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Background • Colorectal cancer is the second most commonly diagnosed cancer world wide in women, third in men • Third leading cause of cancer deaths in the U.S. • The lifetime incidence for patients at average risk is 5 percent, with 90 percent of cases occurring after age 50. • Lifetime probability: 1 in 20 (men),1 in 22 (women) • Both the incidence of and mortality rates from CRC have been declining in the US
Pathology • Adenocarcinoma (90-95% of CRC) Special types within adenoca group: • Mucinousadenocarcinoma (10% of adenoca) • Large quantities of extracellular mucus • Tendency to spread within the peritoneum • Lower sensitivity for PET-CT • Signet-ring cell carcinoma (1% of adenoca) • Large quantities of intracellular mucinous • Probably more aggressive • Other • Squamous cell (anal cancer) • Small cell, carcinoid tumors, adenosquamous, GIST, sarcomas, lymphomas etc.
Pathology - grading • Histologic grade • G1 – well differentiated • G2 – moderately differentiated • G3 – poorly differentiated • Correlates with aggressiveness of the disease
Risk Factors For Colorectal Cancer • Increasing age (highest in people older than 85 years) • Diet: red meet, highly processed meet • High fat, high protein, low fiber diet • High consumption of alcohol • Cigarette smoking • Obesity • Lack of physical activity • DM type II or insulin ressistance
Who is at high risk? • Personal history of: • Colorectal cancer • Adenomatous polyps • Inflammatory bowel disease (UC or Crohn’s) • Family History of: • Colorectal cancer • Polyps • Hereditary Colorectal Cancer Syndromes: • Familial adenomatous polyposis (FAP) • Hereditary non-polyposis colon cancer (HNPCC)
Pathogenesis • Inherited and acquired genetic defects (Adenomas to dysplasia and carcinoma) • Progression takes at least 10 years on average • Most colorectal polyps are adenomatous(2/3) • The risk of CRC increases with adenoma size, number, and histology (villous adenomas>tubular adenomas) • Removal of adenomatous polyps prevents cancer
Sporadic Cancer • All cancer arises from changes in genes…. • But NOT all cancer is inherited • Most CRC is sporadic~75 – 80% (due to acquired mutations throughout a person’s lifetime) • Sporadic cancer generally has a later onset
Proportion of Hereditary CRC Familial ~15% Hereditary ~5% Lynch syndrome ~ 2-5% FAP ~ <1% Sporadic 80%
Compared to sporadic cancer people with hereditary cancer have… • A higher risk of developing cancer • A younger age of onset of cancer • Generally < 50 years of age • Multiple primary cancers • Generally have a family history of cancer
Hereditary Colorectal Cancer Two common syndromes: • Lynch syndrome • Also known as Hereditary Non Polyposis Colorectal Cancer or HNPCC • ~2 - 5% of colorectal cancer • Prevalence of 1 in 200 - 2,000 • Familial Adenomatous Polyposis (FAP) • <1% of colorectal cancer • Prevalence of 1 in 8,000 – 14,000 • Autosomal dominant inheritance
Lynch syndrome (HNPCC) • Lynch syndrome is genetically heterogeneous • Clinical testing available for 4 genes: MLH1 & MSH2 (most common), MSH6 & PMS2 • Characterized by: • Earlier onset than sporadic cancer • More aggressive, proximal, right sided tumours • Risk for extra-colonic tumours • Distinct tumour pathology
Familial Adenomatous Polyposis • Chromosome 5, APC gene • Characterized by: • Early onset • >100 adenomatous polyps • Variant form: • Attenuated FAP may occur with >10 but <100 polyps.
Familial Adenomatous Polyposis • Colorectal adenomatous polyps begin to appear at an average age of 16 years (range 7-36 years) • Average age at diagnosis: 34-43 years, when >95% have polyps
Familial Adenomatous Polyposis • ~50-90% develop small bowel polyps • lifetime risk of small bowel malignancy is 4-12% • ~50% develop gastric polyps • ~10% gastric cancer • ~10% develop desmoid tumours
Colonoscopy • Colonoscopy permits endoscopic evaluation of the entire colorectum. • Dietary restrictions and full cathartic preparation are required prior to the procedure. • In contrast to other endorsed screening options, therapeutic polypectomy can be completed during the baseline procedure. • Sigmodoscopy – max to splenic flexure (60 cm)
Screening tests - imaging • Double contrast Barium Enema (DCBE): detects only 50% of adenomas larger than1.0 cm and 39% of allpolyps. Retrospective studies have found that DCBE may miss 15-22% of CRC • CT colonography (CTC) – „virtualcolonoskopy” • Abnormal results need to be followed up by colonoscopy for excision and tissue diagnosis, or, for smaller lesions, surveillance with CTC • Flat adenomas may have greater malignant potential than polypoid lesions and are more likely to be missed on CTC than colonoscopy
Screening tests – stool based • FOBT : guaiac method • It is not a good test for the detection of polyps, which usually do not bleed. • 3 consecutive stool specimens • Fecal immunochemical test (FIT): • Sensitivities of FIT is 2-3x higher than gFOBT • more specific than guaiac tests because they respond only to human globin and do not detect foods with peroxidase activity. • fewer stool samples (1-2); automated analysis. • Stool DNA: gene amplification technique • detection of low frequency mutations with increased sensitivity for advanced adenomas, with testing for hemoglobin and for patterns of DNA methylation • More sensitive than FIT. More false positives (up to 10%).
Guidelines-Average Risk: American Cancer Society 2008 Begin Screening at Age 50; discontinue when the individual's estimated life expectancy is less than 10 years.
Guidelines-USPTF (US Preventive Services Task Force) 2008 • Three screening options for adults age 50 to 75 years: based on systematic literature review and a simulation decision model • Annual sensitive gFOBT or FIT • Flexible sigmoidoscopy every five years, with sensitive FOBT every three years • Colonoscopy every 10 years • The task force found insufficient evidence of harms and benefit for DCBE, CTC or stool DNA testing.
Guidelines • American College of Gastroenterology 2008- guidelines recommend a "preferred" strategy, prioritizing options listed in the ACS-MSTF guidelines • colonoscopy as the preferred screening/prevention test • FIT as the preferred screening/detection test for patients who decline cancer prevention tests • Additionally, the ACG recommends initiating screening at age 45, rather than 50, for African Americans • National Comprehensive Cancer Network consensus guidelines2013 • colonoscopy every 10 years, when available, as the preferred screening strategy. • alternatives are annual stool testing with guaiac or immunochemical reagent or sigmoidoscopy every five years with or without annual stool testing.
Colonoscopy at age 40 years • Family history contributes to 30% to 35% of all colorectal cancer cases. • Several hereditary cancer syndromes (eg. familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer syndrome) are associated with significantly increased risks for colorectal neoplasia and other malignancies. • Nonsyndromicfamily histories are also associated with increased colorectal cancer risk. • The 2012 American College of Physicians Guidance Statement on colorectal cancer screening recommends initiation of screening in high-risk patients at age 40 years, OR 10 years younger than the earliest colon cancer diagnosis in the family, whichever is earlier. • In the absence of gastrointestinal symptoms, colonoscopy now is not indicated as colon cancer screening can be postponed until age 40 years.
Clinical manifestations • Abdominal pain • Blood in stool • Melena (menatochezia) • Occult blood in stool • Microcytic anemia • Change in bowel habits • Palpable mass • Obstructive symptoms • Nausea, vomiting • Small-caliber (pencil-size) stools • Fatigue • Anorexia
Diagnosis Histopatology • Tissue material obtained in colonoscopy • Biopsy of metastatic lesion • Cytology (e.g. ascites fluid)
Diagnosis Imaging • CT/MRI - chest, abdoment, pelvis • US - abdomen, pelvis • TRUS – rectal cancer • X-ray chest • Bone scan • PET-CT
Diagnosis Laboratory workup – tumor markers • CEA – carcinoembryonic antigen • Membrane glycoprotein • Normal level in adults – up to 5 ng/ml (higher in smokers) • Elevation of CEA depending on cancer stage: • Stage I- 3% • Stage II- 25% • Stage III - 45% • Stage IV - 65% • Elevation occurs in other malignancies and some benign conditions • Other markers, e.g. Ca 19-9
Colorectal ca managemement - overview Diagnosis & Staging Colon Rectum Neoadjuvant CRTH Surgery Surgery Adjuvant CTH Follow-up
Treatment of Colon Cancer (local and locoregional spread) No adjuvant chemotherapy T1-T3N0M0 SURVEILLANCE T4N0M0, no high-risk features No adjuvant chemotherapy T4N0M0 high-risk features:grade 3-4, lymphovascular invasion, bowel obstruction, <12 lymph nodes examined, perforation, +margins Consider adjuvant chemotherapy Adjuvamt chemotherapy (6 months) T any N1-3M0