Pathology of the Stomach

Objectives and aim To learn the congenital disorders of the stomach To learn the congenital disorders of the stomach To learn the inflammatory diseases of the stomach To learn the inflammatory diseases of the stomach To learn the tumors of the stomach To learn the tumors of the stomach

Congenital gastric anomalies Congenital gastric anomalies Inflammatory disorders Inflammatory disorders Tumors Tumors

Congenital gastric anomalies Congenital gastric anomalies Pyloric Stenosis Pyloric Stenosis –Young infant (1 in 300 to 900 live births); M/F=3/1 Projectile vomiting in second to third week of life Projectile vomiting in second to third week of life Visible peristalic contractions seen on abdominal examination Visible peristalic contractions seen on abdominal examination Dehydration and wasting Dehydration and wasting –Muscular hypertrophy of pyloric smooth muscle wall.

Diaphragmatic Hernias Diaphragmatic Hernias –Rare; Acute respiratory problem in newborn –Diaphragmatic defect  herniation into thorax Gastric heterotopia Gastric heterotopia –Uncommon; asymptomatic –Nidus of gastric mucosa  esophagus/small intestine

Inflammatory disorders – –Gastritis Acute gastritis Chronic gastritis – –Gastric ulcerations Acute gastric ulcer Peptic ulcer

Gastritis Acute gastritis Acute gastritis Acute mucosal inflammatory process, usually of a transient nature Acute mucosal inflammatory process, usually of a transient nature may be accompanied by hemorrhage into the mucosa may be accompanied by hemorrhage into the mucosa in severe erosive form of the disease is an important cause of acute gastrointestinal bleeding. in severe erosive form of the disease is an important cause of acute gastrointestinal bleeding.

Acute gastritis is frequently associated with: Nonsteroidal anti-inflammatory drugs, particularly aspirin Nonsteroidal anti-inflammatory drugs, particularly aspirin Excessive alcohol consumption Excessive alcohol consumption Heavy smoking Heavy smoking Treatment with cancer chemotherapeutic drugs Treatment with cancer chemotherapeutic drugs Uremia Uremia Systemic infections (e.g., salmonellosis) Systemic infections (e.g., salmonellosis) Severe stress (e.g., trauma, burns, surgery) Severe stress (e.g., trauma, burns, surgery) Ischemia and shock Ischemia and shock Suicidal attempts, as with acids and alkali Suicidal attempts, as with acids and alkali Gastric irradiation Gastric irradiation Mechanical trauma (e.g., nasogastric intubation) Mechanical trauma (e.g., nasogastric intubation) Following distal gastrectomy (with reflux of bilious material) Following distal gastrectomy (with reflux of bilious material)

Morphology of the Acute gastritis Mild form Edema and slight hyperemia in the lamina propria, Edema and slight hyperemia in the lamina propria, The surface epithelium is intact, The surface epithelium is intact, Scattered neutrophils are present among mucosal epithelial cells. Scattered neutrophils are present among mucosal epithelial cells. The presence of neutrophils above the basement membrane signifies active inflammation of Helicobacter pylori The presence of neutrophils above the basement membrane signifies active inflammation of Helicobacter pylori

Severe form E rosion and hemorrhage (acute erosive gastritis) E rosion and hemorrhage (acute erosive gastritis) Accompanied by mucosal edema, inflammatory infiltrate (neutrophils, few lymphocytes), regenerative proliferation of epithelial cells. Accompanied by mucosal edema, inflammatory infiltrate (neutrophils, few lymphocytes), regenerative proliferation of epithelial cells. Healing within days (complete restitution). Healing within days (complete restitution). Hemorrhage may occur independently, generating punctate dark spots in an otherwise hyperemic mucosa, or in association with erosion. Hemorrhage may occur independently, generating punctate dark spots in an otherwise hyperemic mucosa, or in association with erosion. Concurrent erosion and hemorrhage  acute erosive hemorrhagic gastritis Concurrent erosion and hemorrhage  acute erosive hemorrhagic gastritis

Chronic gastritis Chronic gastritis Chronic mucosal inflammatory changes leading eventually to mucosal atrophy and epithelial metaplasia, Chronic mucosal inflammatory changes leading eventually to mucosal atrophy and epithelial metaplasia, –The major etiologic association of chronic gastritis is chronic infection by Helicobacter pylori : Highest infection rates Highest infection rates H.pylori (enzymes+toxins) + neutrophilic chemicals  gastritis H.pylori (enzymes+toxins) + neutrophilic chemicals  gastritis

Etiology Chronic infection (Helicobacter pylori) Chronic infection (Helicobacter pylori) Immunologic (associated with pernicious anemia) Immunologic (associated with pernicious anemia) Toxic (alcohol and tobacco) Toxic (alcohol and tobacco) Postsurgical (especially following antrectomy and gastroenterostomy with reflux of bilious duodenal secretions) Postsurgical (especially following antrectomy and gastroenterostomy with reflux of bilious duodenal secretions) Motor and mechanical, (obstruction, gastric atony) Motor and mechanical, (obstruction, gastric atony) Radiation Radiation Granulomatous conditions (e.g., Crohn ’ s disease) Granulomatous conditions (e.g., Crohn ’ s disease) Graft-versus-host disease, Graft-versus-host disease, Amyloidosis, Amyloidosis, Uremia Uremia

Morphology –An inflammatory infiltrate within the lamina propria: Lymphocytes, Lymphocytes, Plasma cells, Plasma cells, occasionally neutrophils. occasionally neutrophils. –In the early stages: the infiltrate is usually limited to the upper third of the gastric mucosa (chronic superficial gastritis), the infiltrate is usually limited to the upper third of the gastric mucosa (chronic superficial gastritis), H.pylori within the mucus layer. H.pylori within the mucus layer.

–In severe forms: – The inflammatory infiltrate involves the full thickness of the mucosa. –Intestinal Metaplasia: Metaplastic columnar absorptive cells and mucous goblet cells of intestinal phenotype (primarily small intestine) may partially replace portions of the gastric mucosa  dysplasia  ca. – Lymphoid tissue: H.pylori induced lymphoid aggregates, some with germinal centers  gastric lymphoma.

Complications Peptic ulcer Peptic ulcer Dysplasia  in situ carcinoma Dysplasia  in situ carcinoma Gastric carcinoma Gastric carcinoma

Gastric ulcerations Acute gastric ulcer (stress ulcers) Acute gastric ulcer (stress ulcers) Focal, acutely developing gastric mucosal defects may appear following severe stress. Focal, acutely developing gastric mucosal defects may appear following severe stress. Generally multiple lesions. Generally multiple lesions. Erosion (acute erosive gastritis) or ulceration in Erosion (acute erosive gastritis) or ulceration in –shock –extensive burns (Curling ulcers) –sepsis –severe trauma –intracranial conditions (e.g., trauma, brain surgery; Curling ulcers) –pharmaceutical agents, (NSAIDs).

–Less than 1 cm in diameter, –circular and small, –the ulcer base is frequently stained a dark brown by the acid digestion of extruded blood. –anywhere in the stomach (contrast to chronic peptic ulcers  duodenum/lesser curvature). Microscopically: Microscopically: –acute stress ulcers are abrupt lesions, –with essentially unremarkable adjacent mucosa, –erosion or ulcer. Morphology of Acute Gastric Ulcers

Acute (Erosive) Gastritis

Peptic ulcer Peptic ulcer Chronic, Chronic, Most often solitary, Most often solitary, Any portion of the GI tract exposed to the aggressive action of acid-peptic juices. Any portion of the GI tract exposed to the aggressive action of acid-peptic juices. Remitting/relapsing lesions, Remitting/relapsing lesions, most often diagnosed in middle-aged to older adults, most often diagnosed in middle-aged to older adults, may first become evident in young adult life. may first become evident in young adult life.

Predispositions... alcoholic cirrhosis, alcoholic cirrhosis, chronic obstructive pulmonary disease, chronic obstructive pulmonary disease, chronic renal failure, chronic renal failure, hyperparathyroidism. hyperparathyroidism. –in the last two conditions, we should note that hypercalcemia, whatever its cause, stimulates gastrin production and therefore acid secretion.

Etiology H.pylori H.pylori Patients chronically using NSAIDs, including aspirin. Patients chronically using NSAIDs, including aspirin. Cigarette smoking impairs healing and favors recurrence. Cigarette smoking impairs healing and favors recurrence. Alcoholic cirrhosis. Alcoholic cirrhosis. Corticosteroids. Corticosteroids. Psychological stress. Psychological stress.

Normal Increased Attack Hyperacidity Weak defense Helicobacter pylori, stress, drugs, smoking

Pathogenesis Gastric acid and pepsin. Gastric acid and pepsin. H.pylori (70-90% duodenal; 70% gastric). H.pylori (70-90% duodenal; 70% gastric). H.pylori  cytokines (IL-1, IL-6, IL-8, TNF)  neutrophil activation. H.pylori  cytokines (IL-1, IL-6, IL-8, TNF)  neutrophil activation. H.pylori  urease  toxic compounds  Rebound acid production. H.pylori  urease  toxic compounds  Rebound acid production. H.pylori  phospholipase  damage epithelial cells. H.pylori  phospholipase  damage epithelial cells. H.pylori  protease, phospholipase  breakdown of gastric mucus. H.pylori  protease, phospholipase  breakdown of gastric mucus. H.pylori  enhances gastric acid  impairs duodenal bicarbonate production. H.pylori  enhances gastric acid  impairs duodenal bicarbonate production. H.pylori  immunogenic proteins  activated T & B cells  form follicles. H.pylori  immunogenic proteins  activated T & B cells  form follicles.

H.pylori related disorders H. pylori can be transmitted from person to person through close contact: –Chronic gastritis – 90% –Peptic ulcer disease – % –Gastric carcinoma – 70% –Gastric lymphoma –Reflux Oesophagitis –Non ulcer dyspepsia

Zollinger-Ellison syndrome Zollinger-Ellison syndrome –Carcinoid tumors –Excess gastrin secretion ( Pancreatic Islet cell tumor) –Excess gastric acid production –Multiple peptic ulcerations (stomach, dudenum, jejenum)

Morphology At least 98% of peptic ulcers are located in the first portion of the duodenum or in the stomach (along the lesser curvature). At least 98% of peptic ulcers are located in the first portion of the duodenum or in the stomach (along the lesser curvature). –Most duodenal ulcers occur in the first portion of the duodenum, generally within a few centimeters of the pyloric ring. –The anterior wall of the duodenum is more often affected than the posterior wall. –Gastric ulcers are predominantly located along the lesser curvature. More than 50% of peptic ulcers have a diameter less than 2 cm, More than 50% of peptic ulcers have a diameter less than 2 cm, 10% of benign ulcers are greater than 4 cm. 10% of benign ulcers are greater than 4 cm.

The classic peptic ulcer is a round-to-oval, sharply punched-out defect with relatively straight walls. The classic peptic ulcer is a round-to-oval, sharply punched-out defect with relatively straight walls. The margins are usually level with the surrounding mucosa or only slightly elevated. The margins are usually level with the surrounding mucosa or only slightly elevated. Heaping-up of these margins is rare in the benign ulcer but is characteristic of the malignant lesion. Heaping-up of these margins is rare in the benign ulcer but is characteristic of the malignant lesion. The depth of these ulcers varies : The depth of these ulcers varies : – superficial lesions involving only the mucosa and muscularis mucosa –deeply excavated ulcers having their bases on the tunica muscularis.

The base of a peptic ulcer is smooth and clean to inspection, owing to peptic digestion of any exudate. The base of a peptic ulcer is smooth and clean to inspection, owing to peptic digestion of any exudate. At times, thrombosed or patent blood vessels (the source of life-threatening hemorrhage) are evident in the base of the ulcer. At times, thrombosed or patent blood vessels (the source of life-threatening hemorrhage) are evident in the base of the ulcer. Scarring may involve the entire thickness of the stomach. Scarring may involve the entire thickness of the stomach. The gastric mucosa surrounding a gastric ulcer is somewhat edematous and reddened, owing to the almost invariable gastritis. The gastric mucosa surrounding a gastric ulcer is somewhat edematous and reddened, owing to the almost invariable gastritis.

Kissing ulcers (face-to-face ulcers) Kissing ulcers (face-to-face ulcers) When the entire wall is penetrated, the base of the ulcer may be formed by adherent When the entire wall is penetrated, the base of the ulcer may be formed by adherent –pancreas, –omental fat, –liver.

The histologic appearance varies from active necrosis, to chronic inflammation and scarring, to healing. The histologic appearance varies from active necrosis, to chronic inflammation and scarring, to healing. In active ulcers with ongoing necrosis, four zones are demonstrable: In active ulcers with ongoing necrosis, four zones are demonstrable: –(1) The base and margins have a superficial thin layer of necrotic fibrinoid debris not visible to the naked eye; –(2) beneath this layer is the zone of a nonspecific inflammatory infiltrate, with neutrophils predominating; –(3) in the deeper layers, especially in the base of the ulcer, there is active granulation tissue infiltrated with mononuclear leukocytes; and –(4) the granulation tissue rests on a more solid fibrous or collagenous scar.

Complications Perforation (into the peritoneal cavity) Perforation (into the peritoneal cavity) –Penetration (pancreas, omental fat, liver) Bleeding (frank hemorrhage; anemia) Bleeding (frank hemorrhage; anemia) Gastric cancers Gastric cancers Fibrosis and stenosis (stricture and/or obstruction). Fibrosis and stenosis (stricture and/or obstruction).

Summary...peptic ulcus 90% ulcers in first portion of duodenum or lesser curvature of stomach(4:1). 90% ulcers in first portion of duodenum or lesser curvature of stomach(4:1). 80 to 90% cases single ulcer. 80 to 90% cases single ulcer. Round-small ulcers with sharply punched out edges. Round-small ulcers with sharply punched out edges. Microscopy: 4 zones. Microscopy: 4 zones. –Superficial necrotic layer. –Inflammatory cells zone. –Granulation tissue zone –Collagenous scar layer.

Pyloric Stenosis Acquired type. - Long term complication of gastritis or peptic ulcer disease involving the pylorus. - May also be secondary to carcinoma of the pylorus, head of the pancreas, or gastric lymphoma producing functional obstruction - Same symptoms as congenital stenosis.

TUMORS of the STOMACH Benign tumors Benign tumors –Epithelial Gastric Polyps Gastric Polyps – Mesenchymal lipomas, lipomas, leiomyoma, leiomyoma, neurofibromas neurofibromas Malignant tumors Malignant tumors –Carcinoma (90 to 95%). –Lymphomas (4%), –Carcinoids (3%), –Malignant spindle cell tumors (2%).

Gastric Polyps Nodule or mass that projects above the level of the surrounding mucosa. Nodule or mass that projects above the level of the surrounding mucosa. –hyperplastic nature (80-85%) –fundic gland polyps (10%) –adenomatous polyps (5%) Histologically, these polyps exhibit a mixture of Histologically, these polyps exhibit a mixture of –hyperplastic pyloric-type glandular tissue, –edematous lamina propria, –inflammatory cells.

Gastric Carcinoma Most important and the most common (90 to 95%) Most important and the most common (90 to 95%) Risk factors: Risk factors: –Diet Nitrites derived from nitrates (food, drinking water, preservatives  nitrosamines&nitrosamides) Nitrites derived from nitrates (food, drinking water, preservatives  nitrosamines&nitrosamides) Smoked foods & pickled vegetables Smoked foods & pickled vegetables Excessive salt Excessive salt Decreased intake of fresh vegs&fruits (less antioxidants) Decreased intake of fresh vegs&fruits (less antioxidants) –Chronic gastritis with intestinal metaplasia Infection with H.pylori Infection with H.pylori Pernicious anemia Pernicious anemia –Altered anatomy After subtotal distal gastrectomy After subtotal distal gastrectomy

Morphology The three macroscopic growth patterns of gastric carcinoma: The three macroscopic growth patterns of gastric carcinoma: (1) Vegetan (Exophytic): with protrusion of a tumor mass into the lumen. (2) Ulcerating (Ulcerovegetan; Excavated): when a shallow or deeply erosive crater is present. (3) Diffuse (Infiltrative; Flat or depressed): in which no tumor mass is visibly obvious.

Vegetan (Exophytic; Fungating) Ulcerating Diffuse

Excavated (ulcerating) cancers may closely mimic, in size and appearance, chronic peptic ulcers. Excavated (ulcerating) cancers may closely mimic, in size and appearance, chronic peptic ulcers. A broad region of the gastric wall or the entire stomach is extensively infiltrated by malignancy, creating a rigid, thickened “leather bottle,” termed linitis plastica. A broad region of the gastric wall or the entire stomach is extensively infiltrated by malignancy, creating a rigid, thickened “leather bottle,” termed linitis plastica.

Linitis plastica Linitis plastica

The histologic types of gastric cancer: Intestinal type Intestinal type –neoplastic intestinal glands resembling those of colonic adenocarcinoma, –the neoplastic cells often contain apical mucin vacuoles, –abundant mucin may be present in gland lumina. Diffuse type Diffuse type –gastric-type mucous cells, –do not form glands –“infiltrative” growth pattern. –mucin formation expands the malignant cells and pushes the nucleus to the periphery, creating a “signet-ring” conformation.

Excessive mucin production  large mucinous lakes  dissect tissue planes Excessive mucin production  large mucinous lakes  dissect tissue planes Infiltrative tumors  desmoplastic reaction  fibrosis creates local rigidity of the wall. Infiltrative tumors  desmoplastic reaction  fibrosis creates local rigidity of the wall. Gastric carcinomas Gastric carcinomas penetrate the wall to involve the serosa penetrate the wall to involve the serosa spread to regional and distant lymph nodes spread to regional and distant lymph nodes Virchow’s node: gastric carcinomas may metastasize to the supraclavicular sentinel (Virchow’s) node ( first clinical manifestation of an occult neoplasm) Virchow’s node: gastric carcinomas may metastasize to the supraclavicular sentinel (Virchow’s) node ( first clinical manifestation of an occult neoplasm) Krukenberg tumor: metastatic adenocarcinoma to the ovaries (from stomach, pancreas, and even gallbladder). Krukenberg tumor: metastatic adenocarcinoma to the ovaries (from stomach, pancreas, and even gallbladder).

Spreading...

LYMPHOMA Extra-nodal lymphomas can arise in any tissue, most commonly in the GI tract, particularly the stomach. Extra-nodal lymphomas can arise in any tissue, most commonly in the GI tract, particularly the stomach. Nearly 5% of all gastric malignancies are primary lymphomas, the most common of which are indolent extra-nodal marginal zone B-cell lymphomas. Nearly 5% of all gastric malignancies are primary lymphomas, the most common of which are indolent extra-nodal marginal zone B-cell lymphomas. In the gut these tumors are often referred to as lymphomas of mucosa-associated lymphoid tissue (MALT), or MALTomas. In the gut these tumors are often referred to as lymphomas of mucosa-associated lymphoid tissue (MALT), or MALTomas.

LYMPHOMA Extra-nodal marginal zone B-cell lymphomas usually arise at sites of chronic inflammation. Extra-nodal marginal zone B-cell lymphomas usually arise at sites of chronic inflammation. They can originate in the GI tract at sites of preexisting MALT, such as the Peyer's patches of the small intestine, but more commonly arise within tissues that are normally devoid of organized lymphoid tissue. They can originate in the GI tract at sites of preexisting MALT, such as the Peyer's patches of the small intestine, but more commonly arise within tissues that are normally devoid of organized lymphoid tissue.

LYMHOMA The most common cause of "pro- lymphomatous" inflammation in the stomach is chronic H. pylori infection, which is found in association with most cases of gastric MALToma. The most common cause of "pro- lymphomatous" inflammation in the stomach is chronic H. pylori infection, which is found in association with most cases of gastric MALToma. MALTomas can transform into more aggressive tumors that are histologically identical to diffuse large B-cell lymphomas. MALTomas can transform into more aggressive tumors that are histologically identical to diffuse large B-cell lymphomas.

GASTROINTESTINAL STROMAL TUMOR A wide variety of mesenchymal neoplasms may arise in the stomach. A wide variety of mesenchymal neoplasms may arise in the stomach. GI stromal tumor (GIST) is the most common mesenchymal tumor of the abdomen, and more than half of these tumors occur in the stomach. GI stromal tumor (GIST) is the most common mesenchymal tumor of the abdomen, and more than half of these tumors occur in the stomach.

GIST Symptoms of GISTs at presentation may be related to mass effects. Mucosal ulceration can cause blood loss, and approximately half of individuals with GIST present with anemia or related symptoms. GISTs may also be discovered as an incidental finding during radiologic imaging, endoscopy, or abdominal surgery performed for other reasons. Complete surgical resection is the primary treatment for localized gastric GIST.. Symptoms of GISTs at presentation may be related to mass effects. Mucosal ulceration can cause blood loss, and approximately half of individuals with GIST present with anemia or related symptoms. GISTs may also be discovered as an incidental finding during radiologic imaging, endoscopy, or abdominal surgery performed for other reasons. Complete surgical resection is the primary treatment for localized gastric GIST..

GIST The prognosis correlates with tumor size, mitotic index, and location, with gastric GISTs being somewhat less aggressive than those arising in the small intestine. Recurrence or metastasis is rare for gastric GISTs under 5 cm but common for mitotically active tumors larger than 10 cm The prognosis correlates with tumor size, mitotic index, and location, with gastric GISTs being somewhat less aggressive than those arising in the small intestine. Recurrence or metastasis is rare for gastric GISTs under 5 cm but common for mitotically active tumors larger than 10 cm

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