Inflammatory Disorders of the Stomach

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CHAPTER 15

Inﬂammatory Disorders of the Stomach

Richard H. Lash Gregory Y. Lauwers Robert D. Odze Robert M. Genta

Chapter Outline

Historical Perspective Helicobacter pylori–Negative Chronic Gastritis General Pathologic Features of Gastritis Autoimmune Gastritis Neutrophil Infiltration Special Forms of Gastritis Mononuclear Infiltration Lymphocytic Gastritis Lymphoid Aggregates and Follicles Collagenous Gastritis Eosinophil Infiltration Eosinophilic Gastritis Mucosal Hyperemia and Edema Granulomatous Gastritis Surface Epithelium Degeneration Gastropathies Surface Erosion Reactive (Chemical) Gastropathy Foveolar Hyperplasia Chemotherapy- and Radiation-Induced Intestinal Metaplasia Gastropathy Atrophy Vascular Gastropathies Endocrine Cell Proliferation Gastric Cardia, Carditis, and Parietal Cell Alterations Gastroesophageal Junction Interfoveolar Smooth Muscle Hyperplasia Histology of the Gastroesophageal Junction Updated Sydney System Region Biopsy Protocol Intestinal Metaplasia of the Gastroesophageal Junction Evaluation of Histologic Variables Gastroesophageal Junction Biopsies to Determination of Gradient of Inflammation Differentiate Carditis from Ultrashort Barrett’s Diagnosis Esophagus Reporting Gastritis in the Absence of a Complete Reporting a Biopsy from the Gastroesophageal Biopsy Set Junction OLGA System Stomach in the Young and Elderly Acute Gastritis Lymphoid Hyperplasia Acute Hemorrhagic Gastritis Eosinophils Chronic Gastritis Atrophy Helicobacter pylori Gastritis Gastric Epithelial Dysplasia Gastric Ulcers Dysplasia Precursor Lesions Dieulafoy Lesion Unusual Variants

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Historical Perspective In 1947, at the dawn of gastroscopy, Rudolf Schindler deemed gastritis “one of the most debated diseases of the human body” and predicted that its significance would be discussed “for some time to come.”1 From the mid-1800s, when Cruveiller exposed the inaccuracies of Broussais’s first descriptions of gastritis in autopsy material, to the early 20th century, the concept of gastritis as a disease had been virtually abandoned.2 After gastritis was acknowledged as a distinct entity, the search for its cause began. Since 1870, tiny, curved bacteria within gastric mucosa have been described by human and veterinary pathologists, but the organisms were dismissed as irrelevant contaminants.3 Schindler claimed that the bac- teriologic cause of chronic gastritis had not been proved convincingly in a single case. 1 Instead, a wide range of etiologic theories were proposed, such as improper mastication, FIGURE 15.1 The normal superficial foveolar (neck) region of the a “coarse” or “miserable” diet, alcohol, caffeine, nicotine, gastric body contains rare or no mononuclear cells and no condiments and spices, drugs, heavy metals, thermal injury, neutrophils. chronic infections of tonsils and sinuses, circulatory distur- bances, and psychogenic factors. Not surprisingly, research- and duration of injury. Various degrees of tissue responses ers were successful in debunking theories put forth by their may occur synchronously or metachronously. The correct colleagues but were quite unsuccessful in proving their own. diagnosis of gastritis rests on the pathologic recognition of Subsequently, accurate morphologic data were gathered the types of tissue responses, their intensity, and their loca- by pathologic examination of autopsy material4 and from tion. To recognize pathologic tissue responses, it is essential endoscopic biopsy specimens. Distinct types and patterns to understand the spectrum of the histologic appearance of of gastritis were recognized, which led to the conception, normal gastric mucosa (Figs. 15.1 and 15.2; Table 15.1 ). presentation, dismissal, and replacement of many classifica- The following sections review the normal histologic vari- tion systems. Some systems were based on solid morpho- ability and common pathologic tissue reactions of gastric logic information and proposed valid clinicopathologic mucosa. associations (e.g., peptic ulcer and gastric cancer), but the lack of therapeutic implications reduced almost all classifi- Neutrophil Infiltration cations to little more than an academic exercise. In 1984, when Warren and Marshall proposed that chronic The lamina propria of normal gastric mucosa may contain idiopathic gastritis had a bacterial cause (i.e., Helicobacter a few scattered neutrophils. However, infiltration of the pylori), 5 it was not surprising that their hypothesis was met epithelium by neutrophils represents a pathologic tissue with skepticism. However, within a few years, the associa- response and is considered an active component of gastritis. tions of H. pylori gastritis, peptic ulcer, and gastric cancer The term active is used to indicate a sustained release of were recognized and, ultimately, accepted. 6 In 1990, guidelines for the classification and grading of gastritis were developed by a group of investigators in Sydney, Australia. The Sydney System correlates topographic, morphologic, and etiologic information with clinically useful diagnoses.7 Four years after its introduction, the Sydney System was updated by an international group of pathologists who established consensus terminology for gastritis, improved the guidelines for histologic grading, and streamlined the diagnostic process.8 Subsequently, modifications were made to improve the criteria for evaluation of atrophy.9,10 In 2006, an international consensus was reached on a diagnostic reporting system designed to use the staging of gastritis as a tool for assessing the risk of gastric cancer. 11-15 This chapter provides the terminology and diagnostic approach proposed by the updated Sydney System and its subsequent modifications.

General Pathologic Features FIGURE 15.2 The normal gastric antrum may contain scattered of Gastritis lymphocytes, plasma cells, and eosinophils in the lamina propria, as well as a few thin strands of smooth muscle. Examination of the Injury to the gastric mucosa elicits a variety of inﬂammatory distal antrum reveals an extended neck region that results in a mild and reactive responses that depend on the type, location, tortuosity and villous-like conﬁguration of the epithelium.

Table 15.1 Normal and Pathologic Histology of the Stomach Histopathologic Component Normal Setting Pathologic Settings Neutrophils Rare in lamina propria In active gastritis (Helicobacter pylori) and near Not found in normal epithelium erosion or ulcer Mononuclear cells Scattered isolated lymphocytes and plasma In chronic gastritis (H. pylori, autoimmune) and cells in lamina propria (antrum > corpus), lymphocytic gastritis (if intraepithelial) increase with age None or rare cells in epithelium Lymphoid aggregates Rare aggregates, basally located in oxyntic In H. pylori infection mucosa, without germinal centers Lymphoid follicles None In H. pylori infection Eosinophils Scattered in lamina propria, increase with age Moderate increase in H. pylori gastritis Not present in normal epithelium Severe with clusters or intraepithelial in eosinophilic gastroenteritis Edema of the lamina propria None In chemical injury, particularly bile reflux Hyperemia, congestion None In any form of active inflammation (H. pylori), chemical injury, or vasculopathies (e.g., GAVE) Surface epithelial None In H. pylori infection, chemical injury degeneration Regular, tall cuboidal cells with distinct apical mucin droplet is normal Erosions None In chemical injury (flat, not inflamed); H. pylori infection (elevated, inflamed) Foveolar hyperplasia None In chronic chemical injury; mucosa adjacent to ulcer; H. pylori infection Intestinal metaplasia None Antrum: H. pylori infection; chemical injury Corpus and fundus: multifocal atrophic gastritis, autoimmune gastritis, H. pylori infection Atrophy None Antrum: H. pylori infection (rare without Antrum: orderly pits separated by little matrix, intestinal metaplasia) no fibrosis Corpus and fundus: multifocal atrophic gastritis, Corpus and fundus: parallel, tightly packed autoimmune gastritis, H. pylori infection oxyntic glands reaching muscularis mucosae Endocrine cell hyperplasia None; no obvious G cells on H&E staining; no With chronic PPI therapy; atrophy, particularly clusters or nests autoimmune gastritis Parietal cell alterations No prominent protruding parietal cells; no With chronic PPI therapy lumen or dilations in oxyntic glands Interfoveolar smooth muscle Scattered fibers between antral foveolae; no In chronic chemical injury, GAVE hyperplasia bundles

GAVE , Gastric antral vascular ectasia; H&E, hematoxylin and eosin stain; PPI, proton pump inhibitor. inflammatory mediators and a persistent cause for this location and ethnicity.21 To properly gauge the presence of process. In the United States, neutrophilic infiltration of gastritis, pathologists should set a standard for normal that the epithelium is most commonly caused by H. pylori gas- is relevant to the patient population in their geographic tritis, but other infectious and inflammatory conditions region. Scattered lymphocytes and plasma cells in the (e.g., syphilis,16 Crohn’s disease 17 ) may cause neutrophil lamina propria of the antrum are normal in individuals from infiltration. most countries (see Fig. 15.2 ). In the absence of established If sufficient numbers of biopsy specimens are examined, norms for the particular geographic region, it is recom- neutrophils are detected in almost all patients with H. mended that gastritis not be diagnosed unless there are at pylori infection. 18-20 Evaluation of the intensity of neutrophil least several clusters of five or more mononuclear cells in infiltration may help to differentiate the various types of the lamina propria or the infiltrate is diffuse. In the corpus gastritis. For instance, the acute phase of infectious gastritis and fundus, rare mononuclear cells in the lamina propria are (i.e., phlegmonous gastritis) may have abundant neutro- considered a normal finding. Under normal conditions, phils, and the active phase of Helicobacter-induced gastritis intraepithelial lymphocytes are not found anywhere in the may have moderate to severe levels of neutrophils. Acute gastric mucosa. hemorrhagic gastritis resulting from nonsteroidal anti- Infiltration of the mucosa with lymphocytes, plasma inflammatory drugs (NSAIDs)– or alcohol-induced chemi- cells, and a number of eosinophils and mast cells is charac- cal injury, often shows only minimal neutrophil infiltration, teristic of chronic H. pylori gastritis. In autoimmune gastri- unless ulceration exists. tis, the infiltrate is often diffuse, consists mainly of plasma cells and lymphocytes,22 and usually extends to the deep Mononuclear Infiltration portions of the mucosa, and the corpus and fundus of the stomach are selectively involved. Normal antral mucosa contains few mononuclear inflammatory cells, whereas normal corpus mucosa contains virtually Lymphoid Aggregates and Follicles none. However, the density of mononuclear cells (i.e., lymphocytes and plasma cells) in the lamina propria of normal Normal gastric mucosa, particularly the corpus, may contain persons varies considerably according to their geographic occasional, small lymphoid aggregates, usually located close

FIGURE 15.3 Lymphoid follicle in the antral mucosa of a patient with Helicobacter pylori gastritis. Neither lymphoid aggregates nor follicles are found in the normal antrum. A normal corpus may show rare lymphoid aggregates without germinal centers. Mucosal lymphoid follicles are highly specific for H. pylori gastritis. FIGURE 15.4 Eosinophils may compose some portion of the inflammatory infiltrate in Helicobacter pylori gastritis.

Surface Epithelium Degeneration to the muscularis mucosae at the base of the lamina propria. In contrast, lymphoid aggregates with germinal centers (i.e., Surface epithelium degeneration is considered a nonspecific follicles) are rare in gastric mucosa of normal, H. pylori– response to injury that occurs to some degree in all forms negative adults.23 In studies that have used an extensive of gastritis. However, degenerative changes are particularly standardized biopsy protocol, lymphoid follicles or aggre- conspicuous in two disorders: chemical gastritis (resulting gates have been detected in almost all individuals with H. from bile reflux, ethanol, or NSAIDs) and H. pylori pylori gastritis. The finding of lymphoid follicles is highly gastritis.33-35 Regardless of the cause, epithelial injury and specific for H. pylori infection ( Fig. 15.3 ). In H. pylori– necrosis lead to surface erosions. Degenerative changes may infected children and young adults, lymphoid follicles may result in the appearance of cuboidal (rather than columnar) be quite numerous, which may produce an endoscopic cells and mucin depletion. The former is particularly appearance of nodularity that is often referred to as follicu- common in gastritis occurring after Billroth II surgery and lar gastritis.24,25 thought to result from bile reflux. However, these changes

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 FIGURE 15.5 An increase in the number of mast cells (intact and by an increase in the number of mast cells (Fig. 15.5 ) that degranulated) may be seen in many types of gastritis, particularly occurs in this condition.31,32 those caused by Helicobacter pylori (tryptase stain).

FIGURE 15.6 Surface epithelial degeneration (i.e., mucin-depleted epithelial cells) is typically found in Helicobacter pylori–infected stomachs, even in areas where bacteria are rare or absent. Focal loss of cells (i.e., microerosions) is evident. Bacteria occupy the empty spaces created by dropout of individual cells and areas of mucin depletion (silver triple stain).

FIGURE 15.8 Superficial erosion in Helicobacter pylori gastritis. A may also be found in H. pylori gastritis, even in areas where superficial layer of nonhomogeneous fibrinoid necrosis that contains bacteria are few in number. Alternatively, epithelial regen- granulocytes and cell debris may be found in severe cases of H. pylori eration, a common feature of H. pylori gastritis, may result gastritis. in the accumulation of buds of cells at the surface of the 36 mucosa (Fig. 15.6 ). Foveolar Hyperplasia Surface Erosion Foveolar hyperplasia is defined as proliferation, elongation, and tortuosity of gastric pits that result in a corkscrew Surface erosions are the result of severe epithelial injury configuration. It is a compensatory tissue response to and necrosis. By definition, erosions do not extend beyond increased exfoliation of the surface epithelium and repre- the muscularis mucosae. Endoscopically flat surface ero- sents a visual surrogate for increased cell proliferation and sions often result from the acute effects of drugs, alcohol, turnover (Fig. 15.9 ). Although markedly hyperplastic foveo- bile reflux, or ischemia (Fig. 15.7 ). 37,38 Endoscopically ele- lae are normally recognized microscopically, minimal or vated surface erosions are typically associated with H. mild foveolar hyperplasia can easily be overlooked. True pylori gastritis. These erosions are usually characterized by foveolar hyperplasia may be diagnosed reliably when more a superficial layer of fibrinopurulent debris (i.e., fibrinoid than four cross-sections of the same gastric pit are visualized necrosis, neutrophils, and cellular debris) with hyper- in a single, well-oriented gastric biopsy specimen. 40,41 Other plastic, regenerative-appearing epithelium at the margins (Fig. 15.8 ). 39

FIGURE 15.7 Typical appearance of a flat surface erosion with FIGURE 15.9 Reactive (chemical) gastropathy has marked foveolar homogeneous eosinophilic necrosis resulting from an acute toxic hyperplasia (i.e., elongated and coiled gastric pits), vascular conges- insult, such as nonsteroidal antiinflammatory drugs, alcohol, bile tion, and smooth muscle bundles that extend upward into the reflux, or ischemia. superficial lamina propria.

FIGURE 15.10 Foveolar hyperplasia is commonly seen in Helico- bacter pylori gastritis, but the marked elongation shown in the photomicrograph suggests the possibility of coexistent chemical injury. 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 30 FIGURE 15.11 In the high-power photomicrograph of metaplastic feature of bile reﬂux gastritis and NSAID gastropathy, gastric mucosa stained with a triple stain (hematoxylin and eosin 30,40,41 particularly in long-term users. A mild degree of fove- [H&E], Alcian blue, and a modiﬁed Steiner stain), the goblet cells olar hyperplasia is common in patients with H. pylori gas- are bright blue. Helicobacter pylori organisms adhere only to the tritis; however, marked hyperplasia indicates coexistent nonmetaplastic portions of the epithelium. chemical injury (Fig. 15.10 ). 42

Intestinal Metaplasia (AB/PAS) stain at pH 2.5 is an excellent method for dem- onstrating the type and extent of intestinal metaplasia, par- Intestinal metaplasia is defined as the replacement of ticularly when used in combination with a hematoxylin gastric-type mucinous epithelial cells with small intestinal counterstain (Fig. 15.12 ). Mucin histochemical stains (e.g., cells (e.g., goblet cells, enterocytes) (Fig. 15.11 ). 43 Two high-iron diamine) that were traditionally used to determine types of intestinal metaplasia (I and II) have been described the specific type of intestinal metaplasia by detecting but are of limited clinical importance. Metaplastic epithe- sulfated mucins have been largely replaced by immunohis- lium that closely resembles normal small intestinal epithe- tochemical stains that identify proteins associated with lium, 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. Incom- plete 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 FIGURE 15.12 The Alcian blue stain, periodic acid–Schiff (PAS) stain, metaplasia and the risk of progression to carcinoma. and hematoxylin counterstain highlight the acid mucin-producing Intestinal metaplasia can be identified and its extent goblet cells (purple) and neutral mucin-containing foveolar cells. The evaluated with the use of specific mucin histochemical purple color results from a combination of acid mucins ( blue) and stains. For instance, the Alcian blue/periodic acid–Schiff neutral mucins (red) within goblet cells.

Table 15.2 Mucin Immunohistochemistry Intestinal Metaplasia Intestinal Metaplasia Intestinal Metaplasia Type I Type II Type III Mucin Normal Gastric Expressed* Epithelium GCGCGC MUC1 ++ (foveolar epithelium; − − ++ ++ +++ +++ chief and parietal cells) MUC2 − +++ − ++ + ++ ± MUC5AC +++ (foveolar − − ++ ++ ++ ++ epithelium; all mucous neck cells) MUC6 + (antral glands; − − − ± ± ± mucopeptic cells of neck zone in corpus)

C, Columnar or absorptive cells; G, goblet cells. *Expression of the most common mucin proteins in the normal stomach and the three types of intestinal metaplasia is detected by immunohistochemical staining. Because the intensity of the staining and the percentages of cells assessed as positive vary and interpretation is highly subjective, the use of these stains to determine the type of intestinal metaplasia and any inference of cancer risk in individual patients is strongly discouraged. particular mucin-encoding genes. Although more than 20 occupied within the lamina propria may be replaced by such mucin genes have been identified, only a few (i.e., fibroblasts and extracellular matrix. The result of this MUC1, MUC2, MUC5AC, and MUC6) are used routinely process is loss of functional epithelium (i.e., atrophy). in practice, and even those are used mainly in research set- The native glands may be replaced by those with a tings (Table 15.2 ). pyloric phenotype (i.e., pyloric or pseudopyloric metapla- Intestinal metaplasia may develop in a variety of patho- sia) (Fig. 15.13 ) or an intestinal phenotype (i.e., intestinal logic settings, but it usually indicates an underlying chronic metaplasia), comprising goblet cells and absorptive cells atrophic gastritis (chronic atrophic gastritis does not equal (with or without a brush border). It is important to dif- autoimmune chronic atrophic gastritis). Several studies ferentiate true atrophy from mimics, including normal have shown that intestinal metaplasia occurs more fre- antrum-body transition mucosa, in which pyloric-type quently in patients with H. pylori gastritis. 45,46 Because the glands may be mixed with oxyntic glands at the base of the H. pylori organism does not normally adhere to intestinal- mucosa, and normal fundus-cardia transition mucosa, in type epithelium (see Fig. 15.11 ) but disappears in mucosa which mucous-type glands may be associated with oxyntic with extensive intestinal metaplasia and atrophy, one theory glands. posits that intestinal metaplasia represents a host defense Diffuse fundic atrophy typically occurs in autoimmune against H. pylori infection. Intestinalized epithelium may gastritis as a consequence of immune-mediated destruction 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 FIGURE 15.13 The corpus mucosa shows injured oxyntic glands Atrophy is a histologic finding, not a nosologic entity. When replaced by glands with a pyloric appearance (i.e., pyloric or pseudopyloric metaplasia), as in autoimmune gastritis. A distinction must gastric mucosa is damaged, regardless of the cause, it may be made between pyloric metaplasia and normal antrum-body tran- regenerate to normal (restitutio ad integrum) or undergo an sition mucosa (in which pyloric-type glands occur near the muscu- adaptive reparative change that leads to the replacement of laris mucosae) and normal fundus-cardia transition mucosa (in 48 native glands with other types of tissue. When injured which mucous-type glands are typically found superficial to the glands fail to regenerate, the stromal space they previously oxyntic glands).

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 FIGURE 15.14 Nonmetaplastic atrophy in the antrum, which is glands anywhere in the stomach or pyloric (pseudopyloric) associated with long-standing Helicobacter pylori infection or pro- glands in the corpus (i.e., metaplasia equals atrophy). In longed chemical injury, is uncommon and usually has uncertain both types of atrophy, the degree of gland loss may be biologic significance. However, when associated with H. pylori infec- graded as mild, moderate, or severe, which corresponds to tion and severe atrophic gastritis, the condition can predispose to a scale of 1 to 3 ( Fig. 15.16 ). gastric cancer. Problems may arise when gastric biopsies are labeled as “stomach” or “antrum-body,” in which case it may be dif- of oxyntic epithelium. Less severe and more focal atrophy, ficult to determine whether there is true pyloric metaplasia which is usually limited to the antrum, may also occur in or the biopsy is simply representative of the antrum or reactive gastropathy (Fig. 15.14 ). The updated Sydney antral-fundic transition. In this instance, immunohisto- System recognizes multifocal atrophic gastritis (MAG), chemical staining for gastrin-positive endocrine cells can referred to as environmental atrophic gastritis in the pre– H. help to identify mucosa derived from the antrum. The pylori era, as an entity distinct from nonatrophic gastritis algorithm depicted in Figure 15.17 summarizes an approach and autoimmune atrophic gastritis.8,49 to the evaluation of atrophy in gastric biopsies. The border between gastritis with focal atrophy and atrophic gastritis has not been well defined (Fig. 15.15 ). Endocrine Cell Proliferation This issue is important because scattered foci of intestinal metaplasia are found in the antrum of most patients with Endocrine cell hyperplasia develops as a consequence of H. pylori gastritis and of a small percentage of noninfected functional changes in the stomach and is most prominent adults. It is not appropriate to classify these individuals with in autoimmune atrophic gastritis. In this condition, hypo- atrophic gastritis, a diagnosis that implies altered gastric chlorhydria or achlorhydria may lead to antral G cell

ABC D

EFG H

FIGURE 15.15 Spectrum of atrophy (pink) and metaplasia ( blue). Although it is intuitive that stomach A has nonatrophic gastritis and that stomachs F, G, and H have atrophic metaplastic gastritis, stomachs B through E are difﬁcult to assign to a particular category, particularly when only limited biopsy samples are available.

ATROPHY

Absent Indefinite Present

Nonmetaplastic Metaplastic (intestinal or pseudopyloric)

Mild Mild Moderate Moderate Severe Severe

FIGURE 15.16 The types and degrees of atrophy are based on the Atrophy 2000 classification. (Adapted from Rugge M, Correa P, Genta FIGURE 15.18 Gastrin-producing endocrine cell hyperplasia can be RM, et al. Gastric mucosal atrophy: interobserver consistency using suspected on routine staining by the grouping of cells with distinct new criteria for classification and grading. Aliment Pharmacol Ther. pale cytoplasm and central dark nuclei (i.e., fried egg appearance). 2002;16:1249-1259.) However, confirmation with an antigastrin immunohistochemical stain is necessary. hyperplasia and a secondary elevation of the serum gastrin level.50,51 Hypergastrinemia causes histamine-producing the use of argentaffin and argyrophil-based histochemical enterochromaffin-like (ECL) cells within oxyntic mucosa to stains. In routine practice, staining of endocrine cells helps proliferate. Once thought to be rare and limited to patients to identify cases of autoimmune atrophic gastritis of the with advanced atrophic gastritis, neuroendocrine prolifera- corpus. A mild to moderate degree of ECL cell hyperplasia tion is now frequently seen in routine gastric biopsies as a may occur in a subset of patients who use PPIs for extended result of widespread use of proton pump inhibitors (PPIs).52 periods. However, in these patients, the oxyntic mucosa is Although endocrine hyperplasia can be detected easily on not atrophic and may display parietal cell hypertrophy and hematoxylin and eosin (H&E)–stained tissue sections of the oxyntic gland dilations, which are characteristically seen in antrum (Fig. 15.18 ), hyperplasia of ECL cells in oxyntic chronic PPI users. mucosa is best visualized and quantified with specific immu- The most widely used criteria for the diagnosis and clas- nostains (Fig. 15.19 ). Immunostains have largely replaced sification of gastric endocrine cell proliferation are those

CORPUS BIOPSY

Normal oxyntic mucosa Sparse oxyntic glands Antrum-like mucosa Intestinal metaplasia

No atrophy Nonmetaplastic Certain Uncertain Metaplastic atrophic atrophic gastritis corpus origin origin gastritis (intestinal)

Gastrin stain

No or rare Band of G cells G cells

Biopsy is from antral mucosa

Metaplastic atrophic gastritis (pseudopyloric)

FIGURE 15.17 Algorithm for the diagnosis of atrophy in biopsy specimens obtained from the gastric corpus.

A B

FIGURE 15.19 In normal antral mucosa, a band of G cells is high- FIGURE 15.20 Mild glandular dilation with parietal cell apocrine-like lighted by immunohistochemical staining. blebs (left) and more pronounced dilation with oxyntic cell hypertrophy (right) resulting from proton pump inhibitor therapy. proposed by Solcia and colleagues (see Chapter 29).53 The classification system distinguishes simple or diffuse, linear, micronodular and adenomatoid hyperplasia, dysplasia, and Interfoveolar Smooth Muscle Hyperplasia neoplasia (i.e., carcinoid tumors) and is reviewed in the section on Autoimmune Gastritis and in Table 15.3 . In the normal stomach, smooth muscle fibers are confined to the muscularis mucosae, where they run parallel to the Parietal Cell Alterations mucosal surface. Several studies have shown that chemical injury is often associated with the smooth muscle fibers that Apocrine-like protrusion and pseudohypertrophy of oxyntic run perpendicular to the muscularis mucosae within the cells are frequently attributed to chronic use of PPIs interfoveolar lamina propria (see Fig. 15.9 ). This prolifera- (Fig. 15.20 ). 54,55 However, identical histologic changes have tion may be caused by the pulling effect of prolapsing been reported in other clinical settings, and the findings are mucosa, similar to that seen in the so-called solitary rectal therefore not pathognomonic.56 Use of PPIs may also lead ulcer syndrome. It is unclear whether peristalsis may exert to dilation of oxyntic glands, which in extreme cases may analogous forces on injured gastric mucosa. Another pro- produce multiple fundic gland–type polyps that impart an posed mechanism is the release of platelet-derived growth appearance of the gastric mucosa that inspired the pictur- factor (PDGF), a known smooth muscle stimulant, as a esque description of gastric acne.57,58 Because most chronic result of epithelial damage. However, smooth muscle users of NSAIDs also take PPIs to reduce the risk of hyperplasia is not specific for NSAID-induced gastritis and NSAID-induced ulceration, oxyntic gland alterations are may be seen in a variety of other conditions, such as gastric frequently seen in conjunction with reactive (chemical) antral vascular ectasia (GAVE), bile reflux gastritis, and gastropathy.41,59,60 reactive mucosa adjacent to an ulcer.41,60

Table 15.3 Classification of Enterochromaffin-Like Cell Proliferations Diagnosis Criteria for Increased Endocrine Cells Common Disorders Simple or diffuse hyperplasia >2 × standard deviations (age and gender ZES, primary gastrin cell hyperplasia matched) Linear hyperplasia Linear groups of 5 or more cells inside the ZES, pernicious anemia glandular BM Micronodular hyperplasia Clusters of 5 or more cells within epithelium Autoimmune atrophic gastritis measuring <150 μm in diameter Adenomatoid hyperplasia Aggregates of 5 or more micronodules in Autoimmune atrophic gastritis, MEN-ZES lamina propria Dysplasias Autoimmune atrophic gastritis, MEN-ZES Enlarged micronodules >150 μm Adenomatous micronodules Collections of at least 5 closely adherent micronodules, intervening BM only Fused micronodules Adenomatous micronodules with no intervening BM Microinfiltrative lesions Infiltration of the lamina propria Carcinoids Autoimmune atrophic gastritis, MEN-ZES Intramucosal Expansile or infiltrative nodules > 0.5 mm Invasive Any size tumor within submucosa

Data from Solcia E, Fiocca R, Villani L, et al. Hyperplastic, dysplastic, and neoplastic enterochromafﬁn-like cell proliferations of the gastric mucosa: classiﬁcation and histogenesis. Am J Surg Pathol . 1995;19(suppl 1):S1-S7. BM , Basement membrane; LP , lamina propria; MEN, multiple endocrine neoplasia; ZES, Zollinger-Ellison syndrome.

Updated Sydney System The updated Sydney System provides pathologists with guidelines for generating systematic, uniform diagnostic reports. The goal of the Sydney System is to make gastric biopsy pathology reporting consistent so that pathologists create clinically relevant and precise diagnoses known to all clinicians and to allow clinical studies to be performed and evaluated in an unambiguous manner. To create a pathology report suggested by the updated Sydney System, at least five biopsy specimens should be evaluated and the findings synthesized (Fig. 15.21 ). The system (Table 15.4 ) classifies chronic gastritis into three broad categories on the basis of topography, morphology, and when possible, on the basis of cause as acute, chronic, or special (distinc- 8 FIGURE 15.21 The five biopsy sites (circles) recommended by the tive). The latter category includes entities of uncertain updated Sydney System. pathogenesis and gastropathies. This system also separates chronic gastritis into atrophic and nonatrophic forms (Fig. 15.22 ). and corpus) should be separately designated when submit- ted to the pathology laboratory. Proper specimen orienta- Biopsy Protocol tion is critical for optimal histologic evaluation and is best accomplished in the pathology laboratory at the time of The biopsy protocol depicted in Figure 15.21 is recom- tissue embedding. Unfortunately, in routine clinical prac- mended to obtain satisfactory mucosal sampling. Specimens tice, gastroenterologists do not often adhere to such a rigor- from three compartments (i.e., antrum, incisura angularis, ous sampling and labeling protocol (see Reporting Gastritis

Table 15.4 Sydney System Classification of Gastritis Type of Gastritis Etiologic Factors Gastritis Synonyms Nonatrophic Helicobacter pylori Superficial Other factors (?) Diffuse antral gastritis (DAG) Chronic antral gastritis (CAG) Interstitial-follicular Hypersecretory Type B Atrophic Autoimmune Autoimmunity Type A H. pylori (?) Diffuse corporal Multifocal atrophic gastritis H. pylori Pernicious anemia–associated (MAG) Environmental factors Type B, type AB Environmental Metaplastic Atrophic pangastritis Progressive intestinalizing pangastritis Special forms Chemical Chemical irritation Reactive Bile Reflux Nonsteroidal antiinflammatory drugs (NSAIDs) Other agents (?) Radiation Radiation injury Lymphocytic Idiopathic (?) Varioliform Autoimmune mechanisms (?) Celiac disease associated Gluten (?) Drugs (e.g., ticlopidine) H. pylori (?) Noninfectious granulomatous Crohn’s disease Isolated granulomatous Sarcoidosis Wegener granulomatosis Foreign substances Idiopathic (?) Eosinophilic Food sensitivity Allergic Other allergies (?) Other infectious gastritides Bacteria (other than H. pylori) Phlegmonous, syphilitic, others Viruses Cytomegalovirus Fungi Anisakiasis Parasites

(i.e., antrum and corpus). A minimum of two specimens from the antrum, one from the incisura angularis, and two from the corpus should be evaluated.

Determination of Gradient of Inflammation After evaluation of the histologic variables, the next step in the Sydney System is to document the degree of inflammation in the two main gastric compartments to determine whether the inflammation is similar in intensity (i.e., pangastritis) or more severe in the antrum (i.e., antrum- predominant gastritis) or the corpus (i.e., corpus-predominant gastritis). To conclude that inflammation in one compartment is predominant, the difference in the inflammatory FIGURE 15.22 The Sydney System separates chronic gastritis into atrophic and nonatrophic forms, each representing one of the variables should be at least two grades. This helps to mini- extremes of the spectrum of gastritis. mize the effect of interobserver variability. The degree of atrophy and metaplasia can also be assessed according to the Atrophy 2000 guidelines. 10 The last step in the Sydney classification is to decide whether focal atrophy or diffuse in the Absence of a Complete Biopsy Set ), and this limita- atrophy (metaplastic or nonmetaplastic) is present. tion is not addressed by the Sydney classification. Diagnosis Evaluation of Histologic Variables The final diagnosis according to the Sydney system repre- Each mucosal biopsy specimen should be assessed for sents a synthesis of the observations outlined previously, its suitability for pathologic examination. An acceptable including information regarding possible cause. Examples slide is one that shows several well-oriented sections with of diagnostic reports are “H. pylori antrum-predominant the mucosal surface and the muscularis mucosae visible. gastritis” and “corpus-restricted atrophic gastritis without Each relevant pathologic feature (e.g., density of H. pylori, H. pylori infection, suggestive of autoimmune gastritis” intensity of neutrophilic and mononuclear inflammation, (Fig. 15.24 ). atrophy of the antrum and corpus, intestinal metaplasia) should be graded on a standardized visual analogue scale Reporting Gastritis in the Absence of a (Fig. 15.23 ). Each feature is assigned a numeric or descrip- Complete Biopsy Set tive value: 0 for absent, 1 for mild, 2 for moderate, and 3 for marked or severe. The values of each specimen are The Sydney System guidelines can be applied only when a determined separately for each anatomic compartment full set of biopsy specimens is available (see Fig. 15.21 ). In

Normal Mild Moderate Marked Normal Mild Moderate Marked

H. pylori Atrophy: antrum

Neutrophils Atrophy: corpus

FIGURE 15.23 The visual analogue scale proposed in the updated Sydney System. Mononuclear cells Intestinal metaplasia

tainty persists, a less speciﬁc diagnosis (e.g., chronic inac- 1 tive gastritis with atrophy and intestinal metaplasia) may be used, along with a comment regarding the differential Normal stomach with focal intestinal metaplasia diagnosis, including a suggestion that broader and more extensive sampling would be helpful to determine an exact cause. Other information, such as clinical evidence of pernicious anemia, hypergastrinemia, achlorhydria, and the 2 presence or absence of circulating anti–parietal cell anti- Chronic active H. pylori gastritis, bodies, may help to establish a precise diagnosis of autoim- antrum-predominant mune metaplastic atrophic gastritis.

OLGA System

3 Building on the current knowledge of the natural history of Chronic active H. pylori nonatrophic pangastritis gastritis and its associated cancer risk, an international group of gastroenterologists and pathologists proposed a system of gastritis reporting in terms of stage: the Operative Link for Gastritis Assessment (OLGA) staging system.11,61 The system places the histologic phenotypes of gastritis on a 4 scale of progressively increasing gastric cancer risk, from the Chronic active H. pylori gastritis, lowest (stage 0) to the highest (stage IV). corpus-predominant Use of a well-defined biopsy sampling protocol (Sydney System) is considered the minimum required for reliable staging of chronic gastritis. The stage of gastritis is determined by the combination of the extent of atrophy (scored 5 histologically) with its topographic location (resulting from Chronic active H. pylori multifocal atrophic gastritis the mapping protocol). Consistent with the Sydney recommendations, OLGA staging system reporting includes information about the likely cause of gastritis (e.g., H. pylori, autoimmune). The OLGA system is based on the atrophy score. 6 Corpus-restricted atrophic gastritis, Atrophy is scored as a percentage of the atrophic glands. most likely autoimmune Nonmetaplastic and metaplastic subtypes are considered together. At each biopsy sample level (irrespective of the FIGURE 15.24 Examples of diagnoses generated according to the area from which it originates), atrophy is scored by using a recommendations of the updated Sydney System. Areas of gastritis four-tiered scale: atrophy absent (0%) = 0; mild (1% to (red), intestinal metaplasia (blue), and atrophy (gray) are indicated. 30%) = 1; moderate (31% to 60%) = 2; and severe ( >60%) = 3. The OLGA gastritis stage results by combining the overall antrum score with an overall corpus score for atrophy (Table 15.5 ). Details on how to apply the OLGA scores in routine practice, pathologists are usually asked to make a clinical practice are provided in a step-by-step tutorial by diagnosis based on only one or two gastric biopsy specimens Rugge and colleagues. 13,14 Several retrospective studies have and often from unspecified sites. In these cases, no attempt shown that gastric adenocarcinoma rarely or never develops should be made to use the Sydney System. Instead, an in patients with OLGA scores of 0 to 2; the disease tends empiric approach is recommended. to occur in patients with scores of 3 or 4. 13,15,62 Most types of gastritis, including those caused by A Dutch group modified the OLGA staging system using H. pylori, can be diagnosed without extensive tissue intestinal metaplasia rather than atrophy as the main param- sampling. In contrast, assessment of the degree of atrophy eter for the assessment of gastric cancer risk. The investiga- requires adequate sampling and knowledge of the site tors suggested that their system (i.e., Operative Link for of origin of each specimen to distinguish MAG from Gastric Intestinal Metaplasia [OLGIM]) may be less vul- autoimmune metaplastic atrophic gastritis. A diagnosis of nerable to interobserver variability because intestinal meta- gastritis based on only a few nonrepresentative or inade- plasia can be recognized and quantified more reliably than quately identified biopsy specimens should not include any atrophy. statements regarding topographic distribution of disease. If a specimen labeled as “corpus” contains pyloric-appearing Acute Gastritis glands and lacks parietal and chief cells, suggesting that it may be derived from the antrum, an immunostain for In the Sydney System, the term acute gastritis refers to the gastrin can help to resolve the issue. The finding of numer- initial phase of H. pylori infection (discussed later) or acute ous gastrin-positive cells, typically in the midgland region, bacterial suppurative gastritis (i.e., phlegmonous gastritis), indicates that the biopsy was derived from the antrum, which is rare.63-66 However, acute hemorrhagic gastritis is whereas atrophic pyloric-type glands from metaplastic characterized by sudden onset and rapid evolution, and it corpus contain few or no gastrin-positive cells. If uncer- therefore meets the clinical criteria for an acute illness.

Table 15.5 Operative Link for Gastritis Assessment (OLGA) Staging System Corpus Antrum No Atrophy (score 0) Mild Atrophy (score 1) Moderate Atrophy (score 2) Severe Atrophy (score 3) No atrophy (score 0), Stage 0 Stage I Stage II Stage III including incisura angularis Mild atrophy (score 1), Stage I Stage I Stage II Stage III including incisura angularis Moderate atrophy (score 2), Stage II Stage II Stage III Stage IV including incisura angularis Severe atrophy (score 3), Stage III Stage III Stage IV Stage IV including incisura angularis

Acute Hemorrhagic Gastritis pathologic features helps to determine the precise cause. In extreme cases, erosion of an underlying large blood vessel Clinical Features may cause catastrophic hemorrhage and death. Acute hemorrhagic gastritis is characterized by diffuse Microscopically, acute hemorrhagic gastritis, regardless of mucosal hyperemia associated with bleeding, erosions, its cause, is characterized by dilation and congestion of and ulcers and precipitated by a sudden stress-induced mucosal capillaries, edema, and interstitial hemorrhage imbalance between injurious and protective factors involved within the lamina propria. Surface erosions are usually small in the maintenance of mucosal integrity. This disorder has and appear ischemic. Aggregates of fibrin and neutrophils been a recognized nosologic entity for at least a century. replace the eroded epithelium and often project above the Thomas Blizard Curling, a British surgeon, documented mucosal surface to form small, elevated clumps of necrotic an association between severe burns and duodenal ulcer- debris (Fig. 15.26 ). The foveolar epithelium underneath and ation (i.e., Curling ulcer) in 1842.67,68 The prevalence and adjacent to erosions and ulcers show regenerative changes, clinical importance of stress-induced gastric ulcers have such as elongation, increased tortuosity, mucin depletion, been appreciated recently. Most patients in intensive care enlarged and hyperchromatic nuclei, and increased mitoses; units have mucosal ulcers, approximately 20% develop the latter two features should not be misinterpreted as overt bleeding, and as many as 5% succumb to life- dysplasia. Recalling the location of the normal regenerative threatening hemorrhage.69 zones in the antrum (i.e., gland base) and corpus (i.e., Ingestion of large doses of aspirin or other types of mucous cell neck region) can help to mitigate an overdiag- NSAIDs may cause acute mucosal injury, ranging from nosis of dysplasia. In the absence of concurrent H. pylori edema and hyperemia to erosion and ulceration. These infection, unaffected areas of the stomach do not usually lesions may occur suddenly, without prior pain or discom- show increased chronic inflammation. In the setting of H. fort, in first-time and chronic NSAID users.59 Similar but pylori infection, the pathologist may see chronic active usually less severe changes may be caused by ingestion of inflammation in the mucosa, which may obscure or worsen large quantities of alcohol.70 Because alcohol and aspirin act the changes caused by NSAIDs or alcohol. synergistically to alter mucosal defenses, many cases of hemorrhagic gastritis are caused by alcohol users who Chronic Gastritis consume aspirin to prevent hangover sickness.71 The pathogenesis of stress-induced hemorrhagic gastritis is unknown, Helicobacter pylori Gastritis but luminal acid is essential. Acid exerts its noxious effect by inhibiting and causing loss of integrity of mucosal defense Clinical Features mechanisms (e.g., mucus-bicarbonate barrier). Vascular Chronic H. pylori gastritis affects two thirds of the world’s compromise associated with stasis, vasoconstriction, and population and is one of the most common chronic increased vascular permeability also contributes to loss of mucosal integrity. NSAIDs act by interfering with prostaglandin synthesis, whereas alcohol causes direct damage to the gastric mucosa. At a concentration of 12.5%, alcohol induces hyperemia and petechiae. At concentrations greater than 40%, alcohol causes necrosis of the surface epithelium and capillaries, and causes interstitial hemorrhage.37,70 Suppression of acid secretion with PPIs helps to reduce the severity of mucosal damage and facilitates mucosal healing. Pathologic Features Acute hemorrhagic gastritis is grossly characterized by hyperemic edematous mucosa, surface erosions, and active FIGURE 15.25 Two views showing the endoscopic appearance bleeding (Fig. 15.25 ). The clinical history (e.g., shock, of acute hemorrhagic gastritis. (Courtesy of David Y. Graham, MD, burns, ingestion of large doses of NSAIDs) rather than the Houston, Tex.)

carcinoma, insufficient supportive evidence has prevented widespread acceptance of the proposals.81,82 Critics of these programs cite the increasing resistance of H. pylori to the antibiotics used in current protocols. There is also much attention to the development of an effective vaccine to prevent H. pylori infection. 83 Epidemiology The prevalence of H. pylori infection among adults approaches 90% in many developing countries, particularly those in the tropics. Cross-sectional studies have revealed a high prevalence of infection among children, indicating that exposure to the bacterium probably occurs relatively early in life. In industrialized parts of the world (e.g., Western Europe, United States, Canada, Australia), exposure tends to occur later in life, which results in a lower percentage of FIGURE 15.26 Superficial erosion in the corpus mucosa of a patient infected adults. An average of 20% to 30% of adults are with acute hemorrhagic gastritis. infected by 50 years of age.84,85 In eastern Asia (e.g., Japan, South Korea), where improved sanitation methods have been recently intro- inflammatory disorders of humans.72,73 It is causally related duced, there is a clear trend toward a lower rate of H. pylori to most non–NSAID-induced duodenal and gastric ulcers, infection. The prevalence of H. pylori infection has been and most gastric mucosa-associated lymphoid tissue (MALT) steadily declining in industrialized and emerging countries, lymphomas. In certain regions of the world, atrophic gastri- which probably reflects the improved sanitary conditions tis develops in a considerable proportion of infected persons, and widespread use of antibiotics. Prevalence rates as low and this condition is a precursor to gastric carcinoma. H. as 5% have been reported in Norwegian children between pylori gastritis is a strong risk factor for development of 1 month and 3 years of age, 86 and even in China (Guang- gastric cancer, particularly the intestinal type. zhou province), the infection rate for children between 1 The early phase of H. pylori infection elicits an acute and 5 years was only 19% in 2003. 87 inflammatory response that is asymptomatic or has short- Despite declining rates of H. pylori infection overall, the lived clinical manifestations, such as nausea and vomiting. prevalence of H. pylori among patients who undergo endos- Because most patients with early H. pylori gastritis do copy remains significant. H. pylori should be considered in not undergo endoscopy, information regarding the clinical, all gastric biopsy specimens examined, regardless of the endoscopic, and pathologic aspects of acute H. pylori patient’s age or history. infection is limited to a few well-documented case reports, human ingestion studies,72 and analyses of infec- Pathologic Features tions acquired from inadequately disinfected endoscopic Grossly, there are no distinct endoscopic patterns of chronic instruments.74-76 H. pylori gastritis. Depending on the stage and type of Endoscopically, manifestations of acute H. pylori gastritis gastritis, hyperemia, erosions, hypertrophy, and atrophy are typically found in the antrum and characterized by may coexist in various combinations. Unfortunately, none hemorrhagic lesions and multiple erosions or ulcers. Virtu- of these endoscopic features has proved useful for predict- ally identical findings were previously reported in patients ing the presence or absence of H. pylori gastritis. Endosco- with epidemic gastritis and achlorhydria, a syndrome pists should not attempt to diagnose H. pylori gastritis reported before the identification of H. pylori as the prin- based solely on the gross appearance of the gastric mucosa. cipal cause of most cases of chronic gastritis.77 The diagnosis of H. pylori gastritis rests on pathologic evalu- Although chronic H. pylori gastritis is asymptomatic in ation of gastric mucosal biopsies or detection of urease in most infected individuals, its impact on human health is mucosal specimens by the Campylobacter-like organism profound. H. pylori gastritis confers a 15% to 20% lifetime (CLO) test or the urea breath test.88 Polymerase chain reac- risk for peptic ulcer disease, and 70% of gastric cancers and tion (PCR) testing is discussed later. most primary gastric MALT lymphomas are directly linked Microscopically, the gastric mucosa is covered by a thick to chronic H. pylori infection. In one British community, H. layer of mucus that plays a protective role. This mucous pylori was estimated to be responsible for approximately layer, which is best visualized in Carnoy-fixed tissues, is the 5% of all gastrointestinal (GI) ailments.78 primary site of H. pylori colonization and often contains When H. pylori was initially identified, combination large numbers of organisms.89 When in contact with epithe- treatment with antibiotics and bismuth-containing com- lium, H. pylori organisms characteristically attach to but do pounds was recommended only for patients with gastric not penetrate the surface mucous cells. Intracellular inva- ulcers and known MALT lymphomas. In time, guidelines sion has been observed in surface mucous cells, chief cells, were developed to include treatment for patients with dys- and parietal cells (rare), particularly in patients who have pepsia and, essentially, all patients in whom infection could received PPIs (Fig. 15.27 ). 90-93 Although some authorities be identified.79,80 have suggested that penetration and intracellular invasion Although programs for global eradication of H. pylori may be related to the organism’s ability to promote carci- have been advocated with the goal of preventing gastric nogenesis,92,94 the significance remains unclear.

the local microcirculation results in ischemic loss of epithelial integrity and ultimately in surface erosions and ulcers.99 Mucosal neutrophils are a distinctive histologic feature of H. pylori infection. Neutrophils are more abundant in the antrum and cardia than in the corpus, where they may be rare or completely absent despite the presence of organisms. Neutrophils may be seen in the lamina propria (where they are typically mixed with mononuclear cells and eosinophils) and within the surface and foveolar epithelium (Fig. 15.29 ). Neutrophils may fill the lumen of the gastric pits, forming pit microabscesses and a surface exudate. In patients with atrophy, active neutrophilic inflammation only rarely occurs in areas of metaplasia. After successful eradication therapy, neutrophils disappear rapidly, and their con- tinued presence is considered a valuable indicator of therapeutic failure.18 Gastric mucosa chronically infected by H. pylori typically shows a prominent mononuclear (lymphoplasmacytic) infiltrate. In the corpus, the mononuclear infiltrate is usually most intense in the superficial neck region of the lamina FIGURE 15.27 Helicobacter pylori organisms are identified in the propria (Fig. 15.30 ), which prompted the use of the term deep portion of oxyntic glands and within canaliculi of oxyntic cells chronic superficial gastritis as a synonym for nonatrophic (circles). This feature is seen only in patients who use long-term gastritis.49 In exceptional cases, the pathologist may also find proton pump inhibitors. a significant lymphocytic infiltrate within the glandular portion of the mucosa. In some cases, a diffuse intraepithelial infiltrate may be prominent, which can be mistaken for In severe acute infection, grossly visible pseudomem- lymphocytic gastritis.101-103 In the setting of a focal and branes and pus adherent to inflamed mucosa have been destructive lymphocytic infiltrate (i.e., lymphoepithelial described (Fig. 15.28 ). 95 In chronic H. pylori gastritis, epi- lesion), additional evidence of extranodal marginal zone thelial degeneration is particularly prominent because of lymphoma should be sought. The intensity of the mono- intimate contact of the H. pylori organisms with the surface nuclear cell infiltrate typically declines quite slowly after cell membrane (see Fig. 15.6 ). 96 successful eradication of infection. As many as 30% of The epithelial cells often become irregular and cuboidal, patients have chronic inactive gastritis that persists for have a decreased apical mucin content, and occasionally several years after eradication of the organism. drop out, leaving small gaps in the epithelium that contrib- Lymphoid follicles with germinal centers are found in ute to a ragged, disorderly appearance. The characteristic almost all H. pylori–infected patients, and their presence in alterations in H. pylori infection are caused by bacterial the gastric mucosa is highly specific for H. pylori–associated toxins such as VacA and CagA, urease, ammonia, acetalde- gastritis (see Fig. 15.3 ). 23,104,105 The density of lymphoid hyde, and phospholipases, which have a direct effect on follicles is usually greatest in the region of the angulus and epithelial cells.97-99 lowest in the proximal greater curve of the stomach. These H. pylori causes mast cells to release platelet-activating anatomic sites correspond, respectively, to the most and factors, which leads to thrombosis.100 The disturbance of least common sites of gastric MALT lymphoma. 23 H. pylori infection is a major cause of acquired MALT in the stomach and is a critical factor in the development of primary gastric B-cell lymphoma (MALT lymphoma, which is now classi- fied as extranodal marginal-zone B-cell lymphoma). 106-108 Occasionally, lymphoid infiltrates may be large and irregular, with lymphoepithelial lesions at the periphery. In this circumstance, gastric lymphoma should be considered. Pathologic features that warrant further investigation with immunocytochemical and molecular techniques include: an expansile monotypic infiltrate, a monocytoid appearance of the lymphocytes, lymphoepithelial lesions associated with glandular destruction, and endoscopic evidence of a mass or nodularity. Immunohistochemical and molecular tests often yield equivocal results, and a diagnosis of atypical lymphoid infiltrate may be provided with elaboration of the inconclu- sive findings. If H. pylori infection is detected by direct or indirect FIGURE 15.28 Acute severe Helicobacter pylori infection. Fibrinopu- methods, including serology, eradication therapy with 109-111 rulent material is seen over a superficial erosion. The mucosa is follow-up biopsies of the affected area is warranted. extensively infiltrated by neutrophils. Lymphoid follicles normally decline in number and size,

A B

FIGURE 15.29 A, In Helicobacter pylori infection, neutrophils typically infiltrate the lamina propria and the surface, foveolar, and glandular epithelium. B, In severe cases, pit abscesses may be found. although very slowly, after successful treatment. In some world. It is characterized by moderate to severe inflamma- patients, lymphoid follicles may persist indefinitely. tion of the antrum, normal or mild inflammation of the corpus, and absence of atrophy. This clinical presentation is Subtypes of Helicobacter pylori Gastritis associated with normal or increased acid secretion and a H. pylori infection may show different patterns of gastritis 20% estimated lifetime risk of duodenal ulceration.112-114 and may ultimately be associated with the development of glandular atrophy. Different patterns of H. pylori gastritis Nonatrophic Corpus-Predominant Gastritis are associated with various outcomes. Nonatrophic corpus-predominant gastritis is restricted mainly to patients who use PPIs chronically. The density of Nonatrophic Antrum-Predominant Gastritis H. pylori organisms and the intensity of inflammation are Nonatrophic antrum-predominant gastritis is the most low in the antrum and high in the corpus. Several studies common pattern of H. pylori gastritis (i.e., hypersecretory, have shown that corpus atrophy proceeds at an accelerated diffuse antral, or superficial antral gastritis) in the Western rate in these patients.115,116 Nonatrophic Pangastritis In some individuals chronically infected with H. pylori, marked inflammation is evenly distributed throughout the stomach, with little difference between the antrum and corpus. This pattern of gastritis is particularly common in poorly sanitized areas, where H. pylori infection is highly endemic. Pangastritis is widely thought to be the background condition in which atrophy develops.117-119 Antrum-Restricted Atrophic Gastritis In Western populations, atrophy and intestinal metaplasia are usually minimal, focal, and detected only in the antrum. These findings may be the consequence of current or previous H. pylori infection or chemical gastropathy. These changes do not represent antrum-restricted atrophic gastritis, a term reserved for conditions in which atrophic metaplastic changes are extensive. Biopsies in this condition show patchy intestinal metaplasia and atrophy restricted to the antral mucosa (including FIGURE 15.30 Chronic superficial gastritis. Lymphocytes and plasma cells form a band that fills the lamina propria of the mucous cell the incisura angularis) and usually associated with moderate neck region of the gastric body, a common feature in Helicobacter to severe inflammation and show a normal or mildly inflamed pylori gastritis. Although the term superficial gastritis accurately corpus without atrophy. The relationship between antrum- describes the distribution of inflammation, the Sydney System refers restricted atrophy and MAG is unknown. Although it is to it as mild chronic, active ( H. pylori), nonatrophic gastritis . possible that these entities are biologically different, it is

Downloaded from ClinicalKey.com at Italian Association of Gastroenterology (AIGO) November 14, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved. CHAPTER 15 Inflammatory Disorders of the Stomach 369 also possible that they represent different stages of the same patients with extensive areas of metaplastic atrophy, organ- disease. isms are usually confined to the nonmetaplastic, nonatrophic areas of mucosa. In patients who use PPIs, H. pylori organ- Multifocal Atrophic Gastritis isms tend to be rare or absent in the antrum, and they may MAG was formerly referred to as environmental chronic be difficult to detect in the corpus, even in the setting of atrophic gastritis and, in its most advanced stage, as atro- chronic active inflammation.136 Similarly, patients treated phic pangastritis.7,120 This pattern of gastritis is most prev- with antibiotics before gastric biopsy may demonstrate a alent among populations who live or have recently lived markedly reduced number of organisms and often have in suboptimal sanitary conditions, such as parts of south- atypical (coccoid) forms (Fig. 15.31 ). 137 ern and eastern Asia, Latin America, and Europe. 121-124 As many as 70% of gastric biopsy specimens from H. Exceptions to this epidemiologic association include Japan, pylori–infected subjects reveal organisms by routine H&E where despite high levels of sanitation and personal staining. In the remaining 30% of cases, a more sensitive hygiene, there is one of the world’s highest prevalence stain is usually needed. Many laboratories routinely stain all rates of atrophic gastritis and gastric adenocarcinoma.125-127 gastric biopsies, even those without significant inflamma- In contrast, in Equatorial Africa which has a precarious tion, for H. pylori to ensure identification of organisms. socioeconomic environment, inadequate sanitary condi- Commonly used and relatively inexpensive stains, such tions, and an H. pylori prevalence of almost 90%, there is as Giemsa and Diff-Quik, are adequate for identification of a surprisingly low prevalence of atrophic gastritis and most cases of H. pylori organisms. 138,139 The Hp Blue/Hp gastric adenocarcinoma.128-130 Yellow stain (Anatech, Battle Creek, Mich.) is designed to The determination of H. pylori genotype has not proved make the organisms more discernable by staining the back- reliable in predicting the phenotype of gastritis, including ground mucin yellow.140 The yellow counterstain can be atrophy.131 As a result, other than consideration of the eliminated, which results in a cleaner background. The country of origin, it is difficult to predict the risk for atro- silver-based triple stain simultaneously allows visualization phic gastritis in an individual patient in industrialized of H. pylori organisms while better featuring the histologic countries. changes in the mucosa (Fig. 15.32 ; see Figs. 15.6 and Atrophic gastritis is a risk factor for gastric ulceration 15.11). 141 Because this stain involves application of Alcian and, more importantly, noninvasive neoplasia (i.e., dyspla- blue at pH 2.5, it also allows small, inconspicuous foci of sia) and intestinal-type adenocarcinoma.132-135 In biopsy intestinal metaplasia to be detected easily (see Fig. 15.11 ). specimens with MAG, foci of atrophy and intestinal meta - Immunohistochemical stains for H. pylori increase sensitiv- plasia are found in antral and corpus mucosa. In contrast to ity and are particularly useful for detecting coccoid forms antrum-restricted atrophic gastritis, MAG often displays of the organism, rare organisms located deep within the severe inflammation in the corpus mucosa, and acid secre- glands, and intracytoplasmic organisms.142,143 After H. pylori tion may be reduced, suggesting a more advanced state of treatment, organisms may be best visualized with an immu- disease. nohistochemical stain if chronic gastritis persists. Molecular techniques, specifically PCR, can be used to Differential Diagnosis detect H. pylori organisms in tissue, and claims of higher sensitivity for histologic methods have been published.144,145 Methods of Detecting Helicobacter pylori However, not all of these studies used immunohistochem- H. pylori normally infects antral and corpus mucosa, but in istry for H. pylori detection as the reference group, and the cardia, organisms may be difficult to detect. H. pylori identification rates varied by technique (e.g., nested versus organisms rarely colonize intestinal epithelium, and in quantitative PCR). There is no gold standard to serve as the

A B

FIGURE 15.31 Coccoid forms of Helicobacter pylori (which usually result from unsuccessful eradication therapy) are stained with the H. pylori blue stain (A) and with an anti– H. pylori immunohistochemical stain ( B).

PCR used on gastric tissue has been evaluated for possible identification of antibiotic sensitivity, which could be a valuable clinical application. Most patients are prescribed H. pylori treatment without antibiotic susceptibility testing, but first-line treatment regimens fail to eradicate the organism 20% of the time. The primary culprit appears to be resistance to clarithromycin, which can be significant (about 15% to 20%) in certain populations. Resistance has been related to point mutations in bacterial 23S rRNA, and genotypic (PCR) evaluation of resistance is more sensitive than phenotypic (culture) testing. However, PCR-based testing correlates less well than culture with treatment outcomes and therefore has a low predictive value. 147 Helicobacter heilmannii Infection More than 50 species of Helicobacter have been described, but only a few cause gastritis in humans. They include Helicobacter felis, Helicobacter fennelliae, Helicobacter cinaedi, and Helicobacter heilmannii. Among these, H. heilmannii (formerly known as Gastrospirillum hominis) is the most common,148 with an estimated prevalence of 1% of all human Helicobacter infections. 149-151 In some rural areas in A eastern Europe, infection with H. heilmannii is more common, supporting the hypothesis that it is acquired by zoonotic transmission.152 The organisms are 5 to 9 μm long (twice as long as H. pylori) and have five to seven spirals. Although H. heilmannii organisms are easily visualized with any of the common histochemical H. pylori stains (Fig. 15.33 ), their detection may be difficult because they tend to be less numerous and more focally distributed than H. pylori. Polyclonal immunohistochemical stains for H. pylori also react with H. heilmannii, as do some com- mercially available monoclonal stains. H. heilmannii can be missed by those who rely exclusively on these immunostains for their diagnosis. Gastritis caused by H. heilmannii differs from H. pylori gastritis. It is more common in children and usually milder and patchier, with fewer erosions and ulcers. The inflammation tends to be more circumscribed, mainly affecting the antrum, although cases of severe corpus active gastritis may be seen. The diagnosis rests on the morphologic recognition of the organisms, although differentiation of H. heilmannii from H. felis is not possible by light microscopy. These organisms have not been cultured successfully in vitro, and the specific antibiotic susceptibility of H. heilmannii has B therefore not been well studied. Clinically, H. heilmannii patients are treated identically to those with H. pylori infec- FIGURE 15.32 A, Innumerable Helicobacter pylori organisms (triple tion, and rates of successful outcomes are similar.153 stain) are seen within the lumen of a pit and in the intercellular Similar to H. pylori, H. heilmannii infection has been spaces of the foveolar cells. B, A gastric pit stained with an anti– H. linked to the development of gastric adenocarcinoma154 and pylori immunohistochemical stain. MALT lymphoma. Regression of lymphoma after successful eradication therapy has been reported.155,156 true infection rate to exclude false-positive PCR results, nor is there a clear understanding of the clinical relevance of Natural History and Complications finding trace bacterial DNA in gastric tissue. Gastroenter- H. pylori is a lifelong infection, and if left untreated, it may ologists’ position papers have not specifically recommended progress from nonatrophic to atrophic gastritis and, depend- use of PCR but do concede that it may be useful if the clini- ing on its phenotype, may cause peptic ulcer disease, adeno- cian is prepared to treat a patient with a positive result. 146 carcinoma, and primary MALT lymphoma. The relative It seems that the best application for those inclined to use risk of each of these conditions varies greatly in different this technique is for cases in which there is a histologic populations and is related to bacterial, environmental, and pattern of inflammation suggesting Helicobacter infection genetic factors. More than 90% of gastric MALT lympho- but no organisms detectable by immunohistochemistry. mas are diagnosed in patients with chronic H. pylori

A C

FIGURE 15.33 Helicobacter heilmannii organisms are at least twice as long and considerably thicker than Helicobacter pylori. Their characteristic tightly spiraled shape is clearly visible at high power with the triple stain (A), the H. pylori blue stain ( B), and most polyclonal anti-Helicobacter immunohistochemical stains (C). infection, and more than 75% will regress for extended Eradication of H. pylori facilitates healing of peptic ulcers periods with successful eradication therapy for the infec- and essentially prevents their recurrence. In contrast, more tion.155,157-159 Gastric carcinoma and lymphoma are dis- than 80% of patients treated only with acid inhibitors expe- cussed in Chapters 25 and 31, respectively. rience recurrence within 1 year. 162 Benign and malignant tumors may cause gastric ulceration. Gastric Ulcers Malignant ulcers occur most often with adenocarcinoma and stromal tumors and less commonly with lymphomas, metas- Gastric ulcer, in contrast to erosion, is defined by the loss tases, and direct extension of an adjacent extragastric malig- of the entire mucosa, including the muscularis mucosae. nancy. In immunocompromised patients, cytomegalovirus Ulcers may extend deep into the submucosa and even mus- and histoplasmosis (rare) may cause gastric ulceration. 163-165 cularis propria. Ulcers typically begin as erosions, but not all erosions progress to ulceration. Ulcers may be acute or Pathologic Features chronic. Peptic ulcers are considered chronic and are most Acute stress ulcers are usually multiple. They are more than often solitary. They may occur in any portion of the GI tract 0.5 cm in diameter and form well-delineated craters of that is exposed to acid peptic juices. Approximately 98% of various depths. Fibrin mixed with an acute inflammatory peptic ulcers occur in the stomach and duodenum, with an exudate and necrotic debris is usually found within the incidence ratio of approximately 1 : 4. ulcer bed. Because these ulcers often bleed, blood clots may fill the ulcer crater.69,166 The pathologist usually sees an Etiology abrupt transition between the necrotic edges of the ulcer H. pylori infection is a major cause of peptic ulcers not and adjacent mucosa (Fig. 15.34 ). The surrounding mucosa associated with NSAIDs or the Zollinger-Ellison syn- may be normal, or it may show features of the underlying drome.160,161 H. pylori is detected in the stomach of almost chronic gastritis, depending on the cause of the ulcer. all patients with duodenal peptic ulcer and in more than Most peptic ulcers occur on the lesser curvature of the 90% of gastric ulcer patients who are not NSAID users. stomach in the antrum close to the incisura angularis.

FIGURE 15.36 Low magniﬁcation of a gastric peptic ulcer. The ulcer crater contains a small amount of ﬁbrin and necrotic debris with underlying granulation tissue. The mucosa immediately adjacent to the ulcer shows regeneration.

Perforating ulcers penetrate into adjacent structures, FIGURE 15.34 Stress ulcer with clean borders in the antrum. Some most commonly the pancreas. The mucosa surrounding ulcers have evidence of recent hemorrhage. ulcers may appear normal or show a radiating pattern to the rugal folds endoscopically, unless the ulcer is complicated by extensive fibrosis. This feature is useful in differ- Gastric ulcers that occur in the greater curvature and in entiating benign from malignant ulcers because malignancies other parts of the proximal stomach are more likely to be usually show heaped-up mucosal borders and irregular related to chronic NSAID use than H. pylori infection .167,168 rugal folds. However, ulcers associated with malignant lym- Peptic ulcers are typically sharply demarcated lesions, phomas are often flat or only slightly elevated, frequently which may appear erythematous, edematous, and only multiple, and may reach large sizes (10 to 12 cm in slightly elevated above the level of the surrounding mucosa diameter).171 (Fig. 15.35 ). They are usually small (0.5 to 2.0 cm in diam- Microscopically, the mucosa surrounding peptic ulcers eter), but some can be more than 3.0 cm in diameter. Large typically shows chronic active inflammation and marked (i.e., giant) ulcers may be misdiagnosed endoscopically as regenerative changes, increased mitoses, mucin depletion, malignant.169,170 and foveolar hyperplasia—features that can mimic dysplasia (Fig. 15.36 ). Features that support regeneration include evidence of surface maturation, mitotic activity confined to the deeper foveolar regions, and nuclei without loss of polarity that have even chromatin, thin nuclear mem- branes, and uniform, central punctate nucleoli. A gradual transition from atypical to normal epithelium favors regeneration. The base or crater of peptic ulcers consists of necroin- flammatory debris, granulation tissue, and fibrosis with chronic inflammation from the luminal surface to the deep portions of the gastric wall. Adjacent to ulcers may be found a substantial lymphoid infiltrate arranged in follicles, in some cases mimicking malignant lymphoma.104 At the ulcer’s base, blood vessels proliferate, often showing prominent inflammation and arteritis obliterans. When disrupted, these arteries may bleed profusely. Complications The most common complications of peptic ulcer disease, in order of frequency, are hemorrhage, perforation, and obstruction. Approximately one third of patients experience at least one of these complications during the course of disease. Pyloric channel ulcers are most commonly associated with complications, particularly obstruction. FIGURE 15.35 Endoscopic view of an antral peptic ulcer. Notice the Bleeding occurs when ulcers erode underlying blood discrete border with adjacent flat, normal-appearing mucosa. vessels.

A B

FIGURE 15.37 A, Although this is not a common occurrence, even a normal gastric mucosa can harbor Helicobacter pylori infection. B, Although the pathologist may not suspect infection in such cases, organisms can be detected by an immunohistochemical stain ( arrows).

Dieulafoy Lesion been put forward and tested, commonly offered explana- tions include antibiotic therapy administered to treat other A Dieulafoy lesion refers to a prominent, large-caliber infections, the masking effect of PPIs, and inadequate sam- artery that may protrude into the gut lumen and cause pling or suboptimal staining techniques. recurrent and sometimes massive hemorrhage when the Just as we used to think that chronic active gastritis was overlying mucosa becomes ulcerated. These lesions have virtually synonymous with H. pylori infection, we also been described in all parts of the GI tract, but they are most thought that no H. pylori infection occurred without active common at the gastroesophageal junction and in the lesser gastritis. We were wrong in both cases. When anti– H. pylori curve of the stomach. Dieulafoy lesions account for the immunohistochemical stains for all gastric biopsies are rou- 0.5% to 14% of patients in whom acute upper GI bleeding tinely used, organisms are occasionally found in unexpected develops. Treatment options include endoscopic injection, histologic settings, such as antral mucosa with reactive gas- cautery, ligation, embolization, and surgery. 172,173 tropathy and no active inflammation, antral mucosa with Ulcers may perforate adjacent organs such as the pan- inactive inflammation (Fig. 15.37 ), fundic mucosa with only creas or liver. Chronic organization of a perforated ulcer minimal subepithelial lymphocytes or plasma cells and no may result in an inflammatory pseudotumor that clinically neutrophils, or almost normal mucosa. Having been misled mimics a malignant tumor. Rarely, perforated ulcers may by such cases, we advocate the preemptive use of an immu- form a fistula with the small intestine, transverse colon, or nohistochemical stain in all gastric biopsies. Those who gallbladder. Gastric outlet obstruction may develop as a cannot or choose not to routinely use immunohistochemical result of distortion and narrowing of the pyloric area because or histochemical stains for the detection of H. pylori must of fibrosis, edema, and smooth muscle spasm. It occurs decide when to employ the stains based on patient history, almost exclusively in patients with long-standing peptic histology, and personal experience. ulcers of the pyloric channel or duodenum. Surgical repair Regardless of the method used, it is important to con- or endoscopic pyloric dilation is often necessary to alleviate sider the circumstances that can result in chronic active the symptoms of gastric outlet obstruction.172,173 inflammation of the gastric mucosa in the absence of visible organisms. Two possibilities are a true H. pylori gas- Helicobacter pylori–Negative tritis in which the organisms are undetectable and injuries Chronic Gastritis or disease states unrelated to Helicobacter infection that are characterized by chronic active infiltrates in the gastric Although no studies documenting this phenomenon have mucosa. been published, there is a common perception among In addition to H. heilmannii gastritis, it is difficult or pathologists practicing in the Western world that the inci- impossible to visualize Helicobacter organisms in other dence of chronic active gastritis with no detectable H. pylori circumstances. One is a biopsy specimen with extensive organisms (i.e., H. pylori–negative chronic active gastritis) intestinal metaplasia. Although we have shown significant is increasing.20,174 The often cited 1990s axiom that even a exceptions to the concept that Helicobacter organisms small number of polymorphonuclear neutrophils in a gastric adhere exclusively to native gastric epithelium and are not biopsy is an indicator of active H. pylori infection is no found on areas of intestinal metaplasia,176,177 for practical longer applicable.175 Although no formal hypothesis has purposes, this notion can be considered correct. A biopsy

Downloaded from ClinicalKey.com at Italian Association of Gastroenterology (AIGO) November 14, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved. 374 PART 1 Gastrointestinal Tract specimen that consists primarily or exclusively of intestinalized gastric mucosa is inadequate to evaluate the possibility of H. pylori infection. If the biopsy specimen is the only one available, the pathologist should document this point in a comment and suggest that other samples be obtained. Helicobacter organisms rarely colonize necrotic tissue and regenerative epithelium. The edges of an ulcer, even in a background of severe H. pylori gastritis, are unlikely to show organisms. If specimens from other areas are available, the issue can be easily resolved; unfortunately, the pathologist often receives only one specimen labeled “gastric ulcer—rule out H. pylori.” In these cases, the pathologist can exclude neoplasm but not H. pylori and is therefore obliged to suggest more extensive sampling or the perfor- mance of a noninvasive test. Although we discourage the use of the expression sampling error , which implies that the endoscopist has taken the specimens from the wrong sites, sampling does matter FIGURE 15.38 Patients with Helicobacter pylori gastritis may have because not all areas of an infected stomach contain H. additional proton pump inhibitor–related changes. These changes pylori. In 1994, Genta and Graham evaluated the relative include a milder intensity of antral inflammation accompanied by a greater intensity in the corpus, few or no detectable organisms in yield of biopsies taken from different sites of proven H. 19 the antrum, and a peculiar redistribution of H. pylori in the deeper pylori–infected stomachs from untreated subjects. A com- portions of the oxyntic glands, even reaching the intracellular cana- bination of two specimens (one each from the antrum and liculi of the parietal cells, as demonstrated by this section from the corpus) showed organisms in more than 95% of the patients. corpus stained with an anti-Helicobacter immunohistochemical stain. At that time, the sampling site might have had only a very minor role in the ability to detect H. pylori organisms. However, the results of this study may no longer be valid, tract infections. Because these treatments are usually not because almost all patients undergoing an upper endoscopy coordinated with gastroenterologists, procedures may be are on PPIs, which may alter the dynamics of bacterial colo- done on patients who recently received or are still on anti- nization and gastric inflammation. Supporting this notion, biotics. Some of these antibiotics affect H. pylori, but when data from Lash and co-workers for more than 400,000 used outside of a coordinated triple or quadruple therapy, patients showed a doubling of Helicobacter detection with they rarely cure the infection. They may, however, tempo- sampling of at least two biopsies each from the antrum and rarily decrease the bacterial load and make the infection, corpus.178 which is still active and capable of inducing inflammation, visually undetectable. We suspect that these incidental anti- Proton Pump Inhibitor Use biotic treatments are one of the most common causes of H. PPIs, some of the most commonly prescribed GI medica- pylori–negative gastritis. tions worldwide, have become available over the counter in Antibiotics may also be prescribed by the gastroenterolo- the United States and in many other countries. PPIs are gist. Because almost no gastroenterologist performs endos- highly effective for chronic gastroesophageal reflux disease, copy in a patient treated for H. pylori infection earlier than for prevention of gastric damage associated with NSAIDs, 3 to 6 months after completion of therapy, biopsies from and for dyspepsia.179,180 After they are recommended, most these patients are likely to reveal one of two findings. If the people continue taking them indefinitely. therapy was successful (i.e., H. pylori infection was eradi- Most patients who undergo endoscopy are taking PPIs, cated), the gastric mucosa shows various degrees of chronic and gastroenterologists consider any attempt to discontinue gastritis, possibly some lymphoid follicles, and no active the medication for 2 weeks before the procedure futile. As inflammation.18,188 If the therapy failed, a recrudescence a consequence, most gastric biopsies show a presumed PPI occurs, and the chronic active gastritis is often more severe effect: focally dilated oxyntic glands with flattened or than before the unsuccessful therapeutic trial. Biopsies after hypertrophic parietal cells protruding into the lumen.54,181 eradication treatment are an exceedingly uncommon source Patients with H. pylori gastritis may have additional PPI- of H. pylori–negative active gastritis. related changes, especially a milder intensity of antral inflammation accompanied by a greater intensity in the Causes of Chronic Active Gastritis Unrelated corpus, few or no detectable organisms in the antrum, and to Helicobacter Infection a peculiar redistribution of H. pylori organisms in the deeper In some biopsy specimens, the features of reactive gastropa- portions of the oxyntic glands, even reaching the intracel- thy are accompanied by those of chronic gastritis with or lular canaliculi of the parietal cells182-187 ( Fig. 15.38 ). PPI without foci of active inflammation. Because the features use can cause false-negative results for urea breath tests. of H. pylori gastritis may overlap with those of reactive gastropathy (and the two types may coexist), a careful Recent Antibiotic Treatment search for H. pylori organisms is imperative. Innumerable persons receive antibiotic treatments for a The two causes can usually be discerned. In contrast to variety of verified or suspected infections; among the most H. pylori gastritis, the chronic infiltrate of reactive gastropa- common are dental procedures and ear, throat, and urinary thy is loose, does not form a subepithelial band (formerly

seen, an effort should be made to detect organisms. If none is found, a measured comment can be made indicating that one of the possible causes is inflammatory bowel disease elsewhere in the GI tract. Other Infections Other bacteria, fungi, and viruses may infect the gastric mucosa, but only rarely do they produce the histopathologic appearance of chronic active gastritis. Rather, they typically elicit a more mixed inflammatory infiltrate that is less superficial, as in the case of cytomegalovirus gastritis (Fig. 15.40). Unless specific clinical information is available (e.g., an immunosuppressed patient, a case of disseminated asper- gillosis), a search for infectious agents other than Helico- bacter species in the gastric mucosa is likely to be laborious and, ultimately, unrewarding. Reported Conclusions After the pathologist has reviewed the slides, restained, and used alternate techniques, a well-worded report should state that no H. pylori organisms were found after a meticu- lous search, despite the characteristic histologic appearance. These reports, however, are unlikely to gratify an inquisitive clinician, who will be left wondering what should be done. Calling the clinician and explaining the circumstances that led to an equivocal diagnosis is probably the best way to avoid being perceived as a timid pathologist. Before dis- cussing a case, however, it is necessary to be fully informed. If the pathologist can elicit a history of recent incidental FIGURE 15.39 Two examples of focally enhanced (Helicobacter pylori–negative), chronic active gastritis. It is characterized by patchy antibiotic treatment, he or she can suggest a plausible expla- lymphoplasmacytic and neutrophilic infiltrates, sometimes limited to nation for H. pylori–negative chronic active gastritis. The only one or a few glands. The intervening mucosa is completely pathologist can indicate that the inadequately treated infec- normal (top, triple stain; bottom, hematoxylin and eosin [H&E] tion may reemerge and that a new set of biopsies after a stain). few weeks may show organisms. A tactfully delivered reminder on the effects of PPIs may also help to persuade designated superficial gastritis), and rarely has significant clinicians to start regularly sampling the antrum and the numbers of plasma cells. Any polymorphonuclear neutro- corpus. It is important not to leave the impression that H. phils tend to be confined to the lamina propria, sparing the pylori–negative chronic active gastritis is a final diagnosis glandular epithelium, where they are often associated with without need for further workup. eosinophils. Intraepithelial neutrophils, aggregates of neutrophils, and regenerative epithelium are usually found only Autoimmune Gastritis in the vicinity of erosions, which are often revealed by additional sections into the block. Clinical Features Autoimmune gastritis is a type of corpus-restricted, chronic Focally Active Gastritis atrophic gastritis associated with serum anti–parietal cell The finding of individual or few gastric foveolae or glands and anti–intrinsic factor antibodies with resultant intrinsic discretely surrounded and infiltrated by lymphocytes, mac- factor deficiency with or without anemia.192,193 Autoim- rophages, plasma cells, and occasional neutrophils in a back- mune gastritis does not cause specific clinical manifestations ground of normal gastric mucosa has been referred to as until a critical decrease has occurred in the parietal cell focally enhanced gastritis ( Fig. 15.39 ). 17 Although the mass, beyond which anemia develops. Years before the meaning of the word enhanced in this context remains puz- onset of anemia, patients may show various degrees of hypo- zling to many pathologists, the term has become tacitly chlorhydria, hypergastrinemia, and loss of pepsin and pep- accepted. sinogen secretion. Focal and often intense gastritis has been described in a Achlorhydria, which is a direct result of destruction of high percentage of patients with inflammatory bowel acid-producing parietal cells, typically occurs in the most disease, most notably children with Crohn’s disease, but it advanced stage of disease. However, hypochlorhydria may can be seen in many patients with no inflammatory bowel occur in patients with a large number of preserved parietal disease.189-191 H. pylori infection can also be patchy, although cells, which suggests that there may be a possible role for typically with a less striking contrast between inflamed and anti–proton pump antibodies or inhibitory lymphokines adjacent, normal-appearing mucosa than seen with inflam- released by inflammatory cells in the pathogenesis of this matory bowel disease. Nevertheless, when focal gastritis is disease. Patients with atrophy of the corpus and achlorhydria

A B

FIGURE 15.40 Chronic active gastritis with no detectable Helicobacter pylori organisms. A, The chronic inflammation is located in the lower half of the antral mucosa, and the density of plasma cells is relatively low. B, A single cytomegalovirus inclusion (arrow) is magnified. have a high level of hypergastrinemia that tends to correlate a thorough investigation of the underlying cause. However, with disease severity.194,195 Damage to chief cells leads to a targeted studies suggest an overall prevalence of 2%, with a reduction in pepsin activity in gastric juice and in the level peak of 4% to 5% among elderly women.203 of pepsinogen in serum. The finding of a low pepsinogen I level (<20 ng/mL) is a sensitive and specific indicator for Pathogenesis corpus atrophy.194,196 The cause of autoimmune gastritis is unknown. One theory Iron deficiency anemia or pernicious anemia develops in suggests the disease may be initiated by H. pylori infection. many patients with autoimmune gastritis, and achlorhydria A high prevalence of antibodies with specificity for gastric is a major contributor to the pathogenesis of anemia. Gastric mucosal antigens has been reported for patients with acid is important for absorption of nonheme iron, which H. pylori–associated gastritis.204,205 Twenty percent of H. supplies at least two thirds of the nutritional iron supply in pylori–positive individuals have autoantibodies that react most Western diets. 197 Pernicious anemia, which results from with the canaliculi of parietal cells, which are a primary loss of intrinsic factor production by parietal cells, is usually antibody target in autoimmune gastritis. Studies with cloned preceded by corpus-restricted chronic atrophic gastritis T cells from H. pylori–infected patients and patients with (usually end stage) and reduced or absent acid secretion of autoimmune atrophic gastritis have identified molecular at least 10 years’ duration.198,199 Autoimmune gastritis is a mimicry between H. pylori and hydrogen and potassium risk factor for hyperplastic and dysplastic polyps, carcinoma, receptors and ATPase, suggesting that infection may stimu- and endocrine tumors. Polyps are detected in 20% to 40% of late T cells that target parietal cells. 83 These studies provide patients with pernicious anemia; they are mostly sessile, less support for the concept of a cross-reactive mechanism than 2 cm in diameter, and often multiple. Most are hyper- between H. pylori organisms and gastric epithelial antigens plastic, but as many as 10% contain foci of dysplasia.200,201 that may be responsible for or at least participate in the Gastric cancers associated with pernicious anemia are mostly pathogenesis of autoimmune gastritis.206 The role of immu- intestinal type and arise from intestinal metaplasia, suggest- noglobulin G4 (IgG4) in autoimmune gastritis may be ing that carcinoma in autoimmune gastritis likely develops similar to that in autoimmune pancreatitis, and a study through a metaplasia–dysplasia–carcinoma pathway.202 found IgG4-immunoreactive plasma cells in gastric biopsies to be 100% specific (albeit not highly sensitive) for autoim- Epidemiology mune atrophic gastritis and pernicious anemia.207 Pernicious anemia is an uncommon disease with a reported prevalence rate of approximately 1%, even among older Pathologic Features people and in high-incidence regions of the world. However, Grossly, the mucosa of the corpus in patients with autoim- autoimmune gastritis may be underdiagnosed because most mune gastritis is usually thinner than normal and shows a patients have microcytic or macrocytic anemia and are reduction or complete absence of rugal folds. Fine submu- treated with iron, folate, and cobalamin without undergoing cosal vessels are usually easily recognizable on endoscopic

the full thickness of the lamina propria with some degree of loss of oxyntic glands. Although the histology may suggest the cause, the diagnosis at this stage requires demonstration of circulating anti–parietal cell autoantibodies, a test rarely performed in routine clinical practice.209 The florid phase of autoimmune gastritis is characterized by marked atrophy of oxyntic glands, diffuse lymphoplasmacytic infiltration of the lamina propria, and normal or reduced thickness of the mucosa with a relative increase in the thickness of the foveolar component. Pseudopyloric metaplasia is often extensive, and intestinal metaplasia tends to be more prominent than in the early phase. At this stage of the disease, the pathologic features of autoimmune atrophic gastritis are sufficiently distinctive, particularly if the antrum is normal. However, demonstration of antibodies directed against parietal cell and intrinsic factor antigens is necessary for confirmation. The end stage of disease is characterized by a marked reduction in oxyntic glands, foveolar hyperplasia with elongation and microcystic change, hyperplastic polyp formation, and increasing degrees of pseudopyloric, pancreatic, and intestinal metaplasia. The muscularis mucosae may be thickened threefold to fourfold (Fig. 15.42 ). At this stage, parietal cells are difficult to detect, and inflammation is usually minimal or absent, although scattered lymphoid FIGURE 15.41 Marked lymphocytic infiltration of oxyntic glands aggregates may persist. can be seen in autoimmune gastritis and in Helicobacter pylori infec- During the florid and end stages, hypochlorhydria and tion. It usually precedes the development of atrophic gastritis. achlorhydria cause physiologic hypergastrinemia, which stimulates ECL cell proliferation. ECL cell proliferation may also occur in patients with Zollinger-Ellison syndrome, examination in advanced cases. Hyperplastic polyps are also multiple endocrine neoplasia syndromes, and H. pylori– common in advanced-stage disease. associated, multifocal atrophic gastritis. Solcia and col- Microscopically, the main pathologic features of uncom- leagues proposed a reproducible, albeit arbitrary, classification plicated autoimmune gastritis are diffuse corpus-restricted that helps to distinguish normal from dysplastic and overtly chronic atrophic gastritis with some degree of intestinal malignant ECL cell proliferations. For example, an intramu- metaplasia. In the absence of comorbidities, such as concur- cosal carcinoid tumor is defined as an expansile or infiltra- rent H. pylori infection or bile reflux, the antrum is typically tive endocrine growth that is more than 0.5 mm in diameter. normal. This pattern of involvement is characteristic of Invasive carcinoids are those in which tumor invades the patients with advanced disease and is found in patients with submucosal space (see Table 15.3 and Chapter 29). 53 pernicious anemia. Patients without pernicious anemia but Although ECL cell carcinoids may arise during the florid with anti–parietal cell antibodies have a spectrum of atrophic changes that range from minimal to severe and diffuse atrophy of the oxyntic mucosa, and they have some degree of ECL cell proliferation (see Table 15.3 ). Three pathologic phases can be identified during the course of autoimmune gastritis in corpus mucosa: early, florid, and end stage. The early phase is characterized by diffuse or multifocal, dense lymphocytic and plasma cell infiltration involving the entire thickness of the lamina propria and often mixed with eosinophils and mast cells. Patchy destruction of individual oxyntic glands by lymphocytes may be seen at this stage (Fig. 15.41 ). The pathologist may see patchy pseudopyloric metaplasia and hypertrophic changes of the remaining parietal cells. Hypertrophic changes indicate a high level of functional stimulation, which may be related to hypergastrinemia and can be found in the parietal cells of patients with autoimmune atrophic gastritis, those who have received PPI therapy, and a subset of patients with peptic ulcer disease.56,208 In the early phase of autoimmune gastritis, intestinal FIGURE 15.42 Autoimmune gastritis of the corpus with pseudopy- metaplasia rarely occurs and is often focal. At this stage, loric metaplasia of the deep glands and superficial intestinal various degrees of chronic and active inflammation involve metaplasia.

Downloaded from ClinicalKey.com at Italian Association of Gastroenterology (AIGO) November 14, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved. 378 PART 1 Gastrointestinal Tract phase, they are found most commonly in patients with end- largely unknown to gastroenterologists, it may be the stage disease.202 Carcinoid tumors associated with ECL cell expression of a severe, perhaps acute form of H. pylori hyperplasia occur in 5% to 8% of patients with autoimmune infection. gastritis and severe hypergastrinemia, and they account for Almost all intraepithelial lymphocytes in lymphocytic 70% to 80% of all gastric carcinoid tumors. These tumors gastritis are CD8+ T cells, similar to those found in the are relatively innocuous and are associated with a more than duodenal mucosa of celiac disease patients. An allergic or 95% 5-year survival rate, which sharply contrasts with the autoimmune pathogenesis has been proposed. This hypoth- less common solitary, sporadic type of carcinoid tumors that esis is supported by the increasingly apparent association are biologically more aggressive (<35% 5-year survival between lymphocytic gastritis and celiac disease.211 Some rate).210 It is important to convey to clinicians the clinical investigators have postulated a relationship between lym- and pathologic context in which a gastric carcinoid is phocytic gastritis and Ménétrier disease.216,217 diagnosed. The antral mucosa in autoimmune gastritis may be Pathologic Features normal or show mild, chronic inflammation with small foci On gross examination, most patients with lymphocytic gas- of intestinal metaplasia similar to that observed in the age- tritis (including those with celiac disease) have scattered matched general population. However, most patients have superficial erosions in the corpus or antrum or, in our expe- the characteristic features of reactive gastropathy, with rience, a normal-appearing gastric mucosa. foveolar hyperplasia and mucin depletion of the surface and Microscopically, the severity of inflammatory changes in foveolar epithelium. Hyperplasia of gastrin cells caused by lymphocytic gastritis varies widely. In mild cases, there is achlorhydria is often seen in the antrum. Concurrent H. only a minor increase in chronic inflammation without neu- pylori infection may involve the antrum and cause neutro- trophils. At the other extreme, marked chronic inflamma- philic inflammation in addition to chronic gastritis. tion may be seen in the lamina propria that is occasionally associated with surface erosions. The lamina propria infil- Special Forms of Gastritis trate is composed mainly of lymphocytes, with scattered plasma cells, eosinophils, and mast cells. In lymphocytic Special forms of gastritides include inflammatory conditions gastritis, more than 25 intraepithelial lymphocytes per 100 of the stomach that are of uncertain origin, such as reactive epithelial cells is typical, although counting is usually unnec- and vascular gastropathies, although they are well character- essary (Fig. 15.43 ). 211,218 The histologic features are readily ized topographically and morphologically. distinguishable from those of typical H. pylori gastritis (see Figs. 15.4, 15.6, 15.10 ), in which only rarely are more than Lymphocytic Gastritis 5 or 6 intraepithelial lymphocytes per 100 epithelial cells found, and the lymphocytes are usually more irregularly Clinical Features distributed. In cases with prominent neutrophils, other dis- Lymphocytic gastritis is characterized by large numbers of orders such as H. pylori gastritis should be considered. mature lymphocytes that infiltrate the surface and foveolar Other features of lymphocytic gastritis include degenerative epithelium. Although this pattern of gastritis has reportedly epithelial changes, mucin depletion, foveolar hyperplasia, been seen in 1% to 4% of patients who undergo upper and increased mitoses. The type and intensity of these endoscopy, in our experience with more than 500,000 associated changes may be related to the underlying cause patients with gastric biopsies, the prevalence was less than of the lymphocytic infiltration. 0.3%. Lymphocytic gastritis is most commonly diagnosed in the fifth decade of life, and it affects women more than men, especially when it is associated with celiac sprue.211 Lymphocytic gastritis was initially thought to correspond to an entity described by François Moutier in 1945 as varioliform gastritis , a nodular form of gastritis characterized by central depressions (i.e., octopus sucker gastritis).101,102 However, lymphocytic gastritis may also be observed in patients with celiac disease, Ménétrier disease, H. pylori infection, and, less commonly, lymphocytic or collagenous colitis, and NSAID use. Lymphocytic gastritis is essentially a pathologic reaction pattern without specificity for any particular disease. In one pediatric study of patients with celiac disease, the degree of duodenal and gastric intraepithelial lymphocytosis decreased concurrently with with- drawal of gluten from the patients’ diet. Histologic evidence of lymphocytic gastritis has been reported for patients with endoscopically normal gastric mucosa.211-214 Patients with endoscopic varioliform lymphocytic gastritis have rapid weight loss, anorexia, hypoproteinemia, FIGURE 15.43 Lymphocytic gastritis with marked intraepithelial hypoalbuminemia, and peripheral edema, suggesting a lymphocytosis and a marked plasma cell and lymphocytic infiltrate 215 protein-losing gastroenteropathy. Because this entity has in the lamina propria. This biopsy showed no evidence of Helico- not been described again in the past 2 decades and remains bacter pylori infection.

eosinophils was derived from infrequent and often uncon- trolled case series, isolated case reports, and brief sections in textbooks of GI pathology.225-228 In the Kalixanda study, Talley and colleagues found a mean eosinophil count of 11 eosinophils per 5 high-power fields (HPFs) in biopsies from the cardia, body, and antrum of asymptomatic adult volunteers from Northern Sweden.227 DeBrosse and co-workers found peak eosinophil counts of 8 eosinophils/HPF in antral biopsies and 11 eosinophils/ HPF in oxyntic mucosal biopsies from 19 children. 226 Lwin and colleagues enumerated eosinophils in the lamina propria of patients from a wide age range and from diverse geographic areas in the United States with no known history of relevant GI disease and whose gastric biopsies were diagnosed as unremarkable.27 The mean eosinophil count for 135 normal patients (age range, 4 to 81 years) was 4 FIGURE 15.44 Example of collagenous gastritis showing a thickened eosinophils/HPF (±4 standard deviations [SD]), equivalent 2 and irregular subepithelial collagen plate on a background of chronic to 15 ± 17 SD eosinophils/mm (range, 0 to 110 eosinophils/ gastritis. The surface epithelium may become artifactually detached, mm 2). There were no significant differences between the similar to collagenous colitis. counts in biopsies from the antrum and corpus and no significant variation by age or geographic location. These findings essentially agreed with those of DeBrosse and colleagues 226,227 Collagenous Gastritis and Talley and co-workers. Collagenous gastritis is a rare entity that is histologically Causes of Gastric Mucosal Eosinophilia similar to collagenous colitis and is characterized by a dis- Increased numbers of eosinophils in the lamina propria tinct subepithelial collagenous band and nonspecific inflam- have been documented in a variety of conditions, including matory infiltrate that may or may not be associated with infection with Anisakis spp., 229 Strongyloides stercoralis,230 increased intraepithelial lymphocytosis (Fig. 15.44 ). Similar or H. pylori231-233 and after H. pylori treatment. 18 Other to collagenous colitis, the collagen band typically is 10 to associations include drug-induced injury,59 Crohn’s disease, 27 25 μm thick in well-oriented sections, has an irregular pyloric obstruction,234,235 tumors, 236 connective tissue dis- contour, and demonstrates a ragged interface with the eases, hematopoietic disorders, food allergy, and rare underlying lamina propria. Capillaries are usually entrapped eosinophil-associated GI disorders.26 by the fibrous band. One study reported intestinal metaplasia, ECL cell hyperplasia, and epithelial atypia (considered Idiopathic Eosinophilic Gastritis indefinite for dysplasia) in a case of collagenous gastritis and Idiopathic (isolated) eosinophilic gastritis is a poorly postulated an unproven risk of carcinoma.219 characterized condition. Although rare cases have been Most collagenous gastritis patients can be segregated into reported sporadically in the literature,237-241 H. pylori has two groups: children and young adults with severe anemia, monopolized the efforts of gastric researchers since the endoscopically nodular mucosa, and disease limited to the mid-1980s, and the few descriptions of eosinophilia in the stomach and adults with chronic, watery diarrhea and asso- gastric mucosa have been related to current or treated H. ciated collagenous colitis. One report described a case asso- pylori infection. 18 ciated with lymphocytic gastritis and celiac disease.220-224 Lwin and colleagues reported a series of 60 patients with The differential diagnosis includes fibrosis associated gastric mucosal eosinophil counts of 50 to more than 400 with autoimmune gastritis, healed ulcer, or radiation therapy eosinophils/HPF (i.e., 200 to more than 1000 eosinophils/ in which the collagen deposition is usually more diffuse and mm 2). 27 Epigastric pain was the most common reason for not specifically subepithelial. Similarly, patients with sclero- endoscopy in adults and children, followed by reflux disease derma have fibrosis at all levels of the mucosa, and it may and dysphagia. The most common endoscopic findings were involve deeper levels of the bowel wall. As in the colon, the a normal stomach or erythema and gastritis with or without subsurface basement membrane may be prominent in some erosions. preparations and often is accentuated by basal epithelial cytoplasm. Paying attention to the nature of the fibrosis Practical Suggestions for Diagnosis helps the clinician to avoid an overdiagnosis. Epithelial eosinophilic infiltration (Fig. 15.45, A) is a common finding, particularly if a sufficient number of sec- Eosinophilic Gastritis tions are examined. Sheets of eosinophils (see Fig. 15.45, B) are seen in more than one half of specimens from patients Normal Eosinophil Counts in the Gastric Mucosa with eosinophilic gastritis. Eosinophils tend to surround the Although most observers consider the finding of a few foveolae and infiltrate the epithelium, but they typically do eosinophils in the lamina propria common, the updated not spill into the lumen to form eosinophilic pit abscesses Sydney System posits that intraepithelial eosinophils in (see Fig. 15.45, B). Involvement of the muscularis mucosae gastric mucosa are always abnormal.175 The limited informa- or submucosa may occur. Although reactive epithelial tion available regarding the normal range of gastric mucosal changes similar to those found in chemical gastropathy are

mentioning the possibility of eosinophilic gastritis, among other differential diagnoses deemed appropriate in the context of the patient’s clinical situation.27

Granulomatous Gastritis Granulomatous gastritis is a nonspecific histologic pattern of disease characterized by multiple granulomas in the gastric mucosa (Fig. 15.46, A and B). The morphologic appearance of the granulomas does not provide useful clues about their cause, except when foreign material, acid-fast bacilli, or fungal forms are identified; the latter two entities occasionally cause central necrosis or caseation. In most cases, the cause cannot be determined without specific clinical and laboratory information. Granulomas may be found in the gastric mucosa of patients with many types of infectious, inflammatory, and neoplastic diseases, and they may be seen in otherwise A healthy individuals. The endoscopic appearance of the stomach may be normal, or it may exhibit characteristics of the specific disease entity that caused the granulomas to form. Possible causes of granulomas in the gastric mucosa are provided in Box 15.1 . Mycobacterial and Fungal Infections Worldwide, tuberculosis is the most common cause of granulomatous disease of the GI tract. However, the stomach is rarely affected. Primary gastric tuberculosis has been reported mostly in developing countries with a high prevalence of Mycobacterium tuberculosis infection. 242-245 In almost all cases, gastric tuberculosis manifests as a large, nonhealing ulcer. A few cases of primary infection of the stomach by the dimorphic fungus Histoplasma capsulatum have been reported. Similar to those with gastric tuberculosis, these patients often have signs and symptoms of a large gastric ulcer.246-248 Helicobacter pylori Infection B Unexplained granulomas may be found in less than 10% of patients with H. pylori gastritis, and the role of this organ- FIGURE 15.45 A, There are innumerable eosinophils in the lamina ism in causing granulomas is unknown and controversial.249 propria in this example of eosinophilic gastritis. B, Eosinophils occur Because granulomas in the stomach are not rare and may within the muscularis mucosae. Eosinophils tend to surround the also be seen in healthy individuals, the discovery of granu- foveolae and infiltrate the epithelium, but they typically do not spill lomas in patients with H. pylori gastritis may represent a into the lumen to form eosinophilic pit abscesses. common, neither foveolar hyperplasia nor intestinal metaplasia is characteristic. Box 15.1 Causes of Gastric Granulomas We recommend that the term histologic eosinophilic gas- Infections Xanthogranuloma tritis be used for the diagnosis of patients with gastric Bacterial Tumors biopsies that show at least 30 eosinophils/HPF (on micro- Tuberculosis Carcinoma scopes equipped with wide-lens oculars) in at least five Syphilis Lymphoma separate HPFs (focusing on the most concentrated fields) Whipple disease Plasma cell granuloma and who have no known cause of eosinophilia. If H. pylori Helicobacter (?) Granulomatous diseases of organisms are detected, the diagnosis of eosinophilic gastri- Fungal unknown origin tis can be established only if the mucosal eosinophilia per- Histoplasmosis Immune-mediated sists several months after successful eradication. Parasitic vasculitis Anisakiasis Wegener granulomatosis When regenerative epithelial changes are observed in a Strongyloidosis (?) Crohn’s disease gastric biopsy with significant eosinophilic infiltrates that Foreign bodies Sarcoidosis fall below the recommended quantitative threshold, we Sutures Isolated granulomatous suggest a diagnosis of reactive gastropathy with increased Food gastritis eosinophils. The diagnosis should include a comment

are foreign body granulomas, which are sometimes associated with fragments of helminthic cuticles.28,250 Rarely, fragments of larvae interpreted as Strongyloides stercoralis have been observed in gastric granulomas.251,252 These conditions are discussed further in Chapter 4. Foreign Bodies Suture material is a common cause of granulomas in the stomach in patients who have undergone a partial gastrectomy. Examination under polarized light should always be performed in cases of granulomatous gastritis. In patients with gastric ulcer, food particles may become engulfed by the ulcer crater, where they may cause a foreign body reaction (i.e., cereal granulomas). When granulomas are found in biopsy specimens obtained from active ulcers, their origin is readily apparent. However, diagnostic difﬁculties may arise when granulomas are found in specimens from healed ulcers and the pathologist lacks the appropriate clinical information.

A Tumors Rarely, adenocarcinomas (particularly mucin-producing lesions) may induce the formation of granulomas in the gastric mucosa or in lymph nodes. Granulomas have also been observed in patients with gastric non-MALT lymphomas.253 Other Unusual Causes Granulomatous gastritis is rarely part of an immune- mediated vasculitis syndrome, such as Wegener granulomatosis. Sometimes, it may assume a xanthogranulomatous pattern, akin to that seen in some cases of cholecystitis or pyelonephritis.254,255 Gastric Involvement in Systemic Granulomatous Diseases Granulomas may be detected in the gastric mucosa of patients with established sarcoidosis or Crohn’s disease, and in these settings, they may be assumed to be part of the systemic process without the need for further investiga- tions. However, gastric granulomas are sometimes detected B before the discovery of the primary disease in other organs. In these cases, correct interpretation of the biopsy findings FIGURE 15.46 Granulomas can vary in appearance. For example, may prompt diagnosis of a condition that may otherwise some are less well-defined with abundant inflammatory cells remain obscure for a long time. 256 (A), and others (e.g., those in which a foreign body can be detected) Sarcoidosis involving the GI tract is occasionally discov- tend to be more compact with less inflammation (B). When the ered at autopsy, but it rarely is of clinical importance. Nev- cause of the granulomas is not evident, the pathologist should ertheless, severe disease can produce gastric outlet consider the possibility of Crohn’s disease or sarcoidosis. obstruction or bleeding. Endoscopic findings include nodularity, polyps, erosions, ulcers, and segmental (usually distal) rigidity that may resemble linitis plastica.257,258 Microscopi- coincidental finding. Alternatively, granulomas in this setting cally, sarcoidosis may be suspected when granulomas are may indicate a second disorder, such as a drug reaction, numerous, discrete, and contain Langerhans-type giant cells another type of infection, or foreign body. (see Fig. 15.46, B); Schaumann and asteroid bodies are not typically seen in gastric sarcoidosis. Because there are no Parasites pathognomonic histologic findings of gastric sarcoidosis, the The nematodes most commonly associated with the forma- pathologic findings need to be interpreted in conjunction tion of gastric granulomas are Anisakis spp . Early lesions with clinical and radiologic information. Isolated gastric sar- show interstitial edema accompanied by loose, predomi- coidosis or sarcoidosis initially manifesting in the stomach nantly eosinophilic inflammation, and late lesions may show without involvement of other organs is rare. overt eosinophilic microabscesses. Well-preserved larvae are The common perception that gastric involvement in often detected. In late lesions, the most common findings Crohn’s disease is rare was challenged in a study that found

Downloaded from ClinicalKey.com at Italian Association of Gastroenterology (AIGO) November 14, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved. 382 PART 1 Gastrointestinal Tract gastric granulomas in 10% to 15% of Crohn’s cases.259 Focally enhanced H. pylori–negative chronic active gastritis, Types of Chemical Injury to the Stomach characterized by very localized and intense lymphoplasma- Several chemical agents are commonly associated with cytic and neutrophilic infiltrates with intervening unin- damage to the gastric mucosa. Although some agents cause volved mucosa, has been reported to occur in 30% to 70% acute destructive and ulcerating lesions, others may induce of patients with Crohn’s disease.17,260 In this series, focally only subtle and mild changes of reactive gastropathy. enhanced gastritis was more frequent in the corpus than in the antrum, whereas epithelioid granulomas were twice as Acid, Alkali, and Large Quantities of Ethanol prevalent in the antrum. A much lower proportion of gastric Acid, alkali, and ethanol can cause extensive, severe necrotic involvement in patients with Crohn’s disease was found in lesions that are usually not biopsied. Unless perforation later studies.189 Nevertheless, the finding of granulomas in develops, the lesions typically heal, sometimes with exten- the stomach in a patient with other features of gastric sive scarring and organ deformity. After large quantities of Crohn’s disease should always prompt further investigation strong alcoholic beverages are consumed by an individual in of the remainder of the GI tract for further evidence of a short period of time, endoscopy commonly shows mul- disease tiple subepithelial petechiae. Histologically, localized hemorrhages of the foveolar region usually are associated with Idiopathic Granulomatous Gastritis edema in the surrounding mucosa without prominent After all of the previously discussed diagnoses have been inflammation.37 excluded and appropriate tests have been performed, a specific cause still may not be identified. However, iso- Duodenopancreatic (Bile) Reflux lated or idiopathic granulomatous gastritis should not be Between 10% and 30% of patients who have undergone a considered a separate and distinct nosologic entity but Billroth II partial gastrectomy, which historically was used rather treated as a holding category and applied as a tem- for benign conditions such as peptic ulcer disease, develop porary diagnostic term in cases for which the primary polypoid lesions in the mucosa adjacent to the anastomosis cause of the granulomas awaits determination.261 Support or stoma site. These cystic lesions, also known as gastritis for this approach is derived from several studies that have cystica polyposa or gastritis cystica profunda, are formed shown that most unexplained gastric granulomas represent from dilated, irregular, and cystic foveolae. When the lesion concurrent or incipient Crohn’s disease or another sys- forms a polyp, it is referred to as polyposa; when the lesion temic disorder such as sarcoidosis.256,258,259 A descriptive is predominantly inverted, forming a prominent submucosal diagnosis such as non-necrotizing granulomatous mucosal lesion or mass, the term profunda is used. 271 inflammation is preferable to the use of such terms as The surface epithelium typically shows striking regenera- idiopathic or primary granulomatous gastritis. tive changes with marked mucin depletion. Other features typical of bile reflux–induced (post-Billroth II) gastropathy include thinning of the foveolar epithelium, increased Gastropathies number of mitoses, loss of the normal columnar shape of Reactive (Chemical) Gastropathy the epithelial cells (i.e., cuboidalization), and marked tortuosity of the surface and foveolar epithelium. The more An association between bile in the stomach and gastric proximal (corpus) mucosa may also show atrophy, foveolar mucosal damage was first postulated by William Beaumont hyperplasia, intestinal metaplasia, and pseudopyloric gland in 1833 as part of his decade-long observations of Alexis St. metaplasia.270,272 Martin’s permanent open gastric fistula.262 Changes in Most cases, such as the one depicted in Figure 15.47 , are gastric mucosa exposed to biliary and duodenopancreatic unlikely to pose a diagnostic dilemma if the pathologist is reflux after Billroth II operations were described in the aware of the patient’s surgical history. Some patients may 1960s and 1970s as postoperative gastritis.263 The possible experience delayed gastric emptying or gastric outlet premalignant nature of these changes was observed there- obstruction when the polypoid growth attains a large size, after in cohorts of operated patients.264-266 The pathologic and the symptoms may raise concerns about the possibility changes associated with bile reflux were described system- of neoplasia, prompting endoscopic and radiologic assess- atically for the first time in 1983.267,268 ment. Because the gastric stump (after Billroth II surgery) Initially, the term bile reflux gastritis was proposed to is thought to be at increased risk for dysplasia and carci- describe a distinct clinicopathologic entity. 30,267-270 However, noma,273,274 most authorities recommend regular endoscopic after it was determined that lesions of the gastric mucosa surveillance starting a maximum of 10 years after surgery. 275 associated with NSAID use were similar to those induced With the discovery of H. pylori as the principal cause of by bile reflux, the term chemical gastritis was introduced. peptic ulcer disease and the use of highly effective medical Synonyms include reactive gastritis , type C gastritis , and treatment, Billroth II antrectomies for benign disease have chemical gastropathy. The latter term was recommended by become increasingly uncommon. As the number of patients authors of the updated Sydney System.8 The Sydney who have undergone this procedure decreases, the preva- System defines chemical gastropathy as “the constellation lence of anastomotic and stomal gastropathy and the inci- of endoscopic and histologic changes caused by chemical dence of stump carcinoma are expected to decline. injury to the gastric mucosa.” Implicit in this definition is Reflux of bile or other luminal components of the duo- the absence of independent specific endoscopic or histologic denum into a normal, nonoperated stomach is difficult to features in patients with a history of endogenous or exog- demonstrate in clinical practice, and the relevance of this enous chemical damage to the stomach. condition is a subject of debate. Some degree of bile reflux

However, many of these agents were eventually shown to have no consistently detectable effects on the stomach. The most commonly used drugs and drug categories that can alter or damage gastric mucosa when consumed at therapeutic doses are listed in Table 15.6 . Pathogenesis of Reactive Gastropathy Duodenogastric reflux with alkaline pancreatic and duodenal secretions, acids, bile salts, and lysolecithin results in disruption of the mucus barrier and direct chemical damage to gastric surface epithelium. Loss of this barrier allows back diffusion of hydrogen ions and secondary injury.282 This combined injury leads to accelerated exfoliation of surface epithelial cells and a histamine-mediated vascular response that manifests histologically as edema and hyperemia. Persistent epithelial damage promotes the release of other proinflammatory agents, such as platelet-derived FIGURE 15.47 Stomal gastropathy (after Billroth II chronic gastritis) growth factor, which stimulates smooth muscle and fibro- showing sparse chronic inflammation and marked foveolar hyper- blastic proliferation. Epithelial injury after exposure to plasia, mucin depletion, vascular congestion, edema, and smooth NSAIDs appears to be mediated by a reduction in prosta- muscle hyperplasia. glandin synthesis. Prostaglandins are important cytoprotec- tive agents in the gastric mucosa and exert their effects by is thought to occur in most healthy individuals and particu- maintaining mucosal blood flow, increasing secretion of larly in those who smoke and in patients with duodenal mucus and bicarbonate ions, and augmenting epithelial ulcer, chronic respiratory disease, alcohol abuse, and after defenses against cytotoxic injury. The simultaneous admin- cholecystectomy.276 Gastric mucosa chronically exposed to istration of prostaglandin analogues (e.g., misoprostol) and bile may undergo pathologic changes similar to those that PPIs decrease the incidence of NSAID-induced ulcers occur in the gastric stumps. Patients with bile reflux docu- and bleeding,59,283 but it is unknown whether the use of mented by 24-hour ambulatory monitoring of intragastric these medications influences the development of reactive bilirubin absorbance and pH values were found to have gastropathy. significantly more active and chronic inflammation, intesti- Selective cyclooxygenase-2 inhibitors (e.g., COX-2 nal metaplasia, atrophy, and H. pylori infection (particularly inhibitors, second-generation NSAIDs, selective NSAIDs) in the corpus and incisura) than dyspeptic patients without appear to be better tolerated by gastric mucosa and may bile reflux.277 A high prevalence of H. pylori infection was reduce GI symptoms caused by other drugs, but they still reported for antrectomized patients in Israel.278,279 These cause more GI events than placebos.284,285 Although the data contrast with previous observations that bile reflux indications for use of many of these compounds have been tends to eliminate or suppress H. pylori infection. 280,281 drastically limited because of serious concerns about possible cardiovascular side effects,286 their use persists. Medications Before the discovery of H. pylori as a cause of gastritis, Pathology several types of drugs and commonly used substances, such In postgastrectomy patients with bile reflux, gross examina- as caffeine and hot peppers, were thought to cause gastritis. tion of the mucosa at the anastomotic site may reveal that

Table 15.6 Drug-Induced Gastric Injury Drug or Drug Family Predominant Morphology of Gastric Injury NSAIDs, aspirin, alcohol Erosions, ulcers, reactive gastropathy Proton pump inhibitors Parietal cell hypertrophy and hyperplasia, fundic gland cysts and polyps Iron Erosions with Fe 2+ deposits Sodium polystyrene sulfonate sorbitol (Kayexalate) Crystal deposition (i.e., rhomboid or triangular, nonpolarizable, basophilic crystals adherent to the surface epithelium or within sloughed inﬂammatory exudates) Cholestyramine Crystal deposition (similar to Kayexalate crystals) Colchicine or paclitaxel (Taxol) Abundant metaphase mitoses (especially ring mitoses), epithelial pseudostratiﬁcation, loss of polarity, increased apoptosis in pit epithelium Chemotherapy Mucosal sloughing, enlarged gland cells with normal N : C ratio, gland loss HAIC or SIR-Spheres therapy Ulceration with nuclear atypia; numerous enlarged, bizarrely shaped nuclei with vesicular chromatin and large, irregular nucleoli Bisphosphonates (e.g., alendronate) Ulcerations (rare in the stomach, most common in the esophagus) Corticosteroids Possibly increased acid secretion, synergistic ulcerogenic effect with aspirin and NSAIDs

Fe 2+, Ferrous iron ion; HAIC, hepatic arterial infusion chemotherapy; N : C ratio, nucleus-to-cytoplasm ratio; NSAIDs, nonsteroidal antiinﬂammatory drugs; SIR-Spheres, selective internal radiation microspheres.

in antral biopsies. Specimens from the corpus of a previously nonoperated, intact stomach rarely show chara cteristic findings of reactive gastropathy. However, corpus mucosal biopsies are usually the only ones available for study from patients who have had Billroth II surgery, and in this sce- nario, the effects of duodenopancreatic reflux may reveal changes similar to those described with NSAIDs. Unfortunately, chronic inflammation (particularly when it is moderate or severe) with or without neutrophils or other features of activity tends to obscure the features of chemical gastropathy. Only with the finding of especially prominent foveolar hyperplasia can pathologists suggest (but not diagnose with certainty) a reactive component related to chemical damage. In the absence of significant inflammation, marked foveolar hyperplasia remains the cor- nerstone of chemical injury. If absent, a chemical cause for the patient’s symptoms is considered highly unlikely. FIGURE 15.48 Gastritis cystica polyposa in a patient with chronic atrophic gastritis. Notice the lobular configuration of the submuco- Morphologic Effects of Proton Pump sal epithelium and the rim of normal lamina propria. Inhibitor Therapy In addition to the changes in oxyntic mucosa (i.e., oxyntic cell hyperplasia hypertrophy and dilation) described it has a polypoid appearance, congestion, edema, and increased friability.287,288 Superficial erosions may occur in the more proximal areas of the gastric stump, but they are ANTRAL BIOPSY not specific because they can be caused by a variety of injuries. In patients with duodenogastric bile reflux but no history of gastric surgery, the mucosa may exhibit conges- Chronic active No or mild tion, edema, and surface erosions. In long-term NSAID inflammation inflammation users, the mucosa may appear normal or show erythema, moderate congestion, erosions, or ulcers (see Figs. 15.25 , 15.26). to severe Microscopically, duodenogastric reflux into a previously resected stomach causes a characteristic polypoid mucosa Normal or Prominent Foveolar No foveolar with cystic dilation and regenerative changes (Fig. 15.48 ). slightly foveolar hyperplasia hyperplasia In nonoperated stomachs, the pathologic diagnosis of chem- hyperplastic hyperplasia ical gastropathy is often challenging. Although some histo- foveolae logic features are observed more frequently in long-term H. pylori NSAID users, their specificity and predictive value are H. pylori gastritis No other Reactive uncertain because of the difficulty in obtaining normal con- gastritis likely likely with changes gastropathy trols because many patients fail to declare NSAID use, the possible unlikely ingestion of other substances (e.g., alcohol, spices, salt) that reactive gastropathy may cause mucosal changes similar to those of NSAIDs, and component the possibility of clinically silent bile reflux in asymptomatic patients.42,289 H. pylori infection may induce some of the Edema of Reactive features traditionally considered characteristic of chemical lamina propria, gastropathy interfoveolar can be gastropathy (see Fig. 15.9 ). Changes identical to those of smooth muscle suggested but chemical gastropathy may occur in the mucosa adjacent to fibers not diagnosed ulcers, mass lesions, and a variety of other disorders, such as portal hypertensive gastropathy and GAVE. Capillary Characteristic findings of reactive gastropathy include dilation congestion, edema, foveolar hyperplasia (sometimes severe), smooth muscle proliferation in the lamina propria, regen- Regenerative erative changes (e.g., increased mitoses, mucin depletion, changes nuclear hyperchromasia), and occasional superficial erosions Flat erosions (see Fig. 15.7 ). Pathologists may suspect chemical gastropathy when these features are identified and may communi- cate their suspicion to the clinician, but a firm diagnosis can Reactive be made only when supportive clinical data are available and gastropathy 41 H. pylori infection is excluded. FIGURE 15.49 Diagnostic algorithm for reactive (chemical) gas- The algorithm in Figure 15.49 provides a common sense tropathy. (Adapted from Genta RM. Differential diagnosis of reactive approach to the evaluation of possible chemical gastropathy gastropathy. Semin Diagn Pathol. 2005;22:273-283.)

Downloaded from ClinicalKey.com at Italian Association of Gastroenterology (AIGO) November 14, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved. CHAPTER 15 Inflammatory Disorders of the Stomach 385 earlier, prolonged use of PPIs can lead to the formation of fundic gland polyps.201,290 These lesions have little or no known association with neoplastic progression and are reversible on discontinuation of therapy. Patients with H. pylori gastritis who receive PPIs for prolonged periods may experience significant and potentially detrimental changes in the intensity and distribution of inflammation in the stomach.185,291 Most patients infected with H. pylori have antrum- predominant gastritis with only mild inflammatory changes in the corpus. However, acid suppression with PPIs may cause a reduction in the bacterial and inflammatory burden; after months of therapy, inflammation is often reduced in the antrum and increased in the corpus.136,180 H. pylori organisms may be easier to detect in the corpus or cardia than in the antrum and may be present deep within the FIGURE 15.50 Mucosal erosion associated with chronic iron tablet oxyntic glands and within the canaliculi of oxyntic cells (see intake. The ferrous nature of the pigment in the erosion is high- Figs. 15.27 , 15.38). The increased severity of corpus gastri- lighted by a Prussian blue stain. tis may accelerate the development of atrophy in that portion of the stomach,185,291 but there is no evidence to indicate that this results in an increased incidence of gastric cancer. develop in some users. Histologically, characteristic brown The guidelines of the Maastricht Consensus of the Euro- pigment (representing fragments of iron tablets) is identifi- pean H. pylori Group recommend detection and treatment able among granular debris on the mucosal surface within of H. pylori before initiation of long-term PPI therapy. 80 In the ulcer exudates or within inflamed tissues.292,293 Foveolar the United Sates, no consensus has been reached about the and glandular epithelial cells and the cells within the lamina timing of PPI therapy and H. pylori eradication. propria may contain coarsely granular brown material. The ferrous nature of the pigment can be highlighted by use of Clinical Relevance of a Diagnosis a special stain for iron ( Fig. 15.50 ). of Chemical Gastropathy Although millions of people ingest NSAIDs daily, severe GI Colchicine and Taxol complications such as a bleeding gastric ulcer develop in Colchicine is an alkaloid widely used for the treatment of only approximately 2% per year.59 These patients may rep- gout and a variety of other medical conditions. The effect resent a specific subset who have a genetic predisposition of colchicine at the cellular level is attributed to its to the breakdown of mucosal defense mechanisms in ability to bind tubulin and inhibit its polymerization into response to these medications. Unfortunately, specific risk microtubules, thereby affecting cellular processes such as factors for severe complications from NSAIDs have not degranulation, chemotaxis, and mitosis. GI symptoms been identified. Reactive gastropathy is probably one of the such as abdominal pain, cramping, and diarrhea are well- most common diagnoses of gastric biopsies in the industrial- known side effects. The pathologic features of colchicine ized world.60 However, it remains unclear whether gastro- toxicity include multiple and sometimes numerous meta- enterologists should change or discontinue NSAID use or, phase epithelial mitoses arranged in a distinctive ringlike at a minimum, add a PPI to the daily medication list for configuration (Fig. 15.51 ). Other features include epithe- patients who have developed chemical gastropathy verified lial pseudostratification, loss of nuclear polarity, and on biopsy. Although the search for the clinical significance increased apoptosis, which can mimic dysplasia. These of a diagnosis of reactive gastropathy continues, pathologists findings may be seen anywhere in the GI tract, but they should not use the term reactive gastropathy as a substitute are most prominent in the duodenum and gastric antrum, for almost normal. with relative sparing of the gastric body.294 The differential diagnosis of these findings, particularly the abundant Other Drugs mitotic figures, includes the use of compounds such as In addition to NSAIDs, agents, such as potassium, gold, taxol that disrupt microtubule formation. However, in corticosteroids, and caffeine may cause damage to the addition to mitotic arrest, taxol causes coagulative necrosis gastric mucosa. Although most of them do not cause spe- of the epithelium, a feature not associated with colchicine cific changes, some are associated with more distinctive toxicity. histologic findings that can be identified by analysis of mucosal biopsy specimens. Kayexalate Kayexalate (sodium polystyrene sulfonate in sorbitol) is a Iron cation exchange resin used to treat hyperkalemia in uremic Iron tablets are used widely for the treatment of anemia. patients. GI side effects (resulting from the sorbitol com- Although the severe and sometimes life-threatening effects ponent that is used to prevent constipation) include colonic of iron overdose on the GI tract are well known, less is infarction and erosions and ulcers in the esophagus, stomach, understood regarding the mucosal damage that may be and duodenum. Biopsies may reveal characteristic purple caused by therapeutic doses. Mucosal erosions or ulcers platelike Kayexalate crystals ( Fig. 15.52 ). 295

glands, edema, congestion, and mild mononuclear cell infiltration with or without erosions or ulcers. Radiation therapy causes vascular dilation, prominent and sometimes atypical endothelial or stromal cells, and occasional subendothelial collections of histiocytes. With chemotherapy and, to a lesser extent, radiation therapy, there are often atypical cytologic changes (e.g., striking nuclear pleomorphism with irregular and prominent nucleoli) that mimic dysplasia or adenocarcinoma.296,297 Clues that the cytologic atypia represents radiation therapy or chemotherapy injury includes preservation of the glandular architecture; large, irregular nuclei with a normal or low nucleus-to-cytoplasm ratio (Fig. 15.53 ); cell-to-cell variations in the degree of atypia; cytoplasmic vesiculation (i.e., bubbliness); surface maturation; and an overall gradual transition from cytologically atypical to more normal-appearing epithelium. These same cytologic findings may be apparent in adjacent stromal fibroblasts and endothelial cells. One way to determine that cytologic atypia is irradiation induced is by identifying the causative agent; characteristic selective internal radiation microspheres (SIR-Spheres) can be found in biopsies of gastric mucosa, often in association with ulceration FIGURE 15.51 Colchicine toxicity may be suspected when the (Fig. 15.54 ). 283,298 Chronic changes resulting from radiation gastric epithelium shows prominent metaphase mitoses in a charac- therapy include disruption of the mucosal architecture, teristic ringlike configuration. Epithelial pseudostratification with loss of polarity and apoptosis may mimic epithelial dysplasia. fibrosis, and abnormalities of blood vessels that can persist indefinitely.299,300 Chemotherapy- and Radiation-Induced Gastropathy Vascular Gastropathies Mucosal lesions may result from irradiation of the epigastric Vascular gastropathies are a heterogeneous group of disor- region or infusion of chemotherapeutic agents systemically ders characterized endoscopically by alterations in the or by intraarterial perfusion. Early (acute) changes consist gastric mucosal blood vessels and microscopically by of apoptosis and necrosis of the epithelium and fundic little or no inflammation. The most characteristic of the

A B

FIGURE 15.52 A and B, Rhomboid, purple, platelike crystals are characteristic of the side effects of Kayexalate given for the treatment of hyperkalemia in uremic patients.

FIGURE 15.55 Watermelon stomach (i.e., gastric antral vascular ectasia). A, Endoscopic view of the erythematous lines converging toward the pyloric region of the stomach. B, The mucosal appearance resembles stripes of a watermelon. FIGURE 15.53 Chemotherapy-induced reactive atypia. Although this mucosa is from the duodenum, identical changes occur in the stomach. Maintenance of the normal glandular architecture, nuclear therapeutic endoscopy with argon plasma coagulation of the variability (i.e., some atypical; others not), and a low nucleus-to- affected area of antral mucosa or antrectomy may be neces- cytoplasm ratio are characteristic features. sary in severe cases.302-305 vascular gastropathies are GAVE and portal hypertensive Pathologic Features gastropathy. The term watermelon stomach is derived from the endoscopically visible ectatic vessels coursing along the longitu- Gastric Antral Vascular Ectasia dinal mucosal folds that converge concentrically from the proximal antrum to the pylorus, resembling the stripes on Clinical Features a watermelon ( Fig. 15.55 ). 306 The prominent, dilated GAVE, also known as watermelon stomach, is a rare condi- mucosal blood vessels have also been compared with a large, tion of unknown origin. It is frequently associated with flat mushroom or a honeycomb. Various degrees of bleeding gastric atrophy and with autoimmune and connective tissue and clotting may be seen on the mucosal surface.301 disorders.301 More than 70% of cases occur in women older On light microscopy, GAVE has a characteristic appear- than 65 years of age. Occult bleeding (melena) is the pre- ance, particularly in the antrum. The background setting senting sign in as many as 90% of cases. Sixty percent of resembles reactive (chemical) gastropathy. The foveolar epi- patients have hematemesis, and most patients have chronic thelium shows characteristic elongation, hyperplasia, blood loss that causes iron deficiency anemia. increased tortuosity, mucin depletion, nuclear hyperchro- Treatment of GAVE is empiric. Iron supplements are masia, increased mitoses, and other degenerative changes. usually sufficient for patients with minimal bleeding, but The lamina propria, which typically is not inflamed, may have smooth muscle proliferation with the fibers oriented perpendicular to the mucosal surface, and mild fibrosis. Edema may be prominent. The characteristic findings of GAVE are related to mucosal capillaries, which are significantly dilated, such that the diameter of the lumen often approximates the diameter of adjacent antral mucosal glands.306 In most cases, fibrin thrombi develop within dilated mucosal capillaries, and this feature helps to distinguish GAVE from reactive gastropathy ( Fig. 15.56 ). The finding of fibrin thrombi helps to exclude other causes of mucosal congestion, and although not pathognomonic, it strongly suggests GAVE. 307

Portal Hypertensive Gastropathy Clinical Features Portal hypertensive gastropathy is a bleeding disorder characterized by dilation, congestion, and proliferation of FIGURE 15.54 Radiation-induced cytologic atypia can be deter- mucosal blood vessels, which are most prominent in the mined by identifying the causative agent. The selective internal proximal stomach. It is caused by portal hypertension, 305,308 radiation spheres, which are microspheres used in selective internal which usually results from hepatic cirrhosis. For radiation therapy, can be found in biopsies of gastric mucosa, often patients with severe portal hypertension, the mucosa is in association with ulceration. usually diffusely involved, and there is a high risk of

A B

FIGURE 15.56 A and B, Two examples of gastric antral vascular ectasia show a reactive gastropathy pattern with dilated mucosal blood vessels, some of which contain thrombus material. bleeding. Bypass surgery is the most effective measure for Gastric Cardia, Carditis, and decompressing portal hypertension and reducing the risk of Gastroesophageal Junction hemorrhage. The gastroesophageal junction (GEJ) is a poorly defined Pathologic Features anatomic area between the distal esophagus and the proxi- Grossly, the endoscopic appearance of portal hypertensive mal stomach (i.e., cardia). Gastroesophageal reflux disease gastropathy is nonspecific and does not correlate with the (GERD) and H. pylori infection are the major causes of degree of portal hypertension.309 Endoscopic patterns have been described as resembling snake skin, scarlatina rash, cherry-red spots, or a mosaic ( Fig. 15.57 ). 310,311 In a consensus conference, the mosaic pattern was found to be the most reliable indicator of mild portal hypertensive gastropathy and a low risk of hemorrhage. 311 Red marks suggest more severe degrees of portal hypertension and a greater risk of mucosal hemorrhage. The microscopic changes of portal hypertensive gastropathy include dilation, tortuosity, and occasional thickening of small submucosal arteries and veins. Changes are usually most prominent in the corpus. Although the submucosal blood vessels are most severely affected, the mucosal capillaries are also congested and dilated, giving the appearance of proliferation (Fig. 15.58 ). Because of a reluctance to obtain large, deep biopsy samples from patients with an increased risk of bleeding, the diagnosis of portal hypertensive gastropathy is not usually established by evaluation of mucosal biopsy specimens. In patients with concurrent H. pylori gastritis, it is difficult or impossible to separate the effects of infection from those of portal hypertensive gastropathy. Other features of this condition include foveolar hyperplasia, edema, and a paucity of inflammation, all of which resemble reactive gastropathy. A pathologic diagnosis of portal hypertensive gastropathy on biopsy can be made only with the help of FIGURE 15.57 Characteristic snake skin endoscopic appearance of clinical and endoscopic information.312,313 the antrum in portal hypertensive gastropathy.

individuals are similar to the gastric cardia (composed of pure mucous glands or mixed mucous and oxyntic glands), which leads to difficulty in distinguishing columnar (gastric) metaplasia of the distal esophagus from the true gastric cardia in biopsies from the GEJ region.323,324 This distinction is clinically important because columnar metaplasia of the esophagus is caused by GERD and is considered by some to represent a nonintestinalized precursor of Barrett’s esophagus (defined by the presence of goblet cells).322,325,326 The true gastric cardia is the area of mucosa located distal to the anatomic GEJ and proximal to the portion of stomach composed entirely of oxyntic glands (i.e., corpus and fundus). Inflammation of this anatomic region is called carditis, and it is often caused by H. pylori infection, although accumulating evidence suggests that GERD also may cause carditis.314,319,327,328 Some endoscopists use the term cardia generically to indicate the location of a mucosal FIGURE 15.58 In portal hypertensive gastropathy, numerous biopsy from the GEJ region, even though the biopsy might dilated mucosal capillaries impart an edematous appearance to the have been obtained from the distal esophagus.319,323 mucosa. Intestinal metaplasia in the GEJ region may represent two different entities: ultrashort-segment Barrett’s esopha- inflammation and intestinal metaplasia of the GEJ region.314 gus (i.e., columnar metaplasia of the distal esophagus with In some individuals, both etiologic agents may act synergis- goblet cells less than 1.0 cm long) or chronic carditis with tically to cause inflammation.315-318 Other etiologic factors, intestinal metaplasia (Table 15.7 ). 322,329,330 There is contro- such as NSAIDs, may be responsible for inflammation in versy regarding the origin and histology of the true gastric the GEJ region, but such alternative causes have not been cardia (see Chapter 1).314,317,327,331-333 Some authorities think investigated thoroughly. GERD and H. pylori induce chronic that the neonatal cardia is composed of surface mucinous inflammation and intestinal metaplasia, which increase the columnar epithelium and underlying oxyntic glands identi- risk of neoplasia.319 cal to the gastric corpus, whereas others maintain that the Until recently, a commonly accepted definition of the true anatomic cardia is ab initio composed of mucinous cardia was “the segment of mucosa that extends for about columnar epithelium with underlying mucous glands or 1 to 2 cm distal to the squamocolumnar junction (Z-line) and consists of mucous-type glands similar to those of the antrum and prepyloric region.” Because no particularly interesting pathologic processes were thought to affect this Table 15.7 Comparison of Esophageal minuscule territory of mucosa that connects two well- Columnar Metaplasia and Gastric Carditis characterized segments of the digestive system, the gastric cardia was virtually ignored by gastroenterologists, patholo- Esophageal gists, and physiologists. However, during the past several Columnar Gastric Feature Metaplasia Carditis decades, there has been a dramatic rise in the incidence of adenocarcinoma of the cardia or GEJ region,320 The Clinical Features increased incidence of GEJ cancer affects the same popula- Hiatus hernia + − tions in which the incidence of gastric cancer is decreasing, GERD clinical profile + − and the upsurge is presumed to be related to GERD or Heartburn + ± White, male ++ ± H. pylori, or both. Young age ++ ± Alcohol ++ ± Histology of the Gastroesophageal Tobacco ++ ± Irregular Z-line or tongues + − Junction Region Pathologic Features The true anatomic GEJ corresponds to the most proximal Squamous overlying intestinalized + − aspect of the gastric folds, which is an endoscopically glands apparent transition point in most individuals.321 The ana- Hybrid glands + − tomic GEJ usually corresponds to the histologic transition Esophageal glands or ducts + − Multilayered epithelium + − point between the esophageal squamous epithelium and Marked atrophy or disarray + − the gastric mucinous columnar epithelium. The transition Complete intestinal metaplasia + ± point is called the Z-line. However, most adults, particu- Esophagitis (histologic) ++ ± larly those with physiologic or pathologic GERD, have a Distal gastritis ± ++ proximally displaced (irregular) Z-line, indicating that the Eosinophils ++ ± Neutrophils, lymphocytes, plasma ± ++ histologic squamocolumnar junction is located above the Helicobacter pylori ± ++ 322 anatomic GEJ. Barrett’s CK7/20 staining pattern + ± The histologic characteristics of short segments of columnar mucosa located above the anatomic GEJ in these CK , Cytokeratin; GERD, gastroesophageal reflux disease.

but in some circumstances (e.g., autoimmune gastritis, H. pylori infection), the length of cardia-type mucosa may increase by distal extension into the proximal corpus.339

Intestinal Metaplasia of the Gastroesophageal Junction Almost one third of patients without endoscopic evidence of Barrett’s esophagus have intestinal metaplasia in the GEJ region.314,340 Not surprisingly, the chance of detecting intestinal metaplasia increases proportionally with the number of biopsies obtained.341 Some evidence suggests that the A prevalence of intestinal metaplasia is higher among patients with longer segments of pure cardia-type mucosa, a finding more frequently related to GERD than to H. pylori infection.316,317,336 The type of metaplasia may suggest its cause, because cardia biopsies from H. pylori patients usually show complete (i.e., containing goblet cells and absorptive-type enterocytes) and incomplete (i.e., goblet cells only) types of intestinal metaplasia, whereas metaplasia occurring in GERD-induced carditis and Barrett’s esophagus is usually of the incomplete type.342-344 The most widely accepted theory regarding intestinal metaplasia is that chronic inflammation stimulates its development in the GEJ, regardless of the cause.319,337,345,346 In GERD patients, chronic reflux leads to inflammation and ulceration of the native squamous epithelium. The damaged mucosa repairs itself through metaplasia to cardia-type columnar epithelium (composed of mucinous columnar epi- B thelium and mucous, or mixed mucous and oxyntic, glands) and then to intestinal type mucosa.333,346,347 FIGURE 15.59 A, Medium-power view of the true gastric cardia in an adult without symptoms of gastroesophageal reflux disease. The The cell of origin of metaplastic columnar epithelium in 322,342 mucosa is composed of a mixture of mucous glands ( left) and the esophagus is unknown. However, possible sites of oxyntic-type glands (right) with overlying mucinous columnar epi- multipotential stem cells include the basal layer of the thelium. A mild lymphoplasmacytic infiltrate is typical in the cardia native squamous epithelium, esophageal mucosal or submu- of most adults. This biopsy was obtained immediately distal to the cosal glands and ducts, gastric cardia epithelium, congenital most proximal aspect of the gastric folds, the latter of which is rests of gastric or intestinal epithelium in the esophagus, defined as the anatomic gastroesophageal junction (GEJ). B, Mucosal and the subepithelial mesenchyme of the esopha- biopsy from the GEJ shows squamocolumnar junctional mucosa and gus.322,342,348-350 Studies also suggest that metaplastic and moderate acute and chronic inflammation of the lamina propria in dysplastic epithelium in the stomach may be derived from a patient with Helicobacter pylori carditis. bone marrow cells, but this theory has not been well investigated in the esophagus.351 Animal experiments suggest mixed mucous and oxyntic glands. 322 Proponents of the that metaplastic epithelium in the esophagus is derived former theory think that the mere presence of mucous or from cells native to the esophagus rather than the mixed mucous and oxyntic glands in the mucosa from the stomach.348,352 Esophageal mucosal ducts may harbor stem GEJ region indicates that it is metaplastic in origin.316,317,333 cells that can differentiate into columnar epithelium.342,349 However, several studies have confirmed that the gastric Accumulating evidence indicates that the transition from cardia comprises pure mucous or mixed mucous and oxyntic squamous to columnar cells in the distal esophagus occurs glands underlying mucinous columnar epithelium in most through an intermediate (transitional) phase before intesti- individuals (Fig. 15.59 ). 316,327,331,333-335 nalization.333,342,345,353 In 1993, Shields and colleagues The length of this type of mucosa distal to the GEJ reported a distinctive type of multilayered epithelium that normally ranges from 1 to 4 mm and is considered to be had morphologic and cytochemical characteristics of squa- the true gastric cardia.331 A few individuals have only pure mous and columnar epithelium (Fig. 15.60 ). 354 Multilayered oxyntic glands in biopsies from the cardia region 317,334,335,336; epithelium is phenotypically similar to fully developed Bar- however, this finding is often focal and does not usually rett’s esophagus and has the capacity for cell proliferation involve the entire circumference of the lumen. There is also and differentiation.342 A prospective biopsy study found evidence to suggest that the length of mucosa composed of that multilayered epithelium was strongly associated with pure mucous glands or mixed mucous and oxyntic glands Barrett’s esophagus and GERD-induced inflammation of increases with age, which is presumed to be related to the GEJ.353 Multilayered epithelium is identified in mucosal ongoing physiologic GERD.331,333,336-338.The increased length biopsies from as many as 30% of patients with GERD- most often appears to result from proximal columnar meta- induced inflammation of the GEJ region.345,353 Regardless of plasia of the distal esophagus (above the anatomic GEJ), its putative role in the development of columnar metaplasia

tinal metaplasia, and it is therefore reasonable to hypothe- size that the same pathogenic sequence may occur in the cardia of H. pylori–infected patients, but conﬁrmation is lacking.322 Regardless of the cause, most intestinal-type adenocarcinomas of the esophagus and stomach develop in areas of intestinal metaplasia.356-358 In one study, 86% of junctional adenocarcinomas were associated with intestinal metaplasia in adjacent mucosa. The cause of metaplasia may have impact on the risk of malignancy, because distal esophageal adenocarcinomas are more closely linked to GERD- associated intestinal metaplasia than cardia adenocarcinomas are to H. pylori–associated intestinal metaplasia.329,359

A Gastroesophageal Junction Biopsies to Differentiate Carditis from Ultrashort Barrett’s Esophagus True gastric carditis should be differentiated from columnar (gastric) metaplasia of the distal esophagus or ultrashort Barrett’s esophagus if goblet cells are found, because the cause, pathogenesis, natural history, and risk of malignancy are different for the two conditions (Table 15.8 ). 319,322,356 Because it is often difﬁcult for endoscopists to know the precise anatomic location of a biopsy obtained from the cardia or GEJ region (e.g., whether the biopsy is derived from above or below the anatomic GEJ), pathologists should attempt to establish the precise location and cause of the inﬂammatory condition in mucosal biopsies from the GEJ region when possible. B Helicobacter pylori

FIGURE 15.60 A, Mucosal biopsy from the gastroesophageal junc- Despite some overlap, the clinical, endoscopic, and patho- tion (GEJ) region in a patient with reflux symptoms and an irregular logic features of H. pylori–induced carditis are often dis- 322 Z-line located immediately proximal to the anatomic GEJ. The biopsy tinct from those seen in GERD. For example, a young or shows squamocolumnar junctional mucosa in which there is mild middle-aged white man who consumes alcohol or tobacco chronic inflammation in the lamina propria, mixed mucous and is more likely to have GERD-associated inflammation in oxyntic glands in the lamina propria, and overlying mucinous foveo- biopsies from the GEJ region.322 H. pylori carditis usually lar epithelium with a focus of multilayered epithelium. B, High- affects older patients and is equally common in men and power magnification of multilayered epithelium shows squamoid women. Endoscopically, a hiatal hernia, an irregular and cells at the base and mucinous columnar cells at the surface. Overall, proximally located Z-line relative to the anatomic GEJ the biopsy findings are consistent with columnar metaplasia of the (with or without signs of gastric-type mucosa extending into distal esophagus without goblet cells. in the esophagus, multilayered epithelium in a GEJ biopsy Table 15.8 Ultrashort Barrett’s Esophagus is considered a surrogate marker for GERD and a likely Compared with True Gastric Carditis with indicator of GERD as the cause of metaplastic columnar Intestinal Metaplasia epithelium in the distal esophagus.355 Multilayered epithelium is usually detected at the squamocolumnar junction Ultrashort and often in the vicinity of the openings of the submucosal Barrett’s Gastric gland ducts, supporting the theory that the submucosal Feature Esophagus Carditis gland ducts may contain stem cells that give rise to meta- Clinical Male > female, Male = female, plastic columnar epithelium.342,353,355 characteristics older younger Cause Gastroesophageal Helicobacter In contrast, intestinal metaplasia that develops in the reflux disease pylori, other true gastric cardia because of chronic H. pylori infection (GERD) represents a direct nongoblet-to-goblet cell metaplasia. It is Pathogenesis Squamous → Columnar → unclear whether GERD-induced inflammation in the true columnar columnar gastric cardia can lead to intestinal metaplasia in this manner, Cancer risk Higher Lower although there is some evidence in favor of this mecha- Treatment Acid suppression, Antibiotics, no 315,317,322,336,343 surgery, surveillance nism. Studies of the gastric antrum suggest surveillance that chronic inflammation is a required precursor of intes-

Downloaded from ClinicalKey.com at Italian Association of Gastroenterology (AIGO) November 14, 2016. For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved. 392 PART 1 Gastrointestinal Tract the distal esophagus), and evidence of esophagitis also 90% specific for goblet cells related to Barrett’s esophagus support GERD as the cause of inflammation of the GEJ compared with goblet cells from patients with gastric region. carditis.369 Pathologically, GEJ region biopsies from GERD patients The pattern of cytokeratin 7 and 20 (CK7/20) immu- often show only a mild degree of mononuclear inflammation nostaining has been helpful in distinguishing intestinal meta- (Fig. 15.61 ). 317,337 However, active inflammation of the plasia in the distal esophagus from intestinal metaplasia in deep or surface epithelium with or without surface erosion the true gastric cardia.370 This so-called Barrett CK7/20 may also be seen. Similar to reflux esophagitis, eosinophils staining pattern consists of diffuse, strong CK7 staining of are often a prominent component of the inflammatory infil- the surface and gland epithelium and superficial weak trate.337,345 Plasma cell infiltrates and reactive lymphoid fol- columnar staining with CK20. Several other investigators, licles are uncommon in GERD, unless there is concurrent however, have not been able to confirm these find- H. pylori infection. 345 ings,323,333,346,360,361,371,372 and there are many limitations to In patients with H. pylori infection, the cardia mucosa the use of CK7/20 immunostaining in evaluating biopsies appears similar histologically to that seen in H. pylori antral from the GEJ region. Use of CK7/20 immunostaining is not gastritis, including increased lymphocytes and plasma cells recommended in daily pathology practice to help distin- in the lamina propria, active inflammation, and reactive guish esophageal from gastric intestinal metaplasia in biop- lymphoid aggregates with few or no eosinophils.345 Patients sies from the GEJ region.323 with H. pylori carditis but without GERD have no inflammation of the esophageal squamous epithelium. When the Reporting a Biopsy from the histology suggests H. pylori infection, use of special stains Gastroesophageal Junction is recommended for detection of organisms not visible on routine stains.19,360 H. pylori organisms do not normally The strategy outlined in Figure 15.62 is an easy and reliable colonize intestinal-type epithelium, and detection may be method that pathologists can use to distinguish columnar difficult in biopsies with only a limited amount of gastric metaplasia (gastric or intestinal type) of the distal esopha- foveolar-type epithelium. gus from the true gastric cardia. When H. pylori organisms Identification of certain histologic landmarks, such as are detected in cardiac-type mucosa with chronic active submucosal or mucosal esophageal glands and squamous- inflammation, it is likely that the carditis is part of the lined ducts, can help to prove that a particular biopsy labeled patient’s concurrent distal H. pylori gastritis. It should be as the GEJ region was derived from the tubular esophagus emphasized that H. pylori carditis is not a distinct entity; rather than the gastric cardia. The finding of multilayered rather, it should be viewed as a topographic manifestation epithelium in a biopsy from the cardia and GEJ region con- of H. pylori gastritis. firms the esophageal origin of the sample.322,361 Similarly, the Many patients without clinically apparent GERD and origin of tissue from the esophagus can be inferred from without H. pylori infection have significant inflammation in findings of marked glandular atrophy and disarray, incom- the cardia and GEJ region. Although it is likely that many plete intestinal metaplasia (particularly when it comprises of these individuals have asymptomatic GERD, this idea more than 50% of crypts), squamous epithelium overlying has yet to be proved. In this setting, the term carditis crypts with intestinal metaplasia, and hybrid glands (i.e., (chronic or chronic active) should be used only if the biop- deep glands composed of intestinal metaplasia and mucinous sies are determined by endoscopy to be unequivocally from columnar cells)361 (see Table 15.7 and Fig. 15.61 ). the cardia; otherwise, a brief descriptive diagnosis is prefer- Other findings may help in the differential diagnosis. For able, indicating the type of mucosa, the type and intensity example, most cases of H. pylori carditis show evidence of of inflammation, and the existence of other relevant fea- H. pylori infection in the corpus and antrum, 360 just as tures (e.g., erosions). Mild or moderate forms of chronic active esophagitis in the squamous epithelium (especially in inflammation in biopsies from the cardia and GEJ region the setting of a normal antrum or corpus) is strong evidence are likely within normal limits, and carditis should be diag- in favor of GERD as the cause of inflammation in the GEJ nosed only when there is significant activity or a dense region.345,361 lymphoplasmacytic infiltrate accompanied by lymphoid Basic mucin histochemical stains, such as PAS, Alcian follicles. The diagnosis should mention the presence or blue, and high-iron diamine, have not proved helpful in absence of H. pylori, goblet cells, and esophagitis (if squa- distinguishing esophageal-derived metaplastic columnar mous epithelium is included in the specimen). If the biopsy epithelium from the true gastric cardia.347,362-364 Nongoblet shows the histologic features that are frequently associated and goblet cells may be positive with these stains, regardless with or specific for the tubular esophagus (see Fig. 15.61 ), of the site of origin. Some investigators have advocated the a comment should indicate that “the columnar mucosa use of Alcian blue at pH 2.5 to distinguish distended foveo- most likely represents columnar (gastric) metaplasia of the lar pseudogoblet cells (i.e., light staining) from true goblet distal esophagus” (or Barrett’s esophagus if goblet cells are cells (i.e., dark staining). Others have documented that found). both cell types can stain weakly or strongly with this stain, Small aggregates of pancreatic-type acinar glands are regardless of their site of origin.347,362-364 Immunohistochem- found in 1% to 5% of biopsy specimens from the GEJ ical markers, such as DAS-1, CDX2, HepPar1, and CD10, region, usually in deeper portions of the mucosa (Fig. have been proposed as markers of intestinal metaplasia in 15.63). Although the origin of these glands (i.e., metaplasia the esophagus, but none has been shown to be reliably or heterotopia) is unknown and their significance and asso- specific for routine diagnostic purposes.365-368 One study ciations remain elusive, they are usually reported as pancre- suggested that combined MUC1 and MUC6 staining was atic acinar metaplasia,373 and clinicians need not alter

A B

C D

E F

FIGURE 15.61 Mucosal biopsies for the gastroesophageal junction (GEJ) region from patients without endoscopic evidence of Barrett’s esophagus but with a slightly irregular Z-line. These patients had no evidence of Helicobacter pylori gastritis. A, Reepithelialized squamous epithelium overlies glands with intestinal metaplasia. The lamina propria shows a mild degree of chronic inflammation. B, The mucosa shows diffuse, incomplete intestinal metaplasia with marked glandular atrophy and replacement of the glands with intestinalized epithelium. There is also irregular branching and horizontal growth of the crypts. C, High-power view of the base of the mucosa reveals hybrid glands characterized by incomplete intestinal metaplasia and mucinous columnar epithelium. D, Columnar mucosa with a mild chronic inflammatory infiltrate and a well-formed cluster of esophageal mucosal glands in the center of the field. E, High-power view of a submucosal gland duct. Any of the features depicted in A through E seen in a biopsy from the GEJ region indicate columnar metaplasia of the distal esophagus. F, Mucosal biopsy from the true gastric cardia in a patient with Helicobacter pylori gastritis. There are abundant mucinous foveolar cells, barrel-shaped pseudogoblet cells, and a focus of complete intestinal metaplasia (center). The lamina propria shows a mild degree of lymphoplasmacytic inflammation and scattered neutrophils and eosinophils. This histologic picture, particularly the complete intestinal metaplasia, is highly unusual for Barrett’s esophagus, and in the presence of H. pylori organisms, it is diagnostic of H. pylori carditis.

1. Type of epithelium: Columnar or squamocolumnar mucosa

2. Intestinal metaplasia: No Yes

3. Pathologic features of columnar metaplasia: (see Table 15-7) Yes No Yes No

4. Diagnosis: Columnar metaplasia Diagnosis Barrett’s Diagnosis of distal esophagus depends on esophagus depends on endoscopic endoscopic correlation correlation

FIGURE 15.62 Strategy for signout of a gastroesophageal junction mucosal biopsy. surveillance or other follow-up protocols based on this of prostaglandins.376,377 Because these products represent finding. the first line of protection against luminal acid-pepsin and The presence or absence, grade, and extent of dysplasia exogenous noxious substances, the consequence of a decline should be reported for all biopsies from the GEJ region. is progressive weakening of gastroprotection, leaving the This is particularly true if the patient has clinical or endo- stomach of elderly people more vulnerable to the noxious scopic evidence of Barrett’s esophagus.374 effects of endogenous acid and exogenous substances, particularly NSAIDs. Stomach in the Young and Elderly The second set of processes includes pathologic conditions that affect various proportions of the elderly, depend- The constellation of functional and morphologic changes ing on genetic and environmental factors. By far the most occurring in the gastric mucosa of elderly people has been important of these conditions is H. pylori infection, which described as the aging of the stomach.375 Until recently, is the major cause of gastritis, mucosal atrophy, intestinal these alterations were interpreted as expressions of the metaplasia, peptic ulcer, gastric cancer, and primary gastric normal process of aging, which included decreased produc- MALT lymphoma worldwide. Gastric mucosal atrophy, tion of bicarbonate, mucin, and acid; mucosal inflammation; whether caused by long-standing H. pylori gastritis or auto- atrophy; and metaplasia. immune disease, is the cause of decreased acid production, With the rekindled interest in gastric histopathology that not aging per se. accompanied the discovery of H. pylori, it became apparent that two distinct processes occur in the aging human Lymphoid Hyperplasia stomach. First, a set of physiologic changes affect to some degree the gastric mucosa of every aging human; significant Nodular gastritis, which was described as the goose flesh drops in the levels of gastric bicarbonate, sodium ion, and phenomenon by Takemoto and Mizuno in 1962, was consid- parietal fluid secretion result from a decline in the synthesis ered a physiologic phenomenon that was particularly common in young women. Histologically, it is characterized by hyperplasia of lymphoid follicles in the lamina propria; the prominent follicles cause elevations of the mucosa that appear endoscopically as myriad granules. Although it may occur in adults, the florid lymphoid response that becomes visible endoscopically is more characteristic of children infected with H. pylori.364,365 In light of what we now know about the dynamics of MALT in the gastric mucosa in response to H. pylori,21,366 nodular gastritis should no longer be viewed as a distinct condition. It instead represents the endoscopic correlate of a vigorous lymphoid response to H. pylori infection.

Eosinophils Eosinophils are more common in the gastric mucosa of children than adults. When numerous eosinophils are found aggregated in microabscesses and inﬁltrating the muscularis FIGURE 15.63 Pancreatic acinar metaplasia in the cardia of a patient mucosae, a diagnosis of eosinophilic gastritis or gastroenteri- with chronic gastritis. tis must be entertained and clinical correlation sought.

However, an inﬂammatory inﬁltrate with an abundance or predominance of eosinophils in the gastric mucosa of an H. pylori–infected child (particularly from the less industrialized parts of the world) represents a normal response to the infection in most cases.

Atrophy Atrophy develops in response to years of inﬂammation- induced injury to the gastric mucosa. Atrophic gastritis is an unusual disorder in young children and adolescents from developed countries. However, in regions where H. pylori infection is acquired early in life and environmental factors contribute to a high prevalence of atrophic gastritis in adults (e.g., Japan, East Asia, South America), atrophy and intestinal metaplasia may occur in young children.378-381 For individuals without H. pylori infection or autoimmune gastritis, there is no evidence that atrophic gastritis is more prevalent among older adults compared with children. However, the prevalence of focal intestinal metaplasia, particularly in the distal antrum and pylorus, does increase with age. It is unclear whether this phenomenon is caused by prior H. pylori infection, prior episodes of environmental FIGURE 15.64 Hyperproliferative lesion. This biopsy shows imma- gastritis, or the cumulative effects of repeated subclinical ture tubules with scant goblet cells with nuclear hyperchromasia and mucosal injury. mucin depletion. Notice the mild architectural disarray.

Gastric Epithelial Dysplasia Gastric dysplasia (i.e., intraepithelial neoplasia) is a noninva- appropriate surveillance requires exhaustive mapping of the sive neoplastic epithelial process. In 2010, the World Health gastric mucosa, which is impractical for large population Organization (WHO) stated that dysplasia and gastric programs.394 intraepithelial neoplasia were equally appropriate terms for Frequently categorized as indefinite for dysplasia, the describing this lesion. In this chapter, we use the term dys- neoplastic potential of so-called gastric hyperproliferative plasia, which is favored in North America.382 Gastric dyspla- immature lesions , which are commonly associated with sia results from a combination of predisposing environmental intestinal metaplasia, has been investigated vigorously.395-397 conditions combined with various genetic and epigenetic These lesions, located deep in the mucosa, are formed of abnormalities.383 It shares, albeit at a lower frequency, many immature tubules, are sometimes deficient in goblet cells, of the early molecular alterations characteristic of gastric and display various degrees of nuclear atypia (Fig. 15.64 ). carcinoma. In clinical practice, a diagnosis of gastric dysplasia The estimated prevalence of immature, proliferative lesions is an indication for surveillance and endoscopic therapy. in gastric biopsies with intestinal metaplasia is 2.8%.397 Their neoplastic predictive value is high, with a hazard ratio Dysplasia Precursor Lesions of 8.37, particularly when nuclear atypia is observed and there is associated extensive and severe mucosal atrophy.395,396 Gastric epithelial dysplasia (GED) develops through a well- The neoplastic potential of so-called pseudopyloric meta- defined carcinogenic sequence that begins with chronic gas- plasia of the oxyntic mucosa has been emphasized recently. tritis and ends with intestinal-type adenocarcinoma.44,383-390 First observed in several animal models and in the back- In the United States, H. pylori infection is the most common ground of remnant carcinoma arising in the proximal cause of chronic gastritis. It leads to long-standing chronic stomach, this glandular lesion with antral morphology inflammation in the mucosa and, if untreated, results in the that expresses spasmolytic polypeptide has become recog- formation of pseudopyloric and intestinal metaplasia. nized as a bona fide precursor of gastric adenocarcinoma Intestinal metaplasia is categorized as complete or incom- (Fig. 15.65 ). 135,398 plete (described earlier).390 Incomplete intestinal metaplasia occurs in the background mucosa of as many as 95% of Clinical Features and Incidence gastric intestinal-type cancers but in only 0% to 33% of In the general population, GED is typically diagnosed in diffuse-type carcinomas.44,391 Nevertheless, neither the pres- the patient’s sixth to seventh decade of life.399,400 Men are ence nor type of intestinal metaplasia is of sufficient sensitiv- affected more often than women; the male-to-female ratio ity or specificity to guide surveillance of patients with H. is between 2.4 and 3.9 to 1. 400,401 At clinical presentation, pylori gastritis. The extent and severity of atrophy and symptoms include persistent vomiting, weight loss, anemia intestinal metaplasia is a more important marker of cancer with iron deficiency, and hematochezia. 402 The lesser curva- risk. Some studies have reported an 11% risk of adenocar- ture of the antrum and the incisura angularis are the most cinoma for patients with atrophy or intestinal metaplasia commonly affected regions, although GED may occur any- during a 10-year follow-up period. 46,392,393 Unfortunately, where in the stomach.400,402,403

lesions are nonpolypoid (71%),402 whereas the reverse is observed by others (27% nonpolypoid).430 GED is characterized by a combination of cytologic and architectural atypia. Two histologic subtypes are recognized. Adenomatous (intestinal-type) dysplasia, named for its resemblance to colonic adenomas, is the more common type. Microscopically, adenomatous dysplasia is characterized by crowded tubular glands lined by atypical columnar cells with overlapping, pencillate, hyperchromatic nuclei with pseudostratification and inconspicuous nucleoli (Fig. 15.66). 431 The second, less common and less well recognized histologic variant, referred to as foveolar (gastric) dysplasia (type II) by some authorities, develops in nonmetaplastic gastric epithelium.431 Microscopically, foveolar dysplasia is composed of foveolar-type epithelium with cytologic and architectural atypia. The foveolae have various sizes and shapes, and they occasionally show papillary infoldings and FIGURE 15.65 Pseudopyloric metaplasia. These tight, benign- luminal serration. The dysplastic cells are typically cuboidal looking tubules are characteristic of pseudopyloric metaplasia, which or low columnar, containing clear or eosinophilic cytoplasm is frequently observed in the background of atrophic gastritis and and round to oval, vesicular nuclei with nucleoli (Fig. 15.67 ). intestinal metaplasia. Other common cytologic features, which are more obvious in adenomatous GED, include mucin depletion, crowding, The prevalence of GED closely follows the prevalence loss of polarity, increased mitoses, nuclear pleomorphism, of gastric cancer, although with marked worldwide varia- and lack of surface maturation. Genetic differences between tions. The variation likely results from differences in the these two histologic subtypes of GED support the concept genetic makeup of different populations and in environmen- that they represent distinct pathways.432,433 tal factors, such as the prevalence of H. pylori infection and Adenomatous and foveolar (gastric-type) dysplasia can its different strains. High-risk areas (e.g., parts of Asia and be distinguished on the basis of their mucin phenotypes. South America) have prevalence rates of 9% to 20%, Adenomatous-type dysplasia expresses MUC2 and CD10 whereas in Western countries, the prevalence ranges from in most cases, whereas the foveolar (gastric) type most 0.5% to 4%.404-406 commonly expresses MUC5AC but not CD10. However, The prevalence of GED varies according to the underly- hybrid cases do occur, and there is little practical use for ing cause. For instance, GED is reported in as many as 40% these stains in routine practice. of patients with pernicious anemia,407-409 but the increased A case has been made for a pyloric variant of GED in risk for adenocarcinoma is still relatively modest among which the cells are cuboidal, with granular eosinophilic these patients compared with the general population.410 cytoplasm and round nuclei. This type frequently manifests Patients with familial adenomatous polyposis (FAP) are at as a polypoid lesion in the oxyntic mucosa and is frequently higher risk for flat or, more commonly, polypoid dysplasia found in the setting of autoimmune gastritis, most com- (i.e., adenomas). Among FAP patients, the reported rate of monly in elderly women (Fig. 15.68 ). 434 GED varies between 2% and 50%, with lesions (often mul- As observed in the setting of Barrett’s esophagus, tiple) typically occurring in the antrum.411-420 evidence suggests that cytologic atypia at the base of Although the idea is controversial, some studies suggest glands, although lacking surface involvement, may represent that patients who have undergone a Billroth II partial true initial dysplasia and a transition stage from hyper- gastrectomy and those with Ménétrier disease or Peutz- proliferative immature lesions (described earlier) to Jeghers syndrome are at increased risk for GED and traditional dysplasia discernable at the surface.435 In clinical adenocarcinoma.421-423 In retrospective studies, high-grade practice, a two-tier grading system of GED is most com- dysplasia has been identified close to 40% to 100% of monly used: low and high grade (Table 15.9 ; see Fig. 15.66, early gastric cancers and 5% to 80% of advanced A). 399,426,431,436-439 This method of GED grading has proved adenocarcinomas.424-427 to be more reproducible than a three-tier system (i.e., mild, GED is also a marker of risk for cancer elsewhere in the moderate, and severe).383 It also provides a clinically mean- gastric mucosa. In one Japanese study, as many as 12.5% of ingful method of risk stratification that is used to guide patients with dysplasia or adenoma had concurrent gastric treatment decisions.440 cancer.424 Fifty-seven percent of gastric cancers discovered Low-grade GED is characterized by epithelium with no during follow-up of patients with GED are considered early or minimal architectural distortion. The cells are closely forms and are potentially curable, which underscores the packed, with nuclei usually confined to the basal half of the importance of endoscopic surveillance.133,428,429 cell cytoplasm and showing mild to moderate nuclear hyperchromasia and irregularity (see Fig. 15.66, A). 383,440-442 High- Pathologic Features grade dysplasia is characterized by epithelium with more Endoscopically, GED may appear grossly normal or show significant architectural and cytologic changes. The cells in mucosal irregularity, plaques, nodularity, polypoid growth, high-grade dysplasia are usually cuboidal rather than colum- erosions or ulcers,400 mucosal scars, and diffuse inflamma- nar and have a high nucleus-to-cytoplasm ratio. Large and tory changes.399,428 Some investigators report that most irregular nuclei, with clumped chromatin and prominent

A B

FIGURE 15.66 A, Low-grade, adenomatous-type gastric epithelial dysplasia (GED). The lesion is characterized by mild glandular disarray and increased cellularity. B, Cytologic features of low-grade GED include hyperchromatic, cigar-shaped nuclei confined to the basal half of the cell cytoplasm. Mild nuclear pleomorphism is evident. nucleoli, are common. Mitoses are more numerous, and High-grade dysplasia is characterized by increased archi- atypical mitoses are more conspicuous compared with low- tectural complexity with crowding, branching, and budding. grade dysplasia.440 The dysplastic nuclei frequently occupy Although both are often present, the finding of high-grade the luminal aspect of the cell cytoplasm, and nuclear polarity cytologic or architectural histology is sufficient to establish is partially or completely lost. Intraluminal necrotic debris the diagnosis of high-grade dysplasia. When architectural may be seen in high-grade dysplasia (Fig. 15.69 ). 443 complexity is extensive, it likely indicates intramucosal adenocarcinoma, because desmoplasia is typically absent with invasion of the lamina propria. Japanese and Western pathologists interpret dysplasia differently. For instance, noninvasive intramucosal neoplastic lesions with high-grade cellular and architectural

FIGURE 15.68 Pyloric-type dysplasia. The irregular, crowded, low- grade neoplastic tubules are characterized by hyperchromatic, basally located, round nuclei and eosinophilic cytoplasm reminiscent FIGURE 15.67 Foveolar (gastric-type), low-grade gastric epithelial of non-neoplastic pseudopyloric metaplasia. These lesions are immu- dysplasia has a serrated appearance and tall foveolar cells. noreactive for MUC6.

Table 15.9 Features of Low- and High-Grade Gastric Dysplasia Low-Grade Dysplasia High-Grade Dysplasia Architectural Features Mild glandular crowding and disarray Marked glandular disarray with crowding and back-to-back glands Mild branching Moderate to marked branching and frequent budding Rare glandular budding Intraluminal folds and cribriforming Nuclear Features Elongated hyperchromatic nuclei Vesicular round nuclei Basal location, with maintained polarity Prominent nucleoli Mild or moderate mitotic activity Marked increase in mitotic activity Atypical mitoses variations are often referred to as intramucosal carcinoma tubule neck dysplasia) and pagetoid spread of signet ring by Japanese pathologists, whereas the same lesions are cells have been reported in as many as 50% of patients. usually defined as high-grade dysplasia by Western patholo- Morphologically, the latter condition consists of neoplastic gists. In response to the differences in interpretation, a signet ring cells that are interspersed with normal foveolar consensus scheme (i.e., Vienna classification) was devel- cells and are confined by the basement membrane.449,450 oped.444 In the Vienna classification system ( Table 15.10 ), which also considers management implications, high-grade Polypoid Dysplasia in Familial premalignant lesions without invasion of the lamina propria Adenomatous Polyposis and invasive adenocarcinomas confined to the lamina propria Gastric dysplasia (i.e., adenoma) develops in between 6% (i.e., intramucosal adenocarcinomas) are considered a single and 50% of patients with FAP, 451-453 most commonly in the neoplastic group (category 4), because both are usually ame- fourth decade of life.433 The prevalence increases with age, nable to endoscopic resection.445 similar to colonic adenomas. Dysplastic lesions are usually small and multiple, and they often are interpreted as adeno- Unusual Variants mas when they are polypoid. Dysplasia and carcinoma may develop within fundic Precursor Lesion of Poorly Cohesive Carcinomas gland polyps.453 They are reported in 25% to 62% of FAP Tubule neck dysplasia, characterized by enlarged, pale, and patients with fundic gland polyps. Despite rare reports of polygonal neoplastic cells confined to the basement mem- carcinoma arising in fundic gland polyps,453-455 most gastric brane, typically occupies the neck region of the gastric cancers that develop in patients with FAP are associated foveolae, sparing the mucosal surface and the deep gastric with polypoid areas of dysplasia (i.e., adenomas).412,452 glands (Figs. 15.70 and 15.71). 446,447 Differentiating tubule Dysplasia may also develop within gastric hyperplastic neck dysplasia from marked reactive changes can be polyps, particularly those that are larger than 2 cm in diam- extremely challenging, and morphometric analysis has not eter. Several studies have reported that dysplastic changes been useful in this differential.448 occur in 1.8% to 16.4% of hyperplastic polyps.456-459 In a subpopulation of patients who harbor E-cadherin gene (CDH1) mutations, in situ diffuse carcinoma (i.e., Differential Diagnosis Differentiating inflammatory reactive changes from dysplasia can be challenging, particularly in the setting of active 437,460,461 Table 15.10 Modified Vienna Classification of gastritis or ulceration (Table 15.11 ). The cells of Gastrointestinal Epithelial Neoplasia regenerative epithelium are usually cuboidal and appear immature based on the finding of basophilic cytoplasm and Common Usage mucin depletion. Regenerating nuclei are usually large and Category Definition Equivalent vesicular and may show mild stratification with pleomor- 1 No neoplasia phism and delicate uniform nucleoli, but they do not nor- 2 Indefinite for neoplasia Indefinite for mally show a loss of polarity or marked nuclear membrane dysplasia irregularity. Mitoses are frequently observed, although not 3 Low-grade adenoma Low-grade dysplasia or dysplasia on the surface, and abnormal mitoses are absent. Most 4 High-grade neoplasia High-grade importantly, regenerating epithelium shows cellular differ- dysplasia entiation and maturation near the luminal surface, referred 4.1 High-grade adenoma to as surface maturation. The reactive changes typically or dysplasia blend seamlessly with the adjacent epithelium, whereas an 4.2 Noninvasive carcinoma 462 (carcinoma in situ) abrupt transition favors true dysplasia. For cases in which 4.3 Suspicious for invasive a definite distinction between reactive changes and dyspla- carcinoma sia cannot be made with certainty, the term indefinite for 4.4 Intramucosal Intramucosal dysplasia is appropriate ( Fig. 15.72, A and B). carcinoma carcinoma 5 Submucosal invasive Submucosal Differentiating high-grade dysplasia from intramucosal carcinoma adenocarcinoma carcinoma can be difficult. Intramucosal adenocarcinoma typically shows small, budding glands or single, infiltrating

FIGURE 15.69 A, This eroded lesion shows architectural atypia with a focal back-to-back gland pattern. The stratiﬁed, enlarged, rounded nuclei with prominent nucleoli and increased mitoses merit a diagnosis of high- grade dysplasia. Many Japanese pathologists would consider this lesion intramucosal carcinoma based solely on the degree of nuclear atypia. B, This example of high-grade gastric epithelial dysplasia has markedly disorga- nized glands lined by large, round, and irregular nuclei. Nuclear polarity is partially lost, and several mitoses are identiﬁed. C, Foveolar (gastric-type), high-grade dysplasia. Notice the abnormal architecture and epithelium lined by atypical foveolar-type cells with a high nucleus-to-cytoplasm ratio. A

B C

cells within the lamina propria, typically in the absence of Table 15.11 Features of Epithelial Regeneration desmoplasia463,464 ( Fig. 15.73, A and B). With the develop- and Dysplasia ment of techniques such as endoscopic mucosal resection, Dysplastic Regenerative the distinction between high-grade dysplasia and intramu- Feature Features Changes cosal adenocarcinoma has become less important because Cellular immaturity Marked Mild to moderate the lesions are usually treated similarly. This is true par- Vesicular nuclei None to None to ticularly for well-differentiated lesions as large as 2 cm in moderate moderate diameter.465 Mucin depletion Marked Mild to moderate Nuclear Moderate to Minimal Natural History and Treatment pleomorphism marked Pseudostratiﬁcation Mild to marked None to minimal Gastric dysplasia portends an increased risk of progression Surface maturation Absent Usually present to gastric cancer. However, the natural history of dysplasia Loss of polarity Yes No or minimal has been poorly studied (Table 15.12 ). Abnormal mitosis Yes No In some studies, low-grade dysplasia has regressed in Architectural disarray Mild to moderate None or minimal 38% to 75% of cases and persisted in 19% to 50% of the cases.399,402,405,466 High-grade dysplasia has regressed in 0% to 16% of cases but persisted in 14% to 58% of cases. In

FIGURE 15.70 Tubule neck dysplasia. The tubular epithelial lining contains large globoid cells with clear cytoplasm and atypical vesicular nuclei. Some cells appear to show early lamina propria invasion. one study, progression to adenocarcinoma occurred in 0% to 23% of cases of low-grade dysplasia in a mean interval of 10 months to 4 years. For high-grade dysplasia, the reported rate of malignant transformation ranges from 4.8% to 100% during a median interval of 4 to 48 months. 399-402,428,467-469 A diagnosis of carcinoma established within 3 to 12 months of GED is more likely to represent failure to recognize a preexisting cancer rather than true neoplastic progression.400,402,428 Seventy-ﬁve percent of cancers diagnosed after an initial diagnosis of high-grade GED represent missed lesions rather than interval cancers.402 B

FIGURE 15.72 A, Biopsy at the edge of an ulcer demonstrates atypical, somewhat back to back, glands. B, At high magniﬁcation, the cuboidal epithelium shows basophilic cytoplasm, mucin depletion, and prominent nucleoli without the loss of polarity. Large, regenerating nuclei show mild, focal pleomorphism. However, nuclear strati- ﬁcation and abnormal mitoses are not seen.

The management of GED is an area of controversy. It should take into account the degree of dysplasia and the severity of gastric atrophy, which is sometimes indirectly evaluated by the serologic pepsinogen level (see Chapter 2).43 Because of the low rate of malignant transformation of low-grade dysplasia, annual endoscopic surveillance with repeat biopsy is recommended by some clinicians, whereas FIGURE 15.71 In this rare example of tubule neck dysplasia diag- others suggest a biopsy every 3 months for the first year, 470,471 nosed in a nonsyndromic patient, the neoplastic signet ring cells are along with exhaustive mapping of the entire stomach. confined by the basement membrane and fill almost the entire Surgical resection is not usually warranted and has been foveolar epithelium. supplanted by endoscopic excision.

A B

FIGURE 15.73 A and B, This type of lesion is likely to be diagnosed as intramucosal carcinoma by Japanese pathologists, whereas the same lesion is often interpreted as high-grade dysplasia by Western pathologists. However, we interpreted this lesion as intramucosal adenocarcinoma, primarily on the basis of focally signiﬁcant architectural atypia and intraglandular cribriforming.

Patients with high-grade dysplasia, large dysplastic (ade- Table 15.12 Guidelines for Treatment of nomatous) polyps, or well-differentiated adenocarcinomas Gastric Dysplasia as large as 2 cm in the greatest dimension should undergo Dysplasia Recommendation Comments endoscopic ultrasound (to evaluate the extent and depth of Low grade Annual endoscopic Given the low rate of dysplastic and early cancerous lesions) followed by endo- surveillance with malignant scopic therapy. Complete excision of lesions conﬁned to the repeat biopsy transformation, mucosa may be performed by endoscopic mucosal resec- surgical resection is tion, obviating the need for surgical resection in many not necessary. cases.465 High grade Endoscopic mucosal Chromoendoscopy resection and and endoscopic With progress in endoscopic techniques, larger dysplastic surveillance ultrasound help to lesions and certain adenocarcinomas (i.e., moderately and Surgical resection if evaluate the extent well-differentiated submucosal cancers invading less than endoscopic mucosal and depth of 0.5 mm and without lymphovascular invasion) can be resection cannot be invasion. performed managed conservatively by endoscopic submucosal dissec- tion.472 Other invasive cancers are best managed with surgical resection.

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