The Nonneoplastic Stomach

The Nonneoplastic Stomach

Kevin Turner

Robert M. Genta



The stomach develops from a fusiform foregut swelling at approximately 4 weeks’ gestation. It originates in the neck and descends into the abdomen over the next 8 weeks. The enlarging thoracic contents push the stomach caudally. The gastric curvature develops during the 6th to 7th fetal week. Simultaneously, the dorsal stomach subsequently merges with and lengthens the greater curvature. The stomach rotates 90 degrees to the left. In the 9th week, a diverticulum appears in the upper stomach, from which the greater curvature lies to the left, and the distal end becomes anchored by a short ventral mesentery, the bile duct, and the vitelline artery (1).

Gastric development is more complex than other parts of the gut due to the different epithelial types that populate various areas of the stomach. These areas constitute a complex epithelial system organized in a highly structured, continually renewing architecture. Embryonal differentiation is regulated via several signaling cascades, an important one of which starts with the transcription factor sonic hedgehog (Shh), which binds to its receptor patched (Ptc). The Shh signaling system helps maintain normal gastric glandular architecture (2). Shh is expressed in parietal cells, and its receptor Ptc is present in chief cells (3).

The stomach is initially lined by stratified or pseudostratified epithelium that is later replaced by cuboidal cells. As secretions accumulate, droplets and vacuoles coalesce to form the gastric lumen. The first differentiated cell type to appear is the mucous neck cell, which acts as a progenitor for the other cell types. Gastric pits are well developed by 5 to 7 weeks’ gestation. Gastric glands begin to develop at 11 to 14 weeks (1); they grow by progressively branching, a process that continues until birth. Parietal cells appear by 9 to 11 weeks (Fig. 4.1). Endocrine cells begin to appear at the 2nd week of fetal life; a full spectrum of endocrine cells is present by week 11. Mesoderm surrounding the stomach differentiates into the gastric connective tissue and the muscularis propria by the end of the 2nd fetal month. The muscularis mucosae forms by the 20th week.


The stomach lies intraperitoneally, extending from the lower end of the esophagus at the Z line at the level of the 11th thoracic vertebrae, crossing to the right of the midline, and ending in the duodenum. The opening that connects the esophagus to the stomach is known as the cardiac orifice; the opening from the stomach to the intestine is known as the pyloric orifice. The stomach has two curvatures: The greater curvature, the inferior border of the stomach, is convex in shape, extending from the gastroesophageal junction to the duodenum. It is more freely movable than the lesser curvature. The concave lesser curvature is the upper margin of the stomach. The size and shape of the usually J-shaped stomach (Fig. 4.2) depends on body position and the degree of filling. Its anterior surface abuts the abdominal wall and the inferior surface of the left lobe of the liver. Posteriorly, it abuts the pancreas, splenic vessels, left kidney, and adrenal gland. The lesser curvature is suspended from the inferior aspect of the liver by the hepatogastric ligament and the lesser omentum. The greater omentum extends caudally from the greater curvature. The gastric fundus touches the dome of the left diaphragm, and the upper left margin of the greater omentum rests against the spleen to which it is attached by the gastrosplenic ligament.

The stomach has four layers: mucosa, submucosa, muscularis propria, and serosa (Fig. 4.3). The gastric wall is slightly firm but pliable and, with the exception of the pylorus, usually does not measure more than 0.5 cm in thickness. The stomach is often divided into four anatomic regions: cardia, fundus, body, and antropyloric region (Fig. 4.4). The cardia, a narrow, ill-defined region, is not grossly distinctive and is identified histologically by the presence of cardiac glands. Its anatomy is discussed in Chapter 2. The fundus is that
portion of the gastric body that protrudes over a horizontal line drawn from the esophagogastric junction (Fig. 4.4). It blends into the gastric body, which constitutes most of the stomach. The body is demarcated from the distal portion, called the pyloric antrum, by a notch in the lesser curvature, the incisura angularis. Numerous longitudinal, grayish pink mucosal folds (called rugae) lie parallel to the lesser curvature (Fig. 4.5) and characterize the mucosa of the gastric body.

FIG. 4.1 Gastric mucosa of a 10-week-old fetus. A: Medium power showing the presence of a well-defined lumen lined by columnar epithelial cells with primitive glands. The muscularis mucosae is just beginning to form. B: Higher magnification showing the presence of parietal cells (arrows).

FIG. 4.2 Unopened stomach demonstrating its classic J shape. Esophagus and duodenum are also present.

FIG. 4.3 Full-thickness section of the normal stomach. The four layers are easily discerned.

FIG. 4.4 Diagram of the four anatomic and three histologic regions of the stomach. The depths of the gastric pits (red) and the glandular composition are different in the various areas of the stomach. The color of the glands corresponds to the color of the anatomic regions. The histology of the glands differs in the pink, green, and blue areas. The gastric pits are similar (red) throughout the entire stomach.

FIG. 4.5 Gastric rugae. When the normal stomach is opened, the rugae appear as coarse folds of the mucosa.

The triangularly shaped antrum occupies the distal third of the stomach proximal to the pyloric sphincter extending further along the lesser curvature (5 to 8 cm) than along the greater curvature (6 cm) (4). The antrum is more firmly anchored to the underlying submucosa than the remainder of the stomach. A greatly thickened distal muscular wall forms the pyloric sphincter. A narrow lumen passes through the pyloric sphincter. The pyloric canal, or pyloric channel, measures 2.5 cm in length. The various gastric zones are not fixed anatomic entities; their extent varies between individuals, with age, and with disease processes.

The gastric muscularis propria differs from that of the rest of the gastrointestinal (GI) tract in that it consists of muscle fibers oriented in three different directions: the outer
longitudinal, the middle circular, and the inner oblique layer. Only the middle circular layer is complete. It is the strongest of the three muscle layers, and it becomes hypertrophic proximally and distally at the sphincters. The pyloric musculature consists of two layers: a thick inner circular layer and a thin outer longitudinal layer. The muscularis mucosae consists of two or three muscle layers.

The stomach has a rich blood supply that derives from the celiac, hepatic, and splenic arteries. Mucosal capillaries lie beneath the epithelium. The capillary networks drain into subepithelial venules, which converge into submucosal veins. Venous drainage is through the portal system to the liver. Right and left gastric veins drain the lesser curvature. The left gastric vein arises on the anterior and posterior gastric surfaces. Esophageal veins enter before it reaches the portal vein. Venous drainage from the anterior and posterior surfaces of the antropyloric region forms the right gastric vein, which empties directly into the portal vein. The abundant blood supply explains why gastric ischemia is unusual and why gastric hemorrhages are so life threatening.

Gastric lymphatic distribution resembles that of the colon. Lymphatics are absent from the superficial mucosa but are present in the deep interglandular region (5). They converge into thicker channels piercing the muscularis mucosae and enter the larger submucosal plexus. From there, they drain into the lymphatic plexus between the inner and outer layers of the muscularis propria (5). The lymphatic distribution generally follows that of the main arteries and veins. Gastric lymphatics drain into numerous lymph nodes situated in chains along the greater and lesser curvatures, the cardia, and the splenic hilum. There are four drainage areas. The largest drainage area comes from the lower esophagus and most of the lesser curvature (Fig. 4.6). It follows the left gastric artery and drains into the left gastric lymph nodes. The pylorus drains to the right gastric and hepatic lymph nodes (Fig. 4.6). Lymphatics from the cardia drain into pericardial lymph nodes surrounding the gastroesophageal junction, and efferent channels from the left gastric lymph nodes drain into the celiac lymph nodes. The proximal greater curvature drains into the pancreaticosplenic lymph nodes in the splenic hilum. The distal greater curvature drains into the right gastroepiploic lymph nodes in the greater omentum and to the pyloric lymph nodes at the pancreatic head. The pyloric portion of the lesser curvature drains into the right gastric lymph nodes, which then drain into hepatic nodes located along the course of the common hepatic artery. Efferents from all four lymph node groups ultimately pass to the celiac nodes around the main celiac axis.

FIG. 4.6 Regional gastric lymph node drainage. The node groups are perigastric nodes (1-6), left gastric (7), along the splenic artery (10,11), along the hepatoduodenal ligament (12), para-aortic (9,16), and intra-abdominal nodes (8,13-15).

The stomach is innervated by sympathetic and parasympathetic components of the autonomic nervous system as well as by the peptidergic neural system. The parasympathetic nerve supply derives from the vagus and its branches. Numerous neuropeptides produced and released from nerve fibers in the stomach wall regulate gastric function (6).

A thin translucent serosa (the visceral peritoneum) invests the outer portion of the stomach. The serosa normally appears pink-tan, smooth, and glistening.

Normal Gastric Histology

Histologically, the stomach contains three major epithelial compartments: the gastric pits and surface lining, the mucous neck region, and the glands. The nature and relative thickness of the glands and pits (Fig. 4.4) define each gastric zone. Foveolar (or surface) epithelium lines the entire gastric surface and short, straight, narrow gastric pits (foveolae) that lie parallel to one another. Gastric glands empty into the bottom of the pits. The stomach is divided into the cardiac, oxyntic, and pyloric areas based on its glandular components. The oxyntic mucosa, which secretes acid and pepsinogen, occupies the proximal 80% of the stomach, including the mucosa of the body and fundus. It is thicker than the cardiac and pyloric mucosa due to the presence of specialized acid-secreting glands. Fundic gastric pits are shorter than elsewhere, occupying only 25% of the mucosal thickness (Fig. 4.4). The antropyloric mucosa constitutes the distal 20% of the stomach and contains mucus-secreting glands and endocrine cells. Cardiac mucosa extends distally from the lower esophagus. Transitional zones between the different areas are gradual, and junctional mucosa showing mixed histologic features commonly measures up to 1 cm in width. Each of the gastric epithelial cell types produces a specific cell product (Table 4.1).

Surface Epithelium (Foveolar Epithelium)

Tall, columnar, foveolar epithelium covers the entire gastric mucosa. It consists of a single layer of mucus- and bicarbonate-secreting cells with irregular, basally situated nuclei
and a single inconspicuous nucleolus (Figs. 4.7 and 4.8). Ovoid, spherical, mucin-containing, membrane-bound granules pack the supranuclear cytoplasm. The mucin stains strongly with the periodic acid-Schiff (PAS) stain (Fig. 4.9); it is negative or only weakly positive with mucicarmine stains. Numerous spot desmosomes and gap junctions maintain intercellular communication between the surface mucous cells, regulate cell differentiation (7), and help maintain mucosal barrier integrity. The surface mucous cells are produced in the mucous neck region, migrate upward, and extrude from the surface.


Cell Type


Surface cells

Mucin, carbonic anhydrase, TGF-&agr;, EGFR

Mucous neck cells

Mucin, pepsinogens, weak lipase, TGF-&agr;

Parietal cells

HCl, intrinsic factor, carbonic anhydrase, TGF-&agr;, cathepsins

Chief cells

Pepsinogen, carbonic anhydrase, lipase

Endocrine cells

Numerous hormones (see Chapter 17)

Cardiac and antral cells

Mucin, proteinases, cathepsins, lysozymes

EGFR, epithelial growth factor receptor; TGF-&agr;, transforming growth factor-&agr;.

Gastric Glands

The three types of gastric glands are fundic, cardiac, and pyloric glands. Cardiac and antral glands contain mucin and are compared in Table 4.2. The cardiac mucosa is discussed in detail in Chapter 2. Both cardiac and pyloric glandular cells have ill-defined borders and a bubbly vesicular cytoplasm containing neutral mucin. Unlike foveolar cells, the mucin fills the basal cytoplasm displacing and flattening the nuclei. Pyloric glands contain two major cell types: tall columnar cells, which secrete neutral mucin, and scattered endocrine cells. Rare parietal and chief cells may also be present. The oxyntic mucosa characteristically contains long, tightly packed oxyntic glands and short foveolae. In contrast
to cardiac and pyloric glands, oxyntic glands are straight rather than coiled. Up to three gastric glands empty into the base of a gastric pit. Oxyntic mucosa contains six different cell types: surface foveolar cells, isthmus mucous cells, parietal cells, mucous neck cells, chief cells, and endocrine cells (Fig. 4.10). The gland neck contains undifferentiated, mucous neck, and parietal cells; the glandular bases contain parietal, chief, and endocrine cells.

FIG. 4.7 Mucus-secreting foveolar cells cover the gastric surface and line the upper gastric pits.

FIG. 4.8 Lining of the gastric pits. Variably mature foveolar cells populate the pits. The mucinous contents increase in size as the cells progress toward the surface. Foveolar epithelia characteristically have basal nuclei with supranuclear mucin collections.

FIG. 4.9 Alcian blue-periodic acid-Schiff stain of cardia.





Neutral mucin

Neutral mucin


Coiled, occasionally branched, loosely packed

Coiled, extensively branched, more compact than cardiac glands

Lamina propria


Less abundant than cardiac glands

Cell types

Tall columnar mucinous cells, some endocrine cells

Tall columnar mucinous G cells, enterochromaffin cells

Cystic dilation

May be present

Usually absent

Gastric pits

Length variable up to 50% of mucosa

One third of the mucosal height

Mucous Neck Cells

Mucous neck cells reside in the neck and isthmic region of the gastric glands (Fig. 4.11). They are continuous with, and resemble, foveolar epithelium, but they contain fewer cytoplasmic mucous granules. They derive from mitotically active stem cells in the neck region. These tall, irregularly shaped cells with basal nuclei produce acid glycoproteins, which differ from the neutral mucins secreted by foveolar epithelium. Mucous neck cells may be difficult to recognize in routine sections, but they can be highlighted using a PAS stain. The major function of mucous neck cells is mucosal proliferation and regeneration. However, mitoses are rare unless regeneration is occurring.

FIG. 4.10 A: Normal oxyntic mucosa. The lower portion of the photograph contains densely packed oxyntic glands containing chief cells, parietal cells, and endocrine cells. B: Higher magnification showing the plump eosinophilic parietal cells and basophilic chief cells.

Parietal Cells

Parietal cells constitute approximately one third of the cells in oxyntic glands. They arise from progenitor cells in the lower isthmus and slowly migrate down into the deeper parts of the gland. Intermediate forms exist between immature and mature parietal cells. Parietal cells are easily identifiable by their large size, pyramidal shape, central nuclei, and intensely eosinophilic or clear cytoplasm (Fig. 4.10). Their tapered apical ends tend to bulge into the glandular lumen, whereas their broader basal surfaces rest against the basement membrane. Parietal cells produce hydrochloric acid, intrinsic factor, transforming growth factor alpha (TGF-&agr;), and cathepsins B and H. In the nonsecretory state, an extensive closed system of smooth membranes, the tubulovesicular system, occupies the cytoplasm adjacent to intracellular canaliculi. Stimulation of acid secretion causes the tubulovesicles to fuse with the canaliculi and the apical secretory membrane, resulting in up to a 40-fold expansion of the apical membrane area. The microvilli become more prominent (8). The canaliculi derive from the smooth endoplasmic reticulum and contain the hydrogen ion pump, a unique H+, K+-ATPase that exchanges H+ for K+ across the apical membrane (9). When acid secretion is inhibited, the situation
reverses. The canaliculi collapse, the microvilli recede, and cytoplasmic tubulovesicular structures become prominent again as the cell returns to its resting state.

FIG. 4.11 Mucous neck cells. A: High magnification of the mucous neck region showing the presence of tall cells lacking the differentiated features of either foveolar epithelium or underlying glandular epithelium. Mitoses are absent. B: Ki 67 immunostaining showing the proliferative nature of this region.

The basolateral membranes of parietal cells carry receptors for histamine, gastrin, and acetylcholine (Fig. 4.12). Ligand binding to these receptors stimulates hydrogen ion secretion into the lumen and bicarbonate ions into the interstitium. There is a simultaneous appearance of pathways for K+ and Cl movement coordinated with exchange of H+ for K+ powered by the proton pump located in the membranes. Basolateral uptake of chloride by parietal cells is mediated by an HCO3 Cl anion exchange mechanism (9).

Chief Cells

Chief (zymogenic) cells arise from isthmic stem cells. These triangular low columnar cells contain a coarsely granular, pale gray-blue, basophilic cytoplasm with one or more small nucleoli (Fig. 4.10). Chief cells constitute 20% to 26% of oxyntic glands lying deep within them. The basal cytoplasm contains an extensive rough endoplasmic reticulum, which appears as a striated basophilic region. Chief cells produce lipase and pepsinogen, the pepsin precursor. Pepsinogen secretion is stimulated by the same agents that stimulate acid secretion. Secretory granules form in the Golgi complex and are released by exocytosis. Zymogenic cells degenerate via necrosis or apoptosis. Apoptotic cells are phagocytosed by neighboring zymogenic cells or by lamina propria
macrophages that break through the basement membrane of oxyntic glands.

FIG. 4.12 Parietal cells have various receptors along their basolateral membranes. These include those for histamine, prostaglandin, acetylcholine, and gastrin. Ligands bind their respective receptors and activate protein kinases through cyclic adenosine monophosphate (cAMP). The process involves calcium ions. These events result in cellular secretion of H+ ions. ATP, adenosine triphosphate.

FIG. 4.13 Low magnification of a normal antrum.

Antral and Pyloric Glands

In the antral and pyloric region, the pits occupy approximately 40% of the mucosa. These branch and may not always lie perpendicular to the surface. The deep mucosa contains coiled tubular glands that are lined by faintly granular mucin-secreting cells, often resembling mucous neck cells (Fig. 4.13).

Endocrine Cells

The stomach contains a prominent and diverse endocrine cell population that is discussed further in Chapter 17.

Gastric Transitional Zones

Gastric transitional zones are the junctional zones between the different types of mucosae: cardia/body, body/antrum, and antrum/duodenum. These are dynamic areas that involve a gradual merging of mucosal types so that it may be difficult to determine the exact location of each of the transitional zones. The antral/body transitional zone is usually located approximately two fifths of the way along the lesser curvature; on the greater curvature, it is closer to the pylorus (4). The most useful criteria to determine when one crosses from body into antrum are the absence of chief cells, the appearance of gastrin-producing G cells, and the change from single tubular glands in the body to branched glands in the antrum (10). It may be difficult to determine the site of origin of the gastric mucosa, particularly when it is altered by inflammation, atrophy, and/or metaplasia. In particular, it is often difficult to differentiate between a nonatrophic antral gastritis and an atrophic body gastritis with pyloric metaplasia.

Lamina Propria and Mononuclear Cells

The surface, pits, and glands are supported by a well-developed lamina propria that contains a fine reticulin meshwork with occasional collagen and elastic fibers condensed beneath epithelial basement membranes and blood vessels. The lamina propria is more abundant in the superficial mucosa between the pits than in the lower mucosa. It contains numerous cell types including fibroblasts, macrophages, plasma cells, and lymphocytes. The lymphocytes are predominantly immunoglobulin (Ig) A-producing B cells. IgG- and IgM-secreting cells are also present. Intraepithelial T lymphocytes are present, but they are much less frequent than in the small bowel. These may have a perinuclear halo superficially resembling endocrine cells. There are also a small number of lamina propria T cells, neutrophils, and mast cells. Lymphoid follicles suggest the diagnosis of chronic gastritis. The lamina propria also contains capillaries, arterioles, and nonmyelinated nerve fibers.

Lymphatics appear in the deep lamina propria adjacent to and within the muscularis mucosae. The upper and mid-lamina propria lacks lymphatics. In contrast, the entire mucosa contains a rich supply of capillaries, many of which lie adjacent to the basal lamina of the gastric glands and surface epithelium.

Neuromuscular Relationships

The muscularis mucosae varies from 30 to 200 &mgr;m in thickness. It becomes hyperplastic and extends into the overlying mucosa in certain conditions as discussed later. The muscularis propria consists of smooth muscle cells and contains nerve fibers and a myenteric plexus. There are also interstitial cells of Cajal (ICC), which have contacts with each other and with the smooth muscle cells and nerve endings in the muscularis propria (11). They lie in the myenteric plexus and in the circular muscle (11). They serve as gastric pacemakers. ICC are discussed in more detail in Chapter 10.


The serosa, the outermost gastric layer, consists of connective tissue and a mesothelial lining continuous with the peritoneum.

Gastric Physiology

The stomach exhibits major motor, secretory, digestive, hormonal, and mucosal barrier functions, some of which will be briefly summarized here.

Mucosal Barrier

One of the incredible facets of gastric physiology is that the acid-containing stomach is able to withstand the detrimental effects of its intraluminal contents. In order to do this, a complex mucosal cytoprotection system has evolved that protects the stomach without inhibiting gastric acid secretion. Mucosal defenses include pre-epithelial, epithelial,
and postepithelial mechanisms (Fig. 4.14). Adherent mucus provides a stable unstirred layer that supports surface neutralization of acid by mucosal bicarbonate and acts as a permeability barrier to luminal pepsin (12). (Surface mucus is hydrophobic and water repellent). Surface-active phospholipids are produced by mucous neck cells and parietal cells. Parietal cells pump one HCO3 ion across the basal membranes for every H+ they secrete into the canaliculi (13). HCO3 is picked up by mucosal capillaries and carried to the basal part of surface foveolar cells. The bicarbonate ions are then secreted into the overlying mucous layer, where they are trapped by glycoproteins in the mucus, increasing the pH in the unstirred layer from approximately pH 2.0 in the gastric lumen to approximately 7.0 at the mucosal surface. This creates a pH gradient that traps and neutralizes most hydrogen ions as they enter the unstirred mucous layer (6). Maintenance of the pH gradient depends on both the secretion rate of bicarbonate and the thickness of the mucous gel layer (14). Mucus also lubricates the stomach facilitating food movement along the gastric lining, without causing mucosal abrasions. Its glycoproteins play a major role in resistance to injury by maintaining the viscoelastic and permeability properties of the mucous gel. Foveolar cells secrete lipid into the mucus that coats the epithelium lining the gastric lumen with a nonwettable surface, protecting the mucosa against the action of water-soluble H+ and pepsin (15) (pepsin can destroy the polymeric structure of this glycoprotein layer, solubilizing the surface mucous gel and liberating degraded glycoprotein subunits into the gastric lumen).

FIG. 4.14 Mucosal defenses. A mucous layer that contains a pH gradient overlies the surface epithelium. Bicarbonate ions are pumped into this layer along with lipids secreted by the lining epithelium. The epithelium is bound together by intercellular tight junctions. The epithelial cells lie on an intact basement membrane and produce the epidermal growth factor (EGF) and transforming growth factor-&agr; (TGF-&agr;). The underlying blood supply in the lamina propria brings bicarbonate to the surface-lining cells from the parietal cells where it was produced. The mucosal blood flow also brings oxygen and nutrients. Prostaglandins (PGs) are made within the stroma. The stroma contains antioxidants such as glutathione. Pep, pepsin.

An adequate mucosal blood flow is critical to maintaining the mucosal barrier since it brings oxygen and nutrients to the luminal surface and removes hydrogen ions from the same region (16). The autonomic nervous system, peptidergic nerves (16), nitric oxide (17), prostaglandins (18), epidermal growth factor (EGF), and TGF-&agr; all regulate mucosal blood flow. Interruption of the mucosal blood flow results in decreased intramucosal pH and ulceration. Junctional complexes, basolateral membranes, and the basal lamina are also major structural components of the gastric mucosal barrier (19). Cytoprotectants (prostaglandins, immunoglobulins, sulfhydryl donors such as glutathione, and neuropeptides) are also naturally present in the gastric mucosa (18,20). Prostaglandins aid in mucosal protection (18) by mediating mucus and bicarbonate secretion, inhibiting acid secretion, regulating mucosal blood flow, maintaining surface-active phospholipids, and mediating the protective actions of EGF and TGF-&agr; (21). Prostaglandins also modulate the inflammatory response by inhibiting release of tumor necrosis factor (TNF) from macrophages (22) and TNF plus other inflammatory mediators from mast cells (23).

Another aspect that protects the gastric mucosa is its ability to proliferate and rapidly replace damaged surface epithelial cells. The gastric epithelium maintains a dynamic equilibrium between cell production and cell loss (Figs. 4.15 and 4.16) (16). The surface epithelium is renewed every 4 to 8 days. Gastrointestinal and nongastrointestinal hormones, growth factors, neural mediators, secretions, luminal food, and absorbed nutrients all modulate gastric mucosal growth (24).
EGF, TGF-&agr;, and insulinlike growth factor directly stimulate gastric mucosal growth (24,25). EGF is ideally suited to participate in gastric repair because it is acid stable and stimulates epithelial migration, DNA synthesis, and gastric mucus production. TGF-&agr; shares 35% homology with EGF and mimics its mitogenic effects (26). EGF and TGF-&agr; also modulate parietal cell function and inhibit gastric hydrochloric secretion (27).

Cell progenitors reside in the mucous neck region giving rise to multiple cell types. One type migrates toward the luminal surface and differentiates into foveolar cells. Other cell lineages migrate downward from the mucous neck region slowly differentiating into parietal, chief, mucous, and endocrine cells (Fig. 4.15). Mature parietal cells and chief cells do not divide. Parietal, chief, and endocrine cells turn over more slowly than do surface cells, renewing themselves every 1 to 3 years.

FIG. 4.15 Mucosal renewal. The mucous neck region contains stem cells and is the generative zone. From here, foveolar cells begin to differentiate and migrate toward the surface to be exfoliated. Other cells developing in this area migrate downward to form the epithelium of the oxyntic, cardiac, and antropyloric glands. These glandular cells die by apoptosis.

Acid and Pepsin Secretion

Three separate pathways stimulate acid secretion: (a) a neural pathway, which delivers transmitters such as acetylcholine (ACH) released from postganglionic nerves in the stomach wall; (b) an endocrine pathway, which delivers hormones such as gastrin; and (c) a paracrine pathway, which delivers tissue factors such as histamine (Fig. 4.16) (21). Potentiating interactions between two or three gastric secretagogues amplify oxyntic secretory responses. Histamine released from lamina propria mast cells and from enterochromaffinlike (ECL) cells binds to H2 receptors on oxyntic cells, resulting in up-regulation of cholinergic and gastrin receptors, making them more sensitive to subsequent stimulation by their respective secretagogues. ACH binds to muscarinic cholinergic receptors on oxyntic cells, stimulating acid secretion. ACH in the antral mucosa inhibits somatostatin production, a peptide that inhibits gastrin release (28).

Antral G cells release gastrin when the antrum becomes alkalinized, stimulating acid secretion via gastrin receptors on parietal cells and histamine release from ECL cells (29). Vagal stimuli also liberate gastrin-releasing peptide, prompting G cells to produce gastrin and stimulating ECL cells to release histamine. Pepsinogens synthesized by gastric chief cells (30) have no digestive capacity until they are broken down into pepsin, a reaction that maximally occurs in an acid environment. The stomach produces two immunologically distinct pepsinogens: pepsinogen 1 (PG1) and pepsinogen 2 (PG2). PG1 is only present in fundic chief and mucous neck cells, whereas PG2 is produced by chief cells, fundic mucous neck cells, cardiac and pyloric glands, and Brunner glands (31). Serum levels of PG1 and PG2 reflect the volume of the cells that produce them. PG1 levels below 20 mg/dL indicate a profound loss of fundic gland volume, as occurs in autoimmune gastritis.

Gastric Motor Functions

In addition to its secretory, digestive, hormonal, and mucosal barrier functions, the stomach has three specific motor functions: (a) storage and volume adaptation, (b) mixing of gastric contents, and (c) forward propulsion of its contents, or gastric emptying. When empty, the stomach is at its smallest possible size. Filling the stomach with fluid or food increases the gastric luminal volume without increasing gastric pressure. Gastric motility is regulated by the extrinsic nerves and by the intrinsic myenteric plexus, which contains cholinergic nerves, adrenergic nerves, and nonadrenergic, noncholinergic nerves.

FIG. 4.16 G cells are central to parietal cell secretion. The G cell is positively influenced by acetylcholine release and gastrin-releasing peptide from the vagus as well as from cytokines and growth factors in the gastric mucosa. Mucosal neuroendocrine cells also produce gastrin-releasing peptide, positively influencing the G cell. Vagal stimulation releases acetylcholine, negatively influencing D cells, suppressing somatostatin function. Somatostatin negatively regulates G-cell activity, suppressing gastrin production. G cells, once stimulated, act directly on parietal cells through release of gastrin or indirectly through ECL cells that produce histamine. Histamine released from mast cells or neuroendocrine cells positively influences parietal cells to secrete acid. Somatostatin has a negative influence on acid secretion and forms part of the feedback loop in which acid secretion by parietal cells enhances D-cell function.



Gastric duplications constitute only 3.8% to 10% of all gastrointestinal duplications (32). They affect females more commonly than males. Sixty-five percent of patients present during the first year of life, often with respiratory distress or as an intrathoracic or extragastric mass (32). Occasionally, the lesions present in adults (33). Thirty-five percent of patients have associated developmental anomalies (Table 4.3) (34).


Esophageal duplications

Accessory spleen

Heterotopic pancreas

Abnormally shaped spleen

Gastrointestinal malrotations

Urinary tract anomalies

Meckel diverticulum

Turner syndrome

Thoracic vertebral anomalies

Patent ductus arteriosus

Pulmonary sequestration

Ventricular septal defect

Gastric duplications appear as intramural cylindrical or cystic masses ranging in size from 1.3 to 12 cm. They share a common blood supply with the rest of the stomach; a common musculature invests them. Most duplications occur on the greater curvature (32); one third affect the distal stomach. They may be complete or incomplete, communicating or noncommunicating. Alimentary mucosa lines gastric duplications. This lining resembles and/or differs from that of the normal stomach. Gastric and small intestinal epithelium may coexist within a single duplication. Pancreatic tissue may also be present, as may respiratory mucosa, cartilage, or submucosal glands.

Complications include ulceration, bleeding, rupture, fistula formation, and, rarely, carcinoma (35). Distal duplications cause gastric outlet obstruction, pain, vomiting, fever, weight loss, or hemorrhage (32). Duplication cysts have been successfully managed by surveillance and symptombased intervention. Some advocate for resection based on reports of malignant degeneration (36).


In patients with situs inversus, the stomach lies to the right of the midline, a condition known as dextrogastria. The esophageal diaphragmatic hiatus also lies on the right side; the
first part of the duodenum lies on the left side. Dextrogastria affects approximately 1 of every 6,000 to 8,000 births (37). Situs inversus affecting only the stomach and duodenum (with the remainder of the thoracic and abdominal viscera lying in their normal positions) is extremely rare (37). The stomach lies either completely behind the liver or above it. Although abnormally positioned, gastric structure and function are normal.


The incidence of gastroschisis increased from 0.006 per 1,000 in 1968 to 0.089 per 1,000 in 1977. Young, socially disadvantaged women have the highest risk of giving birth to a child with gastroschisis (38). Gastroschisis presumably results from vascular injury to the abdominal wall causing defective somatopleural mesenchymal differentiation during the 5th to 11th fetal weeks (39). Gastroschisis may complicate premature atrophy or abnormal persistence of the right umbilical vein (39). Portions of the stomach, small intestine, and colon herniate through an abdominal wall defect lateral to the umbilicus. Since no peritoneal sac or sac remnant covers the eviscerated abdominal contents, the herniated organs are exposed to amniotic fluid leading to gastric wall thickening, serosal edema, and fibrinous exudates.

Congenital Hiatal Hernia

A congenital periesophageal gap or congenital elongated esophageal hiatus can result in a congenital hiatal hernia with invagination of abdominal contents into the thorax (Fig. 4.17). The defect results from failure of the pleuroperitoneal folds to develop or from failure of the pleuroperitoneal canal to close. Urinary tract abnormalities are common in patients with congenital posterolateral diaphragmatic defects including renal agenesis, dysplasia, hypoplasia, or hydronephrosis.

FIG. 4.17 Congenital right diaphragmatic defect. The small intestine has herniated into the right thoracic cavity with partial collapse of the right lung and deviation of the trachea to the left. A large thymus overlies the trachea.

Acquired Hiatal Hernia

The freely movable stomach can prolapse through natural and surgically created diaphragmatic defects, coming to lie in the thoracic cavity. Clues that a biopsy may come from the area of a hiatal hernia include the presence of variably inflamed cardiac or oxyntic mucosa with edema, lymphatic dilation, and pronounced muscle hyperplasia, splaying, or stranding.


Congenital Diverticula

Gastric diverticula are rare, ranging in incidence from 0.02% to 0.18% (40). Most arise on the posterior wall, in a juxtacardiac position (40). Congenital diverticula appear as solitary, sharply defined, round, oval, or pear-shaped pouches communicating with the gastric lumen via a narrow or broadbased mouth (Fig. 4.18).

Acquired Diverticula

Acquired diverticula almost always originate in the distal stomach as a complication of antral inflammation. Fibrosis following acute inflammation causes traction on the tissues and mucosa herniates through the gastric wall. Therefore,
antral diverticula should be carefully evaluated to exclude the presence of an underlying pathologic process such as gastritis, peptic ulcer disease (PUD), or neoplasia.

FIG. 4.18 Gastric diverticulum. Endoscopic appearance. The orifice of the diverticulum is indicated by a star. Note the similarity of the mucosal lining both in the native stomach and in the diverticulum.

Atresia, Webs, and Diaphragms

Congenital gastric outlet obstruction due to a membranous antral web is extremely rare with an incidence of 0.0001% to 0.0003% of live births (41). A high incidence of associated extraintestinal anomalies and a strong familial history for pyloric atresia support the theory that atresias and webs result from underlying genetic alterations. Polyhydramnios affects more than 50% of cases. Gastric atresia may associate with trisomy 21, epidermolysis bullosa, or esophageal and anal atresia (42,43). Hereditary multiple gastrointestinal atresias affect the GI tract from the pylorus to the rectum and are inherited in an autosomal recessive fashion. They may associate with immunodeficiency syndromes (43,44).

Most patients with gastric atresia present in the first few days of life with bile-free vomiting and abdominal distension. Type 1 gastric atresia (the most common type) consists of an internal web or diaphragm that completely separates the stomach from the duodenum. Type 2 atresia (the rarest type) consists of a thin, fibrous cord that connects a blind gastric pouch to a distal blind small intestinal segment. Type 3 atresia consists of a blind gastric pouch and a blind distal intestinal pouch without intervening tissue (43,44).

A variably inflamed distal antral mucosal fold with a central aperture measuring from 1 to 10 mm in diameter lies perpendicular to the long axis of the antrum. The serosa may appear indented at the level of the diaphragm. Antral mucosa lines both sides of the diaphragm covering a submucosal core. Heterotopic pancreatic tissue sometimes lies within webs and diaphragms (43,44). In adults, diaphragms and webs complicate inflammatory conditions (33).

Pyloric Stenosis

Pyloric stenosis affects both children and adults and assumes several forms.

Infantile Hypertrophic Pyloric Stenosis (Congenital Pyloric Stenosis)

This disorder is discussed in Chapter 10 since it is primarily a motility-related disorder.

Acquired Pyloric Stenosis

Adult forms of hypertrophic pyloric stenosis result from inflammation associated with antral gastritis and/or PUD, or from inherent neuromuscular abnormalities. Partial gastric obstruction leads to an increased stomach size and weight due to localized or diffuse gastric muscular hypertrophy and hyperplasia, increased mucosal thickness, and G-cell hyperplasia. The pyloric deformity leads to bile reflux and secondary alkaline reflux gastritis.

Torus Hyperplasia

The very rare condition known as focal pyloric hypertrophy (torus hyperplasia) appears as a localized area of circular muscle hypertrophy affecting the lesser curvature near the pyloric torus. The lesion may represent a form of acquired pyloric stenosis, or it may represent persistence of congenital pyloric stenosis into adulthood. Some speculate that the lesion results from chronic gastritis or from repeated spastic pyloric contractions (45).


Normal tissues lie in abnormal locations due to a congenital heterotopia or secondary to metaplasia. Congenital heterotopias differ from metaplastic (acquired) lesions in that they usually retain a normal organizational structure, whereas metaplastic processes tend to consist of a single-cell type lacking normal tissue patterns (Fig. 4.19). Congenital heterotopias result from cellular entrapment during embryonic morphogenetic movements. The congenitally displaced tissues then differentiate along the lines of normal organs in response to the local environment.

Heterotopic Pancreas

Heterotopic pancreas is the most common heterotopia affecting the stomach. It accounts for 25% to 30% of all pancreatic heterotopias (46). It is usually an incidental finding, commonly found in the antrum, and followed by the pylorus, greater curvature, and esophagogastric junction. If a tumor or pancreatitis develops, the heterotopic tissue may become symptomatic. Heterotopic pancreas usually appears as a solitary submucosal, hemispheric, umbilicated mass measuring 0.4 to 4.0 cm in diameter. The entry of single or multiple ducts into the gastric lumen produces a symmetric cone or short, cylindric, nipplelike projection (Fig. 4.20). Heterotopic pancreas may also present as large submucosal mucinous cysts. Multiple or pedunculated pancreatic heterotopias are uncommon. Approximately 75% of pancreatic heterotopias lie in the submucosa (Fig. 4.21), with the remainder involving the muscularis propria. Cross section of larger lesions reveals the typical tan, lobulated tissue characteristic of eutopic pancreas. The deeper the lesion, the more disorderly it tends to appear. The pancreatic lobules contain variable mixtures of pancreatic acini, ducts, islets, glands resembling Brunner glands, and hypertrophic smooth muscle fibers. The islets contain variable numbers of pancreatic polypeptide and insulin-producing cells (47). If only pancreatic acini are present, the lesion may represent pancreatic metaplasia (see below) rather than heterotopia, especially if the cells lie within the mucosa. Sometimes one sees both heterotopic pancreatic and gastric tissue lying side by side in the submucosa.

Heterotopic pancreatic tissue does not pose a diagnostic problem when both pancreatic acini and ducts are present. However, lesions containing only smooth muscle and/or pancreatic ducts have been misinterpreted as adenomyomas.

A clue that the lesion represents heterotopic pancreatic tissue, rather than an adenomyoma, is the finding of hypertrophic circular and longitudinal smooth muscle cells arranged circumferentially around the ducts in a more or less normal fashion (Fig. 4.21). Secondary changes such as pancreatitis, cyst formation, or neoplasia (islet cell tumors, ductal dysplasia [Fig. 4.22], and adenocarcinoma) may also cause confusion, particularly when they distort the underlying tissue (48). Dilated ducts forming submucosal mucin pools containing epithelial clusters and variable degrees of inflammation, without obvious pancreatic tissue adjacent to the mucin, may suggest a diagnosis of mucinous carcinoma. One should not make a diagnosis of invasive cancer in the absence of significant cytologic atypia and stromal desmoplasia.

FIG. 4.19 Pancreatic metaplasia versus heterotopic pancreas. A: Pancreatic metaplasia consists of pancreatic acini that merge with the surrounding gastric mucosa. B: Heterotopic pancreas usually involves the submucosa and may contain pancreatic lobules, islets, and ductules (not shown).

FIG. 4.20 Heterotopic pancreas. The heterotopic pancreas produces a well-defined submucosal mass that is visible endoscopically (A) as well as grossly (B). The submucosal mass distorts the gastric folds (arrow) and appears as a hemispheric lesion with a central umbilication. C: Cross section of the gastric wall demonstrating the presence of a whitish, firm mass lying within the submucosa as indicated by the arrows.

FIG. 4.21 Heterotopic pancreas. A: A lobulated submucosal glandular structure with a central duct. Delicate strands of fibrovascular tissue separate individual lobules. B: Higher magnification of the duct and pancreatic acini on either side of the duct. Prominent smooth muscle fibers also surround the duct.

Heterotopic Gastric Glands

Diffuse or localized submucosal gastric heterotopias occur in up to 14% of stomachs (49). These either are congenital in origin or represent areas of gastritis cystica profunda (discussed below). Congenital gastric heterotopia usually contains oxyntic mucosa with foveolar epithelium arranged in a normal architectural pattern.

Heterotopic Brunner Glands

Heterotopic Brunner glands can accompany heterotopic pancreas, or the heterotopia may contain only Brunner glands and smooth muscle. The heterotopic glands lie in the pylorus and gastric antrum and histologically resemble duodenal Brunner gland hyperplasia (see Chapter 6).

Double Pylorus

Double pylorus is an acquired condition in patients with PUD. Prepyloric ulcers penetrate the pyloric wall, perforate into the duodenum, and create a new mucus-lined channel. Rare examples of congenital double pylorus also exist (50).

Pyloric Mucosal Prolapse

Antral mucosa may prolapse into the duodenum, sometimes forming a mushroom-shaped duodenal or gastric pseudopolyp (Fig. 4.23). It occurs sporadically or complicates gastritis or previous gastric surgery. Submucosal edema (as the result of an underlying inflammation) predisposes to mucosal prolapse. As the edema increases, the tissues fail to return to their normal position; progressive gastric outlet obstruction develops. Patients with mucosal prolapse usually develop crampy abdominal pain, delayed gastric emptying, or vomiting due to the gastric outlet obstruction. The prolapsed mucosa appears variably inflamed, edematous, and necrotic, depending on the duration and severity of the obstruction and the degree of vascular compromise. Pit hyperplasia, pit distortion with cystic serrated branched villiform surfaces, a hyperplastic muscularis mucosae with a muscular lamina propria, erosions, ulcers, glandular atrophy, and variable inflammation may all develop.

FIG. 4.22 Heterotopic pancreas with dysplastic epithelium. A: Numerous cystic structures lie within the gastric wall. Some are lined by flattened epithelium and contain prominent mucinous collections. Others are lined by benign neoplastic epithelial cells. B: Higher magnification of one of the glands showing the junction of more or less normal epithelium with basal nuclei above the arrows with the benign neoplastic hyperchromatic epithelium with an increased nuclear to cytoplasmic ratio and prominent nucleoli beneath the arrows. C: Higher magnification of the neoplastic epithelium showing cytologic atypia, nuclear stratification, and prominent nucleoli. D: Another area with a more complicated glandular architecture. Note the absence of invasion into the surrounding tissues and the absence of a desmoplastic response. The glands are still surrounded by intact smooth muscle fibers.

FIG. 4.23 Mucosal prolapse. The prolapsed mucosa assumes a mushroom-shaped configuration overlying the area of the pylorus.


Gastric volvulus, also known as gastric torsion, affects both children and adults, usually in the presence of a left diaphragmatic abnormality (51,52). It presents acutely or chronically. Acute presentations include hemorrhage, ischemia, and infarction (51,52). Most patients with the chronic form of the disease are elderly. They have recurrent epigastric pain, vomiting, and occasional hematemesis.

Gastric volvulus occurs in several forms. The most common type, organoaxial volvulus, accounts for approximately 60% of cases. The stomach twists around the longitudinal axis of its lesser curvature, causing the stomach to turn upside down (Fig. 4.24), producing both proximal and distal obstructions. Anterior rotation is more common than posterior rotation. Mesenteroaxial volvulus represents 30% of cases. It occurs around a line that runs from the center of the greater curvature to the porta hepatis. Mesenteroaxial and organoaxial volvulus can coexist. The stomach can also twist about the vertical axis of the gastrohepatic omentum producing torsion rather than a true volvulus. As a volvulus develops, the stomach progressively distends, due to accumulated secretions that cannot pass forward or be regurgitated because the volvulus produces both distal and proximal obstruction. Death results from the sequence of obstruction, strangulation, and ischemic necrosis, the latter resulting from compression of the gastric vasculature.

FIG. 4.24 Barium examination showing a gastric organoaxial volvulus. Large thick radiolucent curvilinear defect represents the superiorly located lesser curvature wall and the inferiorly located greater curvature wall. F, fundus; B, body; A, antrum; D, duodenum.


Microgastria, a rare congenital anomaly, often coexists with other anomalies such as midgut malrotations, cardiac abnormalities, and asplenia (53). The underdeveloped lower esophageal sphincter becomes incompetent and gastroesophageal reflux develops. Symptoms appear in infancy and include failure to thrive, vomiting, and recurrent aspiration pneumonia. Barium swallows demonstrate a small tubular stomach. Development can normalize in those who undergo early operative treatment (54). Histologically, the gastric wall appears hypoplastic (55). The stomach is small, often nonrotated without a clear definition of the various zones. The disorder may result from failed development of the mesogastrium.


Inflammatory Cells

The stomach, like many other organs of the body, possesses a limited number of ways it can use to react to an injury. These responses, which have become known as “patterns of injury,” include inflammatory and reactive mechanisms that can be easily recognized histologically. Their intensity and combinations are often characteristic of certain conditions and, when properly recognized, can be used to formulate differential diagnoses.

Polymorphonuclear Neutrophils (Active/Acute Inflammation)

Neutrophilic inflammation in the stomach is termed “active” or “acute” as it is associated either with a relatively recent process or with a process that is actively perpetuating the inflammatory process. In the normal stomach, the lamina propria may show rare neutrophils; however, the neutrophilic infiltration of the glandular or the surface epithelium is a sign of active gastritis. Although active gastritis may result from many disorders with multifactorial etiologies, Helicobacter pylori infection is by far its most common cause. The mostly neutrophilic infiltrate found in the very early stages of H. pylori infection (“acute H. pylori gastritis”) is soon replaced by a mixed population of lymphocytes, plasma cells, and eosinophils, the inflammatory makeup known as “chronic active gastritis.” Much less common conditions that may show similar infiltrates, although with different proportions of the inflammatory cells and topographic patterns, are syphilis (now extremely rare) (56) or Crohn disease (57), and the elusive entity known as “H. pylori-negative chronic active gastritis.” In spite of the often dramatic infiltrates that in some cases appear to cause a massive destruction of the gastric mucosa, active gastritis—particularly when caused by H. pylori infection—causes remarkably mild symptoms.


Increased eosinophils within the gastric lamina propria is a nonspecific finding that may be clinically insignificant or may represent hypereosinophilic syndrome, eosinophilic gastroenteritis, a parasitic infection, mastocytosis, or one of several rare systemic syndromes. Lwin et al. (58) described criteria for the normal density of eosinophils in the stomach. Eosinophilic gastritis is a histopathologic finding with no characteristic clinical manifestations. Most patients with eosinophilic gastritis either are asymptomatic or have nonspecific complaints, such as dyspepsia or vague epigastric pain. Eosinophils may be mildly increased in H. pylori infection, and fleeting surges have been described in the immediate aftermath of eradication treatment, when eosinophils presumably exert their traditional scavenging role.

Given the uncertain significance of the finding, reporting an increase in the gastric mucosal eosinophils may appear like a futile exercise. We suggest that the reluctance to report “nonactionable” diagnoses is one of the causes why some conditions, particularly uncommon ones, remain poorly defined. Pathologists ought to remember that what appears insignificant today may become highly significant tomorrow, after large numbers of cases have undergone thorough clinicopathological studies and their pathogenesis is elucidated. Eosinophilic esophagitis is one of the most recent examples of neglected conditions propelled to center stage by elegant clinicopathologic studies.

Lymphocytes, Plasma Cells, and Mast Cells

Scattered lymphocytes and plasma cells are seen in the lamina propria of healthy gastric mucosa. According to the Sydney System (59), chronic gastritis should be diagnosed when multiple clusters of more than five plasma cells are identified; however, the density of these cells shows topographic, individual, demographic, and geographic variability. Even if these variations are taken into account when setting the local criteria for chronic gastritis, it must be acknowledged that it remains a rather subjective diagnosis. Perhaps the most relevant of the variations is that mononuclear cells have greater density in the cardia and pyloric channel than in the antrum and corpus. Thus, an inexperienced observer might overdiagnose chronic gastritis in biopsy specimens obtained from perfectly normal very proximal or very distal stomachs.

Dense mononuclear inflammation of the lamina propria is one of the hallmarks of H. pylori infection and autoimmune gastritis. In the former, there is a diffuse deep infiltrate in the antrum, which may displace the foveolae, and a subepithelial band of variable thickness in the oxyntic mucosa (hence the old term “superficial gastritis”). In autoimmune gastritis, the mononuclear infiltrate is found exclusively in the oxyntic mucosa, where it displaces and destroys the oxyntic glands.

Intraepithelial lymphocytes have emerged as the hallmarks of distinctive pathologic process in the colon, duodenum, and—more recently—the esophagus (60,61). Lymphocytic gastritis has been described as increased intraepithelial lymphocytes numbering greater than 25 lymphocytes per 100 epithelial cells (61). The establishment of arbitrary numerical cut points to diagnose disease has become a reoccurring theme in pathology, and one that has been met with variable degrees of enthusiasm (62). In the case of lymphocytic gastritis, counting intraepithelial lymphocytes is rarely necessary, since the normal gastric epithelium contains no CD3(+) lymphocytes and any number is to be considered abnormal.

Mast cells are seen scattered throughout the lamina propria of the healthy gastric mucosa. In reactive backgrounds (such as H. pylori gastritis), the density of mast cells can increase considerably, but they never form sheets (63). When mast cells are seen in dense aggregates or take a spindled morphology, the possibility of systemic mastocytosis should be considered (64).

Lymphoid Aggregates

Small lymphoid aggregates without germinal centers may be seen in the lamina propria and the deeper portions of the oxyntic mucosa, particularly in younger patients. In contrast, lymphoid follicles with reactive germinal centers are virtually always associated with H. pylori infection (65) and are believed to be central to the immune responses to the bacteria. “Follicular gastritis” is an antiquated term referring to cases, predominantly seen in young women, where H. pylori-associated lymphoid follicles were so numerous and prominent that they imparted a nodular endoscopic
appearance to the mucosa (66). Lymphoid follicles regress after the successful eradication of H. pylori infection, but they do so very slowly and may be still evident months or even years after treatment (65).

Reactive Changes

Reactive gastropathy (also referred to as “chemical gastropathy”) is a descriptive term applied to the constellation of changes that take place in response to direct damage to the gastric epithelium by a variety of chemical agents, including bile, with or without pancreatic secretions (“alkaline reflux”), and a long list of medicines, mostly aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). Although the pathogenetic details remain poorly understood, interference with prostaglandin-mediated gastroprotection is believed to be at the core of the histologic changes that define reactive gastropathy and include mucosal congestion and edema, surface degeneration, foveloar hyerplasia, fibromuscular hyperplasia, and often erosions or ulcerations (67).

The responses to these injurious chemicals are essentially the same, irrespective of the cause. Thus, in the absence of pertinent clinical history, the etiology remains a matter of speculation.

Mucosal congestion and edema are commonly reported endoscopic findings that often lead to the question of gastritis. Histologically, mucosal congestion and edema are nonspecific findings that may be associated with gastritis or gastropathy. Both findings may also be seen as traumatic changes secondary to the biopsy itself.

Surface epithelium degeneration is a nonspecific epithelial injury characterized by necrosis and erosions or ulcers. Erosions are limited to the lamina propria and are not classified as ulcers until they show full thickness involvement of the mucosa. Often, there will only be fibrinopurulent debris adjacent to gastric tissue on the slide, which is suggestive of an adjacent erosion. By the same token, granulation tissue is suggestive of an adjacent ulcer, as an erosion should not have deep enough involvement to induce granulation tissue formation.

Foveolar hyperplasia is gastric pit elongation and tortuosity, often accompanied by reactive changes and foveolar mucin depletion. These changes along with fibromuscular proliferation in the underlying lamina propria will result in a “corkscrew” appearance of the hyperplastic fronds. In severe cases, the epithelial cells may appear atypical with high nucleus-to-cytoplasm ratio, hyperchromatic nuclei, mucin depletion, and superficial mitoses. These changes may become more pronounced in the vicinity of an erosion or ulcer. It is important to keep the reactive background in mind so the findings are not overinterpreted as dysplasia.

Foveolar hyperplasia is reportedly most frequently associated with bile reflux (68); however, this topic has not been well studied and it is likely that there are numerous etiologies (medications, infections, toxins, etc.) that can produce this change.


Atrophy is defined as the loss of native structures that normally occupy a region of the stomach and is the consequence of an injury that destroys parts of the gastric mucosa. While some rare acute infections, particularly diphtheria, may be highly destructive, only two conditions have clinical and epidemiologic relevance: H. pylori gastritis, which can affect any portion of the stomach, causing patches of destruction and metaplastic remodeling in both antrum and corpus, and autoimmune atrophic gastritis, a progressive destructive process that selectively affects the oxyntic cells, eventually resulting in the annihilation of the acid-producing component of the stomach. Thus, while atrophy in the corpus has significant pathophysiologic consequences, the functional and clinical relevance of the loss of mucin-producing glands in the antrum remains unclear.

As atrophy develops, the lost elements are replaced by other structures not normally found there. This replacement is termed metaplasia.


Metaplasia is the replacement of native tissues with tissues that are not normally found in that location. In the stomach, several types of metaplasia are encountered: intestinal, spasmolytic polypeptide-expressing metaplasia (SPEM), pancreatic, and ciliated.

Intestinal Metaplasia

Intestinal metaplasia (IM) is the replacement of resident gastric components with intestinal components. It is believed to represent a response to chronic injury, often caused by HP infections. There are two types, complete, which resembles small intestine with goblet cells, Paneth cells, and a brush border; and incomplete, which resembles colonic mucosa with disordered and variably shaped goblet cells. IM is seen most frequently in Asian and Latin ethnicities, in regions of high H. pylori infection prevalence, smokers, and people who consume foods high in salt and nitrites (69,70). Thirteen percent of consecutive American Caucasians undergoing upper endoscopy and 50% of Hispanics and Blacks had evidence of gastric IM when routine protocol-mapping biopsies of the normal-appearing mucosa were performed (71).

One of the more contentious issues is the significance of IM at the cardia. IM has been implicated in the development of both gastric and esophageal carcinoma. However, while gastric IM increases the risk of gastric cancer, with the increased risk being proportional to the extent of the metaplasia, the risk is much lower than that of Barrett esophagus (BE) progressing to cancer (72), at least in the United States. Thus, it is important to try to distinguish the IM of BE from the gastric type of IM.

IM begins at the antral-corpus junction in a patchy (Fig. 4.25), multifocal fashion and then spreads both distally and proximally to involve the antrum and fundus. The areas
of IM increase with patient age and often become confluent, replacing large areas of the gastric mucosa. This process can be highlighted by staining gastric resection specimens for alkaline phosphatase activity since only intestinal-type epithelium expresses the enzyme (Fig. 4.25). IM more frequently coexists with gastric cancer than with gastric ulcer, but it shows the same distribution when associated with either condition.

FIG. 4.25 Intestinal metaplasia. Both gastric specimens have been opened along the greater curvature and were stained with alkaline phosphatase to highlight areas of intestinal metaplasia. A: Note the inverted V-shaped configuration of the metaplastic process at the corpus-antral junction with areas of punctate staining as one moves away from this border. The duodenum also stains intensely with the enzyme. There is a benign gastric ulcer (arrows) at the junction zone of the metaplastic epithelium with the native oxyntic mucosa. B: A similar preparation in which the gastritis has extended far more proximally. Patchy metaplastic lesions are also seen in the antral region along the greater curvature. With the extensive replacement of the oxyntic mucosa, it is easy to see how hypo- or achlorhydria can develop. A polypoid carcinoma is present in the metaplastic area (arrows).

IM may result from mutations caused by nitrosative deamination of DNA by nitric oxide generated by inflammatory cells in stem cells in the replicating compartment of gastric glands in response to HP infection (69). IM may also represent a change that raises gastric pH by replacing the oxyntic mucosa with an epithelium that favors the growth of bacteria capable of generating endogenous mutagens. Down-regulation of SOX2 and ectopic expression of CDX2, an intestine-specific transcription factor belonging to the caudal-related homeobox gene family (73), are important in the development of IM (74). CDX2 expression may lead to activation of intestine-specific gene transcripts, thereby directing intestinal epithelial development and differentiation in the metaplastic areas.

In IM, the cells that normally line the gastric mucosa (surface epithelium, foveolar epithelium, and glands) are replaced by an epithelium resembling that of the small or large intestine. The earliest metaplastic changes consist of the appearance of mucin-negative absorptive enterocytes with a brush border alternating with Alcian blue-positive goblet cells. In young individuals with less extensive IM, the metaplastic glands resemble normal small intestinal epithelium. Initially, only the epithelial type changes, but later, the mucosal architecture acquires a small intestinal villiform structure, often containing Paneth cells at the base of the pits. Paneth cells in areas of IM do not have the same uniform distribution seen in the intestine. In some cases, they are limited to the antral corpus border and are lacking in IM in the distal stomach. They may lie in the superficial portions of the metaplastic gland; ultrastructurally, some Paneth cells contain both Paneth cell granules and mucinous vacuoles (69).

Goblet cells are easily seen on H&E-stained sections. However, an Alcian blue/PAS stain is commonly used to identify the goblet cells since it stains all acidic mucins bluepurple and neutral mucins magenta and is easy to perform and interpret. Some metaplastic cells exclusively secrete sialomucins and contain a “complete” set of normal small intestinal digestive enzymes (sucrase, trehalase, and alkaline phosphatase). This type of metaplasia is characterized by weak expression of (intestinal) MUC2 and absence of gastric
(MUC1, MUC5AC, and MUC6) mucins and cytokeratin (CK) immunoreactivity (75). These cells have a complete switch in their differentiation program from a gastric to an intestinal phenotype, and they have been termed small intestinal, complete, or type I IM (Fig. 4.26).

FIG. 4.26 Complete intestinal metaplasia. A: The brush border of the absorptive cells is present, as are numerous goblet cells. B: Brush border highlighted by a CD10 immunohistochemical stain.

Later, as the disease becomes more extensive, the enterocytes disappear and are replaced by columnar cells containing abundant mucous droplets in their cytoplasm. These metaplastic cells lack a well-developed brush border and secrete both sialomucins and sulfomucins (76). They lack the complete set of digestive enzymes. This type of metaplasia has been termed enterocolonic, colonic, type II, or incomplete metaplasia (Fig 4.27). Incomplete metaplasia strongly expresses MUC1, MUC5AC, MUC6, MUC2, Das-1 (a large intestinal antigen), and CK 7. Incomplete IM shows a mixed gastric and intestinal phenotype reflecting aberrant differentiation programs that do not reproduce any phenotype occurring in normal adult gastrointestinal epithelia (75). Several types of metaplastic epithelium may develop within the same stomach. IM occurs concurrently with atrophic gastritis or independently. Incomplete IM frequently associates with areas of dysplasia and carcinoma.

FIG. 4.27 Incomplete intestinal metaplasia. A: Low-power view showing the haphazard arrangement of goblet cells reminiscent of colonic mucosa. B: Higher-power view.

The endocrine cell population in the different types of metaplasia changes with the phenotype of the nonendocrine cells. In patients with antral gastritis, the proportion of gastrin and somatostatin neuroendocrine cells decreases as the glands pass from a mixed gastric-intestinal phenotype to a pure intestinal phenotype. There is a corresponding increase in intestinal-type endocrine cells that produce glicentin, gastric inhibitory polypeptide, and glucagonlike peptide 1 (77). Gastrin-positive cells emerge in the areas of pyloric metaplasia.

A distinct cellular subset consisting of groups of undifferentiated columnar cells lies on the interfoveolar crests of the gastric mucosa (78). These cells differ from both normal foveolar cells and metaplastic cells, and they show a close association with atrophic gastritis, particularly in the presence of sulfomucin-secreting IM. This lesion may provide a link between this type of metaplasia and the intestinal variant of gastric adenocarcinoma that develops in intestinalized areas (78). Histologically, the large, columnar, pseudostratified cells have central nuclei and lack the prominent cup-shaped mucus collection typical of foveolar cells. The cells cluster in groups of up to 25 cells and they show an abrupt transition with the adjacent normal foveolar epithelium.

There is no consensus on the role of the various IM subtypes and subsequent risk of developing carcinoma, and the question then arises as to what to do with a patient with a diagnosis of gastric IM. The answer to this depends on whether the patient has a family history of gastric cancer, has migrated from a high-risk geographic location, lives in a high-risk location, or is a member of an ethnic population with a high risk of developing carcinoma and whether there is evidence of dysplasia on the biopsy. It can be assumed that any person with an increased cancer risk as defined by the factors noted in the previous sentence or with extensive metaplasia is at high risk for gastric cancer and should be subject to periodic screening. The extent of the IM is probably more important than the metaplastic subtype (69).

FIG. 4.28 Pancreatic metaplasia in autoimmune gastritis. A: This stomach shows the presence of prominent pancreatic metaplasia as well as cystic change. Numerous pancreatic lobules lie at the basal portion of the mucosa (arrows). B: Higher magnification of one of the metaplastic areas showing pancreatic acini-surrounded antropyloric glands.

Spasmolytic Polypeptide-Expressing Metaplasia

SPEM is seen exclusively in areas of oxyntic glandular atrophy. In autoimmune gastritis and H. pylori infection, the destroyed oxyntic glands are replaced by a population of glands that resemble those normally found in the distal stomach, particularly the pylorus (hence the designation of “pyloric”). SPEM is the first type of metaplasia that develops in response to a destructive process in the corpus and may be replaced by intestinal metaplasia. Thus, in a severely or completely atrophic corpus, islands of SPEM will be scattered in a background of atrophy and intestinal metaplasia. The presence of SPEM has been associated with gastric adenocarcinomas (79,80) and, therefore, it is considered a preneoplastic lesion.

Pancreatic (Acinar) Metaplasia

Pancreatic metaplasia is present in 12% of patients with autoimmune gastritis, usually developing in the cardia and often coexisting with other types of metaplasia (81). Pancreatic acinar cells can also develop in the gastric antral mucosa in areas of IM or atrophy. The metaplastic foci contain single or multiple pancreatic nests and lobules measuring up to 1.7 mm in diameter (Fig. 4.28). The metaplastic tissue imperceptibly merges with the gastric glands. Less commonly, acinar cells lie scattered individually or in small cellular foci among the gastric glands. Larger lobules contain tubules or small cystic spaces reminiscent of dilated ductules. The layers of smooth muscle cells that circumferentially surround the ducts in heterotopic pancreas are absent. The acinar cells have a truncated pyramidal shape with a rim of deeply basophilic basal cytoplasm and numerous small, acidophilic, weakly PASpositive, refractile granules in the mid- and apical cytoplasm. These granules contain trypsin, amylase, and lipase. The nuclei appear round, relatively small, and centrally or basally located, with a prominent nucleolus. Endocrine cells positive for somatostatin, gastrin, or serotonin intermingle with the acinar cells. Amphicrine cells containing both zymogen and neurosecretory granules are also present.

FIG. 4.29 Ciliated metaplasia. Ciliated metaplastic cyst located near the muscularis mucosae. The cilia are difficult to see on hematoxylin and eosin stain.

The metaplastic cells probably result from aberrant stem cell differentiation (82). PDX-1, a homeodomain transcription factor, plays a key role in both endocrine and exocrine pancreatic differentiation and differentiation of endocrine cells in the gastric antrum. Therefore, it is of interest that both the pancreatic metaplasia and endocrine cell hyperplasia associated with atrophic corpus gastritis express PDX-1 (83).

Ciliated Cell Metaplasia

Ciliated cells may develop deep to areas of intestinal metaplasia; in the mucosa of patients with gastric ulcers, dysplasia, or adenocarcinomas; and at sites away from the main lesion (Fig. 4.29) (84). The ciliated cells show some evidence of an antral phenotype, as demonstrated by their pepsinogen group II activity (69). The cilia in the cells often are structurally abnormal. The ciliated cells line cystically dilated glands, where they may represent an adaptive mechanism aimed at expelling semifluid viscous material and inflammatory cells from the cysts. As cysts enlarge, the intrinsic pressure of the retained mucus results in cellular atrophy and ciliary disappearance (84).


The discovery of the pivotal role of H. pylori in the pathogenesis of gastritis, PUD, gastric cancer, and primary gastric MALT lymphoma has rekindled a long-dormant interest in the pathology of the stomach and the classification of gastric inflammatory conditions. Among the many attempts, mostly short-lived, to produce a set of simple and practical guidelines for the reporting of gastric biopsies, three have survived and become widely used by researchers and, to a lesser extent, clinicians around the world: the Updated Sydney System, the 2000 Atrophy guidelines, and the Operative Link for Gastritis (OLGA and OLGIM).

Sydney System

The Updated Sydney System is currently the most widely used classification scheme although it is most often utilized in research studies. At the time of this writing, it had been cited in more than 3,000 articles and used in the studies reported by at least a third of them. Its popularity among researchers, in contrast to its rare sporadic use in everyday practice, can be explained by the requirement that a set of five biopsies from the stomach be obtained, two from the antrum, two from the corpus, and one from the incisura angularis. While this sampling can be easily incorporated in research protocols, its use in the clinical setting has been constrained by time and financial considerations.

The concept behind the Sydney System was to provide a simple set of topographical and morphologic criteria to classify gastric inflammatory processes using a standardized reporting system that would provide a diagnosis that is both widely understood by gastroenterologists and clinically relevant. The pathologist is required to use a visual analogue scale to grade (on a scale from 0 to 3) the intensity of active and chronic inflammation, the extension of atrophy and intestinal metaplasia, and the density of H. pylori organisms (59). Then, a “diagnostic string” that incorporates all the information, including the negatives (i.e., the absence of H. pylori) and the topographic intensity of the inflammation, in a standardized fashion is generated.

While the system was tilted toward reporting H. pylori gastritis, it also incorporated a number of “special forms” of gastritis (such as reactive, lymphocytic, or eosinophilic gastritis) that could be reported using all pertinent modules depicted in the visual analogue scale (Table 4.4). In part because most nonresearch pathology reports are based on sets of biopsies do not include the required sampling, and in part because pathologists find the grading of the elements of gastritis a timeconsuming exercise with little practical resonance, the Sydney System format is virtually unknown in general practice.


The 2000 Atrophy guidelines were proposed by an international group of gastric pathologists led by Massimo Rugge that met twice (85,86) with the aim of reducing the unacceptable levels of interobserver variability gastrointestinal pathologists continued to display even after following the Sydney System visual analogue scales were put forth. (59). This system attempted to simplify the assessment of atrophy and its reporting by grading it as absent, indefinite, or present. If present, it was further characterized as metaplastic or nonmetaplastic in nature and graded mild, moderate, or severe (87). Using this algorithm, study participants showed moderate to excellent diagnostic agreement. However, it remains unclear whether it has improved the reliability of reports outside the research sphere.


First proposed by Rugge and Genta in 2005 (CIT), grading and staging of gastritis was intended as a simple mechanism to convey the degree of gastric cancer risk based on the extension and location of atrophy in a patient’s stomach. Later, an
international expert group of gastroenterologists and pathologists gathered in Parma, Italy, and devised a system called the Operative Link for Gastritis Assessment (OLGA).




Grading Guidelines

Chronic inflammation

Increased lymphocytes and plasma cells in the lamina propria

Mild, moderate, or severe increase in density


Neutrophilic infiltrates of the lamina propria, pits, or surface epithelium

Less than one third of pits and surface infiltrated = mild; one third to two thirds = moderate; more than two thirds = severe


Loss of specialized glands from either antrum or corpus

Mild, moderate, or severe loss

Intestinal metaplasia

Intestinal metaplasia of the epithelium

Less than one third of mucosa involved = mild; one third to two thirds = moderate; more than two thirds = severe

Helicobacter pylori

H. pylori density

Scattered organisms covering less than one third of the surface = mild colonization; large clusters or a continuous layer over two thirds of surface = severe; intermediate numbers = moderate colonization

In this system, gastritis is staged in a similar manner as hepatitis on a scale of progressing cancer risk (0 to 4). The assessment of atrophy is contingent upon adequate Sydney System sampling and the use of the Atrophy 2000 guidelines. The result of the assessment is expressed as a grade (0 to 4), and a number of studies from several different areas of the world have shown an excellent correlation between stages 3 and 4 and the subsequent development of gastric cancer.

Years later (2010), an alternate system was proposed, in which intestinal metaplasia was utilized instead of atrophy, with the goal of increasing the diagnostic agreement among pathologists (86) and was named Operative Link for Gastritis and Intestinal metaplasia (OLGIM). Both systems have shown good predictive value of progression to adenocarcinoma in the higher stages; however, recent studies have shown the OLGA to be more specific than the OLGIM (88).


Endoscopic examination with mucosal biopsy or, much more rarely, cytologic sampling is the mainstay tool for the diagnosis and follow-up of gastric disease. Essentially all conditions described in this chapter can be diagnosed and, when appropriate, graded or staged, by the competent use and interpretation of gastric mucosal biopsies. As noted previously, in most gastric conditions, the histology can vary considerably in the different gastric compartments and in different areas within the same compartment. Therefore, we cannot overemphasize the importance of obtaining adequate sampling from the body, antrum, and any endoscopically visible lesions. The Sydney System guidelines (five specimens, from the greater and lesser curvature in the antrum, the greater and lesser curvature in the corpus, and the incisura) (59) should be viewed as the minimum sampling, and in the presence of lesions, this sampling should be expanded accordingly. For example, removing a polyp without providing samples from the adjacent mucosa in addition to Sydney System-compliant biopsies will greatly reduce the pathologist’s ability to provide a meaningful diagnosis not only of the type of polyp but of the background on which it arises, thus preventing any assessment of the patient’s risk for gastric cancer and the H. pylori status. Unfortunately, this seldom happens in routine clinical practice, where less than 5% of all gastric biopsy sets are Sydney System compliant (89).




Acute alcoholism

Multiorgan failure


Certain foods

Severe burns

Portal hypertension



Alkaline refluxa

Congestive heart failure



Bile refluxa

Respiratory failure

Corrosive agents

Certain infections

Major surgery

Increased intracranial pressure

a Acute inflammation uncommon.


H. pylori infection and bacterial suppurative gastritis are “acute” according to the Sydney System (59). Acute hemorrhagic gastritis and alcohol-induced gastritis are not etiologically infection; however, because of their often abrupt onset clinically, they commonly fall under the umbrella of acute gastritis (Table 4.5). Although not entirely accurate, for the sake of uniformity, we will adhere to this convention.

Suppurative Gastritis

Most cases of suppurative (phlegmonous) gastritis antedate the antibiotic era. The disease typically affects severely debilitated individuals. Patients present with dramatic episodes of
nausea, vomiting, and severe, acute, noncolicky, epigastric pain. Commonly, peritonitis or pleural effusions develop. The clinical course resembles that of patients with a perforated viscus. The mortality rate approaches 100% unless the affected part of the stomach is resected. Some patients develop abscesses. The most common offending organisms belong to Streptococcus species.

The stomach appears dilated and the wall is thickened, rigid, and purplish. Marked submucosal brawny edema leads to flattening of the rugal folds and hyperemia; fibrinous serous adhesions are also present. In some cases, the mucosa contains focal necrosis; in others, a mucopurulent exudate completely replaces the mucosa. Acute inflammation with or without microabscesses and hemorrhage affects the submucosa. Widespread intravascular thrombosis involving the mural vessels results in secondary ischemic gangrenous necrosis with transmural inflammation. The muscularis propria appears variably inflamed and necrotic. A Gram stain demonstrates bacteria in the tissues.

Emphysematous Gastritis

Emphysematous gastritis, a form of suppurative gastritis, results from infections by gas-forming organisms, most commonly Clostridium, Escherichia coli, Streptococcus, Enterobacter, and Pseudomonas aeruginosa (90). Predisposing conditions include previous surgery, alcohol abuse, corrosive ingestion, pancreatitis, and cancer (90). Clinical features include an acute abdomen, systemic toxicity, and radiographic evidence of air bubbles in the gastric wall. Approximately two thirds of patients die of their disease; long-term complications include gastric fibrosis with stricture formation.

The gastric wall feels crepitant due to the presence of numerous, variably sized, air-filled, intramural spaces. In advanced cases, the gastric wall appears thickened, gangrenous, and necrotic.

The most prominent histologic findings consist of submucosal thickening, edema with transmural neutrophilic collections, a purulent serosal surface, patchy mucosal necrosis, and pneumatosis (Fig. 4.30). The infection rarely spreads to adjacent organs.

FIG. 4.30 Emphysematous gastritis. Photograph of the gastric mucosa showing the presence of an inflamed, partially necrotic, gastric mucosa. Deep in the mucosa, one sees large, dilated, air-filled spaces.

FIG. 4.31 Stress ulcers. A: Multiple small punctate hemorrhagic ulcers in a patient who died of severe head trauma. Scattered small petechiae are also visible. B: Higher-power magnification of individual lesions.

Acute Hemorrhagic, Erosive Gastritis (Stress Gastritis)

Acute erosive gastritis complicates major physiologic disturbances including sepsis, extensive burn injury, head injury, severe trauma, and multiorgan failure. It may also develop following ingestion of NSAIDs, aspirin, or alcohol. Acute gastritis often presents as abdominal discomfort, pain, heartburn, nausea, vomiting, and hematemesis. Bleeding begins 3 to 7 days following the injurious event and may range from occult blood loss to massive hemorrhage originating from innumerable foci of mucosal damage or from larger discrete ulcers (Fig. 4.31). Curling ulcers develop in severe burn
patients within 24 to 72 hours, predominantly in the proximal stomach.


Major factors implicated in the development of stress ulcers include hyperchlorhydria and decreased mucosal protection. The latter results from decreased mucus secretion, mucosal blood flow, prostaglandin synthesis, and mucosal barrier breakdown. Indeed, mucosal ischemia is the common denominator of stress-associated injury. Cardiac dysfunction, hemorrhage, shock, and sepsis redistribute blood flow away from the subepithelial capillaries, causing mucosal hypoxia. The hypoxia may persist after recovery from the initial injury, especially as mucosal arterioles contract, further reducing tissue oxygenation (91). An adequate microcirculation that provides nutrients and removes waste products, particularly oxygen-free radicals, is required to maintain the mucosal barrier. A damaged mucosal barrier allows back-diffusion of acid, resulting in tissue acidosis, vascular compromise, mucosal congestion, and necrosis. The mucosal injury increases significantly during the reperfusion that follows ischemia due to the production of toxic oxygen-free radicals (92) and by infiltrating neutrophils (93). In addition, activated leukocytes release mediators that reduce mucosal blood flow and increase vascular permeability (94,95). The oxygen-free radical-induced injury is further enhanced by mucosal depletion of the endogenous antioxidant-reduced glutathione (GSH) (96). The GSH oxidation/reduction cycle, catalyzed by glutathione peroxidase, reduces H2O2 and breaks the chain reaction that generates highly reactive hydroxyl radicals. GSH acts as a natural scavenger whose superoxide anion protects proteins against oxidation. GSH also plays a major role in restoring other free radical scavengers and antioxidants such as vitamins E and C to their reduced state (97). Prostaglandins limit the initial injury (98). Oxidative stress leads to epithelial growth factor receptor (EGFR) phosphorylation and increased production of its ligands, EGF, and amphiregulin (99). A mucoid cap promotes mucosal restitution by protecting the lamina propria from luminal acid, limiting the extent of the injury (98).

Various factors contribute to the repair of acute gastric mucosal injury. Re-epithelialization requires epithelial migration across an intact basal lamina. This occurs within minutes to hours of the injury to ensure quick restoration of surface epithelial continuity and inhibiting acid back-diffusion (98). In addition, cells in the mucous neck region migrate out of the proliferative zone and progressively differentiate into mature foveolar cells. Gastric mucosal blood flow increases (98). If this is inhibited, mucosal cytoprotective events fail and the mucosal injury progresses with deeper ulceration than would otherwise result from the initial injury.

Pathologic Features

Erosive gastritis and stress ulcers typically appear as multiple lesions located anywhere in the stomach, although they tend to predominate in the oxyntic mucosa (Fig. 4.31). When severe, they extend to the antrum. Stress ulcers tend to be superficial and usually measure less than 15 mm in diameter. The ulcer bases appear grayish yellow and hemorrhagic with slightly raised, congested, regenerative margins. The intervening gastric mucosa appears diffusely congested and contains numerous small petechial hemorrhages. Alternatively, the mucosa is diffusely hemorrhagic without discrete areas of damage. Early lesions center around intensely congested blood vessels, which leak blood into the surrounding tissues (Fig. 4.32). Extensive hemorrhagic mucosal erosions or ulcers develop in more severe cases. Rare cases present with deep linear ulcers coexisting with more discrete, round, superficial lesions. Curling and Cushing ulcers tend to be deep and single.

FIG. 4.32 Close-up gross photograph of the gastric mucosa in a patient who died of multiorgan failure. Note the intensely congested vessels as well as the areas of neovascularization. Pinpoint hemorrhages extend from vessels of all sizes contributing to the diffuse leakage of blood from the gastric surface.

The histologic features depend on the severity and duration of the underlying insult; they are often not as dramatic as the gross features. Features associated with acute gastritis are listed in Table 4.6. Mucosal changes range from hyperemia, surface erosions, and acute inflammation to massive mucosal necrosis (Fig. 4.33), sloughing, and eventual scarring. Lesions seen in biopsies are typically early. More severe

disease shows extreme vascular congestion with dilation and hemorrhage into the superficial lamina propria (Fig. 4.33) often associated with acute inflammation (Fig. 4.33).


Acute phase

Vascular engorgement

Lamina propria hemorrhage

Superficial necrosis

Polymorphonuclear leukocytes in pits and glands

Ulcers and erosions

Superficial fibrin deposits

Healing phase

Epithelial regeneration with nuclear enlargement

Pit elongation

Mucus depletion

Numerous mitoses

FIG. 4.33 Early changes of acute erosive gastritis. A: The earliest changes consist of vascular dilation in the superficial lamina propria. The overlying epithelium remains intact. B: Small thrombi develop (arrow) and the superficial lamina propria becomes increasingly edematous. C: With further disease progression, the tops of the gastric surface become eroded with loss of the surface epithelium. D: In larger lesions, extensive areas of transmucosal necrosis are present. E: Portions of the superficial epithelium degenerate, forming amorphous pinkish fibrinous debris on the surfaces of the mucosa. The glands become widely dilated and the surrounding lamina propria is infiltrated with extravasated red cells. F: Higher magnification of the extravasated red cells.

Erosions appear as discrete, superficial oval or circular areas of mucosal necrosis and tissue loss that do not extend deeper than the muscularis mucosae and have sharply defined, often raised edges; edema; and superficial epithelial necrosis (Fig. 4.33). Numerous neutrophils infiltrate the gastric pits and glandular lumina (Fig. 4.34). The inflammation usually spares the deepest glands. True granulation tissue is absent. Rather, the eroded cavity contains an exudate of proteinaceous fluid, debris, neutrophils, and red cells. The mucosa contains superficial fibrin deposits (Fig. 4.33). Chronic inflammation is absent in the acute phase. Only a minimal reparative fibroblastic response occurs when the injury is minor. Healing occurs in days to weeks following removal of the causative factor(s).

The healing phase (Table 4.6) is characterized by proliferation of stem cells in the mucous neck region, pit elongation, a pseudostratified or syncytial appearance of the superficial epithelium, and vascular congestion (Fig. 4.34). The stem cells differentiate into foveolar cells above and specialized glandular epithelial cells below, reconstituting a normal mucosal architecture within a few days. Proliferating mucous neck cells contain abundant basophilic cytoplasm, increased mitoses, and an increased nuclear:cytoplasmic ratio and appear mucin depleted. Despite their potentially alarming cytologic features (Fig. 4.34), the nuclei of the regenerating epithelium retain a basal orientation and contain vesicular chromatin and a prominent solitary eosinophilic nucleolus. The nuclear pleomorphism and atypical mitoses characteristic of neoplasia are usually absent. Residual clusters of neutrophils may reside within the pits and the surrounding lamina propria may be inflamed. One must be careful not to mistake regenerative changes for carcinoma. Atypical regenerative epithelium still retains a normal glandular architecture. If one can line the glands up parallel with one another in a regular fashion, perpendicular to the mucosal surface, if
there is acute inflammation, and if lamina propria separates the glands, one should be extremely cautious before making a diagnosis of malignancy, even in the face of extreme epithelial atypia.

FIG. 4.34 Evolving erosive gastritis. A: The mucosal surface is eroded, and as a result, mucous neck regions become hyperchromatic and appear regenerative. B: With further disease progression, one sees a marked expansion of the mucous neck region with the regenerative cells showing significant reparative atypia. C: The surface cells acquire a syncytial appearance. D: Eventually, the entire surface becomes re-epithelialized, although the epithelium appears immature and has a large nuclear to cytoplasmic ratio. Some residual syncytial knots remain.

Superficial erosions usually heal completely, without evidence of scarring, providing the inciting agent disappears. In patients with deeper lesions, complete regeneration of the gastric glands rarely occurs. Rather, mild mucosal scarring results.

Ethanol-Induced Gastritis

The extent of alcohol-induced injury results from the quantity of alcohol ingested as well as its mucosal contact time (100). Alcohol contacting the superficial gastric mucosa impairs mucus synthesis and secretion and damages epithelial cells, causing them to become necrotic and slough, leaving the underlying mucosa exposed to the alcohol and to gastric luminal acid (101). Acid back-diffusion increases mucosal blood flow, capillary permeability, and acid secretion. Increased capillary permeability leads to interstitial edema. Vasoactive mediator release from mast cells, endothelial cells, and neutrophils triggers venoconstriction and plasma transudation. The neutrophils generate superoxide anion and hyperchlorous acid in a manner similar to that seen in stress gastritis (102). Arterial and arteriolar dilation rapidly follow, leading to marked congestion, edema, hemorrhage, cellular translocation, ischemia, and cell membrane damage sufficient to cause local edema, hypoxia, hemorrhage, and cellular necrosis (Fig. 4.35). Alcohol penetration into the congested tissues causes hemolysis, vascular congestion, protein precipitation, vascular stasis, thrombus formation, and capillary leakage (103). Neuropeptides stimulated by the alcohol affect blood vessels, leukocytes, and epithelium and aid in activating inflammatory mediators (98). Ethanol gastritis is also associated with ulcer formation in rat models (104).

FIG. 4.35 Alcohol-induced gastric injury. A: Low magnification demonstrates the presence of superficial damage and mucosal congestion in the oxyntic mucosa. B: Another area showing the presence of superficial loss of the epithelium, edema, congestion, and little inflammation.

Individuals who ingest large quantities of alcoholic beverages show multiple areas of subepithelial hemorrhage, prominent mucosal edema in the adjacent nonhemorrhagic mucosa, and only mild inflammation. The edema may be severe enough to extend into the submucosa (105). The foveolar epithelium overlying the lamina propria hemorrhage may appear mucin depleted and show focal loss of nuclear polarity. These resemble the lesions seen in stress gastritis and predominantly involve the proximal stomach. In these patients, there may be focal necrosis of the foveolar epithelium along with focal neutrophilic infiltrates in the gastric pits. Chronic ethanol ingestion increases mucosal expression of EGF and other growth factors (101) leading to increased cell proliferation. Differentiation of cells in the proliferating mucous neck region replaces the damaged cells.


Many drugs produce gastric erosions, hemorrhage, and necrosis, the most common of which are NSAIDs and aspirin. The pathogenesis of the injury varies. Some drug-induced and stress-induced ulcers share common pathogenetic pathways, but the factors that lead to the initial cellular damage may differ. The fact that many drugs produce similar changes whether administered intravenously or orally suggests that mucosal contact need not occur to produce the damage.


The nature of aspirin-related injury depends on whether the drug ingestion is acute or chronic. One-time aspirin ingestion causes subepithelial hemorrhages within an hour, and regular intake over a 24-hour period leads to gastric erosions in many individuals. Chronic ingestion often results in less severe damage than does acute ingestion because mucosal adaptation occurs, making the mucosa resistant to injury. The adaptive response involves decreased neutrophilic
infiltration and extensive epithelial proliferation (106). Aspirin-induced damage results from its direct toxic effects as well as by decreasing mucosal defenses (107). The physicochemical property of aspirin aids in its rapid absorption, mucosal accumulation, and mucosal barrier breaking effects. Salicylates in aspirin become trapped inside gastric epithelia interfering with ATPase-dependent processes and leading to increased membrane permeability. Eventually, osmotic swelling and cell death develop. Additionally, small aspirin fragments may become embedded in the mucosa. These produce circular erosions or ulcers surrounded by hemorrhagic zones. Adjacent erosions become linked by linear mucosal cracks. The aspirin particles then fall into the cracks and become walled off in mucus until they dissolve.

Nonsteroidal Anti-Inflammatory Drugs

NSAIDs are a common cause of grossly visible gastric injury and are responsible for some of the most severe drug injury seen in the United States (108). Gastric injury typically complicates the use of NSAIDs prescribed by physicians. However, consumption of high-dose over-the-counter NSAIDs also causes significant gastrointestinal injury (109). Gastroduodenal lesions develop in one to two thirds of patients on chronic therapy and up to 25% have gastric ulcers (110). The vast majority of individuals utilizing NSAIDs are 60 years of age or older. These patients are particularly susceptible to develop GI hemorrhage and gastric ulcers, in part due to the fact that mucosal prostaglandin levels decrease in the elderly (111).

NSAIDs cause direct local mucosal toxicity and inhibit hydrogen sulfide generation (112) and cyclooxygenase enzymes. The latter leads to reduced prostaglandin synthesis. As noted earlier, prostaglandins are critical to maintaining the integrity of the mucosal barrier. Most NSAIDs are weak organic acids and, in the highly acidic stomach, are deionized so that they are lipid soluble and diffuse freely into the epithelium elevating intracellular pH. The damaged mucosa becomes leaky allowing acid back-diffusion, peptic injury, erosions, hemorrhage, and other damage to occur. Coexisting HP infections increase mucosal susceptibility to NSAID-mediated damage and increase the risk of ulceration and bleeding (113).

NSAIDs may cause acute mucosal lesions within 7 days of administration by the mechanisms shown in Figure 4.36. Altered blood flow and increased leukocyte-endothelial interactions in the gastric microcirculation occlude microvessels, further reducing mucosal blood flow. The inflammatory cells also release various procoagulants, inflammatory mediators, proteases, and oxygen-free radicals that further damage the endothelium and the underlying connective tissue (114). NSAID effects are summarized in Table 4.7 (107).

NSAIDs may cause several types of injury: hemorrhagic gastritis, erosions, reactive (or chemical) gastropathy, ulcers, and perforation. Because of the direct local toxicity caused by NSAIDs, the damage is patchy and is increased in areas of mucosal contact. Thus, injury is more common in dependent parts of the stomach (antrum and body along the greater curvature). Gastric ulcers are of greater clinical significance than
erosions because of their chronicity and their potential for perforation and significant bleeding.

FIG. 4.36 Diagram of the mechanism of nonsteroidal anti-inflammatory drug (NSAID) damage. Following NSAID absorption, there is uncoupling of mitochondrial oxidative phosphorylation leading to reduced adenosine triphosphate (ATP) levels, which in turn result in the loss of intercellular junctional integrity and increased mucosal permeability. Also, as a result of the mitochondrial oxidative phosphorylation uncoupling, an efflux of calcium and hydrogen ions from mitochondria occurs, further depleting ATP stores and promoting oxygen radical damage. The damaged cell releases arachidonic acid, but the conversion of arachidonic acid to prostaglandins is prevented by the NSAID inhibition of cyclooxygenase. As a result, the damage of the gastric mucosa is more prolonged than would ordinarily be the case. As a result of the damage, the mucosa becomes vulnerable to luminal aggressive factors, which include acid, pepsin, bile, and Helicobacter pylori.

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Oct 28, 2018 | Posted by in GASTROENTEROLOGY | Comments Off on The Nonneoplastic Stomach
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