Premalignant states n Tubular GI Tract: 1. Esophagus – Barrett’s epithelium 1. Esophagus – Barrett’s epithelium 2. Stomach – dysplasia, IM due to 2. Stomach – dysplasia, IM due to atrophic gastritis or H. pylori atrophic gastritis or H. pylori 3. Small bowel – celiac & (T-cell) lymphoma 3. Small bowel – celiac & (T-cell) lymphoma 4. Colon – adenomatous polyp, 4. Colon – adenomatous polyp, dysplasia in UC dysplasia in UC 5. Bile ducts – PSC and cholangiocarcinoma 5. Bile ducts – PSC and cholangiocarcinoma n Solid abdominal organ 1. Liver – chronic hepatitis & HCC 1. Liver – chronic hepatitis & HCC 2. Pancreas – Chronic pancreatitis & CA 2. Pancreas – Chronic pancreatitis & CA

1. Esophagus - squamous cell epithelium Pathology:*Esophagitis *Barrett’s epithelium *Dysplasia*Adenocarcinoma

Clinical Correlate - Esophagitis n Reflux esophagitis n Epigastric and chest pain n Regurgitation of acid n Night choking n Laryngitis n Bronchial asthma

2. Stomach - columnar epithelium Pathology: *Antral gastritis due to *Antral gastritis due to Helicobacter pylori Helicobacter pylori *Atrophy and intestinal metaplasia *Atrophy and intestinal metaplasia *Adenocarcinoma *Adenocarcinoma

H. pylori and gastric cancer The histological cascade Normal mucosa Chronic active gastritis Atrophy (Intestinal metaplasia (type I/ II/ III) Dysplasia Gastric cancer Correa et al 1986 Peek & Blaser 2002 H.pylori P53 mutation (30-50%) High expression of IL-1  cag island RAS mutation (10%) Loss of DCC (20-60%)

3. Small bowel - columnar epithelium with villi Pathology: *Villous atrophy - celiac *Lymphocyte proliferation *Lymphoma

Clinical correlates - celiac n Gluten associated enteropathy n Diarrhea n Weight loss n Malabsorption n Malnutrition n Nutrient deficiency n Anemia

4. Colon - columnar epithelium without villi Pathology: *Non-specific inflammation - ulcerative colitis * Dysplasia, DALM *Adenocarcinoma

Clinical correlates - Ulcerative colitis n Inflammation of the colonic mucosa n Bloody diarrhea n Abdominal pain n Weight loss n Anemia n Hypoalbuminemia n Complication - Adenocarcinoma

UC-associated CRC carcinogenesis Sohn (Toronto), Cancer Res 2001;61:6912 n Beta2-microglobulin & IL2 deficient mice spontaneously develop UC and CRC n 11 CRC: Apc mutation – 11 (67 mutations) Apc mutation – 11 (67 mutations) p53 mutation – 6 (7 mutations) p53 mutation – 6 (7 mutations)

Candidate genes for UC carcinogenesis Uthoff (Louisville), Int J Oncol 2001;19:803 n Longstanding UC – high risk of malignant transformation n Nucleic acid arrays different human gene transcripts Activated genes in UC but not in CD: n Secreted apoptosis-related protein 1 = Sarp1 n Frizzled = fz = Sarp1 compatible fz receptor n Disheveled = dv1 Proteins involved in the Wingless-type (Wnt)/beta-catenin signaling pathway

UC induced in mice by dextran sulfate sodium, p53 and p21 expression in neoplasms Takesue (Japan), J Exp Clin Cancer Res 2001;20:413 n 40 mice, DSS colitis, sacrified after 21 days n Tumors in 13/33 (39.4%) n Overexpression of p53: 4/8 invasive CRC, 2/3 HGD, 2/6 LGD n Overexpression of p21: 1/8 invasive CRC

Preventive effect of sulphasalazine on carcinogenesis in mice with UC Suzuki (Japan), In Vivo 2000;14:463 n Repeated mucosal necrosis-regeneration sequence in UC induced 3% DSS led to carcinogenesis in azoxymethane-pretreated mice n Additive sulphasalazine reduced the tumorous regions with HGD n Glands regeneration – growth factors – tumor promotion? n Inflammatory factors may protect against dysplasia? (developed in atrophic areas with no inflammation)

5. Liver - parenchyma of a solid organ Pathology: *Infection - inflammation - hepatitis C inflammation - hepatitis C *Hepatocellular carcinoma (hepatoma)

Clinical correlates - hepatitis n Viral infection of the liver n Elevated liver enzymes n Jaundice n Acute liver failure n Liver cirrhosis n GI bleeding, ascites, hypersplenism n Hepatocellular carcinoma