Definition and Characteristics of Dysplasia in Barrett’s Esophagus

Dysplasia is defined as neoplastic epithelium that remains confined within the basement membrane of the epithelial surface within which it arose. Questions regarding the diagnosis and grading of dysplasia arise commonly. We use a five-tiered system when evaluating Barrett’s metaplastic epithelium for dysplasia or cancer: negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia, and intramucosal adenocarcinoma.
 

Negative for dysplasia: The metaplastic glands consistently show nuclear atypism when contrasted with normal columnar epithelium. This atypism comprises nuclear enlargement, crowding, hyperchromatism, prominence of nucleoli, and occasional mild stratification. These mild abnormalities may be misinterpreted as dysplasia, but can usually be separated from it because they are confined to the lower portion of the glands, while the upper portion of the glands and surface epithelium shows less abnormality or is normal; this feature is best recognized in well-oriented biopsy specimens.
 

Indefinite for dysplasia: This category is reserved for biopsies in which there is doubt as to the significance of the epithelial abnormalities. We use this term in several situations.
 

Often there is mild nuclear stratification of the surface epithelium, but the cytologic features fall short of those typical of dysplasia. The nuclei may be enlarged, but they are uniform in size and shape and have less hyperchromatism and irregularity of nuclear contour than seen in dysplasia.
 

When the nuclear features on the mucosal surface appear dysplastic, but there is prominent active inflammation, granulation tissue, or an adjacent ulcer, the diagnosis of dysplasia is difficult, and unless it is overt, we use the term "indefinite for dysplasia." Active inflammation can cause nuclear changes that mimic dysplasia; therefore we raise our threshold for dysplasia in its presence.
 

In poorly oriented biopsies, or in those with an eroded surface, the glands may appear dysplastic, but no surface epithelium is available for evaluation. We usually classify these biopsies as indefinite for dysplasia, or as dysplastic but without assigning a grade, depending on the degree of abnormality.
 

Low-grade dysplasia: The diagnosis of low-grade dysplasia can be difficult; however, it may be reassuring for the pathologist to know that the difference in patients with biopsies diagnosed as indefinite for dysplasia versus those with low-grade dysplasia may not be clinically relevant. The endoscopist may decrease the time interval between surveillance endoscopies and increase the number of biopsies, but therapeutic interventions are usually not initiated. There is significant interobserver and intraobserver variation in the diagnosis of dysplasia in Barrett’s esophagus, particularly at the indefinite/low-grade interface. For this reason the categories of indefinite and low-grade dysplasia may be combined for clinical management purposes.

When the biopsy contains both abnormal and normal epithelium, or if a different biopsy from the same patient contains abnormal epithelium, the pathologist can obtain helpful clues about the diagnosis by comparing the nuclear features in the areas in question with those in the unaffected areas. The atypical nuclei of dysplastic epithelium extend onto the mucosal surface so both the surface and the glands contain nuclei that are much larger and hyperchromatic than the nuclei in unaffected epithelium.
 
 

We have observed two major phenotypes of abnormal epithelium in Barrett’s esophagus. The first pattern is characterized by glands lined by cells with crowded, stratified, hyperchromatic nuclei that extend onto the mucosal surface. Depending on the degree of cytologic atypism, this pattern may be interpreted as indefinite for dysplasia, or as low-grade dysplasia.
 

The second pattern consists of cells on the mucosal surface with obviously dysplastic nuclei (large, hyperchromatic, irregular contours) that are basally located in the cell with minimal or no stratification. This phenotype of dysplasia may be overlooked at low power as it often lacks goblet cells and may be confused with gastric cardiac epithelium.

Clues to the diagnosis of dyplasia

At low power, certain clues that indicate dysplasia may be present, and they should prompt examination at a higher power to observe the nuclear features.
 

Frequently, both an absence of goblet cells and mucin depletion in the non-goblet columnar cells may be seen in dysplastic epithelium. At low power, these areas appear more hyperchromatic as compared to uninvolved areas. Entire biopsies composed of dysplastic epithelium may not contain goblet cells and may be confused with reactive gastric cardiac epithelium. However, the degree of nuclear atypia can help in differentiating dysplastic epithelium from reactive gastric mucosa.
 

Less frequently, dysplastic epithelium may secrete excessive mucus and once again may be confused with gastric cardiac epithelium. Careful examination of the nuclei in this pattern of dysplasia reveals prominent atypism with indentations in the nucleus produced by the mucin. The presence of obviously dysplastic epithelium elsewhere within the biopsy will help characterize this pre-malignant phase of Barrett’s esophagus.
 

Features of reactive Barrett’s epithelium

One feature that is commonly seen in non-dysplastic epithelium is the presence of apical mucin. We hesitate to make a diagnosis of dysplasia when apical mucin persists and usually make the diagnosis of negative or indefinite for dysplasia, depending on the nuclear features.
 

Reactive metaplastic columnar epithelium shows atypism; but the nuclei are uniformly enlarged with little hyperchromatism, and they maintain a basal orientation. It is the uniformity and lack of pleomorphism that indicate a reactive, rather than a neoplastic, process.
 

High-grade dysplasia: The accurate diagnosis of high-grade dysplasia is critically important because thereapeutic intervention of some form, and often esophagectomy, may be initiated based on this diagnosis. At low power, distortion of glandular architecture usually is present and may be marked; it is composed of branching and lateral budding of crypts, a villiform configuration of the mucosal surface, or intraglandular bridging of epithelium to form a cribriform pattern of "back-to-back" glands. Most importantly, there should be dysplastic epithelium on the mucosal surface with loss of nuclear polarity, characterized by "rounding up" of the nuclei, and absence of a consistent relationship of nuclei to each other, before rendering the diagnosis of high-grade dysplasia.
 

Intramucosal adenocarcinoma: Glandular architecture can be highly complex in high-grade dysplasia. This complexity often makes it difficult to exclude the diagnosis of intramucosal adenocarcinoma. Before making the diagnosis of invasive carcinoma, we require the presence of individual cytologically malignant cells or abortive glands infiltrating the lamina propria. Typically, the desmoplastic stroma often present in carcinomas invading the submucosa is absent when invasion is limited to the lamina propria.