1. 1 Differential Diagnosis of Neoplastic Pancreatic Cysts: The Role of EUS with Guided FNA Erwin M. Santo, MD Head, Invasive Endoscopy Unit Dep. of Gastroenterology & Hepatology Tel-Aviv Sourasky Medical Center

2. 2 Introduction Cystic lesions constitute about 10 % of pancreatic tumors Cystic lesions constitute about 10 % of pancreatic tumors Significant increase in detection due Significant increase in detection due to widespread use of US,CT to widespread use of US,CT Most lesions discovered incidentally Most lesions discovered incidentally

3. 3 Clinical Presentation Asymptomatic Asymptomatic Abdominal pain Abdominal pain Jaundice Jaundice Pancreatitis Pancreatitis

4. 4 Clinical Presentation Asymptomatic Asymptomatic Ca in situ / invasive cancer – 17% Ca in situ / invasive cancer – 17% Lesion with malignant potential – 42% Lesion with malignant potential – 42% Fernandez Del Castillo et al. Arch Surg 2003

5. 5 Classification Non neoplastic (pseudocysts) Non neoplastic (pseudocysts) Neoplastic Neoplastic Mucinous Non Mucinous

6. 6 Classification Non Mucinous Cysts 1. Serous cystadenoma 2. Cystic endocrine tumors 3. Other

7. 7 Classification Mucinous Cysts 1. Mucinous cystadenoma 2. Malignant mucinous cystic tumors 3. Intraductal papillary mucinous neoplasms - IPMN

8. 8

9. 9 Diagnosis CT – microcystic appearance, central CT – microcystic appearance, central fibrosis- Serous fibrosis- Serous Unilocular, macrocystic, peripheral Unilocular, macrocystic, peripheral calcification- Mucinous calcification- Mucinous MRCP – MPD dilatation, mural nodules MRCP – MPD dilatation, mural nodules ductal connection - IPMN ductal connection - IPMN

10. 10 Diagnosis EUS - highly sensitive EUS - highly sensitive FNA – fluid characteristics, tumor markers, cytology FNA – fluid characteristics, tumor markers, cytology CEA in fluid - most accurate marker CEA in fluid - most accurate marker

11. 11 EUS – Serous cyst

12. 12 EUS – Mucinous cyst

13. 13 Diagnosis of Pancreatic Cystic Neoplasms: A report of the Cooperative Cyst Study Brugge WR, M.D. and Colleagues Gastroenterology 2004; 126:1330-1336 Gastroenterology 2004; 126:1330-1336

14. 14 Optimal Cutoff CEA Mucinous vs non-mucinous

15. 15 Differentiating between mucinous and non-mucinous lesions EUSCytologyCEA Sensitivity (%) 32/57 (56.1%) 19/55 (34.5%) 42/56 (75%) Specificity (%) 25/55 (45.4%) 45/54 (83.3%) 46/55 (83.6%) Accuracy (%) 57/112 (50.9%) 64/109 (58.7%) 88/111 (79.2%) *p<.001 vs Cytology, EUS

16. 16 Combination Testing EUS Morphology or Cytology EUS Morphology or Cytology or CEA Cytology or CEA Sensitivity (%) + 709182 Specificity (%) 383171 Accuracy (%) 546277* Area under ROC curve 0.5418 ^ 0.6107 ^.7668 *p<.05 vs EUS morphology -cytology, EUS morphology-cytology-CEA

17. 17 Summary of Findings EUS-FNA is safe for evaluation of pancreatic masses and cystadenomas EUS-FNA is safe for evaluation of pancreatic masses and cystadenomas Cytology results are much better in solid lesions Cytology results are much better in solid lesions EUS-FNA should be used to assist in the selection of patients with a pancreatic lesion for surgical resection. EUS-FNA should be used to assist in the selection of patients with a pancreatic lesion for surgical resection. Cyst fluid CEA levels should be used in conjunction with cytology for pancreatic cystadenomas Cyst fluid CEA levels should be used in conjunction with cytology for pancreatic cystadenomas

18. 18 AIM Evaluation of the various parameters (clinical,morphological,fluid content, cytology) and their contribution to the ability to distinguish between serous and mucinous cystic tumors Evaluation of the various parameters (clinical,morphological,fluid content, cytology) and their contribution to the ability to distinguish between serous and mucinous cystic tumors

19. 19 AIM Validation of the current criteria used to distinguish between various cystic tumors (gold standard based on surgical pathology ) Validation of the current criteria used to distinguish between various cystic tumors (gold standard based on surgical pathology ) Establishing new criteria with higher sensitivity and specificity Establishing new criteria with higher sensitivity and specificity

20. 20 AIM Provide an algorithm for the diagnosis and treatment of pancreatic cystic lesions Provide an algorithm for the diagnosis and treatment of pancreatic cystic lesions

21. 21 Heuristics used in our Institute for Dx of Serous cysts Heuristics used in our Institute for Dx of Serous cysts - Clinical - Microcystic morphology - CEA level < 5 ng / ml - Histology- cuboidal, non secreting cells

22. 22 - Clinical - Morphology – unilocular, thick septa, solid component - High viscosity (mucinous) fluid - CEA - >140 ng/ml - Histology – columnar secreting epithelium Heuristics used in our Institute for Dx of Mucinous cysts

23. 23 Methods

24. 24 Methods Retrospective study Retrospective study 170 patients between 1977-2006 170 patients between 1977-2006 155 patients,195 EUS exams 155 patients,195 EUS exams 40 patients – EUSx2 or more 40 patients – EUSx2 or more 101 women, 54 men 101 women, 54 men Mean age – 64.3±14 years Mean age – 64.3±14 years

25. 25 Methods Demographic data Demographic data Clinical presentation Clinical presentation Imaging – US, CT, EUS Imaging – US, CT, EUS FNA FNA Surgical findings Surgical findings Follow up on all patients ( office visits, data from family physicians, gastroenterologists, patient’s families) Follow up on all patients ( office visits, data from family physicians, gastroenterologists, patient’s families)

26. 26 Methods EUS Cyst location, size, morphology Cyst location, size, morphology FNA – fluid: FNA – fluid: - characteristics - cytology - tumor markers – CEA,CA19-9,CA72-4,MCA Cyst wall sampling (cell block) Cyst wall sampling (cell block)

27. 27 Results

28. 28 Results Clinical Presentation No. % Incidental finding 103 103 69.3 69.3 Abdominal pain 29 29 19.6 19.6 Weight loss 2 1.4 1.4 Jaundice 2 Abdominal pain/weight loss 5 3.4 3.4 Dyspepsia 2 1.4 1.4 Diarrhea 2 Diarrhea/weight loss 3 2.0 2.0

29. 29 Results Location No. % Head 5233.5 Neck 14 9.0 Body 4126.5 Tail 2516.1 Other 2314.8

30. 30 –37 patients had surgery with histological findings. –140 patients had FNA but results were available for 80 patients. Results

31. 31 Results Surgical PathologyNo.% Non neoplastic616.2 Serous410.8 Mucinous1335.1 Mucinous ca.1129.7 IPMN25.4 Neuroendocrine12.7

32. 32 Results FNA HistologyNo.% Non neoplastic1216.0 Serous2733.8 Mucinous2531.3 Carcinoma1417.5 Neuroendocrine22.5

33. 33 –32 patients had both FNA and surgical biopsy. –The agreement rate was 66% of the cases regarding mucinous vs. non-mucinous with kappa=0.33. –Sensitivity and specificity of FNA are 59% and 80% respectively. EUS-FNA vs. Surgical biopsy

34. 34 Results Mean of Ln(CEA) * levels were 2.6 and 5.8 for non mucinous and mucinous cases respectively (p<0.0001) Mean of Ln(CEA) * levels were 2.6 and 5.8 for non mucinous and mucinous cases respectively (p<0.0001) No statistically significant difference with all the other tumor markers tested No statistically significant difference with all the other tumor markers tested Rate of solid component in cyst – the difference was not statistically significant (p=0.14) Rate of solid component in cyst – the difference was not statistically significant (p=0.14) No difference concerning cyst size or morphology No difference concerning cyst size or morphology *CEA is highly skewed distributed and therefore we transformed the CEA level to Ln(CEA)

35. 35 Mucinous Ln(CEA) BoxPlot Non-mucinous

36. 36 95% C.I.for OR VariableBS.E.p-valueORLowerUpper log 10 CEA1.8180.7270.0126.21.4825.6 Age-0.0410.0220.060.960.921.01 Logistic regression results Note that CA-19 is highly correlated with CEA, and when CEA levels are unavailable the CA-19 level should play a role in the diagnostic process.

37. 37 95% C.I.for OR VariableBS.E.p-valueORLowerUpper log 10 CEA1.8180.7270.0126.21.4825.6 Age-0.0410.0220.060.960.921.01 Logistic regression results For example, a patient with CEA value of 10 and probability for mucinous cyst of 40% compared to a patient with CEA level of 100 the probability of mucinous cyst is 86%.

38. 38 ROC of CEA classification of Mucinous vs. Serous 1-specificity sensitivity AUC=0.902 (CI=(0.79-1.0)) A Threshold of CEA=58 ng/ml yields 86.4% and 87.5% sensitivity and specificity respectively

39. 39 Conclusions EUS is a useful tool but it can not alone distinguish between cystic lesions with variable malignant potential EUS is a useful tool but it can not alone distinguish between cystic lesions with variable malignant potential EUS-FNA alone is also limited in its ability to correctly diagnose a cystic lesion – sensitivity 59% specificity 80% EUS-FNA alone is also limited in its ability to correctly diagnose a cystic lesion – sensitivity 59% specificity 80% Combination of parameters – cytology and CEA levels (or CA 19-9 levels) can significantly increase the diagnostic yield Combination of parameters – cytology and CEA levels (or CA 19-9 levels) can significantly increase the diagnostic yield

40. 40 A Practical Decision Algorithm based on the Threshold Decision Model Source: NEJM 1980; 302:1109-17

41. 41 For a patient with a pancreatic cyst there are several management options: Wait and watch approach with a follow up. An initial EUS-FNA is performed and patients with increased cyst fluid CEA or positive cytology undergo a surgical resection. Surgical resection of all cysts without prior EUS evaluation. Wait and watch approach with a follow up. An initial EUS-FNA is performed and patients with increased cyst fluid CEA or positive cytology undergo a surgical resection. Surgical resection of all cysts without prior EUS evaluation.

42. 42 Beside the preferences of the patient, the following parameters are relevant to the decision process: Age of the patient  60 year 61-75 year > 75 year Co-morbidity status (CV diseases, diabetes, other neoplasm diseases) No co-morbidity Co-morbidity Test results (CT, EUS) Age of the patient  60 year 61-75 year > 75 year Co-morbidity status (CV diseases, diabetes, other neoplasm diseases) No co-morbidity Co-morbidity Test results (CT, EUS)

43. 43 Natural history of mucinous cystic neoplasm 78 years old woman with incidental finding - 1977

44. 44 Age <=60 60 - 75 >75 Co-morbidity Yes No Positive Cytology or CEA>60 Yes No Yes No 5< CEA<60 Compliance = Surgical Resection = Wait and Watch Complexity of Surgical resection Yes No Yes No Yes No = Debate Yes No

45. 45 Age <=60 60 - 75 >75 Co-morbidity Yes No Positive Cytology or CEA>60 Yes No = Surgical Resection = Wait and Watch Complexity of Surgical resection Yes No = Debate

46. 46 Age <=60 60 - 75 >75 Co-morbidity Yes No Positive Cytology or CEA>60 Yes No = Surgical Resection = Wait and Watch Yes No = Debate

47. 47 Thank You