Neoplastic vs NonNeoplastic vs Non--Neoplastic Colon PolypsNeoplastic Colon Polyps

Marianne FahmyMarianne FahmyCore Curriculum LectureCore Curriculum Lecture

September 14, 2010September 14, 2010

OutlineOutline

NonNon--Neoplastic PolypsNeoplastic PolypsHyperplasticHyperplasticMucosalMucosalInflammatory PseudopolypsInflammatory PseudopolypsSubmucosal (can be nonSubmucosal (can be non--neoplastic and neoplastic)neoplastic and neoplastic)

HamartomatousHamartomatousJuvenile PolypsJuvenile PolypsPeutzPeutz--JeghersJeghers

Inherited Family Disorders: Polyposis syndromesInherited Family Disorders: Polyposis syndromesNeoplastic Polyps (adenomas and carcinomas)Neoplastic Polyps (adenomas and carcinomas)

I. NonI. Non--Neoplastic Colon PolypsNeoplastic Colon Polyps

Hyperplastic PolypsHyperplastic Polyps

Most common nonMost common non--neoplastic polyp in the colonneoplastic polyp in the colonDo not exhibit dysplasiaDo not exhibit dysplasiaProliferation is mainly in the basal portion of the crypt Proliferation is mainly in the basal portion of the crypt (used to distinguish from adenomas)(used to distinguish from adenomas)Typically located in the rectosigmoid and are < 5mm in Typically located in the rectosigmoid and are < 5mm in sizesizeSmall left sided HP are not a significant marker of Small left sided HP are not a significant marker of colon cancer risk and finding them on sigmoidoscopy is colon cancer risk and finding them on sigmoidoscopy is NOT a routine indication for colonoscopyNOT a routine indication for colonoscopy

Inflammatory PseudopolypsInflammatory Pseudopolyps

Irregularly shaped islands of residual intact Irregularly shaped islands of residual intact colonic mucosa that are the result of the colonic mucosa that are the result of the mucosal ulceration and regeneration that occurs mucosal ulceration and regeneration that occurs in IBD (benign with no malignant potential).in IBD (benign with no malignant potential).Usually multiple, filiform and scattered Usually multiple, filiform and scattered throughout the colitic region of the colonthroughout the colitic region of the colonHowever, their presence can complicate the However, their presence can complicate the recognition of true adenomas and DALM recognition of true adenomas and DALM

Submucosal PolypsSubmucosal Polyps

Lymphoid aggregates, lipomas, leiomyomas, Lymphoid aggregates, lipomas, leiomyomas, pneumatosis cystoid intestinalis, hemangiomas, pneumatosis cystoid intestinalis, hemangiomas, fibromas, carcinoids, and metastatic lesions fibromas, carcinoids, and metastatic lesions Can be neoplastic or nonCan be neoplastic or non--neoplasticneoplasticSmooth overlying mucosaSmooth overlying mucosaLipoma can be diagnosed endoscopically because of its Lipoma can be diagnosed endoscopically because of its yellow color and softness (pillow sign)yellow color and softness (pillow sign)EUS can be useful in defining the site of origin and for EUS can be useful in defining the site of origin and for biopsy of submucosal lesions if the diagnosis is in biopsy of submucosal lesions if the diagnosis is in doubt.doubt.

II. Hamartomatous PolypsII. Hamartomatous Polyps

Hamartomatous PolypsHamartomatous Polyps

Result of faulty development, made up of a mixture of Result of faulty development, made up of a mixture of tissuestissues

Juvenile polyps: Juvenile polyps: consist of lamina propria and dilated cystic glands rather than consist of lamina propria and dilated cystic glands rather than increased numbers of epithelial cellsincreased numbers of epithelial cellsUsually removed because of high likelihood of bleeding.Usually removed because of high likelihood of bleeding.More common in childhood.More common in childhood.

PeutzPeutz--Jeghers PolypsJeghers PolypsGlandular epithelium supported by smooth muscle cells that is Glandular epithelium supported by smooth muscle cells that is contiguous with the muscularis mucosa.contiguous with the muscularis mucosa.Associated with PeutzAssociated with Peutz--Jeghers syndromeJeghers syndromePolyps are benignPolyps are benign-- but may grow progressively and produce but may grow progressively and produce symptoms or undergo malignant transformationsymptoms or undergo malignant transformation

Inherited DisordersInherited Disorders

I: Hamartomatous Polyposis syndrome: PeutzI: Hamartomatous Polyposis syndrome: Peutz--Jeghers Syndrome and Familial Juvenile PolyposisJeghers Syndrome and Familial Juvenile PolyposisII: Adenomatous Polypsosis Syndrome: Familiar II: Adenomatous Polypsosis Syndrome: Familiar

Adenomatous PolyposisAdenomatous PolyposisIII: Hyperplastic Polyposis SyndromeIII: Hyperplastic Polyposis Syndrome

PeutzPeutz--Jeghers SyndromeJeghers Syndrome

Autosomal dominant hamartomatous polyposis syndrome Autosomal dominant hamartomatous polyposis syndrome associated with mucocutaneous hyperpigmentationassociated with mucocutaneous hyperpigmentationFor individuals with a histopathologically confirmed hamartoma, For individuals with a histopathologically confirmed hamartoma, a definite diagnosis of PJS requires two of the following three a definite diagnosis of PJS requires two of the following three findings: findings:

Family history consistent with autosomal dominant inheritanceFamily history consistent with autosomal dominant inheritanceMucocutaneous hyperpigmentation Mucocutaneous hyperpigmentation SmallSmall--bowel polyposisbowel polyposis

Variable penetrance: variable size and variable number of Variable penetrance: variable size and variable number of hamartomatous polypshamartomatous polypsPolyps begin to grow in first decade of life and become Polyps begin to grow in first decade of life and become symptomatic between ages of 10 and 30symptomatic between ages of 10 and 30Presenting symptoms include intussusception, small bowel Presenting symptoms include intussusception, small bowel obstruction, bleeding, and anemiaobstruction, bleeding, and anemia

PJS PJS -- contcont

Increased risk for both GI and nonIncreased risk for both GI and non--GI GI malignancies: malignancies: small intestine, gastric, pancreatic, colorectal, esophageal, ovarian, lung, endometrial, and breastGenetic testing: only identifiable mutations Genetic testing: only identifiable mutations causing PJS affect the tumor suppressor gene causing PJS affect the tumor suppressor gene STK 11STK 11

Screening in PJSScreening in PJS

From birth to age 12. In male patients: history and physical exaFrom birth to age 12. In male patients: history and physical examination with mination with attention to the testicles. Routine blood tests annually (ultrasattention to the testicles. Routine blood tests annually (ultrasound of the ound of the testicles every two years until age 12 offered as an option). Fotesticles every two years until age 12 offered as an option). For female r female patients: History and physical examination with routine blood tepatients: History and physical examination with routine blood tests annually. sts annually. At age 8. For males and females: upper endoscopy and small bowelAt age 8. For males and females: upper endoscopy and small bowel series; if series; if positive, continue every two to three years. positive, continue every two to three years. From age 18 on. In male patients: colonoscopy, upper endoscopy, From age 18 on. In male patients: colonoscopy, upper endoscopy, and small and small bowel series every two to three years. In female patients: Colonbowel series every two to three years. In female patients: Colonoscopy, upper oscopy, upper endoscopy, and small bowel series every two to three years; breaendoscopy, and small bowel series every two to three years; breast selfst self--exam exam monthly. Emerging data suggest that wireless capsule endoscopy mmonthly. Emerging data suggest that wireless capsule endoscopy may be an ay be an alternative for small bowel imaging. Similarly, pushalternative for small bowel imaging. Similarly, push--enteroscopy enteroscopy or doubleor double--balloon enteroscopy may be an alternative for small bowel imaginballoon enteroscopy may be an alternative for small bowel imaging, while also g, while also having the benefit of permitting therapeutic intervention, althohaving the benefit of permitting therapeutic intervention, although they are ugh they are more invasive. more invasive. From age 25 on. For male/female patients: endoscopic ultrasound From age 25 on. For male/female patients: endoscopic ultrasound of the of the pancreas every one to two years (CT scan and/or CA19pancreas every one to two years (CT scan and/or CA19--9 offered as options).9 offered as options).

Familial Juvenile PolyposisFamilial Juvenile Polyposis

Occurrence of 10 or more juvenile polypsOccurrence of 10 or more juvenile polypsAutosomal dominant pattern of inheritance with germline Autosomal dominant pattern of inheritance with germline mutation in SMAD4 gene chromosome 18q21.1 or in the gene mutation in SMAD4 gene chromosome 18q21.1 or in the gene BMPRA1A.BMPRA1A.Associated with increased risk for the development of CRC, and Associated with increased risk for the development of CRC, and in some families, GASTRIC cancer, especially where there are in some families, GASTRIC cancer, especially where there are both upper and lower gastrointestinal polyps. both upper and lower gastrointestinal polyps. JPS may coJPS may co--exist with Oslerexist with Osler--WeberWeber--Rendu syndrome which Rendu syndrome which carries a risk of aortic aneurysm and PEcarries a risk of aortic aneurysm and PEScreening: colonoscopy q1Screening: colonoscopy q1--2 years beginning at age 15; EGD or 2 years beginning at age 15; EGD or UGI with SBFT q1UGI with SBFT q1--2 years beginning at age 252 years beginning at age 25

Familial Adenomatous PolyposisFamilial Adenomatous Polyposis

Autosomal dominant Autosomal dominant linked to the adenomatous linked to the adenomatous polyposis coli (APC) gene located on chromosome polyposis coli (APC) gene located on chromosome 5q215q21Large intestine contains multiple adenomatous polyps Large intestine contains multiple adenomatous polyps (>100)(>100)Disease penetrance is nearly 100% by age 40 (mean age Disease penetrance is nearly 100% by age 40 (mean age of death 42 if left untreated)of death 42 if left untreated)Treatment: Total proctocolectomy with a Brooke Treatment: Total proctocolectomy with a Brooke ileostomy vs subtotal colectomy with ileorectal ileostomy vs subtotal colectomy with ileorectal anastomosisanastomosis

FAP (cont)FAP (cont)

Extracolonic malignances/manifestions: duodenal Extracolonic malignances/manifestions: duodenal ampullary carcinoma, follicular papillary thyroid cancer, ampullary carcinoma, follicular papillary thyroid cancer, childhood hepatoblastoma, gastric carcinomas, CNS childhood hepatoblastoma, gastric carcinomas, CNS tumors (medulloblastomas), Congenital hypertrophy of tumors (medulloblastomas), Congenital hypertrophy of the retinal pigment epitheliumthe retinal pigment epitheliumGenetic testing: should be performed on an affected Genetic testing: should be performed on an affected members. If no mutation found then all atmembers. If no mutation found then all at--risk family risk family members should undergo endoscopic screening (flex sig members should undergo endoscopic screening (flex sig or colonoscopy every year starting at age 10 to 12 and or colonoscopy every year starting at age 10 to 12 and continuing until age 35 or 40 if negative) since continuing until age 35 or 40 if negative) since commercial tests for APC mutations do not detect all commercial tests for APC mutations do not detect all mutations that can cause FAPmutations that can cause FAP

Variants of FAPVariants of FAP

TurcotTurcots syndromes syndromeAssociation with brain tumors (medulloblastomas and Association with brain tumors (medulloblastomas and gliomas) and FAP or HNPCCgliomas) and FAP or HNPCC

GardnerGardners syndrome: extraintestinal lesionss syndrome: extraintestinal lesionsDesmoid tumors, sebaceaous or epidermoid cysts, lipomas, Desmoid tumors, sebaceaous or epidermoid cysts, lipomas, osteomas, supernumery teeth, gastric polyps, juvenile osteomas, supernumery teeth, gastric polyps, juvenile nasopharyngeal angiofibromasnasopharyngeal angiofibromas

Attenuated FAPAttenuated FAPMilder phenotypical FAP variant; < 100 adenomasMilder phenotypical FAP variant; < 100 adenomasFever extracolonic manifestionsFever extracolonic manifestionsDelayed onset of colorectal cancer (delayed by 12 years)Delayed onset of colorectal cancer (delayed by 12 years)

Screening in FAPScreening in FAP

ASGE: Patients with FAP should undergo upper ASGE: Patients with FAP should undergo upper endoscopy with both endendoscopy with both end--viewing and sideviewing and side--viewing viewing instruments. The optimal timing of initial upper instruments. The optimal timing of initial upper endoscopy is unknown, but could be performed around endoscopy is unknown, but could be performed around the time the patient is considered for colectomy, or the time the patient is considered for colectomy, or early in the third decade of life. If no adenomas are early in the third decade of life. If no adenomas are detected, another exam should be performed in five detected, another exam should be performed in five years because adenomatous change may occur later in years because adenomatous change may occur later in the course of the disease the course of the disease Biopsies of gastric polyps should be performed to Biopsies of gastric polyps should be performed to confirm that they are fundic glands and not adenomasconfirm that they are fundic glands and not adenomasPalpation of thyroid annually (thyroid blastoma)Palpation of thyroid annually (thyroid blastoma)

Hyperplastic Polyposis SyndromeHyperplastic Polyposis Syndrome

Characterized by multiple, large, proximal hyperplastic polyps Characterized by multiple, large, proximal hyperplastic polyps (occasionally small numbers of serrated adenomas)(occasionally small numbers of serrated adenomas)Associated with increased risk of CRCAssociated with increased risk of CRCWHO criteriaWHO criteria

At least 5 HP proximal to the sigmoid colon, of which 2 are greaAt least 5 HP proximal to the sigmoid colon, of which 2 are greater than ter than 1 cm or1 cm orAny number of HP occurring proximal to the sigmoid colon in an Any number of HP occurring proximal to the sigmoid colon in an individual who has a first degree relative with hyperplastic polindividual who has a first degree relative with hyperplastic polyposis oryposis orGreater than 30 HP distributed throughout the colonGreater than 30 HP distributed throughout the colon

If there are many polyps in the proximal colon may consider If there are many polyps in the proximal colon may consider colectomycolectomyOnly remaining polyposis condition for which no germline Only remaining polyposis condition for which no germline mutation has been identifiedmutation has been identified11--3 year surveillance colonoscopies have been proposed3 year surveillance colonoscopies have been proposed

Neoplastic PolypsNeoplastic Polyps

Adenomatous PolypsAdenomatous Polyps

2/3 of colonic polyps are adenomas2/3 of colonic polyps are adenomasBy definition they are dysplastic and have malignant By definition they are dysplastic and have malignant potentialpotentialTime for development of adenomas to cancer is about Time for development of adenomas to cancer is about 7 to 10 years.7 to 10 years.Advanced adenomaAdvanced adenoma: high grade dysplasia or adenoma that : high grade dysplasia or adenoma that is > 10 mm in size or with villous componentis > 10 mm in size or with villous componentSynchronous adenomaSynchronous adenoma: adenoma that is diagnosed at same : adenoma that is diagnosed at same time as index colorectal neoplasmtime as index colorectal neoplasmMetachronous adenomaMetachronous adenoma: diagnosed at least six months after : diagnosed at least six months after diagnosis of previous adenomadiagnosis of previous adenoma

Epidemiology of AdenomaEpidemiology of Adenoma

Older age is a major risk factorOlder age is a major risk factorMore common in menMore common in menLarge adenomas (> 9mm) may be more Large adenomas (> 9mm) may be more common in African Americanscommon in African AmericansAfrican Americans have a higher risk of rightAfrican Americans have a higher risk of right--sided colonic adenomas and may present with sided colonic adenomas and may present with cancer at a younger age (< 50 years) than cancer at a younger age (< 50 years) than Caucasians.Caucasians.

Endoscopic ClassificationEndoscopic Classification

Sessile Sessile base is attached to colon wallbase is attached to colon wallPedunculated Pedunculated mucosal stalk is interposed mucosal stalk is interposed between the polyp and the wall (small polyps < between the polyp and the wall (small polyps < 5 mm are rarely pedunculated)5 mm are rarely pedunculated)Flat Flat height less than oneheight less than one--half the diameter of half the diameter of the lesion.the lesion.Depressed lesions appear to be particularly likely Depressed lesions appear to be particularly likely to harbor highto harbor high--grade dysplasia or be malignant grade dysplasia or be malignant even if small.even if small.

Pathologic ClassificationPathologic Classification

Low grade dysplasia: characterized by branching crypts Low grade dysplasia: characterized by branching crypts lined by cells with long, thin nuclei that begin to stratify, lined by cells with long, thin nuclei that begin to stratify, resulting in increased nucleusresulting in increased nucleus--toto--cytoplasm ratio and a cytoplasm ratio and a loss of normal goblet cells.loss of normal goblet cells.High grade dysplasia: do not contain invasive High grade dysplasia: do not contain invasive malignancy, which is defined by breach of the malignancy, which is defined by breach of the muscularis mucosa by neoplastic cells. muscularis mucosa by neoplastic cells.

Represents an intermediate step in the evolution from lowRepresents an intermediate step in the evolution from low--grade adenomatous polyp to cancergrade adenomatous polyp to cancerNot associated with metastasis since there are no lymphatic Not associated with metastasis since there are no lymphatic vessels in the lamina propria..vessels in the lamina propria..

Pathology cont.Pathology cont.

Tubular: account for more than 80 percent of colonic Tubular: account for more than 80 percent of colonic adenomas. Characterized by a complex network of adenomas. Characterized by a complex network of branching adenomatous glands.branching adenomatous glands.Villous: account for 5 to 15 percent of adenomas. They Villous: account for 5 to 15 percent of adenomas. They are characterized by glands that are long and extend are characterized by glands that are long and extend straight down from the surface to the center of the straight down from the surface to the center of the polyp, creating fingerpolyp, creating finger--like projections.like projections.TVA: having 26 to 75 percent villous component TVA: having 26 to 75 percent villous component account for 5 to 15 percent of adenomas; combination account for 5 to 15 percent of adenomas; combination of above.of above.

Serrated PolypsSerrated Polyps

Display features of both hyperplastic and adenomaDisplay features of both hyperplastic and adenomaWere classified in past as HP and benign but new Were classified in past as HP and benign but new evidence shows that they may behave as adenomasevidence shows that they may behave as adenomasNo guidelines for management; it is generally No guidelines for management; it is generally recommended that surveillance intervals should follow recommended that surveillance intervals should follow that of other adenomasthat of other adenomasTwo typesTwo types

Sessile serrated adenoma Sessile serrated adenoma precursors to large HP in precursors to large HP in proximal colon of patients with hyperplastic polyposisproximal colon of patients with hyperplastic polyposisTraditional serrated adenoma Traditional serrated adenoma look and behave as look and behave as conventional adenomas; often pedunculated found more conventional adenomas; often pedunculated found more often in distal colonoften in distal colon

Risk Factors for High grade Risk Factors for High grade dysplasia and cancerdysplasia and cancer

Adenomatous polyps > 1 cm in diameter are risk factor Adenomatous polyps > 1 cm in diameter are risk factor for containing CRCfor containing CRCVillous histology Villous histology adenomatous polyps with > 25 adenomatous polyps with > 25 percent villous histology are a risk factor for developing percent villous histology are a risk factor for developing CRCCRCHighHigh--grade dysplasia grade dysplasia adenomas with highadenomas with high--grade grade dysplasia often coexist with areas of invasive cancer in dysplasia often coexist with areas of invasive cancer in the polyp.the polyp.Number of polyps: three or more is a risk factor for Number of polyps: three or more is a risk factor for development of metachronous adenomas with development of metachronous adenomas with advanced pathologic features.advanced pathologic features.

Molecular Basis of Colorectal CancerMolecular Basis of Colorectal Cancer

Colorectal cancer is the second leading cause of Colorectal cancer is the second leading cause of death from cancer among adults.death from cancer among adults.benign adenomatous polyp benign adenomatous polyp advanced advanced adenoma with high grade dysplasia adenoma with high grade dysplasia invasive invasive cancercancer

Genomic InstabilityGenomic Instability

Chromosomal InstabilityChromosomal Instability most common type of most common type of genomic instability in CRC; changes in chromosomal genomic instability in CRC; changes in chromosomal copy number and structure.copy number and structure.

Loss of tumor suppressor genes: APC, P53, SMAD4Loss of tumor suppressor genes: APC, P53, SMAD4DNADNA--Repair DefectsRepair Defects Inactivation of genes required Inactivation of genes required for repair of basefor repair of base--base mismatches in DNAbase mismatches in DNA

Inherited inactivation: HNPCC (lynch syndrome) Inherited inactivation: HNPCC (lynch syndrome) germ line germ line defects in mismatchdefects in mismatch--repair genes (MLH1 and MSH2); high repair genes (MLH1 and MSH2); high risk of second cancers (endometrial, ovarian, small intestine) risk of second cancers (endometrial, ovarian, small intestine) Acquired inactivationAcquired inactivation

Aberrant DNA MethylationAberrant DNA Methylation causes epigenetic causes epigenetic silencing of genessilencing of genes

Mutational Inactivation of Tumor Mutational Inactivation of Tumor Supressor GenesSupressor Genes

CRC acquire many genetic changesCRC acquire many genetic changesChanges in the Wnt signaling pathway, is Changes in the Wnt signaling pathway, is regarded as the initiating event in colorectal regarded as the initiating event in colorectal cancercancer

The most common mutation in CRC inactives the The most common mutation in CRC inactives the gene that encodes the APC proteingene that encodes the APC proteinIn the absence of functional APC In the absence of functional APC the brake on Bthe brake on B--catenin catenin Wnt signaling is inappropriately and Wnt signaling is inappropriately and constitutively activated.constitutively activated.

Growth Factor PathwaysGrowth Factor Pathways

Increased levels of COXIncreased levels of COX--2 are found in 2 are found in approximately two thirds of CRCapproximately two thirds of CRCLoss of 15Loss of 15--PGDH in 80% of colorectal PGDH in 80% of colorectal adenomas and cancersadenomas and cancersClinical trials have shown that the inhibition of Clinical trials have shown that the inhibition of CoxCox--2 by NSAIDS prevents the development of 2 by NSAIDS prevents the development of new adenomas and mediates regression of new adenomas and mediates regression of established adenomas established adenomas (Steinbach et al. The effect of celecoxib, a cox(Steinbach et al. The effect of celecoxib, a cox--2 inhibitor, in FAP N 2 inhibitor, in FAP N Engl J Med 2000;342:1946Engl J Med 2000;342:1946--52)52)

A 60 year old male presents with recurrent pancreatitis and weigA 60 year old male presents with recurrent pancreatitis and weight loss. He denies ht loss. He denies alcohol use and take no medications. On CT, a cystic mass is foualcohol use and take no medications. On CT, a cystic mass is found in the head of nd in the head of

the pancreas as well as a dilated pancreatic duct. A follow up the pancreas as well as a dilated pancreatic duct. A follow up ERCP reveals a ERCP reveals a mucus protruding from the ampulla. He undergoes a colonoscopy amucus protruding from the ampulla. He undergoes a colonoscopy as part of his s part of his

workwork--up, as he also has iron deficiency anemia.up, as he also has iron deficiency anemia.

What type of polyps are associated with this presentationWhat type of polyps are associated with this presentation

A. Serrated AdenomasA. Serrated AdenomasB. Hamartomatous polypsB. Hamartomatous polypsC. Hyperplastic polypsC. Hyperplastic polypsD. Villous AdenomasD. Villous AdenomasE. Glandular hyperplasiaE. Glandular hyperplasia

Answer is BAnswer is B

The patient shows features typical of intraductal The patient shows features typical of intraductal mucinous neoplasms (IPMN). The final mucinous neoplasms (IPMN). The final diagnosis would be strengthened by cytology diagnosis would be strengthened by cytology and positive mucin stain.and positive mucin stain.One third of patients with IPMN harbor an One third of patients with IPMN harbor an inactivated Peutzinactivated Peutz--Jeghers gene STK 11/LKB1, Jeghers gene STK 11/LKB1, which is associated with hamartomatous polyps which is associated with hamartomatous polyps and increase in colon cancer risk.and increase in colon cancer risk.

Which of the following statements is true regarding the Which of the following statements is true regarding the pathogenesis of colorectal cancer?pathogenesis of colorectal cancer?

A. Colorectal cancers that demonstrate chromosomal A. Colorectal cancers that demonstrate chromosomal instability tend to be diploidinstability tend to be diploidB. Colorectal cancers that demonstrate microsatellite B. Colorectal cancers that demonstrate microsatellite instability often have p53 mutationsinstability often have p53 mutationsC. Colorectal cancers from familial adenomatous C. Colorectal cancers from familial adenomatous polyposis patients tend to follow the chromosomal polyposis patients tend to follow the chromosomal instability pathwayinstability pathwayD. Colorectal cancers that demonstrate microsatellite D. Colorectal cancers that demonstrate microsatellite instability often lack mucin within their tumors.instability often lack mucin within their tumors.E. Colorectal cancers that arise in patients with IBD E. Colorectal cancers that arise in patients with IBD follow the chromosomal instability pathway.follow the chromosomal instability pathway.

Answer is CAnswer is C

The chromosomal instability pathway is observed in 80 to 85% The chromosomal instability pathway is observed in 80 to 85% of sporadic colorectal cancers and also familial adenomatous of sporadic colorectal cancers and also familial adenomatous polyposis cancers. It is mainly characterized by aneuploidy, wipolyposis cancers. It is mainly characterized by aneuploidy, with th loss of heterozygosity at key tumor suppressor gene loci, loss of heterozygosity at key tumor suppressor gene loci, including APC, chromosome 18q, and p53. Tumors that including APC, chromosome 18q, and p53. Tumors that demonstrate microsatellite instability have a different genetic demonstrate microsatellite instability have a different genetic pattern that does not involve p53 and tend to be rightpattern that does not involve p53 and tend to be right--sided sided colon location, poorly differentiated, and more likely to be colon location, poorly differentiated, and more likely to be mucinous. IBD associated colorectal cancers demonstrate a mucinous. IBD associated colorectal cancers demonstrate a different timing and pattern of molecular alterations than the different timing and pattern of molecular alterations than the CIN and MSI pathways, with p53 mutations occurring early but CIN and MSI pathways, with p53 mutations occurring early but with rare APC and Kwith rare APC and K--RAS mutations.RAS mutations.

A 35 year old male with no significant family history presents wA 35 year old male with no significant family history presents with iron deficiency anemia. A ith iron deficiency anemia. A colonoscopy was performed as part of his work up and revealed apcolonoscopy was performed as part of his work up and revealed approximately 200 polyps proximately 200 polyps

distributed throughout the entire colon. Histology of the polypdistributed throughout the entire colon. Histology of the polyp reveals them to be adenomas. reveals them to be adenomas. What is the appropriate next step?What is the appropriate next step?

A. Perform total colectomy with mucosal proctectomy, then A. Perform total colectomy with mucosal proctectomy, then genetic counseling and testing for APC germline mutation.genetic counseling and testing for APC germline mutation.B. Perform surveillance colonoscopies annually, with segmental B. Perform surveillance colonoscopies annually, with segmental resection of cancers.resection of cancers.C. Perform total colectomy with mucosal proctectomy, then C. Perform total colectomy with mucosal proctectomy, then genetic counseling and testing for hMLH1 and hMSH2 germline genetic counseling and testing for hMLH1 and hMSH2 germline mutations.mutations.D. Perform total colectomy with mucosal proctectomy, then D. Perform total colectomy with mucosal proctectomy, then genetic counseling and testing for SMAD4 and BMPR1A genetic counseling and testing for SMAD4 and BMPR1A germline mutations.germline mutations.E. Perform total colectomy with mucosal proctectomy, then E. Perform total colectomy with mucosal proctectomy, then genetic counseling and testing for PTEN germline mutations.genetic counseling and testing for PTEN germline mutations.

Answer is A.Answer is A.

This patient has multiple adenomas, which makes it This patient has multiple adenomas, which makes it most likely that the patient carries a germ line mutation most likely that the patient carries a germ line mutation in APC or has biallelic mutations in the MYH gene. in APC or has biallelic mutations in the MYH gene. Thus, this patient has either an attenuated form of FAP Thus, this patient has either an attenuated form of FAP or MYH polyposis. The risk for colorectal cancer or MYH polyposis. The risk for colorectal cancer development is nearly 100% and the patient should development is nearly 100% and the patient should undergo a total abdominal colectomy and subsequently undergo a total abdominal colectomy and subsequently be referred to genetic counseling and appropriate be referred to genetic counseling and appropriate testing. Additionally, the patient should contact family testing. Additionally, the patient should contact family members for screening and potentially genetic testing members for screening and potentially genetic testing purposes.purposes.

1118 A 50-year-old woman presents for colorectal cancer screening. Her father had colon cancer at age 45 and her sister at age 55. Her colonoscopy reveals a cecal adenocarcinoma. Which of the following statements regarding this syndrome is true?

A. It is inherited in an autosomal recessive fashion.B. It causes less than 1% of all colorectal cancers.C. There is increased frequency of cancer of the female genital tract.D. Germline mutations in the hMSH2 or hMLH1 genes do not occur.E. There is a predominance of distal tumors.

1118 C (S&F, ch123)This family meets the Amsterdam criteria for HNPCC. This syndrome is inherited in an autosomal dominantfashion. There is a predominance of proximal tumors. Germline mutations in the hMSH2 or hMLH1 geneare present in 80% of colon cancers. There is an increased frequency of cancers of the female genital tract.This syndrome accounts for approximately 6% of all the colorectal cancers, whereas FAP accounts for lessthan 1% (see three tables at end of chapter).

1134 A statistician consults you and wants to know precisely which test can prevent him from dying of coloncancer. Which of the following has been shown to decrease mortality from colorectal cancer?

A. Yearly FOBTB. Double-contrast barium enemaC. Virtual colonoscopyD. Yearly digital rectal examination

1134 A (S&F, ch123)FOBT has been shown in large-scale, randomized, controlled studies to decrease mortality from colorectalcancer with yearly and biannual testing. A decrease in colorectal cancer mortality has been demonstratedwith sigmoidoscopy. The National Polyp Study suggests that removal of adenomatous polyps reduces themortality from colorectal cancer. Thus, it has been inferred that colonoscopy should have the same effect.