Eosinophilic esophagitis (EoE) shows characteristic microscopic pathologic features in endoscopically obtained esophageal biopsies, including an eosinophil-rich inflammatory infiltrate in esophageal epithelium, but other inflammatory cells are also increased. Additional alterations are found in epithelium and lamina propria. Esophageal biopsy pathology is a sensitive but not specific marker for EoE related to antigen exposure. Several of the pathologic features of EoE correlate with dysregulated genes in the EoE transcriptome. Eosinophilic gastrointestinal diseases affecting the remainder of the gastrointestinal tract are less well characterized; this article discusses pathologic features in mucosal biopsies that could form the basis for diagnosis and future study.
Key points
- •
Esophageal biopsies from patients who have eosinophilic esophagitis differ significantly from normal esophageal biopsies, and by definition exhibit eosinophil-rich inflammation, often with additional pathologic changes in the epithelium and lamina propria.
- •
Biopsy pathology is a specific but not sensitive marker for allergic disease affecting the esophagus.
- •
Eosinophilic esophagitis biopsy pathology correlates with genetic abnormalities.
- •
A schema is provided to evaluate mucosal biopsies from the remainder of the gastrointestinal tract, and it may provide the basis for eosinophilic gastrointestinal disease diagnosis and entry criteria for research studies.
Introduction
Eosinophilic esophagitis (EoE) is a chronic immune antigen-mediated disease ( Box 1 ). Patients who have EoE respond to antigen elimination, especially elimination of food antigens, consistent with disease associated with a T helper cell type 2 (Th2) reaction to swallowed antigen. The definition of EoE does not differ with patient age or gender, esophageal biopsy pathology does not vary with patient age or gender, and response to antigen elimination occurs in both children and adults of both genders. However, symptoms of EoE differ according to patient age: vomiting and failure to thrive are common among young children, and dysphagia is more typically the predominant symptom among affected adolescents and adults.
Eosinophilic esophagitis
- •
Greater than or equal to 15 intraepithelial eosinophils per HPF in at least one esophageal site ; additional sections should be obtained from nondiagnostic but highly suggestive biopsies, and fewer eosinophils than the recommended threshold value may not eliminate the diagnosis in patients who otherwise would qualify for the diagnosis
- •
Altered eosinophil character manifest as surface layering and abscesses
- •
Epithelial changes such as basal layer hyperplasia, dilated intercellular spaces
- •
Thickened lamina propria fibers
Eosinophilic gastritis
- •
Greater than or equal to 30 eosinophils per HPF in 5 HPF
- •
Altered eosinophil behavior manifest as lamina propria sheets, eosinophilic glandulitis, eosinophilic gland abscesses
- •
Epithelial changes such as reduced mucin, increased nuclear/cytoplasmic ratio, increased epithelial mitotic activity
- •
Altered eosinophil distribution such as one or more per HPF in surface epithelium, or more than one per HPF in gland epithelium ; excess eosinophils in muscularis mucosa or submucosa; concentration of eosinophils in the subepithelial superficial lamina propria instead of deep lamina propria
Eosinophilic enteritis (eosinophilic duodenitis, jejunitis, or ileitis)
- •
More than twice the normal number of eosinophils in the lamina propria per HPF:
- ○
More than 52 eosinophils per HPF in duodenum
- ○
More than 56 per HPF in ileum
- ○
- •
Altered eosinophil behavior manifest as lamina propria sheets, eosinophilic cryptitis, eosinophilic crypt abscesses
- •
Epithelial changes such as reduced mucin, increased nuclear/cytoplasmic ratio, increased epithelial mitotic activity
- •
Altered eosinophil distribution such as:
- ○
More than 2 per HPF and more than 4 per HPF in surface epithelium in duodenum and ileum respectively
- ○
More than 6 per HPF and more than 4 per HPF in crypt epithelium in duodenum and ileum respectively
- ○
Excess eosinophils in muscularis mucosa or submucosa
- ○
Concentration of eosinophils in the subepithelial superficial lamina propria instead of deep lamina propria
- ○
- •
Acute inflammatory cells are not present
Eosinophilic colitis
- •
More than twice the normal number of eosinophils in the lamina propria per HPF:
- ○
More than 100 per HPF in right colon
- ○
More than 84 per HPF in transverse and descending colon
- ○
More than 64 per HPF in rectosigmoid colon
- ○
- •
Altered eosinophil behavior manifest as lamina propria sheets, eosinophilic cryptitis, eosinophilic crypt abscesses
- •
Epithelial changes such as reduced mucin, increased nuclear/cytoplasmic ratio, increased epithelial mitotic activity
- •
Altered eosinophil distribution such as:
- ○
More than 3 per HPF, more than 4 per HPF, more than 2 per HPF in surface epithelium in right, transverse/descending, rectosigmoid colon respectively
- ○
More than 11 per HPF, more than 4 per HPF, more than 9 per HPF in crypt epithelium in right, transverse/descending, rectosigmoid colon respectively
- ○
Excess eosinophils in muscularis mucosa or submucosa
- ○
Concentration of eosinophils in the subepithelial superficial lamina propria instead of deep lamina propria
- ○
- •
Acute inflammatory cells are not present
EoE is the only form of eosinophilic gastrointestinal (GI) disease (EGID) for which there are consensus criteria for diagnosis. Eosinophils normally reside in the mucosa of all parts of the GI tract except the esophagus. Therefore eosinophil-related disorders are easier to recognize in the esophagus compared with the remainder of the GI tract.
Introduction
Eosinophilic esophagitis (EoE) is a chronic immune antigen-mediated disease ( Box 1 ). Patients who have EoE respond to antigen elimination, especially elimination of food antigens, consistent with disease associated with a T helper cell type 2 (Th2) reaction to swallowed antigen. The definition of EoE does not differ with patient age or gender, esophageal biopsy pathology does not vary with patient age or gender, and response to antigen elimination occurs in both children and adults of both genders. However, symptoms of EoE differ according to patient age: vomiting and failure to thrive are common among young children, and dysphagia is more typically the predominant symptom among affected adolescents and adults.
Eosinophilic esophagitis
- •
Greater than or equal to 15 intraepithelial eosinophils per HPF in at least one esophageal site ; additional sections should be obtained from nondiagnostic but highly suggestive biopsies, and fewer eosinophils than the recommended threshold value may not eliminate the diagnosis in patients who otherwise would qualify for the diagnosis
- •
Altered eosinophil character manifest as surface layering and abscesses
- •
Epithelial changes such as basal layer hyperplasia, dilated intercellular spaces
- •
Thickened lamina propria fibers
Eosinophilic gastritis
- •
Greater than or equal to 30 eosinophils per HPF in 5 HPF
- •
Altered eosinophil behavior manifest as lamina propria sheets, eosinophilic glandulitis, eosinophilic gland abscesses
- •
Epithelial changes such as reduced mucin, increased nuclear/cytoplasmic ratio, increased epithelial mitotic activity
- •
Altered eosinophil distribution such as one or more per HPF in surface epithelium, or more than one per HPF in gland epithelium ; excess eosinophils in muscularis mucosa or submucosa; concentration of eosinophils in the subepithelial superficial lamina propria instead of deep lamina propria
Eosinophilic enteritis (eosinophilic duodenitis, jejunitis, or ileitis)
- •
More than twice the normal number of eosinophils in the lamina propria per HPF:
- ○
More than 52 eosinophils per HPF in duodenum
- ○
More than 56 per HPF in ileum
- ○
- •
Altered eosinophil behavior manifest as lamina propria sheets, eosinophilic cryptitis, eosinophilic crypt abscesses
- •
Epithelial changes such as reduced mucin, increased nuclear/cytoplasmic ratio, increased epithelial mitotic activity
- •
Altered eosinophil distribution such as:
- ○
More than 2 per HPF and more than 4 per HPF in surface epithelium in duodenum and ileum respectively
- ○
More than 6 per HPF and more than 4 per HPF in crypt epithelium in duodenum and ileum respectively
- ○
Excess eosinophils in muscularis mucosa or submucosa
- ○
Concentration of eosinophils in the subepithelial superficial lamina propria instead of deep lamina propria
- ○
- •
Acute inflammatory cells are not present
Eosinophilic colitis
- •
More than twice the normal number of eosinophils in the lamina propria per HPF:
- ○
More than 100 per HPF in right colon
- ○
More than 84 per HPF in transverse and descending colon
- ○
More than 64 per HPF in rectosigmoid colon
- ○
- •
Altered eosinophil behavior manifest as lamina propria sheets, eosinophilic cryptitis, eosinophilic crypt abscesses
- •
Epithelial changes such as reduced mucin, increased nuclear/cytoplasmic ratio, increased epithelial mitotic activity
- •
Altered eosinophil distribution such as:
- ○
More than 3 per HPF, more than 4 per HPF, more than 2 per HPF in surface epithelium in right, transverse/descending, rectosigmoid colon respectively
- ○
More than 11 per HPF, more than 4 per HPF, more than 9 per HPF in crypt epithelium in right, transverse/descending, rectosigmoid colon respectively
- ○
Excess eosinophils in muscularis mucosa or submucosa
- ○
Concentration of eosinophils in the subepithelial superficial lamina propria instead of deep lamina propria
- ○
- •
Acute inflammatory cells are not present
EoE is the only form of eosinophilic gastrointestinal (GI) disease (EGID) for which there are consensus criteria for diagnosis. Eosinophils normally reside in the mucosa of all parts of the GI tract except the esophagus. Therefore eosinophil-related disorders are easier to recognize in the esophagus compared with the remainder of the GI tract.
History of EoE pathology
In 1982, eosinophils in esophageal biopsies were correlated with abnormal pH monitoring results. Most of the patients had respiratory problems, but some had signs and symptoms consistent with esophageal disease. Eosinophils in proximal as well as distal esophageal biopsies were found in these patients whose clinical diagnosis was reflux esophagitis. In that report, the number of eosinophils cited in the text and illustrated in photographs was significantly fewer than 15 per high-power field (HPF): intraepithelial eosinophils were found in esophageal biopsies from 18 of 46 patients, fewer than 1 eosinophil per HPF was found in biopsies from 12 of 18 patients, and more than 1 per HPF was found in biopsies from 6 of 18 patients. Additional pathologic features were noted, including marked basal layer hyperplasia in some cases. These findings are consistent with reflux esophagitis or gastroesophageal reflux disease (GERD). Subsequent studies confirmed that intraepithelial eosinophil counts much higher than those indicated in this report occur in esophageal biopsies from some patients who have GERD.
Esophageal biopsies containing eosinophil-rich inflammation were subsequently recognized with increasing frequency. However, marked eosinophilic inflammation in those biopsies was also attributed to reflux esophagitis or GERD, contributing to the delay in recognizing antigen-related esophageal disease. Several laboratories retrieved archived slides, going back to the 1970s, and identified the pathologic changes of EoE in esophageal biopsies. Studies that included analyses of the number of biopsies containing numerous intraepithelial eosinophils compared with the total number of esophageal biopsies obtained in the time period studied documented that the prevalence, but not incidence, of biopsies potentially showing EoE increased over time. Because EoE is a disease requiring correlation of pathology results with clinical findings, and older medical records are often not as complete as current records, retrospective studies cannot determine with certainty when EoE emerged; reports in the early and mid-1990s of esophageal disease that did not respond to anti-GERD therapy and that was significantly improved clinically and histologically by removing antigens from the diet began the series of studies that further defined EoE.
In a unique follow-up survey at an average of 15 years after esophageal biopsies were obtained, individuals who had eosinophils in their biopsies were significantly more likely to report dysphagia compared with age-matched controls, and the probability of reporting dysphagia at follow-up increased with increasing peak eosinophil count. Further, individuals whose biopsies had shown greater than or equal to 15 eosinophils per HPF were more likely to report physician-diagnosed food allergy, history of food impaction, and need for current care from a gastroenterologist compared with individuals whose biopsies had fewer than 15 eosinophils per HPF. Individuals whose prior biopsies had only 5 eosinophils per HPF were more likely than controls to report a history of food impaction, suggesting (similar to an early report of esophageal eosinophilic inflammation ) that fewer intraepithelial eosinophils than the current threshold value for EoE diagnosis may be clinically significant, and in addition that this may portend prolonged esophageal dysfunction. The incidence of pathologic alterations in epithelium and lamina propria increased with increasing intraepithelial eosinophil density.
Esophageal mucosa biopsy histology
The histology (ie, the normal appearance) of esophageal mucosa comprises several layers and components:
- •
Epithelium: the esophageal lumen is lined by nonkeratinized stratified squamous epithelium consisting of a superficial layer near the lumen; a spinous layer below the superficial layer; and the basal zone in the deepest part of the epithelium, overlying the lamina propria. In normal epithelium, the basal zone is not more than 3 cell layers thick, and does not occupy more than 15% of the total epithelial thickness. Intercellular spaces in the basal zone or spinous layer are not visible ( Fig. 1 ).
Fig. 1
Normal esophageal nonkeratinized squamous epithelium. Intraepithelial eosinophils are not seen. The basal zone ( bar ) occupies less than 15% of the total epithelial thickness. The lamina propria ( asterisk ) is composed of delicate collagen fibers. The underlying muscularis mucosa does not appear to be altered (hematoxylin-eosin, original magnification ×200).Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
