Antonia R. Sepulveda and Sun A. Kim George Washington University, Washington, DC, USA The innermost layer of the GI tract is the mucosa, consisting of three components. The submucosa is composed of connective tissue and houses Meissner’s nerve plexus as well as large‐caliber vessels. The muscularis propria is the main wall of the GI tract and is composed of an inner circular and outer longitudinal layer of smooth muscle. Between these layers is Auerbach’s nerve plexus. The outermost component is either adventitia or serosa. The former lacks a mesothelial membrane lining. Parasympathetic ganglion cells are found in the nerve plexi (both Meissner’s and Auerbach’s) but the submucosal Meissner’s plexi contain neuronal cell bodies of the intrinsic sympathetic nerve system that function on the local area of the gut. These are the neurons that have chemoreceptors and mechanoreceptors. They synapse on both other ganglion cells and muscle or secretory cells. Findings in gastroesophageal reflux disease (GERD) can range anywhere from “classic” reflux changes (basal cell hyperplasia, elongation of vascular papillae, and intraepithelial eosinophils) to ulcers, intraepithelial lymphocytosis (which correlates poorly with pH studies), or “balloon” cells, which appear distended and have pale abundant pink cytoplasm (Figure 96.1). Figure 96.1 Reflux esophagitis, displaying mild intraepithelial inflammation. There are a few agents which cause injury that leave a “footprint” that can be recognized on biopsies, although often there is no microscopic clue. Biopsies from patients with graft‐versus‐host disease (GVHD) in the esophagus show intraepithelial lymphocytosis, basilar vacuolization, epithelial apoptosis (Figure 96.3), and necrosis in severe disease. Many patients manifest a characteristic endoscopic appearance, and a bullous presentation akin to that of bullous pemphigoid is one of the possible presentations. Figure 96.2 Taxol effect. This process involves metaplastic columnar mucosa in the esophagus. The ring mitoses are an indication of mitotic arrest. Figure 96.3 Graft‐versus‐host disease. Biopsies from patients with GVHD in the esophagus show intraepithelial lymphocytosis, basilar vacuolization, epithelial apoptosis, and necrosis in severe disease.This image shows extensive squamous epithelial apoptosis such that the nuclear resemble specks of dust. Figure 96.4 Lichen planus involving the esophagus. The characteristic pathological features of esophageal lichen planus are a band‐like inflammatory infiltrate with a predominance of mature T cells and basal layer degeneration, including characteristic Civatte bodies (apoptotic squamous epithelial cells). The epithelium may show parakeratosis. This field shows prominent intraepithelial lymphocytosis and necrotic squamous cells. Figure 96.5 Cytomegalovirus esophagitis. An endothelial cell in the center of the field is affected. There is a large intranuclear inclusion. Figure 96.6 Herpes simplex virus esophagitis. The infected cells are multinucleated with “smudged” nuclei. Figure 96.7 Candida esophagitis. This periodic acid–Schiff (PAS) stain highlights pseudohyphal forms. Figure 96.8 Eosinophilic esophagitis. Numerous eosinophils, some degranulating, are seen in both the epithelium and the lamina propria. Far fewer eosinophils are seen in reflux esophagitis. Compare this image to Figure 96.1. The presence of at least 15 eosinophils per high‐power field is required for a diagnosis, and it is also a cut‐off for a histological remission (<15 intraepithelial eosinophils per high‐power field). Figure 96.9 Crohn’s disease involving the esophagus. There is a prominent lymphoplasmacytic infiltrate. A granuloma is seen in the lower center portion of the field. Figure 96.10 Squamous papilloma of the esophagus. Squamous mucosa coats fibrovascular cores. Dysplasia refers to neoplastic change in epithelium that remains confined to the neoplastic gland in which it arose. In other organ systems, usually the term “intraepithelial neoplasia” is applied, but “old‐fashioned” terminology remains in place for the hollow viscus organs. Figure 96.11 Barrett esophagus, negative for dysplasia. Note the goblet cells characteristic of intestinal metaplasia. There is surface maturation of the metaplastic cells and abundant lamina propria. Figure 96.12 Low‐grade dysplasia in Barrett esophagus. The epithelial changes are seen both in deep glands and on the surface but the nuclei are aligned perpendicularly to the basement membrane (maintained nuclear polarity). Figure 96.13 Immunohistochemistry for TP53 (p53) highlights strong immunoreactivity in the nucleus of BE positive for dysplasia, with positivity involving multiple gland profiles and showing extension to the surface of the mucosa. Figure 96.14 High‐grade dysplasia and intramucosal carcinoma in Barrett esophagus. Hyperchromatic nuclei have lost their polarity relative to the basement membrane and there may be back‐to‐back glands. Recognizing esophageal adenocarcinomas on biopsies is generally not a challenge as they exhibit the same features as other adenocarcinomas (i.e., malignant cells with glandular differentiation in the form of either ductal structures or mucin production) (Figure 96.15). Figure 96.15 Esophageal adenocarcinoma, moderately differentiated, showing irregular glands and marked cytologic atypia. Figure 96.16 Esophageal squamous cell carcinoma. There is a squamous pearl towards the right of the field. In this biopsy, the lesion has invaded the muscularis mucosae, seen as slender pink strips. Figure 96.17 Chemical gastritis/reactive gastropathy. The antral mucosa has a villiform appearance, there is crypt hyperplasia, progressively displaying a corkscrew appearance and there is mucin loss in the epithelium. There is very little inflammation. Figure 96.18 Helicobacter pylori‐associated chronic active gastritis. Note the lymphoid follicles in this low‐magnification field and marked mucosal inflammation (both neurophils and chronic inflammation) that is most prominent toward the surface of the mucosa. Figure 96.19 Helicobacter pylori‐associated chronic active gastritis. At high magnification, neutrophils are seen in the epithelium. Organisms are easily identified on this hematoxylin and eosin stain. Figure 96.20 Chronic active H. pylori gastritis. Immunohistochemistry stain highlights the curved rods in their typical location, adherent to the apical aspect of surface and gastric pit epithelial cells. Metaplastic atrophic gastritis occurs in two distinct types and, because of this, it is best if biopsies are obtained from both the gastric antrum and the body and sent to pathology in separate containers. These two types have been termed autoimmune and “environmental.” Autoimmune metaplastic atrophic gastritis (AMAG) was called “type A” gastritis in the past. This is a disease in which antibodies attack gastric parietal cells (Figure 96.21). Since parietal cells are the type affected, the changes are only in zones where parietal cells are found. Thus there is metaplasia and atrophy only in the body and fundus. Metaplasia may be of the intestinal type or the “pseudopyloric” type. Since the patients are hypoacidic due to loss of parietal cell mass, gastrin levels become progressively elevated in these patients and this gastrin stimulates proliferation of endocrine cells (enterochromaffin‐like or ECL cells) in the gastric body. Figure 96.21 Autoimmune atrophic gastritis. This biopsy is from the gastric body but there are no acid‐producing cells. There is intestinal metaplasia in the right end side of the field (goblet cells). Helicobacter gastritis is probably the most important cause of environmental gastritis that we know. The key feature is that environmental atrophic gastritis is most marked in the antrum. Multiple foci of intestinal metaplasia first appear in the transition zone between antrum and body at the area of the lesser curvature. Over time, the entire antrum is affected but the body is relatively spared. There is less disease in the body, first in the distal body, and over many years affecting more of the proximal body. The body can display pseudopyloric and intestinal metaplasia just as in autoimmune gastritis, but of course the antrum is affected as well. In this condition, longitudinal antral folds have visible reddened vessels radiating from the pylorus in a distribution resembling a watermelon rind (Figure 96.22). Histological examination discloses features that reflect a mucosal prolapse component; there is foveolar hyperplasia with dilated mucosal capillaries, focal thrombi, and fibromuscular hypertrophy. A simple but useful approach to hyperplastic gastritis or “giant folds” is to consider whether the cell type resulting in the thickened folds is foveolar hyperplasia or hyperplasia of oxyntic glands. Figure 96.22 Gastric antral vascular ectasia (GAVE) (watermelon stomach). Even at low magnification, many vascular thrombi are apparent. The syndrome of hypertrophic gastric folds, oxyntic gland loss (and thus achlorhydria), and protein loss is also termed Ménétrier disease (Figure 96.23). On a mucosal biopsy, Ménétrier’ disease appears indistinguishable from a gastric hyperplastic polyp, consisting of hyperplastic foveolar epithelium arranged in a disorderly fashion with loss of oxyntic mucosa in biopsies from the body or fundus. Making a diagnosis requires correlation with the endoscopic and imaging findings. Giant folds may be imparted by marked hyperplasia of the oxyntic component of the mucosa as well as by the surface component (Figure 96.24). This happens in the setting of hypergastrinemia. If there is intact gastric oxyntic mucosa, hypergastrinemia can be the result of a gastrin‐producing neoplasm (“gastrinoma”) and the resultant hypertrophic gastropathy is referred to as a component of Zollinger–Ellison syndrome. Since the gastrin in Zollinger– Ellison syndrome also stimulates endocrine cells, endocrine cell hyperplasia is also a component of this condition. On a mucosal biopsy, the oxyntic component is markedly expanded and thick but the key feature is that parietal cells are seen insinuated in the epithelium near, or even at, the surface between residual foveolar cells instead of nested down deeper in the mucosa. Figure 96.23 Hypertrophic gastropathy/Ménétrier disease. There is striking hyperplasia of foveolar (mucin‐producing) cells. Figure 96.24 Gastric mucosa in Zollinger–Ellison syndrome. There is striking hyperplasia of parietal cells. Contrast this to Figure 96.23. Hyperplastic polyps are the second most common gastric epithelial polyps (GHP). They are composed of characteristic hyperplastic, elongated, and dilated foveolae within an edematous, inflamed stroma (Figure 96.25). The lining of the hyperplastic foveolae is generally that of mature gastric mucin cells, but foci of intestinal metaplasia are found in about 15%. The histological appearance of hyperplastic polyps overlaps significantly with: (1) conditions of generalized gastric mucosal hyperplasia (Ménétrier disease; Cronkhite–Canada syndrome), and (2) hamartomatous polyps and syndromes involving the stomach. As such, diagnosis requires correlation with the endoscopic findings and clinical history. Figure 96.25 Gastric hyperplastic polyp. There is prominence of mucin‐producing epithelium and cystically dilated glands. This lesion has overlap with hypertrophic gastropathy and diagnosis of either condition requires correlation with the endoscopic appearance. Fundic gland polyps (FGPs) occur in two forms: sporadic and familial adenomatous polyposis (FAP) associated. They are typically small (a few millimeters and only rarely more than 1 cm), sessile, and dome shaped. Sporadic FGPs may be single but are commonly multiple (usually a few polyps). Rarely patients without FAP have numerous FGPs proliferating in a manner that resembles a polyposis syndrome. Unlike hyperplastic polyps, FGPs are not particularly associated with any type of inflammatory or atrophic background mucosal pathology and are essentially an incidental finding. Familial adenomatous polyposis‐associated FGPs are more numerous than sporadic FGPs, and hence patients with FAP are more likely to have fundic gland “polyposis.” The morphology of fundic gland polyps overlaps considerably with that of proton pump inhibitor (PPI) effects. An endoscopic nodule correlates with dilated oxyntic glands, some of which contain cells with apocrine‐like snouts (Figure 96.26). Distinguishing between these two processes is principally done by correlation with the presence of an endoscopic lesion. If an epithelial dysplastic lesion produces a polyp, it is referred to as an adenoma and the dysplasia is graded, whereas flat lesions are termed “dysplasia” and are graded using criteria similar to those in the esophagus. The adenomas are classified as intestinal type, containing at least focal goblet cells and/or Paneth cells (Figure 96.27); gastric foveolar type (Figure 96.28), lined entirely by gastric mucin cells, as shown on PAS/Alcian blue staining (PAS/AB); and pyloric gland type (pyloric gland adenoma). Figure 96.26 Fundic gland polyp. The cystically dilated oxyntic (fundic) glands are the key feature. Figure 96.27 Gastric adenoma, intestinal type. This example shows both intestinal metaplasia and high‐grade dysplasia. Figure 96.28 Gastric adenoma, “gastric foveolar type.” Such a lesion, arising in normal background mucosa, is a “low‐risk” lesion unlikely to be associated with either high‐grade dysplasia or invasive carcinoma. Low‐grade B‐cell lymphomas of mucosa‐associated lymphoid tissue (MALT) are believed to arise in organized lymphoid tissue in the gastric mucosa that is usually acquired in response to H. pylori infection (Figures 96.29, 96.30). They are also termed “extranodal marginal zone lymphomas.” Gastric carcinoma is often easy to recognize on biopsies but it can also be extremely subtle (Figure 96.31). Carcinomas of the intestinal type can be extremely subtle on superficial biopsies but there is the correlate of a mass. Diffuse carcinomas are very difficult to spot on biopsies but there is the correlate of a stomach that does not distend on insufflation. Some carcinomas are so poorly differentiated that they require keratin stains for diagnosis (Figure 96.32). Occasional gastric carcinomas have a clear cell pattern. Rare gastric carcinomas have squamous differentiation and still rarer ones have hepatoid differentiation. Figure 96.29 Mucosa‐associated lymphoid tissue (MALT) lymphoma, also called extranodal marginal zone B cell lymphoma. Note the “bottom‐heavy” distribution of the lymphoid infiltrate. Figure 96.30 Mucosa‐associated lymphoid tissue (MALT) lymphoma. This field shows a “lympho‐epithelial lesion” in which lymphoid cells proliferate in the epithelium itself.
CHAPTER 96
Endoscopic mucosal biopsy: histopathological interpretation
Overview of histology of the gastrointestinal tract
Esophagus
Reflux disease
Injury due to chemical or physical agents
Taxol/colchicine (Figure 96.2)
Graft‐versus‐host disease
Dermatological disease affecting the esophagus (Figure 96.4)
Esophagitis caused by infectious agents (Figures 96.5–96.7)
Eosinophilic esophagitis (Figure 96.8)
Crohn’s disease affecting the esophagus (Figure 96.9)
Polyps: squamous papillomas (Figure 96.10)
Dysplasia in Barrett esophagus
Grading dysplasia in Barrett esophagus (Figures 96.11–96.14)
Tumors
Adenocarcinoma
Squamous cell carcinoma (Figure 96.16)
Stomach
Inflammatory disorders
Chemical gastritis/chemical gastropathy/reactive gastropathy (Figure 96.17)
Helicobacter gastritis (Figures 96.18–96.20)
Metaplastic atrophic gastritis
Autoimmune metaplastic atrophic gastritis
Environmental metaplastic atrophic gastritis
Gastric antral vascular ectasia (GAVE/watermelon stomach)
Hyperplastic gastropathy
Foveolar hyperplasia
Hyperplasia of oxyntic glands
Polyps and neoplasms
Hyperplastic polyps
Fundic gland polyps
Tumors
Gastric adenomas and gastric dysplasia
MALT lymphoma
Adenocarcinoma
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