Gastrolearning II modulo/4a lezione Il ruolo dell'ecoendoscopia nella diagnosi delle lesioni solide pancreatiche Prof. A. Larghi - Università Cattolica Sacro Cuore (Roma).

1. Il Ruolo dell’Ecoendoscopia nelle
Lesioni Pancreatiche
Alberto Larghi MD, PhD
Digestive Endoscopy Unit
European Endoscopy Training Centre
Catholic University, Rome

2. Endoscopic Ultrasound
Historical Background
1970
1980
Development of the technique
First studies published in the literature
Hisanaga K. AJR 1980; Di Magno EP. Lancet 1980; Strohm WD. Endoscopy
1980
1984-88
Diagnostic EUS: Staging of luminal GI and
pancreatic cancers
Caletti GC. Scand J Gastroenterol 1984; Tanada Y. Scand J Gastroenterol 1984;
Yasuda K. Gastrointest Endosc 1988.
1992
EUS-FNA
Vilman P. Gastrointest Endosc 1992; Wegener M. Ultraschall Med 1992
1996
Interventional EUS
Wiersema MJ. Gastrointestinal Endoscopy 1996; Gress F. Gastrointestinal
Endoscopy 1996; Giovannini M. Endoscopy 2001
2013
Therapeutic EUS

3. Radial Echoendoscope
Radial
EUS
Ultrasound beam

4. Linear Echoendoscope
Linear
EUS
Mass
Ultrasound beam

5. Pancreatic Lesions
Role of EUS
 Screening
 Equivocal results of previous
imaging modalities
 Differential diagnosis and risk
assessment
 Staging
 Therapy/Interventional EUS

6. High-Risks Individuals*
Risk Group
Gene
Life Time Risk*
PRSS1
40%
STK 11/LKB1
36%
Familial Atypical Multiple Mole
Melanoma (FAMMM)
CDKN2a
17%
Familial Breast-Ovarian Cancer
(FBOC) with one affected FDR
BRCA2
10%-15%
Familial Pancreatic Cancer
unknown
Hereditary Pancreatitis
Peutz-Jeghers Syndrome
PC in ≥ 3 blood relatives (at
least 1 FDR)
PC in ≥ 2 FDR
PC in ≥ 2 blood relatives (at
least 1 FDR)
*>5% lifetime risk, or fivefold increased RR
40
8%-12%
6%
Canto MI. GUT 2013;62:339-47.

7. High-Risks Individuals
How to Screen
MRCP/EUS
When to Start
40 yrs for HP/ 50 yrs for others
How frequently to Surveil
Yearly

8. High-Risks Individuals
Results of Screening
Canto MI. GUT 2013;62:339-47.

9. Pancreatic Lesions
Role of EUS
 Screening
 Equivocal results of previous
imaging modalities
 Differential diagnosis and risk
assessment
 Staging
 Therapy/Interventional EUS

10. Detection of Pancreatic Cancer
EUS vs. CT
Non specific CT changes (enlarged, prominent pancreas)
No. Of
Patients
Rate of
malignancy
Ho, 2006
50
8%
Singh, 2008
107
21%
Horwhat, 2009
69
9%
Reddymasu, 2011
320
9%
Author, yr

11. Detection of Pancreatic Cancer
EUS vs. CT
104 patients with suspected pancreatic cancer
 80 with confirmed PC
 Sensitivity 98% vs. 86%, P=0.012
 for masses ≤25mm, 89% vs. 53%, P=0.07
DeWitt J. Ann Intern Med 2004;141:753-63.
Non specific CT changes (enlarged, prominent pancreas)
All Lesions°
EUS
93
MDHCT*
74
Insulinoma^
84
32
*64-slice CT; °P=0.06; ^P=0.001
Khashab MA. Gastrointest Endosc 2011;73:691-6.

12. Detection of Pancreatic Cancer
EUS Performance
HIGH NEGATIVE PREDICTIVE VALUE
Pts.
negative
EUS
Negative
Predictive
Value
Mean f/u
Catanzaro, ‘03
58
100%
24
Klapman, ‘05
155
100%
25
Author
(mos.)
Catanzaro Al. Gastrointest Endosc 2003;58:836-40.
Klapman JB. Am J Gastroenterol 2005;100:2658-61.

13. Pancreatic Lesions
Role of EUS
 Screening
 Equivocal results of previous
imaging modalities
 Differential diagnosis and risk
assessment
 Staging
 Therapy/Interventional EUS

14. EUS-FNA
Unresectable Tumors
EUS-FNA when available is the procedure of choice
for obtaining a pathologic diagnosis to start chemoRT

15. Unresectable Tumors
EUS-FNA vs CT/US-FNA
Restrospective study on 1050 pancreatic FNAs:
 EUS (843), US/CT (207)
 For lesions ≤ 3cm, EUS accuracy significantly
better than CT/US (p=0.015)
Volmar KE. Gastrointest Endosc 2005;61854-61.
Prospective randomized study on 84 pancreatic FNAs:
 EUS (41), US/CT (43)
 EUS vs. US/CT: sensitivity 84% vs. 62%, p=ns
accuracy 89% vs. 72%, p=0.074
Horwhat JD. Gastrointest Endosc 2006;63:966-75.
Eloubedi M. Gastrointest Endosc 2006;63:622-9.

16. Seeding
EUS-FNA vs. US/CT-FNA
Incidence of peritoneal carcinomatosis


EUS-FNA
Percutaneous FNA
2.2%
16.3%
P < 0.025
Micames C. Gastrointest Endosc 2003;58:690-5.
American Joint Committee on Cancer
EUS-FNA preferred sampling technique for
pancreatic cancer

17. EUS-FNA for Pancreatic Masses
Performance
Meta-analysis and systematic review
(41 studies; 4766 patients)
 Pooled sensitivity 86.8% (95% CI,
85.5-87.9)
 Pooled specificity 95.8% (95% CI,
94.6-96.7)
 Positive likelihood ratio 15.2 (95% CI,
8.5-27.3)
 Negative likelihood ratio 0.17 (95%
CI, 0.13-0.21)
Puli SR. Pancreas 2013;42:20-6.

18. Resectable Tumors
Should FNA be performed?
Probability of cancer-related deaths (<12 mos) after surgical resection
 Patient demands definitive diagnosis
 To exclude other diagnoses
 Preoperative neoadjuvant
Volmar KE, et al. Gastrointest Endosc 2005;61854-61.
Barugola G, et al. Ann Surg Oncol 2009;16:3316:22.

19. EUS for Pancreatic Masses
Tissue is the issue
19G
22G
25G

20. EUS for Pancreatic Masses
Tissue is the issue
Prospective study in 61 consecutive patients
with pancreatic solid masses
 One needle pass performed
 Core biopsy samples in 55/61 (90.1%)
 Sensitivity: 87.5%
 Specificity: 100%
 PPV: 100%
 NPV: 41.7%
 Diagnostic accuracy: 88.5%
Larghi A. Surg Endosc 2013; 27:3733-8.

21. EUS-guided Needle Biopsy
Interobserver Agreement for Grading
 42 patients with ADK with pro-op EUS-NB and
surgical specimen
 4 pathologists (Rome, Marseille, Santiago di
Compostela) independently reviewed biopsy slides
 Overall agreement among the four pathologists
was only fair (k=0.27; 95% CI: 0.14-0.38)
 Agreement well-/moderately differentiated versus
poorly differentiated was only fair (k=0.27; 95% CI:
0.21-0.49)
Larghi A. Am J Gastroenterol 2014;submitted.

22. 3, 2, 2, 3
1, 2, 2, 1
3, 1, 2, 2
2, 1, 3, 2

23. EUS-FNTA
Pancreatic Neuroendocrine Neoplasms
No.pts
30
Mean Age
55.7±14.9
Lesion size
16.9±6.1mm
Location
Uncinate
Head
Isthmus
Body/Tail
3
5
4
18
Larghi A, et al. Gastrointest Endosc 2012;76:570-7.

24. EUS-FNTA
Pancreatic Neuroendocrine Neoplasms
 EUS-FNTA successful in all patients without
complications
 Adequate samples for histological examination
were retrieved in 28/30 patients (92.9%) and in
all of them a diagnosis of PNENs was made
 Ki-67 determination could be carried out in 26/28
patients (86.6% of the initial entire cohort, and in
92.9% of the patients with successful EUSFNTA)
Larghi A, et al. Gastrointest Endosc 2012;76:570-7.

26. EUS-FNTA
Pancreatic Neuroendocrine Neoplasms
EUS-FNTA and surgical pathology agreement in 12 pts
EUS-FNTA
Surgery
≤5%
≤2%
5-20% >20%
2-20%
≤ 5%
2%
8
7
1
5-20%
2-20%
1
3
2
>20%
1
Histological Grading concordance in 10/12
12/12
Larghi A, et al. Gastrointest Endosc 2012;76:570-7.

27. Tissue is the Issue
 Tissue samples may be of additional value
to perform tissue profiling that in the future
will be very important to guide
individualized therapies
 Chemo-sensitivity and Pancreatic Cancer:
can the EUS FNA replace surgical biopsy
on chemo sensitivity assessment?

28. Pancreatic Cancer Stem Cells
Isolation and Culture
 48 hours from
12 days from
isolation
 Magnification
10X

29. Pancreatic Lesions
Role of EUS
 Screening
 Equivocal results of previous
imaging modalities
 Differential diagnosis and risk
assessment
 Staging
 Therapy/Interventional EUS

30. Pancreatic Cancer
T stage
T staging:
T1: Tumor limited to pancreas
Size ≤ 2cm in greatest dimension
T2: Tumor limited to pancreas
Size > 2cm in greatest dimension
T3: Tumor infiltration of bile duct,
papilla, duodenum and PV, SMV
T4: Tumor infiltration of stomach, spleen
colon, major arteries, and PV, SMV

31. EUS Staging
Vascular Invasion
Diagnostic accuracy of EUS for vascular
invasion: a meta-analysis (29 studies)
 Sensitivity
73%, Specificity 90%
 Positive likelihood ratio 9.1 (measure of how
well the test identifies the disease)
 Negative likelihood ratio 0.3 (how well the
test performs in excluding the disease)
EUS is a better test to identify vascular
invasion rather then excluding it
Puri SR. Gastrointest Endosc 2007;65:788-97.

32. Pancreatic Cancer
Vascular Invasion
Sensitivity:
SpecificityLiver
50-90%
Confluence with PV
90-100%
Stomach
PV/confluence:
EUS superior
SMV: Mass
Equivalent (~CT)
Celiac trunk: Encasement of SMV
Equivalent (~CT)
HA, SMA:
CT superior
SMV

33. EUS-FNA in Pancreatic Cancer Staging

34. Pancreatic Cancer
Clinical Impact of EUS-FNA
 Lack of data, besides tissue diagnosis
 99 patients elegible for surgery
 In 12 patients (12%) EUS FNA revealed
 Metastatic distant lymph nodes (6)
 Liver mets (4)
 Malignant ascites (1)
 Retroperitoneal infiltration (1)
Mortensen MB. Endoscopy 2001;33:478-83.

35. Pancreatic Lesions
Role of EUS
 Screening
 Equivocal results of previous
imaging modalities
 Differential diagnosis and risk
assessment
 Staging
 Therapy/Interventional EUS

36. Biliary Access and Drainage
 Candidates:
 Patients with benign and malignant biliary
diseases after ERCP failure
 Approach
 Transgastric or transduodenal
 Procedure
 Rendez-vous
 Direct stent placement

37. EUS-Guided Biliary Drainage
Intrahepatic
Intrahepatic
Extrahepatic
Extrahepatic

38. EUS-Guided Biliary Drainage
Author, yr
Maranki, 2009
Park do, 2011
Shah, 2012
Iwashita, 2012
Dhir, 2012
Vila, 2012
Horaguchi, 2012
Park do, 2013
Dhir, 2013
Khashab, 2013
Dhir, 2013
Kawakubo, 2013
Gupta, 2014
No. of
Patients
Technical
success
Clinical
Success
Complications
49
57
68
40
58
106
21
45
35
35
68
64
240
84%
96%
85%
73%
98%
70%
100%
91%
97%
94%
97%
95%
99%
80%
89%
85%
73%
98%
70%
100%
87%
97%
91%
97%
95%
87%
18%
47%
9%
12%
3%
23%
10%
11%
23%
14%
21%
42%
35%

39. Lumen-Apposing Devices
Axios stent
Hot Axios stent

40. EUS-guided Treatment of Locally
Advanced Pancreatic Adenocarcinoma
 EUS-guided fine needle injection
(EUS-FNI)
 EUS-guided Implantation Therapy
 EUS-guided Tumor Ablation

41. EUS-guided Fine Needle Injection
 Cytoimplant (allogenic mixed lymphocyte culture) for





pancreatic cancer
ONYX-015 for pancreatic cancer in association with
RT + Gemcitabine
TNFerade in pancreatic cancer + RT
TNFerade in esophageal cancer + RT+ 5FU-CDDP
Immature denditric cells against pancreatic cancer
OncoVEX : GM-CSF carried by Oncolytic herpes
Virus

42. Fine Needle Injection
TNFerade
TNFerade in pancreatic adenocarcinoma
Enhanced Tumor Necrosis
IONIZING RADIATION
TNF alpha
Enhanced Radiosensitivity

43. EUS-guided FNI of Pancreatic ADK
TNFerade Injection
 50 pts. locally advanced panc adenocarcinoma
 5 wks treatment of weekly TNFerade (4x109, 4x1010,
4x1011 particles unit in 2ml)
 IV 5-FU (200mg/m2/d x 5d/wk)+Radiation (50.4 Gy)
 Toxicity: mild, well tolerated
 Higher dose vs. Lower doses
 Greater locoregional control
 Longer progression free survival
 Improved median survival
 4/5 pts. tumor resected with negative margins and 3
survived more than 24 mos
Hecht JR. Gastrointest Endosc 2012;75:332-8.

44. EUS-guided FNI of Pancreatic ADK
TNFerade Injection
 304 pts. locally advanced panc adenocarcinoma
 Randomly assigned 2:1 to standard of care plus
TNFerade (SOC 􏰀 TNFerade) versus SOC alone
 SOC: IV 5-FU (200mg/m2/d x 5d/wk)+Radiation
(50.4 Gy), followed by gemcitabine or gemcitabine
plus erlotinib maintenance therapy
 TNFerade: 4x1011 PU, weekly for 5 wks
 Median progression-free survival (PFS): 6.8 mos for
SOC + TNFerade vs 7.0 mos for SOC (P = .51)
 Multivariate analysis: EUS-TNFerade injection was
a risk factor for inferior PFS
Herman JM. J Clin Oncol 2013;31:886-94.

45. Implantation Therapy
 Fiducial markers placement
for IGRT and Cyberknife
 Brachytherapy

46. Implantation Therapy
Fiducial Placement
 Antibiotic prophylaxis
 Sterilized gold fiducials
 3mm in length, 0.8mm in diameter with 19G needle
 10mm in length, 0.35mm in diameter with 22G needle
 Preloaded into the needle
 Needle tip sealed with wax
 Deployed by advancing the stylet or hydrostatic
pressure with sterile water
 4-6 fiducials should be deployed

47. Implantation Therapy
Fiducial Placement
Author (yr)
No.
pts
Fiducial/
needle
Site
Success
Complications
Pishvaian,
2006
13
5x0.8mm
19G
Mediastinal and
abdominal malignancies
11/13
(85%)
1 Infection within 1
month
Yang, 2009
16
5x0.8mm
19G
Prostate
16/16
(100%)
None
Park, 2010
57
2.5x0.8mm
19G
Pancreas
50/53
(94%)
1 Minor bleeding
Varadarajulu,
2010
9
3x0.8mm
19G
Pancreas
9/9
(100%)
None
Sanders,
2010
51
3x0.8mm
19G
Pancreas
45/50
(90%)
1 Pancreatitis
3 Spontaneous
migration
DiMaio, 2010
30
10x0.35mm
22G
Mediastinal and
abdominal malignancies
29/30
(97%)
1 Fever

48. Implantation Therapy
Brachytherapy
EUS-guided implantation of radioactive 125 iodine
seeds for pancreatic cancer
Author
(yr)
Suns,
2006
Jin,
2008
No. Success Results
pts.
Complications
15
15/15
(100%)
Partial remission in 27%,
minimal 20%, stable 33%.
Pain relief in 30% but not
limited in time
AP in 3 pts with
pseudocyst
formation in 2
22
22/22
(100%)
Partial remission in 13.6%,
stable in 45.5%.
Pain relief of 1 month duration
Fever in 54.5%

49. EUS-guided directed Therapy
 Animal Studies
 Photodynamic therapy (Chan HH.
Gastrointest Endosc 2004;59:95-9; Yusuf TE.
Gastrointest Endosc 2008;67:957-61)
 Nd:YAG laser (Di Matteo. Gastrointest Endosc
Gastrointest Endosc 2004;59:95-9.
2010;72:358-63; Di Matteo. Gastrointest Endosc
2013;78:750-5)
 High-Intensity Focused Ultrasound
(Hwang J. Gastrointest Endosc 2011;73:AB155)
 Radiofrequency Ablation

50. EUS-guided treatment of Pancreatic ADK
CryoThermal Ablation
 22 pts. locally advanced panc adenocarcinoma
 Flexible bipolar device that combines bipolar
radiofrequency with cryogenic cooling
 Radiofrequency heating: 18 W; pressure for cooling:
650 psi (Pounds per Square Inch); application time:
depending on tumor size
 Successfully applied in 16 patients (73%)
 Cystic fluid collection formation in one patient
 In 6 patients clear definition of the tumor margins
after ablation was possible and decreased tumor
size was observed (p=.07)
Arcidiacono PG. Gastrointest Endosc 2012; 76;1142-51.

51. Therapeutic EUS and PNENs
Alcohol Ablation
 78 y.o. F with




insulinoma unfit for
surgery
13mm lesion in the
body
8ml of 95% ethanol
injected
Mild transient
pancreatitis
Symptoms
disappearance after
injection
 F with insulinoma
refused surgery
 11 and 7mm lesions in
the body
 2ml of 45% ethanol
injected, 2 sessions
 After second section,
pancreatic necrosis
requiring surgery