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 1288

Gastric Pathology: An Updated

Review And Practical Approach

Gregory Y. Lauwers, MD
Amitabh Srivastava, MD

WEEKEND OF PATHOLOGY

AMERICAN SOCIETY FOR CLINICAL PATHOLOGY

33 W Monroe Ste 1600
Chicago, IL 60603
Program Content and Disclosure
The primary purpose of this activity is educational and the comments, opinions, and/or recommendations expressed by the faculty or authors are their own and
not those of the ASCP. There may be, on occasion, changes in faculty and program content.
In order to ensure balance, independence, objectivity, and scientific rigor in all its educational activities, and in accordance with ACCME Standards, the ASCP
requires all individuals in positions to influence and/or control the content of ASCP CME activities to disclose whether they do or do not have any relevant
financial relationships with proprietary entities producing health care goods or services that are discussed in the CME activities, with the exemption of non-profit
or government organizations and non-health care related companies. These relationships are reviewed and any identified conflicts of interest are resolved prior to
the activity. Faculty are asked to use generic names in any discussion of therapeutic options, to base patient care recommendations on scientific evidence, and
to base information regarding commercial products/services on scientific methods generally accepted by the medical community. All ASCP CME activities are
evaluated by participants for the presence of any commercial bias and this input is utilized for subsequent CME planning decisions.

The individuals below have responded that they have no relevant financial relationships with commercial interests to disclose:
Course Faculty:
Gregory Y. Lauwers, MD

Amitabh Srivastava, MD

Planning Committee/Commission Members and Staff:

Michele Best, MT (ASCP) Gene Siegal, MD, PhD, FASCP Michael D. McNeely, MD, FASCP
Michael Feldman, MD, PhD, FASCP Samuel Yousem, MD, FASCP Ann M. Tiehen, MT(ASCP)SBB
Cyril Fisher, MD, DSc, FASCP William "Wes" Schreiber, MD, FASCP Dawna Yeager, MEd, MT(ASCP)

Syed Hoda, MD, FASCP Michael Henry, MD, FASCP Timothy Uphoff, PhD, MT(ASCP)

Elizabeth Montgomery, MD, FASCP Peter Humphrey, MD, PhD, FASCP Sondra Moran, MT(ASCP)
Powers Peterson, MD, FASCP David Lewin, MD, FASCP
Peggy Soung-Sullivan, MD Sandra Nance, MS, MT(ASCP)SBB

The individuals below have disclosed the following financial relationships with commercial interests:
Course Faculty:

Planning Committee/Commission Members and Staff:

David Dabbs, MD, US Labs, DAKO, Consulting Fees Consulting

FASCP Ventana Medical

Myla-Lai-Goldman, MD, Labcorp, Salary, Stock Employee

FASCP GSK(Spouse)
Dennis O'Malley, MD, US Labs Salary Employee (Former)
FASCP
Robert Petras, MD, AmeriPath Inc, Salary, Stock Options Employee
FASCP Quest Diagnostics
Elizabeth Wagar, MD, Becton Dickinson Honorarium Scientific Advisory Bd
FASCP
Thomas Wright, MD, MediSpectra GSK Salary, Honorarium Medical Director &
FASCP Advisor

Copyright © 2008 by the American Society for Clinical Pathology

All Rights Reserved. Printed in the United States of America.
No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form
or by any means - electronic, mechanical, photocopying, recording, or otherwise -
1288
without the prior written permission of the publisher.
1288 Gastric Pathology: An Updated Review and Practical
Approach
Directors:
Gregory Y. Lauwers, MD, Massachusetts General Hospital and Harvard
Medical School, Boston, MA
Amitabh Srivastava, MD, Dartmouth Hitchcock Medical Center, Lebanon, NH

Effective communication with gastroenterologists and surgeons about gastric pathology

findings demands an understanding of current gastric pathology concepts. This course
will provide an extremely practical and useful review of gastric pathology.

This comprehensive overview will include:

• “Gastritis” and its various classifications

• The pivotal role of Helicobacter pylori in atrophic gastritis, its pathogenesis,
association with development of adenocarcinoma and gastric lymphoma of
MALT type
• Significance of gastric enterochromaffinlike hyperplasia and microcarcinoid in
the setting of autoimmune gastritis as well as potent H2 blocker therapy
• Drug-related gastritides such as NSAIDS-gastritis
• Histologic features of hyperplastic, fundic gland, and adenomatous polyps and
their clinical significance
• Pathology of the postoperative stomach with reflux gastritis and other
precancerous conditions

Drs. Lauwers and Srivastava will also provide a critical assessment of the diagnostic
criteria, significance, and appropriate follow-up of gastric epithelial dysplasia and its
relationship to gastric cancer.

Following this course, you will be able to:

• Understand current concepts and practical considerations in diagnostic gastric
pathology.
• Improve communication with gastroenterologists and surgeons about the nature
and significance of your pathologic findings.
 ASCP MIAMI WEEKEND of PATHOLOGY, APRIL 2008

GASTRIC PATHOLOGY:
AN UPDATED REVIEW AND PRACTICAL
APPROACH TO DIAGNOSIS

Gregory Y. Lauwers, M.D.

Associate Professor
Massachusetts General Hospital and Harvard Medical School
Boston, MA
e-mail:glauwers@partners.org

Amitabh Srivastava, MD
Assistant Professor
Dartmouth Hitchcock Medical Center and Darmouth Medical School
Lebanon, NH
e-mail: Amitabh.Srivastava@Hitchcock.org

1
HOW TO HANDLE GASTRIC BIOPSIES
A step wise evaluation of the different components of the gastric mucosa is of major importance in
the successful assessment of gastric biopsies.
Most information is obtained from multiple biopsy sampling of the gastric mucosa and knowing the
specific location of each biopsy sample. Proper, "on edge," orientation of the biopsy is also
required.

The following schema is suggested:

• Recognition of the topographic origin of the mucosa
ƒ (cardia, fundus/corpus, or antrum)
• Recognition of the basic process, i.e. inflammatory versus tumoral
• Localization of the inflammation
- surface only
- upper half of the lamina propria
(frequently concentrated at the level of the pit/foveolar junction)
- diffuse

• Glandular epithelial changes

- architectural
ƒ hypertrophy
ƒ atrophy
ƒ polypoid changes

- cytologic
ƒ mucin depletion
ƒ reactive alteration (see "gastric epithelial dysplasia")
- = metaplastic (see "Intestinal metaplasia")
ƒ = dysplastic (see "gastric epithelial dysplasia")
ƒ = viral cytopathic effect

• Changes in the lamina propria

• edema and hypervascularity
• increased cellularity
• fibrosis
• foreign bodies

• Typing of the inflammatory process

- acute inflammatory cells (PMNs)
- mixed infiltrate composed of PMNs,
plasma cells and lymphocytes
- chronic lymphoplasmacytic infiltrate
- eosinophils
- granulomas/giant cells

Although a plethora of classifications are available in the literature, we believe that a very simple

2
working classification can be established permitting simple consistent reporting of gastric biopsies.

A WORKING CLASSIFICATION OF GASTRITIS

Acute Gastrtitis
1) "non infectious"
NSAIDs
alcohol
stress
corrosive gastritis
Graft versus host disease
Radiation
2) "infectious"
miscellaneous. (immunosuppressed pts)
phlegmonous (rare)

Chronic Gastritis
1) H. Pylori Gastritis (Antral or Diffuse pangastritis type)
2) Autoimmune Gastritis
3) Granulomatous Gastritis
a) "non infectious"
Sarcoid
Crohn’s
b) "infectious"
syphilis
tuberculosis
parasitic (anisakis/cryptosporidium)
mycosis (candida/aspergillus)

Miscellaneous Distinctive Types:

• Reactive/chemical gastropathy (post-operative stomach, bile reflux)
• Eosinophilic gastritis
• Lymphocytic gastritis
• Collagenous gastritis
• Ischemic gastritis

3
CASE 1: A 35-year-old male is referred for dyspepsia, severe, of several weeks duration. Acid
suppression is ineffective. Upper GI endoscopy reveals a severely inflamed gastric antrum with
an irregular ulcer on the lesser curvature. Urease test in the office is positive. Biopsies of both
the ulcer and the non-ulcer mucosa are sent to pathology.

Diagnosis: H. pylori gastritis with extranodal marginal zone B cell lymphoma, (MALT
lymphoma).

Morphology
The antral mucosal biopsy reveals a regenerative epithelium, with neutrophilic infiltration of the
neck and pit regions, neutrophils extending into the epithelium and filling the pit lumen. High
power examination reveals large numbers of curvilinear organisms within the mucin at the pit
surface. The lamina propria contains a moderate number of plasma cells, and deep basal
lymphoid aggregates with reactive germinal centers are seen. The diagnosis is Helicobacter
pylori gastritis. The biopsy from the region of the ulcer shows a similar acute inflammatory
process involving the pits. However, the lamina proprial infiltrate is marked, with effacement of
the normal glandular compartment by a polymorphous infiltrate of lymphoid cells. Within the
infiltrate are numerous mature appearing plasma cells and lymphocytes, plus a population of
mononuclear cells with a slightly cleaved nucleus and abundant clear cytoplasm – marginal zone
cells (centrocyte-like cells). The infiltrate is vaguely nodular, and extends into and destroys
adjacent glandular structures (lymphoepithelial lesions). Immunohistochemistry reveals a
predominantly B cell population, with light chain restriction, consistent with ?MALT marginal
zone B cell lymphoma.

H. Pylori gastritis – overview

Helicobacter infection is the most common cause of chronic gastritis in the USA. The diagnosis
can be made when the characteristic changes are seen on H+E, but special stains may help in
visualizing the organism. At the MGH we use an immunostain on biopsies suspicious for
H.pylori infection. Other stains include Giemsa and Genta stains, or Warthin-Starry stain,
(considered the gold standard, but difficult and expensive. Immunohistochemistry is a sensitive
method in cases where few organisms are present, a common phenomenon now where most
patients are not biopsied before at least one course of antibiotics.
Helicobacter pylori is a Gram-negative microaerophilic curved bacterium with a worldwide
distribution (it is estimated that 50% of the world population is infected). Infection rates vary,
with early and widespread infection occurring in developing countries in the setting of crowding
and low socioeconomic conditions (80% of these populations will carry the bacterium by age
20). The method of transmission of the bacillus is unclear, but fecal-oral, oral-oral, and water-
borne spreads are possibilities. An insect vector or animal reservoir cannot be ruled out.
After infection the organism colonizes the superficial gastric mucosa, eliciting an acute
superficial gastritis that evolves over weeks into chronic active gastritis, which may persist for
life.
.
The organism
The stomach is an inhospitable home for a bacterium. The organism, to allow it to colonize and

4
persist on the gastric mucosa, must produce certain virulence factors. The basic toxins are
common to all strains, facilitating survival.
The organism is motile, possessing 4-6 flagellae allowing it to move through the mucin
protecting the mucosal surface. Once the organism penetrates through to the epithelium it must
adhere to stay and colonize. For this they produce adhesins, one receptor for which appears to be
the Lewis B blood group antigen, expressed on gastric foveolar cells. The production of urease, a
powerful enzyme that forms ammonia by hydrolysis of urea raises the pH of the bacterium’s
immediate environment allowing it to survive in the stomach’s acid environment
H. Pylori can be divided into 2 types based on possession of other virulence factors; CagA and
VacA, are present in type I strains.
CagA is a surface protein associated with cytotoxin producing strains; it is a powerful antigen.
All patients with duodenal ulcer have antibodies to CagA, with levels varying with the severity
of disease. At the morphological level antibodies to CagA are associated with higher degrees of
neutrophilic infiltration. This may be in part related to upregulation of IL-8 (a mediator of
neutrophilic migration) in patients with CagA+ strains. However, the role of CagA is not
understood; most cytotoxin- (type II) strains do not harbor the gene for CagA, but removal of
CagA gene from toxin-producing strains does not affect toxicity
VacA is a high molecular weight cytotoxic protein causing vacuolization of epithelial cells in
tissue culture, and ulceration of mucosa in mice. All strains carry the gene for VacA, but the
protein is only formed in type I organisms.
.
The host
In humans, H. Pylori infection is associated with several gastric pathologies. 100% of duodenal
ulcer patients are infected, as are >90% of gastric ulcer patients. H. Pylori infection is associated
with an approximately 6-fold increase in gastric adenocarcinomas, and also predisposes to
lymphoma. Non-ulcer dyspepsia may correlate with the neutrophilic infiltrate in chronically
infected patients.
Gastritis may be divided into diffuse antral and multifocal atrophic types based on
morphology.
In antral predominant gastritis, as the name implies, the chronic infiltrate involves
predominantly the antrum, with initially a superficial chronic inflammatory infiltrate in the
lamina propria with prominent plasmacytosis, and evolution of deep lymphoid follicles (a
histological feature strongly associated with helicobacter infection). Neutrophils are seen
clustered around and infiltrating into the deep pit epithelium – “pititis”. The surface epithelium
may be degenerate, with mucin depletion, dishesiveness, and some increase in intraepithelial
lymphocytes. This type of gastritis is associated with ulcer disease. In gastric ulcer disease, the
gastritis will always extend proximal to the ulcer.
In diffuse pangastritis, glandular atrophy with intestinal metaplasia supervenes as the
inflammatory component recedes, leading to multifocal atrophic gastritis (MAG). Evidence of
infection with helicobacter is found in >75% of cases. This form is associated with early age of
infection, and high risk of carcinoma development. The geographic distribution of MAG is
identical to that of gastric adenocarcinoma. The histological appearances differ from the diffuse
form by virtue of the presence of intestinal metaplasia and glandular atrophy. With loss of glands
the first finding is an increase in inter- glandular stroma. Subsequently the deep compartment is

5
replaced by mucous neck cells, and later by intestinal-type mucosa, the extent of which reflects
the duration of disease. As time goes on the inflammatory component diminishes, leaving finally
a picture of gastric atrophy. The pathological features are similar to those seen in autoimmune
disease, but the distribution within the stomach and the lack of ECl-cell hyperplasia should alert
the pathologist to the correct interpretation.

Variant forms of helicobacter gastritis

Other helicobacter species
Not all helicobacter infections are caused by H. pylori. Occasionally on special stains you will
see a tightly coiled spiral bacterium in small clusters in association with a mild chronic gastritis.
This organism is H. heilmanii (previously known as Gastrospirillum hominis). This
multispiralled multiflagellate organism has been identified in many mammals, including cats,
dogs, and baboons. It is thought that household pets may be the source of this infection, which is
considered by some to be a zoonosis. The prevalence is much lower than H. pylori, at ~0.5% in
developed countries. The gastritis is often less severe and antibiotics should eradicate the
organism.
Treated H. pylori gastritis
With antibiotic therapy there is rapid loss (days) of visible organisms. Acute inflammation is
first to disappear (within weeks). Chronic inflammation regresses over months-years. Often,
lymphoid follicles will remain as the historical evidence of helicobacter infection. The presence
of lymphoid follicles (not the triangular-shaped mainly T cell lymphoid aggregates which are
completely non-specific) is associated with past helicobacter infection in 95% of cases. The
other main cause is autoimmune gastritis.
With treatment the pattern of involvement may also change, with decrease in antral gastritis, and
increased proximal involvement, including the “cardia”.
Occasionally after treatment there continues to be symptoms, but histochemical stains reveal
only coccoid bacteria – these are helicobacter, as can be confirmed with immunohistochemistry,
showing morphological changes secondary to treatment effect.
A further common associated morphological change in treated gastritis is the tufting of parietal
cells, indicative of strong acid suppression, a usual component of treatment.
Hypertrophic Lymphocytic Gastritis
Hypertrophy of the gastric folds is well known to be associated with Menetrier’s disease.
However, the commoner association of giant folds is with chronic gastritis, particularly
helicobacter-related. Usually the affected area is not the body/fundic restricted picture of
Menetrier’s disease, and protein-losing enteropathy is rare. The endoscopist may see thickened
mucosal folds with round ulcer-like areas, the so-called “varioliform gastritis”; urease test is
positive, and morphologically there is a chronic gastritis with numerous intraepithelial
lymphocytes, all CD3+ CD8+ T cells.

Extranodal marginal zone B cell lymphoma [MALT (Mucosa-Associated Lymphoid Tissue)

Type]

Overview
In the mid-1980s Isaacson and Wright suggested that tumors in extranodal sites, particularly

6
mucosal in nature, composed of small lymphoid cells and associated with germinal centers and
plasma cells, might derive from Mucosal-Associated Lymphoid Tissue (MALT). This organized
extranodal lymphoid tissue is frequent and normal at many gastrointestinal sites, particularly the
small intestine, and is intimately involved in antigen processing. Low-grade tumors resembling
MALT were previously considered “pseudolymphoma”. These were renamed MALToma, and
most recently under the REAL lymphoma classification as extranodal marginal zone B-cell
lymphoma. These are low grade lymphomas which may be cured by local resection and at some
sites such as the stomach, may regress following antiobiotic therapy to eradicate H.pylori..
The stomach is the most frequent site of extranodal lymphoma., the overwhelming majority of
which are B cell lymphoma. Fifty percent of gastric lymphomas are low grade MALT
lymphoma, and 50% are diffuse large B cell lymphoma; the proportion of the latter that arose
from the former is unknown, but probably high.

Morphology of MALToma
The characteristic small cell of these lymphomas is the marginal zone cell (MZC). The marginal
zone is present in the outer mantle regions of Peyer’s patches, mesenteric lymph nodes and
splenic white pulp. MZC are B cells, small to medium size, with an irregular nucleus, resembling
germinal center centrocytes (hence centrocyte-like cell), but with more abundant pale cytoplasm.
Slightly larger than the MZC is the monocytoid B cells, with more nuclear irregularity and more
cytoplasm, like parafollicular B cells. The cellular infiltrate in MALToma is characteristically
heterogeneous, with small lymphocytes, marginal zone cells, monocytoid B-cells and plasma
cells. When present in mucosa the MALT lymphomas show a characteristic
lymphoepitheliotropism. The B cells infiltrate the epithelium, gradually destroyed the glandular
compartment. These foci have been termed lymphoepithelial lesions, and are one of the most
useful histological features in mucosal biopsy. Lymphoid follicles are often prominent. Usually
these are benign, but may become infiltrated by the neoplastic cells, leaving behind the nodular
architecture still identifiable by reticulin stain (follicular colonization). A number of large cells
are usually present, immunoblastic or centroblastic; there is no clear cut-off number of large
cells to allow confident diagnosis of high grade MALT lymphoma. Once sheets of large cells are
present, the diagnosis of diffuse large cell lymphoma is appropriate. Some but not all large cell
lymphomas will show residual areas of low grade MALT lymphoma.

Immunohistochemistry confirms B cell differentiation (the neoplastic cells express CD19+

CD20+, CD22+). SIg is present (M>G>A), and cytoplasmic immunoglobulin indicates
plasmacytic differentiation (also confirmed by CD79a expression). Light chain restriction is
seen. CD5 and CD10 are not expressed; this is helpful in excluding SLL, mantle cell lymphoma
and follicular lymphoma, all of which are in the morphological differential diagnosis. CD43 is
co-expressed on CD20 positive B-cells in about 50% of cases.

Pathogenesis
The stomach has no normal MALT, unlike the small and large intestine. Under conditions of
chronic antigenic stimulation lymphoid follicles appear. The commonest antigenic stimulus is
Helicobacter infection; reported rates of H.pylori infection in gastric MALT lymphoma exceed
>90% in some countries. Laboratory studies have shown that the proliferation of the B-cells

7
from MALTomas in cell culture experiments is dependent on T cells undergoing antigenic
stimulation by Helicobacter. The host immune response to H. pylori induces and sustains an
actively proliferating B-cell population. However, the H. pylori-sensitive cell is a T cell, not a B
cell. The B cells in fact express autoantibodies, not antibodies to Helicobacter. The B-cell clone
which may emerge from this chronic antigenic stimulation will express immunoglobulin with
autoantigenic properties, precursors of which are frequently found in chronic H. pylori gastritis.
The sensitivity to the Helicobacter antigens to stimulate lymphoid response varies with the stage
of lymphoma. In the early stage of tumor formation the lymphoma remains confined to the
mucosa and is exquisitely sensitive to H. Pylori mediated immunological stimulation. Once
tumor progression occurs, with deep invasion or dissemination to lymph nodes, the dependence
on antigenic stimulation weakens and an autonomous lymphoproliferative state sets in. At this
stage antibiotics may not eradicate the disease. With progression to large cell lymphoma, antigen
sensitivity is lost. This translates at a practical level as the eradication of H. Pylori infection
being effective in eradicating lymphoma in up to 79% of reported cases. Only in some series has
relapse been documented to be associated with progression to large cell lymphoma.

Genetic analysis has shown a translocation t(11;18)(q21;q21) in 25-35% of gastric MALToma.

The translocation results in chimeric fusion of an apoptosis inhibitor (API2) with the MALT1
gene, a paracaspase that participates in NFκB activation. The fusion protein has been shown to
activate NFκB, which is a transcription factor for many survival genes. The presence of this
translocation is associated with antibiotic resistance, and more aggressive biological behavior.
The translocation t(1;14)(p22;q32) is a rare translocation exclusively found in MALToma. It
causes abnormal nuclear accumulation of BCL10, an apoptosis regulator. BCL10 also interacts
with MALT1 to cause NFκB activation. In the absence of this translocation BCL10 nuclear
accumulation in MALToma may be seen in more aggressive tumors. C-myc gene abnormalities,
p53 and p16 inactivation may correlate with large cell transformation. Trisomy 3 is also
reported. Immunoglobulin variable region analysis of these lymphomas is most consistent with a
post-germinal center stage of B cell development. Light chain restriction can also be identified
using PCR based gene rearrangement studies.

Histological scoring scheme for diagnosis of gastric MALT lymphoma versus gastritis
(from Wotherspoon et al.)
Grade Diagnostic category Histological feature
0 Normal Scattered plasma cells in
lamina propria. No
lymphoid follicles
1 Chronic gastritis Small clusters of
mononuclear cells in lamina
propria. No follicles or
lymphoepithelial lesions
(LEL)
2 Chronic follicular gastritis Prominent follicles with
mantle zone and plasma
cells. No LELs

8
3 Atypical lymphoid Lymphoid follicles
infiltrate, probably benign surrounded by small
lymphocytes with
occasional extension into
epithelium
4 Atypical infiltrate, probably Lymphoid follicles
lymphoma surrounded by marginal
zone cells that infiltrate into
epithelium in small clusters
5 Low grade MALT Diffuse infiltrates of
lymphoma marginal zone cells with
prominent LELs

Lecture Outline
Case
Diagnosis
Helicobacter-related pathology
Antral Predominant Gastritis
Diffuse Pangastritis & Multifocal Atrophic Gastritis
Variant forms
H. heilmanii
Treated H. pylori
Lymphocytic Gastritis
Lymphoma
Helicobacter and lymphoma – epidemiology
Morphology
Gastritis vs lymphoma
Immunohistochemistry
Differential diagnosis

9
CASE 2: A 47-year-old female presents with vague abdominal pain and hematemesis.
Upper GI endoscopy reveals an ulcer in the body of the stomach, greater curvature. Biopsy
is non-diagnostic but endoscopic ultrasound reveals a 5cm intramural mass. Partial
gastrectomy is performed. The 35mm slides are from the resection specimen.

Diagnosis: Gastrointestinal stromal tumor, epithelioid-type, at low risk for aggressive behavior
The 35mm slides are from the resection specimen.

Pathology
A partial gastrectomy specimen was received. On opening there was a 5x3x2cm mass on the
greater curvature of the stomach, infiltrating and destroying the muscle wall, with extension into
the mucosa with ulceration. The tumor had a pushing border, and a smooth contour extending
into the subserosal soft tissue, bulging but not invading grossly through the serosa.
Histologically the tumor was composed of spindle and epithelioid cells; the spindle cells had
blunt ended nuclei and perinuclear vacuoles. The cytoplasm was eosinophilic and abundant. The
epithelioid cells had rounded nuclei and abundant cytoplasm. Nucleoli were not prominent. Little
pleomorphism or hyperchromatism was seen, cellularity was moderate. Mitotic rate was 1/50hpf,
and necrosis was absent. The tumor was richly vascular. Cellular areas were interspersed with
paucicellular areas of edema and hyalinization. The cells formed short interdigitating fascicles.

Immunohistochemistry was performed using a panel of antibodies, and the tumor cells were
found to express vimentin, CD34 and CD117 strongly and diffusely. Desmin and smooth muscle
actin were seen in scattered cells, and tumor cells did not express S100. No keratin expression
was seen.

Tissue was sent for analysis for genetic abnormalities involving the c-kit gene. A point mutation
was identified at exon 11.

Diagnosis: GIST, completely excised.

Prognosis: excellent.
Biological behavior: low risk for aggressive behavior

Gastric GIST
Epidemiology:
GISTs are rare tumors, accounting for 1% of all GI malignancies. However, they are the
commonest mesenchymal tumor of the gastrointestinal tract. They occur within a wide age
range, but most are diagnosed in patients between 40 and 70 years of age. Over 50% of GIST
involve the stomach; of these, 90% show a biologically indolent behavior. No definite gender
predominance is seen.
Presentation is the same as for other gastric masses. The commonest clinical presentation (about
50%) is with bleeding, due to ulceration, resulting in hematemesis, melena, or iron-deficiency
anemia. Ulcer-associated pain may also occur, and is more likely to occur in malignant tumors.
Anorexia, nausea, vomiting and palpable mass may also occur. Upper GI endoscopy is usually

10
non-specific, and other studies, CT, MRI, barium, or ultrasound are needed to visualize the
tumor.
GIST are mainly intramural in location; small tumors may be entirely submucosal or within the
muscularis propria; larger tumors extend through both, and may extend into perigastric tissues,
occasionally in a dumbbell configuration. Occasional tumors are located entirely extramurally,
projecting into the omentum, usually from the greater curvature. They vary in size from
millimeters to >40cms, but most are between 3 and 15cm. The cut-surface is solid tan-white,
without the whorled cut surface associated with smooth muscle tumors; many will contain areas
of cystification, hemorrhage, or necrosis, regardless of biological behavior. The tumor edge is
most often well circumscribed, and the consistency is rubbery. Many tumors will show overlying
mucosal ulceration. The gross appearance does not help in determining malignancy, although
definite sarcomas often will have a multinodular appearance. Most gastric GIST are found within
the body of the stomach; antral and proximal gastric tumors are more likely to be epithelioid
than spindled in morphology, with benign in the former areas, and malignant forms in the latter.
These tumors, though well circumscribed, are not usually encapsulated, although a fibrous
pseudocapsule may be seen. Lobulation is common. Large tumors often show areas of central
cystification due to tumor liquefaction, which also may result in acellular areas of edema
alternating with cellular tumor foci, organized as short fascicles forming various architectural
patterns, including herringbone, storiform, organoid and palisades. Areas of hyalinization, dense
collagenization, hemorrhages with hemosiderin deposition are also frequent. Two main
microscopic subtypes are seen, the spindle and epithelioid forms. Some tumors may show areas
of both; often one predominates. The spindle cells have blunt-ended, sometimes contracted
nuclei, and characteristic perinuclear vacuoles. These spindle cells may form very spectacular
palisades; these palisades and perinuclear vacuoles are rarely seen in GIST outside of the
stomach. The epithelioid cells form organoid clusters of large cells with eosinophilic
cytoplasm. Some may appear to have clear cytoplasm, apart from a perinuclear rim of
eosinophilia. This is an artefact of processing. These tumors in the past were known as
leiomyoblastomas. GISTs are vascular, and the amount of stroma is variable. Within the stroma
eosinophilic globules may be seen. These are PAS positive, diastase resistant, and are blue on
Masson’s trichrome stain. They represent extracellular aggregates of collagen fibers and are
known as skeinoid fibersö. They are particularly associated with small intestinal tumors, and the
rare GIST with autonomic nerve features (GANT), but they may be seen in gastric GISTs as
well.
Ultrastructural analysis confirms the dual differentiation in the tumor cells, with interdigitating
filopodia-like cytoplasmic processes and filaments, similar to interstitial cells of Cajal, may
show skeinoid fibers as tangled aggregates of collagen, or may show the dense core granules and
microtubules of a GANT. However, EM is rarely necessary for diagnosis.

Histogenesis.
The recently accepted line of differentiation of GISTs is the interstitial cell of Cajal (ICC). This
cell functions as the pacemaker in GI motility. It has features of myogenic and neural
differentiation and is normally located is close proximity to the enteric nervous system. These
cells, which have long cytoplasmic processes, are found surrounding the myenteric plexus and
within the muscularis propria, and connect with ganglion cells, nerves, and smooth muscle cells

11
by gap junctions. The dual differentiation explains the confusion in nomenclature of GISTs in
the past, as well as their immunohistochemical profile.
The protein, c-kit (CD117), is a type III receptor tyrosine kinase which is the ligand for stem cell
factor. The gene is located on chromosome 4; c-kit is crucial for fetal development of germ
cells, melanocytes, erythrocytes, mast cells and interstitial cells of Cajal. In the gastrointestinal
tract c-kit (CD117) is expressed only on mast cells and interstitial cells of Cajal.
Eighty-100% of GIST will express CD117. The location of GIST exactly parallels the
distribution of interstitial cells; the ultrastructural appearances of ICC and GIST tumor cell is
very similar. These are the main points of evidence for the theory of GIST histogenesis from ICC
Other immunohistochemical markers of GIST include CD34, a glycoprotein found on
hemopoietic cells, endothelium and some fibroblasts. GISTs will express CD34 in 70-80% of
cases. Actin, both muscle and smooth muscle specific, is expressed in >50% of cases, and
desmin in upto 50%. S100 is also expressed in upto 40%, and vimentin in most cases.
Mutational Analysis.
Somatic activating mutations in exon 11 of the c-Kit gene (coding for the inner juxtamembrane
region of the protein) were described in 1998 as being present in 5 of 6 GIST. Germline
mutations of c-kit have been identified in a kindred developing multiple GIST. Mutations have
been identified in over 85% of GISTs studied, and further point mutations (all activating) have
been found, including in exon 9 (extracellular domain), and exon13 (kinase domain). Although
originally suggested as a marker for malignant behavior, this has not held up upon further study.
However, some data has suggested that the type of mutation may help predict response to
chemotherapy, particularily with STI571 (Gleevec). The presence of a mutation in the binding
region of c-kit (exon 9) will render the drug inactive. 5-10% of these tumors may have mutations
in PDGFR-alpha, instead of c-kit. These tumors are often epithelioid in morphology and have
activation of the same tyrosine kinase and will thus be responsive to Gleevec.
Predictive features.
This area has generated great controversy. Experts in these tumors are divided into those that feel
most GISTs in general should be considered malignant, sarcomas, and those that feel that
assigning benignity to many tumors is possible. In view of this divide, no definitive classification
is possible. I will try to give a working scheme, which should help classify most tumors. In
general however, I tend to view these tumors as showing a continuum in terms of behavior,
rather than forming discrete groups of benign or malignant tumors. A feature which GI
pathologists tend to be more aware of than soft tissue pathologists is the difference in location. A
discussion on small intestinal tumors would require a much lower threshold for overt malignancy
than the stomach. This behavioral difference is not well understood.
The features most authors agree on being important are size and mitotic rate. Less often used, but
still crucial is the state of the margins. Other features, including cellularity, pleomorphism,
necrosis are of little use. Five cm is the standard size cutoff for separating definite high-grade
from equivocal or borderline. The lower limit is less easy to define, as metastasis from tumors as
small as 2cm has been recorded. The risk of metastasis rises as tumors enlarge. In one study
metastasis occurred in only 1.5% of gastric GIST (all types) <5.5cm, with 25% metastasis rate in
tumors >6cm. This size criterion however, is most sensitive in GIST with other histological
criteria for malignancy; i.e. large mitotically active GIST metastasize much more frequently than
small mitotically inactive GIST.

12
Mitotic rate, despite all the reported problems of variability, remains an important prognostic
indicator. Many studies with variable numbers are available, but in general after counting at least
50 high power fields, a count of <1/50hpf is considered low, 1-5 borderline, and > 5/50hpf is
significant. Above 5/50hpf there is a significant chance of metastasis, albeit possibly low ( in the
approximately 10% region). As mitotic rate climbs, so does rate of metastasis. At a rate of
50mitoses/50hpf one study reported 100% metastases (Byard). Others reported a metastatic rate
of 100% at 25mitoses/50hpf (Appelman, Ranchod) . Ancillary markers of proliferative activity
such as Ki67, PCNA, and S phase analysis on flow cytometry all corroborate that proliferation is
associated with aggressive behavior. Similarly aneuploidy correlates with poor prognosis,
although it will not reliably distinguish benign from malignant cases. Metastasis may be local
peritoneal spread, or to the liver. Cellularity and individual cell necrosis tend to be prominent in
large tumors or those with high mitotic rate, indicating malignancy, but alone these features are
not of prognostic value..
A large problem with these tumors is that there are reports of 2cm tumors or GIST without
mitoses recurring or possibly metastasizing, so caution in signout and prognostication is
advisable. The consensus classification for assigning risk of aggressive behavior is now widely
used. The treatment is excision. At present no adjuvant chemotherapy is used. In metastatic
disease, a combination of surgery and chemotherapy is appropriate. In large, unresectable
lesions, a neoadjuvant approach may be used to downstage tumors and make them amenable to
surgery.
A few recent developments need to be highlighted here. First, with the advent of neoadjuvant
therapy for esophageal adenocarcinoma, pathologists are submitting more and more sections
from the resected esophagogastrectomy specimens for proper staging. Small incidental GISTs
are thus being increasingly recognized in these specimens. These have been shown to behave in
a benign fashion. Second, the presence of multiple GISTs, particularly if there is evidence of
hyperplasia of the interstitial cells of Cajal, should raise suspicious of NF-1. These GISTs
express c-kit on IHC but do not harbor mutations and are thus behave in an indolent manner
unlike their non-syndromic counterparts. Finally, the phenomenon of de-differentiation has
recently been desribed in GISTs. Thus, a pleomorphic sarcoma in the stomach is most likely an
example of a de-differentiated GIST rather than a primary high-grade mesenchymal sarcoma.
The de-differentiated areas harbor the same c-kit mutation as the background GIST but lose any
morphological or immunophenotypic resemblance to the parent lesion. Extensive sampling of
the tumor is paramount in such examples.
The differential diagnosis for this tumor is relatively short. Leiomyoma and leiomyosarcoma will
not express CD117, and are exceedingly rare in the stomach. Almost all leiomyomas arise in the
cardia, and most are very small, similar to the more common esophageal leiomyoma. Rare
tumors grow large enough to cause obstruction. Morphologically they well-circumscribed
tumors composed of whorls and fascicles of mature smooth muscle cells. Occasionally
epithelioid tumors need differentiation from diffuse poorly differentiated carcinoma û
Immunohistochemistry should help. Metastatic melanoma might similarly be confused
morphologically, but usually not clinically, and some metastatic carcinomas may have a spindled
morphology. Rarely these tumors are considered vascular in origin, due to their high vascularity,
hemorrhage and edema. Stomach is also a common site for schwannomas, glomus tumors and
inflammatory myofibroblastic tumors of the GI tract. Schwannomas are characterized by a

13
spindle cell proliferation and a prominent cuff of lymphoid infiltrate at the periphery of the
lesion. A diffuse, strong S-100 positivity is typical as in other sites. The stomach is virtually the
only site for glomus tumors of the GI tract and these may be confused with epithelioid GISTs or
with carcinoids. Like the soft tissue counterparts, these tumors are positive for myoid markers
(smooth muscle actin, muscle specific actin) but are negative for c-kit, CD34 and S-100.
Inflammatory myofibroblastic tumors have a prominent plasmacytic infiltrate and show a
myofibroblastic phenotype on immunohistochemistry (desmin negative, smooth muscle actin
positive); about 50-60% express ALK-1 protein as well. While these tumors are rare, it is
important to recognize them because of their invariably benign outcome.

Lecture Outline
Case
Diagnosis
Epidemiology of GIST
Morphology of GIST
Immunohistochemical features
Cytogenetics
Definition of GIST
Prognostic factors in GIST
Good prognosis GIST
Poor prognosis GIST
Interstitial cells of Cajal
ICC as cell of GIST
c-kit
Gleevec
Treatment of GIST
Recent advances (incidental GISTs at GE junction, association with NF-1, de-
differentiation)
Differential diagnosis of GIST

14
Case 3: A 53-year-old woman presents with anorexia and fatigue. Her CBC reveals anemia
with macrocytosis. Upper endoscopy reveals a loss of rugal folds in the body/fundic region
of the stomach and a sessile 1cm polyp in the body region. Further testing shows her to
have anti-parietal cell and anti-intrinsic factor antibodies and a high serum gastrin level.
Both basal and stimulated gastric acid secretions are reduced to achlorhydric levels, and
her Schilling test is abnormal, but correctable by intrinsic factor. She undergoes local
resection of the polyp with a sleeve of mucosa, and subsequently a distal gastrectomy is
performed.

Diagnosis: Autoimmune Chronic Atrophic Gastritis With Neuroendocrine Hyperplasia

And Gastric Low Grade (well differentiated) Neuroendocrine (carcinoid) Tumor
Formation.
The 35mm slides are from the polyp and the surrounding body mucosa.

The biopsy from the polyp reveals a monotonous infiltrate of small round cells with polygonal
shape, amphophilic to clear cytoplasma and round small nuclei with stippled chromatin. The
cells are arrayed in lines, acini, with small and larger nests. Little intervening stroma is seen, but
a fine vascular network is apparent. The tumor is well circumscribed, but not encapsulated, with
a peripheral rim of edematous stroma with a brisk mononuclear infiltrate. The tumor expands the
overlying mucosa without ulceration, and extends into the submucosa. The findings are of a
well-differentiated endocrine (carcinoid) tumor.

The flat mucosal biopsy shows a thin mucosa with elongated pits and glands composed of
neutral mucin-producing cells, side by side with intestinal type glands with goblet cells and
occasional paneth cells. The lamina propria contains a moderate plasmacytic infiltrate. The basal
portion of the glands appears cellular. This area is seen to contain many small acini and nodules
of small polygonal cells with clear cytoplasm and a nucleus with finely dispersed chromatin. In
some areas the nodules appear fused together. No mitoses, necrosis, or pleomorphism is seen.
The proliferation is confined to the glandular region, and does not extend into the submucosa.
The diagnosis is chronic atrophic gastritis with ECl-cell endocrine hyperplasia and
dysplasia.

Autoimmune gastric atrophy with pernicious anemia

Type A autoimmune chronic gastritis is characterized by achlorhydria because of destruction of
the parietal cells of the stomach. This is mirrored histologically in the predominant involvement
of the gastric body/fundic mucosa where parietal cells are frequent, and sparing of the antral
mucosa. Many of these patients have circulating autoantibodies directed against the microsomes
of parietal cells. The parietal cells normally secrete acid in the form of hydrochloric acid, but
also secrete intrinsic factor. Intrinsic factor is necessary to facilitate the absorption of vitamin
B12 in the ileum. Intrinsic factor autoantibodies are present in serum in 55%-60% patients with
autoimmune gastritis. Thus, a proportion of patients with Type A chronic gastritis will develop
pernicious anemia due to vitamin B12 deficiency. The accompanying gastric atrophy is slow in
evolving and often clinically silent.

15
Morphology
Histological examination of the mucosa reveals an intense lymphoplasmacytic infiltrate of the
lamina propria of the body/fundic mucosa. The infiltrate lies deep, and may contain lymphoid
follicles. Often the infiltrate hugs the deep glands, and destruction of individual parietal cells can
be appreciated, Some polymorphonuclear cells are often seen. At this point antral biopsies will
show very minor inflammatory changes. As the destruction continues the glands disappear, and
are replaced by neutral mucin-producing glands (pseudopyloric metaplasia). Subsequently
intestinal metaplasia supervenes, and with time, the inflammation recedes, leaving complete
gastric atrophy, with extensive intestinal metaplasia. This may be apparent at endoscopy where
the mucosa of the body/fundus appears markedly thinned with pebble-like elevations of
intestinal metaplasia. The pyloric metaplasia may be identified as metaplastic by
immunohistochemistry due to the absence of G cells. With the reduction in acid production,
gastrin produced from the antral G-cells is stimulated. In addition >20% of patients will show
proliferation of small nodules, ribbons and tubules within the deep comparment of the
body/fundic mucosa, consisting of small cells with clear cytoplasm and round nuclei with finely
dispersed chromatin. A subset of these patients will have gastric NET (carcinoids).

Gastric NET tumors

Gastric NET represent 6% of all GI-NET. However, their incidence appears to be on the
rise. Whether this represents a real increase, or a result of more frequent endoscopy is unclear at
this time. Furthermore, the influence of widespread use of pharmacological gastric acid
suppression agents in the development of gastric NET is equally uncertain. Localized disease is
found in 45% of patients, ~20% show regional spread, and ~20% distant spread at the time of
diagnosis. Although several different NE cell types are located in the stomach, 70% of tumors
are derived from ECL cells. Rare tumors may develop from G cells or EC cells.
Gastric NET (G-NET) are divided into 4 general groups. Types I and II arise in a
background of hypergastrinemia, type I associated with chronic atrophic gastritis and type II
with ZES/MEN I. Both type I and II NET are derived from ECL cells. Types III and IV arise in
patients with normal serum gastrin levels. Type III, are sporadic G-NET . These are generally
aggressive tumors, large in size and are derived mainly from gastric EC cells. Ectopic hormone
production, such as ACTH and growth hormone, may be secreted in these tumors as well. This
group also includes the rare antro-pyloric gastrinomas, which, although aggressive, are usually
quite small in size. Type IV tumors represent a heterogeneous group of tumors that show
evidence of multidirectional differentiation, such as a combination of adenocarcinoma and NET.

A new subgroup may need to be added to the category of hypergastrinemia associated

gastric NET. Gastric NET in Japan are not associated with atrophic gastritis or ZES, but show
strong correlation with Helicobacter pylori infection and gastritis. Helicobacter infection leads to
downregulation of D-cells. The production of somatostatin by these cells is normally the final
common pathway in controlling acid production. In the absence of negative feedback, gastrin
levels and acid production rise; peptic ulceration is one result. NET from ECL cells may be
another. Experimental evidence links helicobacter infections directly to gastric NET formation in

16
gerbils.

Type 1 gastric NET (GI-NET associated with type A autoimmune chronic gastritis (CG-A)
and pernicious anemia)
General Comments
The first report of a gastric NET associated with pernicious anemia appeared in 1952.
Atrophic chronic gastritis (autoimmune gastritis) is characterized by the presence of circulating
autoantibodies directed against microsomes of parietal cells with selective destruction of the
acid-producing cells in the body/fundic of the stomach. Parietal cells normally secrete acid in
the form of hydrochloric acid, but also secrete intrinsic factor. Intrinsic factor autoantibodies are
present in the serum of 55%-60% of patients with autoimmune gastritis, and a proportion of
patients with Type A chronic gastritis will also develop pernicious anemia due to Vitamin B12
deficiency.
Pathogenesis
Gastrin is the primary neuropeptide involved in gastric acid secretion. It is released from
antral and duodenal G cells in response to gastric distention due to food ingestion. Gastrin has a
minor direct effect on parietal cells, causing release of H+, but, the major action is stimulation of
enterochromaffin-like (ECL) cells. ECL cells are the main neuroendocrine cell of the stomach
comprising 70% of the total amount of gastric NE- cells. They are located mainly in the
body/fundic glands, in close proximity to parietal cells. Recently, an antibody to vesicular
membrane transporter-2 (VMAT-2) has been identified as a marker for ECL cells. ECL cells are
scattered within the deep portions of oxyntic mucosa. ECL cells are of the ôclosedö type; that is,
they do not communicate with the lumen of the glands but are in close contact with the bases of
parietal and chief cells. Histamine is the major product of ECL cells . The local release of
histamine is responsible for the majority of acid production . An acidic pH within the stomach
has an inhibitory effect on gastrin production, which results in feedback inhibition of acid
secretion. This occurs via the release of somatostatin, which is produced by D cells. D cells are
located throughout the gastrointestinal tract and act as a final common pathway for the inhibition
of antral gastrin release thereby, inhibiting acid secretion. Thus, a loss of acid production, such
as in chronic atrophic gastritis (autoimmune gastritis) leads to loss of this inhibitory feedback
loop, which results in hypergastrinemia and, eventually, EC1 hyperplasia and potentially
neoplasia.
G cells are normally located in the antrum of the stomach. They are present in the
midzone of the mucosa and are more numerous on the greater curve compared to the lesser
curve. They are ôopen typeö neuroendocrine cells; the apical cytoplasm communicates with the
lumen of the gland. G-cell hyperplasia may be primary or secondary. However, the latter is
much more common. For instance, counts of 200-250 G cells per linear mm of mucosa
represents a definite increase in cell mass (normal 50-100/mm), and correlates with expansion of
the G-cell compartment.
Hypergastrinemia is found in a number of disease states such as atrophic chronic
gastritis, with corresponding G cell hyperplasia, Zollinger-Ellison syndrome (ZES), multiple
endocrine neoplasia type I (MENI), and, more recently pharmacological acid suppression
therapy particularly with proton pump inhibitors. Laboratory studies have shown that blockage

17
of acid production results in hypergastrinemia, which causes an increased risk of
enterochromaffin-like cell hyperplasia, dysplasia, and carcinoid tumor formation in the stomach .

Pathologic Features
Histologically, Type I tumors are usually associated with a is dense lymphoplasmacytic
infiltrate in the lamina propria, primarily involving the body/fundus of the stomach, with antral
sparing, ôpyloric- or antral metaplasiaö, and intestinal metaplasia. Ultimately, when the
inflammation subsides, complete gastric atrophy, with extensive intestinal metaplasia, usually
remains behind. Despite an antral phenotype, G cells are not normally identifiable by
immunohistochemistry, which helps confirm the origin of the mucosa as body/fundus type. The
antrum typically shows minimal inflammatory changes, but usually shows prominent
neuroendocrine cells, representing hyperplastic G-cells.
ECL Hyperplasia is a benign, but potentially pre-neoplastic proliferation. Benign
hyperplasia is present in up to 30% of patients with Type A chronic atrophic gastritis. It is
divided into three morphologic patterns. 1. diffuse or simple hyperplasia represents an increased
number (>2 fold) of ECL cells in gastric mucosa . These cells are scattered amongst the glands
diffusely, and singly. 2. linear hyperplasia represents a chain-forming proliferation of ECL cells,
(figure 12) and 3. micronodular hyperplasia represents an organized collection of ECL cells that
form nodules measuring <150m in size. (figure 13) Further proliferation may lead to
ôdysplasiaö. Dysplastic nodules are seen in only in 6% of cases. In this category, 4 morphologic
groups are recognized;
1. enlarging expansive growth pattern is comprised of nodules that measure >150m,
2. fused micronodules .
3. microinfiltration of the lamina propria or
4. nodules with surrounding newly formed stroma. Large micronodules are often
irregular in shape and configuration. Fused micronodules develop when 2 or more nodules with a
thin strand of connecting ECL, ôfuseö together into a single micronodular growth. In the deep
lamina propria, multiple small buds may protrude from these nodules, which may impart a false
appearance of microinvasion. Unlike true invasion, fused micronodules are limited to the
mucosa in the region of dysplastic foci. Nodules that measure larger than 0.5 mm in size
(500m), but are confined to the mucosa, are classified as microcarcinoid tumors.
Microcarcinoidosis is defined by the presence of numerous, and, widely distributed dysplastic
microcarcinoid tumors. Interestingly, dysplastic nodules are most often seen in association with
true carcinoid tumors. A true carcinoid tumor is defined as a tumor that shows any degree of
endocrine cell growth that penetrates beyond the muscularis mucosa or shows vascular invasion.
These are considered ôinvasiveö carcinoid tumors, regardless of their size.
Carcinoid tumors that arise in a background of diffuse hyperplasia and dysplasia are
usually of low malignant potential. Metastasis occurs in only 14 to 20% of cases, mostly to
lymph nodes, but rarely to the liver as well. The treatment of patients with these tumors is
controversial. Spontaneous regression may occur in some cases. Removal of the antrum, has
been reported to result in rapid regression of hyperplastic ECL. However, regression of
dysplastic nodules, and/or and true carcinoid tumors, is less well established with this
management technique.

18
Type 2 gastric NET (Zollinger-Ellison syndrome(ZES)/multiple endocrine neoplasia
syndrome type I (MENI))
The majority of cases of ZES occur as a result of a functioning pancreatic endocrine
tumor. However, some occur secondary to duodenal or gastric gastrinomas. The least frequent
cause is primary hyperplasia of antral G cells. In these cases, the antral G cells are typically large
in size, and clustered, and often form microadenomas, whereas in tumor cases, G cells are either
normal or decreased in number. In ZES, the fundic glandular compartment is typically
expanded, due to an increase in parietal cell mass. Enterochromaffin cells may also be increased
in number, but to a smaller degree. In 20% of ZES cases, other endocrine tumors, particularly of
the parathyroid and pituitary gland also develop, as a manifestations of multiple endocrine
neoplasia (MEN type I).
Finally, the use of proton pump inhibitors, with resultant induction of hypergastrinemia,
also presents a theoretical risk of developing carcinoid tumors. In laboratory rats, high dose
omeprazole has been associated with the development of carcinoid tumors. However, although
some humans develop hypergastrinemia and an increase in ECL cells secondary to proton pump
inhibitors use, dysplastic nodules and carcinoid tumors have not been reported in the absence of
other predisposing conditions, such as ZES.
Pathologic Features of hypergastrinemia associated gastric NET
The ECL-NET forms small mucosal nodules and polyps mainly located within the gastric body
and fundus, although recently similar tumors have been described in the antrum of ZES patients.
They may form polyps, and are often multiple. Histologically they have a mixed growth pattern,
often with closely associated trabeculae and small acini. Often there is little stroma present
between lobules of NET growth. Immunohistochemistry will confirm neuroendocrine
differentiation. VMAT-2 antibody appears a good marker for definite cell typing as ECL cells.
Growth is confined to the mucosa and submucosa in most cases.

Type 3 gastric NET

The stomach is an extremely uncommon site for NET derived from ECC. However,
rarely, they may arise in any portion of the stomach. At presentation, they are often bulky tumors
with local lymph node metastasis. Ectopic hormone, including ACTH and cacitonin has been
reported. Morphologically these tumors are mixed growth pattern. Transmural invasion with
serosal involvement is common at presentation, as are nodal metastases. Smaller tumors of NET
type arising in the antropyloric region may express gastrin strongly by Immunohistochemistry
and represent the gastric gastrinoma. Cespite their small size, these tumors are malignant.

Type 4 gastric NET (Mixed adeno/endocrine tumors)

This group represents a heterogeneous collection of mixed tumors. Mixed tumors are
defined by the presence of a mixture (>33%) of glandular and NET components in a single
tumor. These tumors can arise from any portion of the stomach. They may be polypoid in
appearance, are often large in size, and their behavior tends to be more aggressive than pure
NET. Metastasis from these tumors may contain both components, or only one cell type.
Amphicrine, composite and collision tumors have all been reported rarely in the stomach,
occasionally in association with NET elsewhere or within the stomach..

19
Table 1: Type I Gastric NET-associated ECl Proliferation

a) hyperplasia -
- linear
-micronodules (<150m)
b)dysplasia - enlarged micronodules (>150 m)
- fused micronodules
- microinfiltration of lamina propria
-new stroma
c)microcarcinoid - nodules >500 microns

Table 2: Grading of gastric NET (WHO classification)

1. Well-differentiated endocrine tumor (carcinoid)
Non-functioning cytologically bland tumors upto 1cm within the mucosa and submucosa,
without angioinvasion. In this grade are found the majority of type 1 ECL-NET.
2. Well-differentiated endocrine carcinoma (malignant carcinoid)
Non-functioning cytologically bland tumor 1-2cm within mucosa and submucosa with or without
angioinvasion.
3. Poorly differentiated endocrine carcinomas
Small cell carcinoma
High-grade
Mixed

Lecture Outline
Autoimmune Gastritis
Gastric NET
Neuroendocrine control of gastric acid production
Neuroendicrine hyperplasia
NET in hypergastrinemia
NET without hypergastrinemia
Grading Gastric NET

20
CASE 4: A 67 year old man with a history of hypertensive cardiovascular disease died six
hours fter admission of acute myocardial infarct. At autopsy the diagnosis of emphysema,
hypertensive heart disease with acute myocardial infarct were confirmed. A well healed
gastrojejunostomy was identified

Diagnosis: Post Operative Stomach Reflux (Or Chemical) Gastritis

The constellation of histologic changes include: (i) foveolar hyperplasia, resulting in tortuosity of
gastric pits and giving a corkscrew appearance (ii) decreased mucin in the surface and foveolar
epithelial cells with nuclear enlargement and hyperchromasia (iii) superficial mucosal edema with
dilated capillaries, (iv) "tongues" of smooth muscle fibers extending from the muscularis mucosal
upward into the lamina propria, and (v) little inflammation.

Pathology Of The Post Operative Stomach

It is important that practicing pathologists be familiar with the full array of gross and histologic
changes that can be recognized in the post operative stomach. These changes can be seen either
after gastrojejunostomy (Billroth II) or gastroduodenostomy (Billroth I) type anastomoses. Two key
pieces of information need to be remembered regarding the prevalence of these changes:1) they
increase with time after surgery ; 2) they differ depending on their location (anastomosis vs rest of
the stomach).

Chronic gastritis, often accompanied by a component of active inflammation, is the most common
finding. It usually develops within 1-3 years after surgery and is ultimately identified in 50-100%
of patients. It is usually more prominent in the proximal remnant than in the peristomal region.
Mucosal atrophy is seen in 20-45% of patients and is more frequent in the proximal gastric
remnant.
Less common findings include Hyperplastic polyps that are usually adjacent to the stoma and are
identified in up to 50% of patients. A rare variant is "gastritis cystica polyposa" in which
foveolar hyperplasia extends into the deeper lamina propria and submucosa as dilated cysts. The
cysts are often surrounded by splayed fibers of the muscularis mucosae and accompanied by
thickened vessels and fibrosis of the submucosa. Gastric xanthomas appear as single or multiple
small (<5 mm diameter) yellow-white nodules on the mucosal surface. They consist of clusters
of lipid-laden macrophages in the lamina propria, located typically just beneath the surface
epithelium and always associated with gastritis. They probably represent a sequel of cellular
injury and are believed to resolve spontaneously. The differential diagnosis includes
muciphages, granular cell tumor, MAI and poorly differentiated gastric adenocarcinoma. (signet
ring cell type).

Epithelial Dysplasia. The prevalence of dysplasia in gastric remnants varies depending on the series.
Mild dysplasia is reported in 8-34% of cases, moderate dysplasia in 3-20%, and severe dysplasia in
approximately 1-15% of patients. The natural history of dysplasia in gastric remnants is not well
known and may not differ from that of dysplasia in the non operated stomach. Available data
suggest that most examples of mild or moderate dysplasia remain stable or regress and that less than
10% progress.

21
Risk of Gastric Carcinoma. Gastric adencarcinoma occurs in gastric remnants after distal gastrecto-
my with gastroenteric anastomosis, but whether the risk is significantly increased compared to that
in the non-operated population remains controversial. Some authors suggest that the risk may be
increased in countries with a high intrinsic incidence of gastric cancer but not in those with lower
rates like the United States. Patient age at surgery and duration of follow-up are the two factors
most strongly associated with cancer risk. Adenocarcinomas are more frequent in patients
undergoing surgery before the age of 40 and most cancers are detected 15 to 20 years after surgery.
Although these cancers may be located in the proximal stomach or involve the remnant diffusely,
most are located at or adjacent to the stoma, particularly on the posterior gastric wall and they
virtually never involve the small intestinal side of the anastomosis. Their microscopic features are
not specific and they encompass roughly equal numbers of intestinal and diffuse carcinomas.
However, in one recent series, 75% of cases were of the diffuse type. If in older reports the cancers
were diagnosed at an advanced stage, with poor survival, more recent series of patients undergoing
endoscopic surveillance showed early gastric carcinoma in 14%-60% of cases.

Bile reflux (and perhaps, pancreatic juice) which leads to chronic gastritis and intestinal metaplasia
may play a role in the development of malignancy. Damage to the fundic mucosa with hypo-and
achlorhydria enhances bacterial proliferation with resultant production of dimethylnitrosamine,
nitrites and N-nitroso compounds all of which are potent carcinogens in animals.

Differential Diagnosis: Chemical Gastritis / Gastropathy

Reactive (chemical) gastropathy is the second commonest diagnosis made on gastric biopsies.
Although the mucosal changes reported in this case have been originally reported in patients with
previous partial gastrectomy, NSAIDs are emerging as the dominant cause (four times more frequent
in NSAIDSs users compared with those not taking the drugs). The cause of many such injuries are
considered to be chemical agents and the basic group of histological alterations has been called
"chemical gastropathy". The basic phenomenon is considered to be the result of increased
exfoliation from the mucosal surface. It can also been seen after cholecystectomy, vagotomy and
pyloroplasty.

ACUTE GASTRITIS
Acute gastritis is characterized by a sudden onset and a rapid resolution after the etiologic
mechanisms/ agents have been corrected/eliminated. The inflammatory response is usually
composed of neutrophils and eosinophils. Acute gastritis can be organized in three groups based
on the etiologies:

Ulcero-hemorrhagic gastritis
Typically these lesions occur in severely debilitated patients (ie. major trauma, sepsis, burns,
major surgery, and hypothermia). Microscopically the lesions are predominantly seen in the
body/fundus but they can extend to the antrum. The mucosa can display petechial changes or be
diffusely hemorrhagic. Microscopically, superficial hemorrhagic and necrotic lesions are
observed. The mucosal surface is replaced by a fibrinopurulent exudates and the residual basal

22
mucosa displays evidence of regenerative changes, with basophilic reactive epithelial cells with
numerous mitoses. Rarely one can see transmural necrosis and deep ulcerations.
The epithelial damage is believed to be directly related to ischemia in some cases (shock/
hypotension) or to the release of vasoconstrictive substances impairing blood flow. In many
cases the etiology remains unknown.
Stress related acute gastritis could be life threatening, leading to uncontrollable hemorrhage
sometimes requiring emergency gastrectomy.
Similar lesions can be seen associated with gastrotoxic drugs (NSAIDs, aspirin, steroids) and
alcohol. If taken chronically those can induce reactive gastropathy type changes.

Graft Versus Host Disease (GVHD)

GVHD usually occurs in patients following allogeneic bone marrow transplantation and much less
commonly following blood transfusion. The lesions are mediated by immunocompetent T cells in
the donor’s graft which target antigens on the transplant recipient’s cells and cause their destruction.
GVHD may be acute (1-2 months post transplant) or chronic (2-3 months or more post transplant).
Chronic GVHD may follow acute GVHD and is more frequent in older patients.
In the intestinal tract there is progressive destruction of gland/crypt cells with eventual complete
obliteration of entire glands/crypts. In the stomach, which is involved in up to 90% of cases, the
mucous neck cell region is affected first by apoptosis with subsequent progressive loss of glandular
elements and atrophy. In the most severe cases there may be ulceration with mucosal fibrosis.
with eventual complete obliteration of entire glands/crypts

Morphological Grading of Acute GVHD (Modified from Sale et al. 1979)

I. Apoptosis with Gland/Crypt Retention
II. Loss of Individual Glands/Crypts
III. Loss of more than two Contiguous Glands/Crypts
IV. Complete Loss of Epithelium

Differential diagnoses of Acute GVHD include: Radiation Injury, Chemotherapeutic Injury, CMV
Infection, AIDS Enteropathy, T-Cell Immunodeficiency, IBD.

Radiation Gastritis
Radiation gastritis is less common than radiation enteritis. It is most frequently seen following
radiation therapy for upper abdominal neoplasia or preceding bone marrow transplantation. Early
changes are seen 8-10 days after irradiation and consist of nuclear karyorrhexis and cytoplasmic
eosinophilia of the pit epithelium. During the next week, mucosal edema and congestion with
submucosal collagen bundle swelling, fibrin deposition and telangiectasia without significant
inflammation ensue. This is followed by glandular necrosis with nuclear atypia. Recovery begins
during the third week and is complete within 2-3 months. If the epithelial necrosis is extensive there
may be ulceration with hemorrhage. Intermediate to late radiation effects are due to progressive
vascular narrowing secondary to endothelial proliferation and vascular mural fibrinoid necrosis and
hyalinization producing ulceration. These ulcers differ from peptic ulcers by epithelial nuclear
atypia which is occasionally seen away from the ulcer area together with atypical fibroblasts, poorly
cellular collagen, prominent endothelial cells and thick walled vascular channels in the ulcer base.

23
Caustic gastritis
Most changes are seen in the antrum and the severity of mucosal alteration varies with the type
of substance ingested. The mucosa is usually edematous and hemorrhagic. In severe cases,
coagulative necrosis, associated with deep ulcerations and even perforations are seen.

Infectious gastritis:
Those are relatively rare and frequently occurs in debilitated patients (i.e., stress,
immunosuppression, surgery, diabetes, alcoholic).

Viral gastritis
The gastrointestinal tract is subject of infection by many different virus. Acute gastritis
accompanying hepatitis, infectious mononucleosis on influenza viral infections is rarely biopsied.
Diarrheagenic viral infection due to adenovirus, rotavirus or Norwalk agent is usually self limited
and does not require gastric biopsy.

CMV gastritis.
This infection usually affects immunocompromised patients following steroid, cytoxic drug, or
radiation therapy, the development of an immunodeficiency syndrome or organ transplantation. In
most transplant recipients CMV infection of the upper GI tract occurs in the 2nd or 3rd months post
transplant which overlaps the time of occurrence of acute GVHD.
CMV gastritis can clinically manifest itself with epigastric pain, nausea and vomiting.
Endoscopically the gastric mucosa may be normal or ulcerated, with or without perforation.
Histologically, the characteristic CMV inclusions may be seen in cells of the non-inflamed mucosa
or in the lamina propria endothelial or other mesenchymal cells in the inflammatory base of ulcers.
Hemorrhage and perforation rarely occur. In the typical form, characteristic intranuclear and
cytoplasmic inclusions are noted within epithelial, stromal and endothelial cells. There is usually
a non-specific mild inflammatory reaction. Immunohistochemistry and in situ hybridization
(more sensitive) can be used in difficult cases.
Herpetic gastritis is also rare, usually seen in individual with systemic infection.

Fundus and Parasitic Gastritis can manifest themselves as acute gastritis, thought they are
classically associated with granulomatous reaction. (see above).

GRANULOMATOUS GASTRITIS.
Granulomatous gastrites are rare representing less than 0.5% of gastritis. It is a heterogeneous
group with numerous etiologies. The granulomas are usually scant but can be numerous. They
are usually composed of a loose aggregate of epithelioid histiocytes with their appearance
varying depending on the etiology. Depending on the etiology, giant cells and necrosis can be
observed.

Non-infectious granulomatous gastritis:

24
The long held belief that inflammatory lesions of the upper gastrointestinal tract in the setting of
inflammatory bowel disease were diagnostic of Crohn disease is now an obsolete dogma. The
recently recognized focally enhancing gastritis although more commonly seen in Crohn disease is
also present in a significant number of patients with ulcerative colitis.

A CROHN DISEASE
Although clinically apparent gastric involvement is seen in only about 2-7% of patients with
Crohn disease, endoscopic and microscopic evidence of disease can be seen in 34-83% of
patients. In most cases, only focal acute and chronic inflammation, and granulomas are seen
while diffuse involvement with multifocal superficial erosions, mural rigidity and fistulas is
uncommon.
The endoscopic appearance is variable, ranging from normal, to nodular or thickened folds, to
aphthous or linear ulcerations. Microscopically, the appearance is that of shallow ulcers, focal
inflammation including lymphoid aggregates and plasma cells, epithelial infiltration by
neutrophils and/or lymphocytes (“focally enhanced gastritis,” see below). Superficial loose
granulomas with or without giant cells may be seen. Their incidence ranges between 0 and 83%
depending on the sampling and the age of the patients since they are more common in the
pediatric population with a short duration of disease. Deep ulcerations and fissures are rare.
Although most patients with gastric Crohn disease have concomitant duodenal and ileal involvement
or evidence of extensive colonic disease, in rare instances the gastric lesions may precede the more
diagnostic lower gastrointestinal manifestations. For example, Oren has reported a case of Crohn
colitis occurring more than ten years after an initial presentation as granulomatous gastritis.

B FOCALLY ENHANCING GASTRITIS

Focally enhanced gastritis (FEG) is defined as presence of focal inflammatory lesions composed
mainly of lymphocytes and histiocytes, and occasionally neutrophils, that involve either one or a few
adjacent foveolae/glands. More frequent in the antrum than in the gastric body mucosa, there is a
single focus in 73.5% of cases that involves 2 to 8 glands. The infiltrate is predominantly composed
of CD3 positive T lymphocytes and CD68 positive histiocytes with admixed granulocytes in 62% of
cases.
First heralded as a lesion specific for Crohn disease, with a prevalence ranging from 43% to 76%,
subsequent studies have shown that FEG is also present in up to 21% of patients with ulcerative
colitis. FEG has since been noted in other settings too, including bone marrow transplant patients. In
the general population, the incidence of FEG is of about 3% once H. pylori gastritis and reactive
gastropathy are excluded. The significance of FEG may be different in the adult and pediatric patient
population, with FEG being a relatively good positive predictive marker for Crohn disease in the
latter. Of note, FEG has also been reported in autistic children, where it may have a distinctive
immunophenotype with dominance of CD8+ T lymphocytes.

Sarcoidosis
Gastric involvement by sarcoidosis is rare and the diagnosis should be confirmed by the
involvement of other organs.

Granulomatous gastritis associated to cancer

25
A granulomatous inflammatory reaction can be associated to a cancer. It can involve the whole
thickness of the mucosa as well as regional lymph nodes.

Foreign body gastritis

Granulomatous reaction to foodstuff, talc, suture material, and drug particles and capsule can be
seen. Granulomas can be single or multiple, sometimes close to the mucosal surface and
associated to mucosal ulcerations. Fibrosis and secondary calcifications can be observed.

A diagnosis of Idiopathic granulomatous gastritis is allowed when all other etiologies have
been excluded.

Infectious granulomatous gastritis:

Several pathogenic agents can produce a granulomatous reaction. Those are tuberculosis,
mycosis, parasites, syphilis and H. pylori. Gastric tuberculosis is rare, noted in only 1% of
patients with pulmonary tuberculosis. It seems to be mostly antral, and may be responsible for
thickening of the gastric wall and the development of fistula. The granulomas may show central
necrosis and AFP stain is diagnostic when positive. Immunosuppressed patients may develop
granulomatous gastritis associated with candida or aspergillosis. Mucormycosis, histoplasmosis
and blastomycosis can also be diagnosed.
Parasitic infections such as anikasis, strongyloides stercoralis and schistosoma mansoni can
generate a granulomatous reactions accompanied by a significant eosinophilic infiltrate.
Because H. pylori is frequently found in patients with granulomatous gastritis its role has role
implicated in the development of granulomas. However, the discrepancy between the frequency
of granulomatous gastritis and H. pylori infection is an argument against an etiologic association.

MISCELLANEOUS GASTRITIS

Lymphocytic gastritis
Lymphocytic gastritis (LG) is a histopathologic entity characterized by the presence of an
increased number of intraepithelial lymphocytes (IELs) predominantly on the surface epithelium
and in superficial pits. Over 25 IELs per 100 epithelial cells are usually counted (mean: 60 IELs
per 100 epithelial cells). Mild secondary epithelial damage with mucin depletion and stratified
nucleimay accompany the IELs. The lamina propria shows also a variable lymphoplasmacytic
infiltrate. In some cases, marked elongation of the crypts is also described. Lymphocytic gastritis
is pan gastric in about 76% of the cases, limited to the body or the antrum in only 18% and 6%
of the cases, respectively.
In its usual form lymphocytic gastritis is usually asymptomatic and in cases of mild form the
stomach is endoscopically normal. . However, severe diffuse lymphocytic gastritis presents as a
hypertrophic gastropathy with pit hyperplasia and accompanied by many of the features of
Menetrier's disease, including protein loss (in about 1/3 of the patients) as well as nausea,
vomiting, and abdominal pain.

26
Endoscopy: lymphocytic gastritis can be associated with several gross appearances. The so-
called varioliform gastritis, not always observed, shows thickened folds, topped by small bumps
or nodules with central aphtous ulcerations. However, the endoscopic appearance can vary from
one examination to another.

Etiologic factors: The etiology in unclear but LG is reported in association with H. pylori
infection (in about 40% of the cases), celiac sprue and Crohn’s disease. In a series of patients
with celiac disease, 50% showed antral LG despite the absence of gross anomaly. The T
lymphocytes are similar in the gastric and small bowel mucosa. We have also seen histologic
evidence of LG at the periphery of gastric cancer and MALT lymphoma.
Differential diagnosis: T cells IELs observed in marginal zone B cell lymphoma (MALT
lymphoma).

Hypertrophic Gastropathies.
Those include: Menetrier’s disease , Zollinger Ellison syndrome and hypertrophic
hypersecretary gastropathy. ZE syndrome shows glandular hypertrophy with hypertrophic and
hyperplastic parietal cells. The latter shows a similar histology with acid hypersecretion without
hypergastrinemia and no protein loss. Bile reflux, gastroenteric anastomosis are easily excluded.
Diffuse hyperplastic polyposis and Cronkhite-Canada gastric polyposis are usually diffuse and
more difficult to exclude.

Menetrier’s Disease. Menetrier’s disease belongs to the group of hypertrophic gastropathies

characterized by thickened gastric folds secondary to mucosal hyperplasia. The clinical
presentation vary from vague abdominal pain, edema, diarrhea to hemorrhage.
Hypoalbuminemia, secondary to protein loss, is constant. At endoscopy, prominent cerebroid
mucosal folds involving either the complete mucosa or only the fundic region are observed.
Histology: The mucosa is usually twice as thick as normal (>1.5 mm vs. ~ 0.8 mm). It shows a
marked hyperplasia of crypts, which appear, tortuous, elongated and frequently distended. The
glands are frequently atrophic, and the edematous lamina propria shows a moderate chronic
inflammatory component. The muscularis mucosa is usually hypertrophic with extension of
muscular bundles piercing the lamina propria toward the mucosal surface.
Gastric adenocarcinoma can complicate Menetrier’s disease but the incidence is low (~5% to
10%) and not accurately established.

Treatment: Total or partial gastrectomy can be advised to eliminate the protein loss as well as the
risk of malignant degeneration. Others have suggested treatment using monoclonal antibody
against the epidermal growth factor receptor.

Differential diagnosis: It includes other hypertrophic gastropathies such as lymphocytic

gastritis, bile reflux gastritis, hyperplastic polyposis. Granulomatous gastritis, eosinophilic
gastritis, and gastric polyposis of Cronkhite-Canada syndrome can also display mucosal
thickening.
Etiology: Helicobacter pylori (HP) infection, by inducing a local immune response, has been
implicated. However, HP infection is present in only 30% of patients with Menetrier’s disease.

27
CMV infection has also been reported in several pediatric cases. The role of TGF alpha,
produced by normal surface mucous cells, has been investigated. It normally inhibits acid
secretion and stimulates gastric cell proliferation. Over expression of TGF alpha is believed to be
responsible of proliferation of cells of the proliferative zone resulting in marked foveolar
hyperplasia.

Eosinophilic gastritis is usually observed in the antrum. To deserve such a diagnosis a biopsy
should show a large number of eosinophils expanding in a sheet like fashion. In most cases no
definite etiologic diagnosis is found. Rare etiologies include systemic connective tissue disorders
such as scleroderma and polymyositis, parasitic infections (“classi”anisakiasis of unsafely
prepared sushi and allergies (cow milk, soy protein) mostly in pediatric patients.

28
CASE 5:A 59 year old man who complained of heart burn and early satiety was referred to the
GI clinic by his family doctor. In his late forties he had a gastric ulcer successfully treated by
Tagamet®. An upper GI endoscopy was advised. During the evaluation the endoscopist
visualized a thickening of the incisura angularis. Otherwise the gastric mucosa appeared
mildly atrophic . Your photomicrographs are from the multiple biopsies taken during the
examination.

Diagnosis: Gastric Epithelial Dysplasia, Low Grade

Gastric Dysplasia
Gastric epithelial dysplasia (GED) is an unequivocal neoplastic (non-invasive) process, precursor
for gastric carcinoma, particularly of the well differentiated ("intestinal") type. Its recognition is
important because it alerts one to the possibility of coexisting carcinoma thus contributes to patient
management in terms of early detection and possible prevention of cancer. GED can be found in 20-
40% of stomachs resected for early gastric cancer, and in up to 80% of stomachs resected for
advanced cancer. In a large European series the median age of patients with GED was 72 years
(range 55-86 years).
Gastric epithelial dysplasia does not present with a specific type of endoscopic pattern and can be
found in biopsies of active or healed ulcers, polypoid lesions, diffuse inflammatory changes and in
the post operative gastric stump.

Histologic features of dysplasia:

The diagnosis relies on architectural and cytologic features. The architectural abnormalities include
architectural glandular disarray, glandular budding with irregular branching and dilatation and
intraluminal epithelial folding. The cytologic abnormalities include cellular pleomorphism, changes
in the size and shape of the nucleus, N/C ratio increase, alteration in mitotic activity and degree of
differentiation, loss of polarity and pseudo stratification, reduced or absent mucus secretion.

Adenomatous dysplasia
This term has been quoted to emphasize the similarity of the histologic features with adenomatous
lesions of the colon. Some confusion exists in relation to the usage of either adenoma or dysplasia.
Gastric dysplasia can arise as a flat or depressed process or present as a raised circumscribed lesion
protruding above the mucosal surface sometimes referred to as an adenoma.

Hyperplastic dysplasia, type II dysplasia

This is an another type of gastric dysplasia also frequently arising in the background of chronic
atrophic gastritis with intestinal metaplasia . The histologic features of this type are less well
established than in adenomatous dysplasia. Architecturally it may display foveolar hyperplasia with
glandular branching and epithelial folding. The lining epithelium is formed of tall columnar cells
with loss of polarity, hyperchromatic ovoid nuclei and few goblet cells. In severe forms prominent
nuclei with increased nuclear/cytoplasmic ratio are noted. Nuclear stratification and numerous
mitoses can be seen.

29
Tubule Neck Dysplasia
The identification of the precursor lesion of the diffuse type of gastric cancer has been difficult.
This carcinoma, characterized by single cell infiltration of the lamina propria, is most associated
with non metaplastic mucosa. Early observations noticed that tumor cells seem to bud off the
glandular neck regions of tortuous gastric tubules. Closer observation of the tubules recognized
crowding of the neck region by enlarged clear cells. The nuclei of these cells appear also enlarged,
vacuolated with prominent nuclei and loss of nuclear polarity, and look very similar to their invasive
counterpart. Theses changes are believed to represent precancerous lesions and have been reported
as tubule neck dysplasia or globoid dysplasia. One animal experiment was successful is reproducing
the same changes. One single study also attempted to characterized different histologic grades based
on the degree of cytologic atypia and the extent of glandular involvement . However,tubule neck
dysplasia is very subtle and not readily recognizable even by morphometric analysis.

Grading of Dysplasia.
According to the severity of histologic abnormalities dysplasia is graded using either a two tier
system of low and high grade dysplasia or three tier system of mild, moderate or severe dysplasia.
Grading is easier and more reproducible in a 2-tier (high and low grade), than in a 3-tiered system
(mild, moderate and severe). These inevitably become 3 or 5 tiered systems (e.g. mild to moderate
dysplasia). In low grade dysplasia the cells show closely packed basal nuclei with dense chromatin.
The nuclei are also elongated in shape and if pseudostratified retain their polarity, and are confined
to the basal half or 2/3 of the cell. In high grade dysplasia, the nuclei regularly extend into the
luminal aspect of the cell in the adenomatous variant but in type II dysplasia are frequently oval,
round or irregularly shaped, with more open and clumped chromatin confined to the lower half or
(2/3) of the cells. Prominent nucleoli are often seen as well as frequent mitoses. More often than
not the nuclei reach the apical region of the cells and their polarity is partially or totally lost.
Because the cells are small and relatively cuboidal and the nuclei relatively large, it is easy for them
to occupy most of the cell so that the distinction between low and high grade dysplasia can be hazy.

Dysplasia Versus Regenerative Hyperplasia

Low grade dysplasia may be difficult to accurately differentiate from atypical reactive/ regenerative
epithelial changes in both of which cellular proliferation is active and prominent. In the latter the
cells usually appear immature, and may be cuboidal with basophilic cytoplasm, large but often
widely opened and relatively widely spaced vesicular nuclei and reduced or absent mucus secretion.
They may or may not be uniform in shape and size with basally or centrally located nuclei. They
are also arranged in a row and if present the pseudostratification is considerably less than in
adenomatous, but not necessarily type II dysplasia. Mitoses are often present but not on the surface
and abnormal mitoses are absent. Increased cellular differentiation and maturation is usually seen
toward the luminal surface.
The difficulty from differentiating reactive from dysplastic changes may account for the reports of
reversibility of low grade dysplasia. In cases where there is a real interpretative problem, the term
“indefinite for dysplasia” is sometimes used. However, operationally this is a diagnosis of exclusion
obtained by getting a negative response to the two questions “is this epithelium unequivocally
negative for dysplasia?” (this including all reparative epithelium) and “is this epithelium

30
unequivocally dysplastic?”. Epithelium that is not unequivocally negative or unequivocally
dysplastic is, by definition indefinite for dysplasia.

DYSPLASIA REGENERATIVE CHANGES

CELLULAR IMMATURITY +++ + to ++

VESICULAR NUCLEI +++ ++
DECREASED MUCUS +++ + to ++
SECRETION

CELLULAR ++ +
PLEOMORPHISM

PSEUDOSTRATIFICATION ++ - to +
SURFACE MATURATION - +
LOSS OF POLARITY ++ - to ++
ABNORMAL MITOSES + -
ARCHITECTURAL DISARRAY ++ - to +

High grade dysplasia also includes the lesion referred to as carcinoma in situ, which are
non-invasive lesions so called because virtually identical changes can be found in invasive
carcinoma. There is no agreement on whether the changes called carcinoma in situ should be
architectural, cytological, either or both. Previously held concepts such as breaching the basement
membrane sound good in theory but are difficult or impossible to apply on haematoxylin and eosin
sections, in which it is not visible. Numerous small glands budding out the lamina propria can be
difficult to distinguished from invasion. Irregularity of pit outlines with irregular infiltration into the
lamina propria is what is used operationally.

Since major therapeutic decisions may be taken following a diagnosis of dysplasia, it has been
suggested that such a diagnosis be confirmed by seeking a second opinion from a gastrointestinal
pathologist.

Natural History of Gastric Epithelial

GED has been shown to be a dynamic process which may progress, remain unchanged or regress.
The type of endoscopic lesion does not correlate with the presence or later evolution of GED within
it. Low grade GED appears to be the most frequent type of dysplasia and the most likely to regress.
Nevertheless within this diagnostic category biologically different lesions including true dysplasia as
well as regenerative change may be included. It has been suggested that in low grade GED, the age
(>60), sex (M) and severity of coexisting atrophic gastritis are important in the tailoring of the
patient's follow up.

31
a) different risks for different grades. Using the three tier classification scheme mild dysplasia was
shown to regress in up to 89% of the cases, to persist in 11% to 19% and to progress to higher grades
in 0% to 19% of the cases. Only between 0% and 5% of patients with an initial diagnosis of mild
dysplasia were eventually diagnosed with gastric adenocarcinoma. The likelihood that many of
these lesions were reactive is apparent, but the possibility that a focal lesion was either not
re-biopsied or had been removed completely by biopsy remains for all lesions that appear to
“regress”. Between 27% and 87% of patients diagnosed with moderate dysplasia show regression of
the lesion, with the same possible interpretation as mild dysplasia ; between 12% and 32%
persistence at the same grade and between 4% and 40% were diagnosed with severe dysplasia during
follow up. Importantly 4% to 38% of patients were eventually found to have an adenocarcinoma.
Up to 30% of patients with severe dysplasia showed regression while between 0% and 12.5% of the
cases persisted. Between 60% and 81% of theses patients were eventually diagnosed with a gastric
cancer.

When the two tier system was used low grade dysplasia was shown to regress between 38% and
49% of cases, to persist in 19% to 28% and to progress to high grade dysplasia between 0% and 15%
of the cases. High grade dysplasia regressed in about 5% of the cases, to persist in 14% and to
progress in 81% to 85% of the cases. These results are significant because they underscore the
predictive value of gastric dysplasia. However the marked variations in the results, may be even
more so when a three tier system is used, undermined the clinical practicality of the diagnosis of
dysplasia.

b) chronology of malignant evolution. The chronology of the progression from one dysplastic grade
to an higher grade or adenocarcinoma is critical in order to recommend appropriate therapy. In
several series the time frame between a diagnosis severe/high grade dysplasia and identification of
gastric cancer was between less than one (1) month to 39 months with a mean between 4 to 23
months. Clearly the possibility that some of these lesions were already carcinomatous, but that the
invasive element was not included in the original biopsy cannot be excluded. Following a diagnosis
of moderate/low grade dysplasia, cancer was found during a mean follow up of 10 months to 30
months with extremes of 1 month and 39 months. Finally, although most cases of mild dysplasia
are believed to regress, rare cases with diagnosis of carcinoma after long median follow up of 34.5
months and 41.5 months have been reported suggesting that either some of these lesions were
unequivocally neoplastic or that they were not included in the original biopsy. The analysis of
several Western series demonstrate that 57% of the cancers discovered during follow up were early
gastric cancer, a figure out of line of prevalence in the population at large, but which underscoring
the importance of close follow up to detect these lesions early.

b) Therapeutic guidelines
Many of the Western publications to date call for close endoscopic follow up of patients with
moderate/ low grade gastric. The frequency of the follow up is variable but given the risk of
malignant transformation endoscopy has been recommended between every three to 12 months at
least during the first year. An open question is how long the follow up should be maintained when
no progression has been detected ? Some suggest suspending the surveillance when two endoscopies
with multiple biopsies are negative at six months interval. Provided that a diagnosis of high grade
dysplasia has been confirmed, many authors suggest surgical resection because of the intimate

32
association with invasive gastric adenocarcinoma. However, others argue that gastric mucosa
endoscopic follow up might be sufficient. Increasingly endoscopic submucosal resection has a place
in the management of these lesions, although it is a skill to which relatively few hospitals in the
West have access compared particularly to Japan where it is the standard of practice for most
centers. Although with some merit, once a synchronous carcinoma has been excluded, this
conservative therapy is not immune to criticisms. First, any dysplastic lesion is not free of risk of
malignant transformation and non surgical resection can be curative. Other issues to enter in the
equation is the patient’ s compliance to protracting and costly follow up.

With advances in endoscopic localization (chromoscopy) and staging techniques (endoscopic

ultrasound) endoscopic mucosal resection can offer non surgical cure for intramucosal
adenocarcinoma. However, these modern interventional endoscopic procedures are not widely
available outside of the specialized centres and their place in the therapeutic armamentarium needs
to be defined and made more widely available. Further, the issue of protracting follow up in these
patients with high risk of developing metachronous adenocarcinoma remains to be settled.

Early Gastric Carcinoma (EGC)

EGCs may occur anywhere in the stomach but is confined to the mucosa and submucosa, regardless
of the presence or absence of lymph node metastases.
The prevalence of EGC and survival rates vary in different geographic areas. In Japan, they account
for 35-50% of all newly diagnosed gastric cancers with a 5-year survival rate with is greater than
90% while comparable studies from Europe and the United States yield prevalence figures between
8 and 27% and a survival rate of approximately 60%.
Although of limited practical interest cuurently , much emphasis has been placed on the
classification of EGC based on the morphologic appearance. Most of this information is derived
from the codification established by the Japanese Endoscopic Society.

Three major subtypes can be summarized as follows:

* Type I: protruding (exophytic ) type, which may be polypoid, nodular, or villous.
* Type II: superficial type, which is subdivided into three variants.

IIa: elevated type, which is slightly raised (maximum height not greater than that
the thickness of the adjacent mucosa)
IIb: flat type (no obvious macroscopic alterations)
IIc: depressed type, which is slightly depressed or associated w/ superficial
erosion

* Type III: excavated type showing an ulcer of variable depth surrounded by early gastric
cancer. Ulcerations may extend into the muscularis propria, although the cancer itself is confined
to the mucosa and submucosa.

EGCs have been further subdivided into strictly mucosal tumors, which have the best prognosis,

33
and tumors involving the submucosa. The latter have in turn been subdivided into two types
according to their growth pattern. Pattern A (PEN-A) is characterized by expansive growth of a
central mass with extensive destruction of the muscularis mucosae. Pattern B (PEN-B) refers to
multiple, small, finger-like protrusions that penetrate the muscularis mucosae independently without
extensive destruction ("fenestration").
EGCs vary greatly in size and may extend over a large surface area (8.0 cm or more in diameter).
The majority (approximately 70%) are the ulcerated variants (IIc and III), either singly or in
combined form.

Histologically, they have the same range of appearances as advanced cancers; approximately
20% are poorly differentiated or signet ring cell tumors. The latter frequently are confined to the
mucosa, in which case they may be extremely difficult to recognize both grossly because they
may only minimally distort the mucosa and microscopically because they may infiltrate the
lamina propria without disturbing the foveolar or glandular architecture. Signet ring cell tumors
are more common in young patients. The highly differentiated cancers tend to be associated
with polypoid and elevated lesions (type I and IIa), whereas poorly differentiated and signet ring
carcinomas are chiefly depressed or ulcerated (types IIc and III); the flat lesions (IIb) are
variable in their microscopic phenotype.

Tumor size and depth of invasion are the two major pathologic variable of prognostic
significance. Statistically, the larger the diameter of the lesion, the greater the probability of
extension into the submucosa, however, even very small lesions may become invasive. The
depth of invasion correlates with the prevalence of lymph nodal metastases and 5 year survival.

For intramucosal EGCs, lymph nodes have been reported as containing metastatic tumor in 0-5% of
cases and the 5 year survival is close to 99%. The low rate of nodal metastasis is not surprising
since the gastric mucosa possesses lymphatic channels only in the lowermost portion of the lamina
propria adjacent to the muscularis mucosae. Early carcinomas that extend into the submucosa have
rates of nodal metastases varying between 8 and 25% with an average 6 year survival of 93%. Of
importance, extremely small cancers may invade the submucosa; in one recent series, 16% of tumors
3-5 mm in diameter had invaded the submucosa. Thus, even minute carcinomas require the same
definitive surgery as larger EGCs. Mortality is attributable to persistent (recurrent) carcinoma in the
gastric remnant and/or to distant (primarily hepatic) metastases (in patients with positive nodes).
Recurrent disease is most often noted in patients with type IIc and type III lesions, which often have
a poorly defined lateral border, in whom the initial resection may not have encompassed the entire
neoplasm.

34
CASE 6:A 55 year old female presented with mild abdominal cramping. Gastric endoscopic
evaluation noted an apparently atrophic gastric mucosa and a single polypoid lesion noted in
the antrum. Endoscopic resection was performed. Your photomicrographs are from the
polypoid lesion.

Diagnosis: Hyperplastic Gastric Polyp

Gastric Polyps
With the increasing use of upper endoscopy gastric polyps are more frequently diagnosed. Their
prevalence is 5% in symptomatic populations undergoing upper endoscopy. The majority of gastric
epithelial polyps arise in a background of chronic gastritis. The three more common types can be
separated into two categories: a) non neoplastic: hyperplastic polyps and b) neoplastic: fundic gland
polyps and adenomas. As expected, the risk of malignant transformation and therefore the clinical
implications differ markedly between the two categories.

Multiple Cancer Risk Polyposis

HYPERPLASTIC Multiple 0.5% average

FUNDIC GLAND Multiple Low F.A.P.C.

POLYP Gardner's
ADENOMATOUS Single 10 to 75% F.A.P.C.
POLYP (average:40%) Gardner's
HAMARTOMATO- Multiple Minimal Peutz-Jeghers

JUVENILE POLYP Multiple Rare? Juvenile Polyposis;

Familial Gastric
Juvenile Polyposis

Hyperplastic Polyps
Hyperplastic polyps are the second most common type of gastric polyps representing about 30% of
the cases. They are frequently found in the antrum, arising in a background of chronic gastritis with
intestinal metaplasia. The stimulus (stimuli) for the development of hyperplastic polyps is/are
unknown. We presume that they representa reactive process to gastic mucosal injury. Often occur
in association with chronic atrophic gastritis and H. pylori gastritis. They tend to be stable often
multiple, are either sessile or pedunculated lesions and the majority measure less than 1.5 cm in
diameter. They are most frequent in patients in their fifties, while adenomatous polyps are most
usually seen in patients in their sixties.
Histologically they are characterized by enlarged foveolae lined by hypertrophic mucous cells
embedded in an inflamed, edematous and hyperemic, lamina propria with a surface which is
frequently eroded.

35
The risk of malignant transformation is small (range, 0% to 4.5%; average, 0.5% overall) and with
very rare exceptions, is confined to hyperplastic polyps that are 2.0 cm or larger in dimension. The
carcinomas arise from areas of dysplastic transformation but have been confined to the polyps
without mural invasion or metastases. Because hyperplastic polyps arise in a background of chronic
gastritis, there is a risk of detecting coexistent cancer elsewhere in the stomach. Recent prospective
endoscopic series have evaluated the risk at between 4.5% and 13.5%.

In terms of management, asymptomatic hyperplastic polyps, if small and adequately biopsied, do not
need complete removal. Large polyps (>2cm), on the contrary, need to be completely excised and
carefully evaluated. The epithelium at the surface of the polyps must be examined carefully to
distinguish reactive/regenerative changes (inflammatory atypia) from true dysplasia and in situ
carcinoma. In addition, sampling of the contiguous mucosa is recommended.

Fundic Gland Polyps (FGP)

First described in patients with familial adenomatous polyposis coli (FAP), they are by no means
specific for this condition and have now been identified in many patients with various degrees of
gastritis and in patients with gastroenteric anastomoses.
FGPs are benign small (1-5 mm diameter), sessile, often multiple (in 40 to 60% of patients), smooth-
contoured, tan nodules that are confined to the oxyntic mucosa. Microscopically, fundic glands are
elongated, with cystic dilatation of the upper half of individual glands. They are lined by varying
proportions of normal fundic epithelial, parietal, chief, and mucous cells. Inflammation is generally
absent. FGPs are associated with gastritis, but the extent and severity of the mucosal chronic
inflammation and atrophic changes are usually much less than those observed with hyperplastic
polyps and adenomas. They are labile with 40% to 50% of cases showing a decrease in size or
number and/or disappearance complete during follow-up. Alternatively, new lesions may develop.
The pathogenesis of FGPs is slowly being deciphered. Recently several genetic alterations
suggesting that these polyps are neoplastic have been recognized. Inactivation of the FAP gene and
ch5q allelic loss have been noted in syndromic patients. Alternatively sporadic polyps show
activating mutations of the beta catenin gene in 60% to 90% of the cases.
FGPs are associated with a variable increased risk of coexistent gastric cancer and dysplasia. The
risk of dysplasia is low in sporadic cases (1% to 3%) and up to 25% in FAP patients. Thus,
surveillance is not indicated for patients with sporadic fundic gland polyps but needed in FAP
patients.

Omeprazole Induced Parietal Cells Hypertrophy & Hyperplasia

Recent publications demonstrated distinctive parietal cells hypertrophy and hyperplasia in patients
receiving omeprazole. Omeprazole is a protein pump inhibitor specifically decreasing gastric acid
secretion by inhibiting parietal cell hydrogen-potassium adenosine triphosphatase (H+/K+-ATPase).
Histologically, the fundic glands appear enlarged with distinctive protrusion of hypertrophied
parietal cells. The changes are more commonly noted in patients treated for more than 12 months
although they can be seen sooner. Ultrastructurally, the enlarged parietal cells demonstrate abundant
cytoplasmic tubulovesicles which is indicative of a functional status.

Clinically, it is important to realize that parietal cell hyperplasia and hypertrophy may account for

36
rebound acid hypersecretion following interruption of chronic therapy. The association between
omeprazole therapy and parietal hyperplasia has been reported to be so strong by some authors that
its presence could presumably be used as a marker for patients compliance to therapy. However,
parietal cell enlargement has also been seen in autoimmune gastritis without total glandular atrophy,
in the mucosa of patients with gastric ulcer disease, H.pylori infection, gastric cancer as well as in
biopsies from patients with ZE syndrome.

Adenoma
In the U.S. these lesions are rare comprising only about 10% of all gastric polyps. They are usually
stable, slow growing, solitary lesions located in the antrum and are most frequently diagnosed after
the age of 50.
Adenomas cannot be endoscopically distinguished from other types of polyps unless they display a
villous appearance. The microscopic diagnosis is easy because they display the typical features of
dysplasia with cellular atypia, nuclear stratification, abnormal differentiation and disorganized
mucosal architecture similar to that seen in colonic adenomas. The dysplastic changes are either
superficial or involve the full thickness of the mucosa. They occur predominantly in a background
of chronic gastritis with intestinal metaplasia. With the increased use of endoscopy, adenomas are
now being detected more often when they are smaller: in one series 93% of adenomas were less
than 2 cm in diameter.

Risk of Gastric Adenocarcinoma

The prevalence of carcinomatous foci in adenomas has varied in different series from 10% to 75%
(average~ 40%) . Follow up series observed development of malignant foci in 5.9% of flat (tubular)
adenomas and up to 33% of large villous and tubulovillous adenoma . Others reported malignant
transformation in 11% of 85 cases examined and sequentially biopsied during an average follow up
of 49 months . Most cancers occur in adenomas > 2 cm and are usually of the intestinal, well-
differentiated type. Patients are at increased risk of having synchronous gastric carcinoma
elsewhere. In recent endoscopic series the prevalence of coexistent cancer varied from 3% to 25%.
The value of surveillance is underlined by the fact that 80% of cancers are "early" tumors.
Gastric adenomas should be completely excised and examined in toto. The remainder of the
stomach should also be examined carefully for other lesions and follow-up endoscopies scheduled,
because of the relatively high risk of developing recurrent or new adenomas. Also, it is prudent to
advise your gastroenterologists to sample the flat mucosa around an adenoma. The presence of
high-grade dysplasia in the flat mucosa places the patient in a higher risk category for the
development of carcinoma and gastrectomy should be entertained in these circumstances (see
"Gastric Epithelial Dysplasia").

Juvenile Polyps
Juvenile polyps are rare smooth contoured polyps composed of dilated mucus filled glands
surrounded by an inflamed edematous stroma. Although predominantly recognized in the colon they
also have been diagnosed in the stomach of both pediatric and adult patients with gastrointestinal
juvenile polyposis. Recessive and dominant genetic transmission has been noted. Juvenile
polyposis restricted to the gastric mucosa has also been reported and its cause is unknown. The
differential diagnosis from hyperplastic gastric polyps and the Cronkhite-Canada Syndrome is
difficult and relies mostly on clinical information and the distribution of the polyps. Extremely

37
 rarely, carcinoma develops either in the polyp or de novo in the surrounding gastric mucosa.

Gastric Polyps In Hereditary Polyposis Syndromes

Because increasing numbers of patients with hereditary adenomatous polyposis syndromes have
been detected at an early age and have undergone prophylactic colectomy with subsequent increased
survival, gastroduodenal polyps have developed in 40-100% of these patients during their prolonged
postsurgical surveillance.
- The prevalence of hyperplastic polyps in these specific populations is poorly defined.
- Fundic gland polyps have been identified in 23-45% of FAP patients. Compared with sporadic
cases, fundic gland polyps associated with FAP occur at a much younger age and are present in
larger numbers (often over 50 polyps).
- Gastroduodenal adenomas occur in 35-100% of patients and are more frequent in the duodenum
than in the distal stomach. In contrast to sporadic cases, adenomas in FAP also occur at a younger
age (mean, 37 years). They increase in prevalence with increasing age, are usually small and
multiple, and may also undergo malignant change. Given the risk, regular surveillance is indicated
in patients with FAPC.
Patients with Peutz-Jeghers syndrome have a slight (2-3%) risk of gastrointestinal adenomas or
carcinomas, particularly in the distal stomach and duodenum, and should undergo endoscopic
surveillance. The other polyposis syndromes are not associated with an increased risk of gastric
cancer.

Inflammatory Fibroid Polyp

Inflammatory fibroid polyps (IFP) represents the most frequently encountered mesenchymal
gastric polyp. They are often pedunculated and located in the antrum. Histologically they are
characterized by gastric surface epithelium overlying a proliferation of inconspicuous spindle cells of
myofibroblastic origin (vimentin and actin+) with thick walled blood vessels and numerous eosinophils
in an edematous stroma. Characteristically, the spindle cells are arranged in an onion skinned pattern of
growth around the vessels. Whether IFP represents a reactive process or a neoplasm is debated.
Excision is curative.

38
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42
 Figure Legends
Case 1 Diffuse helicobacter gastritis with MALT lymphoma
1. Antral biopsy shows active chronic gastritis with neutrophils within the pit opening and
transmigrating across the deep pit epithelium. The lamina propria contains a moderate
plasmacytic infiltrate. (H+E stain)
2. Thiazine stain reveals numerous short chubby bacilli within the mucin at the pit surface.
3. The biopsy from the ulcer reveals effacement of the deep glandular compartment by a extensive
mononuclear infiltrate. (H+E stain)
4. Higher power reveals destructive lymphoepithelial lesions (LELs), with mononuclear cells over-
running and destroying glands in the deep gastric mucosa. (H+E)

Case 2 Chronic Atrophic Gastritis with Neuroendocrine Hyperplasia and Neoplasm Formation
1. Mucosal ellipse with 1cm polyp and surrounding granular, focally nodular mucosa without
normal gastric folds.
2. The polyp appears sessile at low power; the edge is smooth and a mononuclear infiltrate is
evident. (H + E)
3. Low power microscopic examination of gastric body mucosa shows complete loss of the
glandular compartment and proliferation of nests of neuroendocrine cells in the deep mucosa.

Case 3 Gastric Stromal Tumor

1. Local excision of GIST with overlying ellipse of gastric mucosa; The cut surface of tumor is
tan, lobulated with central cystification
2. Low power microscopic examination shows intact mucosa with a smooth pushing tumor border.
(H + E)
3. High power microscopic view shows a proliferation of epithelioid cells in small nests. The cells
have around nucleus eccentric in the cell with moderate amounts of pale-pink cytoplasm. A
single mitotic figure is visible in mid-field. (H + E)

Case 4. Post Operative Stomach Reflux (Or Chemical) Gastritis

1. Low power view of the antral mucosa characterized by marked foveolar hyperplasia.
2. Serrated and extended foveolar region.
3. Cuboidal epithelium with mucin depletion
Asare
Case 5. Hyperplastic gastric polyp.
1. Low power view demonstrating ulcerated polypoid mass with cystic glandular distinction.
2. The irregularly shaped follicular gastric regions are invaded in adenomatous and inflamed
stroma.
3. Irregularly shaped gastric glands lined by mucin secreting epithelium devoid of any cytologic
atypia.

Case 6.Gastric epithelial dysplasia, low-grade.

1. Antral biopsy showing an atrophic mucosa with adenomatous features.
2. Intermediate magnification shows densely cellular gastric glands with hyperchromatic nuclei
and mucin depletion.
3. The cells lining the glands shows the characteristic features of low-grade dysplasia with nuclear
crowding, basally located and mucin depletion.

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