Mucous neck cells reside in the neck and isthmic region of the gastric glands (Fig. 4.18). 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. Their tapered apical ends tend to bulge into the glandular lumen, whereas their broader basal surfaces rest against the basement membrane (Fig. 4.19). Parietal cells produce hydrochloric acid, intrinsic factor, TGF-α, 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 (30). 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 (31). 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. 4.20). 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 (31).

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. Chief cells constitute 20% to 26% of oxyntic glands lying

deep within them (Fig. 4.19). 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.

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% (41). Most arise on the posterior wall, in a juxtacardiac position (41). Congenital diverticula appear as solitary, sharply defined, round, oval, or pear-shaped pouches communicating with the gastric lumen via a narrow or broad-based mouth (Fig. 4.22).

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, 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 peptic ulcer disease, 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 (46).

Heterotopic pancreas is the most common gastric heterotopia. It accounts for 25% to 30% of all pancreatic heterotopias (47). 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. 4.24). 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. 4.25), 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 (48). If only pancreatic acini are present, the lesion may represent foci of pancreatic metaplasia (see below), especially if the cells lie within the mucosa. Sometimes one sees both heterotopic pancreatic and gastric tissue lying side by side in the submucosa (Fig. 4.26).

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. 4.25). Secondary changes such as pancreatitis, cyst formation, or neoplasia (islet cell tumors, ductal dysplasia [Fig. 4.27], and adenocarcinoma) may also cause confusion, particularly when they distort the underlying tissue (49). 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 colloid 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 (50). These are either 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).

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, and DNA and 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 (58). 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 (59) by infiltrating neutrophils (60). In addition, activated leukocytes release mediators that reduce mucosal blood flow and increase vascular permeability (61,62). The oxygen-free radical-induced injury is further enhanced by mucosal depletion of the endogenous antioxidant reduced glutathione (GSH) (63). 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 (64). Prostaglandins limit the initial injury (65). Oxidative stress leads to epithelial growth factor receptor (EGFR) phosphorylation and increased production
of its ligands, EGF and amphiregulin (66). A mucoid cap promotes mucosal restitution by protecting the lamina propria from luminal acid, limiting the extent of the injury (65).

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 (65). 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 (65). 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. 4.32). When severe, they extend to the antrum. Stress ulcers tend to be superficial and usually measure <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. 4.33). 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 4.5. Mucosal changes range from hyperemia, surface erosions, and acute inflammation to massive mucosal necrosis (Fig. 4.34), sloughing, and eventual scarring. Lesions seen in biopsies are typically early. More severe changes are usually seen at the time of autopsy. Mild stress gastritis may be difficult to distinguish from biopsy trauma. More severe disease shows extreme vascular congestion with dilation and hemorrhage into the superficial lamina propria (Fig. 4.34) often associated with acute inflammation (Fig. 4.34).

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. 4.34). Numerous neutrophils infiltrate the gastric pits and glandular lumina (Fig. 4.35). 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. 4.34). 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 4.5) is characterized by proliferation of pluripotential stem cells in the mucous neck region, pit elongation, a pseudostratified or syncytial appearance of the superficial epithelium, and vascular congestion (Fig. 4.35). 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. 4.35), 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 (Fig. 4.36).

HP infections occur worldwide, although there are marked geographic variations in their incidence. The prevalence of HP infections in adults ranges from <15% in some populations to virtually 100% in less well-developed areas. There are also substantial variations among different ethnic groups in the same geographic locale (105). In developing countries, people become infected much earlier in life than in
developed countries. The prevalence of HP infections correlates with lower socioeconomic status (106). The human stomach is the primary reservoir for the organism and it is transmitted via an oral–oral route and possibly via a gastric–oral and fecal–oral route (107). The infection is easily passed from one family member to another, particularly in areas of dense housing. Children under the age of 5 are most susceptible to HP infections. HP infections are present in gastric biopsies of 16.8% to 55% of children with abdominal pain, upper gastrointestinal symptoms, and histologic evidence of acute and/or chronic gastritis (106). The infection prevalence in developing countries can be as high as 75% by age 25. There has been a recent decline in the incidence of HP infections in the developed world, largely due to improved living conditions and a decrease in living density and family size. Even though the prevalence of HP infections is currently decreasing, at least 50% of the world population is infected with the organism (108).

Recurrent infections are usually a persistent infection rather than the acquisition of new infections. Infection with more than one HP strain can also occur (109). When AIDS patients become infected, the disease may exhibit particularly virulent characteristics and large numbers of organisms may be present.

HP is highly adapted to occupy a special ecologic gastric niche with unique features that allow it to enter the mucus of the mucosal barrier, attach to the epithelium, evade immune responses, proliferate, and colonize the gastric mucosa. The eventual outcome of HP infections reflects strain-specific, environmental, and host-related factors. After they are ingested, HP organisms must evade the bactericidal activity of the gastric lumen and enter the mucous layer. Corkscrewlike bacterial movement and enzyme production (particularly urease and lipase) are important early in the infection (110,111). Bacterial proteases digest gastric mucin (194,195,196,197) facilitating bacterial movement and urease protects the HP from the luminal acid by creating an alkaline microenvironment around the bacterium (110,111).

HP bacteria normally reside in the unstirred layer of gastric mucus. They wind down to the epithelial surface, moving easily through the viscous environment above it, to attach themselves to the apical membranes of foveolar cells (Fig. 4.51). Bacterial adhesins recognize cell surface–specific proteins facilitating epithelial colonization. The best characterized adhesin, BabA, is a 78-kD outer bacterial membrane protein that binds to the fucosylated Lewis B blood group antigen (112). The Lewis blood group terminal carbohydrate structures are present on the ends of MUC1 carbohydrate side chains as well as on secreted mucins. MUC1 is highly polymorphic and evidence suggests that functional allelic differences affect infection susceptibility (113). HP bacteria also bind to MUC5AC, a major mucin produced by foveolar cells (114). The specificity of the binding, together with the limited distribution of the receptors, results in a restricted range of HP-colonized tissues. Bacteria unable to adhere to the epithelium are rapidly cleared from the mucosa. HP bacteria preferentially attach at or near intercellular junctions, penetrating the junctional complexes moving down along the lateral cell membranes. This disrupts intercellular tight junctions between viable cells, allowing luminal contents, including acid, to flow between the cells.

Most HP strains secrete the vacuolating cytotoxin VacA (115). The toxin inserts itself into the epithelial cell membrane and forms a hexameric anion-selective, voltage-dependent channel through which bicarbonate and organic anions can be released, possibly providing HP bacteria with their nutrients (116). VacA (117) also inhibits T-lymphocyte activation (118). Certain vacA gene variants produce more severe disease than others (119).

Most HP bacteria possess the cag pathogenicity island (cag PAI) that contains 29 distinct genes (120). Some of these genes facilitate translocation of the CagA protein into foveolar cells (121). Once in the cells, CagA is phosphorylated and binds to the SHP-2 tyrosine phosphatase (122), leading to host growth factor–like cellular responses, cytokine production, and cell proliferation (123). These cytokines mobilize leukocytes to areas of immune challenge. An EPIYA-repeat polymorphism influences the magnitude and duration of phosphorylation-dependent CagA activity (124). CagA also plays a major role in disruption of the apical junctional complexes (125). cagA-positive strains associate with increased epithelial cell apoptosis (126).

The oipA (outer inflammatory protein) gene encodes one of the outer membrane proteins and is an inflammation-related gene near, but not in, the CagA PAI. oipA functional status correlates with clinical presentation, HP density, and gastric inflammation. Cag PAI, babA2, and vacA status may
be a surrogate marker for a functional oipA gene (127). OipA and the cag PAI are both necessary for full activation of the IL-8 promoter (128). Nitric oxidase synthase and cyclooxygenase-2 are induced by HP infections; these enzymes modulate the inflammatory responses.

HP infections cause gastric inflammation (gastritis) in almost all infected persons, although the severity of the changes varies among individuals. The injury results from both the infection and its associated inflammation. Bile reflux and dietary irritants may further enhance the deleterious bacterial effects. Additionally, anti-HP antibodies that cross-react with the gastric mucosa induce further damage (129). Some HP-infected patients develop an autoantibody response directed at the H⁺-K⁺-ATPase pump in parietal cells leading to atrophy of the corpus (129).

Initially neutrophils are recruited to the infected site, followed by the recruitment of T and B lymphocytes, plasma cells, and macrophages. The neutrophilic infiltrate and mononuclear phagocytic activation may be facilitated by bacterial urease production and induction of nitric oxide synthase and cyclooxygenase (130). HP infections generate significant cellular and humoral responses via antigenic stimulation of mucosal monocytes and T cells. The inflammatory cells produce numerous cytokines (TNF-α, interferon-γ, and interleukins 1, 6, and 8), prostaglandins, proteases, and reactive oxygen metabolites that cause epithelial necrosis and mucosal injury. IL-8, a potent neutrophil-activating chemokine expressed by gastric epithelium, plays a central role in the inflammatory response (127,128). HP bacteria containing the cag PAI induce a stronger IL-8 response than cag-negative strains (131). Some cytokines promote leukocyte adhesion to endothelial cells and others recruit additional leukocytes to the infected site. Mediators of local humoral responses, such as mucosal IgA, attract eosinophils, which then degranulate. Stimulated B cells differentiate into IgM, IgA, and IgG antibody–producing cells (132). IgA promotes complement-dependent phagocytosis and HP killing by polymorphonuclear neutrophils (PMNs). Secretory IgA synergizes with IgG to promote antibody-dependent cell-mediated cytotoxicity induced by PMNs, monocytes, and lymphocytes. High anti-HP IgG antibody levels correlate with severe antral gastritis and dense HP antral colonization (132).