Prof/ Walid ELshazly

1. Colorectal polyposis Prof/ Walid ELshazly A Prof Of Colorectal Surgery

2. Colorectal polyps • Visible protrusion above the surface of the surrounding normal large bowel mucosa

3. Classification of colorectal polyps

4. Hyperplastic polyps • Majority of non-neoplastic polyps • Prevalence rates of 20-34% (autopsy and screening colonoscopy studies) • Predominantly located in the distal colon and rectum • Generally small (<0.5cm) in size

5. Classification of colorectal polyps

6. Hamartomatous polyposis syndromes • Juvenile polyps • Peutz-Jeghers polyps • Cronkhite-Canada syndrome

7. Juvenile polyposis • Presence of 10 juvenile polyps in the GI tract • Incidence: 1 in 100,000 persons • Autosomal dominant • Mutation of SMAD4 gene on chromosome 18

8. Juvenile polyposis • Developmental malformations affecting the glands and lamina propria • Commonly occur in children under 5 years old in the rectum. • In adult called retention polyp.

9. Juvenile polyposis • Colon cancer risk 50% • Risk of gastric, duodenal, and pancreatic cancers

10. Peutz-Jeghers syndrome • Incidence: 1 in 200,000 persons Autosomal dominant • Mutations of the STK11 gene on chromosome 19 • Characterized by perioral pigmentationsand hamartomatous polyps throughout the GI tract • GI and non-GI cancers are common

11. Peutz-Jeghers syndrome

12. Cancer risk in P-J syndrome

13. Cronkhite-Canada syndrome • Gastrointestinal hamartomatous polyposis that lead to • Diarrhea, • Weight loss and • Abdominal pain • Extra-intestinal manifestations • Alopecia, • Cutaneous hyperpigmentation, • Onycho-dystrophy

14. Cronkhite-Canada syndrome • Five-year mortality rates as high as 55 percent have been reported with most deaths due to • gastrointestinal bleeding, • sepsis, and • congestive heart failure. • Treatment has included nutritional support, corticosteroids, acid suppression, and antibiotics

15. Classification of colorectal polyps

16. Lymphoid polyps Mucosal nodularity in representing lymphoid hyperplasia

17. Classification of colorectal polyps

18. Inflammatory polyps/ pseudopolyps • These lesions develop as by-products of the ulcers that penetrate into the submucosa, leaving islands of adjacent regenerative mucosa. • Although most common in ulcerative colitis, inflammatory polyps may also be seen in Crohn's disease, ischemia, and other ulcerative conditions of the colon.

19. Inflammatory polyps/ pseudopolyps

20. Classification of colorectal polyps

21. Adenomas – facts and figures • 70% of all colorectal polyps • Increase with age (33% of population by 50yr, and in 50% by 70yr) • 70% located in the left colon • 70% are solitary (30% synchronous) • 70% are small (<1cm in size) • 7% have severe dysplasia, 3-5% have invasive cancer

22. Adenoma CRC Adenoma-carcinoma sequence 10 years Regardless of aetiology, most CRC arise from adenomas

23. Factors determining risk of malignant transformation within adenomas

24. Percent of adenomas containing invasive cancer by size and histology

25. Malignant colorectal polyp • Polyp that contains invasive cancer • Malignant cells that have invaded through the mucularismucosa into the submucosa mm

26. Familial adenomatous polyposis (FAP) • 1% of all CRC • Present in about 1 in 8000 births • Autosomal dominant with near 100% penetrance

27. FAP • >100 adenomas • Patients develop adenomas by the mean age of 16 years, and CRC by 39 years • Adenomas form early, but it takes 20-30 years to develop CRC from adenomas • Disease of abnormal tumour initiation

28. Molecular genetics of FAP • Caused by mutations of APC gene (tumour suppressor gene) on chromosome 5q21 • Encodes for a protein, which functions in cell adhesion and signal transduction • Mutations will result in truncated protein and affect cell growth

29. APC as gatekeeper geneadenoma-carcinoma sequence Loeb 1991

30. Mechanisms of Carcinogenesis in FAP

31. Genotype vs. phenotype Affected part of gene Clinical Presentation Extracolonic manifestations Cell adhesion and structural molecules

32. CHRPE Extracolonic manifestations • Congenital hypertrophy of retinal pigmented epithelium (CHRPE) • Osteomas, desmoid tumours, epidermoid cysts (Gardner’s syndrome) • CNS malignancies including medulloblastoma and glioblastoma (Turcot’s syndrome) • Duodenal, hepatobiliary-pancreatic, thyroid tumours

33. Gardner’s syndrome Desmoid Chest fibroma Mandibular osteoma Skull osteoma

34. Attenuated FAP (AFAP) • Variant of FAP • <100 adenomas • Late age-of-onset (adenomas at 44; CRC at 56) • Proximal distribution of adenomas *Colonoscopy for surveillance *Infrequent involvement of the rectum supports the role of total colectomy and IRA

35. Cancer risks in FAP

36. Mutation Protein truncation test DNA sequencing Diagnosis of FAP Endoscopy Genetic tests

37. Screening of FAP • Genetic screening of family members for APC mutations • Annualflexible sigmoidoscopy beginning at age 10-12 until age 40, then every 3-5 years *If polyposis is present, colectomy should be considered • Upper GIT Endoscopy every 1-3 years is also recommended to evaluate for upper GI adenomas

38. Hereditary nonpolyposis colorectal cancer (HNPCC) Dr. A. S. Warthin and the first HNPCC pedigree, ‘the family G’ 1895 Dr. Henry Lynch first described the term ‘cancer family syndrome’ in 1966 (later renamed as Lynch syndrome and HNPCC)

39. HNPCC • 2-5% of all CRC • Autosomal dominant • 70-80% penetrance • It takes only 3-5 years to develop CRC from adenomas Accelerated progression

40. HNPCC: Lynch syndromes

41. HNPCC related extracolonic tumors Endometrial cancer is the most common extracolonic malignancy

42. Diagnosis: Amsterdam criteria 1 Due to lack of phenotypic markers like polyps Diagnosis is based on family history of CRC only • One member less than 50 years of age • Two involved generations • Three family members affected, one of whom is a first-degree relative of the other two

43. Diagnosis: Amsterdam criteria 2 Same as Amsterdam 1 but includes all HNPCC related tumors

44. Molecular genetics of HNPCC HNPCC is caused by mutations of DNA mismatch repair (MMR) genes Survey DNA for replication errors

45. Molecular genetics of HNPCC • Mutations of these MMR genes will result in replication errors during DNA synthesis (microsatellite instability) leading to acceleration of genetic mutations • HNPCC patients develop adenomas at the same rate as the general population • Once these adenomas develop, however, defective DNA repair ensues and mismatches accumulates • Thus, it takes only 3-5 years to develop CRC from adenomas

46. Molecular genetics of HNPCC

47. Screening of HNPCC • Colonoscopy every 2 years starting at ages 20-25 or 5 years younger than the earliest diagnosis of CRC whichever is earlier until 40yr , and then annually • Flexible sigmoidoscopy is notacceptable, due to the proximal location of tumours • Transvaginal US and endometrial aspiration annually starting at ages 25-35 years are also recommended

48. Management of colorectal polypsFactors Affecting Location: colon or rectum Number: solitary or multiple Morphology: pedunculated or sessile Histology: benign or malignant

49. Management of colorectal polyps Excision Pedunculated Colonoscopic polypectomy usually possible (Snaring)

50. Management of colorectal polyps Excision Sessile • Colonoscopic polypectomy if possible • (larger polyps may require piecemeal removal) • 5-8 snaring excision • > 8 removal of affected segment segmental colectomy • Endoscopic removable not possible  operative removal • Colon: colectomy