PREMALIGNANT CONDITIONS OF THE COLON

WS WIGGETT PROF JHR BECKER 12 Feb 2008

COLONIC INFLAMMATORY BOWEL DISEASE ULCERATIVE COLITIS Nonspecific inflammatory disease involving the mucosa of the colon and the rectum. More common in developed countries comparing to developing countries. Equal gender distribution All ages with peak onset between second and fourth decades. Cause unknown but hypothesis suggest combination of factors leading to dysfunctional immunoregulation in the intestinal wall: o Dietary intake o Genetic predisposition o Imbalance between the normally controlled states of regulated inflammation in bowel wall. Predisposing factors o Low-fiber diet o Food allergies o Food additives o Infectious agents o Shortened durations of breast feedings Current smokers have half the risk of developing UC than non-smokers Patients with UC display specific alleles of group HLA and DR2. Stricture in presence of UC is malignant until proven otherwise. Three important features are more diagnostic of malignant strictures when comparing with benign strictures: o Late appearance of stricture in course of disease (60% after 20yrs vs. 0% before 10 years of disease). o Location proximal to splenic flexure o Cause of large bowel obstruction. Primary sclerosing cholangitis o Extra-intestinal manifestation of UC o Risk of colonic cancer 5x greater when compared with UC alone. o Cancer more on the right side of the colon than with patients with UC alone. Risk of carcinoma o Low-grade dysplasia: 10% o High-grade dysplasia: 30-40% o Dysplasia associated with a lesion or mass (DALM): 50%+) Factors predisposing to cancer o Duration of disease o Age of onset o Extent of involvement of colon Neoplastic lesions can develop with a precursor DALM lesion or as coincidental adenomas.

The risk of carcinoma in pancolitis is directly related to the duration of the disease: o 5-10yrs: 0-3% o 30yrs: 50% o 40yrs: 75% Colonoscopic surveillance o American cancer society Pancolitis: Every 1-2yrs beginning 8yrs after the start of pancolitis Left-sided colitis: Every 1-2yrs beginning 12-15yrs after the start of colitis. 33 colonoscopic biopsies provide 90% chance of detecting dysplasia patchy nature of dysplasia. (4 every 10cm) Chromo-endoscopy and magnifying chromo-endoscopy. 25% of carcinoma diagnosed in patients with UC is not associated with dysplasia elsewhere in the colon. Dysplasia often difficult to diagnose. To improve accuracy: UC should preferably be cooled down. 2 pathologist opinion Molecular tumor markers o May improve sensitivity of surveillance colonoscopy. o Examples: p-53 tumor suppressor gene mutation aneuploidy, Mucin-associated sialosyl-Tn expression. Indications for surgery o High-grade dysplasia-absolute indication o Low-grade dysplasia-controversial Procedures o Total proctocolectomy with ileal-pouch-anal anastamosis. Gold standard 2 Techniques IPAA and anal mucosectomy with hand sewn anastamosis o Rectal dysplasia and/or proctitis o Mucosectomy Technically more difficult Increase nocturnal staining of stool Decrease anal sphincter function Complete removal of potentially malignant tissue IPAA with double stapled anastamosis o Absence of proctitis and/or dysplasia With or without covering ileostomy. Contra-indications: Elderly (>65yrs) Poor anorectal function and anal sphincter tone. Acutely ill patient Laparoscopic o Total Proctocolectomy with End-ileostomy One stage

Removes colon, rectum and anus Indicated: Elderly Incontinent patients o Colectomy with Hartmanns closure of rectum or mucous fistula Indicated: Acutely ill patient (fulminant colitis or toxic megacolon) Pre-operative difficulty differentiating between UC and Crohns

CROHNS COLITIS Inflammatory disease that may affect any segment of the GIT. Disease limited exclusively to the colon occurs in approximately 15% of patients. Bimodal age distribution with peak onset between 15-30 years and smaller second peak between 55-80. Equally between genders. Increased association between oral contraceptives and Crohns. Etiology: theories around combination of events. o Infectious agent o Defective mucosal barrier resulting in increased exposure to antigens o Abnormal host response to intestinal contents o Chromosome 16 and 6 has been implicated in susceptibility to disease. Cancer prevention: o Surveillance as for UC o However, prophylactic operation not recommended to prevent cancer. o Presence of high-grade dysplasia is an indication for colectomy. o Bypassed segment of Crohns should be resected if possible. Cancer o Increased in patients with Crohns o Prognosis directly related to the stage of the disease at the time of operation.

COLORECTAL CANCER GENETICS Specific mutations: o Tumor suppressor genes Produce proteins that inhibit tumor formation by regulating mitotic activity and providing inhibitory cell cycle control. Example, APC gene in FAP and familial colorectal cancer in Ashkenazi Jews. p53 mutations late in adenoma-carcinoma sequence. Earliest mutations in the adenoma-carcinoma sequence occur in the APC gene. The earliest phenotypic change present is known as aberrant crypt formation. o Mismatch repair genes Called the caretaker genes because of their important role in policing the integrity of the genome and correcting DNA replicating errors.

Mutations in MMR genes produce microsatellite instability. (present in 95% of tumors in patients with HNPCC. Microsatellites are repetitive sequences of DNA that seem to be randomly distributed throughout the genome. o Oncogenes Mutation of protooncogene leads to gain-of-function. Products of oncogenes can be divided into categories: Growth factors (example TGF, EGF, insulin-like growth factor.) Growth factor receptor erbB2 Signal transducers (SRC, ABL, RAS) Transcription factors MYC The adenoma-carcinoma sequence o Process through which the most colorectal carcinomas develop. Normal epithelium Hyperproliferative epithelium (dysplasia) Alterations in DNA methylation (early adenoma) Intermediate adenoma Late adenoma Carcinoma Metastasis

COLORECTAL POLYPS Histologic classification Tubular adenoma o 65-80% of all polyps removed o Mostly pedunculated o Less cellular atypia than villous adenoma o <1cm there is less than 5% incidence of carcinoma Tubulovillous adenoma o 10-25% of polyps Villous adenoma o 5-10% of polyps o Mostly sessile o Severe atypia or dysplasia o >2cm there is 50% chance of containing cancer. Carcinoma confined to the muscularis mucosae does not metastasize and the cellular abnormalities should be describe as atypia.

Invasive carcinoma penetrates the muscularis mucosae. Haggits classification for polyps containing cancer according to the depth of invasion: Level 0: carcinoma-in-situ, no invasion of muscularis mucosae. Level 1: carcinoma invades muscularis mucosae into submucosa, but limited to head of polyp Level 2: carcinoma to neck of polyp Level 3: carcinoma in stalk Level 4: carcinoma in submucosa of bowel wall below the stalk, above muscularis propria. Sessile polyps with invasion of muscularis mucosae are a level 4 by definition. Poorly differentiated carcinoma and cancer cells in lymphovascular spaces predict a more than 10% chance of metastasis. Pedunculated polyp level 1-3 with low risk of lymph node metastasis (well differentiated and no lymphovascular infiltration), is managed by complete local excision. Invasive cancer in a sessile polyp has a 10% chance of metastasis to regional lymph nodes, but with well or moderately differentiated cells and no lymphovascular invasion, the lesion can be completely excised. Sessile cancers in the rectum have a high risk for lymph nodes and distant metastasis, and should therefore be treated aggressively. Surveillance (ASGE-guidelines) Prior adenomas: 2; small (< 1cm); tubular; low-grade dysplasia: o 5 year follow up Prior advanced neoplasia( 1cm, villous, high-grade dysplasia, invasive cancer) or 310 adenomas: o 3 years > 10 adenomas: o Within 3 years Large sessile polyp with potential incomplete excision: o 2-6 months

HYPERPLASTIC POLYPS Most common colonic polyps Quite small Composed of cells showing dysmaturation and hyperplasia No neoplastic potential, but some might have adenomatous changes and should therefore be excised for histology.

FAMILIAL ADENOMATOUS POLYPOSIS (FAP) <1% of all colorectal cancers. Autosomal dominant inherited disease, > 100 colorectal adenomas, caused by germline mutations of the tumor suppressor gene APC (detectable in 80-90% of patients with typical FAP). Prevalence 1:10000 with penetrance close to 100%. 25% of patients with FAP do not have positive family history. These are de novo germline mutations.

Polyp development starts in distal colorectum at an average age of 15, and majority of patients become symptomatic with bloody diarrhea by the age of 25-30. Extracolonic manifestation: o Up to 90% of patients with FAP develop polyps in upper GIT o 30-40% gastric fundic gland polyposis and 5-10% gastric adenomas o Risk for gastric cancer not increased. o Major causes of death in colectomized FAP patients are duodenal and ampullary cancer. o Spigelman classification for polyposis in upper GIT to allow adequate follow up. Cancer risk in Spigelman stage IV high. SCORE (points) Polyp count Polyp size(mm) Histology type Grade of intraepithelial neoplasia 1 1-4 1-4 Tubular Low grade 2 5-20 5-10 Tubulovillous Intermediate 3 >20 >10 Villous High grade

Stage 0: 0 points; Stage I: 1-4 points; Stage II: 5-6 points; Stage III: 7-8 points; Stage IV: 9-12 points Extra-intestinal manifestation of FAP include: o Desmoid tumours (10-20%) o Epidermoid cysts (30-50%) o Fibromas o Osteomas (often in the mandibula) o Congenital hypertrophy of the retinal pigment epithelium (70%) o Dental abnormalities. Gardners syndrome: o Polyposis, epidermoid cysts, osteoma Turcots syndrome in FAP o Polyposis, CNS tumours (medulloblastoma) Increased risk observed for: o Hepatoblastoma, follicular thyroid cancer, brain tumours (usually medulloblastoma). Genetic testing and genotype-phenotype correlation o APC germline mutation detectable in 80-90% of FAP patients o > 800 different germline mutations in APC gene. o Patients with mutations proximal to codon 168 or distal to codon 1580 are predominantly diagnosed at age >50 years and display an attenuated phenotype. o Associated mutations in APC gene CHRPE with mutations in central part of APC gene (codon 463-1387) Desmoid tumours- mutations distal to codon 1403 Increase risk of cancer in rectal stump post subtotal colectomy mutations between codons 1250-1500. o Patients with negative family history and negative APC-mutation FAP should be tested for biallelic MYH mutation.

Surveillance o If APC germline mutation identified in index patient predictive germline testing should be offered to all members at risk. At-risk analysis is site specific, that is, the specific familial APC mutation is sought, and not APC mutations in general. o If mutation has been ruled out in patient at risk surveillance can be discontinued for this individual and his offspring. They can be offered sigmoidoscopy every 7-10 years until age 40 years, then colonoscopy every 5 years (ASGE-guidelines) o If mutational status is unclear or the presence of mutation has been verified: Flexible rectosigmoidoscopy annually starting at age 10-12 years. First degree relatives have 50% chance of developing polyposis and should be screened as well. o If adenomas at rectosigmoidoscope: Colonoscopy [or surgery (ASGE-guidelines)] o Upper GIT screening for polyposis to be started at age 30 years with 3 years interval. If adenomas, intervals should be shortened to 1-2 years. o Annual ultrasound of thyroid and abdomen (desmoids) starting at age 10-12 years. Treatment o Timing of surgery depends on individual course of the disease i.e. number of polyps, dysplasia, risk of desmoids (fam.history/DNA) majority of cases gets prophylactic surgery before age 20 years. o Procedure Proctocolectomy with ileal-pouch-anal anastomosis(IPAA) gold standard. Mucosectomy and hand sewn- vs. double stapled anastomosis. Annual pouchoscopy for polyps Total colectomy with ileorectal anastomosis (IRA) Good functioning results Annual sigmoidoscopy of remaining rectum Up to 50% of patients with IRA will need metachronous proctectomy for cancer or severe rectal polyposis. o Upper GIT polyposis Local treatment Endoscopic snaring and polypectomy limited Endoscopic mucosal resection (EMR) sessile polyps Major Duodenectomy (Surg Clin N Am -2006) Proximal pylorus sparing pancreaticoduodenectomy Spigelman stage IV polyposis or invasive cancer o Desmoid tumors (Surg Clin N Am-2006) Small, well-defined abdominal wall tumors surgical resection. Slow growing, mild symptomatic tumors Sulindac, tamoxifen, or vinblastine and methotrexate. Aggressive tumors High dose tamoxifen, antisarcoma combination chemotherapy such as doxorubicin and decarbazine. Possibly radiation therapy

o Chemoprevention Colorectal polyps Cyclooxygenase inhibitors (sulindac) or COX2 inhibitors celecoxib) Reduce number and mass of polyps in some trails Not for presymptomatic gene carriers (Cruz-Correa, Giardiello. Familial adenomatous polyposis. Review. Gastrointestinal endoscopy. 58 (6),2003.) Upper GIT polyps Sulindac failed to show significant effect Celecoxib showed effect in one study. NSAIM (Surg Clin N Am-2006) Inhibits cyclooxygenase (COX) enzymes in conversion of arachidonic acid to prostaglandins. Also effects on non-COXmediated pathways. COX enzymes in 2 isoforms: o COX-1: housekeeping o COX-2: inflammatory, pain, fever. o COX -2 over expressed in 50% of colorectal adenomas and 85% of cancers. Aspirin- low dose(81mg) aspirin COX-2 inhibitors: increased cardiovascular mortality NSAIDS and COX-2 inhibition should not be used as an alternative to surgery in FAP. Calcium carbonate binding of mutagenic bile acids Selenium antioxidant Hormonal replacement therapy reduce bile acid production

ATTENUATED FAMILIAL ADENOMATOUS POLYPOSIS (AFAP) 10% of patients with FAP presents with AFAP. 10-100 polyps (>100 possible in elderly), predominantly in the proximal colon. Mostly diagnosed in patients >45 years of age. Estimated risk for colorectal cancer without treatment is 80%. Genetic testing o APC germline mutation in 20-30% with AFAP o APC-mutation negative and negative family history patients tested for biallelic MYH mutations Surveillance o Starting later than in patients with FAP late teens early 20s o Colonoscopy: Because of proximal location of polyps First at age 15 years If normal- then biannual(annually ASGE-guidelines) colonoscopy starting age 20 years o Upper GIT As for FAP

Treatment o Colectomy only if polyposis cannot be controlled by repeated polypectomies.

MYH-ASSOCIATED POLYPOSIS (MAP) Autosomal recessive inherited disease (most of time a negative family history). MYH-gene is thought to be caretaker gene. Mutation of MYH are thought to lead to somatic mutation of APC (APC is seen as the gatekeeper and initiates neoplasia directly). (Surg Clin N Am-2006) Multiple colorectal adenomas and carcinoma. Difficult to distinguish from FAP/AFAP. Mostly patients are older than 45 years at time of diagnosis, with 10-100 polyps, some more than 100. 50% of MAP patients have cancer at presentation. Duodenal polyposis in 20% of patients. Pilomatrixomas (benign Cutaneous hair follicle neoplasm) have been reported. Risk for other cancers not increased Genetic testing o Biallelic MYH mutations can be identified in 10-20% with APC-mutation negative FAP and AFAP. o MYH germline mutation testing is indicated in patients with 10 or more adenomas after exclusion of an APC mutation. Surveillance o No guidelines o Limited to proven biallelic mutation carriers and to siblings of MAP patients who refuse predictive testing. o Recommendation (Schulmann K, et al) for biannual colonoscopy starting at age 20. o Upper GI endoscopy for duodenal polyps. Treatment o Depend on number of polyps.

HEREDITARY NONPOLYPOSIS COLORECTAL CANCER-HNPCC (Surg Clin N Am-2006) Lynch syndromes Autosomal dominant disorder characterized by colorectal cancer in the absence of marked polyposis. Accounts for 2-4% of all colorectal cancers Median age of cancer diagnosis is 60 years Other cancer at increased risk Lifetime risk for endometrial, ovarian and colorectal cancer is 55%, 15% and 50-60%, respectively. Turcot syndrome in HNPCC (vs. FAPs Turcot syndrome) o Colorectal cancer and glioblastoma multiforme. Muir-Torre o HNPCC variant o Sebaceous gland adenomas or keratoacanthomas and visceral cancers.

Definition of HNPCC (Amsterdam II criteria) o 3/more relatives who have HNPCC-associated cancer (colorectal, endometrial, stomach, ovary, ureter, renal pelvis, brain, small bowel, hepatobiliary tract or sebaceous tumors) o 1 affected individual should be first-degree relative of the other 2 o 2/more successive generations should be affected. o 1/more of these cancers should be diagnosed before age 50 years. o FAP should be excluded. o Tumors should be verified by pathological examination. Colorectal cancer tends to arise proximal to the splenic flexure. Timeframe of adenoma to carcinoma progression is markedly accelerated as compared with sporadic colorectal cancer. Thus, a polyp may progress to invasive cancer in 2-3 years, rather than 8-10 years as in sporadic cancer. Histological features includes, tumor infiltrating lymphocytes, Crohns-like lymphocytic reaction, mucinous- or signet ring differentiation, and medullary growth pattern. Tumors displays a molecular phenotype known as high frequency microsatellite instability (also known as replication error positive [RER+]). Underlying genetic cause of HNPCC is a germline mutation in any one of several genes (MLH1, MSH2, MSH6, PMS2) that participate in a DNA replication proofreading system, known as mismatch repair. As caretaker system, a deficiency in mismatch repair, leads to secondary mutations in the genes, giving rise to various cancers. Additionally, mismatch repair-deficiency causes bystander mutations in short, repetitive DNA repeats, known as micro-satellites. Mutations of micro-satellite DNA have no direct functional consequence on the cell, unless the micro-satellite is located in the coding region of a gene. Immunohistochemical analysis of paraffin-embedded specimens. Individuals fulfilling any of the following Revised Bethesda criteria be genetically assessed for HNPCC: o Colorectal cancer diagnosed in patient <50 years of age o Presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors (as outlined in Amsterdam II criteria), regardless of age o Colorectal cancer with the MSI-H (micro-satellite instability) histology diagnosed in patient who is <60 years of age. o Colorectal cancer diagnosed in one or more first-degree relatives who has an HNPCC-related tumor, with one the cancers being diagnosed under age 50 years. o Colorectal cancer diagnosed in 2/more first- or second-degree relatives who have HNPCC related tumors, regardless of age. If the Revised Bethesda criteria are met, the following approach to genetic testing is recommended: o Micro-satellite instability or immunohistochemical analysis of tumors followed germline testing. o After mutation is identified, at-risk relatives should be referred for genetic counseling and testing o If tissue testing is not feasible, proceed directly to germline analysis of the MSH2/MLH1 genes.

o If no mismatch repair gene mutation is found in a proband with an MSI-H tumor or a clinical history of HNPCC, the test is non-informative. High risk surveillance should be undertaken on patient and at-risk individuals. Screening o At-risk individuals Full colonoscopy (as opposed to flexible sigmoidoscopy, tumors mostly proximal) every 1-2 years, starting between 20-25 years or 10 years younger than the earliest age of diagnosis of CRC in the family. Annual colonoscopy after age 40 years. (ASGE-guidelines) o Transvaginal ultrasonography, endometrial aspiration and p-CA-125, annually, beginning at age 30 years in woman at risk. Surgical management o Controversial prophylactic or extended resection. o American society of colon and rectal surgeons recommendation for HNPCC: Individual who fulfills Amsterdam criteria and who are diagnosed with more than 1 advanced adenoma, or a colon cancer, Offered subtotal colectomy with ileorectal anastamosis Or segmental colectomy Total proctocolectomy with IPAA in patients with rectal polyps or cancer. o Prophylactic hysterectomy and bilateral salpingo-oopherectomy should be considered in woman undergoing other abdominal surgery once family has been completed. Sulindac doubt on the chemopreventative potency of Sulindac and NSAIDs in HNPCC (Rijcken, Hollema, Van der Zee. Sulindac treatment in hereditary nonpolyposis colorectal cancer. European journal of cancer. (43) 1251-1256,2007.) Familial colorectal cancer type X o Syndrome distinct from HNPCC o Individual with family history that satisfies the Amsterdam criteria, but whose colon cancers do not display MSI-H. o Risk for colon cancer more moderate and at later age than HNPCC. o Risk for extra-colonic cancers not significantly raised.

HAMARTOMATOUS POLYPOSIS SYNDROMES PEUTZ-JEGHERS SYNDROME (PJS) Autosomal dominant. Special type of hamartomatous GI polyp (PJ polyp) and mucocutaneous melanin pigmentations. PJ polyps occur throughout alimentary tract with predilection for the small bowel. Mostly jejenal. Esophagus is spared. Rarely nose, gallbladder and ureter. Polyps characterized by extensive smooth muscle aborization throughout polyp. Pigment lesions in 95% of patients but may disappear with age. Mostly lips, peri-oral and intra-oral mucosa. Diagnostic criteria: o 2 or more PJ polyps o One PJ polyp and mucocutaneous pigment lesion o One PJ polyp and positive family history of PJS.

Family history is negative in up to 45% of index cases indicating de novo germline mutations. Recurrent colicky abdominal pain due to intussusception in adolescence or young adulthood. Also occult bleeding with iron-deficiency anemia. Pigmentation not always present in childhood and may fade later in life. Intra-epithelial neoplasia predisposes to cancer hamartoma-adenoma-carcinoma sequence. Cancer risk: o 85% by age 70 years o 57% GI cancer. o Colorectal cancer most common with lifetime risk of 39%. Lifetime pancreatic cancer risk is 11%. o Extraintestinal cancers include breast risk (31-50%), endometrium and ovary. o Cancer uncommon before age 30 years. o Almost all female patients with PJS develop potentially malignant ovarian tumour, the sex cord tumour with annular tubules (SCTAT). Malignant transformation in 20% of all cases. Sertoli cell tumours considered as male equivalent of SCTAT with gynaecomastia. Genetic testing o PJS is caused by germline mutation of the STKII tumour suppressor gene. o Screening for gross deletions of the STKII gene detection rate up to 94%. Surveillance o No evidence-based guidelines. o Schulmann K, et al recommends biannual gastroduodenoscopy and colonoscopy starting at age 12 years. o Screening options for small bowel polyps include enteroclysis, MR enteroclysis, push enteroscopy and capsule endoscopy. Double balloon enteroscopys value still needs to be determined. 2 year screening interval is recommended. o At 18 years, start regular endovaginal ultrasound examination o At 25 years, start screening for breast and pancreatic cancer(EUS/MRCP) o Testis examinations especially in patients with gynaecomastia. Endoscopic or surgical excision of large or symptomatic polyps is recommended.

JUVENILE POLYPOSIS (JP) Autosomal dominant. Multiple hamartomatous polyps of the colorectum (98%), stomach (13%), small bowel (6%). Juvenile polyps are usually pedunculated, smooth, lobulated with a vulnerable surface. On cut surface they show multiple fluid filled cystic areas. Diagnostic criteria: o 5 or more juvenile polyps in the colon or rectum; OR o One juvenile polyp and positive family history of JP; OR o Juvenile polyps outside the colon or rectum, i.e. stomach/small bowel. Family history positive in 20-50%, suggesting high incidence of spontaneous mutations or low penetrance. Children/adolescents often presents with iron deficiency anemia, hypoproteinemia and retarded growth. Also rectal prolaps or other congenital abnormalities (15%) in CVS, UGT and CNS.

Cancer risk: o Increased risk, lifetime risk of 20-60% for colorectal cancer. o Median age at diagnosis is 35-40 years. o Increased risk for gastric and duodenal cancers Genetic testing o Germline mutations of the SMAD4and BMPR1A are detected in 11-25% and 18-30% of patients of JPC. o Gastric polyposis seems to be more frequent and severe in patients with SMAD4 mutations. Surveillance o No evidence-based guidelines o In proven JPC colonoscopy and gastroscopy starting at 10-12 years, every 2nd year, for detection and removal of polyps. o Small bowel imaging (capsule endoscopy / MR enteroclysis) every 2nd year. o Genetic screening may exclude family members from surveillance when germline mutation can be excluded in mutation positive family. Treatment o Colectomy and gastric surgery in severe polyposis.

COWDEN SYNDROME (CS) Autosomal dominant. Facial trichilemmomas, oral papillomas, hyperkeratotic skin lesions, oesophageal glycogenic acanthosis and frequent intestinal hamartomatous polyposis (mostly stomach, colon and oesophagus). Penetrance nearly 100% GI hamartomas include juvenile polyps, lipomas, inflammatory polyps, ganglioneuromas and lymphoid hyperplasia. Juvenile-like polyps that contain neural elements are considered characteristic of this disease. Fibrocystic breast disease and multinodular goiter may occur. Genetic testing o Germline mutation of tumor suppressor gene PTEN. (80% of patients meeting clinical criteria) Cancer risk o Lifetime risk for breast Ca is 50%, and thyroid cancer 10-20%. o GI cancer risk, not increased. Surveillance o Focus on breast and thyroid. Bannayan-Ruvalcaba-Riley syndrome o Shares characteristics with Cowdens and additionally includes slowed psychomotor development and pigmentary spotting of the penis.

EXTREMELY RARE POLYPOSIS SYNDROMES HEREDITARY MIXED POLYPOSIS SYNDROME (HMPS) Two families have been reported so far

HYPERPLASTIC POLYPOSIS SYNDROME (HPS) Defined as: o At least five histologically diagnosed hyperplastic polyps proximal to the sigmoid colon, of which 2 are greater than 1cm; OR o Any number of hyperplastic polyps occurring proximal to the sigmoid colon in an individual who has a first-degree relative with hyperplastic polyposis o >30 hyperplastic polyps of any size distributed throughout the colon. Increased risk for colorectal cancer Surveillance o No evidence-based guidelines o Schulmann K, et al suggests annual colonoscopy starting at 20 years.

SCREENING AND SURVEILLANCE ASGE GUIDELINES 2006 Average risk individuals Screening beginning at age 50 years. Colonoscopy O Preferred modality in 116 average risk patients with established colon cancer proximal to splenic flexure, 58.6% had no distal polyps. (Rex DK, Chaka A, Vaudeville R, et al. Gastrointestinal Endosc 1999) O Colonoscopy with polypectomy reduced colorectal cancer (CRC) incidence with 76-90% O Miss rate is 27% for adenomas 5mm and 6% for lesions 10mm (Rex DK, Cutler CS, Lemmel GT, et al. Gastroenterology 1997) O Every 10 years. FOBT O Annually, 2 samples from each of 3 consecutive stools. O If positive, colonoscopy should follow. Flexible sigmoidoscopy O Reduction in colorectal cancer incidence in portion of the colon examined, and decreased mortality between 59-80%. O Prevalence of proximal neoplasia increases with age, therefore colonoscopy maybe better suited for screening in patients older than 60 years. (Anderson JC, Alpern Z, Messina CR, et al. Am J Gastroenterol. 2004) O Recommended every 5 years. FOBT and flexible sigmoidoscope O No evidence that combination of annual FOBT and flexible sigmoidoscopy every 5 years reduces CRC mortality. O 70.3% of patients with advanced neoplasia were identified by the use of sigmoidoscopy alone and 75.8% with the addition of FOBT. (Lieberman DA, Weiss DG. N Engl J Med. 2001) O Combination of FOBT and flexible sigmoidoscopy every 5 years may be considered. Addition of FOBT have minimal benefit. Double-contrast barium enema (DCBE) O Diagnostic sensitivity inferior to colonoscopy and lacks therapeutic capability. O Not recommended for screening. O If used, it should be done every 5 years.

Virtual colonoscopy (VC) O Sensitivity of 55-100% and specificity of 94-98% for detection of polyps 10mm. O May detect extra-colonic findings. O Prospective study comparing DCBE, VC and colonoscopy for lesions 10mm, the sensitivity was 48%, 59% and 98% respectively. (Rockey DC, Paulson E, Niedzwiecki D. Lancet 2005) O Not recommended for screening. Still evolving technique. Fecal DNA testing. O Not recommended

Individuals with family history of CRC or adenomatous polyps First degree relatives with CRC diagnosed age <60 years O Colonoscopy at age 40 years or 10 years younger than affected relative. Repeat every 3-5 years. First degree relatives with CRC diagnosed age 60 years O Colonoscopy at age 40 years and repeat every 10 years First degree relatives with adenomatous polyp diagnosed age <60 years O Colonoscopy at age 40 years or 10 years younger than affected relative. Repeat every 5 years. First degree relatives with adenomatous polyp diagnosed age >60 years O Colonoscopy age individualized and follow up as for average risk patients. Second- or third degree relative with cancer or polyps O As for average risk patients.

RESEARCH AND FUTURE OPTIONS Optimal managements of upper GI adenomatous polyposis (FAP/AFAP) unknown. Relevance of small bowel polyps in FAP/AFAP is unknown Chemoprevention unknown Genetic markers of prognosis and response to therapy (Surg Clin N Am-2006) o Micro-satellite instability (MSI) Not only in HNPCC but also seen in 15% sporadic colorectal cancer. The risk of dying for a patient with MSI-H cancer is 65% that of a patient with MSS (micro-satellite stable) cancer. Patients with MSI-H cancer appears not to benefit 5-FU chemotherapy, therefore, should 5-FU adjuvant chemotherapy be withheld from the 15-20% MSI-H positive sporadic cancers?

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