The upper gastrointestinal tract consists of oesophagus, stomach, and duodenum. These are distinct from one another histologically. The lining of the oesophagus consists mainly of non-keratinising stratified squamous epithelium, and there is a variable amount of columnar epithelium distally. The stomach has three main histological regions, which from proximal to distal are the cardia, the body/fundus, and the antrum. All of these regions include surface epithelial cells that extend downwards into foveolae. Beneath the foveolae are a short isthmic zone and a deeper glandular layer. In the body/fundus, the glandular layer is thicker and the glands are more closely packed than in the antrum. Parietal cells and chief cells are the main component of the body/fundus glands while in the antrum they are sparse. The gastric cardia is a short segment that usually lacks parietal and chief cells. In the normal state, columnar mucosa extends from the stomach upwards into the distal oesophagus for a variable length. In contrast, Barrett’s oesophagus is pathological replacement of the distal oesophageal mucosa by metaplastic columnar mucosa that may be gastric or intestinal. The duodenal mucosa includes villi and crypts, both lined by columnar absorptive cells. Other epithelial cell types include goblet cells and Paneth cells. Endocrine cells are present at all sites but are difficult to identify and sparse in the oesophagus.

The lower gastrointestinal tract consists of ileum, vermiform appendix, colon, and rectum. The main epithelial cell types are absorptive cells, goblet cells, Paneth cells, and endocrine cells. Structurally the ileum resembles the duodenum, and includes villi and crypts. Gut-associated lymphoid tissue plays an important role in immune defence and has focal and diffuse elements in the small bowel. Lymphoid tissue is particularly prominent in the most distal part of the ileum. The mucosa of the large bowel is less complex than that of the small bowel, with parallel crypts and a smooth surface. In the normal colorectal mucosa, the density of plasma cells is highest in the upper one third and lowest in the lower one third. Eosinophilia in the ileum and large bowel is difficult to diagnose unless numbers are greatly increased. There may be a few neutrophils in the normal lamina propria but intraepithelial neutrophils are very infrequent. Apoptosis is a normal finding but the number of well-developed crypt epithelial cell apoptosis should be small. The intraepithelial lymphocyte count in the ileum is 0–9 per 100 surface epithelial cells and in the colon 0–5 per 100. Knowledge of the range of normality is important and helps pathologists to avoid overdiagnosis of inflammatory changes and of neoplasia.