Gastric Pathology — Ulcers, Gastritis, Carcinoma

Peptic Ulcer Disease: Mucosal Defense and Acid-Pepsin Damage

• Loss of mucosal integrity: Ulcer formation results from imbalance between aggressive luminal factors and mucosal defense mechanisms. The mucosa normally withstands gastric acid (pH 1.0-2.0) through multiple protective layers: a mucus-bicarbonate barrier (adherent mucus layer 1-1.5 mm thick with pH gradient), tight junctions between gastric epithelial cells, prostaglandin E2 and I2 (stimulate mucus and bicarbonate secretion, maintain mucosal blood flow), and mucosal blood flow ensuring epithelial restitution. Disruption of any layer permits acid-pepsin penetration and autodigestion.

• ***Helicobacter pylori* pathogenic mechanisms: This gram-negative microaerophilic bacterium colonizes the gastric mucosa at the junction of foveolae and glands. Pathogenic strains produce urease (generates ammonia to neutralize local acid and facilitate bacterial survival), express cytotoxin-associated gene A (CagA) protein (translocated into epithelial cells via type IV secretion system, triggers inflammatory signaling through phosphorylation of host proteins, disrupts cell polarity and tight junctions), and secrete vacuolating cytotoxin A (VacA)** (creates cytoplasmic vacuoles, induces apoptosis, increases paracellular permeability). The resulting chronic active gastritis with neutrophilic infiltration and cytokine production (IL-8, TNF-α, IL-6) perpetuates mucosal damage. Antral-predominant gastritis increases acid secretion; fundal-predominant gastritis causes atrophic changes and hypochlorhydria.

• NSAID-induced ulceration: NSAIDs inhibit cyclooxygenase (COX-1 and COX-2), decreasing prostaglandin synthesis and reducing mucus secretion, bicarbonate production, and mucosal blood flow. The resulting epithelial damage is compounded by acid-pepsin penetration. Importantly, NSAIDs also inhibit platelet function, impairing hemostasis if ulcer erosion reaches a vessel. Risk increases with age, concurrent corticosteroid use, anticoagulation, and H. pylori infection (synergistic effect).

• Gastric acid hypersecretion: In Zollinger-Ellison syndrome (ZES), gastrin-secreting neuroendocrine tumors drive relentless acid production, overwhelming normal mucosal defenses. Severe, refractory ulceration results, often with diarrhea from acid inactivation of pancreatic enzymes.

Gastritis: Inflammatory Cascade and Mucosal Atrophy

• Acute gastritis: Acute mucosal edema and acute inflammatory infiltrate (predominantly neutrophils) with variable epithelial damage and mucous cell depletion. Erosions (mucosal defects not reaching muscularis mucosae) may occur without frank ulceration. Stress gastritis (from critical illness, severe burns, or trauma) represents acute gastric mucosal injury secondary to splanchnic hypoperfusion and loss of protective mechanisms; histologically shows acute inflammatory exudate and erosive damage.

• Chronic gastritis progression: H. pylori or autoimmune-mediated chronic inflammation causes progressive intestinal metaplasia (replacement of gastric mucosa with intestinal-type epithelium including goblet cells), atrophy (loss of specialized glands), and achlorhydria (loss of acid secretion). These changes follow the Correa cascade: normal mucosa → chronic gastritis → atrophy → intestinal metaplasia → dysplasia → adenocarcinoma. Autoimmune (Type A) gastritis involves IgG antibodies against parietal cells and intrinsic factor, leading to fundal gland atrophy, loss of acid and intrinsic factor secretion, and pernicious anemia.

• Lymphocytic infiltration and follicle formation: Chronic H. pylori gastritis generates prominent lymphocytic infiltrates with reactive germinal centers forming within gastric lymphoid tissue, sometimes progressing to mucosa-associated lymphoid tissue (MALT) lymphoma.

Peptic Ulcer Disease

• ***Helicobacter pylori* infection**: Present in >90% of duodenal ulcers and 70% of gastric ulcers globally. Chronic colonization drives gastritis and disrupts mucosal defenses through the mechanisms outlined above.

• NSAID use: Accounts for 15-20% of PUD in the United States; accounts for nearly all NSAID-induced ulcers (both gastric and duodenal). Dosage, duration, and individual susceptibility determine risk. Concurrent gastroprotection (proton pump inhibitors or H2-blockers) reduces NSAID ulcer risk by >90%.

• Zollinger-Ellison syndrome: Gastrin-secreting neuroendocrine tumor (usually pancreatic) causing severe acid hypersecretion. Suspect in refractory or multiple ulcers, severe esophagitis, or chronic diarrhea.

• Stress ulceration: Critical illness, severe sepsis, extensive burns, major surgery, or head trauma. Occurs via splanchnic hypoperfusion and mucosal ischemia rather than acid hypersecretion.

• Cigarette smoking: Increases ulcer risk and delays healing by reducing prostaglandin synthesis and mucosal blood flow.

• Psychological stress and alcohol: Modest risk factors; alcohol damages mucosa directly and stimulates acid secretion.

Gastritis

• ***Helicobacter pylori* infection**: Most common cause of chronic gastritis globally.

• Autoimmune (Type A) gastritis: IgG antibodies against parietal cells; associated with other autoimmune diseases (thyroiditis, pernicious anemia). Predominantly involves fundus and body, causing atrophy.

• Bile reflux: Post-surgical (post-gastrectomy) or sphincter incompetence; bile damages mucosa directly.

• Infection: H. pylori (discussed above); viral (CMV, HSV) in immunocompromised patients; bacterial overgrowth in achlorhydric states.

• Chemical injury: NSAIDs, alcohol, corrosive ingestion, aspirin.

• Stress: Critical illness, severe burns, sepsis.

• Atrophic gastritis: End-stage H. pylori or autoimmune gastritis with glandular loss and intestinal metaplasia.

Gastric Adenocarcinoma

• ***Helicobacter pylori* infection: Most significant modifiable risk factor; increases gastric cancer risk 2-6 fold. Chronic antral gastritis with acid hypersecretion increases risk of intestinal-type** adenocarcinoma. Eradication before dysplasia develops reduces cancer risk.

• Intestinal metaplasia and chronic atrophy: Precancerous lesions following the Correa cascade. Extensive intestinal metaplasia increases malignant potential.

• Dysplasia: High-grade dysplasia (HGD) has up to 40% risk of concurrent or future adenocarcinoma; low-grade dysplasia (LGD) has lower progression risk but requires surveillance.

• Smoking and alcohol: 1.5-3 fold increased risk; synergistic with H. pylori.

• Family history and genetics: Hereditary diffuse gastric cancer (HDGC) syndrome (germline CDH1 mutations encoding E-cadherin); accounts for 1-3% of gastric cancers. Familial intestinal gastric cancer (FIGC) with TP53 and CDKN2A mutations.

• Dietary factors: High salt intake, processed meats, nitrates/nitrites (converted to carcinogenic N-nitroso compounds by H. pylori). Protective factors include fresh vegetables and vitamin C.

• Socioeconomic status and geography: Higher incidence in East Asia, parts of Europe, and Central/South America; correlates with H. pylori prevalence.

• Obesity: Modest increase in gastric cardia adenocarcinoma, possibly mediated by gastroesophageal reflux.

• Previous gastric surgery: Subtotal gastrectomy increases risk of gastric cancer in remnant stomach (10-20 years post-op) via bile reflux and chronic inflammation.

• Pernicious anemia: Autoimmune gastritis with intrinsic factor loss; 2-3 fold increased gastric cancer risk despite achlorhydria.

Peptic Ulcer Disease

• Epigastric pain: Burning, gnawing quality; may be food-related (relieved by food or antacids in duodenal ulcer; exacerbated by food in gastric ulcer, though overlap is common). Nocturnal awakening is characteristic, reflecting acid secretion during sleep. Pain may radiate to back if ulcer penetrates posteriorly into pancreas.

• Nausea and early satiety: From gastric outlet obstruction or acute inflammation.

• Hematemesis or melena: Indicates erosion into a blood vessel (usually gastroduodenal artery for duodenal ulcer; left gastric artery for proximal gastric ulcer). Brisk bleeding may cause coffee-ground emesis (oxidized blood) or bright red blood; slower bleeding produces melena (tarry stool).

• Perforation signs: Sudden, severe epigastric pain; acute peritonitis with rebound tenderness and guarding; free air under diaphragm on upright chest X-ray. This is a surgical emergency.

• Physical examination: Epigastric tenderness to palpation; signs of peritonitis if perforated; pallor or tachycardia if bleeding.

• Laboratory findings: Elevated BUN/creatinine ratio in bleeding ulcers (from upper GI blood loss with prerenal azotemia). Hemoglobin drop indicating significant bleed. Fasting serum gastrin >1000 pg/mL or gastric pH <2 with detectable gastrin suggests ZES.

Gastritis

• Acute gastritis: Epigastric discomfort, nausea, anorexia; may progress to hemorrhagic gastritis with hematemesis or melena.

• Chronic gastritis: Often asymptomatic in early stages. Progressive anorexia, early satiety, and nonspecific upper abdominal discomfort. Pernicious anemia presents with fatigue, dyspnea, paresthesias (from B12 deficiency).

• MALT lymphoma (gastric): Often asymptomatic, discovered on screening endoscopy. May present with vague dyspepsia or, rarely, obstruction.

• Laboratory findings:
• Pernicious anemia: Macrocytic anemia, elevated methylmalonic acid and homocysteine, low or absent B12, elevated anti-intrinsic factor and anti-parietal cell antibodies.
• Fasting serum gastrin: Elevated in autoimmune (Type A) gastritis with achlorhydria (>100 pg/mL due to loss of feedback inhibition by acid).
• Serological markers: Anti-*H. pylori* IgG (indicates past or current infection); anti-*Cag*A and anti-VacA antibodies correlate with increased ulcer risk.

Gastric Adenocarcinoma

• Early disease (often asymptomatic): Discovered incidentally on screening endoscopy or imaging for unrelated reasons.

• Advanced disease presenting symptoms:
• Progressive dysphagia or early satiety: From proximal/cardia tumors or linitis plastica ("leather bottle stomach").
• Epigastric pain: Often vague, nonspecific; may reflect advanced local invasion.
• Anorexia and weight loss: Resultant from tumor burden and cachexia-inducing cytokines (IL-6, TNF-α).
• Hematemesis or melena: Erosion into mucosa causing frank hemorrhage; more common with ulcerating lesions.
• Abdominal mass and hepatomegaly: Indicating advanced disease and metastases.
• Ascites: From peritoneal carcinomatosis or cirrhosis if *H. pylori*-induced.
• Virchow node (left supraclavicular lymphadenopathy) or Sister Mary Joseph nodule (periumbilical nodule): Distant metastases.

• Laboratory findings:
• Elevated tumor markers: CEA and CA 19-9 in advanced disease; not sensitive for early detection.
• Anemia: From chronic bleeding or iron malabsorption.
• Elevated LDH: Correlates with tumor burden and poor prognosis.

Peptic Ulcer Disease

• Endoscopy (Gold Standard):
• Gross appearance: Ulcer is a break in mucosa with clean, punched-out borders; well-demarcated yellow fibrinous base with red/granulation tissue at margins; surrounding mucosa may show acute/chronic inflammation. Duodenal ulcers (90% of PUD) occur at anterior first portion (prone to perforation into peritoneal cavity) or posterior first portion (erodes into gastroduodenal artery, causing hemorrhage). Gastric ulcers (10% of PUD) occur along lesser curvature and are at greater risk of malignancy.
• Histology (if biopsied): Acute ulcer shows fibrinopurulent exudate with polymorphonuclear leukocytes, granulation tissue with fibroblasts and neovascularization, and underlying chronic inflammatory infiltrate. Chronic ulcer displays fibrosis with collagen deposition in base. H. pylori organism visualized with Warthin-Starry stain (black spirilliform organisms on tan background) or immunohistochemistry.

• H. pylori testing:
• Serology (IgG antibody): Indicates past or current infection; remains positive after eradication (not useful for test of cure).
• Urea breath test (UBT): Gold standard for current infection; detects bacterial urease activity. Can be performed pre- and post-treatment for confirmation of eradication.
• Fecal antigen test: Alternative non-invasive test for current infection.
• Endoscopic biopsy with culture or rapid urease test: Direct detection; rapid urease test results available in 1-2 hours.

• Imaging:
• Upright chest X-ray: Free air under diaphragm in perforation (pneumoperitoneum).
• CT abdomen/pelvis: Perforation with free fluid/air; complications such as penetration into adjacent organs.

• Secretin stimulation test: Used for suspected ZES; gastrin level rises paradoxically >200 pg/mL above baseline with secretin injection (confirming autonomous gastrin production).

Gastritis

• Endoscopy with multiple biopsies (Required for diagnosis):
• Gross appearance in acute gastritis: Edematous, friable mucosa with petechial hemorrhages and possible erosions; in hemorrhagic gastritis, frank bleeding with blood in lumen.
• Gross appearance in chronic gastritis: Nodular, atrophic, or pale mucosa; may show intestinal metaplasia as pale, villous areas.
• Histology - acute gastritis: Acute inflammatory infiltrate predominantly neutrophils within lamina propria and foveolae; edema of lamina propria; **mucous

Immediate stabilisation (bleeding ulcer)

• Resuscitation first: two large-bore IVs, crystalloid, and a restrictive red-cell transfusion strategy with a threshold near 7 g/dL in hemodynamically stable patients (ACG 2021 upper GI bleeding guideline); over-transfusion raises portal/systemic pressure and rebleeding risk.
• IV proton pump inhibitor (e.g., pantoprazole) before endoscopy: raising intragastric pH above ~6 stabilises clot by preventing pepsin-mediated fibrinolysis and platelet disaggregation.
• Upper endoscopy within 24 hours (ACG 2021), with hemostasis for high-risk stigmata (active spurting/oozing, non-bleeding visible vessel). Epinephrine injection must be combined with a second modality — clips or thermal coagulation — never used alone. Failed endoscopic control → repeat endoscopy, then transcatheter arterial embolization before surgery.

First-line medical therapy

• H. pylori eradication: ACG 2017 favours bismuth quadruple therapy (PPI + bismuth subsalicylate + tetracycline + metronidazole) for 14 days, given rising clarithromycin resistance. PPI–clarithromycin–amoxicillin triple therapy is acceptable only where local resistance is low and there is no prior macrolide exposure.
• Salvage regimens: levofloxacin-containing or rifabutin-containing triple therapy; avoid re-using a previously failed antibiotic.
• Test of cure: urea breath test or fecal antigen at least 4 weeks after therapy, with PPI held ~2 weeks; serology cannot be used.
• NSAID ulcers: stop the NSAID; if it must continue, add PPI co-therapy or use a COX-2–selective agent plus PPI.

Definitive/surgical

• Perforation — emergency laparotomy or laparoscopy with Graham omental patch, NPO, IV fluids, broad-spectrum antibiotics.
• Gastric adenocarcinoma (NCCN): endoscopic resection for select early T1a lesions; otherwise subtotal/total gastrectomy with D2 lymphadenectomy plus perioperative chemotherapy; HER2 and PD-L1 testing guides trastuzumab and checkpoint inhibitors in advanced disease. CDH1 carriers are offered prophylactic total gastrectomy.
• Gastric MALT lymphoma: eradication alone induces remission in most early-stage cases.

Contraindicated

• Misoprostol in pregnancy (uterotonic); tetracycline in pregnancy and young children; alcohol with metronidazole (disulfiram-like reaction); clarithromycin with QT-prolonging drugs.

Disease complications

• Hemorrhage (most common): erosion into a submucosal vessel — classically the gastroduodenal artery from a posterior duodenal ulcer. Signalled by hematemesis/melena, tachycardia, and a disproportionately elevated BUN:creatinine ratio from absorbed blood plus prerenal azotemia. Emergency.
• Perforation: full-thickness necrosis, typically an anterior duodenal ulcer, releasing acid into the peritoneum. Sudden severe pain, board-like rigidity, free air under the diaphragm. Surgical emergency.
• Penetration: posterior ulcer burrows into pancreas — pain radiating to the back that loses its meal relationship, with elevated lipase.
• Gastric outlet obstruction: edema then scar-fibrosis of the pylorus/duodenal bulb. Succussion splash, vomiting of undigested food, and hypochloremic hypokalemic metabolic alkalosis with paradoxical aciduria from loss of HCl and secondary hyperaldosteronism.
• Malignant transformation: chronic H. pylori gastritis → atrophy → intestinal metaplasia → dysplasia → intestinal-type adenocarcinoma; the same chronic lymphoid drive produces MALT lymphoma.
• Autoimmune gastritis sequelae: intrinsic factor loss → B12 deficiency with megaloblastic anemia and subacute combined degeneration; achlorhydria → hypergastrinemia → ECL-cell hyperplasia and type 1 gastric carcinoid; also iron deficiency from impaired ferric reduction.
• Advanced carcinoma: peritoneal carcinomatosis with malignant ascites and Krukenberg ovarian metastases; gastric outlet or cardia obstruction; malignant fistula.

Treatment-related complications

• Proton pump inhibitors: acid suppression permits enteric colonisation — Clostridioides difficile infection, and impaired absorption of B12, iron, calcium, and magnesium (hypomagnesemia with tetany/arrhythmia). Fundic gland polyps and rebound acid hypersecretion after abrupt withdrawal.
• Bismuth: harmless black tongue and black stool — the classic distractor for melena.
• Metronidazole/clarithromycin: metallic taste, peripheral neuropathy, QT prolongation.
• Post-gastrectomy: dumping syndrome (osmotic fluid shift plus incretin surge, causing postprandial diarrhea, flushing, and late hypoglycemia), bile reflux gastritis, B12 and iron deficiency, and adenocarcinoma of the gastric remnant a decade or more later.

• Anterior vs posterior duodenal ulcer: anterior perforates (free air, peritonitis); posterior bleeds into the gastroduodenal artery. This anatomic pair is tested relentlessly.
• Every gastric ulcer gets biopsied; duodenal ulcers essentially never harbor malignancy. For a gastric ulcer, the single best next step is EGD with multiple biopsies of the rim and base, plus repeat endoscopy to document healing.
• Alarm features drive endoscopy: dysphagia, weight loss, overt bleeding, vomiting, mass, or new-onset dyspepsia in an older adult (ACG/AGA dyspepsia guidance). Without alarm features, test-and-treat for H. pylori is the correct first move.
• Hold the PPI ~2 weeks before urea breath or fecal antigen testing — acid suppression suppresses urease activity and causes false negatives. Serology never confirms eradication because IgG persists; that is the classic distractor.
• Intestinal type vs diffuse type: intestinal type arises from the Correa cascade, is *H. pylori*–driven, forms glands, and ulcerates along the lesser curvature. Diffuse type shows signet ring cells with loss of **E-cadherin (CDH1), is not tied to the Correa sequence, and produces *linitis plastica*** — a rigid, non-distensible "leather bottle" stomach.
• Metastatic eponyms: Virchow node (left supraclavicular), Sister Mary Joseph nodule (periumbilical), Krukenberg tumor (bilateral ovarian signet ring), Blumer shelf (rectal-shelf drop metastasis). Paraneoplastic acanthosis nigricans and the sign of Leser-Trélat are the dermatologic tells.
• Curling vs Cushing: Curling ulcer follows severe burns (hypovolemia → mucosal ischemia); Cushing ulcer follows CNS injury (vagal overdrive → acid hypersecretion) and is more prone to perforation.
• **Gastric MALT lymphoma regresses with H. pylori eradication alone** — antibiotics before chemotherapy or radiation is the intended answer in early-stage disease.
• Bismuth turns stool and tongue black — do not call it melena.