Definition and Characteristics of Dysplasia in Barrett’s
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
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
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
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.
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
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
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
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.
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.