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

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

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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. Introduction. Cystic lesions constitute about 10 % of pancreatic tumors - PowerPoint PPT Presentation

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

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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

Erwin M. Santo, MDHead, Invasive Endoscopy Unit

Dep. of Gastroenterology & HepatologyTel-Aviv Sourasky Medical Center

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IntroductionIntroduction Cystic lesions constitute about 10 % Cystic lesions constitute about 10 %

of pancreatic tumorsof 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 incidentallyMost lesions discovered incidentally

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Clinical PresentationClinical Presentation AsymptomaticAsymptomatic

Abdominal painAbdominal pain

JaundiceJaundice

PancreatitisPancreatitis

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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

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ClassificationClassification Non neoplasticNon neoplastic (pseudocysts) (pseudocysts)

NeoplasticNeoplasticMucinous

Non Mucinous

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ClassificationClassificationNon Mucinous CystsNon Mucinous Cysts

1.1. Serous cystadenomaSerous cystadenoma

2.2. Cystic endocrine tumorsCystic endocrine tumors

3.3. OtherOther

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ClassificationClassificationMucinous CystsMucinous Cysts

1.1. Mucinous cystadenomaMucinous cystadenoma

2.2. Malignant mucinous cystic tumorsMalignant mucinous cystic tumors

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

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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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Diagnosis of Pancreatic Cystic Diagnosis of Pancreatic Cystic Neoplasms: A report of the Neoplasms: A report of the

Cooperative Cyst StudyCooperative Cyst Study

Brugge WR, M.D. and Brugge WR, M.D. and ColleaguesColleagues

Gastroenterology 2004; Gastroenterology 2004; 126:1330-1336126:1330-1336

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Optimal Cutoff CEAOptimal Cutoff CEAMucinous vs non-mucinousMucinous vs non-mucinous

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Differentiating between Differentiating between mucinous and non-mucinous mucinous and non-mucinous

lesionslesionsEUSEUS CytoloCytolo

gygy CEACEA

SensitivitySensitivity )%()%(

32/5732/57 ((56.1%56.1%

))

19/5519/55 ((34.5%34.5%

))42/5642/56

((75%75%))

SpecificitySpecificity )%()%(

25/5525/55 ((45.4%45.4%

))

45/5445/54 ((83.3%83.3%

))

46/5546/55 ((83.6%83.6%

))

AccuracyAccuracy )%()%(

57/11257/112 ((50.9%50.9%

))

64/10964/109 ((58.7%58.7%

))

88/11188/111 ((79.2%79.2%

))*p<.001 vs Cytology, EUS*p<.001 vs Cytology, EUS

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Combination TestingCombination TestingEUS EUS

MorpholoMorphology or gy or

CytologyCytology

EUS EUS Morphology Morphology

or Cytology or or Cytology or CEACEA

CytologCytology or y or CEACEA

SensitivitySensitivity )%()%(++ 7070 9191 8282

SpecificitySpecificity )%()%( 3838 3131 7171

AccuracyAccuracy )%()%( 5454 6262 7777**

Area under Area under ROC curveROC curve 0.54180.5418^̂ 0.61070.6107^̂ ..76687668

*p<.05 vs EUS morphology -cytology, EUS morphology-cytology-CEA

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Summary of FindingsSummary of Findings EUS-FNA is safe for evaluation of pancreatic EUS-FNA is safe for evaluation of pancreatic

masses and cystadenomasmasses and cystadenomas Cytology results are much better in solid Cytology results are much better in solid

lesionslesions

EUS-FNA should be used to assist in the EUS-FNA should be used to assist in the selection of patients with a pancreatic selection of patients with a pancreatic lesion for surgical resection.lesion for surgical resection.

Cyst fluid CEA levels should be used in Cyst fluid CEA levels should be used in conjunction with cytology for conjunction with cytology for pancreatic cystadenomaspancreatic cystadenomas

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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) fluidHigh viscosity (mucinous) fluid- CEA - CEA - >140 ng/ml>140 ng/ml- Histology – columnar secreting Histology – columnar secreting

epitheliumepithelium

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

cystscysts

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MethodsMethods

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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

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

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MethodsMethodsEUSEUS 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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ResultsResultsClinical PresentationClinical Presentation No.No. %%

Incidental finding 103103 69.369.3

Abdominal pain 2929 19.619.6Weight lossWeight loss 2 2 1.41.4JaundiceJaundice 2 2

1.41.4

Abdominal pain/weight lossAbdominal pain/weight loss 55 3.43.4DyspepsiaDyspepsia 22 1.4 1.4 DiarrheaDiarrhea 2 2 1.41.4Diarrhea/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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ResultsResultsSurgical 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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ResultsResultsFNA 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 testedwith all the other tumor markers tested

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

lnCE

A

Mucinous

Ln(C

EA)

BoxPlot

Non-mucinous

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95% C.I.for ORVariabl

e B S.E.p-

value OR Lower Upperlog10CE

A 1.818 0.727 0.012 6.2 1.48 25.6Age -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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95% C.I.for ORVariabl

e B S.E.p-

value OR Lower Upperlog10CE

A 1.818 0.727 0.012 6.2 1.48 25.6Age -0.041 0.022 0.06 0.96 0.92 1.01

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%.

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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

Sens

itivi

ty

ROC Curve

ROC of CEA classification of Mucinous vs. Serous

1-specificity

sens

itiv

ity

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

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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:

• 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:

• 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)

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0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

2005200320012000199919981997year0

10

20

30

40

50

60

70

80

90C

yst s

ize

(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