COLORECTAL CANCER

1. COLORECTAL CANCER

2. COLORETAL CANCER • NARUEMON

4. INCIDENCE • Relatively unchanged during the past 30 years while mortility rate has decreased,particularly in females • U.S.146,940 new cases occurred in 2004 ,and 56,730 deaths were due to colorectal cancer • Colorectal cancer generally occureds in individuals >= 50 years

5. Polypsandmolecularpathogenesis • Most colorectal cancers regardless of etiology,arise from adenomatous polyps • A polyp protrusion from the mucosal surface classified pathologically as -a nonneoplastic hamartoma(juvenile polyp) -a hyperplastic mucosal proliferation (hyperplastic polyp) -an adenomatous polyp

6. only adenomas are clearly premalignant and only a minority of such lesions ever develop into cancer

7. Populations-screening studies and autopsy surveys : adenomatous polyps may be found in the colons of >30% of middle aged or elderly people <1% of polyp ever become malignant • Occult blood found<5% of patient with such lesions

8. Point mutations in the K-ras protooncogene;hypomethylation of DNA leading to gene activation;loss of DNA at the site of a tumor-suppressor gene( the adenomatous polyposis coli (APC)gene) on the long arm of chromosome 5 (5q21)

9. Allelic loss at the site of a tumor suppressor gene located on chromosome 18q (the deleted in colorectal cancer(DDC)gene) • And allelic loss at chromosome 17p,associated with mutations in the p53 tumor-suppressor gene

10. Thus,the altered prolifferative pattern of the colonic mucosa,which results in progression to a polyp and then to carcinoma(mutation activation of an oncogene + loss of genes normally suppress tumorigenesis

14. Cancers develop more frequently in sessile polyps • Villous adenomas as often as tubular adenomas ,but become malignant more than three times

15. Etiology amd risk factors • DIET often in upper socioeconomic population mortality direct correlated with consumption of calories, meat protein,fat and oil Coloretal cancer increase in Japan ,adpoted more western diet

16. ANIMAL FAT hypothesis; ingestion of animal fats found in red meats and processed meat leads to an increased proportion of anaerobes in the gut microflora,resulting in conversion of normal bile acids into carcinogens Reports of increase fecal anaerobe stool in

17. patients with colorectal cancer • In animals high fat diet ;high cholesteral enhance risk for the development of colorectal adenoma and carcinoma

18. INSULIN RESISTANT • Excess weight gain develop insulin resistant with increased circulating insulin,leading to higher circulating concentrations of insulin like growth factor type 1(IGF-1):stimulate proliferation of the intestinal mucosa

19. FIBER • High diet in fruits and vegetables in preventing the recurrence of colorectal adenoma or development of colorectal cancer

20. HEREDITARY FACTORS AND SYNDROMES • -Polyposis Coli • -Hereditary Nonpolyposis Colon Cancer • INFLAMMATORY BOWEL DISEASE • Other high risk conditions -streptococcus bovis bacteremia -ureterosigmoidostomy -tobacco use

22. Hereditory GI polyposis syndromes • 25% colorectal cancer have family history • 1.Polyposis Coli rare condition thousounds of adenomatous polyps throug out the large bowel AD trait

23. Polyposis Coli • Deletion in the long arm of chromosome 5 (APC gene ) • Soft tissue and bony tumors,congenital hypertrophy of the retinal pigment epithelium,mesenteric desmoid tumors,and of ampullary cancers in addition to the colonic polyps ; subset of polyposis coli known as Gardner ‘s syndrome

24. The appearance of malignant tumors of the central nervous system accompanying polyposis coli defines Turcot’ s syndrome Colorectal cancer in almost patients develop before 40 Once the multiple polyps that constitute polyposis coli are detected,patients should undergo a total colectomy

25. Medical therapy with NSAIDs such as sulindac and cyclooxygenase-2 inhibitors such as celecoxib can decrease the number and size of polyps in patients with polyposis coli; however this effect on polyps is only temporary • Colectomy remains the primary therapy

26. Off spring polyposis coli:prepubertal when diag in parent,50% risk develop premalignant and should be carefully screened by annual flexible sigmoidoscopy until 35 • Proctosigmoidoscopy: screening ,tend to distribute from cecum to anus • Colonoscope or BE unnecessary

27. Testing occult blood stool ; inadequate screening • Alternative method ; testing DNA from peripheral blood mononuclear cells for the presence of a mutated APC gene • The detection germline mutation ;lead to definitive diagnosis(before development of polyps)

28. Hereditary nonpolyposis colon cancer • Lynch syndrome • AD trait • The presence of three or more relatives with histologically documented colorectal cancer • More case diagnosed before 50 • At least two genarations

29. HNPCC;high frequency of cancer arising in the proximal large bowel • Median age aenocrcinoma < 50 (10-15 years younger than general population) • The proximal colon tumors in HNPCC have a better prognosis than sporadic tumors from patients of similar age • The association of colorectal cancer with either ovarian or endometrial CA strong in women

30. Recommended that members of such families : biennial colonoscopy beginning at age 25 years, with intermittent pelvic ultrasonograghy and endometrial biopsy offered for potentially germline mutations of several genes,particularly hMLH1 on Chromosome3

31. Inflammatory bowel disease • Cancer develop more commonly in UC than with granulomatous colitis • Risk colorectal cancer small during initial 10 years of the disease,but increase ~0.5-1% per year , develop 8-30% of patients after 25 years risk higher in younger patients with pancolitis

32. Symptoms ;bloody diarrhea,abdominal cramping and obstruction is signal of tumor • In patient with history of IBD lasting >= 15 years who continue to experience exacerbations, the surgical removal of the colon can significantly reduce the risk for cancer

33. Other high risk conditions • Streptococcus bovis bacteremia; endocarditis or septicemia from fecal bacteremia: high occult colorectal tumors,UGI cancer

34. Ureterosigmoidostomy: colon cancer develops in 5-10% of people 15-30 years after ureterosigmoidostomy to correct congenital extrophy of bladder • Tobacco use: colorectal adenoma after >35 years of tobacco use

35. Primary prevention • Chemopreventive agents is ASA and other NSAIDs; suppress cell proliferation by inhibit prostaglandin synthesis • Regular aspirin use reduces the risk for colonic adenoma and carcinomas • Oral folic acid supplements and oral calcium supplements reduced risk of adenomatous polyps and colorectal cancer ( in case controle studies )

36. Antioxidant : adcorbic acid ,tocopheral ,beta-carotine ;lower rate of colorectal cancer • Estrogen replacement therapy : reduce risk of colorectal cancer in woman (effect on bile acid synthesis and composition ,decrease synthesis of IGF-1)

37. SCREENING • Important in having family history ,relative risk increase 1.75 (before 60) • Proctosigmoidoscopy ; observation 60% early lesions located in rectosigmoid • Large bowel cancers ;rectum decrease in several decades , increase in more proximal descending colon • Rigid proctosigmoidoscopy ;occult neoplasm ,cost effective

38. Flexible,fiberoptic sigmoidoscopes ; 60 cm colon cancer detection leaves proximal half of large bowel unscreened Digital examination,occult blood testing in older than 40 (prostate cancer in men) Documented 50% colorectal cancer have negative fecal hemoccult test, 2-4% positive Cancer <10% test positive, benign polyp 20-30%

39. Positive test ; sigmoidoscopy,barium enema ,and/or colonoscopy • The American Cancer Society fecal Hemoccult screening annually and flexible sigmoidoscopy every 5 years begin 50 no colorectal cancer risk factors • ‘total colon examination’ every 10 years

40. As alternative to Hemoccult testing with periodic flexible sigmoidoscopy • Colonoscopy superior to double-contrast barium enema higher sensitivity for detecting villous or dysplastic adenomas or cancers • Colonoscopy every 10 years beginning after 50 will prove to be cost effective

41. Analysis of stool for mutation in the APC tumor-suppresser gene is being tested

42. CLINICAL FEATURES • Symptoms vary with the anatomic location • Ileocacal valva to right colon,cancer arise in cecum and ascending colon;large without obstruction or bowel habits change,liquid stool • Lesions of the right colon commonly ulcerate chronic insidious blood loss no stool change • Ascending colon present with symptoms such as fatique,palpitations,angina pectoris hypochromic microcytic anemia ;iron deficiency

43. Cancer may bleed intermittently ;occult blood maybe negative • Unexplained presence of iron-def anemia in adult (except premenopause ,multiparous women) ;endoscopic and/or radiographic visualization of the entire large bowel

44. Transverse and descending colon tumors development of abdominal cramping occasional obstruction ,perforation • Radiograph ;annular ,constricting lesions(‘apple core’ or ‘napkin-ring’) • Cancer in rectosigmoid often associated with hematochezia ,tenesmus,and narrowing of caliber of stool anemia infrequent finding • Suspect hemorrhoid (rectosigmoid)

45. Staging and Prognosis of colorectal cancer

46. 5 years survival • A > 90% • B1 85% • B2 70-80% • C 35-65% • D 5%

49. Most recurrent after a surgical resection of a large bowel cancer within the first 4 years • CEA; tumor recurrence • Chromosome deletion 18q DEC gene ; risk for metastatic spread • Median survival after detection of distant metastasis 6-9 mo to 24-30 mo

50. TREATMENT • Tumor resection • Evaluate metastasis : PE ,CXR,LFT,CEA • Large bowel scope ;synchronous neoplasm and or polyp • Radiation therapy ;rectal cancer decrease 20-25% regional recurrence(B2) serosa: high rate