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PATHOLOGY OF THE STOMACH

Stomach mucosa • Gastric mucosa is covered by a layer of mucus. The mucosal glands comprise the cardiac glands, the fundic glands in the fundus and body of the stomach, and the pyloric glands in the antrum. • The surface mucous cells and the cardiac and pyloric glands secrete mucus which protects the stomach from self- digestion. • In fundic glands, the chief cells secrete pepsinogen; the parietal cells secrete HCl, bicarbonate, and intrinsic factor, and the endocrine cells release . • Pyloric endocrine cells secrete gastrin, somatostatine, etc.

Glossary • - of the gastric mucosa associated with gastric mucosal injury • Gastropathy - epithelial cell damage and regeneration without associated inflammation • Erosion - circumscribed necrosis-induced defect of mucosa that does not cross the muscularis mucosae • Ulcer - the defect extends beyond the mucosa

ACUTE GASTRITIS Pathogenesis Common condition, induced by acute damage to the gastric mucosa due to • , NSAIDs (nonsteroidal anti-inflammatory drugs, e.g., aspirin) or steroids • stress situations, e.g., severe burns, hypothermia, shock, CNS trauma, etc. • Helicobacter pylori infection Pathological features • Hemorrhagic-erosive inflammation of gastric mucosa affecting the entire stomach (pangastritis) or the antrum of stomach (antral gastritis) • Mucosal hyperemia, punctate hemorrhages, multiple erosions • + Acute ulcers: anywhere in the stomach (rarely in the proximal ); multiple, <1 cm; usually do not penetrate through the muscularis propria layer • Healing is complete Clinical features • Epigastric pain, nausea, vomiting • On occasion, massive bleeding with and ± hemorrhagic shock • Dg.: via endoscopy of stomach

CHRONIC GASTRITIS • Common features: atrophy of the gastric mucosa and metaplastic transformation of the gastric glands

Helicobacter pylori-induced gastritis (also termed as environmental metaplastic ; EMAG) • Very common; in the absence of antibiotic therapy, it persists for life • Diagnosed histologically in samples obtained endoscopically • Associated with increased risk of peptic ulcer, gastric adenocarcinoma, and gastric MALT-lymphoma • HP eradication therapies reduce the risk of these Pathogenesis • HP microbes colonize on and injure the mucous cells • HP is protected from the acidic gastric juice because the microbes produce urease; the ammonia and bicarbonate produced neutralize the acid Morphology • Chronic active gastritis, most marked in the antrum • Gram-negative, spiral-shaped bacilli are attached to the mucous cells; infiltration of the by lymphocytes and plasma cells + lymphoid follicles; neutrophilic infiltration of the mucous neck region • Longstanding inflammation: multifocal mucosal atrophy, characterized by loss of specialized cells in gastric glands, and their metaplastic replacement by columnar absorptive cells and goblet cells (intestinal metaplasia); fibrosis of the lamina propria; + dysplasia (intraepithelial neoplasia) in the glands Clinical features • No symptoms or epigastric discomfort • Patients with antral predominant gastritis have increased gastrin release and reduced somatostatin release → high HCl production → frequent development of duodenal peptic ulcer • Patients with multifocal atrophic gastritis have decreased acid production, may develop gastric peptic ulcers and have an increased risk for gastric adenocarcinoma

Autoimmune metaplastic atrophic gastritis (AMAG) Pathogenesis • Rare • Autoantibodies to the gastric parietal cells. Can be isolated or associated with other autoimmune disorders Morphology  Chronic atrophic corpus gastritis: lymphoplasmocytic infiltration of the lamina propria, extensive loss of the parietal cells, and intestinal metaplasia in the glands; + dysplasia (intraepithelial neoplasia) in the glands • Antrum: G-cell hyperplasia Clinical features • Reduced acid secretion: hypochlorhydria • Hypergastrinemia: response to hypochlorhydria to stimulate HCl production in the vanishing parietal cells • Intrinsic factor is not produced → disturbed vitamin B12 absorption → pernicious anemia • High risk for the development of gastric adenocarcinoma 1

1. Pathology of the stomach. Ileus. Vascular diseases of the bowels and the peritoneum.

Reactive gastropathy • Frequent condition Pathogenesis • Reflux of bilious duodenal secretions or long-term usage of NSAIDs Morphology • The chemicals cause foveolar hyperplasia, mucosal , congestion of capillaries, and smooth muscle proliferation in the lamina propria • No significant increase in chronic inflammatory cells Clinical features • Mild dyspepsia + epigastric pain

CHRONIC Pathogenesis • Most ulcers are caused by HP infection or drugs (NSAID, steroids), both factors disrupt normal mucosal defense and repair, making the mucosa more susceptible to acid and pepsin • Other ulcerogenic effects: smoking, hypergastrinemia, emotional stress • Duodenal ulcer: increased production of gastric acid and HP-gastritis. The mechanism by which HP promotes duodenal ulcerogenesis is not known. Location • Stomach, usually the antrum and the lesser curvature • Postpyloric duodenum: in the first 2 cm-s distal to the pylorus on the anterior or posterior wall. • Within Barrett’s mucosa in Gross • Single, sharply demarcated round ulcer 1 to 2.5 cm in diameter • Healing: epithelium covers the defect, the smooth muscle cells do NOT regenerate, fibrosis takes place at the site of the injury Clinical features • Epigastrial pain releaved by food or antacids Complications Gastric ulcer • Mild to severe hemorrhage from eroded vessels • Perforation  • due to the progressive shrinkage of fibrotic tissue  proximal stomach becomes greatly dilated; persistent vomiting • Malignant change Duodenal ulcer • Penetration into the pancreas • Profuse bleeding from erosion of branches of the superior pancreatico-duodenal artery  hemorrhagic shock • Perforation  peritonitis • No risk of malignant transformation

Good news: complex therapy has decreased advanced peptic ulcer disease (eradication of H. pylori infection, proton pump inhibitor treatment of hyperacidity, and modification of lifestyle)

Acute upper gastrointestinal bleeding - summary Symptoms • Hematemesis - vomiting of blood • Melena – passage of black tarry stools • On occasion: hemorrhagic shock - life-threatening condition: pallor, cold nose, systolic BP below 100 mmHg, pulse above 100 b.p.m Common causes • Esophageal varices • Mallory-Weiss sy • Chronic peptic ulcer of duodenum or stomach • Acute erosive/hemorrhagic gastritis

GASTRIC EPITHELIAL TUMORS

Benign Hyperplastic (regenerative) polyps • Non-neoplastic small, often multiple polyps; mostly in the antrum • Seen in the setting of chronic gastritis Intestinal-type adenoma • Strong potential for malignant change • Gross: solitary polyp, greater than 1 cm; mainly in the antrum • LM: proliferation of dysplastic tubules that form polyp Clinical features • Extensive metaplastic atrophic gastritis mostly coexists • Mainly asymptomatic; recurrent bleeding of large adenomas may result in anemia

Malignant Adenocarcinoma • High incidence in central and eastern Asia, eastern Europe, South America 2

1. Pathology of the stomach. Ileus. Vascular diseases of the bowels and the peritoneum.

• Peak: between 50-60 ys Etiology • Multifactorial • 90% of cases - sporadic, 10% - familial/hereditary • Environmental factors: H. pylori infection, EBV infection, tobacco smoking, and diet high in smoked and/or salt- preserved foods and low in fruits and vegetables Anatomical location • Usually along the lesser curvature of the antropyloric region • Less common: cardia Gross Early carcinomas • Polypoid (>3 mm) or flat lesions in the form of mucosal patches or a loss of rugae • May not be recognized on endoscopy Advanced carcinomas • Localized growth with a fungating or ulcerated appearance • Infiltrative growth with or without ulceration • Linitis plastica (tube-like alteration of the stomach): no obvious tumour mass is visible on the mucosal surface; however, the gastric wall becomes thickened by the tumorous infiltration

Histological and molecular features, and prognosis 1) Intestinal adenocarcinomas • Well or moderately differentiated; form tubular structures reminiscent of adenocarcinomas of colon • Chromosomally instable tumors; display DNA aneuploidy, translocations, and mutations in proto-oncogens (receptor tyrosine kinase-RAS activation) and tumor suppressor genes (TP53) • Better prognosis than the diffuse type 2) Diffuse carcinomas • Poorly differentiated; composed of poorly cohesive tumor cells or signet-ring cells; desmoplastic reaction leads to linitis plastica • Genomically stable tumors; display epithelial-cadherin gene (CDH1) mutations or RHOA mutations • Highly malignant; poor prognosis 3) Other histological subtypes • Microsatellite instabile tumors, or positive for Epstein-Barr virus

Patterns of spread • Directly to the serosa; local invasion of the duodenum, pancreas, and retroperitoneum • Peritoneal dissemination: carcinosis of peritoneum • Lymphatic metastases: local lymph nodes; Virchow node: supraclavicular lymph node • Retrograde lymphatic spread: signet-ring carcinoma metastasis to both ovaries (Krukenberg tumor) • Hematogeneous metastases: liver

Stage Early carcinoma • Invades no more deeply than the submucosa, without or with regional lymph node metastasis • 5-y survival rate: 80-90%. Advanced carcinoma • Extends into or beyond the tunica muscularis • 5-y survival rate: 10%

Clinical features Early carcinoma • No symptoms Advanced carcinoma • Pain in the upper abdomen, vomiting, melena • Weight loss, weakness or fatigue associated with anemia; tumorous ascites • Survival of patients with HERR2-positive carcinoma can be extended by anti-HER2 therapy Dg • Relies on endoscopy and biopsy

NON-EPITHELIAL MALIGNANT TUMORS - rare • Gastrointestinal stromal tumors (GIST) • Gastric lymphomas • Neuroendocrine tumors

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1. Pathology of the stomach. Ileus. Vascular diseases of the bowels and the peritoneum.

DISEASES OF THE PERITONEUM • Inflammation • Tumors

ACUTE PERITONITIS Induced by • Bacteria • Immune complexes

Bacterial peritonitis

Pathogenesis Three subsets 1. Perforation of an abdominal viscus, as in • peptic ulcer, , , colon carcinoma  mixed infection of E. coli, enterococci, Gram-negative rods, Streptococci, and Clostridia. • Leakage of , gastric juice or pancreatic enzymes  first sterile peritonitis  within hours bacteria appear in the  turns into bacterial peritonitis 2. Bacterial permigration through the intact, but severely inflamed viscus wall, as in cholecystitis or salpingitis 3. Spontaneous bacterial peritonitis develops without an obvious source; occurs in the setting of ascites (e.g., , nephrotic sy).

Morphology • The serosal surface is hyperemic, its glistening sheen is lost, and a creamy (fibrino)purulent exudate covers the surface of the intestines • First it is localized, then becomes diffuse (generalized) • Inflammation of the peritoneal cavity in the minor pelvis: pelveoperitonitis Clinical features • Sy of acute abdomen • In the stage of diffuse peritonitis, paralytic ileus and septic shock ensue  Despite proper surgical treatment, diffuse peritonitis has a high mortality rate; especially in the elderly

Events in survivors • The perforation is „walled off” by loops of intestine, omentum and abdominal parietes  localized abscess(es): intestinal or subdiaphragmatic or subhepatic or pelvic cul-de-sac abscess • Organization: granulation tissue  fibrous tissue () between loops of bowel, which become joined to each other  + intestinal obstruction • Walled-off abscesses serve as new infectious foci and, therefore, require surgical drainage

Syndrome of acute abdomen • Severe abdominal pain, abdominal guarding, absence of bowel sounds  medical emergency • The pain can either be constant usually owing to inflammation (raised temperature, tachycardia + raised white cell count) or colicky because of an obstruction of the gut, biliary system, urinary tract or torsion of an ovarian cyst • Abdominal guarding: involuntary spasm of the abdominal wall; indicates peritonitis

Common causes of acute abdomen • Perforation of an abdominal organ (X-ray: free air under the diaphragm) • Biliary colic • Thrombosis of superior mesenteric artery with infarction of the small bowels • Acute necrotizing-hemorrhagic

Immune complex-induced peritonitis • Called serositis • Frequent in SLE, together with pleuritis and pericarditis; bacterial invasion of the peritoneal cavity does not occur • Morphology: acute serous or serofibrinous peritonitis • Heals with fibrous adhesions

TUMORS OF THE PERITONEUM • Are malignant • Metastatic involvement: very common; in any form of advanced cancer of abdominal organs, direct spread to the peritoneal surface, leading to carcinosis of peritoneum  death within months • Ovarian or pancreatic adenocarcinomas regularly cause carcinosis of peritoneum • Primary: rare; peritoneal mesothelioma due to asbestos exposure

DISEASES OF THE INTESTINES

ILEUS Stop of intestinal peristalsis, associated with stagnation of intestinal contents Classification • Paralytic: lack of peristalsis due to functional causes: after abdominal operations (lasts 2 to 3 days), peritonitis, shock, hypokalemia, etc. • Mechanic: due to intestinal obstruction 4

1. Pathology of the stomach. Ileus. Vascular diseases of the bowels and the peritoneum.

• Vascular: due to occlusion the superior mesenteric artery

Causes of intestinal obstruction Extramural • Incarcerated • Invagination • • Adhesions Mural • Stenosing carcinoma or stenosing • : toxic or congenital (Hirschsprung’s disease) Luminal • Fecolith or seeds of melone or grapes obstruct the large bowel • may occlude the (has become rare)

Incarcerated hernia Hernia: a weakness or defect in the wall of the abdominal cavity permits protrusion of a pouch-like, serosa-lined sac of peritoneum (hernial sac) Usual sites: • inguinal and femoral canals • umbilicus • surgical scars Clinical features • Most are reducable, the herniated contents can be manipuleted back into the abdominal cavity • However, bowel loops may become trapped within the hernia sac (incarceration)  compromise of lymphatic, venous and, finally, arterial circulation (strangulation)  hemorrhagic infarction of the trapped bowel segment

Invagination (intussusception) The proximal loop invaginates („telescopes”) into the immediately distal loop, like the finger of an inverted glove Occurs • In children with very active peristalsis, e.g., in rotavirus-induced • Pedunculeted tumors carried by peristalsis may pull forward the loop to which such a tumor is attached Consequence: the inner loop (intussusceptum) is strangulated by the outer intussuscipient, and becomes necrotic within hours

Volvulus • A rotation (axial twisting) of a mobile loop of intestine around its own mesenteric root • Mostly in the sigmoid colon Consequence: strangulation  hemorrhagic infarction

Adhesions • Organisation and scarring of inflammatory exsudate following surgical procedures, peritonitis or endometriosis (functionally active endometrial tissue outside the uterus) • Carcinosis of peritoneum Morphology: fibrous bridges between loops of intestine and/or the abdominal wall  obstruction + hemorrhagic infarction

Consequences of intestinal obstruction • The bowels proximal to the obstruction undergo progressive dilation, their wall becomes thinned, and their lumen is filled with large amount of fluid and gas because of increased secretion of fluid and electrolytes into the distended bowel segment and gas-producing bacterial overgrowth in the stagnating intestinal content • + Strangulation-induced bowel infarction  peritonitis • Elevation of the diaphragm

Clinical features of intestinal obstruction • Colicky abdominal pain and distension, without passage of wind, progressive vomiting, dehydration • Without surgical treatment and fluid resuscitation, the patient dies within days

VASCULAR DISEASES • Ischemic bowel disease • • (lectured in the first semester)

ISCHEMIC BOWEL DISEASE Ischemia causes pathologic changes when the perfusion of the intestines declines below 50% of normal • Ischemia due to occlusion  transmural infarction • Ischemia due to stenosis  mucosal or mural infarction

Occlusive ischemia The trunk of superior mesenteric artery is occluded by thrombosis over ruptured atheroma (frequent) or embolism Consequence • Transmural hemorrhagic infarction of the small bowel (the necrotic area is reperfused by the blood coming from numerous anastomoses in the intestines) Clinical features

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1. Pathology of the stomach. Ileus. Vascular diseases of the bowels and the peritoneum.

• Progressively increasing abdominal pain (thrombosis) or sudden onset of abdominal pain (embolism) + bloody diarrhoea • Shock and vascular collapse within hours • Mortality rate: 90%

Nonocclusive ischemia In elderly people with severe atherosclerosis of the intestinal arteries • The onset of ischemia is precipitated by sudden drop in intestinal perfusion due to acute myocardial infarction, pulmonary embolism, prolonged hypotension of any cause • Depending on the degree of narrowing of the arteries, the infarction may be mucosal or mural (mucosa + submucosa + tunica muscularis) • The watershed border zones are affected: the splenic flexure of the colon (watershed between the distribution of the superior and inferior mesenteric arteries); the rectosigmoid junction (between the branches of the inferior mesenteric artery) Gross  Mucosa: edema, hemorrhagic thickening; several ulcerations (the necrotic mucosa detaches) which may be covered by pseudomembrane; serosal surface: normal  Healing state („ischemic ”): pseudopolyps may be present in addition to ulceration and fibrosis Healing Mucosal ulcerations heal completely; mural infarctions heal with fibrosis  stricture formation Clinical features • Abdominal pain/discomfort + bloody stool • May mimic both acute from other causes and idiopathic inflammatory bowel disease • The bowel lesions, per se, are not lethal; if the cause of hypoperfusion can be corrected, the outcome is good

ANGIODYSPLASIA • Tortuous dilations of submucosal and mucosal veins, venules and capillaries • Most often in the cecum or right colon, usually after the 6th decade of life • Frequent cause (20%) of lower intestinal bleeding, which may be chronic, intermittent, or acute and massive • Dg.: by angiography or colonoscopy

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