Neutrophil Infiltration

The lamina propria of normal gastric mucosa may contain a few scattered neutrophils. However, infiltration of the epithelium by neutrophils represents a pathologic tissue response and is considered an active component of gastritis. The term active is used to indicate a sustained release of inflammatory mediators and a persistent cause for this process. In the United States, neutrophilic infiltration of the epithelium is most commonly caused by H. pylori gastritis, but other infectious and inflammatory conditions (e.g., syphilis,¹⁶ Crohn’s disease¹⁷) may cause neutrophil infiltration.

If sufficient numbers of biopsy specimens are examined, neutrophils are detected in almost all patients with H. pylori infection.^18–20 Evaluation of the intensity of neutrophil infiltration may help to differentiate the various types of gastritis. For instance, the acute phase of infectious gastritis (i.e., phlegmonous gastritis) may have abundant neutrophils, and the active phase of Helicobacter-induced gastritis may have moderate to severe levels of neutrophils. Acute hemorrhagic gastritis resulting from nonsteroidal anti­inflammatory drugs (NSAIDs)– or alcohol-induced chemical injury, often shows only minimal neutrophil infiltration, unless ulceration exists.

Mononuclear Infiltration

Normal antral mucosa contains few mononuclear inflammatory cells, whereas normal corpus mucosa contains virtually none. However, the density of mononuclear cells (i.e., lymphocytes and plasma cells) in the lamina propria of normal persons varies considerably according to their geographic location and ethnicity.²¹ To properly gauge the presence of gastritis, pathologists should set a standard for normal that is relevant to the patient population in their geographic region. Scattered lymphocytes and plasma cells in the lamina propria of the antrum are normal in individuals from most countries (see Fig. 15.2). In the absence of established norms for the particular geographic region, it is recommended that gastritis not be diagnosed unless there are at least several clusters of five or more mononuclear cells in the lamina propria or the infiltrate is diffuse. In the corpus and fundus, rare mononuclear cells in the lamina propria are considered a normal finding. Under normal conditions, intraepithelial lymphocytes are not found anywhere in the gastric mucosa.

Infiltration of the mucosa with lymphocytes, plasma cells, and a number of eosinophils and mast cells is characteristic of chronic H. pylori gastritis. In autoimmune gastritis, the infiltrate is often diffuse, consists mainly of plasma cells and lymphocytes,²² and usually extends to the deep portions of the mucosa, and the corpus and fundus of the stomach are selectively involved.

Lymphoid Aggregates and Follicles

Normal gastric mucosa, particularly the corpus, may contain occasional, small lymphoid aggregates, usually located close to the muscularis mucosae at the base of the lamina propria. In contrast, lymphoid aggregates with germinal centers (i.e., follicles) are rare in gastric mucosa of normal, H. pylori–negative adults.²³ In studies that have used an extensive standardized biopsy protocol, lymphoid follicles or aggregates have been detected in almost all individuals with H. pylori gastritis. The finding of lymphoid follicles is highly specific for H. pylori infection (Fig. 15.3). In H. pylori–infected children and young adults, lymphoid follicles may be quite numerous, which may produce an endoscopic appearance of nodularity that is often referred to as follicular gastritis.^24,25

Eosinophil Infiltration

Rare, scattered eosinophils may be seen in the gastric mucosa of normal healthy patients, particularly in individuals who live in a suboptimal public health environment. A prominent eosinophilic infiltration usually represents a pathologic process, such as eosinophilic gastritis or gastroenteritis.^26,27 Eosinophil infiltration may occur in a wide variety of disorders, such as gastric anisakiasis and other granulomatous or parasitic infections of the stomach.²⁸

In adults with H. pylori gastritis, a usually mild eosinophil infiltration often composes a portion of the inflammatory infiltrate. A greater eosinophilic component of the inflammatory infiltrate may manifest in children with H. pylori infection (Fig. 15.4).²⁹ After H. pylori eradication, eosinophils may persist for a long time, similar to mononuclear cells.¹⁸

Mucosal Hyperemia and Edema

Mucosal hyperemia (congestion) and edema are often endoscopic or pathologic indicators of chemical injury. In one study, a significant correlation was found between the degree of hyperemia and the concentration of bilirubin within gastric fluid.³⁰ However, congestion and edema may also be features of H. pylori gastritis, which may be caused by an increase in the number of mast cells (Fig. 15.5) that occurs in this condition.^31,32

Surface Epithelium Degeneration

Surface epithelium degeneration is considered a nonspecific response to injury that occurs to some degree in all forms of gastritis. However, degenerative changes are particularly conspicuous in two disorders: chemical gastritis (resulting from bile reflux, ethanol, or NSAIDs) and H. pylori gastritis.^33–35 Regardless of the cause, epithelial injury and necrosis lead to surface erosions. Degenerative changes may result in the appearance of cuboidal (rather than columnar) cells and mucin depletion. The former is particularly common in gastritis occurring after Billroth II surgery and thought to result from bile reflux. However, these changes may also be found in H. pylori gastritis, even in areas where bacteria are few in number. Alternatively, epithelial regeneration, a common feature of H. pylori gastritis, may result in the accumulation of buds of cells at the surface of the mucosa (Fig. 15.6).³⁶

Surface Erosion

Surface erosions are the result of severe epithelial injury and necrosis. By definition, erosions do not extend beyond the muscularis mucosae. Endoscopically flat surface erosions often result from the acute effects of drugs, alcohol, bile reflux, or ischemia (Fig. 15.7).^37,38 Endoscopically elevated surface erosions are typically associated with H. pylori gastritis. These erosions are usually characterized by a superficial layer of fibrinopurulent debris (i.e., fibrinoid necrosis, neutrophils, and cellular debris) with hyper­plastic, regenerative-appearing epithelium at the margins (Fig. 15.8).³⁹

Foveolar Hyperplasia

Foveolar hyperplasia is defined as proliferation, elongation, and tortuosity of gastric pits that result in a corkscrew configuration. It is a compensatory tissue response to increased exfoliation of the surface epithelium and represents a visual surrogate for increased cell proliferation and turnover (Fig. 15.9). Although markedly hyperplastic foveolae are normally recognized microscopically, minimal or mild foveolar hyperplasia can easily be overlooked. True foveolar hyperplasia may be diagnosed reliably when more than four cross-sections of the same gastric pit are visualized in a single, well-oriented gastric biopsy specimen.^40,41 Other features of foveolar hyperplasia include hyperchromatic nuclei, cells with a high nucleus-to-cytoplasm ratio, upper pit mitoses, mucin depletion, and cuboidalization of the epithelial cells.

Foveolar hyperplasia is a characteristic and prominent feature of bile reflux gastritis³⁰ and NSAID gastropathy, particularly in long-term users.^30,40,41 A mild degree of foveolar hyperplasia is common in patients with H. pylori gastritis; however, marked hyperplasia indicates coexistent chemical injury (Fig. 15.10).⁴²

Intestinal Metaplasia

Intestinal metaplasia is defined as the replacement of gastric-type mucinous epithelial cells with small intestinal cells (e.g., goblet cells, enterocytes) (Fig. 15.11).⁴³ Two types of intestinal metaplasia (I and II) have been described but are of limited clinical importance. Metaplastic epithelium that closely resembles normal small intestinal epithelium, containing acid mucin–producing goblet cells and absorptive enterocytes with a brush border, is considered complete metaplasia (type I). Incomplete metaplasia (type II) shows a disorderly mixture of irregularly shaped goblet cells (intestinal and immature intermediate mucous cells) that contain acidic sialomucins and sulfomucins. Incomplete metaplasia is further subdivided into type IIa and type IIb by the finding of sulfomucins within nongoblet (mucinous) cells in the latter.⁴⁴ Although the incomplete forms of intestinal metaplasia (especially type IIb, also unfortunately referred to as type III) are associated with an increased risk of gastric cancer, the practical application of defining the precise type of metaplasia in any single individual is limited because most patients have a mixture of the incomplete and complete types when extensive areas of mucosa are sampled.⁴³ However, because the degree of incomplete intestinal metaplasia (type IIb) parallels the extent of intestinal metaplasia in general, there is a positive correlation between the degree of any type of intestinal metaplasia and the risk of progression to carcinoma.

Intestinal metaplasia can be identified and its extent evaluated with the use of specific mucin histochemical stains. For instance, the Alcian blue/periodic acid–Schiff (AB/PAS) stain at pH 2.5 is an excellent method for demonstrating the type and extent of intestinal metaplasia, particularly when used in combination with a hematoxylin counterstain (Fig. 15.12). Mucin histochemical stains (e.g., high-iron diamine) that were traditionally used to determine the specific type of intestinal metaplasia by detecting sulfated mucins have been largely replaced by immunohistochemical stains that identify proteins associated with particular mucin-encoding genes. Although more than 20 such mucin genes have been identified, only a few (i.e., MUC1, MUC2, MUC5AC, and MUC6) are used routinely in practice, and even those are used mainly in research settings (Table 15.2).

Intestinal metaplasia may develop in a variety of pathologic settings, but it usually indicates an underlying chronic atrophic gastritis (chronic atrophic gastritis does not equal autoimmune chronic atrophic gastritis). Several studies have shown that intestinal metaplasia occurs more frequently in patients with H. pylori gastritis.^45,46 Because the H. pylori organism does not normally adhere to intestinal-type epithelium (see Fig. 15.11) but disappears in mucosa with extensive intestinal metaplasia and atrophy, one theory posits that intestinal metaplasia represents a host defense against H. pylori infection. Intestinalized epithelium may provide additional defense against H. pylori through changes in the composition of the gastric mucus resulting from metaplasia. Alternatively, metaplasia may represent a type of physiologic adaptation to altered bacterial flora; for instance, bacterial overgrowth may underlie the development of intestinal metaplasia in late-stage autoimmune gastritis, and sulfomucins are more resistant than other mucin types to bacterial enzyme–related degradation.

Intestinal metaplasia is frequently found in the corpus of patients with autoimmune gastritis, and foci of intestinal metaplasia are common in patients with reactive gastropathy after Billroth II surgery.⁴¹ Metaplasia is found in individuals with an otherwise completely normal stomach. The biologic significance of intestinal metaplasia remains poorly understood.

Atrophy

Gastric atrophy is defined as a loss of gastric glands.^10,47 Atrophy is a histologic finding, not a nosologic entity. When gastric mucosa is damaged, regardless of the cause, it may regenerate to normal (restitutio ad integrum) or undergo an adaptive reparative change that leads to the replacement of native glands with other types of tissue.⁴⁸ When injured glands fail to regenerate, the stromal space they previously occupied within the lamina propria may be replaced by fibroblasts and extracellular matrix. The result of this process is loss of functional epithelium (i.e., atrophy).

The native glands may be replaced by those with a pyloric phenotype (i.e., pyloric or pseudopyloric metaplasia) (Fig. 15.13) or an intestinal phenotype (i.e., intestinal metaplasia), comprising goblet cells and absorptive cells (with or without a brush border). It is important to differentiate true atrophy from mimics, including normal antrum-body transition mucosa, in which pyloric-type glands may be mixed with oxyntic glands at the base of the mucosa, and normal fundus-cardia transition mucosa, in which mucous-type glands may be associated with oxyntic glands.

Diffuse fundic atrophy typically occurs in autoimmune gastritis as a consequence of immune-mediated destruction of oxyntic epithelium. Less severe and more focal atrophy, which is usually limited to the antrum, may also occur in reactive gastropathy (Fig. 15.14). The updated Sydney System recognizes multifocal atrophic gastritis (MAG), referred to as environmental atrophic gastritis in the pre–H. pylori era, as an entity distinct from nonatrophic gastritis and autoimmune atrophic gastritis.^8,49

The border between gastritis with focal atrophy and atrophic gastritis has not been well defined (Fig. 15.15). This issue is important because scattered foci of intestinal metaplasia are found in the antrum of most patients with H. pylori gastritis and of a small percentage of noninfected adults. It is not appropriate to classify these individuals with atrophic gastritis, a diagnosis that implies altered gastric function and an increased risk of cancer. In the absence of established guidelines, we suggest that a diagnosis of MAG should be made only when there is evidence of atrophy with or without intestinal metaplasia in at least 50% of a properly biopsied stomach (i.e., minimum of two samples from the antrum and two from the corpus or fundus).

Several pathology workshops have been devoted to developing a reproducible method for grading atrophy in mucosal biopies.^9,10 Pathologists have recommended that atrophy be evaluated according to its two subtypes: nonmetaplastic or metaplastic. The subtype known as nonmetaplastic atrophy is an area of mucosa with true glandular depletion (relative to the normal complement for that site) with or without fibrosis. The subtype known as metaplastic atrophy is replacement of native glands by intestinal-type glands anywhere in the stomach or pyloric (pseudopyloric) glands in the corpus (i.e., metaplasia equals atrophy). In both types of atrophy, the degree of gland loss may be graded as mild, moderate, or severe, which corresponds to a scale of 1 to 3 (Fig. 15.16).

Problems may arise when gastric biopsies are labeled as “stomach” or “antrum-body,” in which case it may be difficult to determine whether there is true pyloric metaplasia or the biopsy is simply representative of the antrum or antral-fundic transition. In this instance, immunohistochemical staining for gastrin-positive endocrine cells can help to identify mucosa derived from the antrum. The algorithm depicted in Figure 15.17 summarizes an approach to the evaluation of atrophy in gastric biopsies.

Endocrine Cell Proliferation

Endocrine cell hyperplasia develops as a consequence of functional changes in the stomach and is most prominent in autoimmune atrophic gastritis. In this condition, hypochlorhydria or achlorhydria may lead to antral G cell hyperplasia and a secondary elevation of the serum gastrin level.^50,51 Hypergastrinemia causes histamine-producing enterochromaffin-like (ECL) cells within oxyntic mucosa to proliferate. Once thought to be rare and limited to patients with advanced atrophic gastritis, neuroendocrine proliferation is now frequently seen in routine gastric biopsies as a result of widespread use of proton pump inhibitors (PPIs).⁵² Although endocrine hyperplasia can be detected easily on hematoxylin and eosin (H&E)–stained tissue sections of the antrum (Fig. 15.18), hyperplasia of ECL cells in oxyntic mucosa is best visualized and quantified with specific immunostains (Fig. 15.19). Immunostains have largely replaced the use of argentaffin and argyrophil-based histochemical stains. In routine practice, staining of endocrine cells helps to identify cases of autoimmune atrophic gastritis of the corpus. A mild to moderate degree of ECL cell hyperplasia may occur in a subset of patients who use PPIs for extended periods. However, in these patients, the oxyntic mucosa is not atrophic and may display parietal cell hypertrophy and oxyntic gland dilations, which are characteristically seen in chronic PPI users.

The most widely used criteria for the diagnosis and classification of gastric endocrine cell proliferation are those proposed by Solcia and colleagues (see Chapter 29).⁵³ The classification system distinguishes simple or diffuse, linear, micronodular and adenomatoid hyperplasia, dysplasia, and neoplasia (i.e., carcinoid tumors) and is reviewed in the section on Autoimmune Gastritis and in Table 15.3.

Parietal Cell Alterations

Apocrine-like protrusion and pseudohypertrophy of oxyntic cells are frequently attributed to chronic use of PPIs (Fig. 15.20).^54,55 However, identical histologic changes have been reported in other clinical settings, and the findings are therefore not pathognomonic.⁵⁶ Use of PPIs may also lead to dilation of oxyntic glands, which in extreme cases may produce multiple fundic gland–type polyps that impart an appearance of the gastric mucosa that inspired the picturesque description of gastric acne.^57,58 Because most chronic users of NSAIDs also take PPIs to reduce the risk of NSAID-induced ulceration, oxyntic gland alterations are frequently seen in conjunction with reactive (chemical) gastropathy.^41,59,60

Interfoveolar Smooth Muscle Hyperplasia

In the normal stomach, smooth muscle fibers are confined to the muscularis mucosae, where they run parallel to the mucosal surface. Several studies have shown that chemical injury is often associated with the smooth muscle fibers that run perpendicular to the muscularis mucosae within the interfoveolar lamina propria (see Fig. 15.9). This proliferation may be caused by the pulling effect of prolapsing mucosa, similar to that seen in the so-called solitary rectal ulcer syndrome. It is unclear whether peristalsis may exert analogous forces on injured gastric mucosa. Another proposed mechanism is the release of platelet-derived growth factor (PDGF), a known smooth muscle stimulant, as a result of epithelial damage. However, smooth muscle hyperplasia is not specific for NSAID-induced gastritis and may be seen in a variety of other conditions, such as gastric antral vascular ectasia (GAVE), bile reflux gastritis, and reactive mucosa adjacent to an ulcer.^41,60