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Colon Neoplasia VALERIE P. BAUER, MD DIVISION OF COLON AND RECTAL SURGERY ASSISTANT PROFESSOR DEPARTMENT OF SURGERY UTMB GALVESTON JUNE 8, 2011 Epidemiology COMMON INCREASING INCIDENCE DECREASING MORTALITY Epidemiology Third most common diagnosed cancer and cause of cancer death annually 1 million people develop CRC annually 150,000 cases will be diagnosed in US Probability of individual developing CRC in US is %6 over a lifetime Population risk factors Age Ethnicity Race Socioeconomic status Etiology AGE DIETARY ENVIRONMENTAL PREDISPOSING MEDICAL CONDITIONS: PRIOR HISTORY COLON CANCER OR POLYPS INFLAMMATORY GENETIC Dietary Risk Factors for CRC Saturated animal fat Red meat High in iron- a pro-oxidant May increase free radicals that damage mucosa Charbroiled meat contains aromatic hydrocarbons Increasing RM consumption by 3.5 oz/ day is associated with 1217% increased risk of CRC Fruit and vegetables Contain anti-oxidants Studies show no association between high fruit and vegetable consumption and risk reduction for CRC Dietary Risk Factors for CRC Fiber Conflicting data Increases intestinal transit, decreases exposure to carcinogens May dilute or absorb carcinogens Beneficial effect on colon- not rectum Prostate, Lung, Colorectal, and Ovarian Screening Trial European Prospective Investigation into Cancer and Nutrition Calcium Binds and precipitates bile salts Beneficial in two randomized double blind placebo controlled trials 1200mg/ day for 4 years 2000mg/ day 3 years Dietary Risk Factors for CRC Folate (Vitamin B) Normal DNA methylation Folate deficiency may disrupt DNA synthesis repair or loss of control of proto-oncogene activity High intake reduces the risk of CRC 1998 FDA required folate supplementation of flour, cereals, and grain products Alcohol Increased risk for consumption o f 2 or more drinks a day Environmental Smoking Two to three fold increase of adenoma risk in smokers Defined significant risk as smoking greater than 20 cigarettes for 35-40 years Mechanism Generates replication errors DNA mismatch repair genes Predisposing Medical Conditions Inflammatory Bowel Disease Ulcerative Colitis 2% risk at 10 years/ 8% at 20 years/ 18% at 30 years Crohn’s Disease Cholecystectomy Bile salt irritation Increased risk for proximal small bowel and colon malignancy Ureterosigmoidostomy Ureterosigmoid anastomosis at risk 26 year latency period About 25% will develop neoplasia Radiation Acromegaly Genetic Hereditary Syndromes Familial Adenomatous Polyposis Hereditary Non-Polyposis Colorectal Cancer Others Peutz Jehger’s Syndrome Family History First degree relative with CRC or adenoma Molecular Basis of CRC ALTERATIONS IN REGULATORY MECHANISM MUTATIONS TRANSFORMATION Alterations in Regulatory Mechanisms Six basic changes 1. Self sufficiency in growth signals 2. Insensitivity to anti-growth signals 3. Evading apoptosis 4. Limitless potential for cell replication 5. Sustained angiogenesis 6. Development of ability to invade and metastasize Genetic Mutations Oncogenes K-ras most frequently mutated gene in CRC Involved in transduction of exogenous growth signals Tumor suppressor genes Inhibit cellular proliferation or promote apoptosis Both alleles must be inactivated: Two Hit Theory APC gene mutation Adenoma to cancer pathway Found in 75% of sporadic cases of CRC Causes hyperproliferation Adenoma to Carcinoma Sequence Normal epithelium Hyperproliferative epithelium APC mutation K-ras mutation Adenoma DCC Carcinoma P53 mutations Colon Cancer Screening AVERAGE RISK PERSONAL HISTORY OF ADENOMA OR CRC FAMILY HISTORY OF ADENOMA OR CRC HNPCC FAP IBD Average Risk Who is average risk? No family or personal history of CRC No symptoms to suggest CRC No unexplained anemia No IBD Recommendations: Begin at age 50 FOBT annually Flex sig every 5 years FOBT and flex sig every 5 years Air contrast BE every 5-10 years 15-25% with negative results harbor neoplasia in proximal colon Detects 50-80% stage I and II adenocarcinoma Colonoscopy every 10 years GOLD STANDARD High Risk: Personal History Adenoma or CRC Surveillance Colonoscopy is Test of Choice* Prior adenoma > 3 adenomas or > 1 large adenoma or high risk lesion calls for repeat within 6 to 12 months 1-2 small adenomas- repeat in 3-5 years Prior CRC Post resection colonoscopy 1 year after surgery and every year thereafter until colon is cleared Followed by colonoscopy every 3-5 years thereafter Family History Adenoma or CRC For patients with first degree relatives diagnosed with CRC: Screening colonoscopy at age 40, or 10 years before the age of diagnosis of the affected relative HNPCC Autosomal dominant inherited disorder Mutation in MMR genes (genes that code for proteins responsible for correcting errors during DNA replication) Patients develop CRC between age 40 to 50 Most tumors are proximal to splenic flexure Extra-colonic tumors are common Amsterdam Criteria 3 family members affected by CRC or HNPCC extra-colonic cancer 2 generations with one member being a first degree relative of the other 1 having cancer diagnosis before age 50 HNPCC Screening colonoscopy Begins at age 20-25 Repeat every 1-3 years FAP Autosomal dominant Hundred and thousands of polyps Cancer before age 40 Colonoscopy Puberty Repeat every 1-2 years Increased risk for neoplasia 7-8 IBD years after diagnosis for pancolitis and 12-15 years after dx left colitis Screening colonoscopy 7-8 years after initial diagnosis and every 1-2 years thereafter with multiple biopsies to detect dysplasia 12-15 years for left sided colitis and ever 1-2 years thereafter Colonoscopy Barium Enema Pedunculated Polyp VA study Flat Nonpolypoid Polyp Prevalence 9% Smaller more aggressive polyp Formerly a eastern polyp Best seen after training High definition Narrow band imaging Chromoendoscopy Colon Cancer Evaluation and Staging CLINICAL PRESENTATION STAGING AND PROGNOSTIC FACTORS HISTOLOGIC FACTORS SPREADING PATTERNS Clinical Presentation Symptomatic patients Abdominal pain= MC Vague and non-specific Poorly localized Changes in bowel habits Depends on the side of the lesion Possibilities Pencil thin stool Mucus in BM Rectal bleeding 17.5% patients had colorectal neoplasm in one series 570 patients 50 years or younger undergoing colonoscopy for bleeding Occult blood in the stool Preoperative Preparation Evaluate operative risks Nutrition Co-morbidities (CAD, COPD, DM, Steroids) Localize and confirm tumor Review colonoscopy Pathology Radiography Stage CT CAP w/ oral and iv contrast CEA Bowel Prep Controversial No one likes operating in stool Staging Outdated Dukes A- Cancer limited to bowel wall B- Cancer extends to extracolonic tissue C- Cancer with regional lymph node metastasis Current Staging System TNM Staging: TNM • Tumor T1- Into submucosa T2- Into muscularis propria T3- Through bowel wall T4- Adjacent structures Nodes o N1- 1-3 nodes positive o N2- 4 or more positive Metastasis M0- no metastasis M1- Metastasis Stage I Any T1 or T2, N0, M0 Stage II Any T3 or T4, N0, M0 Stage III A- T1 or 2, N1, M0 B- T3 or 4, N1, M0 C- Any T, N2, M0 Stage IV Histologic Factors Histologic Grade Well/ moderately/ poorly differentiated Mucin Production Signet-cell Low curative resection rate Mean survival 16 months Venous Invasion Perineural Invasion Lymph Node Involvement Most important prognostic indicator Need 13 or more for accurate staging CEA Correlates with metastatic disease > 15 mg/ml predicts increased risk of metastasis in otherwise curable colon cancer Spreading Patterns Spreading Patterns Intramural Spread Rarely spreads this way Extent of average spread is 2cm Basis behind 5 cm margin Transmural Spread En-block resection indicated for cure Margins 5cm proximal and distal margin High ligation of primary feeding vessel Radial Margins Becomes an issue in rectal cancer Pelvic Structures Spreading Patters Lymphatic MC mechanism for metastatic disease Causes metastatic liver disease T1- 9% risk of positive LN T2- 25% risk T3- 45% risk Hematogenous Bypass liver and goes to systemic circulation Explains lung mets in colon cancer Synchronous 6% or less will have synchronous CRC Think HNPCC Give TAC Distant Liver Lung Surgical Management PREOPERATIVE PREPARATION REVIEW OF SURGICAL OPTIONS Surgical Options Right Colectomy Lesion located in cecum/ ascending colon Extended Right Colectomy Lesion located in the transverse colon (hepatic flexure to splenic flexure Left Colectomy Lesion in descending colon Sigmoid Colectomy Total Abdominal Colectomy Ileorectal Anastomosis versus Total Proctocolectomy Ileal Pouch Anal Anastomosis HNPCC Attenuated FAP/ FAP Metachronous colon cancers Distal obstruction with unknown proximal status