Ruolo della ECOENDOSCOPIAnelIa pancreatite cronica e nelle neoplasie cistiche del pancreas

Ruolo della ECOENDOSCOPIAnelIa pancreatite cronica e nelle neoplasie cistiche del pancreas

Dr. L. CuocoU.O. Gastroenterologia

Ospedale S. Bortolo - Vicenza

Le pancreatiti: aspetti di diagnosi e terapiaVicenza 4 febbraio 2011

� Ottima tecnica per:

� Lo studio delle neoplasie esofagee, gastriche e ret tali

� Lo studio di alcune malattie biliari e pancreatiche come:

• Diagnosi e staging del carcinoma del pancreas

• Diagnosi e staging delle lesioni ampollari

• Diagnosi della litiasi della VBP

� La diagnosi dei tumori sottomucosi del tratto diges tivo e delle pliche gastriche giganti

� Anatomia EUS radiale

� Più semplice, necessita comunque di un training spec ifico

EUS RADIALE

� Come EUS radiale e in più

� Possibilità di:

� Biopsie EUS guidate di:

• Masse mediastiniche

• Linfonodi

• Neoplasie pancreatiche

• Masse extraparietali

� Terapie EUS guidate quali:

• Neurolisi del plesso celiaco

• Drenaggio di pseudocisti pancreatiche o di ascessi p elvici

• Iniezioni locali di farmaci

� Anatomia EUS lineare

� Più complessa, necessita anch’essa di un training sp ecifico

EUS LINEARE

EUS pancreatica

� DECUBITO LATERALE Sx

� DIGIUNO DA 8 ORE

�SEDAZIONE PROFONDA (assistenza anestesiologica) propofol

� SEDAZIONE COSCIENTE

�midazolam (0.3 mg/10 kg) + meperidina (0,5 mg/kg)

�SONDA LINEARE O RADIALE

�PROFILASSI (antibiotici, gabesato mesilato) se indic ata

Eus in:

• Cystic pancreatic neoplasms• Chronic pancreatitis

Prevalence of Pancreatic Cystic Neoplasms

• 300 consecutive autopsies

• 186 cystic lesions were found in 73 of 300 autopsies (24.3%)

• Epithelial atypia seen: atypical hyperplasia (16.4%); Ca in situ (3.4%)

• Incidental malignancies of the pancreas are usually cystic in origin

Kimura W et al. Cancer 1998

Morphology of pancreatic cyst lesions

How to think about pancreatic cystic tumors

Nat Rev Cancer

Qualsiasi lesione cistica del pancreas, specie in assenza di

un episodio di pancreatite acuta o di una riacutizzazione in

pancreatite cronica, deve essere considerata come

potenzialmente neoplastica

WHO Histological Classification of Cystic Pancreatic Neoplasms

• Mucinous cystic neoplasms� adenoma� with moderate dysplasia� carcinoma

• Intraductal papillarymucinous neoplasm (IPMN)� adenoma� with moderate dysplasia� carcinoma

NON-MUCINOUS(benign)

MUCINOUS(pre-malignant and malignant)

Kloppel G et al. WHO 1996

• Serous cystic tumors• Cystic endocrine tumors

Does exist a test able to

differentiate between

malignant and benign

cystic lesions of the

pancreas?

Characteristic of Pancreatic Cystic Neoplasms

• Location• Number• Size• Relations with

surrounding organs• Contour• Uni/multilocular• Wall thickness• Wall alterations• Septation• Mass protruding into

EUS provides many informations

98 CASES(48 SURGICAL/PATHOLOGICAL CORRELATION)

2 ENDOSONOGRAPHERS (A & B) REVIEWED IMAGESWALLSOLID COMPONENTSEPTAELYMPHOADENOPATHYNUMBER

Ahmad NA et al, Am J Gastroenterol 2001

Can EUS alone differentiate between

malignant and benign cystic lesions of the pancreas?

A: solid component by EUS as the only statistically signi ficantpredictor of malignancy (however 61% of patients with ben ignlesions were also interpreted by EUS to have solid component )

B: None of the features were found to be significant predi ctor of a malignant lesion

CAN EUS ALONE DIFFERENTIATE

BETWEEN MALIGNANT AND BENIGN

CYSTIC LESIONS OF PANCREAS ?

•The diagnostic accuracy of EUS morphology alone forpancreatic cystic neoplasms varies between 50% and 73 %

in different studies

•Highly operator-dependent

•The agreement among endosonographers is reported tobe poor

Ahmad NA et al. Am J Gastroenterol 2001 Brugge WR et al. Gastroenterology 2004

Frossard JL et al. Am J Gastroenterol 2003

EUS-guided Fine Needle Aspiration

•Cyst Fluid Cytology

•Tumor marker analysis

•Molecular analysis

127 pts (67 SURGICAL/PATHOLOGICAL CORRELATION)

EUS & EUS-FNA for cytological and tumor markers analysis

Results of EUS and EUS-FNA were compared with the final diagnosis

EUS EUS-FNA

sensitivity 71% 97%

specificity 30% 100%

Frossard JL et al. Am J Gastroenterol 2003

EUS / EUS-FNA Complications

10,731 conventional EUS: 5 (.046%) complications808 interventional EUS: 9 (1.11) complications

550/808 EUS guided procedures for pancreatic lesions

EUS-FNA of 479 solid lesions: 0.4% complicationsEUS-FNA of 71 cystic lesions: 8.4% complications

Needed prospective studies to determine the appropriateuse of antibiotic prophilaxis in EUS FNA of pancreatic cysts

Buscarini E et al Dig Liv Dis 2006 38: 762-67

185 patients with known or suspected pancreatic cancerNegative tissue sampling by ERCP or negative CT-guided FNA

EUS-FNA Negative CT-guidedFNA (n=58)

Negative ERCP tissuesampling (n=36)

sensitivity 90% 94%

accuracy 84% 92%

EUS-FNA of pancreatic masses accurately diagnoses pancrea ticmalignancy when prior biopsy techniques have been unsucces sful

Am J Gastroenterol 2002

American Joint Comittee on CancerEUS–FNA preferred sampling technique in pancreatic cancer

EUS - FNA vs US/TC - FNASeeding

Incidence of peritoneal carcinomatosis

• EUS – FNA 2.2%

• Percutaneous FNA 16.3%P < 0.025

C. Micames Gastrointest Endosc 2003

EUS-FNA COMPLICATIONS

Literature data suggest that EUS is associated with a similar rate of perforation compared withstandard endoscopy (<0.03%).No death are reported related tothe procedures, in the recentlarge series

EUS-FNA induced complicationconsists in:

• Pancreatitis (0-2%)• Hemorrhage (0-1,3%)• Infectious disease

Gastrointest Endosc 2005

Fernandez G, Endoscopy 2007Gress F, Gastrointest Endosc 2002O’Toole D, Gastrointest Endosc 2001

Al-Haddad M, Endoscopy 2008Affi A, Gastrointest Endosc 2001Eloubeidi M, Am J Gastroenterol 2003

Cytology

•A number of studies havereported varying accuracy of pancreatic cyst EUS-FNA cytology, but the overall accuracyis around 50%

•Columnar epithelial cells whichstain for mucin (MCN, IPMN)

•Cuboidal epithelial cells whichstain for glycogen (SCA)

van der Waaij LA, Gastrointest Endosc 2005

Tumor Marker Analysis

•Cyst fluid contains glycoproteins secreted from the epithelial lining that may help to differentiate betweenmucinous and non mucinous lesions

•Carcinoembryonic antigen (CEA), cancer antigen72.4, carbohydrate antigen (CA) 19.9, CA 15.3

•CEA appears to hold the most promise fordifferentiating benign from malignant lesions

•High viscosity cyst contents or the detection of extracellular mucin is generally indicative of a mucinous neoplasm

Brugge WR et al. N Engl J Med 2004

EUS CytologyCEA

(Cut-off 192 ng/mL)

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%)*

Differentiating mucinous and non-mucinous lesions

Brugge WR et al. Gastroenterology 2004

The Cooperative Pancreatic Cyst Study341 patients (histology in 112)

*p<.001 vs Cytology, EUS

DNA AnalysisA detailed molecular analysis of pancreatic cystaspirated fluid may be helpful in differentiating

mucinous from non-mucinous lesions

Nonmucinous(25)

Mucinous(88)

p

Mean no. of Mutations

0.8 1.7 <0.001

K-rasmutations

1/25 40/88 <0.0001

K-ras mut. followed byallelic loss

0/25 17/88 <0.01

Khalid A et al. Gastrointest Endosc 2009

p-53 over-expression

MUC2 and MUC5AC in 80% IPMN (carcinoma)

Proteomics…

K-ras mutation:

sensitivity 91% specificity 93%

“Pseudosolid mass”

Cytology not diagnostic

Fluid analysis not possible in the absence of larger cysts

TRU-CUT BIOPSY

SEROUS CYSTADENOMA

SerousCystadenoma

• Microcystic• Glycogen-rich lesion• No ductal communication• Vascular• Benign• Fluid analysis: low fluid

viscosity, low CEA, low amylase

• Small cuboidal cells

MUCINOUS CYSTIC NEOPLASM

Mucinous Cystic Neoplasm

• Macrocystic lesions• No ductal communication• Body or tail• Woman (90%)• Mucin-secreting

epithelial cells, surrounded by an ovarian stroma

• High risk of malignant evolution

• Viscous, mucoid fluid• Fluid analysis: high CEA,

low amylase

Malignant EUS Features

•Calcifications•Thick wall (>2 mm)•Septations•Vegetations•Vascular involvement

EUS-Elastosonography

INTRADUCTAL PAPILLARY MUCINOUS NEOPLASM (IPMN)

Types of IPMN

MainMain ductduct typetype

BranchBranch ductduct typetype

Intraductal Papillary Mucinous Neoplasms (IPMN)

Dottoprincipale

diffuso segmentario

Dotticollaterali

macrocistico microcistico

Misto

Furukawa T, 1992

Kuroda A, 1997

IPMN• Men = women

• pancreatic head

• from hyperplasia…to

carcinoma (malignant potential)

• Viscous, mucoid fluid

• Fluid analysis: ↑↑↑↑ CEA

• Ductal communication

(proliferation of the ductal

epithelium, secretes mucin

causing dilation of pancreatic

ducts)

• main duct type tumor with MPD > 10mm

• branch duct type tumor lesion > 40 mmirregular septalarge mural nodules

Malignant EUS Features

H. Kubo et al. Am J Gastroenterol 2001;96:1429-34

Frequency of malignancy in MPD IPMN: 60-92%, 2/3 invasive

POST-OPERATIVE 5-YEAR SURVIVAL

~ 100% for benign tumors and

non invasive carcinoma.

~ 60% for invasive carcinoma

Main duct type (>1 cm): surgery

Branch duct type: surgery if

- Size >30 mm

- Mural nodules

- (Dilated MPD)

- Positive cytology

- Positive symptoms

INDICATIONS FOR SURGERY

Tanaka et al, INTERNATIONAL CONSENSUS GUIDELINES , Pancreatology 2006

Brugge 2010

Conclusions

• Imaging alone, performed with CT, MRI, or EUS, is not sufficient.

•Cyst fluid analysis can provide diagnostic findings(dedicated cytologists).

• Cyst fluid tumor markers, particularly CEA and CA 72-4, supplement the findings of cytology.

• Don’t forget clinical signs (red flags: i.e. weightloss or the rapid onset of diabetesis highlysuggestive of malignant degeneration)

EUS criteria ofChronic Pancreatitis

Jones SN, Clin Radiol 1988Wiersema MJ, Endoscopy 1993

EUSParenchymal criteria

EUSDuctal criteria

EUSvs.

everybody

• 126 pts ERCP followed by EUS

• EUS sensitivity was greater than 85% when diagnosis of CP was based on the presence of >3 criteria, but the specificity was less than 60%

• Moderate to severe CP was unlikely (NPV>85%) when <3 criteria were present

• EUS is the most useful SINGLE test for diagnosis of chronic pancreatitis*

Sahai A, Gastrointest Endosc 1998*Gardner T. Gastrointest Endosc 2010

EUS in CP: questions, limitations and controversies

• Ideal threshold number of EUS features

• Relative value of each EUS feature• Influence of factors (such age) in EUS features

• Poor interobserver agreement• Accuracy and safety of EUS-FNA

• Accuracy and safety of EUS-Tru-cut biopsy

MAIOR CRITERIA• Hyperechoic foci

with shadowing

• PD calculi• Lobularity with

honeycombing

MINOR CRITERIA• Cysts• Dilated ducts > 3.5 mm• Irregular PD contour• Dilated side branches >1

mm• Hyperechoic duct wall• Strands• Foci no shadowing• Lobularity non contiguous

Criteria based on expert opinion alone and not validated prospectively

The ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ of diagnostic categories ↑↑↑↑ ↑↑↑↑ ↑↑↑↑ inter-observer variability and reduces reproducibility

interobserver agreement poor

κκκκ<0,4 for 7/9 features

EUS-FNA / EUS-TRU-CUT BIOPSY in CP

Not completely safe

Sample often inadequate

Patchy lesions

Gain of NPV in some studies

At this time EUS-FNA/TRU-CUT BIOPSY

cannot be advocated forthe diagnosis of CP

*Gardner T. Gastrointest Endosc 2010

PANCREATIC CANCER OR INFLAMMATORY MASS??

EUS in patients with non specificchange of the pancreas on CT

Author N°Patients FNA Rate of malignancy

Horwhat2009

69 patientsEnlarged pancreas

19/69 8.7% (6/69)

Singh2008

107 patientsEnlarged pancreas

??? 22%

Ho2006

50 patientsEnlarged pancreas

11/5022%

8%4/50

Horwart JD, JOP 2009 Singh S, Dis Dig Sci 2008

Ho S, Clin Gastroenterol Hepatol 2003

Power Doppler EUS for the Differential Diagnosis BetweenPancreatic Cancer and Pseudotumoral Chronic

Pancreatitis

Power doppler Peripancreatic

collaterals

Sensitivity 93% 97%

Specificity 77% 92%

Accuracy 88% 95%

• 42 patients with pancreatic mass• 29 pts final diagnosis of PC

Criteria for malignant lesions•No detectable vascularisationusing conventional power doppler•Appearance of arterial vessels using SonoVue

•No detectable venous vessels inside the lesion

EUS Contrast-enhanced

sens 73.2% 91.1%

spec 83.3% 93.3%

Dietrich CF, World J Gastroenterol 2006

Euselastosonography

differentiating pancreatic mass

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