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.

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.

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 (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.

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).

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

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 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.

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

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.

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).

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.

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 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).

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.

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).

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.

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).

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 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.

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 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).

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.

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.

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).

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.

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.