GI Grand Rounds October 1, 2004

1. GI Grand RoundsOctober 1, 2004 Yoshi Makino, M.D. USC Department of Internal Medicine

2. Case Presentation Patient F.B. is a 64 year old African-American male, referred from an outside M.D. for OB(+) stool and anemia. Patient was scheduled for colonoscopy based on the above indications. PSH: none PMH: HTN hyperlipidemia

3. Case Presentation SH: EtOH: 1-2 beers/day,  6-pack on weekends x 40 years Tobacco: � ppd x 40 years Drugs: Marijuana in youth; without h/o IVDA ROS: Denies h/o BRBPR, melena, stool caliber changes, nor weight loss. Without h/o GERD or other upper GI complaints.

4. Case Presentation Allergies: NKDA Medications Pravachol 40 mg PO daily HCTZ 25 mg PO daily Atenolol/Chlorthalidone 50 mg / 25 mg PO daily Quinapril 40 mg PO daily Norvasc 10 mg PO daily Cardura 2 mg PO daily EC ASA 81 mg PO daily Darvocet or Tylenol 500 mg prn pain/HA

5. Laboratories

6. Colonoscopy Poor prep Anus: small IH Sigmoid: 2 cm flat polyp, s/p bx Transverse colon: one diminutive polyp and a 1.5 cm sessile polyp, s/p bx Ascending colon: multiple 2-9mm sessile polyp, s/p bx

7. Biopsy Results 8 of 11 polyps biopsied showed tubular adenoma Of these 8 polyps, 2 also showed areas of focal increased glandular complexity and high grade dysplasia

8. Colonoscopy Images

9. Colonoscopy Images

10. What Now?

11. Family History

12. Attenuated FAP

13. Objectives Overview Clinical Features Diagnosis Genetics Management

14. FAP Overview Familial colorectal cancers account for < 5% of all cases of colon cancer Yangming et al. AJG 2002;97(7)1822-1827. Familial Adenomatous Polyposis (FAP) was first described by Lockhart-Mummery in 1925 as a disease with clear dominant inheritance Adenomatous Polyposis Coli (APC: 5q21) gene identified by Kinzer and Groden in 1991

15. Attenuated FAP In 1990, Lynch et al described two families with �right-sided colonic flat adenomas� with more polyps than HNPCC but fewer than FAP Lynch also observed later age of onset of colon cancer, and a paucity of rectal adenomas Lynch et al. Cancer. 1990 Sep 1;66(5):909-15. Initially called �hereditary flat adenoma syndrome�, later called attenuated FAP

16. Clinical Features Less than 100 adenomas, typically morphologically flat Polyps primarily located proximal to the splenic flexure, sparing the rectum Diagnosed at mean age of 44 years, and cancers at a mean of 56 years Hernegger et al. Dis Colon Rectum. 2002 Jan;45(1):127-136.

17. Extracolonic Manifestations High association with gastric fundic polyps Extracolonic cancers similar to FAP, including: duodenal and periampullary tumors (5-10%) pancreatic (2%) thyroid (2%) Gastric (0.5%) Congenital Hypertrophic Retinal Pigment Epithelium (CHRPE), osteomas and desmoids are rarely seen Hernegger et al. Dis Colon Rectum. 2002 Jan;45(1):127-136.

18. Comparison of Hereditary Colorectal Diseases

19. Distinguishing Flat Polyps

20. High-resolution Chromoendoscopy

21. High-resolution Chromoendoscopy Conventional dyes (e.g. 0.9% indigo carmine) or florescent dyes used in conjunction with a high-resolution endoscope (410k � 850k pixels vs standard scopes 100k � 200k pixels) Hyperplastic polyps a characteristic �pit� pattern of orderly arranged circular �dots,� morphologically similar to surrounding normal mucosa. Adenomatous Polyps surface �grooves� occasionally with a sulcus-like appearance In a recent multicenter trial by Eisen et al., chromoendoscopy had a sensitivity of 82% and specificity of 82% in distinguishing the above polyps

22. Gastric Fundic Gland Polyps Fundic gland polyps account for 50% of all gastric polyps and are observed in 0.8-1.9% of all patients undergoing EGD Studies estimate 52-88% of FAP patients have gastric fundic glands polyps Unlike colonic adenomas, the number of gastric fundic gland polyps is not attenuated in AFAP Burt. Gastro 2003;125:1462-1469. Prevalence of duodenal and gastric adenomas is unknown, varying from 93% in one series to 0% in another Lynch. Cancer. 1995. / Rozen. Jpn J Cancer Res. 1999

23. Endoscopic Features Polyps are sessile, hemispherical elevations, at times with a �waist� but no clear stalk 1 mm to 5 mm in diameter Color is pale, pink, resembling surrounding mucosa On biopsy, polyps �chunk off� or detach entirely at the base Usually fewer than 10 polyps in sporadic cases, versus hundreds in FAP and AFAP Burt. Gastro 2003;125:1462-1469.

24. Gastric Fundic Gland Polyps

25. Diagnostic Criteria for AFAP Leppert et al suggest a set of diagnostic criteria for the disease A positive family history of colorectal cancer with at least one of the following criteria CRC at any age > 5 colorectal adenomas 2-4 adenomas and multiple gastric fundic polyps Leppert et al. N Engl J Med 1990; 322:9. Later studies suggest a fourth criteria Number of colorectal adenomas must be < 100 Knudsen et al. Familial Cancer. 2003;2:43-55

26. Problems with the Criteria No consensus exists on the exact definition of AFAP Cases of AFAP have been reported with adenomatous polyps in excess of 100 The age at which adenoma counts should be made is undefined Burt et al investigated 120 patients from 2 families with AFAP (5� mutation) revealing median number of 25 polyps, with a range of 0-470 polyps Burt et al. Gastro. 2004;127:444-451

27. Extreme Phenotypic Variability

28. The Genetics of AFAP Spirio et al in 1993 identifies four mutations at the 5� end (exon 3) of the APC gene in seven families with AFAP Spirio et al. Cell. 1993; 75: 951-7. Since then, 38 distinct mutations have been identified 5� to codon 175 (15) 3� to codon 1596 (12) Exon 9 (10) Deletion of entire allele (1)

29. APC Gene Mutations

30. APC Mutation Phenotypes

31. A Model for Mutation and FAP APC gene is a classic tumor suppressor gene, primarily down-regulating intercellular �-catenin activity and ultimately slowing cell cycle entry and progression �Dominant negative model� suggests that the mutated gene product forms homodimers with the wild-type protein, causing lowered or abolished tumor suppressor activity

32. APC, �-catenin and E-cadherin

33. An Explanation for Attenuation? 5� to codon 175 Mutation in this region affect the homodimer forming domain of the APC gene (amino acids 6-57) Interactions between mutated and wild-type proteins are reduced 3� to codon 1596 Gene product not detectable by Western blot analysis Suggests mRNA or protein degradation Exon 9 Even wild-type allele undergoes significant physiological splicing in this region Alternate splicing pathways may �skip over� mutation

34. MYH Mutations MYH along with OGG1 and MTH1 are proteins involved in the repair G:C to T:A transversions due to oxidative stress from 8-hydroxyguanine Recently, inherited variants of the MYH gene have been associated with colorectal polyposis with a recessive pattern of inheritance Al Tassan et al. Nat Genet. 2002;30:227-232. Jones et al. Hum Mol genet. 2002;11:2961-2967.

35. MYH Mutation and AFAP MYH-associated polyposis is phenotypically similar to attenuated FAP Later age of onset of polyposis than FAP Polyps usually < 100, but counts of 500 have also been reported Mutations in MYH may lead to G:C to T:A transversions in the APC gene However, autosomal recessive pattern

36. MYH Mutation and AFAP In a recent study, Wang et al analyzed 984 patients with high risk for genetic mutation 313 patients with 1-3 adenomatous polyps on colonoscopy 444 patients with history of CRC 140 patients referred for probable FAP 18 patients with biallelic mutations were identified 2 patients with colorectal cancer at age > 51 16 patients with 20 - 500 adenomatous polyps No patients with polyp counts < 20 had a biallelic MYH mutaition Wang et al. Gastro. 2004;127:9-16.

37. Genetic Testing for AFAP Clinical criteria for AFAP met Greater than 5 to 10 and less than 100 colorectal adenomas 2-4 adenomas and multiple gastric fundic polyps First-degree relatives of a person with a known APC mutation, regardless of polyp status A person with multiple adenomas who is a relative of a person with a known APC mutation Grady. Gastro. 2003;124:1574�1594

38. Role of MYH Testing in AFAP �At this time, there are insufficient clinical data regarding the role of MYH mutations� in people with adenomatous polyposis to make any recommendations regarding the use of MYH mutation analysis in the clinical management of these individuals.�

39. Recap of Disease Course Generally age at onset and progression to cancer (44 and 56 years respectively) is 15 years later than that of classic FAP Lesions usually proximal to the splenic flexure Rectal sparing Gastric fundic gland polyps commonly seen

40. Surveillance Recommendations Surveillance must be by colonoscopy Due to lesions proximal to splenic flexure Contrasts with screening by flexible sigmoidoscopy in classic FAP Colonoscopy starting at 10�17 years, annually EGD starting at 30 years, every 1�3 years, depending on polyp status in duodenum Grady. Gastro. 2003;124:1574�1594

41. Management Increased risk of colon cancer, but exact risk remains unknown (general consensus is roughly 60-80%) Similar to FAP, disease progression from adenoma to carcinoma is not accelerated Colonoscopy Unlike FAP, there is a sufficiently low number of colonic polyps to make polypectomy practical Burt et all. Gastro. 2004;127:444-451. EGD Best treatment of gastric fundic gland polyps is presently unknown Burt. Gastro 2003;125:1462-1469.

42. When to Perform Colectomy? The exact risk of colon cancer is unknown in AFAP, but estimated between 60 � 80% In FAP patients, The American Society of Colon and Rectal Surgeons recommends colectomy between ages 15 to 18 Church and Simmang. Dis Colon Rectum, August 2003. No clear consensus exists for AFAP 15 year delay in onset of disease would suggest colectomy at age 30 In a series of 120 patient with AFAP by Burt et al., first CRC was at a mean age of 58 years (range of ages 29 to 81), with 12 patients over the age of 60 with intact colons Burt et all. Gastro. 2004;127:444-451.

43. Type of Surgery Three main surgical options Colectomy and ileorectal anastomosis (IRA), Proctocolectomy with ileostomy (TPC) Proctocolectomy with ileal pouch-anal anastomosis (IPAA) As AFAP almost always spares the rectum, present consensus is for IRA, with subsequent surveillance by flexible sigmoidoscopy annually B�low et al. Gastro. 2000;119:1454�1460. Church and Simmang. Dis Colon Rectum, August 2003.

44. Pharmacologic Therapy Treatment with sulindac and celecoxib may also reduce polyp burden Giardiello et al. N Engl J Med 1993;328:1313-1316. Steinbach et al. N Engl J Med 2000;342:1946�52. In 1999, FDA approves celecoxib as a treatment for patients with FAP Dosage: celecoxib 400 mg PO BID �To reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis (FAP), as an adjunct to usual care (e.g., endoscopic surveillance, surgery).� FDA Application NDA 21-156 & 20-998/S007

45. Celecoxib and FAP

46. Sulindac and FAP 15 case series and at least 4 randomized, controlled trials have proven the efficacy of NSAIDs (primarily sulindac) in reducing the adenoma burden of persons with FAP However, in a recent trial by Giardiello, sulindac did not significantly reduce or delay the emergence of colorectal adenomas in prephenotypic FAP patients Definitive clinical outcomes (e.g., reductions in CRC morbidity and mortality or changes in surveillance practices) have yet to be proven. Hawk et al. Gatro. 204;126:1423�1447. Giardiello et al.N Engl J Med 2002;346:1054�1059.

47. Conclusions Attenuated FAP is a rare cause of CRC, accounting for <0.1% annually However, distinguishing AFAP from sporadic polyps is critical as the lifetime risk for CRC may be as high as 60-80% Suspicion for AFAP should be heightened in: the presence of > 5-10 colonic polyps (especially proximal distribution) 2-4 adenomas and multiple gastric fundic polyps Family history should be obtained, and genetic testing should be offered to all first degree relatives

48. Conclusions Annual colonoscopy with polypectomy may be sufficient to prevent progression of disease Pharmacologic therapy with celecoxib/ sulindac may further aid in reducing polyp burden No consensus yet regarding need for colectomy, however when required, IRA is believed to be sufficient

49. The Future of AFAP AFAP remains a poorly defined entity While most literature associates AFAP with specific APC mutations, recent literature suggest MYH mutations may also be seen in this disease Wang et al. Gastro. 2004;127:9-16. Consensus on a gold-standard test for AFAP is required to reliably report and follow the course of this disease Cumulative lifetime polyp counts To better understand progression of disease To reach a consensus regarding age that polyp count should be made

50. Patient Follow-up Patient had an EGD on 9/20/2004 to evaluate for gastric fundic gland polyps and periampullary disease No significant lesions found Patient underwent genetic counseling at Norris Comprehensive Cancer Center on 9/24/2004, and is presently pending results of genetic testing

51. Acknowledgements Dr. Laurie DeLeve Dr. Mark Ewing GI Consult Team This presentation is available at: http://www.makino.net/gastro

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