Histidine decarboxylase and urinary methylimidazoleacetic acid in gastric neuroendocrine cells and tumours

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; Gastric neuroendocrine tumours; High performance liquid chromatography; Histidine decarboxylase; Immunohistochemistry; Urinary excretion of the main histamine metabolite methylimidazoleacetic acid; Vesicular monoamine transporter 2.

Figure 1

Histidine decarboxylase (A) and vesicular monoamine transporter 2 (B) immunostained type I enterochromaffin-like cell neuroendocrine tumour (consecutive sections). Only a few scattered histidine decarboxylase (HDC)-immunoreactive cells are present in the tumour, whereas virtually all neoplastic cells display VMAT-2 immunoreactivity. Bars = 50 μm (A, B).

Figure 2

Co-localization studies. A: Normal human oxyntic mucosa double-immunostained for vesicular monoamine transporter 2 (VMAT-2) (green) and histidine decarboxylase (HDC) (red). Co-localization (yellow) depicts that VMAT-2 and HDC are co-expressed in the same neuroendocrine cell, whereas the remaining immunoreactive (IR) cells in the gastric glands do not display co-expression; B: Oxyntic mucosa adjacent to a type I enterochromaffin-like (ECL) cell neuroendocrine tumour (NET) double immunostained for VMAT-2 (green) and HDC (red). In one focus of neuroendocrine cell hyperplasia identified by VMAT-2 (linear pattern), only a fraction of cells co-express HDC (yellow), whereas another is non-IR for the enzyme; C: Oxyntic mucosa adjacent to a type I ECL cell NET double immunostained for VMAT-2 (green) and HDC (red). The HDC-IR cells display a linear pattern of neuroendocrine cell hyperplasia and do not co-express the transporter protein. In the foci of nodular cell hyperplasia identified by VMAT-2, no cell is HDC-IR. Adjacent tumour cells (T) reveal only VMAT-2 immunoreactivity; D: A malignant type III ECL cell NET accompanied by increased U-MeImAA excretion was double-immunostained for VMAT-2 (green) and HDC (red). Co-localization (yellow) shows that the tumour cells that are HDC-IR co-express the transporter protein. VMAT-2-IR cells slightly outnumber the HDC-IR cells. Bars = 30 μm (A, C, D); 20 μm (B).