Approach to liver biopsies

Stomach

Dr. Dua Abuquteish

Pathology lectures 4 and 5

Anatomy of the stomach

Foveolar cells (mucin-secreting)

Parietal cells (HCL & IF) and chief cells (pepsinogen)

Mucus and endocrine cells- G cells (gastrin)

Anatomy of a child's stomach

Stomach (topics to be discussed)

• GASTRITIS

(Reactive gastropathy, chronic gastritis; including autoimmune gastritis)

• GASTRIC POLYPS AND TUMORS


• GASTRITIS

Chemical (reactive) gastropathy, chronic gastritis ; including autoimmune gastritis


Gastritis – main causes

• Nonsteroidal anti-inflammatory drugs (NSAIDs)

• Infection by urease-secreting H. pylori

• Hypoxemia, decreased oxygen delivery, and reduced blood flow (ex: in people who lives in high altitudes and critically ill-patients with hypovolemia)

• Direct injury to epithelial and stromal cells (ingestion of harsh chemicals, particularly acids or bases). Injury also induced by excessive alcohol consumption, NSAID use, and radiation therapy.

GastritisMechanism of gastric injury and protection

Gastric lumen is strongly acidic (pH ~ 1).

High acidity is important for digestion, but also has the potential to damage the mucosa.

Multiple mechanisms have evolved to protect the gastric mucosa.

GastritisMechanism of gastric injury and protection

Mucin secreted by surface foveolar cells forms a thin layer of mucus that prevents large food particles from directly touching the epithelium.

The mucus layer has a neutral pH as a result of secretion of bicarbonate ions by surface epithelial cells.

The rich blood supply of the gastric mucosa efficiently buffers and removes protons that back diffuse into the lamina propria.

Disruption of any of these protective mechanisms causes gastritis

GastritisDisruption of the adherent mucous

layer

↑ HCL secretion with H ions back-diffusion into the

superficial epithelium

↓ production of bicarbonate

buffer by superficial

epithelial cellsReduced mucosal

blood flow

Direct damage to the epithelium


• GASTRITIS

Chemical (reactive) gastropathy, chronic gastritis, autoimmune gastritis


Chemical (reactive) gastropathy

The most common gastric injury pattern, and is the most common diagnosis of ‘gastritis’ (endoscopic redness) made in practice

Reactive (chemical) gastropathy: occurs when cell injury and regeneration are present but inflammatory cells are rare or absent.


Commonly seen in patients taking medications such as:

NSAIDs (most common), acetylsalicylic acid (Aspirin), bisphosphonates, iron, tetracyclines (especially doxycycline), selective serotonin reuptake inhibitors SSRI, and alcohol

Also post surgical bile reflux

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs inhibit cyclooxygenase (COX)-dependent synthesis of prostaglandins E2 and I2

PG E2 and I2 stimulate all the above defense mechanisms (mucus and bicarbonate secretion, mucosal blood flow, and epithelial restitution).

Although COX-1 plays a larger role than COX-2, both isoenzymes contribute to mucosal protection.

Injury is greatest with nonselective inhibitors (aspirin, ibuprofen, and naproxen), In contrast to selective COX-2 inhibition (celecoxib)


Reactive gastropathy has an acute phase and a chronic phase

Acute phase: Chemical “erosive” gastropathy

Chronic phase: Chemical “non-erosive” gastropathy

Chemical “erosive” gastropathy

• Mucin depletion often dominates the picture, and may be accompanied by erosions, ulcers, and local oedema

An area of erosion; the superficial epithelium is eroded (absent)

Chemical (non-erosive) gastropathy

• Foveolar hyperplasia “corkscrew appearance”, smooth muscle hyperplasia in the lamina propria, and capillary dilatation and congestion.

• There is relative absence of acute and chronic inflammatory cells

smooth muscle hyperplasia

Chemical (non-erosive)gastropathy

“Corkscrew appearance”

Chemical gastropathy

Iron-induced gastropathy:

In patients with iron overdose

A. Therapeutic iron causes brown crystalline iron material in superficial gastric biopsies

B. Iron stains blue by using “Perl’s stain”

A

B


• GASTRITIS Chemical (reactive) gastropathy, chronic gastritis; including autoimmune gastritis


CHRONIC GASTRITIS

The most common cause of chronic gastritis is infection with the bacillus Helicobacter pylori (H. pylori).

• Autoimmune gastritis represents less than 10% of cases of chronic gastritis but is the most common cause in patients without H. pylori infection.

• Chronic NSAID use is a third important cause of gastritis in some populations, as discussed later.

• The signs and symptoms may include nausea and upper-abdominal discomfort.

HELICOBACTER PYLORI GASTRITIS (H .pylori)

• H. pylori is a spiral-shaped or curved bacilli.

• Acute H. pylori infection is subclinical in most cases; rather, it is the chronic gastritis that ultimately brings the patient to medical attention.

• A worldwide pathogen with the highest infection rates in developing countries (Low socioeconomic status).

How was H. pylori discovered

• Barry J. Marshall and Robin Warren, two Australian researchers who discovered the bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease, have been awarded this year's Nobel Prize in Physiology or Medicine.

• In 1985, for example, Marshall underwent gastric biopsy to put evidence that he didn't carry the bacterium, then deliberately infected himself to show that it in fact caused acute gastric illness.

Diseases associated with H. pylori infection

Pathophysiology: mechanism of tissue injury;H. pylori is a noninvasive curvilinear gram-negative rod

Direct (Bacterial virulence): Indirect: Bacterial products lead to:

Flagella: allow the bacteria to be motile in viscous mucus.

↑ production of cytokines as IL-1, IL-6 … that recruits inflammatory cells with subsequent inflammation and tissue damage.Urease: generates ammonia from urea

elevating gastric pH around the organisms and protecting it from the acidic secretions.

Adhesins: enhance bacterial adherence to surface foveolar cells.

Toxins, such as that encoded by cytotoxin-associated gene A (CagA), that may be involved in ulcer or cancer development.

Pathophysiology: mechanism of tissue injury

H. Pylori associated chronic gastritis

Chronic gastritis (commonest form):

Normal acidity and no atrophy

Antral-type gastritis:

High HCL production (hyperchlohydria).

Higher risk for the development of duodenal ulcer (DU).

Pangastritis (involving oxyntic mucosa and causing parietal cell damage):

Multifocal mucosal atrophy

Low HCL production (hypochlorhydria)

Increased risk for gastric ulcer, intestinal metaplasia, & adenocarcinoma.

H. Pylori associated chronic gastritis

MORPHOLOGY:

• Antral biopsies are preferred for evaluation of H. pylori gastritis.

• Histologically: H. pylori organisms are seen within mucus overlying epithelial cells.

• The lamina propria includes superficial lymphoplasmacytic infiltrates, along with scattered neutrophils.

• Gland loss and mucosal atrophy (seen in pangastritis)

Superficial LP lymphoplasmacytic infiltrates

Look for H. pylori within the mucus

This is an antrum biopsy

MORPHOLOGY:A. H&E: small spiral-shaped organisms on the surface

B. Immunohistochemistry for H. pylori

A

B

Morphology (Cont.)

• Lymphoid aggregates, some with germinal centers, are frequently present and represent an induced form of mucosa-associated lymphoid tissue (MALT) that has the potential to transform into lymphoma.

Complications of H. pylori - related gastritis

Peptic ulcer• Duodenal ulcer or gastric ulcer

Intestinal metaplasia:• The replacement of gastric epithelium with intestinal epithelium including

goblet cells.• Dysplasia • Intestinal type adenocarcinoma

Gastric lymphoma• Marginal zone lymphoma of MALT-type.

H. pylori - related gastritisClinical Features

• Asymptomatic

• Upper abdominal discomfort, nausea and Vomiting

• May be hypochlorhydric (pangastritis), but these persons do not develop achlorhydria or pernicious anemia.

• Serum gastrin levels are either normal or only modestly elevated.

H. pylori -related gastritisDiagnosis & treatment:

Noninvasive tests:

• Serologic test for anti–H. pylori antibodies

• Fecal bacterial detection

• The urea breath test based on the generation of ammonia by bacterial urease.

Invasive tests: (Antral biopsy specimen*):

• The rapid urease test, bacterial culture, or PCR

• Histologic identification of the organism

Treatment:

Triple therapy (two antibiotics and PPIs)


• GASTRITIS

Chemical (reactive) gastropathy, chronic gastritis; including autoimmune gastritis


Autoimmune gastritis (AIG)

• 10% of cases of chronic gastritis

• Common in Scandinavians; F>M.

• AIG is characterized by diffuse damage of the oxyntic (acid-producing) mucosa within the body and fundus.

• Spares the antrum and cardia.

• May be seen with other autoimmune diseases as Hashimoto thyroiditis and Addison diseases.

Autoimmune Gastritis (AIG)

Autoimmune gastritis is characterized by the following:

Antibodies to parietal cells and intrinsic factor (can be detected in serum and gastric secretions)

Reduced serum pepsinogen I levels

Antral endocrine cell hyperplasia

Vitamin B12 deficiency leading to pernicious anemia and neurologic changes

Impaired gastric acid secretion (achlorhydria)

Why ECL-cell hyperplasia?

Autoimmune Gastritis (AIG)Pathogenesis:

Immune-mediated loss of parietal cells and subsequent reductions in acid and intrinsic factor secretion.

Deficient acid secretion stimulates gastrin release,resulting in hypergastrinemia.

Lack of intrinsic factor disables ileal vitamin B12 absorption, leading to B12 deficiency and a particular form of megaloblastic anemia called pernicious anemia.

Reduced serum concentration of pepsinogen I reflects chief cell loss.

Autoimmune Gastritis (AIG)

Note

Although H. pylori can cause hypochlorhydria, it is not

associated with achlorhydria or pernicious anemia, because the parietal and chief cell damage is not as severe as in autoimmune

gastritis

Autoimmune Gastritis (AIG)Morphology:

• Endoscopically: diffuse atrophy, the oxyntic mucosa of the body and fundus appears markedly thinned, and rugal folds are lost.

• H&E: Inflammatory reaction are seen deep and centered on the gastric glands. In contrast to H. Pylori gastritis which shows superficial inflammation.

• Damage to the antrum and cardia typically is absent or mild.

The Parietal and chief cell loss can be extensive, and intestinal metaplasia may develop.

Normal endoscopy

AIG

Normal oxyntic (body & fundus) mucosa

High magnification showing parietal cells

Histology of AIG

A. Lymphoplasmacytic infiltrates in the lamina propria, full thickness; rare eosinophils and neutrophilsB. Linear or nodular enterochromaffin-like (ECL) cell hyperplasia due to achlorhydria stimulating increased gastrin secretion from the antral G cells, which may lead to neuroendocrine tumors (carcinoids) Notice the loss of normal

oxyntic glands

Linear ECL hyperplasia

Nodular ECL hyperplasia

Morphology of AIG (Cont.)

Destruction of oxyntic glands is associated with intestinal metaplasia

Intestinal type dysplasia-adenocarcinoma sequence

Intestinal metaplasia

Characteristics of Chronic Gastritis

COMPLICATIONS OF CHRONIC GASTRITIS

There are three important complications of chronic gastritis:

1. Peptic ulcer disease

2. Mucosal atrophy and intestinal metaplasia

3. Dysplasia

ULCERATION & EROSIONdefinitions

Ulcer:

• A breach in the mucosa that extends through the muscularis mucosae into the submucosa or deeper.

Erosion:

• A breach in the mucosa only

• May heal within days

Peptic ulcer disease PUDMainly H. pylori and NSAIDs

Ulcer that is derived from peptic (acid-induced) injury;

So, gastric acid (hyperacidity) is fundamental to the pathogenesis of PUD.

PUD is associated with H. pylori infection (most common >70%) or NSAID use

PUD may occur in any portion of the gastrointestinal tract exposed to acidic gastric juices but is most common in the gastric antrum and first portion of the duodenum

Peptic ulcer diseaseMechanism of gastric injury and protection

• Gastritis and peptic ulcer disease in general results from mucosal injury.

Peptic ulcer disease (PUD)

PUD 4X more common in the proximal duodenum than in the stomach.

Peptic ulcers are solitary in more than 80% of patients.

The classic peptic ulcer is a round to oval, sharply punched-out defect.

The base of peptic ulcers is smooth and clean as a result of peptic digestion of exudate

Ongoing bleeding within the ulcer base may cause life-threatening hemorrhage.

Perforation is a complication that demands emergent surgical intervention

Peptic ulcer disease (PUD)Grossly

Endoscopy : peptic ulcer

Peptic ulcer disease (PUD)clinical features

• Complaints: epigastric burning or aching pain, although a significant fraction manifest with complications such as iron deficiency anemia, frank hemorrhage, or perforation.

• DU: the pain tends to occur 1 to 3 hours after meals during the day, is worse at night, and is relieved by alkali or food.

• Treatment: H. pylori eradication, PPI (to reduce acidity), discontinuation of NSAID use.

Peptic ulcer disease (PUD)

Only, 5% to 10% of H. pylori–infected individuals develop ulcers (?host factors)

Cofactors in peptic ulcerogenesis include chronic NSAID use and cigarette smoking (both impairs mucosal blood flow and healing.

Uncontrolled release of gastrin can be caused by a “gastrin-secreting tumor; Gastrinoma”, this causes massive acid production, as seen in Zollinger-Ellison syndrome.

Zollinger-Ellison syndrome

• ZES is characterized by multiple peptic ulcerations in the stomach, duodenum, and even jejunum.

• Gastrinomas(neuroendocrine tumors) usually occur in pancreas or duodenum

Acute Gastric Ulceration

Definition:

“Focal acute gastric mucosal defects that appear after severe stress”.

• Not precursors of chronic peptic ulcers

Pathogenesis of acute gastric ulcer

Conditions associated with acute ulcerChronic exposure to gastric irritant drugs:

NSAIDs & corticosteroids

Severe trauma (including major surgical procedures)Sepsis, shock & critically ill pts (stress ulcers)

Extensive burns (Curling ulcers)Traumatic or surgical injury to the CNS or an intracerebral hemorrhage (Cushing ulcers)

↑ ICP may stimulate vagal nuclei and cause gastric acid hypersecretionHigh risk of perforation


• GASTRITIS

Chemical (reactive) gastropathy, chronic gastritis, autoimmune gastritis


GASTRIC POLYPS AND TUMORS

GASTRIC POLYPS:

Inflammatory/Hyperplastic Polyps

Fundic Gland Polyps (FGP)

Gastric Adenoma

Inflammatory/Hyperplastic Polyps

75% of all gastric polyps

Arise on a background of chronic gastritis (that initiates the injury and reactive hyperplasia that cause polyp growth).

If associated with H. pylori gastritis, polyps may regress after bacterial eradication.

Risk of dysplasia increased with polyps larger than 1.5 cm.

•Elongated, cystically dilated, architecturally distorted, irregular foveolar epithelium

•Edematous lamina propria with acute and chronic inflammation and congestion

Fundic Gland Polyps (FGP)

FGP occur sporadically and in individuals with familial adenomatous polyposis (FAP)

FGP associated with FAP may show dysplasia; but they almost NEVER progress to malignancy.

Sporadic FGP are mainly related to the use PPI.

FGP are always asymptomatic and are usually an incidental finding.

• Pathogenesis: FGP likely results from increased gastrin secretion

• Polyps occur in the gastric body and fundus, often are multiple FGP are composed of cystically dilated, irregular glands lined by flattened parietal and chief cells.

Gastric Adenomas

10% of all gastric polyps.

Adenomas almost always occur on a background of chronic gastritis with atrophy and intestinal metaplasia.

Adenomas by definition “epithelial dysplasia”; can be classified as low- or high-grade.

The risk of adenocarcinoma is related to the size, more in lesions >2 cm.

Overall, the malignant potential of gastric adenomas is far greater than that of their colonic counterparts.

Carcinoma may be present in up to 30% of gastric adenomas.

GASTRIC POLYPS AND TUMORS

GASTRIC TUMORS:

Gastric Adenocarcinomas

Neuroendocrine tumors

Gastric Lymphomas

Gastrointestinal Stromal Tumor (GIST)

Gastric Adenocarcinoma AC

Commonest gastric tumor > 90%

Early symptoms resemble those of chronic gastritis (dyspepsia, dysphagia, and nausea).

Epidemiology20X times higher in Japan, Chile, Costa Rica, and Eastern Europe than in North America, northern Europe, Africa, and Southeast Asia.

The Lauren classification that separates gastric AC into intestinal and diffuse types

Gastric Adenocarcinoma ACClassificationIntestinal-type AC

• Risk factors: diet containing nitrates, smoked and salted foods, pickled vegetables, lack of citrus fruit, lack of green leafy vegetable; also low socioeconomic status, cigarette smoking.

• Host factors: chronic gastritis (intestinal metaplasia is a precursor lesion), H. pylori infection, autoimmune gastritis, gastric adenomas

• Grossly: either an exophytic mass or an ulcerated tumor.

• Histologically: composed of glandular structures similar to esophageal and colonic adenocarcinoma.

Gastric Adenocarcinoma ACDiffuse gastric AC“Signet ring carcinoma”

Grossly: tumor cells permeate the stomach wall individually. these tumor cells evoke a desmoplastic reaction that stiffens the gastric wall and imparts a “leather bottle” appearance termed linitis plastica.

Histologically: tumor cells are discohesive with large mucin vacuoles that expand the cytoplasm and push the nucleus to the periphery, creating a signet ring cell morphology

Pathogenesis

• Most gastric cancers are NOT hereditary.

• Familial gastric cancer is an example of hereditary gastric cancer: germ line mutations in CDH1, which encodes E-cadherin, a protein that contributes to epithelial intercellular adhesion. The gastric cancer is usually of the diffuse type (signet-ring carcinoma).

Clinical Features of gastric adenocarcinomas:

Intestinal-type gastric cancer: predominates in high-risk areas and develops from precursor lesions such as dysplasia and adenomas. Mean age 55 years, M>F 2:1.

Diffuse gastric cancer incidence uniform across countries, there are no identified precursor lesions, and the disease occurs at similar frequencies in males and females.

Treatment:

• Surgical resection remains the preferred treatment.

• Beside surgery also chemotherapy and individualized therapies. For example, tumors over-express the epidermal growth factor receptor HER2 benefit from agents that inhibit HER2 signaling.

HER2 Positive gastric cancer

Gastric Lymphomas

Stomach is the most common site involved by extranodal marginal zone B-cell lymphomas. In the gut, these tumors often are referred to as lymphomas of MALT, or MALTomas.

• Most gastric MALT lymphomas associated with gastritis caused by H. pylori infection

• H. pylori eradication - first line therapy and is curative in majority of gastric MALTomas.

• If H. pylori eradication therapy fails (chemotherapy and radiation)

• t (11;18) is the most common molecular alteration, and is associated with resistance to H. pylori antibiotic treatment

Neuroendocrine Tumor NET or (Carcinoid)

• NET or carcinoids arise from neuroendocrine organs (e.g., the endocrine pancreas) and neuroendocrine-differentiated gastrointestinal epithelial cells (e.g., G cells and ECL cells).

• These tumors were called “carcinoid” because they are slower growing than carcinomas.

• More than 40% of the gastrointestinal NET occur in the small intestine.

• Gastric NET tumors may be associated with endocrine cell hyperplasia as seen in chronic atrophic gastritis and in Zollinger-Ellison syndrome.

Neuroendocrine Tumor NETMORPHOLOGY

Grossly: NET are intramural or submucosal masses that create small polypoid lesions.

Histologically: NETs are composed of monotonous cells with scant, pink granular cytoplasm and a “salt and pepper” nucleus.

A) Multiple NET B) Near focus for one of them

H&E: Note the uniform morphology of cells

Neuroendocrine Tumor NET or (Carcinoid)Clinical features

The peak incidence of NET is in the 6th decade, but they may appear at any age.

NETs might be functional (secreting hormones) or non-functional.

Symptoms in functional NETs are determined by the hormones produced.

When tumors are in the intestine, the vasoactive hormonal substances that they release are metabolized to inactive forms by the liver—a “first-pass”. Thus, symptoms such as that seen in carcinoid syndrome (cutaneous flushing, sweating, bronchospasm, colicky abdominal pain, diarrhea) are not seen. However, symptoms can occur when there is metastatic disease, and is seen in less than 10% of patients.

The most important prognostic factor for GIT NET is location of tumor:

Foregut neuroendocrine (carcinoid) tumors found within the stomach, duodenum proximal to the ligament of Treitz, and esophagus, rarely metastasize.

Midgut neuroendocrine (carcinoid) tumors arise in the jejunum and ileum, are often multiple and tend to be aggressive.

Hindgut neuroendocrine (carcinoid) tumors arising in the appendix and colorectum are mostly benign and rarely metastasize.

Gastrointestinal Stromal Tumor (GIST)

• The most common mesenchymal tumor of the GIT and > 50% of these tumors occur in the stomach.

• Other mesenchymal tumors that may arise in stomach include smooth muscle tumors (leiomyomas/ leiomyosarcomas), nerve sheath tumors (schwannomas), and those resembling glomus bodies (glomus tumors).

• Only GIST will be discussed here.

Gastrointestinal Stromal Tumor (GIST)Pathogenesis

GIST arises from the interstitial cells of Cajal (ICC), or pacemaker cells, of the gastrointestinal muscularis propria.

The most common genetic alteration is seen in gene encoding the tyrosine kinase KIT (c-KIT).

C-kit mutation are present in 75% to 85% of all GISTs.

An additional 8% of GISTs have mutations involving platelet-derived growth factor receptor A (PDGFRA).

KIT and PDGFRA gene mutations are mutually exclusive.

Gastrointestinal Stromal Tumor (GIST)Morphology

• Grossly: solitary, well-circumscribed, fleshy, submucosal mass

Gastrointestinal Stromal Tumor (GIST)Morphology

Immunohistochemically of c-Kit seen in 95% of GIST

CLINICAL FEATURES

The peak incidence of gastric GIST is around 60 years of age.

GISTs are slightly more common in males. Larger GISTs may present with symptoms related to mass effects or mucosal

ulceration

The prognosis correlates with tumor size (worse prognosis >5 cm), mitotic index (>50 per hpf), and location (small intestine aggressive)

Surgical resection is the primary treatment for localized gastric GIST. Tumors that are unresectable or metastatic often respond, to tyrosine kinase

inhibitors that are active against KIT and PDGFRA, such as imatinib.

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Approach to liver biopsies