Surgical Pathology and Current Molecular Aspects of Dysplasia in the GI Tract
Section 5 -
Gastric Metaplasia and Dysplasia
Robert D. Odze, M.D.
Jonathan Glickman, M.D., Ph.D.
Mark Redston, M.D.
The nomenclature and classification of gastritis and gastric dysplasia has undergone
considerable evolution over the past decades, rendering some past literature confusing. However, certain
themes have persisted despite changing terminology, and the concept that many gastric adenocarcinomas
arise through a sequence of epithelial metaplasia and dysplasia is now well established
The recent development of animal models that allow the direct observation of gastric carcinogenesis in
the setting of Helicobacter infection has already begun to advance our understanding of the basic
epithelial biology of gastric epithelial metaplasia . Indeed, some studies have indicated that bone
marrow derived stem cells contribute to metaplastic and dysplastic epithelial lineages , challenging
traditional assumptions that these changes arise from resident epithelial cells. Further research will
be necessary before the impact of these provocative observations on diagnosis and therapy of gastric
carcinoma can be appreciated.
1. Intestinal Metaplasia
Intestinal metaplasia is defined by the updated Sydney
system as the "replacement of glandular and/or foveolar epithelium by intestinal epithelium."
Intestinal metaplasia occurs in the setting of chronic gastritis secondary to any etiology, and is more
frequent with increasing duration of disease and in individuals greater than 60 years of age.
Population-based studies in Japan and in Europe have identified intestinal metaplasia in up to 26-43% of
H. pylori-positive individuals
with much lower prevalence rates in H.pylori –negative individuals.
One study of patients from the U.S.A. disclosed a prevalence rate of 13 % in Caucasian patients and 50%
in black and Hispanic patients . However, the sensitivity of mucosal biopsies for detecting
intestinal metaplasia in any given individual greatly depends on the number of biopsies obtained. For
example, in one recent study of 733 asymptomatic Mexican patients with a high prevalence of H. pylori
gastritis, intestinal metaplasia was detected in 135 patients in whom seven gastric biopsies were
examined, whereas in 6 (4%) and 24 (18%) patients the metaplasia would have been missed if 5 or 3
biopsies, respectively, had been examined . Intestinal metaplasia may also arise in the setting of
autoimmune gastritis related to pernicious anemia, which accounts for approximately 20% of cases of
chronic gastritis and preferentially involves the body of the stomach
Intestinal metaplasia may be found anywhere in the
stomach; its location corresponds to the location of the underlying gastritis. In H.pylori-associated
chronic gastritis, intestinal metaplasia arises in the antral-corporal junction in the vicinity of the
incisura angularis, but can be found throughout the stomach (antrum, body and cardia) later in the course
of disease. Intestinal metaplasia may be classified based on the types of intestinal epithelial cells
present and by the use of mucin histochemistry, although the latter technique is not used routinely.
"Complete" intestinal metaplasia (type I) is characterized by acid mucin-positive, sulfomucin negative
goblet cells and enterocytes, Paneth cells and endocrine cells, whereas "incomplete" intestinal
metaplasia (types II or III) shows acid mucin-positive goblet cells surrounded by gastric type mucinous
columnar cells (Table 1). Type III metaplasia differs from type II by the presence of sulfomucins
(identified by the high iron diamine/Alcian Blue stain) in the mucinous columnar cells. In contrast to
Barrett's esophagus, which nearly always has incomplete intestinal metaplasia, gastric intestinal
metaplasia secondary to H. pylori gastritis is most commonly a mixture of complete (up to 98% of
patients) and incomplete types (up to 78% of patients) of
Intestinal metaplasia is frequently accompanied by atrophy of the gastric mucosa, which is defined in
the updated Sydney system as "loss of glandular tissue"
However, the histologic
diagnosis of atrophy is independent of the finding of intestinal metaplasia. In the gastric body,
atrophy of the stomach consists of replacement of oxyntic glands by pyloric or pseudopyloric glands, with
or without intestinal metaplasia. Because of a lack of explicit diagnostic criteria for atrophy, there
is a high degree of interobserver variability in evaluating this feature in gastric biopsies
A less common form of metaplasia in the stomach is characterized by the presence of
ciliated epithelial cells, which may be found deep in pyloric glands that also show intestinal metaplasia
in either the distal or proximal stomach . Ciliated cells have been found in non-neoplastic gastric
mucosa in up to 29% of gastrectomies with carcinoma, depending on the patient population . This type
of metaplasia is significantly more common among individuals dwelling in East Asia and the Pacific Basin
compared to those from Europe and the Atlantic Basin, possible as a result of differing environmental
factors . Pancreatic acinar metaplasia is found in the proximal stomach in up to 24-61% of
individuals, but may also be found less commonly in the gastric body and antrum
This type of
epithelium is comprised of nodules of acinar epithelium with apical eosinophilic granules, with or
without mucous cells. The presence of pancreatic acinar metaplasia in the proximal stomach does not
correlate with esophagitis, gastritis, or any type of clinical symptoms in some studies . It can
also be found in children
Therefore, it has been proposed that this epithelium represents a
congenital heterotopia rather than an acquired lesion. However, others have reported an association
between pancreatic acinar epithelium and increased inflammation at the gastroesophageal junction ,
and between autoimmune gastritis and the presence of pancreatic acinar epithelium in the gastric corpus
Natural History and Management
Although gastric intestinal metaplasia is
recognized as a risk factor in the evolution of gastric carcinoma , considerable controversy exists
regarding the prognostic significance of this finding and its implications for surveillance of gastric
carcinoma. Some studies have associated type III intestinal metaplasia with the highest relative risk
(2.7-5.8 times) for the development of gastric carcinoma, and complete intestinal metaplasia with the
However, these studies failed to show that metaplasia is an independent risk factor for
carcinoma when controlling for other variables such as patient age, and it is clear that various comorbid
conditions and host environmental factors influence the progression to dysplasia or carcinoma .
Furthermore, metaplasia is sufficiently common in older age groups and is found at approximately equal
frequency in gastric resections either with or without carcinoma . Therefore, the mere presence of
intestinal metaplasia (type III or otherwise) is neither sufficiently sensitive nor specific to justify
surveillance for gastric carcinoma in low risk populations . Current research interest is focused on
identifying ancillary serologic 
or molecular  markers that may help stratify these patients with
respect to risk for progression to neoplasia.
Gastric epithelial dysplasia may develop in the setting
of chronic gastritis with intestinal metaplasia, but can develop in mucosa without metaplastic change as
well. Most patients are in the fifth to seventh decades of life. The prevalence of dysplasia varies
greatly depending on the population under study. One population-based Scandinavian study found a
prevalence rate of 5% in individuals with atrophic gastritis , whereas studies in higher risk areas
such as China (where atrophic gastritis is nearly universal), found prevalence rates of up to 15-20%
Patients with pernicious anemia develop dysplasia in up to 10% of cases when followed
prospectively . Retained gastric remnants after distal gastrectomy for peptic ulcer disease are also
associated with an increased rate of dysplasia and a mildly increased risk of carcinoma , although
carcinomas occur in only 2-5% of these patients and require a postoperative interval of at least 10-15
Familial adenomatous polyposis (FAP) (see below), hereditary non-polyposis colorectal
cancer syndrome and hereditary colonic flat adenoma syndrome are also at increased risk for gastric
Gastric dysplasia is currently defined as the presence of
unequivocal neoplastic epithelium confined to the basement membrane
However, the terminology
for gastric epithelial dysplasia is potentially confusing and has undergone considerable evolution since
first being recognized as a likely precursor of gastric carcinoma (reviewed in 40,41 and references
therein). Early classifications of dysplasia divided lesions into two (low grade and high grade), three
(for example slight, moderate or severe), or even four levels (grades 1 to 4). However, most of these
systems included regenerative or reactive epithelial changes in the category of "mild" or "low grade"
dysplastic, and numerous follow-up studies demonstrated that these lesions frequently regress or show
minimal malignant potential
An additional source of confusion among classification systems and
published studies relates to the tendency of Japanese pathologists to consider severely dysplastic
epithelium as early carcinoma on the basis of cytologic criteria alone (44,45) (see below).
Currently accepted or proposed classification systems for gastric dysplasia, including the
and WHO  systems, follow the same general approach as for Barrett's
esophagus-associated and IBD-related dysplasia
They divide lesions into low grade and
high-grade dysplasia on the basis of both architectural and cytologic criteria. Lesions that are
suspicious for invasive carcinoma, or that show definite invasion of the lamina propria or submucosa, are
placed into separate diagnostic categories. Controversy remains among pathologists over whether lesions
should be grouped in a purely descriptive manner based on morphologic findings, or based on the favored
clinical management (as proposed in the modified Vienna classification, Table 2)
. Since management
approaches to gastric premalignant and malignant lesions vary significantly among different regions of
the world and different medical centers, this controversy appears likely to continue.
Dysplasia usually occurs in endoscopically flat
mucosa, but may occasionally form a polyp or mass lesion (see adenoma, below). Microscopically,
dysplastic glandular epithelium shows a range of cytologic and architectural abnormalities. Dysplastic
epithelium may occupy the superficial or glandular portions of the mucosa, or both. Similar to BE (see
above), gastric dysplasia may be divided into intestinal "adenoma-like" and gastric "foveolar" (or
non-adenoma-like) types on the basis of cytologic features. Adenoma-like dysplasia (see below) is more
common and resembles the epithelium found in colorectal adenomas, whereas foveolar dysplasia is comprised
of cells resembling gastric foveolar epithelium. However, this distinction appears to be of no clinical
significance. Also, some studies have reported enlarged atypical epithelial cells located in the
foveolar regions of the gastric glands ("tubule neck" or "globoid" dysplasia) and postulated that these
cells represent the precursor of diffuse type gastric carcinoma . However, this is controversial and
has not been extensively studied.
Low-grade dysplastic epithelium contains cells that show mild nuclear enlargement
and pseudostratification limited to the basal half of the cell cytoplasm, hyperchromatic chromatin,
inconspicuous nucleoli, and occasional mitoses (Table 3). Architectural changes are usually modest and
include the formation of tubular or papillary structures and slight crowding. In contrast, high-grade
dysplasia shows a greater degree of nuclear pleomorphism, irregular or rounded nuclei, clumped chromatin,
prominent nucleoli, and frequent mitoses including atypical forms. Nuclear stratification frequently
involves the full thickness of the cell. High-grade dysplasia also displays a greater degree of
architectural complexity and loss of epithelial polarity compared to low-grade dysplasia, with marked
glandular crowding, back-to-back glands, branching, and cribriforming. Biopsies that show mild
architectural distortion and cytologic features of low grade dysplasia, but occur in the context of
significant active inflammation or ulceration, are best classified as indefinite for dysplasia.
Histologic features of low grade and high grade dysplasia are summarized in Table 2.
Different criteria for "dysplasia" and "carcinoma" exist between Eastern and Western pathologists and
have led to significant variability in interpretation between investigators in the two geographic
regions. In one study, a group of Japanese and Western pathologists interpreted a series of 100 gastric
biopsies, each using their own classification schemes. Although each group showed good intragroup
correlation, the intergroup concordance was lower (kappa coefficient 0.54). A principal source of
disagreement involved biopsies that were regarded as dysplasia by Western pathologists but as carcinoma
by Japanese pathologists . Nevertheless, when a group of Japanese and Western pathologists was asked
to categorize a series of lesions as negative/indefinite for dysplasia, dysplastic, or suspicious/
definite carcinoma according to a single classification scheme, they agreed 78% of the time (kappa
coefficient 0.63, good agreement)
Gastric epithelial dysplasia must be distinguished
from reactive foveolar hyperplasia that occurs in the setting of gastritis, ulcer disease, bile reflux,
or radiation/ chemotherapy for esophageal carcinoma. Indeed, these distinctions represent a major source
of diagnostic disagreement, particularly with regard to the differential diagnosis of low-grade dysplasia
versus reactive changes . Mucosa adjacent to ulcers, or in cases of chemical gastropathy, may show
elongated, tortuous foveolar epithelium with mucin depletion, nuclear enlargement and hyperchromasia, and
an increased mitotic index. However, unlike dysplasia, reactive foveolar cells do not show coarse
chromatin, atypical mitoses or loss of nuclear polarity. Furthermore, the overall architecture and
surface maturation are usually well preserved. In addition to the above features, chemotherapy related
epithelial atypia may show prominent nucleoli, and abundant eosinophilic or vacuolated cytoplasm,
features that are not normally observed in dysplasia .
Occasionally, particularly in small or poorly oriented biopsies, distinction between dysplasia and
intramucosal, or invasive, adenocarcinoma may be difficult. The presence of markedly irregular glandular
profiles, confluent clusters of cells, or the presence of single cells in the lamina propria or deeper in
the wall, support a diagnosis of invasive adenocarcinoma. Biopsies that show severely dysplastic
epithelium bordering on adenocarcinoma should be rebiopsied, if necessary, or considered suspicious for
invasion and treated as such.
The natural history of gastric dysplasia is incompletely
understood. Retrospective studies have found that high-grade dysplasia is associated with a synchronous
invasive adenocarcinoma in up to 50% of cases. Prospective follow-up studies have shown that patients
with "severe" dysplasia progressed to carcinoma in 57-80% of cases, whereas patients with "mild" or
"moderate" dysplasia progressed in 20-35% of cases and even regressed in 25-40% of cases, over a
follow-up period that ranged from 2 to 10 years
Recently, one prospective study
utilizing the Padova classification and an extensive biopsy sampling protocol, found that patients with
low and high grade dysplasia progressed to carcinoma in 9% and 69% of cases, and regressed in 53% and 6%
of cases, respectively .
Management Currently there are no generally accepted guidelines in the U.S. for surveillance of
patients with gastric dysplasia. Because of the high rate of progression and the relatively high rate of
association with adenocarcinoma, patients with a biopsy diagnosis of high grade dysplasia should probably
be reendoscoped with extensive mapping biopsies in order to rule out carcinoma. If the dysplasia is
occurring in association with a mass lesion, it may be presumed that the biopsy probably represents the
surface of a carcinoma and a gastrectomy is usually warranted. In Japan , as well as in some Western
centers, an initial diagnosis of flat high-grade dysplasia or intramucosal carcinoma is also considered
an indication for endoscopic mucosal resection . Treatment of patients with low-grade dysplasia is
unclear. However, close and regular endoscopic surveillance (within 3 to 12 months) is usually advisable
to rule out either concurrent high grade dysplasia or carcinoma, or the subsequent development of either
of these lesions.
3. Dysplasia in Gastric Adenomas
Gastric adenomas are defined by the WHO classification as "circumscribed, benign lesions… showing
intraepithelial neoplasia" .
By this definition, any endoscopically discrete (usually elevated)
dysplastic mucosal lesion, whether pedunculated or sessile, is classified as an "adenoma", whereas
dysplasia that occurs in flat mucosa is classified as gastric epithelial "dysplasia". However, this is
controversial since polypoid dysplasia may occur in association with chronic gastritis and, in this
circumstance, it is unclear if this type of lesion should be considered and "adenoma." Adenomas account
for approximately 5-10% of all gastric mucosal polyps
In Japan , the term "adenoma" encompasses
flat or depressed lesions as well . Gastric adenomas are rare in normal individuals but are seen at
increased frequency in patients with chronic gastritis and intestinal metaplasia  or with hereditary
polyposis such as FAP and the hereditary flat adenoma syndrome
The epithelium in adenomas may
show low grade or high-grade dysplasia similar to that found in flat dysplasia. Adenocarcinoma may be
present in up to 20% of adenomas, usually in those greater than 2 cm in greatest dimension, or in lesions
with high-grade dysplasia
Adenomas with intestinalized epithelium are more likely to contain
carcinoma . However, the precise risk of progression of the lesions to carcinoma, or the rate at
which this process may occur, is uncertain. Because of these considerations, all adenomas should be
removed, in total, with negative margins, and thoroughly examined for focal malignant change.
4. Dysplasia in Hyperplastic Polyps
Hyperplastic polyps are among the most common type of gastric polyps
overall prevalence rate of approximately 0.1%. They are more common in patients with chronic gastritis,
being present in up to 10% of affected individuals
Grossly, they may be located anywhere in the
stomach, but are most common in the antrum. They show intestinal metaplasia in 15-25% of cases.
Dysplasia has been reported in 2% to 19% of polyps, particularly in those greater than 2 cm in size .
Adenocarcinoma may be present in up to 15% of polyps with dysplasia
Some authors have
suggested that an intestinal phenotype is more commonly seen in polyps with high-grade dysplasia or
5. Dysplasia in Fundic Gland Polyps
Fundic gland polyps (FGPs) are the second most common type of gastric polyp, with a prevalence rate
estimated between 0.1-1% of the general population
Although they were first described in FAP,
being present in 50-100% of affected patients
sporadic lesions are, in fact, more common
Most FGPs are small (less than 1 cm) sessile lesions located in the body of the stomach.
Approximately 40% of non-FAP patients have multiple FGPs, compared to 80-100% of FAP patients.
Dysplasia of the surface, and/or glandular, epithelium is present in up to 25% of
FAP-associated FGPs, but is extremely uncommon in sporadic FGPs
Dysplasia in FGPs is
generally low grade, and must be differentiated from reactive epithelial changes associated with
inflammation and surface erosion. The development of high-grade dysplasia or adenocarcinoma in these
lesions is extremely uncommon
Therefore, FGPs are associated with a minimal risk of malignancy
in both the general population and FAP patients. In fact, in Western countries, the risk of gastric
cancer in FAP patients is not increased compared to the general population .
Other polyposis syndromes such as juvenile polyposis, Cowden's disease, and
Cronkhite-Canada syndrome, may also involve the stomach, but polyps associated with these syndromes are
only rarely associated with dysplasia or carcinoma.
Table 1: Histologic Subtypes of Intestinal Metaplasia
|Intestinal Metaplasia Type ||Goblet Cells ||Mucinous Columnar Cells ||Other Cell types (Paneth, absorptive) ||Cancer Risk? ||Stomach ||BE|
|Not present ||Present ||No ||+ ||-/+|
|+/- ||Yes? ||+ ||+|
|+/- ||Yes? ||+ ||+|
Table 2: Revised Vienna Classification for Gastric Dysplasia
From Ref 48
|Diagnosis ||Suggested Management|
|Negative for dysplasia ||Optional follow-up|
|Indefinite for dysplasia ||Follow-up|
|Mucosal low-grade neoplasia|
|Followup or endoscopic resection|
|Mucosal high-grade neoplasia|
Suspicious for invasive carcinoma
|Endoscopic or surgical local resection (vs. close followup, rebiopsy)|
|Submucosal invasion by carcinoma ||Surgical resection|
Table 3: Histologic Features of Gastric Dysplasia
| || Dysplasia|
|Histologic Feature || Reactive || Indefinite || Low Grade ||High Grade|
|Surface maturation ||+ ||+/- ||- ||-|
|Villiform architecture ||+/- ||+/- ||+/- ||+/-|
|Mucin depletion ||+/- ||+ ||+ ||++|
|Irregular glands ||- ||+/- ||+ ||++|
|Glandular crowding ||- ||+/- ||+ ||++|
|Cribriform glands ||- ||- ||- ||+|
|Increased N/C ratio ||+/- ||+ ||++ ||+++|
|Nuclear pseudostratification ||- ||-/+ ||++ ||+++|
|Nuclear pleomorphism ||- ||+/- ||+ ||++|
|Increased mitotic rate ||+ ||+ ||+ ||++|
|Abnormal mitoses ||- ||- ||-/+ ||++|
|Inflammation ||++ ||+ ||+/- ||+/-|
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