Polyposis Syndromes of the Colon Current Management, Controversies

and Future Direction

Eric J. Dozois, MD

Division of Colon & Rectal Surgery

Mayo ClinicRochester, Minnesota

Polyposis Schema

Adenomas Hamartomas

Inherited Non-Inherited

Polyposis

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

• 50-100 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 riskRuvalcaba 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 & IRAFamilial 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

0

20

40

60

Normative population IPAA IRA

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 Continence QOL (24 hrs) Day/Night

Cleveland 51 4 82/NA 93Mayo 21 4 83/89 NASt. Marks 62 3 72/NA NASt. Antoine 23 3 98/96 NAToronto 60 6 90/87 80

Functional Outcome after IPAA

Institution N Mean # BMs Continence QOL (24 hrs) Day/Night

Cleveland 62 5 75/74 95Mayo 187 4 84/80 98St. Marks 37 5 60/NA NASt. Antoine 171 4 98/96 NAToronto 50 6 75/51 93

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

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 IRAFunction 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

Genotype–Phenotype Correlation

• Cancer Risk & Severity of Polyposis1:• > 1000 polyps = high risk• < 1000 polyps = 50% less risk

• Severity of Polyposis - APC Mutation2:• Codon 1309 - leads to severe disease • Codons 3,4 – attenuated FAP

1Debinski et al. Gastro 1996;110:1028 2Church. Semin Colon Rectum Surg 1998;9:49

Molecular Genetic Tests as a Guide to Surgical Management of Familial

Adenomatous PolyposisVasen et al. Lancet 1996;348:433-35

“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;348:433-35

Rectal CA Risk after IRA Risk of Rectal Excision

APC mutation beyond codon 1275

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

Results – Risk of Rectal CA

• 10 years 7.7%

• 15 years 13.1%

• 20 years 23.0%

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 1250 - 1464

Bertario et al. Ann Surg 2000;231:538

9-Fold Increase Risk of Rectal

Cancer

Arguments No Longer ValidIRA 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 - codon1250-1450

• 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