Gastrointestinal Pathology

Prasanth’s Review

EsophagusNormal 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)

Congenital AnomaliesAtresia

- Incomplete development

- TE Fistula – Presents with emesis

upon feedingOmphalocoele/Gastroschisis

- Gastroschisis easier to repair because all layers of abdomen defective and thus room to reinsert visceraStenosisDiaphragmatic Hernia

- Can lead to hypoplastic lungsEctopia/Heterotopia

- gastric/pancreatic common

ObstructionsNutcracker esophagusDiffuse esophageal spasm

- Dysmotility due to neural dysfunctionDiverticulum (psuedo) – bc only mucosal outpouching)

- Zenker (Pharyngeo*)-can present with halitosis

- Traction (Mid 1/3)- Epiphrenic (above LES)

Mucosal webs- Mucosal Hyperplasia

Plummer-Vinson syndromeRings/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

Esophagus (cont.) Dysphagia: Oropharyngeal/Esophageal dysphagiaDysphagia to liquid vs. solid (VERY IMPT)

Pain Pyrosis, OdynophagiaAtypical chest pain (“atypical” for CAD)RegurgitationReflux of gastric contents into pharynxAsthmatic symptoms, particularly nocturnal

CS

Motility Dysfunction and Associated LesionsHiatal 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- Superficial longitudinal 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 mediastinitisEsophageal 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

EsophagitisLye Stricture

- Outright necrosis of esophageal wall, likely no PMNsInfectious – Dense PMN infiltrate Candida, Herpes, CMV

PsuedomembraneIntranuclear and Yellow plaques

intracytoplasmic

inclusions within stroma/endothelium

Intranuclear inclusions within the epithelium, punched out ulcersEosinophilic

- Eosinophilic inflammation- Dysphagia, NO acid reflux*- Atopy, Food Intolerance- Incidence

Esophagus (cont.)GERD and Barrett 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

Tumors of the EsophagusAdenocarcinoma (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 TumorsLeiyomyoma (MC)GIST PseudoTumor

StomachNormal 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 secretion4 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 AnomaliesPyloric 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 GastritisTransient, acute inflammatory process affecting the mucosa that can be asymptomatic or cause epigastric pain/nausea. However, can be severe.

Acute Hemorrhagic (Erosive) Gastritis Prostaglandins promote HCO3-, Mucin, Blood Flow, Associated with NSAIDS, EtOH, Smoking and decrease HCl

Micro/Gross: PMNs + Fibrin exudate causing hemorrhage appears as punctuate, dark lesions (HCl/Blood)

Acute Gastric UlcerationAssociated 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)

Stomach (Cont.)Chronic GastritisHelicobacter 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 DysplasiaADCA, Mucosal Atrophy, MALTomaAutoimmune Gastritis

- Auto-antibodies against oxyntic mucosa- Hypochlorhydria (decreased acid production)- Malabsorption and hypergastrinemiaMicro: Atrophy of oxyntic mucosa

G-cell hyperplasia - Sequelae

- Pernicious Anemia, Carcinoid Tumor

Peptic Ulcer Disease95% are near GD Junction, 4:1 Duodenum:Gastric

- MC due to H. Pylori infection -Also NSAIDs or Zollinger-Ellison

syndromeMicro: Ulceration, by definition, means

penetration into submucosa, margins are not raised (benign ulcer)

Gross: May see reactive hypertrophy adjacentMC complication is bleeding and Most lethal complication is perforation hemorrhage/peritonitis

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.)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

Rugae resemble brain gyri

Hypertrophic Gastropathy

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

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

Benign Tumors of the Stomach

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) TypeOccurs anywhere in the gastric

mucosa, no specific precursor lesion, no H. Pylori association, growth pattern is diffuse (Linitis Plastica)

Clinical Features: Early cancer limited to submucosa, Late cancer has penetrated muscularis propria. 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.

Micro/Gross: Diffuse growth pattern, thickened gastric wall due to significant desmoplasiaMalignant Signet Cells (Mucin vacuolated causing crescent nuclei) are present

Stomach (cont.)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 GleevecMicro/Gross: Solid, fleshy well

circumscribed mass. Dense Stromal tissue visualized as sheets of spindle cells

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

IntestinesNormal 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 AnomaliesAtresia and Stenosis

- Rare but most commonly in the small bowel

- Imperforate anusMeckel’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

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 colonMassive Dilation of Colon proximal to aganglionic segment

- Neonate is unable to pass stool

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

Intestines (Cont.)Viral EnteritisRotavirus : 60% infectious diarrhea US, major cause of infantile diarrhea, 1million/yr die worldwideMicro: Lymphocytes within lamina propria and epithelium,

with crypt hypertrophyBacterial Enteritis3 Main Mechanisms – Invasive (Exudative), Toxigenic (Secretory), Pre-formed ToxinV. Cholerae – Classic Toxigenic(Secretory) Diarrhea

- Cholera Toxin increases Cl and H20 secretion into bowel lumen via ADP-ribosylation of Gs-alphaShigella – 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)

Parasitic EnterocolitisAscaris – MC nematode / Cestode – Tapeworm Unicellular – Entamoeba and GiardiaEntamoeba Histolytica – Amebiasis

- ingestion of mature cysts via contaminated H2O

- trophozoites can enter blood and disseminate producing systemic abscesses (LIVER is 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

Diarrheal Disease and Enterocolitis (cont.)

Intestines (cont.)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 and Lymphocytic 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

debilitationAIDS and Diarrhea

- There is no single defect in mucosa assoc with AIDS-Atypical mycobacterium, CMV and C. Parvum - CP impt cause of diarrhea in immunodeficientDrug Induced Intestinal Injury-Most often, NSAID becomes lodged in bowel and releases all its contents in one location leading to focal ulcerationMisc. Intestinal InflammationTransplantation-related DiarrheaRadiation EnterocolitisNeutropenic 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

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)MCCCeliac 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- Gliadin is 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 DIETClinical FeaturesMalabsorption syndrome, Associated Skin lesion - Dermatitis Herpetiformis (IgA), Risk for SI T-Cell Lymphoma or ADCA

Intestines (cont.)Malabsorption Syndromes (continued)Tropical Sprue

- Celiac-like disease that occurs persons living in the tropics with an unknown cause but Invasive E.Coli and Hemophilus have been implicated

- Tx: Broad Spectrum AntibioticsWhipple 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 bacilliLactase Deficiency

- Acquired deficiency leading to inability to breakdown Lactose, preventing absorption and resulting in osmotic diarrheaIrritable Bowel Syndrome

-Diarrheal disease with female predominance Stress implicated, associated with

fibromyalgia- No gross or microscopic findings, R/O IBDCystic Fibrosis Pancreatic InsufficiencyAbetalipoproteinemia

- Apo-B is absent, and thus no way to absorb fats into circulation (no chylomicrons)

- Malabsorption and inability to absorb fat soluble vitamins

- Acanthocytes – RBC membrane lipids altered

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

bleedingDiverticular DiseaseMost commonly occur in sigmoid colonPSUEDOdiverticuli (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 become obstrcutedinflammation Diverticulitis

-presents with cramping, diarrhea/constipation -can perforate, but very rare

Vascular/Bleeding Disorders of the Bowel (cont.)Ischemic Bowel DiseaseBowel supplied by Celiac/SMA/IMA and collateral supply allows GI to tolerate slow, progressive blood lossAcute 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

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.

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.

Intestinal Obstruction

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 EnemaVolvulus – Bowel segment twists on itself, commonly in the sigmoid, risk for infarction/obstruction

Infarcted Bowel

NormalBowel

INFLAMMATORY BOWEL DISEASECrohn’s DiseaseDisease with predominance in female Caucasians with peak incidence in the 2nd and 3rd decadeMajor Findings: Patchy Inflammation (uninvolved segments interspersed)Small Bowel and Colon Involved (can involve Esoph/Stom)Transmural Involvement with linear, mucosal ulcerationFissures and resultant fistulaeNon-Caseating Granulomas

“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”

Gross: Cobblestone appearance(depressed diseased mucosa between normal mucosa). Also see apthous ulcers, linear ulcers and creeping fat (mesenteric fat envelops serosa)

Fissures (Thru Muscularis Propria)Non-Caseating Granulomas PMNS Transmural involvement

Clinical FeaturesChronic, 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.

Micro:

Ulcerative ColitisDisease with predominance in female Caucasians with peak incidence in 3rd decade. Slightly higher incidence than CrohnsMajor 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

Clinical FeaturesChronic 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 extraintestinal manifestations. 75% of UC patients are P-ANCA +. At risk for malabsorption, Toxic Megacolon, and ADCA (sequence of reactive change, dysplasia, ADCA).

Gross: Rectum always involved, with disease moving retrograde, Mucosal ulceration and Psuedopolyps are common. Pancolitis (entire organ is involved).

Gland AtrophyDENSE PMN infiltrateLimited to Mucosa and SubmucosaPit Abscesses

Micro:

Bleeding Disease

OBSTRUCTIVE DISEASE

Air/Fluid Levels = SI

Obstruction

Tumors of the Small IntestineRare and majority are benign (adenomas)

- Duodenal commonlyMalignant Tumors are ADCA and Carcinoid

- Midgut Carcinoid is Poor Prognosis* Exophytic ADCA at

ampulla of Vater – Backup of Bile and Pancreatic Secretions and thus presents with Jaundice and Pancreatitis

Polyps (Vocabulary and Classification)Sessile vs PedunculatedNon-neoplastic vs Neoplastic

- Non-Neoplastic Inflammatory Hamartomatous Hyperplastic Peutz-Jeghers

Lymphoid Juvenile-Neoplastic

- Villous Adenoma (Sessile) Tubular Adenoma (Pedunculated)

Sessile

Pedunculated

Sessile

Pedunculated

Polyps (Entities)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 hemorrhageMicro:

Cystic dilation, mucin, lamina propria expanded by inflammation. NO SMOOTH MUSCLE

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.)

Micro: Complex Glands SMOOTH MUSCLE In L.Propria

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.

Hamartomatous Polyps (cont.) Cowden Syndrome - PTEN LOF mutation resulting in GI polyps and increased risk for Thyroid and Breast malignancy

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 ColonIMPT to distinguish from Sessile Villous Adenoma

Micro:Protrusion of mucosaCrowding creates serrated architecture

Polyps (Entities)