Lecture 22 — GI Pathology Lab

Key Histologic Features

• Lining epithelium: Non-keratinized stratified squamous epithelium — identical in appearance to skin but without keratin layer
• Submucosa: Contains esophageal mucous glands (submucosal glands) that secrete mucus to lubricate food passage
• Muscularis propria: Upper 1/3 = skeletal muscle; Middle 1/3 = mixed; Lower 1/3 = smooth muscle
• No serosa: The esophagus lacks a serosal layer — facilitates rapid spread of esophageal carcinoma into mediastinum
• GEJ (gastroesophageal junction): Abrupt transition from squamous → columnar epithelium (the Z-line/squamocolumnar junction, visible endoscopically)

Key Histologic Features

• Epithelium: Simple columnar mucous epithelium lining the luminal surface and pits
• Rugae: Prominent longitudinal folds of mucosa and submucosa visible grossly; allow distension
• Gastric pits: Surface invaginations leading into glands; vary by region
• Parietal cells (oxyntic cells): Large, pyramidal cells with abundant bright pink eosinophilic cytoplasm; secrete HCl and intrinsic factor; found mainly in fundus/body
• Chief cells (zymogenic cells): Basophilic cells in the lower glands; secrete pepsinogen (activated to pepsin by HCl)
• G cells: Enteroendocrine cells in the antrum; secrete gastrin → stimulates parietal cells
• Mucous neck cells: In upper gland neck; secrete protective mucus

Regional Differences

Key Histologic Features

• Villi: Finger-like mucosal projections unique to the small intestine; dramatically increase absorptive surface area (~200–300× over a flat tube)
• Enterocytes: Tall columnar cells with a brush border (microvilli = striated border) on the apical surface; site of digestion and absorption
• Goblet cells: Scattered among enterocytes; secrete protective mucus; increase in number from duodenum → ileum
• Crypts of Lieberkühn: Tubular glands at base of villi; contain stem cells that renew the epithelium every 3–5 days; also contain Paneth cells (secrete antimicrobial defensins)
• Lamina propria: Contains lacteals (lymphatic capillaries) for fat absorption as chylomicrons
• Brunner's glands: Submucosal mucous glands found only in the duodenum; neutralize gastric acid
• Peyer's patches: Lymphoid aggregates in the submucosa, concentrated in the ileum; immune surveillance (MALT)

Duodenum vs. Jejunum vs. Ileum

Key Histologic Features

• No villi: Unlike the small intestine, the colon has no villi — the luminal surface is flat with straight tubular crypts
• Crypts of Lieberkühn: Prominent, straight, parallel tubular glands extending full thickness of the mucosa
• Abundant goblet cells: Far more goblet cells than in the small intestine — mucus production for lubrication of stool
• Colonocytes: Columnar absorptive cells; primary function = water and electrolyte reabsorption (no brush border enzyme activity)
• Taeniae coli: Three narrow bands of outer longitudinal smooth muscle (instead of a complete layer) — cause haustra (sacculations) visible grossly
• GALT: Lymphoid nodules in submucosa are a normal finding; the gut-associated lymphoid tissue = largest lymphoid organ in the body
• No Brunner's glands, no Peyer's patches

Pathogenesis: Incompetent lower esophageal sphincter (LES) → acid reflux → squamous mucosal damage. Worsened by obesity, fatty foods, alcohol, tobacco, hiatal hernia, pregnancy.

• Symptoms: Heartburn (pyrosis), regurgitation, dysphagia (late)
• Histology: Basal zone hyperplasia of squamous epithelium, elongated papillae, eosinophilic infiltrate (eosinophils in squamous mucosa)
• Complications: Barrett's esophagus, stricture, ulceration, adenocarcinoma

Pathogenesis: Chronic GERD → metaplasia: normal squamous epithelium → intestinal-type columnar epithelium with goblet cells (intestinal metaplasia). This is a pre-malignant condition.

• Risk: 30–40× increased risk of esophageal adenocarcinoma
• Buzzword histology: Goblet cells in esophageal biopsy = Barrett's until proven otherwise
• Progression: Barrett's → low-grade dysplasia → high-grade dysplasia → adenocarcinoma
• Screening: Regular endoscopic surveillance with biopsies in patients with chronic GERD

Pathogenesis: Portal hypertension (most commonly from liver cirrhosis) → increased pressure in portal system → blood diverted through portosystemic anastomoses → esophageal submucosal veins become engorged and dilated.

• Location: Lower 1/3 of esophagus (where esophageal veins connect with portal system via left gastric vein)
• Complication: Variceal rupture → massive upper GI hemorrhage → hematemesis → can be fatal (mortality 20–30% per episode)
• Clinical: Painless, sudden massive hematemesis in a patient with known cirrhosis/portal HTN
• Treatment: Endoscopic band ligation, sclerotherapy, TIPS (transjugular intrahepatic portosystemic shunt), propranolol (prophylaxis)

Causes of acute gastritis / erosions:

• NSAIDs / Aspirin: Inhibit COX → ↓ prostaglandin synthesis → ↓ mucus and bicarb protection → mucosal injury
• Alcohol: Direct mucosal irritant; disrupts mucosal barrier
• H. pylori: See below
• Stress ulcers: Occur in critically ill patients (major trauma, burns, sepsis, shock, CNS injury)

Definition: A breach in the mucosa extending through the muscularis mucosae into the submucosa (or deeper) — distinguishing it from a mere erosion (which is superficial).

• Locations: Duodenum (most common, anterior wall of first part) > Stomach (lesser curvature of antrum/body)
• Pathogenesis: Imbalance between aggressive factors (acid, pepsin) and defensive factors (mucus, bicarb, prostaglandins, mucosal blood flow)
• Symptoms: Epigastric pain; DU classically relieved by eating; GU classically worsened by eating
• Complications: Bleeding (most common — melena/hematemesis), perforation, obstruction, penetration into pancreas

Organism: Helicobacter pylori — gram-negative, microaerophilic, urease-positive spiral rod

• Virulence: Urease → NH₃ → neutralizes acid → allows survival in gastric mucus; also produces CagA protein and vacuolating toxin (VacA)
• Epidemiology: Affects ~50% of the world's population; fecal-oral transmission; higher prevalence in developing nations
• Diagnosis: Urea breath test (gold standard non-invasive); serology (IgG); fecal antigen test; biopsy (CLO test / histology with methylene blue or Giemsa stain)
• Associated diseases: Chronic gastritis (antral), peptic ulcer disease (duodenal > gastric), gastric adenocarcinoma (intestinal type), gastric MALT lymphoma
• Treatment: Triple therapy (PPI + clarithromycin + amoxicillin × 14 days) or quadruple therapy if resistant

Pathogenesis: Sensitivity to gliadin, a protein component of gluten (found in wheat, barley, oats, rye) → immune-mediated destruction of small bowel mucosa → malabsorption

• Genetics: >95% of patients express HLA-DQ2 (or HLA-DQ8); strong genetic basis
• Histology: Villous atrophy, crypt hyperplasia, ↑ intraepithelial lymphocytes (IELs), plasma cell infiltration of lamina propria
• Symptoms: Chronic diarrhea, steatorrhea, bloating; malabsorption → iron deficiency anemia, folate deficiency, fat-soluble vitamin deficiency (A, D, E, K), osteoporosis
• Serology: Anti-tissue transglutaminase (anti-tTG) IgA; anti-endomysial antibodies (IgA)
• Treatment: Strict gluten-free diet → mucosal recovery
• Complication: Enteropathy-associated T-cell lymphoma (EATL) in refractory cases

Embryology: Failure of involution of the vitelline (omphalomesenteric) duct → persistent outpouching from the antimesenteric border of the ileum

• Rule of 2's: 2% of population; 2 feet from ileocecal valve; 2 inches long; 2% become symptomatic; 2 types of ectopic tissue (gastric, pancreatic); presents in first 2 years of life
• Contains: All 3 layers of normal bowel wall (true diverticulum)
• Complications: Painless lower GI bleeding (ectopic gastric mucosa secretes acid → ulceration); intussusception; volvulus; diverticulitis (mimics appendicitis)
• Diagnosis: Technetium-99m pertechnetate scan (detects ectopic gastric mucosa)

Pathogenesis: Broad-spectrum antibiotics (clindamycin, fluoroquinolones, ampicillin, cephalosporins) → disruption of normal colonic flora → overgrowth of Clostridium difficile → toxin A (enterotoxin) + toxin B (cytotoxin) → mucosal damage

• Symptoms: Profuse, watery diarrhea (may become bloody); crampy abdominal pain; fever; leukocytosis (WBC often >15,000)
• Diagnosis: Stool PCR for C. diff toxin genes (most sensitive); GDH antigen + toxin immunoassay
• Treatment: Stop offending antibiotic; oral vancomycin or fidaxomicin (first line); metronidazole (alternative); fecal microbiota transplant (FMT) for recurrent cases
• Complication: Toxic megacolon (life-threatening dilation of colon → perforation → sepsis)

Diverticulosis: Outpouching of colonic mucosa and submucosa through defects in the muscularis propria at sites where nutrient arteries penetrate — these are false (pulsion) diverticula (lack the muscularis layer)

• Epidemiology: Very common (>50% of Americans >60); associated with low-fiber diet → ↑ intraluminal pressure
• Location: Sigmoid colon most common (left colon); right-sided diverticula more common in Asian populations
• Complications:
  • Diverticulitis: Infection/inflammation of a diverticulum → LLQ pain, fever, leukocytosis ("left-sided appendicitis")
  • Diverticular bleeding: Painless hematochezia (most common cause of massive lower GI bleed in elderly) — from erosion of nutrient artery
  • Perforation, abscess, fistula formation

Definition: Rare, tortuous dilation of submucosal and mucosal blood vessels in the cecum or right colon

• Occurs in older adults; often associated with aortic stenosis (Heyde syndrome)
• Presents as painless, recurrent lower GI bleeding → iron deficiency anemia
• Diagnosis: Colonoscopy (cherry-red arteriovenous lesions) or mesenteric angiography during active bleed
• Treatment: Endoscopic cauterization or APC (argon plasma coagulation)

Pathogenesis

Aberrant Th1/Th17 immune response to normal gut flora in genetically predisposed individuals → chronic transmural granulomatous inflammation. Key gene: NOD2/CARD15 mutation (recognizes bacterial muramyl dipeptide).

Clinical Presentation

• Recurrent episodic abdominal pain (often RLQ — mimics appendicitis when terminal ileum involved)
• Chronic non-bloody or mildly bloody diarrhea (steatorrhea if significant ileal disease)
• Weight loss, fatigue, low-grade fever
• Perianal disease: fissures, fistulas, abscesses, skin tags
• Complications: strictures (obstructive symptoms), fistulas (enterovesical → pneumaturia; enterocutaneous; entero-enteric), abscesses

Nutritional / Metabolic Consequences (ileal disease)

• B12 deficiency → macrocytic anemia (ileum absorbs B12-IF complex)
• Bile acid malabsorption → fat malabsorption → steatorrhea + fat-soluble vitamin deficiency (A, D, E, K)
• Calcium oxalate kidney stones: Fat malabsorption → calcium binds fat instead of oxalate → free oxalate absorbed in colon → hyperoxaluria → calcium oxalate nephrolithiasis

Treatment

• 5-ASA compounds (mesalamine) for mild-moderate disease
• Corticosteroids (budesonide, prednisone) for flares
• Immunomodulators: azathioprine, 6-mercaptopurine, methotrexate
• Biologics: anti-TNF-α (infliximab, adalimumab) → for moderate-severe disease; anti-IL-12/23 (ustekinumab); anti-integrins (vedolizumab)
• Surgery: reserved for complications (strictures, fistulas, abscess); NOT curative — recurs

Pathogenesis

Aberrant Th2 immune response → mucosal inflammation limited to the colon; begins at the rectum and extends proximally in a continuous fashion. Associated with HLA-DR2 and p-ANCA positivity.

Clinical Presentation

• Bloody diarrhea with mucus — the hallmark (vs. Crohn's which is less reliably bloody)
• Tenesmus (sensation of incomplete evacuation); urgency; lower abdominal cramping
• Episodic flares separated by remissions
• Extraintestinal manifestations (see below)

Complications

• Toxic megacolon: Severe transmural inflammation → colonic dilation >6 cm → risk of perforation and sepsis; medical emergency
• Colorectal carcinoma: Significant ↑ risk; proportional to extent (pancolitis > left-sided) and duration (>8–10 years); surveillance colonoscopy required
• Primary sclerosing cholangitis (PSC): Fibro-obliterative inflammation of bile ducts → cholestasis, cirrhosis, cholangiocarcinoma risk; 70% of PSC patients have UC

Treatment

• 5-ASA compounds (mesalamine, sulfasalazine) — mainstay for mild-moderate
• Corticosteroids for flares
• Immunomodulators: azathioprine, 6-MP
• Biologics: anti-TNF-α (infliximab, adalimumab); anti-integrin (vedolizumab); JAK inhibitors (tofacitinib)
• Surgery (colectomy) = curative — unlike Crohn's; indicated for refractory disease, toxic megacolon, dysplasia/cancer

• Cell of origin: Interstitial cells of Cajal (pacemaker cells of the myenteric plexus)
• Mutation: Activating mutation of c-KIT (CD117) receptor tyrosine kinase (85% of cases); PDGFRA mutation in remaining cases
• Location: Stomach most common (60%), then small intestine (30%); arise in muscularis propria → submucosal mass
• Histology: Spindle cells in interlacing bundles (most common); ± epithelioid pattern
• Prognosis determinants: Mitotic rate, tumor size, and location (gastric = better prognosis than small intestine)
• Treatment: Surgical resection; imatinib (Gleevec) — tyrosine kinase inhibitor targeting c-KIT — for unresectable/metastatic disease; revolutionary targeted therapy
• IHC: CD117 (c-KIT) positive; CD34 positive; desmin negative (distinguishes from leiomyoma)

• Origin: Neuroendocrine cells (Kulchitsky/enterochromaffin cells) in the gut epithelium; secrete serotonin (5-HT) and other vasoactive substances
• Location: Appendix (most common overall, usually benign); small intestine/ileum (most likely to metastasize); rectum
• Histology: Uniform nests of small round cells with "salt-and-pepper" chromatin; IHC: chromogranin A, synaptophysin positive
• Clinical: Usually asymptomatic; large tumors → pain, obstruction
• Carcinoid syndrome: Occurs when serotonin reaches systemic circulation (requires liver metastases to bypass first-pass hepatic metabolism of serotonin)

• Rare — accounts for only 1–2% of all GI malignancies despite the small bowel comprising 75% of GI length
• Most common in duodenum (near ampulla of Vater) > jejunum > ileum
• Risk factors: Crohn's disease (ileal), celiac disease, FAP, HNPCC/Lynch syndrome
• Presents late: obstructive symptoms, weight loss, occult bleeding, iron deficiency anemia
• Poor prognosis — difficult to detect early

Key features of all adenomatous polyps:

• Epithelial dysplasia is the defining feature (not just glandular architecture)
• Found during colonoscopy; may present as occult blood in stool
• Removal (polypectomy) during colonoscopy is both diagnostic and therapeutic
• Tubulo-villous adenoma = mixed architecture; intermediate malignant potential

• Genetics: APC tumor suppressor gene mutation on chromosome 5q21; autosomal dominant
• Phenotype: Hundreds to thousands of adenomatous polyps throughout the colon beginning in early adolescence
• Cancer risk: 100% lifetime risk of colorectal cancer if untreated; average age of CRC = 39 years
• Treatment: Prophylactic total colectomy (usually by age 20–25)
• Variants: Gardner syndrome (FAP + osteomas + desmoid tumors + epidermoid cysts); Turcot syndrome (FAP + brain tumors)

Adenoma-Carcinoma Sequence (Vogelstein Model):

• APC mutation (loss of tumor suppressor) → hyperproliferative epithelium → small adenoma
• KRAS oncogene mutation → intermediate adenoma (↑ growth signal)
• SMAD4 / DCC loss (18q) → late adenoma
• TP53 mutation → invasive carcinoma
• Process takes ~10–15 years — key rationale for colonoscopy screening at age 45

Staging & Prognosis

• TNM staging: Depth of wall invasion (T), lymph node involvement (N), distant metastasis (M)
• Dukes staging (classic): A = confined to mucosa; B = through wall; C = lymph nodes involved; D = distant mets
• Tumor marker: CEA (carcinoembryonic antigen) — not for screening but for monitoring recurrence after resection
• Metastasis: Liver (hematogenous via portal vein) → lungs → peritoneum; bone/brain less common

Lynch Syndrome (HNPCC)

• Most common hereditary CRC syndrome; autosomal dominant
• Mutations in DNA mismatch repair genes: MLH1, MSH2, MSH6, PMS2 → microsatellite instability (MSI)
• Right-sided colon predominance; mucinous histology; better prognosis than sporadic CRC
• Amsterdam criteria: 3 relatives with Lynch-associated cancers (CRC, endometrial, ovarian, gastric, urinary tract), across 2 generations, with 1 diagnosed <50
• Screening: annual colonoscopy from age 20–25; prophylactic surgery considered