The Gastrointestinal Tract

方嘉郎 老師

Part I: Esophagus and stomach

教學目標

1.      瞭解食道與胃常見良性疾病的致病機轉與病理變化。

2.      瞭解食道癌致癌因子、病理變化、生物行為與預後。

3.      瞭解胃癌致癌因子、致癌機轉、病理變化、生物行為與預後。

內容大綱

1.      Anatomy, histology, and physiology of esophagus

2.      Congenital anomaly of esophagus

Atresia & tracheoesophageal fistula

Esophageal web

3.      Esophageal motor dysfunction

Achalasia

Hiatal hernia

Diverticulum

Mallory-Weiss syndrome

4.      Reflux esophagitis & Barrett esophagus

5.      Esophageal varices

6.      Esophageal carcinoma

7.      Anatomy, histology, and physiology of stomach

8.      Congenital anomaly of stomach- pyloric stenosis

9.      Gastritis

10.  Peptic ulcer

11.  Gastric carcinoma

Part II: Small and large intestines

教學目標

1.      瞭解腸道常見良性疾病的致病機轉與病理變化。

2.      瞭解大腸息肉的組織形態學分類、病理變化與癌化現象。

3.      瞭解大腸直腸癌的致癌因子、致癌機轉、病理變化、生物行為、臨床分期與預後。

內容大綱

1.      Anatomy, histology, and physiology of intestine

2.      Congenital anomaly of intestine

 Meckel’s diverticulum

Hirschsprung's disease

3.      Pseudomembranous colitis

4.      Celiac sprue

5.      Idiopathic inflammatory bowel disease

      Crohn’s disease

      Ulcerative colitis

6.      Ischemic bowel disease

7.      Colonic diverticulosis

8.      Colonic polyp

9.      Colorectal carcinoma

10.  Carcinoid tumor

11.  Acute appendicitis

Pathology of gastrointestinal tract

Esophagus

Anatomy of esophagus

1. mucosa 

      nonkeratinizing stratified squamous epithelium

      lamina propria

2. submucosa: submucosal gland

3. muscularis propria

      proximal 1/3- skeletal muscle

      distal 2/3- smooth muscle

4. adventitia

Function of esophagus

1. food passage

2. prevention of reflux of gastric content: lower esophageal sphincter

Congenital anomaly of esophagus

* atresia & tracheoesophageal fistula

* esophageal web

   atrophic glossitis

   iron deficiency anemia (Plummer-Vinson syndrome)

Esophageal motor dysfunction

1. achalasia

2. hiatal hernia

3. diverticulum

4. Mallory-Weiss syndrome

Achalasia

1. aperistalsis- incomplete relaxation of lower esophageal sphincter      

2. progressive dysphagia

    nocturnal regurgitation

    esophageal squamous cell carcinoma (5%)

3. primary: uncertain cause

  secondary

Pathology of achalasia

1. progressive dilatation of esophagus

2. absence of myenteric ganglia

Hiatal hernia

1. sliding hernia (95%): bell-shaped dilatation of stomach

  paraesophageal (rolling) hernia

2. associated with reflux esophagitis, ulcer, bleeding, perforation

Esophageal diverticulum

1. Zenker diverticulum- above UES

2. traction diverticulum- midesophagus

3. epiphrenic diverticulum- above LES

Mallory-Weiss syndrome

1. esophageal longitudinal tear at ECJ

2. alcoholism- excessive vomiting & refluxing

3. perforation → UGI bleeding

4. Boerhaave syndrome: esophageal rupture

Reflux esophagitis

1. reflux of gastric content into lower esophagus → mucosal injury

2. dysphagia, heartburn sensation

3. consequence: bleeding, stricture, Barrett esophagus

Pathology of reflux esophagitis

1. intraepithelial infiltration of eosinophil, neutrophil, lymphocyte

2. basal cell hyperplasia

3. elongation and congestion of lamina propria papilla

Causative factor of reflux esophagitis

1. ↓ LES tone: drug, hypothyroidism, nasogastric tube, pregnancy, alcohol, smoking

2. sliding hernia

3. ↓ esophageal clearance

4. ↑ gastric emptying time & ↑gastric volume

5. ↓ reparative ability after mucosal injury

Barrett esophagus

1. long-standing & severe reflux esophagitis

2. squamous epithelium replaced by metaplastic columnar epithelium at distal

 esophagus 

Pathology of Barrett esophagus

1. red, velvety GI mucosa

2. metaplastic columnar epithelium

     gastric type

     intestinal type- goblet cell

3. dysplasia of glandular epithelium → adenocarcinoma (30-40X)

Esophageal varices

1. liver cirrhosis → portal hypertension

2. coronary vein → esophageal venous plexus → azygos vein

3. tortuous & dilated vein in mucosa & submucosa of distal esophagus

4. irregular protrusion of overlying mucosa

5. variceal rupture → massive UGI bleeding

  ↑mortality

Squamous cell carcinoma of esophagus

1. 90% of esophageal cancer

2. M > F

3. high incidence area: Central Asia, China, South Africa, Eastern Europe

Pathology of esophageal SCC

1. in situ carcinoma → advanced carcinoma

2. upper 1/3- 20%

  middle 1/3- 50%

  lower 1/3- 30%

3. protruding, excavated (ulcerative), flat

4. local invasion: TE fistula, pericardium, mediastinum

5. lymphatic spreading- submucosa & adventitia

  lymph node metastasis

Adenocarcinoma of esophagus

1. lower 1/3: Barrett esophagus → high-grade dysplasia → adenocarcinoma

2. intestinal type adenocarcinoma

Stomach

Anatomy of stomach

1. mucosa

2. submucosa

3. muscularis propria

4. serosa

Histology of gastric mucosa (1)

1. foveola: mucus-secreting cell, mucous neck cell

2. gastric gland

     cardia- mucus-secreting cell

     fundus (body)- chief cell, parietal cell, endocrine cell

     antrum- mucus-secreting cell, endocrine cell

Histology of gastric mucosa (2)

1. mucus-secreting cell: mucus & pepsinogen

2. parietal cell: acid & intrinsic factor

3. chief cell: pepsinogen I & II

4. endocrine cell

Pyloric stenosis

1. congenital pyloric stenosis

     nonbillous vomiting

     visible peristalsis

     palpable ovoid mass

2. acquired pyloric stenosis

     outlet obstruction due to gastritis, peptic ulcer, carcinoma

Acute gastritis

1. acute inflammation of gastric mucosa

2. transient nature

Pathogenesis of acute gastritis

1. ↑ acid secretion

2. ↓ bicarbonate

3. ↓ blood flow

4. disruption of mucus layer

5. direct damage to glandular epithelium

Factor associated with acute gastritis

* NSAID, esp. aspirin

* alcohol

* smoking

* severe stress

* gastrectomy

Pathology of acute gastritis

1. edema & congestion

2. activity: intraepithelial neutrophil infiltration

3. acute erosive gastritis

     erosion: loss of superficial epithelium with fibrinopurulent exudate

     hemorrhage

Chronic gastritis

1. chronic mucosal inflammation

2. mucosal atrophy

3. intestinal metaplasia

Pathogenesis of chronic gastritis

1. Helicobacter pylori infection

2. autoimmune

3. toxic: alcoholism & smoking

4. postsurgical bile reflux

Helicobacter pylori infection

1. most important etiologic association with chronic gastritis

2. 90% of chronic antral gastritis

3. G(-) curvilinear rod-like bacilli

4. urease → ammonia

  toxin: cag A, vac A, lipopolysaccharide

Autoimmune gastritis

1. autoantibody against parietal cell & intrinsic factor at body-fundus mucosa →

 pernicious anemia

2. ↓ acid production: hypochlorhydria & achlorhydria

3. G cell hyperplasia → hypergastrinemia

4. dysplasia → adenocarcinoma

H. pylori-associated chronic gastritis

1. 90% of chronic gastritis

2. antral / antral & body mucosa

3. bacilli in superficial mucous layer and folveola demonstrated by H&E, silver stain,

Giemsa stain

4. absence in area of intestinal metaplasia

5. high risk to develop peptic ulcer, gastric carcinoma, lymphoma  

Pathology of chronic gastritis

1. red & coarse mucosa → atrophic mucosa

2. lymphocyte & plasma cell infiltration in lamina propria with lymphoid follicle &

 germinal center

3. chronic active gastritis: neutrophil infiltration

4. chronic atrophic gastritis

5. intestinal metaplasia → dysplasia → carcinoma (intestinal type) 

Mucosal protection of stomach

1. mucus secretion

2. bicarbonate secretion

3. epithelial barrier

4. mucosal blood flow

Peptic ulcer

* chronic, remitting, and relapsing gastrointestinal lesion

* aggressive action of acid-peptic juice

* middle to old age

* imbalance between mucosal defense mechanism & damaging force

Location of peptic ulcer

1. duodenal ulcer: 1st portion of duodenum

2. gastric ulcer: esp. antrum

3. esophagocardiac junction

4. gastrojejunostomy

5. Zollinger-Ellison syndrome: duodenum, stomach, jejunum

6. Meckel diverticulum

H. pylori & peptic ulcer

1. 100 % of duodenal ulcer associated with H. pylori infection

70 % of gastric ulcer associated with H. pylori infection

2. urease → ammonia

Pathology of peptic ulcer

1. duodenal ulcer: duodenum, 1st portion, anterior wall

  gastric ulcer: antrum and angle of lesser curvature side

2. round-oval shape, well-defined

  no obvious elevated margin

  mucosa to serosa in depth

  smooth & clear ulcer base

  combined with chronic gastritis

  radiated mucosal fold

Peptic ulcer at active stage

1. necrotic fibrinoid debris

2. nonspecific acute and chronic inflammation

3. granulation tissue

4. fibrous scar

    * thick-walled blood vessel with thrombosis

Clinical feature of peptic ulcer

1. epigastralgia:

    worsen at night

    onset of 1-3 hrs after meal

    relieved by food

    nausea, vomiting, body weight loss

2. ? malignant change

Acute gastric ulceration

1. NSAID- stress ulcer (erosion)

erosion: shedding of superficial epithelium

ulceration: deep mucosa

2. small, multiple or single ulceration at stomach & duodenum

Etiology of stress ulcer

* sepsis

* shock

* severe trauma / surgery

* Curling ulcer: severe burn injury

* Cushing ulcer: IICP (increased intracranial pressure) → head injury, brain tumor

Gastric carcinoma- high incidence area: Japan, Chile, China

1. intestinal type- M:F = 2:1, 55 y/o

      chronic gastritis → IM → dysplasia → adenocarcinoma 

2. diffuse type- M:F = 1:1, 48 y/o

      de novo

Pathology of gastric carcinoma

* location: antrum & pylorus of lesser curvature side

* classification based on:

   1. depth of invasion

   2. gross pattern

   3. histologic typing

Classification of gastric carcinoma- depth of invasion

1. early carcinoma:

confined to mucosa and submucosa, regardless of presence or absence of regional

lymph node metastasis

     * 5 year survival rate: 90-95 %

2. advanced carcinoma: extended to muscularis propria or more

Macroscopic types of early gastric carcinoma

   type 0 I: protruded

   type 0 IIa: elevated

   type 0 IIb: flat

 type 0 IIc: depressed

   type 0 III: excavated 

Borrmann’s classification of advanced gastric carcinoma

   type I: exophytic

   type II: ulcerated with sharp defined elevated margin

 type III: ulcerative with infiltrating margin

   type IV: diffusely infiltrating

Borrmann’s type III carcinoma

* ulcerative tumor

* heaped-up elevated margin

* sharp border

* necrotic dirty ulcer base

Borrmann’s type IV carcinoma- diffuse type adenocarcinoma (linitis plastica)

* rigid, thickened gastric wall

* leather bottle-like (scirrhous) stomach

* signet-ring cell carcinoma

* marked desmoplasia

Gastric adenocarcinoma- Lauren classification

1. intestinal type- glandular formation

    well-differentiated

    moderately-differentiated

2. diffuse type

poorly-differentiated- no obvious glandular formation

individual cell infiltration

anaplastic cell / signet-ring cell

infiltrative pattern     

Clinical behavior of gastric carcinoma

1. lymph node metastasis

    * Virchow node: supraclavicular LN

2. peritoneal seeding

3. Krukenberg tumor

bilateral ovarian metastasis of diffuse type (signet-ring cell) gastric carcinoma

Small and large intestines

Histology of small intestine mucosa

* villi : crypt = 4-5 : 1

* epithelium
  1. columnar absorptive cell
  2. goblet cell
  3. endocrine cell
  4. undifferentiated cell
  5. paneth cell

* Brunner's gland in submucosa of duodenum

Histology of large intestine mucosa

1. columnar absorptive cell

2. goblet cell

3. endocrine cell

4. undifferentiated cell

5. paneth cell 

Meckel's diverticulum

1. incidence: 2 %

2. persistence of vitelline duct

3. terminal ileum- 30 cm. proximal to ileocecal valve, antimesenteric border

4. heterotopic mucosa: gastric mucosa, pancreatic tissue

5. complication: ulcer, bleeding, rupture

Hirschsprung's disease (Congenital aganglionic megacolon)

1. 1 out of 5000 to 8000 live births

2. M : F = 4 : 1

3. 10 % associated with Down syndrome

4. neonatal period

5. failure to pass meconium
obstructive constipation
abdominal distension

Pathogenesis of megacolon

1. arrest of migration of neural crest to anus

2. aganglionosis- absence of Meissner's & Auerbach's plexus

3. functional obstruction with pre-obstructive dilatation

Pathology of megacolon

1. absence of ganglion cells
  short segment- rectum & sigmoid
  long segment- entire colon

2. hypertrophy of nerve fiber

3. megacolon- dilatation & hypertrophy proximal to aganglionic segment

Pseudomembranous colitis

1. acute adherent inflammatory pseudomembrane

2. Clostridium difficile toxin

3. antibiotic-associated        

4. severe mucosal injury: ischemic colitis

Pathology of pseudomembranous colitis

1. Pseudomembrane- plaque-like adhesion of fibrinopurulent-necrotic debris & mucus

 to damaged mucosa

2. Mushrooming cloud- purulent exudate of crypt

3. dense neutrophil infiltration

4. denuded surface epithelium

Celiac sprue (Gluten-sensitive enteropathy, Nontropical sprue)

1. sensitive to gluten (gliadin)

2. Whites, 1:2000 to 3000 in Europe

  rare or nonexistence in orients

3. genetic susceptibility: HLADQw2

4. immune-mediated intestinal injury

5. T cells sensitized to gluten in mucosa

Pathology of celiac sprue

1. flat, scalloped or normal mucosa

2. diffuse enteritis

     duodenum & proximal jejunum

     marked mucosal atrophy

3. surface epithelium

     vacuolar degeneration

     loss of microvilli

     intraepithelial lymphocyte

4. reversible change after gluten-free diet

Idiopathic inflammatory bowel disease

1. Crohn's disease (CD)

  ulcerative colitis (UC)

2. unknown etiology

3. chronic & relapsing   

Crohn's disease (terminal ileitis, regional enteritis)

1. sharply delimited

  transmural

2. noncaseating granuloma

3. fissure & fistula formation

4. systemic manifestations

Epidermiology of Crohn’s disease

1. throughout the world, esp. Western

2. young child to advanced age

* main peak: 2nd to 3rd decade

* minor peak: 6th to 7th decade

Pathology of Crohn’s disease

1. any level of alimentary tract from mouth to anus

2. small intestine- 40%
small intestine & colon- 30%
colon- 30%

3. skip lesion- sharp demarcation of diseased segment from normal mucosa

4. creeping fat- granular & dull-gray serosa, mesentery fat
  mesentery- fibrous thickening, edema
   intestinal wall- rubbery & thick
   lumen narrowing- "string sign" in barium X-ray

5. aphthous / linear ulcer: along axis of bowel

  cobblestone appearance

6. perforation

Histopathology of Crohn’s disease

1. mucosal inflammation & ulcer

2. chronic mucosal damage- atrophy, paneth cell metaplasia

3. transmural inflammation
  * noncaseating granuloma
  * lymphoid aggregation

Ulcerative colitis

1. inflammatory disease limited to colon

2. mucosa & submucosa lesion

3. continuous lesion, skip lesion (-)

4. granuloma (-)

5. systemic disease

6. onset age: 20-25 y/o

Pathology of ulcerative colitis

1. retrograde: rectum to pancolitis

  backwash ileitis

2. pseudopolyp: broad-based ulceration & regeneration with ulcer along axis of colon

3. toxic megacolon: dilatation, swelling, gangrene

4. mucosal atrophy, submucosal fibrosis      

Etiology of Ischemic Bowel Disease

Pathology of transmural infarction

1. mechanical compromise of major mesenteric blood vessel

2. arterial blood flow: acute & total occlusion

3. watershed area: splenic flexure of colon

4. hemorrhagic infarction- gangrene

5. congested, edematous submucosa & subserosa 

6. bloody mucus secretion

Pathology of mucosal & mural infarction

1. hypoperfusion- acute & chronic

2. hemorrhage & edema of mucosa

    superficial ulceration

    sloughing necrosis

    pseudomembranous inflammation

Ischemic colitis

1. chronic vascular insufficiency

2. mucosal inflammation & ulceration

3. stricture- submucosal inflammation & fibrosis

4. segmental & patchy distribution

5. symptoms/signs: non-specific, intermittent bloody diarrhea  

Diverticulum

* blind pouch leading off GI tract

* lined by mucosa communicating with lumen
     congenital
     acquired

Colonic diverticulosis

1. old age, Western

2. multiple

3. sigmoid colon (most common)

  descending colon
entire colon

4. acquired diverticulum

Pathogenesis of colonic diverticulosis

1. focal weakness of colonic wall

2. increased intraluminal pressure

     peristaltic contraction

     low-fiber diet

Colonic polyp

Non-neoplastic polyp of intestine

* no malignant potential

* 90 % epithelial polyp in colon

* increase in frequency with age

Hyperplastic polyp

1. < 5 mm, multiple＞single

2. any age, esp. 6th & 7th decades

3. nipple-like, hemispheric, smooth protrusion

4. proliferive serrated epithelium
infoldings of crowding epithelium

Juvenile polyp

1. hamartomatous change

2. juvenile polyposis syndrome: autosomal dominant

3. children < 5 y/o, 80% in rectum

4. large (1-3 cm), lobulated, pedunculated (with stalk)

5. cystic change of gland

  surface congestion & ulceration

6. retention polyp in adult

Peutz-Jeghers polyp

1. Peutz-Jeghers syndrome: autosomal dominant

   * multiple hamartomatous polyps in GI tract

   * melanotic mucocutaneous pigmentation- lip, oral mucosa, face, genitalia

2. arborizing network of connective tissue & smooth muscle- christmas tree pattern

Neoplastic polyp in intestine

1. adenomatous polyp- dysplasia of glandular epithelium

2. precursor of carcinoma

3. tubular adenoma- tubular gland

  villous adenoma- villous projections

  tubulovillous adenoma

Adenomatous polyp of intestine

1. family predisposition

2. sporadic or hereditary

3. dysplasia: mild, moderate, severe

4. tubular adenoma- small, pedunculated
villous adenoma- large, sessile

Malignant potential in adenomatous polyp

1. polyp size: large＞small

2. dysplasia: severe＞moderate＞mild

3. architecture: villous＞tubulovillous＞tubular

Familial adenomatous polyposis (FAP)

1. autosomal dominant

2. progression to adenocarcinoma (100%)

3. 2nd to 3rd decades, 10-15 year-period

4. a minimum of 100 polyps

5. prophylactic colectomy

6. high risk in sibling & first-degree relatives

Gardner's syndrome

1. variant of FAP, autosomal dominant

2. multiple osteomas (mandible, skull, long bones)

3. epidermal cyst

4. fibromatosis

5. abnormal dentition

"Multi-hit" concept for colorectal carcinogenesis

1. chromosome 5q21: FAP associated gene

     * APC (adenomatous polyposis coli) mutation

2. hypomethylation in DNA

3. ras gene mutation in adenoma & carcinoma

4. DCC (deleted in colon cancer) allelic loss
   * encoded protein: cell adhesion family

5. loss at 17p in colon cancer
   * harbors p53 suppressor gene

   * encoding phosphoprotein in cell cycle

Adenomatous polyposis gene

* APC tumor suppressor gene: 5q21

* APC protein: bind to β-catenin

      1. bind to E-cadherin

      2. degradation of β-catenin

* β-catenin

      1. bind to E-cadherin

      2. bind to Tcf-Lef → carcinogenesis

0* APC gene mutation

      1. ↓ bind to β-catenin →↓cellular adhesion

      2. ↑ β-catenin → bind to Tcf-Lef → FAP → carcinoma

Hereditary Nonpolyposis Colon Carcinoma (HNPCC)

1. family syndrome of HNPCC

2. DNA mismatch repair gene: caretaker gene

  genetic proofreading during DNA replication

3. gene mutation: inherited mutation → somatic mutation

Colorectal carcinoma

1. 60-70 y/o
young patients: UC or polyposis syndrome

2. high incidence in Westerns

  15% of cancer-related death in US

3. predisposing factor: diet

Predisposing factor of colorectal carcinoma

low content of vegetable fiber:

   decreased stool bulk

   increased fecal transit time

   alterned bacterial flora

   toxic product by bacteria

Pathology of colorectal carcinoma

1. "shift to right" tendency
   25%- cecum & ascending colon
   25%- rectosigmoid
   25%- discending colon & proximal sigmoid
   25%- other

2. 1-3% from FAP or IBD

3.

Histopathology of colorectal carcinoma- adenocarinoma

    well-differentiated

    moderately-differentiated

    poorly-differentiated

Clinical manifestation of colorectal carcinoma

Biological behavior of colorectal carcinoma

1. direct extension

2. metastasis- lymphatic & hematogenous spreading
   lymph node, liver, lung, bone

3. single important prognostic factor: extent of tumor

     * clinical staging: modified Dukes' classification

Carcinoid tumor

1. any age, peak incidence: 6th decade

2. neuroendocrine cell from gut, pancreas, lung, biliary tree, liver

3. 50 % of small intestinal malignancies

4. malignant potential: site, depth, and size

   * uncommon metastasis: rectal & appendiceal carcinoid

   * others: 90% spread to LN, distal site

Pathology of intestinal carcinoid

1. favor site:

    appendix (most common)- tip

    small intestine (esp. ileum)

    rectum, stomach, colon

2. multicentricity: stomach & ileum

3. intramural or submucosal tumor, small & polypoid, < 3 cm

4. solid, yellow-tan

Histopathology of intestinal carcinoid

1. neoplastic cell:

    monotonous round to oval nuclei

    fine chromatin pattern (pepper-salt appearance)  

   pink granular cytoplasms

2. growth pattern: island, trabecula, gland, solid

Clinical manifestations of intestinal carcinoid

1. asymptomatic

2. gastrin: Zollinger-Ellison syndrome

  ACTH: Cushing's syndrome

  insulinoma

3. carcinoid syndrome- liver metastasis

    seritonin (5-hydroxytryptamine, 5HT) → liver →

    5-HIAA (5-hydroxyindoleacetic acid) in urine & blood

Clinical features of carcinoid syndrome

* flush & cyanosis

* diarrhea

* asthma

* stenosis of tricuspid and pulmonary valve

Pathogenesis of acute appendicitis

obstruction (fecalith, gallstone, tumor, worm)

↓

accumulation of mucus secretion

↓

increased intraluminal pressure

↓

collapse of drainage of vein

↓

ischemic change

↓

bacterial proliferation

↓

inflammatory edema & exudation

Pathology of acute appendicitis

1. early acute appendicitis
  subserosal congestion
  neutrophil exudate
  perivascular neutrophilic infiltration

2. acute suppurative appendicitis
  abscess
  fibrinopurulent exudate over serosa

3. acute gangrenous appendicitis

4. perforation- suppurative peritonitis