Patients with Unresected Flat LGD Should Undergo Colectomy

1. Patients with Unresected Flat LGD Should Undergo Colectomy Thomas Ullman, M.D., M.Sc. Director Center for IBD The Mount Sinai School of Medicine

2. Cumulative Risk of CRC in UC Clearly, we know that as with sporadic CRC, if we wait until it becomes symptomatic, then the mortality rate will hover at or about 50%. As for the 2nd assumption, we’ll say “yes” but take a look at the next slide which depicts the variability in CRC, knowing always that the further out we go on the curve, the smaller the denominators become.Clearly, we know that as with sporadic CRC, if we wait until it becomes symptomatic, then the mortality rate will hover at or about 50%. As for the 2nd assumption, we’ll say “yes” but take a look at the next slide which depicts the variability in CRC, knowing always that the further out we go on the curve, the smaller the denominators become.

3. Risk of CRC in Crohn’s

7. Dysplasia-Carcinoma Sequence Polyp removal leads to CRC prevention Polyp is surrogate markerPolyp removal leads to CRC prevention Polyp is surrogate marker

8. “Natural” History of Dysplasia in IBD

10. Probability of Finding Cancer DALM 1 17/40 (43%) -- High-grade 1 10/24 (42%) 15/47 (32%) High-grade 2 8/12 (67%) -- High-grade 3 5/11 (45%)

12. OK for Polypectomy

13. Colectomy vs. Polypectomy and continued surveillance

14. Probability of Finding Cancer Bernstein, 1994, DALM 17/40 (43%) Odze, 2004, P-DALM 1/24 (7.5 yrs) Rubin, 1999, D-polyps 0/48 Engelsgjerd, 1999, P-DALM 0/24 (8%) Rutter, 2006, adenoma 2/52 (4%)/5 yrs Rutter, 2006, DALM-L 30% Rutter, 2006, DALM-H 33%

15. Probability of Finding Cancer after LGD Low-grade 1 3/16 (19%) 17/204 (8%) Low-grade 2 2/11 (19%) Low-grade 3 2/10 (20%)

16. Progression of LGD to HGD or Cancer after LGD Study Hospital LGD (n) Rate Connell (‘94) St. Mark’s 9 54% @ 5 yrs Ullman (‘03) Mount Sinai 46 53% @ 5 yrs Ullman (‘02) Mayo Clinic 18 33% @ 5 yrs Rutter (’06) St. Mark’s 36 25% @ 5 yrs Lindberg (‘96) Huddinge 37 35% @ 20 yrs Lim (‘03) Leeds, UK 29 10% @ 10 yrs Befrits (‘02) Karolinska 60 2% @ ~10 yrs

17. Mount Sinai flat LGD experience

18. The next 3 slides will reexamine the results by using timelines. This timeline demonstrates the colonoscopic and surgical histories of the 7 patients who progressed to cancer. Each bar represents one patient, and the x-axis is time in months, with time 0 signifying the time of the initial flat LGD. Each letter represents a finding at colonoscopy, and the notation at the end of the bar indicates the Dukes stage at colectomy. Overall, there were 2 Dukes A, 2 Dukes B, and 3 Dukes C cancers. Note the trend of worsening Dukes stage as the time to colectomy increased. The 2 bars at the bottom represent the 2 patients who went to early colectomy and had Dukes A cancers; one had a colonoscopic finding of HGD prior to surgery, the other had only the initial dx of flat LGD. The remaining 5 bars are patients from the delayed colectomy group. The Dukes B1 cancer developed in a patient who had two additional c’scopic findings of flat LGD prior to colectomy. The Dukes C1 and B2 cancers developed in patients who had findings of CRC at first f/u c’scopies a year or more out from the inclusion exam. Finally, as the top 2 bars indicate, the 2 Dukes C2 cancers arose in patients who had frequent exams with findings ranging from NoD to flat LGD. Importantly, both patients had no dysplasia at the colonoscopies immediately preceding that at which cancer was detected.The next 3 slides will reexamine the results by using timelines. This timeline demonstrates the colonoscopic and surgical histories of the 7 patients who progressed to cancer. Each bar represents one patient, and the x-axis is time in months, with time 0 signifying the time of the initial flat LGD. Each letter represents a finding at colonoscopy, and the notation at the end of the bar indicates the Dukes stage at colectomy. Overall, there were 2 Dukes A, 2 Dukes B, and 3 Dukes C cancers. Note the trend of worsening Dukes stage as the time to colectomy increased. The 2 bars at the bottom represent the 2 patients who went to early colectomy and had Dukes A cancers; one had a colonoscopic finding of HGD prior to surgery, the other had only the initial dx of flat LGD. The remaining 5 bars are patients from the delayed colectomy group. The Dukes B1 cancer developed in a patient who had two additional c’scopic findings of flat LGD prior to colectomy. The Dukes C1 and B2 cancers developed in patients who had findings of CRC at first f/u c’scopies a year or more out from the inclusion exam. Finally, as the top 2 bars indicate, the 2 Dukes C2 cancers arose in patients who had frequent exams with findings ranging from NoD to flat LGD. Importantly, both patients had no dysplasia at the colonoscopies immediately preceding that at which cancer was detected.

19. Low-Grade Tubulo-Glandular Adenocarcinoma (LGTGA) Well-differentiated adenocarcinoma with distinct histological features: rounded, oval or tubular glands minimal desmoplastic reaction minimal intraluminal necrosis low-grade nuclear cytology

22. Low-Grade Tubulo-Glandular Adenocarcinoma (LGTGA) Frequent association with IBD Accounts for 11% of IBD-associated CRC Some patients have multiple LGTGA Occurs in setting of UC or Crohn’s colitis Infrequent pre-operative diagnosis Direct derivation from LGD

25. Inconsistent Practices Among British GI’s 341 UK gastroenterologists responded (83%), 298 completed

26. Biopsy Practices: Mount Sinai

27. Mount Sinai: LGD v. IND v. NoD

30. Prospective Studies Comparing Chromoendoscopy to White Light

32. Beware the “Will Rogers Phenomenon” “When all the Okies moved left Oklahoma and moved to California, they raised the average intelligence level of both states.” Stage Migration: can improve survival at every stage without changing overall survival