ESOPHAGUS

Slide 3:
The topics discussed in the lecture are secondary to “chronic injury”
due to an inciting agent. In response to chronic injury, the cells undergo
metaplasia which is an adaptive response where the original cell type
sensitive to particular stress (chronic injury) is gradually replaced by
another cell type that is better able to withstand that stress. Eventually,
the growth may undergo dysregulation, and metaplasia may progress
to dysplasia and invasive carcinoma.

Slide 5:
The esophagus is a tubular structure connecting the pharynx to the
stomach. The images depict a gross and corresponding microscopic
H&E stained cross-section of the esophagus. The layers of the
esophageal wall are marked from A through D and include mucosa,
submucosa, muscularis propria, and adventitia.

Slide 6:
This figure depicts a higher magnification view of the squamous mucosa
with the underlying submucosa and muscularis propria. The squamous
mucosa is formed by squamous epithelium, sub-epithelium, and
muscularis mucosae.

Slide 7:
The image depicts gastro-esophageal (GE) junction where the
squamous mucosa transitions to the glandular gastric mucosa. It is a
site of chronic injury due to reflux of acid from the stomach into the
esophagus.

Slide 9:
Establishing a diagnosis requires observation, interpretation, and
conclusion of the findings.
When Barrett's esophagus (BE) was first described, it was interpreted as
a congenital disease process where the patients had a small esophagus
with the stomach pulled up into the chest cavity. Ulcers and strictures
seen in association with these changes were thought to be secondary
to acid production by the mediastinal segment of the stomach. The
interpretation while inaccurate makes understanding the diagnosis
easier.

Slide 10:
In response to chronic injury from acid, the squamous mucosa
undergoes changes known as reflux esophagitis

Slide 11:
Long-standing reflux esophagitis results in metaplastic change where
the squamous epithelium is replaced by glandular mucosa which is
better equipped to deal with the acid injury

Slide 13:
The glandular metaplastic change is morphologically represented by
two types of epithelial cells: the foveolar or gastric type and goblet cells
or intestinal type.

Slide 14:
The appropriate terminology for this change is columnar metaplasia
with goblet cells. In the US, the presence of metaplastic goblet cells is
required for a diagnosis of BE; however, in Europe, the presence of
foveolar epithelial cells, even without goblet cells, is sufficient for a
diagnosis of BE.

Slide 17:
The images from Dr. Barrett’s article appear reasonable, except now we
know that BE is not a congenital disease process but a metaplastic
change secondary to chronic acid injury.

Slide 19:
As discussed earlier, metaplasia may progress to dysplasia which is
unregulated growth of cells secondary to acquired genetic
abnormalities

Slide 20:
Microscopically, the metaplastic glands show increased mitosis,
apoptosis, higher nuclear/cytoplasmic ratio and nuclear density/gland

Slide 21:
Dysplasia is still limited to the mucosa. Dysplasia has a 0% risk of
metastasis due to the lack of access to lymphatics, implying endoscopic
resection is curative.

Slide 22:
If left untreated, dysplasia progresses to invasive carcinoma
STOMACH

Slide 24:
The function of the stomach is to produce acid and the intrinsic factor
which are secreted by the parietal cells and pepsin by the chief cells.
The stomach itself and the adjacent organs are protected from the acid
injury by cells that produce mucin. These include the superficial
foveolar cells which line the entire stomach and the lamina propria
mucin-producing cells which include the cardiac, mucus and pyloric
glands. The acid production is controlled by neuroendocrine cells, G
cells, and ECL cells.

Slide 25:
The parietal cells are pink and granular while the chief cells are
amphophilic with zymogen granules.

Slide 26:
Foveolar epithelial cells have a basal nucleus and an apical mucin
vacuole.

Slide 27:
The lamina propria mucin glands have a multi-vacuolated cytoplasm
and basal, peripheral nucleus.

Slide 28-30:
The acid regulating cells are G cells and ECL cells. The G cells produce
gastrin which acts on the ECL cells to release histamine. The histamine
acts on the parietal cells to release H+ which inhibit the release of
gastrin by the G cells.

Slide 31:
The stomach can be grossly divided into body/fundus where the acid
and pepsin secreting cells are present. The transitional zones, cardia
(towards esophagus) and antrum/pylorus (towards duodenum) contain
lamina propria cardiac/pyloric glands. The entire surface of the stomach
is lined with foveolar epithelial cells. The G cells are present in the
antrum, and ECL cells are present in the body/fundic mucosa.

Slide 34:
The observation, interpretation, and diagnosis of autoimmune gastritis
(AIG) were accurate even in the late 1800s because of astute
observations in an autopsy on a patient with malnourishment and no
evidence of carcinoma. On autopsy, the patient was found to be
healthy except for no acid in the stomach and atrophy of the gastric
tubules. The gastric contents were unable to digest egg albumin. The
conclusion was the lack of acid and acid producing cells led to the
patient’s demise. The disease was called pernicious anemia (PA).

Slide 35:
The pathogenesis of AIG involves an immune-mediated attack against
the parietal cells which leads to metaplastic change and less acid in the
stomach. The metaplastic cells that replace the gastric parietal cells are
pyloric-type cells (pseudopyloric metaplasia) and goblet cells (intestinal
metaplasia). The loss of acid leads to increased gastrin and subsequent
ECL-cell hyperplasia.

Slide 36 and 37:

Images showing normal body/fundic mucosa and body/fundic mucosa
affected by AIG

Slide 38:
Spatially, the body/fundic mucosa is the only site affected by AIG; the
remaining gastric mucosa is unaffected.

Slides 39-41:
As discussed earlier, the metaplastic change may progress to dysplasia
and adenocarcinoma.

Slide 42:
Additionally, the ECL cell hyperplasia may progress to a neuroendocrine
tumor.

Slide 43-44:
Although H. pylori is a well-recognized carcinogen now, the diagnosis
was not believed by the medical community until a pathologist and a
gastroenterologist duo (Marshal and Warren, shown here) took it to
themselves to prove the pathogenicity using Koch’s postulate.

Slide 47:
Because of the pH preference, the bacteria live in the antrum at the
preferable pH of 3.5-5.

Slide 48-49:
In comparison with normal antrum, the mucosa in H pylori gastritis in
virtually all infected individuals elicits an inflammatory response to the
bacterial toxins characterized by infiltration of lamina propria with
neutrophils, f/b T and B lymphocytes and plasma cells along with
epithelial cell damage.

Slide 50:
While the bacteria can be visualized with H&E, special stains may be
utilized to confirm their absence. These include a Silver stain for
spirochetes, Alcian blue or Giemsa stain, and immunohistochemistry.

Slide 51:
As discussed earlier, the bacteria live in the antrum because of the pH
preference. The bacteria may migrate to the duodenum, causing a
duodenal ulcer, or to body mucosa causing a gastric ulcer.
Slide 52-58:
Chronic injury leads to metaplastic change where gastric antral mucosal
cells are replaced by intestinal-type cells; the metaplasia may be
followed by dysplasia and adenocarcinoma.

Slide 59-60:
Also seen with H pylori gastritis is lymphoid hyperplasia; in some
individuals, a MALT lymphoma may develop secondary to persistent H
pylori infection.

Slide 62:
Pathogenesis of gastric damage leading to peptic ulcer disease (PUD)
always stems from the imbalances b/w mucosal defense mechanisms
and damaging factors. NSAIDs injury is an emerging cause of PUD in
individuals older than 60 years. While increased acid is central to the
remaining etiologies; the NSAIDS cause injury by lowering the mucosal
defense mechanisms. NSAIDs inhibit the synthesis of mucosal-
protective prostaglandins produced by the constitutive COX-1 activity.
Direct drug-mediated irritant effects on epithelial cells appear to play
only a minor role in GI toxicity. A rare cause of PUD is Zollinger Ellison
Syndrome (ZES) which includes a triad of gastrinoma, diffuse parietal
cell hyperplasia, and peptic ulcer disease.

Slide 63:
A classic benign/peptic ulcer is a round-oval, sharply punched-out
mucosal defect, without heaped up margins. The base is smooth as a
result of peptic digestion of the exudate.

Slide 64:
In contrast, a malignant ulcer has heaped-up borders and central
ulceration.
Slide 65:
Image of a gastric ulcer shows full thickness defect of the mucosa. If the
base of the ulcer involves a submucosal vessel, it may lead to profuse
bleeding.