1. Low Grade DysplasiaWhat Should Be Done? Amitabh Chak, MD University Hospitals Case Medical Center Cleveland, OHIO

2. Cases of LGD Case One: 69 yo man with HTN, CAD. 8 cm BE diagnosed 18 years ago. 11 years ago had LGD on one biopsy No LGD on 7 surveillance EGDs since “Seattle protocol” detects LGD in one jar Case Two: 54 year old man with chronic GERD Screening EGD shows 5 cm of BE with LGD in every jar

3. Questions What is Low Grade Dysplasia (LGD) – definition, interpretation, agreement? What is the risk of progression from LGD to cancer? What is the recommended management of LGD? Should LGD be considered for ablative therapy?

4. Progression (histology, courtesy of JHU website) BE LGD (1.5 – 4 yrs) (0.5 – 1.5 yrs) CA HGD

5. John Goldblum, MD – Cleveland Clinic

6. John Goldblum, MD – Cleveland Clinic

7. Low Grade Dysplasia Preserved glandular architecture Nuclear hyperchromasia Nuclear stratification confined to lower half of epithelium Increased mitotic figures Depleted mucin; decreased goblet cells Difficult to interpret in presence of inflammation

8. Pathology Interpretation E. Montgomery, et al., 2001 12 expert GI pathologists submitted 250 slides containing BE, IND, LGD, HGD, and cancer. One set of 125 slides reviewed twice by each pathologist prior to consensus meeting. Second set of 125 slides reviewed by each pathologist after consensus meeting.

9. Intra and Inter-Observer Agreement For Differentiating Non-dysplastic/IND/LGD vs. HGD/Ca Intraobserver Kappa = 0.82  0.80 (near perfect) Interobserver Kappa = 0.66  0.70 (substantial) For Diagnosing Specific Categories Interobserver Kappa for HGD/Ca = 0.65 (substantial) Kappa for BE = 0.58 (moderate) Kappa for LGD = 0.32 (fair)

10. Natural History of LGD(Lim CH, et al., Endoscopy 2007) 357 patients with BE identified in UK hospital between 1984-95; 34 developed LGD Retrospective follow-up performed on 34 incident LGD and 322 non-dysplastic BE cases HGD/Ca developed in 9/34 (27%) LGD cases and 16/322 (5%) BE cases Interobserver agreement on original LGD diagnosis was only fair (kappa = 0.48)

13. Natural History of LGD(Sharma, et al., Clin Gastro Hep 2006) Multi-center followup of 618 BE patients, mean F/U 4.12 years. BE to LGD incidence 1 in 25 patient years = 4% LGD to Cancer incidence was 1 in 156 patient years = 0.6% Non-dysplastic BE to Cancer incidence was 1 in 212 patient years = 0.5%

15. Biomarkers of LGD Progression(Weston et al., AJG 2001) p53 Negative p53 Positive

16. Followed 48 pts with LGD for a mean of 41 months. Ten patients were p53 positive – 4 regressed, 3 persisted as LGD, and 3 progressed to HGD/Ca

17. Biomarkers of LGD Progression(Skacel, et al. AJG 2002) Followed 16 patients with LGD for a mean of 23 months. 7 of 9 that were p53 positive progressed to HGD/Ca vs. 1 of 7 that were p53 negative

18. Surveillance Guidelines for LGD(Wang et al., AJG 2008) Review biopsies with expert pathologist to confirm diagnosis of LGD Repeat EGD with surveillance in 6 months to ensure there is no HGD or Cancer Perform EGD every year if LGD persists or 3 years if there is no dysplasia on two consecutive surveillance endoscopies

19. Video of RFA

20. Response to RFA(Shaheen, et al. NEJM 2010)

21. Complications of RFA in 119 pts 4 Serious Adverse Events 1 GI bleed 3 hospitalizations for Chest Pain/Nausea 9 (8%) patients developed esophageal strictures that responded to dilation Do not know long-term durability or side effects

22. Approach to Patient with LGD Review current guidelines for surveillance Reassure patients with LGD that their risk of progression to cancer is not much higher than non-dysplastic BE Review data on efficacy and complications of RFA Explain to patient that surveillance is still necessary Let patient decide

23. Cases of LGD – Patient Decisions Case One: 69 yo man with HTN, CAD. 8 cm BE diagnosed 18 years ago. 11 years ago had LGD on one biopsy Elected to continue surveillance. Has had no dysplasia in last two endoscopies Case Two: 54 year old man with chronic GERD Screening EGD shows 5 cm of BE with LGD in every jar Elected to have RFA. Successfully ablated. Continues under surveillance