A Cell Marker Atlas to Distinguish Metaplastic Transitions in Human Esophagus and Stomach

Abstract

Metaplasia is an adaptative response to injury and inflammation and can be a precursor to dysplasia and cancer. Metaplasia in the esophagus, termed Barrett's esophagus, is the replacement of the stratified squamous epithelium by glandular tissue comprising gastric and/or intestinal cell lineages. Metaplasia in the stomach can be divided further into pyloric metaplasia, in which corpus glands become more antral-like, or gastric intestinal metaplasia (GIM), in which gastric cells are replaced by intestinal cell lineages, with the latter subdivided into complete and incomplete. The routine diagnosis of metaplasia and dysplasia is performed by examining hematoxylin and eosin-stained sections and mucin immunohistochemistry. However, these methods fail to capture the cellular diversity across glands and the molecular changes in cells that can predict possible progression to dysplasia or cancer. The use of immunohistochemistry- or immunofluorescence-based biomarkers can improve our understanding of gland phenotypes and aid the differentiation of metaplastic and dysplastic transitions. Here, we provide an overview of the pathophysiology of metaplasia in the esophagus and stomach and detail the current understanding of biomarker expression across metaplastic transitions. We suggest a cohort of biomarkers that can differentiate between metaplastic phenotypes in the esophagus (gastric-type and intestinal-type) and the stomach (pyloric metaplasia, incomplete GIM, and complete GIM) that might be used in research and clinical settings. Importantly, we detail the status of dysplasia biomarkers in both the esophagus and stomach, which may have clinical relevance in stratification of high-risk patients.

Keywords: Cell State; Dysplasia; Esophagus; Intestinal; Metaplasia; Pyloric; Stomach.

Figure 1

Overview of metaplastic phenotypes in the esophagus and stomach. (A) Metaplastic glands in the esophagus can resemble gastric glands (gastric metaplasia) or intestinal glands (IM). Gastric metaplastic glands lack goblet cells, have CDX2-negative foveolar cells, and may contain parietal and chief cells. Intestinal metaplastic glands contain goblet cells and CDX2 positive foveolar cells, lack parietal and chief cells, and may contain Paneth cells in the deep glands. Expression of MUC5AC, CDH17, and TFF3 can distinguish gastric-type and intestinal-type glands in metaplasia of the esophagus. Abnormal p53 expression (increase or absence) is commonly observed in dysplasia. P16 and Cyclin D1 expression is frequently increased in dysplastic glands. (B) PM is characterized by foveolar hyperplasia in the upper gland and SPEM cells in the base of the gland. Incomplete GIM glands also contain SPEM cells at their base along with goblet cells throughout the gland. Complete GIM glands resemble a small intestinal gland with abundant well-defined goblet cells, absorptive enterocytes, and lack of SPEM cells. Complete GIM glands may contain Paneth cells. Pyloric metaplasia glands can be identified by AQP5 and CD44v9 staining of SPEM cells but negative for intestinal cell markers (CDH17, TFF3, CD10, and DEFA5). Incomplete GIM stains positive for SPEM cell markers (AQP5, CD44v9) and intestinal cell markers (CDH17, TFF3) but negative for CD10 and DEFA5. Complete GIM has no SPEM cell marker expression and expresses CDH17, TFF3 and CD10. DEFA5 is only present in complete GIM glands but not all complete GIM glands will be positive for DEFA5. TROP2 and CEACAM5 expression is increased in dysplasia. SOX2 expression is reduced in dysplasia. Colored text denotes expression; red = positive, blue = negative.

Figure 2

Dual expression of p53 and TROP2 in high-grade dysplastic BE. Representative images of high-grade dysplastic BE tissue stained with either H&E or costained with anti-TROP2 and anti-p53 antibodies by immunofluorescence. TROP2 is often coexpressed with p53, which is increased in dysplastic tissues. Scale bar = 100 μm.

Figure 3

Unique staining patterns of gastric metaplasia subtypes and dysplasia. Schematics and representative images denote the different metaplastic phenotypes in the stomach. Normal corpus mucosa contains H/K ATPase-positive parietal cells and UEAI-positive foveolar cells. PM and incomplete IM both have CD44v9-positive SPEM cells at the base of their glands, but incomplete IM glands also express TROP2 and basolateral CEACAM5. In dysplasia, CEACAM5 expression is increased and more diffuse. Complete IM is negative for CD44v9, TROP2, and CEACAM5. Complete IM contains TFF3-positive goblet cells and CD10-positive brush border. Scale bar = 100 μm.