small intestinal pathology - columbia university in … intestinal pathology helen remotti, m.d. cl...
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Small Intestinal Pathology
Helen Remotti, M.D.C l bi U i itColumbia UniversityDepartment of Pathology and Cell [email protected]
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Normal small bowel
Villous/Crypt ratio> 3/1
IEL (intraepithelialIEL (intraepithelial lymphocytes –1 lymphocytes/5 enterocytes
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Celiac Disease
MILD(partial villous
MODERATE(subtotal villous
SEVERE(total villous atrophy)(p
atrophy)(atrophy)
(total villous atrophy)
Villous atrophy – variable degree
Chronic inflammation in lamina propriaChronic inflammation in lamina propria
Increased IELs (intraepithelial lymphocytes)
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Celiac Disease–Celiac DiseaseIntraepithelial lymphocytosis
IELs increased>5 lymph/10 enterocytes>5 lymph/10 enterocytes(NL: 2 lymph/10 enterocytes)
CD3 (T-cell immunostain)
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Celiac Disease (CD)
• Autoimmune disease associated with wheat (gluten) ingestion.S h i di h bd i l i i ht l• Sx: chronic diarrhea, abdominal pain, weight loss, iron deficiency anemia,
• Dx: autoantibodies to gliadin, tissue transglutaminaseDx: autoantibodies to gliadin, tissue transglutaminase (tTG), reticulin, and endomysium.
• CD is strongly associated with HLA-DQ2 and HLA-DQ8 (h 40% f l l ti h tDQ8 (however 40% of general population have at least one of these markers);
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Celiac Disease MechanismCeliac Disease - Mechanism
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Conditions with histologic overlap with Celiac disease.
Increased IEL Villous blunting• H. pylori gastritis• Viral Gastroenteritis
• Common variable immunodeficiency• Viral Gastroenteritis
g
• Protein intolerance• Bacterial overgrowth• Medications
• Protein intolerance• Bacterial overgrowth• Radiation/chemotherapy
• Autoimmune enteropathy
• Tropical sprue
Radiation/chemotherapy• Nutritional deficiencies• Eosinophilic gastroenteritis
R f tTropical sprue• Crohn’s disease
• Refractory sprue• Tropical sprue• Crohn’s disease
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Celiac Disease: Diagnosis
• Documentation of malabsorptionp• Demonstration of villous atrophy and/or
intraepithelial lymphocytosis by smallintraepithelial lymphocytosis by small bowel biopsy
• Improvement of symptoms and mucosal• Improvement of symptoms and mucosal histology after gluten withdrawal
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Non responsive celiac disease (NCD)Non-responsive celiac disease (NCD) (definition)
NCD l k f i iti l t l t f di t (GFD)NCD- lack of initial response to gluten free diet (GFD) or recurrence of symptoms despite maintenance of (GFD)
Diagnostic approach: 1) re-assess initial diagnosis of CD (presence of EMA, tTG antibodies before GFD HLA DQ2 or DQ8 status histology)before GFD, HLA DQ2 or DQ8 status, histology).2) Assess gluten free diet (50% of NCD due to to dietary gluten).3) Exclude other causes of diarrhea (MC,bacterial overgrowth, IBD)
Complications of CD (uncommon)Collagenous sprue (subepithelial collagen); Lymphoma; Carcinomag p ( p g ); y p ;
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Collagenous sprue
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Tropical Sprue
• Post-infectious sprue• Enterotoxic bacteria (E.coli, Hemophilus)• Response to antibiotics• History of foreign travel: (Carribean,
C t l/S th A i C t l/S th Af iCentral/South America, Central/South Africa, India)
• Pathology- patchy distal and proximal smallPathology- patchy distal and proximal small bowel; macrocytic anemia and megalocytosis due to B12 malabsorption.
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Case Study
• 62 y male from Central America had weight loss, diarrhea and macrocytic g , yanemia.
• The blood film showed hypersegmentedThe blood film showed hypersegmented neutrophils and macrocytes. His serum vitamin B12 and folate levels were lowvitamin B12 and folate levels were low.
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I iti l biInitial biopsy
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Lymphangiectasia
• Primary lymphangiectasia: rare congenital disorder; defective lymphatics; normally absorbed nutrients reach the lymphatics butabsorbed nutrients reach the lymphatics but cannot be transported into the circulation.
• Secondary lymphangiectasia: moreSecondary lymphangiectasia: more common; complication of any disorder that causes lymphatic obstruction: enlarged
t i l h d (mesenteric lymph nodes (cancer or inflammatory), heart disease (constrictive pericarditis CHF)pericarditis, CHF)
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Meckel’s DiverticulumMeckel s Diverticulum• Persistence of vitelline duct (connects gut and yolk
sac)- embryologic remnant – true diverticulum (all layers of bowel wall)
• “RULE OF 2s”• RULE OF 2s• 2% of normal population• 2 ft from ileocecal valveo eoceca a e• Approx. 2 cm• 50% have heterotopic mucosa; 2 types – gastric or
pancreatic• Complications: 1) inflammation (mimic appendicitis);
2) bleeding ulcer; 3) small bowel obstruction2) bleeding ulcer; 3) small bowel obstruction.
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Intestinal Ob t tiObstruction
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IntussusceptionIntussusception• Telescoping of one
segment of bowel intosegment of bowel into another.
• Peristalsis propels the invaginated proximal segment farther into the distal segment.g
• Spontaneous in children• Secondary to
intraluminal masses in adults
• Complications:• Complications: obstruction, infarction
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VolvulusVolvulus• Twisting of a loop of• Twisting of a loop of
bowel around its mesenteric base.
• Sigmoid colon, cecum, small intestine, stomach, rarely transverse colon.
• Complications: obstruction, infarction.
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Tumors of the Small Intestine
• Primary Tumors– Benign tumors (often found incidentally atBenign tumors (often found incidentally at
surgery or autopsy)– Malignant tumors (intestinal obstruction or g (
bleeding).• Secondary Tumorsy
– Metastatic carcinoma, melanoma, lymphoma.y p
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Vascular malformations
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Hemangioma - submucosal
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Vascular malformation – small intestine
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Primary malignant neoplasmsPrimary malignant neoplasms of Small Intestine
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Small intestinal neoplasms often have similar signs and symptomsSmall intestinal neoplasms often have similar signs and symptoms.
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C i f th S llCarcinomas of the Small Intestine:
why are they so rare?
• Rapid transit of small bowel contentsS ll b t i l l d• Smaller bacterial load
• Increased lymphoid tissue
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Carcinomas of the Small Intestine
• Most common location: duodenum, periampullary, least common: ileump p y,
• Growth patterns: annular constricting or polypoid massespolypoid masses
• Symptoms: Obstruction and/or bleedingP di i diti C li di• Predisposing conditions: Celiac disease and Crohn’s disease; FAP; HNPCC
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Adenocarcinoma
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Adenocarcinoma
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Small Intestinal tumors – Predisposing conditionsconditions.
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Small Intestinal Carcinomas have similar molecular profile as CRC
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Carcinoid Tumors of the GI Tract
• GI tract is the most common site of i id (67%)carcinoids (67%)
• Small intestine is the most common site of GI carcinoids, followed by rectum and appendix
• Prognosis is SITE and SIZE dependent
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Small intestinal carcinoids
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Terminal ileum- 2.5 cm tumor
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Carcinoid tumor- Ileum
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Ileal carcinoid tumor- “kinking of bowel wall”
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Carcinoid Tumor: Prognosis
• 68% 5 yr survival after resection (as compared to 25-35% for adenocarcinoma).38% 5 i l ft i l t ti• 38% 5 yr survival after incomplete resection
• 21% 5 yr survival with liver mets
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Carcinoid SyndromeCarcinoid Syndrome(small bowel carcinoid tumors)
• Only in patients with liver mets.• Cutaneous flushing, diarrhea, bronchospasm,
i ht h t f ilright heart failure.• Serotonin, bradykinin, substance P,
prostaglandinsprostaglandins.• Elevated 5 HIAA (5 hydroxy-indol-acetic acid
– metabolic product of serotonin) in urine. p )
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GASTROINTESTINAL STROMAL TUMORGASTROINTESTINAL STROMAL TUMOR
Gastrointestinal Stromal Tumors (GISTs) are a distinct group of mesenchymal tumors of the GIdistinct group of mesenchymal tumors of the GI tract.
Most common mesenchymal neoplasms in the GI tract.
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Mesenchymal tumors of the GI tract
GIST (GI stromal tumors)
FibromatosisDesmoid LeiomyosarcomaDesmoid Schwannoma
LeiomyomaMPNST
Granular
NeurofibromaMPNST
Metastatic neoplasmHemangioma
GranularCell tumor
Benign
pLipoma
Benign
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GIST h di i i i hGISTs have a distinctive immunophenotype.
KIT
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KITThe KIT proto-oncogene encodes a type III receptor tyrosine kinase (KIT), the ligand of which isp y ( ), gstem cell factor (SCF).
SCF-KIT interaction is essential for development of : MelanocytesGerm cellsMast cells Interstitial cells of Cajal (ICC) / gut pacemaker cells.
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INTERSTITIAL CELLS OF CAJAL (ICC)INTERSTITIAL CELLS OF CAJAL (ICC)Pacemakers cells of the gut KIT+
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P d GIST hi t iProposed GIST histogenesis
stem cellCD34+KIT+
smooth muscle ICCSMA+ CD34+
KIT+
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KIT mutationsKIT mutations
Loss of function Gain of functionLoss of function(Ws/Ws mice and rats)
Gain of function(Human tumors and animal
models)Defects in:
melanogenesish t i i
models)
Malignant transformation in:hematopoiesisgametogenesisintestinal motility
MelanomaMast cell neoplasms
intestinal motilityGastrointestinal stromal tumors
(Huizinga et al, 1995) (Nagata et al, 1992, Longley et al, 1997).
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KIT receptors bind to Stem Cell Factor (SCF) leading to p ( ) gcross phosphorylation leading to downstream signal
transduction pathways.
KIT
SCF
Mutated KITConstitutive activation of TK activity
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tyrosine kinase inhibitorsKIT wild typeKIT wild type
KIT mutant
SCF
Mutated KITConstitutive activation of TK activity
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GIST Treatment•(STI571 – Tyrosine Kinase Inhibitor)•Gleevec Imatinib (Novartis Basel Switzerland)
GIST Treatment
Gleevec, Imatinib, (Novartis, Basel Switzerland)•Approved for treatment of CML, in which BCR-ABL tyrosine kinase is activated.STI 571 bl k th ATP bi di it f ki•STI 571 blocks the ATP binding site of kinase
domain.•Clinical trials for CML in 1999 showed dramatic response rates 100%. Drug was well tolerated.
1999 in vitro studies with GIST cell lines1999 –in vitro studies with GIST cell lines (D.Tuveson, J. Fletcher) showed that STI571 blocked TK activity.
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STI571-In vivo trial in GIST patient
Fi i i h i GIST d i h STI 1/GlFirst patient with metastatic GIST treated with STI571/Gleevec: 50 yr old female with multiple recurrent, metastatic GIST. Multiple liver mets (>28)p ( )Tumor : KIT ImmunoreactiveDocumented activating mutation in exon 11 of KITProgressive disease despite all available prior therapies:Progressive disease despite all available prior therapies:
Gastrectomy, (Mesna, Adriamycin, Ifosfamide, Dacarbazine), resection of mets, IFN-alpha.
. Joensuu H, et al. NEJM, April 5, 2001, p1052-1056
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STI571-In vivo trial in GIST patient
Tumor mets became metabolically inactive PETon PET scan.
Sho ed marked impro ement in s mptomsShowed marked improvement in symptoms; metastases decreased in size and tumor showed myxoid degeneration.y g
Joensuu H, et al. NEJM, April 5, 2001, p1052-1056.
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First GIST patient treated with STI571/GleevecFirst GIST patient treated with STI571/GleevecFDG-PET scans before and after 4 week treatment
Joensuu H, et al. NEJM, April 5, 2001, p1052-1056.
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PRIMARY GIST
LIVER MET B) before STI571 C)after 4 weeks of STI571J H t l NEJM A il 5 2001 1052 1056Joensuu H, et al. NEJM, April 5, 2001, p1052-1056.
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Aquired STI571/Gleevec resistance inAquired STI571/Gleevec resistance in GISTs
• Majority of patients who initially benefit from tyrosine kinase inhibitors eventually become resistant.
• Median time to progression on imatinib of 22yrs.
• Mechanism of resistance – additional KIT f ff fmutation often affecting binding of drug.
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Metastatic Neoplasms
• Always consider metastatic neoplasms in the small intestine – very commonly y yoccur.
• Think metastatic lesion –if there is noThink metastatic lesion if there is no associated in-situ lesion or if multiple nodules or serosal based nodulesnodules or serosal based nodules present.
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66 y.o. male with 8 cm mass within the wall of the jejunum
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KIT+
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S100+ HMB45+
KIT+ Keratin-
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METASTATIC MELANOMAMETASTATIC MELANOMA
CAUTION: METASTATIC MELANOMA MAY CLINICALLY PRESENT AS A SINGLECLINICALLY PRESENT AS A SINGLE INTRAMURAL MASS IN THE GI TRACT (particularly the small intestine).
MELANOMA CAN SHOW STRONG DIFFUSE KIT IMMUNOREACTIVITY.IMMUNOREACTIVITY.
MALIGNANT KIT+ SPINDLE CELL LESIONS IN THE GI TRACT ARE NOT ALL GISTS!THE GI TRACT ARE NOT ALL GISTS!
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• Questions or Comments…• Please email mePlease email me..
– (all feedback welcome… negative or positive your imput will help improvepositive.. your imput will help improve lectures less for next years medical students…))