Gastrointestinal Neuromuscular Pathology: Guidelines for Histological Techniques and Reporting on Behalf of the Gastro 2009 International Working Group
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Acta Neuropathol (2009) 118:271–301 DOI 10.1007/s00401-009-0527-y CONSENSUS PAPER Gastrointestinal neuromuscular pathology: guidelines for histological techniques and reporting on behalf of the Gastro 2009 International Working Group Charles H. Knowles Æ Roberto De Giorgio Æ Raj P. Kapur Æ Elisabeth Bruder Æ Gianrico Farrugia Æ Karel Geboes Æ Michael D. Gershon Æ John Hutson Æ Greger Lindberg Æ Joanne E. Martin Æ William A. Meier-Ruge Æ Peter J. Milla Æ Virpi V. Smith Æ Jean Marie Vandervinden Æ Be´la Veress Æ Thilo Wedel Received: 22 January 2009 / Revised: 19 March 2009 / Accepted: 22 March 2009 / Published online: 10 April 2009 Ó Springer-Verlag 2009 Abstract The term gastrointestinal neuromuscular dis- abnormalities have been demonstrated by a variety of ease describes a clinically heterogeneous group of methods in these conditions, standards for histopatholo- disorders of children and adults in which symptoms are gical reporting remain relatively neglected. Significant presumed or proven to arise as a result of neuromuscular, differences in methodologies and expertise continue to including interstitial cell of Cajal, dysfunction. Such dis- confound the reliable delineation of normality and speci- orders commonly have impaired motor activity, i.e. slowed ficity of particular pathological changes for disease. Such or obstructed transit with radiological evidence of transient issues require urgent clarification to standardize acquisition or persistent visceral dilatation. Whilst sensorimotor and handling of tissue specimens, interpretation of findings and make informed decisions on risk-benefit of full-thick- ness tissue biopsy of bowel or other diagnostic procedures. Electronic supplementary material The online version of this Such information will also allow increased certainty of article (doi:10.1007/s00401-009-0527-y) contains supplementary material, which is available to authorized users. C. H. Knowles Á J. E. Martin K. Geboes Neurogastroenterology Group, Centres for Academic Surgery Department of Pathology, University Hospital KUL, and Pathology, Institute of Cellular and Molecular Science, Minderbroedersstraat 12, 3000 Louvain, Belgium Barts and the London School of Medicine and Dentistry, Queen Mary University London, London, Whitechapel, UK M. D. Gershon Anatomy and Cell Biology Faculty, Columbia University R. De Giorgio Medical Center, 630 West 168th Street, New York, Department of Clinical Medicine, NY 10032, USA Alma Mater Studiorum University of Bologna, Bologna, Italy J. Hutson R. P. Kapur Urology Departments, Royal Children’s Hospital, Department of Pathology, Seattle Children’s Hospital, University of Melbourne and General Surgery, University of Washington, 4800 Sand Point Way NE, Parkville, VIC, Australia Seattle, WA 98105, USA G. Lindberg E. Bruder Á W. A. Meier-Ruge Department of Medicine, Karolinska Institutet, Institute of Pathology, University Hospital Basel, Karolinska University Hospital Huddinge, Stockholm, Sweden Schoenbeinstrasse 40, 4031 Basel, Switzerland P. J. Milla E. Bruder UCL Institute of Child Health, 30 Guilford Street, Department of Pathology, University Hospital Zurich, London WC1N 1EH, UK Schmelzbergstrasse 12, 8091 Zurich, Switzerland V. V. Smith G. Farrugia Department of Histopathology, Camelia Botnar Hospital, Enteric NeuroScience Program, Division of Gastroenterology Great Ormond Street Hospital NHS Trust, and Hepatology, Mayo Clinic College of Medicine, Great Ormond Street, London WC1N 3JH, UK 200 First Street SW, Rochester, MN 55905, USA 123 272 Acta Neuropathol (2009) 118:271–301 diagnosis, facilitating factual discussion between patients Introduction and caregivers, as well as giving prognostic and therapeutic information. The following report, produced by an inter- The term gastrointestinal neuromuscular disease (GINMD) national working group, using established consensus [85] describes a clinically heterogeneous group of disorders methodology, presents proposed guidelines on histological of children and adults in which symptoms are presumed or techniques and reporting for adult and paediatric gastro- proven to arise as a result of neuromuscular (including intestinal neuromuscular pathology. The report addresses interstitial cell of Cajal and perhaps glial cell) dysfunction the main areas of histopathological practice as confronted [31, 32, 48, 92]. It is accepted that neuromuscular dys- by the pathologist, including suction rectal biopsy and full- function may also arise as a consequence of interactions thickness tissue obtained with diagnostic or therapeutic with other cells such as those of the immune system. intent. For each, indications, safe acquisition of tissue, Common to most types of GINMD are symptoms of histological techniques, reporting and referral recommen- impaired motor activity which manifest as slowed or dations are presented. obstructed transit [166] with or without radiological evi- dence of transient or persistent visceral dilatation. Such Keywords Enteric neuropathy Á Enteric myopathy Á diagnoses include primary and secondary disorders from Interstitial cells of Cajal Á Histopathology Á oesophagus to colon, e.g. achalasia, gastroparesis, intesti- Hirschsprung disease Á Suction rectal biopsy Á nal pseudo-obstruction and severe constipation. Intestinal pseudo-obstruction Pathologic abnormalities of the enteric neuromusculature have been demonstrated by a variety of methods for 70 years Abbreviations [164]. However, despite calls for standardization dating AChE Acetylcholinesterase back to the 1960s [41], standards for the characterization and CIPO Chronic intestinal pseudo-obstruction classification of most gastrointestinal neuromuscular GINMD Gastrointestinal neuromuscular disease pathology (GINMP) remained relatively neglected with GINMP Gastrointestinal neuromuscular pathology previous attempts at consensus confined to specific areas of H&E Haematoxylin and eosin paediatric practice [25, 93, 133]. Apart from excluding major HSCR Hirschsprung disease structural abnormalities, many pathologists abandon even IBS Irritable bowel syndrome meagre efforts to make specific diagnoses. ICC Interstitial cells of Cajal The diagnosis of gastrointestinal neuromuscular IELs Intraepithelial lymphocytes pathology requires adequate morphological study of the IHC Immunohistochemistry different components of the enteric neuromuscular and IND Intestinal neuronal dysplasia ancillary cells. Whilst clear abnormalities such as absence IWG International working group of neuronal cell bodies in ganglia or fibrosis in smooth NOTES Natural orifice transluminal endoscopic surgery muscle cells can be identified by routine histology, other NSE Neuron specific enolase lesions such as reduced or increased numbers of neuronal PAS Periodic acid-Schiff cell bodies may require more elaborate study. The correct PGP 9.5 Protein gene product 9.5 interpretation of pathological findings furthermore depends SRB Suction rectal biopsy upon the age of the patient, duration of symptoms and TEM Transmission electron microscopy underlying or associated abnormalities, as well as the dis- crimination of artefacts from disease [98]. Extraordinary J. M. Vandervinden variability exists in current histopathological techniques Laboratory of Neurophysiology, Faculty of Medicine, used for the study of tissues from patients with suspected Universite´ Libre de Bruxelles, route de Lennik 808, GINMP with wide differences in methodologies and 1070 Brussels, Belgium expertise continuing to confound the significance and B. Veress reliability of a variety of reported histopathological chan- Department of Clinical Pathology and Cytology, ges in terms of clear delineation from normality, specificity University Hospital MAS, Lunds University, Malmo¨, Sweden for, and/or causation of disease. For instance in a recent T. Wedel survey of practice, 86 out of 130 European and US histo- Anatomisches Institut, Christian-Albrechts-Universita¨t zu Kiel, pathology labs processed tissue for suspected GINMP, but Otto-Hahn-Platz 8, 24118 Kiel, Germany only 33 performed more than a single H&E section. Of those that did more specialized tests, none did exactly the C. H. Knowles (&) Centre for Academic Surgery, Royal London Hospital, same tests [107]. Although there have been many studies 3rd Floor Alexandra Wing, London E1 1BB, UK published from experts in the field, most have their own e-mail: [email protected] favoured protocols and techniques, which may be 123 Acta Neuropathol (2009) 118:271–301 273 inaccessible or impractical for general pathology labora- on observations that: (1) distinctions between clinically tories (see comments below). Whilst some report has based disorders are sometimes rather arbitrary with sig- widespread agreement for a particular methodology, pub- nificant overlap regardless of system employed [36, 166] lished consensus in this area does not exist. Clarification of and (2) reported histopathological phenotypes frequently these issues is needed urgently to: overlap several clinical diagnoses, even though the final histological opinion is always given in the clinical context. • standardize acquisition and handling of tissue speci- The report does not aim to establish normal values, but mens, and interpretation of findings, rather suggests standards that might result in the estab- • better understand underlying disease mechanisms and lishment of normal values that would be applicable across thus increase the possibility of development of effective centres. It also avoids extensive discussion of mechanistic (directed/targeted)