Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 21, 2015; 21(47): 13240-13249
Published online Dec 21, 2015. doi: 10.3748/wjg.v21.i47.13240
Histidine decarboxylase and urinary methylimidazoleacetic acid in gastric neuroendocrine cells and tumours
Apostolos V Tsolakis, Lars Grimelius, Göran Granerus, Mats Stridsberg, Sture E Falkmer, Eva T Janson
Apostolos V Tsolakis, Eva T Janson, Section of Endocrine Oncology, Department of Medical Sciences, Uppsala University, SE-75185 Uppsala, Sweden
Lars Grimelius, Section of Genetics and Pathology, Department of Immunology, Uppsala University, SE-75185 Uppsala, Sweden
Göran Granerus, Department of Medical and Health Sciences, Linköping University, SE-58183 Linköping, Sweden
Mats Stridsberg, Section of Biochemical Endocrinology, Department of Medical Sciences, Uppsala University, SE-75185 Uppsala, Sweden
Sture E Falkmer, Department of Pathology, Ryhov County Hospital, SE-55185 Jönköping, Sweden
Author contributions: Tsolakis AV, Grimelius L, Falkmer SE and Janson ET contributed to conception and design of the study; Tsolakis AV, Grimelius L, Granerus G, Stridsberg M, Falkmer SE and Janson ET contributed to acquisition, analysis and interpretation of data; Tsolakis AV, Grimelius L, Granerus G, Stridsberg M, Falkmer SE and Janson ET wrote and revised manuscript.
Supported by The Selander Foundation and the Foundation for Clinical Cancer Research in Jönköping.
Institutional review board statement: The research protocol was reviewed and approved by the local Research Ethics Board at Uppsala University Hospital.
Conflict-of-interest statement: The authors report no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Apostolos V Tsolakis, MD, PhD, Section of Endocrine Oncology, Department of Medical Sciences, Uppsala University, SE-75185 Uppsala, Sweden. apobtsol@hotmail.com
Telephone: +46-18-6114913 Fax: +46-18-553943
Received: April 8, 2015
Peer-review started: April 9, 2015
First decision: June 19, 2015
Revised: August 27, 2015
Accepted: September 13, 2015
Article in press: September 14, 2015
Published online: December 21, 2015
Processing time: 251 Days and 3.7 Hours
Abstract

AIM: To study histidine decarboxylase (HDC) expression in normal and neoplastic gastric neuroendocrine cells in relationship to the main histamine metabolite.

METHODS: Control tissues from fundus (n = 3) and corpus (n = 3) mucosa of six patients undergoing operations for gastric adenocarcinoma, biopsy and/or gastric surgical specimens from 64 patients with primary gastric neuroendocrine tumours (GNETs), as well as metastases from 22 of these patients, were investigated using conventional immunohistochemistry and double immunofluorescence with commercial antibodies vs vesicular monoamine transporter 2 (VMAT-2), HDC and ghrelin. The urinary excretion of the main histamine metabolite methylimidazoleacetic acid (U-MeImAA) was determined using high-performance liquid chromatography in 27 of the 64 patients.

RESULTS: In the gastric mucosa of the control tissues, co-localization studies identified neuroendocrine cells that showed immunoreactivity only to VMAT-2 and others with reactivity only to HDC. A third cell population co-expressed both antigens. There was no co-expression of HDC and ghrelin. Similar results were obtained in the foci of neuroendocrine cell hyperplasia associated with chronic atrophic gastritis type A and also in the tumours. The relative incidence of the three aforementioned markers varied in the tumours that were examined using conventional immunohistochemistry. All of these GNETs revealed both VMAT-2 and HDC immunoreactivity, and their metastases showed an immunohistochemical pattern and frequency similar to that of their primary tumours. In four patients, increased U-MeImAA excretion was detected, but only two of the patients exhibited related endocrine symptoms.

CONCLUSION: Human enterochromaffin-like cells appear to partially co-express VMAT-2 and HDC. Co-expression of VMAT-2 and HDC might be required for increased histamine production in patients with GNETs.

Keywords: Enterochromaffin-like cells; High performance liquid chromatography; Gastric neuroendocrine tumours; Histidine decarboxylase; Immunohistochemistry; Urinary excretion of the main histamine metabolite methylimidazoleacetic acid; Vesicular monoamine transporter 2

Core tip: It is suggested that only a fraction of vesicular monoamine transporter 2 (VMAT-2) immunoreactive neuroendocrine cells in human oxyntic mucosa co-express histidine decarboxylase (HDC), and vice versa, suggesting that the enterochromaffin-like (ECL) cells may not represent a homogeneous cell population when examined for HDC immunoreactivity. Co-expression of VMAT-2 and HDC might be important for giving rise to increased histamine production in patients with ECL cell neuroendocrine tumours. Furthermore, an increase of urinary excretion of the main histamine metabolite methylimidazoleacetic acid was not always associated with hormonal symptoms. This result could be attributed to the rate of histamine release. A sudden rapid release will cause a flush, whereas a slower release will not.