Weeks 5 and 6 (GI) Flashcards
Layers of GI tract
Lumen
Mucosa
Muscularis mucosae
Submucosa
Subumucosal nerve plexus
Muscularis propria (inner circular layer)
Myenteric nerve plexus
Muscularis propria (outer longitudinal layer)
Serosa/adventitia (not in esophagus though)
Symptoms of esophageal disease
Dysphagia (difficulty swallowing): deranged motor function or narrow/obstructed lumen
Heartburn (retrosternal burning pain): usually due to regurgitation of gastric contents in lower esophagus
Hematemesis (vomiting blood) or melena (blood in stool): severe inflammation or laceration of esophagus; massive hematemesis (usually with ruptured varices, is a life threatening emergency)
Achalaisia
Failure of lower esophageal sphincter (LES) to relax
Clinical presentation: young adults, dysphagia, nocturnal regurgitation, aspiration (inability to pass food to stomach), squamous cell carcinoma in 5% is serious complication
Manometric abnormalities: aperistalsis, partial or incomplete relaxation of LES, increased resting tone of LES
Causes: primary or secondary
Primary achalaisia
Loss of intrinsic inhibitory innervation of LES and smooth muscle of body of esophagus (lose parasympathetic inhibitory fibers to LES, so get too much firing and increased LES tone/constriction)
Autoimmune?
Previous viral illness?
Gross morphology: progressive dilation above LES
Microscopic findings: loss of ganglion cells in myenteric plexuses of esophageal body; inflammation in location of myenteric plexus (in some cases there is focal to almost complete replacement of nerves by collagen); mucosal inflammation and ulceration secondary to food stasis (increased risk of SCC)
Secondary achalaisia
“Pseudoachalaisia”
T. cruzi (Chagas disease): destruction of myenteric plexus
Autonomic nerve dysfunction: diabetes
Dorsal root nerve damage: polio
Malignancy
Amyloidosis
Mallory-Weiss tear
AKA esophageal laceration
Longitudinal tears in the esophagus at the gastroesophageal junction
Cause 5-10% of upper GI bleeding episodes
Usually not severe and doesn’t require surgical intervention but life threatening blood loss can occur
Usually occurs with severe vomiting in an acute illness, bulemics or in chronic alcoholics
Mechanism presumed to be inadequate relaxation of musculature of LES during vomiting
Can occur with no history of vomiting or retching (hiatal hernia found in 75% of these cases)
Esophageal varices
Occur when portal venous blood flow is impeded by cirrhosis or other causes (portal hypertension)
Diversion of portal blood flow through communicating veins in the esophagus between the splanchnic and systemic venous circulation causes dilated and tortuous blood vessels
Rupture can lead to massive bleeding
50% subside spontaneously; 20-30% die in episode of bleed
In distal esophagus and proximal stomach, primarily within submucosa of proximal stomach
Histology may be normal, or may have overlying reactive mucosal change
Anatomic lesions of the esophagus
Hiatal hernia
Stenosis
Atresia, fistula
Webs, rings
Diverticula
Esophagitis
Injury to the esophagus with subsequent inflammation
Reflux is most common cause in western countries
Other causes: infection, prolonged intubation, uremia, ingestion of corrosive or irritant substance, radiation or chemotherapy, allergic response
Reflux esophagitis
Reflux is the cause of heartburn and can also be accompanied by “sour brash” regurgitation
Complications of reflux are bleeding, stricture, Barrett esophagus
Gross morphology ranges from redness to confluent erosions or total ulceration
Histology ranges from normal to total ulceration and severity of symptoms not closely related to histology
If chronic, can have eosinophils with or without neutrophils, basal hyperplasia, elongated subepithelial pegs
Eosinophilic esophagitis
Chronic, immune/antigen-mediated esophageal disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation
Gross morphology: rings, vertical furrows, lumen can be narrow
Microscopic features: peak eosinophil value greater than 15 per high powered field, eosinophilic microabscesses, surface layering of eosinophils, extracellular eosinophil granules, basal cell hyperplasia, dilated intercellular spaces, lamina propria fibrosis
Treatment: topical steroids or acid suppression for reflux
Barrett Esophagus
Change in the distal esophagus epithelium of any length that can be recognized as columnar type mucosa at endoscopy and is confirmed to have intestinal metaplasia (with goblet cells) by biopsy of tubular esophagus
Caused by reflux
Affects 15% of people with reflux (symptomatic and asymptomatic)
Inflammation –> ulceration –> healing in low pH –> protective columnar epithelium (not normal, no absorption cells)
Gross morphology: tongues or islands of salmon-pink, velvety epithelium vs. normal pale pink squamous background
Microscopic features: columnar epithelium with goblet cells
Complications: dysplasia –> adenocarcinoma (some consider Barrett a pre-neoplastic condition)
Neoplasm
Abnormal mass of tissue, the growth of which exceeds and is uncoordinated with the normal tissues and persists in the same excesive manner after cessation of the stimuli which evoked the change
Benign neoplasm: will remain localized, cannot spread to different sites and is amenable to surgical removal (adenoma, dysplasia)
Malignant neoplasm: has ability to invade and destroy adjacent structures and spread to distant sites (invasive carcinoma)
Dysplasia
“Premalignant condition”
Non-invasive neoplasia with architectural and/or cytologic alterations of epithelium normally associated with neoplastic growth without evidence of infiltration into lamina propria
Esophageal adenocarcinoma
Barrett esophagus –> dysplasia –> invasive carcinoma
Gross morphology: may be just like Barret’s; carcinoma may be large nodular masses, ulcerative or infiltrative
Microscopic features: dysplasia (nuclear hyperchromasia, pseudostratification, loss of polarity); invasive carcinoma (single cell or infiltrating glands)
Squamous cell carcinoma of esophagus
Dysplasia/carcinoma in situ –> invasive carcinoma
Gross morphology: 20% cervical, 50% mid-thoracic, 30% lower third
Microscopic features: disordered cytologic atypia, invasion of lamina propria in carcinoma
Symptoms of a stomach lesion
Heartburn
Vague epigastric pain
Hematemesis or melena (acid in stomach causes blood to congeal and turn brown: “coffee ground hematemesis”)
Chronic gastritis
Presence of chronic inflamatory changes in mucosa, leading eventually to mucosal atrophy and epithelial metaplasia
Greater than 50% incidence in older patients
Most common causes are H. pylori (usually antral predominant) and autoimmune (usually body/fundus predominant)
Crohn’s disease can be a cause
Gross morphology: variable from normal to erythema to marked inflammation
Microscopic features: increased lymphocytes, eosinophils and plasma cells in lamina propria, maybe neutrophils (active inflammation) in pits, maybe intestinal metaplasia
Two patterns of inflammation in chronic gastritis due to H. pylori
1) Antral pattern: antral predominant; high acid production; increased risk of duodenal and gastric ulcers
2) Pangastritis: multifocal mucosal atrophy; low acidity; increased risk for adenocarcinoma
Autoimmune gastritis (atrophic)
No parietal cells –> pernicious anemia
No acid –> endocrine stimulation –> neuroendocrine tumors
Acute gastritis
Acute mucosal inflammatory process
May be accompanied by erosions (can cause bleeding–acute erosive gastritis) which usually cause hematemesis: alcoholics, aspirin daily for arthritis, smoking, chemotherapy/drugs, uremia, systemic infection, severe stress (trauma, burns, surgery), ischemia and shock, suicide attampts with acids and alkali, bile reflux
Causes of injury: disruption of adherent mucus layer, stimulation of acid secretion with back diffusion of acid, decreased production of bicarb buffer by superficial epithelial cells, decreased mucosal blood flow, direct epithelial damage, acute H. pylori infection
On endoscopy may see localized erosions (as in NSAID injury) or diffuse punctate erosions with hemorrhage (acute erosive gastritis)
Usually not biopsied but histologically would find superficial to full thickness edema, inflammation, regenerative epithelial changes
Ulcer vs. erosion
Ulcer: breach in mucosa that extends through muscularis mucosae into the submucosa or deeper; long healing process
Erosion: breach in mucosal epithelium only; heals within days
Peptic ulcer
Chronic, most often solitary lesions that occur in any portion of GI track exposed to acidic peptic juices
Most often in duodenum or stomach (4:1 ratio)
Usually in middle aged or older, no precipitating influences, can heal then recur
Associated with alcoholic cirrhosis, chronic renal failure, hyperparathyroid (increased Ca2+ leads to increased acid)
Causes: H. pylori (70-90% of cases), NSAID use, Zollinger-Ellison, cigarettes, alcohol, high dose corticosteroids, maybe personality?
Gross morphology: 2-4cm punched-out appearance with clean ulcer base
Microscopic features: defect extends through muscularis mucosae into submucosa and possibly deeper, 4 zones of chronic ulcer are base/margin, active nonspecific inflammatory infiltrate, granulation tissue, fibrous scar
Acute gastric ulceration
Focal, acutely developing gastric mucosal defects
Occur in trauma (surgery), sepsis, shock, grave illness, NSAIDs, corticosteroids, burns (“curling ulcers”), CNS surgery/injury (“cushing ulcers”)
Significance depends on cause and ability to correct underlying problem
Gross morphology: circular and <1cm with dark brown base from hemorrhage, found anywhere in stomach and often multiple lesions
Microscopic features: abrupt change with unremarkable adjacent mucosa, depth from superficial to full thickness ulceration (shallow erosions are not precursors to peptic ulcer disease but just extension of acute erosive gastritis)
Gastric tumors
Polyps (benign): gastric hyperplastic polyp, fundic gland polyp, adenoma
Carcinoma: most common malignant tumor of stomach
Gastric carcinoma
Macroscopic growth patterns: exophytic, flat or depressed, excavated, linitis plastica (leather bottom)
Metastasis: Virchow’s nodes, Krukenberg tumor
Lauren classification of gastric carcinoma
Intestinal: cohesive tumor cells that form recognizable glands regardless of their degree of cytologic differentiation or cell of origin, usually bulky tumors (Borrmann types I-III)
Diffuse: discohesive cells that penetrate diffusely through the stomach embedded in a desmoplastic stroma, usually develops as linitis plastica (Borrmann type IV)
Other gastric tumors
Lymphoma
Neuroendocrine (aka carcinoid)
Stromal tumors (GIST)
Pseudomembranous colitis
AKA antibiotic-associated colitis
Usually but not always caused by C. difficile
Term is applied to diarrhea developing during or after course of antibiotic thearpy
Thought to be caused by disruption of normal flora by antibiotic (3rd gen cephalosporins, and immunosuppression is predisposing factor)
Developmental abnormalities
Atresia
Omphalocele and gastroschisis
Meckel diverticulum
Hirschsprung’s disease
Atresia
Bowel ends in blind pouch
Often along with other anomalies
Accompanied by polyhydramnios since fetus has impaired swallowing and absorption of amniotic fluid
Half duodenal atresias occur with Down syndrome (but few cases of Down syndrome overall have atresia)
Omphalocele
Incomplete closure of abdominal musculature
Abdominal viscera herniate into ventral membranous sac
Gastroschisis
Lack of formation of a portion of abdominal wall, involving all layers from peritoneum to skin
Viscera herniate out, and are not covered by a membrane
Meckel diverticulum
Most common and innocuous anomaly
Occurs in terminal ilium
Diverticulum is blind out pouching of GI tract: lined by mucosa, opens/communicates to main lumen
True diverticulum such as Meckel includes all three layers of bowel wall (mucosa, submucosa, muscularis propria)
Results from failed involution of omphalomesenteric duct, which connects lumen of developing gut to yolk sac
Small pouch extending from anti-mesenteric side of bowel
Rule of 2s: 2% of population, present within 2 feet of ileocecal valve, 2 inches long, 2x as common in males as in females, symptomatic by age 2 (if it is gastric tissue, can get peptic ulceration of adjacent small intestine (mysterious occult bleeding or abdominal pain like appendicitis), could get bacterial overgrowth that depletes vitamin B12)
Hirschsprung disease
Absence of normal postganglionic autonomic cell bodies (ie ganglion cells) in both submucosal and myenteric plexuses
Aganglionic segment becomes narrowed (functional obstruction) with proximal dilation (congenital megacolon)
Results from mutation of susceptible genes interacting with other factors
Half of familial cases and 15% of sporadic cases associated with mutations in RET genes and ligands (RET signaling required for development of myoenteric nerve plexus and provides direction to migrating neural crest cells)
Infants present with delay in passage of meconium, followed by vomiting
Diagnosis established by documenting absence of ganglion cells in nondistended bowel segment
Colonic diverticulosis
Acquired diverticula
Secondary to focal weakness in muscle wall and increased luminal pressure
More common in left colon/sigmoid colon, in older patients, in developed nations with low fiber diet resulting in reduced stool bulk
Flasklike outpouchings
Exaggerated peristalsis induces muscular hypertrophy in affected segments
Can become inflamed leading to diverticulitis and possibly perforation (perforation may lead to localized peritonitis or abscess formation)
Inflammatory bowel disease (IBD)
Chronic inflammatory diseases of intestine with some extra-intestinal manifestations
Idiopathic: resulting from abnormal local immune responses against unknown microbes and/or self antigens in intestine
Two main types: ulcerative colitis and Crohn’s disease
Ulcerative colitis
One type of IBD
Severe ulcerating inflammatory disease that is generally limited to colon (left side) and rectum
Inflammation extends only into mucosa and maybe submucosa with superficial ulcers
Pseudopolyps seen grossly: bulging mass of inflamed residual mucosa surrounded by extensive area of ulceration
Diffusely inflamed mucosal surface from rectum to cecum (but right colon less involved)
Crohn’s disease
Another type of IBD
May involve ANY area of GI tract, but ileum frequently affected
Skip lesions are present (diseased areas sharply demarcated from adjacent uninvolved bowel)
Inflammation typically transmural with non-necrotizing granulomas, ulcerations and fissures
Thick wall due to edema, inflammation, fibrosis and hypertrophy of muscularis propria
Serosa thickened and fibrotic, leading to strictures
Often mesenteric fat wraps around bowel surface (creeping fat)
Crohn’s disease vs. ulcerative colitis
Crohn’s disease: transmural and granulomatous inflammation; ileum and maybe colon, skip lesions, strictures, thick wall, transmural inflammation, marked fibrosis and serositis, deep ulcers, fissures and fistulas
Ulcerative colitis: mucosal inflammation with ulceration; colon only, diffuse distribution, rare strictures, thin wall, inflammation just in mucosa, mild/no fibrosis and serositis, superficial ulcers, no granulomas, no fissures and fistulas
Complications of IBD
Toxic megacolon: rare complication of ulcerative colitis; ulcers lead to perforation and pericolonic abscess formation and exposure of muscularis propria to fecal material may lead to complete shutdown of neuromuscular function –> colon progressively swells and becomes gangrenous
Dysplasia and carcinoma: regular surveillance is needed with colonoscopies and biopsies
Tumors of GI tract
Neoplastic epithelial tumors: adenomas, adenocarcinomas (connection to polyps/adenomas), squamous cell carcinomas
Neoplastic non-epithelial: GI stromal tumors, neuroendocrine tumors, lymphomas
Tumor vs. polyp
Tumor originally applied to swellings caused by inflammation
Polyp is a mass that protrudes into lumen of gut
Colon polyps
Non-neoplastic: due to abnormal mucosal maturation, inflammation or architecture; no malignant potential; can be hyperplastic, inflammatory, hamartomatous (juvenile or Peutz-Jeghers)
Neoplastic epithelial: adenomatous polyps/adenomas; due to epithelial proliferation and dysplasia; precursors of carcinomas; can be benign (tubular, tubulovillous, villous, sessile serrated) or malignant (adenocarcinoma)
Adenomas
Neoplastic epithelial polyps
All adenomas arise as result of epithelial proliferation and dysplasia
Dysplasia may range from mild to severe (carcinoma)
Low or high grade depending on architectural and nuclear atypia
Gross/macroscopic features: pedunculated (stalk) vs. sessile (no stalk)
Microscopic features: tubular, tubulovillous
Adenoma with low grade dysplasia
Architecture: crowding of glands and irregular, branching glands
Cytology: pseudostratification of cells and nuclei; slightly larger and elongated nuclei
Adenoma with high grade dysplasia
Architecture: marked crowding of glands including complex cribriforming structures
Cytology: loss of cell polarity; nuclear enlargement and rounding
Adenoma-carcinoma sequence
Multistep process of progression from normal mucosa to carcinoma (involves series of mutations in multiple genes, like all cancers)
Specific gene mutations correlate with distinct histopathologic changes: normal mucosa –> adenomatous polyp –> carcinoma
Mutations can be inherited (familial) or acquired (somatic)
Most sporadic invasive colorectal adenocarcinomas (CRC) arise in pre-existing adenomas, although a few adenomas become invasive cancers
Patients with adenomas have increased risk of cancer (have lag time to develop cancer though)
Specifics of adenoma-carcinoma sequence
1) APC at 5q21 is “first hit” (inherited or acquired mutation of cancer suppressor gene)
2) APC/beta-catenin is “second hit” (methylation abnormalities and inactivation of normal alleles)
3) K-Ras at 12p12 is protooncogene mutation
4) p53, LOH mutations cause homozygous loss of additional cancer suppressor genes (or overexpression of COX-2)
5) Telomerase or other gene mutations or gross chromosomal alterations
TNM staging of colorectal cancer
As with staging of other cancers, it indicates extent of cancer and is best predictor of survival/prognosis
Unlike with other tumors, the T refers to the depth of penetration into the bowel wall (rather than the size of the tumor)
Squamous cell carcinoma of the anus
Associated with HPV infection
HPV –> squamous intraepithelial dysplasia –> squamous cell carcinoma
Like with other SCC, get pink keratin pearls!
Remember, anus has squamous epithelium unlike intestine which has columnar epithelium
Gastrointestinal stromal tumor (GIST)
Mesenchymal neoplasm
Varies from low risk to overtly malignant
Most have somatic mutation in c-KIT (CD117) gene which encodes a tyrosine kinase receptor
See spindle cells with elongated nuclei, fine chromatin and eosinophilic cytoplasm
Neuroendocrine tumors
NE cells normally dispersed along GI tract mucosa and have role in gut function
Almost all are potentially malignant (except those found with pernicious anemia?!)
Small, polypoid solid, yellow/tan lesions
Can cause kinking of bowel when invade mesentary and produce obstructive symptoms
Monotonous cells arranged in sheets, islands, trabeculae, round to oval nucleus with salt and pepper chromatin, scant eosinophilic cytoplasm, EM shows neurosecretory granules
Lymphoma of the GI tract
Any segment of the GI tract may be involved in dissemination of lymphoma
40% of lymphomas arise in sites other than lymph nodes and GI tract is most common extra-nodal location
1-4% of all GI malignancies are lymphomas
Most common GI lymphoma is MALT lymphoma that originates in B cells of mucosa-associated lymphoid tissue
May arise anywhere in gut but most common in stromach in setting of H. pylori chronic gastritis
Malignant cells are discohesive with prominent nucleoli and occasional mitotic figures
Diverticulosis
Outpocketings of the colonic mucosa and submucosa through weakness of muscle layers in the colon wall
Is actually pseudo-diverticula because doesn’t include all 3 layers of the colon wall! Includes mucosa and submucosa but NOT muscularis propria
Alone, they are not an issue but can lead to diverticular bleeding or diverticulitis
Caused by increased intra-colonic presure (low fiber diet)
Foods high in fiber
Recommended to get 30 grams per day
Beans
Squash
Cereal bran flake
Brown rice
Apple
Symptoms of diverticulosis
No symptoms so no medical attention sought
Diverticular bleeding: BRBPR, usually minor or self-limited but severe in 5%
Diverticulitis: inflammation of a diverticulum; LLQ pain, fever, leukocytosis
Differential diagnosis of lower GI bleeding
Angiodysplasia (AVM), right more than left
Anorectal: hemorrhoids, fissure
Malignancy: colorectal cancer
Inflammatory bowel disease
Other colitides (ischemic)
Upper GI bleeding
Cause of diverticular bleeding
Chronic injury to vasa recta adjacent to lumen of diverticulum
Tests to identify bleeding
Nuclear scan (tagged RBC scan)
Angiography
Colonoscopy
Treatment for diverticular bleeding
Supportive care (most resolves spontaneously): volume resuscitation but if persists then investigate coagulation abnormalities
For ongoing bleeding, do angiography and embolization, colonoscopic intervention, emergency surgery with resection
Diverticultis
Hardened feces trapped in diverticulum and gets infected
Matter inspisates within diverticulum and erodes through wall
Symptoms: LLQ pain, fever, leukocytosis, peritonitis (acute abdomen: rigidity, rebound tenderness, involuntary guarding, consistent with perforation), Less commonly UTI, pneumaturia
DDx of LLQ pain
Gastroenteritis
Crohns
Ulcerative colitis
Cancer
Ischemic colitis
Kidney stones
Ruptured aneurysm
PID (other gyn problem)
Others
Treatment of diverticulitis
If mild (able to eat, just LLQ pain): oral antibiotics
If moderate (unable to eat/drink): antibiotics, bowel rest, supportive care, most improve in 48-72 hours, treat until pain/diet improved, discharge on oral antibiotics, study colon in 4-6 weeks
If severe (perforation): surgical resection
Anatomy of the esophagus
20-22cm long muscular tube
Inner circular and outer longitudinal muscle layer (ICOL)
Upper 5% striated muscle
Middle 35-40% mixed
Lower 50-65% smooth muscles
Upper esophageal sphincter
Lower esophageal sphincter (near diaphragm)
Control of upper striated muscle of esophagus
Control by CNS
Nucleus ambiguus
Sequential motor neuron activation by neurons coming from the nucleus ambiguus
Control of lower smooth muscle of esophagus
Sensory is nucleus tractus solitarious (NTS)
Motor is dorsal vagal motor nucleus (vagus nerve) to the myenteric plexus
Myenteric plexus neurons use NO as a neurotransmitter to hyperpolarize smooth muscle, then when NO broken down after the stimulus, smooth muscle contracts and causes peristalsis (“off response”)
Dysfunction of striated muscle of esophagus
Neuromuscular diseases: CNS (stroke, MS, ALS, Parkinson’s, tumor), PNS (polio, myasthenia, neuropathy), myopathy (muscular dystrophy, polymyositis)
Oropharyngeal dysphagia: food sticks in anterior throat above suprasternal notch; difficulty initiating swallows, cough, choking, nasal regurg, nasal speech; takes a long time to eat
Polymyositis
Cannot get food started down esophagus
Myopathic diseases
Collagen vascular diseases (CREST, scleroderma, SLE)
Muscular dystrophies
Familial visceral myopathies
Pathology: muscle degeneration and replacement by fibrous connective tissue
Esophageal dysphagia
Food sticks at suprasternal notch or substernal
Note: location does not predict level of lesion (obstruction is usually distal to sensation)
Scleroderma
UES functions well and striated muscle contracts, but no function of smooth muscle and LES is weak
Achalasia
Myenteric neuropathy
Failure of peristalsis, LES does not relax (elevated LES pressure), loss of nitric oxide synthase-containing neurons from myenteric plexus
Get powerful random contractions of smooth muscle of esophagus or simultaneous pressure waves that do not cause peristalsis
Clinical presentation: dysphagia (solid more than liquid), regurgitation, chest pain, heartburn, aspiration, weight loss, halitosis
Bird’s beak at LES, dilated esophagus, sigmoid esophagus, failed primary primary peristalsis
Diffuse esophageal spasm
Less than 1% of dysphagia (not common)
Mean age of 40
Chest pain (mimic cardiac pain), dysphagia, heartburn
See increased pressure within smooth muscle of esophagus due to spasm?
Interstitial cells of cajal (ICC)
Pacemakers/conductors that control gastric peristalsis
Between muscles and nerves
Impulse transmitted from nerve through ICC to muscle to allow for contraction (if no ICC then no muscle contraction!), network that initiates/propagates electrical signal in stomach
Causes of gastroparesis
Idiopathic
Diabetes (if glucose over 170, stomach doesn’t work because no ICCs)
Post-gastric
Par. dis.
Symptoms of gastroparesis
Nausea, vomiting, bloating, early satiety, abdominal pain, weight loss
Pathophysiological changes are impaired accommodation, antral hypomotility and distension, dysrhythmia
Abnormal emptying is a marker or neuromuscular dysfunction, rather than a cause of symptoms
Esophageal squamous cell carcinoma
More in men than in women (except northern Iran where SCC associated with Plummer Vinson Syndrome which is iron deficiency anemia and dysphagia due to growths of tissue that cause blockage)
More in AA than caucasians
Causes/risk factors: tobacco, alcohol, achalasia (33x risk!), head and neck SCC, Tylosis, eating lye, ionizing radiation, celiac, HPV 16 and 18, Hot Mate drinking
Esophageal adenocarcinoma
Causes/risk factors: Barrett’s esophagus as result of reflux esophagitis
Symptoms: none early on, dysphagia, odynophagia, anorexia/weight loss, retrosternal pain, cough, hoarseness, bone pain if skeletal metastases
Causes of dysphagia
Benign strictures (peptic acid esophagitis, caustic ingestion)
Malignant stricture
Motility disorder (achalasia, scleroderma)
Esophageal signs
Cachexia
Lymphadenopathy
Hepatomegaly
Fecal occult blood
Diagnosis of esophageal carcinoma
Endoscopy allows for biopsy
Barium swallow
Staging of esophageal cancer
Determinants of survival: depth of invasion, lymph node metastases (distant vs. local), patient factors
Treatment of esophageal cancer
Endoscopic
Surgery: potential for cure; esophagectomy (transthoracic or transhiatal), replacement of esophagus (with stomach, colon, jejunum); mortality is 1-15%
Chemotherapy
Radiation therapy
Palliative: laser, photodynamic, esophageal stent
Gastric cancer
Males more than females
Mean age 68
More in Costa Rica, Japan and less in North America, Africa, India and SE Asia
Etiology: carb-rich diet, high salt, nitrates, alcohol and tobacco maybe, H. pylori, genetics (familial adenomatous polyposis, hereditary non-polyposis coli, E-cadherin mutation)
Symptoms of gastric cancer
None early on
Anorexia, weight loss, epigastric pain, early satiety, meal-induced dyspepsia, abdominal bloating, dysphagia, gastric outlet obstruction, GI bleeding
Occult blood in stool, palpable gastric mass, hepatomegaly, ascites
Treatment for gastric cancer
Early: endoscopic
Local: surgery
Late: chemotherapy, radiation therapy, palliative
Types of pancreatic cancer
Adenocarcinoma
Intraductal papillary mucinous neoplasm (IPMB)
Neuroendocrine (Islet cell tumor)
Cystic neoplasms (serous, mucinous)
Acinar carcinoma
Pancreatic cancer
Almost all die within a year of diagnosis
Risk factors: family history (familial atypical multiple mole melanoma syndrome, BRCA2, Peutz-Jeghers syndrome, hereditary pancreatitis), environmental factors (asbestos, pesticides, dyes), diet (meat and fat), diabetes, older age, male
Typical presentation: weight loss, pain, jaundice, new diagnosis diabetes, pancreatitis, metastatic disease
Note: painless (obstructive) jaundice with palpable gallbladder (Courvoisier’s sign) is cancer in head of pancreas until proven otherwise
Hereditary pancreatitis
Chronic activation of trypsin
Autosomal dominant
Younger patient with pancreatitis for no apparent reason (early progressive fibrosis)
40x risk of pancreatic cancer
Treatment for pancreatic cancer
15-20% resectable (not metastatic, does not involve blood vessels; surgical resection is only treatment associated with cure)
40% metastatic
30-40% locally advanced
5-year survival is 25-35% with pancreatic resection but only 5% with no treatment
Note: most patients present when already have metastatic disease and treatment is difficult; however many patients are not even referred to a surgeon because primary care doctors think pancreatic cancer is not treatable
Survival for pancreatic cancer
Resectable: 10-20 months
Locally advanced: 8-12 months
Metastatic: 3-6 months
Chemotherapy for pancreatic cancer
Chemo is not very effective for pancreatic cancer, but is used (along with resection)
1 year survival for combination chemotherapy is 26-45%
Gemcitabine modestly increases survival compared to 5FU (only prolongs survival 3 weeks though)
Pancreatic intraepithelial neoplasia (PanIN)
Ductal epithelium becomes dysplastic and those (called PanINs) cause pancreatic cancer
PanINs look more “angry” as grade gets higher
Diagnosis of pancreatic cancer
Helical (spiral) CT (best study, gives info on resectability)
Endoscopic ultrasound
PET, MR, MRCP (MR cholangiopancreatography)
ERCP
FNA (percutaneous/EUS)
Laparoscopy
Tumor markers (CA19-9 tells you how far cancer spread)
Candidates for surgical resection of pancreatic cancer
Local disease
No distant metastasis
Regional node involvement OK!
Vascular involvement
Comorbidity
Whipple surgery
Remove entire duodenum
End-to-side pancreatojejunostomy
Pylorus-preserving and non-pylorous-preserving
Adjuvant therapy for pancreatic cancer
Adjuvant therapy is treatment given after “curative” resection (Whipple) with intent to eradicate any remaining tumor with the goal to cure patient or further prolong survival
What kills people with pancreatic cancer?
Systemic recurrent disease is what kills people
However, most people also have local recurrent disease as well
Overview of acid reflux
Chronic condition
Significant morbidity
35% lifetime prevalence
40-50% have monthly symptoms
10-20% have weekly symptoms
5-10% have daily symptoms
Injurious and defensive factors in acid reflux
Injurious factors: acid, potency of refluxate
Defensive factors: acid clearance, mucosal resistance (most important)
Reflux mechanisms
Transient lower esophageal sphincter relaxations (tLESRs): different from swallow-induced relaxation, increased by gastric distension, integrated motor response (crural diaphragm inhibition, esophageal shortening, costal diaphragm contraction), vagally mediated reflex; most mild symptomatic GERD related to tLESRs
Hypotensive lower esophageal sphincter: tonically contracted smooth muscle, reduce LES pressure (gastric distension, foods, smoking), strain induced reflux, free reflux; usually associated with more severe GERD
Hiatal hernia: diaphragm, reduced threshold for tLESRs, “malfunction” of GE barrier (during periods of low LES pressure, during normal swallow LES relaxation, during deep inspiration or straining); severity of esophagitis correlates with size of hernia; usually associated with more severe GERD
Motility disorders and delayed gastric emptying don’t have clear role but some people think they might
Acid clearance of the esophagus
Peristalsis
Acid neutralization by saliva (salivary bicarbonate)
Prolonged clearance in 50% with esophagitis
Prolonged clearance w/hiatal hernia
Gravity assists (so sleeping impairs ability to clear acid)
Development of esophagitis
Just having H+ on top of mucosa is NOT enough to cause acid reflux symptoms!
H+ diffusion into mucosa (usually this involves an injuy)
Cellular acidification and necrosis
Pepsin (zymogen released by chief cells, degrades food proteins) increases mucosal permeability and now H+ can enter
Note: increased gastric acid secretion does not equal esophagitis
Epithelial defense against acid
Pre-epithelial factors: surface mucous and bicarb for pH gradient (poorly developed in the esophagus); not very relevant role
Epithelial factors: tight junctions, lipid rich matrix, Na/H exchanger and Cl/HCO3 exchanger
Post-epithelial factors: blood flow
Gastroesophageal reflux disease (GERD)
Symptoms or mucosal damage from abnormal reflux into esophagus
Esophageal inflammation not required
Pathophysiology is multifactorial
Classic symptoms: heartburn (in retrosternal area), regurgitation (into mouth or hypopharynx), dysphagia (if inflammation or complications)
Atypical symptoms: atypical chest pain, hoarseness, nausea, cough, odynophagia, asthma, globus sensation, recurrent laryngitis, recurrent sore throat, subglottic stenosis, dental enamel loss
Diagnosis of GERD
History: heartburn (pyrosis), regurgitation
Response to empiric trial of therapy (note: don’t need to go beyond this 95% of the time)
Endoscopy (but 50% EGDs are normal)
Radiologic findings
Ambulatory esophageal pH monitoring (this will catch everyone, but is annoying and unncessary so don’t need it if empiric therapy works!)
Endoscopy for esophagitis
Advantages: detection, stratification, management
50% with normal EGD
Interoperator variability (esophagitis grading scheme; LA classification)
For any patient who requires continuous maintenance medical therapy (5 years or more–are looking for Barrett’s esophagus)
EGD is most useful modality to evaluate complicated GERD
Bleeding, dysphagia, unexplained weight loss or significant change in symptoms while on effective therapy
Later age of onset
Double contrast baruim swallow
Granular appearance of mucosa
Thickening of longitudinally oriented esophageal folds
Shallow ulcers and erosions (tiny pooling of barium collections in distal esophagus)
Smooth tapered narrowing (peptic stricture)
