The Stomach
Kathryn M. Law
Elizabeth M. Brunt
I. NORMAL ANATOMY. The stomach, a distensible, J-shaped organ, is traditionally divided into five regions: cardia, fundus, body, antrum, and pylorus. The cardia is a poorly defined region extending up to 3 cm distal to the gastroesophageal junction. The fundus is the region that curves lateral and superior to the level of the gastroesophageal junction. Below the gastroesophageal junction in continuation with the cardia and fundus is the body, which extends to the incisura. The antrum encompasses the distal third of the stomach, begins at the incisura, and extends to the pylorus. This region grossly and endoscopically has more flattened and firmly anchored mucosa than the fundus or the body. The pylorus is a muscular zone of the stomach controlling passage of food into the duodenum.
The mucosal lining is of two types: antral (antrum, pylorus, cardia) and oxyntic (fundus, body). Antral-type foveolar mucosa demonstrates a 1:1 relationship of surface to deeper mucus secretory glands separated by lamina propria (e-Fig. 13.1).* Oxyntic foveolar mucosa has a 1:4 pit to gland relationship (e-Fig. 13.2). The mucus neck cells midway along the foveolar fold harbor the regenerative cells of the stomach. The underlying glands are composed of gastric parietal cells, which produce acid and intrinsic factor, and chief cells, which produce pepsinogen. In the antrum, endocrine cells are located just below the surface foveola and include gastrin-producing G-cells, serotonin-producing enterochromaffin (EC) cells, and somatostatin-producing D-cells. In the fundus, endocrine cells are located at the base of the crypts and consist of histamine-producing enterochromaffin-like (ECL) cells and a small number of EC cells. The lamina propria of the stomach normally contains a few inflammatory cells including lymphocytes, plasma cells, eosinophils, and mast cells. The muscularis mucosae, submucosa, muscularis propria, and serosa of the stomach are histologically similar to that of the intestines.
II. GROSS EXAMINATION AND TISSUE HANDLING
A. Endoscopic biopsies. Endoscopic findings and pertinent history assist in histopathologic interpretation. The gross description should include the number of fragments and overall specimen dimensions to ensure all material has been analyzed microscopically; three levels stained by hematoxylin and eosin (H&E) should be prepared for routine microscopic analysis. Some laboratories order Helicobacter pylori stains at the time of processing; others prefer to evaluate the specimens for specific features of infection (see below) before ordering special stains.
B. Gastrectomy. Gastrectomies may be partial (often including a portion of the duodenum or esophagus) or total. When the specimen is received, the serosal surface should be examined for evidence of tumor penetration and the area overlying the tumor inked (e-Fig. 13.3). After opening longitudinally along the greater curvature without transecting the tumor (e-Fig. 13.4), the specimen should then be pinned on Styrofoam (with the mucosal surface facing out) and fixed in formalin overnight to ensure well-fixed and oriented sections. Standard measurements include the length of the greater and lesser curvatures, circumferences at the resection margins, and wall thickness. If a tumor is grossly identified, its location, shape, maximal dimension, and distance from the margins
should be recorded. The tumor should be cross-sectioned and an estimate of the depth of invasion recorded (e-Fig. 13.5). The presence of any other mucosal abnormalities should also be recorded. Three to four sections of the tumor should be submitted to include the deepest invasion and relationship of tumor to uninvolved mucosa. Sections from other mucosal lesions, and uninvolved antrum and body, should also be submitted.
If a previously diagnosed adenocarcinoma cannot be confirmed by a grossly visible lesion, careful examination of the gastric mucosa should be performed to identify subtle mucosal alterations including erosions and effacement of folds. Multiple sections should be taken of any of the abnormalities noted, and a diagram of the sections constructed for later reference.
If the tumor is distant from the margins, a single shave section from the proximal and distal margins is adequate. However, if the tumor approaches the margins, multiple radial sections demonstrating the relationship of tumor to margin should be taken. A careful lymph node dissection should be performed; all perigastric lymph nodes are considered regional lymph nodes.
III. DIAGNOSTIC FEATURES OF NONNEOPLASTIC CONDITIONS OF THE STOMACH
A. Gastritis. The classification of gastritis lacks universal standardization. The most recent attempt at standardization is the updated Sydney System, which combines topographical, morphologic, and etiologic information to arrive at a theoretically reproducible and clinically usable diagnosis (Am J Surg Pathol. 1996;20:1161). However, in most settings, there is not enough information or sampling to fulfill the requirements of this classification system. Nonetheless, the system describes several parameters that should be evaluated in a gastric biopsy including the presence and degree of neutrophilic (active) inflammation, chronic inflammation, and atrophy (intestinal metaplasia). Additional features to be noted are surface epithelial damage, lymphoid follicles, foveolar hyperplasia, pseudopyloric metaplasia, pancreatic metaplasia, and endocrine cell hyperplasia.
1. Chronic gastritis is the most common pathologic diagnosis in gastric biopsies. The diagnosis is associated with a lymphoplasmacytic infiltrate in the lamina propria, and in many cases is attributable to H. pylori. However, the number of lymphocytes and plasma cells normally present within gastric biopsies varies with different patient populations, and it is therefore difficult to determine how much inflammation constitutes clinically significant chronic gastritis. Certain histologic features suggest a diagnosis of H. pylori associated gastritis, including lymphoid follicles with germinal centers and the presence of neutrophils within the lamina propria, epithelium, or gland lumens (which is termed “active” rather than “acute” gastritis) (e-Fig. 13.6). Patchy or focal activity may be seen with H. pylori but can also be seen in inflammatory bowel disease, especially in children with Crohn’s disease (e-Fig. 13.7).
H. pylori can best be identified on routine H&E stain in pits near foci of exocytosis or surface mucin (e-Fig. 13.8). However, if needed, histochemical (Giemsa) and/or immunohistochemical (IHC) stains can be used to enhance detection of the organisms (e-Figs. 13.9 and 13.10). The chance of finding organisms diminishes in the absence of active inflammation or in regions of intestinal metaplasia, as the organisms do not colonize this type of epithelium. Additionally, in patients on proton pump inhibitors (PPIs), antral inflammation is milder and H. pylori may relocate deeper in the oxyntic glands. Finally, treatment with other antibiotics, while not eradicating the organism, may nonetheless hinder the ability to detect H. pylori.
After treatment for H. pylori, neutrophils disappear within 6 to 8 weeks. However, the lymphoplasmacytic infiltrates can persist for longer (up to a
year in the body and 2 to 4 years in the antrum). Lymphoid follicles and intestinal metaplasia may remain indefinitely.
TABLE 13.1 Clinicopathologic Features of Autoimmune and Nonautoimmune
Atrophic Gastritis
Autoimmune Nonautoimmune
Patient population
Mainly older white women
Universal
Etiology and pathogenesis
Autoantibodies to parietal cells and intrinsic factor
Helicobacter pylori, other environmental factors
Clinical manifestations
Hypochlorhydria, achlorhydria, pernicious anemia
Abdominal pain, dyspepsia, upper GI bleeding
Gastric involvement
Body and fundus only
Mainly antrum, or multifocal
Microscopic findings
Chronic gastritis, progressive destruction of fundic glands, intestinal metaplasia, pyloric metaplasia, ECL cell hyperplasia
Chronic gastritis, intestinal metaplasia, pyloric metaplasia if body is involved
Serum gastrin level
Elevated
Normal or low
Tumor development
Carcinoid, adenocarcinoma
MALT lymphoma
GI, gastrointestinal; ECL, enterochromaffin-like; MALT, mucosa-associated lymphoid tissue.
Atrophic gastritis is a form of chronic gastritis that can be a consequence of H. pylori gastritis, or occur as an autoimmune process (e-Fig. 13.11). Associated findings include intestinal metaplasia and ECL cell hyperplasia (e-Figs. 13.12 and 13.13). Dysplasia, adenocarcinoma, and carcinoid tumor may develop in this background. Table 13.1 summarizes the clinicopathologic features distinguishing autoimmune from nonautoimmune atrophic gastritis. It is worth noting that atrophy may be more difficult to recognize in the antrum than in the body or fundus since atrophic fundic/body mucosa may resemble antral mucosa on H&E stain; hence, knowledge of the location of the biopsy site is important. If necessary, a positive gastrin stain can confirm the antral origin of a biopsy.
2. Lymphocytic gastritis is defined as prominent lymphocytic infiltration of the surface and foveolar epithelium (>25 lymphocytes per 100 epithelial cells) with infiltration of the lamina propria (e-Fig. 13.14), features that should be present away from lymphoid follicles. Conditions that are associated with increased intraepithelial lymphocytes in the stomach include H. pylori gastritis, celiac disease, syphilis, Ménétrier’s disease, and Crohn’s disease, all of which should be considered secondary gastric epithelial lymphocytosis.
3. Collagenous gastritis is an exceedingly rare diagnosis that has been associated with celiac disease and collagenous colitis in some patient populations. Histologically, it is similar to the large intestinal counterpart with a subepithelial collagen layer exceeding 10 μm in thickness, which may be patchy (e-Fig. 13.15).
4. Eosinophilic gastritis is usually associated with eosinophilic gastroenteritis. Peripheral eosinophilia may be present. Presenting symptoms vary depending on which layers of the bowel wall are involved; while mucosal involvement is most common, the process can involve any layer of the bowel wall, and the diagnosis may therefore be missed on endoscopic mucosal biopsy. Mucosal involvement is characterized by a prominent eosinophilic infiltrate with cryptitis and crypt abscesses (e-Fig. 13.16). However, it is important to exclude certain medications as well as inflammatory and infectious conditions such as Crohn’s disease and parasitic infection, which can also result in eosinophilic infiltrates.
5. Granulomatous gastritis. Granulomas in gastric mucosal biopsies are not specific findings. Although they may be associated with gastric involvement in Crohn’s disease (e-Fig. 13.17), they can also be found in a number of other conditions including sarcoidosis, infections, foreign/endogenous material, and less commonly with vasculitis or xanthogranulomatosis.
6. Infectious gastritis. A number of bacterial (e.g., mycobacteria, Treponema pallidum), viral (e.g., cytomegalovirus, Epstein-Barr virus), fungal (e.g., Candida, Histoplasma, Mucoraceae), and rarely parasitic (e.g., Cryptosporidium, Giardia, Strongyloides, Anisakis) organisms can infect the stomach (e-Figs. 13.18 and 13.19). Some of these infections can be associated with eosinophilic infiltrates and granulomas.
7. Ischemic gastritis. As the stomach has a rich vascular supply from five arteries, ischemic gastritis is very rare. It can be seen in the setting of hypoperfusion with findings of erosion, hemorrhage, necrosis, or ulceration (e-Fig. 13.20).
8. Graft versus host disease (GVHD) in the stomach, as in other parts of the gastrointestinal (GI) tract, shows gland apoptosis and destruction (e-Fig. 13.21).
B. Miscellaneous conditions
1. Foveolar hyperplasia is not a specific finding. It may be seen in antral biopsies of chronic gastritis and is characterized by edematous, elongated, villiform foveolar lining of the mucosa (e-Fig. 13.22).
2. Reactive or chemical gastropathy is characterized by foveolar hyperplasia with tortuous gland outlines and smooth muscle fibers within the lamina propria (e-Fig. 13.23). Although focal activity may be present, inflammation is typically mild to absent. However, these histologic features are nonspecific and can also be associated with bile reflux or with medications, particularly nonsteroidal anti-inflammatory drugs (NSAIDs), which can also cause erosions.
3. Ménétrier’s disease is endoscopically characterized by giant gastric folds mainly involving the body and fundus. The histologic findings include marked foveolar hyperplasia and glandular atrophy (loss of oxyntic mucosa in the body and fundus), and may be reminiscent of hyperplastic polyps (HPs). Clinically, patients present with protein-losing gastropathy and low acid production.
4. Parietal cell hyperplasia due to PPI use or Zollinger-Ellison (ZE) syndrome presents secondary to hypergastrinemia, with an increase in size and number of parietal cells resulting in enlarged mucosal folds in the body and fundus (e-Fig. 13.24). Parietal cells can be found as high as the junction with the foveolar epithelium. Some of the glands may be cystically dilated reminiscent of fundic gland polyps. Foveolar hyperplasia is absent. Hypergastrinemia also causes endocrine cell hyperplasia and can result in neuroendocrine tumors (NETs). The final distinction of PPI use or ZE syndrome is based on the clinical setting.
5. Gastric antral vascular ectasia, also known as watermelon stomach because of its endoscopic appearance, is characterized by dilatation of mucosal capillaries in the gastric antrum with or without fibrin thrombi (e-Fig. 13.25), with associated mucosal smooth muscle fibers. Similar changes can be seen in portal hypertension. However, portal hypertensive gastropathy involves the body and fundus and does not classically show fibrin thrombi.
6. Mucosal calcinosis. Calcifications are usually found incidentally in mucosal biopsies from patients with renal failure or in organ transplant recipients (e-Fig. 13.26).
7. Pseudomelanosis results from iron deposition in mucosa in patients taking ferrous sulfate (surface mucosa) or in patients with hemochromatosis (full
thickness or deep) (e-Figs. 13.27 and 13.28). In iron pill gastritis, there may be mild inflammation or erosions (e-Fig. 13.29).
8. Xanthelasma or xanthoma is characterized by collections of lipid-laden foamy macrophages in the lamina propria and is significant for its potential confusion with poorly differentiated signet ring cell adenocarcinoma on biopsy (e-Fig. 13.30). In problematic cases, the diagnosis can be clarified with IHC stains; positivity for pan-cytokeratins and CDX2 is seen in most adenocarcinomas, whereas positivity for CD68 and CD163 would favor xanthoma.
IV. DIAGNOSTIC FEATURES OF COMMON GASTRIC POLYPS
A. Hyperplastic Polyps (HPs) are composed of elongated, dilated, branching foveola in association with inflamed, edematous lamina propria. These polyps can show surface erosions, regenerative changes, and intestinal metaplasia (e-Fig. 13.31). In addition, foci of dysplasia or invasive carcinoma are present in ∽2% of HPs. The likelihood of these findings increases with polyp size, especially in those >2 cm. HPs may occur in a subset of patients with Osler-Weber-Rendu syndrome.
B. Fundic gland polyps are composed of cystically dilated spaces partially lined by parietal cells which may be hyperplastic or attenuated (e-Fig. 13.32). They can be syndromic, where they represent the most common gastric lesion of familial adenomatous polyposis (FAP), or sporadic. A significant proportion of syndromic fundic gland polyps are associated with low grade or indefinite dysplasia. However, high-grade dysplasia and invasive carcinoma are exceedingly rare. Sporadic fundic gland polyps are sometimes associated with PPI treatment for gastroesophageal reflux.
C. Inflammatory fibroid polyp (IFP) is most commonly found in the gastric antrum and consists of a submucosal collection of bland spindle cells, which are characteristically CD34 positive and c-kit negative, in a background of dilated vascular channels and mixed inflammation, which often contains abundant eosinophils (e-Figs. 13.33 to 13.35).
D. Hamartomatous polyps can be seen in patients with Peutz-Jeghers syndrome, juvenile polyposis, and Cowden’s disease. The histologic features of many of these polyps may be reminiscent of hyperplastic gastric polyps.
V. DIAGNOSTIC FEATURES OF COMMON NEOPLASMS OF THE STOMACH. The World Health Organization (WHO) histologic classification of gastric tumors is given in Table 13.2. The American Joint Committee on Cancer (AJCC) staging schema is given in Table 13.3. Molecular tests used in the work-up of stomach specimens are listed in Table 13.4.
A. Adenoma and dysplasia. Unlike colonic adenomas, most gastric adenomas are not sporadic but rather arise in the setting of chronic gastric injury. Adenoma and dysplasia are distinguished by architecture: polypoid = adenoma, flat = dysplasia. Both can contain either low-grade (e-Fig. 13.36) or high-grade dysplasia (e-Fig. 13.37) defined by cytologic features and architectural complexity.
There are three types of stomach adenomas: intestinal type (e-Fig. 13.38), resembling those in the colon and containing goblet cells and/or Paneth cells, and two gastric types, foveolar- and pyloric-type adenomas. Foveolar-type adenomas are composed of foveolar epithelial cells containing neutral mucin with apical mucin caps, stain positively for MUC5AC, and are sometimes associated with FAP. Pyloric gland adenomas are composed of tightly packed pyloric glandtype tubules with a single layer of cuboidal to low columnar epithelium that shows round nuclei and pale to eosinophilic ground glass cytoplasm, and that stains for MUC5AC and MUC6 (e-Fig. 13.39). Pyloric gland adenomas have been shown to occur more commonly in women and are more frequently associated with autoimmune atrophic gastritis (Am J Surg Pathol. 2009;33:186; Virchows Arch. 2003;442:317). Pyloric gland adenomas, as is the case with intestinal-type adenomas, are also associated with a higher rate of dysplasia and malignant transformation than gastric foveolar-type adenomas (Am J Surg Pathol. 2002;26:1276).
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