11

Differential Diagnosis of Differential Diagnosis of Neoplastic Pancreatic Cysts:Neoplastic Pancreatic Cysts:The Role of EUS with Guided The Role of EUS with Guided

FNAFNA

E.M.Santo,Y.Ron,O.Barkay,Y.Kopelman,M.Leshno,S.Marmor

Dep. of Gastroenterology & Hepatology,

Dep.of Pathology

Tel-Aviv Sourasky Medical Center

22

IntroductionIntroduction

Cystic lesions constitute about 10 % Cystic lesions constitute about 10 % of pancreatic tumorsof pancreatic tumors

Significant increase in detection Significant increase in detection due due

to widespread use of US,CT to widespread use of US,CT

Most lesions discovered incidentallyMost lesions discovered incidentally

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Clinical PresentationClinical Presentation

AsymptomaticAsymptomatic

Abdominal painAbdominal pain

JaundiceJaundice

PancreatitisPancreatitis

44

Clinical PresentationClinical Presentation

AsymptomaticAsymptomatic

Ca in situ / invasive cancer – 17%Ca in situ / invasive cancer – 17%

Lesion with malignant potentialLesion with malignant potential – – 42%42%

Fernandez Del Castillo et al. Arch Surg 2003

55

ClassificationClassification

Non neoplasticNon neoplastic (pseudocysts) (pseudocysts)

NeoplasticNeoplastic

Mucinous

Non Mucinous

66

ClassificationClassification

Non Mucinous CystsNon Mucinous Cysts

1.1. Serous cystadenomaSerous cystadenoma

2.2. Cystic endocrine tumorsCystic endocrine tumors

3.3. OtherOther

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ClassificationClassification

Mucinous CystsMucinous Cysts

1.1. Mucinous cystadenomaMucinous cystadenoma

2.2. Malignant mucinous cystic Malignant mucinous cystic tumorstumors

3.3. Intraductal papillary mucinous Intraductal papillary mucinous neoplasms - IPMNneoplasms - IPMN

88

99

DiagnosisDiagnosis

CT – microcystic appearance, centralCT – microcystic appearance, central fibrosis- fibrosis- SerousSerous Unilocular, macrocystic, peripheralUnilocular, macrocystic, peripheral calcification- calcification- MucinousMucinous

MRCPMRCP – – MPD dilatation, mural nodulesMPD dilatation, mural nodules ductal connection - IPMNductal connection - IPMN

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DiagnosisDiagnosis

EUS - highly sensitiveEUS - highly sensitive

FNA – fluid characteristics, FNA – fluid characteristics, tumor markers, cytologytumor markers, cytology

CEA in fluid - most accurate CEA in fluid - most accurate markermarker

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EUS – Serous cystEUS – Serous cyst

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EUS – Mucinous cystEUS – Mucinous cyst

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AIMAIM

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

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AIMAIM

Validation of the current Validation of the current criteria used to distinguish criteria used to distinguish between various cystic between various cystic tumors (gold standard based tumors (gold standard based on surgical pathology )on surgical pathology )

Establishing new criteria Establishing new criteria with higher sensitivity and with higher sensitivity and specificityspecificity

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AIMAIM

Provide an algorithm for Provide an algorithm for the diagnosis and the diagnosis and treatment of pancreatic treatment of pancreatic cystic lesionscystic lesions

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Heuristics used in our Heuristics used in our InstituteInstitute for Dx of for Dx of SerousSerous

cystscysts

- Clinical Clinical - Microcystic morphologyMicrocystic morphology- CEA level CEA level < 5 ng / ml< 5 ng / ml- Histology- cuboidal, non Histology- cuboidal, non

secreting cellssecreting cells

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- ClinicalClinical- Morphology – unilocular, thick Morphology – unilocular, thick

septa, solid componentsepta, solid component- High viscosity (mucinous) High viscosity (mucinous)

fluidfluid- CEA - CEA - >140 ng/ml>140 ng/ml- Histology – columnar Histology – columnar

secreting epitheliumsecreting epithelium

Heuristics used in our Heuristics used in our InstituteInstitute for Dx of Mucinous for Dx of Mucinous

cystscysts

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MethodsMethods

1919

MethodsMethods

Retrospective study Retrospective study 170 patients between 1977-170 patients between 1977-

20062006 155 patients ,195 EUS exams155 patients ,195 EUS exams 40 patients – EUSx2 or more40 patients – EUSx2 or more 101 women, 54 men101 women, 54 men Mean age – 64.3Mean age – 64.3±14 years±14 years

2020

MethodsMethods

Demographic dataDemographic data Clinical presentationClinical presentation Imaging – US, CT , EUSImaging – US, CT , EUS FNAFNA Surgical findingsSurgical findings Follow up on all patients (Follow up on all patients (office visits , office visits ,

data from family physicians, data from family physicians, gastroenterologists, patient’s families)gastroenterologists, patient’s families)

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MethodsMethods

EUSEUS Cyst location, size, morphologyCyst location, size, morphology FNA – fluid:FNA – fluid:

- characteristics- characteristics

- cytology- cytology

- tumor markers –- tumor markers –CEA,CA19-9,CA72-4,MCA CEA,CA19-9,CA72-4,MCA

Cyst wall sampling (cell block)Cyst wall sampling (cell block)

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Results

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ResultsResults

Clinical PresentationClinical Presentation No.No. %%

Incidental finding 103103 69.369.3

Abdominal pain 2929 19.619.6

Weight lossWeight loss 2 2 1.41.4

JaundiceJaundice 2 2

1.41.4

Abdominal pain/weight lossAbdominal pain/weight loss 55 3.43.4

DyspepsiaDyspepsia 22 1.4 1.4

DiarrheaDiarrhea 2 2 1.41.4

Diarrhea/weight lossDiarrhea/weight loss 33 2.02.0

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ResultsResultsLocation No. %

Head 52 33.5

Neck 14 9.0

Body 41 26.5

Tail 25 16.1

Other 23 14.8

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– 37 patients had surgery with histological findings.

– 140 patients had FNA but results were available for 80 patients.

Results

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ResultsResults

Surgical Pathology No. %

Non neoplastic 6 16.2Serous 4 10.8 Mucinous 13 35.1Mucinous ca. 11 29.7IPMN 2 5.4Neuroendocrine 1 2.7

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ResultsResults

FNA Histology No. %

Non neoplastic 12 16.0Serous 27 33.8 Mucinous 25 31.3Carcinoma 14 17.5Neuroendocrine 2 2.5

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– 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

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ResultsResults Mean of Ln(CEA)Mean of Ln(CEA)** levels were 2.6 and levels were 2.6 and

5.8 for non mucinous and mucinous 5.8 for non mucinous and mucinous cases respectively (p<0.0001)cases respectively (p<0.0001)

No statistically significant difference No statistically significant difference with all the other tumor markers with all the other tumor markers testedtested

Rate of solid component in cyst – the Rate of solid component in cyst – the difference was not statistically difference was not statistically significant (p=0.14)significant (p=0.14)

No difference concerning cyst size or No difference concerning cyst size or morphologymorphology*CEA is highly skewed distributed and therefore we *CEA is highly skewed distributed and therefore we transformed the CEA level to Ln(CEA)transformed the CEA level to Ln(CEA)

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10

Class

12.00

10.00

8.00

6.00

4.00

2.00

0.00

-2.00

lnC

EA

Mucinous

Ln

(CEA

) BoxPlot

Non-mucinous

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95% C.I.for OR

Variable B S.E.

p-value OR Lower Upper

log10CEA 1.818 0.727 0.012 6.2 1.48 25.6

Age -0.041 0.022 0.06 0.96 0.92 1.01

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.

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1.00.80.60.40.20.0

1 - Specificity

1.0

0.8

0.6

0.4

0.2

0.0

Sensi

tivi

ty

ROC Curve

ROC of CEA classification of Mucinous vs. Serous

1-specificity

sen

sit

ivit

y

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

A Threshold of CEA=58

ng/ml yields 86.4% and

87.5% sensitivity

and specificity

respectively

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ConclusionsConclusions EUS is a useful tool but it can not EUS is a useful tool but it can not

alonealone distinguish between cystic distinguish between cystic lesions with variable malignant lesions with variable malignant potential potential

EUS-FNA EUS-FNA alonealone is also limited in is also limited in its ability to correctly diagnose a its ability to correctly diagnose a cystic lesion – sensitivity 59% cystic lesion – sensitivity 59% specificity 80%specificity 80%

CombinationCombination of parameters – of parameters – cytology and CEA levels (or CA cytology and CEA levels (or CA 19-9 levels) can significantly 19-9 levels) can significantly increase the diagnostic yieldincrease the diagnostic yield

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A Practical Decision Algorithm based on

the Threshold Decision Model

Source: NEJM 1980; 302:1109-17

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For a patient with a pancreatic cyst there are several management options: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.

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Beside the preferences of the patient, the following parameters are relevant to the decision process:

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 neoplastic 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 neoplastic diseases)

• No co-morbidity

• Co-morbidity

• Test results (CT, EUS)

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0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

2005200320012000199919981997year

0

10

20

30

40

50

60

70

80

90

Cy

st

siz

e (

mm

)

CEA in cyst

CA19-9 in blood

Cyst size

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

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Age

<=60 60 - 75 >75

Co-morbidity Yes YesNo 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

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Age

<=60 60 - 75 >75

Co-morbidity Yes YesNo No

Positive Cytology or CEA>60

Yes No

= Surgical Resection

= Wait and Watch

Complexity of Surgical resection

Yes No

= Debate

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Age

<=60 60 - 75 >75

Co-morbidity Yes No

Positive Cytology or CEA>60

Yes No

= Surgical Resection

= Wait and Watch

Yes No

= Debate

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Thank You