1. Polyposis Syndromes of the Colon Current Management, Controversies and Future Direction Eric J. Dozois, MD Division of Colon & Rectal Surgery Mayo Clinic Rochester, Minnesota

2. Polyposis Schema

3. Inherited Polyposis Syndromes Adenomatous Syndrome: Familial adenomatous polyposis mutY human homologue (MYH) Hamartomatous Syndromes: Peutz-Jeghers Juvenile Cowden’s Ruvalcaba-Myhre-Smith

4. Non-Inherited Polyposis Syndromes Cronkhite-Canada Syndrome Hyperplastic Polyposis Lipomatous Polyposis Nodular Lymphoid Hyperplasia Inflammatory Polyposis Lymphomatous Polyposis

5. Polyposis Syndromes Adenomas and hamartomas Low incidence, Autosomal dominant Colorectal Malignancies Extra-colonic malignancies Controversies in management Need for Genetic Counseling

6. Inherited Polyposis Syndromes Elucidation of underlying gene mutations Understanding of cell biology and molecular mechanisms associated with cancer pathogenesis Allows refined categorization, phenotype and cancer risk

7. Hamartomatous Syndromes

8. Overgrowth of lamina propria, submucosa & muscular tissue

9. Hamartomatous Syndromes CS PJS JP Incidence 1:200,000 1:120,000 1:100,000 Gene PTEN STK11 BMPR1A/SMAD4 Risk of CRC 10% Elevated 50% Extracolonic CA Yes Yes Yes

10. Juvenile Polyposis Sporadic Juvenile polyps (2% Peds) Hamartomas throughout GI tract Rectal bleeding, anemia, intussusception Capsule endoscopy is emerging tool for dx *CRC risk 9% - 68%, mean age 34yrs Extracolonic - Stomach, duodenal, Genetic etiology in 50% remains elusive *Howe et al. Ann Surg Oncol 1998;5:751

11. JP – Surgical Management Colectomy with IRA or IPAA: - Symptomatic bleeding - > 20 polyps - Dysplasia Endoscopic Polypectomy : - < 20 polyps

12. Peutz-Jeghers Sydrome 50-100 Hamartomas: - sb colon rectum stomach Mucocutaneous melanin pigmentation

14. Peutz-Jeghers Syndrome Hamartoma-adenoma-carcinoma sequence* Intestinal & Extraintestinal cancers* Ovarian sex-chord tumors, breast, pancreatic Surgery – complications, malignancy *Wang et al. J Pathol 1999:188:9

15. PJS - Clinical Presentation Abdominal cramping Intussusception Anemia

16. PJS - Management Intussusception & Occult bleeding – Multiple laparotomies Enteroscopy during laparotomy:* – Polyp clearance to reduce recurrent laparotomies – 4 of 25 patients required surgery in 14yrs *Phillips et al. Dis Colon Rectum 2003;46:48

17. Cowden Syndrome Hamartomas of GI, skin, mucus membranes Hallmark – facial trichilemmomas (wart-like) GI CA risk – approx. 10% Extra GI CA – *breast, *thyroid, GYN, retina Surveillance and prevention of associated malignancies Surgery for complications

18. Ruvalcaba-Myhre-Smith Syndrome Described in 1980* Gastrointestinal hamartomas Macrocephaly, mental retardation, lipid storage myopathies, thyroiditis Hyperpigmentation of penile skin Alterations in PTEN gene No CRC or extra-colonic cancer risk Ruvalcaba et al. Clin Genetics 1985;18:413

19. Adenomatous Syndromes

20. MYH-Associated Polyposis (mutY human homologue) Base excision repair gene Autosomal-recessive – family history May account for the 7% - 8% of FAP phenotypes in whom no APC germ-line mutation has been identified* Absence of strong multigenerational family history of polyposis Difficult to distinguish from FAP, AFAP *Al-Tassen et al. Nat Genet 2002;30:227

21. MYH-Associated Polyposis (mutY human homologue) Present between ages 45 – 60 yrs Average number of adenomas = 16 (100s) Carriers of bi-allelic and mono-allelic MYH mutations have a significantly increased risk of CRC* *Croitoru et al. J Natl Cancer Inst 2004;96:1631

22. Familial Adenomatous Polyposis First reported in literature in 1841 Autosomal dominant, APC mutation 825 different germ-line mutations Hundreds to thousands of polyps 100% risk of colon cancer Multiple extra-colonic manifestations

24. Genotype-Phenotype Correlation

26. Familial Adenomatous Polyposis Prophylactic Surgery Timing of Surgery Type of Surgery Choice of Procedure Choice of Technique

27. FAP – Type of Surgery 1.Colectomy with ileorectostomy 2.Proctocolectomy with IPAA 3.Anoproctocolectomy, ileostomy 4.Open or laparoscopic

28. FAP – Choice of Procedure Cancer Prophylaxis Technical feasibility Complications Functional Outcome - QOL

29. Management Controversy Ileal Pouch-Anal Anastomosis vs. Ileo-Rectostomy

30. Quality of Life after IPAA & IRA Familial Polyposis Time: 1981 - 1998 IPAA (152 pts), IRA (32 pts) No Difference in: – Early and late complications – Functional Results Hassan et al. Dis Colon Rectum 2005;48:2032

31. Physical Health Mental Health* Comparison of SF-36 Physical and Mental Health Summary Scores p = 0.4

32. Functional Outcome after IRA Institution N Mean # BMs ContinenceQOL (24 hrs) Day/Night Cleveland 51482/NA93 Mayo 21483/89NA St. Marks 62372/NANA St. Antoine 23398/96NA Toronto 60690/8780

33. Functional Outcome after IPAA Institution N Mean # BMs ContinenceQOL (24 hrs) Day/Night Cleveland 62575/7495 Mayo 187484/8098 St. Marks 37560/NANA St. Antoine 171498/96NA Toronto 50675/5193

34. Rectal Cancer Rates After IRA Study No. Pts F/U Rectal CA Rate (yrs) (%) Bulow 659 11 7 Bertario 200 7 24 De Cosse 294 25 13 Sarre 133 20 12 Jarvinen 100 20 25 Iwama 320 20 37

35. FAP - Rectal Cancer Independent Risk Factors:* – Age at colectomy (>40 yrs) – Length of time after IRA (12%/20yrs) – Number of polyps (> 1000) – Length of distal remnant (ileal-sigmoid) – Presence of colorectal malignancy – Genotype *Bjork et al. Dis Colon Rectum 2000;43:1719

36. FAP - Poor Results From IRA Limited surgical options Treatment and follow-up not routinely performed in specialized centers Poor understanding of genotype- phenoptype correlation Inadequate surveillance programs Focus on “ease” of operation and functional outcome

37. Rectal Cancer Rates After IRA Function of Available Surgical Options Timeline No. Pts F/U Cancer Rate (yrs) (%) Pre-pouch era 62 15 13 (1950-1982) Pouch era 135 5 0 (1983-1990) Church et al. DCR 2003;46:1175-1181

38. Genotype–Phenotype Correlation Cancer Risk & Severity of Polyposis 1 : > 1000 polyps = high risk < 1000 polyps = 50% less risk Severity of Polyposis - APC Mutation 2 : Codon 1309 - leads to severe disease Codons 3,4 – attenuated FAP 1 Debinski et al. Gastro 1996;110:1028 2 Church. Semin Colon Rectum Surg 1998;9:49

39. Molecular Genetic Tests as a Guide to Surgical Management of Familial Adenomatous Polyposis Vasen et al. Lancet 1996;348:433-35 “Might information on the location of the mutation be useful in determining the most appropriate surgical treatment?”

40. Molecular genetic tests as guide to surgical management of FAP Vasen et al. Lancet 1996;348:433-35 Rectal CA Risk after IRARisk of Rectal Excision APC mutation beyond codon 1275

41. Genotype and Phenotype Factors for Rectal Cancer After IRA 1955 – 1997 371 patients had IRA Median follow-up 81 mos. Multivariate analysis: Sex, Age No. rectal polyps, Colon CA APC mutation Bertario et al. Ann Surg 2000;231:538

42. Results – Risk of Rectal CA 10 years7.7% 15 years13.1% 20 years23.0% Bertario et al. Ann Surg 2000;231:538

43. Results – Risk of Rectal CA Univariate Analysis: Colon cancer at initial operation More than 30 polyps in the rectum Mutation between codon1250 – 1464 Multivariate Analysis: Colon CA Codons 1250 - 1464 Bertario et al. Ann Surg 2000;231:538 9-Fold Increase Risk of Rectal Cancer

44. Arguments No Longer Valid IRA over IPAA Functional results significantly better Quality of life significantly better Surgical complications are higher Surveillance prevents cancer Cancer can be cured if occurs Can always do IPAA if CA develops

45. Ileal Pouch Neoplasia Lifetime risk of neoplasia unknown Adenomas form in 35% - 57% Risk of developing adenomas: 5yrs (7%) 10yrs (35%) 15yrs (75%) 13 Cancers reported: – Mucosectomy in 8 pts – CRC, multiple polyps Parc et al. Ann Surg 2001;233:360 Groves et al. Dis Colon Rectum 2005;48:816

46. FAP – Indication for IPAA Age at time of surgery > 40yrs > 1000 colonic polyps > 20 Rectal Polyps CRC at time of surgery APC mutation - codon1250-1450 Unreliable surveillance

47. FAP – IRA Acceptable? Less than 1000 polyps in colon Less than 20 polyps in the rectum Attenuated FAP APC mutation before 1250 or after 1450

48. Conclusions Polyposis Syndromes of the Colon Represent a wide spectrum of rare diseases with predisposition for both CRC and extra- colonic disease A clear understanding of the differences between them ensures accurate diagnosis and proper management Advances in molecular genetics will continue to provide even more insight to guide treatment