PATHOLOGY OF THE STOMACHRobert Stern, M.D. September 23, 2019. Special thanks to Mike Cohen, M.D....
Transcript of PATHOLOGY OF THE STOMACHRobert Stern, M.D. September 23, 2019. Special thanks to Mike Cohen, M.D....
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Robert Stern, M.D.September 23, 2019
Special thanks to Mike Cohen, M.D. and Pier Luigi Di Patre, MD, PhD
PATHOLOGY OF THE STOMACH
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READING
Robbins and Cotran 8th ed. pp. 774-790.
AND
THIS Presentation
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LEARNING OBJECTIVES•Etiology, pathogenesis, morphology and clinical manifestations of different types of acute gastritis, including non-erosive, erosive and hemorrhagic.
•Stress ulcers: in what context they develop.
•Etiology, pathogenesis and manifestations of three types of chronic gastritis: H. Pylori, autoimmune and others (radiation, bile reflux, indwelling tubes, systemic diseases).
•Brief overview of H. pylori and epidemiology of H. Pylori infection.
•H. pylori associated diseases: chronic gastritis, peptic ulcer, gastric adenocarcinoma, gastric lymphoma.
•Diagnosis of H. pylori infection: Urea test, serology, biopsy.
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MORE LEARNING OBJECTIVES•Peptic ulcer disease: Definition, epidemiology, gross and microscopic morphology, clinical manifestations and complications, etiopathogenesis.
•Ménétrier disease.
•Zollinger-Ellison syndrome (gastrinoma).
•Gastric adenocarcinoma: Morphological types (intestinal versus diffuse), epidemiology, molecular pathogenesis, staging and treatment.
•Gastric lymphoma, with emphasis on MALToma.
•Gastrointestinal stromal tumor (GIST): Morphology, pathogenesis, clinical features, treatment with tyrosine kinase inhibitors
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GASTRIC INFLAMMATORY CONDITIONS
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GASTRIC INFLAMMATORY CONDITION TYPESActive or acute gastritisNeutrophils
Chronic (inactive) gastritisPlasma cells Lymphocytes
Chronic active gastritis
GastropathyNon-inflammatory “inflammatory” conditions?
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MUCOSAL DEFENSE
Mucin layer“Unstirred” layer of fluid Neutral pH
Layer of gastric epithelial cells Rapid turnover
Acid/base Acid excreted into the stomach Bicarbonate absorbed into blood vessels
Vessels release substances into to lamina propria Bicarbonate Oxygen Nutrients
Vessels absorb acidProstaglandins
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MUCOSAL DEFENSE MECHANISMS
Protective: Mucus, bicarbonate, regeneration, blood flow, prostaglandins
Damaging: H. pylori, medications, alcohol, tobacco, ischemia, delayed emptying
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Active/Acute Gastritis
Active inflammation versus gastropathy
Active gastritis classically means that acute inflammatory cells (neutrophils) are present. Uncommon without an chronic inflammatory component (chronic/active).
Gastropathy typically is associated with new inflammatory cells Edema Scant acute inflammatory cells Vascular congestion Erosions Hemorrhage Fibrin Reactive epithelial changes
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“ACTIVE/ACUTE GASTRITIS”: CAUSES
Most frequent causes: Helicobacter pylori Drugs (NSAIDs), alcohol
Others: Ingestion of corrosive substances Uremia Radiation Chemotherapy Gastric tubes Bile reflux Major stress: trauma, shock, burns
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DISRUPTION OF PROTECTIVE MECHANISMS
H. pylori - urease secreting with loss of bicarbonate
NSAIDs – COX dependent prostaglandin synthesis (COX-1 versus COX-2)
Age – reduced mucin and bicarbonate
Altitude – reduced oxygen
Harsh chemicals, alcohol, chemotherapy – direct mucosa injury
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STRESS ULCERS (STRESS-RELATED MUCOSAL DISEASE)
Pictures from: “Cushing ulcer: The Eponym and His Own.” Neurosurgery 68:1695–1698, 2011
From Cushing’s original article describing 3 patients who died of perforated ulcer after neurosurgery.Focal hemorrhages and 3 large perforations.
• Shock, burn, head trauma, sepsis– Bleeding or perforation
• Curling ulcers - severe burns: Due to loss of plasma
• Cushing ulcers - closed head injury and increased intracranial pressure– Activation of vagal nuclei
acid secretion• Role of PPI or H2 blockers• RX underlying condition
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ACUTE/ACTIVE GASTRITIS: CLINICAL MANIFESTATIONS
Epigastric discomfort, gnawing/burning pain
Loss of appetite
Nausea, vomiting, bloating
Hematemesis or melena if significant
bleeding present
H. pylori: Often asymptomatic
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NORMAL STOMACH
WikipediaGastrointestinalatlas.com
Endoscopy Histology
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“ACUTE/ACTIVE GASTRITIS”: NON-EROSIVE, EROSIVE, HEMORRHAGIC
Mild acute gastritis
Mild erythema and scattered tiny erosions
Intraepithelial neutrophils
Moderate acute erosive gastritis:Multiple erosions (red spots)
Severe acute hemorrhagic
gastritis
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“ACUTE/ACTIVE GASTRITIS”: Histology
Reactive Gastropathy – scant inflammation, hyperplastic epithelium, vascular ectasia
Erosive Gastropathy – loss of surface epithelium, fibrin deposition along the surface
emedicine.medscape.com
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CHRONIC AND CHRONIC ACTIVE GASTRTIS
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CHRONIC (INACTIVE) GASTRITIS
Helicobacter pylori
Autoimmune gastritis
Other causes: Radiation, chronic bile reflux, indwelling tubes, systemic diseases, idiopathic
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HELICOBACTER PYLORI
Gram-negative, spiral shaped, flagellate, microaerophilic bacteriumPredominately in gastric antrumLives within the mucus layerTransmission: oral-oral, fecal-oralSurvives in the acidic gastric
urease adhesins flagella
Proteases and phospholipases break down mucusVariable virulence, host defense and inflammatory factors
Barry J. Marshall
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H. PYLORI: EPIDEMIOLOGY
Prevalence of H. pylori infection correlates with poverty, household crowding, lack of education, i.e. low socio-economic status
Prevalence increases with age: 50% over age 60, 20% below age 40
In poor countries, infection is acquired in childhood
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H. PYLORI: ASSOCIATED DISEASES
Most infected individuals are asymptomatic (80%)
Diseases associated with H. pylori infection: Chronic (active) gastritis Peptic ulcer Atrophic gastritis Gastric adenocarcinoma Gastric lymphoma
Acquire duodenal ulcer at a rate of 1% per annum
Nearly all patients with duodenal ulcer have H. pylori
Green square: uninfected peopleCircle: total number of infected people
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H. PYLORI: CHRONIC (ACTIVE) GASTRITIS
Endoscopy: Erythema Nodular appearance of mucosa Thickening of rugae
Pathology: Intraepithelial neutrophils Interstitial plasma cells and fewer lymphocytes H. Pylori on the surface (H&E and special stains) Patchy distribution Not commonly seen on intestinal metaplastic or duodenal mucosa
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CHRONIC (ACTIVE) GASTRITS
youtube.comemedicine.medscape.com youtube.com
casereports.bmj.orgresearchgate.net
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H. PYLORI: DIAGNOSIS
Breath urea test
Circulating antibodies (serology)
Esophagogastroduodenoscopy and biopsy
Stool antigen
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H. PYLORI: HISTOLOGICAL IDENTIFICATION
SILVER
MCMULLENGIEMSA
IMMUNOHISTOCHEMISTRY
From: J Clin Pathol, 2000, 53: 756
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H. PYLORI: TREATMENT
Combinations of antibiotics and proton pump inhibitors
Relapses and re-infection can occur
Vaccine – therapeutic and prophylactic (developmental stage)
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AUTOIMMUNE GASTRITIS – 1
Second most frequent form of chronic gastritis
Autoimmune process targeting parietal cells and intrinsic factor: Autoantibodies to parietal cells and IF present early Injury mediated by CD4+lymphocytes, not autoantibodies
Chronic inflammation of mucosa (picture) with mucosal atrophy in body/fundus Antrum and cardia unaffected, in contrast to H. pylori gastritis
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AUTOIMMUNE GASTRITIS
Pathophysiology: Hypochlorydria Compensatory hyperplasia of G-cells in the antrum Carcinoids often develop
Vitamin B12 deficiency: Pernicious anemia (megaloblastic) Neurologic disease Atrophic glossitis
Intestinal metaplasia in atrophic mucosa, leading to risk of adenocarcinoma
Disease develops over decades
Diagnosis made around 60 Intestinal metaplasia:Note goblet cells
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Mucosal Arophy and Intestinal Metaplasia
Long standing gastritis Autoimmune gastritis Helicobacter pylori
Loss of parietal cell mass
Intestinal metaplasia (goblet cells)
Increased risk of adenocarcinoma Possibly due to bacterial overgrowth Carcinogenic nitrosamines
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Mucosal Arophy and Intestinal Metaplasia
Webpathology.com
Unremarkable gastric fundic mucosa
Early intestinal metaplasia
Severe atrophic gastritis
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CHRONIC GASTRITIS: OTHER TYPES
Eosinophilic gastritis Allergic reaction (cow’s milk, soy protein) Immune disorders
Lymphocytic gastritis Associated with celiac sprue
Granulomatous gastritis Infection Sarcoidosis Crohn disease Idiopathic
npplweb.com
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Mucosal Arophy and Intestinal Metaplasia
Long standing gastritis Autoimmune gastritis Helicobacter pylori
Loss of parietal cell mass
Intestinal metaplasia (goblet cells)
Increased risk of adenocarcinoma Possibly due to bacterial overgrowth Carcinogenic nitrosamines
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PEPTIC ULCER DISEASE
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PEPTIC ULCER DISEASE (PUD)
Lifetime risk of developing PUD is 10% for men, 4% for women
Estimated number of people with active PUD: 4 million
Duodenal:Gastric PUD is 4:1
H. pylori associated with 65% gastric and near 100% duodenal disease
From The Helicobacter Foundation
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PEPTIC ULCER
• Gross features:– Solitary, well-circumscribed
mucosal defect– Flat margins and smooth base– Depth up to muscularis propria
• Histology: 4 layers– 1) Superficial fibrinous exudate,
2) acute and chronic inflammation, 3) granulation tissue, 4) fibrosis
• Healing leads to scar
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PEPTIC ULCER VERSUS ULCERATED CANCER
Malignant transformation of peptic ulcers is rare
Gastric cancer often presents as an ulcerated mass
“Malignant ulcers” have heaped-up margins and irregular base
Gastric ulcers should always be biopsied to rule out cancer
Gastric peptic ulcer(Medscape)
Ulcerated gastric carcinoma(http://web2.airmail.net/uthman/index.html)
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PEPTIC ULCER VERSUS ULCERATED CANCER
Above – Peptic ulcer. Note adjacent benign mucosa and base with exudate, granulation tissue and benign gastric wall
Right – Ulcerated gastric cancer. Note minimal exudate, no granulation tissue and base of malignant glands
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PEPTIC ULCER: LOCATION
• Gastric ulcers along lesser curvature at junction between body and antrum
• Duodenal ulcers located in the duodenal bulb within a few cm from pylorus on anterior surface
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PEPTIC ULCER: CAUSES
In total (duodenal + gastric ulcers) 70% of patients with PUD have H. pylori Fewer than 20% of people with H. pylori develop
PUD
Other etiologic factors:
NSAIDS and corticosteroids: Inhibit prostaglandin synthesis
Smoking: Reduces mucosal blood flow
Psychological stress: Increases acid production
Genetic predisposition
Cirrhosis, COPD, chronic renal failure, hyperparathyroidism: Unclear mechanisms
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PEPTIC ULCER: CLINICAL MANIFESTATIONS
Epigastric gnawing, burning pain related to mealtimes
Onset of pain in relation to meals depends on location, duodenal versus gastric: DU: 30 min to 3 hour after meal, relieved by antacids or food GU: immediately before or during meal, precipitated by food
Dyspeptic symptoms: Bloating, nausea, vomiting
Weight: Loss in gastric ulcers. Gain in duodenal ulcers
Hematemesis, melena: Anemia
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PEPTIC ULCER: COMPLICATIONS
• Perforation: Acute, life-threatening• Bleeding:
– From small vessels: Chronic bleeding, iron-deficiency anemia
– From large vessels: Melena, hematemesis, shock
• Gastric outlet obstruction: Ulcers in distal stomach and duodenal bulb may cause reversible obstruction by edema or fixed stenosis by scarring
• Penetration into adjacent organs, liver and pancreas
From Robbins. Acute gastric perforation
Free air under the diagram due to perforated gastric ulcer
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OTHER GASTRIC CONDITIONS
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MÉNÉTRIER DISEASE (HYPERPLASTIC HYPERSECRETORY GASTROPATHY)
Due to hyperproduction of TGF-α
Hyperplasia of foveolar epithelium in body/fundus
Thickening of rugae, with cerebriform appearance
Excessive protein secretion leading to protein-losing enteropathy
Weight loss, diarrhea, edema
Increased risk of adenocarcinoma
Supportive treatment
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ZOLLINGER-ELLISON SYNDROME
• Caused by a gastrinoma,gastrin-secreting neuroendocrine tumor
• Usually in the pancreas or small intestine
• Leads to hyperplasia of parietal cells and hyperchlorydria
• Multiple gastric and duodenal ulcers, chronic diarrhea
• Two thirds of gastrinomas are malignant but slow-growing
• 25% associated with MEN I
Gastrinoma: Uniform epithelial cells with round nuclei and finely dispersed chromatin (“salt-
and-pepper”)
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TUMOR NEOPLASMS
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NEOPLASTIC PATHOLOGY OF STOMACH
• Polyps• Adenocarcinoma• Lymphoma• Gastrointestinal
stromal tumor (GIST)
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GASTRIC POLYPS: 3 TYPES
A. Hyperplastic/inflammatory: Most common, chronic gastritis, unlikely malignant transformation
B. Fundic type: Found in FAP and PPI treatment; no malignant potential
C. Adenomatous: Neoplastic type, with dysplasia (low, high), malignant potential related to degree of dysplasia and size
A
B
C
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GASTRIC ADENOCARCINOMA90% of gastric malignant tumors
Initial symptoms: Non-specific dyspepsia
Advanced stage: Weight loss, anemia
Incidence varies widely throughout the world
Screening is cost-effective in high-incidence countries
Incidence in Western countries dropped in 20th century
Migrants acquire the risk of country to where they move
International Agency for Research on Cancer . Data on the annual incidence of gastric cancer in selected countries according to gender. From Fuchs, CS, Mayer, RJ, N Engl J Med 1995; 333:32.
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ADENOCARCINOMA: 2 TYPESIntestinal type Diffuse type
Ulcerated mass Leather bottle
Gland formation Signet-ring cells
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ADENOCARCINOMA: TWO TYPES
Intestinal type (90%)
Bulky, ulcerated tumors
Glandular structures
Associated with known risk factors: H. pylori, atrophic gastritis, intestinal metaplasia/dysplasia, adenomatous polyps
Predominates in high-risk areas
Diffuse type (10%)
Diffusely infiltrative, with desmoplastic reaction: Linitis plastica
Non-cohesive signet-ring cells
Not associated with H. pylori or other risk factors
Uniform incidence across countries
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GASTRIC CARCINOMA: HISTOLOGY
Intestinal Type Diffuse Type
Gut Volume 53, Issue 6 pathologyoutlines.com
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ADENOCARCINOMA: EPIDEMIOLOGY
Epidemiology supports strong role of environmental factors
H. pylori found in 2/3 of cases
Other risk factors: Smoking and alcohol, atrophic (autoimmune) gastritis, low socioeconomic status
Dietary carcinogens: N-nitroso compounds, benzopyrene
Protective factors: Vegetables, citrus fruits containing Vitamin C and E, beta-carotene
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ADENOCARCINOMA: MOLECULAR PATHOGENESIS
Intestinal and diffuse types follow different pathogenetic pathways
Diffuse type: CDH1 mutations with loss of E-cadherin function (cell adhesion) key event in diffuse type
Intestinal type: Increased risk in FAP, mutations of β-catenin(intracellular signal transducer involved in growth regulation), p53 mutations, polymorphisms of pro-inflammatory genes
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GASTRIC ADENOCARCINOMA: STAGING AND TREATMENT
Stage most important prognostic factor: Depth of invasion and nodal/distant mets
Early stages, limited to mucosa and submucosa : 90% 5-year survival
Early gastric cancer can be treated with endoscopic mucosal resection
Advanced stages: 20% 5-year survival
Overall 5-year survival rate: <30%
Treatment: Surgery plus combination of radiation and chemotherapy
Trastuzumab (Herceptin), a monoclonal antibody that inactivates HER2/neu receptors, approved in 2010 for treatment of gastric adenocarcinoma
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GASTRIC LYMPHOMA
GI tract is the most frequent site of extranodal lymphomas
Lymphoma represents 5% of gastric malignant tumors
Majority of lymphomas are derived from Mucosa-Associated Lymphatic Tissue (MALT) and are thus called MALTomas It’s an extranodal marginal-cell lymphoma
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MALTOMAS: PATHOGENESIS
Arise at sites of chronic inflammation, most commonly due to H. pylori
EARLY STAGE: Reversible Antigen-dependent activation of NF-κB, a growth-promoting transcription factor,
through increased expression of MLT and BCL-10 genes Antibiotic treatment of H. pylori infection results in remission of MALToma
LATE STAGE: Irreversible Specific translocations lead to constitutive activation of NF-κB MALTomas will not regress with antibiotic treatment
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MALTOMAS: MORPHOLOGY
MALTomas are B-cell lymphomas
Dense lymphocytic infiltrate expanding the lamina propria
Neoplastic lymphocytes surround and infiltrate glands producing typical lymphoepithelial lesions
Slow-growing, eventually transform into high-grade lymphomas (diffuse large B-cell lymphoma)
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GASTRO-INTESTINAL STROMAL TUMOR (GIST)
GIST is the most common non-epithelial tumor of the stomach
Other non-epithelial tumors: leiomyoma, schwannoma
All 3 look similar histologically: Spindle-cell tumors
GIST occurs in the 50s-60s
Children with GIST usually have Carney triad (gastric GIST, paraganglioma, pulmonary chondroma) Don’t make confusion with Carney Syndrome, autosomal dominant, cardiac
myxoma, skin hyperpigmentation, endocrine overactivity
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GIST: PATHOGENESIS
GIST originates from interstitial cells of Cajal, pacemaker cells in the muscularis propria
Two genes are mutated in GIST c-KIT (AKA CD117), a tyrosine kinase receptor for stem cell factor, in 90% of cases
OR PDGFRA: Platelet-derived growth factor receptor α, a tyrosine kinase related to c-KIT, in 8% of cases
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GIST: MORPHOLOGY
• Solitary, well-demarcated tumor covered by intact or ulcerated mucosa
• Can grow to large size• Histologically, most tumors are
composed of spindle-shaped cells arranged in long fascicles
• Markers– CD34– CD 117 (c-Kit)– DOG1
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DD: GIST, LEIOMYOMA, SCHWANNOMA
GIST: positive for CD-117 Leiomyoma: Positive for smooth muscle actin
Schwannoma:Positive for S-100
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GIST: CLINICAL
Anemia is the most frequent presenting sign, due to mucosal ulceration and bleeding
Vague abdominal pain, feeling of fullness, vomiting
Late stage: Metastases to the liver and peritoneal cavity
Prognosis: Size, mitoses, location
Treatment: Surgical removal, commonly by laparoscopic surgery
For unresectable and metastatic tumors, treatment with selective tyrosine kinase inhibitors: Imatinib (Gleevec), sunitinib (Sutent)
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COMING NEXT WEEK:
Let’s make Gallbladde
rsGREAT again!
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