Polyposis Syndromes of the Colon Current Management, Controversies and Future Direction Eric J. Dozois, MD Division of Colon & Rectal Surgery Mayo Clinic Rochester, Minnesota
Polyposis Schema
Inherited Polyposis Syndromes Adenomatous Syndrome: Familial adenomatous polyposis mutY human homologue (MYH) Hamartomatous Syndromes: Peutz-Jeghers Juvenile Cowden’s Ruvalcaba-Myhre-Smith
Non-Inherited Polyposis Syndromes Cronkhite-Canada Syndrome Hyperplastic Polyposis Lipomatous Polyposis Nodular Lymphoid Hyperplasia Inflammatory Polyposis Lymphomatous Polyposis
Polyposis Syndromes Adenomas and hamartomas Low incidence, Autosomal dominant Colorectal Malignancies Extra-colonic malignancies Controversies in management Need for Genetic Counseling
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
Hamartomatous Syndromes
Overgrowth of lamina propria, submucosa & muscular tissue
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
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
JP – Surgical Management Colectomy with IRA or IPAA: - Symptomatic bleeding - > 20 polyps - Dysplasia Endoscopic Polypectomy : - < 20 polyps
Peutz-Jeghers Sydrome Hamartomas: - sb colon rectum stomach Mucocutaneous melanin pigmentation
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
PJS - Clinical Presentation Abdominal cramping Intussusception Anemia
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
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
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
Adenomatous Syndromes
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
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
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
Genotype-Phenotype Correlation
Familial Adenomatous Polyposis Prophylactic Surgery Timing of Surgery Type of Surgery Choice of Procedure Choice of Technique
FAP – Type of Surgery 1.Colectomy with ileorectostomy 2.Proctocolectomy with IPAA 3.Anoproctocolectomy, ileostomy 4.Open or laparoscopic
FAP – Choice of Procedure Cancer Prophylaxis Technical feasibility Complications Functional Outcome - QOL
Management Controversy Ileal Pouch-Anal Anastomosis vs. Ileo-Rectostomy
Quality of Life after IPAA & IRA Familial Polyposis Time: IPAA (152 pts), IRA (32 pts) No Difference in: – Early and late complications – Functional Results Hassan et al. Dis Colon Rectum 2005;48:2032
Physical Health Mental Health* Comparison of SF-36 Physical and Mental Health Summary Scores p = 0.4
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
Functional Outcome after IPAA Institution N Mean # BMs ContinenceQOL (24 hrs) Day/Night Cleveland 62575/7495 Mayo /8098 St. Marks 37560/NANA St. Antoine /96NA Toronto 50675/5193
Rectal Cancer Rates After IRA Study No. Pts F/U Rectal CA Rate (yrs) (%) Bulow Bertario De Cosse Sarre Jarvinen Iwama
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
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
Rectal Cancer Rates After IRA Function of Available Surgical Options Timeline No. Pts F/U Cancer Rate (yrs) (%) Pre-pouch era ( ) Pouch era ( ) Church et al. DCR 2003;46:
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 leads to severe disease Codons 3,4 – attenuated FAP 1 Debinski et al. Gastro 1996;110: Church. Semin Colon Rectum Surg 1998;9:49
Molecular Genetic Tests as a Guide to Surgical Management of Familial Adenomatous Polyposis Vasen et al. Lancet 1996;348: “Might information on the location of the mutation be useful in determining the most appropriate surgical treatment?”
Molecular genetic tests as guide to surgical management of FAP Vasen et al. Lancet 1996;348: Rectal CA Risk after IRARisk of Rectal Excision APC mutation beyond codon 1275
Genotype and Phenotype Factors for Rectal Cancer After IRA 1955 – 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
Results – Risk of Rectal CA 10 years7.7% 15 years13.1% 20 years23.0% Bertario et al. Ann Surg 2000;231:538
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 Bertario et al. Ann Surg 2000;231:538 9-Fold Increase Risk of Rectal Cancer
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
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
FAP – Indication for IPAA Age at time of surgery > 40yrs > 1000 colonic polyps > 20 Rectal Polyps CRC at time of surgery APC mutation - codon Unreliable surveillance
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
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