immunohistochemical markers have been proposed to assist in the histopathological analysis of the enteric nervous system. Several of these markers facilitate the identification of other structures of the enteric nervous system, in addition to ganglion cells. These structures may be related to the etiopathogenesis of IND-B and represent new possibilities for the histopathological diagnosis of this disease, providing a view beyond the number of ganglion cells. This review critically discusses the aspects related to the disease definitions and diagnostic criteria of this organic cause of constipation.
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Affiliation(s)
- Simone Antunes Terra
- Department of Pathology, Faculty of Medicine, São Paulo State University (UNESP), Botucatu 18618687, São Paulo, Brazil
| | - Anderson Cesar Gonçalves
- Department of Surgery and Orthopedics, Botucatu Medical School - São Paulo State University (UNESP), Botucatu 18618970, São Paulo, Brazil
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Yoshimaru K, Matsuura T, Yanagi Y, Obata S, Takahashi Y, Kajihara K, Ohmori A, Irie K, Hino Y, Shibui Y, Tamaki A, Kohashi K, Oda Y, Taguchi T. Reevaluation of concurrent acetylcholinesterase and hematoxylin and eosin staining for Hirschsprung's disease. Pediatr Int 2021; 63:1095-1102. [PMID: 33417724 DOI: 10.1111/ped.14596] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 12/23/2020] [Accepted: 01/06/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Acetylcholinesterase (AChE) histochemistry has been widely performed for the histopathological diagnosis of Hirschsprung's disease (HD). However, we occasionally come across diagnostic difficulties. We conducted concurrent AChE histochemistry and hematoxylin and eosin (HE) staining to validate the ancillary value of this technique. METHODS Of 177 patients diagnosed using AChE histochemistry from January 2014 to December 2016, 90 patients underwent formalin-fixed paraffin-embedded HE staining. The histopathological findings and diagnostic abilities were investigated and compared retrospectively. RESULTS The sensitivity, specificity, accuracy, and kappa index of AChE histochemistry and HE staining were 94.1%, 100%, 98.9%, and 0.964 and 76.5%, 84.9%, 83.3%, and 0.530, respectively. The specificity, accuracy and kappa index of AChE histochemistry were significantly higher than those of HE staining (P < 0.001, <0.001, and <0.05). Hematoxylin and eosin staining supported the suspected diagnosis of total colon aganglionosis at the initial biopsy; furthermore, HE staining helped confirm the distinct shape of ganglion cells and hypertrophic nerve bundles. CONCLUSION We re-confirmed that AChE histochemistry is an excellent method for diagnosing HD. Although the diagnostic ability of HE staining is limited, it has acceptable utility as an ancillary method. Thus, AChE staining is a useful test and it should be performed together with HE staining.
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Affiliation(s)
- Koichiro Yoshimaru
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Toshiharu Matsuura
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yusuke Yanagi
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Satoshi Obata
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshiaki Takahashi
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keisuke Kajihara
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Atsuko Ohmori
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keiko Irie
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuko Hino
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuichi Shibui
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akihiko Tamaki
- Department of Pediatric Surgery, Reproductive and Developmental Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenichi Kohashi
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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3
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Zhou T, Liu W, Yu X, Cao Z, Mu W, Hou P, Ren C, Li A. Aberrant Development of Enteric Glial Cells in the Colon of Hirschsprung's Disease. Front Pediatr 2021; 9:746274. [PMID: 34805043 PMCID: PMC8602875 DOI: 10.3389/fped.2021.746274] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Accepted: 10/08/2021] [Indexed: 12/22/2022] Open
Abstract
Objective: The aim of this study was to explore the development of enteric glial cells (EGCs) in different segments of Hirschsprung's disease (HSCR). Methods: Colonic specimens from 35 children with HSCR were selected to analyze the relative expression of glial fibrillary acidic protein and S100 calcium-binding protein B using Western blotting and real-time fluorescence quantitative PCR. Immunofluorescence and immunohistochemical staining were performed to determine the distribution of myenteric EGCs and neuronal cells in different segments of HSCR. Results: There was a trend of diminished protein and mRNA expression of glial fibrillary acidic protein and S100 calcium-binding protein B from the proximal, dilated, and transitional segments to the aganglionic segment (p < 0.05). Immunofluorescence and immunohistochemistry showed that the EGCs in the aganglionic, transitional, and dilated colonic muscles were morphologically abnormal, which was consistent with the dysplasia of myenteric neurons. Conclusion: Aberrant development of myenteric EGCs was observed in the colon of HSCR, which may affect the survival of enteric neurons.
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Affiliation(s)
- Tingting Zhou
- Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wei Liu
- Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xiaofang Yu
- Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zengcai Cao
- Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Weijing Mu
- Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Peimin Hou
- Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chuantao Ren
- Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Department of Pediatric Surgery, Dezhou People's Hospital, Dezhou, China
| | - Aiwu Li
- Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
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Kapur RP, Reyes-Mugica M. Intestinal Neuronal Dysplasia Type B: An Updated Review of a Problematic Diagnosis. Arch Pathol Lab Med 2018; 143:235-243. [DOI: 10.5858/arpa.2017-0524-ra] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Context.—
Intestinal neuronal dysplasia type B (IND B) is a controversial histopathologic phenotype that has been associated with intestinal dysmotility, either as an isolated condition or in conjunction with established pathologic disorders (eg, Hirschsprung disease). Many factors contribute to the debate over the existence and/or clinical significance of IND B, including a large body of published data based on inconsistent diagnostic criteria and methods, which have fostered many unwarranted conclusions that lack sufficient scientific basis.
Objective.—
To critically analyze existing published data regarding IND B to provide supporting evidence-based diagnostic practice and to stimulate necessary and scientifically sound research.
Data Sources.—
This update focuses on published literature related to the pathology of IND B because without a reliable pathologic diagnosis, studies of epidemiology, pathogenesis, natural history, management, and outcome are all suspect. Problems with existing data are identified explicitly with suggestions as to how future investigations should be designed and evaluated to better understand this entity.
Conclusions.—
Inconsistencies in diagnostic criteria and methods used to define IND B justifiably encumber the universal acceptance of IND B as a neuropathologic etiology for intestinal dysmotility. IND B will remain a controversial diagnosis until rigorous, well-controlled scientific studies are conducted to establish reproducible and reliable diagnostic criteria that reliably translate from one laboratory to another.
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Affiliation(s)
- Raj P. Kapur
- From the Department of Laboratories, Seattle Children's Hospital, Seattle, Washington (Dr Kapur); the Department of Pathology, University of Washington School of Medicine, Seattle (Dr Kapur); and the Department of Pathology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Dr Reyes-Mugica)
| | - Miguel Reyes-Mugica
- From the Department of Laboratories, Seattle Children's Hospital, Seattle, Washington (Dr Kapur); the Department of Pathology, University of Washington School of Medicine, Seattle (Dr Kapur); and the Department of Pathology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania (Dr Reyes-Mugica)
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Muto M, Matsufuji H, Taguchi T, Tomomasa T, Nio M, Tamai H, Tamura M, Sago H, Toki A, Nosaka S, Kuroda T, Yoshida M, Nakajima A, Kobayashi H, Sou H, Masumoto K, Watanabe Y, Kanamori Y, Hamada Y, Yamataka A, Shimojima N, Kubota A, Ushijima K, Haruma K, Fukudo S, Araki Y, Kudo T, Obata S, Sumita W, Watanabe T, Fukahori S, Fujii Y, Yamada Y, Jimbo K, Kawai F, Fukuoka T, Onuma S, Morizane T, Ieiri S, Esumi G, Jimbo T, Yamasaki T. Japanese clinical practice guidelines for allied disorders of Hirschsprung's disease, 2017. Pediatr Int 2018; 60:400-410. [PMID: 29878629 DOI: 10.1111/ped.13559] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 02/27/2018] [Accepted: 03/07/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Despite the presence of ganglion cells in the rectum, some patients have symptoms similar to those of Hirschsprung's disease. A consensus has yet to be established regarding the terminology for these diseases. We defined this group of diseases as "allied disorders of Hirschsprung's disease" and compiled these guidelines to facilitate accurate clinician diagnosis and provide appropriate treatment strategies for each disease. METHODS These guidelines were developed using the methodologies in the Medical Information Network Distribution System (MINDS). Of seven allied disorders, isolated hypoganglionosis; megacystis-microcolon-intestinal hypoperistalsis syndrome; and chronic idiopathic intestinal pseudo-obstruction were selected as targets of clinical questions (CQ). In a comprehensive search of the Japanese- and English-language articles in PubMed and Ichu-Shi Web, 836 pieces of evidence related to the CQ were extracted from 288 articles; these pieces of evidence were summarized in an evidence table. RESULTS We herein outline the newly established Japanese clinical practice guidelines for allied disorders of Hirschsprung's disease. Given that the target diseases are rare and intractable, most evidence was drawn from case reports and case series. In the CQ, the diagnosis, medication, nutritional support, surgical therapy, and prognosis for each disease are given. We emphasize the importance of full-thickness intestinal biopsy specimens for the histopathological evaluation of enteric ganglia. Considering the practicality of the guidelines, the recommendations for each CQ were created with protracted discussions among specialists. CONCLUSIONS Clinical practice recommendations for allied disorders of Hirschprung's disease are given for each CQ, along with an assessment of the current evidence. We hope that the information will be helpful in daily practice and future studies.
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Affiliation(s)
- Mitsuru Muto
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Hiroshi Matsufuji
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Tomoaki Taguchi
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Takeshi Tomomasa
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Masaki Nio
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Hiroshi Tamai
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Masanori Tamura
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Haruhiko Sago
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Akira Toki
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Shunsuke Nosaka
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Tatsuo Kuroda
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Masahiro Yoshida
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Atsushi Nakajima
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Hiroyuki Kobayashi
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Hideki Sou
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Kouji Masumoto
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Yoshio Watanabe
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Yutaka Kanamori
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Yoshinori Hamada
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Atsuyuki Yamataka
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Naoki Shimojima
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Akio Kubota
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Kosuke Ushijima
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Ken Haruma
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Shin Fukudo
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Yuko Araki
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Takahiro Kudo
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Satoshi Obata
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Wataru Sumita
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Toshihiko Watanabe
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Suguru Fukahori
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Yoshimitsu Fujii
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Yoshiyuki Yamada
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Keisuke Jimbo
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Fujimi Kawai
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Tomoya Fukuoka
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Shinsuke Onuma
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Toshio Morizane
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Satoshi Ieiri
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Genshiro Esumi
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Takahiro Jimbo
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
| | - Tomoko Yamasaki
- The guideline establishment group for allied disorders of Hirschsprung's disease, Science Research, Ministry of Health Labour and Welfare, Fukuoka, Japan
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Furukawa T, Takeuchi Y, Tanaka T, Yoshimaru K, Taguchi T, Tajiri T. Localized isolated hypoganglionosis in an infant. JOURNAL OF PEDIATRIC SURGERY CASE REPORTS 2018. [DOI: 10.1016/j.epsc.2017.09.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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7
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Terra SA, de Arruda Lourenção PL, G Silva M, A Miot H, Rodrigues MAM. A critical appraisal of the morphological criteria for diagnosing intestinal neuronal dysplasia type B. Mod Pathol 2017; 30:978-985. [PMID: 28304401 DOI: 10.1038/modpathol.2017.4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Revised: 01/03/2017] [Accepted: 01/03/2017] [Indexed: 01/23/2023]
Abstract
Intestinal neuronal dysplasia type B is a controversial entity expressed by complex changes in the enteric nervous system. Diagnosis depends on rectal biopsy histopathology and diagnostic criteria, both qualitative and quantitative, have changed over time, hindering the diagnostic practice. We analyzed the morphological criteria for the histological diagnosis of intestinal neuronal dysplasia type B in a series of patients with intestinal neuronal dysplasia type B according to the 1990 Frankfurt Consensus criteria and verified the applicability of the numerical criteria proposed by Meier-Ruge et al in 2004 and 2006. Qualitative criteria adopted for the histological diagnosis of intestinal neuronal dysplasia type B included hyperplasia of the submucous plexus with hyperganglionosis and hypertrophy of the nerve trunks. Quantitative criteria considered more than 20% giant ganglia in the submucosa, with more than eight neurons each on 25 ganglia, and children aged over 1 year. Distal colon surgical specimens from 29 patients, aged 0-16 years, diagnosed with intestinal neuronal dysplasia type B were retrospectively analyzed using sections processed for conventional histology (H&E) and calretinin immunohistochemistry. Hyperplasia of the submucosal nerve plexi with hyperganglionosis and hypertrophy of the nerve trunks was observed in all cases. Ganglia with small, immature neurons were detected in the majority of cases. Quantitative analysis confirmed hyperganglionosis (mean number=10.7 neurons per ganglion) and hypertrophy of the nerve trunks (median=44.6 μm thickness). Neurons showed immunostaining for calretinin, but neuron counts in calretinin-stained sections were lower compared with H&E (P<0.01). No significant differences were verified between children aged under and over 1 year regarding hyperganglionosis (P=0.79), neuron counts (P=0.36), and immature ganglia (P=0.66). Only one patient met the numerical criteria proposed by Meier-Ruge et al in 2004 and 2006. In conclusion, the numerical criteria showed limited applicability when transposed to conventional histopathology. Children aged over 1 year presented very similar histological features of neuronal immaturity to younger children, questioning the need for an age criterion when diagnosing intestinal neuronal dysplasia type B.
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Affiliation(s)
- Simone A Terra
- Department of Pathology, Botucatu School of Medicine, São Paulo State University (Unesp), Botucatu, Brazil
| | - Pedro L de Arruda Lourenção
- Department of Surgery, Division of Pediatric Surgery, Botucatu School of Medicine, São Paulo State University (Unesp), Botucatu, Brazil
| | - Márcia G Silva
- Department of Pathology, Botucatu School of Medicine, São Paulo State University (Unesp), Botucatu, Brazil
| | - Hélio A Miot
- Department of Pathology, Botucatu School of Medicine, São Paulo State University (Unesp), Botucatu, Brazil
| | - Maria A M Rodrigues
- Department of Pathology, Botucatu School of Medicine, São Paulo State University (Unesp), Botucatu, Brazil
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Immunostaining for Hu C/D and CD56 is useful for a definitive histopathological diagnosis of congenital and acquired isolated hypoganglionosis. Virchows Arch 2017; 470:679-685. [PMID: 28424865 DOI: 10.1007/s00428-017-2128-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 03/03/2017] [Accepted: 04/11/2017] [Indexed: 12/12/2022]
Abstract
Isolated hypoganglionosis (IHG) has been proposed as a distinct entity with two subtypes: congenital IHG (CIHG) and acquired IHG (AIHG). However, due to the rarity of the disease and the lack of defining histological criteria, the concept of IHG is not widely accepted. We studied paraffin-embedded intestinal specimens from 79 patients diagnosed with Hirschsprung's disease (HD) (n = 49), CIHG (n = 25), and AIHG (n = 5) collected between January 1996 and December 2015. Histopathological diagnosis of HD, CIHG, and AIHG was confirmed by hematoxylin and eosin staining and immunohistochemical staining using Hu C/D and CD56. We evaluated (immuno)histopathological findings, counted the number of ganglion cells, and measured the size of Auerbach's plexus. Hu C/D labeled neuronal cell bodies, whereas CD56 was detected in all neuronal components. In HD, all ganglion cells in Auerbach's plexus in the normoganglionic segment (NGS) were immunoreactive for Hu C/D, whereas in the aganglionic segment (AGS), these were replaced by CD56-positive extrinsic nerve fibers and bundles. The number of ganglion cells in AIHG and CIHG was significantly lower than in the NGS of HD (p < 0.05). Auerbach's plexus was significantly smaller in CIHG (p < 0.05) but in AIHG equivalent to the NGS in HD. In summary, immunostaining for Hu C/D and CD56 is useful for definitive histopathological diagnosis of IHG.
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Chronic intestinal pseudo-obstruction: systematic histopathological approach can clinch vital clues. Virchows Arch 2014; 464:529-37. [DOI: 10.1007/s00428-014-1565-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2013] [Revised: 02/14/2014] [Accepted: 02/18/2014] [Indexed: 12/28/2022]
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Kim HK, Cheong H, Kang H, Bae JY, Song DE, Cho MS, Sung SH, Han WS, Koo H. Histopathological Evaluation of Pediatric Intestinal Pseudo-Obstruction: Quantitative Morphometric Analysis of Pathological Changes in the Enteric Nervous System. KOREAN JOURNAL OF PATHOLOGY 2010. [DOI: 10.4132/koreanjpathol.2010.44.2.162] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Affiliation(s)
- Hyung Kyung Kim
- Department of Pathology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Harin Cheong
- Department of Pathology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Hanna Kang
- Department of Pathology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Ji Yoon Bae
- Department of Pathology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Dong Eun Song
- Department of Pathology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Min Sun Cho
- Department of Pathology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Sun Hee Sung
- Department of Pathology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Woon Sup Han
- Department of Pathology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
| | - Heasoo Koo
- Department of Pathology, Ewha Medical Research Institute, Ewha Womans University School of Medicine, Seoul, Korea
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Abstract
AIM: To describe a new clinical and pathological subtype of microscopic colitis in children.
METHODS: A selected group of children with abdominal pain, constipation and/or diarrhoea showing discrete or no macroscopic abnormalities on endoscopy was described.
RESULTS: Multiple biopsies of colon showed large mononuclear clear cells in lamina propria of mucous membrane provided that good quality histological sections were performed and observed under a higher magnification. Otherwise, they could be misinterpreted as artefacts. Their presence in routine histology might suggest a systemic storage disease (Whipple’s disease), and neuronal intestine dysplasia. Using immunohistochemical staining and electron microscopy we confirmed their origin from CD68 positive mononuclear macrophages.
CONCLUSION: The presence of large clear cells is a constant microscopic feature. Failure of transient large bowel stationary macrophages plays a role in the pathogenesis of this benign microscopic clear cell colitis, sometimes coexisting with allergy.
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Li K, Zheng S, Xiao X, Wang Q, Zhou Y, Chen L. The structural characteristics and expression of neuropeptides in the esophagus of patients with congenital esophageal atresia and tracheoesophageal fistula. J Pediatr Surg 2007; 42:1433-8. [PMID: 17706510 DOI: 10.1016/j.jpedsurg.2007.03.050] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE The aim of this study was to investigate the structural characteristics and the expression of a group of neuropeptides in the esophagus of patients with congenital esophageal atresia and tracheoesophageal fistula (EA-TEF), as well to elucidate the roles of these neuropeptides in the pathogenesis of postoperative incoordination of esophagus after successful surgical repair of EA-TEF. METHODS Twenty-four specimens from distal tracheoesophageal fistulas of patients with EA-TEF (EA-TEF group) and 10 esophageal specimens from neonates who died of nonesophageal diseases (control group) were studied. All of the specimens were subjected to routine pathologic study, ultrastructural observation, and immunohistochemical staining for neuron-specific enolase, substance P, vasoactive intestinal polypeptide, and nitric oxide synthase. RESULTS In the EA-TEF group, mitochondria were distributed along the membrane of smooth muscle cell, whereas mitochondria in the control group were distributed along the karyotheca of the smooth muscle cells. The ratio of granulated vesicles to clear vesicles in the varicosity of the intramuscular motor nerve ending of the EA-TEF group (0.520 +/- 0.137) was much higher than that in the control group (0.192 +/- 0.020, P < .05). The percentages of specimens shown to have positive expression of neuron-specific enolase and substance P in the EA-TEF group (20.8% and 12.5%, respectively) were significantly lower than those in the control group (90% and 80% respectively, P < .05). The percentages of specimens shown to have positive expression of vasoactive intestinal polypeptide and nitric oxide synthase in the EA-TEF group (83.3% and 75%, respectively) were significantly higher than that in the control group (30% and 10% respectively, P < .05). CONCLUSION Imbalance of neurotransmitters excretion in nerve vesicle, abnormal intrinsic dysplasia of nerve plexus and increased expression of certain neuropeptides were the main characteristics of esophagus with abnormal intrinsic innervation, which may be responsible for the postoperative esophageal dysfunction of EA-TEF.
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Affiliation(s)
- Kai Li
- Department of Surgery, Children's Hospital, Medical Center of Fudan University (Former Shanghai Medical University), Shanghai 200032, PR China
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Abstract
Intramucosal ganglion cells are incompletely understood. Reviewed were 100 normal specimens from colorectal biopsies of nonconstipated adults to firmly establish the existence of intramucosal ganglion cells in normal adult colorectal mucosa, determine whether intramucosal giant ganglia exist, and compare the prevalence of colorectal intramucosal ganglion cells between men and women. Fifty specimens from each gender were examined. Twenty specimens contained intramucosal ganglion cells, including 15 from women (75%) and only 5 from men (25%). Intramucosal ganglion cells occurred singly or in clusters. One woman had large disciform and globular clusters with 7 ganglion cells, resembling giant ganglia. Awareness of ganglion cells and large ganglia in normal mucosa is necessary to avoid potential confusion with ectopic ganglion cells and submucosal giant ganglia seen in adult intestinal neuronal dysplasia. Intramucosal ganglion cells in normal colorectal mucosa are particularly common in women. This disparity might contribute to colorectal neurophysiologic differences between genders.
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Affiliation(s)
- Vonny Tunru-Dinh
- Department of Pathology and Laboratory Medicine, University of California Irvine School of Medicine, Irvine, California, USA
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Estevão-Costa J, Fragoso AC, Campos M, Soares-Oliveira M, Carvalho JL. An approach to minimize postoperative enterocolitis in Hirschsprung's disease. J Pediatr Surg 2006; 41:1704-7. [PMID: 17011273 DOI: 10.1016/j.jpedsurg.2006.05.041] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
BACKGROUND/PURPOSE Enterocolitis (EC) is a common and severe complication after pull-through for Hirschsprung's disease; its pathogenesis remains unclear, but the role of coexistent intestinal neuronal dysplasia (IND) in the proximal colon may be relevant. This study evaluated the relationship between postoperative EC and IND and assessed whether a surgical protocol including resection of coexistent IND could prevent postoperative EC. METHODS Between June 1993 and June 2002, 36 patients with aganglionosis were submitted to definitive surgical treatment. There were 2 sequential sets of patients: group I (n = 17), in whom the resection was confined to the aganglionic colon, and group II (n = 19), who were additionally submitted to resection of the coexistent IND segment; excision was restricted to the hepatic flexure in long segmental IND. The prevalence of postoperative EC and anorectal function were evaluated and compared between the 2 groups. RESULTS There was no mortality. Fifteen patients had isolated aganglionosis, and 21 presented with aganglionosis plus proximal IND. All 6 children who developed postoperative EC had coexistent IND. In group I, 9 patients had coexistent IND and 5 developed postoperative EC (5/17, 29%). In group II, 12 patients had coexistent IND but only 1 patient, with long segmental IND, developed postoperative EC (1/19, 5%). Among the patients with proximal IND, the prevalence of postoperative EC was 29%; but it was significantly lower in group II than in group I (1/12 or 8% vs 5/9 or 56%; P = .02). Anorectal function was excellent or good in more than 80% of the patients in both groups. CONCLUSIONS Postoperative EC was associated with retained proximal IND, suggesting that coexisting IND may be, at least, a predictive marker for this complication. Histochemical characterization of the proximal colon with no radical resection of the IND segment seems to be an effective and safe approach to minimize the prevalence of postoperative EC.
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Affiliation(s)
- José Estevão-Costa
- Division of Pediatric Surgery, Faculty of Medicine of Porto, Hospital S. João, 4200-319 Porto, Portugal.
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Matsuda H, Hirato J, Kuroiwa M, Nakazato Y. Histopathological and immunohistochemical study of the enteric innervations among various types of aganglionoses including isolated and syndromic Hirschsprung disease. Neuropathology 2006; 26:8-23. [PMID: 16521475 DOI: 10.1111/j.1440-1789.2006.00649.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
We investigated enteric innervations in 15 isolated and five syndromic cases of Hirschsprung disease (HSCR) with immunohistochemistry for the S100 protein (S100), class III a-tubulin (TUJ1), peripherin, neuronal nitric oxide synthase (nNOS) and CD34. The number of neurites per smooth muscle unit of the circular muscle layer (CML) was counted in the longitudinal sections. TUJ1 was the best marker to detect whole neuritic networks of the enteric nervous system. There were differences in the innervation patterns between isolated rectosigmoid aganglionosis (RS) and long segment aganglionosis (LS) including total colonic aganglionosis and extensive aganglionosis. In the aganglionic bowel (AGB) of LS, no nerve fibers innervated smooth muscle units in the CML in the area from the small bowel to the terminal descending colon. In the rectosigmoid region of every type of isolated HSCR, we observed transmural nerve fibers forming meshworks in the CML with TUJ1 and S100 antibodies. In RS, the neurites running parallel with smooth muscle cells gradually decreased in number in the distal portion. However, in the rectosigmoid AGB in LS, those neurites were absent and most neurites perpendicularly crossed the CML. Hypertrophic nerve trunks (HNT) in the submucous and myenteric plexuses were observed more frequently in the rectosigmoid region than in the rostral portion. Based on these data, it is suggested that the neuritic meshworks in the CML of the rectosigmoid AGB might derive from not only the sacral plexus, via HNT, but also intrinsic neurons in the oligoganglionic bowel. All of the syndromic HSCR were RS. In the AGB of RS with Down syndrome, the distribution of neurite meshworks in the CML is markedly reduced. In the AGB of RS with mental retardation suspected of having Mowat-Wilson syndrome, the density of intramuscular innervation was comparatively higher. In the rostral portion to the AGB of syndromic HSCR, myenteric ganglia were clearly small in size, and more numerous per smooth muscle unit with scarce internodal strands. These dysplastic features fall under neither hyperganglionosis nor hypoganglionosis classifications. We considered that syndromic HSCR might occur on the basis of a dysplastic enteric nervous system caused by genetic alteration.
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Affiliation(s)
- Hadzki Matsuda
- Department of Human Pathology, Gunma University Graduate School of Medicine, Maebashi, Japan
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Tou JF, Li MJ, Guan T, Li JC, Zhu XK, Feng ZG. Mutation of RET proto-oncogene in Hirschsprung’s disease and intestinal neuronal dysplasia. World J Gastroenterol 2006; 12:1136-9. [PMID: 16534860 PMCID: PMC4087911 DOI: 10.3748/wjg.v12.i7.1136] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the genetic relationship between Hirschsprung’s disease (HD) and intestinal neuronal dysplasia (IND) in Chinese population.
METHODS: Peripheral blood samples were obtained from 30 HD patients, 20 IND patients, 18 HD/IND combined patients and 20 normal individuals as control. Genomic DNA was extracted according to standard procedure. Exons 11,13,15,17 of RET proto-oncogene were amplified by polymerase chain reaction (PCR). The mutations of RET proto-oncogene were analyzed by single strand conformational polymorphism (SSCP) and sequencing of the positive amplified products was performed.
RESULTS: Eight germline sequence variants were detected. In HD patients, 2 missense mutations in exon 11 at nucleotide 15165 G→A (G667S), 2 frameshift mutations in exon 13 at nucleotide 18974 (18974insG), 1 missense mutation in exon 13 at nucleotide 18919 A→G (K756E) and 1 silent mutation in exon 15 at nucleotide 20692 G→A(Q916Q) were detected. In HD/IND combined patients, 1 missense mutation in exon 11 at nucleotide 15165 G→A and 1 silent mutation in exon 13 at nucleotide 18888 T→G (L745L) were detected. No mutation was found in IND patients and controls.
CONCLUSION: Mutation of RET proto-oncogene is involved in the etiopathogenesis of HD. The frequency of RET proto-oncogene mutation is quite different between IND and HD in Chinese population. IND is a distinct clinical entity genetically different from HD.
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Affiliation(s)
- Jin-Fa Tou
- Department of Pediatric Surgery, Children's Hospital, Medical College of Zhejiang University, Hangzhou 310003, Zhejiang Province, China
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Guan T, Li JC, Li MJ, Tou JF. Polymerase chain reaction-single strand conformational polymorphism analysis of rearranged during transfection proto-oncogene in Chinese familial hirschsprung’s disease. World J Gastroenterol 2005; 11:275-9. [PMID: 15633231 PMCID: PMC4205417 DOI: 10.3748/wjg.v11.i2.275] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between mutations of rearranged during transfection (RET) proto-oncogene and Chinese patients with Hirschsprung’s disease (HD), and to elucidate the genetic mechanism of familial HD patient at the molecular level.
METHODS: Genomic DNA was extracted from venous blood of probands and their relatives in two genealogies. Polymerase chain reaction (PCR) products, which were amplified using specific primers (RET, exons 11, 13, 15 and 17), were electrophoresed to analyze the single-strand conformational polymorphism (SSCP) patterns. The positive amplified products were sequenced. Forty-eight sporadic HD patients and 30 normal children were screened for mutations of RET proto-oncogene simultaneously.
RESULTS: Three cases with HD in one family were found to have a G heterozygous insertion at nucleotide 18974 in exon 13 of RET cDNA (18974insG), which resulted in a frameshift mutation. In another family, a heterozygosity for T to G transition at nucleotide 18888 in the same exon which resulted in a synonymous mutation of Leu at codon 745 was detected in the proband and his father. Eight RET mutations were confirmed in 48 sporadic HD patients.
CONCLUSION: Mutations of RET proto-oncogene may play an important role in the pathogenesis of Chinese patients with HD. Detection of mutated RET proto-oncogene carriers may be used for genetic counseling of potential risk for HD in the affected families.
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Affiliation(s)
- Tao Guan
- Department of Lymphology, Institute of Cell Biology, Zhejiang University Medical College, Hangzhou 310031, Zhejiang Province, China
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Yanai T, Kobayashi H, Yamataka A, Lane GJ, Miyano T, Hayakawa T, Satoh K, Kase Y, Hatano M. Acetylcholine-related bowel dysmotility in homozygous mutant NCX/HOX11L.1-deficient (NCX-/-) mice-evidence that acetylcholine is implicated in causing intestinal neuronal dysplasia. J Pediatr Surg 2004; 39:927-30. [PMID: 15185227 DOI: 10.1016/j.jpedsurg.2004.02.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND/PURPOSE Homozygous mutant Ncx/Hox11L.1-deficient (Ncx-/-) mice develop mega-ileo-ceco-colon (mega-ICC) with a caliber change in the proximal colon. The authors investigated the mechanism of intestinal dysmotility in these mice. METHODS Five-week-old Ncx-/- mice with mega ICC were compared with age-matched BDF1 control mice. Jejunum, ileum, and colon were excised from all mice and 1.0-cm-long strips of each organ, each with a resting tension of 0.5g, were suspended in an organ bath filled with Tyrode's solution at 37 degrees C and bubbled with a mixture of 95% oxygen and 5% carbon dioxide. Contractile responses to acetylcholine chloride (ACh), histamine, serotonin, and barium chloride (BaCl2) were recorded isometrically. RESULTS For ACh, Ncx-/- mice had decreased distal colon circular muscle contraction only at lower doses and decreased distal colon longitudinal muscle contraction for all doses compared with controls (P <.05 or P <.01). In the proximal colon, Ncx-/- mice had increased circular muscle contraction only at higher doses and decreased longitudinal muscle contraction only at lower doses compared with controls (P <.01 or P <.05). ACh did not affect jejunum, and there were no significant effects on ileum. There was no response to histamine and serotonin by any part of the bowel, and the response to BaCl2 was the same for both Ncx-/- mice and controls. CONCLUSIONS Only ACh differentially affected muscle contraction in Ncx-/- mice in the proximal and distal colon. Thus, ACh is implicated in causing the bowel dysmotility seen in Ncx-/- mice and human IND.
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Affiliation(s)
- Toshihiro Yanai
- Department of Pediatric Surgery, Juntendo University School of Medicine, Tokyo, Japan
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Abstract
Intestinal neuronal dysplasia is a rare cause of bowel obstruction in neonates and infants, the diagnosis of which poses a formidable challenge to both clinicians and pathologists alike. The importance of this entity lies not only in the fact that it mimics Hirschsprung's disease, but also in that untreated cases, particularly of type A, may prove fatal. The authors describe one such case of intestinal neuronal dysplasia of type A, which was diagnosed at autopsy.
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Affiliation(s)
- T Rajalakshmi
- Department of Pathology, St. John's Medical College, Bangalore, India
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Kapur RP. Neuronal dysplasia: A controversial pathological correlate of intestinal pseudo-obstruction. ACTA ACUST UNITED AC 2003; 122A:287-93. [PMID: 14518065 DOI: 10.1002/ajmg.a.20470] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The infant or child with intestinal pseudo-obstruction poses many challenges for geneticists and other specialists. Although a well-defined anatomic diagnosis (e.g., Hirschsprung disease) can be established for a subset of patients, the pathological correlates for many patients are non-existent or controversial. Intestinal neuronal dysplasia (IND) is frequently considered in the differential diagnosis, despite the fact that existence and significance of the abnormal histopathological features that characterize IND are hotly debated. This review highlights some of the concerns regarding this diagnosis including problems with the diagnostic criteria, the manner in which these criteria are applied in contemporary pathology practices, and the likelihood that many of the pathological findings are secondary consequences of impaired motility with no other clear clinical significance. Possible genetic and developmental bases for IND are also discussed.
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Affiliation(s)
- Raj P Kapur
- Department of Laboratories, Children's Hospital and Regional Medical Center, University of Washington, Seattle, Washington 98105, USA.
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