Acute Gastritis Chronic Gastritis PEPTIC ULCER DISEASE Gastric Polyps and Tumors

transient mucosal inflammatory process Acute Gastritis Acute gastritis is a transient mucosal inflammatory process asymptomatic or cause variable degrees of epigastric pain, nausea, and vomiting In more severe cases mucosal erosion, ulceration, hemorrhage

Acute Gastritis Pathogenesis Acute or chronic gastritis can occur following disruption of gastroduodenal mucosal protective mechanisms

Mechanisms which protect the gastric mucosa Mucin secreted by surface foveolar cells forms a thin layer of mucus bicarbonate ion secretion by surface epithelial cells rich vascular supply to the gastric mucosa epithelial barrier Elaboration of prostaglandin Epithelial regenerative capacity

Etiopathogenesis NSAID (e.g., aspirin) H. pylori infections alcohol smoking stress (trauma, burns, surgery) Uremia Treatment with cancer chemotherapeutic drugs Systemic bacterial or viral infections

Etiopathogenesis Ischemia and shock Suicidal attempts, as with acids and alkali Gastric irradiation or freezing Mechanical trauma (e.g., nasogastric intubation) Distal gastrectomy

Morphology of acute gastritis surface epithelium is intact presence of neutrophils above the basement membrane in direct contact with epithelial cells is abnormal in all parts of the GI tract and signifies active inflammation

Morphology of acute gastritis severe mucosal damage, erosions and hemorrhage (erosion denotes loss of the superficial epithelium, generating a defect in the mucosa that is limited to the lamina propria) Concurrent erosion and hemorrhage is termed acute erosive hemorrhagic gastritis

ACUTE GASTRIC ULCERATION Focal, acutely developing gastric mucosal defects Stress ulcers - shock, sepsis, or severe trauma Curling ulcers - severe burns or trauma Cushing ulcers - intracranial disease

Chronic Gastritis Chronic infection by H. pylori Immunologic (autoimmune), in association with pernicious anemia Toxic, as with alcohol and cigarette smoking Postsurgical, especially following antrectomy with gastroenterostomy with reflux of bilious duodenal secretions

Less common etiologies Radiation Granulomatous conditions (e.g., Crohn disease) Miscellaneous-amyloidosis, graft-versus-host disease, uremia

Pathogenesis result of an imbalance between gastroduodenal mucosal defenses and damaging forces that overcome those defenses

Pathogenesis H. pylori infection is the most common cause of chronic gastritis H. pylori gastritis may progress to pangastritis resulting in multifocal atrophic gastritis

Four features are linked to H. pylori virulence Flagella - allow the bacteria to be motile in viscous mucus Urease - generates ammonia from endogenous urea and thereby elevates local gastric pH Adhesins - enhance their bacterial adherence to surface foveolar cells Toxins - such as cytotoxin-associated gene A (CagA)

Morphology H. pylori are typically found in the antrum demonstrate H. pylori in superficial mucus overlying epithelial cells

Morphology H. pylori–infected antral mucosa is erythematous & nodular appearance inflammatory infiltrate includes -variable numbers of neutrophils -large numbers of plasma cells - Lymphocytes& macrophages pit abscesses thickened rugal folds

Morphology Long-standing H. pylori gastritis extend to involve the body and fundus, and the mucosa can become atrophic Lymphoid aggregates, some with germinal centers represent an induced form of mucosa-associated lymphoid tissue, or MALT, that has the potential to transform into lymphoma

Clinical Features symptoms less severe but more persistent Nausea and upper abdominal discomfort , vomiting fecal bacterial detection urea breath test (+)ve noninvasive serologic test for antibodies to H. pylori

AUTOIMMUNE GASTRITIS Antibodies to parietal cells and intrinsic factor that can be detected in serum and gastric secretions Reduced serum pepsinogen I concentration Antral endocrine cell hyperplasia Vitamin B12 deficiency Defective gastric acid secretion (achlorhydria)

AUTOIMMUNE GASTRITIS < 10% of gastritis cases seen with other autoimmune diseases a) type 1 diabetes b) Addison's disease c) Hashimoto thyroiditis high risk of gastric CA and endocrine tumors (carcinoid tumors)

AUTOIMMUNE GASTRITIS diffuse mucosal damage a) fundus and body b) lymphocytes and plasma cells c) active inflammation  neutrophils ! d) atrophy is frequently associated; and with pangastritis (H. pylori) e) hyperplasia of G cells ( gastrin) i) due to  H+ production ii) hypergastrinemia

Complications of Chronic Gastritis PEPTIC ULCER DISEASE Peptic ulcers are chronic, most often solitary, lesions that occur in any portion of the gastrointestinal tract exposed to the aggressive action of acidic peptic juices

Peptic Ulcers SITE most common in the gastric antrum and first portion of the duodenum occur in the esophagus as a result of GERD Gastric mucosa within a Meckel diverticulum

Pathogenesis Two conditions are key for the development of peptic ulcers (1) H. pylori infection, which has a strong causal relationship with peptic ulcer development (2) mucosal exposure to gastric acid and pepsin

Pathogenesis peptic ulcers are created by an imbalance between the gastroduodenal mucosal defenses and the damaging forces that overcome such defenses

Pathogenesis The gastric hyperacidity that drives PUD may be caused by H. pylori infection parietal cell hyperplasia excessive secretory responses impaired inhibition of stimulatory mechanisms such as gastrin release For example, Zollinger-Ellison syndrome

Pathogenesis More common cofactors in pepticulcerogenesis include chronic NSAID use cigarette smoking high-dose corticosteroids

Pathogenesis Duodenal ulcers are more frequent in individuals with alcoholic cirrhosis chronic obstructive pulmonary disease chronic renal failure self-imposed or exogenous psychologic stress

Helicobacter pylori Causes 80% of gastric peptic ulcers Causes 100% of duodenal peptic ulcers Causes chronic gastritis Causes gastric carcinomas Causes MALT lymphomas 32

Morphology SITE Peptic ulcers four times more common in the proximal duodenum than in the stomach Duodenal ulcers few centimeters of the pyloric valve and involve the anterior duodenal wall Gastric ulcers along the lesser curvature near the interface of the body and antrum 33

Morphology 2 to 4 cm in diameter SIZE NUMBER SHAPE Usually Solitary less than 0.3 cm in diameter tend to be shallow while those over 0.6 cm are likely to be deeper ulcers NUMBER Usually Solitary SHAPE round to oval, sharply punched-out defect 34

Morphology Margin overhang the base slightly or level with the surrounding mucosa Depth limited by the thick gastric muscularis propria or by adherent pancreas, omental fat, or the liver Hemorrhage and fibrin deposition are often present on the gastric serosa 35

Morphology BASE OF ULCER smooth and clean as a result of peptic digestion of exudate with evident blood vessels In active ulcers the base may have a thin layer of fibrinoid debris neutrophilic inflammatory infiltrate active granulation tissue infiltrated with mononuclear leukocytes fibrous or collagenous scar forms the ulcer base 36

Clinical Manifestations

“PEPTIC” ULCERS Epigastric pain (burning, aching,) Fe deficiency anemia Acute hemorrhage Penetration, perforation: Pain in BACK Pain in CHEST Pain in LUQ Malignant transformation of peptic ulcers is very rare 39

PEPTIC ULCERS Bleeding Perforation Obstruction from edema or scarring Occurs in 15% to 20% of patients Most frequent complication May be life-threatening Perforation Occurs in about 5% of patients Accounts for two thirds of ulcer deaths Obstruction from edema or scarring Occurs in about 2% of patients Most often due to pyloric channel ulcers May also occur with duodenal ulcers Causes incapacitating, crampy abdominal pain Rarely, may lead to total obstruction with intractable vomiting 40

GASTRIC TUMORS BENIGN: MALIGNANT POTENTIALLY MALIGNANT POLYPS (HYPERPLASTIC vs. ADENOMATOUS) LEIOMYOMAS (Same gross and micro as sm. muscle) LIPOMAS (Same gross and micro as adipose tissue) MALIGNANT (ADENO)Carcinoma LYMPHOMA POTENTIALLY MALIGNANT G.I.S.T. (Gastro-Intestinal “Stromal” Tumor) CARCINOID (NEUROENDOCRINE) 42

WHO GASTRIC NEOPLASMS Epithelial Tumors: Adenomatous polyps Adenocarcinoma (papillary, tubular, mucinous, signet ring, adenosquamous, unclassified), Small cell, Carcinoid (neuroendocrine) Nonepithelial Tumors: Leiomyooma, Leimyosarcoma, Schwannoma, GIST, Granular Cell Tumor, Kaposi sarcoma Malignant Lymphomas: 43

ADENOCARCINOMA H. pylori associated, MASSIVELY!!! Japan, Chile, Costa Rica, Colombia, China, Portugal, Russia, and Bulgaria M>>F Socioeconomically related

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

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 Barrett esophagus Increased risk of gastroesophageal junction tumors

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)

ADENOCARCINOMA RISK FACTORS H. pylori Nitrites, smoked meats, pickled, salted, chili peppers, socioeconomic, tobacco Chronic gastritis, Barrett’s, adenomas Family history

Morphology SITE - Favoured location is the lesser curvature of the antropyloric region Gastric carcinoma is classified on the basis of - depth of invasion - macroscopic growth pattern - histologic subtype

Morphology Early gastric carcinoma lesion confined to the mucosa and submucosa regardless of the presence or absence of perigastric lymph node metastases Advanced gastric carcinoma neoplasm that has extended below the submucosa into the muscular wall spread more widely

Morphology (1) exophytic, with protrusion of a tumor mass into the lumen (2) flat or depressed, in which there is no obvious tumor mass within the mucosa (3) excavated, whereby a shallow or deeply erosive crater is present in the wall of the stomach.

ADENOCARCINOMA GROWTH PATTERNS I hope these are logical anatomic or “geometric” descriptions, and NOT exact classifications. 52

Morphology Exophytic tumors may contain portions of an adenoma. Flat or depressed malignancy presents only as regional effacement of the normal surface mucosal pattern Excavated cancers may mimic, in size and appearance, chronic peptic ulcers, although more advanced cases show heaped-up margins

Morphology a broad region of the gastric wall, or the entire stomach, is extensively infiltrated by malignancy. The rigid and thickened stomach is termed a leather bottle stomach, or linitis plastica; metastatic carcinoma from the breast and lung may generate a similar picture.

Morphology Histologic appearances of gastric cancer are best classified into the intestinal type and diffuse type intestinal variant is composed of malignant cells forming neoplastic intestinal glands resembling those of colonic adenocarcinoma diffuse variant is composed of gastric-type mucous cells that generally do not form glands but rather permeate the mucosa and wall as scattered individual "signet-ring" cells or small clusters in an "infiltrative" growth pattern.

Morphology all gastric carcinomas eventually penetrate the wall to involve the serosa, spread to regional and more distant lymph nodes, and metastasize widely. The earliest lymph node metastasis may sometimes involve a supraclavicular lymph node (Virchow node) Intraperitoneal spread in females is to both the ovaries, giving rise to the so-called Krukenberg tumor

Morphology Gastric carcinoma. showing an ill-defined, excavated central ulcer surrounded by irregular, heaped-up borders.

Gross: Linitis plastica carcinoma diffusely infiltrates the entire gastric wall without forming an intraluminal mass. The wall of the stomach is typically thickened to about 2-3 cm. and has a leathery, inelastic consistency.

Gastric carcinoma. Intestinal type gland formation by malignant cells, Diffuse type demonstrating signet-ring carcinoma cells.

Clinical Features The symptoms include weight loss, abdominal pain, anorexia, vomiting, altered bowel habits, less frequently dysphagia, anemic symptoms hemorrhage

Prognosis depends primarily on the depth of invasion and the extent of nodal and distant metastasis at the time of diagnosis The prognostic value of biomarkers p53 mutation and c-ERB-B2 Early gastric cancer five-year survival rate of surgically treated is 90% to 95% Advanced gastric cancer five-year survival rate for remains below 15%.

G.I.S.T. TUMORS Can behave and/or look benign or malignant Usually look like smooth muscle, i.e., “stroma” Are usually POSITIVE for c-KIT (CD117), i.e., express this antigen on immunochemical staining, the tumor cells are derived from the interstitial cells, of Cajal, a “neural” type of cell

G.I.S.T. TUMORS c-KIT (receptor for stem cell factor) mutations platelet-derived growth factor receptor-a. (PDGFRA) mutations tyrosine kinase inhibitor (STIS71) has been shown to be effective in treatment

CARCINOID TUMOR arise from the diffuse components of the endocrine system majority are found in the GI tract, and more than 40% occur in the small intestine tracheobronchial tree and lungs

Gastric carcinoids may be associated with endocrine cell hyperplasia chronic atrophic gastritis Zollinger-Ellison syndrome well-differentiated neuroendocrine carcinomas

Gastric carcinoids release peptide and nonpeptide hormones to coordinate gut function carcinoids are intramural or submucosal masses that create small polypoid lesions

Gastric carcinoids Histologically composed of islands, trabeculae, strands, glands, or sheets of uniform cells with scant, pink granular cytoplasm and a round to oval stippled nucleus Immunohistochemical stains are typically positive for endocrine granule markers, such as synaptophysin and chromogranin A

Gastric carcinoids Symptoms are determined by the hormones produced Zollinger-Ellison syndrome carcinoid syndrome

Carcinoid syndrome characterized by cutaneous flushing, sweating Bronchospasm colicky abdominal pain & diarrhea right-sided cardiac valvular fibrosis

Foregut carcinoid tumors Midgut carcinoid tumors The most important prognostic factor for GI carcinoid tumors is location Foregut carcinoid tumors rarely metastasize and are generally cured by resection Midgut carcinoid tumors Aggressive, greater depth of local invasion, increased size, and presence of necrosis and mitosis are associated with poor outcome Hindgut carcinoids occur in appendix & rectum in appendix almost uniformly benign < 2cm Rectal carcinoid rarely metastsize

lymphoepithelial lesion (LEL) is a hallmark GASTRIC LYMPHOMA Primary : Mucosa (gut)-associated lymphoid tissue tumor Previously called MALToma, MALT-type lymphoma, or MALT lymphoma, Now called Extranodal marginal zone B-cell lymphoma of MALT type lymphoepithelial lesion (LEL) is a hallmark Secondary spread from adjacent lymph nodes

Predisposing factors: Gastric LYMPHOMA Predisposing factors: Helicobacter pylori-associated chronic gastritis Autoimmune diseases Immunodeficiency syndromes (eg, AIDS) Long-standing immunosuppressive therapy (eg, post transplantation)

Distribution of GI Lymphoma 55-65% 20-35% 7-20% Courtesy of Dr. Alyssa Krasinskas 73

Molecular MALT Genetics t(11;18)(q21;q21) API2/MALT1 gene fusion ~25% of gastric MALT lymphomas t(1;14)(p22;q32) BCL10 deregulated by coming under control of Ig gene Some intestinal MALT lymphomas t(14;18)(q32;q21) MALT1/Ig fusion <5% of gastric MALT lymphomas Trisomy 3, 12, 18 (often associated with t(1;14) p53 mutation; methylation of p15 and p16 promoters Mutations of fas 74