A. Characteristics

1. Epidemiology [29]
   1. Polyps found in about 33% of general population by age 50
   2. Polyps found in nearly 50% of population by age 70
   3. Certain types of polyps are major risk factors for development of colon cancer
   4. Colon cancer nearly always develops from dysplastic polyps
2. Colonic polyps often cause of diarrhea or mild bleeding
3. Most commonly occur in rectosigmoid area
4. Should all be biopsied if >1cm (main concern is in situ neoplasia)
5. Relatives of persons with polyps have ~2X increased risk of developing colon Ca
6. Special consideration in patients with hereditary gastrointestinal polyposis syndromes
7. General population screening for colonic polyps begins age 50
   1. Sigmoidoscopy is highly recommended as initial study
   2. Colonoscopy is probably the most optimal screening method
   3. Colonoscopy is ~2-2.5 fold more sensitive than barium enema or sigmoidoscopy [27,30]
   4. Non-invasive virtual colonoscopy with high resolution CT scan and 3 dimensional reconstruction has similar sensitivity and specificity as optical colonoscopy [9]
8. Impact of Diet on Adenoma Risk
   1. Low fat, high fiber diet does not appear to reduce risk of colonic adenomas [25,26]
   2. High fiber or calcium supplementation had no significant effect on adenoma formation [32]
   3. In other studies, high fiber diet associated with 27% reduced risk for colonic adenomas [37] and 40% reduced risk of colorectal cancer [38]

B. Hyperplastic Polyps

1. 90% of polyps (0% incidence of neoplasia)
2. Well formed glands and crypts lined with colonic epithelium with differentiated cells

C. Tubular Polyps

1. Generally benign
2. Low risk of transformation to malignancy
3. Overall risk is probably ~2X above general population
4. Finding a single <5mm tubular adenoma has very low risk of advanced proximal polyps [18]
5. Mutation in APC gene (I1307K) associated with adenomatous polyps in Ashkenazi Jews [33]

D. Villous Adenoma

1. Most concerning as carcinoma in situ may occur in 10% of these
2. Usually found in patients >50 years old
3. Tubulovillous polyps have also been found; should be considered higher risk than tubular

E. Related Syndromes [1,20,22]

1. Adenomatous Polyposis Syndromes (see below)
   1. Familial Adenomatous Polyposis (Gardner) Syndrome
   2. Turcot Syndrome
2. Hamartomatous Polyposis Syndromes
   1. Peutz-Jeghers Syndrome: STK11 mutations
   2. Juvenile Familial Polyposis: typical, with HHT, with ENG mutations (see below) [5]
   3. Cowden Syndrome: PTEN mutations
   4. Birt-Hogg Dube Syndrome: BHD Mutations
   5. MYH Adenomatous Polyposis: MYH mutations
   6. Hereditary Mixed Polyposis Syndrome: CRAC1 mutations
   7. Basal Cell Nevus Syndrome
   8. Neurofibromatosis
3. Hereditary Nonpolyposis Colorectal Cancer Syndrome (HNPCC; Lynch Syndrome)
   1. Most common hereditary colon cancer syndrome
   2. Colonic polyps are NOT found
   3. Due to mutations found in mismatch repair genes hMSH2, hMLH1, hPMS1, hPMS2
   4. Most commonly mutations in gene hMSH2 on chromosome 2p16 and MLH1
   5. May be responsible for up to 10% of cases of colorectal cancer
   6. Amsterdam I Criteria families without mismatch repair deficiency appear not to have an increased risk of cancer [41]
   7. Bethesda (revised) Guidelines are useful for identifying patients at high risk for HNPCC [42]
   8. ~2.2% of patients with colorectal adenocarcinoma have mutations causing HNPCC [43]
   9. Routine molecular screening of patients with colon cancer identifies HNPCC mutations and can aide in identifying family members at risk [43]
   10. Prophylactic bilateral salpingo-oophorectomy prevents development of endometrial and ovarian cancer in Lynch syndrome patients [4]
4. Nonhereditary Polyposis Syndromes
   1. Cronkite-Canada Syndrome
   2. Inflammatory Polyposos
   3. Benign or Malignant Lymphoid Polyposis
   4. Pneumatosis cystoides intestinalis

F. Familial Adenomatous Polyposis (Gardner) Syndrome (FAP or FPC) [1,3]

1. Genetic Abnormality
   1. Prevalence is ~1:12,000; ~20,000 patients in USA with disease
   2. Autosomal dominant inheritance due to mutations in APC (adenomatous polyposis coli) gene
   3. APC gene located on chromosome 5q21-22
   4. Mutations in APC gene may predict clinical course
   5. Mutations in exon 15, codons 1255-1467, associated with thousands of polyps
   6. Mutations in the proximal 5' area often have heterogeneous progression, reduced risk of colon cancer compared to those with mutations in distal 5' area [13]
   7. Protein and allele specific PCR assays now available, detect ~87% of patients
   8. Also called Bussey-Gardner polyposis
   9. Similar clinical syndrome occurs with mutations in excision repair protein MYH [2]
   10. MYH syndrome can be transmitted as autosomal recessive [7]
   11. MYH mutations should be considered in syndromic patients with normal APC
2. Type of Polyps
   1. Polyps usually small, <1cm in diameter (>100 polyps in colon)
   2. Adenomatous polyps increased in Ashkenazi Jews with APC I1307K mutation [33]
   3. Villous type may occur, with malignant transformation (high risk of cancer)
   4. Small intestine and even stomach may be involved
   5. Polyps are histologically identical to sporadic polyps
   6. Patients with colectomy are at risk for extracolonic polyps
   7. Upper endoscopy including evaluation of duodenum and periampulary region required
3. Essentially 100% lifetime risk of developing colon cancer
4. Increased risk of papillary thyroid cancer, usually minimally aggressive [12]
5. Chemoprevention of Polyps [28,29]
   1. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDS) are best studied
   2. Polyp growth is believed to be dependent on cyclo-oxygenase 2 (COX2)
   3. Celecoxib, a COX2 specific inhibitor, reduces polyp generation in dose-dependent manner
   4. Celecoxib, 400mg po bid, for 6 months reduced polyps by 28% [28]
   5. Sulindac 75-150mg po bid did not reduce polyps in FAP over 48 month study [34]
   6. Non-cyclo-oxygenase pathways may also be involved in NSAID effects
   7. Increased folate, calcium, and estrogen intake associated with reduction in polyps
6. Colectomy recommended in all patients > 30 years old
   1. Ileorectal anastomosis is preferred for patients with mutations prior to codon 1250
   2. Full restorative proctocolectomy preferred for higher risk patients (mutant after 1250)

G. Turcot Syndrome

1. Colorectal adenomatous polyps
2. Brain tumors, usually cerebellar medulloblastoma or glioblastoma
3. Genetics
   1. Autosomal dominant
   2. Mutations in the APC gene in families with predominantly cerebellar medulloblastomas
   3. Mutations in MLH1 or PMS2 in families with primarily glioblastomas
4. Rare syndrome compared with others
5. Clinical testing of APC and MLH1 genes is available

H. Cowden Disease (Multiple Hamartoma Syndrome) [1]

1. Multiple hamartomatous tumors of any embryologic layer
2. Polyps are common, anywhere in GI tract, most commonly colon and stomach
3. Other Components of Syndrome
   1. Mucocutaneous lesions are very common
   2. Thyroid adenomas and goiter; 10% risk of thyroid cancer [12]
   3. Breast fibroadenomas and fibrocystic disease; 50% risk of breast Ca in affected women
   4. Uterine leiomyomas
   5. Macrocephaly
4. Rare autosomal dominant disorder of PTEN (MMAC1, DEP1) gene on chromosome 10q
5. Research testing for mutations in PTEN gene available

I. Familial Juvenile Polyposis (FJP) [1]

1. Juvenile polyps found mainly in colon, also elsewhere
2. Congenital abnormalities found in ~20%
   1. Malrotation
   2. Hydrocephalus
   3. Cardiac Lesions
   4. Meckel's Diverticulum
   5. Mesenteric Lymphangioma
   6. Increased risk of intususception
3. Colon cancer risk is 25% or less
4. Increased risk of gastric, duodenal and pancreatic cancer
5. Genetics are Complex [1,23]
   1. Autosomal dominant in some families
   2. BMPRIA mutations in typical Juvenile Polyposis Syndrome
   3. Germline mutation in SMAD4 (DPC4) gene on chromosome 18q (mainly with HHT; see below)
6. Juvenile Polyposis with HHT [44,45]
   1. Hereditary hemorrhagic telangiectasia (HHT) with FJP
   2. Due to mutations in SMAD4
   3. SMAD4 is a co-SMAD, an integral downstream effector of TGFß signaling
   4. SMAD4 (DPC4) coded by MADH4
   5. Consider genetic testing for these mutations in patients with relevant symptoms
   6. High risk of invasive cancers; upper and lower endoscopy should begin by age 15
7. Juvenile Polyposis with ENG Mutations [5]
   1. Endoglin is a coreceptor and accessory pathway in TGFß signaling
   2. Germline mutations in ENG associated with juveile polyposis without HHT

J. Peutz-Jeghers Syndrome [1,21]

1. Occurs in ~1 in 15,000 live births
2. Polyposis Syndrome
   1. Hamartomas an hamartomatous polyps
   2. Small numbers of polyps throughout gastrointestinal tract
   3. Most polyps in small intestine
   4. May present with intussusception of small bowel (due to hamartoma / polyp)
   5. Nasal polyps also found
3. Mucocutaneous Pigmentation
   1. Genital and anal area are most common
   2. Face, mouth, nose lips, buccal mucosa, hands and feet also affected
4. Autosomal Dominant Inheritance
   1. Germline mutation in LKB1 (STK11) gene on chromsome 19p13.3 in ~70% of families
   2. T insertion at codon 66 (exon 1) leads to stop codon 162 (exon 4)
   3. This leads to inactivation of the LKB1 gene
5. Lifetime Risk of Cancer ~85% [21]
   1. Gastrointestinal tumors including pancreatic cancer
   2. Sex cord tumors
   3. Sertoli cell only tumors
   4. Adenoma malignum of the cervix
   5. Breast cancer may be increased
   6. Women have ~18X increased cancer risk, men have ~6X increased cancer risk

K. Ruvalcaba-Myhre-Smith (Bannayan-Zonana) Syndrome [1,22]

1. Hamartomatous GI polyps
   1. Lipomas
   2. Hemangiomas
   3. Lymphangiomas
2. Other components of syndrome
   1. Dysmorphic facial features
   2. Microcephaly
   3. Seizures
   4. Intellectual impairment
   5. Pigmented macules (speckled) on shaft and glans of penis
3. Malignant GI tumors identified (unknown overall risk)
4. Autosomal dominant inheritance of PTEN gene anomalies (chromosome 10q)

L. Screening [1,22]

1. Guidelines for screening are being reviewed
2. General (usual risk patients)
   1. Distal rectal exam annually beginning age 40
   2. Fecal occult blood testing starting age 50
   3. Positive occult blood followed up with colonoscopy
   4. Flexible sigmoidoscopy at age 50, repeating every 3-5 years
   5. Repeat sigmoidoscopy 3 years after initial negative exam lead to polyp or mass removal in ~14% of cases; therefore, repeat exams every 3-5 years recommended [39]
   6. Screening colonoscopy beginning age 50-60 increasingly recommended
   7. Optical (standard) colonoscopy has sensitivity of >85% and can miss even >10mm adenomas, usually located behind a fold or near anal verge [8]
   8. Single <5mm tubular adenoma on sigmoidoscopy has low risk of advanced polyps [18]
   9. However, 29% of large flat lesions contained carcinoma and should be biopsied [24]
   10. Nonpolypoid (flat and depressed) colorectal growths occur in >9% of veterans [17]
   11. Of these nonpolypoid growths, >8% contain in situ or submucosal invasive carcinoma [17]
   12. For individuals with high risk (at least 3 adenomas or any advanced adenoma), repeat colonoscopy at 3 years is recommended (6.6% risk of advanced adenoma on repeat) [47]
3. Computerized Tomographic Colonography (CTC) [8,14,15,16]
   1. Three-dimensional reconstruction of colonic images
   2. High specificity 92-97%
   3. Sensitivity for polyps 48% for <6mm, 70% for 6-9mm, 85% for >9mm
   4. In large prospective study, identified as many high risk (mainly >9mm) polyps as standard colonoscopy with reduced actual polypectomy and no perforations [15]
   5. Patients with >9mm polyps on CTC need to undergo colonoscopic polypectomy
   6. Patients with <10mm polyps may be followed by CTC or standard colonoscopy
   7. Increasing use due to non-invasive nature of test
4. Sigmoidoscopy and Colonoscopy
   1. Colonoscopy is ~2 fold more sensitive than barium enema and is strongly preferred [27]
   2. Colonoscopy detects ~2.5 fold more significant adenomas than sigmoidoscopy [30,31]
   3. Colonoscopy is preferred over sigmoidoscopy for general, intermittent screening
   4. Colonoscopy interval of 10 years is recommended after initial negative exam [6]
   5. Noninvasive CTC (see above) has similar or lower sensitivity and specificity as optical colonoscopy but similar identification of >9mm polyps [8,9,15,16]
5. High Risk
   1. Colonoscopy done earlier and more frequently depending on risk
   2. Family history of colon cancer puts at high risk
   3. HNPCC and other Hereditary Syndromes are high risk (see below)
   4. Chronic inflammatory bowel disease is also high risk for colon cancer
6. HNPCC [19]
   1. Surveillance colonoscopy begins age 25, every 1-3 years
   2. Prophylactic immediate colectomy adds ~15.8 years
   3. Frequent colonoscopy with action based on findings adds ~13.5 years
   4. Colonoscopy with colectomy at time of cancer (or high grade dysplasia) diagnosis had greatest overall quality adjusted life expectancy benefit

M. Removal of Polyps

1. Most polyps are removed from patients with high risk syndromes
2. Polyps >0.5-1cm are generally removed from all patients
3. Persons having any large bowel endoscopic proceedure have ~45% reduction in risk for development of colorectal cancer compared with controls without proceedure [5]
4. Colonoscopy has ~1% complication rate, 0.1% perforation rate, 0.05% death rate
5. Finding a single <5mm tubular adenoma has very low risk of advanced proximal polyps [18]

N. Chemoprevention

1. Colonic Adenomas]
   1. Aspirin (ASA) >650mg/week associated with reduction in colorectal adenomas 20-30% (dose dependent effect) in a prospective study in an average risk population [40]
   2. In other studies, 81mg or 325mg qd reduces number of polyps ~40% [35,36]
   3. ASA reduces number of patients developing new polyps by ~40%
   4. ASA prolongs time to first new polyp in patients with history of colonic adenomas
   5. ASA reduces number of >1cm as well as villous polyps ~40%
   6. ASA 81mg po qd propably as effective as and safer than 325mg po qd
2. Celecoxib (Celebrex®) [10,11]]
   1. Prevents polyp progression in small studies
   2. Reduces new sporadic polyps in general population with history of adenomas by ~33%
   3. Increases risk of cardiovascular events over 3 years by 1.3-3.4X (dose dependent)
   4. Not recommended for routine chemoprophylaxis due to cardiovascular risk
3. FAP (APC) Syndrome [3]
   1. Celecoxib (Celebrex®), a COX II selective inhibitor, prevents polyp progression
   2. Aptosyn (selective apoptotic anti-neoplastic agent) in development
   3. Sulindac reduce the growth of polyps in familial polyposis
4. In a randomized prevention study, folic acid showed no benefit on colonic adenomas [46]

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