# Upper GI Biopsy Interpretation: Esophagus and Stomach

## Overview

Upper GI biopsies rank among the highest-volume specimens in surgical pathology. Accurate interpretation requires systematic assessment of epithelial changes, inflammatory patterns, and neoplastic precursors, with particular emphasis on Barrett esophagus surveillance and Helicobacter pylori-associated gastritis.

## Esophageal Biopsies

### Normal Esophageal Mucosa

The normal esophagus is lined by non-keratinized stratified squamous epithelium. Lamina propria papillae extend less than two-thirds of the total epithelial thickness, and the basal cell layer comprises less than 15 percent of epithelial thickness. No significant intraepithelial eosinophils, neutrophils, or lymphocytes should be present.

### Reflux Esophagitis (GERD)

Gastroesophageal reflux disease produces a constellation of histologic changes. Basal cell hyperplasia exceeds 15 percent of epithelial thickness, and lamina propria papillae elongate beyond 66 percent of epithelial thickness. Dilated intercellular spaces (spongiosis) may be visible on H&E or highlighted by electron microscopy. Scattered intraepithelial eosinophils and neutrophils are present, usually fewer than 5 eosinophils per high-power field. Balloon cells (superficial pale-staining squamous cells) may appear, and severe cases show erosion or ulceration.

### Eosinophilic Esophagitis (EoE)

The diagnosis of EoE requires 15 or more eosinophils per high-power field (using the peak count) in at least one biopsy. Additional supportive features include eosinophil microabscesses (clusters of 4 or more eosinophils), superficial layering of eosinophils (surface predominance), basal zone hyperplasia with spongiosis, and subepithelial fibrosis in deeper biopsies. Other causes must be excluded, including GERD, eosinophilic GI disease, infections, and drug reactions. Biopsies should be taken from both proximal and distal esophagus, since EoE often involves the proximal esophagus while GERD predominantly affects the distal segment.

### Barrett Esophagus

#### Definition and Diagnosis

Barrett esophagus is defined as the replacement of normal squamous epithelium by columnar epithelium with intestinal metaplasia (goblet cells), which is required for diagnosis in the United States. Goblet cells are mucin-filled cells with lateral nuclear displacement, confirmed with Alcian blue stain at pH 2.5. Both endoscopic documentation of a columnar-lined esophagus and histologic confirmation are required. Segment length is classified as short-segment (less than 3 cm) or long-segment (3 cm or greater).

#### Dysplasia Grading in Barrett Esophagus

| Category | Key Features |
|---|---|
| Negative for dysplasia | No cytologic atypia beyond reactive changes |
| Indefinite for dysplasia | Atypia present but reactive vs. neoplastic uncertain (often with inflammation) |
| Low-grade dysplasia | Nuclear enlargement/stratification confined to basal half; preserved polarity |
| High-grade dysplasia | Full-thickness stratification, loss of polarity, cribriform glands, luminal necrosis |
| Intramucosal carcinoma | Invasion into lamina propria (single cells, angulated glands, desmoplasia) |

Biopsies are classified as negative for dysplasia when intestinal metaplasia shows no cytologic atypia beyond reactive changes. The indefinite for dysplasia category is used when cytologic atypia is present but the distinction between reactive and neoplastic changes cannot be made, often in the setting of active inflammation or ulceration.

Low-grade dysplasia shows nuclear enlargement, hyperchromasia, and stratification (pseudostratification) confined to the basal half of the epithelium with preserved nuclear polarity. Architectural complexity includes crowding and villiform surfaces, and surface maturation is present but reduced.

High-grade dysplasia shows nuclear stratification extending to the luminal surface with loss of nuclear polarity, marked cytologic atypia (irregular nuclear membranes, prominent nucleoli, atypical mitoses), full-thickness involvement of glands, architectural complexity (cribriform patterns, back-to-back glands, luminal necrosis), and loss of surface maturation.

Intramucosal carcinoma represents invasion through the basement membrane into the lamina propria, characterized by single cells, angulated glands, or desmoplastic stroma.

#### Ancillary Studies

p53 immunohistochemistry is the most valuable adjunct: overexpression (diffuse strong nuclear staining) or complete loss (null pattern) supports dysplasia over reactive atypia. Alpha-methylacyl-CoA racemase (AMACR) is positive in dysplasia and carcinoma but negative in non-dysplastic Barrett epithelium. Ki-67 showing surface extension of the proliferative zone suggests dysplasia.

## Gastric Biopsies

### Gastric Anatomy for the Pathologist

The gastric cardia contains mucus-secreting glands in a narrow zone at the gastroesophageal junction. The fundus and body (oxyntic mucosa) contain parietal cells (producing hydrochloric acid) and chief cells (producing pepsinogen). The antrum and pylorus have mucus-secreting glands along with G cells (producing gastrin) and D cells (producing somatostatin). Identifying the biopsy site matters for the correct interpretation of metaplasia and atrophy.

### Helicobacter pylori Gastritis

H. pylori organisms appear as small curved bacilli on the mucosal surface and within gastric pits. The histologic pattern is active chronic gastritis, with neutrophilic infiltration of glands (activity) superimposed on a chronic lymphoplasmacytic infiltrate. The antral-predominant pattern is most common. Lymphoid follicles and aggregates with germinal centers are frequently present. Detection methods vary in sensitivity: H&E alone detects organisms in only 60 to 70 percent of positive cases, while special stains (Giemsa, Warthin-Starry) and immunohistochemistry achieve sensitivity above 95 percent. IHC is the gold standard for detection on biopsy.

### Gastric Intestinal Metaplasia (GIM)

Complete (Type I) intestinal metaplasia shows a small intestinal phenotype with goblet cells and absorptive cells bearing a brush border; it carries a decreased cancer risk relative to incomplete metaplasia. Incomplete (Type II/III) metaplasia shows a colonic phenotype with goblet cells admixed with gastric-type mucus cells (MUC2-positive, MUC5AC/MUC6-positive) and carries a higher cancer risk. Intestinal metaplasia is a risk factor for gastric adenocarcinoma, and surveillance depends on its extent and subtype. The OLGIM staging system (Stages 0 through IV) provides a standardized framework based on biopsy mapping.

### Gastric Atrophy and the Correa Cascade

The Correa cascade describes the stepwise progression from normal mucosa through chronic gastritis, atrophic gastritis, intestinal metaplasia, and dysplasia to adenocarcinoma. Autoimmune gastritis targets the body and fundus, causing parietal cell loss, enterochromaffin-like (ECL) cell hyperplasia, and carrying a risk of Type I gastric neuroendocrine tumors. H. pylori-associated atrophy typically follows an antral or multifocal pattern.

### Gastric Polyps

#### Fundic Gland Polyps

Fundic gland polyps are the most common gastric polyp, occurring either sporadically or in association with proton pump inhibitor use. They consist of dilated, cystically dilated oxyntic glands lined by parietal and chief cells. Sporadic lesions have a low dysplasia risk and require no surveillance. Syndromic fundic gland polyps (in familial adenomatous polyposis) are multiple, may harbor dysplasia, and are associated with APC mutations.

#### Hyperplastic Polyps

The second most common gastric polyp, hyperplastic polyps are associated with H. pylori gastritis and autoimmune gastritis. They show elongated, tortuous, branching foveolar epithelium with edematous, inflamed stroma. The risk of dysplasia is approximately 2 to 5 percent in polyps larger than 1 cm. They may harbor intestinal metaplasia.

#### Gastric Adenomas

These are true neoplastic polyps, either intestinal-type or foveolar-type (pyloric gland adenoma). Intestinal-type adenomas show tubular or villous architecture with dysplastic epithelium. Pyloric gland adenomas have ground-glass cytoplasm and round nuclei, and are associated with autoimmune gastritis and Lynch syndrome. Both have significant malignant potential, and excision is recommended.

### Gastric Dysplasia

Low-grade gastric dysplasia shows nuclear enlargement, hyperchromasia, and pseudostratification with maintained glandular architecture. High-grade dysplasia demonstrates marked atypia, loss of polarity, cribriform or back-to-back glands, and intraluminal necrosis. Diagnostic thresholds differ between Western and Japanese practice, and multidisciplinary review is recommended.

<image>A medical illustration of Barrett esophagus biopsy findings. Panel A: Low-power view showing the squamocolumnar junction with transition from stratified squamous epithelium to columnar epithelium containing goblet cells (intestinal metaplasia). Panel B: High-power view of goblet cells stained with Alcian blue at pH 2.5, showing blue-staining acid mucin within distended goblet cells interspersed among columnar cells. Panel C: Low-grade dysplasia showing nuclear pseudostratification confined to the basal half of the epithelium with pencillate hyperchromatic nuclei, maintained surface maturation. Panel D: High-grade dysplasia showing full-thickness nuclear stratification, loss of nuclear polarity, prominent nucleoli, and cribriform glandular architecture.</image>

<image>A medical illustration of Helicobacter pylori gastritis. Panel A: Low-power view of antral mucosa showing dense chronic inflammatory infiltrate in the lamina propria with lymphoid follicle formation. Panel B: High-power view showing active inflammation with neutrophils infiltrating gastric pit epithelium (pit abscesses) superimposed on lymphoplasmacytic infiltrate. Panel C: Warthin-Starry silver stain highlighting small curved bacilli (H. pylori) adherent to the surface epithelium within the mucus layer. Panel D: H. pylori immunohistochemistry showing strong membrane staining of organisms along the mucosal surface, demonstrating superior sensitivity over H&E alone.</image>

<image>A medical illustration of common gastric polyps. Panel A (Fundic gland polyp): Cystically dilated oxyntic glands lined by flattened parietal and chief cells, with no surface inflammation. Panel B (Hyperplastic polyp): Elongated, tortuous, branching foveolar epithelium with edematous and inflamed lamina propria, smooth muscle fibers in stalk. Panel C (Pyloric gland adenoma): Well-circumscribed polyp composed of tightly packed glands lined by cells with ground-glass cytoplasm and round basal nuclei, with mild nuclear atypia. Panel D: p53 immunostain showing diffuse strong nuclear overexpression pattern in a focus of high-grade dysplasia arising in a gastric adenoma.</image>

## Clinical Pearls

In Barrett surveillance biopsies, p53 immunohistochemistry should always be used when the morphology is ambiguous between reactive and dysplastic changes. Aberrant p53 (either overexpression or null pattern) strongly supports true dysplasia and should prompt expert review. Barrett dysplasia grading has significant interobserver variability, so all cases of indefinite, low-grade, and high-grade dysplasia should be confirmed by a second GI pathologist before clinical management decisions are made.

When H. pylori is not identified on H&E in a biopsy showing active chronic gastritis, special stains or IHC should be reflexively ordered, since false-negative H&E rates are 30 to 40 percent, particularly with low organism density or after proton pump inhibitor therapy. Autoimmune gastritis targets the body and fundus (not the antrum); the presence of antral-sparing atrophy with ECL cell hyperplasia should prompt evaluation for pernicious anemia and Type I gastric neuroendocrine tumors. Pyloric gland adenomas in the setting of autoimmune metaplastic atrophic gastritis should raise suspicion for Lynch syndrome, and mismatch repair immunohistochemistry should be considered.

## References
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- Rugge M, et al. Gastric mucosal atrophy: interobserver consistency using new criteria for classification and grading. *Aliment Pharmacol Ther*. 2002;16(7):1249-1259.
- Dellon ES, et al. ACG clinical guideline: Evidenced based approach to the diagnosis and management of esophageal eosinophilia and eosinophilic esophagitis. *Am J Gastroenterol*. 2013;108(5):679-692.