1. INFLAMMATIONS OF THE STOMACH CHRONIC AUTOIMMUNE GASTRITIS Extensive multifocal atrophy (atrophic gastritis) Extensive multifocal atrophy (atrophic gastritis) Endemic in some parts of the world, e.g. Japan Endemic in some parts of the world, e.g. Japan Pathogenesis: Pathogenesis: –Autoantibodies to gastric glands parietal cells –Gland destruction & mucosal atrophy –Loss of acid & IF production (pernicious anemia) Pathology: variable gland loss, atrophy & intestinal metaplasia; dysplasia of metaplastic epithelium Pathology: variable gland loss, atrophy & intestinal metaplasia; dysplasia of metaplastic epithelium If severe parietal cell loss: hypo- or achlorhydria & hypergastrinemia If severe parietal cell loss: hypo- or achlorhydria & hypergastrinemia Px: 2 - 4% risk of developing gastric carcinoma Px: 2 - 4% risk of developing gastric carcinoma

2. PATHOLOGY OF THE STOMACH HYPEPTROPHIC GASTRITIS Group of uncommon conditions characterized by enlargement of rugal folds of gastric mucosa Group of uncommon conditions characterized by enlargement of rugal folds of gastric mucosa Three main variants: Three main variants: –Menetrier ’ s disease: rare idiopathic disease; may be asymptomatic or produces pain, nausea, vomiting & bleeding; protein-losing gastroenteropathy –Hypersecretory gastropathy: associated with hyperplasia of parietal and chief cells –Gastric gland hyperplasia: secondary to excessive gastrin secretion by a gastrinoma (Zollinger-Ellison syndrome) Radiologically or endoscopically may mimic carcinoma Radiologically or endoscopically may mimic carcinoma

4. PATHOLOGY OF THE STOMACH GASTRIC EROSIONS & ULCERATIONS Erosion: loss of superficial epithelium of mucosa Erosion: loss of superficial epithelium of mucosa –May heal within days Ulcer: breach in the mucosa, which extends through the muscularis mucosa into the submucosa or deeper Ulcer: breach in the mucosa, which extends through the muscularis mucosa into the submucosa or deeper –Needs longer time to heal Main types: Main types: –Acute gastric erosions & ulcerations –Peptic ulcers

5. GASTRIC ULCERATIONS PEPTIC ULCER Chronic, most often solitary, lesions that occur in any part of GIT exposed to aggressive action of acid- peptic juices Chronic, most often solitary, lesions that occur in any part of GIT exposed to aggressive action of acid- peptic juices Sites: 98% occur in either the duodenum or stomach (4:1 ratio) Sites: 98% occur in either the duodenum or stomach (4:1 ratio) Patients: common in industrialized countries: 1-2% of population have active disease; autopsy studies: 6- 14% for men, 2-6% women Patients: common in industrialized countries: 1-2% of population have active disease; autopsy studies: 6- 14% for men, 2-6% women Remitting-relapsing lesions, mostly in middle-aged to older adults Remitting-relapsing lesions, mostly in middle-aged to older adults Pathogenesis: unclear, but 2 key facts are known: Pathogenesis: unclear, but 2 key facts are known: –1) Mucosal exposure to gastric acid & pepsin is a requisite ( “ no acid, no ulcer ” ) –2) Strong causal relationship with H. pylori infection

6. PATHOGENESIS OF PEPTIC ULCER 1) Impaired host defense mechanisms play an essential role in gastric ulcers. 1) Impaired host defense mechanisms play an essential role in gastric ulcers. Host mechanisms include: Host mechanisms include: –Surface epithelial mucus secretion –Bicarbonate secretion into mucus (buffered environment) –Apical surface membrane transport of acid & pepsin –Rapid epithelial regenerative capacity –Mucosal blood flow (to remove back-diffused H + –Mucosal elaboration of prostaglandins

8. PATHOGENESIS OF PEPTIC ULCER 2) Helicobacter pylori infection: mechanisms: 2) Helicobacter pylori infection: mechanisms: –Secretion of urease, protease & phospholipases –Attracted PMNs release myeloperoxidase, which produces hypochlorous acid, & monochloramine (in the presence of ammonia) –Colonization & direct damage of mucosal epithelial cells & lamina propria endothelial cells by release of bacterial enzymes & other factors e.g. LPS –Leakage of tissue nutrients into surface sustaining bacillus –Thrombotic occlusion of surface blood vessels by bacterial PAF –Only 10-20% of infected individuals develop PUD

9. PATHOGENESIS OF PEPTIC ULCER Other factors have been associated with PUD: Other factors have been associated with PUD: –Zollinger-Ellison syndrome: excess gastrin secretion by tumor leading to excess acid production –Chronic use of NSAIDs & aspirin suppresses mucosal PG synthesis –Cigarette smoking: impairs mucosal blood flow & healing –Alcohol: unproven direct cause; alcoholic cirrhosis –Repeated use of high doses of corticosteroids –Personality & psycological stress

10. PATHOLOGY OF PEPTIC ULCER Usually round sharply punched-out craters 2-4 cm Usually round sharply punched-out craters 2-4 cm Sites: Sites: –Duodenum: ant. & post. walls of first part –Stomach: Lesser curvature Associated chronic gastritis (DU 85-100%;GU 65%) Associated chronic gastritis (DU 85-100%;GU 65%) Histology: 4 zones: Histology: 4 zones: –1) base of thin necrotic fibrinoid debris –2) active nonspecific inflammation, underlied by –3) granulation tissue & –4) fibrous collagenous scar With healing, crater fills with granulation tissue, with re-epithelialization from margins, nearly restoring normal architecture with a fibrous scar remaining With healing, crater fills with granulation tissue, with re-epithelialization from margins, nearly restoring normal architecture with a fibrous scar remaining

12. CLINICAL FEATURES OF PEPTIC ULCER Chronic remitting & relapsing disease Chronic remitting & relapsing disease c/o epigastric pain, worse at nights, 1-3 hrs after meals, may be relieved by alkalis or food; nausea, vomiting, bloating, belching, weight loss c/o epigastric pain, worse at nights, 1-3 hrs after meals, may be relieved by alkalis or food; nausea, vomiting, bloating, belching, weight loss May present with complications: May present with complications: –hemorrhage: minimal to massive –Perforation:uncommon but serious; peritonitis –Pyloric channel obstruction: rare –Malignant “ transformation ” : gastric ulcers Rx: medical & surgical Rx: medical & surgical

13. PEPTIC ULCER GASTRIC ULCER DUODENAL ULCER PEPTIC ULCER GASTRIC ULCER DUODENAL ULCER M:F= 1.5-2:1 M:F= 1.5-2:1 Genetics plays no role Genetics plays no role Low-to-normal acid output Low-to-normal acid output Major cause: decreased mucosal resistance against acid & pepsin Major cause: decreased mucosal resistance against acid & pepsin H. pylori present in 70% H. pylori present in 70% Pain within 30 min. after meal, not relieved by eating Pain within 30 min. after meal, not relieved by eating Associated with malignant “ transformation ” Associated with malignant “ transformation ” M:F=3:1 Genetics play important role Higher acid output Major cause: Exposure of mucosa to excessive amounts of acid & pepsin H. pylori present in all cases Pain 1.5-3 hrs after meal, relieved by ingestion of milk or food Malignant transformation is unknown

14. PATHOLOGY OF THE STOMACH ACUTE GASTRIC ULCERS Acute stress erosions & ulcers: focal gastric mucosal defects that develop acutely after severe stress: Acute stress erosions & ulcers: focal gastric mucosal defects that develop acutely after severe stress: –shock –extensive burns (Curling ’ s ulcers) –severe trauma, including major surgery, sepsis.. –conditions with increased intracranial pressure, e.g. hemorrhage, trauma, surgery, tumor (Cushing ’ s ulcers). Pathogenesis: Gastric acid hypersecretion, systemic acidosis, vagal stimulation, gastric mucosal hypoxia, exogenous ulcerogenic agents (alcohol, smoking, caffeine, aspirin..) may potentiate appearance of stress ulcers Pathogenesis: Gastric acid hypersecretion, systemic acidosis, vagal stimulation, gastric mucosal hypoxia, exogenous ulcerogenic agents (alcohol, smoking, caffeine, aspirin..) may potentiate appearance of stress ulcers Pathology: Small, one/multiple, variable depth, no gastritis Pathology: Small, one/multiple, variable depth, no gastritis

16. STOMACH TUMORS Benign gastric tumors are more common than malignant tumors, but infrequently cause clinical problems; reported in 5-25% of autopsies Benign gastric tumors are more common than malignant tumors, but infrequently cause clinical problems; reported in 5-25% of autopsies Classification of benign tumors: Classification of benign tumors: –Polyps –GI Stromal tumors (GIST): spindle cell tumors –Lipomas, hemangiomas, granular cell tumors, heterotopic pancreatic rests Classification of malignant tumors: Classification of malignant tumors: –Carcinomas –Lymphomas –Sarcomas (malignant GI stromal tumors)

17. TUMORS OF THE STOMACH GASTRIC POLYPS Nodule projecting above level of surrounding mucosa Nodule projecting above level of surrounding mucosa 2-6% of patients undergoing endoscopy; 0.5% of autopsies 2-6% of patients undergoing endoscopy; 0.5% of autopsies Classification: Classification: –1) Hyperplastic (inflammatory) polyps [85%] & fundic gland polyps [10%]; no malignant transformation –2) Multiple hamartomatous polyps (Peutz-Jeghers syndrome): rare –3) Neoplastic polyps (tubular adenoma or villous adenoma) [5%]: contain dysplastic epithelium, 50% chance of malignant transformation

21. TUMORS OF THE STOMACH GASTRIC CARCINOMA Approximately 90% of gastric malignant tumors Approximately 90% of gastric malignant tumors Variable geographic distribution: Japan, Latin America.. Variable geographic distribution: Japan, Latin America.. 3% of all cancer; dismally poor px: 5 yr survival 5- 15% 3% of all cancer; dismally poor px: 5 yr survival 5- 15% Histologic types of gastric adenocarcinoma: Histologic types of gastric adenocarcinoma: –1) Intestinal type –2) Gastric diffuse type Risk factors (for intestinal type): Risk factors (for intestinal type): –Diet: nitrites, smoked & pickled food, salt,... –Gastric disease: H. pylori, intestinal metaplasia,... –Altered anatomy: post-subtotal gastrectomy

22. Table 17-5. Factors Associated with Increased Incidence of Gastric Carcinoma Environmental Factors Infection by H. pylori Present in most cases of intestinal-type carcinoma Diet Nitrites derived from nitrates (water, preserved food) Smoked and salted foods, pickled vegetables, chili peppers Lack of fresh fruit and vegetables Low socioeconomic status Cigarette smoking

23. Host Factors Chronic gastritis Hypochlorhydria: favors colonization with H. pylori Intestinal metaplasia is a precursor lesion Partial gastrectomy Favors reflux of bilious, alkaline intestinal fluid Gastric adenomas 40% harbor cancer at time of diagnosis 30% have adjacent cancer at time of diagnosis Barrett esophagus Increased risk of gastroesophageal junction tumors

24. Genetic Factors Slightly increased risk with blood group A Family history of gastric cancer Hereditary nonpolyposis colon cancer syndrome Familial gastric carcinoma syndrome (E-cadherin mutation

26. GASTRIC ADNENOCARCINOMA INTESTINAL TYPE DIFFUSE TYPE Arise from gastric mucous cells that have undergone intestinal metaplasia Arise from gastric mucous cells that have undergone intestinal metaplasia Proliferation of well formed glands Proliferation of well formed glands Expanding growth Expanding growth Well or moderately differentiated Well or moderately differentiated Associated with risk factors Associated with risk factors Usually >50 yrs; M>F Usually >50 yrs; M>F Decreasing in frequency Decreasing in frequency Arise de novo from native gastric mucous cells Proliferation of “ signet-ring ” cells Infiltrative growth Poorly differentiated Undefined risk factors Usually <50 yrs; M=F Increasing in frequency

29. PATHOLOGY GASTRIC CARCINOMA Sites: Pylorus & antrum 50-60%, cardia 25%, body & fundus 15-25%; lesser 40% & greater curvature 12% Sites: Pylorus & antrum 50-60%, cardia 25%, body & fundus 15-25%; lesser 40% & greater curvature 12% Gross appearance: Gross appearance: »1) Exophytic »2) Flat or depressed (focal effacement of mucosa or linitis plastica) »3) Excavated (ulcer-like) Histology: Dysplasia carcinoma in situ Histology: Dysplasia carcinoma in situ Depth of invasion (stage): Depth of invasion (stage): »Early gastric carcinoma: confined to mucosa & submucosa regardless of LN status »Advanced gastric carcinoma: extended beyond submucosa

32. CLINICAL FEATURES OF GASTRIC CARCINOMA Early gastric carcinoma is generally asymptomatic; usually discovered by endoscopy while screening persons at high risk; excellent prognosis Early gastric carcinoma is generally asymptomatic; usually discovered by endoscopy while screening persons at high risk; excellent prognosis Advanced carcinoma may be asymptomatic; may cause abdominal discomfort, weight loss, or obstructive symptoms; dismal prognosis Advanced carcinoma may be asymptomatic; may cause abdominal discomfort, weight loss, or obstructive symptoms; dismal prognosis Spread to regional & distant lymph nodes; earliest lymph node metastasis may be to supraclavicular (Virchow ’ s) LN Spread to regional & distant lymph nodes; earliest lymph node metastasis may be to supraclavicular (Virchow ’ s) LN Krukenberg tumor: intraperitoneal spread of gastric carcinoma to both ovaries Krukenberg tumor: intraperitoneal spread of gastric carcinoma to both ovaries

33. TUMORS OF THE STOMACH GASTRIC LYMPHOMA May be primary or secondary May be primary or secondary GL represent 5% of all gastric malignacies GL represent 5% of all gastric malignacies Classification similar to nodal lymphoma; mostly B-cell type Classification similar to nodal lymphoma; mostly B-cell type Stomach is the most common site of extranodal lymphomas (20%) Stomach is the most common site of extranodal lymphomas (20%) Patients: middle aged & elderly; clinical features depend on type, grade and stage of lymphoma Patients: middle aged & elderly; clinical features depend on type, grade and stage of lymphoma MALT (mucosa-associated lymphoid tissue) lymphomas (MALToma) are most common: MALT (mucosa-associated lymphoid tissue) lymphomas (MALToma) are most common: –low grade, limited to mucosa or submucosa –lymphoepithelial lesions are characteristic –hypothesized to be related to H. pylori gastritis, with chronic antigenic stimulation giving rise to one or more clones of lymphoid cells –Px: relatively good;Rx: antibiotics, surgery, chemo