12
Stomach: Normal
Structures and
Developmental
Abnormalities
Chapter Outline
EMBRYOLOGY
Stomach
Cardia
Duodenum
NORMAL STRUCTURE OF THE STOMACH
Anatomy
Gastric surfaces (relations of the
stomach)
Anatomic regions
Blood vessels and lymphatics
Nerve supply
Histology
EMBRYOLOGY
Stomach
The stomach appears at 14 weeks as a fusiform dilation of the caudal part of the foregut. The dorsal border grows faster than the ventral border, establishing
the greater curvature of the stomach. As the stomach
acquires its adult shape, it rotates 90 degrees in a clockwise direction on its longitudinal axis. The adult orientation of the stomach is established as the ventral border
(lesser curvature) moves to the right, the dorsal border
(greater curvature) moves to the left, the original left
side becomes the ventral surface, and the original right
side becomes the dorsal surface. These changes explain
why the left vagus nerve supplies the anterior (ventral)
wall of the adult stomach and the right vagus innervates the posterior (dorsal) wall (Fig. 12-1).1
The epithelial lining and gastric glands develop
from foregut endoderm. Splanchnic mesoderm produces gastric smooth muscle, the lesser omentum, and
the dorsal mesentery (dorsal mesogaster and greater
omentum). Gastric epithelial cells express a range of
peptide hormones known to regulate gastric functions
including digestive enzymes, mucus, and hormones
that regulate gastric motility. At 8 weeks, the developing human stomach has gastrin-containing cells in the
antrum, and somatostatin cells in both the antrum and
the fundus. At 10 weeks, glucagon-containing cells are
seen the gastric fundus; these are preceded by glicentin
­(enteroglucagon—the precursor of glucagon) but have
Mucosa
Submucosa
Muscularis propria, ICCs, and serosa
DEVELOPMENTAL ABNORMALITIES OF
THE STOMACH
Pathogenesis and Clinical Features
disappeared ­postnatally, although occasional glicentin
or glucagon-containing cells can be found in various
poly and cancers.2 Serotonin-containing cells are seen
in the antrum and fundus by 11 weeks.3–6
Cardia
There has been considerable controversy regarding whether the cardia is normal or is acquired in
response to reflux.7,8 In embryos, there can be either
a direct transition from oxyntic to esophageal squamous mucosa or a transition from oxyntic to cardiac
to esophageal7,9 suggesting that cardia is physiological
and may even develop in response to gastroesophageal
reflux in utero. The issue assumes potential importance in adults, where a direct oxynto-squamous transition is rare, so that an argument can be made for the
cardia being acquired in at least some adults. While
this should be analogous to how much gastric metaplasia is present in the first part of the duodenum, which
likely also develops in response to acid reaching that
part of the duodenum, it assumes potential importance
in the esophagus if it is acquired in response to gastroesophageal reflux disease. This could potentially be
interpreted as acquired and therefore to have potential
for neoplastic transformation—with or without goblet
cells. It can therefore be argued that, unless this starts
acquiring intestinal mucosa features, it likely has little
risk.10 However, this is a moving target, as in some studies intestinal metaplasia can be present in over a third
of the ­population if looked for.11 We therefore suspect
that normal cardia has no increased risk of neoplasia.
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that projects ventrally. The junction of the foregut
and the midgut is at the apex of this embryonic duodenal loop usually immediately below the ampulla
of Vater. Because of its derivation from both the
foregut and the midgut, the duodenum is supplied
by branches of the celiac and superior mesenteric
arteries. During the 5th and 6th weeks, the duodenal
lumen is reduced and may be obliterated by epithelial cells, but it recanalizes by the end of the embryonic period (8th week).1 Most of the duodenal ventral
mesentery disappears, but the free border remains
and forms the ventral border of the epiploic foramen.
NORMAL STRUCTURE OF
THE STOMACH
Figure 12-1. The adult orientation of the stomach is established as the ventral border (lesser curvature) moves to the
right, the dorsal border (greater curvature) moves to the left, the
original left side becomes the ventral surface, and the original
right side becomes the dorsal surface.
Duodenum
The duodenum develops from the most caudal part
of the foregut and the most cranial part of the midgut.
These parts grow rapidly and form a C-shaped loop
The stomach is J-shaped, although there is considerable variation, depending on the degree of distention and the body habitus. Between its two areas of
fixation at each end, the stomach is quite mobile. It
is fixed above at the esophagogastric junction and
below at the gastroduodenal junction. The two curvatures of the stomach are designated the lesser and
greater curvatures (Fig. 12-2). Externally, the stomach
is covered completely by peritoneum, except where
the blood vessels run along its curvatures (Fig. 12-2),
and a small bare area posterior to the cardiac orifice.
The peritoneum is reflected at the lesser curvature
forming the lesser omentum that extends to the liver.
Likewise, the peritoneum is reflected at the greater
curvature to become the greater omentum (a double
layer of fatty peritoneum suspended from the greater
Figure 12-2. Outline of the stomach with its
rich blood supply from all three branches of the
celiac trunk, namely the left gastric, splenic, and
common hepatic arteries (a. = artery).
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Anatomy
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curvature). The greater omentum is an apron-like
structure hanging off the stomach that has a remarkable ability to stick to damaged or perforated parts of
the gastrointestinal tract, sealing off leaks and giving
some protection against peritonitis. Excess fat may
be stored on the greater omentum, especially in men
(hence beer belly).12
Gastric surfaces (relations of the stomach). The
antero-superior surface of the stomach is in contact
with the diaphragm (fundal region), gastric surface of
the spleen, left and quadrate lobes of the liver, the
anterior abdominal wall, and the transverse colon—
when the stomach is empty. The postero-inferior
­surface (stomach bed) is formed by the posterior wall
of the omental bursa and retroperitoneal structures
between it and the posterior abdominal wall. Superiorly, the stomach bed includes part of the diaphragm
(left crus), the spleen, the left suprarenal gland, and
upper pole of the left kidney. Inferiorly, the stomach
bed includes the body and tail of pancreas, transverse
mesocolon, left colic flexure, the splenic artery, and,
in some people, the transverse colon.
Anatomic regions. Anatomically, the stomach is subdivided arbitrarily into four regions: the fundus, body
(corpus), cardia, and antrum (Fig. 12-3). It connects
with the esophagus and duodenum through the cardia
and pyloric canal, respectively. The fundus (superior
part of the stomach) is a dome-shaped area that lies
above an imaginary horizontal plane passing through
the cardiac orifice. The fundus extends to the left
and superiorly from the cardia region. The body lies
between the fundus and the antrum. It is the ­largest
Figure 12-3. Areas of the stomach shown in this total gastrectomy specimen in a patient with an E-cadherin germline mutation but no gross abnormality. The pyloric sphincter is clearly
identified on the left as a circular constriction.
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part of the stomach and extends to the level of the
incisura angularis on the lesser curve. Confusion can
arise when fundus is used as a gross anatomic term
including both the body and the fundus, and this use
of the term should be avoided.13 The term “oxyntic
mucosa” is a useful term to describe acid-producing
mucosa. It is useful histologically when biopsies are
clearly “oxyntic” but their precise site is unknown.
The antrum occupies the lower one-quarter to onethird of the stomach. Its approximate boundaries can
be defined by a line drawn from the incisura angularis
to the opposite wall; its junction on the greater curve
is determined by the approximate ends of the gastric
rugae (Fig. 12-3). When the stomach is distended with
air at endoscopy to permit visualization, the antrum is
designated as beginning on the greater curvature at the
point where the gastric body folds end and where the
smooth, “foldless” antrum begins. The opening into the
duodenum is the pyloric orifice, and its position is usually indicated by a circular groove on the surface of the
organ, termed the pyloric constriction, which indicates
the position of the pyloric sphincter.
The pyloric sphincter is the most distal part of
the antrum and controls the flow of gastric contents
into the duodenum. The pyloric sphincter, similar to
the lower esophageal sphincter, is several centimeters long (Fig. 12-3). Its narrow lumen, which passes
between the antrum and the duodenum, is referred
to as the pyloric canal. In endoscopic parlance, the
term pylorus is commonly used interchangeably with
pyloric canal and pyloric sphincter region. Some use the
term pyloric antrum to designate the gastric antrum
and pyloric canal to indicate the pyloric sphincter
region. We prefer to avoid the prefix term pyloric in
order to avoid confusion and to use the simpler terms
antrum and pylorus.
The cardia region refers to a short zone measuring
from a few millimeters to several centimeters where
the stomach immediately adjoins the esophagus. It is so
named because of the mucus-secreting glands (cardiac
glands) it contains. When the term cardia region is used
in clinical or macroscopic terms, it usually denotes
the most proximal (juxtaesophageal) stomach. The
gastric cardia starts at the gastroesophageal junction
where the squamous mucosa terminates (in patients
in whom Barrett’s esophagus is not a consideration).
There is no consensus on the endoscopic landmarks
for the gastric cardia. Western gastroenterologists arbitrarily define the distal extent of the cardia as the level
of the most proximal gastric folds (Fig. 12-4).14 Japanese gastroenterologists define the proximal extent
of the EGJ as the distal end of the lower esophageal
palisade vessels.15,16 These palisades are the termination of esophageal vessels that run longitudinally in
the submucosal layer of the body of the esophagus,
where their structure is truncal and consists of a few
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Chapter 12 Stomach: Normal Structures and Developmental Abnormalities
Figure 12-4. Endoscopic image of the cardia region. In Western countries, the cardia begins distally at the proximal end of
the gastric longitudinal folds in the partially deflated stomach
(P). In Japan, the lower end of the cardia is determined by the
lower limit of palisade vessels (L). While both of these definitions are almost the same, as can be seen here, the palisade vessels actually extend a little distal to the upper end of the gastric
folds. The upper end of the cardia is the squamocolumnar junction or Z-line (Z). (Image courtesy of Dr. Worth Boyce.)
large columns.16 At the cardia, the veins penetrate the
muscularis mucosae and become s­ uperficial, forming
the palisade vessels in the lamina propria beneath the
epithelium. At the distal end of the palisade vessels,
these veins merge with the submucosal venous network of the stomach. These two landmarks are similar
but not always identical (Fig. 12-4).
The squamocolumnar junction between the
esophagus and the stomach is not an abrupt horizontal transition. Rather, there are grossly visible interdigitating tongues referred to as the ora serrata or,
more commonly in endoscopic circles, as the Z-line
(Fig. 12-4).
As indicated subsequently in the section on histology, the histologic zones of the stomach do not
­correspond precisely to the gross anatomic regions.
The mucosa in the body of the stomach, especially on
the greater curvature, is thrown into numerous thick
folds, or rugae, which run in a longitudinal direction.
In the fundus, the lesser curvature of the body and, in
the antrum, the mucosal folds commonly flatten when
the stomach is distended with air or barium. With isotopically labeled meals, a midgastric transverse band
can be identified in the food-filled stomach. There is
no known anatomic correlate to explain its appearance.17 When the gastric body mucosa is viewed with
a hand lens or close up at endoscopy, shallow slits or
furrows, the areae gastricae, are seen. These represent
the furrows between undulations of the mucosa that
range up to 5 mm in diameter.
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Blood vessels and lymphatics
Arterial Supply The stomach has a rich blood supply
from all three branches of the celiac axis (left gastric,
splenic, and common hepatic arteries. The lesser curvature receives blood from two sources. The lesser
curvature of the stomach is supplied by the right
gastric artery (that arises from the hepatic branch
of the celiac near the pylorus) inferiorly and the left
gastric artery (that arises directly from the celiac
artery) superiorly, which also supplies the cardiac
region. The greater curvature receives blood from
two sources. The greater curvature is supplied by the
right gastroepiploic artery (that originates from the
gastroduodenal branch of the hepatic artery) inferiorly and the left gastroepiploic artery (which arises
from the splenic artery) superiorly. The fundus of the
stomach is supplied by short gastric branches from
the splenic artery.
Venous Drainage The lesser curvature is drained by
the right and left gastric veins, which run next to the
arteries and drain into the portal vein. The fundus is
supplied by short gastric veins that ultimately join
the splenic vein, again finishing in the portal vein.
Branches of the short gastric veins and the left coronary gastric vein at the cardia drain the lower esophagus. Blood from the lower portion of the greater
curvature is drained by the right gastroepiploic vein,
which enters the superior mesenteric vein and thence
the portal vein.
Lymphatics The lymphatic drainage from the stomach generally follows the main arteries and is named
accordingly. Beginning in the gastric mucosa, the lymphatics pass through the gastric wall and go toward one
or the other of the curvatures, draining to four main
areas, along the routes of the arteries and veins. The
largest is for most of the lesser curvature and the lower
end of the esophagus, along the left gastric artery to the
left gastric nodes. The distal portion of the lesser curvature in the region of the pylorus drains to the right gastric nodes that drain to the hepatic nodes. The proximal
part of the greater curvature drains along the gastroepiploic and splenic vessels, terminating in splenic nodes
in the hilum of the spleen. The distal portion of the
greater curvature drains to the right gastroepiploic nodes
in the greater omentum and to pyloric nodes at the head
of the pancreas. Ultimately, the branches from all of
these groups drain into the celiac nodes located around
the celiac trunk as it arises from the abdominal aorta.
From the celiac nodes, lymph drains directly into the
thoracic duct. It is important to understand gastric lymphatic drainage as veins provide routes for spread of
gastric cancer, when present, directly to the liver, while
from the celiac nodes, the thoracic duct provides direct
access to the systemic circulation.
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Nerve supply. The parasympathetic nerve supply is
from the vagus nerve and its branches. The right vagus
nerve enters the abdomen as one or two trunks on the
posterior side of the esophagogastric junction. It supplies branches to both surfaces of the stomach. The left
vagus nerve also has one or two trunks, and it enters
the abdomen on the anterior surface of the stomach,
where it is present because of the rotation of the stomach early in its development (see “Embryology” section
above). Shortly after entering the abdomen, the anterior vagal nerve gives off a hepatic branch and the posterior trunk gives off a celiac branch. Thus, transection
of these trunks below these branches only results in
gastric denervation. Even more selective denervation
of the fundic gland mucosa (highly selective vagotomy)
can be achieved by preserving the terminal portions
of the vagal nerves that supply the gastric antrum.
Vagal nerve fibers connect with ganglion cells located
between the circular and longitudinal fibers of the muscularis propria (Auerbach’s plexus) and with submucosal ganglion cells (Meissner’s plexus). From these plexi,
postganglionic fibers innervate both glands and muscle.
The sympathetic nerve supply to the stomach is
from the celiac plexus via branches that follow the gastric
and gastroepiploic arteries. There are also sympathetic
branches from the right and left phrenic nerves. These
nerves contain afferent pain fibers as well as motor fibers
to the pyloric sphincter region. Vagal stimulation from
ghrelin mediated pituitary stimulation produces release
of ghrelin and orexin that stimulates gastric secretion
prior to food ingestion, the former resulting in increased
gastric acid secretion via acetyl choline, and the latter
that also stimulates a craving for food.
At the microscopic level, this esophagogastric
transition zone frequently contains alternating islands
of squamous and columnar epithelium. Similarly, in
the pyloric sphincter region, there may be short segments containing a blend of gastric columnar and
small intestinal columnar epithelial cells.
The Superficial Zone (Surface and Pit Epithelium)
The gastric mucosa is covered by tall (20–40 mm) columnar mucous cells that are invaginated to form the pits or
foveolae. The surface epithelial cells are replaced every
4 to 6 days.21 The mucus in the surface epithelial cells
occupies the luminal part of the cells (Fig. 12-5), occupying up to about 80% of the cell. Nuclei are regularly
oriented and are normally located in the basal part of the
cell, and no more than one-fifth of the distance toward
the lumen; when reactive changes are present, the
A
Histology
This section focuses on the light microscopic appearance
of the stomach. Comprehensive reviews of the electron
microscopic appearance are available.18–20 All parts of the
stomach have the same basic structural layers (mucosa,
submucosa, muscularis propria, subserosa, and serosa).
Mucosa. Traditionally, but for no good reason that we
are aware of, the term crypt (crypts of Lieberkuhn) is
applied to the small and large intestine, but in the stomach, they are pits. We are willing to accept either terminology but will use “pit” as terms such as “pit pattern”
are now generally accepted. Gastric pits are divided
into three histologic zones: superficial zone (surface
and pit epithelium); neck zone, which is the regenerative region of the stomach; and deep or glandular zone.
While the surface and neck zone cells are uniform
throughout the stomach, the underlying glands differ
in structure and function by region, and the ­histologic
zones of the stomach are classified according to these
types of glands: cardiac, oxyntic, antral.
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B
Figure 12-5. A: In the gastric pits (P), superficial cells in the stomach are mucin-producing throughout the entire stomach. Each
nucleus has an apical mucin vacuole that usually occupies well
over 50% of the cell (red arrows). Occasional intraepithelial lymphocytes are also visible (blue arrows). Depending on the staining
technique employed, the mucous cells maybe almost clear as in
(A), or eosinophilic as in (B).
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Table 12-1 Endocrine Cells of the Stomach
HORMONE
SILVER STAIN
CELL TYPE
CORPUS
ANTRUM
AMINE
PEPTIDE
MARKER (ANTIBODY)
MASSON–FONTANA
OTHERS
ECL
30%
0
Histamine
Unknown
Negative
Positive
EC
7%
10%
Serotonin
(5HT)
Unknown
Positive
Positive
D
22%
20%
Somatostatin
Negative
Positive
G
0
60%
Gastrin
Negative
Positive
D1, A/X
20%
Unknown
Ghrelin
Synaptophysin,
Chromogranin A, VMAT2,
Histamine
Synaptophysin,
Chromogranin A ­serotonin
Synaptophysin,
Chromogranin A
somatostatin MAb
Synaptophysin,
Chromogranin A Gastrin
Chromogranin, Ghrelin
Negative
Positive
mucin is reduced and the nuclei occupy correspondingly
more of the cell (see Chapter 13). Mucous cells lining
the gastric lumen secrete mucus as well as bicarbonate ions. The bases of these pits are in direct continuity
with the underlying glands. The surface epithelial cells
appear similar to each other in all gland zones except
those in the cardia region, where they may be taller and
narrower. Occasional intraepithelial lymphocytes are
normally present. Sometimes, the surface configuration
of the mucosa of the antral and cardiac gland mucosa
has a villous configuration. This appearance is a normal
variant and should not be confused with intestinal metaplasia of the stomach, because the epithelial cells are
normal, not metaplastic. The entire superficial zone of
the stomach including the superficial part of the mucous
secreting glands are immunoreactive to MUC5, and the
deeper parts with MUC6, a staining pattern also seen in
antral mucosa, Table 12-1, and illustrated in Chapter 14.
These cells are strongly diastase PAS positive but do not
stain with Alcian blue except in the cardia.
Cardiac Gland Mucosa The gastric cardia has
branched tubular glands that are primarily mucoustype glands, oxyntic-type glands, or both.22,23 Those
that are mucous but clearly have residual specialized
elements are called cardio-oxyntic. Unlike the antrum,
in which the deep glands are diffuse, in the cardia,
they often are compartmentalized, akin to lobules,
which in normal stomachs allow ease of identification
at low power. Mucus-secreting glands are similar in
appearance on conventional stains to those of the gastric antrum and Brunner’s glands, except for the compartmentalization and lack of overt endocrine cells so
readily seen in the gastric antrum (Fig. 12-7). In contrast to antral glands, portions of the cardiac glands
may contain sialomucins that stain with Alcian blue at
pH 2.5. Parietal cells are commonly ­scattered within
the cardiac glands, although endocrine and chef cells
are rare. Mucous cell–lined cysts are a frequent ­finding
Chapter 12
Modified from Sachs G, Zeng N, Prinz C. Physiology of isolated gastric endocrine cells. Annu Rev Physiol. 1997;59:243–256; and Rindi G, Leiter AB,
Kopin AS, et al. The “normal” endocrine cell of the gut: changing concepts and new evidences. Ann N Y Acad Sci. 2004;1014:1–12.
The Neck Zone (Middle Zone) The neck zone (middle zone) has mucous cells as well as immature stem
cells. This is the generative zone for the stomach, and
all cells above and below are derived from this region.
Mitotic figures are surprisingly sparse, although stains
for Ki-67 show virtually all of the cells to be in the
proliferative phase (Fig. 12-6). The immature stem
cells migrate upward to renew the surface epithelium
or downward to form the differentiated cells of the
glands. These cells are also PAS positive.
The Deep (Glandular) Zone Glands are found in the
deep zone. In contrast to surface mucous cell that is
continuous over the entire stomach surface, regional
differences are mainly in the composition of gastric
tubular glands within each compartment.
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Figure 12-6. Mucous neck region stained with Mib-1 to show
the marked proliferation of this region. The paradox is how
inconspicuous mitotic figures are in this region.
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Figure 12-9. Transitional mucosa (mutilayered epithelium)
that is sometimes seen in the cardiac region. The most superficial cells are mucous secreting, but beneath that, the cells and
their nuclei are stratified as seen in squamous mucosa of the
esophagus. These are discussed further in Chapter 10.
Figure 12-7. Cardiac gland mucosa. The glands in the bottom
half of the section are a mix of mucous glands (cardiac glands)
and fundic gland elements. Mucosal cysts, as seen here, are
a common finding in cardiac gland mucosa. Note the vague
lobularity that is very characteristic of cardia. Occasionally,
­pancreatic-type cells can be seen in these glands but appear to
be without significance.
(Fig. 12-7). The pits in the cardiac region are very shallow, occupying less than one-quarter of the overall
mucosal thickness (Fig. 12-8)—ranging from 0.5 to
1.5 mm—and are immunoreactive with MUC6.
There are at best rare endocrine cells in the gastric
cardia—there are no data to suggest that they have
physiologic or pathologic significance.
Occasionally, pancreatic-type glands can be seen
in the cardia in the form of exocrine cells that are
­immunoreactive with lipase or trypsin. They can be
Figure 12-8. Cardiac glands with pancreatic-type cells (arrows).
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admixed with simple mucous-producing cells or oxyntocardiac mucosa with parietal and mucous-producing glands. Chief cells appear to be rare in the cardia.
Endocrine components admixed with heterotopic
pancreas are vanishingly rare, and endocrine neoplasms even more so. Also, at the squamocolumnar
junction, the so-called multilayered epithelium can
be seen (Fig. 12-9), which seems to be associated with
the development of Barrett’s esophagus. They are
sometimes ciliated. They are discussed in more detail
in Chapter 10.
Oxyntic Mucosa (Fundic and Corpus Gland Mucosa)
Oxyntic gland literally means acid producing so is
a good name for normal corpus and fundic gland
mucosa. Surprisingly, the thickness of the oxyntic
mucosa varies. It is thickest in the greater curve, gradually thins as the antrum is approached, and is thinnest on the lesser curve (Fig. 12-10).
In the oxyntic gastric corpus, pits have four major
cell types (Fig. 12-11): chief cells responsible for pepsinogen production, which can be demonstrated using
pepsinogen 1 (Fig. 12-11A), parietal (oxyntic) cells
that secrete acid and the intrinsic factor necessary
for vitamin B12 absorption and apart from antibodies
to H+K+ ATPase can be demonstrated with PDGFRa
(Fig. 12-11B), mucous neck cells, and a ­variety of endocrine cells (Fig. 12-11C,D). At the interface between
the pits and the parietal cell zone, and scattered
throughout it, are tiny (∼7 mm-wide) ­mucin-containing
neck cells. They are not easily seen with conventionally stained sections, but they can be visualized with
the use of the PAS (neutral mucin) stains and sometimes with Alcian blue pH 2.5. In addition, there are a
­scattering of mucous-­producing cells seen ­throughout
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Figure 12-10. Oxyntic mucosa varies in thickness depending on its location.
vitamin B12, iron, and calcium. It also prevents bacterial
overgrowth and reduces the chances of enteric infection. However, parietal cells also secrete intrinsic factor, transforming growth factor-alpha, amphiregulin,
heparin-binding epidermal growth factor–like growth
factor, and sonic hedgehog.25 The major stimulants of
acid secretion are gastrin, histamine, and acetylcholine, along with ghrelin (centrally but also produced
in the stomach) and orexin (produced ­centrally and
stimulating a craving for food). Indeed, the weight loss
following ­gastrectomy, ­especially proximal, is due to
the loss of this stimulus to eat. The main inhibitor of
acid secretion is somatostatin, along with nitric oxide
and dopamine.
Figure 12-11. Specialized cells of
the oxyntic mucosa can be appreciated with (A) immunostains for
pepsinogen 1, which stains chief
cells and (B) platelet-derived growth
factor receptor alpha (PDGFRa) that
appears to outline the secretory
apparatus (canliculi) of the parietal
cells. In addition, (C) endocrine cells
of the gastric body can be demonstrated with either argyrophylic
stains, here surrounding chief cells
at the base of the glands, or (D)
overview of the numerous diffusely
immunoreactive endocrine cells in
the oxyntic mucosa, here stained
with chromogranin A, which contrasts markedly with the band-like
distribution consisting mainly of G
cells, seen in the antrum.
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Chapter 12
the specialized mucosa in a small proportion of
patients, and they appear to be present and increase
toward the distal end of the oxyntic mucosa.
In the oxyntic mucosa, parietal cells predominate
in the upper half of the glands, and chief cells dominate in the lower half Figure 12-12. The parietal cells
have a round or pyramidal shape, an eosinophilic cytoplasm, and a centrally placed nucleus. The cytoplasm
appears vacuolated or finely reticular, especially in the
perinuclear area, because of the extensive secretory
canaliculae. These can be demonstrated with electron
microscopy,24 or as shown in Figure 12-12B. Parietal
cells produce hydrogen ions as hydrochloric acid which
facilitates the ­digestion of protein and absorption of
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The chief cells contain zymogen granules that are
basophilic, but the degree of basophilia can vary and
can be quite faint, especially in transition zones. Chief
cells have a large basal nucleus and a more cuboidal
shape. They secrete pepsinogens I and II, and these
products can be demonstrated immunocytochemically (Fig. 12-11A).26,27 However, in addition, chief
cells also release pepsinogen, gastric lipase, and the
protease chymosin (formerly known as ­
rennin—to
be distinguished from renin), which commercially is
used to produce cheese from milk. Chief cells release
the zymogen pepsinogen when stimulated by a variety of factors including cholinergic activity from the
vagus nerve and acidic condition in the stomach. Gastrin and secretin may also act as secretagogues. These
cells have the same gastrin and CCK2 receptors found
on parietal cells, enterochromaffin-like (ECL) cells,
and D (somatostatin) cells suggesting similar control.
The parietal and chief cell turnover rates have not
been clearly defined because they are much slower.
In rodents, the turnover for parietal cells has been
estimated to be about 164 days.28 The key feature is
that the specialized compartment in the stomach is
renewed, but the turnover time is in months. Under
stress, both parietal and chief cells appear to be able
to undergo cell division, parietal cells with hypergastrinemia from, for example, PPIs, while chief cells
may also be able to replicate.
The endocrine cells of the fundic gland mucosa
are distributed fairly diffusely throughout the ­oxyntic
mucosa. The presence of endocrine cells is sometimes
suggested by a degree of perinuclear clearing (halo),
although far less than that seen in G-cells in the antrum,
while the nuclei are far less hyperchromatic than
the intraepithelial lymphocytes that may be ­present.
­ ndocrine cells can sometimes be identified on H&E
E
sections in the oxyntic mucosa as nuclei immediately
above the basal lamina of the gland that are not in the
middle of parietal cells and not clearly associated with
chief cell granules (Fig. 12-6B). ­However, the nuclei
need to be observed carefully, for, if very densely
hyperchromatic, they could represent intraepithelial
lymphocytes (demonstrable on CD3 immunostains).
Antral Mucosa The antral glands are coiled branched
tubular glands that appear diffusely located with no,
or at best minimal, hint of the lobular compartmentalization seen in the cardia (Fig. 12-13B), unless atrophy
is present. Glands are predominantly mucous, and
while most are clear, in some patients, the mucous
cells have distinctly eosinophilic granules that can be
either very fine or almost as large as Paneth cell granules, which they can resemble. All (like Paneth cells)
secrete lysozyme. Gastric cells can also upregulate
specific defensins in response to Helicobacter infection, but it is so far unclear if these are produced by
lysozyme-producing cells.29
Numerous endocrine cells are also present
and are primarily gastrin-producing cells (G cells),
sertonin-producing (EC) cells, and somatostatin-­
­
producing cells (D cells) (Fig. 12-14). ­Endocrine cells
appear more frequent in the antrum than in the corpus22
but are concentrated in a band (Fig. 12-12) rather than
being diffusely dispersed (see Fig. 12-11D) and with a
little practice are readily visible at scanning power on
H&E sections (Fig. 12-13). They are easily seen at high
power with virtually any stain (Fig. 12-14). Specific
immunostaining for gastrin shows that the vast majority of these are G cells (Figs. 12-13 and 12-15). If there
is any doubt about whether a specific biopsy is antral
A
Figure 12-12. Oxyntic mucosa. A: Sketch showing that most of the mucosa is composed of the glands with very shallow pits.
Contrast this with the antral gland sketch in Figure 13-6A. (Courtesy of John Petrini, M.D.) B: Overview of oxyntic mucosa in which
the pink parietal cells with their central nuclei (red arrow) predominate in the upper part of the glands and are readily distinguished
from the more purple staining chief cells (dark blue arrow) with their nuclei against the edge of the gland. Probable ECL cells are
insignificant but have a central nucleus and pale cytoplasm (light blue arrows) and occasional mucous-producing cells are also present (green arrow).
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A
561
B
Chapter 12
Figure 12-13. Antral gland mucosa. A: Sketch showing that the thickness of the mucosa is usually less than that of the fundic gland
mucosa. The gastric pits occupy one-half or more of the mucosal thickness. (Courtesy of John Petrini, M.D.) B: Low-power histologic
section in which the “fried egg” or “halo” (originally “waterclear” cells) are readily seen (arrowed).
Figure 12-14. A: Antral mucosa with occasional endocrine “halo” cells scattered regularly down the sides of the midportion of
each crypt. B–D: Immunostains for chromogranin A, which immunostains virtually all of the endocrine cells, and specific stains for
gastrin (C) and serotonin (D), which make up about 2/3 and 1/3 of the cells, while somatostatin are about 5%.
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Figure 12-15. Immunohistochemical stain for gastrin showing the band of G cells in the antrum, here accentuated as there
is hyperplasia from long term PPIs.
or not, additional immunostaining for pepsinogen 1,
if available, help, as they stain oxyntic glands but are
immunonegative in antral mucosa (Fig. 12-16). However, there is a transition zone between antrum and
oxyntic mucosa; in this location, practically, the presence of gastrin cells puts the biopsy in the antrum. In
chromogranin A stains staining (for some ­reason, this
seems to detect G cells much more readily than synaptophysin, but this may vary from lab to lab), the band
of G cells can be detected. Differences between these
two endocrine cell stains are shown in Figure 12-17.
However, in the transition zones, these become more
diffuse and intermixed with oxyntic endocrine cells,
so absolute distinction can be difficult. It also needs to
be appreciated that the G-cell containing portion of the
antrum is relatively distal in the “anatomical” antrum,
the more proximal mucosa being more transitional
as it acquires oxyntic characteristics. This becomes
important as biopsies from histological antrum need
to be taken quite distally—ideally from the prepyloric
region, to guarantee getting the endocrine portion of
the antrum. Whether this matters in looking at biopsies for Helicobacter has not been determined. Gastric
endocrine cells are also discussed subsequently.
Parietal cells can be quite conspicuous in the
antrum and should not be taken as an indication that
one is not in the antrum (Fig. 12-18); indeed, they
often appear to increase in density toward the pylorus, rather than petering out as might be expected, but
detection of the G-cells, even on H&E stains, is usually
easy and confirms the location as being antrum. The
density of parietal cells in the antrum decreases in the
face of moderate to severe antral gland gastritis.30
Mucosal Transition Zones As indicated previously,
all of the cardiac gland mucosa may contain scattered
fundic gland elements, especially parietal cells. This
mixed-gland phenomenon may be equally prominent
in antral–fundic gland transition zones. The transition
zone between fundic gland and antral gland mucosa
does not usually follow the gross anatomic boundaries. It is not uncommon to find a mixed-gland mucosa
extending 5 cm or more, especially along the lesser
curvature. At endoscopy, biopsy specimens taken
from what is considered to be the proximal third of the
antrum may consist entirely of fundic gland mucosa,
Figure
12-16. Typical immunophenotype of gastric antrum with no
pepsinogen 1 immunoreactivity and
strong gastrin immunoreactivity.
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Chapter 12 Stomach: Normal Structures and Developmental Abnormalities
563
which likely does matter if looking for Helicobacter in
what is thought to be antral mucosa; these need to be
taken more distally (we advise from the distal or prepyloric antrum). Furthermore, parietal cells are commonly found scattered throughout the antral gland
mucosa down to the pylorus (Fig. 12-18).30 The presence of parietal cells in a biopsy does not therefore
preclude an antral origin. Although chief cells may be
found in the immediate transition zone between fundic gland and antral gland mucosae, they are usually
absent in the more distal antrum.
Gastric Mucins The gastric mucosa is covered by
mucin-producing cells that play important roles in
protecting gastrointestinal mucosa from a variety of
physical, chemical, and microbial damage.31–33 Mucins
are highly glycosylated glycoproteins and their core
proteins (mucin core proteins: MUC).34 The expression
A
of these mucins and intestinal enzyme are cell-type
specific; hence, they are useful phenotypic indicators
of cell differentiation in normal, metaplastic, or neoplastic epithelial cells in the gastrointestinal tract.35–37
MUC5AC (sometimes just abbreviated to MUC5) is
expressed in gastric surface mucous cells, MUC6 is
expressed in gastric gland mucous cells (cardiac gland
cells, mucous neck cells, and pyloric gland cells), and
MUC2 is expressed in intestinal goblet cells,38–40 The
histochemistry and immunohistochemistry of gastrointestinal mucins are discussed in Chapter 14.
Histochemically, mucins of the surface and pit
epithelium are predominantly of the neutral polysaccharide type and thus stain positively with the periodic acid–Schiff (PAS) stain.41 Much fainter staining
with PAS is seen in parietal cells and in the mucous
glands of the antral and cardiac gland regions. Acid,
nonsulfated mucins (sialomucins) are absent from the
Chapter 12
Figure 12-17. Comparative immunoreactivity
of chromogranin A and synaptophysin in normal antrum and body. Synaptophysin seems to
stain G cells preferentially, while in the oxyntic
mucosa, they are much more similar, with perhaps chromogranin A getting the edge in numbers of endocrine cells stained.
B
Figure 12-18. Parietal cells in the antrum. A: At scanning power, numerous parietal cells are visible. B: Detail shows the parietal
cells (red arrows) and endocrine cells (blue arrows), the latter confirming that this is antral mucosa.
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surface epithelium but are present in small amounts in
the deep pit regions and mucous neck cells. These can
be highlighted by staining with Alcian blue at pH 2.5.41
Gastric Endocrine Cells Enteroendocrine cells (also
defined as the diffuse endocrine system) are specialized endocrine cells of the gastrointestinal tract that
produce hormones such as gastrin, histamine, ghrelin,
serotonin, and somatostatin.42,43 The enteroendocrine
cells are derived from the same stem cells as the rest
of the epithelium and are not derived from the migratory neural crest source that provides the enteric nervous system.44 The enteroendocrine system of the gut
is heterogeneous and is composed of as many as 14
highly specialized cells, some with unknown function.42,43 Table 12-2 lists gastric endocrine cells with
known function.
Most endocrine cells historically can be identified immunohistochemically or with silver stains,
which were among the first methods to assess gastric
­endocrine cells. Endocrine cells in the antrum can be
identified without special stains. The staining properties of endocrine cells displaying intrinsic silver
­reducing power either with or without ammonium ions
being provided. Interaction of some of these cells with
chromium salts (hence enterochromaffin [EC] cells)
proved to be the same cells that could precipitate silver salts in the absence of ammonium ions (e.g., Masson–Fontana stain—argentaffin cells), while all other
cells required the addition of ammonium ions for the
silver to precipitate (e.g., Grimelius, or Sevier–Munger
stains—argyrophil cells). (It will not have escaped
some that the terms argyrophil and argentaffin have
identical meanings, except that the first is of Greek
derivation and the second of Latin.) The staining
of endocrine cells requiring the ­
presence of added
reducing agents (argyrophilia) resulted in the term
enterochromaffin-like cells (ECL cells).43 Because silver stains tend to be capricious, numerous arghyrophil
stains exist, and some were found to be more specific
for certain cell types (e.g., Sevier–Munger for G cells).
Silver impregnation techniques, although effective
and reproducible, have now been largely replaced
with immunohistochemistry (Table 12-1).
In the antral mucosa, most endocrine cells are G
cells, producing gastrin, while most of the remainder
are D (somatostatin-producing) cells (see Table 12-1).
In the oxyntic mucosa, ECL cells secrete histamine
and directly stimulate acid secretion; they can specifically be demonstrated with antibodies to Human
Vesicular Monoamine Transporter 2 (VMAT2). Ghrelin is a peptide hormone that has been localized to the
oxyntic mucosa X/A-like (Gr) cells.45,46 X/A-like cells
that resemble pancreatic A cell (glucagon-producing
cells—hence the A part of the name) are the most
abundant endocrine cells in the stomach after the
Riddell_Chap12.indd 564
histamine-producing cells.46,47 Though ghrelin most
widely known function is growth hormone release
from the pituitary gland; it also plays a role in mediating immune and inflammatory processes.48 Ghrelin
plays an important role in regulating appetite, feeding, and energy metabolism49 in addition to stimulating gastric motility.50 D cells are also the “turn-off” cell
in the oxyntic mucosa.
Acid Secretion Gastric acid secretion is regulated by a complex set of mechanisms acting at the
central, peripheral, and cellular level. A detailed
description of neural regulation (both central and
peripheral) is beyond the scope of this chapter
(interested readers should refer to 22,25). This section is a simplified view of acid secretion in the normal physiologic state, but is required to understand
gastric pathophysiology.
Though the capacity of the stomach to secrete
acid is almost linearly related to parietal cell mass,
the major endocrine cells known to play an important
role in acid secretion are the ECL cell of the fundus,
the gastrin (G) cell of the antrum, and the somatostatin (D) cells of the fundus and antrum. Physiologically, the thought of food enhances release of ghrelin
that initiates acid secretion prior to food ingestion and
orexin that stimulates a craving for food. Gastric distension and the presence of food in the stomach stimulate the release of gastrin from antral G cells. Gastrin
diffuses into the circulation via an autocrine process
to stimulate the parietal cell to produce gastric acid,
both directly acting on parietal cells and indirectly by
stimulating ECL cells to secrete histamine51 via the
CCK2 receptors25 that are found on D cell, ECL cells,
and parietal cells. Parietal cells specifically have the
H2-histaimine receptor, which is why suppression of
acid secretion with H2-receptor antagonists was key
in acid suppressive therapy, especially prior to the
PPI era.
Histamine (and possibly gastrin directly) activates the parietal cell to secrete acid. Thus, in a
normal physiologic state, acid secretion is directly
related to histamine receptor stimulation by ECL
cells. Histamine release from ECL cells is continuous
in the presence of gastrin. As the acidity of the stomach and duodenum increases, further acid secretion
is inhibited through the release of somatostatin by D
cells.52–54 Somatostatin inhibits the secretion of gastrin
and histamine and appears to have a direct inhibitory
effect on the parietal cell.22 Figure 12-19 is a simplified diagram of mechanisms involved in gastric acid
secretion.
Lamina Propria The lamina propria is located between
the pits and contains smooth muscle cells that have very
eosinophilic, and sometimes wavy, ­cytoplasm and are
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Cephalad
displacement
of pancreatic
bud during
embryonic life
Found in
anencephalics
Arrested phase
of normal
development;
vascular factors;
autosomal
recessive
Arrested
Very rare
development of
foregut; familial;
autosomal trait
Embryonic epithelial Very rare account
nodules that fail to
for ~ 4% of
regress
gastrointestinal
duplications;
more common in
females than in
males
As for duplications
Very rare
Pancreatic
Heterotopias68,69
Microgastria74,75
Very rare
Developmental
defect in muscle
Long gastric
ligaments
Muscle defect84,85
Volvulus86,87
Chapter 12
Very rare
Very rare
Very rare
Rare
2% of population
at autopsy
Positional Defects83
Diverticula81,82
Duplications62,76–80
Atresia62,70–79
Aplasia62,70
Persistence of mild
infantile form
Adult67
CLINICAL FEATURES
Gastric perforation more
common in premature
babies
Vomiting
Young patients;
symptoms depend
on location and size;
most gastric emptying
problems; upper
abdominal mass;
perforation; peritonitis
As for duplications
Depends on severity of
lesion and age; infants:
outlet obstruction,
vomiting, gastric
distention; older
children and adults:
peptic ulcer symptoms
Feeding abnormalities
Often asymptomatic;
epigastric pain or
outlet obstruction;
1–3 cm in diameter
within 6 cm of pylorus
0.3% of live
Projectile vomiting in
births, mainly
3rd wk of life; visible
firstborn and male;
gastric peristalsis;
rare in blacks
palpable pylorus
Very rare
Nausea, vomiting
May be familial
Pyloric stenosis
Infantile62–66
PREVALENCE
PATHOGENESIS
DISORDER (REF.)
Table 12-2 Developmental Abnormalities of the Stomach
Hypertrophy and
hyperplasia of circular
muscle; normal
autonomic ganglia
Hypertrophy and
hyperplasia of circular
muscle
Usually submucosal;
pancreatic ducts or
acini; islets less
common
HISTOLOGY
Antrum rotates up and to left or
right
Posterior wall 2 cm below
esophagogastric junction
Right-sided stomach
Inversion: pylorus
more cephalad than
esophagogastric junction
Mainly greater curvature rupture
and perforation
Variably sized cyst; often greater
curvature
Usually no communication with
gastric lumen
All layers of stomach;
rarely lined by
squamous epithelium
Complete segmental defect;
Gastric mucosa;
stomach ends blindly
rarely, squamous
Fibrous cord. Atretic strand of
epithelium
mucosa and seromuscular layer
Webs: by endoscopy, portion
distal to web can be mistaken
for duodenal bulb
Small stomach
Failure to rotate and differentiate
into different parts
Gastric filling defect with central
umbilication; may be cystic
Pyloric channel elongated and
narrowed
A 2- to 3-cm ovoid mass in
­pylorus; knob-like projection
into duodenum
GROSS APPEARANCES
Situs inversus
As for duplications
May also involve
esophagus; onethird of patients
have other
anomalies
Other congenital
malformations
Pancreatitis,
carcinoma (rare)
Exclude peptic ulcer
and malignancy
COMMENT
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Figure 12-19. Diagram of known mechanisms involved
in gastric acid secretion.
frequently confused with other cells, very few fibroblasts, macrophages, eosinophils, plasma cells, and lymphocytes. Mast cells are scattered in the interpit regions
as well as between the fundic glands.55 In the gastric corpus, glands are so tightly packed that it may be hard to
see the lamina propria, except just beneath the surface
mucous cells. Small lymphoid follicles may be seen just
above the muscularis mucosae; these are normal and
physiological56—we disagree with the notion that no lymphoid aggregates are present normally. They are usually
small but present nonetheless. There is also a finely dispersed network of reticulin and collagen fibers. These,
as well as fibers of smooth muscle, extend upward from
the muscularis mucosae and may appear as fern-like
streamers in the lamina propria, reaching the superficial
portion of the mucosa. This is a more prominent finding
in the antrum, especially near the pylorus.
Tiny vessels are seen in the lamina propria, but
it may be impossible to differentiate lymph capillaries from blood capillaries without the use of
immunohistochemistry. With electron microscopy,
­
it has been demonstrated that, like the large bowel,
lymph capillaries are primarily confined to the basal
portion of the mucosa just above the muscularis
mucosae. In contrast, blood capillaries are distributed
throughout the mucosa.57
There is considerable normal variation in the
density of the lamina propria cells located between
the pits. This variability is more prominent in antral
gland mucosa, where the pits are longer. However,
while occasional lymphocytes, histiocytes, mast cells,
Riddell_Chap12.indd 566
and eosinophils are present, plasma cells are uncommon, and more that occasional cells reflect chronic
inflammation. Neutrophils are normally absent.
Muscularis Mucosae As elsewhere throughout the
intestinal tract, the muscularis mucosae has both a
thin layer of internal, primarily circular, muscle and
an outer longitudinal layer. In the cardiac and antral
glands, mucosal strands of muscle fibers may radiate
into the lamina propria from the muscularis mucosae. This may be very prominent in the distal antrum
and, on first glance, may be misinterpreted as fibrosis.
Sometimes, lymphoid follicles are located at the bases
of the glands above the muscularis mucosae, or they
may actually breach it and occupy part of the upper
submucosa.
Submucosa. The submucosa consists of loose connective tissue, a rich plexus of blood vessels, sizable
lymphatic vessels, the ganglion cells of Meissner’s
plexus, scattered mast cells, and mononuclear cells.
Muscularis propria, ICCs, and serosa. The muscularis propria consists of three layers: outer longitudinal, middle circular, and inner oblique. The outer
longitudinal layer is most concentrated along both
curvatures. The middle circular zone encircles the
body of the stomach and is thickened distally to form
the pyloric sphincter. The inner oblique fibers pass
down from the fundus over both the anterior and
posterior walls.
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Chapter 12 Stomach: Normal Structures and Developmental Abnormalities
A
567
B
Figure 12-20. Heterotopic islands of endocrine mucosa (A) in the oxyntic mucosa (adjacent normal oxyntic mucosa is seen right)
and (B) in the antrum. In both, the waterclear “halo” cells are present in abundance.
DEVELOPMENTAL ABNORMALITIES
OF THE STOMACH
With the exception of infantile pyloric stenosis and
pancreatic heterotopia, most of the other developmental abnormalities of the stomach are rare. Some
findings, such as goblet cells in the stomach of adults,
are difficult to classify as a rare congenital cause,59,60
because intestinal metaplasia is such a common
accompaniment of nonerosive gastritis or focal injury.
Gastric heterotopias, in which gastric tissue is
located outside of the stomach, are not discussed here.
These are discussed in the chapters dealing with specific regions of the gastrointestinal tract as in gastric
heterotopia in the upper esophagus and in Meckel’s
diverticulum. Gastric heteroptopia occurs in a variety of organs and is discussed there. Gastric hamartomas are discussed in Chapter 14. Within the stomach,
occasionally, small islands of islet tissue can be found
in both the antral or oxyntic mucosa in the absence of
any other features (Fig. 12-20).
Riddell_Chap12.indd 567
Pathogenesis and Clinical Features
The pathogenesis of developmental disorders is poorly
understood.61 Table 12-2 outlines and references the
various disorders. With the exception of pancreatic
heterotopia, most congenital anomalies present in the
postnatal period or in childhood. Rarely, pyloric stenosis gastric duplications and gastric webs present in
adulthood.
References
1. Moore KL, ed. The Developing Human: Clinically Oriented
Embryology. 7th ed. Philadelphia, London, Toronto: W.B.
Saunders Company; 2013.
2. Tsutsumi Y. Immunohistochemical studies on glucagon,
glicentin and pancreatic polypeptide in human stomach: normal and pathological conditions. Histochem J.
1984;16(8):869–883.
3. Stein BA, Buchan AM, Morris J, et al. The ontogeny of
regulatory peptide-containing cells in the human fetal
stomach: an immunocytochemical study. J Histochem
Cytochem. 1983;31(9):1117–1125.
4. Yasugi S. Regulation of pepsinogen gene expression in epithelial cells of vertebrate stomach during development.
Int J Dev Biol. 1994;38(2):273–279.
5.Johnson LR. Functional development of the stomach.
Annu Rev Physiol. 1985;47:199–215.
6. Deren JS. Development of structure and function in the
fetal and newborn stomach. Am J Clin Nutr. 1971;24(1):
144–159.
7. Park YS, Park HJ, Kang GH, et al. Histology of gastroesophageal junction in fetal and pediatric autopsy. Arch
Pathol Lab Med. 2003;127(4):451–455.
8. Chandrasoma PT. Fetal “cardiac mucosa” is not adult cardiac mucosa. Gut. 2003;52(12):1798; author reply 9.
9. De Hertogh G, Van Eyken P, Ectors N, Geboes K. On the
origin of cardiac mucosa: a histological and immunohistochemical study of cytokeratin expression patterns in the
developing esophagogastric junction region and stomach.
World J Gastroenterol. 2005;11(29):4490–4496.
Chapter 12
The muscularis propria is bounded on its outer
surface by a serosa similar to that of the other regions
of the gut. It consists of loose connective tissue
and contains blood vessels, lymphatics, and nerve
fibers. The muscularis propria is richly innervated
with nerves, while interstitial cells of Cajal are present both in and immediately around the myenteric
plexus, while intramuscular interstitial cells are also
present in all layers of the muscle. If interstitial cells
are being assessed, it is very wise to have normal controls, ideally from the same area of the stomach, with
which they can be compared.58
2/6/2014 12:41:33 PM
568
Lewin, Weinstein, and Riddell’s Gastrointestinal Pathology and Its Clinical Implications
10. Riddell RH, Odze RD. Definition of Barrett’s esophagus:
time for a rethink–is intestinal metaplasia dead? Am J Gastroenterol. 2009;104(10):2588–2594.
11. Ronkainen J, Aro P, Storskrubb T, et al. Prevalence of Barrett’s esophagus in the general population: an endoscopic
study. Gastroenterology. 2005;129(6):1825–1831.
12. Schutze M, Schulz M, Steffen A, et al. Beer consumption
and the ‘beer belly’: scientific basis or common belief? Eur
J Clin Nutr. 2009;63(9):1143–1149.
13. Owen DA. Normal histology of the stomach. Am J Surg
Pathol. 1986;10(1):48–61.
14.Gottfried MR, McClave SA, Boyce HW. Incomplete
intestinal metaplasia in the diagnosis of columnar
lined esophagus (Barrett’s esophagus). Am J Clin Pathol.
1989;92(6):741–746.
15. Ishimura N, Amano Y, Kinoshita Y. Endoscopic definition of esophagogastric junction for diagnosis of Barrett’s
esophagus: importance of systematic education and training. Dig Endosc. 2009;21(4):213–218.
16. Sato T, Kato Y, Matsuura M, et al. Significance of palisading longitudinal esophagus vessels: identification of
the true esophagogastric junction has histopathological
and oncological considerations. Dig Dis Sci. 2010;55(11):
3095–3101.
17. Moore JG, Dubois A, Christian PE, et al. Evidence for a
midgastric transverse band in humans. Gastroenterology.
1986;91(3):540–545.
18.Rubin W, Ross LL, Sleisenger MH, et al. The normal
human gastric epithelia. A fine structural study. Lab
Invest. 1968;19(6):598–626.
19. Helander HF. The cells of the gastric mucosa. Int Rev
Cytol. 1981;70:217–289.
20. Day DW, Morson BC. Structure and infrastructure. Front
Gastrointest Res. 1980;6:1–19.
21. Macdonald WC, Trier JS, Everett NB. Cell proliferation and
migration in the stomach, duodenum, and rectum of man:
radioautographic studies. Gastroenterology. 1964;46:405–417.
22. Hersey SJ, Sachs G. Gastric acid secretion. Physiol Rev.
1995;75(1):155–189.
23. el-Zimaity HM, Verghese VJ, Ramchatesingh J, et al. The
gastric cardia in gastro-oesophageal disease. J Clin Pathol.
2000;53(8):619–625.
24. Helander HF, Leth R, Olbe L. Stereological investigations
on human gastric mucosa: I. Normal oxyntic mucosa.
Anat Rec. 1986;216(3):373–380.
25. Schubert ML. Gastric exocrine and endocrine secretion.
Curr Opin Gastroenterol. 2009;25(6):529–536.
26. Samloff IM. Cellular localization of group I pepsinogens in
human gastric mucosa by immunofluorescence. Gastroenterology. 1971;61(2):185–188.
27.Samloff IM, Liebman WM. Cellular localization of the
group II pepsinogens in human stomach and duodenum
by immunofluorescence. Gastroenterology. 1973;65(1):
36–42.
28. Li H, Helander HF. Parietal cell kinetics after administration of omeprazole and ranitidine in the rat. Scand J Gastroenterol. 1995;30(3):205–209.
29. Otte JM, Neumann HM, Brand S, et al. Expression of
beta-defensin 4 is increased in human gastritis. Eur J Clin
Invest. 2009;39(2):126–138.
30. Tominaga K. Distribution of parietal cells in the antral mucosa
of human stomachs. Gastroenterology. 1975;69(6):1201–1207.
31. Slomiany BL, Slomiany A. Role of mucus in gastric mucosal protection. J Physiol Pharmacol. 1991;42(2):147–161.
32. Ota H, Katsuyama T. Alternating laminated array of two
types of mucin in the human gastric surface mucous layer.
Histochem J. 1992;24(2):86–92.
Riddell_Chap12.indd 568
33. Matsuo K, Ota H, Akamatsu T, et al. Histochemistry of
the surface mucous gel layer of the human colon. Gut.
1997;40(6):782–789.
34. Moniaux N, Escande F, Porchet N, et al. Structural organization and classification of the human mucin genes. Front
Biosci. 2001;6:D1192–D1206.
35.Akamatsu T, Katsuyama T. Histochemical demonstration of mucins in the intramucosal laminated structure of
human gastric signet ring cell carcinoma and its relation
to submucosal invasion. Histochem J. 1990;22(8):416–425.
36. Tatematsu M, Tsukamoto T, Inada K. Stem cells and gastric cancer: role of gastric and intestinal mixed intestinal
metaplasia. Cancer Sci. 2003;94(2):135–141.
37. Ota H, Katsuyama T, Ishii K, et al. A dual staining method
for identifying mucins of different gastric epithelial
mucous cells. Histochem J. 1991;23(1):22–28.
38.Buisine MP, Devisme L, Maunoury V, et al. Developmental mucin gene expression in the gastroduodenal
tract and accessory digestive glands. I. Stomach. A relationship to gastric carcinoma. J Histochem Cytochem.
2000;48(12):1657–1666.
39. Buisine MP, Devisme L, Degand P, et al. Developmental mucin gene expression in the gastroduodenal tract
and accessory digestive glands. II. Duodenum and
liver, gallbladder, and pancreas. J Histochem Cytochem.
2000;48(12):1667–1676.
40. Nakajima K, Ota H, Zhang MX, et al. Expression of gastric
gland mucous cell-type mucin in normal and neoplastic
human tissues. J Histochem Cytochem. 2003;51(12):1689–1698.
41. Filipe MI. Mucins in the human gastrointestinal epithelium: a review. Invest Cell Pathol. 1979;2(3):195–216.
42. Sachs G, Zeng N, Prinz C. Physiology of isolated gastric
endocrine cells. Annu Rev Physiol. 1997;59:243–256.
43. Rindi G, Leiter AB, Kopin AS, et al. The “normal” endocrine cell of the gut: changing concepts and new evidences. Ann N Y Acad Sci. 2004;1014:1–12.
44. Thompson M, Fleming KA, Evans DJ, et al. Gastric endocrine cells share a clonal origin with other gut cell lineages. Development. 1990;110(2):477–481.
45. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growthhormone-releasing acylated peptide from stomach.
Nature. 1999;402(6762):656–660.
46. Date Y, Kojima M, Hosoda H, et al. Ghrelin, a novel growth
hormone-releasing acylated peptide, is synthesized in a
distinct endocrine cell type in the gastrointestinal tracts of
rats and humans. Endocrinology. 2000;141(11):4255–4261.
47. Simonsson M, Eriksson S, Hakanson R, et al. Endocrine
cells in the human oxyntic mucosa. A histochemical
study. Scand J Gastroenterol. 1988;23(9):1089–1099.
48. Tesauro M, Schinzari F, Caramanti M, et al. Cardiovascular and metabolic effects of Ghrelin. Curr Diabetes Rev.
2010;6(4):228–235.
49. Suzuki K, Simpson KA, Minnion JS, et al. The role of gut
hormones and the hypothalamus in appetite regulation.
Endocr J. 201057(5):359–372.
50. Falken Y, Hellstrom PM, Sanger GJ, et al. Actions of prolonged ghrelin infusion on gastrointestinal transit and
glucose homeostasis in humans. Neurogastroenterol Motil.
201022(6):e192–e200.
51. Prinz C, Zanner R, Gratzl M. Physiology of gastric enterochromaffin-like cells. Annu Rev Physiol. 2003;65:371–382.
52. Lloyd KC, Wang J, Aurang K, et al. Activation of somatostatin receptor subtype 2 inhibits acid secretion in rats. Am J
Physiol. 1995;268(1 pt 1):G102–G106.
53. Martinez V, Curi AP, Torkian B, et al. High basal gastric
acid secretion in somatostatin receptor subtype 2 knockout mice. Gastroenterology. 1998;114(6):1125–1132.
2/6/2014 12:41:33 PM
Chapter 12 Stomach: Normal Structures and Developmental Abnormalities
54. Schubert ML, Edwards NF, Makhlouf GM. Regulation of
gastric somatostatin secretion in the mouse by luminal
acidity: a local feedback mechanism. Gastroenterology.
1988;94(2):317–322.
55.Steer HW. Mast cells of the human stomach. J Anat.
1976;121(pt 2):385–397.
56. Graham DY, Opekun AR, Osato MS, et al. Challenge model
for Helicobacter pylori infection in human volunteers.
Gut. 2004;53(9):1235–1243.
57. Lehnert T, Erlandson RA, Decosse JJ. Lymph and blood
capillaries of the human gastric mucosa. A morphologic
basis for metastasis in early gastric carcinoma. Gastroenterology. 1985;89(5):939–950.
58. Harberson J, Thomas RM, Harbison SP, et al. Gastric neuromuscular pathology in gastroparesis: analysis of fullthickness antral biopsies. Dig Dis Sci. 2010;55(2):359–370.
59. Kimura K. Chronological transition of the fundic-pyloric
border determined by stepwise biopsy of the lesser and
greater curvatures of the stomach. Gastroenterology.
1972;63(4):584–592.
60. Salenius P. On the ontogenesis of the human gastric epithelial cells. A histologic and histochemical study. Acta
Anat Suppl (Basel). 1962;50(46):1–76.
61. Berant M, Aviad I, Jacobs J. Heterotopic duodenal mucosa
in the stomach. Am J Dis Child. 1965;110(5):566–569.
62.Simstein NL. Congenital gastric anomalies. Am Surg.
1986;52(5):264–268.
63. Shim WK, Campbell A, Wright SW. 276 cases of pyloric
stenosis in Hawaii. II. Racial aspects. Hawaii Med J.
1970;29(4):292–295.
64. Friesen SR, Pearse AG. Pathogenesis of congenital pyloric
stenosis: histochemical analyses of pyloric ganglion cells.
Surgery. 1963;53:604–608.
65.Grant GA, McAleer JA. Increasing incidence of infantile hypertrophic pyloric stenosis, 1971–1983. Ir Med J.
1986;79(5):118–119.
66. Leahy PF, Farrell R, O’Donnell B. 300 infants with hypertrophic pyloric stenosis: presentation and outcome. Ir Med
J. 1986;79(5):114–116.
67. Wellmann KF, Kagan A, Fang H. Hypertrophic Pyloric Stenosis in Adults. Survey of the Literature and Report of a
Case of the Localized Form (Torus Hyperplasia). Gastroenterology. 1964;46:601–608.
68. Dolan RV, ReMine WH, Dockerty MB. The fate of heterotopic pancreatic tissue. A study of 212 cases. Arch Surg.
1974;109(6):762–765.
69.Rose C, Kessaram RA, Lind JF. Ectopic gastric pancreas: a review and report of 4 cases. Diagn Imaging.
1980;49(4):214–218.
Riddell_Chap12.indd 569
569
70. Guttman FM, Braun P, Garance PH, et al. Multiple atresias and a new syndrome of hereditary multiple atresias
involving the gastrointestinal tract from stomach to rectum. J Pediatr Surg. 1973;8(5):633–640.
71. Bar-Maor JA, Nissan S, Nevo S. Pyloric atresia. A hereditary congenital anomaly with autosomal recessive transmission. J Med Genet. 1972;9(1):70–72.
72. Clements JL Jr, Jinkins JR, Torres WE, et al. Antral mucosal diaphragms in adults. Am J Roentgenol. 1979;133(6):
1105–1111.
73.Feliciano DV, van Heerden JA. Pyloric antral mucosal
webs. Mayo Clin Proc. 1977;52(10):650–653.
74. Shackelford GD, McAlister WH, Brodeur AE, et al. Congenital microgastria. Am J Roentgenol Radium Ther Nucl
Med. 1973;118(1):72–76.
75.Kessler H, Smulewicz JJ. Microgastria associated with
agenesis of the spleen. Radiology. 1973;107(2):393–396.
76.Chen YM, Teague RS, Ott DJ, et al. Gastric duplication cyst simulating leiomyoma. Gastrointest Endosc.
1987;33(3):250–252.
77.Bidwell JK, Nelson A. Prenatal ultrasonic diagnosis of
congenital duplication of the stomach. J Ultrasound Med.
1986;5(10):589–591.
78. Tihansky DP, Sukarochana K, Hanrahan JB. Pyloroduodenal duplication cyst. Am J Gastroenterol. 1986;81(3):
189–191.
79. Abrami G, Dennison WM. Duplication of the stomach.
Surgery. 1961;49:794–801.
80. Wieczorek RL, Seidman I, Ranson JH, et al. Congenital
duplication of the stomach: case report and review of the
English literature. Am J Gastroenterol. 1984;79(8):597–602.
81. Meeroff M, Gollan JR, Meeroff JC. Gastric diverticulum.
Am J Gastroenterol. 1967;47(3):189–203.
82. Mc LN, Purves JK, Saunders RL. The genesis of gastric and
certain intestinal diverticula and enterogenous cysts. Surg
Gynecol Obstet. 1954;92(2):135–141.
83.Hewlett PM. Isolated dextrogastria. Br J Radiol. 1982;
55(657):678–681.
84. Shaw A, Blanc WA, Santulli TV, et al. Spontaneous rupture
of the stomach in the newborn: a clinical and experimental study. Surgery. 1965;58:561–571.
85. Bayatpour M, Bernard L, McCune F, et al. Spontaneous
gastric rupture in the newborn. Am J Surg. 1979;137(2):
267–269.
86.Patel NM. Chronic gastric volvulus: report of a case
and review of literature. Am J Gastroenterol. 1985;80(3):
170–173.
87. Idowu J, Aitken DR, Georgeson KE. Gastric volvulus in
the newborn. Arch Surg. 1980;115(9):1046–1049.
Chapter 12
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