Gastrointestinal Pathology

1. Gastrointestinal Pathology Prasanth’s Review

2. Esophagus Normal A/P, Histology: Hollow tube serving as a conduit to transport food from oral cavity to stomach via peristaltic contractions coordinated via CN10 and the ENS. 4 Layers: Mucosa (Sq. Epithelium, Lamina Propria, Muscularis Mucosae), Submucosa (Blood Vessels, Meissner’s plexus, Lymphatics, Mucin secreting glands), Muscularis Propria (Outer longitudinal Layer (Skeletal UE, Smooth LE) and Inner circular layer (Smooth Muscle)), Minimal Serosa (encased by fascia  No Mesentery) Obstructions Nutcracker esophagus Diffuse esophageal spasm - Dysmotility due to neural dysfunction Diverticulum (psuedo) – bc only mucosal outpouching) - Zenker (Pharyngeo*) -can present with halitosis - Traction (Mid 1/3) - Epiphrenic(above LES) Mucosal webs - Mucosal Hyperplasia Plummer-Vinson syndrome Rings/Schatzki rings -Circumferential hyperplasia of mucosa and submucosa and sometimes muscularis propria (A = above GEJ, B= below GEJ) Stenosis/Stricture - can be cause by chronic irritation, caustic injury, or radiation Congenital Anomalies Atresia - Incomplete development - TE Fistula – Presents with emesis upon feeding Omphalocoele/Gastroschisis - Gastroschisis easier to repair because all layers of abdomen defective and thus room to reinsert viscera Stenosis Diaphragmatic Hernia - Can lead to hypoplastic lungs Ectopia/Heterotopia - gastric/pancreatic common

3. CS Dysphagia: Oropharyngeal/Esophageal dysphagia Dysphagia to liquid vs. solid (VERY IMPT) Pain Pyrosis, Odynophagia Atypical chest pain (“atypical” for CAD) Regurgitation Reflux of gastric contents into pharynx Asthmatic symptoms, particularly nocturnal Esophagus (cont.) Motility Dysfunction and Associated Lesions Hiatal Hernia – risk for GERD ( LES tone) - 95% Rolling (GEJ above diaphragm) Achalasia - TRIAD - LES relaxation, LES tone, aperistalsis - Attributed to loss of inhibitory neurons - Can be secondary to T. Cruzi (Chagas Disease) - Present with dysphagia and weight loss* Mallory Weiss Tear - Superficiallongitudinal tear that leads to ulceration - Occurs in the setting of acute, prolonged emesis - Due to loss of “anti-receptive relaxation” - Presents with hematemesis, no surgical intervention req. **Boerhaave Syndrome – rare, catastrophic event resulting in perforation and mediastinitis Esophageal Varices - Tortuous dilations of esophageal venous complexes in the submucosa and even lamina propria - Risk of rupture, which carries 50% mortality - Occur in presence of Portal Hypertension or Schistosomiasis Esophagitis Lye Stricture - Outright necrosis of esophageal wall, likely no PMNs Infectious – Dense PMN infiltrate Candida, Herpes, CMV PsuedomembraneIntranuclear and Yellow plaquesintracytoplasmic inclusions within stroma/endothelium Intranuclear inclusions within the epithelium, punched out ulcers Eosinophilic - Eosinophilic inflammation - Dysphagia, NO acid reflux* - Atopy, Food Intolerance - Incidence

4. Esophagus (cont.) GERD and Barrett Esophagus Tumors of the Esophagus GERD - Esophagitis due to reflux of gastric contents - M >40 / overweight / EtOH - Pyrosis and Dysphagia Micro: Mild GERD – no change Moderate GERD – eosinophil infiltrate Severe GERD – PMN infiltrate Basal Zone Hyperplasia (>20% Thickness) Gross: Erythema maybe only change in mild/ moderate GERD Barrett Esophagus - Intestinal Metaplasia (Goblet Cells*), due to complications of chronic GERD - M >40 / overweight / EtOH - MOST IMPT RISK FACTOR FOR ADCA Adenocarcinoma (ADCA) (Lower 1/3 of Esoph.**) - Increasing incidence (50% of Esophageal Malignancy in US) - M>40 (Whites)/ overweight / EtOH - Highest Risk Factor is high grade dysplasia in the presence of Barrett Esophagus - Poor Prognosis (Infiltrates before symptoms) Squamous Cell Carcinoma (Mid 1/3 of Esoph.**) - 90% of Esophageal Cancer in the world - M >40 (Blacks)/ Smoking / EtOH, HPV* - Exophytic or Inverted Growth - Poor Prognosis (Infiltrates before symptoms) Other Tumors Leiyomyoma (MC) GIST PseudoTumor

5. Stomach Normal A/P, Histology: Serves as a reservoir for food as well as reduces the size of food particles so they are acceptable for absorption in the small bowel + HCl, Intrinsic Factor, and Pepsinogen secretion 4 Layers: Mucosa (Foveloar (Mucin secreting) Columnar epithelium, Pits containing Parietal/Chief Cells), Submucosa (Blood Vessels, Meissner’s plexus, Lymphatics), Muscularis Propria (Outer longitudinal Layer and underneath an outer circular layer, and a 3rd oblique layer), Serosa (Mesothelium and CT) Congenital Anomalies Pyloric Stenosis - Hypertrophy of Smooth muscle at the Pylorus - Presents with projectile emesis upon feeding (4:1 / M:F) and as a palpable “olive” mass in the abdomen Pancreatic Heterotopia - Submucosal or mucosal, can present as a mass Acute Gastritis Transient, acute inflammatory process affecting the mucosa that can be asymptomatic or cause epigastric pain/nausea. However, can be severe. Acute Hemorrhagic (Erosive) GastritisProstaglandins promote HCO3-, Mucin, Blood Flow, Associated with NSAIDS, EtOH, Smokingand decrease HCl Micro/Gross: PMNs + Fibrin exudate causing hemorrhageappears as punctuate, darklesions (HCl/Blood) Acute Gastric Ulceration Associated with Severe Stress (Shock, Burns (Curling), Sepsis, Head Trauma (Cushing {CN10 dysfunction}) Micro/Gross: Sharply demarcated lesions that penetrate the submucosa, adjacent mucosa is normal Can occur anywhere in the stomach, and have non-elevated margins. Can be painful, lead to hematemesis, or more seriously  perforation and peritonitis (most lethal complication)

6. Chronic Gastritis Helicobacter Pylori - MCC of Chronic Gastritis - Infection of non-oxyntic mucosa (antrum) Micro: PMNs indicate active infection Gastric Pit Abscesses Ag Stain to visualize organism Lymphoid proliferation (+ plasma cells) - Sequelae - Peptic Ulcer Disease, Intestinal Metaplasia DysplasiaADCA, Mucosal Atrophy, MALToma Autoimmune Gastritis - Auto-antibodies against oxyntic mucosa - Hypochlorhydria (decreased acid production) - Malabsorptionand hypergastrinemia Micro: Atrophy of oxyntic mucosa G-cell hyperplasia - Sequelae - Pernicious Anemia, Carcinoid Tumor Uncommon forms of Chronic Gastritis include Granulomatous (Sarcoidoisis, Chron’s disease), Eosinophilic(atopy), Reactive ( Foveolar Glands + Edema), GAVE ( dilatation of vasculature), Lymphocytic (Celiac Sprue) Stomach (Cont.) Peptic Ulcer Disease 95% are near GD Junction, 4:1 Duodenum:Gastric - MC due to H. Pylori infection -Also NSAIDs or Zollinger-Ellison syndrome Micro: Ulceration, by definition, means penetration into submucosa, margins are not raised (benign ulcer) Gross: May see reactive hypertrophy adjacent MC complication is bleeding and Most lethal complication is perforation hemorrhage/peritonitis

7. Hypertrophic Gastropathy Stomach (cont.) Menetier’s Disease - Increased TGF-alpha (idiopathic) - Pathologic hypertrophy of rugae - Diffuse Epithelial Hyperplasia - Leads to atrophy of oxyntic mucosa - Protein losing enteropathy - No Pepsinogen/Pepsin Malignant Tumors of the Stomach Adenocarcinoma - Intestinal Type Spawned from adenomatous polyp or intestinal metaplasia (thus, associated with H.Pylori) and occurs in the non-oxyntic mucosa Micro/Gross: Usually exophytic mass with glandular malignant cells. If excavated type, ulceration will have “volcanic” or raised borders - Diffuse (Signet) Type Occurs anywhere in the gastric mucosa, no specific precursor lesion, no H. Pylori association, growth pattern is diffuse (LinitisPlastica) Rugae resemble brain gyri Zollinger Ellison Syndrome - Due to gastrin secreting tumors (gastrinoma) - commonly Small Bowel or Pancreas - Results in Hyperplasia of Oxyntic Mucosa - Severe Peptic Ulcerations, Hyperchlorhydria - Associated with MEN-1 • Micro/Gross: Diffuse growth pattern, thickened gastric wall due to significant desmoplasia • Malignant Signet Cells (Mucin vacuolated causing crescent nuclei) are present Benign Tumors of the Stomach Hyperplastic Polyps (90-95%) - Form in response to chronic gastritis or injury - NO neoplastic potential Adenomatous Polyps (5%) - Can form in the setting of chronic gastritis and intestinal metaplasia - Present with dysplasia - Thus, risk for ADCA Clinical Features: Early cancer limited to submucosa, Late cancer has penetrated muscularispropria. Metastasis to sentinel supraclavicular node (Virchow’s node) associated with poor prognosis. Metastasis to periumbilical node is also possible (Sister Mary Joseph's node). Metastases from Lung/Breast grow in Diffuse pattern.

8. Tumors of the Stomach (continued) Lymphoma (MALToma) - Extra-Nodal Marginal Zone B-Cell Lymphoma is MC primary lymphoma of stomach, normally indolent but can transform in DLBCL if untreated - Arise at sites of chronic inflammation (and thus associated with H. Pylori) - H. Pylori stimulates NF-Kb, and thus removal of H. Pylori removes stimulus, and thus 50% of MALToma’s are cured via antiobiotics Micro: Lymphoepithelial lesions – infiltration of lymphocytes through lamina propria and into glands, Lymphoid follicles, CD19/20 + Gastrointestinal Stromal Tumor (GIST) -Thought to arise from the interstitial cells of cajal, these tumors are characterized GOF mutation of a Tyrosine Kinase (c-KIT, IHC- CD117) that results in constitutive activation and cell proliferation - Indolent tumor, responds to Gleevec Micro/Gross: Solid, fleshy well circumscribed mass. Dense Stromal tissue visualized as sheets of spindle cells Stomach (cont.) Carcinoid Tumor - Well differentiated neuroendocrine carcinomas that are commonly found in GI tract (40% Small Bowel) - Gastric carcinoid associated with G Cell hyperplasia, ZE syndrome, atrophic gastritis - Secrete neuropeptide hormones (especially Serotonin) that can have systemic effects – SOB, skin flushing, cardiac valvular disease, diahrrea– “Carcinoid Syndrome”, but must be from tumor outside the portal system (in the case of a GI Carcinoid, a metastasis) b/c first pass metabolism by liver - Location is most important for prognosis, Midgut is associated with poor prognosis - Because it is a neuroendocrine tumor –IHC Chromogranin, Synaptophysin positive Micro: Variable organization of cells with scant cytoplasm and salt/pepper chromatin within the nucleus

9. Intestines Normal A/P, Histology: Serves as major site of absorption of water, vitamins, nutrients and MALT is important in fighting off pathogenic organisms. Approx. 6 meters in length and separated in duodenum (Fe absorption), jejunum (Folate absorption), ileum (B12 absorption). Small bowel is comprised of goblet cell containing columnar epithelium arranged in villi with associated microvilli as well as crypts. Duodenum contains Brunner’s glands, unique glands in the submucosa. Ileum contains Peyer’s Patches (lymphoid). Colonic mucosa is also made up of goblet cell containing columnar epithelium with a more flat surface (no villi). Congenital Anomalies Atresia and Stenosis - Rare but most commonly in the small bowel - Imperforate anus Meckel’s Diverticulum - True diverticulum, occurs in the ileum due to failure of the vitelline duct to involute - “Rule of 2’s” - Can present with pain or bleeding - Mimics Acute Appendicitis Diarrheal Disease and Enterocolitis Secretory diarrhea: isotonic and persists during fasting, usually infectious, viral or enterotoxin Osmotic diarrhea: Abates with fasting; stool is hypertonic to plasma classically lactase deficiency Exudative disease: mucosal destruction leads to purulent, bloody stools that persist on fasting, usually bacterial or IBD Deranged motility: improper gut neuromuscular function, can be neural, hormonal, surgical Malabsorption: Improper absorption of gut nutrients; bulky stool with excess stool fat (steatorrhea), abates on fasting, classically Celiac disease, Giardia Hirschsprung’s Disease(Aganglionic Megacolon) - Failure of NCC to migrate and form Auerbach’s or Meissner’s plexuses in the rectum and commonly the sigmoid colon Massive Dilation of Colon proximal to aganglionic segment - Neonate is unable to pass stool

10. Diarrheal Disease and Enterocolitis (cont.) Viral Enteritis Rotavirus : 60% infectious diarrhea US, major cause of infantile diarrhea, 1million/yr die worldwide Micro: Lymphocytes within lamina propria and epithelium, with crypt hypertrophy Bacterial Enteritis 3 Main Mechanisms – Invasive (Exudative), Toxigenic (Secretory), Pre-formed Toxin V. Cholerae– Classic Toxigenic(Secretory) Diarrhea - Cholera Toxin increases Cland H20 secretion into bowel lumen via ADP-ribosylation of Gs-alpha Shigella– Invasive organism that destroys mucosa leading to painful, bloody diarrhea (Shiga Toxin can lead to HUS) C. Dificile– Pseudomembranous colitis due to organism’s over proliferation due to antibiotics destroying competitive flora. MUST USE CYTOTOXIN ASSAY TO DIAGNOSE (A/B Tox) Intestines (Cont.) Parasitic Enterocolitis Ascaris – MC nematode / Cestode – Tapeworm Unicellular – Entamoeba and Giardia Entamoeba Histolytica – Amebiasis - ingestion of mature cysts via contaminated H2O - trophozoites can enter blood and disseminate producing systemic abscesses (LIVERis common) Giardia – Giardiasis - MC pathogenic parasitic infection, affects small bowel - Peak incidence is during summer (H20 parks) and in developing countries - Can be asymptomatic, cause acute diarrhea, or cause malabsorption (chronic disease) Note: E. Histolytica engulfs RBCs

11. Diarrheal Disease and Enterocolitis (cont.) Necrotizing Enterocolitis - Acute necrotizing inflammation leading to transmural necrosis - MC intestinal emergency in neonates - MC presents when neonates begin oral food\ - Tx: resection of involved bowel. Collagenous Colitis andLymphocytic Colitis - Distinct disorder of the colon : occurring primarily in middle-aged and older women; in older males and females -Chronic watery diarrhea (3-20 times/day) -Both relatively benign without debilitation AIDS and Diarrhea - There is no single defect in mucosa assocwith AIDS -Atypical mycobacterium, CMV and C. Parvum - CP impt cause of diarrhea in immunodeficient Drug Induced Intestinal Injury -Most often, NSAID becomes lodged in bowel and releases all its contents in one location leading to focal ulceration Misc. Intestinal Inflammation Transplantation-related Diarrhea Radiation Enterocolitis Neutropenic Colitis (Typhlitis): life-threatening acute inflammatory destruction of the mucosa of the cecal region. Commonly leads to perforation (40% mortality) Diversion Colitis. -Inflammation of blind segment of colon in ostomy patients Intestines (cont.) Malabsorption Syndrome - characterized by steatorrhea, weight loss, anorexia, borborygmi, muscle wasting - Leads to systemic symptoms such as B12 deficiency (megaloblastic anemia and CNS symptoms), osteopenia, hypocalcemia,amenorrhea, Fe deficiency (microcytic anemia) MCCCeliac Dz, Chron’s Disease, Pancreatic Insufficiency Celiac Disease - Autoimmune processes resulting in Inflammatory disease of the small bowel that results from gluten ingestion - HLA-DQ2 / HLA-DQ8 - Gliadinis inciting agent (a protein segment of gluten) - Strong CD8 response - results in epithelial destruction and blunting of villi Normal Villi Diagnosis Serum Abs (IgA) – Anti-endomysium Abs, Anti-Gliadin Abs, Anti-Transglutaminase (enzyme that cleaves gluten into immunogenic peptide) Abs + Jejunal Biopsy +SYMPTOMS RESOLVE WITH GLUTEN FREE DIET Clinical Features Malabsorption syndrome, Associated Skin lesion - Dermatitis Herpetiformis (IgA), Risk for SI T-Cell Lymphoma or ADCA

12. Malabsorption Syndromes (continued) Tropical Sprue - Celiac-like disease that occurs personsliving in the tropics with an unknown cause but Invasive E.Coli and Hemophilus have been implicated - Tx: Broad Spectrum Antibiotics Whipple Disease - SI mucosal infection by bacillus T. Whipelii - Chronic relapsing GI + multisystem disease Clinical: Malabsorption, Arthritis, Lymphadenopathy leading to weight loss, joint pain, diarrhea Micro: Invasion of foamy macrophages into lamina propria, macrophages also engulf bacilli Lactase Deficiency - Acquired deficiency leading to inability to breakdown Lactose, preventing absorption and resulting in osmotic diarrhea Irritable Bowel Syndrome -Diarrheal disease withfemale predominance Stress implicated, associated with fibromyalgia - No gross or microscopic findings, R/O IBD Cystic Fibrosis  Pancreatic Insufficiency Abetalipoproteinemia - Apo-B is absent, and thus no way to absorb fats into circulation (no chylomicrons) - Malabsorptionand inability to absorb fat soluble vitamins - Acanthocytes – RBC membrane lipids altered Intestines (cont.) Vascular/Bleeding Disorders of the Bowel Angiodysplasia - malformed, distended mucosal and submucosal blood vessels - usually occurs cecum or R colon - Accounts for 20% of Lower GI bleeding Diverticular Disease Most commonly occur in sigmoid colon PSUEDOdiverticuli (only mucosa and subucosa) Due to focal weakness in colonic wall and increased intraluminal pressure (enhanced by low fiber diet) Patients normally asymptomatic, however, diverticuli can becomeobstrcutedinflammation Diverticulitis -presents with cramping, diarrhea/constipation -can perforate, but very rare

13. Intestinal Obstruction Vascular/Bleeding Disorders of the Bowel (cont.) Ischemic Bowel Disease Bowel supplied by Celiac/SMA/IMA and collateral supply allows GI to tolerate slow, progressive blood loss Acute occlusion however, can lead to infarction of several meters of bowel \ Mucosal/Mural associated with hypoperfusion - Congestive Heart Failure, shock Transmural associated with acute occlusion - Severe Atherosclerosis, Emboli, Vasculitis Inguinal Hernia – Reduced (can be pushed back into abdominal cavity) vs. Incarcerated (risk of ischemia/obstruction and perforation) Adhesions – Usually after surgery, fibrous adhesions between bowel segments, risk for internal herniation (infarction/obstruction) Intussusception – Bowel segment telescopes into distal segment, risk of infarction/obstruction – Tx: Air/Barium Enema Volvulus – Bowel segment twists on itself, commonly in the sigmoid, risk for infarction/obstruction Initial injury is hypoxic injury, and due to anatomical structure of vascular supply, surface epithelium affected while crypts remain perfused. Crypts contain stem cells to repopulate epithelium, so hypoxic injury can be tolerated. Reperfusion injury (PMNs, Free Radicals, Complement) causes the severe damage to the bowel. Infarcted Bowel Normal Bowel Clinically, acute occlusion presents with sudden pain and tenderness, with vomiting/diarrhea. Resection of infarcted bowel is treatment, and thus malabsorption syndrome is an important consequence.

14. Crohn’s Disease Disease with predominance in female Caucasians with peak incidence in the 2nd and 3rd decade Major Findings: Patchy Inflammation (uninvolved segments interspersed) Small Bowel and Colon Involved (can involve Esoph/Stom) Transmural Involvement with linear, mucosal ulceration Fissures and resultant fistulae Non-CaseatingGranulomas • “resulting from inappropriate and persistent activation of the mucosal immune system, driven by presence of normal intraluminal flora in genetically susceptible individuals” • Two key pathogenic abnormalities • “Strong immune response against normal flora” (CD4) • “Defects in epithelial barrier function” INFLAMMATORY BOWEL DISEASE Ulcerative Colitis Disease with predominance in female Caucasians with peak incidence in 3rd decade. Slightly higher incidence than Crohns Major Findings: Ulceroinflammatory disease limited to the colon and affecting only the mucosa and submucosa in the most severe cases. Extends in a continuous fashion proximally from the rectum Gross: Cobblestone appearance(depressed diseased mucosa between normal mucosa). Also see apthous ulcers, linear ulcers and creeping fat (mesenteric fat envelops serosa) Gross: Rectum always involved, with disease moving retrograde, Mucosal ulceration and Psuedopolyps are common. Pancolitis (entire organ is involved). Micro: Fissures (Thru Muscularis Propria) Non-CaseatingGranulomas PMNS Transmural involvement Micro: Gland Atrophy DENSE PMN infiltrate Limited to Mucosa and Submucosa Pit Abscesses Clinical Features Chronic disease with bouts of painful bloody/mucoid diarrhea and weight loss. Outlook depends on severity of disease and duration of disease. Patients have migratory arthritis and primary sclerosing cholangitis as common extraintestinalmanifestations. 75% of UC patients are P-ANCA +. At risk for malabsorption, Toxic Megacolon, and ADCA (sequence of reactive change, dysplasia, ADCA). Clinical Features Chronic, lifelong condition with periods of painful diarrhea and weight loss interspersed with periods of normalcy. Patients have migratory arthritis and erythema nodosum as common extraintestinal manifestations. At risk for malabsorption, stricture (“String Sign” on Barium Swallow), and Cancer.

15. Bleeding Disease

16. OBSTRUCTIVE DISEASE Air/Fluid Levels = SI Obstruction

17. Polyps (Entities) Tumors of the Small Intestine Rare and majority are benign (adenomas) - Duodenal commonly Malignant Tumors are ADCA and Carcinoid - Midgut Carcinoid is Poor Prognosis* Hamartomatous Polyps - arise sporadically or in genetic context Juvenile Polyps - Sporadic are solitary lesions in the rectum presenting with bleeding before the age of 5 - AD Juvenile Polyposis presents with 3-100 polyps within the colon, and may require colectomy due to risk of sever hemorrhage Exophytic ADCA at ampulla of Vater – Backup of Bile and Pancreatic Secretions and thus presents with Jaundice and Pancreatitis Micro: Cystic dilation, mucin, lamina propria expanded by inflammation. NO SMOOTH MUSCLE Polyps (Vocabulary and Classification) Sessile vsPedunculated Non-neoplastic vsNeoplastic - Non-Neoplastic Inflammatory Hamartomatous Hyperplastic Peutz-Jeghers Lymphoid Juvenile -Neoplastic - Villous Adenoma (Sessile) Tubular Adenoma (Pedunculated) Peutz-Jeghers Syndrome - Rare AD disorder where by age 11, present with GI polyps (MC small bowel) and hyperpigmentation Develop Malignancies elsewhere (pancreas, lung, etc.) Pedunculated Sessile Micro: Complex Glands SMOOTH MUSCLE In L.Propria Pedunculated Sessile

18. Hamartomatous Polyps (cont.) Cowden Syndrome - PTEN LOF mutation resulting in GI polyps and increased risk for Thyroid and Breast malignancy Polyps (Entities) Inflammatory Polyps -forms as a result of chronic injury/healing -Micro: Epithelial Hyperplasia, Superficial Erosions, and Inflammatory Infiltrate Example – Solitary Rectal Ulcer Syndrome Incomplete relaxation of Anorectal sphincter produces sharp angle at rectum, resulting in abrasion and erosion (chronic injury). Patients present with rectal bleeding, mucous discharge, and anterior rectal wall injury. Hyperplastic Polyps -Forms from decreased shedding/increased proliferation of epithelium leading to piling up of absorptive and goblet cells - Common in the 5th or 6th decade, L Colon IMPT to distinguish from Sessile Villous Adenoma Micro: Protrusion of mucosa Crowding creates serrated architecture