Colorectal polyps and polyposis syndromes Division of Colorectal Surgery The Chinese University of Hong Kong Intensive Surgery Course for Medical Year 5 (2006/2007)

Colorectal polyps

• visible protrusion above the surface of the surrounding normal large bowel mucosa • Detected by endoscopy or by DCBE

Classification of colorectal polyps

Histological classification Non-neoplastic Neoplastic (adenoma) Polyp type Hyperplastic Hamartomatous (juvenile, Peutz-Jeghers) Lymphoid Inflammatory Tubular adenoma (0-25% villous tissue) Tubulovillous adenoma (25-75% villous tissue) Villous adenoma (75-100% villous tissue) Malignant potential No Yes

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

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

Adenoma-carcinoma sequence

10 years Adenoma CRC Regardless of aetiology, most CRC arise from adenomas

Factors determining risk of malignant transformation within adenomas High risk Large size ( >1.5cm) Sessile or flat Severe dysplasia Villous architecture Polyposis syndrome (multiple polyps) Low risk Small size ( <1cm) Pedunculated Mild dysplasia Tubular architecture Single polyp

Percent of adenomas containing invasive cancer by size and histology

Malignant colorectal polyp

• Polyp that contains invasive cancer • Malignant cells that have invaded through the mucularis mucosa into the submucosa mm

Management of colorectal polyps (1) Factors Location: colon or rectum Morphology: pedunculated or sessile Histology: benign or malignant

Management of colorectal polyps (2) Excision Pedunculated Colonoscopic polypectomy usually possible Sessile Colonoscopic polypectomy if possible (larger polyps may require piecemeal removal) Endoscopic removable not possible  operative removal • Colon: colectomy • Rectum: staged with EUS or MRI • Benign / Early malignant (T1No) : Transanal local excision or TEMS (may need further radical surgery) • Other malignant : radical excision (APR /anterior resection)

Management of colorectal polyps (3) Definitive Mx (histology) Benign Malignant Depends on histological characteristics Surveillance colonoscopy Radical Surgery

Surveillance after polypectomy Benign polyps Characteristics of polyps small rectal hyperplasic polyps (=average risk) Next FU colonoscopy 10 years one or two small (<1cm) tubular adenomas 3 to 10 adenomas, or adenoma ≥ 1cm, or villous features, or high grade dysplasia >10 adenomas 5-10 years 3 years <3 years sessile adenomas removed piecemeal 2-6 months Guidelines for colonoscopy surveillance after polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer and the American Cancer Society (2006)

Malignant Polyp Factors determining need of radical surgery Histology • Poorly differentiated • Margin <2mm • Stalk invasion • Lymphovascular invasion Increase risk of recurrence and LN 2 o

Familial Colorectal Cancer Syndromes

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

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

Molecular genetics of FAP

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

APC as gatekeeper gene adenoma-carcinoma sequence

Loeb 1991

Mechanisms of Carcinogenesis in FAP

Genotype vs. phenotype

Affected part of gene Clinical Presentation Extracolonic manifestations Cell adhesion and structural molecules

Extracolonic manifestations

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

Gardner’s syndrome

Desmoid Mandibular osteoma Chest fibroma Skull osteoma

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

Cancer risks in FAP

Cancer Colon Duodenal or periampullary Pancreatic Thyroid Gastric CNS, usually cerebellar medulloblastoma (Turcot's syndrome) Hepatoblastoma Cancer risks Near 100% 5-10% About 2% About 2% About 0.5% <1% 1.6% of children <5 years of age

Diagnosis of FAP

Endoscopy Genetic tests Mutation Protein truncation test DNA sequencing

Screening of FAP

• Genetic screening of family members for APC mutations • Annual flexible sigmoidoscopy beginning at age 10-12 until age 40, then every 3-5 years *If polyposis is present, colectomy should be considered • OGD every 1-3 years is also recommended to evaluate for upper GI adenomas

Prophylactic colectomy for FAP

FAP CRC • The aim of surgical treatment of FAP is to intervene in the adenoma-carcinoma sequence by removing the adenomas before the transformation to malignancy occurs

Timing of surgery

Clinical presentation Asymptomatic patient with modest number of small adenomas Timing of surgery Able to wait for a few years for surgery, as long as colonoscopic surveillance is performed yearly Symptomatic patient with large number of adenomas Suspicious of CRC Early surgery Very early/urgent surgery

Standard surgical treatment

Restorative proctocolectomy with ileal pouch-anal anastomosis Suitable for most patients with FAP

Other surgical options

Total colectomy with ileorectal anastomosis (IRA) Proctocolectomy with ileostomy Attenuated FAP low rectal cancers poor sphincters Desmoid tumors

Medical treatment of FAP?

• Sulindac (NSAID) and celecoxib (COX-2 inhibitor) shown to control and reduce the number of colorectal adenomas in FAP • Not definitive treatment • Temporizing treatment (eg when surgery needs to be delayed) • May control pouch and rectal polyposis after initial prophylactic surgery

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)

HNPCC

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

HNPCC: Lynch syndromes

Lynch syndrome I Lynch syndrome II Early onset of CRC (40-45 years) Features of Lynch Syndrome I + extracolonic malignancies Predominantly proximal to the splenic flexure (60-70%) *Gastric, small bowel, hepatobiliary, endometrial, ovarian, ureteral and renal tumours Increase frequency of synchronous and metachronous lesions (33%)

HNPCC related extracolonic tumors

100% 80% 78% 60% 43% 40% 20% 19% 18% 10% 9% 0% Colorectal Endometrial Stomach Biliary tract Urinary tract Ovarian Endometrial cancer is the most common extracolonic malignancy

Diagnosis: Amsterdam criteria 1

Due to lack of phenotypic markers like polyps Diagnosis is based on family history of CRC only 1. One member less than 50 years of age 2. Two involved generations 3. Three family members affected, one of whom is a first-degree relative of the other two

Diagnosis: Amsterdam criteria 2

Same as Amsterdam 1 but includes all HNPCC related tumors

Molecular genetics of HNPCC

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

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

Molecular genetics of HNPCC

Demonstration of MSI

DNA Normal Tissue DNA Tumor Tissue Microsatellite Markers Amplify by Polymerase Chain Reaction Compare normal and tumor profiles of amplified microsatellite on gel to detect genetic mutations in these microsatellites

D5S346

NORMAL MUCOSA

MSS Tumor

BAT 26 BAT 25 D17S250

TUMOR

D2S123

NORMAL TUMOR

MSI Tumor

HNPCC: Mutation detection for MLH1 and MSH2 Microsatellite instability testing Negative: Stop?

Positive Sequence MLH1 No protein Sequence MSH2 No protein Immunohistochemistry MLH1 MSH2 Normal Stop?

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 not location of tumours acceptable, due to the proximal • Transvaginal US and endometrial aspiration annually starting at ages 25-35 years are also recommended

Surgical treatment of HNPCC

• Total colectomy with ileorectal anastomosis • Restorative proctocolectomy with ileal pouch-anal anastomosis • Segmental colectomy not of metachronous CRC recommended because of high rate • TAHBSO for endometrial cancer

Hamartomatous polyposis syndromes

Peutz-Jeghers syndrome

• Incidence: 1 in 200,000 persons Autosomal dominant • Mutations of the STK11 gene on chromosome 19 • Characterized by perioral pigmentations polyps and hamartomatous throughout the GI tract • GI and non-GI cancers are common Site of polyps Stomach Small bowel Colon Rectum Frequency 38% 78% 42% 28%

Cancer risk in P-J syndrome

GI cancers Colon Pancreatic Stomach Small bowel Esophagus Non-GI cancers Breast Ovarian Uterine Sex cord tumour with annular tubules (SCTAT) Sertoli cell tumour Lung Cancer risks 39% 36% 29% 13% 0.5% Cancer risks 54% 21% 9% 20% become malignant 10-20% become malignant 15%

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 Polyps are most commonly found in colon Colon cancer risk 50% Risk of gastric, duodenal, and pancreatic cancers